Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:26]1([CH2:32][CH2:33][NH2:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([NH:34][CH2:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:8]
Reactant: NCCc1ccccc1
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NCCc2ccccc2)cc1OC
Reaction time: 2 h
Yield: 65.5 %

Procedure:
A solution of 3,4-dimethoxybenzoic acid (9.1 g, 0.05 mol) and carbonyldiimidazole (8.1 g, 0.05 mol) in 100 ml of THF was stirred for 3 h protected from moisture. The resulting solution was treated with 2-phenylethylamine (6.1 g, 0.05 mol) dissolved in 10 ml of THF. After 2 h of stirring, the solvent was evaporated and the solid residue was washed with dilute NaOH, dilute HCl, and water. The crude Al was recrystallized from 75 ml of EtOH to afford 9.35 g (57%) of N-(3,4-dimethoxybenzoyl)-2-phenylethylamine, mp 123-124°.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([Br:28])[CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.[H-].[Na+].Br[CH2:33][CH2:34][O:35][CH2:36][CH3:37]>>[Br:28][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:22]=1[N:21]([CH2:33][CH2:34][O:35][CH2:36][CH3:37])[CH:20]=[C:19]2[CH:16]1[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:2])=[O:29])[CH2:18][CH2:17]1
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3c(Br)cccc23)CC1
Reactant: CCOCCBr
Agent: [H-]
Agent: [Na+]
Product: CCOCCn1cc(C2CCN(CCOc3ccccc3C(=O)O)CC2)c2cccc(Br)c21

Procedure:
This compound was prepared following the procedure described in Example 138 (part B) starting with 1.4 g (3.1 mmol) of 2-{2-[4-(7-bromo-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester (prepared as in Example 138, part A), 0.16 g (3.7 mmol) of NaH in 60% of mineral oil and 0.42 mL (3.7 mmol) of bromoethylethyl ether. The crude mixture was hydrolised following the procedure described in Example 138 (part C) and purified by chromatography over silica gel affording 0.34 g (28% of yield) of the desired product.
Reaction SMILES: [C:1]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[OH-].[Na+].[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC.F[C:48]([N:50]([S:52][N:53]([C:55]([O:57][N:58]=[C:59]([S:61][CH3:62])[CH3:60])=[O:56])[CH3:54])[CH3:51])=[O:49]>O.C(Cl)Cl>[CH2:11]([O:10][C:1](=[O:9])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][C:48]([N:50]([CH3:51])[S:52][N:53]([CH3:54])[C:55]([O:57][N:58]=[C:59]([S:61][CH3:62])[CH3:60])=[O:56])=[O:49])[CH2:12][CH2:13][CH3:14]
Reactant: CSC(C)=NOC(=O)N(C)SN(C)C(=O)F
Reactant: CCCCOC(=O)c1ccccc1O
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCOC(=O)c1ccccc1OC(=O)N(C)SN(C)C(=O)ON=C(C)SC
Reaction time: 1 h

Procedure:
A 5.8 g portion of n-butyl salicylate was added to a solution of 1.2 g of sodium hydroxide in 75 ml of water, producing a thick suspension. To the above suspension was added 100 ml of methylene chloride and 0.3 g of tricaprylylmethyl ammonium chloride. The reaction mixture was stirred vigorously while a solution of 8.1 g of methyl N-[[N-[(fluorocarbonyl-N-methylamino)thio]-N-methylaminocarbonyloxy]]ethanimidothioate in 50 ml methylene chloride was added dropwise. When addition was complete, stirring was continued for one hour. The organic phase was separated and washed with 200 ml of water followed by 100 ml of saturated sodium chloride solution. The organic solution was dried over anhydrous magnesium sulfate, and the solvent was distilled under reduced pressure. On scratching and standing, the crude reaction product partially solidified. The title compound was isolated by dissolving the crude reaction product in 25 ml of ethanol, cooling the solution and diluting with hexane to afford 5.7 g of 2-[N-methyl-N-[N-methyl-N-[(1-methylthioethylidene)aminooxycarbonyl]aminothio]aminocarbonyloxy]benzoic acid butyl ester, m.p. 87° -89° C. Absorption bands characteristic of the title compound were observed in the infrared and NMR spectrums.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:31]1[C:40]2[C:35](=[CH:36][C:37]([CH2:41]O)=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1COCC1>[N:31]1[C:40]2[C:35](=[CH:36][C:37]([CH2:41][N:2]3[C:3](=[O:10])[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:1]3=[O:11])=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: OCc1ccc2ncccc2c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2ncccc2c1
Temperature: 30 °C
Reaction time: 20 h
Yield: 94.9 %

