Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[C:9]([C:12]([O:14]C)=[O:13])[CH:8]=1)=[O:5].O[Li].O.O.Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=1)=[O:5]
Reactant: COC(=O)c1cc(NC(=O)c2ccccc2Cl)[nH]n1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(NC(=O)c2ccccc2Cl)[nH]n1

Procedure:
A solution of 1.0 eq. of 22 and 5.0 eq. of LiOH.H2O in THF, MeOH, and H2O (2:1:1) was stirred at rt. After a time sufficient for reaction completion, the reaction mixture was rotary evaporated. The mixture was acidified with concentrated HCl. As the pH of the solution reached about 2, a precipitate formed. The solid was collected by filtration and after drying under vacuum, product 23 was obtained.
Reaction SMILES: [BH4-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[O:9][C:10]([CH3:23])=[C:11]([CH2:13][O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][N:16]=2)[N:12]=1.O1CCCC1.C(O)C>O>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[O:9][C:10]([CH3:23])=[C:11]([CH2:13][O:14][C:15]2[N:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:21][CH:22]=2)[N:12]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(C=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
Sodium borohydride (410 mg) was added to a mixture of 6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]nicotinaldehyde (3.10 g), tetrahydrofuran (50 ml) and ethanol (50 mL) at room temperature, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated to obtain 6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-pyridylmethanol (2.86 g, yield 92%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 120–121° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11]N(C)C.[CH2:15]([O:17][C:18](=[O:28])[CH:19]([NH:25][CH:26]=[O:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:16].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:23]([O:22][C:20](=[O:21])[C:19]([CH2:11][C:7]1[C:6]2[C:10](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=2)[NH:9][CH:8]=1)([NH:25][CH:26]=[O:27])[C:18]([O:17][CH2:15][CH3:16])=[O:28])[CH3:24]
Reactant: CN(C)Cc1c[nH]c2c(F)cccc12
Reactant: CCOC(=O)C(NC=O)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1c[nH]c2c(F)cccc12)(NC=O)C(=O)OCC
Yield: 101.9 %

Procedure:
A suspension of (7-fluoro-1H-indol-3-ylmethyl)-dimethyl-amine (550 mg, 0.0028 mol.), 2-formylamino-malonic acid diethyl ester (640 mg, 0.0031 mol.), and NaOH (30 mg) in toluene (20 mL) under argon was refluxed for 3 days. The reaction mixture was concentrated and purified by column chromatography on silica gel using 40% ethyl acetate-hexane to give 2-(7-Fluoro-1H-indol-3-ylmethyl)-2-formylamino-malonic acid diethyl ester (1.0 gm, 99%): mp 164-166° C., 1H NMR (500 MHz, CDCl3): 1.28 (t, J=7.5 Hz, 6H), 3.87 (s, 2H), 4.17-4.31 (m, 4H), 6.80 (s, 1H), 6.86-6.86 (dd, J=8.0 and 8.0 Hz, 1H), 6.97-7.01 (m, 2H), 7.27 (s, 1H), 8.18 (d, J=1.5 Hz, 1H), 8.27 (s, 1H).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C:10](=[CH2:17])[C:11]([O:13][CH2:14][CH2:15][NH2:16])=[O:12].[F:18][C:19]([F:25])([F:24])[S:20](Cl)(=[O:22])=[O:21]>C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C(#N)C>[CH3:17][C:10](=[CH2:9])[C:11]([O:13][CH2:14][CH2:15][NH:16][S:20]([C:19]([F:25])([F:24])[F:18])(=[O:22])=[O:21])=[O:12]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: C=C(C)C(=O)OCCN
Agent: Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCNS(=O)(=O)C(F)(F)F
Temperature: -30 °C
Yield: 18.9 %

