Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1)([OH:3])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CC1C=CC(C)=CC=1CC(N1CCC(C2SC=C([C:75]([N:77](C)[C@@H:78]([C:81]3[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=3)[CH2:79][CH3:80])=O)N=2)CC1)=O>C(#N)C>[CH3:75][N:77]([C@@H:78]([C:81]1[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=1)[CH2:79][CH3:80])[C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Reactant: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCN(C(=O)Cc3cc(C)ccc3C)CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
1-(1,1-Dimethylethyl) 4-(4-carboxy-2-thiazolyl)-1-piperidinecarboxylate (i.e. the product of Example 1, Step B) (3.1 g, 9.9 mmol) was suspended in 10 mL of dry acetonitrile and treated with triethylamine (3.0 mL, 21 mmol) to give a homogeneous solution. To this was added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.98 g, 10.5 mmol) followed by (α,R)-α-ethyl-N-methylbenzenemethanamine (i.e. the product of Example 1, Step C) (10 mmol, 1.50 g). The mixture was stirred at ambient temperature for 4 days, concentrated under reduced pressure, diluted with ethyl acetate, washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dried over MgSO4 and concentrated under reduced pressure to give 5.1 g of a dark oil. Purification by silica gel chromatography using 25% ethyl acetate in hexanes gave 3.6 g of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[CH:9]1[CH2:13][CH2:14][CH:5]2[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:8]1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])[C:25]([Cl:39])=[CH:24][N:23]=1.Cl.O1CCOCC1>CC(O)C>[Cl:39][C:25]1[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])=[N:27][C:22]([NH:1][C:2]2[CH:3]=[C:4]3[C:10](=[CH:11][CH:12]=2)[CH:9]2[CH2:13][CH2:14][CH:5]3[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[CH2:8]2)=[N:23][CH:24]=1
Reactant: Nc1ccc2c(c1)C1CCC2CN(C(=O)C(F)(F)F)C1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(C(=O)C(F)(F)F)C2)ncc1Cl
Temperature: 120 °C
Yield: 77.9 %

Procedure:
1-(4-Amino-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-2,2,2-trifluoro-ethanone (30 mg, 0.106 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (34.5 mg, 0.116 mmol, 1.1 eq) were dissolved in IPA (1.5 mL). 4.0 M HCl in dioxane (29 μL, 0.116 mmol, 1.1 eq) was added and the reaction was heated at 120° C. in a microwave for 20 minutes. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (10 mL) and washed with sat. NaHCO3 (10 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-75% EtOAc/hex as the eluting solvent to obtain 2-{5-chloro-2-[10-(2,2,2-trifluoro-acetyl)-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide as a yellow foam (45 mg, 78%). LCMS (m/e) 545 (M+1); 1H-NMR (CDCl3, 400 MHz) major rotomer δ 11.01 (s, 1H), 8.61 (d, 1H, J=8.4 Hz), 8.10 (s, 1H), 7.53-7.40 (m, 3H), 7.36-7.26 (m, 1H), 7.13-6.95 (m, 3H), 6.22 (bs, 1H), 4.31-4.17 (m, 1H), 3.92-3.82 (m, 1H), 3.40-3.28 (m, 1H), 3.22-3.08 (m, 2H), 3.04 (d, 3H, J=4.5 Hz), 2.10-1.98 (m, 2H), 1.88-1.72 (m, 2H), 1.30-1.20 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:6][CH2:5][CH2:4][CH2:3]1.[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[NH:23][CH2:22][C:21]=12>>[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:7]4[CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]=4)=[CH:16][CH:15]=3)=[O:14])[CH2:22][C:21]=12
Reactant: CC1CCCC=C1c1ccc(C(=O)O)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Product: CC1CCCC=C1c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Yield: 96.8 %

