Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][CH:7]=1.[CH3:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[C:16]=1[C:17]([O:19][CH3:20])=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[CH3:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:2][C:3]3[N:4]=[C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[O:6][CH:7]=3)[CH:28]=2)[C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1c(C)cccc1COc1cccc(O)c1
Reactant: ClCc1coc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cccc1COc1cccc(OCc2coc(-c3ccccc3)n2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloromethyl-2-phenyl-oxazole (100 mg, 0.5 mmol, example 19) in DMF (2 mL) is added methyl 2-methyl-6-[(3-hydroxy-phenoxy)-methyl]-benzoate (136 mg, 0.5 mmol, example 5) followed by K2CO3 (75 mg, 0.54 mmol). The resulting mixture is heated to 60° C. and stirred at this temperature for 8 h. This mixture is then cooled to room temperature, diluted with ether, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 20% ethyl acetate in hexanes) to give the title compound. MS (ESI) 429 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)([OH:27])[CH3:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].I[CH3:46]>O1CCCC1>[F:40][C:37]([F:38])([F:39])[C:35]1[CH:34]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:36]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)([O:27][CH3:46])[CH3:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: CI
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(C)(O)C2CCCCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a solution of 1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-1-cyclohexylethanol (26 mg; 0.043 mmol) in tetrahydrofuran (0.7 mL) was added sodium hydride (11 mg; 0.275 mmol; 60% dispersion in mineral oil). After stirring for 30 minutes at room temperature, iodomethane (30 uL; 0.485 mmol) was added. The reaction was stirred for 16 hours. More sodium hydride (12 mg; 0.3 mmol; 60% dispersion in mineral oil) and iodomethane (30 uL; 0.485 mmol) were added. After 1 hour more sodium hydride (12 mg; 0.3 mmol; 60% dispersion in mineral oil) was added. After 30 minutes, iodomethane (30 uL; 0.485 mmol) was added. The reaction was stirred for 2 hours. The reaction was quenched with aqueous 2N hydrochloric acid (6 drops). The mixture was diluted with ethyl acetate and filtered over sodium sulfate/silica plug. Then the solution was concentrated. The residue was purified by 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-25% ethyl acetate in heptane) to give 19 mg (71% yield) of a colorless gum. MS (ES+): Calc: 623.5, Found: 592.5 (M-OCH3). 1H NMR (400 MHz, CDCl3) δ ppm 7.78 (s, 1H), 7.73 (s, 2H), 7.46 (s, 1H), 7.45 (d, J=7.47 Hz, 1H), 7.27 (d, J=8.30 Hz, 1H), 5.25 (d, J=17.43 Hz, 1H), 5.07 (d, J=17.43 Hz, 1H), 4.79 (q, J=16.60, 16.18 Hz, 2H), 4.19 (s, 3H), 3.02 (s, 3H), 2.01 (d, J=11.2 Hz, 1H), 1.78-1.67 (m, 2H), 1.66-1.55 (m, 2H), 1.53 (s, 3H), 1.11-0.83 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][NH:7][C:8](=[O:23])[CH2:9][N:10]1[C:16](=[O:17])[C:15]2[CH:18]=[C:19]([NH2:22])[CH:20]=[CH:21][C:14]=2[O:13][CH2:12][CH2:11]1)[CH3:2].[CH2:25]([N:32]=[C:33]=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][NH:7][C:8](=[O:23])[CH2:9][N:10]1[C:16](=[O:17])[C:15]2[CH:18]=[C:19]([NH:22][C:33]([NH:32][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:34])[CH:20]=[CH:21][C:14]=2[O:13][CH2:12][CH2:11]1)[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: CCOC(=O)CCNC(=O)CN1CCOc2ccc(N)cc2C1=O
Product: CCOC(=O)CCNC(=O)CN1CCOc2ccc(NC(=O)NCc3ccccc3)cc2C1=O

Procedure:
Treatment of 3-[2-(7-amino-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-acetylamino]-propionic acid ethyl ester (0.17 g, 0.5 mmol) with benzylisocyanate as described in Example 1 d) yielded 3-{2-[7-(3-benzyl-ureido)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino}-propionic acid ethyl ester (0.2 g, 0.42 mmol): mp. 70-75° C.; MS (ISP): 469 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.O>[CH3:1][C:2]1[C:7]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27](=[O:29])[CH3:28])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[N:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncccc1-c1nc(C(F)(F)F)cn1-c1ccc(S(N)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cccnc2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
A mixture of 4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide (0.5 g, 1.3 mmol), acetic anhydride (0.40 g, 3.9 mmol), DMAP (0.09 g, 0.7 mmol) and triethylamine (0.16 g, 1.6 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was recrystallized from ethyl acetate and hexane to afford 0.55 g (99%) of N-[[4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl]sulfonyl]acetamide as a colorless solid: mp (DSC) 243-245° C. Anal. Calc'd. for C18H15F3N4O3S: C, 50.94; H, 3.56; N, 13.20; S, 7.56. Found: C, 50.64; H, 3.43; N, 12.64; S, 7.37.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:30]2[S:34][C:33]([C:35]3([O:39][CH2:40][O:41][CH3:42])[CH2:38][CH2:37][CH2:36]3)=[N:32][CH:31]=2)=[C:4]2[CH:10]=[C:9]([C:11]([O:13]/[N:14]=[C:15](/[CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)\[NH2:16])=O)[NH:8][C:5]2=[N:6][CH:7]=1.O>CN1CCCC1=O>[Cl:1][C:2]1[C:3]([C:30]2[S:34][C:33]([C:35]3([O:39][CH2:40][O:41][CH3:42])[CH2:36][CH2:37][CH2:38]3)=[N:32][CH:31]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[O:13][N:14]=[C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[N:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(C(=O)O/N=C(\N)C5CCN(C(=O)OC(C)(C)C)CC5)cc34)s2)CCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5nc(C6CCN(C(=O)OC(C)(C)C)CC6)no5)cc34)s2)CCC1
Temperature: 25 °C

Procedure:
A solution of Example 46D (0.66 g, 0.107 mmol) in 1-methyl-2-pyrrolidinone (1.2 mL) was heated at 110° C. for 5 hours. The reaction was cooled to ambient temperature and poured into water (5 mL). The resulting suspension was filtered, and the solid collected was washed with water and dried under vacuum to provide the title compound. MS ESI(+) m/z 601.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[C:38]1[C:43](=[O:44])[C:42]2[CH:45]=[CH:46][C:47]3[N:48]=C[O:50][C:51]=3[C:41]=2[O:40][C:39]=1[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:38]3[C:43](=[O:44])[C:42]4[C:41](=[C:51]([OH:50])[C:47]([NH2:48])=[CH:46][CH:45]=4)[O:40][C:39]=3[C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=c1c(I)c(-c2ccccc2)oc2c1ccc1ncoc12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(O)c(N)ccc4c3=O)cc2)CCC1
Yield: 14 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-iodo-8-phenyl-chromeno[7,8-d]oxazol-6-one was reacted to give the title compound as a yellow oil (25 mg, 14%). LCMS (Method G): RT=3.75 min, [M+H]+=499.
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:17]1([NH:20][C:8]([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH2:19][CH2:18]1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: NC1CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)N(c1ccccc1)c1ccccc1

Procedure:
The thus formed solution of diphenylcarbamic acid chloride was then added dropwise upon stirring to a mixture of 114 g of cyclopropylamine, 202 g of triethylamine and 500 ml of toluene. During the addition the temperature inside the flask rose to 85° C. Subsequently the reaction mass was heated to boiling point for 15 minutes and then cooled. The precipitated triethylammoniumchloride was removed by suction and the solvent was distilled off in a vacuum. The remaining residue was subjected to recrystallization from diisopropylether. The yield in 1-cyclopropyl-3,3-diphenylurea was 440.2 g (87.2% of the theoretical value). The melting point was 98° C.
