Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][CH2:11][O:10][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:13].ClCCl.CO>C(O)C>[C:1]1([C@H:7]([CH2:12][CH2:11][OH:10])[C:8]([NH2:13])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=C1OCC[C@H]1c1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: NC(=O)[C@@H](CCO)c1ccccc1
Yield: 63.3 %

Procedure:
(S)-2-phenylbutyrolactone (1 gram) was dissolved in 5 ml of absolute ethanol, followed by the addition of 0.5 gram of gaseous ammonia. The solution was kept in a stoppered flask, and the progress of the reaction was followed by thin layer chromatography (eluent dichloromethane/methanol 20:1). After the reaction was judged complete, the ethanol was evaporated and the resulting residue redissolved in ethyl acetate. Ammonia was removed by extraction with 1% HCl, and the ethyl acetate solution was dried over MgSO4, filtered, and rotary evaporated to leave 0.7 grams of (S)-2-phenyl-4-hydroxybutyramide.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[O:37][N:36]=[C:35]([CH2:38][CH3:39])[N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:38]([C:35]1[N:34]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[O:37][N:36]=1)[CH3:39]
Reactant: CCc1noc(CCl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (7.70 g; compound B50) is reacted with 5-(chloromethyl)-3-ethyl-1,2,4-oxadiazole (2.64 g; compound D7) in the presence of potassium carbonate (2.49 g) in DMF (50 ml). Using WU1 a solid is obtained which is recrystallized from EtOAc (400 ml) at 65° C. to give the title compound.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.[Cl:15][CH2:16][C:17]([CH2:19][Cl:20])=O>C(OCC)(=O)C>[Cl:15][CH2:16][C:17]([CH2:19][Cl:20])([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:5]#[N:6]
Reactant: Cc1ccc(N)cc1
Reactant: O=C(CCl)CCl
Reactant: C[Si](C)(C)C#N
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(C#N)(CCl)CCl)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
Trimethylsilyl cyanide (0.27 ml, 2 mmol) was added dropwise to a mixture of p-toluidine (0.107 g, 1 mmol) and 1,3-dichloroacetone (0.254 g, 2 mmol). The reaction mixture was heat to 80° C. and stirred for 6 h. To the mixture was added 20 ml of ethyl acetate and then wash with water (2×20 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane) to yield 21a (0.192 g, 0.79 mmol, 79%) as a brown powder.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[CH2:14]([O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[N:20]=[C:19]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:18]=1)[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:24]([O:23][C:21]1[CH:22]=[C:17]([O:16][CH2:14][CH3:15])[N:18]=[C:19]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:28][CH2:27]2)[N:20]=1)[CH3:25]
Reactant: CCOc1cc(OCC)nc(N2CCNCC2)n1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(OCC)nc(N2CCN(Cc3ccc(CNC(C)=O)cc3)CC2)n1
Yield: 115.5 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (1.2 g), 1-(4,6-diethoxypyrimidin-2-yl)piperazine (1.7 g) and potassium carbonate (1.3 g) in dimethylformamide (20 ml) was stirred at 80° C. for 4.5 hr. The reaction mixture was poured into water(150 ml) and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown oil (2.9 g). The obtained brown oil was purified by silica gel column chromatography to give a pale-yellow oil (2.4 g). The obtained pale-yellow oil was crystallized from ethyl acetate/hexane (2:1, 30 ml) to give the title compound (1.7 g) as white crystals, m.p.=119-120° C.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([CH:12]=O)[CH:5]=[CH:4][C:3]1=2.[NH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].CCN(CC)CC.[BH3-]C#N.[Na+].[CH:31]1([C:37]2[CH:45]=[CH:44][C:40]([CH2:41][O:42][NH2:43])=[CH:39][C:38]=2[C:46]([F:49])([F:48])[F:47])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CO.CC(O)=O>[CH:31]1([C:37]2[CH:45]=[CH:44][C:40]([CH2:41][O:42][N:43]=[C:2]3[CH2:11][CH2:10][CH2:9][C:8]4[CH:7]=[C:6]([CH2:12][NH:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:5]=[CH:4][C:3]3=4)=[CH:39][C:38]=2[C:46]([F:47])([F:48])[F:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: O=Cc1ccc2c(c1)CCCC2=O
Reactant: NCCC(=O)O
Reactant: NOCc1ccc(C2CCCCC2)c(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)CCNCc1ccc2c(c1)CCCC2=NOCc1ccc(C2CCCCC2)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carbaldehyde (0.1 mmol) in MeOH (1 mL) is added β-alanine (0.2 mmol) and Et3N (0.16 mmol). The mixture is heated at 50° C. with stirring for 1 hour. After cooling to room temperature, NaBH3CN (0.3 mmol) is added in one portion and the resulting mixture is stirred for 30 minutes. O-(4-Cyclohexyl-3-trifluoromethyl-benzyl)-hydroxylamine (0.12 mmol) is then added to the above reaction mixture and the pH of the solution is tuned to 5-6 by adding AcOH. Purification by preparative LCMS results in 3-{[5-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl]-amino}-propionic acid; 1H NMR (600 MHz, CD3OD) δ 8.00 (d, 1 H), 7.65 (s, 1 H), 7.59 (d, 1 H), 7.52 (d, 1 H), 7.35-7.26 (m, 2 H), 5.22 (s, 2 H), 4.21 (s, 2 H), 3.30 (t, 2 H), 2.94 (m, 1 H), 2.78 (m, 6 H), 1.90-1.70 (m, 7 H), 1.60-1.45 (m, 2 H), 1.45-1.30 (m, 3 H); MS (ES+): 503.2 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2C(F)=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.C([NH:24]O)(=O)C.[C:26](=[O:29])([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:26]3[O:29][N:24]=[C:11]([NH2:12])[C:10]=3[CH:13]=[CH:14][CH:15]=2)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12
Reactant: Cn1ncc2c(Cl)cc(-c3cccc(C#N)c3F)nc21
Reactant: CC(=O)NO
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ncc2c(Cl)cc(-c3cccc4c(N)noc34)nc21
Temperature: 50 °C
Yield: 40 %