Procedure:
In a 1 L three-neck flask equipped with a thermometer and a reflux condenser were placed 350 g of acetonitrile, 70.7 g (0.699 mol) of triethylamine, 33.1 g (0.200 mol) of 2-aminoethyl 2-methylacrylate hydrochloride, and 0.2 g of phenothiazine, followed by cooling to −30° C. with stirring. After the inner temperature reached −30° C., 40.3 g (0.239 mol) of trifluoromethanesulfonyl chloride was introduced into the slurry as a gas over a period of 1 hour. After completion of the introduction, the mixture was continued to stir for further 1 hour and then warmed to room temperature. The solvent acetonitrile and unreacted trifluoromethanesulfonyl chloride were removed by evaporation from the reaction solution under reduced pressure. One litter of diisopropyl ether was added thereto to form a suspension and the precipitated triethylamine hydrochloride was removed by filtration. The filtrate was washed with 200 mg of a 10% aqueous sodium chloride solution three times. The organic layer was dried over 40 g of magnesium sulfate. After removal of the magnesium sulfate by filtration, 0.2 g of phenothiazine was added thereto and the solvent was removed by evaporation to obtain 22.5 g of a crude organic matter. The crude organic matter was distilled under reduced pressure and a fraction of 105 to 115° C./13 Pa was collected, whereby 9.9 g of 2-{[(trifluoromethyl)sulfonyl]amino}ethyl 2-methylacrylate was obtained. Gas chromatographic investigation of composition thereof revealed that objective 2-{[(trifluoromethyl)sulfonyl]amino}ethyl 2-methylacrylate was 98.0%. The yield was 18.6%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][CH2:19][O:20][CH3:21]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][O:16][CH2:18][CH2:19][O:20][CH3:21])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCBr
Reactant: COC(=O)c1cc(CO)cc(C(C)(C)C)c1
Product: COCCOCc1cc(C(=O)OC)cc(C(C)(C)C)c1

Procedure:
Methyl 3-tert-butyl-5-hydroxymethylbenzoate (6.0 g) was reacted analogously to O5.043 with 1-bromo-2-methoxyethane to give methyl 3-tert-butyl-5-(2-methoxyethoxymethyl)benzoate. The latter was then converted to the title compound analogously to the sequence O4.043 to O2.043. 508 mg of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[N:5]=[C:4]([NH:21][C:22]2[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[NH:24][N:23]=2)[CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][NH2:39])[CH2:33][CH2:32]1>C(O)CCC.CO>[CH:27]([C:25]1[NH:24][N:23]=[C:22]([NH:21][C:4]2[CH:3]=[C:2]([NH:39][CH2:38][CH2:37][N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)[N:7]=[C:6]([NH:8][CH2:9][C:10]3[O:14][N:13]=[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:11]=3)[N:5]=2)[CH:26]=1)([CH3:29])[CH3:28]
Reactant: CC(C)c1cc(Nc2cc(Cl)nc(NCc3cc(-c4ccccc4)no3)n2)n[nH]1
Reactant: CN1CCN(CCN)CC1
Solvent: CO
Solvent: CCCCO
Product: CC(C)c1cc(Nc2cc(NCCN3CCN(C)CC3)nc(NCc3cc(-c4ccccc4)no3)n2)n[nH]1
Temperature: 180 °C
Yield: 29.5 %

Procedure:
A mixture of 6-chloro-N4-(5-isopropyl-1H-pyrazol-3-yl)-N2-(3-phenylisoxazol-5-ylmethyl)-pyrimidine-2,4-diamine (250 mg, 0.611 mmol) and 2-(4-methylpiperazin-1-yl)-ethylamine (500 mg, 3.50 mmol) in 1-butanol (2 mL) was heated to 180° C. in a 50 mL sealed tube. The mixture was heated for 1 h, then cooled to room temperature and diluted with methanol (10 mL). The mixture thus obtained was purified via preparative reverse phase HPLC to give the desired product (93 mg, 29%) as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12]>O.C(Cl)Cl.CO>[CH2:11]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)[CH2:15][CH2:14]1)[CH3:12]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: CCN1CCNCC1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A mixture of 2-fluoro-4-nitrobenzene (3.2 mL, 29.7 mmol) and 1-ethylpiperazine (7.6 mL, 59.4 mmol, 2 equiv) was heated to reflux for 117 h. After cooling to rt, the reaction mixture was diluted with H2O and DCM/MeOH, 9:1. The aqueous layer was separated and extracted with DCM/MeOH, 9:1. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH, 1:0→95:5) afforded 6 g of the title compound as a brown oil: ESI-MS: 236.0 [M+H]+; tR=2.49 min (System 1); TLC: Rf=0.26 (DCM/MeOH, 95:5).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[C:12]([O:25][CH3:26])=[C:13](/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[C:14]([CH3:18])=[C:15]([Cl:17])[CH:16]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2.O.[N+:39]([CH3:42])([O-:41])=[O:40]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[C:12]([O:25][CH3:26])=[C:13]([CH:19]([CH2:42][N+:39]([O-:41])=[O:40])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:14]([CH3:18])=[C:15]([Cl:17])[CH:16]=1)[CH3:10])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)/C=C/c1c(C)c(Cl)cc(C(C)NC(=O)OC(C)(C)C)c1OC
Reactant: C[N+](=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CC(C[N+](=O)[O-])c1c(C)c(Cl)cc(C(C)NC(=O)OC(C)(C)C)c1OC
Temperature: 25 °C
Yield: 53 %

