Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1.[CH:34](=O)[CH2:35][CH3:36].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:34][CH2:35][CH3:36])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccccc2)CC1
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccccc1

Procedure:
4-Amino-N-((1-(5-benzylaminopentyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide (2.0 g) as starting compound, propionaldehyde (0.13 ml) and sodium cyanoborohydride (0.35 g) were reacted and treated in the same manner as in Example 136 to give 1.05 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(N-n-propyl-N-benzylamino)pentyl)piperidin-4-yl)methyl)-benzamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[NH2-].[Na+].[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12]>>[CH2:11]([N:13]([CH2:14][CH3:15])[C:7]1[CH:2]=[C:3]([OH:8])[CH:4]=[CH:5][CH:6]=1)[CH3:12]
Reactant: CCNCC
Reactant: Oc1ccccc1Cl
Agent: [NH2-]
Agent: [Na+]
Product: CCN(CC)c1cccc(O)c1
Yield: 76 %

Procedure:
32.1 g (0.25 mol) of o-chlorophenol were slowly added dropwise under nitrogen to a mixture of 20.5 g (0.5 mol) of 95% by weight pure crystalline sodium amide and 750 ml of diethylamine. The reaction mixture was refluxed under nitrogen for 72 h with stirring. The workup comprised hydrolysis with 100 ml of saturated aqueous ammonium chloride solution, distillative removal of excess diethylamine, neutralization with dilute hydrochloric acid up to a pH of 7.5, extraction of the residue with a total of 600 ml of methylene chloride, drying over sodium sulfate and concentrating of the organic phase. Thereafter the crude oil thus obtained (46.3 g) was distilled, which yielded 31.5 g (76%) of 3-diethylaminophenol (purity>96% (GC)).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1B(O)O.[CH2:16]([O:23][CH2:24][C:25]1[N:30]=[CH:29][N:28]=[C:27]([O:31][CH2:32][CH2:33][CH3:34])[C:26]=1I)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO.C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:16]([O:23][CH2:24][C:25]1[N:30]=[CH:29][N:28]=[C:27]([O:31][CH2:32][CH2:33][CH3:34])[C:26]=1[C:6]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=1[O:4][CH2:3][O:2][CH3:1])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COCOc1cc(OC)ccc1B(O)O
Reactant: CCCOc1ncnc(COCc2ccccc2)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCOc1ncnc(COCc2ccccc2)c1-c1ccc(OC)cc1OCOC
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.8 %

Procedure:
To a solution of 2-methoxymethoxy-4-methoxyphenyl boronic acid (2.89 g, 13.65 mmol) in MeOH (8-10 ml) and 6-benzyloxymethyl-5-iodo-4-propoxy-pyrimidine (5 g, 13 mmol) in toluene (75 ml) was added an aqueous solution of 2 M sodium carbonate (14 ml) followed by Tetrakis(triphenylphosphine)palladium (0) (1.25 g, 1.08 mmol). The reaction was allowed to stir at 90-95° for 18 h. The mixture was cooled to room temperature then diluted with ethyl acetate, washed with water, sat'd NH4Cl, 5% NaHCO3 solution, brine and dried (MgSO4). After removing the solvent, flash chromatography of the residue (silica gel, 1:1 t-butyl methyl ether/hexane) provided the title compound as a solid (3.41 g, 62%).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([NH:18]C=O)/[C:6](/[CH3:17])=[CH:7]/[CH2:8][P:9]([O:14]CC)([O:11]CC)=[O:10])C>Cl>[NH2:18][CH:5](/[C:6](/[CH3:17])=[CH:7]/[CH2:8][P:9]([OH:14])([OH:11])=[O:10])[C:4]([OH:21])=[O:3]
Reactant: CCOC(=O)C(NC=O)/C(C)=C/CP(=O)(OCC)OCC
Agent: Cl
Product: C/C(=C\CP(=O)(O)O)C(N)C(=O)O

