Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]([CH2:13][CH2:14][O:15][CH3:16])[C:9](=[O:12])[NH:10][N:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(#N)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][N:10]1[C:9](=[O:12])[N:8]([CH2:13][CH2:14][O:15][CH3:16])[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:11]1)[CH3:29]
Reactant: CCOC(=O)CCl
Reactant: COCCn1c(-c2ccc(Cl)s2)n[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cn1nc(-c2ccc(Cl)s2)n(CCOC)c1=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2.4 g (9.24 mmol) of the compound of Example 13A and 2.55 g (18.48 mmol) of potassium carbonate were suspended in 48 ml of acetonitrile. 1.08 ml (10.17 mmol) of ethyl chloroacetate were then added, and the mixture was heated under reflux at 80° C. for 4.5 h. Another 113 mg (0.92 mmol) of ethyl chloroacetate were added, and the mixture was stirred at 80° C. for 2 h. The suspension was filtered through a layer of silica gel, the silica gel was washed with ethyl acetate and the filtrate was evaporated on a rotary evaporator and dried under HV. This gave 3.24 g (100% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[O:15][N:14]=[C:13]([NH2:17])[C:12]=3[CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]2[N:18]([CH3:21])[N:19]=[CH:20][C:3]=12.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:21][N:18]1[C:4]2=[N:5][C:6]([C:8]3[C:16]4[O:15][N:14]=[C:13]([NH2:17])[C:12]=4[CH:11]=[CH:10][CH:9]=3)=[CH:7][C:2]([O:32][C:29]3[CH:28]=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:31][CH:30]=3)=[C:3]2[CH:20]=[N:19]1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4c(N)noc34)nc21
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ncc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(-c3cccc4c(N)noc34)nc21
Temperature: 155 °C
Yield: 21.7 %

Procedure:
A mixture of 7-(4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)benzo[d]isoxazol-3-amine 17 (0.032 g, 0.106 mmol), 4-methylsulfonyl phenol 8a (0.036 g, 0.213 mmol) and potassium carbonate (0.15 g, 1.06 mmol) in 2 mL DMF was heated in a microwave at 155° C. for 30 minutes. The reaction mixture was filtered, solvent removed and diluted with ethyl acetate. The organic portions were pooled and washed with saturated bicarbonate solution and brine, dried over anhydrous sodium sulfate and solvent was removed. The crude material was purified using mass directed purification to give 10 mg of 121. 1H NMR (400 MHz, DMSO) δ=8.02-7.58 (m, 8H), 7.58 (dd, J=26.9, 35.7, 2H), 6.53 (s, 1H), 4.15-4.01 (m, 3H), 3.3-3.06 (m, 3H). MS (ESI) m/z 436.0 (M+1)+
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[F:19][C:20]1[C:40]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[CH:39][C:23]2[NH:24][C:25]([C:27]3[C:31]([NH2:32])=[CH:30][N:29]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)[N:28]=3)=[N:26][C:22]=2[CH:21]=1>C1COCC1>[F:19][C:20]1[C:40]([N:41]2[CH2:42][CH2:43][O:44][CH2:45][CH2:46]2)=[CH:39][C:23]2[NH:24][C:25]([C:27]3[C:31]([NH:32][C:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:8])=[CH:30][N:29]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)[N:28]=3)=[N:26][C:22]=2[CH:21]=1
Reactant: Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCOCC3)cc2[nH]1
Reactant: O=C(Cl)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCOCC3)cc2[nH]1)N1CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
10 mL of piperidinecarbonyl chloride and 13.55 mL of N,N-diisopropylethylamine are added to a solution of 10 g of 3-(5-fluoro-6-morpholin-4-yl-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine in 200 mL of THF. The reaction mixture is refluxed for 3 hours and then left stirring at ambient temperature for 48 hours. After concentration of the medium vacuum in a rotary evaporator, the reaction crude is purified by flash chromatography on 1200 g of 40-63 μM silica, elution being carried out with a 90:10 mixture of dichloromethane/acetone. 10.4 g of piperidine-1-carboxylic acid [3-(5-fluoro-6-morpholin-4-yl-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide are isolated. 1H NMR (300 MHz, (CD3)2S, δ in ppm): 1.50-1.79 (m: 10H); 1.91-2.04 (m: 2H); 3.00 (m: 4H); 3.50 (m: 4H); 3.66 (m: 1H); 3.77 (m: 4H); 3.96 (broad d J=11 Hz: 1H); 5.46 (dd, J=10 and 2 Hz: 1H); 7.10 (very broad s: 1H); 7.40 (very broad s: 1H); 8.13 (s: 1H); 9.96 (broad s: 1H); 13.00 (very broad s: 1H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH2:5]=[C:6]1[O:10][C:8](=[O:9])[CH2:7]1>O1CCCC1>[CH:1]1([NH:4][C:8](=[O:9])[CH2:7][C:6](=[O:10])[CH3:5])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NC1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81578.9 %

