Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].[OH:11]O.[CH3:13][O:14][C:15]1[C:16]([CH3:38])=[C:17]([C:29]([O:36][CH3:37])=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH3:28])=[C:23]([CH:26]=1)[CH:24]=[O:25]>O.C(#N)C>[CH3:13][O:14][C:15]1[C:16]([CH3:38])=[C:17]([C:29]([O:36][CH3:37])=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH3:28])=[C:23]([CH:26]=1)[C:24]([OH:11])=[O:25]
Reactant: COc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1C=O
Reactant: OO
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: COc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
An aqueous solution (5 ml) of sodium dihydrogenphosphate (1.06 g, 8.86 mmol), an aqueous solution (7 ml) of sodium chlorite (0.460 g, 5.11 mmol) and aqueous hydrogen peroxide (0.502 ml, 30%) were added to an acetonitrile solution (10 ml) of 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-methoxybenzaldehyde (0.409 g, 1.14 mmol) and the resulting solution was stirred at room temperature for 5 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium hydrosulfite (Na2S2O4) solution and saturated brine, then dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the titled compound (0.260 g, 0.691 mmol, 61%).
Reaction SMILES: Cl.[CH2:2]([C:9]1([N:19]([CH3:21])[CH3:20])[CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O>[CH2:2]([C:9]1([N:19]([CH3:20])[CH3:21])[CH2:10][CH2:11][C:12](=[O:13])[CH2:17][CH2:18]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)C1(Cc2ccccc2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Product: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Reaction time: 24 h
Yield: 76.5 %

Procedure:
200 ml hydrochloric acid (32 wt. %) were diluted with 120 ml water, 78.4 g crude (8-benzyl-1,4-dioxa-spiro[4.5]dec-8-yl)-dimethyl-amine were added to this approx. six molar hydrochloric acid and the mixture was stirred for 24 hours. The reaction mixture was washed three times with 100 ml diethyl ether each time, rendered alkaline (pH>10) with 100 ml sodium hydroxide solution (32 wt. %), while cooling on an ice-bath, and extracted three times with 100 ml methylene chloride each time. The extracts were combined, dried over sodium sulfate and filtered and the filtrate was concentrated. 50.4 g 4-benzyl-4-dimethylamino-cyclohexanone were obtained.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]1[N:14]=[CH:15][CH:16]=[CH:17][C:8]2=1)=O.[NH2:18][C:19]([NH2:21])=[S:20]>CCO>[N:14]1[C:9]2[NH:10][C:11]3[C:7]([C:8]=2[CH:17]=[CH:16][CH:15]=1)=[CH:6][C:5]([C:3]1[N:18]=[C:19]([NH2:21])[S:20][CH:2]=1)=[CH:13][CH:12]=3
Reactant: NC(N)=S
Reactant: O=C(CBr)c1ccc2[nH]c3ncccc3c2c1
Solvent: CCO
Product: Nc1nc(-c2ccc3[nH]c4ncccc4c3c2)cs1
Temperature: 70 °C
Yield: 99 %

Procedure:
To a stirred suspension of 2-Bromo-1-(9H-pyrido[2,3-b]indol-6-yl)ethanone (100 mg, 0.346 mmol) in EtOH (2 mL) was added thiourea (26 mg, 1 equiv.) and the mixture was heated at 70° C. for 2 h. After cooling to room temperature, the solvent was evaporated to dryness. The resulting solid was stirred in a mixture of EtOAc/saturated aqueous NaHCO3 solution (2:1) until dissolution, and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. Compound 13 was obtained as a white powder in 99% yield after trituration of the crude product in MeOH and filtration; 1H-NMR (300 MHz; DMSO-d6): δ 12.07 (bs, 1H), 8.57-8.45 (m, 2H), 8.47 (dd, 1H, J=1.5, 4.9 Hz), 7.85 (dd, 1H, J=1.7, 8.5 Hz), 7.57 (d, 1H, J=8.5 Hz), 7.28 (dd, 1H, J=5.0, 7.7 Hz), 7.08 (s, 1H); 13C-NMR (75 MHz; DMSO-d6): δ 170.1 (C), 150.9 (C), 145.1 (CH), 140.3 (C), 139.2 (C), 130.0 (CH), 125.0 (CH), 121.1 (C), 120.4 (C), 119.2 (CH), 116.0 (C), 115.6 (CH), 112.0 (CH), 100.7 (CH); MS (ESI) m/z 267.1 [M+H+]; HRMS (ESI): Calcd for C14H10N4S: 267.0704. Found: 267.0703
