Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:22]=[C:13]3[CH2:14][N:15]([CH:18]4[CH2:21][O:20][CH2:19]4)[CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:5][C:4](B(O)O)=[CH:3]1.[C:26]([O:29][CH2:30][C:31]1[C:36]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[CH:35][C:34]([F:51])=[CH:33][C:32]=1Br)(=[O:28])[CH3:27].C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:26]([O:29][CH2:30][C:31]1[C:36]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[CH:35][C:34]([F:51])=[CH:33][C:32]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:22]=[C:13]3[CH2:14][N:15]([CH:18]4[CH2:21][O:20][CH2:19]4)[CH2:16][CH2:17][N:12]3[N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)(=[O:28])[CH3:27]
Reactant: Cn1cc(B(O)O)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C3COC3)C4)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 130 °C
Yield: 32.7 %

Procedure:
A 25 mL vial was charged with 143a (238 mg, 0.7 mmol), 2-bromo-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydro-pyrazino[1,2-a]indol-2(1H)-yl)benzyl acetate 197d (300 mg, 0.7 mmol), Na2CO3 (147 mg, 1.4 mmol), PdCl2(dppf) (56 mg, 0.07 mmol) suspended in DME (15 mL), and H2O (1 mL). The resulting orange mixture was heated for 30 minutes in a Biotage microwave reactor at 130° C. After reaction the residue was purified by reverse phase Combi-flash eluting with 0.3% NH4HCO3 in 1:7 water/CH3CN to give 143b as a brown solid (150 mg, 33%). MS: (M+H)+ 656.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][OH:6].[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C:18]#[N:19]>CO.O>[OH:6][N:5]=[C:18]([NH2:19])[CH2:17][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([Br:7])[CH:9]=2)[NH:13][CH:12]=1
Reactant: NO
Reactant: N#CCc1c[nH]c2ccc(Br)cc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(Cc1c[nH]c2ccc(Br)cc12)=NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.2 %

Procedure:
To a solution of sodium methoxide (16.92 mL, 0.074 mol, 25 wt %/methanol) in methanol (120 mL) was added powdered hydroxylamine hydrochloride (5.66 g, 0.0814 mol). The mixture was heated at reflux for 1 hour. 5-Bromo-3-indolylacetonitrile (8.8 g, 0.37 mol) was added and refluxing was continued overnight. Refluxing was continued for a further 3 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to obtain a pale yellow solid. The solid was suspended in water (100 mL), stirred for 1/2 hour, filtered, air dried and stirred in ether (40 mL) to give 7.91 g (71%) of product as a white solid.
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8](=[O:36])[N:9]=[C:10]([S:34][CH3:35])[C:11]([C:25]1[CH:30]=[C:29]([OH:31])[CH:28]=[C:27]([C:32]#[CH:33])[CH:26]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][CH2:45][O:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][O:48]1>O>[CH3:6][O:7][C:8](=[O:36])[N:9]=[C:10]([S:34][CH3:35])[C:11]([C:25]1[CH:30]=[C:29]([O:31][CH2:44][CH2:45][O:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)[CH:28]=[C:27]([C:32]#[CH:33])[CH:26]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: C#Cc1cc(O)cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1cc(OCCOC2CCCCO2)cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 6 ml of a DMF solution containing 512 mg of {2-(3-ethynyl-5-hydroxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (45b)), 1.3 g of potassium carbonate and 0.64 ml of 2-(2-bromoethoxy)tetrahydropyran were added. The resulting mixture was stirred at room temperature overnight, and then water was added thereto and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to give [2-{3-ethynyl-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (491 mg, isomer mixture) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=2[F:17])=[CH:4][N:3]=1.[C:18]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O)(=[O:25])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[C:26]([S:23]([NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:24])=[O:25])=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:12][C:11]=2[F:17])=[C:6]([C:8]#[N:9])[CH:7]=1
Reactant: N#Cc1cc(N)ncc1-c1ccc(Br)cc1F
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cc2C#N)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 2-amino-5-(4-bromo-2-fluorophenyl)pyridine-4-carbonitrile and (2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid. MS (ESI): mass calcd. for C22H21FN4O2S, 424.14; m/z found, 425.1 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.18 (d, J=7.8, 1H), 8.01 (s, 1H), 7.64-7.58 (m, 1H), 7.57-7.51 (m, 1H), 7.46-7.28 (m, 4H), 3.91 (s, 1H), 1.04 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]=[C:5]1[C:10]2[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1.[H][H].COC(=O)CC1C2C=C(Cl)C=CC=2OCC1.[OH-].[K+]>[Pd].C.C(OCC)(=O)C.O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]2[O:8][CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:16])=[O:2])[C:10]=2[CH:11]=1
Reactant: [H][H]
Reactant: COC(=O)C=C1CCOc2ccc(Cl)cc21
Agent: [Pd]
Agent: COC(=O)CC1CCOc2ccc(Cl)cc21
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)CC1CCOc2ccc(Cl)cc21
Yield: 34.2 %

