Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.IC(C)C>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH:37]([CH3:41])[CH3:38])[C:23]([O:25][CH3:26])=[O:24]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(C)I
Solvent: CN(C)C=O
Product: COC(=O)C(c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3)C(C)C
Yield: 53.5 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF (0.75 mL; 0.75 mmol), 2-iodopropane (0.100 mL; 1 mmol) in DMF (2.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.109 g (54%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]=[C:36]=[S:37])=[O:34])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:35][C:33](=[O:34])[C:30]2[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=2)=[S:37])=[CH:18][CH:17]=1
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (73 mg, yield 92%).
Reaction SMILES: [C:1](=[C:3]1N=C2C=CC=CC2=N1)=O.[CH:12]([S:15]([N:18]1[C:22]2[CH:23]=[C:24]([C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[NH2:35])(=[O:17])=[O:16])([CH3:14])[CH3:13].C([Li])C>CO>[CH:12]([S:15]([N:18]1[C:22]2[CH:23]=[C:24]([C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([OH:34])[CH2:1][CH3:3])[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[NH2:35])(=[O:16])=[O:17])([CH3:14])[CH3:13]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=O)c3ccccc3)cc21
Reactant: O=C=C1N=c2ccccc2=N1
Agent: [Li]CC
Solvent: CO
Product: CCC(O)(c1ccccc1)c1ccc2nc(N)n(S(=O)(=O)C(C)C)c2c1

Procedure:
Specifically the carbonyl benzimidazole, 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole, is reacted with ethyl lithium to form the desired carbinol, 1-isopropylsulfonyl-2-amino-6-(1-phenyl-1-hydroxy-1-propyl)benzimidazole.
Reaction SMILES: Cl[C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:14][CH3:15])[N:3]=1.[CH2:16]([NH:19][CH2:20][CH2:21][CH3:22])[CH2:17][CH3:18]>O1CCCC1.O>[CH2:16]([N:19]([CH2:20][CH2:21][CH3:22])[C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:14][CH3:15])[N:3]=1)[CH2:17][CH3:18]
Reactant: CCCNCCC
Reactant: COc1cccc2nc(Cl)n(C)c(=O)c12
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)c1nc2cccc(OC)c2c(=O)n1C
Temperature: 80 °C
Reaction time: 60 h
Yield: 45.5 %

Procedure:
A mixture of 2-chloro-5-methoxy-3-methylquinazolin-4(3H)-one (75 mg, 0.334 mmol) and dipropylamine (0.137 ml, 1.00 mmol) in tetrahydrofuran (1 ml) was stirred at 80° C. for 60 h and diluted with water. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting with 50% ethyl acetate/n-hexane to afford 44 mg (45%) of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:26]1[C:27]([F:37])=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:31]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:26]4[C:27]([F:37])=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:33])=[O:34])[CH:31]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and 5-bromo-2,4-difluoro-benzenesulfonamide (68 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (85 mg, 65%). MS (ISN) 517.0 [(M−H)−]; mp 255-257° C.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[OH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[CH2:25][OH:24])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: OCc1ccccc1B(O)O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccccc3CO)cc1OCC2

Procedure:
Following the procedures of Example 475, 8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene 194 was reacted with 2-(hydroxymethyl)phenylboronic acid to give 478. MS (ESI+) 402.1. 1H NMR (400 MHz, DMSO) δ 8.46 (d, J=8.3 Hz, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.41 (td, J=7.4, 1.1 Hz, 1H), 7.38-7.32 (m, 1H), 7.28 (d, J=7.4 Hz, 1H), 7.20 (dd, J=8.3, 1.6 Hz, 1H), 7.09 (d, J=1.5 Hz, 1H), 6.02-5.83 (m, 1H), 5.16 (t, J=5.3 Hz, 1H), 4.56 (q, J=6.1 Hz, 4H), 4.45 (d, J=5.3 Hz, 2H), 1.50 (d, J=6.6 Hz, 6H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.Br[C:28]1[CH:29]=[N:30][C:31]([Cl:34])=[N:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:12]=[CH:13][C:14]([C:28]3[CH:29]=[N:30][C:31]([Cl:34])=[N:32][CH:33]=3)=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: Clc1ncc(Br)cn1
Reactant: COC(=O)CC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)CC1CCC(c2ccc(-c3cnc(Cl)nc3)cc2)CC1
Temperature: 120 °C

