Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C:4]([NH:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([I:16])[CH:10]=1)[CH3:8])=[CH2:5].Cl[CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1>C(Cl)Cl>[CH3:18][C:2]([CH3:17])([CH3:1])[CH2:3][C:4]([NH:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:22]([CH:21]=[CH2:20])(=[O:24])=[O:23])=[C:11]([I:16])[CH:10]=1)[CH3:8])=[CH2:5]
Reactant: O=S(=O)(Cl)CCCl
Reactant: C=C(CC(C)(C)C)NC(C)c1ccc(N)c(I)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CS(=O)(=O)Nc1ccc(C(C)NC(=C)CC(C)(C)C)cc1I
Temperature: 0 °C
Reaction time: 48 h
Yield: 36 %

Procedure:
4-{1-[1-(2,2-Dimethylpropyl)vinylamino]ethyl}-2-iodophenylamine (218.1 mg, 0.65 mmol) was dissolved in methylene chloride. The reaction mixture was cooled down to 0° C. 2-Chloroethane sulfonyl chloride (3 eq, 1.95 mmol, 203.64 μl) and Pyridine (3 eq, 1.95 mmol, 157.71 μl) were added into mixture. The reaction mixture was stirred for 48 hrs. After confirming the completion of the synthesis, a reaction solvent was removed in vacuo. A residue was extracted with methylene chloride. A combined organic layer was washed with H2O and brine, dried over NaSO4, and concentrated in vacuo. The residue was purified with column chromatography (n-Hx:EA=3:1) to yield title compound (104.9 mg, 78%) as a brownish solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br)([O-:3])=[O:2].[CH3:12][S:13]([O-:15])=[O:14].[Na+]>C(O)C>[CH3:12][S:13]([CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:15])=[O:14]
Reactant: CS(=O)[O-]
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
164 a) A suspension of o-Nitrobenzylbromide (5.71 g, 26.4 mmol) and sodium methanesulfinate (4.0 g, 40.0 mmol) in ethanol (70 mL) was stirred at room temperature for 18 hours. The volatiles were evaporated under reduced pressure. To the residue was added water (50 mL) and stirred for 30 minutes. The suspension was filtered, rinsed with water and air dried. 1-Methanesulfonylmethyl-2-nitro-benzene was isolated as a yellow solid (5.36 g, 94%). MP=115-117° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.10 (d, J=8.1 Hz, 1H), 7.74-7.65 (m, 2H), 7.62-7.58 (m, 1H), 4.80 (s, 2H), 2.91 (s, 3H). 164 b) 2-Methanesulfonylmethyl-phenylamine was prepared from 1-methanesulfonylmethyl-2-nitro-benzene (1.0 g, 4.6 mmol) in a manner analogous to Example 111a. Product isolated as an off-white solid (0.84 g, 98%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.20 (t, J=7.5 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.86-6.76 (m, 2H), 4.30 (s, 2H), 4.28 (br s, 2H), 2.87 (s, 3H). MS=186 (MH)+. 164 c) (2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonylmethyl-phenyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and 2-methanesulfonylmethyl-phenylamine (440.0 mg, 2.375 mmol) in a manner analogous to Example 2d. Product isolated as a tan solid (0.62 g, 51%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.02 (d, J=5.9 Hz, 1H), 7.71 (s, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.47-7.41 (m, 3H), 6.89-6.81 (m, 2H), 4.41 (s, 2H), 2.93 (s, 3H). MS=337, 339 (MH)+. 164 d) N(8)-(2-Methanesulfonylmethyl-phenyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepare from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonylmethyl-phenyl)-amine (75.0 mg, 0.223 mmol) and 4-(4-Methyl-piperazin-1-yl)-phenylamine (47.0 mg, 0.246 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 brown foam (0.013 g, 12%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.96 (d, J=6.8 Hz, 1H), 7.70 (s, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.43-7.37 (m, 2H), 7.18 (t, J=7.4 Hz, 1H), 6.96 (d, J=8.8 Hz, 2H), 6.83 (d, J=7.8 Hz, 1H), 6.70 (s, 1H), 6.67 (t, J=7.1 Hz, 1H), 4.45 (s, 2H), 3.18-3.13 (m, 4H), 2.94 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:24])[CH2:15][NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:9][CH:8]=2)[N:6]=1.[CH:25]1([C:31]([OH:33])=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:24])[CH2:15][N:16]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:31]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)=[O:33])=[CH:9][CH:8]=2)[N:6]=1
Reactant: O=C(O)C1CCCCC1
Reactant: Nc1nc(-c2ccc(NC(=O)CNCc3ccccc3)cc2)cs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-c2ccc(NC(=O)CN(Cc3ccccc3)C(=O)C3CCCCC3)cc2)cs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.1 %