Procedure:
6-chloro-3,4-dihydro-2H-1-benzpyran-4-ylidene-acetic acid methyl ester (2.0 g.) was reduced with hydrogen using a 10% Pd-charcoal catalyst (0.20 g.) by stirring at 25° C. in ethyl acetate for 4 hours. The reduction product, 6-chloro-3,4-dihydro-2H-1-benzopyran-4-acetic acid methyl ester (1.0 g.), was heated for 3 days at reflux temperature with potassium hydroxide (2.4 g.) in 25 ml. water. The solution was acidified and extracted with chloroform. Recrystallization from cyclohexane gave 6-chloro-3,4-dihydro-2H-1-benzopyran-4-acetic acid (650 mg. 60%), m.p. 115°-117° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([P:7]([OH:9])[OH:8])[CH2:5][CH3:6].[CH3:10][Si](C)(C)N[Si](C)(C)C.C(N(C(C)C)C(C)C)C.CI.C1OC1C>CO.COCCOCCOC>[NH2:1][CH2:2][CH2:3][CH:4]([P:7]([CH3:10])(=[O:9])[OH:8])[CH2:5][CH3:6]
Reactant: CCC(CCN)P(O)O
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: CC1CO1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOCCOC
Product: CCC(CCN)P(C)(=O)O
Reaction time: 16 h

Procedure:
A mixture of 4,53 g (30 mmol) of P-(5-aminopent-3-yl)phosphonous acid and 24.21 g (150 mmol) of hexamethyldisilazane is refluxed under argon while stirring for 16 hours. To the resulting solution 15 ml of diethylene glycol dimethyl ether are added and boiling is continued for additional 2 hours. The reaction mixture is cooled to 100° and 19.38 g (150 mmol) of N-ethyl-N,N-diisopropyl-amine are added over a period of 20 minutes. After cooling to 25°, 21.29 g (15 mmol) of methyliodide are added over a period of 20 minutes, the reaction temperature being kept at 25° with external cooling. The reaction mixture is stirred for 4 days, then cooled to 10°. The white precipitate is filtered off. The filtrate is evaporated under reduced pressure, and the residue diluted with 100 ml of cold dichloromethane and extracted three times with 50 ml each of 2N hydrochloric acid. The extracts are combined, evaporated to dryness and co-evaporated 2 additional times with 50 ml each of water to give a colourless oil. This oil is dissolved in 50 ml of methanol, 300 ml of propylene oxide are added and the mixture is kept at 4° overnight and then evaporated under reduced pressure. The crude product is purified by chromatography on 150 g of Opti-Up® C12 with water as eluent. The fractions containing the desired product are combined and evaporated under reduced pressure. The solid residue is dried under reduced pressure yielding P-(5-aminopent-3-yl)-P-methylphosphinic acid ×0.52 H2O (hygroscopic).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[N:5][C:6]2[C:7](=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)[N:8]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([CH2:2][C:3]2[N:4]=[N:5][C:6]3[C:7](=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=3)[N:8]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Nc1nc(N)c2nc(CCl)nnc2n1
Reactant: C1CCNCC1
Product: Nc1nc(N)c2nc(CN3CCCCC3)nnc2n1
Temperature: 80 °C

