Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([O:7][CH3:8])=[O:6].[Cu][C:17]#[N:18].C(OCC)(=O)C>CN1CCCC1=O>[C:17]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([O:7][CH3:8])=[O:6])#[N:18]
Reactant: N#C[Cu]
Reactant: COC(=O)c1ccc(OC(C)C)c(Br)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1

Procedure:
Methyl 3-bromo-4-iso-propoxybenzoate (2.0 g, 7.3 mmol) and copper(I) cyanide in N-methylpyrrolidone (50 ml) were heated under vigorous reflux for 4 h. Work-up with ethyl acetate gave the title compound (1.0 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:21][O:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[N:12][C:24](=[O:25])[CH2:23][O:22][CH3:21])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COCC(=O)Cl
Reactant: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)N=S(C)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 78.6 %

Procedure:
100 mg (0.5 mmol) (RS)—S-(4-nitrophenyl)-S-methylsulfoximide (Example 1b) are dissolved in 3.33 ml dichloromethane, cooled in the ice-bath and treated with 0.1 ml (0.75 mmol) triethylamine. 0.068 ml (0.75 mmol) 2-methoxy-acetyl chloride are added dropwise with ice cooling. The mixture is stirred for 30 minutes in the ice-bath and for 15 hours at room temperature. After chromatographic purification (silica gel, hexane/ethyl acetate (0-50% ethyl acetate)), 107 mg (79%) of the desired product is obtained.
Reaction SMILES: C1(S([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)=[C:22]([Cl:35])[CH:21]=2)=[N:16][CH:15]=[N:14]3)=O)C=CC=CC=1.[NH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.NC1CCN(CC2C=CN3C=2C(NC2C=CC(OCC4C=CC=C(F)C=4)=C(Cl)C=2)=NC=N3)CC1.C(O)(C(F)(F)F)=O>CO>[Cl:35][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[C:18]3=[C:10]([CH2:9][N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[CH:11]=[CH:12][N:13]3[N:14]=[CH:15][N:16]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1
Reactant: O=S(Cc1ccn2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12)c1ccccc1
Reactant: C1CNCCN1
Agent: NC1CCN(Cc2ccn3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Fc1cccc(COc2ccc(Nc3ncnn4ccc(CN5CCNCC5)c34)cc2Cl)c1

Procedure:
The title compound was prepared from 7B and excess piperazine by a route analogous to that used for the preparation of 7C. Analytical HPLC retention time=1.68 min. (YMC Xterra S7 C18, 3.0×50 mm column, 10–90% aqueous methanol over 2 minutes containing 0.1% TFA, 5 mL/min, monitoring at 220 nm) and a LC/MS M++1=467.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:33])=[C:4]([N:10]2[CH2:15][CH2:14][C@@H:13]([N:16](C)[C:17](=O)OC(C)(C)C)[C@H:12]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:11]2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][C@@H:13]([NH:16][CH3:17])[C@H:12]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:11]2)[C:3]=1[Cl:33])[C:8]#[N:9]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@H]1O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@H]1O[Si](C)(C)C(C)(C)C
Yield: 86.5 %

Procedure:
(+/−)-tert-butyl ((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)(methyl)carbamate (Example 186B, 78 mg, 0.158 mmol) was treated with TFA (25% in 1,2-dichloroethane, 0.012 mL, 0.158 mmol) at rt for 1 h. LCMS showed completion of reaction. The reaction mixture was diluted with dichloromethane and washed with cold saturated sodium bicarbonate/1N aqueous sodium hydroxide (pH 10). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 1-10% 2 N ammonia in methanol/dichloromethane) to give (+/−)-3-amino-5-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-(methylamino)piperidin-1-yl)-4-chlorobenzonitrile (54 mg) was obtained as a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][O:26][C:27](=[O:30])[CH2:28]Br>>[CH3:25][O:26][C:27](=[O:30])[CH2:28][N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:13]1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: COC(=O)CBr
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 28.1 %

