Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][S:7][CH2:6][C@@H:5]([C:15]([OH:17])=[O:16])[NH:4][C:3]1=[O:18].[CH2:19](O)[CH3:20]>>[CH2:1]=[C:2]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][S:7][CH2:6][C@@H:5]([C:15]([O:17][CH2:19][CH3:20])=[O:16])[NH:4][C:3]1=[O:18]
Reactant: C=C1CCCCCCCSC[C@@H](C(=O)O)NC1=O
Reactant: CCO
Product: C=C1CCCCCCCSC[C@@H](C(=O)OCC)NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3R)-6-Methylidene-5-oxo-1-thia-4-azacyclotridecane-3-carboxylic acid (0.16 g), 0.62 mmol) is dissolved in ethanol (5 ml) and hydrogen chloride gas is bubbled through the solution for 5 minutes. The solution is stirred overnight at room temperature and the solvent is evaporated to give ethyl (3R)-6-methylidene-5-oxo-1-thia-4-azacyclotridecane-3-carboxylate, m.p. 146°-147° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([O:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:5]=[CH:4][CH:3]=1.[CH:17]([C:19]1[CH:29]=[CH:28][C:22]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])=[CH:21][CH:20]=1)=O.O.[OH-].[K+]>C(O)C.[C].[Pd]>[C:25]([CH2:24][CH2:23][C:22]1[CH:21]=[CH:20][CH:19]([CH:17]=[CH:9][C:8]([C:7]2[C:2]([OH:1])=[CH:3][CH:4]=[CH:5][C:6]=2[O:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[CH2:29][CH:28]=1)([OH:27])=[O:26]
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: COC(=O)COc1cccc(O)c1C(C)=O
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCC1=CCC(C=CC(=O)c2c(O)cccc2OCC(=O)O)C=C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a suspension of 6′-hydroxy-2′-(methoxycarbonylmethoxy)acetophenone (1 g) and 4-formylcinnamic acid (0.79 g) in ethanol (10 mL) were added water (2 mL) and potassium hydroxide (3 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 10% palladium-carbon powder (0.2 g), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration. The solvent of the filtrate was removed under reduced pressure. To the residue was added 2 mol/L hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give 4-(2-carboxyethyl)-2′-(carboxymethoxy)-6′-hydroxydihydrochalcone (1.55 g). This material was dissolved in acetic acid (12 mL). To the solution were added sodium acetate (8.6 g) and acetic anhydride (8.6 mL), and the mixture was stirred at 115° C. overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water twice. To the extract was added 1 mol/L aqueous sodium hydroxide solution, and the aqueous layer was separated. The aqueous layer was acidified by addition of 2 mol/L hydrochloric acid, and the resulting mixture was extracted with diethylether. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give the title compound (0.29 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].[CH:17]([C:19]1[CH:24]=[CH:23][C:22](OB(O)O)=[CH:21][CH:20]=1)=[O:18]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:23]=[CH:24][C:19]([CH:17]=[O:18])=[CH:20][CH:21]=2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: O=Cc1ccc(OB(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2cc(F)c(F)c(F)c2)cc1
Temperature: 60 °C
Yield: 96.9 %

Procedure:
In a nitrogen atmosphere, a solution prepared by mixing 15.00 g of 3,4,5-trifluorobromobenzene, 0.25 g of tetrakis-triphenylphosphine palladium, 30 mL of an aqueous potassium carbonate solution (2 mol/L), and 75 mL of THF was heated to 60° C., and 10.71 g of 4-formylphenylboric acid was added to the solution over 20 minutes. After the resultant mixture was stirred at 60° C. for 3 hours, the mixture was allowed to cool, and an organic layer was separated by adding hexane. The organic layer was washed with saturated brine and dried by adding sodium sulfate, and then the solvent was distilled off under reduced pressure. As a result of purification by silica gel column chromatography, 14.77 g of 4-(3,4,5-trifluorophenyl)benzaldehyde was yielded.
Reaction SMILES: CS[C:3]1[N:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=1.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>ClCCl>[C:11]([O:10][C:8]([N:7]1[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=[C:3]1[NH:25][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([F:19])=[CH:21][CH:22]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CSC1=N[C@@H]2CCCC[C@@H]2N1C(=O)OC(C)(C)C
Reactant: NCc1ccc(F)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(NCc2ccc(F)cc2)=N[C@@H]2CCCC[C@@H]21
Temperature: 100 °C
Yield: 98.1 %

