Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])([OH:7])[C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:29][C:30]1[CH:43]=[CH:42][C:33]([C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:35])=[CH:32][CH:31]=1>O1CCCC1>[C:36]1([C:34]([C:33]2[CH:32]=[CH:31][C:30]([NH:29][C:4](=[O:5])[C:3]([OH:7])([C:8]([F:11])([F:10])[F:9])[C:2]([F:13])([F:12])[F:1])=[CH:43][CH:42]=2)=[O:35])[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C(O)C(O)(C(F)(F)F)C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccc(NC(=O)C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 23 °C
Reaction time: 1.5 h

Procedure:
Tetrahydrofuran (35 ml,dry) was added to a mixture of 2,2-bis-trifluoromethyl 2-hydroxyacetic acid (1.08 g, 5.1 mmol) and 1,1'-carbonyldiimidazole (0.83 g, 5.1 mmol), while under a nitrogen atmosphere. There was an immediate evolution of carbon dioxide. The reaction was refluxed for 0.5 hrs and cooled to 23° C. The reaction was treated with 4-aminobenzophenone (1.0 g,5.1 mmol), stirred at 23° C. for 1.5 hrs, and then at reflux 18 hrs. The reaction was evaporated to a yellow oil-solid mixture. The mixture was dissolved in ethyl ether, treated with hydrogen chloride in ethyl ether, and filtered. The filtrate was evaporated to a yellow oil-solid mixture. Chromatography of this mixture on silica gel, eluting with 5% ethylether in methylenechloride provided the title compound as an off-white solid; mp 143°-146° C. 1H--NMR (250 MHz,d6 --DMSO): 7.67(m, 2H, ArH), 7.83(m, 5H, ArH),7.96(d, J=8.8, 2H, ArH), 9.82(s, 1H, OH), 10.82(s, 1H, NH). MS(CI,CH4): 392 (M+1).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[CH3:27][N:28]([CH3:43])[CH2:29][CH2:30][CH2:31]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:31][CH2:30][CH2:29][N:28]([CH3:43])[CH3:27])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCCN(C)C)cc1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCCN(C)C)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 200 °C
Yield: 403.1 %

Procedure:
A 5 mL microwave vial was charged with Compound 157 (290 mg, 0.79 mmol), 3-(dimethylamino)propyl-4-methylbenzenesulfonate (224 mg, 0.87 mmol), potassium carbonate (218 mg, 1.58 mmol) and 2 mL of anhydrous DMF, under nitrogen atmosphere. The reaction mixture was heated at 200° C. for 30 min. in microwave with high absorption. The reaction was quenched with addition of water, and the solid precipitate out was collected by filtration and purified through preparative HPLC to provide title compound (1438 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.33 Hz, 3 H) 1.99 (qd, J=6.61, 6.44 Hz, 2 H) 2.20 (s, 6 H) 2.26 (s, 3 H) 2.53-2.56 (m, 2 H) 3.41 (q, J=7.33 Hz, 2 H) 4.25 (t, J=6.19 Hz, 2 H) 7.05-7.09 (m, 1 H) 7.11-7.14 (m, 1 H) 7.54 (d, J=1.52 Hz, 1 H) 7.85 (t, J=7.83 Hz, 1 H) 7.98 (t, J=6.95 Hz, 2 H) 8.06-8.08 (m, 1 H) 8.27 (d, J=1.77 Hz, 1 H) 12.13 (s, 1 H); [M+H] calc'd for C25H30N3O3S, 452.2; found, 452.4.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:9][O:8][C:7]2([CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)[O:6]1.[Cl:23][C:24]1[S:25][C:26]([CH2:29]Cl)=[CH:27][N:28]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[S:25][C:26]([CH2:29][O:3][CH2:4][CH:5]2[CH2:9][O:8][C:7]3([CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:13][CH2:14]3)[O:6]2)=[CH:27][N:28]=1
Reactant: OCC1COC2(CCN(CCc3ccccc3)CC2)O1
Reactant: ClCc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ncc(COCC2COC3(CCN(CCc4ccccc4)CC3)O2)s1
Temperature: 28 °C