Procedure:
To a solution of isoindoline-1,3-dione (6.47 g, 44.0 mmol) and triphenylphosphine (11.53 g, 44.0 mmol) in THF (70 mL) at 0° C. was added a solution of quinolin-6-ylmethanol (7 g, 44.0 mmol) in THF (30 mL) and (E)-diisopropyl diazene-1,2-dicarboxylate (8.89 g, 44.0 mmol) dropwise over a period of 30 min. The mixture was heated at 30° C. and kept stirring for 20 h. After cooling and concentration, the resulting residue was purified by Analogix silica gel with gradient hexanes/EtOAc to provide 2-(quinolin-6-ylmethyl)isoindoline-1,3-dione (12.04 g, 95%). LCMS (method A): [MH]+=289, tR=4.89 min.
Reaction SMILES: Br[CH:2]1[CH2:5][CH2:4][C:3]1=[CH:6][CH:7]=O.C(OCC)(=S)C(N)=O.C(C1[N:21]=[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[S:23]C=1)(C)C>>[CH2:28]([O:27][C:25]([C:22]1[S:23][CH:7]=[C:6]([CH:3]2[CH2:2][CH2:5][CH2:4]2)[N:21]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)c1nc(C(C)C)cs1
Reactant: O=CC=C1CCC1Br
Agent: CCOC(=S)C(N)=O
Product: CCOC(=O)c1nc(C2CCC2)cs1
Yield: 64 %

Procedure:
4-Cyclobutylthiazole-2-carboxylic acid ethyl ester 265b was synthesized from compound 264b (23.87 g, 1 eq.) and ethyl thiooxamate (21.41 g, 1 eq.) as a yellow oil in 64% yield, following the procedure as described for compound 212. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 1.32 (t, J=7.12 Hz, 3H), 1.82-1.89 (m, 1H), 1.92-2.02 (m, 1H), 2.15-2.33 (m, 4H), 3.65-3.74 (m, 1H), 4.36 (q, J=7.12 Hz, 2H), 7.76 (d, J=0.64 Hz, 1H); MS (ESI, EI+): m/z=212 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8][N:7]=1)=O)C.[BH4-].[Na+].O>C(O)C>[OH:3][CH2:4][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8][N:7]=1
Reactant: CCOC(=O)c1nnc(-c2ccccn2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1nnc(-c2ccccn2)s1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(5-ethoxycarbonyl-1,3,4-thiadiazol-2-yl)-pyridine (8 gm) in ethanol (80 ml), was added sodium borohydride (2.51 gm) in lots at 30° C. It was stirred at 30° C. over a period of 2 h. The solvent was evaporated under vacuum to provide a crude mass. To the crude mass, water (100 ml) was added and it was extracted with dichloromethane (200 ml×2). Combined organic layers was washed with water and concentrated under vacuum to provide title compound in 6.1 gm quantity (92%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH2:5][CH2:4][C@@H:3]4[NH:2][S:30]([CH3:29])(=[O:32])=[O:31])=[N:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4NS(C)(=O)=O)s2)cc1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
Prepared using General Procedure 12. To a stirred solution of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 (20 mg, 0.04 mmol) and TEA (14.7 mg, 0.14 mmol) in DCM (2 mL) was added methane sulfonylchloride (8.3 mg, 0.07 mmol) and the mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue purified by preparative HPLC to afford 12 mg (55%) of (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide 33 as white solid. LCMS-ESI (m/z) calculated for C22H22N4O3S2: 454.1; found 455.1 [M+H]+, tR=3.48 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[CH:10][C:11]=1[NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:5])C.Cl>C(O)C.O1CCCC1.[OH-].[Na+].O>[CH:14]1([CH2:13][NH:12][C:11]2[CH:10]=[C:9]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:23][CH:22]=3)[N:8]=[CH:7][C:6]=2[C:4]([OH:5])=[O:3])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)c1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NCC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NCC1CCCCC1
Temperature: 100 °C
Yield: 106.8 %