Procedure:
The title compound (0.09 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 1 mmol) using 2-bromoacetic acid methyl ester (1.5 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C16H18ClN3O2, 319.11; found, m/z 320.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.31 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 4.93 (s, 2H), 3.56 (s, 3H), 3.27-3.25 (br m, 2H), 3.19-3.17 (br m, 2H), 3.04-3.03 (br m, 2H), 2.90-2.88 (br m, 2H).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1C(C)C.O.FC(F)(F)C(O)=O>C(Cl)Cl>[O:2]=[CH:3][CH2:4][N:5]1[C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1
Reactant: COC(=O)c1cccc2nc(C(C)C)n(CC(OC)OC)c12
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc2ncn(CC=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To a stirred solution of methyl 1-(2,2-dimethoxyethyl)-2-isopropyl-1H-benzo[d]imidazole-7-carboxylate from Step D above in methylene chloride were added water and trifluoroacetic acid and the reaction was stirred at room temperature for 2 h and then heated at reflux for 3.5 h. The reaction mixture was concentrated under reduced pressure to remove the excess trifluoroacetic acid, diluted with methylene chloride, washed with saturated aqueous sodium bicarbonate, re-extracted with methylene chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 1-(2-oxoethyl)-1H-benzo[d]imidazole-7-carboxylate (0.2 g, 44% over two steps): 1H NMR (500 MHz, DMSO-d6) δ 9.69 (s, 1H), 7.97 (dd, J=8.0, 1.0 Hz, 1H), 7.81 (dd, J=7.5, 1.0 Hz, 1H), 7.33 (t, J=8.0 Hz, 1H), 5.48 (s, 2H), 3.84 (s, 3H); MS (ESI+) m/z 218 (M+H).
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)[CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)=[O:6].C=O.[C:30]([BH3-])#N.[Na+]>C(O)(=O)C>[OH:1][CH:2]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)[CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:30])[CH2:11][CH2:10]2)=[O:6]
Reactant: COc1cc(C(O)CNC(=O)c2ccc3[nH]ccc3c2)cc(OC)c1OC
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(C(O)CNC(=O)c2ccc3c(c2)CCN3C)cc(OC)c1OC
Reaction time: 18 h
Yield: 100.7 %

Procedure:
A suspension of indole-5-carboxylic acid, (N-[2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]) amide (207 mg, 0.56 mmol) and paraformaldehyde (168 mg, 5.6 mmol) in acetic acid (5 mL) was treated with sodium cyanoborohydride (176 mg, 2.79 mmol), stirred for 18 hours, and concentrated. The concentrate was partitioned between ethyl acetate and 10% NaHCO3, washed sequentially with 10% NaHCO3 and brine, dried (MgSO4), filtered, and concentrated to provide 218 mg of the desired product. MS (ESI(+)) m/z 387 (M+H)+;
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([OH:12])=[O:11].O.Cl[CH:15]([F:17])[F:16]>C(O)(C)C.[OH-].[Na+]>[Br:8][C:7]1[CH:6]=[C:5]([Br:9])[CH:4]=[C:3]([S:10]([CH:15]([F:17])[F:16])(=[O:12])=[O:11])[C:2]=1[NH2:1]
Reactant: FC(F)Cl
Reactant: Nc1c(Br)cc(Br)cc1S(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Nc1c(Br)cc(Br)cc1S(=O)(=O)C(F)F
Temperature: 40 °C

Procedure:
A solution of 2-amino-3,5-dibromobenzenesulfinic acid (7.98 g; 0.025 mol) in a mixture of isopropyl alcohol (100 ml) and sodium hydroxide (8.0 g of 50% aqueous) and water (2 ml) is warmed to 40° C. Chlorodifluoromethane is added slowly through a gas inlet tube over a period of 3 hours. The reaction mixture exotherms to 55° C. The reaction mixture is poured into water (500 ml) and the solution is extracted with methylene chloride (2×100 ml). The combined extracts are washed with saturated NaHCO3 (100 ml), saturated NaCl (100 ml), then dried over MgSO4. The solvent is evaporated under vacuum yield 0.9 g of the title product, m.p. 84°-88° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@:4]([NH2:28])([C@@H:13]([CH2:21][C:22](=[O:27])[CH:23]=[CH:24][CH2:25][CH3:26])[O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[NH:5][C:6]([O:8]C(C)(C)C)=[O:7].N1C(C)=CC=CC=1C.[Si:38](OS(C(F)(F)F)(=O)=O)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39].[Cl-].[NH4+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[C@:4]([NH2:28])([C@@H:13]([CH2:21][C:22](=[O:27])[CH:23]=[CH:24][CH2:25][CH3:26])[O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[NH:5][C:6]([O:8][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])=[O:7]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCC=CC(=O)C[C@@H](OC1CCCCO1)[C@](N)(NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCC=CC(=O)C[C@@H](OC1CCCCO1)[C@](N)(NC(=O)O[Si](C)(C)C(C)(C)C)C(=O)OC
Reaction time: 0.25 h