Procedure:
A solution of methyl (2E)-3-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)acrylate (1.5 g, 3.9 mmol) in nitromethane (11 mL) at 0° C. was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.59 mL, 3.9 mmol) and allowed to warm to room temperature. The reaction mixture was heated at 60° C. for 21 h, cooled to room temperature, poured into water (100 ml) and extracted with EtOAc (2×75 mL). The organic layer was separated, washed with brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give a orange foam. The crude material was dissolved in dichloromethane and purified by flash column chromatography using EtOAc in hexanes (0%-30% over 30 min) to give the desired product (0.93 g, 53%) as a white foam. LCMS for C20H29ClN2O7Na (M+Na)+: m/z=467.2. Found: 467.1.
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.C(N(CC)CC)C.[CH2:25]([O:27][C:28](=[O:42])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:33][CH:32]=1)[CH3:26]>C1COCC1>[CH2:25]([O:27][C:28](=[O:42])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:14]([NH2:17])=[N:13][C:11]([C:4]2[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=2)=[O:12])=[CH:33][CH:32]=1)[CH3:26]
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CCOC(=O)COc1ccc(CCCCN)cc1
Agent: I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl)-2-methylisothiourea hydriodide (0.74 g, 1.9 mmol) and triethylamine (0.5 mL) were sequentially added into a solution of 48 (0.62 g, 2.47 mmol) in THF (10 mL). The reaction mixture was stirred in the boiling solvent for 4 h and at room temperature overnight. The solvent was evaporated and the residue was purified by column chromatography (silica gel, 6:1:0.1 chloroform/ethanol/concentrated ammonium hydroxide) to provide 49 (0.5 g, 57%) as a yellow solid. The purity of the product was confirmed by HPLC. m/z (APCI)=464 [C20H26ClN7O4+H]+.
Reaction SMILES: [OH-:1].[Na+].BrC(Br)[C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)=[O:6]>O>[C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)([OH:6])=[O:1]
Reactant: O=C1CCc2cc(C(=O)C(Br)Br)ccc2N1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C1CCc2cc(C(=O)O)ccc2N1
Yield: 54.5 %

Procedure:
Into 250 ml of water, 26 g sodium hydroxide was dissolved, then at a temperature of 90°-100° C. and under stirring condition, 35 g of 6-dibromoacetyl-3,4-dihydrocarbostyril was added thereinto and reacted for 3 hours. After the reaction was completed, the reaction mixture was cooled and insoluble matters formed in the mixture were removed by filtration. The mother liquor was acidified with concentrated hydrochloric acid and the crystals precipitated were collected by filtration and washed with water. The crystals thus obtained were recrystallized from ethanol twice to obtain 10.5 g of 6-carboxy-3,4-dihydrocarbostyril in the form of light yellow amorphous crystals. Melting point: 324.5°-327° C. (decomposed).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12])=[N+:2]=[N-:3].C(N(CC)CC)C.[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:27][C:26]1[CH:28]=[CH:29][C:23]([S:20]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: [N-]=[N+]=NCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.9 %