Procedure:
A mixture of 3-Chloromethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine 3 (70 mg; 0.33 mmol) and 1.0 mL of piperidine were heated to 80° C. in a sealed tube for 7 h. The mixture was then allowed to cool to room temperature and concentrated in vacuo. The crude product was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 30% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 111 mg of yellow colored 3-Piperidin-1-ylmethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine as the trifluoroacetate salt.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O[CH:20]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])C.Cl>COCCOC>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][CH:20]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC=CC(=O)OCC
Reactant: CCOC(=O)c1cc(NC(N)=O)ccc1Cl
Agent: Cl
Solvent: COCCOC
Product: CCOC(=O)C=CNC(=O)Nc1ccc(Cl)c(C(=O)OCC)c1

Procedure:
6.0 g of ethyl 2-chloro-5-ureidobenzoate and 6.4 g of ethyl 3-ethoxyacrylate are heated at reflux temperature in 100 ml of 1,2-dimethoxyethane and subsequently heated at this temperature with 12 ml of 2N hydrochloric acid for 5 minutes. The reaction mixture is evaporated to dryness under reduced pressure and the residue is purified by chromatography on 300 g of silica gel using ethyl acetate/n-hexane (1:3) as the eluent. There is obtained ethyl 2-chloro-5-{3-[2-(ethoxycarbonyl)vinyl]ureido}-benzoate, m.p. 116°-117° C.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].Cl.[O:16]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)C.[BH4-].[K+]>O>[OH:4][CH:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)[CH2:2][N:26]1[CH2:27][CH2:28][CH:23]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24][CH2:25]1
Reactant: c1ccc(OC2CCNCC2)cc1
Reactant: O=C1Cc2cc(C(=O)CCl)ccc2N1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1Cc2cc(C(O)CN3CCC(Oc4ccccc4)CC3)ccc2N1
Reaction time: 0.25 h

Procedure:
A mixture of 4.19 g (20 mmoles) 5-chloroacetyl-3H-indol-2-one 4 g dry sodium carbonate, 4.27 g (20 mmoles) 4-phenoxypiperidine hydrochloride and 100 ml ethanol is heated under reflux fo 1 h 15 min under an argon atmosphere. The mixture is left to cool, 10 ml water, then 8 g potassium borohydride are added and stirring is continued for 2 h 30 min at ambient temperature. A further 200 ml water are added, the mixture is stirred for 30 min and filtered, and the solid is washed with water and dried. 4.67 g of oohre orystals are obtained, which are purified by chromatography on a silica column, eluting with a 95/5 mixture of dichloromethane/ methanol.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][C:11]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12])=O)(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[CH3:6][NH:8][CH2:9][CH2:10][C:11]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:12]
Reactant: CN(CCC(=O)N1CCOCC1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNCCC(=O)N1CCOCC1

Procedure:
A solution of 4-(N-t-butoxycarbonyl-N-methyl-β-alanyl)morpholine (1.37 g) in trifluoroacetic acid (20 ml) was stirred at 0° C. for 1 hour. The solvent was evaporated to give 4-(N-methyl-β-alanyl)morpholine trifluoroacetic acid salt (1.44 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[S:20](=[O:23])(=[O:22])[CH2:21][C:12]=3[C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.N1C(C)=CC(C)=CC=1C.[C:38]1([O:44][C:45](Cl)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[O:44]([C:45]([NH:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[S:20](=[O:23])(=[O:22])[CH2:21][C:12]=3[C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:10]2)[CH:6]=[CH:7][CH:8]=1)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)c1nn(-c2cccc(N)c2)c2c1CS(=O)(=O)c1ccccc1-2
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(-c2cccc(NC(=O)Oc3ccccc3)c2)c2c1CS(=O)(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
To a solution of ethyl 1-(3-aminophenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide hydrochloride (100 mg, 0.243 mmol) in THF (10 mL) are added 2,4,6 collidine (0.06 mL, 0.487 mmol), phenylchloroformate (0.04 mL, 0.365 mmol) then stirred at RT for 18 h. After this time, reaction mixture is concentrated under reduced pressure, diluted with water, and extracted with EtOAc. The organic layer is separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 100 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]([CH2:21][C:22]([OH:24])=[O:23])[O:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C[O-].[Na+:27].CO.CCOC(C)=O>CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][CH:14]([CH2:21][C:22]([O-:24])=[O:23])[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]\3=4)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Na+:27]
Reactant: O=C(O)CC1OC(=C2C(=O)Nc3cc(F)ccc32)c2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C([O-])CC1O/C(=C2/C(=O)Nc3cc(F)ccc32)c2ccccc21
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a slurry of [3-(6-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-yl]-acetic acid (521 mg, 1.60 mmol) in MeOH (100.0 ml) at room temperature was added 0.5M NaOMe/MeOH (3.20 ml). The solution was rapidly stirred for 15 minutes and then rotary evaporated (combined 16 mg of product obtained from previously run reaction). The solid was chased with MeOH (20 ml) and then EtOAc (15 ml) to give sodium [(3E)-3-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-1,3-dihydro-2-benzofuran-1-yl]acetate as a yellow solid (557 mg, 100%).
Reaction SMILES: [C:1]([N:4]1[C:8]([NH:9][C:10](=[O:12])[CH3:11])=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5]1)(=[O:3])[CH3:2].[I:19](O)(=O)=O.II>C(O)C>[C:1]([N:4]1[C:8]([NH:9][C:10](=[O:12])[CH3:11])=[C:7]([I:19])[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: [O-][I+2]([O-])O
Reactant: CC(=O)Nc1cc(-c2ccccc2)nn1C(C)=O
Agent: II
Solvent: CCO
Product: CC(=O)Nc1c(I)c(-c2ccccc2)nn1C(C)=O
Temperature: 50 °C