Procedure:
26 ml (0.38 mmol) cyclopropylamine was added dropwise to a solution of 30 g of diketene (0.36 mol) in 300 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 43.83 g (0.31 mol, 87% yield) of a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([NH2:13])[NH:4][N:3]=1.[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.CS(O)(=O)=O>C(OCC)(=O)C>[CH3:1][C:2]1[C:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:19]([C:18]3[CH:21]=[CH:22][C:15]([OH:14])=[CH:16][CH:17]=3)=[N:13][C:5]=2[NH:4][N:3]=1
Reactant: Cc1n[nH]c(N)c1-c1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3)c3ccccc3c12
Temperature: 120 °C
Yield: 15 %

Procedure:
To 3-methyl-4-phenyl-1H-pyrazol-5-amine (173 mg, 1 mmol) was added 4-hydroxybezaldehyde (244 mg, 2 mmol) and methanesulfonic acid (3 mL). The mixture was heated to 120° C. for 16 h. After cooling to rt, the mixture was diluted with ethyl acetate and then filtered through celite. The product was then extracted from the organic phase with NaOH (aq). The organic phase was discarded, and the aqueous extract was carefully neutralized with HCl (conc) and then extracted with ethyl acetate. The ethyl acetate extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (ethyl acetate) to provide 41.2 mg of 4-(1-methyl-3H-pyrazolo[3,4-c]isoquinolin-5-yl)phenol (0.15 mmol, 15% yield). 1H-NMR (400 MHz, DMSO-d6): δ13.42 (s, 1H), 9.81 (s, 1H), 8.34 (d, 1H), 8.11 (d, 1H), 7.87 (t, 1H), 7.50 (d, 2H), 6.94 (d, 2H), 2.79 (s, 3H); MS (EI) for C17H13N3O: 276 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]([Br:24])(Br)Br.[C:25]([O:29][C:30]([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH:41]=O)=[CH:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CCCCCC>C(Cl)Cl>[C:25]([O:29][C:30]([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH:41]=[C:21]([Br:24])[Br:20])=[CH:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)n1cc(C=O)c2ccccc21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cc(C=C(Br)Br)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
Triphenylphosphane (17.2 g, 65.5 mmole) was added in portions at 0° C., while stirring and within 60 min to a solution of tetrabromocarbon (10.9 g, 32.7 mmole) in DCM (120 ml) and post-stirred for 1 h at 0° C. 3-formyl-indole-1-carboxylic acid-tert-butylester (4 g, 16.4 mmole) dissolved in DCM (30 ml) was subsequently added dropwise within 30 min and the mixture stirred for 4 h at 0° C. After heating the solution to RT, hexane (300 ml) was added and the mixture stirred for 30 min at RT. The mixture was suction filtered and post-washed with hexane. The filtrate was evaporated, a yellow solid being obtained. Chromatographic purification on silica gel was carried out using cyclohexane/EE (95:5). 6.26 g 3-(2,2-dibromovinyl)-indole-1-carboxylic acid-tert-butylester were obtained (white solid, mp. 101 to 104° C.). A solution of 3-(2-2,-dibromovinyl)-indole-1-carboxylic acid-tert-butylester (2.97 g, 7.4 mmole) in THF (20 ml) was introduced at −78° C. under argon, and subsequently a 1.6 M solution of n-butyllithium in hexane (5.7 ml, 9.1 mmole) was added within 30 min, the mixture stirred for 1 h at −78° C., brought to room temperature and then added to a solution, cooled to −78° C., of 4-dimethylamino-4-phenylcycohexane carbaldehyde (580 mg, 2.5 mmole) in THF (10 ml). The mixture was stirred for 8 h at −78° C., brought to room temperature and water (20 ml) was added. For working up, the aqueous phase was extracted with toluene (3×15 ml). The combined organic phase was washed with saturated NH4Cl, 0.2M NaOH and water (about 20 ml in each case), dried over sodium sulfate, filtered and evaporated. First chromatographic purification of the substance mixture obtained was carried out using acetonitrile/methanol/1M NH4Cl (9:1:1) on silica gel. Three compounds were obtained following a second column chromatographic separation with methanol on silica gel:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.