Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.S(O)(O)(=O)=O.[NH2:7][C:8]1[NH:17][C:16](=[O:18])[C:15]2[C:14]3[CH:19]=[CH:20][C:21]([N+:23]([O-])=O)=[CH:22][C:13]=3[CH2:12][CH2:11][C:10]=2[N:9]=1.[H][H]>[Pd].Cl.O>[NH2:7][C:8]1[NH:17][C:16](=[O:18])[C:15]2[C:14]3[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:13]=3[CH2:12][CH2:11][C:10]=2[N:9]=1
Reactant: [H][H]
Reactant: Nc1nc2c(c(=O)[nH]1)-c1ccc([N+](=O)[O-])cc1CC2
Agent: [Pd]
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1ccc2c(c1)CCc1nc(N)[nH]c(=O)c1-2

Procedure:
A suspension of 3-amino-5,6-dihydro-8-nitrobenzo[f]quinazolin-1(2H)-one sulfate monohydrate (2.0 g, 5.3 mmoles) and 5% palladium on carbon (10 mg) in 1 N HCl (20 ml) was reacted with hydrogen using a Parr hydrogenation apparatus. When uptake of hydrogen ceased, the mixture was filtered and the filtrate was evaporated, leaving a white residue which was resuspended in water (20 ml) with stirring, and filtered. The crude product was recrystallized from 2 M H2SO4 to give, after drying, 3,8-diamino-5,6-dihydrobenzo[f]quinazolin-1(2H)-one as a white solid. (1.1 g, 61%) 1H NMR (DMSO-d6, 80 MHz) δ: 2.60-2.65 (m, 4H, CH2CH2); 4.99-5.69 (br s, 2H, NH2); 6.75-6.79 (m, 4H, NH2+Ar); 8.24-8.35 (d, J=9 Hz, 1H, Ar). Anal. Calculated for C12H12N4O.H2SO4.1/2H2O: C, 42.98; H, 4.51; N, 16.71; S, 9.56. Found: C, 42.95; H, 4.54; N, 16.66; S, 9.57.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[F:36])[C:30](Cl)=[O:31].O>N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([NH:18][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:35]([F:36])=[C:27]([F:26])[CH:28]=3)[CH2:16][CH2:17]2)=[CH:3][CH:2]=1
Reactant: N[C@H]1CC[C@H](Oc2ccnc3ccccc23)CC1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccncc1
Product: O=C(N[C@H]1CC[C@H](Oc2ccnc3ccccc23)CC1)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
trans-4-(4-Quinolyloxy)cyclohexylamine (400 mg, 1.65 mmol) was put in pyridine (12 mL) and catalytic amounts of triethylamine were added. At 0° C., 3,4-difluorobenzoyl chloride (291 mg, 1.65 mmol) was added. Then the reaction mixture was stirred at room temperature overnight. Water was added, and the precipitate was filtered off with suction. After drying, the desired product was obtained at 96% yield (610 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:28])=[CH:4][C:5]([F:27])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:20]([O-:22])=[O:21])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:23])[C:10]([C:24]([OH:26])=[O:25])=[CH:9]2)[CH:7]=1.[CH3:29][NH2:30].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:28])=[CH:4][C:5]([F:27])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:20]([O-:22])=[O:21])=[C:15]([NH:30][CH3:29])[C:16]=3[F:18])[C:11](=[O:23])[C:10]([C:24]([OH:26])=[O:25])=[CH:9]2)[CH:7]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc([N+](=O)[O-])c(F)c(F)c32)c(F)cc1F
Reactant: CN
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: CNc1c([N+](=O)[O-])cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(5-Amino-2,4-difluorophenyl)-7,8-difluoro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (70 mg) was added to a mixed liquid of a 40% aqueous solution (80 mg) of methylamine and pyridine (2 ml), and the mixture was stirred at room temperature for 1 hour. The solution was acidified with 3% citric acid (10 ml), and solids formed were collected by filtration. The solids were washed with water, ethanol and hexane to obtain the title compound (56 mg) as a yellow powder.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:28]2[O:29][C@@H:27]2[C@@:26]2([CH3:30])[C:7](=[CH:8][C@@H:9](OC(OC)=O)[C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH3:21])[CH:16]([O:19][CH3:20])[O:17][CH3:18])[CH2:6]1)(=[O:3])[CH3:2].C(O[C@H]1[C@@H]2O[C@@H]2[C@@]2(C)C(=C[C@@H](OC(OC)=O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C2OCC(C)(C)CO2)C)C1)(=O)C>>[C:1]([O:4][C@H:5]1[C@@H:28]2[O:29][C@@H:27]2[C@@:26]2([CH3:30])[C:7](=[CH:8][CH:9]=[C:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH3:21])[CH:16]([O:17][CH3:18])[O:19][CH3:20])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C(OC)OC)CC[C@H]3[C@H]12
Agent: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Product: COC(OC)C(C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(C)=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Yield: 45.4 %

