Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:11]CN2C(=NCCC2)[CH2:3][CH2:2]1.BrCCCCBr.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]2[C:26]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:27]3[C:36]4[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([O:37][CH3:38])[CH:35]=4)[CH2:30][CH2:29][N:28]3[C:41]=2[CH3:42])[CH:22]=[CH:23][CH:24]=1>CN(C=O)C>[CH3:40][O:39][C:33]1[CH:32]=[C:31]2[C:36](=[CH:35][C:34]=1[O:37][CH3:38])[C:27]1=[C:26]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[C:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([N:18]4[CH2:3][CH2:2][CH2:1][CH2:11]4)[CH:20]=3)=[C:41]([CH3:42])[N:28]1[CH2:29][CH2:30]2
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOC(=O)c1c(-c2cccc(N)c2)c(C)n2c1-c1cc(OC)c(OC)cc1CC2
Solvent: BrCCCCBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2cccc(N3CCCC3)c2)c(C)n2c1-c1cc(OC)c(OC)cc1CC2
Temperature: 120 °C
Reaction time: 20 h

Procedure:
168.5 mg (1.11 mmol) of DBU and 79.9 mg (0.37 mmol) of 1,4-dibromobutane were added to a solution of 150 mg (0.37 mmol) of ethyl 2-(3-aminophenyl)-8,9-dimethoxy-3-methyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-1-carboxylate obtained as described above in 3 mL of DMF. The mixture was stirred at 120° C. for 20 hours, the solvent was evaporated under reduced pressure, and the residue was taken up in an ethyl acetate/water mixture. The layers were separated, the aqueous layer was extracted with ethyl acetate, and the combined organic phases were washed with water, dried over Na2SO4 and the solvent was evaporated under reduced pressure. Chromatography on a short silica gel column using a dichloromethane/ethyl acetate 10:1 mixture as eluant, followed by crystallization from diethyl ether gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([CH3:26])([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:9](N[C@H](C2C=CC=CC=2)CO)=[O:10])=[CH:4][CH:3]=1.FC1C=CC([C@@](C)(CCC(C)C)C(N[C@H](C2C=CC=CC=2)CO)=[O:36])=CC=1>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([CH3:26])([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:9]([OH:10])=[O:36])=[CH:6][CH:7]=1
Reactant: CC(C)CC[C@@](C)(C(=O)N[C@@H](CO)c1ccccc1)c1ccc(F)cc1
Reactant: CC(C)CC[C@](C)(C(=O)N[C@@H](CO)c1ccccc1)c1ccc(F)cc1
Solvent: CCO
Product: CC(C)CC[C@](C)(C(=O)O)c1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure of Example 22E, substituting the product of Example 23A, for the product of Example 22D. 1H NMR (300 MHz, CDCl3): δ 0.88 (m, 7 H) 1.06 (m, 1 H) 1.48 (m, 1 H) 1.55 (s, 3 H) 1.96 (m, 2 H) 3.76 (m, 2 H) 5.03 (m, 1 H) 5.83 (d, J=6.99 Hz, 1 H) 7.06 (m, 4 H) 7.29 (m, 5 H). Specific rotation: [α]D+12.4° (c 2.16, EtOH).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O.C1(C)C=CC=CC=1>CN(C)C=O>[C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:20])=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Yield: 91 %

Procedure:
4-Benzoylbenzoic acid (BBA), 1.0 kg (4.42 moles), was added to a dry 5 liter Morton flask equipped with reflux condenser and overhead stirrer, followed by the addition of 645 ml (8.84 moles) of thionyl chloride and 725 ml of toluene. Dimethylformamide, 3.5 ml, was then added and the mixture was heated at reflux for 4 hours. After cooling, the solvents were removed under reduced pressure and the residual thionyl chloride was removed by three evaporations using 3×500 ml of toluene. The product was recrystallized from 1:4 toluene:hexane to give 988 g (91% yield) after drying in a vacuum oven. Product melting point was 92-94° C. Nuclear magnetic resonance (NMR) analysis (1H NMR (CDCl3)) was consistent with the desired product: aromatic protons 7.20-8.25 (m, 9H). All chemical shift values are in ppm downfield from a tetramethylsilane internal standard. The final compound was stored for use in the preparation of a monomer used in the synthesis of Compound III.