[NH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:13]=1[C:14]([OH:16])=O>C1COCC1>[NH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:13]=1[C:14]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16]
Reactant: Nc1cccc(C(F)(F)F)c1C(=O)O
Reactant: Nc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc(C(F)(F)F)c1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-amino-N-phenyl-6-trifluoromethyl-benzamide was prepared by addition of aniline (1.0 eq.) to a suspension of 2-amino-6-(trifluoromethyl)-benzoic acid trihydrate (1.0 g, 4.0 mmol, 1.3 eq.) and polystyrene-carbodiimide (3.6 g, 1.1-1.7 eq.) in THF (40 mL). The reaction was stirred at ambient temperature for 18 hours, then filtered. The filtrate was concentrated in vacuo and purified by flash chromatography to provide 2-amino-N-phenyl-6-trifluoromethyl-benzamide as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[N+:23]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1N
Yield: 77.2 %

Procedure:
Prepared from [4-(4-fluoro-phenylethynyl)-2-nitro-phenyl]-carbamic acid tert.-butyl ester (Example F9) (10.0 g, 28.1 mmol) by reduction with SnCl2.2H2O (31.7 g, 140.5 mmol) according to the general procedure G (method b). Obtained as a yellow solid (7.08 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[C:5]([C:34]([O:36]CC1C=CC(OC)=CC=1)=[O:35])=[N:6][N:7]2[CH2:32][CH3:33].[OH-].[K+]>CO.O>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[C:5]([C:34]([OH:36])=[O:35])=[N:6][N:7]2[CH2:32][CH3:33]
Reactant: CCn1nc(C(=O)OCc2ccc(OC)cc2)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCn1nc(C(=O)O)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Yield: 64.5 %

Procedure:
To the solution of 4-methoxybenzyl 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (24 g, 37.2 mmol) in methanol (400 mL) and water (133 mL) was added potassium hydroxide (8.35 g, 149 mmol). The reaction mixture was heated to reflux for 3 h. Solvent was removed under vacuum. The residue was suspended in water and the resulting mixture was acidified to pH4 with 2N hydrochloric acid. The precipitated solid was filtered and dried to afford 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carboxylic acid (12.6 g, 24.00 mmol, 64.5% yield). LCMS: (M+H)+: 525.2
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:40])=[C:7]([C:29]([CH3:39])([CH3:38])[CH2:30][O:31]C2CCCCO2)[CH:8]=[C:9]([CH:28]=1)[CH:10]=[C:11]1[C:16](=[O:17])[N:15]([CH2:18][C:19]2[NH:23][N:22]=[N:21][N:20]=2)[C:14]2[CH:24]=[CH:25][CH:26]=[CH:27][C:13]=2[S:12]1)([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl-].[Na+]>CO.C(Cl)(Cl)Cl>[C:1]([C:5]1[C:6]([OH:40])=[C:7]([C:29]([CH3:39])([CH3:38])[CH2:30][OH:31])[CH:8]=[C:9]([CH:28]=1)[CH:10]=[C:11]1[C:16](=[O:17])[N:15]([CH2:18][C:19]2[NH:23][N:22]=[N:21][N:20]=2)[C:14]2[CH:24]=[CH:25][CH:26]=[CH:27][C:13]=2[S:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=C2Sc3ccccc3N(Cc3nnn[nH]3)C2=O)cc(C(C)(C)COC2CCCCO2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)c1cc(C=C2Sc3ccccc3N(Cc3nnn[nH]3)C2=O)cc(C(C)(C)CO)c1O
Temperature: 60 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
2-[5-tert.-Butyl-4-hydroxy-3-[1,1-dimethyl-2-(tetrahydropyran-2-yloxy)ethyl]benzylidene]-3,4-dihydro-3-oxo-4-(1H-tetrazol-5-ylmethyl)-2H-1,4-benzothiazine (compound No. 2-2, 0.31 g) was dissolved in a mixture of methanol (5 ml) and chloroform (1 ml). To the mixture, p-toluenesulfonic acid monohydrate (0.05 g) was added and the mixture was stirred for 3 hours at 60° C. Saturated sodium chloride solution was added to the mixture and the whole was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by silica gel column chromatography to give 0.16 g (60.7%) of the titled compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH3:25])=[O:23]>C(Cl)Cl>[CH3:25][O:24][C:22]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)=[O:23]
