Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[C:26]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[CH3:27]I.O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[C:26]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: CI
Reactant: COc1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(Cc3cn(C)c4ncccc34)CC2)cc1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Sodium hydride (80% dispersion in oil; 0.13 g, 4.3 mmol) was added to a solution of 3-(4-(4-methoxyphenyl)piperazin-1-yl)methyl-1H-pyrrolo[2,3-b]pyridine (1.06 g, 3.29 mmol) in dimethylformamide (30 ml) at 0° C. The cooling bath was removed and the mixture stirred at room temperature for an hour. Methyl iodide (0.22 ml, 3.53 mmol) was added and the reaction mixture stirred for 2 h at room temperature. The mixture was poured into water (300 ml), extracted with ethyl acetate (2×150 ml), and the extracts washed with brine (150 ml). The combined extracts were dried (MgSO4) and evaporated to give a yellow solid. Purification by flash chromatography, eluting with 5% then 7.5% methanol in dichloromethane, gave the title compound (0.87 g, 79%). Recrystallisation from ethyl acetate/petrol (60°-80° C.) gave fine needles, m.p. 92°-94° C.; (Found: C, 71.25; H, 7.18; N, 16.49. C20H24N4O requires C, 71.40; H, 7.19; N, 16.65%); δH (CDCl3) 2.65 (4H, m, 2×piperazinyl CH2), 3.09 (4H, m, 2×piperazinyl CH2), 3.74 (2H, s, CH2N), 3.75 (3H, s, ArOCH3), 3.87 (3H, s, N-CH3), 6.85 (4H, m, ArH), 7.05 (1H, dd, J 7.8, 4.7 Hz, 5-H), 7.15 (1H, br s, 2-H), 8.04 (1H, dd, J 7.8, 1.5 Hz, 4-H), and 8.33 (1H, dd, J 4.7, 1.5 Hz, 6-H); m/z (CI+, NH3) 337 (M+1)+.
Reaction SMILES: F[C:2]1[C:3]([O:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[C:28]#[N:29])=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)=O)[CH:7]=1.[CH2:30]([S:32]([C:35]1[N:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH3:31]>>[F:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([C:28]#[N:29])[C:21]=1[O:20][C:3]1[C:2]([O:41][C:38]2[CH:39]=[N:40][C:35]([S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])=[CH:36][CH:37]=2)=[CH:7][C:6]2[NH:8][C:9]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)=[N:17][C:5]=2[CH:4]=1
Reactant: CCS(=O)(=O)c1ccc(O)cn1
Reactant: N#Cc1cccc(F)c1Oc1cc([N+](=O)[O-])c(NC(=O)c2cnccn2)cc1F
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2c(F)cccc2C#N)cn1

Procedure:
The entitled compound was obtained as a white solid in the same method as in Example 400 (step 3) or in accordance with the method or by combining it with an ordinary method but using pyrazine-2-carboxylic acid (5-fluoro-4-(2-cyano-6-fluoro-phenoxy)-2-nitro-phenyl)-amide obtained in Example 400 (step 2) and 6-ethanesulfonyl-pyridin-3-ol.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:7][C:8]#[CH:9].[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>C1COCC1>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[O:10][CH2:6][CH2:7][C:8]#[C:9][Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#CCCOC1CCCCO1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](C#CCCOC1CCCCO1)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.9 %