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH2:18]([Li])[CH2:19][CH2:20][CH3:21].Br[C:24]1[CH:25]=[C:26]([C:31]2[N:36]=[C:35]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)[N:34]=[C:33]([C:44]3[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=3)[N:32]=2)[CH:27]=[C:28](Br)[CH:29]=1>O1CCCC1.CCCCCC.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>[N:9]1[C:8]2[C:21](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:20]=[CH:19][C:18]=1[C:25]1[C:26]([C:31]2[N:36]=[C:35]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)[N:34]=[C:33]([C:44]3[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=3)[N:32]=2)=[CH:27][C:28]([C:15]2[CH:10]=[CH:11][CH:12]=[C:13]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)=[CH:4][CH:3]=3)[CH:14]=2)=[CH:29][CH:24]=1
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3)nc(-c3cc(Br)cc(Br)c3)n2)cc1
Reactant: Brc1ccc(-c2ccc3ccccc3n2)cc1
Reactant: [Li]CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3)nc(-c3cc(-c4cccc(-c5ccc(-c6ccc7ccccc7n6)cc5)c4)ccc3-c3ccc4ccccc4n3)n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
In a stream of argon, 2.58 g (9.09 mmol) of 2-(4-bromophenyl) quinoline was dissolved in 20 mL of tetrahydrofuran. To the thus-obtained solution, 6.01 mL of a solution in hexane of 9.70 mmol of butyllithium was dropwise added at −78° C. The resultant mixture was stirred at −78° C. for 15 minutes, and then 2.45 g (9.70 mmol) of dichloro(tetramethylethylene-diamine)zinc(II) was added. Temperature of the resultant mixture was elevated to room temperature, and stirred for 1.5 hours. The resultant mixture, and 1.50 g (3.03 mmol) of 2-(3,5-dibromophenyl)-4,6-di-p-tolyl-1,3,5-triazine, and 420 mg (0.364 mmol) of tetrakis(triphenylphosphine)palladium were suspended in 30 mL of tetrahydrofuran, and the obtained suspension was heated under reflux with stirring for 15 hours. The reaction mixture was cooled to room temperature, and was then distilled under a reduced pressure to remove low boiling ingredients. Methanol was added to the concentrate and the thus-deposited solid was filtered. The thus-obtained crude product was purified by silica gel chromatography using a methanol/chloroform (1:100-2:100) mixed liquid as a developing solvent to give 2.03 g of the target 2-[4,4″-di(2-quinolyl)-1,1′:3′,1″-terphenyl-5-yl]-4,6-di-p-tolyl-1,3,5-triazine as a white solid (yield: 90%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[I:8][CH2:9][CH2:10][CH2:11]I>C(OCC)(=O)C>[I-:8].[I:8][CH2:9][CH2:10][CH2:11][N+:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccncc1
Reactant: ICCCI
Solvent: CCOC(C)=O
Product: Cc1cc[n+](CCCI)cc1
Product: [I-]

Procedure:
In the first step, 2-methylthiobenzothiazole (Aldrich Chemical Company, Milwaukee, Wis.) is quaternized by heating at 120° C. with an equivalent of methyl p-toluenesulfonate to yield N-methyl-2-methylthiobenzothiazolium p-toluenesulfonate (Compound 1A is also commercially available from TCI, Portland, Oreg.). N-(3-iodopropyl)-4-methylpyridinium iodide (Compound 1 B) is prepared by heating 4-methylpyridine (1.00 g) with 5 mL of 1,3-diiodopropane without a solvent at 120° C. for about 1 hour. Ethyl acetate is added and the product is filtered. Compounds 1A and 1B are condensed to yield 1'-(3'-iodopropyl)-3-methyl-4'-thiacyanine iodide (Compound 1C) using methods known in the art [e.g. Brooker, et al. J. AM. CHEM. SOC. 64, 199 (1942)]. For instance when 2.93 g of 1A is stirred with 3.3 g of 1 B with the addition of 1.15 mL of triethylamine in 20 mL of CH2Cl2 for 16 hours at room temperature followed by the addition of 80 mL of ethyl acetate about 1.1 g of 1 C is obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[CH3:12][C:13]1[CH:14]=[C:15]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:12][C:13]1[CH:14]=[C:15]([N:19]2[CH2:24][CH2:23][N:22]([C:2]3[N:3]=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:7]=3)[CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: CS(=O)(=O)c1ccc(Cl)nn1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cccc(N2CCN(c3ccc(S(C)(=O)=O)nn3)CC2)c1
