Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3](CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:54]=[CH:55][C:56]=1[N+:57]([O-:59])=[O:58])[C:40]([C:42]1[N:46]2[CH:47]=[C:48]([C:51](O)=[O:52])[CH:49]=[CH:50][C:45]2=[CH:44][N:43]=1)=[O:41].N>CN(C)C=O.O1CCCC1>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:54]=[CH:55][C:56]=1[N+:57]([O-:59])=[O:58])[C:40]([C:42]1[N:46]2[CH:47]=[C:48]([C:51]([NH2:3])=[O:52])[CH:49]=[CH:50][C:45]2=[CH:44][N:43]=1)=[O:41]
Reactant: CCN(CC)CC
Reactant: COc1cc(C(=O)c2ncc3ccc(C(=O)O)cn23)ccc1[N+](=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)c2ncc3ccc(C(N)=O)cn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.16 ml (1.12 mmol) of triethylamine and then 0.49 g (1.12 mmol) of BOP are added to 0.346 g (1.01 mmol) of 3-(3-methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridine-6-carboxylic acid obtained in example 182 in 10 ml of N,N-dimethylformamide. The reaction medium is stirred at ambient temperature for 30 minutes, then 1.35 ml of a 1N solution of ammonia in tetrahydrofuran are added and the mixture is stirred at ambient temperature for 18 hours. The precipitate formed is filtered off and then washed with water. 0.25 g of a yellow solid is collected. Melting point: 289° C.; 1H NMR (d6-DMSO): 4.02 (3H, s), 7.82 (1H, d), 7.98 (1H, s), 8.06-8.10 (3H, m), 8.15 (1H, s), 10.21 (1H, s)
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:54](O)(=[O:63])[C@@H:55]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[OH:56].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH:25][C:54](=[O:63])[C@@H:55]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[OH:56])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(SC(Sc2c[nH]nn2)C(c2ccccc2)(c2ccccc2)c2ccccc2)CS[C@@H]2[C@H](NC(=O)[C@H](O)c3ccccc3)C(=O)N12
Reaction time: 1 h
Yield: 49.5 %

Procedure:
To a solution of 7β-amino-3-(trityl-1,2,3-triazol-4-ylthiomethylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester (800 mg : 1.06 mMol.) and D-(-)-mandelic acid (242 mg 1.59 mMol.) in dichloromethane (4 ml) is added dicyclohexylcarbodiimide (328 mg : 1.59 mMol.}, and the mixture is stirred under ice cooling for 1 hour. The reaction mixture is concentrated, diluted with ethyl acetate, and filtered to remove solid. The filtrate is washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by Lobar column chromatography (toluene : ethyl acetate=2:1) to give 7β-D-mandelamido-3-(trityl-1,2,3-triazol-4-ylthiomethylthio) -3-cephem- 4-carboxylic acid diphenylmethyl ester (466 mg) as yellow foam. Yield : 50%.
Reaction SMILES: [C:1]([C:3]([C:20]#[N:21])=[C:4](OC)[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)#[N:2].O.[NH2:23][NH2:24].O>C(O)C>[NH2:2][C:1]1[C:3]([C:20]#[N:21])=[C:4]([C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:6]=2)[NH:24][N:23]=1
Reactant: NN
Reactant: COC(=C(C#N)C#N)c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Solvent: O
Product: N#Cc1c(N)n[nH]c1-c1ccc(Oc2ccccc2)cc1

Procedure:
1,1-Dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (22.5 g) and 1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene oil (15 g) are treated with a solution of hydrazine hydrate (18 mL) in ethanol (25 mL) and heated on the steambath for 1 hour. Ethanol (15 mL) is added followed by water (10 mL). The precipitated solid is collected and washed with ethanol:water (4:1) and then dried in air to give 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole as a pale orange solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([N:36]([CH3:37])[CH3:38])=[CH:34][CH:35]=2)[CH2:26][CH3:27])=[O:25])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCNCc1ccc(N(C)C)cc1
Product: CCN(Cc1ccc(N(C)C)cc1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with (4-ethylaminomethyl-phenyl)-dimethyl-amine
Reaction SMILES: Cl.[F:2][C:3]([C:6]1[CH:20]=[CH:19][CH:18]=[CH:17][C:7]=1[O:8][C:9]1[C:14]([C:15]#N)=[N:13][CH:12]=[CH:11][N:10]=1)([F:5])[F:4].[OH2:21].[CH3:22][OH:23]>>[F:2][C:3]([C:6]1[CH:20]=[CH:19][CH:18]=[CH:17][C:7]=1[O:8][C:9]1[C:14]([C:15]([O:23][CH3:22])=[O:21])=[N:13][CH:12]=[CH:11][N:10]=1)([F:5])[F:4]
Reactant: O
Reactant: CO
Reactant: N#Cc1nccnc1Oc1ccccc1C(F)(F)F
Agent: Cl
Product: COC(=O)c1nccnc1Oc1ccccc1C(F)(F)F
Temperature: 25 °C

