Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[NH:4][CH2:3][C:2]1=[O:11].[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH:16]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CC(O)=O.C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][N:4]1[C@@H:5]2[C@H:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[NH:1][C:2](=[O:11])[CH2:3]1
Reactant: O=C1CN[C@H]2CCCC[C@@H]2N1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(CN2CC(=O)N[C@H]3CCCC[C@@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.3 %

Procedure:
A mixture of (4aS,8aS)-octahydroquinoxalin-2(1H)-one (8.82 g, 57.19 mmol), 2,4-dimethoxybenzaldehyde (9.50 g, 57.19 mmol), and sodium triacetoxyborohydride (36.31 g, 171.57 mmol) in 1% HOAc in CH2Cl2 (250 mL) was stirred at room temperature for 16 h. The mixture was neutralized with saturated aqueous NaHCO3 solution (200 mL). The organic layer was separated and washed with H2O (100 mL), brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0% to 100% 90:9:1 CH2Cl2/CH3OH/NH4OH in CH2Cl2) afforded (4aS,8aS)-4-(2,4-dimethoxybenzyl)octahydroquinoxalin-2(1H)-one (1.10 g, 11.1% over two steps). 1H NMR and MS consistent.
Reaction SMILES: C(O)(=O)C.[BH4-].[Na+].[C:7]([O:11][C:12](=[O:30])[NH:13][C@@H:14]([C:18]([CH:20]1[C:25](=[O:26])[O:24][C:23]([CH3:28])([CH3:27])[O:22][C:21]1=[O:29])=O)[CH:15]([CH3:17])[CH3:16])([CH3:10])([CH3:9])[CH3:8]>CCCCCCC.ClCCl>[C:7]([O:11][C:12](=[O:30])[NH:13][C@@H:14]([CH2:18][CH:20]1[C:25](=[O:26])[O:24][C:23]([CH3:28])([CH3:27])[O:22][C:21]1=[O:29])[CH:15]([CH3:17])[CH3:16])([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)C1C(=O)OC(C)(C)OC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)[C@H](CC1C(=O)OC(C)(C)OC1=O)NC(=O)OC(C)(C)C
Temperature: 3 °C
Reaction time: 1.5 h

Procedure:
In a 5 L one-neck flask four-necked flask (equipped with mechanical stirrer, nitrogen inlet, thermocouple, and glass stopper), was charged the solution of (R)-[1-(2,2-dimethyl-4,6-dioxo-[1,3]dioxane-5-carbonyl)-2-methyl-propyl]-carbamic acid, tert-butyl ester in dichloromethane prepared in Step A above, (˜3.2 L). The reaction was chilled to ˜3° C. in an ice bath, and acetic acid was added (437 g, 7.27 mol). The reaction mixture was then treated with sodium borohydride granules (62.5 g, 1.65 mol), which were added in portions over 1 h. During the addition the reaction temperature increased to ˜9° C. and was stirred at that temperature 1.5 h and then was split into two portions. Each portion was poured into brine (1 L), stirred (magnetically) for 20 minutes, and partitioned. Each organic phase washed with brine (3×750 mL) and distilled water (2×500 mL). The combined organic phases were dried (MgSO4) and concentrated to yield crude product. The crude product was dissolved in heptane-dichloromethane (˜1:1) and loaded onto a Biotage 150M cartridge (2.5 kg silica gel) and then eluted with heptane (2 L), 15:85 (14 L), 3:7 (16 L), and 1:1 ethyl acetate-heptane (8 L) to give two main fractions. The first fraction yielded the desired material contaminated with minor impurities.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH3:20][CH:21]([NH:23][CH2:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:22].N12CCCN=C1CCCCC2>C(#N)C>[CH3:20][CH:21]([NH:23][CH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:19])[CH2:26]1)[CH3:22]
Reactant: CC(C)NCC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)NCC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.6 %