Reaction time: 24 h
Yield: 89 %

Procedure:
A mixture of 3.2 parts of 3-chloro-6-(methylsulfonyl)pyridazine, 3 parts of 1-(3-methylphenyl)piperazine, 2 parts of N,N-diethylethanamine and 180 parts of benzene was stirred for 24 hours at reflux. The reaction mixture was evaporated. Water was added to the residue. The precipitated product was filtered off, washed with water and dissolved in trichloromethane. The solution was dried, filtered and evaporated. The residue was crystallized from methanol. The product was filtered off and dried, yielding 5 parts (89%) of 3-[4-(3-methylphenyl)-1piperazinyl]-6-(methylsulfonyl)pyridazine; mp. 201° C. (compound 209).
Reaction SMILES: C[O-].[Na+].Cl[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([CH3:14])=[C:7]([CH3:15])[N:6]=1.[CH2:16]([O:18]CC)C.O>CO>[CH3:14][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]([O:18][CH3:16])=[N:6][C:7]=1[CH3:15]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)nc1C
Reactant: CCOCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(C)c(C)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 7 h
Yield: 82.6 %

Procedure:
To a solution of 28% sodium methoxide (1.11 mL) and methanol (5.5 mL) was added dropwise a solution of 2-chloro-5,6-dimethyl-3-nitropyridine (1-013-05) (837 mg) in methanol (6.6 mL) for 5 min at room temperature under nitrogen atmosphere, and the reaction mixture was heated with stirring, in oil-bath at 50° C. for 7 h. To the reaction mixture was added diethyl ether and the reaction mixture was poured into water, extracted with twice with diethyl ether, washed once with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5,6-dimethyl-2-methoxy-3-nitropyridine (1-013-06) (675 mg, 82.6%, m.p.: 71-73° C.) as an orange crystal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][N:7](N)[C:6]=2[CH:15]=1.[C:16]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][N:7]3[C:6]=2[C:15]=1[C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=13
Reactant: CN1CCc2ccc(F)cc2N(N)CC1
Reactant: O=C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCO
Solvent: ClCCl
Solvent: O
Product: CN1CCc2ccc(F)c3c4c(n(c23)CC1)CCCC4
Temperature: 25 °C
Yield: 24.6 %

Procedure:
To a solution of 9-fluoro-4-methyl-3,4,5,6-tetrahydro-2H-benzo[e][1,4]diazocin-1-ylamine (1.79 g, 8.5 mmole) in 1-propanol (100 mL) was added cyclohexanone (9 ml, 86.8 mmole), followed by p-toluenesulfonic acid monohydrate (3.5 g, 18.1 mmole), and the resulting reaction mixture was refluxed for 30 hours. The reaction mixture was cooled to room temperature and solvent removed in vacuo to produce a brown residue. The residue was diluted with methylene chloride (300 mL) and washed with saturated aqueous sodium bicarbonate (200 mL), saturated aqueous sodium chloride (200 mL), dried (sodium sulfate) and concentrated in vacuo. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 1:1) provided 0.57 g of the title compound. 50 mg of the free amine was treated with one equivalent of fumaric acid in ethanol to form a fumarate salt 63.7 mg, mp 206-208° C. MS (ESI) m/z 273 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]3C(=O)C4C(=CC=CC=4)C3=O)([CH3:16])[C:4]=2[CH:3]=1.O.NN.Cl.ClCCl>C(O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])([CH3:16])[C:4]=2[CH:3]=1
