Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([NH2:15])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C(Cl)Cl.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(N)cc1OC1CCCC1
Reactant: O=C(Cl)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(NC(=O)c2ccncc2)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
7.0 g (33.8 mmol) of 3-cyclopentyloxy-4-methoxy-phenylamine (Garcia et al., JOC, 2005, 70, p 1050) were dissolved in 150 ml of DCM. The solution was cooled to 0° C. and 5.74 g (40.5 mmol) isonicotinoyl chloride in 50 ml DCM were added to the solution. A precipitate was formed. The reaction mixture was subsequently stirred at room temperature during two hours. A solution of 2.7 g NaOH in 100 ml water was added to the reddish reaction mixture. The organic layer was separated, dried over Na2SO4 and evaporated. The crude product was purified by flash chromatography on silica gel (ethyl acetate/n-hexane 2:1) to afford 7.2 g (62%) of the desired product. MS (ESI): 313.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[N:30]=[CH:29][CH:28]=1>C1COCC1>[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:38])=[O:39])=[CH:34][CH:35]=2)[N:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)ccnc2c1
Reactant: COc1ccc(CNc2nccs2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ccnc3c2)cc1
Temperature: -78 °C

Procedure:
A solution of N-(4-methoxybenzyl)thiazol-2-amine (0.306 g, 1.389 mmol) in THF (5.29 ml) was cooled to −78° C. for 10 minutes, and lithium bis(trimethylsilyl)amide (1.0M solution in THF) (1.323 ml, 1.323 mmol) was added drop wise. The cold bath was removed for 5 minutes, and then the reaction vessel was re-cooled to −78° C. for 10 minutes. A solution of perfluorophenyl 4-chloroquinoline-7-sulfonate (0.542 g, 1.323 mmol) in THF (2.65 ml, 1.323 mmol) was added drop wise, and the reaction was stirred for 15 minutes until complete conversion to the desired product. After warming to RT, the reaction was quenched with sat. aq ammonium chloride solution, diluted with EtOAc (5 mL) and washed with water (10 mL×2). The combined organics were dried over sodium sulfate, filtered and concentrated. The material was then purified via silica gel chromatography (40-g column) eluting with 0 to 100% ethyl acetate in heptanes, to yield 4-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (0.481 g, 1.079 mmol, 82% yield) as a white solid. m/z (ESI) 446.1 (M+H)+.
Reaction SMILES: [CH:1]12[NH:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH:3]([NH:10][C:11]([C:13]1[N:17]3[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=4[F:31])[C:16]3=[N:15][C:14]=1[CH3:32])=[O:12])[CH2:2]2.[CH2:33]1COC[CH2:34]1.[H-].[Na+].ICC>C(OCC)(=O)C>[F:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([F:31])[C:24]=1[CH2:23][O:22][C:21]1[C:16]2[N:17]([C:13]([C:11]([NH:10][CH:3]3[CH2:2][CH:1]4[N:9]([CH2:33][CH3:34])[CH:5]([CH2:6][CH2:7][CH2:8]4)[CH2:4]3)=[O:12])=[C:14]([CH3:32])[N:15]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1CC2CCCC(C1)N2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCI
Product: CCN1C2CCCC1CC(NC(=O)c1c(C)nc3c(OCc4c(F)cccc4F)cccn13)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
60 mg of N-(9-azabicyclo[3.3.1]non-3-yl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]-pyridine-3-carboxamide (Example 27, 0.14 mmol) were initially charged in 1.4 ml of abs. THF, 4.2 mg of sodium hydride (purity 95%, 0.16 mmol) were added and the mixture was stirred at RT for 15 min. 0.011 ml of iodoethane (0.14 mmol) were then added dropwise, and the mixture was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate and washed twice with water. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and filtered. The filtrate was concentrated and dried. The crude product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated and the residue taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulphate and filtered and the filtrate was concentrated and lyophilized. This gave 35 mg of the title compound (55% of theory).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11](Cl)[N:10]=[C:9]([Cl:14])[CH:8]=2)[CH2:3][CH2:2]1.[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[H-].[Na+]>O1CCCC1>[Cl:14][C:9]1[CH:8]=[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[N:12]=[C:11]([O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:10]=1
Reactant: OCCN1CCOCC1
Reactant: Clc1cc(N2CCOCC2)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc(N2CCOCC2)nc(OCCN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
6-Morpholino-2,4-dichloropyrimidine (4.6 g; 20 mmol) and 4-(2-hydroxyethyl)-morpholine (3.3 g; 25 mmol) were dissolved in tetrahydrofuran (200 mL), and chilled in an ice bath. To the solution was added sodium hydride (600 mg; 25 mmol), and it was stirred overnight at room temperature. The solvents were evaporated, and the solid was dissolved in dichloromethane (200 mL) which was then washed with water (2×100 mL). The organic layer was dried over magnesium sulfate, evaporated, and purified by column chromatography to give 4-[2-(4-Chloro-6-(morpholin-4-yl)-pyrimidin-2-yloxy)-ethyl]-morpholine (4.5 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:12]#[N:13].[SH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[O-]CC.[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:12]([C:3]1[C:2]([S:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2)#[N:13]
Reactant: CCOC(=O)CS
Reactant: N#Cc1c(Br)ccc2ncccc12
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ccc2ncccc2c1C#N

