Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([CH:11]=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.Cl.[NH2:20][OH:21]>C1COCC1>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8](/[CH:11]=[N:20]/[OH:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(C=O)ccc(C#N)c1Cl
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1c(/C=N/O)ccc(C#N)c1Cl
Temperature: 70 °C
Reaction time: 4 h

Procedure:
2-chloro-4-formyl-3-methylbenzonitrile (5.0 g, 27.8 mmol) was dissolved in dry THF (60 ml). Pyridine (6.7 ml, 84.0 mmol) and hydroxylamine hydrochloride (3.87 g, 55.7 mmol) were added to the solution. The mixture was heated to 70° C. and stirred for 4 h. THF was evaporated and ice water (50 ml) was added. The mixture was stirred for 1 h and the precipitate was filtered off and washed twice with cold water. After drying (5.3 g) of the title compound was obtained. 1H-NMR (400 MHz; d6-DMSO): δ 2.48 (s, 3H), 7.79 (m, 2H), 8.45 (s, 1H), 11.93 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[CH:15]=[C:16]([CH3:18])[CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34].[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:15]=[C:16]([CH3:18])[CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34]
Reactant: CCOC(=O)CCc1cc(C)cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(COc3cc(C)cc(CCC(=O)O)c3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
To a solution of ethyl 3-(3-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-methylphenyl)propanoate (400 mg) in methanol (4.0 ml) and THF (8.0 mL) was added 1N aqueous sodium hydroxide solution (8.0 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid was added to the residue to adjust to pH<4. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (249 mg) as a pale-yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[CH2:9][C@H:8]2[C:10]([O:12]CC)=[O:11])=[CH:3][CH:2]=1.[OH-].[Li+]>C1COCC1.O.Cl>[N:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[CH2:9][C@H:8]2[C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccncc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C[C@H]1c1ccncc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl trans-2-pyridin-4-ylcyclopropanecarboxylate (0.918 g, 4.80 mmol) in THF (10 mL) and water (10 mL) was added lithium hydroxide (0.345 g, 14.4 mmol). The reaction mixture was allowed to stir at rt for 24 h and then diluted with 2N HCl (10 mL). The mixture was concentrated to give trans-2-pyridin-4-ylcyclopropanecarboxylic acid which was used without purification in the next step. LCMS: (FA) ES+ 164.0, ES-162.1.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:13])[CH3:2].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Br:20]>>[Br:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:13]
Reactant: BrCCCCCBr
Reactant: CCC1C(=O)Nc2cc(F)ccc21
Product: CCC1(CCCCCBr)C(=O)Nc2cc(F)ccc21

Procedure:
The title compound is prepared according to process E starting from 3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 1,5-dibromopentane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][NH2:26]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:26][O:25][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][O:19]1)=[O:14]
Reactant: NOC1CCCCO1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NOC1CCCCO1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-(tetrahydro-2H-pyran-2-yloxy)isonicotin-amide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.4 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.52 mmol of O-(tetrahydro-pyran-2-yl)-hydroxylamine. LC/MS [9.07 min; 458 (M+1)]
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH:3]=1.[CH3:16]CCCCCC.C(OCC)(=O)C>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:16])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH:3]=1
Reactant: CCCCCCC
Reactant: Cc1ccccc1-c1cc(Cl)nnc1N
Solvent: CCOC(C)=O
Product: CNc1nnc(Cl)cc1-c1ccccc1C
Yield: 17 %

