Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.C(N(C(C)C)CC)(C)C.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.O>C(Cl)Cl>[CH3:1][O:2][CH2:3][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: COCCl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.4 %

Procedure:
Chloromethyl methyl ether (0.5 ml, 6.59 mmol) and diisopropylethylamine (1.44 ml, 8.24 mmol) were added to a solution of 4′-hydroxy-1,1′-biphenyl-4-carbonitrile (1.07 g, 5.49 mmol) in methylene chloride (10 ml), and the mixture was stirred at room temperature for 16 hours. After water was added to the reaction mixture and the mixture was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=5/1) to give 4′-methoxymethoxy-1,1′-biphenyl-4-carbonitrile (1.03 g, yield: 78%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[NH4+:15]>CO>[CH2:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH2:15])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH3:13]
Reactant: [NH4+]
Reactant: CCS(=O)(=O)c1ccc(CBr)cc1
Agent: [OH-]
Solvent: CO
Product: CCS(=O)(=O)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of 1-(bromomethyl)-4-(ethylsulfonyl)benzene (6.62 g, 25.2 mmol) in MeOH (30 mL) was added 28% aqueous ammonium hydroxide solution (30 mL). The mixture was stirred at rt overnight. The mixture was then concentrated under reduced pressure. The residue was purified by basic preparative HPLC separation to afford (4-(ethylsulfonyl)phenyl)methanamine (1.5 g, 30%) as a yellow solid. LC-MS tR=1.747 min in 0-30CD—3 min chromatography (Durashell C18, 2.1*30 mm, 3 um), MS (ESI) m/z 200.0 [M+H]+ and 399.0 [2M+H]+. 1H NMR (CDCl3, 400 MHz): δ 7.85 (d, J=8.0 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 3.98 (s, 2H), 3.10 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H). Preparative Basic HPLC Method mobile phase A: water with 0.05% NH3H2O solution; mobile phase B: MeCN; flow rate: 30 mL/min; detection: UV 220 nm/254 nm; column: Synergi 200 mm×25 mm×5 μm; column temperature: 30° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:13][C:12](=[O:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:11][O:14][C:12](=[O:41])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCCCCCCCCCCCCCC1(COCc2ccccc2)CC(=O)C1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCC1(COCc2ccccc2)COC(=O)C1
Temperature: 25 °C

Procedure:
A stirred solution containing 2.27 g (5.1 mmol) of the compound prepared in (b) above and 2.2 g (12.75 mmol) of m-chloroperbenzoic acid in 30 ml of anhydrous methylene chloride was refluxed for 10 hours under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature, washed with 10 ml of a 2M sodium bisulfite solution, washed twice with 10 ml of a 2M sodium bicarbonate solution and washed with 10 ml of brine, after which time it was dried over magnesium sulfate, filtered and evaporated to afford a colorless liquid. The liquid was then chromatographed on silica gel employing a mixture of petroleum ether and methyl-t-butyl ether in a ratio of 7:3 as the eluent to yield a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]2([CH2:18][NH2:19])[CH2:17][CH2:16]2)=[N:4][CH:5]=[C:6]([CH:8]2[CH2:10][CH:9]2[C:11]([F:14])([F:13])[F:12])[CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.[Cl:32][C:33]1[C:34]([C:39](O)=[O:40])=[N:35][CH:36]=[CH:37][N:38]=1.ON1C2C=CC=CC=2N=N1>ClCCl.O.C(N(CC)CC)C>[Cl:32][C:33]1[C:34]([C:39]([NH:19][CH2:18][C:15]2([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([CH:8]4[CH2:10][CH:9]4[C:11]([F:14])([F:12])[F:13])=[CH:5][N:4]=3)[CH2:17][CH2:16]2)=[O:40])=[N:35][CH:36]=[CH:37][N:38]=1
Reactant: NCC1(c2ncc(C3CC3C(F)(F)F)cc2Cl)CC1
