Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]1(C(C2C=CC=CC=2)OC2CCN(CCCOC3C=CC=CC=3N)CC2)C=CC=CC=1.C(S(Cl)(=O)=O)C.CS(Cl)(=O)=O>>[C:1]1([CH:7]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:26]([CH2:29][CH3:36])(=[O:28])=[O:27])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Nc1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: Nc1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: CCS(=O)(=O)Cl
Agent: CS(=O)(=O)Cl
Product: CCS(=O)(=O)Nc1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1

Procedure:
The procedure of Example 1 (c) was repeated except for using 4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine obtained in Example 1 (b) and ethanesulfonyl chloride instead of 4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine and methanesulfonyl chloride to give the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]1[CH2:23][O:22]1)([CH3:16])([CH3:15])[CH3:14]>CCO.O>[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]([OH:22])[CH2:23][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCC[C@@H](O)CNc1ccc2c(c1)NC(=O)CO2
Yield: 40.2 %

Procedure:
A solution of 6-amino-4H-benzo[1,4]oxazin-3-one (commercial; 6.49 g, 39.5 mmol) and (2R)-tert-butyl-dimethyl-(2-oxiranyl-ethoxy)-silane (first eluting compound of step 18.i, 8.0 g, 39.5 mmol) in 9-1 EtOH/H2O (240 mL) was heated at 80° C. for 2 days. The mixture was concentrated under reduced pressure. Residual starting aniline could be removed by addition of Et2O/MeOH followed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by CC (DCM/MeOH/NH4OH 1000:50:4) to afford the title intermediate as a brown oil (5.82 g, 40% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][CH2:10]Cl)=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][CH2:10][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: OC(CCCl)c1ccc(Br)cc1
Solvent: CN(C)C=O
Product: OC(CCn1ccnc1)c1ccc(Br)cc1
Yield: 44 %

Procedure:
A solution of 1-(4-Bromo-phenyl)-3-chloro-propan-1-ol* (1.5 g, 6.01 mmol) and imidazole (1.23 g, 18.03 mmol) in dimethylformamide (18 ml) was heated at 100° C. for 18 hrs then partitioned between water and ethyl acetate. The organic extracts were combined, dried (MgSO4), filtered, concentrated and purified by column chromatography (SiO2), eluting with methanol:dichloromethane (2:98) to methanol:dichloromethane (6:94) to afford the title compound (0.75 g, 44% yield). LC/MS: (PS-B3) Rt 2.48 [M+H]+ 281.14, 283.11. *This starting material can be made by the method described in Example 43A.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:17][C:4]=1[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:8].C(Cl)Cl.CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>CN(C1C=CN=CC=1)C.CCOC(C)=O>[Cl:2][C:3]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[CH2:23][CH2:24][N:25]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:26][CH2:27]2)=[CH:17][C:4]=1[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(NC(=O)NCc2cc(CN3CCNCC3)ccc2Cl)cn1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(NC(=O)NCc2cc(CN3CCN(S(C)(=O)=O)CC3)ccc2Cl)cn1
Reaction time: 16 h