Procedure:
PdCl2dppf (120 mg, 0.140 mmol) is added to a degassed mixture of {4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (1.00 g, 2.79 mmol), 5-bromo-2-chloro-pyrimidine (540 mg, 2.79 mmol), 2 M Na2CO3 (2.8 mL), and DME (7.5 mL). The mixture is sealed in a glass tube and heated to 120° C. for 20 min by microwave irradiation. The reaction is diluted with EtOAc (150 mL), and the resulting suspension filtered. The filtrate is extracted with 1 N HCl (25 mL) and the organic layer dried over Na2SO4. Concentration followed by silica gel chromatography (20% EtOAc/Hexanes) affords {4-[4-(2-chloro-pyrimidin-5-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester as a white solid: 1H NMR (400 MHz, CHLOROFORM-d) δppm 1.14-1.27 (m, 2H) 1.49-1.61 (m, 2H) 1.86-1.98 (m, 5H) 2.28 (d, J=6.82 Hz, 2H) 2.56 (tt, J=12.22, 3.19 Hz, 1H) 3.70 (s, 3H) 7.37 (d, J=8.08 Hz, 2H) 7.49 (d, J=8.34 Hz, 2H) 8.81 (s, 2H); (M+H)+345.1.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:10]=[CH:11][N:12](C)C)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].N[C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:17]=1[S:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>C(O)(=O)C>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][O:22][C:20]2[CH:19]=[CH:18][C:17]([S:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)=[C:16]([NH:2][C:1]3[C:3]4[CH:8]=[CH:7][C:6]([CH3:9])=[N:5][C:4]=4[N:10]=[CH:11][N:12]=3)[CH:21]=2)=[CH:29][CH:28]=1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Reactant: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c(N)c2)cc1
Solvent: CC(=O)O
Product: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c(Nc3ncnc4nc(C)ccc34)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 35.3 %

Procedure:
A solution of the product of Example 9B (28.4 mg, 0.151 mmol), and the product of Example 9E (53.3 mg, 0.151 mmol) in acetic acid (1 mL) was stirred in an oil bath preheated to 130° C. for 20 minutes. The mixture was then cooled to room temperature, the acetic acid removed under vacuum, and the resultant residue triturated with methanol to provide the title compound as a tan solid (26.5 mg, 35%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.92 (s, 1 H), 9.63 (s, 1 H), 8.70 (d, J=8.09 Hz, 1 H), 8.55 (s, 1 H), 7.52 (d, J=8.46 Hz, 1 H), 7.38 (d, J=8.82 Hz, 2 H), 7.27 (s, 1 H), 7.06-7.18 (m, 3 H), 6.94 (d, J=8.46 Hz, 3 H), 6.61-6.72 (m, 2 H), 5.02 (s, 2 H), 3.75 (s, 3 H), 2.66 (s, 3 H); MS (ESI+) m/z 497.2 (M+H)+, (ESI−) m/z 495.3 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:13](OC(Cl)(Cl)Cl)=[O:14]>O1CCOCC1>[N:1]([C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[C:13]=[O:14]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cccc(S(N)(=O)=O)c1
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cccc(N=C=O)c1

Procedure:
To a vigorously stirred solution of 3-aminobenzenesulphonamide (1 g, 5.8 mmol) in dry dioxane (25 ml) is added trichloromethyl chloroformate (1.72 g, 8.7 mmol) and the reaction mixture is heated to reflux for 3 hours. The solvent is removed in vacuo to yield the title product which is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH3:18].O>CN(C=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1
Reactant: CCCBr
Reactant: OCCCOc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In DMF (100 ml) was dissolved 3-(4-bromophenoxy)-1-propanol (10.0 g). To the mixture was added under ice-cooling 65% sodium hydride (2.4 g),and the mixture was stirred at room temperature for 2 hours. To the mixture was added dropwise bromopropane (5.5 ml), and the mixture was stirred for 3 hours. To the mixture was added 65% sodium hydride (0.8 g), and the mixture was stirred at 70 for 1 hour and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=5/1) to give 1-bromo-4-(3-propoxypropoxy)benzene (6.7 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)C=O>[CH:21]1([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH:11]([F:12])[F:13])[CH:5]=[O:6])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(OC2CCCC2)c1
Temperature: 50 °C
Yield: 91.1 %