Procedure:
To 8.64 g (0.36 mole) of sodium hydride in toluene (250 ml) was added 2-hydroxymethyl-8-phenethyl-1,4-dioxa-8-azaspiro[4,5]decane (compound 1.50 gm, 0.18 mole) in toluene (350 ml) with stirring at 28° C. The phase transfer catalyst tetrabutylammonium bromide TBAB 2 gm was added and 31 gm of 2-chloro-5-chloromethylthiazole in toluene (225 ml) was then added drop wise at 10° C. and the reaction mixture was refluxed for 15 hrs. The reaction mixture was washed with water and the product was extracted with methylene chloride 100 ml. The solvent was distilled off to get thick dark colored liquid. The yield of the product was 85%.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]2[C:13]([NH:15][C:16]2([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[CH2:18][CH2:17]2)=[O:14])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32].O[Li:36].O>>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]2[C:13]([NH:15][C:16]2([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O-:25])=[O:24])=[CH:21][CH:20]=3)[CH2:18][CH2:17]2)=[O:14])=[CH:4][C:3]=1[C:31]([F:34])([F:32])[F:33].[Li+:36]
Reactant: [Li]O
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3ccc(F)c(C(F)(F)F)c3)CC2)cc1
Solvent: O
Product: O=C([O-])c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3ccc(F)c(C(F)(F)F)c3)CC2)cc1
Product: [Li+]

Procedure:
The title compound (E13) (11.1 mg) was prepared according to the general procedure for esters hydrolysis starting from (R)-methyl 4-(1-(1-(4-fluoro-3-(trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclopropyl)benzoate (D30) (35 mg). (LiOH H2O: 3 eq; reaction time: 3 hrs)
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])=[N+:2]=[N-:3].[C:28]1(C)[C:29]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=1.N1C=CC=C[CH:40]=1>CN(C)C1C=CN=CC=1>[C:32]1([CH3:40])[CH:33]=[CH:28][C:29]([S:34]([O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])(=[O:35])=[O:36])=[CH:30][CH:31]=1
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCCOCCOCCOCCO
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: c1ccncc1
Agent: CN(C)c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOCCOCCOCCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 25 %

Procedure:
A solution of 23-azido-3,6,9,12,15,18,21-heptaoxatricosan-1-ol (800 mg, 2.02 mmol) in pyridine (4 mL) was added dropwise to the solution of toluenesulfonyl chloride (771 mg, 4.04 mmol) and 4-dimethylaminopyridine (100 mg) in pyridine (10 mL) at room temperature. The mixture was stirred for 24 hours at room temperature. The solvent was evaporated and the crude product was purified on SiO2 column using hexanes/ethylacetate gradient 0-100% followed by ethylacetate/methanol gradient 0-100%, then purified on semipreparative HPLC (System E) to yield 280 mg (25%) of 3 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.45 (s, 3H), 3.38 (t, J=5.02 Hz, 2H), 3.58-3.70 (m, 28H), 4.16 (t, J=5.00 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.80 (d, J=8.4 Hz, 2H); 13C NMR (100.6 MHz, CDCl3): δ 21.6, 50.7, 68.7, 69.2, 70.0, 70.5-70.8, 128.0, 129.7, 133.1, 144.7; MS ESI (m/z): [M+H]+ calcd. for C23H39N3O10S 549.24; found 549.9.
Reaction SMILES: [CH2:1]([OH:10])[C@H:2](O)[CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH3:8].[H-].[Na+].C(C1C=CC(S(Cl)(=O)=O)=C(C(C)C)C=1C(C)C)(C)C>C1COCC1>[CH2:3]([C@@H:2]1[CH2:1][O:10]1)[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH3:8]
Reactant: CC/C=C\CC[C@@H](O)CO
Agent: CC(C)c1ccc(S(=O)(=O)Cl)c(C(C)C)c1C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC/C=C\CC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (R,Z)-oct-5-ene-1,2-diol (8.50 g, 58.9 mmol) in THF (230 mL) at 0° C. was added NaH (60% dispersion in mineral oil, 7.06 g, 177 mmol) (7.06 g as dispersion). The mixture was warmed to ambient temperature and stirred for 40 min. The reaction was cooled to 0° C. and triisopropylbenzenesulfonyl chloride (20.7 g, 61.8 mmol) was added. The reaction was warmed to room temp, stirred for 1 h, quenched with H2O and extracted with Et2O. The organics were washed with brine, dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (2% Et2O in pentane gradient to 8% Et2O in pentane) gave (R,Z)-2-(hex-3-enyl)oxirane. It was determiined that slight racemization occurred at this step (98% ee to 84% ee). In order to ensure optical purity the enantioenriched product was further resolved using Jacobsen's hydrolytic kinetic resolution (HKR, Step E). 1H NMR (400 MHz, CDCl3): δ 5.41 (1H, m), 5.35 (1H, m), 2.93 (1H, m), 2.75 (1H, dd, J=5.2, 4.4 Hz), 2.49 (1H, dd, J=5.2, 2.8 Hz), 2.20 (2H, q, J=6.8 Hz), 2.06 (2H, quin, 7.6 Hz); 1.59 (2H, m), 0.97 (3H, t, J=7.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1.[H+].[B-:27]([F:31])([F:30])([F:29])[F:28]>C(Cl)Cl>[F:28][B-:27]([F:31])([F:30])[F:29].[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([S+:7]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=2)[CH2:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(CSc2ccc(Cl)cc2)cc1
Reactant: OCc1ccc(Cl)cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Product: Clc1ccc(C[S+](Cc2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Yield: 77.4 %