Procedure:
3-(4-Chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-fluorobenzonitrile 15 (90 mg, 0.299 mmol) was added to a mixture of acetohydroxamic acid, CH3C(O)NHOH (0.0675 g, 0.899 mmol) and potassium carbonate (0.145 g, 1.049 mmol) in 4 mL dimethylformamide and the resultant reaction mixture was heated for 2 hours at 50° C. The solvent was removed, diluted with ethyl acetate and washed with saturated sodium bicarbonate (1×20 mL) followed by brine (1×20 mL), dried over anhydrous sodium sulfate, concentrated and purified by a Biotage purification system eluting with ethyl acetate and hexanes to obtain 17 (35 mg, 40%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2].[F:21][C:22]([F:31])([F:30])[C:23]1[S:27][C:26]([CH2:28]O)=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.O>[CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:28][C:26]4[S:27][C:23]([C:22]([F:31])([F:30])[F:21])=[CH:24][CH:25]=4)=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Reactant: OCc1ccc(C(F)(F)F)s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2ccc(-n3ccc(OCc4ccc(C(F)(F)F)s4)cc3=O)cc2n1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 17.6 %

Procedure:
To a solution of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (120 mg), (5-(trifluoromethyl)-2-thienyl)methanol (162 mg) and tributylphosphine (270 mg) in THF (8 ml) was added 1,1′-(azodicarbonyl)dipiperidine (337 mg), and the reaction mixture was stirred at 60° C., for 2 h. The reaction mixture was cooled to room temperature. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by NH silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH to give the title compound (33.9 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[H-].[Na+].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:3]=1
Reactant: OCc1cccc(Br)c1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(COCc2cccc(Br)c2)cc1
Reaction time: 0.17 h
Yield: 97.5 %