Procedure:
A suspension of 1.13 g (3.0 mmole) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 0.63 g (4.4 mmole) of 3-[(2-propyl)aminomethyl]pyrrolidine, 1.22 g (8.0 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 30 ml of acetonitrile was stirred at room temperature for two hours. The precipitate was removed by filtration, washed with acetonitrile, and dried in vacuo to give 1.3 g (84%) of the title compound, mp 240°-243° C.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[O:22][CH3:23])[C:10]([CH3:12])([CH3:11])[C:6]=2[C:5]([F:25])=[C:4]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]2[NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:47][N:48]1[CH:52]=[C:51](B2OC(C)(C)C(C)(C)O2)[CH:50]=[N:49]1>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.CN(C=O)C>[CH3:23][O:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[CH2:13][N:9]1[C:10]([CH3:12])([CH3:11])[C:6]2[C:5]([F:25])=[C:4]([NH:26][C@@H:27]3[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]3[NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:39])[CH3:37])[N:3]=[C:2]([C:51]3[CH:50]=[N:49][N:48]([CH3:47])[CH:52]=3)[C:7]=2[C:8]1=[O:24]
Reactant: COc1ccc(CN2C(=O)c3c(Cl)nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)c(F)c3C2(C)C)c(OC)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)c3c(-c4cnn(C)c4)nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)c(F)c3C2(C)C)c(OC)c1
Temperature: 160 °C
Yield: 15.4 %

Procedure:
In a sealed tube, a mixture of tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1,1-dimethyl-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (30 mg, 0.052 mmol), Na2CO3 aq (2M, 0.065 mL, 0.130 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (12.98 mg, 0.062 mmol), bis(triphenylphosphine)palladium chloride (3.65 mg, 5.20 μmol), and DMF (1 mL) was heated at 160° C. for 0.5 h in a microwave oven. The reaction mixture was then heated at 160° C. for an additional 4 h in a microwave oven and was subsequently purified by preparative HPLC to give the title compound as a light yellow solid (5 mg, 18%). [M+H] calc'd for C28H35FN6O3, 524. found 524.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.[Br:10][C:11]1[C:19]([F:20])=[CH:18][C:14](/[CH:15]=[N:16]/O)=[C:13]([F:21])[CH:12]=1>CN(C=O)C.O>[Br:10][C:11]1[C:19]([F:20])=[CH:18][C:14]([C:15]#[N:16])=[C:13]([F:21])[CH:12]=1
Reactant: O/N=C/c1cc(F)c(Br)cc1F
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(F)c(Br)cc1F
Reaction time: 1 h
Yield: 67.7 %

Procedure:
A solution of cyanuric chloride (3.12 g, 16.94 mmol) and dry DMF (8.5 mL) was stirred for 30 min or until the formation of white solid. Disappearance of cyanuric chloride was confirmed by TLC. (E)-4-bromo-2,5-difluorobenzaldehyde oxime (4.0 g, 16.94 mmol) in DMF (26 mL) was added dropwise to the suspension and stirred for 1 h. The reaction mixture was diluted with water and extracted with hexanes. The organic extract was washed with water, washed with saturated brine solution, dried (Na2SO4), filtered, and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (SiO2, eluting with 2-20% ethyl acetate in hexanes) to provide the title compound as a white solid (2.5 g, 68%): 1H NMR (400 MHz, CDCl3) δ 7.40 (dd, J=5.36, 7.10 Hz, 1H), 7.52 (dd, J=5.40, 7.66 Hz, 1H); EIMS m/z 218.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]#[N:15])=[C:4]([CH:16]=[CH2:17])[N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[N:3]=[C:4]([CH2:16][CH3:17])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: C=Cc1nc(N)nc(-c2ccccc2)c1C#N
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCc1nc(N)nc(-c2ccccc2)c1C#N
Yield: 34.7 %

