Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:28]([CH3:38])[S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:26]=[CH:27][C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:41][N:40]=[N:39][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[CH:24]=[C:25]([N:28]([CH3:38])[S:29]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)(=[O:31])=[O:30])[CH:26]=[CH:27][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccc(N(C)S(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2ccc(N(C)S(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 41 from 4'-[[2-n-propyl-6-(N-benzenesulphonyl-methylamino)-benzimidazol-1-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: O[C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22]CC)=[O:21].C1OC2C=CC(C3C4C(=CC=CC=4)C(=O)C=3C(OCC)=O)=CC=2O1.COC1C=C([Mg]Br)C=CC=1>C1COCC1>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]([C:11]3[CH:16]=[CH:15][C:14]4[O:17][CH2:18][O:19][C:13]=4[CH:12]=3)[CH:3]2[C:20]([OH:22])=[O:21])[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1cccc(OC)c1
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Agent: COc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: COc1cccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)c1
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Ethyl (1RS)-1-Hydroxy-1-(3-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate. To a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (100 mg, 0.31 mmol) in THF (2 ml) under an argon atmosphere at 0° C. was added a solution of freshly prepared 3-methoxyphenyl magnesium bromide (0.31 mmol). After stirring for 15 min, additional 3-methoxyphenyl magnesium bromide (0.06 mmol) was added. Stirring was continued for 45 min, at which time thin layer chromatographic analysis indicated that the reaction was incomplete. Additional 3-methoxyphenyl magnesium bromide (0.12 mmol) was added. After stirring for 2 h more, the mixture was partitioned between 3 M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 15% EtOAc/hexanes to afford the title compound (150 mg, 100%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.S(Cl)([Cl:23])=O>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([Cl:23])=[O:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Temperature: 25 °C

Procedure:
The product from Example 10C (3.5 g, 11.36 mmol) in thionyl chloride (25 mL) was heated at 90° C. for 4 hours. The solution was allowed to cool to ambient temperature and then the mixture was evaporated to dryness to provide the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([O:15][C:16]2[CH:17]=[C:18]([CH:29]=[C:30]([O:32][C:33]3[CH:38]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:36]=[C:35]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:34]=3)[CH:31]=2)[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=2)=[O:20])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>Br.[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC>[C:11]([C:9]1[CH:8]=[C:7]([O:15][C:16]2[CH:17]=[C:18]([CH:29]=[C:30]([O:32][C:33]3[CH:38]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:36]=[C:35]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:34]=3)[CH:31]=2)[C:19]([C:21]2[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=2)=[O:20])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: COc1ccc(C(=O)c2cc(Oc3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc(Oc3cc(C(C)(C)C)cc(C(C)(C)C)c3)c2)cc1
Agent: Br
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: CC(C)(C)c1cc(Oc2cc(Oc3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc(C(=O)c3ccc(O)cc3)c2)cc(C(C)(C)C)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
2.80 g (4.5 mmoles) of 3,5-bis-(3,5-di-tert.-butylphenyloxy)4′-methoxybenzo-phenone are dissolved under argon in 100 ml of hydrobromic acid solution (33% in acetic acid). 0.23 g (0.5 mmole) of: hexadecyltributylphosphonium bromide is added thereto. The solution is stirred for 3 hours at 50° C. The course of the reaction is followed by thin layer chromatography. An additional 100 ml of hydrobromic acid (33% in glacial acetic acid) and 20 ml of aqueous hydrobromic acid (48%) are added to the reaction solution. The solution is stirred for a further 18 hours under reflux. After cooling the solution, the reaction mixture is poured onto ice and extracted several times with diethyl ether. The combined organic phases are washed with saturated NaCl solution. The product is dried over magnesium sulfate and the solvent is removed in vacuo. The crude product is chromatographed on silica gel (silica gel 60, 0.040-0.063 mm, Merck) using a mixture of n-hexane/ethyl acetate (9:1). After removing the solvent and drying the residue in a high vacuum, 2.47 g (90%) of a white solid are obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:28])[C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)[C@H:14]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:28])[C:19]([C:20]3[CH:25]=[CH:24][C:23]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:22][CH:21]=3)=[O:27])[C@H:14]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3ccc(Br)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3ccc(-c4ccccc4)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Temperature: 100 °C
Reaction time: 14 h
Yield: 70.3 %

