Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([N:34]3[CH2:39][CH2:38][C:37]([CH3:41])([CH3:40])[CH2:36][CH2:35]3)=[C:17]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26]CC)=[O:25])[C:18]([CH3:22])=[N:19][C:20]=2[CH3:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CCO.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([N:34]3[CH2:35][CH2:36][C:37]([CH3:41])([CH3:40])[CH2:38][CH2:39]3)=[C:17]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([OH:26])=[O:25])[C:18]([CH3:22])=[N:19][C:20]=2[CH3:21])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccccc3)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCc2ccccc2)cc1
Yield: 85 %

Procedure:
A mixture of (S)-ethyl 2-(5-(4-(benzyloxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.0224 g, 0.040 mmol) and LiOH (9.60 mg, 0.401 mmol) in 9:1 EtOH/H2O (2 mL) was refluxed for 3 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(5-(4-(benzyloxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetic acid (0.018 g, 0.034 mmol, 85% yield) as white solid. 1H NMR (400 MHz, CDCl3) δ 7.32-7.49 (m, 5H), 7.12-7.16 (m, 1H), 6.97-7.08 (m, 3H), 5.65 (br. s., 1H), 5.09-5.18 (m, 2H), 2.81 (s, 3H), 2.29 (s, 3H), 1.23-1.38 (m, 4H), 1.20 (s, 9H), 0.77 (br. s., 6H). 4H of piperidine were not resolved. LCMS (M+H)=531.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[N:26]=[CH:25][NH:24][N:23]=2)=[N:10]1.Cl.[NH:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]([OH:36])([CH3:35])[CH3:34]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:28]2[CH2:32][CH2:31][CH2:30][C@H:29]2[C:33]([OH:36])([CH3:35])[CH3:34])[NH:12][C:11]([C:22]2[N:26]=[CH:25][NH:24][N:23]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Reactant: CC(C)(O)[C@@H]1CCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCC[C@H]2C(C)(C)O)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Yield: 25.6 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (0.75 g, 1.53 mmol) was reacted with (S)-2-(pyrrolidin-2-yl)propan-2-ol hydrochloride (0.25 g, 1.53 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.21 g, 26%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH:17][CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].C1C=CC=CC=1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[O:17][CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[CH:4][CH:3]=1
Reactant: CC(=O)NCCO
Reactant: Fc1ccc(C(Cl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)NCCOC(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
A mixture of 25.4 g (0.1 mole) of bis(p-fluorophenyl)methyl chloride, 10.3 g (0.1 mole) of N-(2-hydroxyethyl)acetamide (prepared according to F. J. McQuillin et al., J. Chem. Soc. 1955, 2966), 14 g of potassium carbonate and 100 ml of benzene is refluxed for 5 hours. After cooling, the reaction mixture is poured into water. The aqueous layer is extracted with dichloromethane and the combined organic layers are dried over potassium carbonate and concentrated by evaporation of solvent. The residue is crystallised from toluene. N-{2-[Bis(p-fluorophenyl)methoxy]ethyl}acetamide, m.p. 112°-113.5° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:25][CH3:26])=[C:11]([CH:13]3[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[O:16][C:15]([CH3:23])([CH3:22])[C:14]3=[O:24])[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:25][CH3:26])=[C:11]([C:13]3[C:14](=[O:24])[C:15]([CH3:23])([CH3:22])[O:16][C:17]([CH3:20])([CH3:21])[C:18]=3[O:19][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1sc(-c2ccc(Cl)cc2)nc1C1=C(OC(=O)C(C)(C)C)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 4-[2-(4-chlorophenyl)-5-ethylthiazol-4-yl]-2,2,6,6-tetramethylpyran-3,5-dione (49 mg, 0.125 mmol) in dichloromethane (2 ml) is added triethylamine (87 μl, 0.625 mmol), followed by pivaloyl chloride (78 μl, 0.625 mmol), and the reaction mixture is stirred at room temperature for 17 hours. The reaction mixture is purified by flash chromatography on silica gel to give 2,2-dimethylpropionic acid 4-[2-(4-chlorophenyl)-5-ethylthiazol-4-yl]-2,2,6,6-tetramethyl-5-oxo-5,6-dihydro-2H-pyran-3-yl ester.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.C([O-])(=O)C.[Ca+2:37].C([O-])(=O)C.CCCCCCC>C(O)C.O>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[Ca:37]
Reactant: [Ca+2]
Agent: CC(=O)[O-]
Agent: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Solvent: O
Solvent: CCO
Solvent: CCCCCCC
Product: [Ca]
Temperature: 67.5 °C
Reaction time: 6 h

