Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:8]([CH3:19])=[CH:9][N:10]2[CH:14]([CH2:15][C:16]([OH:18])=O)[CH2:13][S:12][C:11]=12)=[O:6])([CH3:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH:1]([O:4][C:5]([C:7]1[C:8]([CH3:19])=[CH:9][N:10]2[CH:14]([CH2:15][C:16]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:18])[CH2:13][S:12][C:11]=12)=[O:6])([CH3:2])[CH3:3]
Reactant: C1COCCN1
Reactant: Cc1cn2c(c1C(=O)OC(C)C)SCC2CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1cn2c(c1C(=O)OC(C)C)SCC2CC(=O)N1CCOCC1
Yield: 54.8 %

Procedure:
1.54 g of (7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo[2,1-b]thiazol-3-yl)acetic acid, 0.70 g of morpholine and 0.12 g of 4-N,N-dimethylaminopyridine were dissolved in 50 ml of dichloromethane. 1.44 g of N,N'-dicyclohexylcarbodiimide was added thereto under ice-cooling and stirring. Then the mixture was stirred at room temperature for 9 days. After filtering off the insoluble matters, the solvent was distilled off. The oily residue thus obtained was purified by silica gel column chromatography. After crystallizing from ether/n-hexane, 1.05 g of the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[CH3:22])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:13][CH:14]=1)([CH3:20])([CH3:21])[CH3:19]
Reactant: Cc1ccccc1B(O)O
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(Br)ccc32)cc1
Product: Cc1ccccc1-c1ccc2c(ccn2Cc2ccc(C(C)(C)C)cc2)c1

Procedure:
The title compound was prepared from 5-bromo-1-[4-(tert-butyl)benzyl]-1H-indole (Step 1 of Example 34) and 2-methylphenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as a brown oil. Mass spectrum (ESI, [M+H]+) m/z 354. 1HNMR (400 MHz, DMSO-d6): δ 7.53 (d, 1H, J=3.06 Hz), 7.50 (d, 1H, J=8.55 Hz), 7.46 (d, 1H, J=0.95 Hz), 7.33 (d, 2H, J=7.96 Hz), 7.26-7.18 (m, 5H), 7.05 (d, 1H, J=8.40 Hz), 6.48 (d, 1H, J=3.06 Hz), 5.38 (s, 2H), 2.22 (s, 3H), and 1.22 ppm (s, 9H). Elemental Analysis for C26H27N: Calculated: C, 88.34; H, 7.70; N, 3.96. Found: C, 88.28; H, 7.58; N, 3.75.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][CH2:16][CH2:17][CH:18](O)[CH3:19]>O1CCCC1>[CH2:18]([C:17]1[C:10]2[C:9](=[O:14])[CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][C:11]=2[NH:15][CH:16]=1)[CH3:19]
Reactant: CC(O)CCN
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Solvent: C1CCOC1
Product: CCc1c[nH]c2c1C(=O)CC(c1ccccc1)C2
Temperature: 150 °C
Reaction time: 5 h
Yield: 51.1 %

Procedure:
A mixture of 5-phenylcyclohexane-1,3-dione (4.0 g), 4-aminobutan-2-ol (2.5 g), molecular sieves 4A (24 g) and tetrahydrofuran (60 ml) was refluxed for 13 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in dimethylformamide (100 ml). To the solution were 2-bromomesitylene(4.2 g), tetrakistriphenylphosphine palladium (0.6 g) and potassium carbonate (5.9 g), and the mixture was stirred at 150° C. for 5 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane) to give colorless crystals of 3-ethyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (2.6 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[SH:9][CH2:10][C:11]([OH:13])=[O:12]>[OH-].[Na+]>[C:11]([CH2:10][S:9][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])([OH:13])=[O:12]
Reactant: O=C(O)CS
Reactant: OCCCCCCCl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CSCCCCCCO
Temperature: 50 °C