Procedure:
To a methylene chloride solution (1.0 ml) of N-(t-butoxycarbonyl)-2-amino-4-pentenoyl-O-(tetrahydropyranyl)threonine methyl ester (37 mg, 0.09 mmol) and 2,6-lutidine (0.021 ml, 0.18 mmol) was added dropwise t-butyldimethylsilyltrifluoromethane sulfonate (TBDMSOTf) (0.031 ml, 0.14 mmol) at room temperature in a nitrogen atmosphere. After the mixture was stirred for 15 minutes, a saturated aqueous solution of ammonium chloride (2 ml) was added to quench the reaction and extraction with ether was conducted. The organic layer was dried over anhydrous magnesium sulfate and filtered. By distilling off the solvent under vacuum, the titled compound was obtained in an amount of 45.8 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N([CH2:15][CH3:16])CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:55])C=[C:31]([CH2:37][C:38]2[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[C:40]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:39]=2)[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:55])[C:15]([CH3:16])=[C:31]([CH2:37][C:38]2[CH:46]=[CH:45][C:41]([C:42]([NH:7][C:6]3[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:43])=[C:40]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:39]=2)[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(OCc3ccccc3)c2)=CC1=O
Reactant: CCN(CC)CC
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)Nc3ccc(OC)cc3)c(OCc3ccccc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
p-Methoxyaniline (26 mg, 0.2113 mmol), triethylamine (29 mg, 0.2871 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (48 mg, 0.2840 mmol) were added to a methylene chloride solution (10 ml) of 4-(5,6-dimethoxy-1,4-benzoquinon-2-yl)methyl-2-benzyloxybenzoic acid (60 mg, 0.1421 mmol) and the resulting solution was stirred at room temperature for 3 hours. The reaction solution was poured into ice water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) to obtain the titled compound (55 mg, 0.1143 mmol, 73%).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[F:5][C:6]1[CH:7]=[C:8]([NH:12]N=C2CCCC(O)=C2)[CH:9]=[CH:10][CH:11]=1>O>[F:5][C:6]1[CH:7]=[C:8]2[C:9]([C:11]3[C:1](=[O:4])[CH2:2][CH2:8][CH2:7][C:6]=3[NH:12]2)=[CH:10][CH:11]=1
Reactant: OC1=CC(=NNc2cccc(F)c2)CCC1
Reactant: CC(=O)O
Solvent: O
Product: O=C1CCCc2[nH]c3cc(F)ccc3c21

Procedure:
A mixture of glacial acetic acid (25 ml), 3-(3-fluorophenylhydrazono)-1-cyclohexen-1-ol (1.1 g) and fused zinc chloride (1.0 g) was heated at 100° for 20 h. The cooled reaction mixture was poured into water (35 ml) and extracted with dichloromethane (2×30 ml). The combined, dried organic extracts were evaporated to give an oil which was purified by SPCC eluting with ethyl acetate:hexane (3:2) to give the title compound (0.15 g) as a powder, m.p. 231°-233°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]([C:13]2[C:17]([CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[N:16][O:15][N:14]=2)SC)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:30][OH:31]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:13]2[C:17]([CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[N:16][O:15][N:14]=2)=[N:30][OH:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CSC(=Nc1ccc(F)c(Cl)c1)c1nonc1CO[Si](C(C)C)(C(C)C)C(C)C
Reactant: NO
Solvent: CCO
Product: CC(C)[Si](OCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Temperature: 75 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
Methyl N-(3-chloro-4-fluorophenyl)-4-[(triisopropylsilyl)oxy]methyl-1,2,5-oxadiazole-3-carbimidothioate (3.0 g, 6.5 mmol) was dissolved in EtOH followed by addition of 4 mL hydroxylamine (99.9% in water solution). The reaction was stirred at 75° C. for 6 hrs and monitored by HPLC. The reaction was concentrated in vacuo to a yellow oil which was dissolved in chloroform and chromatographed on 120 g of silica gel eluting with (1:4), EtOAc/hexane. The product was concentrated to give the desired product as a white solid (2.57 g, 89%); MF=C19H28ClFN4O3Si; LCMS calculated for C19H29ClFN4O3Si(M+H)+: m/z=443.168.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:16]([C:17]#[N:18])=[CH:15][NH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.N1C=CC=CC=1.Cl>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:14]2[CH:15]=[C:16]([C:17]#[N:18])[C:12]([NH:11][C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=3)=[N:13]2)=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)c1ccc(Nc2n[nH]cc2C#N)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(Nc2nn(-c3ccc(Cl)cc3)cc2C#N)cc1