Procedure:
A suspension of N-(2-acetyl-5-phenyl-pyrazol-3-yl)acetamide (25.1 g, 0.103 mol), iodic acid (4.5 g, 0.026 mol) and iodine (15.7 g, 0.062 mol) in ethanol (250 mL) was heated at 50° C. for 3 h and cooled to room temperature. The reaction mixture was concentrated in vacuo and partitioned between CH2Cl2 and 2 M Na2S2O3 aq. solution. The layers were separated and the organic washed with brine, dried (phase separator cartridge), and concentrated in vacuo to provide a mixture of the title compound and starting material (2.2:1, 30.3 g). The mixture was put in reaction again using iodic acid (1.6 g, 9.6 mmol) and iodine (9.7 g, 38 mmol) in ethanol (250 mL) under the same conditions, to provide the title compound as a solid (31.9 g).
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([CH:8]([CH2:18][CH3:19])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:34])[NH:28]2>>[F:33][C:30]1[CH:31]=[CH:32][C:23]([N:22]=[CH:11][C:10]([OH:17])([C:13]([F:14])([F:15])[F:16])[CH2:9][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[O:20][CH3:21])[CH2:18][CH3:19])=[C:24]2[C:29]=1[NH:28][C:27](=[O:34])[CH:26]=[CH:25]2
Reactant: CCC(CC(O)(C=O)C(F)(F)F)c1cccc(F)c1OC
Reactant: Nc1ccc(F)c2[nH]c(=O)ccc12
Product: CCC(CC(O)(C=Nc1ccc(F)c2[nH]c(=O)ccc12)C(F)(F)F)c1cccc(F)c1OC

Procedure:
In the same way as in Example 29, 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal and 5-amino-8-fluoroquinolin-2(1H)-one are condensed to give 8-fluoro-5-{[4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}quinolin-2(1H)-one. Reaction with 1 M boron tribromide solution after column chromatography on silica gel (hexane/ethyl acetate 33-100%) and preparative HPLC yield not only the desired product but also the methyl ether cleaved compounds Example 35 and 44.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:29]>>[F:1][C:2]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[NH:29])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: N
Reactant: COc1ccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c(F)c1
Product: COc1ccc(COc2cccnc2NC(=N)Nc2ccc(Cl)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of yellow mercuric oxide (0.54 g, 0.0025 mol), N-[3-(2-fluoro-4-methoxybenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (0.8 g, 0.0021 mol) and methanolic ammonia solution (40 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by trituration with ether and recrystallisation from acetonitrile gave the desired product. Yield 0.37 g, (45%), m.p. 158°-161 ° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][CH:8]=[C:9]([CH2:11][OH:12])[N:10]=1.Cl[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)=[CH:16][N:15]=1>>[N:23]1([CH2:22][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:12][CH2:11][C:9]3[N:10]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[O:7][CH:8]=3)=[N:15][CH:16]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: Clc1ccc(CCCn2ccnc2)cn1
Reactant: OCc1coc(-c2cccs2)n1
Product: c1csc(-c2nc(COc3ccc(CCCn4ccnc4)cn3)co2)c1
Yield: 67 %

