Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][C:10]1[CH:11]=[C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:13]=[C:14]2[C:18]=1[NH:17][CH:16]=[C:15]2[CH2:19][CH3:20])(=[O:8])=[O:7].CCN(CC)CC>CCO>[O:7]=[S:6]1(=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][N:9]1[C:10]1[CH:11]=[C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:13]=[C:14]2[C:18]=1[NH:17][CH:16]=[C:15]2[CH2:19][CH3:20]
Reactant: CCOC(=O)c1cc(NS(=O)(=O)CCCCCl)c2[nH]cc(CC)c2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cc(N2CCCCS2(=O)=O)c2[nH]cc(CC)c2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
To a solution of ethyl 7-{[(4-chlorobutyl)sulfonyl]amino}-3-ethyl-1H-indole-5-carboxylate (D242) (230 mg, 0.59 mmol, 1 equiv) in EtOH (10 ml) was added NEt3 (249 μl, 1.78 mmol, 3 equiv) and the resulting solution was stirred at 70° C. for 3 h. NEt3 (1 ml, excess) was added and the solution was stirred at the same temperature for 15 h then cooled to room temperature and concentrated in vacuo. The residue was dissolved in AcOEt and the organic phase was washed with a 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (AcOEt/iso-hexane: 3/7) gave ethyl 7-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-3-ethyl-1H-indole-5-carboxylate (B148) (150 mg, 72%) as a colorless oil. [M−H]−=349.3, RT=3.10 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1.[Cl:30][CH2:31][CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35].CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][N:19]([S:34]([CH2:33][CH2:32][CH2:31][Cl:30])(=[O:36])=[O:35])[CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2Cl)n[nH]1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(S(=O)(=O)CCCCl)CC4)cc3C)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (78 mg, 0.19 mmol) and TEA (0.52 mL, 3.78 mmol) in DCM (10 mL) was added 3-chloropropane-1-sulfonyl chloride (63 mg, 0.36 mmol, in 1 mL DCM). After stirring at rt for one hour, EtOAc (100 mL) was added. The mixture was sequentially washed with water (10 mL), brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica chromatography (0-100% EtOAc in hexanes gradient) to give 5-chloro-N2-(4-(1-(3-chloropropylsulfonyl)piperidin-4-yl)-2,5-dimethylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as an off white solid; ESMS m/z 552.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[NH3:14]>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: Fc1ccc(C(F)(F)F)c(F)c1F
Reactant: N
Solvent: C1CCOC1
Product: Nc1ccc(C(F)(F)F)c(F)c1F
Temperature: 130 °C
Reaction time: 6 h

Procedure:
200 g of 2,3,4-trifluorobenzotrifluoride in 500 ml of tetrahydrofuran are introduced in an autoclave, and 60 ml of liquid ammonia are forced in. The mixture is stirred at 130° C. for 6 hours (maximum pressure 18 bar), cooled, and released. By distillation, 72 g of 2-amino-3,4-difluoro-benzotrifluoride are obtained at a boiling point of 60° to 64° C. at 26 mbar and 92 g of 2,3-difluoro-4-amino-benzotrifluoride are obtained at a boiling point of 92° to 93° C. at 26 mbar.
Reaction SMILES: [CH3:1][NH2:2].CCO.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]=[C:15]=[O:16]>C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]([NH:2][CH3:1])=[O:16]
Reactant: CN
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)Nc1ccc(Cl)cc1Cl
Temperature: 65 °C
Yield: 74 %

Procedure:
A cooled (0° C.) solution of methylamine in EtOH (50 mL, 400 mmol, 8.0 M) in anhydrous THF (300 mL) was treated with 2,4-dichlorophenylisocyanate (25.0 g, 133 mmol). The cooling bath was removed and the mixture was warmed to 65° C. for 20 min. The reaction mixture was then cooled to 0° C. The solid was collected on a Buchner funnel, washed with cold ether, and dried under vacuum to afford N-(2,4-dichlorophenyl)-N′-methyl-urea (21.7 g, 74% yield) as a colorless solid: mp 213.5-214.5° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.17 (d, J=9.2 Hz, 1H), 8.11 (s, 1H), 7.55 (d, J=2.5 Hz, 1H), 7.32 (dd, J=8.8, 2.6 Hz, 1H), 6.91 (d, J=4.8 Hz, 1H), 2.65 (d, J=4.4 Hz, 3H); LRMS (APCI) m/e 259.9 [(M+H+CH3CN)+, calcd for C10H12N3OCl2, 260.0].
Reaction SMILES: C([O:3][C:4]([C:6]1([S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)(=[O:29])=[O:30])=[CH:32][CH:33]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(OCCN3CCCCC3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(OCCN4CCCCC4)cc3)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester (5.4 g, 10 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.0 g (77%); off white powder; mp 174° C.; MS: 517.6 (M+H)+.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11].C(P(CCCC)CCCC)CCC>C1COCC1>[OH:12][CH:7]([C:2]1[C:1](=[O:6])[CH2:5][CH2:4][CH:3]=1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=C1C=CCC1
Reactant: CCCCC=O
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCCC(O)C1=CCCC1=O
Yield: 92 %

