Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6](=[O:12])[N:5]3[C@H:13]([CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]4)[CH2:14][N:3]1[C:4]=23.[ClH:30].CO>C(Cl)(Cl)Cl>[ClH:30].[ClH:30].[NH2:22][CH:19]1[CH2:18][CH2:17][N:16]([CH2:15][C@H:13]2[N:5]3[C:4]4[N:3]([C:2](=[O:1])[CH:11]=[CH:10][C:9]=4[CH:8]=[CH:7][C:6]3=[O:12])[CH2:14]2)[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 114.2 %

Procedure:
A solution of 1,1-dimethylethyl (1-{[(1R)-4,9-dioxo-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridin-1-yl]methyl}-4-piperidinyl)carbamate (see Example 1 (i) above) (4.282 g, 10.69 mmol) in CHCl3 (20 ml) under Ar at room temperature was treated with HCl (4M solution in 1,4-dioxane, 20 ml, 80 mmol) and stirred at rt for 15 min, MeOH (20 ml) was then added. After stirred for 15 min, the reaction was evaporated and triturated with Et2O (20 ml). The obtained solid was dried in vacuo to give (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride (4.55 g, 12.21 mmol, 100%) as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[O:4][N:3]=1.C([O-])(=O)C.[Na+].[CH2:20]=[C:21]1[O:25][C:23](=[O:24])[CH2:22]1>C1C=CC=CC=1>[C:23]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)(=[O:24])[CH2:22][C:21]([CH3:20])=[O:25]
Reactant: Cc1cc(CCCCCCCO)on1
Reactant: C=C1CC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(=O)CC(=O)OCCCCCCCc1cc(C)no1
Yield: 70 %

Procedure:
To a mixture of 7-(3-methylisoxazol-5-yl)heptan-1-ol (1.97 g, 0.01 mol) and anhydrous sodium acetate (0.080 g) in benzene (20mL) was added a solution of diketene (1.84 g, 0.022 mol) in benzene (6 mL) dropwise. The mixture was refluxed for 12 h. After the removal of benzene under reduced pressure, the crude product was purified by elution from a silica gel column using dichloromethane-hexane (9:1 v/v) as eluant to give 5-(7-acetoacetoxyhept-1-yl)-3-methylisoxazole (21) (70%) as a yellow oil. IR (neat) 1740 (CO2), 1718 (CO)cm-1 ; NMR (CDCl3) 1.12-1.95 (m, 10H, (CH2)5), 2.35 (S, 6H, Me-Het, CO-Me), 2.70 (t, J=9 Hz, 2H, CH2 --Het), 3.49 (S, 2H, CO--CH2 --COMe), 4.14 (t, J=6 Hz, 2H, O--CH2), 5.80 (S, 1H, H-Het). Analysis found: C, 64.11; H, 8.31; N, 4.72. Required: C, 64.02; H, 8.24; N, 5.00 (C15H23NO4). ##STR8##
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C@@H:4]([OH:8])[C:5]([OH:7])=[O:6].P(=O)(Cl)(Cl)Cl.[CH3:18]O>>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C@@H:4]([OH:8])[C:5]([O:7][CH3:18])=[O:6]
Reactant: O=C(O)[C@H](O)c1ccccc1Cl
Reactant: CO
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)[C@H](O)c1ccccc1Cl
Yield: 95 %

Procedure:
15 g of (R)-2-chloromandelic acid was mixed with methanol (CH3OH, 150 ml) and phosphorus chloride oxide (POCl3, 0.76 ml) in a flask by stiffing using a magnetic stirrer at the room temperature for 6 hours. When the reaction was completed, the obtained product was washed with an aqueous solution of sodium sulfite (Na2SO3) and ethylacetate (EA). Then, the organic layer was dehydrated with anhydrous magnesium sulfate (MgSO4), filtrated, and concented under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (15.64 g, yield 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[C:28]4[S:24][C:25](=[O:30])[NH:26][C:27]4=[O:29])=[CH:18][CH:17]=3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cccc(Oc3ccc(C=O)cc3)c2)cc1
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc(-c2cccc(Oc3ccc(C=C4SC(=O)NC4=O)cc3)c2)cc1
Yield: 77.5 %

