Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:22][CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:53])(=O)=O)=CC=1>O1CCCC1>[C:1]([O:5][C:6]([C@@:8]1([CH2:22][CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:31])([CH3:30])[CH3:32])([CH3:28])[CH3:27])[CH:12]([F:53])[C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: C[C@H](c1ccccc1)N1C[C@@](CCCO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)CC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@@](CCCO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)C(F)C1=O
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 26.1 %

Procedure:
(3S)-3-[3-(tert-Butyldimethylsilyloxy)-1-propyl]-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (30 g) was dissolved in tetrahydrofuran (280 mL), and the atmosphere was replaced with argon. Then, lithium hexamethyldisilazide (1.0 M solution in tetrahydrofuran) (78.0 mL) was added dropwise at −15° C., and the mixture was stirred at −5° C. for 30 minutes. After cooling to −15° C. again, a solution of N-fluorobenzenesulfonimide (26.6 g) in tetrahydrofuran (220 mL) was added dropwise, and the mixture was stirred at room temperature for 17 hours. The reaction solution was extracted with a 10% citric acid solution and ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. Thereafter, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=9:1→8:2) to give 8.15 g of the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11](#[N:14])[CH:12]=[CH2:13].[OH-].[Na+]>O.C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]2[O:10][CH2:13][CH:12]([C:11]#[N:14])[CH:5]([OH:6])[C:4]=2[CH:3]=1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: C=CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#CC1COc2ccc(Cl)cc2C1O
Reaction time: 8 h

Procedure:
To a stirred, refluxing mixture of 50 g of 3-chloro-6-hydroxybenzaldehyde and 62 ml of acrylonitrile in 50 ml of water was added dropwise over a three-hour period a solution of 12.8 g of sodium hydroxide in 120 ml of water. Then an additional 62 ml of acrylonitrile was added and the stirred mixture was refluxed for 2 hours, then allowed to stand at room temperature overnight. The crystals which formed were filtered off, washed with water and dried to give a solid, which was dissolved in ethanol. The solution was cooled and filtered to give 6-chloro-3,4-dihydro-4-hydroxy-(2H)- 1-benzopyran-3-carbonitrile (5A), a solid. A mixture of 5A with 250 ml of methanol containing 2 ml of sulfuric acid, was refluxed for 4 days and stripped of solvent. The resulting residue was dry column chromatographed over silica gel, using Solvent No. 3 as eluent. The product obtained on workup was recrystallized from ether to give methyl 6-chloro-2H-1-benzopyran-3-carboxylate (5B), as light yellow needles, m.p.: 106°-109°.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Br:15])=[CH:10][CH:9]=1)([O-:7])=[O:6].[Br-]>CC(C)=O>[BrH:15].[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:3][C:2](=[NH:4])[NH2:1])=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: NC(N)=S
Agent: [Br-]
Solvent: CC(C)=O
Product: Br
Product: N=C(N)SCc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 94.1 %

Procedure:
Thiourea (8c) (1.55 kg) and acetone (30 L) were added to a 72-L reactor under a nitrogen atmosphere. The mixture was agitated. 4-nitrophenylmethyl bromide (8d) (4.00 kg) and acetone (15 L) were added to a separate flask. The mixture was stirred until the bromide dissolved (warming may be required). The solution of the bromide was added to the mixture of thiourea, keeping the temperature below 40° C. A thick solution formed within 30 minutes. After stiffing for 2 h, HPLC analysis of the mixture shows >99% conversion. The mixture was filtered, and the filter cake was rinsed with a 1:1 MTBE: acetone solution (8 L). The solids were dried to give 5.09 kg (93% yield) of the desired product (8a) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[C:11]([N:18]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C([N-]C(C)C)(C)C.[Li+].[I:32]I>O1CCCC1>[OH:23][C:20]1([C:2]2[S:1][C:5]([I:32])=[CH:4][N:3]=2)[CH2:21][CH2:22][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19]1
