Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH:14]([CH:18]([OH:28])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1)[C:15]([OH:17])=[O:16].[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.[Pd]>[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][CH:18]([OH:28])[CH:14]([CH2:13][CH2:12][N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])[C:15]([OH:17])=[O:16])=[CH:22][CH:23]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: O=C(O)C(CCN1C(=O)c2ccccc2C1=O)C(O)CCc1ccc(I)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)C(CCN1C(=O)c2ccccc2C1=O)C(O)CCc1ccc(-c2cc3ccccc3o2)cc1
Temperature: 150 °C
Yield: 12.4 %

Procedure:
A solution of 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(4-iodophenyl) pentanoic acid (25 mg, 50 μmol) in dimethylformamide (1.0 mL) was added in one portion to a mixture of -benzofuran-2-ylboronic acid (11 mg, 70 μmol) and fibrecat FC1001 (2.71% Pd; 20 mg, 5.0 μmol) in a Smith microwave reaction vial. Cesium carbonate (41.0 mg, 125 μmol) was added and the vial capped. The crude reaction mixture was heated at 150° C. for 15 min using a Smith Synthesiser microwave reactor. On cooling the vial was opened and the contents partitioned between methanol/dichloromethane (10:90; 10 mL) and aqueous hydrochloric acid solution (2.0 M; 10 mL). The organic phase was separated and filtered through a Whatman 5 μM filter tube, washing the filter cake with methanol (2×1 mL). The filtrate was evaporated and the resulting residue was purified using mass directed auto-preparative reverse phase HPLC to give the title compound (3.0 mg, 12%) as a pale yellow solid. LC/MS: 3.69 min; z/e 484, calcd (M+1) 484. 1H NMR (400 MHz: DMSO-d6): 7.80 (6H), 7.65 (2H), 7.30 (5H), 3.65 (1H), 3.60 (2H), 2.75 (1H), 2.55 (1H), 2.40 (1H major), 2.25 (1H minor), 1.85 (2H), 1.65 (2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=3)[N:6]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:7]=2)[CH:3]=1.[CH:28]1([N:34]=[C:35]=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CCN(CC)CC>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=3)[C:35]([NH:34][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:36])[N:6]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:7]=2)[CH:3]=1
Reactant: O=C=NC1CCCCC1
Reactant: CCOc1cccc(Nc2c3cc(Cl)ccc3nn2-c2ccc(Cl)cc2)c1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCOc1cccc(N(C(=O)NC2CCCCC2)c2c3cc(Cl)ccc3nn2-c2ccc(Cl)cc2)c1

Procedure:
In analogy to the procedure described in example 1.2, [5-chloro-2-(4-chloro-phenyl)-2H-indazol-3-yl]-(3-ethoxy-phenyl)-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 4 days under reflux conditions to give the title compound as colorless foam. MS: m/e=523.3 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH2:13]([S:16](Cl)(=[O:18])=[O:17])[CH2:14][CH3:15]>N1C=CC=CC=1>[CH2:13]([S:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)(=[O:18])=[O:17])[CH2:14][CH3:15]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1ccc(C(=O)O)cc1

Procedure:
In a manner similar to Preparation 9 react ethyl 4-aminobenzoate with 1-propanesulfonyl chloride and pyridine to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]([C:10]1[CH:11]=[C:12]([N+:16]([O-])=O)[CH:13]=[CH:14][CH:15]=1)[S:6]([CH3:9])(=[O:8])=[O:7]>[Pd]>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]([C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[NH2:16])[S:6]([CH3:9])(=[O:8])=[O:7]
Reactant: CN(C)CCN(c1cccc([N+](=O)[O-])c1)S(C)(=O)=O
Agent: [Pd]
Product: CN(C)CCN(c1cccc(N)c1)S(C)(=O)=O