Procedure:
A solution of cyclopentenone (1.23 g, 15 mmol), pentanal (1.94 g, 22.5 mmol), rac-1,1′-bi-2-naphthol (429 mg, 1.5 mmol) and tributyl phosphine (606 mg, 3 mmol) in dry THF (12 ml) was stirred at 20° C. under Argon for 3 hours. The solution was then passed through a short column of SiO2 (cyclohexane/Et2O 6:4) to obtain the pure title compound in 92% yield.
Reaction SMILES: [F:1][C:2]([F:13])([CH2:8][NH:9][CH:10]([CH3:12])[CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=1>CC(C)=O.ClCCl>[Cl:20][C:21]1[N:26]=[C:25]([N:9]([CH:10]([CH3:12])[CH3:11])[CH2:8][C:2]([F:13])([F:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=1
Reactant: CCOC(=O)C(F)(F)CNC(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
Ethyl 2,2-difluoro-3-(isopropylamino)propanoate (1.50 g, 7.68 mmol) was dissolved in acetone and K2CO3 (2.12 g, 15.3 mmol) was added. The solution was purged with nitrogen gas and cooled to 0° C. A solution of 2,4-dichloro-5-nitropyrimidine (1.64 g, 8.45 mmol) in acetone (10 mL) was added dropwise at 0° C. over 1 h. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. It was diluted with dichloromethane (50 mL) and filtered thru a celite plug. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography on silica gel (120 g SiO2, hexanes:ethyl acetate 10:1-3:1) to afford the title compound as a yellow oil (1.96 g, 72%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (d, J=6.82 Hz, 6H) 1.34 (t, J=7.20 Hz, 3H) 3.63-3.75 (m, 1H) 4.24 (t, J=13.14 Hz, 2H) 4.34 (q, J=7.07 Hz, 2H) 8.74 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3C(O)=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C>C(Cl)Cl.C(OCC)(=O)C.C(O)C>[Br:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2cccc(Br)c2C1=O
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN1Cc2cncn2-c2cccc(Br)c2C1=O

Procedure:
19.1 g (56.8 mmol) of 7-bromo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid are decarboxylated at 290°-300°. The melt was taken up in methylene chloride, the solution was diluted with ethyl acetate and ethanol and decolorized with animal charcoal. After evaporation and recrystallization from ethyl acetate and ethanol there was obtained 7-bromo-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 196°-197°.
Reaction SMILES: [NH2:1][C:2]1N(C2C=CC=CC=2OC)[N:5]=[CH:4][C:3]=1[C:15]#N.[F:17][C:18]1([F:26])[CH2:23][CH2:22][CH:21]([NH:24][NH2:25])[CH2:20][CH2:19]1>>[NH2:5][C:4]1[N:24]([CH:21]2[CH2:22][CH2:23][C:18]([F:26])([F:17])[CH2:19][CH2:20]2)[N:25]=[CH:15][C:3]=1[C:2]#[N:1]
Reactant: COc1ccccc1-n1ncc(C#N)c1N
Reactant: NNC1CCC(F)(F)CC1
Product: N#Cc1cnn(C2CCC(F)(F)CC2)c1N

Procedure:
Following the procedure for the preparation of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carbonitrile but substituting 1-(4,4-difluorocyclohexyl)hydrazine provided the title compound. 400 MHz 1H NMR (CDCl3) δ 7.5 (m, 1H), 3.90 (m, 1H), 2.40-1.00 (m, 8H).
Reaction SMILES: [CH2:1]([CH2:11][C:12](=O)[CH3:13])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.O>C1(C)C=CC=CC=1>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][CH:12]([CH3:13])[CH2:11][CH2:1][C:2]2[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=2)=[CH:19][CH:18]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COc1cc(CCC(C)=O)ccc1O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(CCC(C)NCc2ccc(C(F)(F)F)cc2)ccc1O
Temperature: 0 °C
Yield: 74 %