Procedure:
A mixture of 57 (1.23 g, 4.0 mmol), 2,4-thiazolidinedione (0.48 g, 4.0 mmol), benzoic acid (0.60 g, 4.8 mmol) and piperidine (0.61 mL, 6.0 mmol) in toluene (30 mL) was heated to a vigorous reflux until most of the solvent had evaporated. A yellow suspension was achieved by addition of acetic acid (25 mL) followed by sonication. Filtration of the suspension followed by washing with acetic acid (10 mL) yielded 58 (1.25 g, 75%) after filtration and oven drying. 1H NMR (400 MHz, DMSO-d6): δ 12.57 (br s, 1H), 7.78 (s, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 7.49 (d, J=5.2 Hz, 2H), 7.36 (t, J=1.6 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.03 (m, 1H), 7.01 (d, J=8.8 Hz, 2H), 3.7 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]CC3C=CC=CC=3)[CH:13]=2)[C:7]([CH:26]=[CH:27][CH2:28][CH2:29][CH3:30])=[C:6]([CH:31]([CH3:33])[CH3:32])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C:7]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:6]([CH:31]([CH3:32])[CH3:33])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(OCc2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(O)c1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3-benzyloxyphenyl)-5-(pent-1-enyl)pyridine (Example 152) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): δ 0.78 (t, J=7.0 Hz, 3 H), 1.28 (m, 18 H), 2.28 (m, 2 H), 3.22 (m, 1 H), 3.39 (m, 1 H), 4.34 (m, 2 H), 5.52 (s, 1 H), 6.63 (m, 1 H), 6.71 (d, J=8.0 Hz, 1 H), 6.81 (m, 1 H), 7.26 (m, 1 H). FAB-MS: calculated for C23H33NO2 356; found 357 (M+H, 100%). Elemental analysis: calculated for C23H33NO2: C 77.70; H 9.36; N 3.94, found: C 76.51; H 9.49; N 3.85. Rf 0.21 (10% ethyl acetate/n-hexane). mp 121-122° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][C:4]=1[C:15]#[C:16][C:17]1([OH:25])[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1)=[O:2].CO.[BH4-].[Na+]>O>[OH:2][CH2:1][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][C:4]=1[C:15]#[C:16][C:17]1([OH:25])[CH:22]2[CH2:21][CH2:20][N:19]([CH2:24][CH2:23]2)[CH2:18]1
Reactant: COC(=O)CCc1ccc(C#CC2(O)CN3CCC2CC3)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CCc1ccc(C#CC2(O)CN3CCC2CC3)c(CO)c1
Reaction time: 8 h
Yield: 27.7 %