Procedure:
To a solution of N-{4-(2-amino-4-thiazolyl)phenyl}-2-{(phenylmethyl)amino}acetamide (352 mg, 1.04 mmol, described in example 2), cyclohexanecarboxylic acid (140 mg, 1.09 mmol) and DIPEA (269 mg, 2.08 mmol) in DMF (5.2 mL) was added TBTU (350 mg, 1.09 mmol). The mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with EtOAc (125 mL). The resulting solution was washed with saturated aqueous NaHCO3 (40 mL), H2O (40 mL), and brine (40 mL), then dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, CHCl3 : EtOH, 15:1) to yield the title compound (341 mg, 73% yield) as a white solid: M.p. 214.5-215.5°; 1H NMR (400 MHz, DMSO-d6) δ (2 rotamers, 1:1) 10.06, 9.92 (2 s, 1H), 7.73, 7.71 (2 d, J=8.5 Hz, 2H), 7.56, 7.55 (2 d, J =8.5 Hz, 2H), 7.20-7.41 (m, 5H), 7.01, 7.00 (2 s, 2H), 6.89, 6.88 (2 s, 1H), 4.70, 4.51 (2 s, 2H), 4.13, 4.02 (2 s, 2H), 2.64, 2.56 (2 broad t, J=10.5 Hz, 1H), 1.61-1.70 (m, 5H), 1.12-1.46 (m, 5H); MS (FAB) m/z 449 (MH)+ ; Anal. Calcd for C25H28N4O2S: C, 66.94; H, 6.29; N, 12.49. Found: C, 66.54; H, 6.29; N, 12.32.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([N:21]1[CH2:25][CH:24]([CH:26]([OH:28])[CH3:27])[CH2:23][N:22]1[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:27][C:26]([CH:24]1[CH2:25][N:21]([C:19]([O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:20])[N:22]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:23]1)=[O:28]
Reactant: CC(O)C1CN(C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)C1CN(C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 9.2 %

Procedure:
To a solution of oxalyl chloride (23 ml) in dichloromethane was added dropwise dimethyl sulfoxide (374 ml) while keeping the temperature below -50° C. After the mixture was stirred for 30 minutes at -50° C.~-60° C., 1.2-bis(benzyloxycarbonyl)-4-(1-hydroxyethyl)pyrazolidine (675 g) was added dropwise below -50° C. After the mixture was stirred for 45 minutes at -50° C.~-60° C., triethylamine (122 ml) was added dropwise below -50° C. The reaction mixture was allowed to warm to 0° C. and quenched with water (500 ml). The aqueous layer was separated and extracted twice with dichloromethane (200 ml×2). The combined organic layer was washed with 1N hydrochloric acid (200 ml×2), saturated sodium bicarbonte (200 ml), and 5% sodium chloride (200 ml), dried over magnesium sulfate, and evaporated under reduced pressure. The residue was chromatographed on silica gel (820 ml, hexane:ethyl acetate=2:1~1:1) to give 1,2-bis(benzyloxycarbonyl)pyrazolidin-4-yl methyl ketone (61.5 g).
Reaction SMILES: Cl.Cl.Cl.Cl.[NH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][NH2:18].[OH-:19].[Na+].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[S:27]([C:17]([S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28])([CH2:16][CH2:15][NH:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][CH2:6][NH2:5])[N:18]([S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28])[S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:28])=[O:19])([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCNCCCCNCCCN
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N(C(CCNCCCCNCCCN)(S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To spermine tetrahydrochloride (4.53 g, 13.0 mmol) and 10% aqueous NaOH (200 mL, 132 mmol) at 0° is added dropwise p-toluene-sulfonyl chloride (9.98 g, 52.3 mmol) in CH2Cl2 with rapid stirring. After 1 hr the mixture is allowed to warm to room temperature and to stir for 2 days. The organic phase is separated and washed with 0.5N HCl, H2O, and brine, dried over Na2SO4 and purified on silica gel (450 g, 3% MeOH/CHCl3) to give 9.69 g, 91% yield of tetratosylspermine.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[N:11][C:12]2[C:13](/[CH:18]=[CH:19]/[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:7][CH:8]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:41][CH2:40][N:39]([C:10]3[N:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:27])([F:1])[F:28])[CH:4]=4)[CH:18]([CH2:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[C:13]4[N:14]=[CH:15][CH:16]=[CH:17][C:12]=4[N:11]=3)[CH2:38][CH2:37]2)=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ncccc1N=C=Nc1cccc(C(F)(F)F)c1
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: CC(C)(C)OC(=O)CC1c2ncccc2N=C(N2CCN(c3ccc(F)cc3)CC2)N1c1cccc(C(F)(F)F)c1

