Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([N:4]1[C:8]2[CH:9]3[CH2:20][CH:11]([C:12]4[CH:17]=[C:16]([F:18])[C:15](I)=[CH:14][C:13]=4[C:7]=2[N:6]=[C:5]1[C:21]([NH2:23])=[O:22])[CH2:10]3)[F:3].[CH3:24][C:25]([OH:29])([C:27]#[CH:28])[CH3:26]>N1CCCCC1.[Cu]I.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>[F:1][CH:2]([F:3])[N:4]1[C:8]2[CH:9]3[CH2:20][CH:11]([C:12]4[CH:17]=[C:16]([F:18])[C:15]([C:28]#[C:27][C:25]([OH:29])([CH3:26])[CH3:24])=[CH:14][C:13]=4[C:7]=2[N:6]=[C:5]1[C:21]([NH2:23])=[O:22])[CH2:10]3
Reactant: NC(=O)c1nc2c(n1C(F)F)C1CC(C1)c1cc(F)c(I)cc1-2
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC(C)(O)C#Cc1cc2c(cc1F)C1CC(C1)c1c-2nc(C(N)=O)n1C(F)F
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 39.7 %

Procedure:
To a solution of -(difluoromethyl)-8-fluoro-9-iodo-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide (12 mg at 80% purity LCMS-UV215) in piperidine (0.5 mL) was introduced 2-methyl-3-butyn-2-ol (12 mg, 0.14 mmol) and copper(I) iodide (0.3 mg, 0.001 mmol). The solution was de-oxygenated by nitrogen bubbling for five minutes, then tetrakis(triphenylphosphine)palladium(0) (0.6 mg, 0.001 mmol) added and bubbling continued for a further two minutes. The pressure tube was closed under an atmosphere of nitrogen and the reaction mixture warmed to 40° C. for 2 hr. After evaporation of the reaction mixture in vacuo, the residue was suspended in ethyl acetate (20 mL) and washed with saturated aqueous sodium bicarbonate (2×7 mL), water (2×7 mL) and brine (7 mL). The organic extract was dried over sodium sulfate, filtered, and the filtrate adsorbed onto silica gel in vacuo. Partial purification of the dry-loaded material by silica gel flash column chromatography (eluent: heptane/ethyl acetate gradient) was followed by suspension of the product in acetonitrile/water (3:1, 0.4 mL). Filtration furnished the title compound (4.5 mg, 0.011 mmol, 6% over 3 steps) as a colorless solid: 1H NMR (500 MHz, CDCl3) δ 1.67 (s, 6H), 1.73 (d, J=11.35 Hz, 2H), 2.93-3.04 (m, 2H), 3.60 (td, J=7.96, 3.31 Hz, 1H), 3.84-3.92 (m, 1H), 5.56 (br. s., 1H), 6.87 (d, J=10.09 Hz, 1H), 7.42 (br. s., 1H), 8.40 (d, J=7.57 Hz, 1H), 8.75 (t, J=58.40 Hz, 1H); M+H=390.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:29]=1)[C:7]([N:9]=[S@@:10]([CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:30]([C:32]1[CH:33]=[C:34]([NH:38][C:39]([C:41]2[O:42][CH:43]=[CH:44][C:45]=2[CH3:46])=[O:40])[CH:35]=[CH:36][CH:37]=1)#[CH:31].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C.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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Si:22]([O:21][CH2:20][CH2:19][CH2:18][S@:10](=[O:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N:9][C:7](=[O:8])[C:6]1[CH:29]=[C:2]([C:31]#[C:30][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C:39]([C:41]3[O:42][CH:43]=[CH:44][C:45]=3[CH3:46])=[O:40])[CH:33]=2)[CH:3]=[N:4][CH:5]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: C#Cc1cccc(NC(=O)c2occc2C)c1
Reactant: CC(C)(C)[Si](C)(C)OCCC[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCO[Si](C)(C)C(C)(C)C)c3ccccc3)c2)c1
Temperature: 60 °C
Yield: 89.7 %