Procedure:
6.3 g of E-2-formylamino-3-methyl-5-diethylphosphono-3-pentenoic acid ethylester are heated for 30 hours at 100°-100° under nitrogen in 400 ml of 4.35N hydrochloric acid. Working up as in Example 11 yields E-2-amino-3-methyl-5-phosphono-3-pentenoic acid in the form of a white powder, m.p. 168°, 1H-NMR (D2O): 1.50 (d, 3H, CH3); 2.4 (m, 2H, CH2); 4.30 (s, 1H, C(2)--H); 5.60 (m, 1H, C(4)--H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.S([O-])([O-])(=O)=O.[OH:16][NH3+:17].O[NH3+].[OH-].[Na+].[C:22]1([CH3:28])C=CC=CC=1>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]1[CH2:28][CH2:22][O:16][N:17]=1
Reactant: Cc1ccccc1
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: [NH3+]O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: Clc1cccc(Cl)c1C1=NOCC1

Procedure:
Starting from 2,6-dichlorobenzaldehyde 75 g (0.43 mol) of 2,6-dichlorobenzaldehyde were dissolved in 400 ml of toluene and then 155 g (0.24 mol) of 25% strength hydroxylammonium sulfate solution were added. At 75° C., 38 g of 50% strength NaOH were added dropwise. After stirring for half an hour, the phases were separated at 75° C., and the organic phase was washed with water and then cooled. At 25° C., 276 g (0.46 mol) of 12.5% strength sodium hypochlorite solution were added dropwise over 4-6 h while simultaneously passing in ethylene. After addition of the hypochlorite solution was complete, the mixture was stirred for 1 h, the phases were separated, the organic phase was washed with water, and the solvent was distilled off under reduced pressure. 82 g (89% of theory) of the required product were obtained with a purity (by GC) of 96%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl:9][CH2:10][CH2:11][C:12](Cl)=[O:13]>CC(C)=O.O>[Cl:9][CH2:10][CH2:11][C:12]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])=[O:13]
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)CCCl
Solvent: O
Solvent: CC(C)=O
Product: O=C(CCCl)Nc1ccccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a stirred solution of 2-aminophenol (2.18 g, 20 mmol) in acetone (20 mL) a solution of 3-chloropropionyl chloride (1.28 g, 0.87 mL, 10 mmol) in acetone (20 mL) was added dropwise. After the addition was completed, the reaction mixture was stirred at room temperature for 0.5 h and then diluted with water (50 mL). Acetone was removed in vacuo, the precipitate formed was collected by filtration, washed with water, and dried to give the subtitle compound (1.53 g, 77%).
Reaction SMILES: O[CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[H-].[Na+].Br[CH2:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17](C)[N:16]=1>C1(C)C=CC=CC=1>[CH2:5]([O:4][P:3]([CH2:2][C:17]1[CH:18]=[C:19]([CH3:21])[CH:20]=[C:15]([CH3:14])[N:16]=1)([O:7][CH2:8][CH3:9])=[O:10])[CH3:6]
Reactant: Cc1cc(C)nc(CBr)c1
Reactant: CCOP(=O)(CO)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1cc(C)cc(C)n1)OCC