Procedure:
Starting from 53 mg (0.14 mmol) of the carbodiimide from Example 14A and 24 mg (0.14 mmol) of 4-fluorophenylpiperazine, general procedure [C] and purification on preparative HPLC result in 38 mg (48% of theory) of product.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]2)(=O)=O)=CC=1.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:20][C:16]1([CH3:19])[O:15][CH2:14][CH:13]([CH2:12][NH:26][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:18][O:17]1
Reactant: NC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)OC2)cc1
Product: CC1(C)OCC(CNC2CCCC2)CO1
Temperature: 80 °C
Yield: 93.8 %

Procedure:
A mixture of 1.5 g (5 mmol) of (2,2-dimethyl-1,3-dioxan-5-yl)methyl 4-methylbenzenesulfonate and 10 mL (101 mmol) of cyclopentylamine is heated for 12 hours at 80° C. The medium is concentrated under reduced pressure and then taken up in 200 mL of Et2O, washed with water (2×50 mL) and then dried over Na2SO4 and concentrated under reduced pressure. 1 g of N-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]cyclopentanamine is obtained in the form of an oil, which is used without further purification in the following step.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[N:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:32])=[C:18]([C@:20]2([CH3:31])[CH2:25][S:24](=[O:27])(=[O:26])[C:23]([CH3:29])([CH3:28])[C:22]([NH2:30])=[N:21]2)[CH:19]=1>>[NH2:30][C:22]1[C:23]([CH3:28])([CH3:29])[S:24](=[O:26])(=[O:27])[CH2:25][C@:20]([C:18]2[CH:19]=[C:14]([NH:13][C:9]([C:6]3[CH:5]=[N:4][C:3]([CH:2]([F:1])[F:12])=[CH:8][N:7]=3)=[O:11])[CH:15]=[CH:16][C:17]=2[F:32])([CH3:31])[N:21]=1
Reactant: CC1(C)C(N)=N[C@](C)(c2cc(N)ccc2F)CS1(=O)=O
Reactant: O=C(O)c1cnc(C(F)F)cn1
Product: CC1(C)C(N)=N[C@](C)(c2cc(NC(=O)c3cnc(C(F)F)cn3)ccc2F)CS1(=O)=O
Yield: 47.9 %

Procedure:
Prepared from commercially available 5-(difluoromethyl)pyrazine-2-carboxylic acid (CAS-no. 1174321-06-2) (48.9 mg, 281 μmol, Eq: 1.2) and (R)-5-(5-amino-2-fluoro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (70 mg, 234 μmol, Eq: 1.00) as described for example 2 (method b) to give the title compound (51 mg, 112 μmol, 47.9% yield) as a light yellow foam. MS (ISP): m/z=456.5 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=2)=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Nc1ccc(Br)cn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Clc1ccc(CNc2ccc(Br)cn2)cc1
Reaction time: 8 h

Procedure:
5-Bromo-pyridin-2-ylamine (9, 4.0 g, 23 mmol) was dissolved in 100 mL of acetonitrile and 4-chloro-benzaldehyde (10, 3.2 g, 23 mmol) was added. Triethylsilane (11.0 mL, 69 mmol) was added followed by trifluoroacetic acid (5.0 mL, 65 mmol). The reaction was heated to reflux and stirred overnight. The solvent was removed under vacuum and the residue was poured into a solution of 1M potassium carbonate. This was extracted with ethyl acetate and the organic portion was isolated and washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting solid was washed with ether to give the desired compound. The remaining material was purified with silica gel chromatography eluting with a gradient of 0-25% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide additional compound (11, 6.36 g, 92%).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:29][O:30][CH3:31])[C:12]([NH:14][CH:15]2[C:27](=[O:28])[N:17]3[C:18]([C:24]([OH:26])=[O:25])=[C:19]([O:22][CH3:23])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=O.O.O.O.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.O1CCCC1.O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:29][O:30][CH3:31])[C:12]([NH:14][CH:15]2[C:27](=[O:28])[N:17]3[C:18]([C:24]([OH:26])=[O:25])=[C:19]([O:22][CH3:23])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(OC)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(OC)CS[C@H]12)c1csc(N)n1
Yield: 89.6 %