Procedure:
To a solution in which the 2-(2-(2-azidoethoxy)ethoxy)ethanol (3.05 g, 17.40 mmol) compound of Chemical Formula 8 was dissolved in methylene chloride (15 mL), 4-dimethylaminopyridine (DMAP) (212.6 mg, 1.74 mmol), triethylamine (TEA) (7.28 mL, 52.20 mmol) and tosyl chloride (3.98 g, 20.88 mmol) were added consecutively at room temperature. The post-reaction mixture obtained after stirring the reaction mixture for 12 hours at room temperature was partitioned to distilled water (40 mL) and ethyl acetate (120 mL). The organic layer was separated, washed with saturated salted water (15 mL), dried with anhydrous sodium sulfate, and vacuum distilled to give 2-(2-(2-azidoethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (5.15 g, 90%). 1H NMR (500 MHz, CDCl3) δ 7.79 (d, 2H, J=8.2 Hz), 7.33 (d, 2H, J=8.2 Hz), 4.15 (t, 2H, J=5.0 Hz), 3.69 (t, 2H, J=5.0 Hz), 3.63 (t, 2H, J=5.5 Hz), 3.59 (s, 4H), 3.36 (t, 2H, J=5.0 Hz), 2.44 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 144.9, 133.0, 129.9 (2), 128.0 (2), 70.8, 70.7, 70.1, 69.3, 68.8, 50.7, 21.7.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:6]2[N:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:7]=2[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17][CH2:18][CH3:19])[N:10]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:18]([S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:10]=[C:5]([NH:2][NH2:3])[C:6]2[N:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:7]=2[N:8]=1)[CH3:19]
Reactant: NN
Reactant: CCSc1ccccc1-c1nc(Cl)c2ncc(C(F)(F)F)cc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCSc1ccccc1-c1nc(NN)c2ncc(C(F)(F)F)cc2n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
41 μl of hydrazine monohydrate was added to a mixture of 263 mg of 4-chloro-2-(2-ethylsulfanylphenyl)-7-trifluoromethylpyrido[3,2-d]pyrimidine and 4 ml of THF, under ice cooling, and the mixture was stirred at room temperature for 15 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water and then concentrated under reduced pressure to obtain 246 m of [2-(2-ethylsulfanylphenyl)-7-trifluoromethylpyrido[3,2-d]pyrimidin-4-yl]-hydrazine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19](#[N:21])[CH3:20]>>[CH2:12]([O:11][CH2:10][CH2:9][CH2:8][NH:21][CH:19]1[CH2:15][CH2:14][CH:13]([CH3:18])[CH2:12][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCCOCc1ccccc1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1CCC(NCCCOCc2ccccc2)CC1

Procedure:
4-Trans-methyl-cyclohexylamine (6.65 g, 44.4 mmol) and potassium carbonate (12.3 g, 88.8 mmol) in acetonitrile (50 mL) was heated to reflux before a solution of (3-bromo-propoxymethyl)-benzene (10.2 g, 44.4 mmol) in acetonitrile (25 mL) over a period of 30 min. The reaction mixture was refluxed for 2 hours before the solvent was removed in vacuo. The residue was divided between diethyl ether (100 mL) and aqueous sodium hydroxide (1N, 50 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified using column chromatography (SiO2, heptane-ethyl acetate 1:1) to give 8.4 g (3-benzyloxy-propyl)-(4-methyl-cyclohexyl)-amine. To this was added a solution of bis-tert-butyldicarbonate (32 mmol, 1N in THF) and the reaction mixture was stirred at room temperature for 18 hours before the solvent was removed in vacuo. The residue was dissolved in diethyl ether (150 mL) and washed with water (2×100 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo to give 10.6 g of (3-benzyloxy-propyl)-(4-methylcyclohexyl)-carbamic acid tert-butyl ester. This was subsequently dissolved ethanol (100 mL) and Pd/C (10%, 1 g) was added. The reaction mixture was stirred under H2 (1 atm) for 4 hours. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to give 7.9 g of (3-hydroxy-propyl)-(4-methyl-cyclohexyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH:13]([CH3:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][C:4]=1CC)#[CH:2].[C:18](O)(=O)[C:19]1C=CC=CC=1.[CH2:27]([O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=1)[CH3:28]>C(N(CC)CC)C.[Cu]I.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>[CH:13]([O:12][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:34]3[CH:35]=[CH:36][C:31]([C:30]([O:29][CH2:27][CH3:28])=[O:38])=[CH:32][CH:33]=3)=[CH:8][C:7]=2[CH2:18][CH3:19])[CH2:10][CH2:11]1)([CH3:14])[CH3:15]
Reactant: O=C(O)c1ccccc1
Reactant: C#Cc1ccc(C2(OC(C)C)CC2)cc1CC
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC(C)C)CC3)c(CC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
Using General Procedure F; 4-ethynyl-1-(1-isopropoxycyclopropyl)-3-ethyl-benzene (Intermediate 95, 108.0 mg, 0.47 mmol) and ethyl-4-iodo benzoate (Reagent A, 130.0 mg, 0.47 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (110 mg, 0.16 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 125.0 mg (71%) of the title compound as an oil.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[N:33][C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)=[CH:28][CH:27]=1.CC(C)=[O:43]>O>[CH3:40][C:37]1[CH:38]=[CH:39][C:34]([N:33]=[N:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:43][C:5]3[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:3][CH:2]=[CH:12][C:6]=3[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:27][CH:28]=2)=[CH:35][CH:36]=1
Reactant: CCOC(=O)c1cc(O)cc(C(=O)OCC)c1
Reactant: CC(C)=O
Reactant: Cc1ccc(N=Nc2ccc(OCCCCCCBr)cc2)cc1
Solvent: O
Product: CCOC(=O)c1cccc(C(=O)OCC)c1OCCCCCCOc1ccc(N=Nc2ccc(C)cc2)cc1
Yield: 83 %