Reactant: CC1(CCCCN2C(=O)c3ccccc3C2=O)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: Cl
Agent: NN
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CC1(CCCCN)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
2-(4-(2,7-dibromo-9-methyl-9H-fluoren-9-yl)butyl)isoindoline-1,3-dione (3.08, 5.71 mmol) was dissolved in ethanol (250 mL) under nitrogen. To the mixture was added hydrazine monohydrate (2.77 mL, 57.1 mmol), and the reaction was refluxed at 80° C. for 3.0 hours. The reaction was cooled to room temperature, and added 1M HCl (˜100 mL). The mixture was stirred for 30 minutes or until all solids were dissolved. Dichloromethane was added to the solution and the organic layer was extracted with saturated NaHCO3 three times, and washed with water. The organic layers were collected and removed solvent by vacuo to give an yellow oil (2.33 g, 100%). 1H NMR (500 MHz, CD2Cl2): δ=7.57 (d, 2H), 7.52 (d, 2H), 7.46-7.48 (dd, 2H), 2.39-2.42 (t, 2H), 1.95-1.98 (t, 2H), 1.44 (s, 3H), 1.17-1.23 (m, 2H), 0.59-0.65 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[C:10](=[O:15])([O:12][CH2:13][CH3:14])N.N.[CH2:17]([OH:19])[CH3:18].[CH2:20]([OH:22])C>>[CH2:13]([O:12][C:10]([NH:1][C:2]1[CH:7]=[C:6]([NH:8][C:20]([O:19][CH2:17][CH3:18])=[O:22])[CH:5]=[CH:4][C:3]=1[CH3:9])=[O:15])[CH3:14]
Reactant: CCOC(N)=O
Reactant: CCO
Reactant: Cc1ccc(N)cc1N
Agent: N
Product: CCOC(=O)Nc1ccc(C)c(NC(=O)OCC)c1
Temperature: 40 °C
Reaction time: 5 h
Yield: 64.1 %

Procedure:
122 g (1 mol) of 2,4-Diaminotoluene and 1782 g (20 mol) of ethyl carbamate are heated to 200° C. in the presence of 320 g of ethanol, with stirring, in a 5-liter stirrer autoclave, and 1300 ml of an ammonia/ethanol mixture are distilled off per hour. The autoclave is adjusted to a pressure of from 6 to 10 bar by means of a control valve and the ethanol concentration is kept constant by pumping in fresh ethanol. After a reaction time of 5 hours, the autoclave is left to cool down, emptied, and the alcohol is distilled at 40° to 90° C./90 mbar. The distillation residue (1224 g) is taken up with 1200 g of water at 95° C. and intensively stirred. 260 g of 2,4-bis-(ethoxycarbonylamino)-toluene precipitate after cooling of the solution to 40° C. and are filtered off. The 2,4-bis-(ethoxycarbonylamino)-toluene is again taken up with 300 g of boiling water, and reprecipitated at 40° C. 170.4 g (64.1% of theoretical) of 2,4-bis-(ethoxycarbonylamino)-toluene are obtained after drying over night in a drying cupboard at 90° C./100 mbar.
Reaction SMILES: [H][H].[C]=O.[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[Pd]>[CH:5]1([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: [C]=O
Product: c1ccc(C2CCCCC2)cc1

Procedure:
In addition, U.S. Pat. No. 5,146,024 discloses that benzene can be reacted with hydrogen in the presence of carbon monoxide and a palladium-containing zeolite X or Y to produce cyclohexylbenzene, which can then be converted in high yield to phenol and cyclohexanone by autooxidation with subsequent acid treatment. The hydroalkylation reaction is carried out at a liquid hourly space velocity (LHSV) of the benzene feed of about 1 to about 100 hr−1, a total reaction pressure of about 345 to about 10,350 kPa, a molar ratio of H2 to benzene of about 0.1:1 to about 10:1, a molar ratio of carbon monoxide to H2 of about 0.01:1 to about 0.3:1, and a temperature of about 100 to about 250° C. Preferred operating conditions are said to include a LHSV of the benzene feed of about 5 to about 30 hr−1, a total reaction pressure of about 1,380 to about 4,830 kPa, a molar ratio of H2 to benzene of about 0.2:1 to about 1:1, a molar ratio of CO to H2 of about 0.02:1 to about 0.1:1, and a reaction temperature of about 140 to about 200° C.
