Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([NH:20][C:21]([NH2:23])=[S:22])=[N:9][CH:10]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:25][CH:26]=O>CN(C=O)C>[CH:1]1([O:6][C:7]2[C:8]([NH:20][C:21]3[S:22][CH:25]=[CH:26][N:23]=3)=[N:9][CH:10]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CCCl
Reactant: NC(=S)Nc1ncc(Oc2ccccc2)cc1OC1CCCC1
Solvent: CN(C)C=O
Product: c1ccc(Oc2cnc(Nc3nccs3)c(OC3CCCC3)c2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
(3-Cyclopentyloxy-5-phenoxy-pyridine-2-yl)-thiourea (0.29 mmol) is dissolved in DMF (1 ml) and chloro-acetaldehyde (1.1 eq., 55% in water) is added and stirred 3 h at 100° C. After cooling to room temperature the suspension is pored into ice-water and extracted with methyl-ter.-butyl ether. The combined organic phases are washed with brine and dried over MgSO4. The solvent is removed in vacuo. (3-Cyclopentyloxy-5-phenoxy-pyridine-2-yl)-thiazole-2-yl-amine (“A21”) is obtained after reversed phase chromatography (water/acetonitrile+0.1% TFA) as yellow solid in a yield of 47%; 138.2-139.7°; HPLC (method C): 2.00 min; LC-MS (method A): 2.00 min, 354.1 (M+H+);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>C(Cl)Cl>[Br:34][CH2:12][CH2:11][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1cccc(Cl)c1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(Cl)c1CCBr
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of 2-(2-chloro-6-nitrophenyl)ethanol (33.0 g, 0.16 mole) in methylene chloride (500 mL) was added triphenylphosphine (43.0 g, 0.16 mole) and the mixture was cooled to 0° C. Carbon tetrabromide (54.4 g, 0.16 mole) in methylene chloride (100 mL) was added dropwise through an addition funnel. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue purified by flash column chromatography (silica gel, ethyl acetate:hexanes 1:9) to provide 39.0 g of the title compound as a yellow solid. 1H NMR (CDCl3): 7.70 δ (d, 1H); 7.60 δ (d, 1H); 7.35 δ (t, 1H); 3.60 δ (t, 2H); 3.45 δ (t, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([CH:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[C:18]([O:23]C(=O)C(C)(C)C)[CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:2].Cl.[N:31]1([CH2:38][CH2:39][O:40][C:41]2[CH:49]=[CH:48][C:44]([C:45](O)=O)=[CH:43][CH:42]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:38][CH2:39][O:40][C:41]2[CH:49]=[CH:48][C:44]([CH2:45][CH2:2][CH2:1][NH:3][C:4]3[C:5]([CH:13]4[CH2:14][CH2:15][C:16]5[CH:17]=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=5[CH2:22]4)=[CH:6][C:7]4[O:11][CH2:10][O:9][C:8]=4[CH:12]=3)=[CH:43][CH:42]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Reactant: CCNc1cc2c(cc1C1CCc3cc(OC(=O)C(C)(C)C)ccc3C1)OCO2
Agent: Cl
Product: Oc1ccc2c(c1)CCC(c1cc3c(cc1NCCCc1ccc(OCCN4CCCCCC4)cc1)OCO3)C2
Yield: 76.5 %

Procedure:
Synthesized from pivalic acid 6-(6-ethylaminobenzo[1,3]dioxol-5-yl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride (80 mg) according to an analogous synthetic method to Example 337 described below, the title compound (42 mg) was obtained.
Reaction SMILES: [O:1]1[C:3]2[CH2:4][CH2:5][CH2:6][C:2]1=2.[F:7][C:8]1[CH:13]=[C:12]([SH:14])[CH:11]=[CH:10][C:9]=1[CH:15]([CH3:20])[C:16]([O:18]C)=[O:17]>ClCCl>[F:7][C:8]1[CH:13]=[C:12]([S:14][C@H:2]2[CH2:6][CH2:5][CH2:4][C@@H:3]2[OH:1])[CH:11]=[CH:10][C:9]=1[CH:15]([CH3:20])[C:16]([OH:18])=[O:17]
Reactant: C1CC2=C(C1)O2
Reactant: COC(=O)C(C)c1ccc(S)cc1F
Solvent: ClCCl
Product: CC(C(=O)O)c1ccc(S[C@H]2CCC[C@@H]2O)cc1F
Temperature: 25 °C
Reaction time: 39 h
Yield: 83.9 %