Procedure:
A solution of 7-[2-{2-(2,2,2-trifluoroacetamido)-4-thiazolyl}-2-methoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer, 0.55 g.) and sodium acetate trihydrate (1,76 g.) in ethyl acetate (3 ml.), tetrahydrofuran (3 ml.) and water (5.5 ml.) was stirred at room temperature overnight. The aqueous layer was separated from the resultant mixture, washed with dichloromethane, and then evaporated under reduced pressure to remove the organic solvent. The aqueous solution was adjusted to pH 4.2 under ice-cooling, and subjected to column chromatography on Diaion HP-20 resin (Trade mark: manufactured by Mitsubishi Chemical Industries Ltd., 15 ml.). After washing the column with water, the object compound was eluted with 20% aqueous isopropyl alcohol. The eluate was concentrated under reduced pressure and the residue was lyophilized to give 7-{2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido}-3-methoxy-3-cephem-4-carboxylic acid (syn isomer 0.4 g.), m.p. 185° to 190° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]([NH:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)=[O:12])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18](=[O:20])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:22]=2)=[O:12])(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)NS(=O)(=O)c1ccc(Cl)s1
Reactant: Nc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)Nc2ccccc2)cc1)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 28 h
Yield: 34.8 %

Procedure:
To a solution of 4-({[(5-chloro-2-thienyl)sulfonyl]amino}carbonylamino)benzoic acid (69 mg) in DMF (0.7 mL) was added aniline (21 uL, 0.23 mmol), DIEA (3 eq.) then PyBOP (85 mg, 0.16 mmol). The reaction mixture was stirred at room temp for 28 hr, acidified and HPLC purified to give {[(5-chloro(2-thienyl))sulfonyl]amino}-N-[4-(N-phenylcarbamoyl)phenyl]carboxamide (29 mg, 45%). ES-MS (M+H)+=436, 438 (Cl).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)[N:17]=4)[S:12][C:11]=3[C:10]([O:34]C)=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.C(S)C.[H-].[Na+].Cl>CN(C=O)C.O>[CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][N:27]5[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]5)[N:17]=4)[S:12][C:11]=3[C:10]([OH:34])=[CH:9][CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: COc1ccc(C(=O)NC2CC2)c2cc(-c3nc(NCCCN4CCN(C)CC4)ncc3Cl)sc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCS
Solvent: CN(C)C=O
Product: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)ccc(O)c4s3)n2)CC1
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 23.9 %

Procedure:
To a solution of 2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-7-methoxybenzo[b]thiophene-4-carboxylic acid cyclopropylamide (500 mg, 0.970 mmol) and ethanethiol (0.718 mL, 9.71 mmol) in dry DMF (10 mL) is added in one portion sodium hydride (388 mg, 9.71 mmol) at 0° C. The mixture is stirred for 5 minutes and heated to 110° C. in a preheated oil bath for 10 minutes. The mixture is cooled to room temperature and a solution of HCl (12%, 3.5 mL) is added. The mixture is diluted with water (100 mL) and concentrated. The residue is diluted with MeOH and filtered off. The filtrate is purified on silica gel, eluting with dichloromethane in MeOH 90:10 to 60:40, to give the title compound as a yellow solid (116 mg, 24% yield). ES+(m/z) 501 (35Cl) and 503 (37Cl) [M+H].
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[H-].[Na+].[H][H].[F:30][CH2:31][CH2:32]Br>CN(C)C=O>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:32][CH2:31][F:30])=[CH:23][CH:24]=3)[N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: FCCBr
Reactant: CCN1CCN(c2nc(-c3ccc(O)cc3)cc3ccccc23)CC1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCN(c2nc(-c3ccc(OCCF)cc3)cc3ccccc23)CC1
Temperature: 25 °C