Procedure:
To the solution of (S)-5-bromo-N-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)(oxido)phenyl--sulfanylidene]nicotinamide (1.9 g, 3.82 mmol) in anhydrous DMF (19 mL) under nitrogen atmosphere was added sequentially 3-methyl-furan-2-carboxylic acid (3-ethynyl-phenyl)-amide (1.72 g), triethylamine (2.13 mL), bis(triphenylphosphine)palladium(II) dichloride (268 mg), and triphenylphosphine (25 mg). The reaction system was placed under a N2—H2 (1:1) atmosphere and CuI (145 mg) was added in one portion. After the reaction mixture was stirred and heated at 60° C. for 1.5 hours, it was poured into saturated aqueous NaHCO3. The aqueous was extracted with EtOAc (1×), which was subsequently washed with aqueous NaHCO3 (1×), brine (1×), and dried (anhydrous Na2SO4). The organic layer was decanted, evaporated and wrapped with silica gel. Two times column chromatography (EtOAc-Hex:from 1:4 to 1:2; and MeOH—CH2Cl2: 1:100) gave the title compound as yellow foam (2.2 g, 90%).
Reaction SMILES: COC([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8][C:7]1=[O:16])=O.[CH3:17][Si](I)(C)C>C(#N)C.C(OCC)(=O)C>[NH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][N:8]([CH3:17])[C:7]1=[O:16]
Reactant: COC(=O)NC1C(=O)NCc2ccccc21
Reactant: C[Si](C)(C)I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1Cc2ccccc2C(N)C1=O
Temperature: 65 °C

Procedure:
Step D—Removal of the Methoxyoxycarbonyl Group (MOC): To the 4-methoxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-one (3.4 mmoles) in 30 mL of acetonitrile was added 2 mole equivalents of trimethylsilyliodide (TMSI). The reaction mixture was heated to 50-80° C. for 3 hrs and then cooled and poured into a seperatory funnel. The reaction mixture was diluted with ethyl acetate and washed with 1 molar K2CO3 and then with 5% NaHSO3. The organic layer was dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to give the 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one derivative. Typical yields range from 50-87%.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.CN(C)CCN(C)C.[Li]CCCC.Cl[C:37]([O:39][CH2:40][Cl:41])=[O:38]>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]2[N:7]([C:37]([O:39][CH2:40][Cl:41])=[O:38])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)[C:4]=2[CH:3]=1
Reactant: O=C(Cl)OCCl
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc2c(s1)N(C(=O)OCCl)c1ccccc1N=C2N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.4 %

Procedure:
To a solution of olanzapine (5.0 g, 16 mmol) in tetrahydrofuran (50 mL) at −78° C. was added tetramethylethylenediamine (2.4 mL, 16 mmol), followed by 2M n-BuLi in hexanes (8.0 mL, 16 mmol) over 5 min. The reaction mixture was stirred for 15 min and then chloromethyl chloroformate (2.1 mL, 24 mmol) added and the reaction mixture stirred a further 30 min. The reaction mixture was then warmed to room temperature, stirred for 1 h and quenched with water (50 mL). This mixture was diluted with brine (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was dried over MgSO4, evaporated and the residue further purified by column chromatography on silica eluting with 0.2:1:1 methanol/dichloromethane/ethyl acetate to give chloromethyl 2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate [C] (5.6 g, ˜50% pure by 1H NMR and LCMS). This was used directly in the next reaction without further purification. 1H-NMR (300 MHz, CDCl3) δ 7.02-7.30 (4H, m), 6.45 (1H, s), 5.78-5.92 (1.5H, m), 5.52-5.60 (0.5H, m), 3.50-3.70 (4H, m), 2.35-2.55 (7H, m), 2.32 (3H, s). [M+H]+=405.0
Reaction SMILES: [OH:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])[CH3:20]
Reactant: O=C(O)CCC1OC(=O)C(O)=C1c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1=C(c2ccccc2)C(CCC(=O)O)OC1=O
Reaction time: 8 h