Procedure:
To a mixture of the compound obtained in Example 18 (0.20 g) in toluene (10 mL) and water (0.5 mL) were added phenylboronic acid (0.083 g), tetrakis(triphenylphosphine)palladium(0) (0.039 g) and potassium carbonate (0.047 g), and the mixture was stirred under an argon atmosphere at 100° C. for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with aqueous ammonium chloride solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 75→100% ethyl acetate/hexane) to give the title compound (0.14 g, 69%) as a white powder.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2I.C([Mg]Cl)(C)C.Cl[Sn:21]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1>[F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[Sn:21]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: FC(F)Oc1ccc2[nH]nc(I)c2c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2ccc(OC(F)F)cc12
Temperature: -25 °C
Reaction time: 0.33 h
Yield: 79.3 %

Procedure:
In a flask, 5-(difluoromethoxy)-3-iodo-1H-indazole (1.2 g, 2.93 mmol) was dissolved in THF (30 mL). The solution was cooled to −25° C. Isopropylmagnesium chloride (8.8 mL, 8.8 mmol, 1M in THF) was added drop-wise at −25° C. The reaction mixture was stirred at −25° C. for 20 min. Then chlorotributyltin (1.6 mL, 5.86 mmol) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 h. The reaction mixture was quenched with saturated NH4Cl solution and then extracted with EtOAc (3×20 mL), organics were washed with water (10 mL), brine (2×10 mL) and dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (8:1) to give 5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazole (1.1 g, 79%) as an oil. 1H NMR (300 MHz, CDCl3): δ 7.52-7.46 (m, 2H), 7.19 (d, 1H, J=7.9 Hz), 6.51 (t, 1H, J=88.6 Hz), 1.68-1.57 (m, 6H), 1.45-1.14 (m, 12H), 0.93-0.84 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8](S(CCC)(=O)=O)[S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])=[CH:4][C:3]=1[C:21]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[N:26]2)=[O:22].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])=[CH:4][C:3]=1[C:21]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[N:26]2)=[O:22]
Reactant: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1)S(=O)(=O)CCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a solution of N-(4-fluoro-3-(quinoxaline-6-carbonyl)phenyl)-N-(propylsulfonyl)propane-1-sulfonamide (50 mg, 0.10 mmol, 1.0 eq.) in MeOH (10 mL) was added NaOH aqueous solution (1 N, 0.22 mL, 0.22 mmol, 2.2 eq.). The resulting mixture was stirred at it for 1 h, then concentrated. The resulting residue was purified by flash column chromatography (PE/EA=1/1, v/v) to afford N-(4-fluoro-3-(quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide (33.4 mg, 89.5%). LRMS (M+H+) m/z calculated 374.1, found 374.1. 1H NMR (CDCl3, 400 MHz) δ 8.94-8.97 (dd, 2 H), 8.46-8.47 (m, 1 H), 8.31-8.34 (m, 1 H), 8.23-8.25 (m, 1 H), 7.50-7.54 (m, 1 H), 7.46-7.48 (m, 1 H), 7.19-7.23 (t, 1 H), 6.80 (s, 1 H), 3.10-3.14 (m, 2 H), 1.86-1.92 (m, 2 H), 1.04-1.08 (t, 3 H).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:24][C:23]([S:25](Cl)(=[O:27])=[O:26])=[N:22][N:21]=2)=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:25]([C:23]1[S:24][C:20]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[N:21][N:22]=1)(=[O:26])=[O:27])[CH3:4]
Reactant: CCOC(=O)CNCCN
Reactant: O=S(=O)(Cl)c1nnc(-c2ccc(Cl)cc2)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To a solution of N-(2-aminoethyl)-glycine ethyl ester 2HCl (1.4 g, 6.4 mmol), prepared as described by Will (D. W. Will et al., Tetrahedron, 1995, 51, 12069.), in dichloromethane (50 mL) was added 5-(4-chlorophenyl)-1,3,4-thiadiazole-2-sulfonyl chloride (1.5 g, 5.1 mmol) at 0° C. Then triethylamine (2.7 mL) was slowly added. The resulting reaction mixture was stirred for additional 2 h. at room temperature and washed with water (30 mL). The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated, followed by column chromatography to give the title compound (1.1 g, 2.7 mmol, 53%) as a solid. 1H NMR (500 MHz; DMSO-d6) δ 8.08 (d, 2H), 7.66 (d, 2H), 4.03 (q, 2H), 3.26 (s, 2H), 3.15 (t, 2H), 2.64 (t, 2H), 1.14 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH2:25].[CH2:26]([N:28]=[C:29]=[S:30])[CH3:27]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH:25][C:29]([NH:28][CH2:26][CH3:27])=[S:30]
Reactant: CCN=C=S
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Solvent: ClCCl
Product: CCNC(=S)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and ethyl isothiocyanate (0.053 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.14 g, 60%): mp 88-91° C.; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=8 Hz, 1H), 7.41 (d, J=7.2 Hz, 2H), 7.26 (m, 2H), 6.50 (d, J=16 Hz, 1H), 6.35 (dd, J=16.0, 8.0 Hz, 1H), 6.0 (br s, 1H), 5.73 (br s, 1H), 4.80 (br s, 2H), 4.09 (m, 1H), 1.23 (m, 3H); ESIMS m/z 515.01 ([M+H]+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:26])=[C:8]([N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Cl.[OH-].[Na+]>C(OCC)(=O)C>[CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:26])=[C:8]([N:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: Cc1c(C)c(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Temperature: 50 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
tert-butyl 4-(2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine-1-carboxylate (16.1 g, 44.7 mmol) synthesized in Reference Example 55 was added to an ethyl acetate solution containing 2N hydrogen chloride, and the mixture was stirred at 50° C. for 3 hours. The reaction solution was poured into an aqueous solution of 2N sodium hydroxide, and the mixture was extracted using ethyl acetate. The extract was washed with saturated saline, and dried using anhydrous sodium sulfate. After that, the solvent was removed under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (ethyl acetate-methanol 90:10) to give 11.3 g of the title compound as an oily product (yield: 97%).
Reaction SMILES: CS(O)(=O)=O.[CH3:6][N:7]([CH2:9][C:10]1[O:14][C:13]([CH2:15][OH:16])=[CH:12][CH:11]=1)[CH3:8].[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21]O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O>[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:16][CH2:15][C:13]1[O:14][C:10]([CH2:9][N:7]([CH3:6])[CH3:8])=[CH:11][CH:12]=1
Reactant: NCCCCO
Reactant: CN(C)Cc1ccc(CO)o1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1ccc(COCCCCN)o1
Yield: 29.2 %

