Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:13]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=3)=[O:15])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnc2cc(C)ccc2c1O
Reactant: NCc1ccc(Cl)cc1
Product: Cc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Temperature: 200 °C
Reaction time: 1 h

Procedure:
A mixture of 0.50 g of ethyl 4-hydroxy-7-methyl-3-quinolinecarboxylate (J. Indian Chem. Soc., 31 (1954)) and 5.0 mL of 4-chlorobenzylamine is stirred 1 hour at 200° C. The mixture is cooled to 25° C. and it is diluted with 25 mL of hexanes. After stirring for an additional 1 h the solid precipitate is collected by filtration and washed with 10 mL of hexanes. It is dried in a stream of air and then it is suspended in 20 mL of glacial acetic acid. The mixture is heated until the solid is completely dissolved and the resulting solution is diluted with 200 mL of distilled water. The mixture is allowed to cool to 25° C. and the solid is collected by filtration. It is washed with a small volume of 10% aqueous acetic acid and then it is dried at torr and 45° C. for 18 h. The yield is 0.23 g.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[C:8]([C:17](O)=[O:18])[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=2)[N:6]([CH3:20])[CH:5]=1)([CH3:3])[CH3:2].Cl.[NH2:22][CH2:23][C:24]1[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=1[CH3:30].ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:30][C:29]1[CH:28]=[C:27]([CH3:31])[NH:26][C:25](=[O:32])[C:24]=1[CH2:23][NH:22][C:17]([C:8]1[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[C:12]2[C:7]=1[N:6]([CH3:20])[CH:5]=[C:4]2[CH:1]([CH3:2])[CH3:3])=[O:18]
Reactant: CC(C)c1cn(C)c2c(C(=O)O)cc(S(C)(=O)=O)cc12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(CNC(=O)c2cc(S(C)(=O)=O)cc3c(C(C)C)cn(C)c23)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 19 h
Yield: 75.9 %

Procedure:
3-Isopropyl-1-methyl-5-(methylsulfonyl)-1H-indole-7-carboxylic acid (80.7 mg, 0.27 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone hydrochloride (66.2 mg, 0.35 mmol) and 1-hydroxy-7-azabenzotriazole (56.7 mg, 0.42 mmol) were stirred in 3 mL of DMSO for 10 min under nitrogen. N-methylmorpholine (0.12 mL, 1.09 mmol) was added along with EDC (78.3 mg, 0.41 mmol) and the mixture was stirred at room temperature for 19 hours. Ice-water (15 mL) and a concentrated solution of potassium carbonate were added to pH 10 and the solution was stirred for 40 minutes at room temperature. The solids were filtered, washed with water and dried. DMF was added along with water, solids were filtered and dried in vacuum-oven overnight to give N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-isopropyl-1-methyl-5-(methylsulfonyl)-1H-indole-7-carboxamide (88 mg, 73%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31 (d, J=6.8 Hz, 6H) 2.12 (s, 3H) 2.24 (s, 3H) 3.18-3.26 (m, 4H) 3.71-3.75 (m, 3H) 4.36 (d, J=4.80 Hz, 2H) 5.89 (s, 1H) 7.33 (s, 1H) 7.51 (d, J=1.77 Hz, 1H) 8.14 (d, J=2.02 Hz, 1H) 8.65 (t, J=4.93 Hz, 1H) 11.52 (s, 1H). MS (ES) [M+H]+ 430.3.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.C1C[O:13][CH2:12]C1.[Li+].CC([N-]C(C)C)C.CN(C=O)C>O>[Br:1][C:2]1[S:6][C:5]([CH:12]=[O:13])=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1
Reactant: O=C(O)c1csc(Br)c1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1sc(Br)cc1C(=O)O
Temperature: -30 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Under a nitrogen atmosphere, 5-bromo-3-thiophenecarboxylic acid (12 g, 58 mmol) was added to THF (300 ml), and LDA (174 mmol, 232 ml, 0.75 M) was slowly dropped at −78° C. Then, the mixture was stirred for two hours at −30° C., and DMF was slowly dropped at −78° C. Then, water was added to the reaction solution. The reaction solution was then extracted with ethyl acetate, and an organic layer was washed with a saturated saline solution and water. The organic layer was dried with anhydrous magnesium sulfate, and, after filtration, the solvent was distilled off under reduced pressure. With this, a target substance was obtained as a solid (95% yield, crude product). 1H-NMR (400 MHZ, CDCl3, TMS) δ 10.44 (s, 1 H), 7.63 (s, 1 H)
Reaction SMILES: N.[Na].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=2)[CH:5]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[N+]([O-])([O-])=O.[Fe+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(Cl)(Cl)Cl.C(O)C.O>[C:20]1([CH2:19][CH2:3][C:4]2[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([C:11]3[CH:16]=[C:15]([CH2:17][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=[C:13]([CH3:18])[N:12]=3)[CH:5]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(C)nc(-c2cc(C)cc(C)n2)c1
Agent: [Fe+3]
Agent: N
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(CCc2ccccc2)cc(-c2cc(CCc3ccccc3)cc(C)n2)n1
Temperature: -50 °C
Reaction time: 1.5 h