Procedure:
Prepared analogously to Example 1d by catalytic hydrogenation of 1.9 g (6.8 mmol) of 3-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-nitrobenzene over palladium/charcoal.
Reaction SMILES: [OH:1][C:2]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][C:5]([CH:6]=[N:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][C:3]=1[C:19]([CH3:22])([CH3:21])[CH3:20].C([BH3-])#N.[Na+]>C(O)(=O)C>[OH:1][C:2]1[C:14]([C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:13][C:5]([CH2:6][NH:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][C:3]=1[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cc(C=Nn2ccnc2)cc(C(C)(C)C)c1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(CNn2ccnc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.9 g of 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)imidazole are suspended in 10 ml of glacial acetic acid and treated with 1.61 g of sodium cyanoborohydride, whereby a solution results. The solution is stirred at room temperature overnight and then evaporated in a vacuum. The residue is treated with 10 ml of water, neutralized (pH=7) with ice-cold saturated sodium bicarbonate solution and extracted three times with 30 ml of methylene chloride each time. The combined organic phases are dried over sodium sulfate, filtered and evaporated in a vacuum. The residue is crystallized with ehter. The product is removed by filtration and reprecipitated from ethanol/water. There is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylamino)imidazole of m.p. 171°-174°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2ncc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2ncc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
0.66 g of 5-(4-chlorophenyl)-4-(3,5-dichloro-2-pyridyl)-6-methyl-2H-pyridazin-3-one and 6 g of phosphorus oxychloride were mixed. The mixture was stirred for 2 hours on an oil bath of 110° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.67 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.47 g of 3-chloro-5-(4-chlorophenyl)-4-(3,5-dichloro-2-pyridyl)-6-methylpyridazine (hereinafter, described as compound (11) of the present invention.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20](O)=[O:21])[CH2:9]2)=[C:4]([F:23])[CH:3]=1.S(Cl)([Cl:26])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([Cl:26])=[O:21])[CH2:9]2)=[C:4]([F:23])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2F)C1
Product: O=C(Cl)C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2F)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
5-(4-Bromo-2-fluoro-phenyl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (2.5 g, 6.3 mmol) prepared in Step 4 was added to thionyl chloride (30.0 mL). The reaction mixture was stirred at 100° C. for 2 hours and then concentrated under reduced pressure. The resulting residue was concentrated under reduced pressure three times, along with using toluene, to give 5-(4-bromo-2-fluoro-phenyl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carbonyl chloride as a dark brown liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11])([O-:3])=[O:2].[CH:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=O>O1CCCC1.[O-]CC.[Na+].C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])/[CH:11]=[CH:13]\[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]1)([O-:3])=[O:2]
Reactant: CC(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(/C=C\C(=O)c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.3 %

Procedure:
1-(2-Nitrophenyl)ethanone (1.04 g) and tert-butyl 4-formylpiperidine-1-carboxylate (1.47 g) were suspended in dry tetrahydrofuran (20 mL) and 20 drops of sodium ethoxide in ethanol (21% by weight) was added. The reaction mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 15% ethyl acetate/hexane) to furnish the title compound (1.30 g) with the following physical properties.
Reaction SMILES: CC1C=C(C)N=C(C)C=1.Br[CH2:11][C:12]1[CH:17]=[C:16]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:15]=[CH:14][C:13]=1[F:24].CS(C)=[O:27]>>[CH:19]1([O:18][C:16]2[CH:15]=[CH:14][C:13]([F:24])=[C:12]([CH:17]=2)[CH:11]=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Fc1ccc(OC2CCCC2)cc1CBr
Reactant: CS(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: O=Cc1cc(OC2CCCC2)ccc1F
Temperature: 150 °C

Procedure:
1.9 ml of s-collidine (14.3 mmol) are introduced into a solution of 3 g of 2-bromomethyl-4-cyclopentyloxy-1-fluorobenzene (11 mmol) in 65 ml of dimethylsulfoxide. The mixture is heated at 150° C. for 25 minutes and is then cooled to room temperature. The solvent is evaporated off and the title product is isolated by chromatography on a column of silica (eluent: 96/4 cyclohexane/ethyl acetate). 1.1 g of a yellow oil are obtained:
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:32])([CH3:31])[CH2:4][O:5][CH2:6][C:7]1[NH:8][C:9]([CH3:30])=[C:10]([C:26]([O:28][CH3:29])=[O:27])[CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[Cl:25])[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].CN(C)/[CH:35]=[N:36]/[N:37]=[CH:38]/N(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:25][C:19]1[C:20]([Cl:24])=[CH:21][CH:22]=[CH:23][C:18]=1[CH:11]1[C:10]([C:26]([O:28][CH3:29])=[O:27])=[C:9]([CH3:30])[NH:8][C:7]([CH2:6][O:5][CH2:4][C:3]([OH:32])([CH3:31])[CH2:2][N:1]2[CH:38]=[N:37][N:36]=[CH:35]2)=[C:12]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CN(C)/C=N/N=C/N(C)C
Reactant: CCOC(=O)C1=C(COCC(C)(O)CN)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(COCC(C)(O)Cn2cnnc2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 65.1 %

