Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[N:9][C:8]([C@@H:20]([NH2:22])[CH3:21])=[CH:7]2.Cl[C:24]1[C:25]2[N:32]=[CH:31][S:30][C:26]=2[N:27]=[CH:28][N:29]=1.C(N(CC)CC)C>CCCCO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[N:9][C:8]([C@@H:20]([NH:22][C:24]1[C:25]3[N:32]=[CH:31][S:30][C:26]=3[N:27]=[CH:28][N:29]=1)[CH3:21])=[CH:7]2
Reactant: Clc1ncnc2scnc12
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(CCN2CCOCC2)n1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2scnc12)c1cc2cccc(Cl)c2c(CCN2CCOCC2)n1
Temperature: 25 °C

Procedure:
A mixture of (S)-1-(8-chloro-1-(2-morpholinoethyl)isoquinolin-3-yl)ethanamine 71 (100 mg, 0.31 mmol, 1 eq), 7-chlorothiazolo[5,4-d]pyrimidine (E-4) (108 mg, 0.63 mmol, 2 eq) and triethylamine (130 mg, 1.25 mmol, 4.0 eq) in n-BuOH (40 mL) was stirred at reflux for 16 h. The reaction mixture was cooled to RT and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product (S)—N-(1-(8-chloro-1-(2-morpholinoethyl)isoquinolin-3-yl)ethyl)thiazolo[5,4-d]pyrimidin-7-amine 72. ESI-MS m/z: 455.0 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].[OH-].[K+].[CH3:13]I>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:13])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1O
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: COc1ccccc1C(C)C
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
To a solution of 2-isopropylphenol (30 g, 220.3 mmol) in CH2Cl2 (300 mL) was added tetrabutylammonium hydrogen sulfate (7.5 g, 22.1 mmol). After the entire solid was dissolved, a solution of potassium hydroxide (61.8 g, 1.1 mol in 300 mL H2O) was added to the previous mixture. After 15 minutes of stirring, methyl iodide (47 g, 20.6 mL, 331 mmol) was added. The mixture was left to stir overnight (ca. 15 hours). The organic layer was separated and then washed with brine (2×100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The solid material in the concentrate was removed by filtration. The precipitate was washed with hexane (100 mL). The filtrate was concentrated in vacuo to give 32.15 g of yellow oil as a crude product. The crude product was filtered through a pad of silica gel (250 g) and washed with 5% EtOAc in hexane to give 30.7 g (93%) of compound 1a as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[OH:20][CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C.[I-].[K+]>CN(C)C=O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11][N:26]2[CH2:27][CH2:28][CH:23]([CH2:22][CH2:21][OH:20])[CH2:24][CH2:25]2)=[CH:4][CH:3]=1
Reactant: OCCC1CCNCC1
Reactant: Fc1ccc(C(CCCBr)c2ccc(F)cc2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCC1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
20 g (62 mmol) of 4,4-bis(4-fluorophenyl)butyl bromide, 8.8 g (68 mmol) of 4-hydroxyethylpiperidine, 12.5 g (124 mmol) of triethylamine and 0.1 g of potassium iodide were stirred in 200 ml of absolute dimethylformamide at 80° C. for 4.5 hours. The solvent was stripped off in vacuo, the residue was taken up in methylene chloride, the mixture was extracted by shaking with 2N HCl, water and NaCl solution and the extract was dried and concentrated.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:7]=2[OH:13])=[O:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][C:23](=[O:26])[CH2:24]Br)[CH3:21]>CC(C)=O.C(OCC)(=O)C>[CH2:20]([O:22][C:23](=[O:26])[CH2:24][O:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:6]=1[C:4]([CH:1]1[CH2:2][CH2:3]1)=[O:5])[CH3:21]
Reactant: O=C(c1c(O)cccc1O)C1CC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(O)c1C(=O)C1CC1