Reactant: O=C(O)c1nccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(NCC1(c2ncc(C3CC3C(F)(F)F)cc2Cl)CC1)c1nccnc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
147 mg [1-[3-chloro-5-[2-(trifluoromethyl)cyclopropyl]-2-pyridyl]cyclopropyl]methanamine (step 3) was dissolved in 3 ml of dichloromethane and 0.142 ml triethylamine was added. After cooling to 0° C., 193 mg 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride, 84 mg 3-chloropyrazine-2-carboxylic acid and 141 mg 1-hydroxybenzotriazole were added. The mixture was stirred overnight at ambient temperature. Then water was added. The layers were separated, the organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. Crude material was obtained as an orange oil, which was purified by flash chromatography on silica gel with heptane/ethyl acetate as a solvent. Thus, 161 mg of 3-chloro-N-[[1-[3-chloro-5-[2-(trifluoromethyl)cyclopropyl]-2-pyridyl]cyclopropyl]methyl]pyrazine-2-carboxamide was obtained as a yellow sticky solid. 1H-NMR (CDCl3): 8.42 ppm (d, 1H), 8.38 ppm (d, 1H), 8.18 ppm (s, 1H), 7.78 ppm (s, 1H, broad), 7.31 ppm (s, 1H), 3.66 ppm (d, 1H), 2.26 ppm (m, 1H), 1.78 ppm (m, 1H), 1.57 ppm (m, 1H), 1.39 ppm (m, 1H), 1.18 ppm (m, 4H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:12])[CH:4]=1.[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Br-:1].[C:7]([C:6]1[CH:10]=[CH:11][C:3]([CH2:2][P+:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][C:5]=1[F:12])([OH:9])=[O:8]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)c1ccc(CBr)cc1F
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1F
Product: [Br-]
Temperature: 25 °C
Yield: 105.9 %

Procedure:
To a suspension of 4-(bromomethyl)-2-fluorobenzoic acid (914.2 mg, 3.923 mmol) in toluene (20 ml) was added triphenylphosphine (1.029 g, 3.923 mmol). After heating the mixture under reflux for 6 hr, the reaction mixture was cooled to room temperature. The precipitate was collected by filtration, and dried under reduced pressure to give (4-carboxy-3-fluorobenzyl)(triphenyl)phosphoniumbromide (2.057 g, quantitative) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@:12]1([CH3:19])[C:16](O)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>ClCCl.CN(C)C=O>[Cl:23][C:16]([C@:12]1([CH3:19])[CH2:13][CH2:14][CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:17]
Reactant: C[C@@]1(C(=O)O)CCCN1C(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@]1(C(=O)Cl)CCCN1C(=O)OCc1ccccc1

Procedure:
A solution of (S)-1-(benzyloxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (1.50 g) in dichloromethane (30 mL) was treated with oxalyl chloride (0.65 mL) and 3 drops of N,N-dimethylformamide at ambient temperature for 1.5 hours. The mixture was concentrated and the crude material used in the next step without further purification.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C@@H:21]4[CH2:26][CH2:25][C@H:24]([CH2:27][S:28][C:29]5[NH:30][C:31]([NH2:34])=[N:32][N:33]=5)[CH2:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.CC#N.O>C(O)(C(F)(F)F)=O>[N:12]1[C:11]2[NH:7][CH:8]=[CH:9][C:10]=2[C:15]([C:16]2[CH:17]=[N:18][N:19]([C@@H:21]3[CH2:26][CH2:25][C@H:24]([CH2:27][S:28][C:29]4[NH:30][C:31]([NH2:34])=[N:32][N:33]=4)[CH2:23][CH2:22]3)[CH:20]=2)=[N:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](CSc5nnc(N)[nH]5)CC4)c3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: Nc1nnc(SC[C@H]2CC[C@@H](n3cc(-c4ncnc5[nH]ccc45)cn3)CC2)[nH]1
Reaction time: 2 h

Procedure:
5-[(cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl)thio]-4H-1,2,4-triazol-3-amine (9a) was dissolved in TFA (1 mL) and was stirred for 2 h. The solution was concentrated using a rotary evaporator to remove TFA. The residue was dissolved in methanol (1 mL) and ammonium hydroxide (1 mL) added. The solution was stirred overnight. LCMS showed complete de-protection. The solution was concentrated using a rotary evaporator. The product was isolated by prep LCMS using a 30 mm×100 mm C18 column; 11% CH3CN—H2O (0.1% TFA), 1.5 min, to 33% at 6 min; 60 mL/min; detector set at m/z 396; retention time, 5.5 min (2 runs). The eluate was freeze dried. Yield 21 mg (di-TFA salt). LC/MS (M+H)+: 396, 1H NMR (d6-DMSO) δ 12.9 (br s, 1H, NH); 8.9 (2 singlets, 2H); 8.5 (s, 1H); 7.9 (m, 1H); 7.3 (m, 1H); 4.4 (m, 1H, NCH); 3.1 (d, 2H); 2.2 (m, 2H); 1.9 (m, 3H); 1.7 (m, 2H); 1.6 (m, 2H). MS (ES) 396 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.[H-].[Na+].[Cl:20][C:21]1[C:26](Cl)=[N:25][CH:24]=[CH:23][N:22]=1>CN(C=O)C.O>[Cl:20][C:21]1[C:26]([O:17][CH:14]2[CH2:13][CH2:12][N:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH2:16][CH2:15]2)=[N:25][CH:24]=[CH:23][N:22]=1
Reactant: Clc1nccnc1Cl
Reactant: OC1CCN(c2ccc3ccccc3n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nccnc1OC1CCN(c2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of 1-(quinolin-2-yl)piperidin-4-ol (see PREPARATION P1.1; 2.0 g, 8.7 mmol) in DMF (30 mL) at room temperature was added sodium hydride (60% wt in mineral oil) (0.47 g, 17.4 mmol) at 0° C. The mixture was stirred at room temperature for 60 min and then 2,3-dichloro-pyrazine (1.2 g, 8.7 mmol) was added. The reaction mixture was heated to 90° C. overnight and then diluted with water (60 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (40 mL) and brine (40 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (10% to 30% EtOAc in petroleum ether) to give the title product (2.0 g, 5.8 mmol, 70% yield) as white solid. ESI-MS (M+1): 341 calc. for C18H17ClN4O 340.
Reaction SMILES: [CH:1]([O:4][C:5]([O:7][CH:8]([O:10][C:11]([C:13]1[N:14]=[C:15]([C:44]([F:47])([F:46])[F:45])[N:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:43])[CH2:23][C@H:24]([NH:35]C(OC(C)(C)C)=O)[CH2:25][C:26]3[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:27]=3[F:34])[CH2:18][C:17]=12)=[O:12])[CH3:9])=[O:6])([CH3:3])[CH3:2].[ClH:48]>C(OCC)(=O)C>[ClH:48].[CH:1]([O:4][C:5]([O:7][CH:8]([O:10][C:11]([C:13]1[N:14]=[C:15]([C:44]([F:45])([F:46])[F:47])[N:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:43])[CH2:23][C@H:24]([NH2:35])[CH2:25][C:26]3[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:27]=3[F:34])[CH2:18][C:17]=12)=[O:12])[CH3:9])=[O:6])([CH3:2])[CH3:3].[ClH:48].[CH:1]([O:4][C:5]([O:7][CH:8]([O:10][C:11]([C:13]1[N:14]=[C:15]([C:44]([F:45])([F:46])[F:47])[N:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:43])[CH2:23][CH:24]([NH2:35])[CH2:25][C:26]3[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:27]=3[F:34])[CH2:18][C:17]=12)=[O:12])[CH3:9])=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)OC(=O)OC(C)OC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)OC(C)OC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)CC(N)Cc1cc(F)c(F)cc1F)CC2
Product: CC(C)OC(=O)OC(C)OC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 1-isopropoxycarbonyloxy-ethyl ester 37a (0.29 g, 0.43 mmol) and 5 mL of ethyl acetate were added into the reaction flask. A solution of 6.5 N hydrochloric acid in 3 mL of ethyl acetate was then added to the flask. The reaction mixture was stirred at room temperature for 4 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 1-isopropoxycarbonyloxy-ethyl ester hydrochloride 37 (0.24 g, yield 91.2%) as a white solid.