Procedure:
Raltegravir (10 gm) was suspended in ethanol (60 ml) and then added a solution of calcium acetate (4 gm) in water (2 ml) at 25 to 30° C. The contents were heated to 65 to 70° C. and distilled off solvent completely under vacuum at 45° C. to obtain residue. To the residue was added n-heptane (50 ml) and again distilled to obtain residue. n-Heptane (100 ml) was added to the residue and stirred for 6 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 9.9 gm of raltegravir calcium.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[C:11]([O:10][C:8]([N:15]1[CH2:20][CH2:19][CH:18]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][CH2:16]1)=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: Nc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccnc2)CC1
Yield: 1135.7 %

Procedure:
Using general procedure A, 3-aminopyridine (1.43 g, 1.01 mmol) and 1-Boc-4-piperidone (3.0 g, 1.0 mmol) afforded 4-(pyridin-3-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (3.15 g, 92%).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[NH:8][C:9](=O)[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].B.C1COCC1>C1COCC1>[N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCCc2cc([N+](=O)[O-])ccc2N1
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)CCCCN2
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
A solution of 7-Nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (0.34 g, 1.65 mmol) in THF (10 mL) was treated with borane-THF (5 mL, 4.95 mmol) and heated to 60° C. and stirred for 2 h. The mixture was poured in saturated aqueous sodium bicarbonate/ice. The mixture was extracted 2×EtOAc, the organic layers washed with brine and dried (MgSO4), filtered and concentrated on SiO2. Purification by ISCO chromatography (40 gram column, SiO2, gradient 0% to 100% EtOAc in hexane) gave 7-Nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (220 mg, 63%). MP: 73-75° C.; 1H-NMR (CDCl3) δ 7.97 (s, 1H), 7.89 (dd, J=2.6, 8.7 Hz, 1H), 6.61 (d, J=8.7 Hz, 1H), 4.42 (br s, 1H), 2.88-2.84 (m, 2H), 1.89-1.78 (m, 4H); LC/MS (ESI+): 193.02 (M+H).
Reaction SMILES: N(C(OC(C)(C)C)=O)CC(N1CCC[C@H]1C(O)=O)=[O:4].C1C([N+]([O-])=O)=CC=C(O)C=1.[CH2:30]1[CH2:35][CH2:34][CH:33]([N:36]=[C:37]=[N:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:32][CH2:31]1>C(Cl)Cl>[C:37]([NH:36][CH:33]1[CH2:32][CH2:31][CH2:30][CH2:35][CH2:34]1)([NH:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:4]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
Boc-Gly-Pro-OH (2.8 g, 0.01 mol.) and p-nitrophenol (1.7 g, 0.012 mol.) were dissolved in DCM (100 ml) and DCC (2.1 g, 0.01 mol.) was added to the solution by portions while stirring the solution. A precipitate (dicyclohexylurea, DCU) soon formed. After stirring the solution at room temperature for 3.5 hours, TLC analysis (developing solvents:ethyl acetate/hexane, 3:1) showed that all the starting material Boc-Gly-Pro-OH was consumed. The Rf for the product Boc-Gly-Pro-ONp is 0.45 in this solvent system. DCU was removed by filtration and DCM was removed under reduced pressure. Ethyl acetate was added to the remaining oil and the resulting solution was chilled to 0° C. More precipitate formed and was removed by filtration. The above procedures were repeated and a brownish oil was obtained. The product was directly used in the synthesis of Boc-Gly-Pro-Hyp(OBz)-OH without further purification and characterization.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]1[O:16][CH2:15][C:14](=O)[N:13]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH2:12]1)(C(C)(C)C)(C)C>O1CCCC1>[Cl:25][C:20]1[CH:19]=[C:18]([N:13]2[CH2:14][CH2:15][O:16][C@H:11]([CH2:10][CH2:9][OH:8])[CH2:12]2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CN(c2ccc(Cl)c(Cl)c2)C(=O)CO1
Solvent: C1CCOC1
Product: OCC[C@@H]1CN(c2ccc(Cl)c(Cl)c2)CCO1
Reaction time: 2 h
Yield: 91.2 %