Procedure:
To a mixture of cyclopropyl-(2,6-dihydroxy-phenyl)-methanone (398 mg) and potassium carbonate (500 mg) in acetone (5 ml) was added bromoacetic acid ethyl ester (300 μl) at room temperature. The suspension was heated to reflux for 1.5 hours and diluted with ethyl acetate (10 ml), washed with diluted hydrochloric acid (5 ml) and brine (5 ml), dried over anhydrous sodium sulfate, then concentrated in vacuo. The mixture was purified by silica gel column chromatography developed by hexane-ethyl acetate to give (2-cyclopropanecarbonyl-3-hydroxy-phenoxy)-acetic acid ethyl ester as a pale yellow solid (382 mg). EI-MS: m/z 264 (M+); 1H-NMR (CDCl3): δ 1.04-1.09 (2H, m), 1.23-1.29 (2H, m), 1.28 (3H, t, J=7.26 Hz), 2.26-2.35 (1H, m), 4.29 (2H, q, J=7.26 Hz), 4.70 (2H, s), 6.27 (1H, dd J=0.99 Hz, 8.25 Hz), 6.62 (1H, dd, J=0.99 Hz, 8.25 Hz), 6.41 (2H, d, J=8.25 Hz), 7.31 (1H, dd, J=8.25 Hz, 8.25 Hz), 12.89 (1H, s).
Reaction SMILES: C(C1N=C(OCC)C(C2N([C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[O:36])C(C3C=CC(Cl)=CC=3)(C)C(C3C=CC(Cl)=CC=3)(C)N=2)=CN=1)(C)(C)C.[CH2:43]1[O:45][C@@H:44]1[CH2:46][OH:47]>C(O)C>[OH:45][C@H:44]([CH2:46][OH:47])[CH2:43][N:40]1[CH2:39][CH2:38][N:37]([CH:35]=[O:36])[CH2:42][CH2:41]1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1
Reactant: OC[C@@H]1CO1
Solvent: CCO
Product: O=CN1CCN(C[C@H](O)CO)CC1
Temperature: 120 °C
Yield: 185.9 %

Procedure:
The mixture of [2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (170 mg, 0.28 mmol) and R-glycidol (63 mg, 0.84 mmol) in ethanol (1 mL) was heated in the microwave at 120° C. for 10 min. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification of the crude residue by flash column chromatography (silica gel, eluting with 0-20% methanol in ethyl acetate) gave cis-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-[4-((S)-2,3-dihydroxy-propyl)-piperazin-1-yl]-methanone (98 mg). The diastereomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% ethanol in carbon dioxide) to give the title compound (post peak, 40 mg). HR-MS (ES, m/z) calculated for C35H45N6O4Cl2 [(M+H)+] 683.2874, observed 683.2871.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O-]CC.[Na+].C(Cl)(=O)C(Cl)=O.[Cl:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([S:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])=[O:39])[CH:32]=[CH:31]2>C1COCC1.ClCCl.N1C=CC=CC=1>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:12]([N:44]2[CH2:43][CH2:42][N:41]([S:38]([C:33]3[CH:32]=[CH:31][C:30]4[C:35](=[CH:36][CH:37]=[C:28]([Cl:27])[CH:29]=4)[CH:34]=3)(=[O:40])=[O:39])[CH2:46][CH2:45]2)=[O:14])[CH2:15][CH2:16]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CC[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Yield: 69.4 %

Procedure:
To a stirring solution of N-Boc-isonipecotic acid (1.99 g, 8.7 mmol) in THF (50 mL) was added sodium ethoxide (0.592 g, 8.7 mmol) After 0.5 h, the solvent was removed in vacuo and the residue was suspended in dichloromethane (50 mL). To this mixture was added a couple drops of DMF, followed by oxalyl chloride (1.32 g, 10.4 mmol). After stirring for another hour, the solvent was removed in vacuo and the crude acid chloride resuspended in dichloromethane (25 mL). To this solution was added a solution of 1-(6-chloronaphthalen-2-ylsulfonyl)piperazine (1.8 g, 5.8 mmol) and pyridine (5 mL) in dichloromethane (25 mL) After stirring overnight, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed twice with 1 M citric acid, once with brine, twice with satd aq NaHCO3 and twice again with brine, then dried with MgSO4, filtered and concentrated in vacuo. The residue was then dissolved in a minimum amount of dichloromethane and chromatographed over silica gel, eluting with a step gradient of 35% ethyl acetate in hexanes through 75% ethyl acetate in hexanes. The product containing fractions were combined and concentrated in vacuo to give 2.1 g (69%) of a white foam.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]12[CH2:19][CH:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=31)[C:11]1[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=1.S(Cl)([Cl:22])=O>C1C=CC=CC=1>[Cl:22][CH2:2][CH2:3][CH2:4][C:5]12[CH2:19][CH:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=31)[C:11]1[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: OCCCC12CC(c3ccccc31)c1ccccc12
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClCCCC12CC(c3ccccc31)c1ccccc12