Procedure:
3-(4-Hydroxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)-propionic acid (100 mg) was dissolved in pyridine (2 ml), and acetic anhydride (1 ml) was added. The mixture was allowed to stand overnight. The excess reagent and solvent were removed by distillation under reduced pressure, and the residue was dried to give 3-(4-acetoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionic acid (116 mg) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:9][C:10](OCC)=[O:11])=[O:5])[CH3:2].[O-]CC.[Na+].[Na]>C1C=CC=CC=1.C(O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:8]2[CH2:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:10](=[O:11])[CH2:9]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCN(CC(=O)OCC)c1ccc(OC)cc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: c1ccccc1
Solvent: CCO
Product: CCOC(=O)C1CN(c2ccc(OC)cc2)CC1=O
Temperature: 25 °C
Yield: 96.2 %

Procedure:
A solution of ethyl N-(b-ethoxycarbonylethyl)-N-(4-methoxyphenyl)glycinate (106.7 g, 0.345 mol) in dry benzene (400 mL) is added to a mixture of ethanolic sodium ethoxide in benzene (prepared by dissolving 13.1 g of sodium metal in 300 mL of ethanol and then the ethanolic sodium ethoxide solution is diluted with 500 mL of benzene) at room temperature over a period of 90 minutes. The mixture is heated at reflux for 30 minutes and then is cooled to room temperature. The solid is collected by filtration, and then is suspended in an ice-water mixture (1 L). The mixture, after being neutralized with 1 N hydrochloric acid, is extracted with diethyl ether (3×500 mL). The combined extracts are washed with water, dried over sodium sulfate, concentrated, and the residue is crystallized from n-hexane-diethyl ether to afford 1-(4-methoxyphenyl)-4-ethoxycarbonylpyrrolidine-3-one (87.4 g, 64%), mp 58°-60° C. 1H NMR (CDCl3) d 1.34 (3H, dt, CH2Me), 3.76 (3H, s, OMe), 3.75 (2H, dq, CH2Me), 4.14 (2H, s, 2-CH2), 4.12-4.39 (3H, m, H-4 and 5-CH2), 6.46 and 6.86 (each 2H, m, Ph).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@@H:14]([OH:15])[CH2:13][C@H:12]([O:16][C@H:17]3[C@@H:22]([OH:23])[CH2:21][C@H:20]([O:24][C@@H:25]4[CH2:30][C@H:29]5[CH2:31][CH2:32][C@H:33]6[C@@:38]7([OH:48])[CH2:39][CH2:40][C@H:41]([C:42]8[CH2:47][O:46][C:44](=[O:45])[CH:43]=8)[C@@:37]7([CH3:49])[C@H:36]([OH:50])[CH2:35][C@@H:34]6[C@@:28]5([CH3:51])[CH2:27][CH2:26]4)[O:19][C@@H:18]3[CH3:52])[O:11][C@@H:10]2[CH3:53])[CH2:5][C@H:4]([OH:54])[C@@H:3]1[OH:55].[CH2:56](O)C>>[CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@@H:14]([OH:15])[CH2:13][C@H:12]([O:16][C@H:17]3[C@@H:22]([OH:23])[CH2:21][C@H:20]([O:24][C@@H:25]4[CH2:30][C@H:29]5[CH2:31][CH2:32][C@H:33]6[C@@:38]7([OH:48])[CH2:39][CH2:40][C@H:41]([C:42]8[CH2:47][O:46][C:44](=[O:45])[CH:43]=8)[C@@:37]7([CH3:49])[C@H:36]([OH:50])[CH2:35][C@@H:34]6[C@@:28]5([CH3:51])[CH2:27][CH2:26]4)[O:19][C@@H:18]3[CH3:52])[O:11][C@@H:10]2[CH3:53])[CH2:5][C@H:4]([OH:54])[C@@H:3]1[O:55][CH3:56]
Reactant: CCO
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H](O[C@H]4CC[C@@]5(C)[C@H](CC[C@@H]6[C@@H]5C[C@@H](O)[C@]5(C)[C@@H](C7=CC(=O)OC7)CC[C@]65O)C4)O[C@@H]3C)O[C@@H]2C)C[C@H](O)[C@@H]1O
Product: CO[C@H]1[C@@H](O)C[C@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H](O[C@H]4CC[C@@]5(C)[C@H](CC[C@@H]6[C@@H]5C[C@@H](O)[C@]5(C)[C@@H](C7=CC(=O)OC7)CC[C@]65O)C4)O[C@@H]3C)O[C@@H]2C)O[C@@H]1C