Procedure:
A solution of diethyl hydroxymethylphosphonate (1 mmole) in toluene was treated with sodium hydride (1.1 mmole) at 0° C., and after 15 min 2-bromomethyl-4,6-dimethylpyridine (1 mmole) was added. After 3 h the reaction mixture was subjected to extraction and chromatography to give 2-diethylphosphonomethyl-4,6-dimethylpyridine.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([NH2:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)=[O:5].C(N(CC)CC)C.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](Cl)=[O:32].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([NH:16][C:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)=[O:32])([CH2:9]3)[CH2:7]1)[CH2:13]2)=[O:5]
Reactant: O=C(Cl)c1ccccn1
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C12CC3CC(CC(NC(=O)c4ccccn4)(C3)C1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a round bottom flask was added 3-amino-adamantane-1-carboxylic acid methyl ester hydrochloride (20.0 g, 81.4 mmol) and methylene chloride (500 mL) and the solution was cooled at 0° C. To this solution was then added triethylamine (57 mL, 0.41 mol) followed by picolinoyl chloride hydrochloride (15.2 g 85.4 mmol; TCI America, Wellesley Hills, Mass., USA) and the reaction was stirred at 0° C. for 30 minutes, then at room temperature for 6 hours. To the reaction was added saturated aqueous sodium bicarbonate (500 mL) and the biphasic mixture was stirred vigorously for a few minutes, then transferred to a 2-L separatory funnel. The mixture was extracted, the layers separated and the aqueous layer was extracted again with methylene chloride (2×200 mL). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 24.8 g (97%) of the title compound, 3-[(pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid methyl ester, as a pale brown solid. 1H NMR (400 MHz, CDCl3) δ 8.54-8.49 (m, 1H), 8.16 (dt, J=7.8, 1.0 Hz, 1H), 7.96 (br s, 1H), 7.83 (td, J=7.8, 1.8 Hz, 1H), 7.40 (ddd, J=7.6, 4.8, 1.3 Hz, 1H), 3.66 (s, 3H), 2.34-2.30 (m, 2H), 2.29-2.23 (m, 2H), 2.17-2.13 (m, 4H), 1.97-1.80 (m, 4H), 1.78-1.62 (m, 2H). ESI-MS m/z: 315.0 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[C:10]([F:18])[C:11]([F:17])=[CH:12][CH:13]=2)[C:8]=1[F:19])(=O)=O.[CH2:22]([C:25]1[CH:30]=[CH:29][C:28](OB(O)O)=[CH:27][CH:26]=1)[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.O1CCCC1>[CH2:22]([C:25]1[CH:30]=[CH:29][C:28]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[C:10]([F:18])[C:11]([F:17])=[CH:12][CH:13]=3)[C:8]=2[F:19])=[CH:27][CH:26]=1)[CH2:23][CH3:24]
Reactant: CCCc1ccc(OB(O)O)cc1
Reactant: O=S(=O)(Oc1ccc2ccc(F)c(F)c2c1F)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccc(-c2ccc3ccc(F)c(F)c3c2F)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
1,7,8-Trifluoronaphthalene-2-yl trifluoromethanesulfonate (15 g), 4-propylphenylboric acid (11.2 g), potassium carbonate (18.8 g), tetrakis(triphenylphosphine)palladium(0) (1 g), toluene (50 ml), tetrahydrofuran (50 ml), and water (20 ml) were added in an autoclave and stirred for 4 hours at 90° C. under pressurized nitrogen (2 kg/cm2). The reaction solution was poured into water. The organic layer was removed, and the aqueous layer was extracted with toluene. The organic layers were combined, washed with 10% hydrochloric acid and brine, and concentrated. The residue was purified by column chromatography (silica gel, hexane), and 2-(4-propylphenyl)-1,7,8-trifluoronaphthalene was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-])=[O:10])=[C:4]([NH:12][C:13]([C:15]([O:17]CC)=O)=[O:14])[CH:3]=1.CN(C)C=O.N>O1CCCC1.[Pd]>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[N:9]([OH:10])[C:15](=[O:17])[C:13](=[O:14])[NH:12]2
Reactant: CCOC(=O)C(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: N
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cl
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2n(O)c1=O
Yield: 87.2 %

Procedure:
To a solution of 0.4 g (1.3 mmol) 4,5-dichloro-2-ethoxalylamino-1-nitrobenzene in 30 ml tetrahydrofuran was added 10 ml dimethylformamide and 0.4 ml 25% aqueous ammonia. The mixture was hydrogenated at atm. pressure by using 50 mg 5% Pd-C as a catalyst. The precipitate was filtered off and washed with tetrahydrofuran. The filter cake was washed several times with 5% aqueous potassium hydroxide. Acidification of the filtrate with 4N hydrochloric acid gave 0.14 g (45%) of 6,7-dichloro-1-hydroxyquinoxaline-2,3(1H,4H)-dione. M.p. decomp. 1H-NMR (DMSO-d6): 12.2 (2H, m), 7.50 (1H, s), 7.27 (1H, s). MS (m/e): 246 (M+, 35%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:14]I>C1(C)C=CC=CC=1>[CH3:14][O:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CI
Reactant: CCOC(=O)c1cc(C)nc(O)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C)nc(OC)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
20.0 g (111.4 mmol) of ethyl 2-hydroxy-6-methylisonicotinate (20a) were suspended in 330 ml of toluene. After addition of 36.54 g (132.5 mmol) of Ag2CO3 and 23.5 g (165.6 mmol) of methyl iodide, the mixture was heated to 100° C. with KPG stirring. After 4 hours, the reaction mixture was allowed to cool to RT and it was filtered through Celite. The filtrate was washed twice with water, dried with Na2SO4 and concentrated, 16.9 g of the title compound being isolated as a yellowish oil.
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.O.[F:11][C:12]([F:17])([F:16])[CH2:13][NH:14][NH2:15]>C(O)(=O)C>[F:11][C:12]([F:17])([F:16])[CH2:13][N:14]1[C:1](=[O:7])[CH2:2][C:3]([CH3:5])=[N:15]1
Reactant: NNCC(F)(F)F
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC1=NN(CC(F)(F)F)C(=O)C1