Procedure:
108 mg of 4-[(cyclohexylmethyl)amino]-6-[(4-morpholinophenyl)amino]pyridine-3-carboxylic acid ethyl ester was dissolved in 4 mL of ethanol-tetrahydrofuran (1:1), to which 2 mL of 2 mol/L sodium hydroxide in water was added at room temperature, and stirred while heating at 100° C. for 2 hours. Under ice cooling, hydrochloric acid was added to acidify (about pH 4) the reaction mixture, extracted with chloroform, the extract was washed with water, and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain 108 mg of 4-[(cyclohexylmethyl)amino]-6-[(4-morpholinophenyl)amino]pyridine-3-carboxylic acid as a light brown crystalline powder. This was dissolved in 1 mL of N,N-dimethylformamide, to which 52 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 41 mg of 1-hydroxybenzotriazole monohydrate were added, and stirred at room temperature for 20 minutes. Then 1 mL of 28% ammonia water was added, and stirred at the same temperature for 16 hours. To the reaction mixture 10 mL of water was added, extracted with chloroform, and the extract was dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=5:1) to obtain 44 mg (yield 37%) of the title compound as a light yellow crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH3:30])[CH:24]=[N:23]2.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[C:25]([CH3:30])[CH:24]=[N:23]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Cc1cnc2cc(N)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cnc2cc(NS(=O)(=O)c3cccc(Cl)c3C)ccc2n1
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (119 mg, 0.528 mmol) in dichloromethane (3 mL) was added pyridine (100 μL, 1.26 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-amino-2-methylquinoxaline (80 mg, 0.50 mmol) was added. The resulting mixture was stirred for 5 h. at room temperature, then saturated NaHCO3 solution (8 mL) was added and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a pale pink solid (161 mg, 92%), single spot at Rf 0.67 (ethyl acetate). mp 158.7-159.3° C., HPLC purity 99+% (tR 2.23 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 8.66 (1H, s), 8.02 (1H, d, J=7.7 Hz), 7.89 (1H, d, J=8.9 Hz), 7.61 (1H, d, J=2.5 Hz), 7.55 (1H, d, J=8.2 Hz), 7.46 (11H, dd, J=8.9, 2.5 Hz), 7.23 (1H, t, J=7.9 Hz), 7.08 (1H, s, N—H), 2.76 (3H, s), 2.71 (3H, s). LCMS: 346.11 (M−). FAB-MS (MH+, C16H14ClN3O2S): calcd 348.0573, found 348.0589.
Reaction SMILES: Cl.[N:2]1[N:3]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:5][CH:6]=1.[Cl:11][C:12]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:13]=1[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:4]1[N:3]([CH2:7][C:8]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:12]=3[Cl:11])[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:10])[N:2]=[CH:6][CH:5]=1
Reactant: O=C(O)Cn1nccn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2Cl)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2Cl)CN1C(=O)Cn1nccn1

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acidhydrochloride and (2S,4R)-4-(2-chloro-4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 5, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(2-chloro-4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide. 1H-NMR (400 MHz, CDCl3): δ 9.15 (s, 1H), 7.70 (s, 2H), 7.40-7.36 (m, 2H), 7.23-7.12 (m, 2H), 7.02-6.84 (m, 7H), 5.31 (s, 2H), 4.80 (d, 1H), 3.62-3.57 (m, 1H), 3.24 (t, 1H), 3.04-2.95 (m, 1H), 2.90-2.85 (m, 1H), 2.53 (dd, 1H), 1.79-1.70 (m, 1H). MS (EI) for C28H25ClF2N5O3 found 552 (MH+).
Reaction SMILES: O[CH:2]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)(Cl)Cl.C(N(S(F)(F)[F:30])CC)C>[Cl-].[Na+].O>[CH2:14]([O:13][P:12]([CH:2]([F:30])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1)([O:16][CH2:17][CH3:18])=[O:19])[CH3:15]
Reactant: CCOP(=O)(OCC)C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)S(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(OCC)C(F)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 10 %