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: c1cscn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ncc(I)s2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.) solution of thiazole (0.382 mL, 5.41 mmol) in tetrahydrofuran (30 mL) was added n-butyllithium (3.38 mL, 5.41 mmol, 1.6 M in hexane) dropwise. After 15 minutes, N-boc-3-pyrrolidinone (0.49 mL, 5.41 mmol) was added in a single portion. After 30 minutes, lithium diisopropylamide (5.41 mL, 5.41 mmol, 1.0 M in tetrahydrofuran) was added dropwise. The reaction was allowed to stir for an additional 30 minutes, after which a solution of I2 (1.37 g, 5.4 mmol) in tetrahydrofuran (10 mL) was added dropwise. After 10 minutes, the reaction was then quenched by the addition of saturated aqueous Na2S2O3 (100 mL) and ethyl acetate (100 mL) and allowed to warm to ambient temperature. The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×100 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated to give a dark solid. The residue was purified by chromatography on SiO2 gel, eluting with 50% ethyl acetate in hexanes, to give the title product as a solid. MS (ESI) m/z 397 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH2:28][CH3:29])=[C:22]([O:25][CH3:26])[CH:23]=3)[C@@H:18]3[C@@H:13]([CH2:14][CH2:15][C@@H:16]([OH:30])[CH2:17]3)[N:12]=2)=[CH:7][N:6]=1)=N.O.P(=O)(O)(O)[OH:33].P([O-])([O-])(O)=O.[Na+].[Na+]>C1COCC1>[CH2:28]([O:27][C:21]1[CH:20]=[C:19]2[C:24]([C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:2])=[O:33])=[N:6][CH:7]=3)=[N:12][C@H:13]3[C@@H:18]2[CH2:17][C@H:16]([OH:30])[CH2:15][CH2:14]3)=[CH:23][C:22]=1[O:25][CH3:26])[CH3:29]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=N)OC)nc1)=N[C@@H]1CC[C@@H](O)C[C@H]21
Reactant: O=P(O)(O)O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)nc1)=N[C@@H]1CC[C@@H](O)C[C@H]21
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Analogously as described for Example 35 acidic acid (2R,4aR,10bR)-6-(6-cyano-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-yl ester (compound 172) is converted in a first step into the corresponding imino ester 5-((2R,4aR,10bR)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-pyridine-2-carboximidic acid methyl ester. In a second step, 443 mg (1.08 mmol) of 5-((2R,4aR,10bR)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-pyridine-2-carboximidic acid methyl ester are dissolved in 3 ml of THF. A solution of 51 mg (2.16 mmol) LICH.H2O is added and the solution stirred at 60° C. for 18 hrs. The pH is adjusted to 5 using phosphoric acid and Disodiumhydrogenphosphate. The solvent is removed and the solid residue extracted with chloroform/methanol. After filtering off and removing the volatiles 350 mg (82%) of the title compound are obtained.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=2)[N:31]=1.O.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:41])([CH3:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 193 °C
Reaction time: 4.5 h
Yield: 92.5 %

Procedure:
In 13.4 mL of N-methyl-2-pyrrolidinone were dissolved 6.49 g (20 mmol) of 4-(diphenylmethoxy)-1-piperidinepropaneamine and 2.68 g (10.0 mmol) of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate, heated to 191-195° C. under a nitrogen atmosphere and stirred for 4.5 hours. After cooling to room temperature, 20 mL of water and 1.01 g (2 mmol) of sodium hydrogencarbonate were added and extracted twice with 30 mL of ethyl acetate. The extract was washed with 20 mL of water three times and the organic layer was concentrated under reduced pressure. The residue was subjected to silica gel chromatography to be eluted with ethyl acetate:methanol:triethylamine (100:5:1). The desired fraction was collected and concentrated to provide 5.14 g of the crude title compound. Purity 83%, yield 77%, determined from the integral values of the proton NMR.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[C:35](=[O:40])[NH:36][CH2:37][CH2:38][OH:39]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:29]4[CH:30]=[CH:31][C:26]([F:25])=[C:27]([CH:28]=4)[C:35]([NH:36][CH2:37][CH2:38][OH:39])=[O:40])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: O=C(NCCO)c1cc(B(O)O)ccc1F
