Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[OH:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC.Cl.O>C(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:23][C:22]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[CH:11]([OH:12])[C:8]1[N:6]2[N:7]=[C:2]([C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: OC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1ccc2ncc(C(O)c3cc4cccnc4cc3F)n2n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A flask was charged with tetrakis-(triphenylphosphine)-palladium (176 mg, 0.15 mmol) under nitrogen. A solution of (6-chloroimidazo[1,2-b]pyridazin-3-yl)(7-fluoroquinolin-6-yl)methanol (500 mg, 1.52 mmol) in CH2Cl2 (20 mL) was added. The system was purged with nitrogen gas three times and tributyl-(1-ethoxy-vinyl)-stannane (0.54 ml, 1.59 mmol) was added. The temperature was increased to 100° C. and stirred overnight. The reaction mixture was cooled to room temperature, 3N HCl was added and the mixture was stirred for additional 4 hrs. Water was added and the mixture was then extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (3% to 10% MeOH in CH2Cl2) to afford 500 mg (yield: 88%) title compound. LCMS (method B): [MH]+=337, tR=1.88 min.
Reaction SMILES: [Na+].[I-:2].CN[C@@H]1CCCC[C@H]1NC.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(O)CCCC>[Cu]I>[I:2][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Brc1ccccc1C1CCCCC1
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: CCCCCO
Product: Ic1ccccc1C1CCCCC1
Temperature: 130 °C
Reaction time: 40 h
Yield: 98.9 %

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %), NaI (300 mg, 2.00 mmol), evacuated and backfilled with argon. Racemic trans-N,N′-dimethyl-1,2-cyclohexanediamine (16 μL, 0.10 mmol, 10 mol %), 1-bromo-2-cyclohexylbenzene (97% pure; Lancaster; 186 μL, 1.00 mmol), n-pentanol (1 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 130° C. for 40 h. The resulting suspension was allowed to reach room temperature and filtered through silica gel (1×0.5 cm) eluting with hexane (50 mL). The filtrate was concentrated, and the residue was purified by flash chromatography on silica gel (hexane) to provide the known 1-iodo-2-cyclohexylbenzene (283 mg, 99% yield; ca. 97% pure) as a colorless liquid. See McGuine, T. H.; Dull, M. F. J. Am. Chem. Soc. 1947, 69, 1469. 1H NMR (400 MHz, CDCl3): δ 7.85 (dd, J=7.5, 1.2 Hz, 1H), 7.32 (td, J=7.5, 1.2 Hz, 1H), 7.23 (dd, J=7.5, 1.7 Hz, 1H), 6.90 (td, J=7.5, 1.7 Hz, 1H), 2.81 (tt, J=11.7, 3.0 Hz, 1H), 1.97-1.74 (m, 5H), 1.55-1.23 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 149.3, 139.5, 128.4, 127.6, 126.6, 101.5, 48.5, 33.4, 26.8, 26.1.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[Br-:24].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Br:24][CH2:20][C:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:14]=1)=[O:21]
Reactant: CC(=O)c1cccc(OCCCOCc2ccccc2)c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CBr)c1cccc(OCCCOCc2ccccc2)c1

Procedure:
To a solution of 1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanone (10.59 g) in tetrahydrofuran (50 mL) was added methanol (50 mL) and a solution of tetrabutylammonium tribromide (16 g) in tetrahydrofuran (50 mL). The reaction was stirred at ambient temperature for 45 min at which time tetrabutylammonium tribromide (0.89 g) was added, followed by further addition of 0.6 g. 10% aqueous sodium thiosulfate was added to the reaction and the mixture was concentrated in vacuo to a minimum volume. Ethyl acetate was added and the resultant organic solution was washed with aqueous sodium thiosulfate, saturated sodium bicarbonate and brine and concentrated to an oil to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([C:13]([OH:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][C:3]=1[F:17].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CS(C)=O>O>[F:17][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1)[N:9]([CH3:12])[CH:8]=[C:7]([C:13]([OH:15])=[O:14])[C:6]2=[O:16]
Reactant: Cn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C)CC1
Yield: 40.7 %

