Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][N:5]([CH2:31][C:32]([O:34]C)=[O:33])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:7]=1.[OH-].[Na+]>CO>[C:3]([CH2:4][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:7]=1)[CH2:31][C:32]([OH:34])=[O:33])([OH:36])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOc1cccc(N(CC(=O)OC)CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1cccc(N(CC(=O)O)CC(=O)O)c1
Reaction time: 17 h
Yield: 58.5 %

Procedure:
A solution of 0.56 g (1.11 mmol) of N-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)phenyl]glycine methyl ester and 4.4 ml (4.4 mmol) of 1N NaOH in 50 ml of methanol was stirred at reflux under an talon atmosphere for 75 minutes. After standing at room temperature for 17 hours the precipitate was removed by filtration. The solid was suspended in 100 ml of 1N HCl and extracted with ethyl acetate. The dried extract was concentrated at reduced pressure and the resultant solid was recrystallized from methanol-water to give 0.31 g (60% yield, mp135°-138°) of N-(carboxymethyl)-N-[3-(octadecyloxy)phenyl]glycine.
Reaction SMILES: N1([CH2:6][CH2:7][OH:8])C=CN=C1.C(N(CC)CC)C.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>C(Cl)Cl>[C:22]1([CH3:23])[CH:24]=[CH:25][C:19]([S:16]([O:8][CH2:7][CH3:6])(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCn1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
A portion of the crude 2-(imidazol-1-yl)ethanol (10 g, 89 mmol) and triethylamine (10.1 g, 100 mmol) were dissolved in methylene chloride (250 ml), tosyl chloride (17.5 g, 92 mmol) was added over 5 minutes as a solid, giving an exotherm to reflux. The reaction was stirred for 30 minutes at ambient temperature then quenched into 250 ml of 1M hydrogen chloride and 250 ml of methylene chloride. The organic phase was washed with brine and dried by passing it through a phase separator paper. Removal of the solvent by evaporation and purification by flash chromatography using methylene chloride/methanol/ammonia (100/10/1) gave 2-(imidazo]-1-yl)ethyl paratoluene sulphonate (10.95 g, 46%, impure). 4-Hydroxy-5-methoxy-2-nitrobenzamide (3 g, 15.3 mmol), (prepared as described for the starting material in Example 23), and 2-(imidazol-1-yl)ethyl paratoluene sulphonate (7 g, impure) were mixed in the presence of potassium carbonate (5 g, 72 mmol) and anhydrous DMF (20 ml) and heated at 100° C. for 3 hours. The reaction mixture was allowed to cool to ambient temperature and the DMF was removed by evaporation. The residue was resuspended in methylene chloride/methanol/ammnonia (100/10/1) and silica (15 g) was added. The solvent was removed by evaporation and the resulting powder was placed on the top of a silica gel column and eluted using first methylene chloride and slowly increasing the solvent polarity up to methylene chloride/methanol/ammnonia (100/10/1). Removal of the solvent by evaporation gave 4-(2-(imidazol-1-yl)ethoxy)-5-methoxy-2-nitrobenzaride as a cream solid (2.53 g, 55%).
Reaction SMILES: [F:1]/[CH:2]=[C:3](/[CH2:13]O)\[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.CS(Cl)(=O)=O.[Br-:27].[Li+]>CC(C)=O>[Br:27][CH2:13]/[C:3](=[CH:2]/[F:1])/[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NC/C(=C\F)CO
Reactant: [Br-]
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC/C(=C\F)CBr
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a stirring solution of (E)-tert-butyl 3-fluoro-2-(hydroxymethyl)-allylcarbamate (1.20 g, 5.85 mmol) in acetone (20 mL) at 0° C. under N2 was added sequentially triethylamine (1.22 mL, 8.77 mmol) and methanesulfonyl chloride (0.54 mL, 7.02 mmol). The resulting mixture was stirred at this temperature for 30 min. The reaction mixture was filtered to remove the precipitated salts and the filter cake was washed with further acetone (10 mL). The filtrate was charged with lithium bromide (2.54 g, 29.24 mmol) and the resulting suspension was stirred at room temperature for 1 h. The reaction mixture was partitioned between water (25 mL) and ethyl acetate (25 mL) and the aqueous layer was extracted with further ethyl acetate (25 mL). The combined organics were washed with brine (25 mL), dried over Na2SO4 and concentrated in vacuo to give (E)-tert-butyl 2-(bromomethyl)-3-fluoroallylcarbamate as a pale yellow oil (1.46 g, 93%). 1H-NMR (300 MHz; CDCl3) δ ppm: 1.47 (9H, s), 3.97 (2H, dd, J 3.5, 0.7 Hz), 4.02 (2H, br d, J 6.1 Hz), 4.78 (1H, br s), 6.79 (1H, d, J 81.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13]CC)=[O:12])[N:10]=2)[CH:7]=1.O.[OH-].[Li+:18]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O-:13])=[O:12])[N:10]=2)[CH:7]=1.[Li+:18]
Reactant: CCOC(=O)c1cn2cc(Cl)ccc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])c1cn2cc(Cl)ccc2n1
Reaction time: 1 h

