Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][C:7]([C:22]([NH2:24])=[O:23])=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>[Pd].CO.C(Cl)Cl>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH:8]=[C:7]([C:22]([NH2:24])=[O:23])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)C1=Cc2ccccc2-c2cc3ccc(C(N)=O)cc3n2C1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: NC(=O)C1=Cn2c(cc3ccc(C(N)=O)cc32)-c2ccccc2C1
Reaction time: 8 h

Procedure:
10% Palladium on carbon (77 mg, 0.07 mnol) was added to a solution of 7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide, 13-cyclohexyl-N10-[(dimethylamino)sulfonyl]-3-methoxy-N6-(2-methoxyethyl)-N6-methyl- (65 mg, 0.11 mmol) in MeOH/CH2Cl2 (1:1, 4 mL) and the reaction mixture was vacuum flushed with nitrogen (3×) and then with hydrogen (3×). The reaction was stirred under a balloon of hydrogen overnight, filtered through a pad of celite and concentrated to yield 5H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide, 13-cyclohexyl-N10-[(dimethylamino)sulfonyl]-6,7-dihydro-3-methoxy-N6-(2-methoxyethyl)-N6-methyl- (60 mg, 0.10 mmol, 92%) as a light yellow solid. Mixture of atrope diastereomers. 1HNMR (300 MHz, CD3OD) δ 8.10-7.92 (m, 1H), 7.91-7.83 (m, 1H), 7.62-7.51 (m, 1H), 7.42-7.33 (m, 1H), 7.10-6.84 (m, 2H), 4.67-4.44 (m, 1H), 3.93-3.86 (m, 3H), 3.84-3.21 (m, 1H), 3.06-2.86 (m, 8H), 2.83-2.64 (m, 2H), 2.18-1.19 (m, 10H). LCMS: m/e 611 (M+H)+, ret time 2.12 min, column C, 2 minute gradient.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:12])=[CH:5][N:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2.[N+:13]([C:16]1[CH:17]=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>>[CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([S:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)(=[O:23])=[O:24])[N:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: COc1c(C)cn2ccccc12
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Product: COc1c(C)c(S(=O)(=O)c2cccc([N+](=O)[O-])c2)n2ccccc12
Yield: 98 %

Procedure:
This compound is prepared according to the protocol described for the example above, by sulphonylation of 1 g (6.2 mmol) of 1-methoxy-2-methylindolizine with 3-nitrobenzenesulphonyl chloride. 540 mg of a yellow oil are obtained.
Reaction SMILES: C([O:8][N:9]([CH2:13][C:14]1[CH:44]=[CH:43][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([O:35]CC3C=CC=CC=3)[C:32]([NH2:34])=[O:33])=[CH:26][CH:25]=2)=[CH:16][CH:15]=1)[C:10]([NH2:12])=[O:11])C1C=CC=CC=1.[H][H]>CN(C)C=O.C(O)C.[C].[Pd]>[OH:35][N:31]([CH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:17]2[CH:43]=[CH:44][C:14]([CH2:13][N:9]([OH:8])[C:10]([NH2:12])=[O:11])=[CH:15][CH:16]=2)=[CH:25][CH:26]=1)[C:32]([NH2:34])=[O:33]
Reactant: NC(=O)N(Cc1ccc(OCCCCOc2ccc(CN(OCc3ccccc3)C(N)=O)cc2)cc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: NC(=O)N(O)Cc1ccc(OCCCCOc2ccc(CN(O)C(N)=O)cc2)cc1
Yield: 62 %

Procedure:
1,4-Bis[4-[(1-benzyloxyureido)methyl]phenoxy]butane (1.94 g) was dissolved in 45 ml of dimethylformamide-ethanol (8:1), mixed with 0.29 g of 10% palladium carbon and then the mixture was stirred for 22 hours at room temperature in an atmosphere of hydrogen. The catalyst was removed by filtration using Celite, and the solvent was evaporated under a reduced pressure to obtain 0.84 g of 1,4-bis[4-[(1-hydroxyureido)methyl]phenoxy]butane.