Procedure:
The procedure of Example 17 was repeated except that 40.4 mg (0.0798 mmole) of 1α,2α-epoxy-21,21-dimethoxy-7α-methoxycarbonyloxy-20-methylpregn-5-en-3β-yl acetate was used in lieu of 43.6 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-yl acetate to give 15.6 mg of 1α,2α-epoxy-21,21-dimethoxy-20-methylpregna-5,7-dien-3β-yl acetate. In addition, 14.1 mg of the starting compound 1α,2α-epoxy-21,21-dimethoxy-7α-methoxycarbonyloxy-20-methylpregn-5-en-3β-yl acetate was recovered. The yield of 1α,2α-epoxy-21,21-dimethoxy-20-methylpregna-5,7-dien-3β-yl acetate was 70% based on consumed 1α,2α-epoxy-21,21-dimethoxy-7α-methoxycarbonyloxy-20-methylpregn-5-en-3β-yl acetate.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])C)(C)(C)C>ClCCl>[CH3:13][NH:14][C@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:17][NH:18][S:19]([CH3:22])(=[O:20])=[O:21]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CNS(C)(=O)=O)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](CNS(C)(=O)=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 101.7 %

Procedure:
At 0° C., trifluoroacetic acid (5 ml) was added to a solution of N-((1R)-1-benzyl-2-((methylsulfonyl)amino)ethyl)-N-methylcarbamic acid tert-butylester (913 mg, 2.67 mmol) in dichloromethane (5 ml). The reaction mixture was stirred for 15 min at 0° C. The solvent was removed in vacuo without warming. The residue was dissolved in dichloromethane (50 ml) and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (20 g), using dichloromethane/methanol/25% aqueous ammonia as eluent, to give 658 mg of N-((2R)-2-methylamino-3-phenylpropyl)methansulfonamide.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[N:2]=1.[CH3:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=[C:30]([C:36]([F:39])([F:38])[F:37])[N:29]=2)[CH2:24][CH2:23]1.C(N(CC)CC)C>CS(C)=O.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12]([NH:35][CH2:34][C:33]2[C:28]([N:25]3[CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23][CH2:24]3)=[N:29][C:30]([C:36]([F:39])([F:37])[F:38])=[CH:31][CH:32]=2)=[O:20])[N:2]=1
Reactant: O=C(Nc1cc2ccccc2cn1)Oc1ccccc1
Reactant: CC1CCN(c2nc(C(F)(F)F)ccc2CN)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC1CCN(c2nc(C(F)(F)F)ccc2CNC(=O)Nc2cc3ccccc3cn2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.1 %

Procedure:
Phenyl isoquinolin-3-ylcarbamate (100 mg, 0.38 mmol) and (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (109 mg, 0.40 mmol) was dissolved in dimethyl sulfoxide. Then triethylamine (0.11 mL, 0.76 mmol) was added to it. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The crude was purified by column chromatography to give 1-(isoquinolin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea (example compound 21) (130 mg, 77%).
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([F:12])[CH:5]=1)C=C.C[N+]1([O-])CC[O:17][CH2:16]C1.[CH3:21][OH:22]>O.O=[Os](=O)(=O)=O>[OH:22][CH:21]([CH2:16][OH:17])[CH2:1][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([F:12])[CH:5]=1
Reactant: CO
Reactant: C=CCc1ccc(C#N)c(F)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: N#Cc1ccc(CC(O)CO)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-allyl-2-fluorobenzonitrile (1.3 g, 8.1 mmol) in 30 mL of methanol and 10 mL of water was added OsO4 (200 mg) and NMO (2.7 g, 20 mmol), and the mixture was stirred at ambient temperature overnight. Remove the methanol under reduced pressure, the residue was dissolved in EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by fast column chromatograph to give 4-(2,3-dihydroxypropyl)-2-fluorobenzonitrile. MS m/z: 196 (M+1)+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:10]([NH:12][C@H:13]([C:29](=[O:31])[NH2:30])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH:22]=2)=[CH:17][CH:16]=1)=[O:11].[CH2:39]([O:41][P:42]([C:47]([F:59])([F:58])[C:48]1[CH:53]=[CH:52][C:51]([CH2:54][C:55](O)=[O:56])=[CH:50][CH:49]=1)([O:44][CH2:45][CH3:46])=[O:43])[CH3:40]>>[CH2:39]([O:41][P:42]([C:47]([C:48]1[CH:49]=[CH:50][C:51]([CH2:54][C:55](=[O:56])[NH:8][C@H:9]([C:10](=[O:11])[NH:12][C@H:13]([C:29](=[O:31])[NH2:30])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH:22]=3)=[CH:19][CH:20]=2)[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:52][CH:53]=1)([F:59])[F:58])(=[O:43])[O:44][CH2:45][CH3:46])[CH3:40]
Reactant: NC(=O)[C@H](Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(CC(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(CC(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(C3=CC(=O)NS3(=O)=O)cc2)C(N)=O)cc1