Procedure:
3-[2-(2-formyl-4-(2-methoxycarbonylethyl)phenyl]ethynyl]quinuclidin-3-ol (575 mg) was stirred with methanol (25 ml) at ambient temperature under an atmosphere of argon. Sodium borohydride (329 mg) was added portionwise over 5 minutes to the reaction mixture and stirring continued at ambient temperature overnight. Water (25 ml) was added and the mixture was extracted with ethyl acetate (25 ml). The organic phase was separated, washed with saturated aqueous sodium carbonate (3×25 ml), water (3×25 ml), dried (MgSO4) and evaporated. The residue was purified by elution through silica gel (10 g Bond elut column) with a gradient of 0-30% methanol in dichloromethane to give 3-[2-(2-hydroxymethyl-4-(2-methoxycarbonylethyl)phenyl)ethynyl]quinuclidin-3-ol (160 mg) as a solid, m.p. 35.8° C.; microanalysis, found: C, 69.2; H, 7.5; N, 3.9% C20H25NO4 0.2 H2O requires: C, 69.2; H, 7.38; N, 4.04%; NMR(CDCl3): 1.4(1H,m), 1.66(1H,m), 2.02(3H,m), 2.62(2H,t), 2.8(3H,m), 2.95(2H,t), 3.03(1H,d), 3.27(1H,d), 3.66(3H,s), 4.75(2H,s), 7.07(1H,m) and 7.3(2H,m); m/z 344 (M+H).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21](C)[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl.O1CC[CH2:36][CH2:35]1>O>[CH:20]1([NH:19][N:16]2[C:17](=[O:18])[C:12]([C:4]3[NH:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[S:2](=[O:28])(=[O:1])[N:3]=3)=[C:13]([OH:27])[C:14]3[S:26][CH:25]=[CH:24][C:15]2=3)[CH2:21][CH2:22][CH2:36][CH2:35]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: C1CCOC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1NC1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.040 g, 0.09 mmol) in tetrahydrofuran (3 mL) and methanol (0.008 mL, 0.19 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.07 mL, 0.14 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid a pH of approximately 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 98:2 dichloromethane/methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54 (m, 6 H) 1.74 (m, 2 H) 3.75 (m, 1 H) 5.77 (d, J=3.68 Hz, 1 H) 7.12 (d, J=5.15 Hz, 1 H) 7.19 (d, J=7.72 Hz, 1 H) 7.26 (t, J=7.17 Hz, 1 H) 7.54 (m, 1 H) 7.64 (d, J=7.72 Hz, 1 H) 7.74 (d, J=5.52 Hz, 1 H) 15.91 (s, 1 H). MS (ESI−) m/z 429 (M−H)−.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:13]=1[NH2:14]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:14][C:13]1[CH:15]=[CH:16][C:17]([F:20])=[C:18]([F:19])[C:12]=1[F:11]
Reactant: Nc1ccc(F)c(F)c1F
Reactant: Clc1nc2ccccc2[nH]1
Product: Fc1ccc(Nc2nc3ccccc3[nH]2)c(F)c1F

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 2,3,4-trifluoroaniline by Procedure A. The product was isolated by filtration and preparative LCMS to give the title compound as the free base (white solid, mp 182-183° C.). MS(ES+) m/z 264 ([M+1]+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][C@H:37]([OH:39])[CH3:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH2:36][C@H:37]([OH:39])[CH3:38])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Reactant: C[C@@H](O)CN
Product: C[C@@H](O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2R)-1-amino-2-propanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.10 (d, J=6.32 Hz, 3 H), 1.55-1.65 (m, 4 H), 2.04 (t, J=5.79 Hz, 2 H), 3.15-3.28 (m, 2 H), 3.40-3.53 (m, 4 H), 3.81 (br. s., 1 H), 4.16 (s, 2 H), 4.39 (t, J=6.42 Hz, 2 H), 4.95 (d, J=3.58 Hz, 1 H), 7.11-7.17 (m, 2 H), 7.38-7.43 (m, 2 H), 8.20 (d, J=1.47 Hz, 1 H), 8.56 (d, J=1.68 Hz, 1 H), 10.42 (t, J=5.16 Hz, 1 H), 17.23 (s, 1 H); ES+ MS: 497 (M+H+).
Reaction SMILES: C(OC([NH:11][CH:12]([C:14]1[C:15]([O:33][CH3:34])=[C:16]([CH:22]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]2)[C:17]([Cl:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13])=O)C1C=CC=CC=1.O.[H][H]>CO.Cl.[Pt]>[NH2:11][CH:12]([C:14]1[C:15]([O:33][CH3:34])=[C:16]([CH:22]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:23]2)[C:17]([Cl:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13]
Reactant: COc1c(C(C)NC(=O)OCc2ccccc2)cc(Cl)c(Cl)c1C1CN(C(=O)OC(C)(C)C)C1
Reactant: [H][H]
Agent: [Pt]
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1c(C(C)N)cc(Cl)c(Cl)c1C1CN(C(=O)OC(C)(C)C)C1
Yield: 98.2 %