Reaction SMILES: [CH3:1][N:2]([CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18](=[O:35])[C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[CH:21][CH:20]=2)[CH2:10][CH2:9][CH2:8]1)[CH2:3][CH:4]1[CH2:6][O:5]1.FC(F)(F)C(O)=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][N:2]([CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18](=[O:35])[C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[CH:23][CH:24]=2)[CH2:10][CH2:9][CH2:8]1)[CH2:3][CH:4]([OH:39])[CH2:6][OH:5]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CC3CO3)c3ccccc32)cc1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CC(O)CO)c3ccccc32)cc1
Reaction time: 4 h

Procedure:
To 5-(N-methyl-N-oxiranylmethylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.62 g) is added trifluoroacetic acid (1.22 ml) under ice-cooling and the mixture is stirred for 4 hours. The reaction solution is neutralized with aqueous sodium carbonate solution, and extracted three times with dichloromethane. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is dissolved in methanol (10 ml). Thereto is added 40% aqueous sodium hydroxide solution (10 ml) and water (10 ml), and the mixture is stirred at room temperature overnight. Methanol is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30:1) to give 5-[N-methyl-N-(2,3-dihydroxypropyl)amino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.23 g) as colorless amorphous.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1.[OH:26][C:27]1([CH3:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[OH:26][C:27]1([CH3:33])[CH2:32][CH2:31][N:30]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:13][C:12]3=[O:25])=[CH:5][CH:4]=2)[CH2:29][CH2:28]1
Reactant: CC1(O)CCNCC1
Reactant: O=c1cc(OCc2ccccn2)ccn1CCc1ccc(CBr)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(O)CCN(Cc2ccc(CCn3ccc(OCc4ccccn4)cc3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 140 mg (0.26 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 3.3a) in 1.5 mL DMF is added 61 mg (0.53 mmol) 4-hydroxy-4-methylpiperidine and 0.12 mL (0.66 mmol) N-ethyl-diisopropylamine at RT. The reaction mixture is stirred 2 h at RT and is directly transferred to a reverse HPLC for purification (Waters symmetry, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>[O-2].[O-2].[Hf+4]>[C:9](=[O:10])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Hf+4]
Agent: [O-2]
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
Example 1 was repeated at 140° C. with 14.1 g of a powdered hafnium dioxide from the Aldrich company. After 2 h reaction time, the phenol conversion was 3.7%, whereby 3.5 g phenyl chloroformate and 3.3 g diphenyl carbonate were formed. The selectivity to carbonate esters was ca. 97%.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[C:3]([NH:5][C:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)=[O:4].[H-].[Na+].I[CH3:16].O>CN(C)C=O>[CH3:16][N:5]([C:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)[C:3](=[O:4])[CH:2]([CH3:12])[CH3:1]
Reactant: CI
Reactant: CC(C)C(=O)Nc1ccn(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(=O)N(C)c1ccn(C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Methyl-N-(1-methylpyrrol-3-yl)propanamide (2.50 g, 0.015 mol) in dry dimethylformamide (10 ml) was cooled to below 0° C. and stirred under nitrogen during the addition of 50% sodium hydride/oil (0.73 g, 0.0152 mol). After the addition, the mixture was stirred at 0° C. for 30 minutes and then brought to 15° C. when iodomethane (4.30 g, 0.0302 mol) was added. The mixture was stirred at room temperature overnight and then poured into water (200 ml) and the mixture extracted with ether (4 × 50 ml). The combined extracts were washed with water (3 × 50 ml) and dried over magnesium sulphate. The solvent was removed in vacuo to leave a solid which separated from pentane at -10° C as white flakes (2.11 g, 78%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[N+:11]([O-])([OH:13])=[O:12]>>[N+:11]([C:5]1[N:1]=[C:2]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[NH:3][CH:4]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ncc[nH]1