Procedure:
Vanillylacetone (5.00 g, 25.7 mmol) was dissolved in toluene (250 mL) and 4-trifluoromethylbenzylamine (4.73 g, 27.0 mmol) was added. The mixture was maintained under an atmosphere of nitrogen and heated at reflux with removal of water by Dean-Stark distillation for 16 hours. At this time the Dean-Stark trap was removed and the reaction mixture was cooled to 0° C. on an ice bath. A solution of sodium borohydride (5 g) in methanol (100 mL) was added portion-wise over 30 minutes with vigorous stirring. When the addition was complete the mixture was heated at reflux for 16 hours. At this time the reaction mixture was cooled to room temperature and poured into saturated aqueous sodium bicarbonate solution (300 mL). The resulting mixture was concentrated by rotary evaporation and the aqueous residue was partitioned between water and chloroform. The chloroform layer was dried over anhydrous sodium sulfate and then filtered and concentrated. The product was then purified using silica gel column chromatography employing a mobile phase of 5% ammonia-methanol in chloroform. Product-containing fractions were combined and concentrated then dried under high vacuum overnight to provide a light brown oil (6.72 g, 74%). 1H NMR, 13C NMR, and Mass Spectrum of the product were substantially the same as those in Example 2, A (made by the Conditioned Extraction method).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.CO.[F:14][CH2:15][C:16](=O)[CH3:17].N1CCCC1>CC(OC)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8](=[O:10])[CH2:9][C:16]([CH2:15][F:14])([CH3:17])[O:11]2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(Cl)cc1O
Reactant: CC(=O)CF
Solvent: C1CCNC1
Solvent: COC(C)(C)C
Solvent: CO
Product: CC1(CF)CC(=O)c2ccc(Cl)cc2O1
Reaction time: 72 h
Yield: 94.3 %

Procedure:
1-(4-Chloro-2-hydroxyphenyl)ethanone (10.2 g, 59.8 mmol), MeOH (100 mL), fluoroacetone (5.00 g, 65.8 mmol), and pyrrolidine (5.44 ml, 65.8 mmol) were stirred at ambient temperature. After 3 days, LCMS showed complete reaction. The reaction mixture was diluted with MTBE (250 mL), washed with water (100 mL), 2N HCl (2×50 mL), brine (50 mL), 2N NaOH (2×50 mL), and brine (2×50 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to provide the title compound (12.9 g, 56.4 mmol, 94% yield) as a brown oil. MS (DCI/NH3) m/z 246 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]=2[CH3:21])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[O:30][C:9]2([CH3:21])[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]3)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=C(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)C1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(c3ccc(Cl)cc3)OC2(C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4-(4-chlorophenyl)-3-methyl-5,6-dihydropyridine-1(2H)-carboxylate (1.09 g, 3.54 mmol) in methylene chloride (15 mL) was cooled to 0° C. and treated dropwise with a solution of m-CPBA (1.111 g, 4.96 mmol) in methylene chloride (15 mL). The reaction was stirred at 0° C. for 1 hour, then allowed to slowly warm to room temperature and stirred overnight. The mixture was cooled to 0° C., treated with saturated aqueous sodium sulfite (20 mL), and stirred for 1 hour. The layers were separated, and the organic phase was washed once with water, 3× with saturated sodium carbonate, once with water, and once with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified over a 120 g silica gel column, eluting at 85 mL/min with a 0% to 17% ethyl acetate/hexanes gradient followed by 17% ethyl acetate/hexanes to yield the title compound as a colorless oil. MS (ESI+)=268.2 (M−tert-Bu)+, 250.1 (M−tert-BuO)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11]C(C#N)=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)[CH2:3][CH2:2]1.[CH3:26][CH2:27][OH:28].[OH-:29].[K+].Cl>O>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:26]([C:27]([OH:29])=[O:28])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)[CH2:3][CH2:2]1
Reactant: CCO
Reactant: [OH-]
Reactant: CCOc1ccc(Cc2nc3cc(C#N)ccc3n2CC2CC2)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCOc1ccc(Cc2nc3cc(C(=O)O)ccc3n2CC2CC2)cc1
Yield: 99 %