Procedure:
4.75 l. of eluate with 40% ethanol contain 3.91 g. of solid material. The mixture contains all non-reacted digoxin, α-metildigoxin and β-metildigoxin and can again be separated on the column. The following fraction of 5 l. contains 4.73 g. of slightly contaminated β-metildigoxin. If the ethanol content is increased, diethers and higher ethers of digoxin are eluted. The main fraction with metildigoxin is reprecipitated from methanol/water, boiled up with chloroform and stirred up with acetone.
Reaction SMILES: [CH:1]12[CH2:10]C3CC(CC(C3)[CH:2]1OCC1C(Cl)=CC(C(NS(C)(=O)=O)=O)=C(F)C=1)C2.Cl[C:29]1[C:30]([O:43][CH2:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=1)[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35]>>[CH:45]1([CH2:44][O:43][C:30]2[C:29]([CH:10]3[CH2:1][CH2:2]3)=[CH:41][C:33]([C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35])=[C:32]([F:42])[CH:31]=2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CCCCC2)cc1F
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(COC2C3CC4CC(C3)CC2C4)cc1F
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 49 and making variations as required to replace 4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide with 5-chloro-4-(cyclohexylmethoxy)-2-fluoro-N-(methylsulfonyl)benzamide, the title compound was obtained as a colorless solid (0.19 g, 14%): 1H NMR (300 MHz, CDCl3) δ8.77-8.66 (m, 1H), 7.61-7.52 (m, 1H), 6.62-6.52 (m, 1H), 3.86-3.78 (m, 2H), 3.41 (s, 3H), 2.12-1.99 (m, 1H), 1.95-1.66 (m, 6H), 1.40-1.03 (m, 5H), 0.99-0.89 (m, 2H), 0.69-0.61 (m, 2H); MS (ES−) m/z 368.3 (M−1).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:9]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>O1CCCC1>[C:1]([NH:5][C:6]([C:8]1[C:9]([CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1ccccc1Cc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccccc1C(C(=O)C(C)(C)C)c1ccccc1
Temperature: 5 °C

Procedure:
To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube and maintained under a nitrogen atmosphere there is added at room temperature 59 g. (0.221 mole) of N-tert.butyl-α-phenyl-o-toluamide in 1000 ml. dry tetrahydrofuran. The flask is immersed in an ice bath and cooled to an internal temperature of 5° C. Stirring is initiated and 336.5 ml. (0.490 mole) of n-butyl lithium (15% in hexane) is added dropwise in about 1 hour maintaining the temperature below 8° C. The resulting solution is stirred 2 hours at room temperature, cooled to 5° C., and 26.6 g. (0.221 mole) of pivaloyl chloride in 250 ml. of dry tetrahydrofuran is added dropwise maintaining temperature below 8° C. After addition, the mixture is stirred 2 hours at room temperature and hydrolyzed with 150 ml. of saturated ammonium chloride, the resulting solution is filtered and the layers separated. The organic layer is dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is triturated with ether to give N-tert.butyl-α-phenyl-α-pivaloyl-o-toluamide; m.p. 157°-161° C.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([N+:17]([O-])=O)=[CH:11][CH:12]=3)[C:7](=[CH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[NH2:38])=[O:30])=[O:22])[C:6]=2[CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:17][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:16][CH:15]=3)[C:7](=[CH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[NH2:38])=[O:30])=[O:22])[C:8]=2[CH:9]=1
Reactant: [H][H]
Reactant: Nc1ccccc1NC(=O)CCCCCNC(=O)C=C1c2cc([N+](=O)[O-])ccc2-c2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)C(=CC(=O)NCCCCCC(=O)Nc1ccccc1N)c1cc(N)ccc1-2
Yield: 95.9 %