Procedure:
To liquid ammonia (20 ml) at -50° C. enough sodium was added to maintain a blue colored solution. Iron (III) nitrate (20 mg) was added and then sodium (0.19 g, 0.008 gr.atom). After 45 minutes 4,4',6,6'-tetramethyl-2,2'-bipyridine (26) (1.06 g, 5.00 mmoles) was added in small portions and the mixture was stirred for 1.5 hours at -50° C. Benzyl bromide (1.88 g, 11.0 mmoles) was added at -50° C. during 2 hours. The mixture was allowed to warm and water (50 ml), ethanol (20 ml) and chloroform (30 ml) was added. The organic phase was extracted with saturated ammonium sulfate solution, dried with magnesium sulfate and evaporated. By addition of ethyl acetate some pure compound was precipitated. The rest was purified by means of flash chromatography (silica, 0-6% methanol/dichloromethane).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:20]([C:22]3[O:23][C:24](=[O:51])[C:25]4[C:30]([C:31]=3[C:32]3[CH2:33][CH2:34][N:35]([C:38]([CH:40]5[CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41]5)=[O:39])[CH2:36][CH:37]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:21])[N:10]=[C:11]([C:12]3[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([F:19])[CH:13]=3)[C:4]=12.O.CC#N.C(O)=O>O1CCOCC1>[CH:24]([OH:51])=[O:23].[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:20]([C:22]3[O:23][C:24](=[O:51])[C:25]4[C:30]([C:31]=3[C:32]3[CH2:33][CH2:34][N:35]([C:38]([CH:40]5[CH2:41][NH:42][CH2:43]5)=[O:39])[CH2:36][CH:37]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:21])[N:10]=[C:11]([C:12]3[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([F:19])[CH:13]=3)[C:4]=12
Reactant: CC(c1oc(=O)c2ccccc2c1C1=CCN(C(=O)C2CN(C(=O)OC(C)(C)C)C2)CC1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Agent: Cl
Solvent: O
Solvent: O=CO
Solvent: CC#N
Product: CC(c1oc(=O)c2ccccc2c1C1=CCN(C(=O)C2CNC2)CC1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 131.3 %