Procedure:
A solution of 6-bromoquinoline-5-carbonitrile (16b) (300 mg, 1.29 mmol), ethyl mercaptoacetate (212 μL, 1.93 mmol) and sodium ethoxide (122.6 mg, 1.80 mmol) in dimethylformamide (10 mL) was stirred at room temperature for 15 hours. A saturated aqueous solution of sodium bicarbonate was added to the mixture. It was extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The intermediate ethyl 2-[(5-cyanoquinolin-6-yl)sulfanyl]acetate obtained was reacted with sodium ethoxide (122.6 mg, 1.80 mmol) in dimethylformamide (8 mL) by stirring at 90° C. for 3 hours. The reaction was cooled to room temperature and water was added (10 mL). The resulting precipitate was filtered and washed with water twice and dried under vacuum with phosphorus pentoxide to afford the desired product (16c) as a solid (299 mg, 1.10 mmol, 85%).
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:12]([O:14][C@H:15]([O:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH3:16])=[O:13])=[C:6]([CH2:9][O:10][CH3:11])[CH2:7][S:8][C@@H:3]12.[NH2:26][C:27]1[S:28][CH:29]=[C:30](/[C:32](=[N:45]/[O:46]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:33]([O:35]C2SC3C=CC=CC=3N=2)=S)[N:31]=1.O.[C:67]1([CH3:77])[CH:72]=[CH:71][C:70]([S:73]([OH:76])(=[O:75])=[O:74])=[CH:69][CH:68]=1>CN(C)C=O.C(O)CC>[C:67]1([CH3:77])[CH:68]=[CH:69][C:70]([S:73]([OH:76])(=[O:74])=[O:75])=[CH:71][CH:72]=1.[NH2:26][C:27]1[S:28][CH:29]=[C:30](/[C:32](=[N:45]/[OH:46])/[C:33]([NH:1][CH:2]2[C:24](=[O:25])[N:4]3[C:5]([C:12]([O:14][C@H:15]([O:17][C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])[CH3:16])=[O:13])=[C:6]([CH2:9][O:10][CH3:11])[CH2:7][S:8][C@@H:3]23)=[O:35])[N:31]=1
Reactant: COCC1=C(C(=O)O[C@@H](C)OC(=O)OC(C)C)N2C(=O)C(N)[C@@H]2SC1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=S)Oc2nc3ccccc3s2)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCCO
Solvent: O
Product: COCC1=C(C(=O)O[C@@H](C)OC(=O)OC(C)C)N2C(=O)C(NC(=O)/C(=N\O)c3csc(N)n3)[C@@H]2SC1

Procedure:
905 mg (2.42 mmol) of 1-(1R,S)-(isopropyloxycarbonyloxy)ethyl 7-amino-3-methoxymethyl-3-cephem-4-carboxylate and 1.5 g (2.6 mmol) of 2-benzothiazolyl (Z)-2-(2-aminothiazol-4-yl)-2-trityloxyiminothioacetate are reacted in 10 ml of N,N-dimethylformamide analogously to Example 5. The trityl-protected title compound is heated at 90° C. for 25 minutes with 475 mg (2.5 mmol) of p-toluenesulfonic acid hydrate in 10 ml of n-propanol. After cooling, 900 mg (52% of theory) of the title compound crystallize. If the trityl group is first removed with formic acid and the tosylate is then formed analogously to Example 5, the yield is 231 mg (13% of theory).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=1>Cl>[N:14]1([CH:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:19])=[O:2])=[CH:5][CH:6]=2)[CH2:11][CH2:12][CH3:13])[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: CCCC(c1ccc(C(=O)OC)cc1)n1ccnc1
Agent: Cl
Product: CCCC(c1ccc(C(=O)O)cc1)n1ccnc1