Procedure:
The title compound was prepared in analogy to example 1, intermediate a, from 6-chloro-4-o-tolyl-pyridazin-3-ylamine and using a gradient of n-heptane:ethyl acetate (100:0 to 0:70) eluant for the chromatographic purification. A second purification step on a 20 g column using an MPLC (Flashmaster) system (gradient of n-heptane:ethyl acetate (100:0 to 40:60)) furnished the title compound as a colorless solid (17%). MS (ESI+): m/z=234.080 ([M+H]+).
Reaction SMILES: [CH:1]1[C:6](Cl)=[CH:5][C:4]2[NH:8][C:9]([O:11][C:3]=2[CH:2]=1)=[O:10].[C:12]([O:16][C:17]([NH:19][CH2:20][CH:21]=[CH2:22])=[O:18])([CH3:15])([CH3:14])[CH3:13].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C(#N)C>[C:12]([O:16][C:17]([NH:19][CH2:20][CH:21]=[CH:22][C:6]1[CH:1]=[CH:2][C:3]2[O:11][C:9](=[O:10])[NH:8][C:4]=2[CH:5]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: C=CCNC(=O)OC(C)(C)C
Reactant: O=c1[nH]c2cc(Cl)ccc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC=Cc1ccc2oc(=O)[nH]c2c1
Temperature: -78 °C
Reaction time: 60 h

Procedure:
A mixture of chlorzoxazone, 3-(t-butoxycarbonylamino)-1-propene, palladium diacetate, tritolylphosphine, and acetonitrile is cooled to −78° C., degassed, and sealed in a reaction tube. The mixture is kept at 50° C. with stirring for 60 hours, then cooled and opened and the acetonitrile removed under vacuum. The residue is dissolved in ethyl acetate and washed successively with 5% aqueous NaHCO3 and brine. After drying over Mg2SO4, the mixture is filtered and evaporated. Silica gel chromatography gives 5-(3-(t-butoxycarbonylamino)-1-propenyl)-2-benzoxazolone.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1.[CH3:27][CH:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>>[O:23]=[C:21]1[NH:20][C:19]2[CH:24]=[CH:25][C:16]([NH:15][C:14]3[C:9]4[C:6]5[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][S:30]([CH:28]([CH3:29])[CH3:27])(=[O:32])=[O:31])[CH2:4][C:5]=5[S:26][C:10]=4[N:11]=[CH:12][N:13]=3)=[CH:17][C:18]=2[S:22]1
Reactant: NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Reactant: CC(C)S(=O)(=O)Cl
Product: CC(C)S(=O)(=O)NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1

Procedure:
75 mg (196 μmol) (RS)-6-{[7-(aminomethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]amino}-1,3-benzothiazol-2(3H)-one (prepared according to example 20), were transformed in analogy to example 21 using propane-2-sulfonyl chloride to give after working up and purification 5.7 mg (6%) of the title compound.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:27])[CH2:7][C:8]1[N:21]=[C:20]([N:22]([CH:24]2[CH2:26][CH2:25]2)[CH3:23])[C:11]2[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]=3[S:19][C:10]=2[N:9]=1)C.O>C1COCC1.Cl>[CH:24]1([N:22]([CH3:23])[C:20]2[C:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]=4[S:19][C:10]=3[N:9]=[C:8]([CH2:7][C:6]([OH:27])=[O:5])[N:21]=2)[CH2:25][CH2:26]1
Reactant: CCOC(=O)Cc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCCC3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1nc(CC(=O)O)nc2sc3c(c12)CCCCC3)C1CC1
Yield: 90.5 %

Procedure:
The LiOH (0.615 g, 0.0150 mol) was added to a solution of [4-(cyclopropyl-methyl-amino)-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benz[a]azulen-2-yl]-acetic acid ethyl ester (1.8 g, 0.0050 mol) in 20 ml of (5:1) THF:water, and the mixture was stirred for 18 h at ambient temperature. The solvent was reduced under vacuum and the residue was diluted with 50 ml dilute aqueous HCl. The mixture was extracted with dichloromethane (50 ml×3) and the combined organic phase was separated, dried over Na2SO4 and concentrated under vacuum. The crude was purified by chromatography on silica gel using 2% MeOH-DCM to give [4-(cyclopropyl-methyl-amino)-6,7,8,9-tetrahydro-5H-10-thia-1,3-diazabenz[a]azulen-2-yl]-acetic acid (1.5 g, 94%) as pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 15.52 (brs, 1H), 3.96 (s, 2H), 3.09 (s, 3H), 2.85-2.98 (m, 4H), 2.72-2.80 (m, 1H), 1.85-1.95 (m, 2H), 1.68-1.78 (m, 2H), 1.85-1.67 (m, 2H), 0.88-0.98 (m, 2H), 0.52-0.67 (m, 2H); LC-MS: [M+H]=332.2 m/z.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][O:26]C1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:25][O:26][C:5]1[CH:6]=[C:1]([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Product: CCOC(=O)c1c(NS(=O)(=O)c2cccc(OC)c2)sc2c1CCCC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxlyate and 3-methoxybenzenesulphonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[N:1]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ccccn1
Solvent: CCO
Product: CCOC(=O)c1cn2ccccc2n1
Yield: 62.8 %