Procedure:
A mixture of intermediate 76 (200 mg, 0.0.740 mmol), 4-fluorobenzylamine (0.5 mL, 4.4 mmol) is heated at 100° C. (reaction block) overnight. The reaction mixture is cooled to RT. The reaction mixture is diluted with dichloromethane, washed with 0.1N HCl, and brine. The solvent is evaporated, and the residue triturated with EtOAc, and the insoluble material filtered to give 252 mg of the product 193. 1H NMR (CDCl3) δ 8.55 (s, 1 H), 7.55-7.35 (m, 2 H), 7.10-7.00 (m, 2 H), 5.10-4.90 (m, 2 H), 4.30-4.10 (m, 2 H), 2.70-2.55 (m, 1 H), 2.20-2.05 (m, 1 H), 1.80-1.05 (m, 15 H); MS: m/z 348 (M++1)
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:8][CH:7]=[CH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>C(Cl)Cl>[O:19]([C:17]([NH:2][N:3]1[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8]1)=[O:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NN1CC=CCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NN1CC=CCC1)Oc1ccccc1
Temperature: 5 °C
Reaction time: 4 h
Yield: 92.1 %

Procedure:
To a solution of N-amino-1,2,3,6-tetrahydropyridine hydrochloride (1.346 g) and triethylami-ne (2.024 g) in methylene chloride (60 ml) was added a solution of phenyl chloroformate (1.566 g) in methylene chloride (40 ml) and the mixture was stirred for 4 hours at 5° C. Evaporation of the solvent gave a residue, which was extracted with ethyl acetate (150 ml). The extract was washed with water and dried over magnesium sulfate. The solvent was evaporated in vacuo to give N-(phenoxy- carbonylamino)-1,2,3,6-tetrahydropyridine (2.01 g), which was recrystallized from diisopropyl ether to give the desired compound (0.732 g) as colorless needles. mp: 124°-125.5° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[N:4]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:3]=1.C([Mg]Cl)(C)C.[C:27]([O:31][C:32](=[O:52])[N:33]([C:43]1[CH:44]=[N:45][C:46]([O:49][CH2:50][CH3:51])=[CH:47][CH:48]=1)[C:34]1[CH:39]=[CH:38][C:37]([CH:40]=[O:41])=[C:36]([F:42])[N:35]=1)([CH3:30])([CH3:29])[CH3:28].O>O1CCCC1>[C:27]([O:31][C:32](=[O:52])[N:33]([C:43]1[CH:44]=[N:45][C:46]([O:49][CH2:50][CH3:51])=[CH:47][CH:48]=1)[C:34]1[CH:39]=[CH:38][C:37]([CH:40]([OH:41])[C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([CH3:11])[CH:9]=3)[N:4]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:3]=2)=[C:36]([F:42])[N:35]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C=O)c(F)n2)cn1
Reactant: Cc1cnc2c(c1)c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncc(C)cc34)c(F)n2)cn1
Temperature: -5 °C
Yield: 83.2 %

Procedure:
To a solution of 3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (8, 0.43 g, 1.0 mmol) in 5 mL of tetrahydrofuran at −40° C. under nitrogen, isopropylmagnesium chloride (0.51 mL, 2.00 M in tetrahydrofuran, 1.0 mmol) is added slowly. The reaction is allowed to warm to −5° C. over 60 minutes, then cooled to −45° C., followed by addition of (6-ethoxy-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (69, 0.06 g, 0.2 mmol) in 2.0 mL of tetrahydrofuran. The reaction is allowed to warm to room temperature over 2 hours, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (70, 108.1 mg).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])[CH:10]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(Cl)ccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(Cl)ccn1
Reaction time: 18 h
Yield: 67 %