Procedure:
This compound was prepared according to the procedure of Example 1.1, Step 10, using 1.38-B of Step 2 and {4-[(diethoxy-phosphoryl)-difluoro-methyl]-phenyl}-acetic acid (Biochemistry, 2003, 42, 12792) as the starting materials. LCMS found for C34H38F2N4O9PS (M+H)+: m/z=747.
Reaction SMILES: N[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([O:21][CH3:22])=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=2)[CH:3]=1.[CH2:23]=O.[BH3-][C:26]#[N:27].[Na+]>CO.CC(O)=O>[CH3:23][N:27]([CH3:26])[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([O:21][CH3:22])=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=2)[CH:3]=1
Reactant: [BH3-]C#N
Reactant: C=O
Reactant: COc1ccc(-c2cc(N)c(=O)n(C)c2)cc1NS(C)(=O)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(N(C)C)c(=O)n(C)c2)cc1NS(C)(=O)=O
Temperature: 30 °C
Yield: 42.7 %

Procedure:
To a solution of compound from Example 109 (64.6 mg, 0.2 mmol) in MeOH (3 mL) and AcOH (0.3 mL) was added HCHO (30.0 mg, 1.0 mmol) dropwise with stirring at 30° C. NaBH3CN (61 mg, 1.0 mol) was added in portions at 30° C. The reaction mixture was stirred for 2 h at 30° C. It was then quenched with saturated aqueous NH4Cl (5 mL), extracted with EtOAc (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA=2:3) to give the title compound (30 mg, 43%) as a light green solid. 1H NMR (Methanol-d4 400 MHz): δ 7.54 (d, J=2.4 Hz, 1H), 7.47 (d, J=2.4 Hz, 1H), 7.37 (dd, J1=2.4, J2=8.4 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 3.93 (s, 3H), 3.63 (s, 3H), 2.94 (s, 3H), 2.86 (s, 6H). LCMS (M+H)+ 352.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(Cl)Cl.[C:9]([O:13][C:14]([NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23][CH3:24])[CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])O.[Na+]>O.C(N(CC)CC)C>[C:9]([O:13][C:14]([NH:16][C@H:17]1[CH2:18][CH2:19][C@H:20]([N:23]([CH3:24])[S:2]([CH3:1])(=[O:4])=[O:3])[CH2:21][CH2:22]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CN[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CN([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
254 μl of methanesulfonyl chloride was added to a methylene chloride solution containing 500 mg of N-tert-butoxycarbonyl-N′-methyl-trans-1,4-cyclohexanediamine (Reference Example 10-14 (1)) and 763 μl of triethylamine, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture were added water, followed by an aqueous saturated sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium hydrogencarbonate, water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was suspended in diisopropyl ether, and collected by filtration to obtain N-tert-butoxycarbonyl-N′-methyl-N′-methylsulfonyl-trans-1,4-cyclohexanediamine. Subsequently, this compound was treaded with hydrochloric acid to obtain-N-methyl-N-methyl-sulfonyl-trans-1,4-cyclohexanediamine (Reference Example 10-18 in Table 11).
Reaction SMILES: CC1C(C)=CC(C)=CC=1O.[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([OH:19])=[C:14]([CH3:20])[C:13]=1[CH3:21].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=1)=[O:25]>C(OCC)(=O)C.CCCCCC>[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH2:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[O:25])=[C:14]([CH3:20])[C:13]=1[CH3:21]
Reactant: Cc1cc(O)c(C)c(C)c1Br
Reactant: CC(C)c1ccc(C(=O)CBr)cc1
Agent: Cc1cc(C)c(C)c(O)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(OCC(=O)c2ccc(C(C)C)cc2)c(C)c(C)c1Br
Yield: 51 %