Reaction SMILES: P(=O)(O)(O)O.CC(C)CC(=O)C.[NH2:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1/[C:19](=[CH:21]/[CH:22]([CH3:24])[CH3:23])/[CH3:20].NC1C=CSC=1/C(=C\C(C)C)/C>O>[NH2:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]([CH2:21][CH:22]([CH3:24])[CH3:23])=[CH2:20]
Reactant: C/C(=C\C(C)C)c1sccc1N
Agent: C/C(=C/C(C)C)c1sccc1N
Agent: O=P(O)(O)O
Solvent: CC(=O)CC(C)C
Solvent: O
Product: C=C(CC(C)C)c1sccc1N
Temperature: 25 °C
Yield: 34 %

Procedure:
3-aminothiophene phosphate (5.0 g, 16.1 mmol) was added into water (100 g) in an ice water bath for dissolving. Toluene (50.0 g) was added in an ice water bath, and then a 10% aqueous sodium hydroxide solution was added under stirring in an ice water bath for adjusting the reaction solution to the alkaline side. The organic layer was separated, and then the aqueous layer was further extracted with toluene. To the toluene solution of 3-aminothiophene obtained as described above were added 85% phosphoric acid (0.9 g, 8.1 mmol) and 4-methyl-2-pentanone (50.0 g, 499.2 mmol) at room temperature, and the resulting solution was stirred under reflux under nitrogen atmosphere for 5 hours with removing water. The reaction solution was cooled to room temperature, and then washed with a 10% aqueous sodium hydroxide solution two times, and the obtained organic layer was concentrated under reduced pressure to give an oily substance. The resulting concentrate was purified by silica gel column chromatography to give 1.0 g of an oily substance as a mixture of three compounds including 3-amino-2-{(E)-(4-methyl-2-penten-2-yl)}thiophene, 3-amino-2-{(Z)-(4-methyl-2-penten-2-yl)}thiophene and 3-amino-2-(4-methyl-1-penten-2-yl)thiophene (yield: 34%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=O.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.CN(C)C=O>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:9])[NH:10][C:14]([C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[Cl:11])=[N:1][C:2]=2[CH:6]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NC(=O)c1sc(Br)cc1N
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=c1[nH]c(-c2ccccc2Cl)nc2cc(Br)sc12
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-amino-5-bromothiophene-2-carboxamide (100 mg), 2-chlorobenzoylchloride (57 μL), N,N-dimethylpyridin-4-amine (55 mg), pyridine (1.0 mL) and N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1.5 hr. The reaction system was concentrated under reduced pressure, 2M aqueous sodium hydroxide solution was added to the residue, and the mixture was heated to 120° C. After 1 hr, insoluble material was removed by filtration, and the filtrate was neutralized with 1M hydrochloric acid. The precipitate was collected by filtration and washed with water to give the title compound (120 mg) as a dark orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[S:17](N)(N)(=[O:19])=[O:18]>COCCOCCOC>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:16][S:17]2(=[O:19])=[O:18])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1ccccc1Nc1ccc(F)c(F)c1
Reactant: NS(N)(=O)=O
Solvent: COCCOCCOC
Product: O=S1(=O)Nc2ccccc2N1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.7 %

Procedure:
Dry diglyme (10 mL) was added to a flask equipped with a dropping funnel under a nitrogen atmosphere and brought to a vigorous reflux. N-(3,4-difluorophenyl)benzene-1,2-diamine (1.03 g, 4.7 mmol) and sulfamide (0.54 g, 5.6 mmol) were dissolved in 5 mL of diglyme and placed in the dropping funnel. The mixture was added dropwise to the flask over 15 minutes and then refluxing was continued for an additional 15 minutes. The mixture was cooled to ambient temperature and the reaction mixture was evaporated using high temperature. The crude reaction product was purified by flash chromatography (SiO2, 3-50% ethyl acetate/hexane) to provide 1-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.62 g, 47%) as a pink solid:
Reaction SMILES: [C:1]([O:5][C:6]([C@@:9]12[CH2:18][CH2:17][CH2:16][CH2:15][C@:14]1([OH:19])[CH2:13][CH2:12][CH2:11][CH2:10]2)([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:20]=[C:21]1[O:25][C:23](=[O:24])[CH2:22]1.C(N(CC)CC)C>O1CCCC1>[C:23]([O:19][C@@:14]12[CH2:15][CH2:16][CH2:17][CH2:18][C@:9]1([C:6]([O:5][C:1](=[O:4])[CH:2]=[CH2:3])([CH3:8])[CH3:7])[CH2:10][CH2:11][CH2:12][CH2:13]2)(=[O:24])[CH2:22][C:21]([CH3:20])=[O:25]
Reactant: C=CC(=O)OC(C)(C)[C@]12CCCC[C@@]1(O)CCCC2
Reactant: C=C1CC(=O)O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OC(C)(C)[C@]12CCCC[C@@]1(OC(=O)CC(C)=O)CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 100 mmol of 4a-(1-acryloyloxy-1-methylethyl)-8a-hydroxy-cis-decalin prepared in the same manner as in Example 4, 110 mmol of diketene, 110 mmol of triethylamine, and 300 ml of tetrahydrofuran was stirred at room temperature for 2 hours. The resulting reaction mixture was subjected to chromatography on a silica gel to yield 8a-acetoacetyloxy-4a-(1-acryloyloxy-1-methylethyl)-cis-decalin represented by the following formula (yield: 89.1%). The conversion rate from 4a-(1-acryloyloxy-1-methylethyl)-8a-hydroxy-cis-decalin was 99%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:9])[CH3:8].[C:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][CH:20]([NH:9][CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH3:8])[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(N)c1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(NC1CCN(C(=O)OC(C)(C)C)CC1)c1ccccn1

Procedure:
Using General Procedure B: Reaction of 1-Pyridin-2-yl-ethylamine and 1-Boc-4-piperidone with NaBH(OAc)3 in CH2Cl2 gave 4-(1-Pyridin-2-yl-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)=[C:7]([NH2:9])[CH:8]=1.[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25].[Cl-].[NH4+]>O1CCCC1.C(N(CC)C(C)C)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)=[C:7]([NH:9][C:22](=[O:26])[O:23][CH2:24][CH3:25])[CH:8]=1
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(C2=Cc3ccc(OC)cc3CC2)c(N)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Nc1cc(OC)ccc1C1=Cc2ccc(OC)cc2CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methoxy-2-(6-methoxy-3,4-dihydronaphthalen-2-yl)phenylamine (400 mg) in tetrahydrofuran (10 ml) and N,N-diisopropylethylamine (0.5 ml) was added ethyl chlorocarbonate (0.2 ml) on an ice bath, and the solution was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added thereto, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide ethyl [5-methoxy-2-(6-methoxy-3,4-dihydronaphthalen-2-yl)phenyl]carbamate (445 mg). This compound (438 mg) was used according to an analogous synthetic method to Example 337 described below to provide the title compound (286 mg).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][N:9]1[C:13]([CH2:14][OH:15])=[CH:12][CH:11]=[N:10]1.F[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1>O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([O:15][CH2:14][C:13]2[N:9]([CH3:8])[N:10]=[CH:11][CH:12]=2)=[N:18][CH:19]=1
Reactant: Cn1nccc1CO
Reactant: Fc1ccc(F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nccc1COc1ccc(F)cn1
Reaction time: 2 h
Yield: 58.4 %

Procedure:
60% Sodium hydride (390 mg) was added to a dimethylformamide (9.0 mL) solution of (1-methyl-1H-pyrazol-5-yl)methanol (1.00 g) at a room temperature, and the obtained solution was then stirred for 2 hours. Thereafter, 2,5-difluoropyridine (1.17 g) was added to the reaction solution, and the mixed solution was then stirred for 16 hours. Subsequently, water was added to the reaction solution, and the obtained mixture was then extracted with hexane/ethyl acetate (1/2). The organic layer was concentrated under a reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate=95:5 to 60:40), so as to obtain the title compound (1.08 g) in the form of a colorless solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[O:12][C:13]([CH3:22])([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])(=O)=O.