Procedure:
In a 20 mL scintillation vial equipped with a stir bar, 1-(2-chloro-5-(piperazin-1-ylmethyl)benzyl)-3-(6-methylpyridin-3-yl)urea hydrochloride salt (367 mg, 654 □mol) and DMAP (2 mg) were sealed with a septum cap and maintained under a positive nitrogen pressure. To the mixture was added 6 mL of anyhydrous CH2Cl2, followed by DIPEA (520 □L, 2.94 mmol) and methanesulfonyl chloride (70 □L, 785 □mol). The reaction mixture was stirred for 16 h. The reaction mixture was diluted with 6 mL of EtOAc. The organic solution was washed with 4 mL each of water and saturated NaCl solution, dried over Na2SO4, filtered and concentrated to afford 1-(2-chloro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)benzyl)-3-(6-methylpyridin-3-yl)urea as beige foam (209 mg).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O-:14])(=[O:13])[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8].[Na+].N1C=CC=CC=1>ClCCl>[C:5]([OH:14])(=[O:13])[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8].[OH:13][CH2:5][C:6]1[C:7]([OH:8])=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C([O-])c1ccccc1O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(O)c1ccccc1O
Product: OCc1ccccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
Thionyl chloride (1 mol) in dichloromethane (400 ml) was added dropwise and with constant stirring to a dispersion of sodium salicylate (1 mol) in dichloromethane (800 ml). The mixture was stirred for a further hour, then left to cool to room temperature, care being taken to avoid absorption of atmospheric moisture. This solution was then added dropwise and with vigorous stirring to a solution of Product A mol) and pyridine (2 mol) in dichloromethane (1200 ml). After addition was completed, the mixture was heated to 40° C., held at this temperature for 10 minutes and then allowed to cool. The reaction mixture was then washed several times with water and dilute acid until no traces of pyridine remained. The organic phase was then dried over anhydrous sodium sulphate, filtered and stripped of solvent to obtain saligenin salicylate in 60% yield.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([NH:12][C:13](=[O:15])[CH3:14])[N:6]=1)(=O)C.IC>CO.C(Cl)Cl>[CH3:1][O:4][C:5]1[N:6]=[C:7]([NH:12][C:13](=[O:15])[CH3:14])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: CC(=O)Nc1ccc(C)c(OC(C)=O)n1
Solvent: CO
Solvent: ClCCl
Solvent: CI
Product: COc1nc(NC(C)=O)ccc1C
Temperature: 35 °C
Reaction time: 18 h
Yield: 143.6 %