Procedure:
A stream of dry hydrogen chloride is passed into a solution of 5.3 g (20 mmol) of 2-(trifluoromethylphenoxy)-3-cyanopyrazine in 320 ml of dry methanol at 0° C. until saturation is reached. The reaction mixture is cooled to room temperature and, after 2 hours, 320 ml of distilled water are added. The solution is extracted with diethyl ether and the organic phase is washed with distilled water, dried over magnesium sulfate, filtered and freed from the solvent under reduced pressure. The crude product is purified by chromatography (silica gel, cyclohexane/ethyl acetate 10/1 (v/v)). 2.2 g (37%) of colorless, crystalline solid of melting point 83-85° C. are obtained.
Reaction SMILES: O=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[CH3:13][NH:14][CH:15]1[CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH:15]1([N:14]([CH3:13])[CH:2]2[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)[CH2:18][CH2:17][CH2:16]1
Reactant: CNC1CCC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C1CCC1)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 20 °C
Reaction time: 3 h
Yield: 48.7 %

Procedure:
Combined a solution of tert-butyl 3-oxoazetidine-1-carboxylate (500 mg, 2.92 mmol) and N-methylcyclobutanamine (0.373 mL, 3.50 mmol) in methylene chloride (15 mL) and added sodium triacetoxyborohydride (929 mg, 4.38 mmol) and the solution stirred at 20° C. for 3 h. The solution was concentrated in vacuo to give a white solid. The solid was taken up in ethyl acetate (50 mL), washed with saturated sodium bicarbonate (50 mL) and brine, dried with magnesium sulfate, and concentrated in vacuo to give a residue which was purified on a 40 g silica gel column eluted with 0 to 70% ethyl acetate in hexanes to give the title compound (342 mg, 1.423 mmol, 48.7%) as a clear, colorless oil. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.43 (s, 9H) 1.60-1.75 (m, 2H) 1.85-2.04 (m, 4H) 2.07 (s, 3H) 2.81-2.94 (m, 1H) 3.27-3.30 (m, 1H) 3.81-3.88 (m, 2H) 3.88-3.97 (m, 2H); MS: 241 (M+H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[N:8]([CH2:16][O:17][CH3:18])[C:7]=2[CH:19]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]2[C:31](=[O:32])[C:30]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]3[C:28]2=[O:37])[CH:21]=1>CN(C)C=O>[Cl-:1].[CH3:18][O:17][CH2:16][N:8]1[C:7]2[CH:19]=[C:3]([CH2:2][N+:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]4[C:31](=[O:32])[C:30]5=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]5[C:28]4=[O:37])[CH:21]=3)[CH:4]=[CH:5][C:6]=2[S:11][C:10]2[N:12]=[CH:13][CH:14]=[N:15][C:9]1=2
Reactant: COCN1c2cc(CCl)ccc2Sc2nccnc21
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccnc1
Solvent: CN(C)C=O
Product: COCN1c2cc(C[n+]3cccc(CN4C(=O)c5ccccc5C4=O)c3)ccc2Sc2nccnc21
Product: [Cl-]
Yield: 46 %