Procedure:
To a solution of 6-(2-(2,7-dinitro-9H-fluoren-9-ylidene)acetamido)-N-(2-aminophenyl)-hexanamide (515 mg, 1 mmol) in methanol (20 ml) was added 5% palladium on charcoal (0.50 g). Then the mixture was stirred under an atmosphere of hydrogen at room temperature until hydrogen uptake ceased. The solution was filtered through celite, and the filtrate was evaporated under vacuum to give the title compound (437 mg, 96% yield) as a white solid. LC-MS (m/z) 456 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CO.N([O-])=O.[Na+].[N-:27]=[N+:28]=[N-].[Na+]>Cl.O.C(OCC)(=O)C>[N:20]([C:17]1[CH:16]=[CH:15][C:14]([N:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[N:11]=2)[CH3:13])=[CH:19][CH:18]=1)=[N+:27]=[N-:28]
Reactant: Cc1nc(N(C)c2ccc(N)cc2)c2ccccc2n1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(N(C)c2ccc(N=[N+]=[N-])cc2)c2ccccc2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
To a solution of (2-methyl-quinazolin-4-yl)-(4-amino-phenyl)-methylamine (20 mg, 0.076 mmol) in 1.2 mL of 1N HCl was added 100 uL of methanol and it was cooled 0° C. One drop of concentrated HCl was added and the solution was stirred at 0° C. for 0.25 h. To the solution was added dropwise a solution of sodium nitrite (25 mg, 0.36 mmol) in 200 uL of water. The reaction mixture was stirred for 0.5 h, then was added a solution of sodium azide (25 mg, 0.38 mmol) in 300 uL of water followed by another batch of sodium azide (25 mg, 0.38 mmol). The reaction mixture was stirred at the 0° C. for 1 h. The reaction mixture was diluted with 50 mL of ethyl acetate, washed with saturated sodium bicarbonate followed by saturated sodium chloride. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (20-25% ethyl acetate/hexanes) on silica gel to give the title compound (19.8 mg, 0.068 mmol, 90%). 1H NMR (CDCl3): 7.76 (m, 1H), 7.56 (ddd, J=8.1, 6.3, 1.8, 1H), 7.13 (m, 2H), 6.98-7.13 (m, 4H), 3.61 (s, 3H), 2.74 (s, 3H).
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[CH:5]1(Br)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>[N+](CC)([O-])=O>[CH:5]1([NH:4][C:1](=[O:3])[CH3:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CC(N)=O
Reactant: BrC1CCCCC1
Solvent: CC[N+](=O)[O-]
Product: CC(=O)NC1CCCCC1
Yield: 55.8 %

Procedure:
To 200 ml of nitroethane, were added 12 g of acetamide, 105 of MP-500, which was also used in Example 68, and 41 g of cyclohexylbromide. They were reacted at 60° C. for 5 hours with stirring. After the reaction, the ionexchange resin was filtered off and the resulting filtrate was distilled under reduced pressure to remove the solvent and unreacted raw materials. The resulting distillation residue was recrystallized from petroleum ether, thereby obtaining 16 g of N-cyclohexylacetamide having a melting point of 108°-109° C.(yield: 57%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH3:29][NH:30][CH3:31]>>[CH3:29][N:30]([CH3:31])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Reactant: CNC
Product: CN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(F)c(N3CCCCC3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI): predicted mass calcd. for C19H21FN6O2, 384.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:4][CH:3]=1.C(O[CH:20](N(C)C)[N:21]([CH3:23])[CH3:22])(C)(C)C>>[CH3:20][N:21]([CH3:23])[CH:22]=[C:10]1[C:9](=[O:14])[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: O=C1CCCCC1c1ccc(Cl)cc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C1CCCC(c2ccc(Cl)cc2)C1=O