Procedure:
A solution of 100 mg (0.45 mmol) 2-amino-4-phenyl-6-vinyl-pyrimidine-5-carbonitrile in 10 ml ethanol was stirred with a spatula end of 10% palladium on charcoal under 1 atm of hydrogen for 16 h at room temperature. After filtration to remove the catalyst, the reaction mixture was concentrated in vacuo and the residue triturated in ether to afford 35 mg (35%) 2-amino-4-ethyl-6-phenyl-pyrimidine-5-carbonitrile as a white crystalline solid. EI-MS m/e (%): 224 (M+, 44), 223 ([M—H]+, 100).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[C:12](OS(C(F)(F)F)(=O)=O)=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH2:35]>>[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH:35][C:12]1[C:9]2[CH2:10][CH2:11][N:5]([C:3](=[O:4])[C:2]([F:1])([F:28])[F:29])[CH2:6][CH2:7][C:8]=2[CH:15]=[CH:14][C:13]=1[C:16]([F:17])([F:18])[F:19]
Reactant: NCc1cccc(F)c1
Reactant: O=C(N1CCc2ccc(C(F)(F)F)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: O=C(N1CCc2ccc(C(F)(F)F)c(NCc3cccc(F)c3)c2CC1)C(F)(F)F
Yield: 52.8 %

Procedure:
Use a method similar to the General Procedure 5-1 to couple 3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (110 mg, 0.24 mmol) and 3-fluorobenzyl amine (90 μL, 0.7 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (95:5) followed by SCX chromatography to give 6-(3-fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (55 mg, 53%). MS (ES+) m/z: 435 (M+H)+.
Reaction SMILES: Br[C:2](Br)([CH2:5][CH3:6])[CH2:3][CH3:4].[C:8]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[K].C([O-])(C)(C)C.Cl>C1(C)C=CC=CC=1>[C:8]1(=[O:14])[C:13]2([CH2:6][CH2:5][CH2:2][CH2:3][CH2:4]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1CCCCC1
Reactant: CCC(Br)(Br)CC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K]
Solvent: Cc1ccccc1
Product: O=C1CCCCC12CCCCC2