Procedure:
23 g of the ester of example 1 is refluxed in 200 ml of concentrated hydrochloric acid for 20 hours. After concentration by evaporation in a vacuum, the residue is dissolved in water and brought to pH 8 with 50% sodium hydroxide solution. Then it is adjusted to pH 5-6 with 1M hydrochloric acid and evaporated to dryness. The crystalline residue is boiled several times with ethyl acetate and filtered. After concentration by evaporation, 20 g of 4-[1-(1-imidazolyl)-butyl]-benzoic acid with a melting point of 171°-172° C. is obtained.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]=2[C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[CH:24]=3)[CH:19]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C>[CH:1]1([CH2:6][CH:7]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]=2[C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[CH:24]=3)[CH:19]=2)[OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2cc(-c3oc4ccccc4c3C(=O)CC3CCCC3)ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2cc(-c3oc4ccccc4c3C(O)CC3CCCC3)ccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.2 %

Procedure:
To a mixture of 2-cyclopentyl-1-[2-(6-methoxy-2-naphthyl)-1-benzofuran-3-yl]-1-ethanone (2.03 g, 5.28 mmol) in ethanol (25 mL) cooled in an ice bath was added sodium borohydride (1.05 g, 27.7 mmol) in three portions. The reaction mixture was stirred for about 18 hours at room temperature and then concentrated. The residue was partitioned in warm ethyl acetate and water. The organic phase was washed with water and brine. It was dried over anhydrous magnesium sulfate, filtered and concentrated to afford 2-cyclopentyl-1-[2-(6-methoxy-2-naphthyl)-1-benzofuran-3-yl]-1-ethanol as a cream-colored solid (1.84 g), mp 176-177° C. 1HNMR (200 MHz, DMSO-d6): δ8.2 (s, 1H), 7.8-8.0 (m, 4H), 7.6 (d, 1H, J=7.5 Hz), 7.2-7.45 (m, 4H), 5.4 (s, 1H), 5.1-5.2 (br, 1H), 3.9 (s, 3H), 1.95-2.15 (br m, 1H), 1.8-1.95 (br m, 2H), 1.2-1.6 (br m, 4H), and 1.0-1.2 ppm (br m, 2H).
Reaction SMILES: [Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].C(C1C=C(C2C=CC=CC=2)C=CC=1[C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[C:43]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:44]=2)[CH:39]=1)=O>C1COCC1.C(OCC)C>[C:48]1([C:43]2[CH:44]=[C:45]3[C:40](=[CH:41][CH:42]=2)[CH:39]=[CH:38][CH:47]=[CH:46]3)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: O=Cc1cc(-c2ccccc2)ccc1-c1ccc2cc(-c3ccccc3)ccc2c1
Agent: CC(C)(C)[O-]
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
In an atmosphere of argon, 823 g (2.40 mol) of (methoxymethyl)triphenylphosphonium chloride and 4 L of dehydrated diethyl ether were charged in a flask. Then, 2.4 L (2.40 mol) of a THF solution of 1M potassium-t-butoxide was added, and the resultant was stirred for 2 hours at room temperature. Then, 6 L of a THF dispersion of 370 g (961 mmol) of 2-(3-formylbiphenyl-4-yl)-6-phenylnapthalene was added dropwise, followed by stirring at room temperature for 17 hours. After the reaction, undissolved matters were filtered, and a filtrate was concentrated. Residues were purified by silica gel chromatography, whereby 330 g of 2-[3-(2-methoxy)ethenyl-1-yl]biphenyl-4-yl]-6-phenylnaphthalene (yield: 83%) was obtained.
Reaction SMILES: [CH3:1][C:2](=[O:23])[C:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([C:18](=[O:22])[CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:29]>C(Cl)(Cl)Cl>[O:29]1[C@H:12]2[CH2:11][C@H:10]3[C@:15]([CH3:16])([CH2:14][C@@H:13]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@:20]([CH3:21])([CH2:19][C:18]1=[O:22])[C:3]([C:2](=[O:23])[CH3:1])=[CH:4][CH2:5]2)[CH2:8][CH2:9]3
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: ClC(Cl)Cl
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a solution of 5α-pregna- 2,16 -diene-11,20-dione (2.5 g.) in chloroform (50 ml.) was added m-chloroperoxybenzoic acid (85%, 1.8 g.), and the mixture was stirred at room temperature overnight. More chloroform was then added, and the solution was washed with dilute sodium bicarbonate solution and with water, dried over magnesium sulphate and evaporated to an oil which was triturated with ether/petrol to give title compound (1.9 g.) as colourless needles, m.p. 154°-156° , [α]D + 100°.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH:3]=[O:4].[C:7]([Li])([CH3:10])([CH3:9])[CH3:8]>O1CCCC1>[C:2]([CH:3]([C:7]([CH3:10])([CH3:9])[CH3:8])[OH:4])([CH3:6])([CH3:5])[CH3:1]
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)C(O)C(C)(C)C