Procedure:
0.25 Mole (32.5 g) of ethyl acetoacetate and 0.25 mole (42 g) of 2,2,2-trifluoroethylhydrazine hydrate were stirred and refluxed for 2 hours in 125 ml of acetic acid. The acetic acid was distilled off in vacuo. The distillation residue was rubbed with water and recrystallized from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([O:23][CH2:24][C:25]#[N:26])[C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:6]([F:8])[CH:7]=1.S(C)C.CO>C1COCC1>[NH2:26][CH2:25][CH2:24][O:23][C@@H:9]([C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC#N)c2cc(F)cc(Cl)c2)C1
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cc(F)cc(Cl)c2)C1
Temperature: 0 °C
Yield: 27.9 %

Procedure:
(R)-tert-Butyl 3-((R)-(3-chloro-5-fluorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylate (4.4 g, 10.2 mmol, crude) was dissolved in anhydrous THF (60 mL), and the solution was heated to reflux under nitrogen. A solution of 10 M of BH3.Me2S (3 mL, 30.6 mmol) in THF was added dropwise and stirring was continued under reflux overnight. The resulting solution was cooled to 0° C., CH3OH was added dropwise to quench the reaction. Evaporation of the solvent to give the crude product, which was purified by silica column to give (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chloro-5-fluorophenyl)methyl)piperidine-1-carboxylate (1.1 g, yield 28%), which was used in the next step without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.CS([C:14]1[N:19]=[C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=3)[N:22]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:21]=2)[C:17]([C:43]#[N:44])=[CH:16][N:15]=1)(=O)=O.[OH2:45]>C(#N)C>[OH:45][C:14]1[N:19]=[C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=3)[N:22]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:21]=2)[C:17]([C:43]#[N:44])=[CH:16][N:15]=1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Reaction time: 1 h

Procedure:
DIPEA (7.421 g, 10.00 mL, 57.42 mmol) was added to a suspension of 2-(methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (1 g, 1.918 mmol) in acetonitrile (20 mL). The reaction mixture was stirred for 1 hour then water (5 mL) was added. The mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to give the desired product (880 mg, quantitative yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[NH2:17].CO>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:17][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1)=[O:6]
Reactant: Nc1ccc2ccccc2c1
Reactant: O=C=NCCCl
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCCCl)Nc1ccc2ccccc2c1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
1-Chloro-2-isocyanato-ethane (0.81 mL, 9.42 mmol) was added dropwise to a stirred solution of naphthalen-2-ylamine (900 mg, 6.28 mmol) in toluene (50 mL) over a period of 30 minutes at 0° C. The reaction temperature was maintained at room temperature for 5 hours. The reaction was monitored by TLC (5% MeOH in chloroform). The reaction mixture was filtered, washed with toluene and dried under reduced pressure to afford 1.3 g (83% yield) of 1-(2-chloro-ethyl)-3-naphthalen-2-yl-urea.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[O:13]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:27]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][CH:32]=1)[CH:28]=[CH2:29]>CN(C)C=O>[CH2:27]([N:30]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][CH:32]=1)[C:1]([NH:24][C:23]1[CH:22]=[CH:21][C:20]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:26][CH:25]=1)=[O:2])[CH:28]=[CH2:29]
Reactant: C=CCNc1ccc(OCc2ccccc2)cc1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: C=CCN(C(=O)Nc1ccc(Oc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Carbonyldiimidazole (136 mg) was added to a solution of 4-phenoxyaniline (155 mg) in dimethylformamide (3 mL) at 0° C. After 30 minutes, allyl-(4-benzyloxyphenyl)amine (200 mg) was added and the temperature was increased to 80° C. for 2 hours. A further 2 hours at 120° C., the reaction solution was cooled and then purified by preparative HPLC. The product with the molecular weight of 450.54 (C29H26N2O3); MS (ESI): 451 ([M+H]+), was obtained in this way.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:11]([NH:14][CH2:15][C:16]([OH:18])=[O:17])(=O)[CH3:12].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C>[CH3:12][C:11]1[O:18][C:16](=[O:17])/[C:15](=[CH:7]/[C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)/[N:14]=1
Reactant: CC(=O)NCC(=O)O
Reactant: CSc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CSc1ccc(/C=C2\N=C(C)OC2=O)cc1
Temperature: 25 °C
Yield: 36.5 %