Product: CCOC(=O)c1nc([N+](=O)[O-])c[nH]1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
While cooling on ice, 16.08 g (114.7 mmol) of ethyl imidazole-2-carboxylate are dissolved in 71.7 ml of concentrated sulpfuric acid. 71.7 ml of 100% fuming nitric acid are then added dropwise. The reaction solution is stirred at 50 to 60° C. for 3 h and, after cooling, poured onto 800 ml of an ice/water mixture. The precipitated crystals are collected by suction filtration and washed with 1500 ml of ice-water.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C1COCC1>[CH2:12]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: c1ccsc1
Reactant: CCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCc1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of thiophene (15 g, 0.178 mole) in 200 mL of dry THF at −78° C., n-BuLi (103 mL, 0.165 mol, 1.6M hexane) was added. The reaction mixture was warmed to RT and stirred for 1 h. After the mixture was cooled to −78° C., 23.15 mL (0.165 mole) of 1-bromohexane was added. The solution was warmed from −78° C. to RT and was stirred overnight. At the end of the reaction, the mixture was poured into ice water, the aqueous layer was extracted with ether, and the organic layer was dried over anhydrous MgSO4. The solvent was removed by rotary evaporation. The residue was redistilled under vacuum to get a colorless liquid (yield=75%). 1H-NMR (300 MHz, CDCl3) δ 7.12 (dd, 1H), 6.92-6.97 (m, 1H), 6.8 (dd, 1H). 2.8 (t, 2H), 1.6-1.9 (q, 2H), 1.30-1.49 (m, 6H), 0.82 (t, 3H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)(=O)=O.[NH2:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1>CN(C)P(N(C)C)(N(C)C)=O>[CH:8]1([CH2:7][CH2:6][NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CS(=O)(=O)OCCC1CCCC1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCC2CCCC2)cc1

Procedure:
A solution of 5 g. of 2-cyclopentylethyl methanesulfonate and 8.59 g. of ethyl p-aminobenzoate in 30 ml. of hexamethylphosphoramide is stirred at 110° C. under argon atmosphere for 18 hours. The cooled solution is diluted with 30 ml. of water and the resulting tan solid is collected by filtration. Recrystallization from ethanol-water furnishes ethyl p-[2-(cyclopentyl)ethyl]aminobenzoate as off-white crystals.
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[C:15]2[CH:16]=[N:17][S:18][C:14]=2[CH:13]=[CH:12][C:11]=1[C:19]([OH:21])=O.CCN(C(C)C)C(C)C.[CH:31]([O:33][CH2:34][CH2:35][O:36][NH2:37])=[CH2:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1>[CH:31]([O:33][CH2:34][CH2:35][O:36][NH:37][C:19]([C:11]1[CH:12]=[CH:13][C:14]2[S:18][N:17]=[CH:16][C:15]=2[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21])=[CH2:32]
Reactant: C=COCCON
Reactant: O=C(O)c1ccc2sncc2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)c1ccc2sncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
To a solution of 4-(2-fluoro-4-iodo-phenylamino)-benzo[d]isothiazole-5-carboxylic acid (240 mg, 0.58 mmol) in THF (6 mL) was added DIPEA (396 μL, 2.34 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (119 mg, 1.15 mmol), HOBt (156 mg, 1.15 mmol) and EDCI (221 mg, 1.15 mmol) before the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the resultant residue was partitioned between ethyl acetate and water. The organic extract was washed with aqueous saturated sodium bicarbonate solution then water, dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-10% methanol in DCM) to yield the title compound (258 mg, 89%). LCMS (Method B): RT=3.83 min, [M+H]+=500.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]2)[C:5]1=[O:24].[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>ClCCl.C(N(CC)CC)C>[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:1][CH2:2][CH2:3][N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]3([C:16]4=[CH:17][C:18]5[O:22][CH2:21][O:20][C:19]=5[CH:23]=[C:15]4[O:14][CH2:13]3)[C:5]2=[O:24])=[O:34])=[CH:28][CH:27]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: NCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21)Nc1ccc(F)cc1