Procedure:
4-(6-Methyl-cyclohex-1-en-1-yl)-benzoic acid of Step B (0.070 g, 0.324 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.066 g, 0.356 mmol) were reacted in the manner of Example 15, Step D. The title compound was purified by recrystallization from a mixture of diethyl ether and petroleum ether to afford 0.120 g of white crystals, m.p. 108–109° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:29])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:10]=2)[CH2:2]1.[CH2:30]([O:32][C:33]([CH:35]1[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([CH:35]1[CH2:40][CH2:39][CH:38]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:29])[CH2:7][NH:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=4)[N:11]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:10]=3)[CH2:4]2)[CH2:37][CH2:36]1)=[O:34])[CH3:31]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: O=C(CNc1nn(Cc2ccccc2)c2ccc(C(F)(F)F)cc12)NC1CNC1
Product: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3nn(Cc4ccccc4)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-benzyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide and 4-oxo-cyclohexanecarboxylic acid ethyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]([CH2:29][CH3:30])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[CH:14][CH:13]=3)[CH:7]=[CH:6][C:5]=12.[CH3:31][NH2:32]>CO>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]([CH2:29][CH3:30])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:32][CH3:31])=[CH:14][CH:13]=3)[CH:7]=[CH:6][C:5]=12
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2nsnc2c1
Reactant: CN
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccc2nsnc2c1
Temperature: 85 °C

Procedure:
To a stirred solution of 4-(2-(benzo[c][1,2,5]thiadiazol-5-yl)-1-(4-(2-chloro-ethoxy)phenyl)but-1-enyl)phenol (83 mg) in 10 mL MeOH was added 3 mL CH3NH2 (30% aq.) and heated at 85° C. for 15 h. The organic solvent was removed in vacuo, and the remaining mixture was extracted with EtOAc. The extract was washed with water and brine, dried over Na2SO4, filtered, concentrated, and purified by column chromatography (CH2Cl2/MeOH(NH3 gas)=50/1) to give the desired product (11 mg, Z/E=1/1) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.68 (d, J=9.2 Hz, 1H), 7.15 & 7.06 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.8 Hz, 1H), 6.79 (d, J=8.4 Hz, 2H), 6.78 & 6.72 (d, J=8.6 Hz, 2H), 6.48 & 6.42 (d, J=8.6 Hz, 2H), 4.12 & 3.92 (t, J=4.8 Hz, 2H), 3.03 & 2.91 (t, J=4.8 Hz, 2H), 2.60 (q, J=7.2 Hz, 2H), 2.55 & 2.47 (s, 3H), 0.97 (t, J=7.2 Hz, 3H); m/z=432[M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][C:4]#[C:5][C:6]1[CH:7]=[N:8][C:9]([CH3:15])=[C:10]([N+:12]([O-])=O)[CH:11]=1>CCO.[Ni]>[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([CH3:15])=[N:8][CH:7]=1
Reactant: Cc1ncc(C#CCN(C)C)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Cc1ncc(CCCN(C)C)cc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.9 %

Procedure:
To a solution of N,N-dimethyl-3-(6-methyl-5-nitropyridin-3-yl)prop-2-yn-1-amine (3.18 g, 13.8 mmol) in EtOH (50 mL) under an atmosphere of N2 was added Raney 2800 nickel (50% water slurry; 760 mg, 4 mmol) using 5 mL of ethanol to transfer. The mixture was purged with H2 (1 atm) and allowed to stir at rt under an atmosphere of N2 for 20 h. More Raney nickel (620 mg, 3.6 mmol) was added using 5 mL of ethanol to transfer. The mixture was purged with H2 (1 atm) and allowed to stir at rt under an atmosphere of H2 for 20 h. The mixture was filtered through Celite® and the filtrate was concentrated to give 5-[3-(dimethylamino)propyl]-2-methylpyridin-3-amine (2.45 g, 93%) as a brown solid. LCMS (AAL): Rt=0.98 min, m/z=194.4 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][NH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:23]([CH3:25])[CH3:24]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH:23]([CH3:25])[CH3:24])[C:6]=2[N:7]=1
Reactant: CCOC(=O)c1cc(Br)nc2[nH]ncc12
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nc2c1cnn2C(C)C
Yield: 58.2 %