Procedure:
3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carbonitrile (64 mg, 0.244 mmol), copper(II) acetate (66.5 mg, 0.366 mmol), (4-chlorophenyl)boronic acid (76 mg, 0.488 mmol) and pyridine (0.079 mL, 0.976 mmol) were stirred in DCM (8 mL) at room temperature overnight. 2 N HCl was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue twice by MPLC (5-60% EtOAc-hexanes) gave 1-(4-chlorophenyl)-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carbonitrile as a white solid. 1-(4-chlorophenyl)-5-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carbonitrile was also isolated.
Reaction SMILES: [CH:1]1([C:4](=O)[CH:5]([N:7]2[CH:12]=[C:11]([I:13])[CH:10]=[CH:9][C:8]2=[N:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH3:6])[CH2:3][CH2:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:29]>C1COCC1>[C:21]1([CH3:24])[CH:20]=[CH:19][C:18]([S:15]([OH:16])(=[O:17])=[O:29])=[CH:23][CH:22]=1.[CH:1]1([C:4]2[N:14]=[C:8]3[CH:9]=[CH:10][C:11]([I:13])=[CH:12][N:7]3[C:5]=2[CH3:6])[CH2:3][CH2:2]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)N=c2ccc(I)cn2C(C)C(=O)C2CC2)cc1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(I)cn12
Product: Cc1ccc(S(=O)(=O)O)cc1
Reaction time: 3 h

Procedure:
To a solution of N-(1-(1-cyclopropyl-1-oxopropan-2-yl)-5-iodopyridin-2(1H)-ylidene)-4-methylbenzene sulfonamide (30.5 g) in THF (300 ml) was added trifluoroacetic anhydride (18.3 ml) dropwise. After 3 h, the resulting precipitate was collected by filtration, and washed with ether to give p-toluenesulfonic acid salt of the title compound as a white solid. The solid obtained was dissolved in a mixture of 1 M NaOH, EtOAc and THF. Then the organic layer was washed with brine, dried over MgSO4 and concentrated. The resulting solid was triturated with IPE, and collected to give the title compound (17.7 g) as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6](/[CH:8]=[CH:9]/[CH2:10]P(OCC)(OCC)=O)=[O:7].[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH:22]=O>C1COCC1>[CH2:4]([O:5][C:6](=[O:7])[CH:8]=[CH:9][CH:10]=[CH:22][C:21]1[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:20]=1[Cl:19])[CH3:3]
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=CC=Cc1ccc(Cl)cc1Cl
Reaction time: 2 h
Yield: 31 %

Procedure:
To a suspension of 60% NaH in mineral oil (16 g) in 1 L THF was added triethyl 4-phosphonocrotonate (100 g). The resulting solution was stirred for 2 hr, and then a solution of 2,4-dichlorobenzaldehyde (54 g) in 200 mL THF was added thereto. The mixture was stirred at room temperature for 1 hr. The reaction was quenched by the addition of 1 L of aq. NH4Cl and the THF was evaporated. The mixture was extracted with 4×200 ml ethyl acetate and the combined organic layer washed with water, brine and dried over MgSO4 then evaporated to provide the crude product. This was purified by silica gel chromatography using 5% ethyl acetate-hexanes to give 25.9 g of 5-(2,4-dichloro-phenyl)-penta-2,4-dienoic acid ethyl ester. MS: m/e 271.04 (MH+)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:28][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[C@H:14]([C@H:18]2[CH2:23][CH2:22][C@H:21]([O:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:19]2)[C:15]([OH:17])=O)(=[O:12])=[O:11])=[CH:6][CH:5]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[C:53]([O:57][NH2:58])([CH3:56])([CH3:55])[CH3:54].Cl.CN(CCCN=C=NCC)C>C(Cl)Cl.O>[C:53]([O:57][NH:58][C:15](=[O:17])[C@H:14]([N:13]([S:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=1)(=[O:11])=[O:12])[CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[C@H:18]1[CH2:23][CH2:22][C@H:21]([O:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:19]1)([CH3:56])([CH3:55])[CH3:54]
Reactant: CCCO[C@H]1CC[C@H]([C@H](C(=O)O)N(Cc2ccncc2)S(=O)(=O)c2ccc(OC)cc2)CC1
Reactant: CC(C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCO[C@H]1CC[C@H]([C@H](C(=O)NOC(C)(C)C)N(Cc2ccncc2)S(=O)(=O)c2ccc(OC)cc2)CC1
Reaction time: 8 h