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])[CH:2]=[CH2:3].[OH-].[Na+].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:12]=[C:11]([NH:13][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])[CH:2]=[CH2:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C=CCOc1cc(N)ccc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CCOc1cc(NC(=O)C(C)(C)C)ccc1C#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a solution of 10B (1.9 g, 10.9 mmol) in anhydrous CH2Cl2 (16 mL) cooled at 0° C. was added 1 N aqueous NaOH solution (16.4 mL, 16.4 mmol), followed by pivaloyl chloride (1.9 mL, 15.3 mmol). After the addition, the reaction mixture was stirred at 0° C. for 2 h, then concentrated under reduced pressure to remove most of the CH2Cl2 solvent. The remaining residue was diluted with water, and the resulting precipitate collected by filtration, washed with water, hexane, and dried under vacuum to furnish the title compound as a light brown solid (2.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15]C)=[O:14])=[C:11]([O:17][CH3:18])[N:10]=[C:9]([S:19][CH3:20])[N:8]=1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:17][CH3:18])[N:10]=[C:9]([S:19][CH3:20])[N:8]=1
Reactant: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(SC)nc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CNc2nc(SC)nc(OC)c2C(=O)O)cc1Cl

Procedure:
A mixture of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-methoxy-2-methylthiopyrimidine (prepared in the above (1)) 271 mg, a 2.0M aqueous sodium hydroxide solution 3.53 ml, water 2 ml and dimethyl sulfoxide 6 ml is stirred at 65° C. for 14 hours. After cooling the reaction mixture is neutralized with a 10% aqueous citric acid solution and extracted with ethyl acetate. The ethyl acetate layer is washed, dried and concentrated in vacuo and the resulting powder is triturated with isopropyl ether to give 4-(3-chloro-4-methoxybenzylamino)-5-carboxy-6-methoxy-2-methylthiopyrimidine as a colorless crystalline powder, 210 mg. mp 167-170° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6](=[N:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C:7]([NH2:10])=[N:8][N:9]=1.C(N(CC)CC)C.S(OCCOS(C1C=CC(C)=CC=1)(=O)=O)(C1C=CC(C)=CC=1)(=O)=O.[C:51]([O:54][CH2:55][CH3:56])(=O)[CH3:52]>CN(C=O)C>[F:19][C:15]1[CH:14]=[C:13]([NH:12][N:11]=[C:6]2[C:5]([CH2:4][CH2:3][CH2:2][N:1]3[CH2:56][CH2:55][O:54][CH2:51][CH2:52]3)=[N:9][N:8]=[C:7]2[NH2:10])[CH:18]=[CH:17][CH:16]=1
Reactant: NCCCC1=NN=C(N)C1=NNc1cccc(F)c1
Reactant: CCOC(C)=O
Agent: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC1=NN=C(CCCN2CCOCC2)C1=NNc1cccc(F)c1
Temperature: 96 °C

Procedure:
A suspension of 5-(3-aminopropyl)-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine, obtained in Example 32, (400 mg, 1.53 mmole) and triethylamine (6 mmole) in 10 mL of DMF was heated to 96° C. To this solution was slowly added a solution of ethylene glycol ditosylate (3 mmole) in 10 mL DMF. The reaction was worked up by the addition of saline and ethyl acetate. The organic phase was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography and further by preparative TLC. The resulting 34 mg of oil was dissolved in a minimum amount of diethyl ether and then mixed with hexanes to yield 22 mg of the title compound as a yellow powder. MS (m/z, ES+): 333 (M+1, 100%).