Procedure:
A solution of n-butyllithium in hexanes (1.6 M, 18.8 mL, 30 mmole) was added in a stream over 2 min to a solution of 2-(3-butynyloxy)tetrahydro-2H-pyran (4.7 mL, 30 mmole) in dry THF (60 mL) at 0° C. under argon. After 0.5 hr, tributyltin chloride (8.1 mL, 30 mmole) was added all at once, and the reaction was warmed to RT. After 3 hr, the reaction was diluted with hexanes (300 mL) and washed sequentially with H2O (2×60 mL), 10% KF (2×30 mL), and saturated brine (60 mL). Drying (Na2SO4), concentration, and silica gel chromatography (3% EtOAc/hexanes) gave the title compound (3.58 g. 27%) as a nearly colorless oil: TLC (5% EtOAc/hexanes) Rf0.37; 1H NMR (400 MHz, CDCl3) δ4.66 (narrow t, 1 H), 3.75-3.96 (m, 2 H), 3.49-3.62 (m, 2 H), 2.56 (app t, 2 H), 1.76-1.91 (m, 1 H), 1.65-1.78 (m, 1 H), 1.42-1.65 (m, 10 H), 1.22-1.41 (m, 6 H), 0.82-1.08 (m, 15 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[N:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][CH:17]=2)[N:12]([CH2:26][CH2:27][CH:28]=[O:29])[N:11]=1.[BH4-].[Na+]>C(O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[N:14][C:15]([NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][CH:17]=2)[N:12]([CH2:26][CH2:27][CH2:28][OH:29])[N:11]=1
Reactant: Cc1cccc(C)c1Nc1nn(CCC=O)c2nc(Nc3ccccc3)ncc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(C)c1Nc1nn(CCCO)c2nc(Nc3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A slurry of 27 mg (0.07 mmol) of crude 3-(3-(2,6-dimethylphenylamino)-6-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propanal 36 (Example 4, Step A) in 4 mL of absolute ethanol was treated with 17 mg (0.4 mmol) of NaBH4. The resulting orange slurry was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and concentrated. The residue was extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (eluens CH2Cl2:MeOH, 96:4) to give the title compound 37. 1H-NMR (CD3OD) δ1.96-2.04 (m, 2H), 2.26 (s, 6H), 3.54 (t, J=6.3 Hz, 2H), 4.20 (t, J=6.7 Hz, 2H), 6.99 (dt, J=7.4 Hz, 0.9 Hz, 1H), 7.09-7.17 (m, 3H), 7.30 (t, J=7.6 Hz, 2H), 7.75 (dd, J=8.6 Hz, 0.9 Hz, 2H), 8.09 (s, 1H). Mass Spectrum (ESI) m/e=389.2 (M+1).
Reaction SMILES: C(O[C:4](=[O:24])[CH2:5][CH:6]([C:13]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[NH:25]1C2C(=CC=CC=2C(C2C=CC=CC=2)=CC(NC)=O)C=[CH:26]1>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:13]([CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][C:4]([NH:25][CH3:26])=[O:24])=[C:14]2[C:18]=1[NH:17][CH:16]=[CH:15]2
Reactant: CNC(=O)C=C(c1ccccc1)c1cccc2cc[nH]c12
Reactant: CCOC(=O)CC(c1ccccc1)c1ccc(OC)c2[nH]ccc12
Product: CNC(=O)CC(c1ccccc1)c1ccc(OC)c2[nH]ccc12

Procedure:
3-(7-Methoxy-1H-Indol-4-yl)-N-methyl-3-phenyl-propionamide LV was prepared from 3-(7-Methoxy-1H-Indol-4-yl)-3-phenyl-propionic acid ethyl ester using the procedure described for 3-(1H-indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH:19]=[O:20])[CH:6]=1.[BH4-].[Na+].O.CCOC(C)=O>CO>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][OH:20])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CO)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.4 %

Procedure:
To [3-(4-bromo-2-formyl-phenoxy)-phenyl]-acetic acid methyl ester (4.8 g, 13.7 mmol) in MeOH (50 mL) was added sodium borohydride (0.78 g, 20.6 mmol), and the reaction was stirred at room temperature for 5 minutes. The mixture was worked-up with H2O and EtOAc, and the crude material was purified by silica gel chromatography to give the desired product as a colorless oil (3 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][C@H:4]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:5]([O:7]C(C)(C)C)=[O:6].[ClH:19]>O1CCOCC1>[ClH:19].[CH3:1][CH:2]([CH3:18])[CH2:3][C@H:4]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:5]([OH:7])=[O:6]
Reactant: CC(C)C[C@@H](C(=O)OC(C)(C)C)N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C[C@@H](C(=O)O)N1CCOCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(S)-tert-Butyl 2-amino-4-methylpentanoate (1.0042 g, 5.36 mmol), potassium carbonate (2.446 g, 17.69 mmol), and 1-bromo-2-(2-bromoethoxy)ethane (1.368 g, 5.90 mmol) were combined in acetonitrile (30 mL). The reaction was heated at 80° C. overnight. The reaction was cooled and filtered and the solvent removed in vacuo. The crude material was purified by silica gel chromatography using 5-50% ethyl acetate/hexanes to give (S)-tert-butyl 4-methyl-2-morpholinopentanoate: 1H NMR (300 MHz, CDCl3) δ ppm 3.76-3.58 (m, 4H), 3.11 (dd, J=6.9, 8.1, 1H), 2.74-2.53 (m, 4H), 1.71-1.55 (m, 2H), 1.51-1.34 (m, 10H), 0.92 (dd, J=6.6, 7.3, 6H). (S)-tert-Butyl 4-methyl-2-morpholinopentanoate (0.637 g, 2.475 mmol) and 4 N hydrochloric acid in dioxane (5 mL) were combined. The reaction mixture was stirred at ambient temperature for 24 hours, then the solvent removed in vacuo to give (S)-4-methyl-2-morpholinopentanoic acid hydrochloride: MS (DCI+) m/z 202 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCC(=O)c1cccc(OCc2c(C)cccc2F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(F)c1COc1cccc(C(=O)CCC(=O)O)c1
Reaction time: 3 h