Procedure:
4 M HCl in 1,4-dioxane (2 ml, 8.00 mmol) was added to a stirred solution of tert-butyl 3-(4-(3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl)azetidine-1-carboxylate (0.153 g, 0.224 mmol) in 1,4-dioxane (1 ml). After 1 h stirring at rt volatiles were removed under reduced pressure. Purification by RP flash chromatography (Biotage Isolera, 30 g C18 column, gradient elution from 100:0 to 80:20 A/B in 15 CV; A: water/MeCN 95/5+0.01% HCOOH, B: water/MeCN 5/95+0.01% HCOOH) yielded title compound (92.2 mg, 0.147 mmol, 65.5% yield) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[NH:12][CH:13]=O.CSC.B.Cl>C1COCC1.CCOCC.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[NH:12][CH3:13]
Reactant: COc1ccc([N+](=O)[O-])cc1NC=O
Agent: B
Agent: Cl
Solvent: CCOCC
Solvent: CSC
Solvent: C1CCOC1
Product: CNc1cc([N+](=O)[O-])ccc1OC
Yield: 95.1 %

Procedure:
2-Methoxy-5-nitroformanilide (D84) (0.80 g, 4.1 mmole) was stirred in dry THF (30 ml) under Ar as borane dimethyl sulphide complex (2M in toluene, 5.3 ml, 10.6 mmole) was added dropwise. The mixture was stirred at reflux for 3 h, cooled and treated with methanol (5 ml). The resultant mixture was stirred for 1 h, acidified (1M HCl in ether, 5 ml), and then stirred at reflux for 1 h. It was then diluted with methanol, evaporated in vacuo, and partitioned between dil. potassium hydroxide solution and ethyl acetate. The organic portion was separated off, dried (Na2SO4) and evaporated in vacuo to give the title compound as a red-orange solid (0.71 g, 95%). 1H NMR (250 MHz, CDCl3) δ(ppm): 7.63 (dd, 1H), 7.37 (d, 1H), 6.75 (d, 1H), 4.48 (bs, 1H), 3.95 (s, 3H), 2.94 (d, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:13]([Cu])#[N:14]>CN1C(=O)CCC1>[C:13]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6])#[N:14]
Reactant: COC(=O)c1ccc(O)c(Br)c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 200 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 3-bromo-4-hydroxybenzoate (2.50 g, 10.8 mmol) and CuCN (1.10 g, 12.3 mmol) in NMP (10 mL) was stirred at 200° C. under N2 atmosphere for 3 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted in ethyl acetate (100 mL) and washed with water (50 mL×3) and brine (50 mL), then dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE/EtOAc=8/1).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB(/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]1([C:24]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH2:23])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC1(C)OB(/C=C/c2ccccc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(c1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
To a solution of tert-butyl 4-bromobenzoate (616 mg, 2.4 mmol) in 1,4-dioxane and water (4:1, 10 mL) were added (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (553 mg, 2.4 mmol), tetrakis(triphenylphosphine)palladium (58.9 mg, 0.05 mmol) and sodium carbonate (164 mg, 1.55 mmol). The mixture was stirred at 90° C. under nitrogen atmosphere for 18 hours. Once the start material was consumed, the resultant mixture was concentrated to give a residue and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=30:1) to give tert-butyl 4-(1-phenylvinyl)benzoate (0.59 g, 87.5%). 1H NMR (300 MHz, CDCl3): δ 7.96 (d, J=4.8 Hz, 2H), 7.41-7.26 (m, 7H), 5.55-5.53 (m, 2H), 1.61 (s, 9H).
Reaction SMILES: C[C:2]1(C)[CH2:7][O:6][P:5]([CH2:9][OH:10])(=[O:8])[O:4][CH2:3]1.[CH3:12]C1(C)COP(=O)OC1>>[OH:10][CH2:9][P:5]1(=[O:8])[O:6][CH:7]([CH3:12])[CH2:2][CH2:3][O:4]1
Reactant: CC1(C)COP(=O)(CO)OC1
Reactant: CC1(C)CO[PH](=O)OC1
Product: CC1CCOP(=O)(CO)O1