Procedure:
To an aqueous solution (19 mL) of borax (0.1 g, 0.26 mmol), 1,2-epoxycyclopentene (0.8 mL, 9.3 mmol) and compound (9) (1.60 g, 7.5 mmol) were sequentially added. The mixture was stirred at room temperature for 39 hours and dichloromethane (50 mL) was added thereto. The organic layer was washed with water and dried (over sodium sulfate). The solvent was distilled off, and the residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (8:1) solution followed by conventional hydrolysis to give 1.79 g (84%) of compound (16) of interest as yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:6]=2[C:5](=[O:27])[NH:4][C:3]1=[O:28].C(=O)([O-])[O-].[K+].[K+].[CH2:35](I)[CH2:36][CH2:37][CH3:38]>CN(C=O)C.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][N:7]3[C:6]4[C:5](=[O:27])[N:4]([CH2:35][CH2:36][CH2:37][CH3:38])[C:3](=[O:28])[N:2]([CH3:1])[C:10]=4[N:9]=[CH:8]3)=[CH:17][CH:16]=2)=[O:26])=[CH:20][CH:21]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Yield: 21 %

Procedure:
A solution of 3-methyl-7-[4-(4-chlorobenzoyl)-benzyl]xanthine (612 mg), potassium carbonate (228 mg) and butyl iodide (430 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =1:1) and recrystallized from ethyl acetate to provide the title compound as colorless solid (147 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:20])[CH2:11][CH2:12][CH:13]2[O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O.CC#[N:30].CCOCC>>[NH2:30][N:2]=[CH:1][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:20])[CH2:11][CH2:12][CH:13]2[O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14]2)=[CH:7][CH:8]=1
Reactant: CC#N
Reactant: N#Cc1ccc(NC(=O)CCC2CCCC(=O)O2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: NN=Cc1ccc(NC(=O)CCC2CCCC(=O)O2)cc1

Procedure:
The title compound was prepared from the product of step B (770 mg, 2.83 mmol) in a manner similar to example 1, step G to give 430 mg (38%) of product as TFA salt after reverse phase chromatography and trituration with CH3CN/Et2O (m.p. 151°-153° C. dec.).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([C:13]1[C:14](OS(C(F)(F)F)(=O)=O)=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[CH:24]=1)=[CH:20][C:19]([Cl:32])=[CH:18][CH:17]=2)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[C:6]([O:10][C:11]([C:13]1[C:14]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:30])[CH3:31])[CH:24]=1)=[CH:20][C:19]([Cl:32])=[CH:18][CH:17]=2)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: C1CCNC1
Reactant: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(OS(=O)(=O)C(F)(F)F)nc3ccc(Cl)cc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(N3CCCC3)nc3ccc(Cl)cc23)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
To a solution of pyrrolidine (0.093 ml, 1.13 mmol) in DMSO (7 ml) was added 6-chloro-4-(3-isopropyl-phenyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid tert-butyl ester (prepared as described in example 78 step C, 400 mg, 0.76 mmol) and potassium carbonate (313 mg, 2.026 mmol) at 25° C. The resulting reaction mixture was stirred at 90° C. for 3 h. The reaction mixture was diluted with water (15 ml), and extracted with EtOAc (2×30 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (5-10% EtOAc in hexane) to afford 6-chloro-4-(3-isopropyl-phenyl)-2-pyrrolidin-1-yl-quinoline-3-carboxylic acid tert-butyl ester (250 mg, 73%) as pale yellow solid. LC-MS (ESI): LC-MS (ESI): 451 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:13]C(=O)C)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.Cl>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: CC(=O)Oc1ccc(Br)c2c1CCC(=O)N2
Agent: Cl
Product: O=C1CCc2c(O)ccc(Br)c2N1
Yield: 78.2 %