Reactant: NCCSc1cccc2nccn12
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCSc1cccc2nccn12
Yield: 66.9 %

Procedure:
To a solution of 5-[2-(amino)ethylthio]imidazo[1,2-a]pyridine (1.93 g, 10 mmoles) and triethylamine (1.53 ml, 11 mmoles) in methylene chloride (30 ml) was added methyl chloroformate (0.77 ml, 10 mmoles) under ice-cooling with stirring and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was washed in turn with aqueous sodium bicarbonate and water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography [eluent: ethanol/etyl acetate (1:10)] to obtain 1.68 g of the desired product (66.9%, colorless crystals).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=O.[CH2:13]([C:16]#[N:17])[C:14]#[N:15].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O.C(OCC)(=O)C>[C:14]([C:13]([C:16]#[N:17])=[C:2]([C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)[CH3:1])#[N:15]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: N#CCC#N
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=C(C#N)C#N)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4Nitro acetophenone (2.0 g, 12.1 mmoles, 1 eq) and malonodinitrile (2.4 g, 36.3 mmoles, 3 eq) were dissolved in 20 mL of anhydrous toluene. To the solution were added glacial acetic acid (0.40 mL, 7.0 mmoles, 0.19 eq) and ammonium acetate (0.26 g, 3.3 mmoles, 0.09 eq). The system was heated to reflux using a Dean-Stark trap and a condenser. After 1 hour, the reaction mixture was cooled to room temperature and poured into brine (50 mL) and ethyl acetate (100 mL). The aqueous layer was washed with 3×10 mL ethyl acetate. The combined organic layers were washed with 50 mL brine, dried over anhydrous sodium sulfate and concentrated to dryness. The dark residue was partially purified using a silica plug (40% ethyl acetate-hexane) affording crude 1,1-dicyano-2-(4-nitrophenyl)-propene. The product was used as such in the next step. TLC (40% ethyl acetate-hexane)=0.61. LC-MS (m/e)=214.2 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[CH:13]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.ClC1C=CC=C(C(OO)=O)C=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[CH:13]=1)=[O:25]
Reactant: ClCCCCSCc1ccc2nccn2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=S(CCCCCl)Cc1ccc2nccn2c1
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
11.79 g of the 6-((4-chlorobutyl)thiomethyl)-imidazo[1,2-a]pyridine prepared in the Preparative Example 7 was dissolved in 160 ml of dichloromethane. The obtained solution was cooled with ice, followed by the addition of 7.99 g of m-chloroperbenzoic acid in about 40 minutes. The obtained mixture was stirred. After 30 minutes, 0.4 g of m-chloroperbenzoic acid was further added thereto. The obtained mixture was additionally stirred for one hour, followed by the addition of an aqueous solution of sodium thiosulfate. The obtained mixture was vigorously stirred at room temperature for 30 minutes and extracted with chloroform. The organic phase was washed with an aqueous solution of potassium carbonate, dried over anhydrous magnesium sulfate, and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (30:1 to 10:1)] to give 9.51 g of the title compound as a dark-creamy oil (yield: 78%).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].C([Li])CCC.[Cl:17]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:17][C:10]1[N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[N:7]=[CH:8][CH:9]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CN(C)S(=O)(=O)n1cccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1nccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