Procedure:
(3-Bromophenyl)methanol (500 mg) was mixed with DMF (10 ml), and sodium hydride (55% suspended in oil) was added thereto at 0° C., followed by stirring for 10 minutes under ice-cooling. 1-(Chloromethyl)-4-methoxybenzene (520 mg) was added to the reaction mixture, followed by stirring at room temperature for 2 hours. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/hexane) to obtain 1-bromo-3-{[(4-methoxybenzyl)oxy]methyl}benzene (801 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>CO.CC#N>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:30][C:29]2[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[CH:10][C:11]3[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[N:13][C:12]=3[N:28]=2)=[O:40])=[CH:34][CH:33]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Solvent: CO
Solvent: CC#N
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(NC(=O)Nc4ccc(Cl)cc4)nc3n2)CC1
Yield: 62.7 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.344 g of 4-chlorophenyl isocyanate according to the general procedure of Example 37 to give 0.8424 g of 1-(4-Chloro-phenyl)-3-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH+DMSO): M+ +H=601; mp 175.5°-181° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[CH2:1]([N:3]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCNc1ccccc1
Reactant: OCc1ccccc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: CCN(Cc1ccccc1)c1ccccc1
Temperature: 210 °C
Yield: 87 %

Procedure:
182 parts of N-ethylaniline, 170 parts of benzyl alcohol and 10 parts of triphenyl phosphite are mixed whilst stirring and next heated to an internal temperature of 184° C, at which the elimination of water commences. The mixture is then heated to an internal temperature of 210° C in the course of 8 hours. During this time, 25 parts of water have distilled off and the condensation has ended. The excess ethylaniline and unconverted benzyl alcohol are then distilled off. 276 parts of N-ethyl-N-benzyl-aniline, corresponding to a yield of 87% of theory, distil at a boiling point of 140° - 144° C/5 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:18]([NH:20][N:21]1[C:27](=[O:28])[CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]2[CH:39]=[CH:40][CH:41]=[CH:42][C:24]=2[C:23]2[CH:43]=[CH:44][CH:45]=[CH:46][C:22]1=2)=[O:19])[CH3:17]>>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:18]([NH:20][N:21]1[C:27](=[O:28])[CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:25]2[CH:39]=[CH:40][CH:41]=[CH:42][C:24]=2[C:23]2[CH:43]=[CH:44][CH:45]=[CH:46][C:22]1=2)=[O:19])[CH3:17])=[O:8]
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21
Agent: Cl
Product: C[C@H](NC(=O)[C@@H](O)c1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-alaninyl)-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-S), the title compound was prepared. The product was purified by chromatography (silica, 1–2% MeOH/CHCl3).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[CH2:10][CH2:11][Si:12](Cl)([Cl:14])[Cl:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C(N(CC)CC)C>>[CH2:1]([O:8][C:9](=[O:16])[CH2:10][CH2:11][Si:12]([Cl:14])([Cl:13])[CH2:20][N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=C(CC[Si](Cl)(Cl)Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CC[Si](Cl)(Cl)C[N+](=O)[O-])OCc1ccccc1
Temperature: 0 °C

Procedure:
298 g (1 mole) of 3-(trichlorosilyl) propionic acid benzyl ester (I) is dissolved in 540 ml (10 mol) of nitromethane and cooled to 0° C. Added dropwise 139 ml (1 mol) of triethylamine over a period of 2 hours. The mixture is then distilled through a 22 mm×4 ft. Podbielniak column packed with Heli-pak to give 3-(dichloronitromethylsilyl) propionic acid benzyl ester (II).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20]([C:24](O)=[O:25])=[CH:19][CH:18]=[CH:17]4)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[C:27]1([NH2:34])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH2:33]>>[NH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[NH:34][C:24]([C:20]1[C:21]2[C:16](=[CH:15][C:14]([O:13][C:7]3[C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[CH:23][CH:22]=2)[CH:17]=[CH:18][CH:19]=1)=[O:25]
Reactant: Nc1ccccc1N
Reactant: COc1ccc2c(Oc3ccc4c(C(=O)O)cccc4c3)ccnc2c1
Product: COc1ccc2c(Oc3ccc4c(C(=O)Nc5ccccc5N)cccc4c3)ccnc2c1
Yield: 90.9 %

