Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[C:12]([CH3:13])=[C:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:27])=[C:22]([C:25]#[N:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[NH:28][C:29]([NH:31][CH:32]1[CH2:34][CH2:33]1)=[O:30].CC1C=CC(S(O[CH2:46][C@@H:47]2[O:49][CH2:48]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[C:25]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH2:46][C@H:47]1[CH2:48][O:49]1)[N:18]=[CH:17][CH:16]=[C:15]2[O:14][C:11]1[CH:10]=[CH:9][C:8]([NH:28][C:29]([NH:31][CH:32]2[CH2:33][CH2:34]2)=[O:30])=[C:7]([CH3:6])[C:12]=1[CH3:13])#[N:26]
Reactant: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(O)c(C#N)cc23)c1C
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(OC[C@H]4CO4)c(C#N)cc23)c1C
Temperature: 50 °C
Yield: 49.6 %

Procedure:
Dimethylformamide (4 ml) was added to N-(2,3-dimethyl-4-(6-cyano-7-hydroxy-quinolin-4-yloxy)-phenyl)-N′-cyclopropylurea (476 mg), and then (2R)-(−)-glycidyl p-toluenesulfonate (365 mg) and potassium carbonate (340 mg) were further added and the mixture was heated at 50° C. for 4 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was washed with ethyl acetate to obtain the title compound (270 mg) as light yellow crystals.
Reaction SMILES: [CH:1]([N:4]([CH:16]([CH3:18])[CH3:17])[CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH:16]([CH3:18])[CH3:17])=[CH:15][CH:14]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)N(CCc1ccc(C(=O)O)cc1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)N(CCc1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
To a DMF (10 ml) solution of 4-(2-diisopropylaminoethyl)benzoic acid (300 mg) was added 1,1-carbonyldiimidazole (215 mg), and the solution was stirred at room temperature for 15 minutes. To the solution was added 1-tert-butoxycarbonylpiperazine (247 mg), and the solution was stirred at room temperature for 4 hours. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate, washed with water and sodium chloride solution, dried and concentrated to give colorless oil of the title compound (483 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[N:8]([C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=1)[CH2:7][CH2:6]2.Cl[Sn]Cl.O>C1COCC1.CC(O)=O.O>[NH2:34][C:31]1[CH:32]=[CH:33][C:28]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:16][CH:15]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc2c(c1)CCN(c1ccc([N+](=O)[O-])cc1)C2Cc1ccc(OCc2ccccc2)cc1
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN(c1ccc(N)cc1)C2Cc1ccc(OCc2ccccc2)cc1
Temperature: 60 °C
Yield: 95.8 %

Procedure:
A suspension of 6-methoxy-2-(4-nitrophenyl)-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.70 g, 1.46 mmol) and SnCl2.H2O (1.35 g, 6.0 mmol) in 20 mL of THF/HOAc (1:1) and 3 mL of water was heated at 60° C. for 3 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was quenched by the addition of saturated aqueous NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL) and the combined organic layer was dried over MgSO4 then concentrated. The crude product was purified by flash chromatography to provide the title compound (0.63 g, 95% yield). ES−MS, (m/z) 451 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](Cl)(=[O:16])[CH2:13][CH2:14][CH3:15]>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCc1ccccc1
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Product: CCCC(=O)OCCCCc1ccccc1
Reaction time: 36 h
Yield: 98.9 %

Procedure:
To 4-phenyl-1-butanol (7.0 g, 0.047 mol) was added anhydrous dichloromethane (20 mL). A solution of butyryl chloride (4.79 g, 0.045 mol) in anhydrous dichloromethane (20 mL) was added dropwise. The solution was stirred for 36 hours. At this point the reaction was concentrated under reduced pressure to give a crude oil. Column chromatography [silica gel; eluent hexanes-ethyl acetate (3:1)] provided the desired product (9.8 g, 94%) as a clear viscous liquid. 1H (CDCl3) δ(ppm): 0.94 (t, 3H); 1.61-1.71 (m, 6H); 2.27 (t, 2H); 2.64 (t, 2H); 4.08 (t, 2H); 7.16-7.19 (m, 3H); 7.25-7.29 (m, 2H),
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH2:10]
Reactant: N#CCc1ccccc1Br
Solvent: C1CCOC1
Product: NCCc1ccccc1Br
Temperature: 0 °C