Reaction SMILES: CO.[OH-].[K+].Cl.C[O:7][C:8]([CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[C:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)=[O:9]>O>[O:30]=[C:28]1[NH:27][C:26](=[O:31])/[C:25](=[CH:24]/[C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH:13]3[CH2:12][CH2:11][CH:10]([C:8]([OH:9])=[O:7])[CH2:15][CH2:14]3)=[CH:19][CH:20]=2)/[S:29]1
Reactant: COC(=O)C1CCC(COc2ccc(C=C3SC(=O)NC3=O)cc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1NC(=O)/C(=C/c2ccc(OCC3CCC(C(=O)O)CC3)cc2)S1

Procedure:
To 30 ml of methanol in which methyl-4-((4-((2,4-dioxothiazolidine-5-ylidene)methyl)phenoxy)methyl)cyclohexane carboxylate prepared in Example 66 was dissolved, 2N KOH (30 ml) was added while stirring. The mixture was stirred for 1 hour under reflux, then diluted with water and acidified by HCl. Subsequently, the precipitate thus formed was washed with water and dried to afford 4-({4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy}methyl)cyclohexane carboxylic acid (Derivative 111 having the above formula) as white solid (0.74 g, yield: 77.1%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([CH2:21][CH2:20][O:19][CH2:18][C:17]([NH2:22])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:23])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:32][C:33]1[C:38](B(O)O)=[CH:37][CH:36]=[CH:35][N:34]=1.O1CCOCC1>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1N(C)C)(C)(C)C.O>[Cl:23][C:12]1[N:11]=[CH:10][C:9]2[O:8][C:5]3[C:4]([C:15]4([CH2:21][CH2:20][O:19][CH2:18][C:17]([NH2:22])=[N:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:38]1[C:33]([F:32])=[N:34][CH:35]=[CH:36][CH:37]=1)=[CH:7][CH:6]=3
Reactant: NC1=NC2(CCOC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Reactant: OB(O)c1cccnc1F
Agent: CN(C)c1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC1=NC2(CCOC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Temperature: 90 °C

Procedure:
To a vial was added (E)-7-bromo-3-chloro-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine (80 mg, 0.203 mmol), potassium phosphate (129 mg, 0.608 mmol), 2-fluoropyridin-3-ylboronic acid (30.0 mg, 0.213 mmol), 1,1-bis[(di-t-butyl-p-dimethylaminophenyl]palladium(ii) chloride (7.18 mg, 10.14 μmol), dioxane (1014 μL), water (338 μL). The resulting mixture was purged with N2 gas and heated at 90° C. in microwave reactor for 25 mins. It was diluted with water and extracted into EtOAc. The organic extract was washed with saturated NaCl aqueous solution, dried over MgSO4, filtered and concentrated to give the crude material as a orange solid. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a gold Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 50% to 80% DCM/MeOH/NH4OH (90/10/1) in 40% EtOAc in Heptane, to provide (E)-3-chloro-7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine as off-white solid.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Br:5][CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>O.C(O)(=O)C>[OH:3][N:1]=[C:8]([C:7]([CH2:6][Br:5])=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)CBr
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)CBr
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A solution of sodium nitrite (12.4 g.) in water (150 ml.) was dropwise added with stirring at 5° to 7° C. to a solution of ethyl 4-bromoacetoacetate (30 g.) in acetic acid (200 ml.) and the mixture was stirred for 2 hours at 10° C. Water (200 ml.) was added to the reaction mixture and the resultant mixture was extracted with ether (500 ml.). The extract was washed twice with water (200 ml.) and with a sodium chloride aqueous solution (200 ml.) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give yellowish brown crystals of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (32.6 g.).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].CS(O[CH:13]1[CH2:30][CH2:29][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:15][CH2:14]1)(=O)=O>CN(C=O)C.O>[N:1]1([CH:13]2[CH2:30][CH2:29][C:16]3([CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:20][CH2:21]3)[CH2:15][CH2:14]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(OS(C)(=O)=O)CC2)CC1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(n3ccnc3)CC2)CC1
Reaction time: 0.33 h
Yield: 59 %

Procedure:
Imidazole (1.17 g, 17.3 mmol, 3.0 eq.) was added to a stirred suspension of NaH (20.16 mmol, 3.5 eq.) in DMF (10 ml) at 0° C. and the reaction mixture was allowed to stir at the same temperature for 20 min. A solution of tert-butyl 9-(methylsulfonyloxy)-3-azaspiro[5.5]undecane-3-carboxylate (2.0 g, 5.76 mmol, 1.0 eq.) in DMF (5 ml) was added to the reaction mixture at 0° C. and it was stirred at RT for 16 h. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (60 ml) and dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain the crude product which was purified by column chromatography (silica gel; 3% MeOH/MC) to yield the desired product as a colorless oil. Yield: 59% (1.10 g, 3.45 mmol).