Procedure:
To a mixture of 3-hydroxy-4-difluoromethoxybenzaldehyde 2.9 g, 15 mmol) and powdered potassium carbonate (3.2 g, 23 mmol) in dimethylformamide (15 mL) under an argon atmosphere was added bromocyclopentane (2.5 mL, 23 mmol) and the mixture was stirred and heated at 50° C. for 1 h and at 80°-85° C. 1.5 h. The mixture was allowed to cool and was partitioned between ethyl acetate and water. The organic extract was washed three times with water, was dried (sodium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 20-30% ether/hexanes, provided a yellow solid (3.5 g, 89%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=O.[CH3:16][C:17]1[CH:18]=[C:19]2[N:24]([CH:25]=1)[CH:23]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:21]=[CH:20]2>ClCCl>[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[CH2:8][C:25]1[N:24]2[C:19]([CH:20]=[CH:21][C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23]2)=[CH:18][C:17]=1[CH3:16]
Reactant: COC(=O)c1ccc2cc(C)cn2c1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(C)c(Cc3ccc(Cl)cc3Cl)n2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.7 %

Procedure:
To a suspension of anhydrous aluminum chloride (3.18 g) in dichloromethane (19 ml) was added 2,4-dichlorobenzoyl chloride (2.93 g) under ice-cooling, and the mixture was stirred for 10 min. To this solution was added methyl 2-methylindolizine-6-carboxylate (1.89 g) and the mixture was stirred for 4 hr at room temperature. The reaction mixture was slowly poured into ice water and the resulting product was extracted with ethyl acetate. The organic layer was washed successively with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give the objective compound (2.39 g) as a pale-yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[O:6][CH2:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:34]([O:36][CH:37]([CH2:43][C:44]1[CH:49]=[CH:48][C:47](O)=[CH:46][CH:45]=1)[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:35].C(OC([N+](C(OC(C)C)=O)=[N-])=O)(C)C>C1(C)C=CC=CC=1.O>[CH2:34]([O:36][CH:37]([CH2:43][C:44]1[CH:45]=[CH:46][C:47]([O:1][CH2:2][CH2:3][N:4]2[C:9](=[O:10])[C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[O:6][CH2:5]2)=[CH:48][CH:49]=1)[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:35]
Reactant: O=C1c2ccccc2OCN1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CC(C)OC(=O)[N+](=[N-])C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCN2COc3ccccc3C2=O)cc1)OCC
Reaction time: 0.17 h
Yield: 75.9 %

Procedure:
To a stirred mixture of 3-(2-hydroxyethyl)-4-oxo-3,4-dihydro-1,3-benzoxazine (325 mg, 1.68 mmol) and triphenylphosphine (660 mg, 2.52 mmol) in toluene (10 mL) was added a solution of (+)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate (400 mg, 1.68 mmol) at 25° C. and stirred for 10 min. To the reaction mixture was added diisopropyldiazodicarboxylate (0.5 mL, 2.52 mmol) at 25-30° C. and stirred for further 40 h. Water was added to the reaction mixture and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was chromatographed on silica gel using a gradient of 5-15% ethyl acetate in pet ether as eluent to afford the title compound (527 mg, 76%): mp 76-78° C.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([C:20]1[N:24]=[C:23]([CH2:25][S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:22][N:21]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-]S([O-])(=S)=O.[Na+].[Na+].CCOCC>C(Cl)Cl>[C:12]([C:20]1[N:24]=[C:23]([CH2:25][S:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:6])[O:22][N:21]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(c1ccccc1)c1noc(CSc2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(c1ccccc1)c1noc(CS(=O)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
A solution of 5.5 g of m-chloroperoxybenzoic acid (85%) in 125 ml of CH2Cl2 was added dropwise at -70° C. under N2 to a solution of 7.5 g of 3-benzoyl-5-phenylthiomethyl-1,2,4-oxadiazole in 150 ml of CH2Cl2. The temperature of the reaction was maintained below -65° by controlling the rate of addition. After stirring further for 30 minutes, the reaction mixture was added directly to a separatory funnel containing 250 ml of 10% Na2S2O3 and 500 ml of Et2O. The organics were washed with saturated NaHCO3 and dried over MgSO4. Concentration gave an oil which solidified on standing. Recrystallization from acetone/hexane gave 3.7 g (44%) of needles, m.p. 79°-81°.
Reaction SMILES: Cl[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[Na+].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([O-:18])=[O:17])[CH:11]=1.CS(C)=O>O>[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[CH:7]=[O:8])(=[O:18])=[O:17])[CH:11]=1
Reactant: O=Cc1sccc1Cl
Reactant: O=S([O-])c1cccnc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1sccc1S(=O)(=O)c1cccnc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 28.6 %