Procedure:
Triethylamine (6.8 mL, 48.6 mmol) was added to a stirred solution of 4-chloro-2-aminopyridine, 11, (Townsend, L. B. et al Synthetic Commun. 1997 27, 861-870) (5 g, 38.9 mmol) in dichloromethane (75 mL). After cooling to 0° C. a solution of trimethylacetyl chloride (5.3 mL, 42.8 mmol) in dichloromethane (10 mL) was added dropwise over 15 min. The mixture was allowed to warm to 23° and stirred for 18 h then washed with saturated sodium bicarbonate. The organic layer was dried (Na2SO4) and evaporated in vacuo to give an off-white solid. This was recrystallised from isopropyl ether to afford the title compound as white crystals (5.5 g, 67%). MS(EI) m/e 213, 215 [M+H]+.
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][O:10][CH:11]([O:15][CH3:16])[CH2:12][C:13]#[N:14].C[O-].[Na+]>CO>[CH3:9][O:10][CH:11]([O:15][CH3:16])[C:12](=[CH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:13]#[N:14]
Reactant: COC(CC#N)OC
Reactant: O=CC1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(OC)C(C#N)=CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclohexanecarboxaldehyde (50.0 g, 0.45 mol) was added to a stirred mixture of 3,3-dimethoxypropionitrile (11.5, g, 1.0 mol) and sodium methoxide (54.0 g, 1.0 mol) in methanol over a period of 15 minutes. The mixture was then stirred overnight at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([OH:15])=[O:14])[CH:7]=[CH:6]2.[Si](C=[N+]=[N-])(C)(C)[CH3:17]>C1C=CC=CC=1.CO>[CH3:17][O:14][C:13]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)=[O:15]
Reactant: COc1ccc2cc(C(=O)O)ccc2c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc2cc(OC)ccc2c1
Reaction time: 1 h
Yield: 81 %

Procedure:
To a stirred solution of 6-methoxy-2-naphthoic acid (10.0 g, 49.5 mmol) in benzene:MeOH (4:1, 200 mL) at 0° C. was added TMS diazomethane (29.7 mL, 2.0 M in hexnae, 59.4 mmol) dropwise. After initial addition of reagent, TLC showed reaction was not quite complete, so another 4 mL of TMS diazomethane added. The reaction was then stirred for 1 h before total completion. After concentration, the residue was recrystallized from MeOH:H2O to afford the product (8.67 g, 81%) as a solid; 1H NMR (DMSO-d6) δ3.85 (s, 3H), 3.87 (s, 3H), 7.22 (dd, J=2.6, 9.0 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.85-7.92 (m, 2H), 8.00 (d, J=9.0 Hz, 1H), 8.51 (s, 1H); mass spectrum [(+) ESI], m/z 217 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[C:11]([N+:19]([O-])=O)[CH:10]=2)=[CH:5][CH:4]=1>C(O)(=O)C.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:12]([CH2:15][C:16](=[O:17])[NH:19]3)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(CC(=O)O)c([N+](=O)[O-])c2)cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Temperature: 100 °C
Yield: 45 %

Procedure:
Iron chips (3.6 g) were added in one portion to 7.2 g 4′-methoxy-3-nitrobiphenyl-4-acetic acid in 50 mL glacial acetic acid and heated at 100° C. overnight. The reaction mixture was concentrated to dryness, sonicated in ethyl acetate and filtered to remove the insolubles. The filtrate was washed twice with 1 N hydrochloric acid, then with brine, dried over anhydrous sodium sulfate and concentrated to give 2.7 g (54% yield based on 5-bromo-2-fluoronitrobenzene) of 6-(4-methoxyphenyl)-2-oxindole as a rose colored solid.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])=[C:8]1[CH:34]([CH3:36])[CH3:35])C.Cl>CC(C)=O>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]2[N:7]([CH2:6][CH2:5][CH:4]=[O:3])[C:8]([CH:34]([CH3:36])[CH3:35])=[C:9]([C:25]([NH:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[C:10]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][CH:16]=1
Reactant: CCOC(CCn1c(-c2ccc(F)cc2)c(-c2ccccc2)c(C(=O)Nc2ccccc2)c1C(C)C)OCC
Agent: Cl
Solvent: CC(C)=O
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCC=O
Yield: 94.3 %