Procedure:
4.5 ml (0.04M) of 6-chloro-1-hexanol is added to a solution of 2.8 ml (0.04M) of mercaptoacetic acid in 120 ml of 1N NaOH. The solution is warmed to about 50° C. for 16 hours, then acidified and extracted repeatedly with ethyl acetate. The combined extracts are concentrated to dryness and the residue purified by recrystallization.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH3:14][C:15]([CH3:20])([CH2:18][CH3:19])[CH2:16][OH:17].ClCCl.Cl>C(OCC)(=O)C.N1C=CC=CC=1>[N+:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][C:2](=[O:3])[O:17][CH2:16][C:15]([CH3:20])([CH3:14])[CH2:18][CH3:19])=[CH:10][CH:9]=1)([O-:13])=[O:12]
Reactant: CCC(C)(C)CO
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(C)(C)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 4-nitrophenyl chloroformate (1.97 g), 2,2-dimethylbutan-1-ol [CAS No. 1185-33-7] (1 g), and dichloromethane (30 mL), pyridine (1.58 mL) was added, and the resulting mixture was stirred at room temperature for 3 days. To the mixture, ethyl acetate and 1 N hydrochloric acid were added. After shaking the resulting mixture, the organic layer was collected, sequentially washed twice with water and with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain the captioned compound (2.23 g).
Reaction SMILES: [CH3:1]I.[Br:3][C:4]1[CH:5]=[CH:6][C:7](=[O:10])[NH:8][CH:9]=1>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:1])=[N:8][CH:9]=1
Reactant: CI
Reactant: O=c1ccc(Br)c[nH]1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: COc1ccc(Br)cn1
Temperature: 50 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
Silver carbonate (16.0 g, 57.8 mmol) and methyl iodide (6.5 mL, 103 mmol) were sequentially added to a solution of 5-bromopyridin-2(1H)-one (15.0 g, 86.2 mmol) in benzene (225 mL). The mixture was stirred for 16 h at 50° C. After cooling to room temperature, the mixture was filtered through celite and concentrated. Purification by chromatography using 1-5% ethyl acetate in pet ether provided 12 g of the desired compound: 1H NMR (300 MHz, CDCl3) 8.15-8.25 (narrow m, 1H), 7.63 (dd, J=9, 3 Hz, 1H), 6.63 (d, J=9 Hz, 1H), 3.92 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:9])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:8][C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(N)cccc1F
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(F)c1C
Temperature: 100 °C

Procedure:
To the solution of 3-fluoro-2-methylphenylamine (40 mmol) in toluene (50 mL) was added acetic anhydride (47 mmol). The mixture was heated to 100° C. for 1 h, then concentrated to give N-(3-fluoro-2-methylphenyl)acetamide as an off-white solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ccnc23)CC1

Procedure:
Starting from 7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-N-piperidin-4-yl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f1) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH2:9][C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].C(N(C(C)C)CC)(C)C.[N:27]([CH2:30][C:31]([O:33]CC)=[O:32])=[C:28]=[O:29]>ClCCl>[CH2:13]([N:7]1[C:8]([OH:12])=[C:9]([C:28]([NH:27][CH2:30][C:31]([OH:33])=[O:32])=[O:29])[C:10](=[O:11])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN1C(=O)CC(=O)N(CCCC)C1=O
Reactant: CCOC(=O)CN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCn1c(O)c(C(=O)NCC(=O)O)c(=O)n(CCCC)c1=O
Reaction time: 24 h
Yield: 64 %

Procedure:
A mixture of 1,3-dibutyl-2,4,6(1H,3H,5H)-pyrimidinetrione (1.3 g mg, 5.5 mmoles) and diisopropylethylamine (1.9 mL, 11.0 mmoles) in dichloromethane (20 mL) was treated with ethyl isocyanatoacetate (673 uL, 6.0 mmoles) and stirred for 24 hours. The mixture was washed with 1 molar hydrochloric acid (×2), dried and evaporated. The residue was taken up in ethanol (5 mL) and treated with 6 molar sodium hydroxide (3 mL) and stirred for 2 hours. The mixture was acidified with 1 molar hydrochloric acid and stirred for 30 minutes to give a solid which was recrystallized from acetic acid-water to afford the title compound (1.2 g, 64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s., 1 H), 10.11 (t, J=6.19 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 3.81 (t, 4 H), 1.43-1.63 (m, 4 H), 1.14-1.41 (m, 4 H), 0.89 (t, J=7.33 Hz, 6 H).
Reaction SMILES: [Fe:1].O=[Al-]=O.[Na+].[OH-].[K+].[N+:8]([O-:11])([O-:10])=[O:9].[Fe+3].[N+:13]([O-:16])([O-:15])=[O:14].[N+]([O-])([O-])=O>[OH-].[Na+].O>[N+:8]([O-:11])([O-:10])=[O:9].[Fe+2:1].[N+:13]([O-:16])([O-:15])=[O:14]
Reactant: [Fe]
Agent: [Fe+3]
Agent: O=[Al-]=O
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: [Fe+2]
Temperature: 25 °C