Procedure:
To a stirred solution of 6-acetamido-3-methylpyridin-2-yl acetate (3.44 g, 16.5 mmol) in 2:1 MeOH/DCM (105 mL) at rt was added Ag2CO3 (9.11 g, 33.0 mmol) followed by iodomethane (3.09 mL, 49.6 mmol). The resulting mixture was stirred at 35° C. for 18 h then stood at rt for 2 d. The reaction mixture was combined with 2 previous batches derived from 6-acetamido-3-methylpyridin-2-yl acetate (590 mg, 2.83 mmol and 3.44 g, 16.5 mmol) and the combined batches were filtered through celite, rinsing with DCM. After concentration of the filtrate in vacuo purification by gradient column chromatography eluting with 20-50% EtOAc in heptane yielded the title compound (4.27 g, 23.7 mmol) as a white solid.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]3[N:23]=[N:24][CH:25]=[CH:26]C=3)[C@H:16]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.S([O-])([O-])(=O)=O.[Mg+2].C([N:44](CC)CC)C.C(C=O)=O>C(O)C>[F:34][C:2]([F:35])([F:1])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]3[N:23]=[N:24][CH:25]=[CH:26][N:44]=3)[C@H:16]2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCCN(Cc3cccnn3)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: CCN(CC)CC
Agent: O=CC=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Product: FC(F)(F)c1cc(CO[C@H]2CCCN(Cc3nccnn3)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
The amidrazone hydrochloride of (b) above (200 mg) was dissolved in ethanol (2 ml). Magnesium sulphate was added (100 mg) and the mixture stirred for 30 min. Triethylamine (0.06 ml) was added followed by glyoxal (90 mg, trimeric dihydrate). This mixture was allowed to stir for 12 h. The solvent was removed in vacuo and the residue was dispersed between ethyl acetate and water. The organic layer was dried (MgSO4) and concentrated to afford a brown oil. This was purified by column chromatography on silica using hexane in ethyl acetate (95%) to afford the title compound. 1H NMR (360 MHz, CDCl3) δ1.53-1.72 (2H, m, CH2), 1.98-2.22 (2H, m, CH2), 2.42-2.53 (1H, m, NCHH), 3.14-3.22 (1H, m, NCHH), 3.61 (1H, bs, CHO), 3.74-3.81 (2H, m, NCHPh+OCHH), 4.04 (1H, d, J=12 Hz, NCHHtriazine), 4.19 (1H, d, J=12 Hz, OCHH), 4.47 (1H, d, J=12 Hz, NCHHtriazine), 7.24-7.37 (4H, m, ArH), 7.48-7.6 (4H, m, ArH), 7.70 (1H, s, ArH), 8.6 (1H, s, ArH). MS (CI+) m/z 497 (M+ +1, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH3:26][O:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH2:30][CH2:31][CH2:32][CH:33]2[NH2:38]>>[CH2:24]([O:23][C:21]([C:3]1[C:4]([CH3:20])=[N:5][C:6]2[C:11]([C:2]=1[NH2:1])=[C:10]([O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:38][CH:33]1[C:34]3[C:29](=[C:28]([O:27][CH3:26])[CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:31][CH2:32]1)=[O:17])[CH:9]=[CH:8][CH:7]=2)=[O:22])[CH3:25]
Reactant: COc1cccc2c1CCCC2N
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC3CCCc4c(OC)cccc43)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and 5-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine as a brown solid (40%). MS 506 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:18])=[N:5][C:6]([O:16][CH3:17])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH:8]=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[C:6]([O:16][CH3:17])=[N:5][C:4]([CH3:18])=[C:3]([CH2:2][N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1nc(C)c(CCl)cc1-c1cccc(Cl)c1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1nc(C)c(Cn2cncn2)cc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution of 3-(chloromethyl)-5-(3-chlorophenyl)-6-methoxy-2-methylpyridine (Intermediate 8, 87 mg, 0.31 mmol), in acetone (12 mL), was added 1H-1,2,4-triazole (32 mg, 0.46 mmol), and cesium carbonate (150 mg, 0.63 mmol). The reaction mixture stirred at room temperature for 2 h, then filtered and concentrated under reduced pressure. Purification (FCC, SiO2, 0-100%, EtOAc/hexanes) afforded the title compound (82.4 mg, 84%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.98 (s, 1H), 7.52 (s, 1H), 7.45-7.37 (m, 2H), 7.37-7.29 (m, 2H), 5.34 (s, 2H), 3.98 (s, 3H), 2.52 (s, 3H). [M+H]=315.22.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22](O)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].O[N:31]1[C:35]2C=CC=CC=2N=N1.N=C=N.CN.CN=C=O>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22]([NH:31][CH3:35])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(C(=O)O)ccc1F
Agent: CN
Agent: CN=C=O
Agent: N=C=N
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a reaction vessel (borosilicate culture tube) was added 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoic acid (0.300 g, 0.708 mmol) and 1-hydroxybenzotriazole (0.048 g, 0.45 mmol). N,N-Dimethylformamide (3 mL) was added to the reaction vessel followed by approximately 1.2 g of the polymer bound carbodiimide resin (1.38 mmol/g). Additional N,N-dimethylformamide (2 mL) was then added to the reaction vessel. The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 15 minutes. N-Methyl amine (1 mL, 2 mmol) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. At this time the reaction was diluted with tetrahydrofuran (20 mL) and treated with approximately 2.17 g of polyamine resin (2.63 mmol/g) and approximately 2.8 g of methylisocyanate functionalized polystyrene (1.5 mmol/9) and the orbital shaking was continued at 200 RPM at room temperature for 3 hours. The reaction vessel was then opened and the solution phase product was separated from the insoluble quenched byproducts by filtration and collection into a vial. After partially evaporation the insoluble byproducts were rinsed with tetrahydrofuran (2×10 mL). The filtrate was evaporated by blowing N2 over the vial and the resulting solid was triturated with diethyl ether to give an off-white solid. (0.168 g, 59%) 1H NMR (400 MHz, CD3OD) δ 8.02 (dddd, J=2, 4.4, 7.2 and 8.4 Hz, 1H), 7.80 (dd, J=2 and 6.8 Hz, 1H), 7.62 (q, J=8 and 14.4 Hz, 1H), 7.34 (t, J=8.8 Hz, 1H), 7.04 (m, 2H), 6.69 (s, 1H), 5.36 (s, 2H), 3.29 (s, 3H), 1.98 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ−108.94 (1 F), −113.55 (1 F), −117.76 (1 F) ppm. ES-HRMS m/z 437.0861 (M+H calcd for C21H17ClF3N2O3 requires 437.0874).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].Cl.[CH3:20][NH:21][CH3:22]>C(N(CC)CC)C>[CH3:20][N:21]([CH3:22])[C:16]([C:14]1[S:15][C:11]([C:3]2[C:2]([CH3:1])=[C:6]([C:7]([F:10])([F:9])[F:8])[O:5][N:4]=2)=[CH:12][CH:13]=1)=[O:18]
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(C(=O)N(C)C)s2)noc1C(F)(F)F
Yield: 72 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and dimethylamine hydrochloride by the method described in Example 2 Method B utilizing an additional equivalent of triethylamine. The reaction mixture was evaporated to a solid then triturated and filtered with the aid of water to afford product as a colorless solid (110 mg, 72%). 1H NMR (CDCl3) 2.37 (s, 3 H), 3.22 (br s, 6 H), 7.41 (d, J=4.0, 1 H), 7.47 (d, J=4.0, 1 H). 13C NMR 7.9, 37.0 (br), 39.8 (br), 114.7, 118.8 (q, J=271), 128.0, 129.7, 131.6, 140.9, 155.7 (q, J=41), 158.0, 163.7. 19F NMR −63.2. LC/MS 6.03 min, [M+1]+ 305.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.CN(C)C.[CH2:17]([O:19][C:20]([C:22]1([CH2:37][OH:38])[CH2:26][CH2:25][N:24]([C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH2:23]1)=[O:21])[CH3:18].C(N(CC)CC)C>ClCCl.O>[CH2:17]([O:19][C:20]([C:22]1([CH2:37][O:38][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:26][CH2:25][N:24]([C:27](=[O:36])[C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[CH2:23]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)C1(CO)CCN(C(=O)c2ccc(OC)cc2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1(COS(=O)(=O)c2ccc(C)cc2)CCN(C(=O)c2ccc(OC)cc2)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 101.8 %