Procedure:
To a stirred solution of ethyl 6-bromo-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (20 g, 74.3 mmol) in acetonitrile (200 mL), K2CO3 (15.39 g, 111.52 mmol) and 2-bromopropane (18.13 g, 148.64 mmol) was added to it. The reaction mixture was refluxed for 8 h. On completion, acetonitrile was removed under reduced pressure and water was added to it. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate (13.5 g, 58.3%).
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH:17]1([C:23]2[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>N1C=CC=CC=1>[CH:17]1([C:23]2[CH:24]=[CH:25][C:26]([S:29]([NH:16][C:13]3[S:14][CH:15]=[C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=4)[N:12]=3)(=[O:31])=[O:30])=[CH:27][CH:28]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=S(=O)(Cl)c1ccc(C2CCCCC2)cc1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(-c2csc(NS(=O)(=O)c3ccc(C4CCCCC4)cc3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.4 %

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 0.46 g of 4-cyclohexyl-benzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 25 ml of 1N hydrochloric acid and the organic phase was separated and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated as an oil upon neutralization. Thereupon, 20 ml of ethanol were added, the mixture was boiled and insoluble material was filtered off. Crystals separated upon cooling and, after recrystallization from 40 ml of 50% ethanol, yielded 0.15 g of 4-cyclohexyl-N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide as beige crystals.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][C:7]=1[C:11]([C:13]1[N:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]2[C:20]([C:21]=1[NH2:22])=[CH:19][CH:18]=[C:17]([Cl:23])[CH:16]=2)=[O:12])(=[O:3])[CH3:2].[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>>[C:1]([O:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][C:7]=1[C:11]([C:13]1[N:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]2[C:20]([C:21]=1[NH:22][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])=[CH:19][CH:18]=[C:17]([Cl:23])[CH:16]=2)=[O:12])(=[O:3])[CH3:2]
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2occc2COC(C)=O)c(N)c2ccc(Cl)cc21
Product: CCOC(=O)n1c(C(=O)c2occc2COC(C)=O)c(NC(=O)C(C)C)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 employing 2-(3-acetoxymethyl-2-furoyl)-3-amino-6-chloro-1-(ethoxycarbonyl)indole (step 1) and isobutyryl chloride.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[N:6]([CH3:23])[C:5]1=[O:24])[C:14](=[O:17])[CH:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11]3.Br[CH2:26][CH2:27][CH2:28][Cl:29].O>CN(C)C=O>[Cl:29][CH2:28][CH2:27][CH2:26][C:13]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11][C:10]2[C:15](=[CH:16][C:7]3[N:6]([CH3:23])[C:5](=[O:24])[N:4]([CH3:3])[C:8]=3[CH:9]=2)[C:14]1=[O:17]
Reactant: ClCCCBr
Reactant: CCOC(=O)C1CCc2cc3c(cc2C1=O)n(C)c(=O)n3C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(CCCCl)CCc2cc3c(cc2C1=O)n(C)c(=O)n3C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
60% Oily sodium hydride (832 mg) was added to a solution of ethyl (±)-1,3-dimethyl-2,5-dioxo-2,3,5,6,7,8-hexahydro-1H-naphtho[2,3-d]imidazole-6-carboxylate (5.0 g) obtained in Reference Example 138 in dimethylformamide, and the mixture was stirred at 60° C. for 1 hour. 1-Bromo-3-chloropropane was added thereto, and the mixture was stirred at 60° C. for 4 hours. The reaction mixture was allowed to cool, and water was added to decompose excessive sodium hydride. Then, the mixture was extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].S(=O)(=O)(O)O.[O-:13][C:14]#[N:15].[K+]>O>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[C:14]([NH2:15])=[O:13]
Reactant: OCCNCCO
Reactant: N#C[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: NC(=O)N(CCO)CCO
Temperature: 90 °C