Procedure:
2.55 g (0.01 mol) of 7-chloro-6-fluoro-1-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 4.5 cm3 of 1-methylpiperazine (0.011 mol) and 32 cm3 of DMSO were heated at 110° C. for 4 hours. After cooling, the mixture was taken up in 150 cm3 of water. The crystalline precipitate was filtered off, washed and recrystallised from 100 cm3 of methylcellosolve. 1.3 g of 6-fluoro-1-methyl-7-(4-methylpiperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, m.p. 304° C. (decomposition), were obtained.
Reaction SMILES: C([C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([NH:7][CH:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:11][NH:10][CH2:9]1)=[O:6])C.[N:28]([CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][O:33]1)=[C:29]=[O:30].C(N(CC)CC)C>C1COCC1>[C:4]1([C:5]([NH:7][CH:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=3)[CH2:11][N:10]([C:29]([NH:28][CH2:31][CH:32]3[CH2:36][CH2:35][CH2:34][O:33]3)=[O:30])[CH2:9]2)=[O:6])[CH:24]=[CH:25][CH:26]=[CH:27][CH:3]=1
Reactant: CCc1ccccc1C(=O)NC1CNCC(c2ccc(C(F)(F)F)cc2)C1
Reactant: O=C=NCC1CCCO1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)NCC2CCCO2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80 mg (0.23 mmol) of ethyl-N-{5-[4-(trifluoromethyl)phenyl]piperidin-3-yl}benzamide were initially charged in 2 ml of THF, and 29 mg (0.23 mmol) of 2-(isocyanatomethyl)tetrahydrofuran and 35 μl (0.25 mmol) of triethylamine were added. The mixture was stirred at RT overnight. The reaction mixture was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 88 mg (81% of theory)
Reaction SMILES: [CH2:1](Br)[CH:2]([CH3:4])[CH3:3].[OH:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([O:12]CC)=[O:11].C(=O)([O-])[O-].[K+].[K+].C(OC1C=C(C=CC=1)C(O)=O)CC>>[CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([OH:12])=[O:11])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CBr
Reactant: CCOC(=O)c1cccc(O)c1
Agent: CCCOc1cccc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)COc1cccc(C(=O)O)c1

Procedure:
The reaction of isobutyl bromide and ethyl 3-hydroxybenzoate in the presence of potassium carbonate was performed as described for Compound 24 to give 3-isobutoxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.94 (s, COOH); 7.48 (m, 1 arom. H); 7.40 (m, 2 arom. H); 7.12 (m, 1 arom. H); 3.76 (d, J=6.4, (CH3)2CHCH2O); 2.00 (m, (CH3)2CHCH2O); 0.96 (d, J=6.4, (CH3)2CHCH2O). 13C-NMR (100 MHz, d6-DMSO): 167.11 (—C═O); 158.73; 132.12; 129.68; 121.42; 119.35; 114.46; 73.46; 27.66; 18.98 (2 C).
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][CH:6]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7]1>CS(C)=O.O>[C:1]([CH2:5][CH:6]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7]1)#[N:2]
Reactant: [C-]#N
Reactant: BrCC1COc2ccccc2O1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCC1COc2ccccc2O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Potassium cyanide (2.05 g, 31.5 mmol) was added to 2-bromomethyl-(2,3 dihydrobenzo[1,4]dioxine) (6.87 g, 30 mmol) in DMSO (90 mL) and stirred at ambient temperature for 20 h. The reaction mixture was then diluted with water (250 mL) and extracted twice with diethyl ether. The diethyl ether was washed with water, then washed twice with brine, dried (Na2SO4) and evaporated in vacuo to yield 2-cyanomethyl-(2,3 dihydrobenzo[1,4]dioxine) as a white solid.
Reaction SMILES: [CH:1]1([C:6]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:7]2[CH2:31][C:30]([CH3:33])([CH3:32])[C:10]3[CH:11]=[C:12]4[C:20](=[CH:21][C:9]=3[C:8]2([CH3:35])[CH3:34])[CH2:19][C:18]2[CH:17]=[C:16]3[C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][C:25]([CH3:27])([CH3:26])[C:15]3=[CH:14][C:13]4=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.CCCCCC.[Li]CCCC.Cl[Si:60]([CH3:63])([CH3:62])[CH3:61]>C1COCC1>[CH3:61][Si:60]([CH3:63])([CH3:62])[C:3]1[CH:4]=[CH:5][CH:1]([C:6]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:7]2[CH2:31][C:30]([CH3:32])([CH3:33])[C:10]3[CH:11]=[C:12]4[C:20](=[CH:21][C:9]=3[C:8]2([CH3:34])[CH3:35])[CH2:19][C:18]2[CH:17]=[C:16]3[C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][C:25]([CH3:27])([CH3:26])[C:15]3=[CH:14][C:13]4=2)[CH:2]=1
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CC(C(c1ccccc1)(c1ccccc1)C1C=CC=C1)C2(C)C
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CC(C(c1ccccc1)(c1ccccc1)C1C=CC([Si](C)(C)C)=C1)C2(C)C
Yield: 60.8 %