Procedure:
The thus-obtained 21 g of 8-bromo-5-acetyloxy-3,4-dihydrocarbostyril are dispersed in 150 ml of 8N-hydrochloric acid. The dispersion is heated under reflux conditions for 3 hours and then cooled. Insoluble matter thus formed is separated by filtration, washed with water and dried, and recrystallized from methanol-water to obtain 14 g of 8-bromo-5-hydroxy-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 212°-213° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH:12]1[CH:17]=[C:16]([CH:18]=[O:19])[C:15]([OH:20])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([O:20][C:15]2[CH:14]=[CH:13][CH:12]=[CH:17][C:16]=2[CH:18]=[O:19])[N:3]=1
Reactant: COc1cc(OC)nc(Cl)n1
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(OC)nc(Oc2ccccc2C=O)n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
A 500-ml four-necked flask was charged with a mixture of 105 g (0.6 mole) of 2-chloro-4,6-dimethoxypyrimidine, 79.4 g (0.65 mole) of salicylic aldehyde, 48.3 g (0.35 mole) of potassium carbonate and 450 ml of dimethylsulfoxide. The mixture was gradually heated, and stirred at 120° C. for 3 hours. After the reaction mixture was cooled, it was poured into 2 l of water. Through the procedures of benzene extraction, washing with water, drying over anhydrous sodium sulfate and concentration, 156 g of the target product were obtained as a crude oil. It was purified further by silica gel chromatography to obtain 117.1 g of white crystals (yield: 75.0%). Melting point: 76.0° about 76.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([N+:13]([O-])=O)[CH2:11][N:10]([CH3:16])[CH2:9]2)=[CH:4][C:3]=1[F:17].C(O)(=O)C>CO.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:9][N:10]([CH3:16])[CH2:11][C@H:12]2[NH2:13])=[CH:4][C:3]=1[F:17]
Reactant: CN1C[C@@H]([N+](=O)[O-])[C@H](c2ccc(Cl)c(F)c2)C1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CN1C[C@@H](N)[C@H](c2ccc(Cl)c(F)c2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
Zinc dust (5.76 g, 88 mmol) was added into a mixture of (+/−)-(3R,4S)-3-(4-chloro-3-fluorophenyl)-1-methyl-4-nitropyrrolidine (2.28 g, 8.81 mmol) in MeOH (29.4 mL) and acetic acid (30 mL, 524 mmol). The reaction mixture was stirred at room temperature for 5 h and filtered. Solvent was removed under vacuum. The residue was neutralized to pH 9, then extracted by IPA:CHCl3 (3:7). The organic was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (DCM/Methanol/NH3 90:9:1) to obtain (+/−)-(3S,4R)-4-(4-chloro-3-fluorophenyl)-1-methylpyrrolidin-3-amine in 40% yield. LCMS (m/z): 229.2 (MH+), 0.25 min.
Reaction SMILES: O[C:2]([CH3:15])([CH3:14])[CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[NH:5]1.S(Cl)([Cl:18])=O>>[Cl:18][C:2]([CH3:15])([CH3:14])[CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[NH:5]1
Reactant: CC(C)(O)CC1NC(=O)c2ccccc21
Reactant: O=S(Cl)Cl
Product: CC(C)(Cl)CC1NC(=O)c2ccccc21
Temperature: 25 °C

Procedure:
1,3-Dihydro-3-(2-hydroxy-2-methylpropyl)-2H-isoindol-1-one (12 g, described in Example 2) is added portionwise to thionyl chloride (72 ml) while stirring at room temperature. After 2 hr the reaction is evaporated and the residue is chromatographed on silica gel using acetone-toluene (3:7). The eluates are evaporated and crystallized from ethyl acetate-diethyl ether to give the title compound (2.2 g); mp 153°-155° C. and Anal. Calcd for C12H14ClNO: C, 64.43% H, 6.31% N, 6.27% and Found: 64.25% H, 6.26% N, 6.17%.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:1]([NH:14][CH2:16][CH2:17][CH2:18][Cl:19])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCNC(c1ccccc1)c1ccccc1
Temperature: 75 °C
Yield: 100.1 %

Procedure:
A mixture of 0.1 mole of benzhydrylamine, 39.3 g (0.25 moles) of 1-bromo-3-chloropropane, 13.8 g (0.1 mole) of potassium carbonate, 20.0 ml of dimethylformamide and 20.0 ml of water were heated at 75° C. for 2 hr. The organic layer was separated and concentrated on a rotary high vacuum evaporator to give 26 g of title compound of 85-90% purity of title compound containing about 5% each of benzhydrylamine and 1-benzhydrylazetidine. The following 1NNMR analysis was obtained:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH:8]([C:13]([O:15]CC)=[O:14])[CH2:7][CH2:6][C:5]=2[N:4]=1.[OH-].[Na+]>CO>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH:8]([C:13]([OH:15])=[O:14])[CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: CCOC(=O)C1CCc2nc(C(F)(F)F)ccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCc2nc(C(F)(F)F)ccc2C1
Yield: 77.7 %