Procedure:
0.587 g of 8-chloromethyl-10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine and a solution of 0.524 g of N-(3-pyridylmethyl)phthalimide in 10 ml of dimethylforamide were heated to 80° C. in a nitrogen atmosphere for 4 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 0.489 g of the title compound as yellow crystals.
Reaction SMILES: [N:1]([C@:4]12[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[CH:12][CH2:11]3)[CH2:8][CH2:7]1)=[C:2]=[O:3].C(N(CC)C(C)C)(C)C.[CH3:52][N:53]([CH3:57])[CH2:54][CH2:55][NH2:56].Cl>C1COCC1.CCOC(C)=O>[CH3:52][N:53]([CH3:57])[CH2:54][CH2:55][NH:56][C:2](=[O:3])[NH:1][C@:4]12[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[CH:12][CH2:11]3)[CH2:8][CH2:7]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N=C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CN(C)CCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)NCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.4 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (610.0 mg, 1.071 mmol) in THF (10 mL) was added N,N-diisopropylethylamine (0.559 mL, 3.21 mmol) and N,N-dimethylethylenediamine (0.353 mL, 3.21 mmol). The reaction mixture was stirred at 25° C. After 18 h, the reaction mixture was diluted with EtOAc (50 mL) and treated with 1N HCl (5 mL). The mixture was concentrated to a paste and then triturated with EtOAc, filtered and washed with Et2O. The white solid was saved and the liquid filtrate was concentrated and the trituration and filtration steps were repeated twice more. The combined white solid product was dried in a vacuum oven to give the title compound (650.0 mg, 0.958 mmol, 90% yield). LCMS: m/e 658.4 (M+H)+, 4.25 min (method 8). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.9 (2H, d, J=8.5 Hz), 7.2 (2H, d, J=8.2 Hz), 5.3 (1H, dd, J=6.3, 1.7 Hz), 4.8 (1H, s), 4.6 (1H, s), 3.9 (3H, s), 3.7-3.8 (1H, m), 3.5-3.6 (1H, m), 3.2 (2H, br. s.), 2.9 (6H, br. s.), 2.7-2.7 (1H, m), 2.6 (1H, d, J=13.4 Hz), 2.4 (1H, dd, J=11.6, 8.2 Hz), 2.1 (1H, dd, J=17.2, 6.3 Hz), 2.0-2.1 (1H, m), 1.8-1.9 (1H, m), 1.8 (1H, d, J=12.8 Hz), 1.7 (3H, s), 1.7 (1H, d, J=6.7 Hz), 1.6-1.7 (1H, m), 1.5-1.6 (2H, m), 1.5 (4H, d, J=2.7 Hz), 1.3-1.4 (5H, m), 1.2-1.3 (1H, m), 1.1 (3H, s), 1.0-1.1 (2H, m), 1.0 (3H, s), 1.0-1.0 (3H, m), 0.9 (6H, s). 13C NMR (CHLOROFORM-d) δ ppm 14.2, 15.8, 16.3, 18.4, 19.2, 19.5, 20.7, 21.1, 25.0, 27.1, 29.1, 29.5, 29.6, 33.3, 35.3, 35.4, 36.0, 37.2, 37.3, 40.3, 41.4, 41.7, 43.4, 46.7, 49.3, 51.7, 52.6, 53.4, 58.9, 63.9, 77.3, 109.8, 123.9, 127.6, 128.2, 129.8, 145.9, 148.5, 149.4, 157.5, 167.0.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=O.[NH2:14][C@H:15]([C:23]([NH:25][C@H:26](C=O)[CH2:27][C:28](=[N:34][NH:35][C:36]([NH2:38])=[O:37])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.CC[O:54]CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:14][C@H:15]([C:23]([NH:25][C@@H:26]([OH:54])[CH2:27][C:28](=[N:34][NH:35][C:36]([NH2:38])=[O:37])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: CCOCC
Reactant: CC(C)(C)OC(C[C@@H](C=O)NC(=O)[C@@H](N)Cc1ccccc1)=NNC(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1c(C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](O)CC(=NNC(N)=O)OC(C)(C)C)cc2ccccc21
Reaction time: 4 h
Yield: 82 %