Procedure:
A solution of tert-butyl 3-[3-(1-{[(benzyloxy)carbonyl]amino}ethyl)-5,6-dichloro-2-methoxyphenyl]azetidine-1-carboxylate [peak 2 isomer from step 6] (0.29 g, 0.57 mmol) in methanol (17 mL) and 0.25 M HCl in water (5.7 mL, 1.4 mmol) was degassed with nitrogen, treated with 5% Pt/C (Degussa type) (73 mg, 25 wt %), and stirred under a balloon of hydrogen for 1 hour. The reaction mixture was treated with additional 5% Pt/C (Degussa type) (100 mg) and stirred under a balloon of hydrogen for an additional 1 hour. The reaction mixture was filtered over Celite and neutralized with saturated sodium bicarbonate solution. The reaction mixture was concentrated to remove the methanol, extracted with dichloromethane, and concentrated to give the desired product (0.21 g, 99%) as a colorless foam that was used without further purification. LCMS for C13H14C12NO3 (M−[NH2]−[t-Bu]+H)+: m/z=302.0, 304.0. Found: 301.9, 304.0.
Reaction SMILES: [BH4-].[Li+].C1COCC1.[CH3:8][O:9][C:10]1[CH:24]=[CH:23][C:13]([CH2:14][O:15][C:16]([CH3:22])([CH3:21])[C:17](OC)=[O:18])=[CH:12][CH:11]=1>O>[CH3:8][O:9][C:10]1[CH:24]=[CH:23][C:13]([CH2:14][O:15][C:16]([CH3:22])([CH3:21])[CH2:17][OH:18])=[CH:12][CH:11]=1
Reactant: COC(=O)C(C)(C)OCc1ccc(OC)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COC(C)(C)CO)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To a mixture of lithium borohydride (2.29 g) and THF (200 mL) was added dropwise methyl 2-[(4-methoxybenzyl)oxy]-2-methylpropanoate (12.5 g) under ice-cooling, followed by stirring at 60° C. for 2 hours. To the reaction mixture was added water under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80) to obtain 2-[(4-methoxybenzyl)oxy]-2-methylpropan-1-ol (6.72 g) as a colorless oily substance.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:23]=[CH:22][C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(O)C>[N:1]1([C:6]([C:8]2[CH:23]=[CH:22][C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1)N1CCCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Cc2ccc(C(=O)N3CCCC3)cc2)cc1
Reaction time: 16 h
Yield: 102.5 %

Procedure:
A mixture of 4-(4-pyrrolidin-1-ylcarbonylbenzyl)-nitrobenzene (202 mg, 065 mmol), 10% palladium on carbon (110 mg), and ethanol (20 mL) was hydrogenated at 40 psi for 16 hours. The mixture was filtered through a Celite pad, and solvents evaporated to give 4-[4-(1-pyrrolidinecarbonyl)benzyl]-phenylamine as a white solid (187 mg, 99%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[C:16]([CH:37]=[CH:38][CH:39]=2)[C:17]([NH:19][C:20]2[CH:21]=[C:22]([NH:27][C:28]([C:30]3[CH:35]=[CH:34][N:33]=[C:32](Cl)[CH:31]=3)=[O:29])[CH:23]=[CH:24][C:25]=2[CH3:26])=[O:18])[CH2:9][CH2:8]1.CS(C)=O>O>[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[C:16]([CH:37]=[CH:38][CH:39]=2)[C:17]([NH:19][C:20]2[CH:21]=[C:22]([NH:27][C:28]([C:30]3[CH:31]=[CH:32][N:33]=[C:34]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:35]=3)=[O:29])[CH:23]=[CH:24][C:25]=2[CH3:26])=[O:18])[CH2:9][CH2:8]1
Reactant: C1CCNC1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Temperature: 120 °C
Yield: 2.6 %

Procedure:
Pyrrolidine (0.3 g) was added to a stirred mixture of N-{3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-4-methylphenyl}-2-chloropyridine-4-carboxamide (0.5 g) and DMSO (5 ml) and the mixture was stirred and heated to 120° C. for 16 hours. The resultant solution was cooled to ambient temperature and poured into water and extracted with methylene chloride. The organic phase was evaporated and the residue was purified by column chromatography on an isolute SCX ion exchange column using a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound (0.014 g); Mass Spectrum: M+H+513.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=1.[Cl:25][C:26]1[CH:32]=[C:31]([P:33]([CH3:36])([CH3:35])=[O:34])[CH:30]=[CH:29][C:27]=1[NH2:28]>>[Cl:25][C:26]1[CH:32]=[C:31]([P:33]([CH3:35])([CH3:36])=[O:34])[CH:30]=[CH:29][C:27]=1[NH:28][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:16])=[O:17])[C:5]([C:21]([F:24])([F:22])[F:23])=[CH:4][N:3]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)ncc1C(F)(F)F
Reactant: CP(C)(=O)c1ccc(N)c(Cl)c1
Product: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Nc2ccc(P(C)(C)=O)cc2Cl)ncc1C(F)(F)F

