Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)Cl.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]([C:13]2[N:14]=[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]3[CH:21]=2)[CH:12]=1.O.CN([CH:28]=[O:29])C>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]([C:13]2[N:14]=[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]3[C:21]=2[CH:28]=[O:29])[CH:12]=1
Reactant: COc1ccc(Br)cc1-c1cn2ccccc2n1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Br)cc1-c1nc2ccccn2c1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
POCl3 (0.39 g, 2.5 mmol) was added to DMF (0.43 g, 6 mmol) by dropwise at 0° C. Then 2-(5-bromo-2-methoxyphenyl)imidazo[1,2-a]pyridine (0.1 g, 0.33 mmol) in DMF (3 mL) was added. Then warmed to 25° C. and heated to 120° C. and stirred for 30 minutes and at 80° C. for 2 hours and then cooled to 25° C. H2O (20 mL) was added and extracted with EtOAc (3*50 mL), washed by aq NaHCO3 (3*50 mL) and brine (50 mL). After concentrated, the resulting residue was purified using prep-TLC (petroleum ether:EtOAc=3:1) to provide 2-(5-bromo-2-methoxyphenyl)imidazo[1,2-a]pyridine-3-carbaldehyde (100 mg, yield: 90%). 1H-NMR (CDCl3, 400 MHz) δ 9.85 (s, 1H), 9.60 (s, 1H), 7.77˜7.81 (m, 2H), 7.54˜7.58 (m, 2H), 7.12˜7.15 (m, 1H), 6.92˜6.94 (m, 1H), 3.82 (s, 3H). MS (M+H)+: 331/333.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CI.[C:11](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:11])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 75 %

Procedure:
p-Chlorophenol (2 g, 15 mmol), methyl iodide (1.36 ml, 21.8 mmol) and potassium carbonate (2.07 g, 15.6 mmol) in dry acetone (15 ml) were taken in a 50 ml flask. After refluxing for 3 hrs at 60° C., acetone was removed using a rotary evaporator. Water was added and the product was extracted with CH2Cl2 to afford 2.2 g of crude product, which was purified by column chromatography using hexane as eluent to yield p-chloroanisole in 75% yield (1.59 g).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.O>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:16]1[CH2:15][CH2:14][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH2:18][CH2:17]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
To an ice-cold solution of chloroacetyl chloride (1.27 g, 10 mmol) in 15 mL of methylene chloride was added N-tert-butoxycarbonylpiperazine (1.27 g, 11 mmol) in 10 mL of methylene chloride containing triethylamine (2.17 g, 20 mmol). The reaction mixture was stirred at 5° C. for 30 minutes, then warmed to room temperature and stirred for 24 hours. Water (20 mL) was added at 5° C., and the reaction mixture was diluted with methylene chloride (200 mL). The organic layer was separated, washed with saturated aqueous NaHCO3 (2×100 mL), brine (2×100 mL), dried over MgSO4, filtered, and concentrated at reduced pressure. The concentrated residue was purified by flash column chromatography on silica gel eluting with ethyl acetate to give 2.20 g (84.0%) of 1-(2-chloroacetyl)-4-(tert-butoxycarbonyl)piperazine as a yellow liquid. 1H NMR (300 MHz / CDCl3): δ 1.46 (s, 9H), 3.41-3.60 (m, 8H), 4.07 (s, 2H). HRMS: calcd for C11H19NO3 Cl1 262.1084, found 262.1079.
Reaction SMILES: CC[N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C.[Br:10][C:11]1[C:12](Cl)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]>CC#N.CCOCC>[Br:10][C:11]1[C:12]([N:3]2[CH2:4][CH2:6][C:20]([O:22][CH3:23])([CH3:19])[CH2:9][CH2:7]2)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Reactant: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CC#N
Product: COC1(C)CCN(c2c(Br)c(C)nc(C)c2C(=O)C(=O)OC(C)C)CC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 121.7 %

Procedure:
To a solution of 4-methoxy-4-methylpiperidine, HCl (1.0 g, 6.04 mmol) and DIEA (4.2 mL, 24.5 mmol) in anhydrous CH3CN (30 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (3.4 g, 6.04 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 24 h; cooled, diluted with ether, washed with water, brine, and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient eluted (5-35% EtOAc/hexanes) using an Isolera chromatography station gave isopropyl 2-(5-bromo-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate 1.57 g (61%). 1H NMR (500 MHz, DMSO-d6) δ 5.08-5.03 (m, 1H), 3.44-3.40 (m, 4H), 3.11 (s, 3H), 2.60 (s, 3H), 2.29 (s, 3H), 1.67 (d, J=13.2 Hz, 2H), 1.43 (br. s., 2H), 1.29 (d, J=6.2 Hz, 6H), 1.11 (s, 3H). UPLC (M+H)=429.3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.O>C(O)C>[CH3:11][C:6]1[CH:5]=[C:4]([NH:12][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:23])[F:24])=[CH:22][CH:21]=2)[CH:3]=[C:2]([CH3:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(N)cc(C)c1[N+](=O)[O-]
Solvent: O
Solvent: CCO
Product: Cc1cc(NCc2ccc(C(F)(F)F)cc2)cc(C)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 85 %