Procedure:
In a 30 ml Schlenk flask purged with nitrogen, 0.92 g (1.48 mmol, 1 eq) of 1-(cyclopentadienyl)-1-(1,1,4,4,7,7,10,10-octamethyl-1,2,3,4,7,8,9,10-octahydrodibenzo(b,h)-fluorenyl)diphenylmethane was placed at room temperature. Then, 20 ml of dehydrated THF was added, and the mixture was stirred by a magnetic stirrer to give a solution. The solution was cooled with an ice bath (light orangy brown solution). To the solution, 1.0 ml (1.63 mmol, 1.10 eq) of a hexane solution of n-BuLi was dropwise added. Then, the ice bath was removed, and the solution was stirred at room temperature for 18 hours (dark red solution). The solution was cooled with an ice bath, and to the solution, 1.05 ml (8.28 mmol, 5.59 eq) of chlorotrimethylsilane was dropwise added by a syringe (dark brown solution). The ice bath was removed, and the solution was stirred at room temperature for 3 hours. The resulting dark brown solution was poured into 50 ml of a diluted hydrochloric acid solution to perform quenching. After the soluble component was extracted with 30 ml of diethyl ether, the organic phase was washed with 50 ml of a saturated saline solution. The organic phase was dried over MgSO4, then the MgSO4 was filtered off, and from the filtrate the solvent was vacuum distilled off by a rotary evaporator to obtain a yellowish brown amorphous product. The amorphous product was purified by silica gel column chromatography (developing solvent: hexane:dichloromethane=19:1) to obtain 0.62 g a light yellow amorphous product (yield: 61%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl[C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14][N:13]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[CH3:18][C:16]1[N:15]=[CH:14][N:13]=[C:12]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:17]=1
Reactant: Cc1cc(Cl)ncn1
Reactant: C1CC2(CCN1)OCCO2
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCC3(CC2)OCCO3)ncn1

Procedure:
A solution of 1,4-dioxa-8-azaspiro[4.5]decane (3.04 g, 2.72 mL, 21.2 mmol), 4-chloro-6-methylpyrimidine (3.00 g, 23.4 mmol) and N,N-diisopropylethylamine (4.12 g, 5.56 mL, 31.8 mmol) in dioxane (50 mL) was heated to 140° C. in the microwave for 40 minutes. The reaction mixture was concentrated, then directly purified by flash chromatography (silica gel, 70 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). The title compound was obtained as orange oil (4.64 g, 93%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][C:14]=2/[CH:19]=[CH:20]/[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=2)=[O:22])=[CH:9][CH:8]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:1]([N:3]([CH2:4][CH3:5])[C:31](=[O:32])[CH2:30][C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21](=[O:22])/[CH:20]=[CH:19]/[C:14]2[CH:15]=[N:16][N:17]([CH3:18])[C:13]=2[C:10]2[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=2)=[CH:29][CH:28]=1)[CH3:2]
Reactant: Cn1ncc(/C=C/C(=O)Nc2ccc(CC(=O)O)cc2)c1-c1ccc(F)cc1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)Cc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 59.9 %