Reaction SMILES: ClC1C=CC([N+]([O-])=O)=CN=1.N[C:12]1[N:17]=[C:16]([NH:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[NH:29][CH:30]=[CH:31][N:32]=3)=[C:24]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=3[Cl:40])[N:23]=2)[CH:15]=[CH:14][C:13]=1[N+:41]([O-:43])=[O:42]>>[Cl:40][C:34]1[CH:35]=[C:36]([Cl:39])[CH:37]=[CH:38][C:33]=1[C:24]1[N:23]=[C:22]([NH:21][CH2:20][CH2:19][NH:18][C:16]2[CH:15]=[CH:14][C:13]([N+:41]([O-:43])=[O:42])=[CH:12][N:17]=2)[CH:27]=[CH:26][C:25]=1[C:28]1[NH:32][CH:31]=[CH:30][N:29]=1
Reactant: Nc1nc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: O=[N+]([O-])c1ccc(Cl)nc1
Product: O=[N+]([O-])c1ccc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
[6-(2,4-dichlorophenyl)-5-imidazolyl(2-pyridyl)]{2-[(5-nitro(2-pyridyl)) amino]ethyl}amine was prepared from 2-chloro-5-(nitro)pyridine using the general method for {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[6-(2,4-dichlorophenyl)-5-imidazolyl(2-pyridyl)]amine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[NH2:13][C:14]1[C:15]([CH3:21])=[N:16][N:17]([CH3:20])[C:18]=1[CH3:19]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:13][C:14]2[C:15]([CH3:21])=[N:16][N:17]([CH3:20])[C:18]=2[CH3:19])(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: Cc1nn(C)c(C)c1N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Solvent: c1ccncc1
Product: Cc1nn(C)c(C)c1NS(=O)(=O)c1ccc(Br)cc1F
Yield: 59.3 %

Procedure:
Prepared from 4-bromo-2-fluorobenzenesulfonyl chloride (0.75 g, 2.7 mmol) and 4-amino-1,3,5-trimethyl-1H-pyrazole (0.35 g, 2.8 mmol) in pyridine (4.5 ml) according to the method of intermediate 1, to give the title compound as an orange solid (0.59 g, 1.6 mmol, 60%). δH (D-6 DMSO, 300K) 9.60 (1H, s), 7.90 (1H, d J 9.4 Hz), 7.56 (1H, d J 8.2 Hz), 7.51 (1H, d J 7.7 Hz), 3.56 (3H, s), 1.89 (3H, s), 1.69 (3H, s). m/z (ES+, 70V) 364.0 (MH+).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=O)[CH2:5][CH2:4]1)[CH3:2].S(Cl)([Cl:14])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([Cl:14])=[O:11])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC[C@H]1CC[C@H](C(=O)Cl)CC1

Procedure:
First, 1.0 g (6.1 nmmol) of trans-4-ethylcyclohexane carboxylic acid was mixed with 1.1 g (9.2 mmol) of thionyl chloride, 0.1 ml of pyridine, and 3 ml of toluene, and reacted at 60° C. for hours. Excess amount of thionyl chloride and toluene were distilled off at a reduced pressure to obtain a crude trans-4-ethylcyclohexylcarbonylchloride.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[C:11]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][C:9]([C:16]2[C:17](=[O:27])[N:18]([CH3:26])[C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[C:8]([F:28])[CH:7]=1.Cl.CN.[CH2:32]([N:34](CC)CC)C>O>[Cl:5][C:6]1[C:11]([S:12](=[O:14])(=[O:13])[NH:34][CH3:32])=[CH:10][C:9]([C:16]2[C:17](=[O:27])[N:18]([CH3:26])[C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[C:8]([F:28])[CH:7]=1
Reactant: CCN(CC)CC
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc(S(=O)(=O)Cl)c(Cl)cc2F)c1=O
Agent: CN