Procedure:
To a solution of 1-(cyclopropylmethyl)-2-(4-ethoxybenzyl)-1H-benzimidazole-5-carbonitrile (500 mg, 1.51 mmol) in 1:1 EtOH:H2O (16 mL) was added KOH (338 mg, 6.04 mmol). The resulting mixture was refluxed for 36 h. The mixture was acidified with 1 N HCl to pH˜6.0, the precipitate was collected by filtration to give white solids (520 mg, 99%) which was used for the next step without further purification. The analytically pure compound was obtained by recrystallization (from EtOH:H2O). 1H NMR (400 MHz, CD3OD): δ 8.25 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.18 (d, J=8.2 Hz, 2H), 6.82 (d, J=8.2 Hz, 2H), 4.28 (s, 2H), 4.06 (d, J=6.8 Hz, 2H), 3.89 (q, J=7.6 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.06–0.92 (m, 1H), 0.50–0.48 (m, 2H), 0.32–0.26 (m, 2H). MS (ESI) (M+H)+=351. Anal. Calcd for C21H22N2O3.0.7HCl: C, 67.09; H, 6.09; N, 7.45. Found: C, 66.98; H, 6.31; N, 7.09.
Reaction SMILES: [N:1]1[CH:6]=CC=C[CH:2]=1.Cl.C([C:11]1[N:15]2[CH2:16][CH2:17][CH2:18][N:19]=[C:14]2SC=1C(Cl)=O)CC.C(SC1C=CC(N)=CC=1)CCCCCC>CN(C)C=O>[CH3:11][NH:15][C:16]1[CH:2]=[N:1][CH:6]=[C:18]([NH:19][CH3:14])[CH:17]=1
Reactant: CCCC1=C(C(=O)Cl)SC2=NCCCN21
Reactant: c1ccncc1
Agent: CCCCCCCSc1ccc(N)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CNc1cncc(NC)c1

Procedure:
In the mixture of 50 ml of pyridine and 5 ml of dimethylformamide was suspended 1.07 g of 3-propyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonylchloride hydrochloride (described in Example 13). To the suspension were added 850 mg of 4-n-heptylthioaniline obtained in Reference Example 6, and 56 mg of 3,5-dimethylaminopyridine, followed by stirring at 70° C. for 12 hours. The reaction mixture was concentrated and to the concentrate was added saturated sodium hydrogencarbonate aqueous solution. The mixture was extracted with chloroform. The extract was washed with saturated sodium chloride aqueous solution, dried over anhydrous potassium carbonate and treated with active carbon. The solvent was removed under reduced pressure. The residue was dissolved in ethanol. To the mixture was added saturated hydrogenchloride diethylether solution, followed by stirring at room temperature. The solvent was removed under reduced pressure. The residue was precipitated from ethanol-diethylether to collect by filtration. The precipitated powder was recrystallized from methanoldiethylether to yield 992 mg of the titled compound.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:31])=[C:7]([C:18]([NH:21][S:22]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[CH:19][CH:20]=1)[C:8]([O:10]CC1C=CC=CC=1)=[O:9])[CH2:2][CH2:3][CH3:4].O>CO.C1COCC1.[Pd]>[CH2:1]([C:5]1[C:6]([CH3:31])=[C:7]([C:18]([NH:21][S:22]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)(=[O:23])=[O:24])=[CH:19][CH:20]=1)[C:8]([OH:10])=[O:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(NS(=O)(=O)c2cccnc2)c(C(=O)OCc2ccccc2)c1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCc1ccc(NS(=O)(=O)c2cccnc2)c(C(=O)O)c1C
Reaction time: 1 h
Yield: 68 %

Procedure:
A solution of Example 114A (87 mg) in methanol (4 mL), THF (4 mL), and water (1 mL) was treated with 5% Pd/C (100 mg), stirred under a hydrogen atmosphere for 1 hour, and filtered through diatomaceous earth (Celite®), and concentrated to provide the desired product (47 mg). 1H NMR (DMSO-d6) δ 0.89 (t, 3H), 1.29-1.34 (m, 2H), 1.40-1.45 (m, 2H), 2.21 (s, 3H), 2.52 (t, 2H), 6.81 (d, 1H), 7.07 (t, 1H), 7.58 (t, 1H), 8.07 (d, 1H), 8.77 (d, 1H), 8.83 (s, 1H); MS (ESI(−)) m/e 347 (M−H)−.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]3[N:20]=[CH:21][CH:22]=[CH:23][C:11]=3[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].O>CN(C)C=O>[O:38]=[C:29]1[C:30]2[C:31](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:33])[N:28]1[CH2:27][CH2:26][CH2:25][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:10][C:11]2[CH:23]=[CH:22][CH:21]=[N:20][C:12]1=2
Reactant: c1ccc(C2=Nc3cccnc3Nc3ccccc32)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCN1c2ccccc2C(c2ccccc2)=Nc2cccnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.9 %