Procedure:
5.2 g (19.4 mmol) of 4-chlorophenyl 4-chlorobenzyl sulfide, 4.14 g (29.0 mmol) of 4-chlorobenzyl alcohol and 14.15 g (87 mmol) of hydrogen tetrafluoroborate (54% in diethyl ether) in 20 ml of methylene chloride are reacted as in Example 6(a) to give 7.23 g (77.4% of theory) of 4-chlorophenylbis(4-chlorobenzyl)sulfonium tetrafluoroborate in the form of white-beige crystals of melting point 147°-148° C.
Reaction SMILES: ClCCl.B(Br)(Br)Br.[CH3:8][O:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([CH3:34])=[C:28]3[N:27]=[C:26]2[CH2:35][O:36]C)=[CH:20][CH:19]=1)=[O:11]>CO>[OH:36][CH2:35][C:26]1[N:25]([CH2:24][C:21]2[CH:22]=[CH:23][C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:10]([O:9][CH3:8])=[O:11])=[CH:19][CH:20]=2)[C:29]2=[N:30][CH:31]=[CH:32][C:33]([CH3:34])=[C:28]2[N:27]=1
Reactant: COCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccccc1-c1ccc(Cn2c(CO)nc3c(C)ccnc32)cc1
Yield: 75.5 %

Procedure:
50 ml (50 retool) of a dichloromethane solution of 1M boron tribromide was added little by little dropwise to 100 ml of a dichloromethane solution of 3.3 g (8.2 mmol) of 3-[(2'-methoxycarbonyl-biphenyl-4-yl)methyl]-2-methoxymethyl-7-methyl-3H-imidazo[4.5-b]pyridine, while stirred and cooled with ice. The mixture was further stirred at a room temperature for 12 hours. Methanol was added dropwise to the product mixture, while stirred and cooled with ice, and the solvent was distilled out at a reduced pressure. The residue was mixed with water and neutralized with sodium bicarbonate. It was weakly acidified with acetic acid and decanted to remove the water. Methanol was added to the residue and distilled out at a reduced pressure. It was re-crystallized from ethanol-isopropylether to obtain 2.4 g of the intended compound.
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][C:11]([C:17]([O-:19])=[O:18])=[C:12]([CH2:14][CH2:15][CH3:16])[CH:13]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[N+:20]([O-:23])(O)=[O:21].[C:24](OC(=O)C)(=O)[CH3:25]>C(Cl)Cl.C(O)(=O)C>[C:1]([NH:8][C:9]1[S:10][C:11]([C:17]([O:19][CH2:24][CH3:25])=[O:18])=[C:12]([CH2:14][CH2:15][CH3:16])[C:13]=1[N+:20]([O-:23])=[O:21])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1cc(NC(=O)C(=O)OCC)sc1C(=O)[O-]
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCc1c(C(=O)OCC)sc(NC(=O)C(=O)OCC)c1[N+](=O)[O-]
Temperature: -10 °C