Procedure:
Dibromopentane (5 mmol) is added to a solution of cyclohexanone (5 mmol) and potassium-tert-butanolate (10 mmol) in toluene (7.5 ml) and the reaction mixture is refluxed for 48 hours. After cooling to room temperature 25% hydrochloric acid is added and extraction is carried out with diethyl ether. The combined organic phases produce, after drying over sodium sulphate, removal of the solvent in a vacuum and chromatography of the residue using silica gel (ethyl acetate/heptane, 1:5) pure spiro[5.5]undecan-1-one (Tetrahedron 1964, 20, 2553-2573): tR 1.90 min. (LC-2); ESI-MS (+): m/z 167.27 [M+H]+.
Reaction SMILES: C([C@@H]1COC(=O)[N:9]1[C:14](=[O:40])[C@@H:15]([CH2:30][C:31]1[CH:36]=[C:35]([CH3:37])[C:34]([F:38])=[C:33]([CH3:39])[CH:32]=1)[CH2:16][CH2:17][N:18]([CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH3:19])C1C=CC=CC=1.[C-]#N.[K+].Cl.C1C[O:48]CC1.CO>>[F:38][C:34]1[C:35]([CH3:37])=[CH:36][C:31]([CH2:30][C@@H:15]([CH2:16][CH2:17][N:18]([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:19])[C:14]([NH:9][OH:48])=[O:40])=[CH:32][C:33]=1[CH3:39]
Reactant: Cc1cc(C[C@@H](CCN(C)CCCc2ccc(F)cc2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc(C)c1F
Reactant: C1CCOC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: Cc1cc(C[C@@H](CCN(C)CCCc2ccc(F)cc2)C(=O)NO)cc(C)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of (R)-4-benzyl-3-((S)-2-(4-fluoro-3,5-dimethyl-benzyl)-4-{[3-(4-fluoro-phenyl)-propyl]-methyl-amino}-butyryl)-oxazolidin-2-one (0.033 g, 0.0601 mmol) in 2.5 mL of THF/MeOH/50% NH2OH—H2O (2:2:1), was added KCN (0.001 g, 0.006 mmol). After stirring at room temperature overnight, the reaction mixture was acidified with concentrated HCl to pH=2 and filtered. The product was isolated by RP-HPLC eluting with 20-100% acetonitrile (0.025% TFA)/water (0.025% TFA) to give the title compound as an off-white solid (0.016 g, 66% yield). LC-MS: tR=5.5 min, m/z 405 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:15][N:16]3[CH2:20][CH:19]([CH:21]=[C:22]([F:24])[F:23])[CH2:18][C:17]3=[O:25])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:26]([NH:30][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:15][N:16]3[CH2:20][CH:19]([CH:21]=[C:22]([F:24])[F:23])[CH2:18][C:17]3=[O:25])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN
Reactant: O=C1CC(C=C(F)F)CN1Cc1c(C(F)(F)F)nc2ccc(Cl)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCNc1ccc2nc(C(F)(F)F)c(CN3CC(C=C(F)F)CC3=O)n2n1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one 33 (200 mg, 0.48 mmol, 1 eq) and n-butylamine (0.14 g, 0.96 mmol, 2 eq) in acetonitrile (2 ml) is heated in microwave apparatus (300 W, Tmax 150° C.) until complete conversion (2 h). After cooling to room temperature, a potassium carbonate aqueous saturated solution (10 ml) is added and the crude reaction mixture is extracted with dichloromethane (3×20 ml). Subsequent drying of cumulated organic layers over MgSO4, filtration and solvent evaporation under reduced pressure furnished the crude reaction mixture which is purified by preparative chromatography over silicagel (CH2Cl2/MeOH/NH4OH: 95/5/0.5) to afford 1-{[6-(butylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one 73.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=2)[CH:5]=[C:6]([C:8]([NH2:10])=[O:9])[CH:7]=1.[CH2:16]([C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:19]=1[CH2:20]Cl)[CH3:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CO.C(Cl)Cl.CC(C)=O>[CH3:14][C:12]1[N:13]=[C:3]2[C:2]([NH:1][CH2:20][C:19]3[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:18]=3[CH2:16][CH3:17])=[CH:7][C:6]([C:8]([NH2:10])=[O:9])=[CH:5][N:4]2[C:11]=1[CH3:15]
Reactant: CCc1cccc(C)c1CCl
Reactant: Cc1nc2c(N)cc(C(N)=O)cn2c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CCc1cccc(C)c1CNc1cc(C(N)=O)cn2c(C)c(C)nc12
Yield: 51.4 %

Procedure:
8-Amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide (3.3 g, 16.2 mmol), 2-ethyl-6-methylbenzylchloride (2.73 g, 16.2 mmol), potassium carbonate (8.0 g, 58 mmol) and potassium iodide (1.1 g, 6.6 mmol) were added to acetone (150 ml) and refluxed for 20 h. An additional amount of 2-ethyl-6-methylbenzylchloride (1.0 g, 5.9 mmol) was added and the reaction mixture was refluxed for 7 h. Methylene chloride (60 ml) and methanol (30 ml) were added. The reaction mixture was filtered and the solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride: methanol (100:7) as eluent. Crystallization from ethyl acetate gave 2.8 g (50%) of the title compound. 1H-NMR (300 MHz, CDCl3): δ 1.2 (t, 3H), 2.34 (s, 3H), 2.36 (s, 3H), 2.38 (s, 3H), 2.7 (q, 2H), 4.4 (d, 2H), 4.9 (bs, 1H), 6.0 (bs, 2H), 6.45 (s, 1H), 2H), 6.45 (s, 1H), 7.0-7.2 (m, 3H), 7.9, (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][C:5]2[CH2:6][C:7](=[O:15])[N:8]([CH2:11][CH2:12][CH2:13]Cl)[CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH3:26][NH:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=1>>[OH:1][C:2]1[C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][C:5]2[CH2:6][C:7](=[O:15])[N:8]([CH2:11][CH2:12][CH2:13][N:27]([CH3:26])[CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=3)[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: O=C1Cc2cc(OCc3ccccc3)c(O)cc2CCN1CCCCl
Product: COc1ccc(CCN(C)CCCN2CCc3cc(O)c(OCc4ccccc4)cc3CC2=O)cc1OC