Procedure:
1-Methylindole-2-carboxylic acid (72 mg, 0.41 mmol) and 3(S)-(phenylalaninyl]amino-4-oxobutanoic acid, t-butyl ester semicarbazone (154 mg, 0.41 mmol) were dissolved in methylene chloride (2 mL) and both DMAP (53 mg, 0.43 mmol) and EDAC (109 mg, 0.57 mmol) were added to the solution under a nitrogen atmosphere at 0° C. Stirring was continued for 1 hour at 0° C. and an additional 4 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution, successively, dried over sodium sulfate, and concentrate to give a white solid. Trituration of the solid with ether afforded the title product as a white powder (179 mg, 82%). TLC (methanol/methylene chloride: 5/95, silica gel): Rf=0.44.
Reaction SMILES: [OH-].[K+].CO.[Cl:5][C:6]1[C:7]([O:17][CH3:18])=[C:8]([C:13]([Cl:16])=[CH:14][CH:15]=1)[C:9]([NH:11][OH:12])=[O:10].[CH3:19][O:20][C:21](=[O:24])[CH2:22]Br>C(Cl)Cl>[Cl:5][C:6]1[C:7]([O:17][CH3:18])=[C:8]([C:13]([Cl:16])=[CH:14][CH:15]=1)[C:9]([NH:11][O:12][CH2:22][C:21]([O:20][CH3:19])=[O:24])=[O:10]
Reactant: COC(=O)CBr
Reactant: COc1c(Cl)ccc(Cl)c1C(=O)NO
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CONC(=O)c1c(Cl)ccc(Cl)c1OC

Procedure:
To a solution of 2.15 g. of potassium hydroxide in 50 ml. of methanol was added 7.55 g. of 3,6-dichloro-2-methoxy benzohydroxamic acid followed by stirring until dissolution was obtained. To this solution was added dropwise 3.03 ml. methylbromoacetate in 25 ml. of methanol. The reaction mixture was refluxed for 2 hours and allowed to stir overnight at ambient temperature. To the reaction mixture was added 0.36 g. of additional potassium hydroxide and the mixture heated to reflux for 4 hours, then cooled, filtered, and the filtrate concentrated in vacuo to give a crude semi-solid product. This crude product was taken up in methylene chloride and washed with water, 5% aqueous NaHCO3, brine, then dried over MgSO4, filtered and evaporated in vacuo to give a viscuous oil. The oil crystallized from an ethyl acetate-hexane mixture to the title product as a white solid, m.p. 102°-105° C.
Reaction SMILES: C(OC([N:8]1[CH2:36][CH2:35][C:11]2([N:15]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]4[CH2:26][CH2:25]4)=[C:20]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[N:19]=3)=[O:17])[CH2:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:16]([N:15]3[C:11]4([CH2:35][CH2:36][NH:8][CH2:9][CH2:10]4)[CH2:12][CH2:13][CH2:14]3)=[O:17])=[N:19][C:20]=2[CH2:27][C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCN2C(=O)c2ccc(C3CC3)c(Cc3ccc(F)cc3)n2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1)N1CCCC12CCNCC2
Yield: 92.4 %

Procedure:
A solution of tert-butyl 1-(5-cyclopropyl-6-(4-fluorobenzyl)picolinoyl)-1,8-diazaspiro[4.5]decane-8-carboxylate (Example 111, 19 mg, 38.5 μmol) and 2,2,2-trifluoroacetic acid (43.9 mg, 29.5 μL, 385 μmol) in DCM (0.4 mL) was stirred for 12 h at ambient temperature. The reaction mixture was poured onto 20 mL saturated aqueous NaHCO3 solution/ice and extracted with EtOAc (2×20 mL). The combined extracts were washed with ice-water/brine (20 mL), dried over Na2SO4 and brought to dryness to give the title compound (14 mg, 92%) as colorless oil; MS (EI): m/e=394.5 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH:22]3[CH2:26][CH2:25][C:24](=[O:27])[NH:23]3)[C@H:16]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:9]([CH3:34])[C:8](=[O:35])[CH2:7][CH2:6]2.[H-].[Na+].[CH3:38]I.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C@@H:22]3[CH2:26][CH2:25][C:24](=[O:27])[N:23]3[CH3:38])[C@H:16]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:9]([CH3:34])[C:8](=[O:35])[CH2:7][CH2:6]2
Reactant: CI
Reactant: COc1cc2c(cc1CN[C@H]1CCCN(CC3CCC(=O)N3)[C@H]1c1ccccc1)N(C)C(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cc1CN[C@H]1CCCN(C[C@@H]3CCC(=O)N3C)[C@H]1c1ccccc1)N(C)C(=O)CC2
Reaction time: 0.33 h
Yield: 12.5 %