Procedure:
The starting 9-γ-chloropropyl-9,10-dihydro-9,10-methanoanthracene was prepared by reacting 9-γ-hydroxypropyl-9,10-dihydro-9,10-methanoanthracene with thionyl chloride in benzene.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[N:11]=[CH:12][O:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].[Li+].CC([N-]C(C)C)C.CON(C)[C:28](=[O:44])[CH:29]([O:42][CH3:43])[C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>C1COCC1>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[N:11]=[C:12]([C:28](=[O:44])[CH:29]([O:42][CH3:43])[C:30]3[CH:31]=[CH:32][C:33]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[CH:34][CH:35]=3)[O:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Reactant: COc1cc(-c2cocn2)cc(OC)c1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2coc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)n2)cc(OC)c1Br
Temperature: -15 °C
Reaction time: 0.83 h
Yield: 33.5 %

Procedure:
To a −20° C. solution of 4-(4-bromo-3,5-dimethoxyphenyl)oxazole (0.158 g, 0.56 mmol) in anhydrous THF (2 mL) in an oven-dried flask under argon was added a solution of LDA (2.0 M in THF/heptane/ethylbenzene; 0.37 mL, 0.74 mmol) dropwise. The mixture was stirred at −20 to −10° C. for 50 min then cooled to −20° C. A solution of N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide (0.245 g, 0.83 mmol) in anhydrous THF (3 mL) was added then the mixture was allowed to slowly warm to room temperature and stirred for a total of 21 hours. The reaction mixture was quenched with H2O and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4 and concentrated. Purification by chromatography (50-60% EtOAc-hexanes) provided 1-(4-(4-bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-methoxy-2-(4-morpholinophenyl)-ethanone as a yellow solid (0.097 g, 34% yield). MS: m/z 517.1 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[F:26])[C:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[CH:16]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:15]2)=[O:13])=[CH:7][CH:6]=1)=[O:4].[CH3:42][NH:43][CH3:44]>O1CCCC1>[CH3:42][N:43]([CH3:44])[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[F:26])[C:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[CH:16]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:15]2)=[O:13])=[CH:7][CH:6]=1)=[O:4]
Reactant: CNC
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(=O)CBr)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: C1CCOC1
Product: CN(C)CC(=O)c1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
To the solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-bromo-acetyl)-phenyl]-amide (30 mg, 0.045 mmol) in tetrahydrofuran (1 mL) was added a tetrahydrofuran solution (2 M) of dimethylamine (0.057 mL, 0.11 mmol). The reaction mixture was stirred at room temperature for 30 min. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-dimethylamino-acetyl)-phenyl]-amide as a yellow solid (10 mg, 35%)
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Br[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(Cl)Cl>[CH2:13]([O:12][C:10](=[O:11])[C:9](=[O:15])[CH2:8][S:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1)[CH3:14]
Reactant: Sc1nccs1
Reactant: CCOC(=O)C(=O)CBr
Solvent: ClCCl
Product: CCOC(=O)C(=O)CSC1=NCCS1
Yield: 94.3 %

Procedure:
A solution of 2-mercaptothiazole (238 mg, 2 mmol) and ethyl bromopyruvate (0.264 mL, 2.1 mmol) in methylene chloride (7 mL) was shaken at 20° C. for 3 hours under nitrogen. The obtained solid was filtered, washed with methylene chloride, and dried under vacuum. This gave the expected product, 3-(4,5-dihydro-thiazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester (440 mg, yield 71%) as a solid. 1H-NMR (300 Hz, D3COD) δ (ppm): 4.63 (d, J=13.1 Hz, 1H), 4.30-4.15 (m, 6H), 4.10 (d, J=13.1 Hz, 1H), 1.34 (t, J=7.1 Hz, 3H). MS (ESI) m/z: 234 (M+H, 100).
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:29]>C(O)C.[Pd]>[ClH:29].[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:17]1[C:18]2[C:19]3[CH2:20][CH2:21][NH:8][CH2:9][CH2:10][C:11]=3[NH:12][C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: Fc1ccccc1-c1cccc2[nH]c3c(c12)CCN(Cc1ccccc1)CC3
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Fc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Yield: 17.9 %