Procedure:
580 mg (1.43 mmole) of 2-[(2 R)-(3,4-dichlorophenyl)-5-oxomorpholin-2-yl]ethanol t-butyldimethylsilyl ether [prepared as described in step (b) above] were dissolved in 6 ml of anhydrous tetrahydrofuran. The solution was then heated under reflux under a stream of nitrogen and 0.60 ml (6.0 mmole) of a 10 M borane-dimethyl sulfide complex was added dropwise. The mixture was then stirred for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and 5 ml of 1 N aqueous hydrochloric acid were added. The mixture was then stirred at 100° C. for 1 hour. The reaction mixture was air-cooled, made basic by the addition of a 1 N aqueous solution of sodium hydroxide, diluted with a saturated aqueous solution of sodium chloride and then extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of methylene chloride and methanol ranging from 9:1 to 17:3 by volume as the eluent, to obtain 360 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][N:14]([C:17]2[S:18][C:19]([C:23](O)=[O:24])=[C:20]([CH3:22])[N:21]=2)[C:13](=[O:26])[CH:12]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:23]([C:19]2[S:18][C:17]([N:14]3[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][C:13]3=[O:26])=[N:21][C:20]=2[CH3:22])=[O:24])=[CH:4][CH:3]=1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)O
Reactant: NCc1ccc(F)cc1
Product: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 37 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 4-fluorobenzylamine in place of benzylamine to react with 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 37% yield: mp 280-282° C. (methanol/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 8.74 (t, J=5.9 Hz, 1H), 8.56 (d, J=8.0 Hz, 1H), 7.34-7.29 (m, 2H), 7.12 (t, J=8.9 Hz, 2H), 6.22 (dd, J=8.0, 2.5 Hz, 1H), 5.75 (d, J=2.5 Hz, 1H), 4.35 (d, J=5.8 Hz, 2H), 2.52 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.9, 162.0, 161.6, 154.1, 150.2, 139.9, 132.6, 128.7, 127.7, 127.2, 123.6, 104.4, 98.0, 43.1, 17.5; MS (ES+) m/z 360.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[CH:2].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[C:1]([C:3]1[CH:4]=[C:5]([NH:6][CH:12]([C:14]2[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:7]=[CH:8][CH:9]=1)#[CH:2]
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: C#Cc1cccc(N)c1
Agent: Br
Product: C#Cc1cccc(NC(C)c2cc(C(=O)N(C)C)cc3c(=O)cc(N4CCOCC4)oc23)c1
Yield: 64.8 %