Procedure:
To a solution of trimethylacetaldehyde (5.12 g, 59.4 mmol) in anhydrous tetrahydrofuran (15 ml) at -78° C. under an argon atmosphere is added 40.9 ml of a solution of t-butyllithium in hexanes (1.6M, 65.4 mmol). The mixture is allowed to warm from -78° to room temperature over 2 hours. The reaction is quenched with 25 ml of 1M hydrochloric acid and the resulting mixture extracted with two 25 ml portions of ether. The combined ethereal extracts were washed with saturated sodium bicarbonate solution and water, dried over magnesium sulfate, and the solvent evaporated to yield a yellow oil (9.3 g) which is purified by vacuum distillation to yield a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9]([C:11]2[C:12]([CH3:27])=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=2)[S:17](=[O:23])(=[O:22])[CH2:16][C:15]([CH3:25])([CH3:24])[C:14]3=[O:26])=[O:10])[CH:5]=[N:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:34]([S:37](Cl)(=[O:39])=[O:38])[CH2:35][CH3:36]>ClCCl.O.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[CH2:1]([N:3]1[C:7]([O:8][S:37]([CH2:34][CH2:35][CH3:36])(=[O:39])=[O:38])=[C:6]([C:9]([C:11]2[C:12]([CH3:27])=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=2)[S:17](=[O:22])(=[O:23])[CH2:16][C:15]([CH3:24])([CH3:25])[C:14]3=[O:26])=[O:10])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc(C(=O)c2cc(C)c3c(c2C)C(=O)C(C)(C)CS3(=O)=O)c1O
Reactant: CCCS(=O)(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)(=O)Oc1c(C(=O)c2cc(C)c3c(c2C)C(=O)C(C)(C)CS3(=O)=O)cnn1CC
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.7 %

Procedure:
2.3 Grams (5.9 mmol) of 6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonyl-3,3,5,8-tetramethylthiochroman-4-one-1,1-dioxide was dissolved in 15 ml of dichloromethane. Separately, 1.22 g (8.8 mmol) of potassium carbonate was dissolved in 20 ml of water, and these two solutions were mixed. Then, a solution of 1.26 g (8.8 mmol) of n-propanesulfonyl chloride in 5 ml of dichloromethane was added. Further, a small amount (about 50 mg) of benzyltrimethylammonium chloride was added, and the mixture was stirred at room temperature for about 15 hours. The reaction mixture was diluted with dichloromethane and water and separated into two phases, and an organic layer was washed with diluted hydrochloric acid, then with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 3.02 g of the resultant oil was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate, 2:1 v/v) to give 2.6 g (yield 89%) of the titled compound. Table 25 shows the structural formula of the titled compound, and Table 27 shows the physical property data thereof.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12>C(O)C.[C].[Pd]>[CH3:15][C:14]1[C:3]2[C:4](=[N:5][C:6]3[C:11]([CH:2]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:13]=1
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Agent: [Pd]
Solvent: CCO
Product: Cc1nn(-c2ccccn2)c2nc3ccccc3cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
To a solution of 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.0 g, 3.39 mmol) in ethanol (30 mL), 5% palladium-carbon (0.8 g, 50% hydrate) was added and the mixture was stirred at room temperature under hydrogen atmosphere for 1 hour. The solution was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure, and the residue thus obtained was purified by silica gel column chromatography (ethyl acetate:hexane=6:4) to give the title compound (380 mg, 43% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:5]=[CH:4][N:3]=1.[Br:12]N1C(=O)CCC1=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[N:6][C:5]([Br:12])=[CH:4][N:3]=1
Reactant: COC(=O)c1nccnc1N
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 2-aminopyrazine-3-carboxylate (5.0 g, 32.65 mmol) was dissolved in 100 mL of THF and treated with N-Bromosuccinimide (6.9 g, 39.18 mmol) all at once. The mixture was stirred at room temperature for 1.5 hrs, and then another 0.5 equivalents of N-bromosuccinimide was added and stirring continued for 1 hr. 10 grams of sodium sulfate were added, the mixture was vigorously stirred for 15 minutes, and the solvent was removed in vacuo. The residue obtained was suspended in 250 mL of water and stirred rapidly. Filtration afforded the title compound, methyl 3-amino-6-bromopyrazine-2-carboxylate, as a tan solid (6.33 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=3)=[CH:32][C:31]=2[C:46]2[CH:51]=[CH:50][N:49]=[N:48][CH:47]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:43])([F:44])[F:45])=[CH:38][CH:37]=3)=[CH:32][C:31]=2[C:46]2[CH:51]=[CH:50][N:49]=[N:48][CH:47]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnnc3)cc2F)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2-c2ccnnc2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.8 %