Procedure:
A solution of 2-amino-pyridine (2 g, 21 mmol) and ethyl bromopyruvate (4.14 g, 21 mmol) in ethanol (31 mL) was stirred under reflux for 24 h. The solvent was evaporated, and the residue was dissolved in a minimum volume of water. The solution was neutralized (pH==8) with saturated NaHCO3. The aqueous layer was extracted with AcOEt and the organic layer was washed with saturated NaCl. The solvent was removed under pressure to afford 2.51 g of ethyl imidazo[1,2-a]pyridine-2-carboxylate (Yield: 62%) as an orange oil which can be used without further purification.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:7][CH:8]=1.CN(CCN(C)C)C.[Li]CCCC.[I:31]I>C1COCC1>[I:31][C:5]1[C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:13])[CH3:14])=[N:7][CH:8]=[C:3]([C:2]([F:16])([F:1])[F:17])[CH:4]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cn1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncc(C(F)(F)F)cc1I
Temperature: -75 °C
Reaction time: 2 h

Procedure:
N-(5-(trifluoromethyl)pyridin-2-yl)pivalamide (22 g, 89.4 mmole) and TMEDA (33.3 ml, 223.4 mmole) were dissolved in THF (400 ml) under nitrogen and n-BuLi (139.6 ml, 223.4 mmole; 1.6 M solution in n-hexane) was added dropwise at −75° C. The mixture was stirred for 2 hours at −75° C. While maintaining this temperature a solution of iodine (56.7 g, 223.4 mmole) in THF (280 ml) was added dropwise and the reaction mixture was stirred for 2 hours. The reaction mixture was heated to 0° C. and quenched with saturated aqueous sodium thiosulfate solution. The aqueous phase was extracted with DCM (2×150 ml) and the combined organic phases were dried over MgSO4. After filtering off the drying agent and removing the solvent on a rotary evaporator the residue was purified by means of column chromatography (ether: cyclohexane=1:1) and N-(3-iodo-5-(trifluoromethyl)pyridin-2-yl)pivalamide (13 g, 39.1%) was thereby obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([S:30][CH3:31])[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:41])C=1>ClCCl.CO>[C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([S:30]([CH3:31])=[O:41])[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of {4-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 8 supra) (800 mg, 1.8 mmol) in a mixture of dichloromethane and methanol (200 mL, 1:1) was added m-CPBA (710 mg, 1.8 mmol) slowly. The reaction mixture was stirred at room temperature for 25 minutes. The solvent was then removed under reduced pressure and the residue was purified by column chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1) to afford {4-[3-(2-Methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 440 mg, 53.1%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][C:14]12[CH2:21][CH2:20][CH2:19][N:18]1[CH2:17][CH2:16][CH2:15]2>>[N:18]12[CH2:19][CH2:20][CH2:21][C:14]1([CH2:13][CH2:12][NH:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH2:15][CH2:16][CH2:17]2
Reactant: NCCC12CCCN1CCC2
Reactant: O=[N+]([O-])c1ccccc1Cl
Product: O=[N+]([O-])c1ccccc1NCCC12CCCN1CCC2