Procedure:
To a mixture of diethyl α-hydroxy-4-nitrobenzylphosphonate (1.0 g) and chloroform (10 mL) was added diethylaminosulfur trifluoride (1.4 mL) at −78° C. and the reaction mixture was warmed to room temperature. Saturated brine was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated and the residue was purified by preparative HPLC to give 4-[(diethylphosphono)(fluoro)methyl]nitrobenzene (0.1 g, yield 10%) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[C:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][O:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.Cl.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:25]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[C:15]3[CH2:16][CH2:17][N:18]([C:31](=[O:32])[CH2:30][C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[CH2:19][CH2:20]3)[C:7]3[C:12]([CH2:13][O:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: Clc1ccc2c(c1)OCc1cccnc1C2=C1CCNCC1
Reactant: O=C(O)Cc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3OCc3cccnc32)CC1

Procedure:
The title compound was prepared according to the method of Example 4 from 4-(8-chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-ylidene)-piperidine, 3-pyridine-acetic acid hydrochloride, HOBT, EDCl and NMM in DMF. 4-(8-Chloro-5,11-dihydro[1]benz-oxepino[4,3-b]pyridin-11-ylidene)-1-(3-pyridine-acetyl)piperidine was obtained as a white foam; MS (CI, M+H)=432; anal.: found: C, 68.85; H, 5.53; N, 9.49; C25H22ClN3O2 requires: C, 69.52; H,5.13; N,9.73.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:33]=[CH:32][C:8]([CH2:9][NH:10][C:11]([C@H:13]2[CH2:18][NH:17][CH2:16][CH2:15][N:14]2[S:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[O:12])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH3:34][O:35][C:36]([C:38]1[CH:43]=[N:42][C:41](Cl)=[CH:40][N:39]=1)=[O:37].C(N(CC)CC)C>CN(C)C=O>[CH3:34][O:35][C:36]([C:38]1[N:39]=[CH:40][C:41]([N:17]2[CH2:16][CH2:15][N:14]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C@@H:13]([C:11](=[O:12])[NH:10][CH2:9][C:8]3[CH:7]=[CH:6][C:5]([CH:2]([CH3:4])[CH3:3])=[CH:33][CH:32]=3)[CH2:18]2)=[N:42][CH:43]=1)=[O:37]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: CC(C)c1ccc(CNC(=O)[C@H]2CNCCN2S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)[C@@H](C(=O)NCc3ccc(C(C)C)cc3)C2)cn1
Temperature: 60 °C
Reaction time: 14 h
Yield: 102.7 %

Procedure:
A mixture of the compound (61 mg) obtained in Example 1, 5-chloropyrazine-2-carboxylic acid methyl ester (25 mg) and triethylamine (42 μl) in N,N-dimethylformamide (0.3 ml) was stirred at 60° C. for 14 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (5% methanol/chloroform) to give the title compound (75 mg).
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]3[C:12]([CH3:20])([CH3:19])[CH2:13][S:14][CH2:15][C:16]([CH3:18])([CH3:17])[C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:22].[Na+]>CO.O>[C:1]1([C:7]2[NH:11][C:10]3[C:12]([CH3:20])([CH3:19])[CH2:13][S:14](=[O:22])[CH2:15][C:16]([CH3:18])([CH3:17])[C:9]=3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC1(C)CSCC(C)(C)c2[nH]c(-c3ccccc3)nc21
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)CS(=O)CC(C)(C)c2[nH]c(-c3ccccc3)nc21
Temperature: 2 °C