Procedure:
A variety of Fe-containing X-zeolites were each prepared. First, sodium aluminate was dissolved with stirring and heated in sodium hydroxide and potassium hydroxide solutions until the resultant solution became transparent, so that the solution had the formulation shown in Table 1 below. Subsequently, it was cooled to room temperature. On the other hand, iron (III) nitrate was dissolved in pure water to form an iron nitrate solution. Then, pure water was added to a sodium silicate solution so that each resultant had the formulation in Table 1 below, and then it was stirred at 200 to 10,000 rpm, slowly adding sodium aluminate solution prepared above thereto. Next, the iron nitrate solution was added thereto, thereby obtaining an amorphous gel having the formulation mentioned before. The temperature of the reaction solution for generating this gel was increased to about 50° C.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C@H:7]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:8]([OH:10])=O)(=[O:3])[CH3:2].[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CCOC(C)=O.C(Cl)Cl>[C:1](=[O:3])([S:4][CH2:5][CH2:6][C@H:7]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:8]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[O:10])[CH3:2]
Reactant: CC(=O)SCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NCCCCCO
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)SCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCCCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.4 %

Procedure:
To a round bottom flask was added (S)-4-(acetylthio)-2-(benzyloxycarbonylamino)butanoic acid (312 mg, 1.00 mmol), 5-aminopentan-1-ol (119 mg, 1.15 mmol), DCM (5 mL), EDC (211 mg, 1.10 mmol) and HOBt (184 mg, 1.20 mmol). The light yellow mixture was stirred at rt for 16 hr. The reaction mixture was diluted with EtOAc (60 mL), washed with 5% aqueous KHSO4 (2×), saturated aqueous NaHCO3 (2×), water, and saturated aqueous NaCl. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (S)—S-3-(benzyloxycarbonylamino)-4-(5-hydroxypentylamino)-4-oxobutyl ethanethioate (311 mg, 0.784 mmol, 78% yield) as a white solid. Anal. Calcd. for C19H28N2O5S m/z 396.5. found: 397.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.47-7.28 (m, 5H), 6.41 (s, 1H), 5.59 (d, J=6.7 Hz, 1H), 5.11 (s, 2H), 4.13 (d, J=6.7 Hz, 1H), 3.63 (dd, J=11.6, 6.1 Hz, 2H), 3.28 (dd, J=12.7, 6.3 Hz, 2H), 2.97 (dt, J=14.5, 7.4 Hz, 1H), 2.91-2.75 (m, 1H), 2.34 (s, 3H), 2.21-2.00 (m, 1H), 1.91 (dt, J=14.4, 7.2 Hz, 1H), 1.72-1.48 (m, 5H), 1.48-1.34 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH:20]1([C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[CH2:22][CH2:21]1>>[CH:20]1([C:23]([N:25]2[CH2:30][CH2:29][N:28]([C:17]([C:15]3[CH:16]=[C:11]([C:5]4[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=4[CH3:10])[CH:12]=[N:13][CH:14]=3)=[O:19])[CH2:27][CH2:26]2)=[O:24])[CH2:21][CH2:22]1
Reactant: O=C(C1CC1)N1CCNCC1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)N3CCN(C(=O)C4CC4)CC3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 4-cyclopropanecarbonyl-piperazine to afford the title compound. MS: m/e=395 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[NH:12][C:13](=[O:15])[CH3:14]>O1CCCC1.C(O)(=O)C.[Zn]>[NH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([NH:12][C:13](=[O:15])[CH3:14])=[C:4]([CH3:11])[CH:5]=1
Reactant: CC(=O)Nc1c(C)cc([N+](=O)[O-])cc1C
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)Nc1c(C)cc(N)cc1C
Temperature: 0 °C
Yield: 27.5 %