Procedure:
A mixture of methanesulphonic acid (86 g), 5-[(dimethylamino)methyl]-2-furanmethanol (15.5 g) and 4-aminobutanol (17.8 g) in dry tetrahydrofuran was heated at 100° for 11/2 h. Excess sodium carbonate was added to the cooled solution, the suspension was filtered and the filtrate was evaporated to give a red oil which was dissolved in water and extracted with ether. The extract was distilled to give the title compound as an oil (6.6 g) b.p. 100°-110°, 0.08 mm. TLC silica, methanol/ammonia 0.88 80:1, Rf 0.3.
Reaction SMILES: [C:1]([S:4][CH:5]([CH:17]([C:22]([NH:24][C@H:25]([C:35]([NH:37][CH3:38])=[O:36])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6][C:7]([O:9]CC1C=CC=CC=1)=[O:8])(=[O:3])[CH3:2]>C(O)=O.CO.[Pd]>[C:1]([S:4][CH:5]([CH:17]([C:22]([NH:24][C@H:25]([C:35]([NH:37][CH3:38])=[O:36])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6][C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)OCc1ccccc1)SC(C)=O
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)O)SC(C)=O

Procedure:
A solution of 3-acetylmercapto-6-methyl-4-[[[1-(S)-[(methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoic acid, benzyl ester (E3; 300 mg, 0.55 mmol) in 4.5% formic acid/methanol (6 ml) was added, under nitrogen, to a stirred suspension of palladium black (310 mg) in the same solvent (15 ml). After 90 min the mixture was filtered through kieselguhr and evaporated in vacuo. Column chromatography using reverse phase silica (30 g) and eluting with 25% aqueous methanol gave two single diastereoisomers of the title compound, as monohydrates.
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:11]=[C:12]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:24]1[CH:25]=[C:26]([CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1.Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:1][C:28]4[CH:29]=[CH:24][CH:25]=[C:26]([CH:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH:27]=4)[N:22]=3)[CH:9]=[CH:8][CH:7]=2)[CH:11]=1)[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CN(c1cccc(-c2cccn3nc(N)nc23)c1)S(C)(=O)=O
Reactant: CN1CCC(c2cccc(Br)c2)CC1
Agent: Cl
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2cccc(Nc3nc4c(-c5cccc(N(C)S(C)(=O)=O)c5)cccn4n3)c2)CC1