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed 2-(2-bromophenyl)acetonitrile (9.8 g, 49.99 mmol, 1.00 equiv), tetrahydrofuran (50 mL). This was followed by the addition of BH3 solution (250 mL, 1N in tetrahydrofuran) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of H2O. The pH value of the aqueous solution was adjusted to 2 with aq. hydrogen chloride (5 N). The aqueous solution was washed with 3×20 mL of EA and adjusted to pH to 11 with sodium hydroxide. The resulting aqueous solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 5 g (50%) of 2-(2-bromophenyl)ethanamine as brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:25]5[C:26](Br)=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.CC1(C)C(C)(C)OB([C:41]2[CH2:42][CH2:43][O:44][CH2:45][CH:46]=2)O1>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:25]5[C:26]([C:41]6[CH2:46][CH2:45][O:44][CH2:43][CH:42]=6)=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[F:24][C:22]1[CH:21]=[CH:20][C:19]([C:25]2[C:26]([C:41]3[CH2:42][CH2:43][O:44][CH2:45][CH:46]=3)=[N:27][CH:28]=[CH:29][CH:30]=2)=[C:18]2[C:23]=1[C@H:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([OH:32])=[O:2])[CH2:6][O:7][C:8]=3[CH:13]=1)[CH2:16][CH2:17]2
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5C5=CCOCC5)ccc(F)c43)ccc21
Product: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5C5=CCOCC5)ccc(F)c43)ccc21

Procedure:
The methyl ester of the title compound is prepared from {(S)-6-[(R)-4-(2-bromo-pyridin-3-yl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydropyran following a procedure analogous to that described in Step 1 of Intermediate 56. Saponification of the methyl ester, {(S)-6-[(R)-7-fluoro-4-(3,6-dihydropyran-4-yl-pyridin-3-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester, gives the title compound following a procedure analogous to that described for Example 4. LC (method 9): tR=0.93 min; Mass spectrum (ESI+): m/z=488 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:34])[CH2:15][N:16]([CH2:30][C:31]([OH:33])=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[C:41](O)=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:37]=1[F:46].C(N=C=NCCCN(C)C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:34])[CH2:15][N:16]([CH2:30][C:31]([O:33][C:41]2[C:40]([F:43])=[C:39]([F:44])[C:38]([F:45])=[C:37]([F:46])[C:36]=2[F:35])=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:18]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(CC(=O)O)c2cccc(Oc3ccccc3)c2)C1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)c2cccc(Oc3ccccc3)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [[2-((S)-3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-oxo-ethyl]-(3-phenoxyphenyl)amino]acetic acid 27 (4.36 g, 9.39 mmol) in DMF (30 mL) were added pentafluorophenol (1.88 g, 10.21 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (1.96 g, 10.22 mmol). The reaction mixture was stirred overnight at room temperature. It was then diluted with ethyl acetate, washed with 10% hydrochloric acid (×2), brine (×2), dried (Na2SO4) and concentrated in vacuo. The resultant solid was evaporated twice from diethyl ether to give the title compound as a colourless, glassy solid (3.4 g, 57%) which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:53]=[C:54]([CH:60]=[CH:61][CH:62]=1)[O:55][CH2:56][CH2:57]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:57][CH2:56][O:55][C:54]2[CH:60]=[CH:61][CH:62]=[C:52]([F:51])[CH:53]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: OCCCOc1cccc(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCCOc4cccc(F)c4)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 58.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (79 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (110 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(3-fluorophenoxy)-1-propanol (62 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (74 mg, yield 54%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[N:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)=[CH:16][N:17]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Br)cn4ccnc34)nc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1cn2ccnc2c(Nc2ccc(N3CCNCC3)cn2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 106a (260 mg, 0.5 mmol) in CH2Cl2 (3 mL) was added TFA (0.5 ml) and the reaction mixture was stirred at 25° C. for 2 h. The reaction solution was concentrated to give 106b as a pale yellow liquid without purification for next step (210 mg, 97%). MS: [M+H]+ 374.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[NH:20][CH3:21])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:8])([O-])=O.C1COCC1>CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[NH:20][CH3:21])[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([Br:16])=[CH:14][CH:15]=1)=[O:8]
Reactant: CNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1N
Reaction time: 4 h

Procedure:
A mixture of 3-Nitro-N-(4-bromophenyl)-4-methylaminobenzamide (120 mg, 0.34 mmol), 10 ml THF, 10 ml MeOH and 30 mg 5%-Pt-on-carbon was stirred for 4 h under a hydrogen atmosphere (3.5 bar). The catalyst was removed by filtration and the mixture was concentrated and used in the next step without further purification.
Reaction SMILES: C([NH:20][C:21]1[S:25][C:24]([CH2:26][C:27]([NH:29][CH:30]2[C:53](=[O:54])[N:32]3[C:33]([C:37]([O:39]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:38])=[CH:34][CH2:35][S:36][C@H:31]23)=[O:28])=[N:23][N:22]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:55]1(OC)C=CC=C[CH:56]=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C(Cl)Cl>[NH2:20][C:21]1[S:25][C:24]([CH2:26][C:27]([NH:29][CH:30]2[C:53](=[O:54])[N:32]3[C:33]([C:37]([OH:39])=[O:38])=[C:34]([CH:55]=[CH2:56])[CH2:35][S:36][C@H:31]23)=[O:28])=[N:23][N:22]=1
Reactant: O=C(Cc1nnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)s1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Reactant: COc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3nnc(N)s3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.3 %