Procedure:
5,5-dimethyl-2-(hydroxymethyl)-2-oxo-1,3,2-dioxaphosphorinan from 5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:3]=1[C:4]=23.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O>[N:8]1[C:9]2[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:2]([O:1][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:3]3[CH2:18][CH2:17][CH2:16][C:5]([C:4]=23)=[CH:6][CH:7]=1
Reactant: Oc1c2c3c(ccnc3c3ccccc13)CCC2
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c2c3c(ccnc3c3ccccc13)CCC2
Temperature: 20 °C
Yield: 46 %

Procedure:
7-Hydroxy-5,6-dihydro-4H-dibenzo[de,h]quinoline (27 g) [prepared as described in Example 2] is added to a suspension of sodium hydride (50% dispersion in mineral oil; (5.75 g) in anhydrous dimethylformamide (520 cc) and then, after stirring for 4 hours, ethyl bromoacetate (21.3 g) in solution in anhydrous dimethylformamide (20 cc) is added. The reaction mixture is maintained for 22 and a half hours at about 20° C., is distilled water (10 cc) is added, the mixture is concentrated to a volume of 400 cc, distilled water (4600 cc) is added and the mixture is extracted eight times with diethyl ether (total 3500 cc). The combined organic solutions are washed four times with distilled water (total 4000 cc), dried over anhydrous sodium sulphate, treated with decolourising charcoal (5 g), filtered and evaporated to dryness. The residue is dried by azeotropic distillation with methylene chloride (150 cc) and then crystallised from ethanol (16 cc). After cooling for 21 hours at about 5° C., the resulting crystals are filtered off, washed twice with ethanol (total 18 cc), which has been cooled to -20° C., and dried under reduced pressure (20 mm Hg) at 20° C. Ethyl (5,6-dihydro-4H-dibenzo[de,h]quinol-7-yloxy)acetate (16.95 g), melting at 70° C., is thus obtained.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[CH:16][C:15]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[CH:16][C:15]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1cccc2c(=O)cc(-c3cccc(OCc4ccccc4)c3)oc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)c1cccc2c(=O)cc(-c3cccc(O)c3)oc12
Temperature: 25 °C
Yield: 51 %

Procedure:
3'-Benzyloxy-8-ethoxycarbonylflavone (1 eq.) was dissolved in methanol, followed by the addition of ammonium formate (8 eq.) and 10% wt/wt palladium-carbon. The resulting mixture was refluxed. Subsequent to the completion of the reaction, the catalyst was eliminated by hot filtration. The mother liquor was allowed to cool down to room temperature. The resulting crystals were collected by filtration, washed with water and then recrystallized from DMF-ethanol, whereby the title compound was obtained (yield: 51%).
Reaction SMILES: CO[C:3](=[O:32])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2([NH:13][C:14]([C:16]3[C:17]4[CH:24]=[N:23][N:22]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[C:18]=4[CH:19]=[N:20][CH:21]=3)=[O:15])[CH2:12][CH2:11]2)[CH:5]=1.[CH3:33][NH2:34].CO>>[CH3:33][NH:34][C:3]([C:4]1[CH:5]=[C:6]([C:10]2([NH:13][C:14]([C:16]3[C:17]4[CH:24]=[N:23][N:22]([C:25]5[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=5)[C:18]=4[CH:19]=[N:20][CH:21]=3)=[O:15])[CH2:11][CH2:12]2)[CH:7]=[CH:8][CH:9]=1)=[O:32]
Reactant: CN
Reactant: COC(=O)c1cccc(C2(NC(=O)c3cncc4c3cnn4-c3ccc(F)cc3)CC2)c1
Solvent: CO
Product: CNC(=O)c1cccc(C2(NC(=O)c3cncc4c3cnn4-c3ccc(F)cc3)CC2)c1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A mixture of 3-(1-{[1-(4-fluoro-phenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-cyclopropyl)-benzoic acid methyl ester (70.0 mg, 0.163 mmol) in a 2M solution of methylamine in methanol (3.0 mL, 6.0 mmol) is stirred at 90° C. in a sealed pressure tube. After 18 hours, the reaction vessel is cooled to room temperature, vented and opened. The reaction mixture is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with a gradient of 0-8% methanol in methylene chloride to afford the title compound as a solid.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([SH:16])=[N:13][C:12]=12)C.Br[CH2:23][CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([CH:25]=[CH:24][CH2:23][S:16][C:14]2[S:15][C:11]3[CH2:10][CH2:9][C:8]4[C:17](=[CH:18][CH:19]=[CH:20][C:7]=4[O:6][CH2:5][C:4]([OH:3])=[O:21])[C:12]=3[N:13]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: BrCC=Cc1ccccc1
Product: O=C(O)COc1cccc2c1CCc1sc(SCC=Cc3ccccc3)nc1-2
Yield: 56 %