Procedure:
A mixture of 2-ethoxalylamino-4-propylthiophene-5-carboxylate (9.0 g, 28.7 mmol) in 52 ml of acetic anhydride and 58 ml of methylene chloride was stirred in a dry nitrogen atmosphere and cooled to -10° C. A mixture of nitric acid (1.78 ml, d=1.52) in 40 ml of acetic acid was added dropwise during 0.5 hours. The reaction mixture was stirred at 0°-5° C. for 16 hours and poured into ice water. The organic phase was separated and carefully neutralized with saturated aqueous sodium hydrogen carbonate. The neutral organic phase was washed with water, dried (Na2SO4) and the solvent was evaporated. The residue was dissolved in methanol and water was added to favour precipitation. The precipitate was filtered off, washed with cold aqueous methanol and dried. Yield 4.77 g (46%) of ethyl 2-ethoxalylamino-3-nitro-4-propylthiophene-5-carboxylate. M.p. 73°-75° C. 1H-NMR (DMSO-d6, δ): 0.98 (t, 3H), 1.39 (t, 3H), 1.45 (t, 3H), 1.55 (hex, 2H), 3.20 (t, 2H), 4.31 (q, 2H), 4.38 (q, 2H), 12.02 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[CH:17]=[C:16]([CH3:18])[O:15][N:14]=1)=[O:12].[Cl:19][C:20]1[CH:21]=[C:22]([C@H:26]([NH2:28])[CH3:27])[CH:23]=[CH:24][CH:25]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:28][C@@H:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=2)[CH3:27])=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[CH:17]=[C:16]([CH3:18])[O:15][N:14]=1)=[O:12]
Reactant: C[C@@H](N)c1cccc(Cl)c1
Reactant: Cc1cc(C(=O)Nc2cc(C=O)ccc2Cl)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)Nc2cc(CN[C@H](C)c3cccc(Cl)c3)ccc2Cl)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
To a solution of N-(2-chloro-5-formylphenyl)-5-methylisoxazole-3-carboxamide 3 (0.117 g, 0.44 mmol) in DCE (3 mL) was added (R)-1-(3-chlorophenyl)ethanamine (0.079 g, 0.51 mmol), acetic acid (0.030 mL, 0.52 mmol), and NaBH(OAc)3 (0.108 g, 0.51 mmol). The reaction mixture was stirred at room temperature for 16 h and diluted with EtOAc. The organic phase was washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 20% to 60% EtOAc in hexanes) gave (R)—N-(2-chloro-5-((1-(3-chlorophenyl)ethylamino)methyl)phenyl)-5-methylisoxazole-3-carboxamide 4 (0.131 g, 73% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.36 (d, J=6.5 Hz, 3H), 2.53 (s, 3H), 3.60 (d, J=13.7 Hz, 1H), 3.66 (d, J=13.7 Hz, 1H), 3.79 (q, J=6.5 Hz, 1H), 6.53 (s, 1H), 7.04 (d, J=8.2 Hz, 1H), 7.21-7.36 (m, 6H), 8.41 (s, 1H), 9.10 (s br, 1H). Mass spectrum: calculated for C20H19Cl2N3O2 403.1. found 404.1 (M++1).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:10](F)=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH2:5][CH2:4]1)[CH3:2].C([OH:22])C#CC.CC(C)([O-])C.[K+].Cl>CS(C)=O>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:10]([OH:22])=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(c2cccc(C#N)c2F)CC1
Reactant: CC#CCO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CCN1CCC(c2cccc(C#N)c2O)CC1
Temperature: 125 °C

Procedure:
To a solution of 3-(1-ethylpiperidin-4-yl)-2-fluorobenzonitrile (10 mg, 0.031 mmol) in dimethylsulfoxide (1 ml) was added 2-butyn-1-ol (4.3 mg, 0.062 mmol) and potassium-tert-butoxide (7 mg, 0.063 mmol). The mixture was heated to 125° C. in a sealed tube under microwave radiation for 120 s. Aqueous hydrochloric acid (10%, 10 ml) was added and the aqueous phase was washed with diethyl ether (2×20 ml). The aqueous phase was basified by addition of sodium hydroxide (5 M, 5 ml) and extracted with ethyl acetate (3×20 ml). The combined organic phase was dried (MgSO4) and evaporated under reduced pressure to give the title compound. MS m/z (relative intensity, 70 eV) 230 (M+, 60), 229 (24), 216 (23), 215 (bp) 110 (30).
Reaction SMILES: [I-].[CH3:2][N+:3]12[CH2:18][CH2:17][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:6][CH2:5][CH2:4]2.[Li].COCC(O)C.N>C1C=CC=CC=1.CCCCCC>[CH3:2][N:3]1[CH2:4][CH2:5][CH2:6][CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]2[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]=2[CH2:17][CH2:18]1
Reactant: C[N+]12CCCC1(c1ccccc1)c1[nH]c3ccccc3c1CC2
Agent: N
Agent: [I-]
Agent: [Li]
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: COCC(C)O
Product: CN1CCCC(c2ccccc2)c2[nH]c3ccccc3c2CC1