Procedure:
The procedures described in Example 12 were repeated except that 1-chloro-2-nitrobenzene (2.04 g, 12.9 mmol) and 5-(2-aminoethyl)-1-azabicyclo[3.3.0]octane (4.00 g, 25.9 mmol) were employed. In this case, the desired compound was obtained as a orange liquid (3.32 g, 98.54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[C:26](Cl)=[O:27]>ClCCl>[C:9]([C:3]1[CH:4]=[C:5]([NH:8][C:26](=[O:27])[C:25]2[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:23]([O:22][CH3:21])[CH:24]=2)[CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:11])[CH3:10]
Reactant: CC(=O)c1cc(N)ccc1Cl
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(OC)cc(C(=O)Nc2ccc(Cl)c(C(C)=O)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a magnetically stirred solution of 2′-chloro-5′-amino-acetophenone (0.72 g, 4.2 mmol) in 20 ml of dichloromethane was added diisopropylethylamine (2.2 ml, 12.6 mmol). 3,5-dimethoxybenzoyl chloride (1.39 g, 6.9 mmol) in a single portion. The reaction was stirred for 2 h at room temperature, and a second portion of 3,5-dimethoxybenzoyl chloride (1.26 g, 6.3 mmol) was added, followed by diisopropylethylamine (1.0 ml, 5.7 mmol). The resulting solution was stirred an additional 3 h, and then quenched by the addition of 30 ml 1N HCl. The layers were separated and the aqueous layer was extracted with EtOAc (3×30 ml). The combined organics were washed with saturated NaHCO3 (1×20 ml), dried with solid anhydrous MgSO4, then concentrated. The crude product was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (0:1 to 2:5) to afford the desired N-(3-acetyl-4-chlorophenyl)-3,5-dimethoxybenzamide.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:42]/[CH:43]=[CH:44]\[C:45]([CH3:55])([O:47][Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50])[CH3:46]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:42]/[CH:43]=[CH:44]\[C:45]([CH3:55])([O:47][Si:48]([CH2:51][CH3:52])([CH2:53][CH3:54])[CH2:49][CH3:50])[CH3:46])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[Si](CC)(CC)OC(C)(C)/C=C\CBr
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)/C=C\CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 85.2 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5(10 μl) and (Z)-1-bromo-4-methyl-4-triethylsilyloxy-2-pentene (125 mg, 0.428 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=30:1, developed once) to give the title compound as a colorless oil (70.3 mg, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([Cl:10])[CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([Cl:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1Cl
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1cc(Br)ccc1CN1CCCCC1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To a pre-stirred solution of 4-bromo-2-chlorobenzaldehyde (1.01 g, 4.6 mmol) and piperidine (500 μL, 5.0 mmol) in DCM (20 mL) at 0° C. was added sodium triacetoxyborohydride (1.46 g, 6.9 mmol) in portions. The reaction mixture was allowed to warm to ambient temperature and then partitioned between water (50 mL) and dichloromethane (50 mL). The organic phase was separated, washed with saturated aqueous sodium carbonate (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resultant residue was loaded onto a 20 g SCX-2 cartridge which was washed with methanol then 2N ammonia in methanol. Concentration of the combined basic fractions in vacuo afforded the title compound as a colourless oil (1.15 g, 87%). 1H NMR (CDCl3, 400 MHz): 7.50-7.48 (m, 1H); 7.40-7.33 (m, 2H); 3.50 (s, 2H); 2.46-2.38 (m, 4H); 1.62-1.53 (m, 4H); 1.49-1.40 (m, 2H). LCMS (Method B): RT=2.03 min, M+H+=288.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:19]>CN(C=O)C>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18](=[O:19])[CH2:17][N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc([N+](=O)[O-])cn1CC(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of ethyl 4-nitro-1H-pyrrole-2-carboxylate (884 mg, 4.8 mmol) in DMF (11 ml) was added NaH (60% dispersion in mineral oil, 190 mg, 4.8 mmol) at 0° C. After 5 min the reaction mixture was added to a solution of 2-bromo-1-(4-methoxy-phenyl)-ethanone (1 g, 4.4 mmol) at 0° C. and the resultant mixture was allowed to warm to room temperature. After one hour the LCMS analysis showed the presence of the desired product and the complete consumption of the bromo-ketone stating material was confirmed by TLC (EtOAc/Hexanes 1:1). An aqueous solution of HCl (1M) was then added until a white precipitate appeared. Water was added and the white solid filtrated, rinsed with water and dried in vacuo to give ethyl 1-[2-(4-methoxyphenyl)-2-oxoethyl]-4-nitro-1H-pyrrole-2-carboxylate as a white solid (1.32 g, yield 83%). 1H-NMR (400 MHz, CDCl3): δ 1.29 (t, 3H, J 7.1 Hz), 3.90 (s, 3H), 4.22 (q, 2H, J 7.2 Hz), 5.77 (s, 2H), 6.98-7.20 (m, 2H), 7.50 (d, 1H, J 1.8 Hz), 7.63 (d, 1H, J 1.8 Hz), 7.95-8.00 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([I:19])[CH:17]=2)[N:12]=[CH:11][C:10]=1[C:20]#[N:21].[H-].[K+]>C1COCC1>[I:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:20]#[N:21])=[C:9]2[O:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1cnc2ccc(I)cc2c1OC1CCOCC1