Procedure:
To a stirred suspension of 0.56 g (0.023 mole) of sodium hydride in 25 ml of anhydrous dimethylformamide was added, portionwise, 5.0 g (0.0184 mole) of 6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine. The reaction mixture was warmed to 80°±2° C. for 1 hr and cooled to room temperature. A solution of 5.55 g (0.020 mole) of N-(3-bromopropyl) phthalimide in 10 ml of anhydrous dimethylformamide was added dropwise and after stirring for 16 hr the reaction mixture was poured into 650 ml of water and stirred for 30 min. The yellow solid was collected by filtration and recrystallized three times from isopropyl alcohol to give 3.7 g of product, m.p. 170°-172° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.F[B-](F)(F)F.[O:24]=[N+:25]=[O:26].O>C(#N)C>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([N+:25]([O-:26])=[O:24])[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CC1(C)CC(c2ccccn2)c2ccccc2O1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: CC1(C)CC(c2ccccn2)c2cc([N+](=O)[O-])ccc2O1
Yield: 15.7 %

Procedure:
1.32 g of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 20 ml of acetonitrile and 0.73 g of nitronium tetrafluoroborate was added at room temperature. After 1 hour the mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with sodium chloride solution, dried over sodium sulphate and evaporated to give an oil. This oil was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution. 245 mg of 3,4-dihydro-2,2-dimethyl-6 -nitro-4-(2-pyridyl)-2H-1-benzopyran were obtained in the form of an oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH2:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][S:2]([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(CN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of methyl 4-(chlorosulfonyl)benzoate (Example 5-10c) (4 g, 17.09 mmol) in dichloromethane (40 mL) at 0° C. in an ice bath, was added (4-methoxyphenyl)methanamine (2.56 mL, 19.65 mmol) and triethylamine (2.38 mL, 17.1 mmol). The ice bath was then removed and the mixture was allowed to warm to ambient temperature with stirring for an additional 2 hours. Upon completion (monitored by TLC 40% ethyl acetate/hexanes), the solvent was removed in vacuo. The residue was re-dissolved in ethyl acetate (200 mL), washed with 1N HCl (aq, 20 mL), water (20 mL) and brine (20 mL) then dried over magnesium sulfate. The solution was concentrated and the product purified by re-crystallization with hot ethyl acetate/hexanes to afford pure methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (4.3 g, 74.8%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.67 (s, 3H), 3.78 (s, 3H), 3.93 (s, 2H), 6.78 (m, 2H), 7.09 (m, 2H), 7.87 (m, 2H), 8.08 (m, 2H), 8.25 (br, s, 1H).
Reaction SMILES: C1(CCC[NH2:10])C=CC=CC=1.[C:11]([OH:19])(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]1[C:29]([NH:31][C:32]1[CH:40]=[CH:39][C:35](C(O)=O)=[CH:34][CH:33]=1)=[O:30]>>[C:11]([NH:10][CH2:33][CH2:34][CH2:35][CH2:39][CH2:40][CH2:32][NH:31][C:29]([N:21]1[CH2:20][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:30])(=[O:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccccc1
Reactant: NCCCc1ccccc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Product: O=C(NCCCCCCNC(=O)N1Cc2ccccc2C1)c1ccccc1

Procedure:
The title compound was prepared as described in Example 1C, substituting N-(6-aminohexyl)isoindoline-2-carboxamide for 3-phenylpropan-1-amine and benzoic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.42 (t, J=5.35 Hz, 1H) 7.76-7.90 (m, 2H) 7.36-7.58 (m, 3H) 7.20-7.36 (m, 4H) 6.28 (t, J=5.55 Hz, 1H) 4.57 (s, 4H) 3.21-3.30 (m, 2H) 3.07 (q, J=6.74 Hz, 2H) 1.24-1.66 (m, 8H); (ESI(+)) m/e 366 (M+H)+.