Procedure:
To 6-Methoxy-1-methyl-7-{[1-(5-oxo-pyrrolidin-2-ylmethyl)-(2S,3S)-2-phenyl-piperidin-3-ylamino]-methyl}-3,4-dihydro-1H-quinolin-2-one (194 mg, 0.408 mmol) in 5 mL of THF at room temperature was added 18 mg (0.448 mmol) of 60% sodium hydride suspended in mineral oil and stirred for 20 minutes. Methyl iodide (0.028 mL, 0.448 mmol) was then added and stirred for 1 hour 18 mg (0.448 mmol) of 60% sodium hydride suspended in mineral oil was added and stirred overnight. A small amount of water was added and the solvent was removed under vacuum. The residue was dissolved in ethyl acetate, washed twice with water, dried over MgSO4, filtered, and concentrated. Silica gel chromatography using (95:5 ethyl acetate/methanol) as the eluent gave 25 mg (13%) of the title compound, a pale yellow oil. Rf=0.07 (9:1 ethyl acetate/methanol). MS (M+H)+=491.2; 1H NMR (400 MHz, CDCl3): δ 1.42–1.60 (m, 3H), 1.84–1.88 (dd, J=13.4 Hz, 4.8 Hz, 1H), 2.01–2.14 (m, 5H), 2.17–2.24 (m, 2H), 2.54–2.57 (t, J=7.3 Hz, 3H), 2.67–2.73 (m, 1H), 2.76–2.78 (t, J=7.3 Hz, 2H), 2.88 (s, 3H), 3.13 (s, 3H), 3.21–3.24 (d, J=10.9 Hz, 1H), 3.32–3.33 (d, J=3.0 Hz, 1H), 3.36–3.40 (d, J=14.3 Hz, 1H), 3.56 (s, 3H), 3.61–3.68 (m, 2H), 6.49 (s, 1H), 6.65 (s, 1H), 7.18–7.34 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 20.4, 23.9, 25.5, 27.5, 29.6, 31.8, 45.4, 54.2, 55.5, 56.3, 58.0, 59.9, 72.7, 109.9, 116.0, 127.1, 128.1, 129.0, 133.6, 140.9, 152.8, 170.0, 175.0. The dihydrochloride salt was prepared by the addition of 2 M HCl In ether to a solution of the product in ethyl acetate. Concentration gave a white solid.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[N:22]([C:23]([CH3:25])=[CH2:24])[C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[N:19]=1)(C1C=CC(C)=CC=1)(=O)=O.[SH:30][C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1.C(N(CC)CC)C.O>C(#N)C>[N:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[NH:35][C:31]=1[S:30][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[N:22]([C:23]([CH3:25])=[CH2:24])[C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[N:19]=1
Reactant: C=C(C)n1c(OCCCCCOS(=O)(=O)c2ccc(C)cc2)nc2ccccc21
Reactant: Sc1nc2ccccc2[nH]1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(C)n1c(OCCCCCSc2nc3ccccc3[nH]2)nc2ccccc21
Temperature: 25 °C
Yield: 71.4 %

Procedure:
0.415 g of the compound obtained in Example 14b and 0.15 g of 2-mercaptobenzimidazole were refluxed for 5 hours in 10 ml of acetonitrile solvent containing 0.15 g of triethylamine. After cooling to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 0.28 g of the title compound (yield: 71%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:20](=[O:22])(=[O:21])[CH2:19][CH2:18][C:17]([C:23]([O:25]CC)=[O:24])=[CH:16][C:15]=3[CH:28]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1.CO.O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:20](=[O:21])(=[O:22])[CH2:19][CH2:18][C:17]([C:23]([OH:25])=[O:24])=[CH:16][C:15]=3[CH:28]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OCC)CCS3(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Reaction time: 1 h
Yield: 95.9 %

Procedure:
Ethyl 7-(4-propoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxlate (495 g, 1.24 mol) was dissolved in 4.95 L of tetrahydrofuran and 2.48 L of methanol. Crystals were formed by adding a potassium carbonate (342 g, 2.47 mol) solution in 4.2 L of water and the mixture was heated under reflux for 6.5 hours. Under reflux, 1.85 L of a 3N hydrochloric acid was dropped to form crystals. After cooling, 84 ml of a 6N hydrochloric acid was added at room temperature (pH 2-3) and stirred for 1 hour while cooling in ice. After filtration, the residue was washed with 2.97 L of a mixed solution of tetrahydrofuran/methanol/water=1/1/3 . After vacuum drying (40° C.), 443 g (Yield 96%) of 7-(4-propoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid was obtained as pale yellowish white crystals.