Procedure:
To a solution of Ethyl 4-(3-(2-Fluoro-6-methylbenzyloxy)phenyl)-4-oxobutyrate (Step D, 8.56 g, 24.9 mmol) in abs ethanol (100 ml) was added 1N NaOH (40 ml) at room temperature. The reaction mixture was stirred for 3 hours, acidified with 1M HCl and concentrated. The residue was taken in chloroform and washed with 0.1 M HCl, brine, dried over Na2SO4, filtered and concentrated. The purification was done by flash chromatography on silica gel column (chloroform:methanol 95:5 spiked with acetic acid) to provide the title compound as white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:30]([C:31](=[O:42])[NH:32][C:33]3[CH:41]=[C:40]4[C:36]([CH:37]=[N:38][NH:39]4)=[CH:35][CH:34]=3)=[CH:29][C:17]3[N:18]=[C:19]([NH:21][C@H:22]4[CH2:27][C@H:26]5[CH2:28][C@@H:23]4[CH2:24][CH2:25]5)[NH:20][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:39]1[C:40]2[C:36](=[CH:35][CH:34]=[C:33]([NH:32][C:31]([C:30]3[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:15][C:16]4[NH:20][C:19]([NH:21][C@H:22]5[CH2:27][C@H:26]6[CH2:28][C@@H:23]5[CH2:24][CH2:25]6)=[N:18][C:17]=4[CH:29]=3)=[O:42])[CH:41]=2)[CH:37]=[N:38]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3[nH]c(N[C@H]4C[C@@H]5CC[C@H]4C5)nc3cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc2cn[nH]c2c1)c1cc2nc(N[C@H]3C[C@@H]4CC[C@H]3C4)[nH]c2cc1N1CCNCC1

Procedure:
The product from Example 169 was treated with 4M HCl in dioxane employing the procedure described for Example 156 to afford 2-((1S,2S,4R)-bicyclo[2.2.1]hept-2-ylamino)-6-piperazin-1-yl-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)amide as a hydrochloride salt. MS: m/z 471 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3ccc(Cl)cc3)nc2c1
Yield: 41.1 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 4-chlorophenylboronic acid (87 mg, 0.56 mmol, 1.50 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (5:1)) afforded 43 mg (37%) of 3-(4-chlorophenyl)-2-phenylquinoxaline-6-carboxylic acid as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:17]([OH:19])=O)[C:10](=[O:27])[CH:9]=2)[CH:7]=1.[NH2:30][C:31]1[CH:41]=[CH:40][C:34]([C:35]([O:37]CC)=[O:36])=[CH:33][CH:32]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:17]([NH:30][C:31]3[CH:41]=[CH:40][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=3)=[O:19])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CCOCC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COc1cn(C(CC2CCOCC2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
1.38 g (3.31 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-4-yl)propanoic acid (racemate), 547 mg (3.31 mmol) of ethyl 4-aminobenzoate, 471 mg (3.31 mmol) of Oxima and 516 μl (3.31 mmol) of DIC in 33 ml of dimethylformamide were reacted according to General Method 5B. The crude product was purified by flash chromatography (120 g cartridge, 85 ml/min, cyclohexane/ethyl acetate gradient). Yield: 1.10 g (58% of theory)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][C:19]=1[F:20])[C:16]1[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([OH:21])[CH:10]=[CH:9]3)[C:6](OC)([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:24][CH:23]=1)[O:5]2.C(N(CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][C:19]=1[F:20])[C:16]1[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([OH:21])[CH:10]=[CH:9]3)[CH:6]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)=[CH:26][CH:27]=1)[O:5]2
Reactant: COC1(c2ccc(OCCN3CCCCC3)cc2)Oc2cc(F)c(F)cc2-c2ccc3cc(O)ccc3c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Oc1ccc2c3c(ccc2c1)-c1cc(F)c(F)cc1OC3c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
Dissolve 8,9-Difluoro-5-methoxy-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-2-ol (1.1 gm, 21. mmoles) in 30 ml of methylene chloride and add 2 ml of triethylamine and 2 ml of trifluoroacetic acid. Stir at room temperature for 1 hour, neutralize with sodium bicarbonate solution and separate the organic layer. Wash the water layer with methylene chloride and combine the organic layers. Dry the liquid over sodium sulfate and remove the solvent. Purify as described in Preparation 17 to obtain an 18% yield of the racemic. Obtain the individual enantiomers by chiral chromatography using a Chiralpak AD column eluting with ethanol containing 0.2% dimethylethylamine and monitoring at 225 nm.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([CH:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14]([O:20][C:21](=[O:23])[CH3:22])=[CH:15][CH:16]=3)[O:11][CH2:10]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>C(OCC)(=O)C.[Pt](=O)=O>[C:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([C@H:9]2[C@@H:18]([OH:19])[C:17]3[C:12](=[CH:13][C:14]([O:20][C:21](=[O:23])[CH3:22])=[CH:15][CH:16]=3)[O:11][CH2:10]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C2COc3cc(OC(C)=O)ccc3C2=O)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc([C@@H]2COc3cc(OC(C)=O)ccc3[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 55 h