Procedure:
A mixture of 3-benzyl-10-(2-fluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.11 g, 0.30 mmol), 1 N hydrochloric acid (0.3 mL, 0.3 mmol) and Pd/C (10%, 0.2 g) in ethanol (50.0 mL) was reacted in a manner similar to Example 8 to give 0.017 g of the title compound as a pale green solid: mp>259° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 11.29, 9.29, 7.51-7.41, 7.39-7.25, 7.08, 6.77, 3.33-3.20, 3.20-3.09, 3.09-2.99, 2.63-2.50; MS (EI) m/z 294 (M+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[NH:15][NH2:16].[C:17]([C:19](=[CH:25]OCC)[C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18].C(OCC)C.CCCCC>C(O)C>[NH2:18][C:17]1[N:15]([C:3]2[C:2]([F:1])=[C:7]([F:8])[C:6]([C:9]([F:12])([F:11])[F:10])=[C:5]([F:13])[C:4]=2[F:14])[N:16]=[CH:25][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNc1c(F)c(F)c(C(F)(F)F)c(F)c1F
Solvent: CCO
Solvent: CCOCC
Solvent: CCCCC
Product: CCOC(=O)c1cnn(-c2c(F)c(F)c(C(F)(F)F)c(F)c2F)c1N
Yield: 8.7 %

Procedure:
To a stirred solution of 15.7 grams (0.634 mole) of 2,3,5,6-tetrafluoro-4-trifluoromethylphenylhydrazine in 40 mL of anhydrous ethanol was added 10.7 grams (0.634 mole) of ethyl 2-cyano-3-ethoxyacrylate. The reaction mixture was heated at reflux for 21 hours, then cooled, and the solvent was removed by distillation under reduced pressure, leaving a residue. This residue was suspended in 80 mL of a 50:50 mixture of diethyl ether/n-pentane. A solid formed and was removed by filtration to yield 20.4 grams of ethyl 5-amino-1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)pyrazol-4-ylcarboxylate, m.p. 166-168° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1)[C:3]([NH:5][C@@H:6]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C@@H:7]([OH:13])[C@H:8]([CH:10]1[CH2:12][CH2:11]1)[OH:9])=[O:4].[NH:27]([C:39]([O:41][CH2:42][CH:43]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49]2[C:44]1=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:40])[C@H:28]([C:36](O)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH:15]1([CH2:14][C@H:6]([NH:5][C:3]([C@@H:2]([NH:1][C:36]([C@@H:28]([NH:27][C:39](=[O:40])[O:41][CH2:42][CH:43]2[C:55]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[C:49]3[C:44]2=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:37])[CH2:21][C:22]2[N:23]=[CH:24][NH:25][CH:26]=2)=[O:4])[C@@H:7]([OH:13])[C@H:8]([CH:10]2[CH2:11][CH2:12]2)[OH:9])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1)OCC1c2ccccc2-c2ccccc21