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1cc(-c2ccc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 25 ml of chloroform, 0.6 g (1.5 mmol) of 3-(4-chloro-5-chlorosulfonyl-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone and 1.8 g (26.7 mmol) of methylamine hydrochloride were added, and 6.0 g (59.4 mmol) of triethylamine was dropwise added thereto under cooling with ice, followed by stirring at room temperature for 2 hours. This reaction solution was poured into water and extracted with chloroform. After washing with water and a 10% citric acid aqueous solution, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.4 g (yield:67) of the desired product. Melting point: 150-151° C.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[F:34][C:35]([F:40])([F:39])[C@@H:36]([OH:38])[CH3:37]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:38][C@@H:36]([CH3:37])[C:35]([F:40])([F:39])[F:34])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: C[C@H](O)C(F)(F)F
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1
Product: C[C@H](Oc1ccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)NC3(C#N)CC3)[C@H](C(=O)N3CCC(F)(F)C3)C2)c(Cl)c1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 134 using (1R,2R,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 186 step 7) and (S)-1,1,1-trifluoro-propan-2-ol (CAS #: 3539-97-7). White solid (92%). MS (EI): 600.1 (M+H)+.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]#[N:13])(=O)OCC)C.[CH2:14]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)=[O:18])[CH3:15]>O1CCCC1>[CH2:14]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=[CH:11][C:12]#[N:13])[CH2:21][CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(=CC#N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 12.85 g (321.28 mmol) of sodium hydride (60% suspension in mineral oil) in 500 ml of anhydrous tetrahydrofuran at 0° C., was added 56.91 g (321.28 mmol) of diethyl-(cyanomethyl)-phosphonate over a 10-min period. The reaction mixture was stirred for 2 h at room temperature and then 44.05 g (292.07 mmol) of 4-oxo-piperidine-1-carboxylic acid ethyl ester in 230 ml of anhydrous tetrahydrofuran was added dropwise over 30 min. The resulting mixture was stirred at room temperature for 16 h.
Reaction SMILES: [F:1][C:2]([F:30])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([CH2:23][CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].C[Sn]([N:35]=[N+:36]=[N-:37])(C)C.C1COCC1.Cl>C1(C)C=CC=CC=1>[F:1][C:2]([F:30])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([C:15]2[CH:22]=[CH:21][CH:20]=[C:17]([C:18]3[NH:37][N:36]=[N:35][N:19]=3)[CH:16]=2)[CH2:23][CH:24]([OH:29])[C:25]([F:27])([F:28])[F:26])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4]
Reactant: N#Cc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(-c2nnn[nH]2)c1)C(F)(F)F
Temperature: 105 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
To a solution of 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]benzonitrile (76 mg, 0.17 mmol) in 2 mL of toluene was added trimethyltin azide (41 mg, 0.20 mmol). The reaction mixture was heated to 105° C. and stirred overnight. TLC showed starting material to still be present so additional trimethyltin azide (41 mg, 0.20 mmol) was added. The reaction mixture was stirred overnight at 105° C., cooled to room temperature, then THF (800 μL) and concentrated HCl (500 μL) were added. HPLC analysis showed 2 peaks after 5 hours, so additional concentrated HCl (200 μL) was added. After stirring overnight, HPLC analysis showed the reaction to be complete. The mixture was filtered through a celite plug and evaporated in vacuo. The residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to give 27.2 mg (33%) of the desired tetrazole product as an oil. HRMS calcd. for C19H16F7N5O2: 480.1270 [M+H]+, found: 480.1252. 1H NMR (CDCl3) δ3.66-3.99 (m, 2H), 4.45-4.75 (m, 3H), 5.80 (dt, 1H), 6.49-6.70 (m, 1H), 6.95 (s, 1H), 6.97-7.06 (m, 3H), 7.18-7.28 (m, 3H), 7.34 (s, 1H).