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccc(F)c(C(=O)NCCO)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 12.2 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-fluoro-3-(2-hydroxyethylcarbamoyl)phenylboronic acid (23 mg, 0.106 mmol). The mixture was heated at 120° C. in a microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 5-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-2-fluoro-N-(2-hydroxyethyl)benzamide (3.1 mg, 12%). 1H-NMR (MeOD): 2.48 (m, 1H), 2.61 (m, 1H), 3.34 (s, 3H), 3.57 (m, 2H), 3.72 (m, 2H), 5.27 (d, 0.3H), 5.89 (d, 0.8H), 7.18 (m, 1H), 7.30 (m, 1H), 7.45 (m, 1H), 7.52 (m, 4H), 7.67 (m, 1H), 7.79 (m, 1H), 8.01 (m, 1H), 8.32 (m, 1H).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]([OH:8])[CH3:7])[CH2:2][CH3:3].[OH-:9].[Na+].[C:11](Cl)(=[O:14])[CH:12]=[CH2:13]>C(Cl)(Cl)Cl>[C:1]([N:4]([CH2:5][CH:6]([OH:8])[CH2:7][N:4]([CH2:1][CH2:2][CH3:3])[C:11](=[O:14])[CH:12]=[CH2:13])[CH2:5][CH2:6][CH3:7])(=[O:9])[CH:2]=[CH2:3]
Reactant: CCCNCC(C)O
Reactant: C=CC(=O)Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C=CC(=O)N(CCC)CC(O)CN(CCC)C(=O)C=C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
17.43 g (0.100 mol) of 1,3-bis-(propylamino-propan-2-ol was mixed with 110 ml (0.220 mol) of 2N caustic soda solution and stirred at room temperature for 10 minutes. The mixture was cooled to 0° C. A solution of 19.46 g (0.215 mol) of acrylic acid chloride and 20 mg of BHT in 120 ml of chloroform was added dropwise at 0° C. within 3 hours 30 minutes. After the addition was completed the reaction mixture was stirred at 0° C. for 2 hours 30 minutes. Organic and aqueous phases were separated. The aqueous phase was saturated with NaCl and extracted with 5×80 ml of methylene chloride. The combined organic phases were dried over Na2SO4, filtered, concentrated in a rotary evaporator after addition of 20 mg of BHT and dried in a fine vacuum. The raw product was purified by means of two-fold column chromatography (silica gel 60, 0.035-0.070 mm, ethyl acetate). 11.92 g (42.2 mmol; 42%) of the pure product was obtained as a yellowish oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][NH:7]1.Br[CH2:26][C:27](Br)=[O:28].[NH2:30][CH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:26][C:27]([NH:30][CH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32]1)=[O:28]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1Br
Reactant: O=C(Br)CBr
Reactant: NC1CCc2ccccc21
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1Br

Procedure:
prepared by reaction of 1-(3-Bromo-4-methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-indane
Reaction SMILES: CN1C(=O)CCC1.N1(O[C:18]2[N:23]=[C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=3)[C:21]([C:32]([NH2:34])=[O:33])=[CH:20][N:19]=2)C2C=CC=CC=2N=N1.[Br:35][C:36]1[CH:37]=[C:38]([CH2:43][CH2:44][NH2:45])[CH:39]=[CH:40][C:41]=1[OH:42].C(N(C(C)C)CC)(C)C>O>[Br:35][C:36]1[CH:37]=[C:38]([CH2:43][CH2:44][NH:45][C:18]2[N:23]=[C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=3)[C:21]([C:32]([NH2:34])=[O:33])=[CH:20][N:19]=2)[CH:39]=[CH:40][C:41]=1[OH:42]
Reactant: Cc1cccc(Nc2nc(On3nnc4ccccc43)ncc2C(N)=O)c1
Reactant: NCCc1ccc(O)c(Br)c1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Nc2nc(NCCc3ccc(O)c(Br)c3)ncc2C(N)=O)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