Procedure:
Using ethyl[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate and 3-bromo-1-phenyl-1-propene, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 56%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:13]([OH:15])=O)[CH:4]=1.C(Cl)(=O)[C:17]([Cl:19])=O.[Si](C=[N+]=[N-])(C)(C)C.CCN(CC)CC.Cl>C(Cl)Cl.CCOCC.CN(C=O)C>[Cl:19][CH2:17][C:13]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)=[O:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C(=O)O)nc2ccccc12
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)CCl)nc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-methoxyquinoline-2-carboxylic acid and DMF (50 μL) in DCM at 0° C. was added dropwise oxalyl chloride (1.2 eq). The cooling bath was removed and the mixture was stirred for 2 hr at RT, then the solvent was removed under reduced pressure. The residue was dissolved in THF/MeCN (1:1) and cooled to 0° C., a pre-cooled solution (0° C.) of TMSCHN2 (1.2 eq) and Et3N (1.2 eq) was added dropwise and the resulting mixture was stirred for 2 hr at 0° C. An excess of 2M HCl solution in Et2O was added and the reaction was stirred for further hour at 0° C. and then partitioned between sat. aq. NaHCO3 solution and DCM. The organic phase was separated, dried (Na2SO4), and concentrated under reduced pressure to afford a dark brown solid which was used as such in the next step. 1H NMR (300 MHz, CDCl3) δ: 8.47 (1H, d, J=8.0 Hz), 8.09 (1H, d, J=8.4 Hz), 7.81-7.73 (1H, m), 7.66-7.58 (1H, m), 7.51 (1H, s), 5.31 (2H, s), 4.13 (3H, s). MS (ES) Cl2H10ClNO2 requires: 235, found: 236 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:21][C:22]1([CH3:29])[C:26]([CH3:28])([CH3:27])[O:25][BH:24][O:23]1.C(N(CC)CC)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1>[CH3:21][C:22]1([CH3:29])[C:26]([CH3:28])([CH3:27])[O:25][B:24]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[O:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)cc2)CC1
Reactant: CC1(C)OBOC1(C)C
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 110 °C
Yield: 59.4 %

Procedure:
To a solution of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (13.5 g, 39.7 mmol) in dioxane (40 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.64 mL, 59.5 mmol) and triethylamine (16.6 mL, 119 mmol). The solution was purged with argon for 5 minutes. Dichlorobis(acetonitrile) palladium (0.309 g, 1.19 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.95 g, 4.76 mmol) were then added, and the reaction mixture was again purged with argon for 5 minutes. The reaction mixture was then sealed and heated at 110° C. for 90 minutes. The reaction mixture was cooled to ambient temperature and filtered through a glass fiber filter paper. The filtrate was concentrated under reduced pressure and the residue purified by silica gel column chromatography, eluting with 5-10% EtOAc in hexanes to afford tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (9.13 g, 23.6 mmol, 59.4% yield) as a solid. MS (apci) m/z=288.3 (M+H-Boc).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][CH:32]=[CH:31][C:4]=1[C:5]([C:7]1[N:8]([CH2:12][CH:13]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:14][CH2:15][O:16]C2CCCCO2)[CH:9]=[CH:10][N:11]=1)=[O:6]>CO>[Cl:30][C:25]1[CH:24]=[C:23]([CH:13]([CH2:12][N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[C:5](=[O:6])[C:4]2[CH:31]=[CH:32][CH:33]=[CH:34][C:3]=2[O:2][CH3:1])[CH2:14][CH2:15][OH:16])[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: COc1ccccc1C(=O)c1nccn1CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Solvent: CO
Product: COc1ccccc1C(=O)c1nccn1CC(CCO)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 33.8 %