Procedure:
A solution of 1-amino-3-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}-2-hydroxy-2-methylpropane (0.25 g), N,N-dimethylformamide azine (0.21 g) and para-toluenesulphonic acid (10 mg) in toluene (10 ml) was heated under reflux for 1.5 hours and then partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with water, dried over Na2SO4 and evaporated. The residue was purified by chromatography on SiO2 (5 g) using dichloromethane plus 0-5% methanol as the eluant. Appropriate fractions were combined and evaporated and the residue triturated with ether. The resulting solid was collected, washed with ether and dried to give the title compound (0.18 g), m.p. 172°-176° C.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:5]2[C:6]([C@H:10]3[CH2:12][C@@H:11]3[CH2:13][NH:14]C(=O)OC(C)(C)C)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[ClH:23].CO>CO>[ClH:23].[ClH:23].[CH3:1][C:2]1[CH:22]=[C:5]2[C:6]([C@H:10]3[CH2:12][C@@H:11]3[CH2:13][NH2:14])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cc1cc2c([C@H]3C[C@@H]3CNC(=O)OC(C)(C)C)cccn2n1
Agent: Cl
Solvent: CO
Product: Cc1cc2c([C@H]3C[C@@H]3CN)cccn2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a solution of tert-butyl {[(1S,2S)-2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methyl}carbamate (1.84 g, 6.11 mmol) in methanol (6 mL) was added hydrochloric acid-methanol reagent (manufactured by TCI, 18 mL) solution, and the mixture was stirred at room temperature for 15 hr. The solvent was concentrated under reduced pressure to give the title compound (1.69 g, yield 100%).
Reaction SMILES: [C:1]([NH2:4])(=[NH:3])[CH3:2].[Cl:5][C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH:9]=[CH:10][S:11](Cl)(=[O:13])=[O:12]>>[Cl:5][C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH:9]=[CH:10][S:11]([NH:3][C:1](=[NH:4])[CH3:2])(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=N)N
Product: CC(=N)NS(=O)(=O)C=Cc1ccc(Cl)c(Cl)c1

Procedure:
Reaction of acetamidine with 3,4-dichlorostyrylsulfonyl chloride according to the above procedure affords N-[(3,4-DICHLOROSTYRYL)SULFONYL]ACETAMIDINE, m.p. 197.5°-198.5° C. (corr.), crystallized from acetone-isopropanol.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34]>>[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([NH:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=2)[CH2:7][CH2:6]1)=[O:34]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3cccc(Cl)c3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-chlorobenzoyl chloride: ESMS m/e: 518.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>>[F:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:3]=1[CH:4]=[CH:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(F)cc(F)c1F
Product: O=C(O)C=Cc1cc(F)cc(F)c1F

Procedure:
According to the previously described general procedure (GP1), Knoevenagel condensation (75° C.; 3h20) between 2,3,5-trifluorobenzaldehyde (9.730 g; 60.777 mmol) and malonic acid (12.016 g; 115.477 mmol) gave the product 3-(2,3,5-trifluoro-phenyl)-acrylic acid as a colorless solid (8.310 g; 68%). LC-MS: tR=0.84 min.; [M+H]+: no ionisation.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:9](=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:27][C:28]1[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=1[C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:9](=[O:19])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([O:32][CH3:33])=[O:31])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCN(Cc1ccccc1)C(=O)CCc1ccc(O)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCN(Cc1ccccc1)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 66 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
N-benzyl-N-hexyl-3-(4-hydroxyphenyl)propanamide (183 mg, 0.54 mmol), methyl 2-(bromomethyl)benzoate (136 mg, 0.59 mmol) and potassium carbonate (112 mg, 0.81 mmol) were mixed in acetonitrile. The mixture was stirred at 66° C. overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The organic phase was washed (water ×2, brine ×1), dried (Na2SO4) and evaporated. Further purification by preparative HPLC (using a gradient of CH3CN/10% CH3CN-waterphase containing 0.1M NH4OAc as eluant) gave 91 mg (yield 34%) of the desired product.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8](Br)[C:9]#[CH:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:10]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]#[CH:8]
Reactant: Oc1ccccc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1ccccc1
Temperature: 85 °C
Yield: 84 %