Under a nitrogen atmosphere, a solution of N,N-dimethyl-1H-pyrazole-1-sulfonamide (5.0 g, 28 mmol) (i.e. the product of Example 12, Step A) in tetrahydrofuran (50 mL) was cooled to −78° C. and then treated with n-butyllithium (2 M solution in cyclohexane, 15.0 mL, 30 mmol) dropwise. The reaction mixture formed a thick precipitate, and stirring was continued for 30 minutes after the addition. To the stirred suspension, a solution of hexachloroethane (7.1 g, 30 mmol) in tetrahydrofuran (20 mL) was added dropwise. After 30 minutes the resulting clear solution was warmed to ambient temperature and quenched with the addition of water (70 mL). The reaction mixture was extracted with dichloromethane and dried over MgSO4. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (50% hexanes in dichloromethane as eluant) to give 1.71 g of 5-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide. The 5-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide was heated to 110° C. for 12 h with a catalytic amount of pyrazole to isomerize to the title compound.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:11]([OH:32])[CH2:12][N:13]([CH3:31])[C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([O:20]CC1C=CC=CC=1)=[O:19])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[OH-].[Pd+2].C(O)C.C(OCC)(=O)C>[C:1]([NH:9][C@@H:10]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH:11]([OH:32])[CH2:12][N:13]([CH3:31])[C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CC(O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(CC(O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
A mixture of 1-[[[(3S)-3-(benzoylamino)-2-hydroxy-4-phenylbutyl]methylamino]carbonyl]-L-proline, phenylmethyl ester (isomer A) (790 mg., 149 mmole), palladium hydroxide on carbon catalyst (110 mg.) and ethanol: ethyl acetate (1:1, 20 ml.) is stirred under hydrogen gas (balloon) for one hour. The solution is filtered (millipore), and the solvent removed at reduced pressure to give the desired product as a colorless solid. Drying under vacuum over phosphorus pentoxide yields 569 mg. of 1-[[[(3S)-3-(benzoylamino)-2-hydroxy-4-phenylbutyl]methylamino]carbonyl]-L-proline (isomer A); m.p. 108°-117°; [α]D20 =-77.5° (c=1.4, methanol). TLC (silica gel; chloroform:methanol:acetic acid; 18:1:1) Rf =0.39, trace at Rf =0.58.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[C:4]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][C@H:37]1[C:42]([OH:44])=[O:43]>>[CH2:34]([O:33][C:31]([C:4]1[CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=2)[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]=1[CH2:2][N:36]1[CH2:41][CH2:40][O:39][CH2:38][C@H:37]1[C:42]([OH:44])=[O:43])=[O:32])[CH3:35]
Reactant: O=C(O)[C@@H]1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1-c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1-c1ccc(C(F)(F)F)cc1
Yield: 50 %

Procedure:
Ethyl 6-(bromomethyl)-4-(5-fluoro-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (3 g, 5.3 mmol) was reacted with (S)-morpholine-3-carboxylic acid (0.69 g, 5.3 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (1.64 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:8])=[C:5]([OH:20])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].O.Br[CH2:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32]>CN(C=O)C>[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[CH2:15][CH3:16])=[O:8])=[C:5]([O:20][CH2:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:4]=1
Reactant: CC(C)C(=O)CBr
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(=O)C(C)C
Reaction time: 20 h
Yield: 73 %

Procedure:
A mixture of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (5.82 g, 18 mmoles), anhydrous potassium carbonate (12.48 g; 90 mmoles) in DMF (30 ml) and 1-bromo-3-methyl-2-butanone [4.5 g, 27 mmoles; prepared according to M. Gaudry and A. Marquet, Org. Syn. 55, 24 (1976)] was stirred for 20 hours under nitrogen. The mixture was poured into water (150 ml) and the solid collected, dried and crystallized from toluene to give the title compound (4.86 g, 73%), mp. 109°-110°. The NMR spectrum (90 MHz) gave the following resonances: δ8.56 (bt, 1H); 8.24 (s, 1H); 6.18 (s, 1H); 4.8 (s, 2H); 4.44 (s, 2H); 3.56 (m, 2H); 2.62 (m, 7H); 1.2 (d, 6H); 1.06 (t, 6H).