A 6 ml portion of NMP solution containing 600 mg of 2-(benzotriazol-1-yloxy)-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamide was mixed with 538 mg of 2-(3-bromo-4-hydroxyphenyl)ethylamine and 0.72 ml of diisopropylethylamine, followed by stirring at 80° C. for 2 hours. The reaction mixture was cooled down to room temperature, and then mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, the solvent was evaporated, and then the resulting residue was recrystallized (ethanol-THF) to obtain 200 mg of 2-{[2-(3-bromo-4-hydroxyphenyl)ethyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamide as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH3:27][N:28]([CH3:35])[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:32]3[CH2:33][CH2:34][CH:29]([N:28]([CH3:35])[CH3:27])[CH2:30][CH2:31]3)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: CN(C)C1CCNCC1
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 7.8 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol) in DMF (2 mL) were added N,N-dimethylpiperidin-4-amine (40 mg, 0.30 mmol), diisopropylethylamine (DIPEA) (105 μL, 0.60 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (125 mg, 0.33 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by preparative HPLC yielding Compound 59 as a solid (10 mg).
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[H-].[Na+].[C:9](=[S:11])=[S:10].[CH3:12]I>C1COCC1>[CH3:12][S:10][C:9]([P:1]([O:4][CH3:5])([O:2][CH3:3])=[O:6])=[S:11]
Reactant: CI
Reactant: COP([O-])OC
Reactant: S=C=S
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COP(=O)(OC)C(=S)SC
Temperature: 6 °C

Procedure:
Dimethyl phosphite (11.0 g 0.1 mol) was added dropwise to a stirred solution of 2.4 g (0.1 mole) of sodium hydride in 50 mL of dry THF at 25-30° C. under N2. The mixture was stirred under reflux until H2 evolution ceased. It was then cooled to 6° C. and was added with stirring to carbon disulfide (38 g, 0.5 mol) at 2-8° C. over 15 min. Methyl iodide (14.2 g 0.1 mol) was then added at 5° C. over 15 min. The mixture was quenched with 350 mL of ice-water and extracted with ether (100 mL×3). The ether layers were combined, dried with anhydrous magnesium sulfate, filtered, evaporated to remove ether and distilled in vacuo. The fraction boiling between 92-94° C./50μ was collected, 6.5 g, Y=32.5%. (Put footnote 2 here) 1H NMR: δ(ppm) 3.85 (d, 6H, 3JHP=10 Hz, POCH3), 2.69 (d, 3H, JHP=1 Hz CSCH3); 13C NMR: δ(ppm) 228(d, 1JCP=175 Hz, CS), 54.5 (d, 2JCP=6 Hz, POCH3), 10.9 (s, CSCH3); 31P NMR {H}: δ(ppm) 0.30(s); 31P NMR: δ(ppm) 0.30 (m, 3JPH=11 Hz); HRMS: 199.9732 (Found); 199.9731 (Calcd).
Reaction SMILES: [C:1](O)(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[NH:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl.CN(C)C=O>[C:1]([C:27]1[CH:26]=[C:25]([C:29]([O:31][CH3:32])=[O:30])[NH:24][CH:28]=1)(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: COC(=O)c1ccc[nH]1
Reactant: CCCCCCCCCCCCC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCC(=O)c1c[nH]c(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
In 480 ml of methylene chloride, were dissolved 102.9 g (0.48 mol) of tridecanoic acid, to which 52.6 ml (0.72 mol) of thionyl chloride and 0.2 ml of N,N-dimethylformamide were added to obtain a solution. The solution was allowed to stand over night and was evaporated under a reduced pressure. The remaining oil was added to 400 ml of methylene chloride containing 106.6 g (0.8 mol) of anhydrous aluminum chloride, to which 200 ml of methylene chloride solution containing 50.05 g (0.4 mol) of methyl pyrrole-2-carboxylate was added dropwise in 40 minutes at a temperature of 3° to 9° C. After the addition, the temperature of the mixture was elevated slowly up to room temperature and the mixture was stirred for 2 hours. Then, the mixture was poured into 800 ml of ice-water, and 1000 ml of methylene chloride was added thereto to dissolve all the crystals precipitated, followed by liquid separation. The organic layer was washed with water three times, dried over anhydrous magnesium sulfate and condensed under a reduced pressure. The residue was recrystallized from 400 ml of ethyl acetate and 400 ml of hexane to obtain 107.2 g of methyl 4-tridecanoylpyrrole-2-carboxylate as white crystals. The yield was 83% and the melting point was 92° to 93° C.