Procedure:
This compound can be prepared as described in Example 80 by reacting 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-amine with 2-chloro-4-(dimethylphosphoryl)-aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[C:16]#[CH:17]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:20]([O:19][C:15](=[O:18])[C:16]#[C:17][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:21]
Reactant: Clc1ccc(I)cc1
Reactant: C#CC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1ccc(Cl)cc1
Temperature: 35 °C
Reaction time: 41 h

Procedure:
A mixture of 1-chloro-4-iodobenzene (120.4 g, 0.50 mol) and cesium carbonate (352.8 g, 1.0 mol) in tetrahydrofuran (1.275 L) was evaporated and flushed with argon. Then cuprous iodide (3.81 g, 20.0 mmol) and bis(triphenylphosphine)palladium(II) chloride (7.02 g, 10.0 mmol) were added and then ethyl propiolate (100 g, 1.01 mol) was added dropwise over a period of 20 min. The resulting dark brown suspension was stirred for 41 h at 35° C., then filtrated over Hyflo® and washed with THF (5 L). The solution was concentrated and treated with toluene/heptane 1:2 (1.5 L) and stirred for 1 h at 45° C. under reduced pressure (250 mbar). The resulting suspension was filtered and the residue was washed with further toluene/heptane 1:2 (1.5 L). The solid was dried affording 181.64 g (MS m/e: 209.0/211.2 [M+H]+) of a dark brown oil as crude product which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:17])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].[C:18](OC(=O)C)(=[O:20])[CH3:19].I>>[C:18]([C:14]1[CH:13]=[C:12]([CH3:17])[N:11]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH3:10])=[C:2]([Cl:1])[CH:3]=2)[C:15]=1[CH3:16])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1ccc(-n2c(C)ccc2C)cc1Cl
Agent: I
Product: CCOc1ccc(-n2c(C)cc(C(C)=O)c2C)cc1Cl

Procedure:
Utilizing the general procedure outlined in EXAMPLE 1, 1-(3-chloro-4-ethoxyphenyl)-2,5-dimethylpyrrole (1.21 g, 4.8 mmol), acetic anhydride (5 mL), and hydriodic acid (0.07 mL, 0.83 mmol) reacted to give 3-acetyl-1-(3-chloro-4-ethoxyphenyl)-2,5-dimethylpyrrole as a tan solid: 1H NMR (CDCl3, 500 MHz) δ 7.21 (d, 1H), 7.04-6.98 (m, 2H), 6.29 (s, 1H), 4.17 (q, 2H), 2.41 (s, 3H), 2.30 (s, 3H), 1.98 (s, 3H), 1.52 (t, 3H); MS (ESI) 292 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][C:6]([CH3:11])([CH2:9][OH:10])[CH2:7][OH:8].C(O[CH:19](OCC)[CH2:20][Cl:21])C>>[Cl:21][CH2:20][CH:19]1[O:10][CH2:9][C:6]([O:5][CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[Cl:1])([CH3:11])[CH2:7][O:8]1
Reactant: CC(CO)(CO)OCc1ccccc1Cl
Reactant: CCOC(CCl)OCC
Product: CC1(OCc2ccccc2Cl)COC(CCl)OC1