Reaction time: 16 h
Yield: 77.4 %

Procedure:
To a mixture of 1′-(2-aminoethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.15 mmol) and triethylamine (0.01 mmol) in anhydrous dichloromethane was added 1-fluoro-4-isocyanatobenzene (0.14 mmol) at ambient temperature. The mixture was stirred for 16 h, diluted with of dichloromethane (5.00 mL), washed with 10% HCl solution and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to dryness to give the title compound (0.05 g) in 82% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.35-7.25 (m, 3H), 7.19 (d, 1H), 7.11 (d, 1H), 7.06-6.91 (m, 3H), 6.67 (s, 1H), 6.52 (t, 1H), 5.94-5.84 (ABq, 2H), 4.74 (d, 1H), 4.61 (d, 1H), 3.91-3.69 (m, 2H), 3.49-3.34 (m, 2H); MS (ES+) m/z 462 (M+1), 484 (M+23).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][C:18](=[O:24])[NH:19]2.N1CCCCC1>C(O)C>[CH3:13][C:7]1[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:10][NH:9][C:8]=1[CH:11]=[C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[CH:23][C:15]=2[CH3:14])[NH:19][C:18]1=[O:24]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: Cc1cccc2c1CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cccc2c1C(=Cc1[nH]cc(CCC(=O)O)c1C)C(=O)N2
Yield: 51.9 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90 mg), 74 mg 4-methyl-2-oxindole, and 75 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 80 mg (52%) of the title compound as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=O.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccncc1
Reactant: CCOC(=O)c1cccc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(Cc1ccncc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a solution of ethyl 3-fluorobenzoate (2.0 g, 11.9 mmol) and 4-methylpyridine (1.1 mL, 1.0 g, 10.8 mmol) in THF (9 mL) at 0° C. under nitrogen atmosphere was added dropwise lithium bis(trimethylsilyl)amide (23.8 mL, 1.0M in hexane, 23.8 mmol) During the addition a precipitate was formed and the suspension was stirred at room temperature overnight. The reaction was diluted with hexane (40 mL) and filtered. The solid was partitioned between ethyl acetate and a saturated solution of ammonium chloride. The organic phase was dried (MgSO4) and evaporated under reduced pressure to give the title compound as a yellow solid (2.09 g, 82%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH:19]1[CH2:24][N:23]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:22](=[O:30])[CH2:21][CH2:20]1.C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:49]=[N+:50]=[N-:51])(=O)=O)(C)C.CC(O)=O>C1COCC1>[N:49]([CH:21]1[CH2:20][CH:19]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=2[F:11])[CH2:24][N:23]([CH2:25][C:26]([F:29])([F:27])[F:28])[C:22]1=[O:30])=[N+:50]=[N-:51]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: O=C1CCC(c2cccc(F)c2F)CN1CC(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: [N-]=[N+]=NC1CC(c2cccc(F)c2F)CN(CC(F)(F)F)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 26.3 mL, 26.3 mmol) in THF (120 mL) at −78° C. was added a cold (−78° C.) solution of 5-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)piperidin-2-one (6.42 g, 21.9 mmol) in THF (100 mL) dropwise, keeping the internal temperature of the reaction mixture below −65° C. The resulting mixture was stirred at −78° C. for 30 min, then a cold (−78° C.) solution of 2,4,6-triisopropylbenzenesulfonyl azide (Harmon et al. (1973) J. Org. Chem. 38, 11-16) (8.81 g, 28.5 mmol) in THF (80 mL) was added dropwise, keeping the internal temperature of the reaction mixture below −65° C. The reaction mixture was stirred at −78° C. for 45 min, then AcOH (6.0 mL, 105 mmol) was added. The resulting mixture was allowed to warm slowly to ambient temperature and was partitioned between saturated aqueous sodium bicarbonate (1 L) and CH2Cl2 (1.5 L). The organic layer was washed with brine, then dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 40:60, to give the title compound. MS: m/z=334.9 (M+1).