Procedure:
212.4 g diethanolamine in 212.4 g of water was neutralized with 101.85 g concentrated sulfuric acid to a pH of 4. A solution of 168.99 g potassium cyanate in 260 g of water was then added and the mixture was heated to 90° C. for 3 hours. After cooling to ambient temperature, potassium sulfate precipitated and was filtered out. The filter cake was washed with 425 g of hot ethanol. The recovered ethanol was then added to the contents of the filtrate, causing the filtrate to become cloudy. The white precipitate was removed by filtration and then the ethanol was removed by distillation to give a viscous liquid solution of N,N-bis(2-hydroxyethyl)urea. The product similarly could be obtained using other acids to neutralize the amine, e.g. sulfuric acid. Also, other cyanate salts could be used, e.g. sodium cyanate.
Reaction SMILES: [C:1]1([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36]>CN(C)C=O>[C:1]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:24][CH2:25][N:26]3[C:27](=[O:36])[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:34]3=[O:35])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2cccc3ccccc23)CC1
Temperature: 90 °C

Procedure:
A suspension of 1.17 g (5.52 mmol) of 1-(1-naphthyl)piperazine (Tetrahedron Letters, 1998, 39(15), 2219-2222), 0.99 g (7.15 mol) of potassium carbonate and 1.68 g (6.62 mmol) of 2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione in 15 ml of N,N-dimethylformamide is heated at 90° C. for 2 hours.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH2:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[S:35]([CH2:39][CH2:40][CH2:41][C:42](O)=[O:43])(=[O:38])(=[O:37])[NH2:36].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8](=[NH:9])[C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH:31][C:42](=[O:43])[CH2:41][CH2:40][CH2:39][S:35](=[O:38])(=[O:37])[NH2:36])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Reactant: NS(=O)(=O)CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCS(N)(=O)=O)c1
Reaction time: 24 h
Yield: 60 %

Procedure:
{[4-(2′-Amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.013 g, 0.025 mmol) [example 25, step c] was added to a solution of 4-sulfamoyl-butyric acid (0.011 g, 0.068 mmol), EDCI (0.013 g, 0.068 mmol) and HOBt (0.009 g, 0.068 mmol) in DMF [0.5 mL] at room temperature. The reaction was stirred for 24 hours and then evaporated. Column chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (0.010 g, 60%) as a solid. ESI-MS (m/z): Calcd. for C28H34N4O7S4: 666.13; found: 666.8.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[NH2:5][C:6]1[CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:10][CH:11]=1.C([O-])([O-])=O.[K+].[K+].C>O.CS(C)=O>[F:15][C:12]([F:13])([F:14])[C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[NH:5][CH2:2][C:3]#[N:4]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCNc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 73.7 %

Procedure:
Chloroacetonitrile (16 g), m-aminobenzotrifluoride (32.2 g), K2CO3 (39.2 g) and DMSO (40 ml) were heated with stirring in a round-bottomed three-necked flask at 70°-80° C. for 4.0 hours. Pouring the reaction mixture into approximately 1 liter of ice and water resulted in the formation of an oil. The mixture was extracted with CH2Cl2 and the extracts obtained treated with diatomaceous earth and activated charcoal, and then filtered. The filtrate was taken to dryness, which gave 29.5 g of m-trifluoromethylanilinoacetonitrile as a dark oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH:10]=[CH:9]1.[CH3:28][NH2:29]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12]([NH:29][CH3:28])[C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Reactant: CN
Product: CNc1nc2c(OCC(F)(F)F)cccc2c2c1ccn2-c1ccccc1C
Temperature: 180 °C

Procedure:
1-(2-methylphenyl)-4-chloro-6-β,β,β-trifluoroethoxypyrrolo[3,2-c]quinoline(600 mg, 1.5 mmol) was dissolved in aqueous solution of methylamine(40%, 10 ml) in the pressure tube, and the resultant was refluxed at 180° C. for 3 hours. After removing the excess solvent by distillation under reduced pressure, the residue was diluted in dichloromethane(20 ml), and washed with water(15 ml) for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 446 mg of desired compound as solid in 77% of yield.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13]C)=[O:12])=[O:7])(=[O:4])=[O:3].[OH-].[Na+]>CO.O>[CH3:1][S:2]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([OH:13])=[O:12])=[O:7])(=[O:4])=[O:3]
Reactant: COC(=O)c1cccc(C(=O)NS(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)NC(=O)c1cccc(C(=O)O)c1
Yield: 41.2 %