Procedure:
By the method of Example 39, 2-(2-chlorobenzyloxy)-2-methyl-1,3-propanediol was reacted with chloroacetaldehyde diethyl acetal to yield a mixture of isomers which were separated by column chromatography. The cis-isomer was a solid, m.p. 53°-54° C. The trans-isomer was a liquid, b.p. 104°-107° C/0.02 mm Hg; nD25 1.5280.
Reaction SMILES: [CH:1]1([C@:7]2([NH:31]S(C(C)(C)C)=O)[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]4[C:17]([CH3:22])=[N:18][O:19][C:20]=4[CH3:21])[CH:14]=3)[N:9](C(OC(C)(C)C)=O)[C:8]2=[O:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1>[NH2:31][C@@:7]1([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[C:17]([CH3:22])=[N:18][O:19][C:20]=3[CH3:21])[CH:14]=2)[NH:9][C:8]1=[O:30]
Reactant: Cc1noc(C)c1-c1ccc2c(c1)[C@@](NS(=O)C(C)(C)C)(C1CCCCC1)C(=O)N2C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1ccc2c(c1)[C@@](N)(C1CCCCC1)C(=O)N2
Reaction time: 0.25 h
Yield: 64.5 %

Procedure:
To a solution of (S)-tert-butyl 3-cyclohexyl-3-(1,1-dimethylethylsulfinamido)-5-(3,5-dimethyl-isoxazol-4-yl)-2-oxoindoline-1-carboxylate (53 mg, 0.1 mmol) in 2 mL of dioxane was added, a HCl saturated dioxane solution (1.0 mmol) at room temperature. The reaction mixture was stirred for 15 min. The reaction was quenched with 6 mL of aqueous NaHCO3, and the organic phase was extracted with CH2Cl2, dried, and evaporated under reduced pressure to afford pure (S)-3-amino-3-cyclohexyl-5-(3,5-dimethylisoxazol-4-yl)indolin-2-one (21 mg, 65%) as a solid. 1H NMR (400 MHz, DMSO-d6): δH 10.32 (s, 1H), 7.17-7.19 (m, 2H), 6.88 (d, J=8.8 Hz, 1H), 2.39 (s, 3H), 2.21 (s, 3H), 1.90-1.93 (m, 1H), 1.53-1.63 (m, 5H), 0.95-1.11 (m, 4H), 0.68-0.72 (m, 1H). MS (ESI) m/e [M+1]+ 326. MS (ESI) m/e [M+1]+ 326.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:23][C:24]([NH:27][OH:28])([CH3:26])[CH3:25]>O1CCCC1.CN(C)C=O.[OH-].[Na+]>[CH:1]1([CH:7]2[CH2:8][CH2:9][CH:10]([C:13]([N:27]([C:24]([CH3:26])([CH3:25])[CH3:23])[OH:28])=[O:15])[CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)C1CCC(C2CCCCC2)CC1
Reactant: CC(C)(C)NO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)N(O)C(=O)C1CCC(C2CCCCC2)CC1
Reaction time: 1 h
Yield: 9.4 %

Procedure:
To a solution of 4-cyclohexyl-cyclohexanecarboxylic acid (1.47 g, 7 mmol) in 20 ml of tetrahydrofuran was added oxalyl chloride (0.67 ml, 7.7 mmol) and a few drops of dimethylformamide. After stirring for one hour, the reaction mixture was added dropwise into a cold (~0° C.), stirred solution of N-(1,1-dimethylethyl)hydroxylamine hydrochloride (1.75 g, 14 mmol) in 40 ml of 1N sodium hydroxide. The mixture was stirred for two hours, from 0° C. to room temperature and extracted three times with ethyl acetate. The combined ethyl acetate extracts were then washed twice with water, dried with anhydrous sodium sulfate and concentrated. Purification by flash chromatography provided 0.186 g of the 4-cyclohexyl-N-(1,1-dimethylethyl)-N-hydroxy-cyclohexane-carboxamide as a white solid (m.p. 119°-120° C.).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:12][C:11]=1[F:32]>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([N:7]4[C@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]4=[O:8])=[C:11]([F:32])[CH:12]=3)=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@H]4CO)c(F)c3)CC2)c(C)c1
Yield: 36.4 %

Procedure:
Using (S)-5-hydroxymethylpyrrolidin-2-one (127 mg) and (4-bromo-3-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (392 mg) described in Preparation Example 125 and by the reaction and treatment in the same manner as in Example 1, the title compound (155 mg) was obtained.