Procedure:
Ethyl 6-chloroimidazo[1,2-a]pyridine-2-carboxylate (Japanese Patent Application Laid-Open No. 11-500123 through PCT route) (150 mg) was dissolved in tetrahydrofuran (4 ml), and water (1 ml) and lithium hydroxide (18 mg) were added at room temperature to stir the mixture for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain crude lithium 6-chloroimidazo[1,2-a]pyridine-2-carboxylate. This product was dissolved in N,N-dimethylformamide (4.0 ml), and (±)-cis-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexane-diamine hydrochloride (232 mg), 1-hydroxybenzotriazole monohydrate (180 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (256 mg) and triethylamine (371 μl) were added to this solution to stir the mixture at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and water and a saturated aqueous solution of sodium hydrogencarbonate were added to the residue to conduct extraction with dichloromethane. The resultant organic layer was then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by column chromatography on silica gel (dichloromethane:acetone=1:1→dichloromethane:acetone:methanol=5:5:1) to obtain a white solid. To this solid, were added dichloromethane, methanol and 1N hydrochloric acid, and the resultant mixture was concentrated to obtain the title compound (224 mg) as a pale brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][NH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:23]1[CH2:26][O:25][CH2:24]1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH:23]3[CH2:26][O:25][CH2:24]3)[C:6]=2[N:7]=1
Reactant: BrC1COC1
Reactant: CCOC(=O)c1cc(Br)nc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nc2c1cnn2C1COC1

Procedure:
Ethyl 6-bromo-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1 equiv.) was suspended in acetonitrile and K2CO3 (1.5 equiv.) and 3-bromooxetane (2 equiv.) was added to it. The reaction mixture was refluxed for 8 h. On completion, acetonitrile was removed under reduced pressure and water was added to it. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1.[S:17]1[C:21]([C:22]2[O:23][C:24]([CH3:29])=[C:25]([CH2:27]Cl)[N:26]=2)=[CH:20][C:19]2[CH:30]=[CH:31][CH:32]=[CH:33][C:18]1=2>>[S:17]1[C:21]([C:22]2[O:23][C:24]([CH3:29])=[C:25]([CH2:27][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[N:15][CH:14]=[N:13]4)=[CH:4][CH:3]=3)[N:26]=2)=[CH:20][C:19]2[CH:30]=[CH:31][CH:32]=[CH:33][C:18]1=2
Reactant: Cc1oc(-c2cc3ccccc3s2)nc1CCl
Reactant: Oc1ccc(CCCCn2cncn2)cc1
Product: Cc1oc(-c2cc3ccccc3s2)nc1COc1ccc(CCCCn2cncn2)cc1
Yield: 59 %