Procedure:
3-ethynylaniline (0.083 mL, 0.73 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (0.09 g, 0.18 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(3-ethynylphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (52 mg, 64%) as a white solid. Mass Spectrum: M+H+ 446.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:5]([SH:12])=[N:6][C:7]([SH:11])=[N:8][C:9]=1[NH2:10].[F:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br.O>CO>[F:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][S:11][C:7]1[N:8]=[C:9]([NH2:10])[C:4]([NH2:3])=[C:5]([S:12][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:14]=2[F:13])[N:6]=1
Reactant: Fc1cccc(CBr)c1F
Reactant: Nc1nc(S)nc(S)c1N
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1nc(SCc2cccc(F)c2F)nc(SCc2cccc(F)c2F)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a solution of potassium hydroxide powder (7.72 g) in methanol (250 ml) was added first 5,6-diamino-2,4-pyrimidinedithiol (10.9 g) followed by 2,3-difluorobenzyl bromide (22.5 g). The reaction mixture was stirred for one hour at room temperature then poured into water (500 ml), giving a brown precipitate. This was isolated by filtration, washing with isopropanol and diethyl ether, to give the subtitled compound as a pale brown solid (15.0 g).
Reaction SMILES: NC1C=CC(C(O)=O)=CC=1OC(F)(F)F.Cl.Cl.N[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=1[O:29][C:30]([F:33])([F:32])[F:31].N([O-])=O.[Na+].[Br-:38].[Na+].[O-]S([O-])=O.[Na+].[Na+]>CO.O.Br.[O-]S([O-])(=O)=O.[Cu+2].C1C=CC=CC=1>[Br:38][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=1[O:29][C:30]([F:33])([F:32])[F:31]
Reactant: [Br-]
Reactant: COC(=O)c1ccc(N)c(OC(F)(F)F)c1
Agent: [Cu+2]
Agent: Br
Agent: Cl
Solvent: c1ccccc1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(Br)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-3-(trifluoromethoxy)benzoic acid (2.00 g, 9.10 mmol) in MeOH (25.0 mL), was slowly added HCl (1.0 mL, 1.0 M in ether) at room temperature. The resulting reaction mixture was stirred at room temperature overnight. Benzene (20 mL) was added, and the reaction was heated at reflux with a Dean-Stark trap to remove the half volume of the solvent. The rest of the solvent was then evaporated to give the product. MS (ESI) m/e=235.9 [M+1]+, Calc'd for C8H6F3NO3, 235.1. The crude product was used in the next step without further purification. To an ice-cooled suspension of methyl 4-amino-3-(trifluoromethoxy)benzoate hydrogen chloride salt (8.60 g, 31.70 mmol) in 17.1 mL of water and concentrated HBr (48%, 17.1 mL), was slowly added a prepared 2.5 M solution of sodium nitrite (2.20 g in 12.7 mL) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes. Meanwhile, a solution of CuSO4 (6.68 g) in 35 mL of water was heated and sodium bromide (6.52 g) was added. The solution became a green color, and a solution of Na2SO3 (2.80 g) in water (10 mL) was then added to it. The solution was cooled at 0° C. and washed with water (25×3 mL). The water was then decanted off. Concentrated HBr (16.7 mL) was added, and the solution became a purple color. The solution of CuBr was slowly added to the diazonium salt (prepared above) at 0° C. After addition, the ice-bath was removed, and an oil-bath was placed under the reaction vessel. The reaction mixture was then heated to 60° C. for 15 minutes, at 80° C. for 15 minutes, and then at 100° C. for 20 minutes. The reaction mixture was next cooled to room temperature and made basic with Na2CO3 to a pH 8. The aqueous solution was extracted with EtOAc (100×2 mL). The organic layer was washed with brine (25 mL) and dried with MgSO4. The solvent was removed to give the crude product 28.2. 1H NMR (CDCl3) δ 3.96 (s, 3H), 7.75 (d, J=8.4 Hz, 1 H), 7.86 (d, J=8.4 Hz, 1 H), 7.98 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:30]>>[CH:18]([N:13]1[C:12]([C:34]2[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[CH:32][CH:33]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)n1nc2c(c1-c1ccc(C#N)cc1)CCNCC2
Yield: 70.7 %

Procedure:
The title compound (95 mg) was prepared as in Example 177, Steps C and D, using 205 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 211 mg of 4-cyanophenylboronic acid. MS (ESI): exact mass calculated for C17H20N4, 280.17; found, m/z 281.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.57 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 4.36 (m, 1H), 3.42-3.40 (m, 2H), 3.19-3.17 (m, 2H), 2.79-2.77 (m, 2H), 1.40 (d, J=6.6 Hz, 6H).
Reaction SMILES: [C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19](C(OC(C)(C)C)=O)[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:27]>C(OCC)(=O)C>[ClH:27].[ClH:27].[C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][NH:19][C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc([C@@H]2Nc3ccccc3[C@@H]3NCC[C@H]23)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
tert-Butyl (3aR*,4R*,9bR*)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (2.65 g, 7.56 mmol) was dissolved in ethyl acetate (10 ml), and a 4N hydrogen chloride in ethyl acetate solution (20 ml) was added, and the mixture was stirred at room temperature for 12 hrs. The precipitated crystals were collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound (2.60 g, 77%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17](=[O:27])[C:18]2[C:24]([O:25][CH3:26])=[N:23][CH:22]=[CH:21][C:19]=2[N:20]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17](=[O:27])[C:18]2[C:24]([O:25][CH3:26])=[N:23][CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: COc1nccc2nc(-c3ccccc3OCc3ccccc3)n(CCc3ccccc3)c(=O)c12
Agent: [Pd]
Solvent: CO
Product: COc1nccc2nc(-c3ccccc3O)n(CCc3ccccc3)c(=O)c12