Procedure:
To a suspension of benzhydryl 7-[2-(5-tritylamino-1,3,4-thiadiazol-2-yl)acetamido]-3-cephem-4-carboxylate (2.6 g) in methylene chloride (30 ml) and anisole (2.1 g) was added trifluoroacetic acid (7.6 g) under ice-cooling, followed by stirring at ambient temperature for 1.5 hours. The reaction mixture was poured into diisopropyl ether (300 ml), and the precipitates were collected by filtration and suspended in water (40 ml). After adjusting to pH 7 with 10% aqueous sodium hydroxide, the aqueous solution was washed with ethyl acetate and then adjusted to pH 5 with 10% hydrochloric acid. The organic solvent included in the resultant aqueous solution was completely removed by evaporation, and the resultant aqueous solution was adjusted to pH 4 with dilute acetic acid, which was chromatographed on a non-ionic adsorption resin "Diaion HP-20" (50 ml). After washing with water, elution was carried out with 30% isopropyl alcohol, and the fractions containing a desired compound were collected and then concentrated under reduced pressure. The concentrate was lyophilized to obtain 7-[2-(5-amino-1,3,4-thiadiazol-2yl)-acetamido]-3-vinyl-3-cephem4- carboxylic acid (0.31 g).
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[C:10]([N:12]([CH:14]([CH:39]([CH3:41])[CH3:40])[C:15]([NH:17][CH:18]([C:31]1[NH:36][C:35](=[O:37])[CH:34]=[C:33]([CH3:38])[N:32]=1)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=1)=[O:16])[CH3:13])=[O:11])=O)CCC>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:8][CH:9]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[C:10]([N:12]([CH:14]([CH:39]([CH3:41])[CH3:40])[C:15]([NH:17][CH:18]([C:31]1[NH:36][C:35](=[O:37])[CH:34]=[C:33]([CH3:38])[N:32]=1)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=1)=[O:16])[CH3:13])=[O:11]
Reactant: CCCCOC(=O)NC(Cc1ccc(F)cc1)C(=O)N(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nc(C)cc(=O)[nH]1)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(=O)[nH]c(C(Cc2ccc(O)c(C(C)(C)C)c2)NC(=O)C(C(C)C)N(C)C(=O)C(N)Cc2ccc(F)cc2)n1
Yield: 88.3 %

Procedure:
To a solution of 2-(1-(2-((2-butoxycarbonylamino-3-(4-fluorophenyl)propionyl)-N-methylamino)-3-methyl-butyrylamino)-2-(3-tert-butyl-4-hydroxyphenyl)ethyl)-6-methyl-4-pyrimidinone (B) (93 mg) in methylene chloride (5 ml), TFA (1 ml) was added under cooling with ice. The resultant mixture was stirred at room temperature for 1.5 hours and evaporated under reduced pressure to remove the solvent; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:methanol=15:1), giving the titled compound (70 mg, 91.8%).
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]#[N:8].[S:9](Cl)(=[O:12])(=[O:11])[NH2:10]>CC(N(C)C)=O.CCOC(C)=O>[S:9]([NH:1][C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]#[N:8])(=[O:12])(=[O:11])[NH2:10]
Reactant: NS(=O)(=O)Cl
Reactant: N#CC1=C(N)CCC1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#CC1=C(NS(N)(=O)=O)CCC1

Procedure:
To a solution of 2-aminocyclopent-1-enecarbonitrile (440 mg, 4.07 mmol) in 10 mL of DMA was added sulfamoyl chloride (941.3 mg, 8.15 mmol), and the resultant mixture was stirred at room temperature under nitrogen for 2 h. Then it was diluted with EtOAc, the organic layer was washed with brine and dried down under vacuum, and the residue was purified by chromatography on silica gel eluting with EtOAc/Hexane to give the title compound. 1H NMR (400 MHz, CDCl3) δ 2.04-1.97 (m, 2H), 2.61-2.57 (m, 2H), 2.9-2.86 (m, 2H), 5.66 (s, 2H), 8.04 (s, 1H).
Reaction SMILES: I.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:16][C:17](SC)=[NH:18])[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[N:13][C:12]([CH3:15])=[N:11]1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]([F:39])[F:38])=[CH:32][CH:31]=1)[C:27](O)=O.[NH2:40][NH2:41]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:41][N:40]=[C:17]([NH:16][C:6]2[CH:7]=[CH:8][C:9]([N:10]3[CH:14]=[N:13][C:12]([CH3:15])=[N:11]3)=[C:4]([O:3][CH3:2])[CH:5]=2)[N:18]=1)[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]([F:38])[F:39])=[CH:32][CH:31]=1
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(C)n1
Reactant: NN
Reactant: O=C(O)C(CCCCCl)c1ccc(OC(F)F)cc1
Agent: I
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(OC(F)F)cc3)n2)ccc1-n1cnc(C)n1