Procedure:
The title compound (39.6 mg, 91% yield) was prepared as a brown solid from 6-(7-methoxyquinolin-4-yloxy)-1-naphthoic acid (34.5 mg, 0.1 mmol) and o-phenylenediamine (43.2 mg, 0.4 mmol) by an analogous procedure to that described in example 16. LC-MS (m/z) 1H NMR (DMSO-d6) δ 3.95 (s, 3H, —OCH3), 4.97 (s, 2H, benzene-NH2), 6.60 (d, J=5.2 Hz, 1H, Ar—H), 6.64 (t, J=7.6 Hz, 1H, Ar—H), 6.82 (d, J=7.8 Hz, 1H, Ar—H), 6.99 (t, J=7.4 Hz, 1H, Ar—H), 7.31 (dd, J=2.5 and 9.1 Hz, 1H, Ar—H), 7.38 (d, J=7.6 Hz, 1H, Ar—H), 7.45 (d, J=2.4 Hz, 1H, Ar—H), 7.57 (dd, J=2.4 and 9.2 Hz, 1H, Ar—H), 7.65 (t, J=7.8 Hz, 1H, Ar—H), 7.87-7.88 (m, 2H, Ar—H), 8.07 (d, J=8.2 Hz, 1H, Ar—H), 8.25 (d, J=9.2 Hz, 1H, Ar—H), 8.43 (d, J=9.2 Hz, 1H, Ar—H), 8.65 (d, J=5.2 Hz, 1H, Ar—H), 9.84 (s, 1H, benzene-NH). 436 (M+1).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[N:12]=[C:13]2[N:18]([CH:19]=1)[CH2:17][CH2:16][C@H:15]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=1)[O:14]2)([O-:10])=[O:9].[CH3:34][S:35](Cl)(=[O:37])=[O:36].Cl>C(Cl)Cl>[CH3:34][S:35]([N:31]1[CH2:32][CH2:33][N:28]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:20][C@@H:15]3[O:14][C:13]4=[N:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:19][N:18]4[CH2:17][CH2:16]3)=[CH:23][CH:24]=2)[CH2:29][CH2:30]1)(=[O:37])=[O:36]
Reactant: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCNCC3)cc1)CC2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Reaction time: 14 h

Procedure:
Triethylamine (0.31 ml) was added to a methylene chloride suspension (6 ml) of (R)-2-nitro-7-(4-piperazin-1-ylphenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (0.40 g). Subsequently, methanesulfonyl chloride (0.09 ml) was added thereto dropwise under ice cooling, and the mixture was stirred for 14 hours while it gradually returned to room temperature. A 0.5 N hydrochloric acid aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride:methanol=90:10) and recrystallized from methylene chloride-methanol to afford the title compound as a beige powder (0.15 g).
Reaction SMILES: O=C1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:5]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=2)[CH:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:30][CH:29]=2)[O:3]1.[OH-].[Na+].O>CO>[OH:3][CH:4]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:30][CH:29]=1)[CH:5]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:26])([F:27])[CH:23]([F:24])[F:25])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccc(Oc3ccccn3)cc2)C1Cc1cccc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (4RS,5SR)-2-oxo-5-[4-(pyridin-2-yloxy)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate (3.00 g, 5.33 mmol) in methanol (20 ml) was added a solution (12.8 ml, 6.4 mmol) of 0.5N sodium hydroxide in methanol, and the mixture was stirred at room temperature for 1 hr. To the reaction solution was added water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the objective substance (2.67 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[N:14]([CH3:16])[CH3:15])[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>O1CCCC1.O>[CH3:16][N:14]([CH3:15])[C:13]1[CH:12]=[CH:11][C:4]([C:5](=[O:6])[N:7]([O:9][CH3:10])[CH3:8])=[CH:3][C:2]=1[NH:1][C:24](=[O:25])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CON(C)C(=O)c1ccc(N(C)C)c(N)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)c1ccc(N(C)C)c(NC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of EXAMPLE 458B in a mixture of tetrahydrofuran (20 mL) and water (20 mL) was added cesium carbonate (6.02 g, 18.58 mmol) and benzyl chloroformate (1.5 mL, 10.16 mmol). The reaction mixture was stirred at room temperature for 16 hours, and concentrated. The residue was partitioned between ethyl acetate (100 mL) and brine (75 mL). The organic layer was washed with brine, and concentrated. The residual oil was purified by flash chromatography eluting with 40% ethyl acetate in hexanes to provide the title product. MS (DCI/NH3) m/z 358 (M+H)+.
Reaction SMILES: [O:1]([CH2:8][CH2:9][O:10][C:11]1[C:12]([OH:21])=[CH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(=O)O[CH2:25][CH2:24][O:23]1>[Br-].C([N+](CC)(CC)CC)C.ClCCl>[O:1]([CH2:8][CH2:9][O:10][C:11]1[C:12]([O:21][CH2:25][CH2:24][OH:23])=[CH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCCO1
Reactant: Oc1cc2ccccc2cc1OCCOc1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: ClCCl
Product: OCCOc1cc2ccccc2cc1OCCOc1ccccc1
Yield: 73.1 %