Procedure:
2(R)-[(4-methoxybenzenesulfonyl)(4-picolyl)amino]-2-(trans-4-propoxycyclohexyl) acetic acid hydrochloride (2.65 g, 4.82 mmol), 1-hydroxybenzotriazole (0.65 g, 4.81 mmol), 4-methylmorpholine (2.93 mL, 26.5 mmol), and O-t-butylhydroxylamine hydrochloride (1.81 g, 14.4 mmol) are dissolved in methylene chloride (100 mL). N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (1.1 g, 5.8 mmol) is added, and the reaction is stirred overnight. The reaction is then diluted with water and extracted with methylene chloride. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (5% methanoilmethylene chloride) to give N-(t-butyloxy)-2(R)-[(4-methoxybenzenesulfonyl)-(4-picolyl)amino]-2-(trans-4-propoxy-cyclohexyl)-acetamide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.CS(O[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH2:35][CH3:36])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:34]([O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1)[CH2:35][CH3:36]
Reactant: CCCOc1ccccc1CCCOS(C)(=O)=O
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1ccccc1CCCOc1ccc2c(c1)C=C(C(=O)OC)CCS2(=O)=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 125.5 %

Procedure:
Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 3-(2-propoxyphenyl)propyl methanesulfonate (1.06 g) and potassium carbonate (309 mg) were suspended in DMF (15 ml), and the resulting suspension was stirred at 60° C. for 3 hours. The reaction mixture was diluted with ethyl acetate and was washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain methyl 7-[3-(2-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (832 mg) as a yellow oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.CCN(CC)CC.[Br:29][C:30]1[CH:63]=[CH:62][C:33]([C:34]([NH:36][NH:37][C:38](=[O:61])[C@H:39]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[C:53]([Cl:59])[C:52]=2[CH3:60])[C@@H:40]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH3:41])=O)=[CH:32][CH:31]=1>C(Cl)Cl>[Br:29][C:30]1[CH:31]=[CH:32][C:33]([C:34]2[O:61][C:38]([C@H:39]([NH:50][C:51]3[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[C:53]([Cl:59])[C:52]=3[CH3:60])[C@@H:40]([O:42][Si:43]([C:46]([CH3:48])([CH3:49])[CH3:47])([CH3:44])[CH3:45])[CH3:41])=[N:37][N:36]=2)=[CH:62][CH:63]=1
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(Br)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(Br)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.5 %

Procedure:
To a solution of triphenylphosphine (4.23 g, 16.1 mmol) in DCM (200 mL) was added I2 (4.1 g, 16.2 mmol) at 0° C. After I2 was dissolved completely, Et3N (4.5 mL, 32.3 mmol) was added, followed by a solution of 4-bromo-N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-benzohydrazide (4.68 g, 8.1 mmol) in DCM (100 mL). The reaction mixture was allowed to warm to room temperature and stirred for additional 15 min. The reaction was quenched with saturated sodium thiosulfate (50 mL) and diluted with DCM (400 mL). The organic layer was separated and washed with water, brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash chromatography to provide the title compound (4.03 g, 89%), which was used directly in the next step
Reaction SMILES: ClC1C(NC2C=C(C)NN=2)=NC(N[C@H:9]([C:11]2[N:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])=NC=1.[BH4-].[Na+].C[OH:28]>>[F:17][C:14]1[CH:13]=[N:12][C:11]([CH:9]([OH:28])[CH3:10])=[N:16][CH:15]=1
Reactant: CO
Reactant: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2Cl)n[nH]1
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1ncc(F)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
1-(5-Fluoropyrimidin-2-yl)ethanone (Method 5, 0.77 g) was dissolved in MeOH (15 ml), and the solution was cooled to 0° C. NaBH4 (0.210 g, 5.55 mmol) was added. The mixture was stirred at room temperature for 1 hour and then partitioned between EtOAc and H2O. The organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated to give the title compound as a yellowish oil (0.79 g, 99%). 1H NMR (CDCl3) δ 8.65 (s, 2H), 5.20 (m, 1H), 4.00 (br s, 1H), 1.80 (d, 3H).