Procedure:
Then 2,3,5,6,11,11b-hexahydro-4-methyl-11b-phenyl-1H-indolizino[8,7-b]indolium iodide (8.09 g.), 286 mg. lithium, 2.03 g. 1-methoxy-2-propanol and 2 liters liquid ammonia are reacted according to the method of Example I-(a). The white foam isolated from the 1:9 and 1:4 benzene-hexane elutes is crystallized from hexane to provide 4.38 g. base. A 300 mg. portion is crystallized (twice) from hexane thereby yielding 200 mg. of title compound, m.p. 117°-119°C., NMR (CDCl3): δ 2.45 (singlet, 3-methyl), 5.70 (triplet, J 8 cps., 7-hydrogen) ppm.
Reaction SMILES: Br[C:2]1[C:6](=[O:7])[C:5]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[O:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:3]2[O:4][C:5]3([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)[C:6](=[O:7])[C:2]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: OB(O)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)C3(CCCCC3)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C2=C(c3ccccc3)C(=O)C3(CCCCC3)O2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 49.4 %

Procedure:
To 102 mg of 3-bromo-2-{4-(methylsulfonyl)phenyl}-1-oxa-spiro[4,5]dec-2-en-4-one dissolved in 3 ml toluene and 15 ml ethanol, were added 16 mg of tetrakis(triphenylphosphin)palladium(0), 3 ml of 2 M aqueous sodium carbonate and 35 mg of benzeneboronic acid. The reaction mixture was stirred at 90° C. for 12 hours. The reaction mixture was then purified by a procedure similar to the procedure in Step 6 of Example 53 to afford 50 mg of 2-{4-(methylsulfonyl)phenyl}-3-phenyl-1-oxa-spiro[4,5]dec-2-en-4-one as a solid. mp: 126-127° C. NMR: δ1.77-1.85 (m, 10H), 3.06 (s, 3H), 7.27 (m, 2H), 7.35 (m, 3H), 7.83 (d, J=8.1 Hz, 2H), 7.94 (d. J=8.1 Hz, 2H). IR (cm−1): 2936, 1693, 1621, 1404, 1318, 1147, 1129, 730.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:14][Mg]Br>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:7]([OH:8])[CH3:14])[CH:9]=1
Reactant: COc1cc(Cl)cc(C=O)c1OC
Reactant: C[Mg]Br
Solvent: CCOCC
Product: COc1cc(Cl)cc(C(C)O)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a stirred solution of 5-chloro-2,3-dimethoxy-benzaldehyde (7.0 g, 34.90 mmol) in dry diethyl ether (500 mL) at 0° C. was added methylmagnesium bromide of 3.0 M in diethyl ether (29 mL, 87.22 mmol). The reaction mixture was brought to room temperature and stirred for 30 min; refluxed for 3 h; then cooled to 0° C. and quenched by adding saturated aqueous NH4Cl. The two liquid layers were separated. The aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water, dried, and concentrated to the crude compound which was purified by silica gel column (10-25% ethyl acetate in hexanes) to afford 1-(5-chloro-2,3-dimethoxy-phenyl)-ethanol (5.67 g, 75%): 1H NMR (400 MHz, CDCl3): δ 7.00 (d, 1H), 6.81 (d, 1H), 5.11 (m, 1H), 3.86 (s, 6H), 2.30 (d, 1H), 1.48 (d, 3H).
Reaction SMILES: ON1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2N=N1.C(Cl)CCl.C(OCC)(=O)C.C[N:22](C)[CH:23]=[O:24]>>[C:23]([NH2:22])(=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: On1nnc2ccccc21
Reactant: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