Procedure:
Similar procedure as described in example 28a was used, starting from 4-hydroxy tetrahydropyran, 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c) and potassium hydride in a solvent system of THF to give 6-iodo-4-(tetrahydro-pyran-4-yloxy)-quinoline-3-carbonitrile. LC-MS m/e 381 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.N1CCCCC1>C(O)C>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[CH:13][CH:14]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(C=C2C(=O)Nc3ccccc32)cc1
Yield: 70.4 %

Procedure:
2.0 g of oxindole was dissolved in 40 ml of ethanol, and 2.0 g of p-anisaldehyde was added thereto at room temperature. Subsequently, 1.5 ml of piperidine was added, and the mixture was refluxed with heat for 13 hours. After completion of reaction, the reaction mixture was cooled. Crystals that precipitated were collected by filtration. The resultant crude product was washed with methanol, to thereby obtain 2.6 g (yield 71%) of the title compound in the form of yellow crystals. The melting point and elementary analysis data are shown in Table 13, and NMR and MS spectrum data are shown in Table 14.
Reaction SMILES: [ClH:1].[CH2:2]([N:6]1[CH2:11][CH2:10][C@@H:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C@H:8]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[CH2:7]1)[CH2:3][CH2:4][CH3:5].[Br:30]Br.[OH-].[Na+]>C(Cl)Cl>[ClH:1].[Br:30][C:26]1[CH:25]=[C:24]2[O:27][CH2:28][O:29][C:23]2=[CH:22][C:21]=1[O:20][CH2:19][C@H:8]1[C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[CH2:10][CH2:11][N:6]([CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7]1
Reactant: BrBr
Reactant: CCCCN1CC[C@@H](c2ccc(F)cc2)[C@H](COc2ccc3c(c2)OCO3)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCN1CC[C@@H](c2ccc(F)cc2)[C@H](COc2cc3c(cc2Br)OCO3)C1

Procedure:
(-)-trans-1-butyl-4-(4-fluorophenyI)-3-(3,4-methylenedioxyphenoxymethyl)-piperidine hydrochloride (1 g) was dissolved in CH2Cl2 (50 ml). Bromine (0.124 ml) was added dropwise at R.T. After stirring for 2 h aqueous NaOH was added, and the CH2Cl2 layer was isolated, dried over Na2SO4, filtered and evaporated to dryness. The residue was dissolved in acetone, excess conc. HCl was added and the above mentioned bromo compound was precipitated by addition of ether. M.p. 116° C.