Procedure:
N-Methyl-N-(3-{2-[3-(1-methyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 4-(3-bromo-phenyl)-1-methyl-piperidine; hydrochloride (76.0 mg, 0.262 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.093 g, 80%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.46 (d, J=6.6 Hz, 1H), 8.10-8.07 (m, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.46-7.40 (m, 2H), 7.27 (t, J=7.9 Hz, 1H), 6.98 (t, J=7.1 Hz, 1H), 6.88 (d, J=7.7 Hz, 1H), 6.83 (s, 1H), 3.42 (s, 3H), 3.03-2.96 (m, 2H), 2.90 (s, 3H), 2.55-2.45 (m, 1H), 2.34 (s, 3H), 2.12-2.00 (m, 2H), 1.90-1.80 (m, 4H). MS=491 (MH)+.
Reaction SMILES: C(OC([NH:8][O:9][S:10]([C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21])(=[O:12])=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>O>[O:9]([S:10]([C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21])(=[O:11])=[O:12])[NH2:8]
Reactant: Cc1cc(C)c(S(=O)(=O)ONC(=O)OC(C)(C)C)c(C)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reaction time: 0.5 h

Procedure:
To the solid product N-(tert.-butoxycarbonyl)-O-(mesitylsulfonyl)-hydroxylamine (2.1 g, 6.6 mmol) is added trifluoroacetic acid (20 mL) slowly at 0° C. under a nitrogen atmosphere. The reaction mixture is stirred for 30 minutes followed slowly by water (60 mL). The reaction is left at 0° C. for 15 minutes. The solid precipitated is filtered and washed several times with water until the pH of the filtrate was neutral. The white solid (1.4 g, 98%) is dried in the Buchner funnel and used immediately for the next reaction; 1H NMR (400 MHz, DMSO-d6): δ6.73 (s, 2H), 2.48 (s, 6H), 2.15 (s, 3H).
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=2[CH2:3][CH2:2]1.C[O-].[Na+].[O-2].[K+].[K+].Br[CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20]>CO.C1C=CC=CC=1.O>[CH2:1]1[C:9]2[C:4](=[C:5]([O:10][CH:18]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=4)=[CH:25][CH:24]=3)[C:19]([O:21][CH3:22])=[O:20])[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Oc1cccc2c1CCC2
Agent: C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CO
Product: COC(=O)C(Oc1cccc2c1CCC2)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 3.36 g of 4-indanol, 1.188 g of sodium methoxide and 50 mg of potassium oxide in 40 ml of methanol is added 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. The mixture is refluxed overnight and then poured into 100 ml of water. The mixture is extracted with 2 × 75 ml of ether. The combined extracts are washed with 50 ml of 5% NaOH, 50 ml of water, 50 ml saturated brine, and dried (MgSO4). Evaporation of the solvent yields a yellow oil. Chromatography on 100 g of silica gel (benzene, 400 ml) yields the product as a light yellow oil which solidifies on standing.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[C:14](OCC)(=[O:19])[CH2:15][C:16]([CH3:18])=O>C(O)(=O)C>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:14]([OH:19])=[CH:15][C:16]([CH3:18])=[N:13]2)=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(NN)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(O)n(-c2ccc(C(C)(C)C)cc2)n1
Yield: 78.5 %

Procedure:
4-t-Butylphenylhydrazine hydrochloride (24.2 g, 120 mmol) in acetic acid (600 mL) was stirred with ethyl acetoacetate (16.4 mL, 129 mmol) at 100° C. for 22 hours. The solvent was removed by distillation under reduced pressure, and the resulting solid was recrystallized from chloroform (70 ml, 40° C.)-diethyl ether (200 mL, 0° C.), washed with diethyl ether and dried under reduced pressure to give 21.7 g of the desired product (78% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[CH:14]=[CH:15][C:16]([N+:18]([O-])=O)=[CH:17][C:12]=3[O:11][C:10]([CH3:22])([CH3:21])[N:9]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+].C(O)C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:12]=3[O:11][C:10]([CH3:22])([CH3:21])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)N=C(c2ccc(F)cc2)c2ccc([N+](=O)[O-])cc2O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC1(C)N=C(c2ccc(F)cc2)c2ccc(N)cc2O1
Temperature: 25 °C

Procedure:
A mixture of the compound obtained in (2) described above (2.2 g), reduced iron (2.0 g), ammonium chloride (780 mg), ethanol (40 mL) and water (10 mL) was heated under reflux for an hour. After cooling to room temperature, the reaction solution was filtered through Celite and the filtrate was concentrated in vacuo. Dichloromethane (50 mL) and water (50 mL) were added to the residue, and the aqueous layer was separated and extracted with dichloromethane (40 mL×2). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the titled compound (2.0 g) as a yellow powder, which was used in the next step without further purification.