Procedure:
In an analogous manner to that described in Example 19, by condensing (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide with Fmoc-Phe-OH there was obtained 9H-fluoren-9-ylmethyl [(S)-α-[[(S)-1-[[(1S,2R, 3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate which, by reaction with piperidine in methylene chloride, was converted into (S)-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-α-[(3-phenyl-L-alanyl)amino]imidazole-4-propionamide. Further condensation with Boc-D-Pro-OH, analogously to Example 19, yielded (R)-2-[[(S)-α-[[(S)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]-1-pyrrolidinecarboxylic acid tert-butyl ester as an amorphous solid, MS: 709 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[N:6]([CH2:7][CH2:8][C:9](=O)[CH2:10][N:11]([CH3:19])C(=O)OC(C)(C)C)[C:5]2[CH:21]=[CH:22][CH:23]=[CH:24][C:4]=2[N:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl.[NH2:33][OH:34].N1C=CC=CC=1.Cl>C(O)C.C(OCC)C.O1CCOCC1.CO.ClCCl>[O:1]=[S:2]1(=[O:31])[N:6]([CH2:7][CH2:8]/[C:9](=[N:33]/[OH:34])/[CH2:10][NH:11][CH3:19])[C:5]2[CH:21]=[CH:22][CH:23]=[CH:24][C:4]=2[N:3]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: NO
Reactant: CN(CC(=O)CCN1c2ccccc2N(c2ccccc2)S1(=O)=O)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CNC/C(CCN1c2ccccc2N(c2ccccc2)S1(=O)=O)=N\O
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
tert-butyl [4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-2-oxobutyl]methylcarbamate (50 mg, 0.112 mmol), hydroxylamine hydrochloride (50 mg, 0.720 mmol), and pyridine (1.5 mL) were stirred in ethyl alcohol (3 mL) in a sealed vial at 70° C., for 3 hr. The reaction was allowed to cool to room temperature and transferred to a separatory funnel with dichloromethane and washed with a saturation aqueous solution of sodium bicarbonate, brine, dried (MgSO4), filtered and the solvent removed, in vacuo, to give a clear oil. This material was adsorbed onto silica gel and purified via Isco chromatography (Redisep, silica, gradient 0-50% ethyl acetate in hexane to afford a white solid. This material was dissolved in diethyl ether and methanol and 4N HCl in dioxane was added a precipitate formed. The mixture was filtered to afford 0.028 g (62% Yield) of (2Z)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)butan-2-one oxime as an off white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([OH:19])=O)[N:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]1[C@H:41]2[C@@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:35][CH2:34][NH:33]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:15][O:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([C:3](=[O:4])[C:2]([CH3:21])([CH3:1])[CH3:20])=[N:6][N:7]2[CH2:16][C:17]([N:33]2[CH2:34][CH2:35][C@H:36]3[C@@H:41]([CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:32]2)=[O:19])=[CH:12][CH:11]=1
Reactant: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Reactant: C1CC[C@H]2CNCC[C@@H]2C1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)N3CC[C@@H]4CCCC[C@H]4C3)c2c1
Temperature: 25 °C

Procedure:
To a solution of 29.0 mg [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetic acid in 1 mL DMF was added 23.0 mg HOBt, 20.9 mg trans-decahydroisoquinoline, 38.3 mg EDC, and 45.2 mg DIEA in that order. The mixture was stirred at room temperature over night and purified by RP-HPLC using 65-100% MeCN gradient. The pure product fractions were pooled and lyophilized to give the title compound. LC-MS: 4.29 min. (m/Z=412.3, 434.3).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[Cl:13])[NH:9][C:8](=[O:14])[CH2:7]2.[N:15]1([C:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[S:23][N:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.O.C1CCCCC1>[CH:27]1[CH:28]=[CH:29][C:24]2[S:23][N:22]=[C:21]([N:15]3[CH2:16][CH2:17][N:18]([CH2:2][CH2:3][C:4]4[CH:5]=[C:6]5[CH2:7][C:8](=[O:14])[NH:9][C:10]5=[CH:11][C:12]=4[Cl:13])[CH2:19][CH2:20]3)[C:25]=2[CH:26]=1
Reactant: O=C1Cc2cc(CCCl)c(Cl)cc2N1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: C1CCCCC1
Solvent: O
Product: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc2N1
Temperature: 98.5 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
Charged 5-(2-chloroethyl) -6-chloro oxindole (50 gm), 3-(1-piperazinyl)-1,2-benzisothiazole (47.5 gm) and cyclohexane (500 mL) into an autoclave. To this sodium carbonate (46 gm), sodium iodide (3.2 gm), tetra butyl phosphonium bromide (14.8 gm) was added and the reaction was maintained at a temperature of 95-102° C. and the pressure was kept at 2.5 kg/cm2 till the reaction was completed. The reaction mass was cooled to 30° C. and water (250 mL) was added. The resulting compound was filtered and washed with water (100 mL). The wet compound was further slurred in water (500 mL), filtered and washed with water (100 mL). To the water wet compound was added acetone (500 mL) and was stirred at room temperature for 2 hours and 30 minutes. The solid was filtered, washed with acetone (100 mL) and dried at a temperature of 60-65° C. to afford the Ziprasidone base (65.7 gm).