Procedure:
A mixture of ethyl 2-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-6-carboxylate (0.47 g, 1.7 mmol), 1 M aqueous sodium hydroxide (3.4 mL, 3.4 mmol, 2 equiv.) and methanol (10 mL), was heated at reflux for 16 h. The mixture was concentrated to remove MeOH, diluted with 1M aqueous NaH2PO4 (15 mL) and buffered to pH 3 with 1M H3PO4, depositing a voluminous precipitate. The mixture was extracted with DCM (3×30 mL), and the combined organic layers were dried (Na2SO4), filtered and concentrated. The solid residue was purified by reverse-phase HPLC (40-55% acetonitrile in 0.1% HCO2H/H2O). The combined HPLC fractions were concentrated to remove acetonitrile, buffered with 1M NaH2PO4 (10 mL) and extracted with DCM (3×30 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to afford the acid as a solid (324 mg, 77%). 1H NMR (400 MHz, DMSO-d6) [δ] 12.45 (s, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.63 (d, J=7.9 Hz, 1H), 3.12-2.86 (m, 4H), 2.83-2.76 (m, 1H), 2.22-2.14 (m, 1H), 1.97-1.86 (m, 1H); m/z=246.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].[K].[C:11]([NH:14][C:15]1[S:16][C:17](Cl)=[CH:18][N:19]=1)(=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:11]([NH:14][C:15]1[S:16][C:17]([S:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)Nc1ncc(Cl)s1
Reactant: Fc1ccc(S)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2ccc(F)cc2F)s1
Temperature: 130 °C
Reaction time: 7 h
Yield: 38.5 %

Procedure:
A mixture of salt of potassium 2,4-difluorothiophenol (20 g), 2-acetamido-5-chlorothiazole (21 g) and potassium carbonate anhydrous (29.8 g) in N,N-dimethylformamide (400 ml) was stirred at 130° C. for 7 hours. The reaction mixture was concentrated under reduced pressure. The residue was triturated with water and the precipitates were collected by filtration, washed with water and dried in vacuo to give solid. The solid was subjected to column chromatography on silica gel (silica gel, 70-230 mesh; Merck: 750 g) and eluted with a mixture of chloroform and methanol (50:1). The fractions containing the objective compound were combined and evaporated to dryness in vacuo to give 2-acetamido-5-(2,4-difluorophenylthio)thiazole (11.91 g, yield: 38.5%). mp: 156°-170° C. (dec.) IR (Nujol): 3160, 3060, 1695, 1585, 1560, 1295 cm-1
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([Cl:25])[CH:19]=1>ClCCl>[Cl:25][C:20]1[CH:19]=[C:18]([NH:17][C:14]([C:10]2[CH:9]=[C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[N:13]=[CH:12][N:11]=2)=[O:16])[CH:23]=[CH:22][C:21]=1[OH:24]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Solvent: ClCCl
Product: O=C(Nc1ccc(O)c(Cl)c1)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-amino-2-chlorophenol (Aldrich), the title compound was obtained as a white solid after trituration in dichloromethane.
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1.[CH2:35]([SH:39])[CH2:36][CH2:37][CH3:38].[OH-].[K+].CN1CCCC1=O.Cl>C(OCC)(=O)C>[CH2:35]([S:39][C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Reactant: CCCCS
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCCCSc1ccc2nn(-c3cc(C(C)(C)CC(C)(C)C)cc(C(C)(C)c4ccccc4)c3O)nc2c1
Temperature: 170 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
5-Chloro-2-(2-hydroxy-3-α-cumyl-5-tert-octylphenyl)-2H-benzotriazole (38.1 g, 0.08 mol), n-butyl mercaptan (9 g, 0.10 mol), potassium hydroxide (10.1 g, 0.18 mol) and N-methylpyrrolidone (99 g, 1.0 mol) are charged to a reactor and heated to 170° C. The reaction mass is held at 170° C. with vigorous stirring for five hours. The reaction is judged as complete using thin layer chromatogrphy. The temperature is reduced to 5° C. and 100 mL of aqueous 2N hydrochloric acid are then added to the reactor. The liquid is decantedand the solids are dissolved in ethyl acetate. The organic layer is washed with aqueous 2N hydrochloric acid followed by water. The ethyl acetate is stripped off and the product is crystallized from ethanol and toluene. The tide compound is obtained as a yellow crystalline product in 83% yield. The structure is verified by 1Hnmr.
Reaction SMILES: [CH:1]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3][CH2:2]1.[Li+].[CH3:11]C([N-]C(C)C)C.IC>C1COCC1>[CH3:11][C:1]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of ethyl cyclobutanecarboxylate (20.0 g, 156.0 mmol) in THF (160 mL) was added dropwise to a cold (−78° C.) solution of LDA (164 mmol of 2M solution) in THF (40 mL). The solution was warmed to 0° C. and then cooled again to −40° C. before the addition of iodomethane (10.2 mL, 163.8 mmol). The solution was slowly warmed to room temperature and stirred overnight. The reaction was quenched with an aqueous saturated solution of ammonium chloride and ether was added. The layers were separated and the aqueous layer was washed with ether. The combined organic layers were washed with 1N HCl then dried over MgSO4. The product was purified by distillation: 1H NMR (400 MHz, MeOD) δ 4.20-4.05 (m, 2H), 2.57-2.33 (m, 2H), 2.08-1.94 (m, 1H), 1.94-1.77 (m, 3H), 1.40 (s, 3H), 1.27 (tt, J=7.1, 1.5 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=2)[CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)#[CH:13]>>[F:20][C:16]1[CH:15]=[C:14]([C:12]#[C:13][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=3)[CH:7]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc2ncc(Br)cn2n1
Reactant: C#Cc1cccc(F)c1
Product: Cc1cc2ncc(C#Cc3cccc(F)c3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=252.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 1-ethynyl-3-fluoro-benzene.
Reaction SMILES: O.NN.[Br:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[CH2:15][N:16]1C(=O)C2C(=CC=CC=2)C1=O>C(#N)C>[Br:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[CH2:15][NH2:16]
Reactant: Cc1cc([N+](=O)[O-])cc(CN2C(=O)c3ccccc3C2=O)c1Br
Agent: NN
Solvent: CC#N
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(CN)c1Br
Temperature: 25 °C
Yield: 75 %