Procedure:
Platinum(IV)oxide (Adam's catalyst) (0.05 g) was added to a solution of 4′,7-diacetoxyisoflavanone (0.25 g, 0.7 mmol) in ethyl acetate (40 ml) and the mixture was stirred at room temperature under a hydrogen atmosphere for 55 h. The catalyst was removed by filtration through Celite and the filtrate was evaporated in vacuo to yield predominantly the cis-4′,7-diacetoxyisoflavan-4-ol.
Reaction SMILES: [C:1]([C:3]1([C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1)#[N:2].[ClH:24]>O1CCOCC1>[ClH:24].[N:18]1([C:16]([C:3]2([C:1]#[N:2])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]2)=[O:17])[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(C(=O)N2CCOCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1(C(=O)N2CCOCC2)CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-Butyl 4-cyano-4-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (I-2) (11.95 g, 40 mmole) was added 4M HCl in dioxane (80 mL). The resulting reaction mixture was stirred for 1 h at room temperature. After this time, LCMS indicated that the reaction was complete. The reaction was concentrated to afford the title compound (I-3) as a white solid. This product was pure enough for next step reaction. Analytical LCMS: single peak (214 nm), 0.548 min.
Reaction SMILES: [N+](C1C=C([O:11][C:12]([F:15])([F:14])[F:13])C=CC=1N)([O-])=O.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[C:26]2[CH:27]=[CH:28][C:29](C(F)(F)F)=[CH:30][C:25]=2[N:24]=[C:23]1/[CH:35]=[CH:36]/[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[C:26]2[CH:27]=[CH:28][C:29]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:30][C:25]=2[N:24]=[C:23]1/[CH:35]=[CH:36]/[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: FC(F)(F)c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Reactant: Nc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Product: FC(F)(F)Oc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
The titled compound was prepared from 2-nitro4-trifluoromethoxyaniline according to the preparation of (E)-1-(2-pyridyl)-2-styryl-5-trifluoromethyl-1H-benzimidazole (Example 57). MW: 381.36; mp: 92.0-93.0° C.; 1H-NMR (CDCl3) δ: 8.81-8.77 (1H, m), 8.02 (1H, d, J=16.5 Hz), 8.05-7.98 (1H, m), 7.71-7.68 (1H, m), 7.54-7.45 (4H, m), 7.45 (1H, d, J=8.8 Hz), 7.42-7.30 (3H, m), 7.17-7.10 (1H, m), 7.10 (1H, d, J=16.1 Hz)
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.CCN(CC)CC.Cl>C(Cl)Cl.CCOC(C)=O.O>[S:30]([O:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1)([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCc1ccc(C#Cc2ccccc2CCO)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1ccc(C#Cc2ccccc2CCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 10 °C