Procedure:
2-(4-Chloro-phenyl)-cyclohexanone (104 mg, 0.5 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (134 mg) as a red oil which was used directly in the next step. MS ISP (m/e): 264.0 [(M+H)+].
Reaction SMILES: [N:1]1([C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:15]=[C:11]3[N:10]=[C:9]([NH:22][NH2:23])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:24][C:25]1[O:26][C:27]2[C:33]([CH:34]=O)=[CH:32][CH:31]=[CH:30][C:28]=2[CH:29]=1.C(O)(=O)C>C(O)C>[CH3:24][C:25]1[O:26][C:27]2[C:33]([CH:34]=[N:23][NH:22][C:9]3[CH:8]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:12]4[N:13]=[C:14]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH:15]=[C:11]4[N:10]=3)=[CH:32][CH:31]=[CH:30][C:28]=2[CH:29]=1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: Cc1cc2cccc(C=O)c2o1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc2cccc(C=NNc3cc(N4CCOCC4)n4nc(-c5ccccc5)cc4n3)c2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
To a solution of 7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl-hydrazine (25 mg, 0.081 mM) in absolute ethanol (2.0 mL), there were added 2-methyl-7-formyl-benzofuran (19 mg, 0.12 mM) and acetic acid (2.0 μL) and the mixture was stirred at room temperature for 3 hours. The precipitated solid was recovered through filtration and washed with ethanol to thus give the title compound (28 mg, yield: 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([NH:28]CC5C=CC(OC)=CC=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([NH2:28])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: COc1ccc(CNc2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 80 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(4-methoxy-benzyl)-amine (1.2 g, 2.3 mmol) was dissolved in TFA (20 mL). The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated in vacuo, and dissolved in DCM (30 mL). The organic layer was washed by water, dried by Na2SO4, concentrated in vacuo, and separated by preparative TLC (DCM/EtOAc=4:1) to give 134 (800 mg, yield: 87%) 1H NMR (D2O, 400 MHz): δ8.05 (s, 2 H), 7.05 (d, J=8.8 Hz, 1H), 7.23 (t, J=2.0 Hz, 1H), 7.14 (s, 1 H), 6.99-6.97 (m, 3 H), 6.51 (d, J=8.8 Hz, 1H). LC-MS (ESI): m/z=398 [M+H]+
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[Li]CCCC.[C:35]([C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:49])[CH:47]=O)=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36].O>C1COCC1>[C:35]([C:39]1[CH:40]=[CH:41][C:42]([CH2:45][CH:46]([CH3:49])[CH:47]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=2)=[CH:43][CH:44]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C=CC(C)Cc2ccc(C(C)(C)C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
A solution of (4-methoxyphenyl)methyltriphenylphosphonium bromide (2.40 g, 5.18 mmol, 1.0 equiv.) in THF (10 mL), was cooled to 0° C. After adding n-BuLi (1.6 M in hexanes, 3.2 mL, 5.18 mmol, 1.0 equiv.) at 0° C., the red suspension was stirred at 0° C. for 15 min. 3-(4-tert-Butylphenyl)-2-methylpropanal (1.59 g, 7.77 mmol, 1.5 equiv.) in THF (4 mL) was added, and the mixture was stirred at 0° C.→25° C. for 12 h. After addition of H2O at 25° C., the aqueous layer was extracted with hexanes, the combined organic phases were dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane/EtOAc 995:5→99:1) to yield 1.33 g (83%) of the title compound as a colorless oil.