Reaction SMILES: CO.C([Cl:6])(=O)C.Cl.[CH3:8][C:9]1([CH3:30])[O:22][C:13]2=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=[C:12]2[C@H:11]([NH:23]S(C(C)(C)C)=O)[CH2:10]1>C(OC)(C)(C)C>[Cl-:6].[CH3:8][C:9]1([CH3:30])[O:22][C:13]2=[N:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=[C:12]2[C@H:11]([NH3+:23])[CH2:10]1
Reactant: CC(=O)Cl
Reactant: CC1(C)C[C@@H](NS(=O)C(C)(C)C)c2ccc(C(F)(F)F)nc2O1
Agent: Cl
Solvent: CO
Solvent: COC(C)(C)C
Product: CC1(C)C[C@@H]([NH3+])c2ccc(C(F)(F)F)nc2O1
Product: [Cl-]
Yield: 100 %

Procedure:
To a 0° C. solution of methanol (2.22 mL, 55 mmol) was added acetyl chloride (0.868 mL, 12.21 mmol) dropwise. This methanolic HCl solution was added to a room temperature mixture of Example 62C (2.14 g, 6.11 mmol) in methyl tert-butyl ether (20 mL). After 2 hours the solid was collected by filtration (200 mL MTBE wash) and dried at 60° C. overnight in a vacuum oven to provide the title compound (2.14 g, 6.11 mmol). 1H NMR (300 MHz, DMSO-d6) δ 8.97 (bs, 2H), 8.43 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.7 Hz, 1H), 4.75-4.66 (m, 1H), 2.51-2.36 (m, 2H), 1.50 (s, 3H), 1.30 (s, 3H). MS (ESI+) m/z 247 (M+H)+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[C:18]=[O:19]>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:18](=[O:19])[NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[F:10])[CH2:2]2
Reactant: O=C=Nc1ccccc1F
Reactant: OC1CN2CCC1CC2
Product: O=C(Nc1ccccc1F)OC1CN2CCC1CC2
Yield: 79 %

Procedure:
3-Quinuclidinol and 2-fluorophenyl isocyanate were used. The reaction solution was evaporated under reduced pressure, and the residual solid was recrystallized from ethyl acetate to afford the title compound (79%) as a white solid: mp 124.0-126.0° C.; FAB LRMS m /z (relatively intensity, %) 265 (MH+, 22), 110 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](/[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[CH:9]\[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:33])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27]C(=O)C)=[C:21]([O:31][CH3:32])[CH:20]=2)[CH2:14][CH2:13]1)=[O:11].C(=O)([O-])[O-].[K+].[K+].O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](/[C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)=[CH:9]\[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:33])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([OH:27])=[C:21]([O:31][CH3:32])[CH:20]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: COc1ccc(/C(=C/C(=O)N2CCN(C(=O)c3cc(OC)c(OC(C)=O)c(OC)c3)CC2)c2ccccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(/C(=C/C(=O)N2CCN(C(=O)c3cc(OC)c(O)c(OC)c3)CC2)c2ccccc2Cl)cc1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of a compound of Example 91 (0.500 g) in methanol (20 ml) was added an aqueous solution saturated with potassium carbonate (10 ml), and the resulting mixture was stirred at room temperature for an hour. The reaction mixture was poured into water and extracted thrice with methylenechloride. The combined extract was washed with water, dried and concentrated. The residue was purified by liquid chromatography under medium pressure through two Lobar B columns. Fractions eluted with a 19:1 mixture of ethyl acetate and methanol were collected and worked up to afford the title compound (0.464 g) as a powder.