Procedure:
4-Toluenesulphonyl chloride (131 g, 687 mmol) and trimethylamine hydrochloride (43.8 g, 458 mmol) were added to 3-hydroxymethyl-1-(4-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (140.7 g, 457.8 mmol) (see Preparation 10) and triethylamine (160 mL, 1140 mmol) in dichloromethane (1400 mL) at 0° C. The reaction mixture was stirred at 0° C. for 4 hours then at RT for 18 hours. Cooled to 0° C. and trimethylamine hydrochloride (21.9 g, 229 mmol) was added, followed by 4-toluenesulphonyl chloride (17.45 g, 91.6 mmol). The reaction mixture was stirred at 0° C. for 4 hours. Water (500 mL) was added and stirred for 10 minutes. The reaction mixture was washed with 2M citric acid aqueous solution (1400 mL) and saturated aqueous NaHCO3 (1400 mL). The organic layer was separated, washed with water (1300 mL) then concentrated under reduced pressure to afford the title compound as a brown oil (215.15 g, 100%).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]4[CH2:26][CH2:25][CH2:24][CH:23]([CH2:27][C:28]#[N:29])[CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33].C(N)CN>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[N:12]1[C:11]2[NH:7][CH:8]=[CH:9][C:10]=2[C:15]([C:16]2[CH:17]=[N:18][N:19]([CH:21]3[CH2:26][CH2:25][CH2:24][CH:23]([CH2:27][C:28]#[N:29])[CH2:22]3)[CH:20]=2)=[N:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4CCCC(CC#N)C4)c3)ncnc21
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCC1CCCC(n2cc(-c3ncnc4[nH]ccc34)cn2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylacetonitrile (30.1 mg, 0.0689 mmol) was added DCM (1.0 mL) and TFA (1.0 mL). The resulting mixture was stirred for 1 hour at ambient temperature, at which point LCMS indicated complete cleavage to the N-hydroxymethyl intermediate. The solvent was removed and to the residue was added methanol (1.0 mL) followed by ethylenediamine (37 μL, 0.55 mmol), after which the reaction was stirred for 5 hours, at which point LCMS indicated complete reaction. The solvent was removed and the residue was purified by preparative LCMS to provide the product as a TFA salt (24 mg, 83%). 1H NMR (400 MHz, CD3OD): δ 8.91 (s, 1H), 8.82 (s, 1H), 8.45 (s, 1H), 7.84 (s, 1H), 7.31 (s, 1H), 4.69 (s, 1H), 2.58 (d, 2H), 2.5-1.5 (m, 9H). MS (EI) m/z=307.10 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[C:9]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:21])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[C:9]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:21])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1S(C)(=O)=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)Cl)ccc(S(C)(=O)=O)c1S(C)(=O)=O
Yield: 90.7 %