Procedure:
Methyl 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide (0.250 g, 0.617 mmol), from preparation F) and 6-chloro-2-(4-(difluoromethoxy)phenyl)hexanoic acid (0.271 g, 0.925 mmol, from preparation AZ) were coupled and then reacted with hydrazine (0.078 mL, 2.47 mmol) using a procedure analogous to Step A of Example 13. After an aqueous workup, 5-(5-chloro-1-(4-(difluoromethoxy)phenyl)pentyl)-N-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine was obtained as a brown residue. The crude product was used in the next step without purification. LC-MS (M+H)+ 518.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([F:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)O1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]([F:11])([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:28]=[N:29][NH:30][CH:31]=3)=[CH:3][CH:4]=2)[CH2:9][NH2:10])=[CH:13][CH:14]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: NCC(F)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: NCC(F)(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Reaction time: 0.08 h

Procedure:
2,2-Bis-(4-chloro-phenyl)-2-fluoro-ethylamine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 except that heating was carried out at 100° C. for 5 minutes using 300 W power in a CEM microwave, to obtain the title compound. LCMS (PS-B4) Rt 6.69 min [M−F−]+296. 1H NMR (Me-d3-OD) δ 4.04 (2H, d), 7.47-7.55 (6H, m), 7.77 (2H, d), 8.41 (2H, d).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[CH:19]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].Cl>ClC(Cl)C>[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:14]=[CH:13][CH:12]=[C:9]([C:10]#[N:11])[CH:8]=3)[CH2:2][CH2:3]2)[CH:19]=1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: N#Cc1cccc(N2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cccc(CN2CCN(c3cccc(C#N)c3)CC2)c1
Reaction time: 24 h
Yield: 80.5 %

Procedure:
Dissolve 3-piperazin-1-yl-benzonitrile (0.19 g, 1.00 mmol), 3-formyl-benzoic acid methyl ester (0.33 g, 2.00 mmol) and AcOH (0.64 mL, 10.0 mmol) in 5 mL dichloroethane. Add NaBH(OAc)3 (0.42 g, 2.00 mmol) and stir the mixture overnight. Add another portion of NaBH(OAc)3 (0.42 g, 2.00 mmol) and stir the mixture an additional 24 h. Concentrate the crude reaction mixture under a stream of N2. Dissolve the residue into 5% HCl and apply to a Dowex column. Wash the column with 1×50 mL 5% HCl, 2×50 mL H2O, 2×50 mL of MeOH and 2×50 mL of dichloromethane. Liberate the basic residues by washing the resin with 3×30 mL of 10% NH3/MeOH and 2×20 mL of dichloromethane. Concentrate the basic washings to give 0.27 g of 3-[4-(3-cyano-phenyl)-piperazin-1-ylmethyl]-benzoic acid methyl ester as a clear oil. 1H NMR indicates some contamination with starting amine. The mixture is carried on without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:28])[F:27])[O:14][N:13]=[C:12]([C:15]3[S:19][C:18]([C:20](O)=[O:21])=[C:17]4[CH2:23][CH2:24][CH2:25][C:16]=34)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].C(N(CC)CC)C.Cl.[CH3:38][O:39][C:40](=[O:43])[CH2:41][NH2:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:38][O:39][C:40](=[O:43])[CH2:41][NH:42][C:20]([C:18]1[S:19][C:15]([C:12]2[CH2:11][C:10]([C:4]3[CH:3]=[C:2]([Cl:1])[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=3)([C:26]([F:28])([F:27])[F:29])[O:14][N:13]=2)=[C:16]2[CH2:25][CH2:24][CH2:23][C:17]=12)=[O:21]
Reactant: COC(=O)CN
Reactant: O=C(O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of compound 3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid (10.0 g, 21.4 mmol) in dichloromethane (100 mL) is added triethylamine (6.49 g, 64.2 mmol), glycine methyl ester hydrochloride (3.2 g, 25.7 mmol) and HATU (12.2 g, 32.1 mmol), after the addition the mixture is stirred at room temperature for 1 hour. After being detected by TLC and LCMS, the reaction mixture is diluted with dichloromethane, then the solution is washed with water and brine, dried over anhydrous Na2SO4, filtered, concentrated and the residue is dried in vacuum to give 11 g crude product, which is used directly in next step.