Procedure:
A stirred mixture of 3-(2-phenoxyethoxy)-2-naphthol (3.9 g), ethylene carbonate (1.4 g) and tetraethylammonium bromide (0.8 g) was heated at 155°-160° C. for 2 hours. The cooled reaction was diluted with dichloromethane and washed with 1N sodium hydroxide and with water. The organic layer was dried (Na2SO4), filtered, and evaporated to give crude material which was purified by HPLC (dichloromethane-ethyl acetate; 20:1 ) and crystallized from dichloromethane-diethyl ether to give 3.3 g of 2-[[3-(2-phenoxyethoxy)2-naphthalenyl]oxy]ethanol as a colorless solid, mp 119°-120° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH:31]=[C:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([C:42]#[N:43])[CH:40]=3)[NH:35][CH:34]=2)[CH2:29][CH2:28]1.C(O)(=O)/C=C/C(O)=O>CS(C)=O.C(O)C>[CH3:24][C:21]1[O:22][C:23]2=[C:15]3[C:16](=[CH:17][CH:18]=[C:19]2[N:20]=1)[O:25][CH2:26][CH:13]([CH2:12][N:27]1[CH2:28][CH:29]=[C:30]([C:33]2[C:41]4[C:36](=[CH:37][CH:38]=[C:39]([C:42]#[N:43])[CH:40]=4)[NH:35][CH:34]=2)[CH2:31][CH2:32]1)[O:14]3
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Reactant: N#Cc1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1nc2ccc3c(c2o1)OC(CN1CC=C(c2c[nH]c4ccc(C#N)cc24)CC1)CO3
Temperature: 77.5 °C

Procedure:
[(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl 4-methylbenzenesulfonate (0.60 g, 1,6 mmole) and 3-(1,2,3,6-tetrahydro4-pyridinyl)-1H-indole-5-carbonitrile (0.85 g, 3.8 mmole) were combined in 70 mL of DMSO under nitrogen. This solution was heated to 75-80° C. under nitrogen. After completion, the reaction was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The crude residue was column chromatographed on silica gel using 30% hexane/ethyl acetate to remove impurities. Ethyl acetate eluted the product, which was a yellow oil (0.24 g, 42%). The oil was crystallized from ethanol with the addition of a solution of fumaric acid (0.12 g, 1.02 mmole) in hot ethanol to give 0.20 g of the (S)-enantiomer of the title compound as a yellow solid difumarate•0.50 hydrate, m.p. 119° C. MS (ESI) m/z 427 (M+H)+.