Reaction SMILES: [CH:1]1([SH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[N:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:9]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Cl:23][C:21]1[CH:20]=[CH:19][C:9]([C:10]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:11])=[C:8]([S:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:22]=1
Reactant: O=C(NC1CCCCC1)c1ccc(Cl)nc1Cl
Reactant: SC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)c1ccc(Cl)nc1SC1CCCC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
Cyclopentanethiol (7.84 mL, 73.22 mmol) was added in one portion to 2,6-dichloro-N-cyclohexylnicotinamide (20 g, 73.22 mmol) and sodium carbonate (23.28 g, 219.65 mmol) in DMF (150 mL). The resulting suspension was stirred at 60° C. for 3 hours. The mixture was cooled, evaporated, DCM (250 mL) was added and the mixture was washed with water (3×100 mL) and brine (50 mL), dried (MgSO4), filtered and evaporated to a sticky pale yellow solid. This was triturated with 4:1 hexane:ethyl acetate, filtered and dried to give 6-chloro-N-cyclohexyl-2-(cyclopentylthio)nicotinamide (13.8 g, 55.6%) as a white solid.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]([C:13]2([OH:20])[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][CH2:14]2)[CH:9]=[CH:10][C:11]=1[Cl:12].[S:21](=[O:23])=[O:22].[ClH:24]>O.C(O)(=O)C.O.O.[Cu](Cl)Cl>[Cl:12][C:11]1[CH:10]=[CH:9][C:8]([C:13]2([OH:20])[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][CH2:14]2)=[CH:7][C:6]=1[S:21]([Cl:24])(=[O:23])=[O:22]
Reactant: Cl
Reactant: CN1C(=O)CCC1(O)c1ccc(Cl)c(N)c1
Reactant: O=S=O
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN1C(=O)CCC1(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1

Procedure:
A solution of 9.9 g of sodium nitrite in 60 ml of water is metered into, below the surface of, a solution of 30.5 g of 5-(3-amino-4-chlorophenyl)-5-hydroxy-1-methyl-2-pyrrolidone in 300 ml of half-concentrated hydrochloric acid at at 0° to 5° C. The reaction mixture is stirred while cooling for a further 10 min, and then a mixture of 15.2 g of copper(II)chloride dihydrate and 450 ml of a saturated solution of sulfur dioxide in glacial acetic acid is added in portions. The mixture is stirred for a further 30 min, and then the sulfonyl chloride is precipitated by addition of water, and the crystals are filtered off. Melting point 137°-139° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:20][CH3:21]>C1COCC1>[I-:20].[C:1]([O:5][C:6]([NH:8][C@H:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:14][CH2:15][CH2:16][N+:17]([CH3:21])([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: COC(=O)[C@H](CCCN(C)C)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCC[N+](C)(C)C)NC(=O)OC(C)(C)C
Product: [I-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-methyl 2-(tert-butoxycarbonylamino)-5-(dimethylamino)pentanoate (5.62 g, 20.5 mmol, 1.0 eq) in THF (40 mL), was added iodomethane (1.4 mL, 22.5 mmol, 1.1 eq). The mixture was stirred at room temperature for 1 h, until the starting material was consumed as determined by LCMS analysis. The reaction mixture was concentrated and then dried under high vacuum to provide (S)-4-(tert-butoxycarbonylamino)-5-methoxy-N,N,N-trimethyl-5-oxopentan-1-aminium iodide as a white solid, which was used in the next step without purification. MS (EI) m/z 289 (M+).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][O:8][S:9]([C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])(=[O:11])=[O:10].C(OC(C)C)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:18][C:17]1[CH:16]=[C:15]([CH3:19])[CH:14]=[C:13]([CH3:20])[C:12]=1[S:9]([O-:11])(=[O:10])=[O:8].[NH2:7][N+:6]1[CH:5]=[CH:4][S:3][C:2]=1[CH3:1]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Cc1nccs1
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Cc1scc[n+]1N
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of 2-methyl-1,3-thiazole (6.6 g, 67 mmol) in toluene (60 mL) was added a solution of 2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene obtained in the above in ethyl acetate-toluene under ice-cooling, and the mixture was stirred for 2 hr. Diisopropyl ether (200 mL) was added to the reaction system, and the resulting solid was collected by filtration to give the title compound (13 g, 63%) as a white solid. The filtrate was concentrated under reduced pressure to about 100 mL, diisopropyl ether (100 mL) was added, and the resulting solid was collected by filtration to give the title compound (3.8 g, 18%) as a white solid (total yield 81%).