Procedure:
In substantially the same manner as in Working Example 37, 1-[4-(4-hydroxyphenyl)butyl]-1,2,4-triazole was allowed to react with 2-(2-benzo[b]thienyl)-4-chloromethyl-5-methyloxazole to give 1-[4-[4-[2-(2-benzo[b]thienyl)-5-methyl-4-oxazolylmethoxy]phenyl]butyl]-1,2,4-triazole. The yield was 59%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 131-132° C.
Reaction SMILES: CO[N:3]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.B.C1COCC1.N1C=CC=CC=1.CCOC(C)=O>C1COCC1>[NH2:3][CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1
Reactant: CON=C(Cc1ccc(F)cc1)c1ccccc1
Agent: B
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: NC(Cc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
To a solution of 2-(4-fluorophenyl)-1-phenyl-1-ethanone-O-methyl oxime (1.34 g, 4.62 mmol) in 30 ml dry THF under nitrogen was added borane-THF complex (1.0M in THF, 23.1 ml, 23.1 mmol) and dry pyridine (10 ml) by syringe at 25° C. The resulting bi-phasic solution was refluxed with vigorous magnetic stirring for 16 hours. After the reaction was cooled to 25° C. and was quenched with 10% NaOH solution, hexanes (50 ml) were added and the layers were separated. The aqueous portion was extracted with hexanes again (40 ml). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to yield a cloudy colorless syrup (3.55 g, 66% yield for two steps). Rf : 0.24 (EtOAc).
Reaction SMILES: [C:1]([N:4]1[CH2:10][C@H:9]([NH2:11])[C:8](=[O:12])[N:7]([CH2:13][CH3:14])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)(=[O:3])[CH3:2].[CH3:19][C:20]([CH3:35])([C:24]([NH:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[O:25])[C:21](O)=[O:22]>>[C:1]([N:4]1[CH2:10][C@H:9]([NH:11][C:21](=[O:22])[C:20]([CH3:19])([CH3:35])[C:24]([NH:26][CH2:27][C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])=[O:25])[C:8](=[O:12])[N:7]([CH2:13][CH3:14])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(C)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: CCN1C(=O)[C@@H](N)CN(C(C)=O)c2ccccc21
Product: CCN1C(=O)[C@@H](NC(=O)C(C)(C)C(=O)NCC(F)(F)C(F)(F)F)CN(C(C)=O)c2ccccc21

Procedure:
In an analogous manner to that described in Example 20 d) and 27, the condensation of (S)-5-acetyl-3-amino-1-ethyl-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one and 2,2-dimethyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid yielded the title compound as a white solid; MS: m/e=493 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[CH3:38][NH:39][CH3:40]>C1COCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:39]([CH3:40])[CH3:38])(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: CNC
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN(C)C)CC2)n1
Reaction time: 0.25 h