Procedure:
Methyl 3-(4-((2-(2-hydroxyethyl)phenyl)ethynyl)phenyl)propanoate (200 mg, 0.65 mmol) in CH2Cl2 (5 ml) was added para-toluenesulfonyl chloride (136 mg, 0.71 mmol). The mixture was cooled to 10° C. and NEt3 (72 mg, 0.71 mmol) in CH2Cl2 (1 ml) was added dropwise. The reaction was allowed to reach room temperature and reacted overnight. The reaction was added 1 M HCl (0.5 ml), water (10 ml) and extracted with CH2Cl2. The organic phases were combined, washed with aq. NaHCO3, dried over MgSO4, concentrated and purified by flash chromatography (SiO2, EtOAc:PE, 1:3) to give 153 mg (51%): Rf=0.20 (EtOAc:PE, 1:3); 1HNMR (CDCl3): δ 7.66 (d, J=6.3 Hz, 2H), 7.44-7.42 (m, 1H), 7.39 (d, J=6.3 Hz, 2H), 7.26-7.23 (m, 1H), 7.22-7.19 (m, 6H), 4.32 (t, J=5.1 Hz, 2H), 3.68 (s, 3H), 3.21 (t, J=5.7 Hz, 2H), 2.98 (t, J=6.0 Hz, 2H), 2.65 (t, J=5.4 Hz, 2H), 2.38 (s, 3H); 13CNMR (CDCl3): δ 173.1, 144.5, 141.2, 137.8, 133.0, 132.3, 131.7, 129.9, 129.7, 128.5, 128.5, 127.8, 127.0, 123.1, 120.9, 93.6, 86.8, 51.7, 35.4, 34.4, 30.9, 21.6.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:12]=2[NH2:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:25][O:26][C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)=[O:28].O>C(Cl)Cl>[C:1]1([S:7]([NH:10][C:11]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:12]=2[NH:13][C:33]([C:32]2[CH:36]=[CH:37][C:29]([C:27]([O:26][CH3:25])=[O:28])=[CH:30][CH:31]=2)=[O:34])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2cc(Cl)ccc2NS(=O)(=O)c2ccccc2)cc1
Reaction time: 6 h
Yield: 79.1 %

Procedure:
To a solution of 2-phenylsulfonylamino-5-chloroaniline (90 mg; prepared in Reference Example 12.) and pyridine (0.05 ml) in methylene chloride (5 ml), 4-methoxycarbonylbenzoic acid chloride (70 mg) was added at room temperature in a stream of argon. The mixture was stirred for 6 hours. After the termination of reaction, water was added to the reaction mixture. The mixture was extracted with ethyl acetate. The organic layer was washed, dried over and concentrated under the reduced pressure. The residue was purified by the recrystallization from AcOEt-hexane mixture solvent to give the title compound (112 mg) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[OH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:13]2[CH2:14][CH2:15][C@@H:11]([OH:10])[CH2:12]2)=[CH:6][CH:7]=1
Reactant: O[C@@H]1CCNC1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O[C@@H]1CCN(Cc2ccc(Cl)nc2)C1
Temperature: 80 °C
Yield: 76.9 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (1.0 g, 6.3 mmole) in 10 mL of dry acetonitrile is added 1.05 mL (12.6 mmol) of (R)-3-hydroxy-pyrrolidine followed by 858 mg (6.2 mmol) of potassium carbonate. The reaction is heated at 80° C. for 2 h. After cooling, the reaction mixture is quenched with 20 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 1.03 g (77% yield) of (R)-1-(6-Chloro-pyridin-3-ylmethyl)-pyrrolidin-3-ol. Diagnostic C13 NMR (100 MHz, CDCl3) 35.1, 52.5, 56.7, 63.0, 71.4, 124.2, 133.4, 139.6, 149.9, 150.4; MS 213.2 (M+H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](Cl)[C:10]([F:16])=[C:11]([Cl:15])[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.C(N)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([Cl:15])[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(Cl)c(F)c(Cl)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: NCc1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(Cl)c(F)cc2c1=O
Yield: 83.9 %

Procedure:
58.3 g of ethyl 1-cyclopropyl-5,7-dichloro-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylate (0161 mol), 15.4 ml of benzyl amine, and 37.0 g of anhydrous K2CO3 in 220 ml of acetonitrile were stirred at 100-110° C. for 1 hour. The reaction was monitored by TLC. After the solvent was evaporated, the residue was re-crystallized from ethanol to give 58.3 g of ethyl 1-cyclopropyl-7-chloro-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (0.135 mol) in 83.7% yield.