Reaction SMILES: C(O[C:4](=[O:33])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH:6]=1)C.[C:34]1([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:34]1([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:4](=[O:33])[C:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=3)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[CH:6]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: NCCCCCCCCc1ccccc1
Product: COc1ccc(-c2cc(C(=O)NCCCCCCCCc3ccccc3)cc(-c3cccc(C(F)(F)F)c3)c2OCCO)cc1

Procedure:
The product was prepared as a viscous yellow oil (0.165 g, 61%) from 3-(4-methoxyphenyl)-5-(3-trifluoromethylphenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester and 8-phenyloctylamine using a procedure similar to step 2 of example 1; 1H NMR (300 MHz, DMSO-d6) δ 1.21-1.34 (m, 8H), 1.45-1.58 (m, 4H), 2.50 (t, J=7.5 Hz, 2H), 3.10 (q, J=6 Hz, 2H), 3.20-3.30 (m, 4H), 3.80 (s, 3H), 4.38 (t, J=6 Hz, 1H), 7.01-7.05 (m, 2H), 7.10-7.25 (m, 5H),7.60 (d, J=9 Hz, 2H), 7.68-7.78 (m, 2H), 7.84-7.88 (m, 2H), 7.90-7.95 (m, 2H), 8.54 (t, J=5 Hz, 1H); mass spectrum [(+)ESI], m/z 620 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[CH2:14][N:15]1[C:23]2[CH:22]=[CH:21][C:20]([C:24]#[N:25])=[CH:19][C:18]=2[C:17]2[CH2:26][C@H:27]([NH:29][C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][C:16]1=2)=O)(C)(C)C.Cl>CO.O1CCOCC1>[CH:33]([O:32][C:30](=[O:31])[NH:29][C@@H:27]1[CH2:28][C:16]2[N:15]([CH2:14][C@@H:9]3[C@@H:10]([OH:13])[CH2:11][CH2:12][NH:8]3)[C:23]3[CH:22]=[CH:21][C:20]([C:24]#[N:25])=[CH:19][C:18]=3[C:17]=2[CH2:26]1)([CH3:35])[CH3:34]
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(C[C@@H]3[C@@H](O)CCN3C(=O)OC(C)(C)C)c3ccc(C#N)cc23)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(C[C@H]3NCC[C@@H]3O)c3ccc(C#N)cc23)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
A solution of (2R,3S)-2-((S)-7-cyano-2-isopropoxycarbonylamino-2,3-dihydro-1H-cyclopenta[b]indol-4-ylmethyl)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.04 mmol) in methanol (20 mL) is treated with 4 N hydrogen chloride in 1,4-dioxane (20 mL), stirred at room temperature for 3 h and concentrated. The residue is suspended in ethyl acetate (200 mL) and treated with 2 N aqueous sodium hydroxide solution (20 mL). The organic layer is washed with brine, dried over sodium sulfate, and concentrated. The resulting residue is purified by medium pressure liquid chromatography, eluting with methanol:chloroform (5:95). Fractions containing pure product are combined and concentrated to afford 0.38 g (96%) of the title compound. LC-ES/MS/MS m/z 383.2 [M+H]+, TR=1.86 min.