Procedure:
Referring to FIG. 39, phenol (14.6 g. 0.155 mol), propargyl bromide (19 m 0.171 mol) and potassium carbonate (32.1 g, 0.232 mol) in DMF (100 mL) were heated at 85° C. overnight. The reaction was diluted with water and extracted with ether. The extract was washed with brine, dried (MgSO4) and evaporated. The residue was purified by Biotage flash column chromatography (10% EtOAc/Hep) to give product as an oil (17.2 g, 84%).
Reaction SMILES: OO.[CH:3]([OH:5])=O.[C:6]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)C[CH2:9][CH2:8][CH:7]=1>>[C:11]1([CH:6]2[CH2:7][CH2:8][CH2:9][C:3]2=[O:5])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1=C(c2ccccc2)CCC1
Reactant: O=CO
Agent: OO
Product: O=C1CCCC1c1ccccc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
A mixture of 30% hydrogen peroxide (23 mL, 149 mmol) and 85% formic acid (100 mL, 2619 mmol) was heated at 40° C. for 15 minutes. The mixture was carefully added to cyclopentenylbenzene (21.49 g, 149 mmol) and the resulting two-phase system was vigorously stirred at room temperature for 4 h. An exothermic reaction was observed in the beginning. In the end of the stirring the solution became homogeneous. The reaction mixture was carefully quenched with saturated aqueous solution of sodium bicarbonate. The product was extracted with ether. The combined etherial layers were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the product was purified by column chromatography on silica gel to give 2-phenylcyclopentanone (19.995 g, 125 mmol, 84% yield) as brown oil. LC-MS (M+H)+=161.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.38 (1H, t, J=7.3 Hz), 7.30-7.35 (2H, m), 7.19 (2H, d, J=7.3 Hz), 3.28-3.37 (1H, m), 2.71 (1H, td, J=4.6, 2.7 Hz), 2.58-2.63 (1H, m), 2.43-2.55 (1H, m), 2.29 (1H, ddd, J=19.0, 10.5, 9.0 Hz), 2.07-2.21 (1H, m), 1.88-1.99 (1H, m).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[CH:11]([C:17]([CH3:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[CH3:19][C:17]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[S:8][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC(=S)c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccncc2)nc1C
Yield: 40.3 %

Procedure:
A mixture of thioisonicotinamide (2.76 g) and ethyl 2-chloroacetoacetate (3.6 g) in ethanol (30 ml) was heated for 20 hours under reflux and the solvent was evaporated. To the residue was added saturated sodium hydrogen carbonate solution, and the solution was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was subjected to silica gel chromatography, and eluted with hexane-ethyl acetate (2:1) to give the title compound as crystals (2.0 g, 40.3%).
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:9][CH:6]([CH2:7][O:8]1)[N:5](C(OC(C)(C)C)=O)[CH2:4]2.[CH3:17][C:18](OCl)=[O:19]>C(Cl)Cl>[CH:6]12[CH2:9][C:3]([CH2:2][NH:1][C:18](=[O:19])[CH3:17])([O:8][CH2:7]1)[CH2:4][NH:5]2
Reactant: CC(C)(C)OC(=O)N1CC2(CN)CC1CO2
Reactant: CC(=O)OCl
Solvent: ClCCl
Product: CC(=O)NCC12CNC(CO1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 4-(aminomethyl)-5-oxa-2-azabicyclo[2.2.1]heptane-2-carboxylate (Wuxi AppTec, CAS 1357351-98-4) (50 mg, 0.22 mmol), TEA (44.4 mg, 0.44 mmol) in DCM (2 mL) was added CH3CO2Cl (26 mg, 0.33 mmol) at 0° C. After 2 hours, the solvent was removed under reduced pressure. The residue was treated with TFA in DCM. After stirring for 2 hours at room temperature, the residue was used in next step without purification. MS: calc'd (MH+) 271, measured (MH+) 271.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][CH2:33][CH2:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:36]=1[CH2:37][C:38](=[O:44])[NH:39]2.[CH:45]([C:48]1[CH:49]=[C:50](O)[CH:51]=[CH:52][CH:53]=1)([CH3:47])[CH3:46]>O1CCCC1>[CH:45]([C:48]1[CH:53]=[C:52]([CH:51]=[CH:50][CH:49]=1)[O:32][CH2:33][CH2:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:36]=1[CH2:37][C:38](=[O:44])[NH:39]2)([CH3:47])[CH3:46]
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: CC(C)c1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1cccc(OCCc2cccc3c2CC(=O)N3)c1
Reaction time: 0.25 h
Yield: 13.5 %