Reaction SMILES: C(O[C:4](=[O:21])[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:7][C:6]=1[CH:18]([F:20])[F:19])C.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1.C[Al](C)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:4](=[O:21])[C:5]2[C:10]([CH3:11])=[CH:9][C:8]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[CH:7][C:6]=2[CH:18]([F:19])[F:20])=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1c(C)cc(N2CCOCC2)cc1C(F)F
Reactant: NCc1ccc(Cl)cc1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCOCC2)cc(C(F)F)c1C(=O)NCc1ccc(Cl)cc1
Temperature: 110 °C
Yield: 13 %

Procedure:
A mixture of 2-(difluoro-methyl)-6-methyl-4-morpholin-4-yl-benzoic acid ethyl ester (0.30 g, 1.00 mmol), 4-chlorobenzylamine (1.42 g, 10.0 mmol) and trimethylaluminium (2M in toluene) (3.50 ml, 7.00 mmol) in toluene (10 ml) is heated at 110° C. for 18 h. After completion of the reaction (monitored by TLC), a 2M aqueous solution of sodium hydroxide is carefully added and the mixture is extracted with ethyl acetate (2×15 ml). The combined organic layers are washed with 2M aqueous solution of sodium hydroxide (10 ml), brine (10 ml) and dried over sodium sulfate. The solvent is evaporated to get the crude product, which is purified by column chromatography (silica gel, 30% ethyl acetate/cyclohexane) to afford N-[(4-chlorophenyl)-methyl]-2-(difluoro-methyl)-6-methyl-4-morpholin-4-yl-benzamide (example 20) (0.05 g, 0.13 mmol, 13%). [M+H]+ 395.1.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[CH:5]1([C:11]2[CH:22]=[CH:21][C:14]([O:15][CH2:16][C:17]3([CH3:20])[CH2:19][O:18]3)=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>CO>[CH:5]1([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]3([CH3:20])[O:18][C:2](=[NH:3])[NH:1][CH2:19]3)=[CH:21][CH:22]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CC1(COc2ccc(C3CCCCC3)cc2)CO1
Reactant: N#CN
Agent: [Na]
Solvent: CO
Product: CC1(COc2ccc(C3CCCCC3)cc2)CNC(=N)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
Methanol (250 ml) and sodium hydrogen cyanamide (1.92 g, 30 mmol) were added to a flask containing 2-(4-cyclohexyl-phenoxymethyl)-2-methyl-oxirane (6.15 g, 25 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. The residue was dissolved in methylene chloride and washed with water, then saturated potassium carbonate. The methylene chloride layer was dried over 4 A molecular sieves, filtered and concentrated in vacuo to yield 5.46 g of a white solid. The white solid was recrystallized from ether to yield 1.11 g of the title compound as white crystals. A second crop yielded 0.64 g of white crystals.