Procedure:
Zinc dust (30 g) was added in portions over 10 minutes to N-(2,6-dimethyl-4-nitro-phenyl)-acetamide (5.09 g) in tetrahydrofuran (200 mL) and acetic acid (60 mL) cooled to 0° C. The reaction mixture was filtered after 30 minutes through silica-(50 g), which was washed with methanol/ethyl acetate (20:80, 100 mL). The organic phase was washed with saturated aqueous sodium bicarbonate (100 mL) and treated with heptane until the title compound precipitated, which was collected, washed with heptane and dried in vacuo to furnish 1.20 g (28% yield) of the title compound as a pale red solid. 1H NMR (500 MHz, DMSO-d6): 1.95 (s, 3H), 1.96 (s, 6H), 4.82 (s, 2H), 6.23 (s, 2H), 8.79 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10](N)[CH:9]=[CH:8][N:7]=1.[Br-:14].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+].[OH-].[Na+]>O.S([O-])([O-])(=O)=O.[Cu+2]>[Br:14][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:13])[CH3:1])[CH:11]=1
Reactant: CN(C)CCOc1cc(N)ccn1
Reactant: [Br-]
Agent: [Cu+2]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: CN(C)CCOc1cc(Br)ccn1
Temperature: 0 °C

Procedure:
A mixture of 1.2 g of 2-(2-dimethylamino-ethoxy)-pyridin-4-ylamine, 0.749 g of sodium bromide and 1.16 g of copper sulfate is cooled to 0° C. and treated with 12 mL of 9 M sulfuric acid with stirring. The resulting dark suspension is treated at 0° C. with a solution of 0.503 g of sodium nitrite in water (0.8 mL) and stirred at 0° C. for 1.5 h and at room temperature for 1.5 h. The reaction mixture is pored onto ice-water, brought to basic pH with 30% sodium hydroxide, and extracted with methylene chloride. The organics are dried (magnesium sulfate), concentrated and purified by silica gel chromatography (7:3 ethyl acetate/methanol) to give [2-(4-bromo-pyridin-2-yloxy)-ethyl]-dimethyl-amine as an oil. MS (m/z): 245 (M+1); Rf 0.25 (7:3 ethyl acetate/methanol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:68]=[CH:67][C:53]2[NH:54][C:55]([C@@H:57]([NH2:66])[CH2:58][CH2:59][CH2:60][CH2:61][NH:62][C:63]([NH2:65])=[O:64])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:68]=[CH:67][C:53]2[NH:54][C:55]([C@@H:57]([NH:66][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][CH2:59][CH2:60][CH2:61][NH:62][C:63]([NH2:65])=[O:64])=[N:56][C:52]=2[CH:51]=1
Reactant: NC(=O)NCCCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](CCCCNC(N)=O)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-5-ureidopentylamine in tetrahydrofuran. Yield: %; Rf value: 0.07 (silica gel: dichloromethane/ethanol=9:1); C26H31ClN6O3 (511.03); mass spectrum: (M+H)+=511/513 (chlorine isotope).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[S:3]([O-])=O.[K+].C1(C)C=CC(S(O)(=O)=O)=CC=1.CNC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S(Cl)(Cl)=O.[Cl:39][C:40]1[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[C:42]([Cl:50])[C:41]=1[N:51]1[C:55]([NH:56][CH2:57][C:58]2[CH:63]=[N:62][CH:61]=[CH:60][N:59]=2)=[CH:54][C:53]([C:64]#[N:65])=[N:52]1.C(=O)([O-])O.[Na+]>ClCCCl>[Cl:50][C:42]1[CH:43]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:45]=[C:40]([Cl:39])[C:41]=1[N:51]1[C:55]([NH:56][CH2:57][C:58]2[CH:63]=[N:62][CH:61]=[CH:60][N:59]=2)=[C:54]([S:3][C:2]([F:7])([F:6])[F:1])[C:53]([C:64]#[N:65])=[N:52]1
Reactant: O=S([O-])C(F)(F)F
Reactant: N#Cc1cc(NCc2cnccn2)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Agent: CNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClCCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NCc2cnccn2)c1SC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