Procedure:
2-(2-Benzyloxy-phenyl)-5-methoxy-3-phenethyl-3H-pyrido[4,3-d]pyrimidin-4-one dissolved in methanol (0.05M) was subjected to H-cube hydrogenation (room temperature, Pd/C cartridge). Solvent was then removed and product purified on preparative TLC plate to afford the desired 2-(2-Hydroxy-phenyl)-5-methoxy-3-phenethyl-3H-pyrido[4,3-d]pyrimidin-4-one.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C([Li])CCC.B(OC)(OC)[O:29]C.C(OO)(=O)C.S([O-])(O)=O.[Na+]>C1COCC1>[OH:29][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: COB(OC)OC
Reactant: CC(=O)NC(C)CCc1ccc(Oc2ncc(Br)cn2)cc1
Agent: CC(=O)OO
Agent: O=S([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)NC(C)CCc1ccc(Oc2ncc(O)cn2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
N-{3-[4-(5-Bromopyrimidin-2-yloxy)phenyl]-1-methylpropyl}acetamide (509 mg, 1.397 mmol) were dissolved in 5 ml of THF and, at −78° C., n-butyllithium (1.6 M in hexane, 2.18 ml, 3.49 mmol) was added dropwise. This was followed after 20 min by addition of trimethyl borate (0.25 ml, 2.26 mmol), stirring at −78° C. for 2 h and then addition of peracetic acid (35 percent strength, 0.475 ml, 2.26 mmol) and stirring for 10 min. The reaction mixture was warmed to 0° C., stirred for 1 h and hydrolyzed at −10° C. with 5 ml of 10 percent strength sodium hydrogen sulfite solution. The solvent was removed in a rotary evaporator, the aqueous phase was extracted with ethyl acetate, the organic phase was washed with sodium chloride solution, and dried with magnesium sulfate and concentrated. The crude product was purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 129 mg, M+H+: 302.15. Fraction contains the desired substance only partially.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4].Cl[CH2:9][C:10](Cl)=[O:11]>C(O)C>[CH3:4][CH:3]([CH:2]1[NH:1][C:10](=[O:11])[CH2:9][O:7][CH2:6]1)[CH3:5]
Reactant: O=C(Cl)CCl
Reactant: CC(C)[C@H](N)CO
Solvent: CCO
Product: CC(C)C1COCC(=O)N1

Procedure:
Treatment of valinol in basic ethanol with chloroacetyl chloride using the procedure of Surry, et. al., J. Am. Chem. Soc. (1955) 77, 633, gives 5-(2-propyl)-3-morpholinone. Deprotonation of the latter with NaH in DMF solution and reaction with methyl iodide gives the title compound.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH2:18][C:19]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)([C:22]([F:25])([F:24])[F:23])[CH2:20][N:21]=2)=[CH:9][CH:8]=1)(=O)=O.O.[NH3:35]>C1COCC1.CO>[Cl:32][C:30]1[CH:31]=[C:26]([C:19]2([C:22]([F:25])([F:24])[F:23])[CH2:18][C:17]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:7]([CH2:6][NH2:35])=[CH:8][CH:9]=3)=[N:21][CH2:20]2)[CH:27]=[C:28]([Cl:33])[CH:29]=1
Reactant: CS(=O)(=O)OCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: N
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: NCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reaction time: 12 h

Procedure:
{4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]naphthalen-1-yl}methyl methanesulfonate (0.7 g) was dissolved in a mixed solvent of THF (20 ml) and methanol (20 ml), and aqueous ammonia solution (28%, 20 ml) was added thereto. The mixture was stirred for 12 hour, and then added water. The mixture was extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, to obtain the desired compound as crude product (0.48 g).