Procedure:
Using 2,3,5-trimethylphenol, 4-bromo-2,3,5-trimethylphenol was synthesized in the same manner as in Reference Example 23. Using this compound and 2-bromo-1-(4-isopropylphenyl)ethanone obtained in Reference Example 164, the title compound was synthesized in the same manner as in Reference Example 159. Yield 51%. Melting point: 71-72° C. (ethyl acetate-hexane).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3](C(O)=O)[CH2:2]1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[NH2:26][C:27]1[C:28]([OH:38])=[C:29]([S:34]([NH2:37])(=[O:36])=[O:35])[C:30]([Cl:33])=[CH:31][CH:32]=1.C[N:40]([CH:42]=[O:43])C>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:42]([NH:40][CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)=[O:43])=[C:28]([OH:38])[C:29]=1[S:34](=[O:36])(=[O:35])[NH2:37]
Reactant: CN(C)C=O
Reactant: O=C(O)C1CCOC1
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)NC2CCOC2)c1O
Temperature: 70 °C
Reaction time: 18 h
Yield: 5 %

Procedure:
To a solution of Tetrahydro-furan-3-carboxylic acid (0.093 mL, 1.0 mmol) in DMF (0.5 mL) was added DPPA (0.25 mL, 1.2 mmol) and TEA (0.25 mL, 1.8 mmol) and the reaction heated at 70° C. After 18 hrs, 3-Amino-6-chloro-2-hydroxy-benzenesulfonamide (1.0 mmol) was added and the reaction heated at 70° C. After 18 hrs, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude residue was purified via HPLC to give 18 mg (5%) of N-[4-chloro-2-hydroxy-3-sulfamylphenyl]-N′-(3-tetrahydrofuryl)urea. LC-MS (m/z) 336 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: ClCCCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(OCCCCl)cc1
Temperature: 40 °C
Reaction time: 48 h
Yield: 91.1 %

Procedure:
The mixture of ethyl 4-hydroxybenzoate(50.0 g), 1-bromo-3-chloropropane (56.8 g), and potassium carbonate (125 g) in acetonitrile (500 ml) was stirred 40° C. for 48 hr. The reaction mixture was concentrated and the residue was diluted with water, then extracted with diethyl ether. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (hexane to hexane:ethyl acetate=20:1) to yield the entitled compound (66.5 g) as an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[S:8]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=1[OH:19])(=[O:10])=[O:9].C(N(CC)C(C)C)(C)C.[C:43](N1C=CN=C1)(N1C=CN=C1)=[O:44].Cl.[Cl:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1>CN(C=O)C>[Cl:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[N:63]1[CH2:68][CH2:67][N:66]([C:43]([NH:1][CH2:2][C:3]2[CH:33]=[CH:32][CH:31]=[C:5]([CH2:6][N:7]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=3)[S:8]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=3[OH:19])(=[O:9])=[O:10])[CH:4]=2)=[O:44])[CH2:65][CH2:64]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: NCc1cccc(CN(Cc2ccc(C(F)(F)F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(CN(Cc2ccc(C(F)(F)F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)N1CCN(c2ccccc2Cl)CC1
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a solution of N-(3-(aminomethyl)benzyl)-3,5-dichloro-2-hydroxy-N-(4-(trifluoromethyl)benzyl)benzenesulfonamide (60 mg, 0.12 mmol) in DMF (2 mL) were added N,N-diisopropylethylamine (0.08 mL, 0.46 mmol) and 1,1′-carbonyldiimidazole (20.6 mg, 0.13 mmol). The resulting mixture was stirred at it for 1 h under nitrogen, then 1-(2-chlorophenyl)piperazine monohydrochloride (29.6 mg, 0.13 mmol) was added. The mixture was stirred overnight. The mixture was concentrated and purified by preparative HPLC. Fractions containing the desired product were combined, concentrated and lyophilized to give white solid (54 mg, 62%). 1H NMR (MeOD-d4): δ 7.57 (d, J=2.8 Hz, 1H), 7.52 (d, J=2.8 Hz, 1H), 7.40 (d, J=8.3 Hz, 2H), 7.28 (m, 1H), 7.21 (d, J=8.3 Hz, 2H), 7.15 (m, 1H), 7.06 (m, 4H), 6.92 (m, 1H), 6.88 (m, 1H), 4.45 (s, 2H), 4.41 (s, 2H), 4.21 (s, 2H), 3.50 (t, J=5.0 Hz, 4H), 2.93 (t, J=5.0 Hz, 4H); MS (ESI): (M+H)+=743.2.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]1[C:23]([CH3:24])=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:36][CH3:37])=[C:30]([C:32](=[N:34]O)[NH2:33])[CH:31]=1.CCN(C(C)C)C(C)C>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:36][CH3:37])=[C:30]([C:32]2[N:33]=[C:19]([C:18]3[CH:22]=[C:23]([CH3:24])[C:15]([N:11]4[CH2:12][CH2:13][CH2:14][CH:10]4[CH2:9][O:8][CH3:7])=[N:16][CH:17]=3)[O:21][N:34]=2)[CH:31]=1
Reactant: COc1ccc(F)cc1C(N)=NO
Reactant: COCC1CCCN1c1ncc(C(=O)O)cc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCC1CCCN1c1ncc(-c2nc(-c3cc(F)ccc3OC)no2)cc1C