Into 5.0 ml of 1,2-dichloroethane were suspended 1.725 g (10.0 mmol) of potassium trifluoromethanesulfinate, 895 mg (4.1 mmol) of dimethylamine p-toluenesulfonate, 951 mg (5.0 mmol) of p-toluenesulfonic acid monohydrate, and then 1.506 g (12.6 mmol) of thionyl chloride was added under ice-cooling. After 3 hours of stirring at room temperature, 1.03 g (2.5 mmol) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(pyrazin-2-ylmethylamino)pyrazole-3-carbonitrile was added thereto, and the mixture was warmed to 40° C. and stirred for 5 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and then extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the resulting oil was purified to isolate 487 mg (yield 38%) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfenyl-5-(pyrazin-2-ylmethylamino)pyrazole-3-carbonitrile.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:16])[C:9]([CH2:12][C:13]([OH:15])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:29]([NH2:32])[CH2:30][CH3:31]>C(Cl)(Cl)Cl>[CH2:29]([NH:32][C:13](=[O:15])[CH2:12][C:9]1[C:8](=[O:16])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)[CH2:30][CH3:31]
Reactant: Cc1cccc2ncc(CC(=O)O)c(=O)n12
Reactant: CCCN
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCNC(=O)Cc1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
A mixture containing 2.18 g (0.01 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-acetic acid and 1.55 ml (0.011 mol) of triethylamine in 60 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 0.945 g (0.01 mol) of methyl chloroformate in 5 ml of chloroform is dropped to the above mixture at -12° C. during 7 minutes. After stirring for 5 minutes, 0.65 g (0.011 mol) of propylamine dissolved in 10 ml of chloroform is dropped to the above solution at -15° C. during 10 minutes. The reaction mixture is stirred at -15° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 40 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 40 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated. Alter thoroughly triturating the residue with cold ethyl acetate, 0.8 g (30.9%) of the named compound is obtained, m.p.: 96°-98° C. after recrystallization from ethyl acetate.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([CH2:10][C:11]#[N:12])[S:7][CH:6]=1)=[O:4]>O.C(O)C>[C:11]([CH2:10][C:8]1[S:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:9]=1)#[N:12]
Reactant: COC(=O)c1csc(CC#N)c1
Solvent: O
Solvent: CCO
Product: N#CCc1cc(C(=O)O)cs1
Yield: 73.1 %

Procedure:
A solution of 5-cyanomethyl-thiophene-3-carboxylic acid methyl ester (4.4 g, 22.1 mmol) and NHCO3 (4.1 g, 48.6 mmol) in water (35 mL) and ethanol (35 mL) is heated to reflux for 4 h. After cooling, the reaction mixture is diluted with water and washed with ether. The aqueous layer is acidified with 1 N HCl and extracted with dichloromethane (4×). The combined organic layers are washed with saturated aq NaCl, dried over Na2SO4, filtered and concentrated in vacuo to give 5-cyanomethyl-thiophene-3-carboxylic acid (2.7 g, 73%) as a light yellow solid: mp 154-159° C.; 1H NMR (DMSO-d6, 300 MHz) δ 12.72 (s, 1 H), 8.20 (s, 1 H), 7.30 (s, 1 H), 4.23 (s, 2 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Cl)=[CH:36][CH:35]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:38][C:37]2[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(CN([C@H]2CCN(Cc3cccc(C#N)c3)C2=O)S(=O)(=O)c2ccc3ccc(OC)cc3c2)cc1

Procedure:
The title compound is prepared as described in EXAMPLE 90, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as described in EXAMPLE 43, part A, and 4-methoxybenzyl chloride. The crude product is purified by column chromatography eluting with 50% EtOAc/hexanes to afford the title compound as a white foam.