Procedure:
1.43 g of 2-phenyl-4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino[4,5-d]imidazole are dissolved in 75 ml of methanol and cooled to 2° C. with stirring. The solution is treated dropwise at this temperature with a solution of 1.3 g of sodium periodate in 28 ml of water. The mixture is left to react-out at the same temperature for 3 hours. Thereupon, 25 ml of methanol are added. After stirring for 5 hours at room temperature, the solution is concentrated. The product is left to crystallize-out while cooling with ice. The precipitate is removed by filtration and the crystals are covered with acetone and ether. After filtration, the 2-phenyl-4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino-[4,5-d]-imidazole 6-oxide is recrystallized from ethanol/n-hexane, m.p. 273°-275° C.; m.p. of the hydrochloride: 300° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:33]=[CH:32][C:22]([CH2:23][NH:24][C:25](=[O:31])OC(C)(C)C)=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.Cl.[C:35](OCC)(=O)[CH3:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:33]=[CH:32][C:22]([CH2:23][NH:24][C:25](=[O:31])[CH2:35][CH3:36])=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1
Reactant: Cn1ncc(/C=C/C(=O)Nc2ccc(CNC(=O)OC(C)(C)C)cc2)c1-c1ccc(F)cc1
Reactant: CCOC(C)=O
Agent: Cl
Product: CCC(=O)NCc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
A mixture of tert-butyl [4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)benzyl]carbamate (2.0 g) and 4N hydrogenchloride in ethyl acetate (80 mL) was stirred at 70° C. for 15 hrs. The precipitated crystals were collected by filtration, and washed with ethyl acetate. Triethylamine (0.39 g) was added to a solution (10 mL) of the obtained crystals (1.00 g) in N,N-dimethylacetamide at room temperature. The reaction mixture was stirred at room temperature for 30 min. and propionyl chloride (0.27 g) was added. The reaction mixture was further stirred at room temperature for 2.5 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-{4-[(propionylamino)methyl]phenyl}acrylamide as colorless crystals (0.51 g). Recrystallization thereof from acetone-hexane gave colorless prism crystals. melting point: 271-272° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]([C@@H:15]([NH:19]C(OC(C)(C)C)=O)[CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1>CO>[Cl:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]([C@@H:15]([NH2:19])[CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Solvent: CO
Product: CC(C)[C@H](N)C(=O)N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
1 N ethereal hydrogen chloride solution (80 ml, 80 mmol) was added to a solution of 1(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylcarbonyl]-N-(tert-butoxycarbonyl)-2-methylpropylamine (4.28 g, 9.64 mmol) in methanol (50 ml) and the reaction mixture was heated at 70° C. After 2.5 h, the reaction mixture was concentrated and the solid was suspended in ether and filtered to give 1-(S)-[4-(3,4-dichlorobenzyl)piperazin-1-yl carbonyl]-2-methylpropylamine as the bis hydrochloride salt. The product was dissolved in water, treated with triethylamine (4.0 ml, 28.9 mmol) and the free amine was extracted into ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated to give 1-(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylcarbonyl]-2-methyl-propylamine (3.2 g) as the free amine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[C:25](O)([CH3:28])([CH3:27])[CH3:26].[Li]CCCC>C(Cl)Cl.CN(C=O)C.C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:17])[CH:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1cccc(-c2ccc([N+](=O)[O-])cc2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cccc(-c2ccc([N+](=O)[O-])cc2)c1
Yield: 57 %

Procedure:
To a solution of 15 (1.215 g, 5 mmol) in 30 mL of methylene chloride was added oxalyl chloride (0.65 mL, 7.45 mmol) and one drop of DMF. The mixture was stirred until no further bubbling was observed. The clear solution was exaporated to dryness to give the crude acid chloride. To another flask containing 7.0 mL of tert-butanol was added n-BuLi (1.8 M in hexane, 2.8 mL, 5.04 mmol) under a water bath. The turbid solution was stirred for 5 min at room temperature and then the above acid chloride in 20 mL of THF was added through a dropping funnel. The mixture was stirred overnight before the solvents were evaporated. The residue was dissolved into methylene chloride and washed with 0.5 N NaOH. The organic layer was dried over MgSO4 and evaporated. The residue was recrystallized from methanol to give pale yellow crystals (851 mg, 57%). m.p. 110.5-111.0° C. 1H NMR (CDCl3) δ 8.32 (d, 7.8 Hz, 2H), 8.24 (s, 1H), 8.06 (d, 7.7 Hz, 1H), 7.77 (m, 3H), 7.56 (t, 7.7 Hz, 1H), 1.63 (s, 9H). 13C NMR (CDCl3) δ 165.1, 147.1, 146.5, 138.7, 132.8, 131.0, 129.6, 129.0, 128.2, 127.8, 124.0, 81.4, 28.0, LRMS (EI) for C17H17O4N 299 (M+, 20), 243 (70), 266 (30), 152 (25; HRMS (EI) calcd 299.1157, obsd 299.1192. Anal. (C17H17NO4) C, H, N.