Procedure:
In substantially the same manner as in Working Example 125, 2-(2-thienyl)-4-oxazolylmethanol was allowed to react with 2-chloro-5-[3-(1-imidazolyl)propyl]pyridine to give 5-[3-(1-imidazolyl)propyl]-2-[2-(2-thienyl)-4-oxazolylmethoxy]pyridine. The yield was 67%. Recrystallization from ethyl acetate-hexane gave brown prisms, mp 86-87° C.
Reaction SMILES: Cl[CH:2]([SiH3:4])Cl.[C:5]([C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]2[C:20]([OH:33])=[C:21]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:22]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=2)[C:10]=1[OH:34])([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:15]([C:13]1[CH:14]=[C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:10]2[O:34][SiH:4]([CH3:2])[O:33][C:20]3[C:21]([C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:22][C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:24][C:19]=3[C:11]=2[CH:12]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: [SiH3]C(Cl)Cl
Reactant: CC(C)(C)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[SiH]1Oc2c(cc(C(C)(C)C)cc2C(C)(C)C)-c2cc(C(C)(C)C)cc(C(C)(C)C)c2O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a flame-dried flask under a dry nitrogen atmosphere, a stirred solution of 23.0 grams (0.20 mole) of dichloromethylsilane in 200 ml toluene is treated slowly with a solution of 82.1 grams (0.20 mole) of 3,3',5,5'-tetra-tert-butyl-biphenyl-2,2'-diol and 40.5 grams (0.40 mole) of triethylamine in 250 ml toluene at 5°-10° C. The reaction mixture is stirred at room temperature for 12 hours following the addition, is then filtered to remove triethylamine hydrochloride, and the solvent removed in vacuo. The residue is recrystallized from acetonitrile-toluene giving 69.4 grams (77%) of white crystals, mp 191°-198° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]=1[CH2:17][NH2:18].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:18][CH2:17][C:16]3[C:19]([O:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:21]=[CH:22][C:15]=3[Cl:14])[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1c(Cl)cccc1Oc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(NCc3c(Cl)cccc3Oc3ccccc3)ccc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 2-chloro-6-phenoxy-benzylamine (150 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-chloro-6-phenoxy-benzylamino)-2H-phthalazin-1-one: 39 mg (16.3%): m/z (M+H)=412. 1H-NMR (DMSO-d6) δ: 12.34 (s, 1H), 7.90 (d, 1H), 7.35 (m, 5H), 7.21 (dd, 1H), 7.15 (m, 1H), 7.02 (m, 2H), 6.95 (d, 1H), 6.84 (dd, 1H), 4.50 (d, 2H).
Reaction SMILES: [C:1]([SH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([CH3:17])=[CH2:16])=[CH:13][CH:12]=1>CCCCCC>[C:1]([S:9][C:15]([C:14]1[CH:18]=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=1)([CH3:17])[CH3:16])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)c1ccc(Cl)cc1
Reactant: S=C(S)c1ccccc1
Solvent: CCCCCC
Product: CC(C)(SC(=S)c1ccccc1)c1ccc(Cl)cc1
Temperature: 70 °C
Yield: 34.2 %

Procedure:
Dithiobenzoic acid (6.3 g) and 4-chloro-a-methylstyrene (6 g) were combined and the mixture heated at 70° C. overnight. The residue was subjected to column chromatography (Kieselgel-60, 70-230 mesh, n-hexane as eluent) which gave the title compound as a purple solid (34.2% yield) m.p. 77-78° C. 1H-nmr (CDCl3) d (ppm): 1.97 (s, 6H, 2×CH3), 7.20-7.52 (m, 7H, ArH) and 7.86 (d, 2H, ArH). 13C-nmr (CDCl3) d (ppm): 28.4, 55.7, 126.5, 128.1, 131.9, 132.4, 142.8, 146.0. The signal due to C═S (d>220.0 ppm) was beyond the frequency range of the spectrum.