Reaction SMILES: C1C=C(C(O)=[O:8])C(C(OO)=O)=CC=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:30][CH2:29]1.[OH-].[Na+]>CCOCC.CO>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N+:22]([O-:8])=[CH:21][CH:20]=[C:19]2[CH2:26][CH2:27][CH:28]1[CH2:29][CH2:30][N:31]([C:34](=[O:41])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:32][CH2:33]1
Reactant: O=C(O)c1ccccc1C(=O)OO
Reactant: COc1ccc2nccc(CCC3CCN(C(=O)c4ccccc4)CC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: COc1ccc2c(c1)c(CCC1CCN(C(=O)c3ccccc3)CC1)cc[n+]2[O-]
Temperature: 10 °C
Reaction time: 4 h

Procedure:
269 ml of a 0.09M solution of monoperphthalic acid in ether (prepared according VOGEL--Textbook of Practical Organic Chemistry, 1978, 307) are added rapidly to a solution of 7.9 g of 6-methoxy-4-[2-(1-benzoyl-4-piperidyl)-ethyl]-quinoline in 45 ml of methanol, stirred and cooled to 10° C. After four hours at the ambient temperature, a further 20 ml of the same monoperphthalic acid solution are added, and the stirring is then maintained for 15 hours. The reaction mixture is then made alkaline with 100 ml of a 0.7N aqueous solution of sodium hydroxide. The organic phase, separated, is again washed with 100 ml of a 0.5N solution of sodium hydroxide, dried, then concentrated. The residue obtained, after recrystallization from cyclohexane, gives 5.1 g of 6-methoxy-4-[2-(1-benzoyl-4-piperidyl)-ethyl]quinoline-N-oxide melting at 138° C.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:7][C:6]=1[CH3:28])C.[OH-].[Na+]>C(O)C.O>[Cl:27][C:22]1[CH:21]=[C:20]([C:14]2([C:16]([F:18])([F:17])[F:19])[O:13][N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:29])=[O:3])=[C:6]([CH3:28])[CH:7]=3)[CH2:15]2)[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
In a solution of 10.79 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoic acid ethyl ester in 50 ml of ethanol and 10 ml of water, a solution of 2.0 g of sodium hydroxide in 10 ml of water was slowly added with stirring at room temperature. Then, the reaction mixture was stirred at 80° C. for 2 hours, after the completion of the reaction, ethanol was distilled off under reduced pressure. The residue was adjusted to pH 1-2 with concentrated hydrochloric acid with stirring at 50° C., then continued to stir at the same temperature for 1 hour and then at 5° C. for 1 hour. Precipitated crystal was filtered off, washed with water and dried to obtain 9.36 g of the aimed product as white crystal.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][CH:10]([CH3:13])[C:11]#[CH:12]>CCN(CC)CC.CCOCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][CH:10]([CH3:13])[C:11]#[C:12][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccccc1I
Reactant: C#CC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)C#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-iodoaniline (Aldrich, 5.0 g, 22.8 mmol) in Et3N (50 ml) in a re-sealable pressure tube was added copper (I) iodide (22 mg, 0.114 mmol), Pd(PPh3)2Cl2 (80 mg, 0.114 mmol), and 3-methylbut-1-yne (Alfa Aesar, 3.1 g, 45.7 mmol). The mixture was stirred at room temperature for 20 h and was diluted with Et2O, filtered through Celite, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 30% Et2O-hexanes to yield 2-(3-methylbut-1-ynyl)aniline (Compound 37) as orange oil.