Procedure:
To a nitrogen purged flask fitted with an overhead stirrer, a thermometer, and a condenser is added 20 kg (37.8 mol) of 1-(3,3-diethoxypropyl)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl- 1 H-pyrrole-3-carboxamide along with 200 L of acetone. The solution is stirred and 100 L of 2N hydrochloric acid solution is added. The mixture is heated to reflux for four hours then cooled to 50° C.±5° C., seeded, and cooled to 0° C.±5° C. The produce is collected by filtration, washed with 100 L 2-propanol-water (1:1) and dried in vacuo at 50° C. for 64 hours to yield 16.2 kg of 5-(4-fluorophenyl)-2-(1-methylethyl)-1-(3-oxopropyl)-N,4-diphenyl-1 H-pyrrole-3-carboxamide as an off-white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH:20]1[C:24]([C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])=[N:23][N:22]=[N:21]1>>[F:19][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)=[N:7][C:2]([NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[C:25]([C:24]3[NH:23][N:22]=[N:21][N:20]=3)[CH:26]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Fc1cnc(Nc2cccc(-c3nnn[nH]3)c2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 2-chloro-5-fluoro-N4-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine with 3-(tetrazol-5-yl)aniline gave 5-fluoro-N4-(3,4-ethylenedioxyphenyl)-N2-[3-(tetrazol-5-yl)phenyl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.91 (s, 1H), 9.74 (s, 1H), 8.29 (s, 1H), 8.18 (d, 1H, J=4.5 Hz), 7.76 (bdd, 1H, J=1.5 and 8.1 Hz), 7.64 (d, 1H, J=8.1 Hz), 7.46 (t, 1H, J=8.1 Hz), 7.29 (m, 1H), 7.13 (dd, 1H, J=2.4 and 8.7 Hz), 6.64 (d, 1H, J=8.7 Hz), 4.11 (m, 4H); LCMS: purity: 91%; MS (m/e): 407 (MH+).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[NH:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[CH:39]=[CH:38][C:24]3[N:25]([CH:28]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:29](O)=[O:30])[CH:26]=[N:27][C:23]=3[CH:22]=2)=[N:13][N:12]=[N:11]1.C(N(CC)C(C)C)(C)C.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[O:30]=[C:29]([N:5]1[CH2:6][CH:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8])[CH:28]([N:25]1[C:24]2[CH:38]=[CH:39][C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]3[N:10]=[N:11][NH:12][N:13]=3)=[CH:22][C:23]=2[N:27]=[CH:26]1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: O=C(O)[C@@H]1CC(O)CN1
Reactant: CCCCCCC(C(=O)O)n1cnc2cc(-c3ccccc3-c3nnn[nH]3)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCCC(C(=O)N1CC(O)C[C@H]1C(=O)O)n1cnc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52.2 %

Procedure:
4-Hydroxy-L-proline lacetone hydrobromide (0.74 mmoles, 143 mg) and 2-[5-(2-tetrazol-5-ylphenyl)benzimidazol-1-yl]octanoic acid (0.74 mmoles, 300 mg) were dissolved in 30 ml DMF and cooled to 0° C. N,N-Diisopropylethylamine (0.74 moles, 0.15 ml) was added. The solution was stirred for 10 minutes. Hydroxybenzotriazole (0.74 mmoles, 100 mg) and then dicyciohexylcarbodiimide (0.74 mmoles, 153 mg) were added. The solution was stirred at room temperature for 3 days. The intermediate was extracted in ethyl acetate. The ethyl acetate solution was washed with water, dried over sodium sulfate, concentrated. The residue was chromatographed over silica gel eluted with 10% methanol in ethyl acetate. The reaction yielded 200 mg of 1-[1-oxo-2-[5-[2-(2H-tetrazol-5-yl)phenyl]-1H-benzimidazol-1-yl]octyl]-4-hydroxy-L-proline lacetone. (MS). The lactone was dissolved in 2.0 ml methanol/2.0 ml 2N NaOH and stirred at room temperature for 16 hours The solvent was removed in vacuo. Water was added. The solution was extracted with ether. The pH of the aqueous layer was adjusted to 3.2 using 2N HCl. The precipitate was filtered, washed with water, and dried to yield 37 mg. The aqueous phase was extracted with ethyl acetate, dried and concentrated to yield an additional 60 mg of 1-[1-oxo-2-[5-[2-(2H-tetrazol-5-yl)phenyl]-1H-benzimidazole-1-yl]octyl]-4-hydroxy-L -prolite. (MS)
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([C:29]([O:31][CH3:32])=[O:30])[C@H:8]1[C:17]2[C:12](=[C:13]([Br:22])[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[N:11]([C:23](Cl)=[O:24])[C@@H:10]([CH:26]2[CH2:28][CH2:27]2)[CH2:9]1.[CH:42]([OH:45])([CH3:44])[CH3:43]>>[CH:42]([O:45][C:23]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:13]=2[Br:22])[C@H:8]([N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:40])([F:41])[F:1])[CH:35]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:33]=2)[C:29]([O:31][CH3:32])=[O:30])[CH2:9][C@@H:10]1[CH:26]1[CH2:28][CH2:27]1)=[O:24])([CH3:44])[CH3:43]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)N(C(=O)Cl)c2c(Br)cc(C(F)(F)F)cc21
Reactant: CC(C)O
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)N(C(=O)OC(C)C)c2c(Br)cc(C(F)(F)F)cc21