Procedure:
Oxalyl chloride (122 μL; 1.44 mmol; 3 eq.), Intermediate 40 (120 mg; 0.48 mmol; 1 eq.), Intermediate 23 (88 mg; 0.48 mmol, 1 eq.) and DIEA (245 μL; 1.44 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 50/50) afforded the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:21][O:22][CH2:23][C:24](Cl)=[O:25].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:24](=[O:25])[CH2:23][O:22][CH3:21])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COCC(=O)Cl
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)N1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)CC1
Reaction time: 2 h
Yield: 63.6 %

Procedure:
1-(5-chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with methoxyacetyl chloride (0.014 mL, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4 and then concentrated. The resulted residue was purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (23 mg, 61%). LCMS calculated for C18H21ClN3O3 (M+H)+: m/z=362.1; Found: 362.0
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:5]2.[CH:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=O.C([O-])(O)=O.[Na+].[BH4-].[Na+]>C(O)(=O)C.CO.O>[CH2:12]([N:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][CH2:16][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[NH:24][C:25](=[O:30])[C:26]([CH3:28])([CH3:27])[CH3:29])[CH:3]=2)[C:7]1=[O:11])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN1Cc2cc(N)ccc2C1=O
Reactant: CC(C)(C)C(=O)Nc1ccncc1C=O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCCCN1Cc2cc(NCc3cnccc3NC(=O)C(C)(C)C)ccc2C1=O
Reaction time: 120 h

Procedure:
5-Amino-2-butylisoindolin-1-one (49.5 mg, 0.242 mmol) was added to a solution of N-(3-formylpyridin-4-yl)pivalamide (50 mg, 0.242 mmol) in acetic acid (1 mL). After stiffing for 5 days, water and sat aqueous NaHCO3 solution were added. The mixture was extracted with EtOAc, the combined organic layers were washed with water, dried over MgSO4 and the solvent was removed in vacuo. The residue obtained was dissolved in MeOH (3 mL) and NaBH4 (18.3 mg, 0.485 mmol) was added. After stirring overnight, water and sat. aqueous NaHCO3 solution were added. Extraction with EtOAc, washing of the combined organic layers with water and drying over MgSO4 provided the crude product which was purified by HPLC (24 mg, 19%). ESI-MS [M+H]+=395.2.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:18])[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>O1CCOCC1>[C:1]1([C:7]2[N:8]=[C:9]([NH:18][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:20]([CH3:19])=[CH:21][CH:22]=3)[S:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2nc(-c3ccccc3)c(-c3ccccc3)s2)cc1

Procedure:
4,5-Diphenyl-thiazol-2-ylamine (50.5 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1,4-dioxane (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). The reaction mixture was subjected to microwave irradiation for 5 minutes at 200° C. The crude product was filtered, evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (18.6 mg, 0.0502 mmol, 25.1%). ESI-MS m/z calc. 370.1. found 371.2 (M+1)+ Retention time 4.13 minutes.