Procedure:
1-[2-(2-Methoxybenzoyl)imidazol-1-yl]-2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butane (1.1 g) (see Preparation 57) was dissolved in methanol (20 ml), Amberlyst 15 (trade mark) ion-exchange resin (0.11 g) added and the mixture stirred at room temperature for 5 days. The resin was removed by filtration through a short column of Arbacel (trade mark) filter aid and the solvent removed from the filtrate under reduced pressure to give a residue. This was chromatographed on silica gel eluting with 97:3, by volume, dichloromethane:methanol to give 3-(3,4-dichlorophenyl)-4-[2-(2-methoxybenzoyl)-imidazol-1-yl]butan-1-ol (0.31 g) as a white foam.
Reaction SMILES: Cl[C:2]1[C:7]([O:8]C)=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:5]=[CH:4][N:3]=1.C1N2CC[N:19](CC2)[CH2:18]1.[C-]#N.[K+].Cl>CN(C=O)C.ClCCl.CN1C(=O)CCC1>[OH:8][C:7]1[C:2]([C:18]#[N:19])=[N:3][CH:4]=[N:5][C:6]=1[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1
Reactant: COc1c(Cl)ncnc1-c1ccc(C)cc1
Reactant: C1CN2CCN1CC2
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2ncnc(C#N)c2O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-chloro-5-methoxy-6-p-tolylpyrimidine P5 (100 mg, 0.43 mmol) in DMF (2 mL) and NMP (0.5 mL) was added triethylenediamine (62 mg, 0.55 mmol) and potassium cyanide (55 mg, 0.85 mmol). The reaction mixture was stirred at room temperature for 18 hours. Dichloromethane and 1 N hydrochloric acid were added. The organic layer was dried over anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to afford the desired 5-hydroxy-6-p-tolylpyrimidine-4-carbonitrile P69 (70 mg, 0.33 mmol).
Reaction SMILES: [Si]([O:8][CH:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C@H:18]([NH:19][CH2:20][CH2:21][CH2:22]2)[CH2:17][C@@H:16]3[CH3:30])[CH2:13][CH2:12]1)[CH3:10])(C(C)(C)C)(C)C.F.C(=O)(O)[O-:33].[Na+]>C(#N)C>[OH:8][CH:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C@H:18]([NH:19][C:20](=[O:33])[CH2:21][CH2:22]2)[CH2:17][C@@H:16]3[CH3:30])[CH2:13][CH2:12]1)[CH3:10]
Reactant: O=C([O-])O
Reactant: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NCCC[C@]4(C)[C@H]3CC[C@]12C
Agent: F
Agent: [Na+]
Solvent: CC#N
Product: CC(O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a slurry of crude 20-tert-butyldimethylsilyloxy-7β-methyl-5α-4-azapregnane (25.2 g, product of Step 9) in acetonitrile (300 mL) was added an aqueous solution of hydrofluoric acid (12 mL). After stirring for 8 hr at room temperature, the reaction mixture was cooled to 0° C. and saturated sodium bicarbonate solution was slowly added. The mixture was extracted with methylene chloride (3×500 mL) and the combined extracts washed with water, saturated salt solution and dried over anhydrous sodium sulfate. The solvent was removed by rotoevaporation to give the title compound which was used without purification in the subsequent reaction.