Procedure:
This compound was prepared analogous to Example 5(b) by reacting 1-(7-hydroxy-8-benzyloxy-1,3,4,5-tetrahydro-2-H-3-benzazepin-2-on-3-yl)-3-chloro-propane with N-methyl-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:34])[F:35])=[CH:30][CH:29]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)c2cc1OC
Yield: 86.7 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg, 0.3 mmol) and 4-(trifluoromethyl)phenyl isocyanate (42 uL, 0.3 mmol) using the procedure in Example 182 to give 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(4-(trifluoromethyl)phenyl)urea (130 mg, 0.26 mmol, 87%). 1H NMR (300 MHz, DMSO-d6) δ 9.19 (s, 1H), 9.03 (s, 1H), 8.70 (s, 1H), 7.83 (s, 1H), 7.68-7.60 (m, 4H), 7.56 (d, 1H), 7.44 (t, 1H), 7.35 (d, 2H), 7.27 (d, 1H), 3.99 (s, 6H); LC-MS (ESI) m/z 501 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5](=[CH:10][CH3:11])[C:6](=O)[CH2:7]Cl)[CH3:2].C([O-])(=O)C.[Na+].[NH2:18][C:19]([NH2:21])=[S:20]>O1CCCC1.O>[CH2:1]([O:3][C:4]([C:5]([C:6]1[N:18]=[C:19]([NH2:21])[S:20][CH:7]=1)=[CH:10][CH3:11])=[O:12])[CH3:2]
Reactant: CC=C(C(=O)CCl)C(=O)OCC
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC=C(C(=O)OCC)c1csc(N)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
to a solution of 190 g of the product of example 81 in 400 ml tetrahydrofuran were added first a solution of 82 g sodium acetate in 150 ml of water and then 76 g thiourea. The solution was stirred at room temperature for 20 hours, then the THF was distilled off and acetic acid ethyl ester was added to the residue.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([OH:23])=O)[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl.[NH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:28].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:27](=[O:28])[CH2:26][NH:25][C:21]([CH:17]2[CH2:18][CH2:19][CH2:20][N:15]([C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])[CH2:16]2)=[O:23])=[CH:34][CH:33]=1
Reactant: NCC(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)NCC(=O)c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
Triethyl amine (1.52 mL, 10.4 mmol) was added dropwise to a solution of piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (600 mg, 2.6 mmol) and 2-amino-1-(4-fluorophenyl)ethanone hydrochloride (500 mg, 2.6 mmol) in THF (12 mL), followed by T3P (propylphosphonic anhydride) (1.7 mL, 2.6 mmol, 50% in EtOAc) at 0° C. The reaction mixture was stirred 30 min, allowed to warm up to room temperature and stirred for an additional 8 h. The reaction mixture was then concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with aqueous 10% NaHCO3, water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by purified by column chromatography (silica gel 60-120 mesh, eluent 20-25% EtOAc in petroleum ether) to afford tert-butyl 3-((2-(4-fluorophenyl)-2-oxoethyl)carbamoyl)piperidine-1-carboxylate (500 mg, yield 52%). 1H NMR (400 MHz, DMSO-d6) δ 8.33-8.30 (t, J=5.6 Hz, 1H), 8.08-8.04 (dd, J=8.5 Hz, 5.8 Hz, 2H), 7.39-7.35 (t, J=8.7 Hz, 2H), 4.57-4.56 (m, 2H), 3.99-3.86 (m, 2H), 2.39-2.32 (m, 1H), 1.87-1.84 (m, 1H), 1.66-1.62 (m, 1H), 1.56-1.46 (m, 2H), 1.40 (s, 9H), 1.32-1.23 (m, 2H).
Reaction SMILES: Cl[SiH:2]1[CH2:7][CH2:6][CH:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1>C1COCC1>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][CH2:15][CH2:14][C@H:11]2[CH2:12][CH2:13][C@H:8]([C@H:5]3[CH2:6][CH2:7][Si@H:2]([CH2:7][CH2:6][CH2:5][CH:4]=[CH2:3])[CH2:3][CH2:4]3)[CH2:9][CH2:10]2)=[CH:19][CH:20]=1)#[N:25]
Reactant: N#Cc1ccc(CCCC[C@H]2CC[C@H](C3CC[SiH](Cl)CC3)CC2)cc1
Solvent: C1CCOC1
Product: C=CCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCCCc3ccc(C#N)cc3)CC2)CC1