Procedure:
A 1 l three-neck flask was charged with 16.6 g (0.07 mol) of diethyl 5-hydroxyisophthalate, 26.1 g (0.07 mol) of 4-(6-bromohexyloxy)-4′-methylazobenzene and 15.1 g (0.11 mol) of potassium carbonate anhydride. To the mixture was added 300 ml of acetone and the system was refluxed under heating to react for 24 hours. After the reaction was completed, the system was poured into 1500 ml of cool water to obtain diethyl {6-[4-(4-methylphenylazo)phenoxy]hexyloxy}isophthalate, which was then separated by filtration and dried under reduced pressure (yield: 83% (35.1 g)). The product was recrystallized from acetone twice to obtain 30.1 g (80.1%) of a target product, diethyl (5-{6-[4-(4-methylphenylazo)phenoxy]hexyloxy}isophthalate. It was found from an analysis using high performance liquid chromatography that the purity of the product was 98.5% or more. The resulting compound was subjected to measurements of infrared absorption spectrum (IR) and nuclear magnetic resonance (NMR). The results are shown in the following.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[C:37]=[O:38]>>[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]2[C:16]3[C:11](=[C:12]([C:25]([F:26])([F:28])[F:27])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:19]=1)=[O:38]
Reactant: Cc1ccccc1-c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(N)c1
Reactant: O=C=Nc1ccccc1F
Product: Cc1ccccc1-c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(NC(=O)Nc2ccccc2F)c1

Procedure:
The title compound was prepared from {3-[3-(2-methylphenyl)-8 (trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-fluorophenyl isocyanate in substantially the same manner as described in Example 65; off-white solid: mp 218-220° C.; MS (EI) m/z 516 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:26]=[N:25][C:24]2[NH:23][CH2:22][CH2:21][O:20][C:19]=2[CH:18]=1.Br[C:28]1[CH:33]=[CH:32][CH:31]=C[C:29]=1[S:34]([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])(=[O:36])=[O:35]>>[O:20]1[CH2:21][CH2:22][NH:23][C:24]2[N:25]=[CH:26][C:17]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[C:29]([S:34]([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])(=[O:36])=[O:35])=[CH:28][CH:33]=[CH:32][CH:31]=4)=[CH:7][C:2]=3[F:1])=[CH:18][C:19]1=2
Reactant: CCN(CC)S(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OC(c2ccc(-c3cnc4c(c3)OCCN4)c(F)c2)OC1(C)C
Product: CCN(CC)S(=O)(=O)c1ccccc1-c1ccc(-c2cnc3c(c2)OCCN3)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 444 using 7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine and 2-bromo-N,N-diethylbenzenesulfonamide. MS (ESI): mass calcd. for C23H24FN3O3S, 441.15; m/z found, 442.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.03-8.00 (m, 1H), 7.82 (d, J=1.0, 1H), 7.73-7.65 (m, 2H), 7.62-7.55 (m, 2H), 7.40-7.36 (m, 1H), 7.31 (s, 1H), 7.30-7.28 (m, 1H), 4.39-4.35 (m, 2H), 3.74-3.70 (m, 2H), 2.99 (q, J=7.1, 4H), 1.01 (t, J=7.1, 6H).