Reaction SMILES: [C:1]1([S:7]([CH2:9][Cl:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1.[F:19][C:20]([F:33])([F:32])[S:21]([O:24]S(C(F)(F)F)(=O)=O)(=[O:23])=[O:22]>C(OCC)C>[O-:24][S:21]([C:20]([F:33])([F:32])[F:19])(=[O:23])=[O:22].[Cl:10][CH2:9][S+:7]([C:17]1[CH:16]=[C:15]([CH3:18])[CH:14]=[CH:13][C:12]=1[CH3:11])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(CCl)c1ccccc1
Reactant: Cc1ccc(C)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: Cc1ccc(C)c([S+](CCl)c2ccccc2)c1
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
Chloromethyl phenyl sulfoxide (300 mg, 1.94 mmol) of example 21 was dissolved in dry diethyl ether (7.5 mL) under an argon atmosphere. p-Xylene (227 mg, 1.1 eq) was added to the previous solution and the mixture was cooled to a temperature below −60° C. After stabilizing the temperature, trifluoromethanesulfonic anhydride (0.326 mL, 1 eq) was added slowly maintaining the same temperature. The mixture was stirred until the reaction was complete. The precipitate triflate salt formed was isolated by filtration and washed with cold diethyl ether at 0° C. 602 mg (75%) of the desired product was obtained as a oily solid after heating at room temperature. δ 7.91 (2H, d, J=7.9 Hz), 7.85 (1H, s), 7.73-7.64 (3H, m), 7.44 (1H, d, J=7.8 Hz), 7.33 (1H, d, J=7.9 Hz), 5.97 (2H, s), 2.52 (3H, s), 2.44 (3H, s). 13C NMR (CDCl3, 100 MHz): δ 140.3, 138.6, 136.1, 135.1, 132.7, 131.5, 131.0, 129.3, 122.2, 121.8, 120.3, 118.7, 51.6, 20.7, 19.3. FT-IR (NaCl): 3025, 2956, 1494, 1448, 1251, 1168, 1029 cm−1.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[CH:6]1([NH:9][C:10](=[O:38])[C:11]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:12][C:13]2[CH:30]=[CH:29][C:16]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](OC)=[O:26])=[O:18])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1>CO.C(Cl)Cl.O>[CH:6]1([NH:9][C:10](=[O:38])[C:11]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)=[CH:12][C:13]2[CH:30]=[CH:29][C:16]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:2][OH:3])=[O:26])=[O:18])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1
Reactant: NO
Reactant: COC(=O)CCCCCNC(=O)c1ccc(C=C(C(=O)NC2CC2)c2ccc(F)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=C(CCCCCNC(=O)c1ccc(C=C(C(=O)NC2CC2)c2ccc(F)cc2)cc1)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
Hydroxylamine hydrochloride (0.55 g, 8 mmol) in methanol (3 mL) was mixed with KOH (0.45 g, 8 mmol) in methanol (3 mL) at 0° C., and sonicated for 2 minutes and the white precipitate formed was filtered. The filtrate was added to the methyl 6-(4-(3-(cyclopropylamino)-2-(4-fluorophenyl)-3-oxoprop-1-enyl)benzamido)hexanoate (0.2 g, 0.4 mmol) in DCM (1.5 mL) and the mixture was stirred at room temperature, for 30 minutes. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). The ethyl acetate layer was washed with water (100 mL), dried over anhydrous Na2SO4 and concentrated to afford the title compound (0.040 g, 20% yield). 1H NMR (DMSO-d6) δ (ppm): 0.52 (2H, m, 0.63-0.64 (2H, m, —CH2), 1.23-1.25 (2H, m, CH2), 1.44-1.50 (4H, m, CH2), 1.90-1.94 (2H, m, CH2), 2.74-2.75 (1H, m, —CH), 3.17-3.19 (2H, m, CH2), 7.04 (2H, d, Ar—H), 7.16-7.22 (4H, m, Ar—H), 7.28 (1H, s, ═C), 7.63 (2H, d, Ar—H), 7.89 (1H, d, NH), 8.36 (1H, t, NH), 8.66 (1H, s, —OH), 10.32 (1H, s, NH), MS m/z: 452.2 (M+−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([NH2:19])=[O:18])[CH:11]=2)=[C:4]([CH3:20])[CH:3]=1.[H][H]>CO.C(Cl)Cl.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([NH2:19])=[O:18])[CH:11]=2)=[C:4]([CH3:20])[CH:3]=1
Reactant: [H][H]
Reactant: Cc1cc(F)ccc1C#Cc1ccnc(NC(N)=O)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(F)ccc1CCc1ccnc(NC(N)=O)c1
Yield: 70.8 %

Procedure:
[4-(4-Fluoro-2-methyl-phenylethynyl)-pyridin-2-yl]-urea (25 mg, 0.093 mmol) is dissolved in methanol (1.0 mL) and DCM (1.0 mL). Then 5% palladium on carbon (20 mg, 0.0090 mmol) is added. The reaction is stirred for 16 hrs under the hydrogen atmosphere. The palladium on carbon is filtered and the filtrate is concentrated to give the crude product. Methanol (1 mL) is added into the crude and a white solid is formed. The solid is filtered, rinsed with more methanol and dried to give 18 mg of the titled product.