Reaction SMILES: C(N(CC)CC)C.[C:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])#[CH:9].Br[C:15]1[C:16]([C:22]#[N:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=1>[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].CN(C)C=O>[Cl:21][C:19]1[CH:20]=[C:15]([C:9]#[C:8][Si:10]([CH3:13])([CH3:12])[CH3:11])[C:16]([C:22]#[N:23])=[N:17][CH:18]=1
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1ncc(Cl)cc1Br
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(Cl)cnc1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
A pressure vessel was charged with triethylamine (7.65 mL, 55.2 mmol), ethynyltrimethylsilane (2.32 mL, 16.6 mmol), copper (I) iodide (0.263 g, 1.380 mmol), palladium (0) tetrakis(triphenylphosphine) (0.558 g, 0.483 mmol), 3-bromo-5-chloropicolinonitrile (3.0 g, 13.8 mmol), and N,N-dimethylformamide (50 ml). The vessel was flushed with argon, sealed, stirred at ambient temperature for 15 minutes, and then heated at 50° C. for 4 hours. The solution was diluted with water and extracted with ethyl acetate. The combined organic layers were concentrated, and the residue was purified by silica-gel chromatography, eluting 0-50% ethyl acetate in hexane, to afford the title compound (1.3 g, 5.5 mmol). MS m/z=235 (M+H).
Reaction SMILES: NCC1C=NC=CC=1.[O:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH2:14][NH2:15].[F:16][C:17]1([F:36])[CH2:19][CH:18]1[CH2:20][N:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]([C:32](O)=[O:33])=[C:29]([CH3:31])[N:30]=2)[C:22]1=[O:35]>>[F:36][C:17]1([F:16])[CH2:19][CH:18]1[CH2:20][N:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]([C:32]([NH:15][CH2:14][C:10]3[O:9][CH:13]=[CH:12][N:11]=3)=[O:33])=[C:29]([CH3:31])[N:30]=2)[C:22]1=[O:35]
Reactant: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1C(=O)O
Reactant: NCc1ncco1
Agent: NCc1cccnc1
Product: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1C(=O)NCc1ncco1
Yield: 69 %

Procedure:
Following the procedure as describe in Example 16, making variations as required to replace 3-(aminomethyl)pyridine with (oxazol-2-yl)methylamine to react with 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colourless solid in 69% yield: mp 156-158° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.55 (t, J=5.7 Hz, 1H), 8.09 (s, 1H), 7.12 (s, 1H), 4.44 (d, J=5.7 Hz, 2H), 3.99 (t, J=8.4 Hz, 2H), 3.64-3.47 (m, 3H), 3.19-3.12 (m, 1H), 2.44 (s, 3H), 2.05-1.89 (m, 1H), 1.68-1.55 (m, 1H), 1.37-1.36 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 163.8, 163.1, 159.5, 156.8, 153.4, 141.5, 128.9, 119.2, 43.9, 43.6, 42.6, 42.6, 38.4, 21.8 5 (t, 1JC-F=42 Hz), 19.0, 16.4 5 (t, 1JC-F=42 Hz); MS (ES+) m/z 399.0 (M+1).