Procedure:
A solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-8-bromo-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic carbonyl chloride (Example 100D) (1.5 g) in isopropanol was heated to reflux for 48 h. The reaction was cooled and concentrated, and the residue was chromatographed (5-10% EtOAc/hexane) to afford the title product (1.0 g). MS m/z 705.4 (M+); 1H NMR (CDCl3) δ 3.8 (s, 3H), 7.1 (s, 1H), 7.8 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1([C:23]#[C:24][Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[OH:16][C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]1)([CH3:15])[C:24]#[C:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Br[Mg]C#Cc1ccccc1
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(C)(O)C#Cc2ccccc2)CC1
Temperature: -10 °C
Reaction time: 8 h

Procedure:
Into a solution of 4-acetylpiperidine-1-carboxylic acid tert-butyl ester (0.67 g, 2.95 mmol), prepared as described in WO2004041777, in THF (20 mL) cooled at −10° C. was dropped a 1M solution of phenylethynylmagnesium bromide in THF (4.5 mL, 4.5 mmol). The reaction mixture was stirred at room temperature overnight. Afterwards, it was quenched with a saturated aq. solution of ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether-EtOAc 7:3, affording the title product as a pale yellow oil.
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(N(CC)CC)C.[S:15](F)(F)(=[O:17])=[O:16].[OH-].[K+:21]>C(#N)C>[CH3:5][C:3]1[O:4][S:15](=[O:17])(=[O:16])[N:7]=[C:1]([O-:6])[CH:2]=1.[K+:21]
Reactant: O=S(=O)(F)F
Reactant: CC(=O)CC(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1=CC([O-])=NS(=O)(=O)O1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
10.1 g (0.1 mol) of acetoacetamide, 50.5 g (0.5 mol) of triethylamine and 100 ml of acetonitrile were introduced into a round-bottomed flask fitted with a stirrer and a solid carbon dioxide condenser, as in Example 1. 15.3 g (0.15 mol) of sulfuryl fluoride gas were passed in over a period of 20 minutes. The reaction mixture was then allowed to warm up to room temperature, with stirring. After stirring for 2 hours, 230 ml (0.46 mol) of 2N methanolic KOH were added dropwise and the product was filtered off with suction. 9.7 g (48% of theory) of Acesulfam K were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[N:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:16]1[N:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ncc(Cl)cn1
Yield: 48.6 %

Procedure:
(S)-2-Aminomethyl pyrrolidine-1-carboxylic acid tert-butyl ester (3.38 g), 2,5-dichloropyrimidine (2.50 g), potassium carbonate (4.67 g) and diisopropylethylamine (8.79 ml) were heated in xylene (60 ml) at 100° C. for 3.75 h. The cooled reaction mixture was filtered and the filtrate evaporated to a gum which was chromatographed on silica gel, eluting with ethyl acetate-pentane fractions, to afford the title compound as a pale yellow solid (2.55 g). Mass Spectrum (API+): Found 213 (MH+−tBoc). C14H2135ClN4O2 requires 312.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:21])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[C:13]([Cl:20])[CH:12]=3)[CH:6]=[N:7][CH:8]=1.[F:22][C:23]([F:30])([F:29])[CH2:24][S:25](Cl)(=[O:27])=[O:26]>>[Cl:20][C:13]1[CH:12]=[C:11]2[C:16]([C:17]([C:18]#[N:19])=[C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][S:25]([CH2:24][C:23]([F:30])([F:29])[F:22])(=[O:27])=[O:26])[CH:8]=[N:7][CH:6]=3)[N:10]2[CH3:21])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccc(Cl)cc21
Product: Cn1c(-c2cncc(CNS(=O)(=O)CC(F)(F)F)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
2-(5-Aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (Example 186e) and 2,2,2-trifluoro-ethanesulfonyl chloride are processed according to the method described in Example 186f to give 2,2,2-trifluoro-ethanesulfonic acid [5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]amide. 1H NMR (400 MHz, MeOD) δ ppm 3.84 (s, 3H), 4.29 (q, J=9.6 Hz, 2H), 4.54 (s, 2H), 7.39 (dd, J=8.6, 1.8 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.78 (d, J=1.8 Hz, 1H), 8.18 (t, J=2.0 Hz, 1H), 8.81 (d, J=2.0 Hz, 1H), 8.83 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 443.0557 [(M+H)+ Calcd for C18H15N4O2F3SCl: 443.0556].