Procedure:
4.4 mL of hydrazine hydrate was added to 2-[(2-bromo-3-methyl-5-nitrophenyl)methyl]-2,3-dihydro-1H-isoindole-1,3-dione (4.4 g, 11.7 mmol) in 220 mL of acetonitrile. The mixture was stirred under reflux overnight and then was allowed to cool to room temperature. The phtalhydrazide side product was remove by filtration and washed with 100 mL portions of acetonitrile. The combined acetonitrile filtrates were evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was extracted with two 100 mL portions of aqueous HCl 1 M. The combined acidic aqueous layers were basified to pH=10 with solid potassium hydroxide and then extracted with ethyl acetate. The organic layer was dried over Na2SO4 filtered and evaporated to yield expected compound as an orange solid (2.15 g, 75% yield). m/z (ESI) 245.0 [M+H]+;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]([C:21](OCC)=[O:22])=[C:13](O)[CH2:12][S:11]2(=[O:28])=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][CH2:35][NH2:36])=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][CH2:35][NH:36][C:21]([C:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:10]([CH2:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[S:11](=[O:27])(=[O:28])[CH2:12][C:13]=2[NH:36][CH2:35][CH2:34][C:33]2[CH:37]=[CH:38][C:30]([Cl:29])=[CH:31][CH:32]=2)=[O:22])=[CH:32][CH:31]=1
Reactant: CCOC(=O)C1=C(O)CS(=O)(=O)N(Cc2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: NCCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=C(NCCc1ccc(Cl)cc1)C1=C(NCCc2ccc(Cl)cc2)CS(=O)(=O)N(Cc2ccc(Cl)c(Cl)c2)c2ccccc21

Procedure:
A mixture of 1.7 g of ethyl 1-(3,4-dichlorophenylmethyl)-1,3-dihydro-4-hydroxy-2,1-benzothiazepine-5-carboxylate-2,2-dioxide, 0.6 g of 4-chlorophenethylamine in 100 ml of toluene is heated at reflux for 2 days. The reaction mixture is evaporated to dryness. The residue is crystallized from ether - hexane (charcoal) to yield N-(4-chlorophenethyl)-1-(3,4-dichlorophenylmethyl)-1,3-dihydro-4-(4-chlorophenethylamino)-2,1-benzothiazepine-5-carboxamide-2,2-dioxide; m.p. 119°-121°.