Procedure:
Methyl 3-(methylsulfonylcarbamoyl)benzoate (700 mg, 2.72 mmol) was dissolved in methanol at 25° C. with stirring then 1.0 N NaOH (5.56 mL, 5.56 mmol) was added. The reaction mixture was stirred for 20 hours, diluted with water, and the methanol removed in vacuo. The aqueous was washed with diethyl ether (2×) then acidified to pH=3 with 1N HCl. The resulting solution was extracted with ethyl acetate to give 3-(methylsulfonylcarbamoyl)benzoic acid (285 mg, 1.12 mmol, 42% yield). MS found: (M+H)+=244.00.
Reaction SMILES: [F:1][C@@H:2]([CH3:24])[CH2:3][N:4]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[OH:23])[CH2:19][CH2:18][CH2:17]2)[S:5]([C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)(=[O:7])=[O:6].Br[CH2:26][C:27]1[S:28][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][N:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C@@H:2]([CH3:24])[CH2:3][N:4]([S:5]([C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)(=[O:7])=[O:6])[C:14]1[CH:15]=[C:16]2[C:20]([CH2:19][CH2:18][CH2:17]2)=[CH:21][C:22]=1[O:23][CH2:26][C:27]1[S:28][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][N:31]=1
Reactant: Cc1csc(S(=O)(=O)N(C[C@H](C)F)c2cc3c(cc2O)CCC3)n1
Reactant: CCOC(=O)c1cnc(CBr)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(COc2cc3c(cc2N(C[C@H](C)F)S(=O)(=O)c2nc(C)cs2)CCC3)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
137 mg of N-[(2S)-2-fluoropropyl]-N-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-4-methyl-1,3-thiazole-2-sulfonamide was dissolved in 1.05 mL of DMF, and 139 mg of ethyl 2-(bromomethyl)-1,3-thiazole-5-carboxylate and 102 mg of potassium carbonate were added thereto, followed by stirring at room temperature for 2 hours. To the reaction liquid was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 154 mg of ethyl 2-{[(6-{[(2S)-2-fluoropropyl][(4-methyl-1,3-thiazol-2-yl)sulfonyl]amino}-2,3-dihydro-1H-inden-5-yl)oxy]methyl}-1,3-thiazole-5-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].Cl.[CH3:13]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:13])=[O:7])=[CH:4][C:3]=1[OH:11]
Reactant: Nc1ccc(C(=O)O)cc1O
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(N)c(O)c1
Reaction time: 48 h
Yield: 96 %

Procedure:
Through a solution of 4-amino-3-hydroxybenzoic acid (75 g, 0.49 mol) in 2.0 L of dry methanol at room temperature was bubbled anhydrous HCl gas until the solution was saturated. The solution was stirred for 48 hours, then concentrated in vacuo. The product was partitioned between EtOAc and saturated aq. NaHCO3 solution, and the organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to provide the titled compound (79 g, 96% yield).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8][N:9]([CH3:19])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][S:2]([O:6][CH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8][N:9]([CH3:19])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11])(=[O:4])=[O:3]
Reactant: CN(CC(O)c1ccccc1)S(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(CC(OS(C)(=O)=O)c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
Methanesulfonyl chloride (0.028 mL, 41 mg, 0.36 mmol) was added dropwise over 5 min to a 0° C. solution of N-(2-hydroxy-2-phenylethyl)-N-methylbenzenesulfonamide (100 mg, 0.357 mmol) and triethylamine (0.075 mL, 54 mg, 0.054 mmol) in 1.0 mL of ethyl acetate. After 15 min., the resulting suspension was poured into 40 mL of ice cold ethyl acetate and washed succesively with 20 mL of ice water, 20 mL of ice cold 2.0 N HCl, 20 mL of ice water and 20 mL of brine. The ethyl acetate layer was dried over sodium sulfate and evaporated to give 128 mg of crude N-(2-methanesulfonyloxy-2-phenylethyl)-N-methylbenzenesulfonamide.