Procedure:
A mixture of diethylamine (0.17 g), [4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)phenyl]acetic acid (0.70 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.35 g), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.44 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ((2E)-N-{4-[2-(diethylamino)-2-oxoethyl]phenyl}-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylamide as colorless crystals (0.48 g, yield 62%) from a fraction eluted with ethyl acetate-methanol (20:1, v/v). Recrystallization thereof from acetone-hexane gave colorless prism crystals. melting point: 175-176° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>C(Cl)Cl>[C:21]([O:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: C=C(C)C(=O)Cl
Reactant: CCS(=O)(=O)Nc1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1cccc(NS(=O)(=O)CC)c1
Yield: 82.5 %

Procedure:
To 20.0 g (0.099 mol) of N-(3-hydroxyphenyl)ethanesulfonamide, 10.06 g (0.099 mol) of triethylamine and 150 ml of methylene chloride cooled to 0° C., was added a solution of 10.39 g (0.099 mol) of methacryloyl chloride in 100 ml of methylene chloride, dropwise. Stirring was continued at reduced temperature for 4 hours, after which the solution was washed once with 2 percent hydrochloric acid, twice with water and dried over magnesium sulfate. Concentration of the solution in vacuo gave 22.0 g (82.5 percent yield) of non-crystallizable oil.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH:8]([CH3:9])[CH2:7][C:6](=[O:10])[NH:5]1)[CH3:3].OO.O.[OH-].[Na+]>C(O)(=O)C>[CH3:1][CH:2]([N:4]1[C:8]([CH3:9])=[CH:7][C:6](=[O:10])[NH:5]1)[CH3:3]
Reactant: CC(C)N1NC(=O)CC1C
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(=O)[nH]n1C(C)C
Temperature: 22.5 °C
Reaction time: 15 h

Procedure:
1-(1-methylethyl)-5-methyl-3-pyrazolidinone (390 g; 2.74 mol) is dissolved in acetic acid (170 ml) with warming. 35% aqueous hydrogen peroxide (260 ml; 3.0 mol) is added within 3 h while keeping the temperature at about 65° C. The reaction mixture is then stirred at about 20 to 25° C. for 15 h. Water (1.2 L) is then added and the pH of the mixture is adjusted to about 7 by means of addition of approx. 1 L 50%-weight aqueous sodium hydroxide solution. Upon cooling to 5° C. the reaction mixture is filtered. The product is washed with water and dried at about 50° C. Colourless crystals are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: COC(=O)C(=O)Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)C(=O)OC)cc1

Procedure:
A mixture of 0.10 mole of methyl p-aminophenylpyruvate, 0.10 mole of 1-bromohexadecane, and 0.10 mole of anhydrous potassium carbonate in 40 ml. of hexamethylphosphoramide is heated at 80° C. for 20 hrs. The mixture is then cooled, diluted with water and extracted with ether. The ethereal solution is then evaporated, yielding methyl (4-hexadecylaminophenyl)pyruvate.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:27]=[CH:26][C:7]2[N:8]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH2:9][CH2:10][CH2:11][CH:12]([NH:13][C:14]3[S:18][N:17]=[C:16]([CH3:19])[CH:15]=3)[C:6]=2[CH:5]=1.[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:33]Br>O1CCCC1.C(OCC)(=O)C>[F:28][C:29]([F:42])([F:43])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=1)[CH2:33][N:13]([C:14]1[S:18][N:17]=[C:16]([CH3:19])[CH:15]=1)[CH:12]1[CH2:11][CH2:10][CH2:9][N:8]([C:20]([O:22][CH:23]([CH3:24])[CH3:25])=[O:21])[C:7]2[CH:26]=[CH:27][C:4]([Br:3])=[CH:5][C:6]1=2
Reactant: Cc1cc(NC2CCCN(C(=O)OC(C)C)c3ccc(Br)cc32)sn1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C2CCCN(C(=O)OC(C)C)c3ccc(Br)cc32)sn1