To a solution of 175 mg (1.15 mmol) of 3-hydroxy-2-1methylbenzoic acid and 203 mg (1.5 mmol) of N-hydroxybenzotriazole in 6 mL of anhydrous N,N-dimethylformamide at 0° C., was added 220 mg (1.15 mmol) of EDC. After 20 minutes of activation at 0° C. and 1 hour at room temperature, 392 mg (1.0 mmol) of 2R-hydroxy-3-[(2-methylpropyl)(4-aminophenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine was added. After 15 hours at room temperature, ethyl acetate was added, washed with 5% citric acid, saturated sodium bicarbonate, brine, dried, filtered and concentrated to afford 590 mg of crude material. This was chromatographed on silica gel using 50-80% ethyl acetate/methylene chloride as eluent to afford 255 mg of pure benzamide, N-[2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino)-1S-(phenylmethyl)propyl]-3-hydroxy-2-methyl, m/e=526(M+H).
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])C.C1COCC1.Cl.[CH3:27][NH:28][O:29][CH3:30].C([Mg]Cl)(C)C>C(OCC)(=O)C>[CH3:30][O:29][N:28]([CH3:27])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH2:7]1)=[O:5]
Reactant: CCOC(=O)C1CCCN(Cc2ccc(OC)cc2)C1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN2CCCC(C(=O)N(C)OC)C2)cc1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
Combine 1-(4-Methoxy-benzyl)-piperidine-3-carboxylic acid ethyl ester (9.3 g, 33.5 mmol), THF (200 mL), N,O-Dimethylhydroxylamine hydrochloride (4.9 g, 50.3 mmol) at −10° C. (Acetone/ice bath) under a Nitrogen atmosphere. By dropwise addition, add Isopropylmagnesium chloride (50.3 mL, 100.6 mmol). Stir the reaction for 6 hours allowing the reaction mixture to warm to room temperature. Quench the reaction mixture with sat NH4Cl (aq) and extract product from the water using Ethyl acetate. Wash the organic layer with brine and then dry over Na2SO4. Concentrate under reduced pressure and flash chromatograph using 1:1 Hexanes:Ethyl acetate and then 1:1 Hexanes:Ethyl acetate with 3% 1N NH3MeOH to give 9.13 g (93% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.4-1.7 (3H, m), 1.8 (1H, d), 1.9 (1H, t), 2.1 (1H, t), 2.8-3.0 (3H, m), 3.1 (3H, s), 3.5 (2H, d), 3.6 (3H, s), 3.8 (3H, s), 6.8 (2H, d), 7.2 (2H, d); MS m/z 293 (M+1).
Reaction SMILES: C(=O)=O.CC(C)=O.C[O:9][C:10]([C:12]1[C:13]([CH2:28][CH3:29])=[N:14][N:15]([C:19]2[C:24]([CH3:25])=[CH:23][C:22]([Br:26])=[CH:21][C:20]=2[CH3:27])[C:16]=1[CH2:17][CH3:18])=O.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[Br:26][C:22]1[CH:21]=[C:20]([CH3:27])[C:19]([N:15]2[C:16]([CH2:17][CH3:18])=[C:12]([CH2:10][OH:9])[C:13]([CH2:28][CH3:29])=[N:14]2)=[C:24]([CH3:25])[CH:23]=1
Reactant: CCc1nn(-c2c(C)cc(Br)cc2C)c(CC)c1C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C=O
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCc1nn(-c2c(C)cc(Br)cc2C)c(CC)c1CO
Reaction time: 0.25 h
Yield: 73.6 %

Procedure:
To a dry ice/acetone bath-chilled solution of 1-(4-bromo-2,6-dimethylphenyl)-3,5-diethyl-1H-pyrazole-4-carboxylic acid methyl ester (1.1 g, 3.1 mmol) in anhydrous tetrahydrofuran (8 ml), diisobutylaluminum hydride (1.0 M in toluene; 10 ml, 10 mmol) was added dropwise. After 15 minutes, the reaction mixture was warmed to 0°-5° C. and stirred at that temperature for 2.5 hours. The reaction was then quenched by addition of 2 ml of water, and the organic solvent was removed in vacuo. Extraction of the residual mixture with ethyl acetate, anhydrous sodium sulfate drying of the resulting extract, and its concentration in vacuo afforded the title compound as a yellow oil (0.77 g).