Procedure:
4-(Methylsulfanyl)benzaldehyde (31.8 g), (acetylamino)acetic acid (24.5 g) and acetic anhydride (35 ml) were combined, and then sodium acetate (8.57 g) was added to the suspension at room temperature under nitrogen atmosphere. The reaction mixture was refluxed for 3.5 hours. After cooled to room temperature, the mixture was poured into ice-water and ethyl acetate with stirring, and filtered in vacuo. The filtrate was separated. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue and the previously obtained solid were combined, and the mixture was purified by flash column chromatography over silica gel with chloroform/ethyl acetate (30:1) as an eluent, and triturated with isopropyl ether to give (4Z)-2-methyl-4-(4-(methylsulfanyl)benzylidene)-1,3-oxazol-5(4H)-one (17.8 g) as a brown solid.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]=O>[CH2:12]1[O:10][C:9]2[C:2](=[C:3]([CH:6]=[CH:7][CH:8]=2)[CH:4]=[O:5])[O:1]1
Reactant: BrCBr
Reactant: O=Cc1cccc(O)c1O
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc2c1OCO2
Yield: 85.6 %

Procedure:
A mixture containing 2,3-dihydroxybenzaldehyde, (50 g) dibromomethane (188 g), potassium carbonate (150 g) and copper (II) oxide (1.4 g) in dimethylformamide (2 L) was heated at reflux for 4 hours. The reaction mixture was cooled, filtered and evaporated. The residue was dissolved in toluene and the organic layer was washed with staurated sodium bicarbonate and brine. The layer was then dried, filtered and evaporated to yield 46.5 g of 2,3-methylenedioxybenzaldehyde mp 32°-33° C.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1C2[C:22](=CC=CC=2)[CH2:21][C:20]1=[O:28].[Cl-].[Cl-].[Cl-].[Al+3].[C:33](Cl)(=[O:40])[C:34]1[CH:39]=CC=CC=1>>[C:1]([C:9]1[CH:17]=[CH:16][C:15]2[NH:14][C:13](=[O:18])[C:12]3[NH:19][CH:20]=[CH:21][C:22]=3[C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:34]([C:33]([O-:40])=[O:28])[CH3:39]
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1Cc2cc(C(=O)c3ccccc3)ccc2N1
Reactant: O=C1Cc2ccccc2N1
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(=O)[O-]
Product: O=C(c1ccccc1)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1

Procedure:
Synthesis of 5-benzoyl-1,3-dihydro-indol-2-one is described by McNutt (WO99/10325). This compound was prepared according to this procedure from 665 g (5 mmol) of 1,3-dihydro-indol-2-one, aluminium trichloride (15 mmol) and benzoyl chloride (10 mmol) to give, after trituration in water and drying, 880 mg (74%) of 5-benzoyl-1,3-dihydro-indol-2-one in the form of a beige solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14](C=O)[C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH2:24][CH3:25])=[O:22].Cl[CH2:47]Cl>>[CH2:24]([O:23][C:21](=[O:22])[CH:26]=[CH:47][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[CH:11][N:10]2[S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])[CH3:25]
Reactant: O=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCCl
Product: CCOC(=O)C=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Yield: 100 %

Procedure:
A solution of 1-(benzenesulphonyl)-1H-indole-4-carboxaldehyde (2.0 g, 7 mmol) and (carbethoxymethylene)triphenylphosphorane (2.69 g,7.7 mmol) in anhydrous dichloromethane (50 ml) was heated to reflux for 3 h under a nitrogen atmosphere. The reaction was concentrated and purified by dry flash chromatography (dichloromethane) to give the title compound as a colourless solid (2.49 g, 100%). δH (360 MHZ, CDCl3), 1.34 (3H, t, J=7.2 Hz), 4.27 (2H, q, J=7.2 Hz), 6.51 (1H, d, J=17.2 Hz), 6.94 (1H, d, J=0.72 Hz), 7.32 (1H, t, J=7.9 Hz), 7.43-7.67 (4H, m), 7.67 (1H, d, J=3.6 Hz), 7.68-7.89 (2H, m), 7.94-8.03 (2H, m).