Procedure:
A few drops of dimethylformamide were added to a solution of 63 g (0.22 mol) of 2-methyl-3,4-di(methylsulfonyl)benzoic acid in 550 ml of toluene, and 36 g (0.3 mol) of thionyl chloride were then added dropwise. The reaction mixture was heated at reflux for 1.5 hours. After cooling, the reaction mixture was concentrated. This gave 62 g (93% yield) of 2-methyl-3,4-di(methylsulfonyl)benzoyl chloride as a beige solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].O>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CCNCc1ccco1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCN(Cc1ccco1)C(=O)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.4 %

Procedure:
Ethyl 3-[(furan-2-ylmethyl)amino]propionate (10.8 g) prepared in the step 2 and 18.3 mL of triethylamine were dissolved in 180 mL of methylene chloride, 7.14 g of ethyl chloroformate was added by slowly dropping thereinto under cooling with ice and the mixture was stirred at room temperature for 5 hours. Water (200 mL) was added to the reaction solution and the mixture was subjected to extraction with methylene chloride. The organic layer was washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo therefrom. The residue was purified by silica gel column chromatography to give 13.77 g of the objective compound as yellow liquid.
Reaction SMILES: [C:1]1([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][CH:2]=1.ClC1C=C(C2C=CC(N)=C(Cl)C=2)C=CC=1[NH2:22].[NH3:31]>[Cu]>[NH2:31][C:10]1[CH:9]=[C:8]([C:1]2[CH:2]=[CH:3][C:4]([NH2:5])=[C:6]([NH2:22])[CH:7]=2)[CH:14]=[CH:13][C:11]=1[NH2:12]
Reactant: Nc1ccc(-c2ccc(N)cc2)cc1
Reactant: N
Reactant: Nc1ccc(-c2ccc(N)c(Cl)c2)cc1Cl
Agent: [Cu]
Product: Nc1ccc(-c2ccc(N)c(N)c2)cc1N

Procedure:
A method according to Patent Document 2 is known as a method directly utilizing a benzidine skeleton. 3,3′-Dichlorobenzidine is treated with ammonia in the presence of a copper catalyst at high temperature (150 to 250° C.) and high pressure (1 to 10 MPa) to yield 3,3′,4,4′-tetraaminobiphenyl (Patent Document 2, Scheme 3).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:5]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=[CH2:30])C=C.CCN(CC)CC>C(Cl)Cl>[CH:17]1([C:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:12]=3[N:4]3[CH2:1][CH:30]=[CH:29][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:5]=23)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C=CCn1c(-c2ccccc2C=C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC=Cc1ccccc1-3
Yield: 84 %

Procedure:
Crude methyl 1-allyl-3-cyclohexyl-2-(2-vinylphenyl)1H-indole-6-carboxylate was dissolved in DCM (0.02M) and treated with Zhan catalyst I (0.3 eq) at 35° C. for 1 h. NEt3 (7 eq) were added and the solvent was removed in vacuo. The residue was purified by chromatography (PE/EtOAc 95:5) to afford the title compound (84%); MS (ES+) m/z 372 (M+H)+.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Cl:13][C:14]1[CH:15]=[C:16]([SH:21])[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([S:21][C:2]2[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Sc1ccc(Cl)c(Cl)c1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)c(Cl)c2)s1

Procedure:
Prepared according to the procedure described as in Step B for example 1 from 1-(5-Chloro-4-nitro-2-thienyl)ethanone (0.502 g, 2.45 mmol) and 3,4-dichlorobenzenethiol (0.438 g, 2.45 mmol). The title compound was obtained as an off-white solid (0.631 g, 74.6% yield). 1H NMR (300 MHz, CDCl3) δ: 8.10 (1H, s), 7.80 (1H, s), 7.70 (1H, d), 7.50 (1H, d), 2.50 (3H, s).