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.[K].O>CN(C)C=O>[C:26]1(=[O:36])[N:30]([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]([CH3:22])([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCOS(C)(=O)=O)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-[3-(3-methanesulfonyloxypropyl)phenoxy]-2-methylpropionate (1.93 g, 5.18 mmol) was dissolved in dimethylformamide (10.0 mL). Subsequently, potassium phthalimide (1.15 g, 6.22 mmol) was added thereto, and the mixture was stirred overnight at 80° C. Water was added thereto, and the resultant mixture was extracted with diethyl ether. The reaction mixture was subjected to drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate=5/1), thereby the target compound was obtained (1.8 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[O:10]1[CH2:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].CN(C)C(N(C)C)=N.C(OCC)(=O)C>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:12]2[C:13](=[O:15])[CH2:14][O:10][C:11]2=[O:16])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=C1COC(=O)N1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1COC(=O)N1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
A solution of 1.50 g (6 mmol) of 4-bromobenzyl bromide and 0.73 g (7.2 mmol) of 1,3-oxazolidine-2,4-dione in 6 ml of tetrahydrofuran is admixed dropwise with a solution of 1.39 g (12 mmol) of 1,1,3,3-tetramethylguanidine in 6 ml of tetrahydrofuran. The mixture is stirred at ambient temperature overnight. 50 ml of ice-cold aqueous hydrochloric acid (1N) and 100 ml of ethyl acetate are added. The organic phase is separated after settling out and washed successively with 25 ml of water and 25 ml of saturated aqueous sodium chloride solution. It is dried over sodium sulphate and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on silica gel, eluting with an 80/20 mixture of cyclohexane and ethyl acetate. 1.14 g of product are obtained in the form of white crystals.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:16](Cl)(=[O:18])=[O:17])[CH:8]=2)[NH:3]1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(CC)CC>>[CH2:20]([NH:27][S:16]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[CH:11]=[C:10]2[C:12]([F:15])([F:14])[F:13])(=[O:18])=[O:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=c1cc(C(F)(F)F)c2cc(S(=O)(=O)Cl)ccc2[nH]1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1cc(C(F)(F)F)c2cc(S(=O)(=O)NCc3ccccc3)ccc2[nH]1
Yield: 92.3 %

Procedure:
Condensation of 2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonyl chloride (Preparation 3, 16 mg, 51 μmol) with BnNH2 (7 μL, 54 μmol), employing NEt3 (8 μL, 57 μmol) as base as delineated in Example 1, gave the title compound (18 mg, 90%): δH ((CD3)2SO) =4.00 (d, 2H), 7.05 (s, 1H), 7.10–7.20 (m, 5H), 7.50 (d, 1H), 7.95 (dd, 1H), 8.00 (d, 1H), 8.30 (t, 1H); m/z (ES−)=381.0 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[NH:34][CH2:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.N1C=CC=CC=1.[C:52](Cl)(=[O:56])[CH2:53][CH2:54][CH3:55].Cl>C(Cl)Cl>[F:43][C:40]([F:41])([F:42])[C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:39]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([C:52](=[O:56])[CH2:53][CH2:54][CH3:55])[CH2:35][CH3:36])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: CCNc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-ethylamino-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (100 mg) and pyridine (19 μl) are dissolved in methylene chloride (1 ml) and thereto is added butyryl chloride (19 μl) at room temperature. The reaction solution is stirred at room temperature for 30 minutes, and thereto are added methylene chloride and 1N-hydrochloric acid, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyryl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (84 mg). MS (m/z): 723 [M+H]+