Procedure:
1-(4-Ethylpiperazin-1-yl)-3-(4-hydroxyphenyl)isoquinoline (0.514 g) obtained in Example 7 was dissolved in N,N-dimethylformamide (5 ml), followed by the addition of 60% sodium hydride (0.075 g). After the evolution of hydrogen was ceased, 2-fluoroethyl bromide (230 μl) was added thereto, and then heated under reflux for 8 hr. After the reaction solution was cooled to room temperature, it was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried and evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 0.582 g of 1-(4-ethylpiperazin-1-yl)-3-[4-(2-fluoroethoxy)phenyl]isoquinoline as a white powder. The compound was converted into a hydrochloride in a conventional manner, to give the title compound as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C:4]([CH3:7])=[CH:5][CH:6]=1>[Ni].CO>[CH3:1][C:2]1[N:3]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)(=[O:10])=[O:9])[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)n1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CO
Product: Cc1ccc(C)n1S(=O)(=O)c1ccc(N)cc1
Reaction time: 3 h
Yield: 98.3 %

Procedure:
A mixture of 4-[(2,5-dimethyl-1H-pyrrol-1-yl)sulfonyl]nitrobenzene (Step 1) (7.3 g, 26 mmol) and Raney Nickel (0.7 g) in 70 mL of methanol was hydrogenated in a Parr apparatus at a pressure of 50 psi. After 3 hours, the catalyst was filtered and the filtrate was concentrated to give 4-[(2,5-dimethyl-1H-pyrrol-1-yl)sulfonyl]benzenamine (6.4 g) as a pale yellow solid: mp (DSC): 110–111° C. Anal. Calc'd. for C12H14N2O2S: C, 57.58; H, 5.64; N, 11.16; S, 12.81. Found: C, 57.44; H, 5.78; N, 11.11; S. 12.30.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[OH-].[K+].ClC1C=C(Cl)C=C(F)C=1O[C:13]1[CH:18]=[C:17]([O:19][C:20]2[C:25]([F:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=2[Cl:28])[CH:16]=[CH:15][C:14]=1[N+:29]([O-:31])=[O:30].CCOCC>O1CCOCC1.O>[N+:29]([C:14]1[CH:13]=[CH:18][C:17]([O:19][C:20]2[C:25]([F:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=2[Cl:28])=[CH:16][C:15]=1[O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1ccc(Oc2c(F)cc(Cl)cc2Cl)cc1Oc1c(F)cc(Cl)cc1Cl
Reactant: OC1CCOC1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2c(F)cc(Cl)cc2Cl)cc1OC1CCOC1
Yield: 94.5 %

Procedure:
3.9 g (0.045 mole) of 3-hydroxytetrahydrofuran, 2.5 g (0.045 mole) of potassium hydroxide and 100 ml of dioxane were mixed with stirring. To the resulting solution was added at room temperature, a solution of 7.2 g (0.015 mole) of 2,4-bis(2,4-dichloro-6-fluorophenoxy)-nitrobenzene in 20 ml of dioxane. Then, the mixture was stirred for 2 hours while maintaining at 60° to 70° C. to perform ether exchange reaction. The reaction mixture was allowed to cool, and poured into 300 ml of cold water. It was extracted with 200 ml of benzene with shaking. The benzene layer was fully washed with water and dried over anhydrous sodium sulfate. The benzene was distilled off under reduced pressure to afford 5.5 g (94.7%) of a pale yellow oily product. The oily product was chromatographed on a silica gel column using chloroform as an eluent to afford 4 g (68.9%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[C:14](OS(C(F)(F)F)(=O)=O)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1.[CH2:30]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[CH2:31][CH2:32][C:33]#[CH:34].C(NCC)C.C(#N)C>C(OCC)(=O)C.[Cu]I>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[C:14]([C:34]#[C:33][CH2:32][CH2:31][CH2:30][N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1
Reactant: C#CCCCN1CCOCC1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1OS(=O)(=O)C(F)(F)F
Agent: [Cu]I
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C#CCCCN1CCOCC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
Trifluoromethanesulfonic acid 1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazin-5-yl ester (0.935 g, 2 mmoles), prepared as described in example 73, 4-pent-4-ynyl-morpholine (0.37 g, 2.4 mmoles), diethylamine (9 ml) and dry acetonitrile (6 ml), then bis(triphenylphosphine)PdCl2 (0.014 g, 0.02 mmole) and CuI (0.004 g, 0.02 mmole) were charged in a flask under N2 and the mixture was stirred at room temperature overnight, brought to dryness, the residue taken up in ethyl acetate and washed with water. The organic phase was washed with water, anhydrified and concentrated to give an oil which was flash chromatographed (eluent: CH2Cl2/CH3OH/NH3 95:5:0.5) to give an oil which was dissolved in ethyl acetate and precipitated by adding HCl in ethyl ether. There was yielded 0.09 g of the title compound. m.p.: 129-13 1° C. (dec.).