Procedure:
Add sodium hydride to a stirring solution of isopropyl 7-bromo-5-(3-methylisothiazol-5-ylamino)-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate in anhydrous tetrahydrofuran at room temperature under nitrogen. After the appropriate stirring time, treat the mixture with 3,5-bis(trifluoromethyl)benzyl bromide and continue stirring for an appropriate time. Dilute the mixture with ethyl acetate, wash with water and brine and dry over sodium sulfate. Remove the solvents under reduced pressure and purify the residue by flash column chromatography on silica gel to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].Br[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([CH2:11][NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(CN)OCC
Reactant: BrCC1CCCCC1
Product: CCOC(CNCC1CCCCC1)OCC
Reaction time: 8 h
Yield: 29.6 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-5 with the modification that the reaction was carried out overnight, 2,2-diethoxyethanamine (5.82 ml, 40 mmol) was reacted with bromomethylcyclohexane (2.77 ml, 20 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: chloroform:methanol=100:0 to 98:2) to obtain the title compound (1.36 g, 30%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][C:4]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In an oven-dried flask placed under a nitrogen atmosphere biphenyl (50 g) was stirred in dichloromethane (450 mL). The flask was placed in an ice bath and to it was added benzoyl chloride (46 mL) via addition funnel slowly over 20 minutes. To that mixture was added anhydrous aluminum chloride (51 g) via solid addition funnel, slowly over 10 minutes. After the aluminum chloride addition was complete the reaction mixture allowed to warm to room temperature and to stir for 16 hours. The reaction mixture was slowly poured into a beaker containing ice and a 10% aqueous solution of hydrochloric acid (600 mL) while stirring vigorously. A separatory funnel was used to separate the organic and aqueous layers. The recovered organic layer was then washed with water (2×500 mL), washed with a saturated aqueous solution of sodium chloride (500 mL), dried over sodium sulfate and concentrated by rotary evaporation. The resulting solid was slurried in a 25% v/v mixture of ethyl acetate in hexanes. The solid was collected by vacuum filtration, and then washed with cold diethyl ether (2×200 mL) to yield 57 g of [1,1′-biphenyl]-4-yl(phenyl)methanone.
Reaction SMILES: [F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.Cl[C:50]1[N:55]=[CH:54][C:53]([CH:56]=[O:57])=[CH:52][N:51]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[F:48][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:50]4[N:55]=[CH:54][C:53]([CH:56]=[O:57])=[CH:52][N:51]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=2)[CH2:4][CH2:3]1
Reactant: O=Cc1cnc(Cl)nc1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(C=O)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a solution of 1.00 g (1.48 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, in 5 ml of 1-methyl-2-pyrrolidone, 0.23 g (1.6 mmol) of 2-chloro-5-formyl pyrimidine and 265 μl (1.78 mmol) of diazabicycloundecene were added, and the reaction solution was stirred at room temperature for 1 hour. Then, 0.023 g (0.16 mmol) of 2-chloro-5-formyl pyrimidine was added thereto and the reaction solution was further stirred at room temperature for 0.58 hours. Furthermore, 0.023 g (0.16 mmol) of 2-chloro-5-formyl pyrimidine was added thereto and the reaction solution was stirred at room temperature for 1.5 hours. After completion of the reaction, the reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=40/10 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 1.00 g of the title compound as a light yellow solid (yield: 87%).