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (0.536 g, 1 mmol) and 40% aqueous dimethylamine (10 mL) in THF (200 mL) was warmed gently until a clear solution was obtained. After 15 min, the THF was removed under vacuum and the residue was diluted with water to give N-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine: 1H NMR (CDCl3) δ 7.86 (dd, J=8.4, 0.6 Hz, 1H), 7.45 (t, JHF=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 4.05 (s, 3H), 4.00 (m, 4H), 3.89 (m, 4H), 3.79 (m, 4H), 3.39 (m, 4H), 3.11 (dd, J=8.1, 6.4 Hz, 2H), 2.78 (dd, J=8.1, 6.4 Hz, 2H), 2.26 (s, 6H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:22]=[C:23]([F:25])[CH:24]=1)[O:8][CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)[CH3:3].[ClH:26].O1CCOCC1>C(Cl)Cl>[ClH:26].[ClH:26].[F:25][C:23]1[CH:24]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH:6]=[C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:22]=1
Reactant: CN(C)Cc1cc(F)cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(C)Cc1cc(F)cc(OC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
To a solution of tert-butyl 4-{3-[(dimethylamino)methyl]-5-fluorophenoxy}piperidine-1-carboxylate (180 mg, 0.51 mmol) in DCM (2.4 mL) was added 4.0M hydrogen chloride in dioxane (1.0 mL, 4.1 mmol). The reaction solution was stirred at room temperature for 6 hours. The solvent was removed to give the desired product as white solid (145 mg, 87%). LCMS (M+H)+: 253.1.
Reaction SMILES: [CH:1]1([CH:6]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:33](=[O:34])[CH2:32][O:31][C:30]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[N:29]3)=[CH:23][CH:22]=2)[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][CH:12]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[Cl-].[NH4+]>O1CCOCC1.O>[CH:1]1([CH:6]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:33](=[O:34])[CH2:32][O:31][C:30]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[N:29]3)=[CH:23][CH:22]=2)[C:7]([NH:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([OH:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(CNC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C2CCCC2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(CNC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
969 mg (1.757 mmol) of methyl 4-{[(cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetyl)amino]methyl}benzenecarboxylate (Example 113A) were dissolved in 30 ml of dioxane/water (3:1 v/v), and 3.87 ml (3.865 mmol) of 1 N aqueous sodium hydroxide solution were added. The mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was then added, and the mixture was extracted repeatedly with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. This gave 803 mg (1.53 mmol, 87% of theory) of the title compound.
Reaction SMILES: [CH:1]([Si:4]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[O:5][CH2:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[N:16]3[CH:17]=[C:18]([O:21][C@H:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C@@H:25]([NH2:32])[CH2:24][CH2:23]4)[CH:19]=[CH:20][C:15]3=[N:14][N:13]=2)[CH2:8]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:42][C:43](=O)[NH:44][C:45]1[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=[C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:49]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:50]([C:48]1[CH:49]=[C:45]([NH:44][C:43]([NH:32][C@@H:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:22]([O:21][C:18]3[CH:19]=[CH:20][C:15]4[N:16]([C:12]([N:9]5[CH2:8][CH2:7][CH:6]([O:5][Si:4]([CH:1]([CH3:2])[CH3:3])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[C@@H:10]5[CH3:11])=[N:13][N:14]=4)[CH:17]=3)[CH2:23][CH2:24]2)=[O:42])[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)[Si](OC[C@H]1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(O[Si](C(C)C)(C(C)C)C(C)C)[C@@H]5C)n4c3)c3ccccc32)cc1
Yield: 79 %

Procedure:
A solution of Intermediate 92c (210 mg, 0.39 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 159 mg, 0.390 mmol) in 1,4-dioxane (4 mL) and DIPEA (105 μL, 0.600 mmol) was stirred at 65° C. for 15.5 h and at 90° C. for 1.5 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as a pale brown solid (242 mg, 79%). LCMS (Method 3): Rt 5.18 min, m/z 791 [MH+].
Reaction SMILES: C([O:4][C@@H:5]1[C@@:22]2([CH3:23])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C:16]2=[O:24])[CH2:8][C@@H:7]([O:25]C(=O)C)[CH2:6]1)(=O)C.C[O-].[Na+]>CO>[OH:4][C@@H:5]1[C@@:22]2([CH3:23])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C:16]2=[O:24])[CH2:8][C@@H:7]([OH:25])[CH2:6]1
Reactant: CC(=O)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@]12C(=CC=C3[C@@H]1CC[C@]1(C)C(=O)CC[C@@H]31)C[C@@H](O)C[C@@H]2O
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.1 %