Procedure:
Diethyl azodicarboxylate (0.47 mL, 3 mmol) was added to a solution of triphenylphosphine (0.786 g, 3 mmol) in tetrahydrofuran (10 mL) under nitrogen atmosphere. The mixture was stirred for 15 minutes. To it was then added 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (0.53 g, 3 mmol) (Hayler, J. D.; Howic, S. L. B.; Giles, R. G.; Negus, A.; Oxley, P. W.; et al; J. Heteocycl. Chem.; 32; 3; 1995; 875-882), followed by 3-isopropylphenol (0.41 mL, 3 mmol). The mixture was stirred at room temperature for one day and the solvent was evaporated. The residue was chromatographed on silica gel eluting with ethyl acetate: hexane 1:9 to give 120 mg (14%) of 4-[2-(3-isopropyl-phenoxy)-ethyl]-1,3-dihydro-indol-2-one.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[O:1]
Reactant: O=C(O)Cc1ccc(CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(CC(=O)O)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 59.6 %

Procedure:
To [4-(hydroxymethyl)phenyl]acetic acid (3 g, 18 mmol) in CHCl3 (50 mL) under N2 was added manganese dioxide (7.7 g, 90 mmol) and the reaction mixture was stirred at 50° C. for 18 h. The crude was filtered through a pad of celite, washed with DCM (50 mL) and concentrated under reduced pressure to give the desired product (1.76 g, 59%). 1H NMR (300 MHz, d6-DMSO) δ: 12.49 (1H, br s), 9.99 (1H, s), 7.89-7.84 (2H, m), 7.50 (2H, d, J=7.9 Hz), 3.72 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[CH:4][C:5]([I:9])=[C:6]([CH:8]=1)[NH2:7].[C:14](=O)(OC(Cl)(Cl)Cl)[O:15]C(Cl)(Cl)Cl>O1CCOCC1>[Cl:1][C:2]1[CH:8]=[C:6]([N:7]=[C:14]=[O:15])[C:5]([I:9])=[CH:4][C:3]=1[C:10]([F:13])([F:11])[F:12]
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1I
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=C=Nc1cc(Cl)c(C(F)(F)F)cc1I
Temperature: 100 °C

Procedure:
5-Chloro-2-iodo-4-(trifluoromethyl)aniline D10 (7.7 mmol, 2.2 g), bis(trichloromethyl) carbonate (0.35 eq., 2.7 mmol, 800 mg) were dissolved in 1,4-dioxane (10 ml) and the mixture was heated to 100° C. for 15 minutes; the mixture was then cooled to room temperature and it was filtered. The filtrate was concentrated to afford 1-chloro-4-iodo-5-isocyanato-2-(trifluoromethyl)benzene which was dissolved in dichloromethane (10 ml) and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (2 eq., 11.4 mmol, 2.28 g) was added at room temperature; the mixture was stirred at room temperature for 1.5 hours. Solvent was subsequently evaporated and the crude obtained was purified by chromatography (ethyl acetate-n-hexane) to afford the title compound, 1.46 g, 46%, M+−H=546.