Procedure:
A solution of 200 ml of THF and 14.0 g of zinc chloride was dropped in 130 ml (0.13 mols) of a THF solution of 1M of 4-pentenylmagnesium bromide to obtain an organozinc reagent. The resultant mixture was added to a solution of 300 ml of THF and 37.4 g (0.1 mol) of 1-chloro-4-(trans-4-(4-(4-cyanophenyl)butyl)cyclohexyl)-1-silacyclohexane. The resultant product was found to be a mixture of trans and cis isomers with respect to the silacyclohexane ring. The product was subjected to ordinary aftertreatments such as removal of solvent and salts, followed by isolation through chromatography to obtain 30.9 g (yield: 76%) of the intended trans isomer product.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C@H:6]([NH:10][C:11]([C:13]1[N:17]2[C@@:18]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)([CH3:30])[C:19](=[O:29])[N:20]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)[C:16]2=[N:15][CH:14]=1)=[O:12])[C:7](O)=[O:8])(=[O:3])[NH2:2].Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH:69]1[CH2:74][CH2:73][CH2:72][CH:71]([C:75]([NH2:77])=[O:76])[CH2:70]1>CN(C=O)C.O>[NH2:2][C:1](=[O:3])[CH2:4][CH2:5][C@H:6]([NH:10][C:11]([C:13]1[N:17]2[C@@:18]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]#[N:39])=[CH:36][CH:37]=3)([CH3:30])[C:19](=[O:29])[N:20]([C:21]3[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=3)[C:16]2=[N:15][CH:14]=1)=[O:12])[C:7]([N:69]1[CH2:74][CH2:73][CH2:72][CH:71]([C:75](=[O:76])[NH2:77])[CH2:70]1)=[O:8]
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)N[C@@H](CCC(N)=O)C(=O)O)n21
Reactant: NC(=O)C1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)N[C@@H](CCC(N)=O)C(=O)N3CCCC(C(N)=O)C3)n21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.3 %

Procedure:
To a solution of (S)-4-carbamoyl-2-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-butyric acid (50 mg, 0.088 mmol) in DMF (1 mL) was added (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (25 mg, 0.132 mmol), benzotriazol-1-ol (18 mg, 0.132 mmol) and triethylamine (47 μL, 0.395 mmol). The reaction mixture was stirred at room temperature for 20 min then piperidine-3-carboxylic acid amide (17 mg, 0.132 mmol) was added. The reaction mixture was stirred at room temperature for 64 h. The reaction mixture was then diluted with water and filtered through a glass frit. The solution was then extracted with CH2Cl2 (×3). The combined organic layers were then washed with water (×3). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified via reverse phase HPLC to afford 60 mg of the title compound as a white solid, m/z 679.6 [M+1]+.