Procedure:
A 3-L three-necked flask equipped with a mechanical stirrer was charged with 114.5 g (296 mmol) of (1α,3β)-1,3-bis (acetyloxy)androsta-5,7-dien-17-one, a known compound, 586 mL of methanol, and 29 mL of 25% sodium methoxide in methanol. After stirring at room temperature for 20 hr, the reaction was quenched by the addition of 7.4 mL of acetic acid. Then, 880 mL of water was added dropwise over 1 h, and the mixture was stirred for another hour and then stored in a refrigerator overnight. The precipitate was filtered and washed with 3×200 mL of methanol:water (1:2). The brown solid was dried by suction for 1 hr and then under high vacuum to afford 60.1 g of (1α,3β)-1,3-dihydroxyandrosta-5,7-dien-17-one.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:34])([CH3:33])[C:13]([C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[O:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][Mg]Br.[Cl-].[NH4+]>CCOCC>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:34])([CH3:33])[C:13]([C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[O:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1)([CH3:35])[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CCCCOc1ccccc1)C(=O)c1cccc(OCc2ccc3ccccc3n2)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(CCCCOc1ccccc1)C(C)(O)c1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
To a solution of the ketone, 2-(3-(6-phenoxy-2,2-dimethyl hexanoyl)phenoxymethyl) quinoline (3.6 g) in dry ether (100 ml) at 0° C., was added dropwise, an ethereal solution of methyl magnesiumbromide (7.7 ml, 23.8 mmol, 3 eqv.) under an atmosphere of nitrogen. The clear orange solution was stirred overnight at room temperature. To this solution, a saturated ammonium chloride solution was added when the magnesium salts precipitated. The ether layer was separated, washed with water and brine, and then dried over MgSO4. All volatiles were removed to obtain the crude product (4.2 g). This was purified by chromatography on silica gel (25% ethyl acetate in hexanes, 20% ethyl acetate in hexanes and finally 10% ethyl acetate in hexanes) to obtain the pure product as a yellow liquid (0.9 g).
Reaction SMILES: C([O:8][CH2:9][C:10]([C:13]1[NH:17][C:16](=[O:18])[N:15]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]4[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=4)[CH:27]=3)=[C:21]([CH3:38])[N:20]=2)[N:14]=1)([CH3:12])[CH3:11])C1C=CC=CC=1.C(O)=O>CCOC(C)=O.[Pd]>[OH:8][CH2:9][C:10]([C:13]1[NH:17][C:16](=[O:18])[N:15]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]4[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=4)[CH:27]=3)=[C:21]([CH3:38])[N:20]=2)[N:14]=1)([CH3:12])[CH3:11]
Reactant: Cc1nc(-n2nc(C(C)(C)COCc3ccccc3)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O=CO
Product: Cc1nc(-n2nc(C(C)(C)CO)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Reaction time: 12 h
Yield: 15.7 %

Procedure:
3-(1-(Benzyloxy)-2-methylpropan-2-yl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.41 g, 0.80 mmol), and palladium(0) on carbon (10% w/w, 0.20 g, 0.19 mmol) were combined in EtOAc (4.0 mL) under an atmosphere of Ar. The reaction flask was depressurized and back-filled with H2 (g). This process was repeated (2×) and the reaction mixture was stirred under a balloon of H2 (g) for 12 h. Formic acid (0.5 mL) was added and stirring was continued an additional 12 h at RT. The reaction mixture was transferred to a Parr hydrogenation shaker and reaction was continued under 40 psi H2 (g) atmosphere. After 5 h, the Pd was removed by filtration through a pad of diatomaceous earth and the filter cake was washed with EtOAc (4×25 mL). The combined filtrates were concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 3-(1-hydroxy-2-methylpropan-2-yl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.053 g, 15%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.85-11.83 (m, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 6.65 (dd, J=5.7, 2.4 Hz, 1H), 4.92-4.91 (m, 1H), 3.84 (s, 3H), 3.45-3.43 (m, 2H), 2.33 (s, 3H), 1.20 (s, 6H); MS (ESI) m/z: 422.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[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]=[C:19]([Cl:23])[CH:18]=3)[CH2:7]2)[N:6]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27]>C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].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>[NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]4[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=4)[C:26]#[N:27])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CN1C(=O)C2(CC(c3cccc(Cl)c3)Oc3ccc(Br)cc32)N=C1N
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: Cc1ccccc1
Product: CN1C(=O)C2(CC(c3cccc(Cl)c3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Yield: 3.2 %

Procedure:
Pd(PPh3)4 (27 mg, 0.072 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-2-(3-chlorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (30 mg, 0.072 mmol) in toluene (5 mL), Na2CO3 (2 N, 2 mL), and 4-cyanophenylboronic acid (12.9 mg, 0.088 mmol). The mixture was refluxed under Ar overnight. The reaction mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC followed by preparative HPLC to give pure 3-(2′-amino-2-(3-chlorophenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (1.03 mg, 3%). 1H-NMR (MeOD): 2.63 (m, 2H), 3.22 (s, 3H), 5.34 (m, 1H), 7.18 (m, 1H), 7.41 (m, 3H), 7.54 (m, 2H), 7.10 (m, 1H), 7.17 (m, 2H), 7.89 (m, 1H), 7.98 (m, 1H).