Procedure:
A mixture of 3-chlorothiophene-2-carbaldehyde (0.16 g), pyridine-3-sulfinic acid sodium salt (0.30 g) and dimethyl sulfoxide (2.0 mL) was heated at 80° C. for 3 hours and then at 90° C. for 3 hours. The mixture was diluted with water, extracted with ethyl acetate and the combined organic extract was dried over magnesium sulfate. The solvent was removed under reduced pressure to afford the title compound as a grey solid (0.079 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C@@H:14]23)[CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][NH:26][CH2:27][C@@H:14]23)[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: O=Cc1cccc(Cl)c1
Product: Clc1cccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c1

Procedure:
Using 3-chlorobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 156. 1H NMR (CDCl3) δ: 7.37 (s, 1H), 7.29-7.20 (m, 2H), 6.34 (d, 1H, J=2.2 Hz), 6.24 (d, 1H, J=2.6 Hz), 4.25 (broad s, 2H), 3.67 (s, 2H), 3.57-3.50 (m, 1H), 3.42-3.31 (m, 2H), 3.20-2.85 (m, 6H), 2.60 (dd, 1H, J=12.8, 9.9 Hz), 2.15-1.97 (m, 2H). LRMS (ES)+: 386.3 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:20]2[CH:25]=[CH:24][C:23](Cl)=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)O1.Cl>O1CCOCC1>[NH:37]1[CH:36]=[C:35]([C:23]2[CH:22]=[CH:21][C:20]([C:11]3([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:25][CH:24]=2)[CH:39]=[N:38]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccncc2)(c2ccc(Cl)cc2)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: c1cc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)ccn1

Procedure:
4-(4-Chloro-phenyl)-3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-carboxylic acid tert-butyl ester was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, followed by treatment with 4M HCl in dioxane, to obtain the title compound. LCMS (PS-B4) Rt 4.28 min [M+H]+ 305. 1H NMR (Me-d3-OD) δ 2.76 (2H, br.t), 3.01 (2H, br.d), 3.24 (2H, br.t), 3.39 (2H, br.d), 7.58 (2H, d), 7.76 (2H, d), 8.17 (2H, d), 8.37 (2H, s), 8.82 (2H, d).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C(N(C(C)C)CC)(C)C.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1>CN(C)C=O>[Br:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:25][CH:26]2[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Br)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)c(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 75 °C
Yield: 57.7 %

Procedure:
A stirred solution of 2-bromo-4-fluoro-5-nitrobenzotrifluoride (1.15 g, 4.0 mmol) in dimethylformamide (15 ml) at room temperature under argon was treated with diisopropylethylamine (1.8 ml, 10 mmol) and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (0.90 g, 4.5 mmol), then heated at 75° C. for 3 hrs. The solution was concentrated under vacuum and the residue treated with 10% Na2CO3 solution (30 ml) and extracted with ethyl acetate (2×40 ml). The combined extract was washed with brine (40 ml), then dried (Na2SO4) and concentrated under vacuum to leave an orange solid which was purified by chromatography on silica gel (20 g) eluting with dichloromethane to afford the title compound as a yellow solid (1.08 g, 58%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][OH:21])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30]([O:21][CH2:20][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:4]=1[O:3][CH2:1][CH3:2])[CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[O:31]
Reactant: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1CO
Reactant: O=C=Nc1ccccc1Cl
Product: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1COC(=O)Nc1ccccc1Cl

Procedure:
Using dimethyl 2-[4-ethoxy-3-(hydroxymethyl)benzyl]-malonate and 2-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31]>>[OH:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1
Reactant: NCCCCCO
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCCCCCO)cn1
Yield: 14 %

Procedure:
As described for example 220, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (180 mg, 0.55 mmol) was converted, using 5-amino-1-pentanol instead of 3-amino-1-propanol, to the title compound (31 mg, 14%) which was obtained as a white solid. MS: m/e=396.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:16])([CH3:15])[C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C(O)C.O>[CH3:17][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([CH3:15])([CH3:16])[C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(N(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)c1ccc(C(C)(C)C(=O)O)cc1
Yield: 92 %

Procedure:
A mixture of ethyl (4-dimethylaminophenyl)-2,2-dimethylacetate (1.00 g, 4.25 mmol) and sodium hydroxide (0.85 g) in ethanol (20 mL) and water (9 mL) was heated under reflux for 18 hours. The mixture was cooled, acidified with 10% HCl, and washed with ethyl acetate. The aqueous phase was evaporated. The residue was dissolved in aqueous saturated sodium bicarbonate, and extracted with ethyl acetate. The organic phase was dried, filtered and evaporated to give (4-dimethylaminophenyl)-2,2-dimethylacetic acid as a faint red solid (0.81 g, 92%).