Procedure:
5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[3-pyridazin-4-yl-4′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 24, 213 mg, 0.28 mmol) was dissolved a in 4M solution of hydrogen chloride in 1,4-dioxane (7 mL) and stirred at room temperature for 3 hours. A precipitate formed which was collected by filtration and purified by reverse phase preparative HPLC (Trilution method) to afford the title compound as a solid (44 mg, 26%).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:27]([Cu])#[N:28].Cl>CN1C(=O)CCC1.C(Cl)Cl>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:27]#[N:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: N#C[Cu]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(SC3CCCCC3)ccc2c1O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCCCOC(=O)c1nc(C#N)c2cc(SC3CCCCC3)ccc2c1O
Temperature: 132.5 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
A mixture of 1-Bromo-7-cyclohexylsulfanyl-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (686 mg, 1.57 mmol) and CuCN (279 mg, 3.13 mmol) in 3.6 mL of NMP was heated in a 130-135° C. oil bath for 3 h. Reaction mixture was diluted with CH2Cl2 (120 mL) and stirred at room temperature overnight. Then 100 mL of 0.5 N HCl aqueous solution was added and the resultant mixture was stirred vigorously for 30 min Two phases were separated and organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Crude residue was purified by silica gel chromatography, eluting with 5-60% EtOAc/hexanes, to provide the title compound 470 mg (1.22 mmol) in 78% yield. 1H NMR (200 MHz) CDCl3, δ in ppm: 12.36 (s, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.68 (d, J=8.8 Hz, 1H), 4.50 (t, J=6.8 Hz, 2H), 3.50 (br m, 1H), 2.10 (m, 2H), 1.87-1.39 (m, 12H), 1.00 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[OH:11])([CH3:3])[CH3:2].[H-].[Na+].[P:14]([Cl:18])(Cl)(Cl)=[S:15]>>[P:14]([Cl:18])([O:11][C:5]1[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])([O:11][C:5]1[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])=[S:15]
Reactant: S=P(Cl)(Cl)Cl
Reactant: Cc1ccc(C(C)C)c(O)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C(C)C)c(OP(=S)(Cl)Oc2cc(C)ccc2C(C)C)c1
Yield: 63 %

Procedure:
2-isopropyl-5-methylphenol was reacted with sodium hydride and thiophosphoryl chloride using the procedure of Example 21 to form bis(2-isopropyl-5-methylphenyl) chlorothiophosphate (31PNMR, singlet, 57 ppm). This compound was reacted with diphenylphosphonothioic amide by the General Method C(ii) (THF) yielding the compound of Formula I in which R1 =R2 =phenyl and R3 =R4 =2-isopropyl-5-methylphenoxy. Yield 63%; titration purity, 90%, MW593; 31PNMR, quartet 53 ppm. Test 2 (Table 2) showed that the product is a very strong extractant for zinc; however on long standing it crystallised from ESCAID solution.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])[NH:9][N:8]=[N:7][C:6]=2[CH:12]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[N:13]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[O:11])[NH:9][N:8]=[N:7][C:6]=3[CH:12]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=c1[nH]nnc2cc(F)ccc12
Reactant: C1COCCN1
Product: O=c1[nH]nnc2cc(N3CCOCC3)ccc12

Procedure:
32.5 g (0.196 mol) of 7-fluoro-3H-benzo[d]-1,2,3-triazin-4-one were heated at 120° C. for 5 hours in 300 ml of morpholine with stirring. The precipitated product was filtered off with suction at 50° C., the precipitate was washed with water, filtered off with suction and dried in a vacuum drying cabinet for 48 hours, giving 30.5 g of 7-morpholin-4-yl-3H-benzo[d]-1,2,3-triazin-4-one as solid; 1H NMR (500 MHz, DMSO) δ 8.00 (d, J=9.0, 1H), 7.52 (dd, J=9.0, 2.6, 1H), 7.39 (dd, J=22.8, 2.6, 1H), 3.78 (dd, J=17.1, 12.3, 4H), 3.45 (dd, J=17.1, 12.3, 4H).