Reaction SMILES: [Na].[C:2](=[N:5][N:6]1[C:10]([SH:11])=[N:9][N:8]=[N:7]1)([CH3:4])[CH3:3].[BH4-].[Na+]>O1CCCC1.CO>[CH:2]([NH:5][N:6]1[C:10]([SH:11])=[N:9][N:8]=[N:7]1)([CH3:4])[CH3:3]
Reactant: CC(C)=Nn1nnnc1S
Agent: [BH4-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Nn1nnnc1S
Reaction time: 1 h
Yield: 87.3 %

Procedure:
1-Isopropylidenamino-5-mercapto-1H-tetrazole sodium salt (5.37 g) was dissolved in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml), and sodium borohydride (1.14 g) was added gradually thereto at 5°-6° C. under stirring. The mixture was stirred at the same temperature for one hour, and then at room temperature for one hour. The mixture was evaporated to remove solvent, and the residue was dissolved in icewater. The aqueous solution was adjusted to pH 2.8 with 6N-hydrochloric acid, and the solution was extracted with ethyl acetate (20 ml) three times repeatedly. The extracts were washed with a saturated sodium chloride solution, dried and then evaporated to remove solvent. n-Hexane was added to the residue thus obtained, and crystalline precipitates were collected by filtration. 4.14 g of 1-isopropylamino-5-mercapto-1H-tetrazole were obtained as colorless needles. mp 92°-95° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:34])([CH3:33])[C:13](=[O:32])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:25]=4[CH3:31])=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:36][C:37]1[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:44].[OH-].[Na+]>C(O)C>[Cl:43][C:42]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:44])[C:37]=1[CH2:36][O:30][C:28]1[CH:27]=[CH:26][C:25]([CH3:31])=[C:24]([C:22]([N:19]2[CH2:20][CH2:21][CH:16]([N:14]3[C:13](=[O:32])[C:12]([CH3:34])([CH3:33])[C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:15]3)[CH2:17][CH2:18]2)=[O:23])[CH:29]=1
Reactant: Clc1cccc(Cl)c1CBr
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(O)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCc5c(Cl)cccc5Cl)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 0.40 g of 5-(3,4-dimethoxyphenyl)-2-{1-[(5-hydroxy-2-methylphenyl)carbonyl]piperidin-4-yl}-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 85) and 0.41 g 2-(bromomethyl)-1,3-dichlorobenzene in 5 ml ethanol is treated with 0.17 ml 10n aqueous sodium hydroxide solution and stirred under a blanket of nitrogen for about 6 h at 80° C. until the reaction is completed largely according to TLC analysis. The solvent is evaporated under reduced pressure, and the resulting crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](O)=[O:10])[CH:5]=[CH:6][CH:7]=1.B#B.O>O1CCCC1>[OH:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: B#B
Solvent: O
Solvent: C1CCOC1
Product: OCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.3 %

Procedure:
To a solution of 3-bromophenylacetic acid (10 g, 46.5 mmol) in tetrahydrofuran (100 ml) at 0° C. was added diborane (70 ml, 1.0M solution in tetrahydrofuran). The reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was cooled to 0° C. and water was added dropwise (50 ml). The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: 40-60% ethyl acetate/hexane) to give 3-(2-hydroxyethyl)bromobenzene (9.0 g).