Procedure:
3,5-Dimethyl-4-nitro-phenylamine (3.95 g) and 4-trifluoromethyl-benzaldehyde (4.87 mL) were dissolved in ethanol (50 mL) and refluxed for 16 h. The reaction mixture was poured into water (75 mL) and the precipitate collected by filtration. Sodium cyanoborohydride (3.1 g) and acetic acid (7.0 mL) were added to the precipitate dispersed in methanol (130 mL) and stirred for 60 minutes. The reaction mixture was filtered, water (350 mL) was added and the organic solvent was removed in vacuo. The product was allowed to precipitate at 25° C. and collected by filtration and washed with water (300 mL) to furnish 6.7 g (85% yield) of the title compound as a yellow solid. LC-MS (m/z) 325 (MH+); tR=2.00, (UV, ELSD) 92%, 93%. 1H NMR (500 MHz, CDCl3): 2.30 (s, 6H), 4.45 (broad, 3H), 6.25 (s, 2H), 7.45 (d, 2H), 7.60 (d, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.Cl[C:24]1[N:29]=[CH:28][N:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2/[C:37](=[CH:42]\[O:43][CH3:44])/[C:38]([O:40][CH3:41])=[O:39])[CH:25]=1>C1(C)C=CC=CC=1.O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:24]1[N:29]=[CH:28][N:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2/[C:37](=[CH:42]\[O:43][CH3:44])/[C:38]([O:40][CH3:41])=[O:39])[CH:25]=1)#[N:2]
Reactant: N#Cc1ccccc1O
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Temperature: 105 °C
Reaction time: 1 h

Procedure:
A mixture of 2-cyanophenol (13.2 g), potassium carbonate (20.7 g), N-methyl-2-pyrrolidinone (15.0 g), (E)-methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (32.8 g) and water (35 g) was heated at 105° C. for 15 hours. Any distillates were allowed to come off under atmospheric conditions. The reaction mixture was mixed with toluene. The organic layer was then separated. Toluene and N-methyl-2-pyrrolidinone were removed from the organic phase by vacuum distillation (110° C., 20 mmHg). The melt was cooled to 90° C. after which methanol (40 ml) was added to help cooling to 65-75° C. The resulting mixture was cooled to ambient and kept at this temperature overnight. It was then further cooled to 0-5° C. and held for another 1 hour period. The mixture was filtered to leave (E)-methyl 2-[2-(6-(2-cyanophenoxy)pyrimidin-4-yloxy)phenyl]-3-methoxypropenoate as the residue (68.2% isolated yield).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]([Cl:12])[C:5](Cl)=[C:6]([N+:8]([O-])=O)[CH:7]=1.ClC1C([N+]([O-])=O)=C(Cl)C(Cl)=C(Cl)C=1Cl.C1(O)C=CC=CC=1.I.[H][H]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:12])[CH:3]=1)[NH2:8]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1Cl
Agent: I
Agent: O=[N+]([O-])c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Solvent: Oc1ccccc1
Product: Nc1cc(Cl)cc(Cl)c1
Yield: 92 %

Procedure:
150 parts of a mixture of tetrachloronitrobenzene and pentachloronitrobenzene, the composition of which corresponds to that of the polychloroaniline mixture of Example 3, 200 parts of phenol and 10 parts of aqueous hydroiodic acid (57% strength) are reacted with hydrogen in the presence of 20 parts of ruthenium-on-charcoal catalyst (5% strength), starting at approximately 60° C. to a maximum of 165° C. under a pressure of 20 bars, at the beginning, to a maximum of 50 bars, during the course of 10 hours. After working up, 84.5 parts of 3,5-dichloroaniline are obtained. Yield 92% of theory.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH:10]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C.Cl[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C)C=O>[CH2:19]([O:18][C:16]([NH:15][CH:10]([CH2:9][NH:8][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:11]([O:13][CH3:14])=[O:12])=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)C(CN)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)CCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCC(NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of methyl 3-amino-2-([(benzyloxy)carbonyl]amino]propanoate trifluoroacetate (8.9 g) and triethylamine (30.6 ml) in dimethylformamide (89 ml) was treated by a slow dropwise addition of a solution of ethyl chloroacetate (7.8 ml) in dimethylformamide (20 ml). After stirring at room temperature for 12 hours, triethylamine (20.4 ml) was added again, and the mixture was treated by a slow dropwise addition of a solution of ethyl chloroacetate (5.2 ml) in dimethylformamide (15 ml) and stirred at room temperature for further 6 hours. The system was partitioned between water and ethyl acetate and the organic phase was washed with saturated brine, dried (MgSO2) and concentrated under reduced pressure. The residue was purified by a column chromatography on a silica gel (hexane:ethyl acetate=1:4) to obtain methyl 2-[[(benzyloxy)carbonyl]amino]-3-((2-ethoxy-2-oxoethyl)amino]propanoate (6.6 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C@H:11]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)[CH:10]=1.CCN(C(C)C)C(C)C.C(Cl)(Cl)(Cl)Cl.[P:40]([O-:57])([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CC#N.CN(C1C=CN=CC=1)C>[P:40]([O:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C@@H:11]2[CH:10]=[C:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])[CH2:13][N:12]2[C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH:20]=1)([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:57]
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1cccc(O)c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1cccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2S)-4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N,N-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxamide (4-2, 97 mg, 0.28 mmol) in anhydrous CH3CN (1.0 mL) at 0° C. was treated sequentially with iPr2NEt (0.10 mL, 0.6 mmol), CCl4 (0.14 mL, 1.5 mmol), DMAP (catalytic) and lastly dibenzyl phosphite (0.09 mL, 0.40 mmol) and the resulting off-yellow solution was stirred 2 h at 25° C. Upon completion, the reaction was concentrated and directly subjected to flash column chromatography (SiO2, 0-100% EtOAc/hexanes gradient) to provide dibenzyl 3-{(2S)-4-(2,5-difluorophenyl)-1-[(dimethylamino)carbonyl]-2,5-dihydro-1H-pyrrol-2-yl}phenyl phosphate (8-1) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.30 (m, 11H), 7.15 (m, 2H), 7.05 (m, 2H), 6.96 (m, 2H), 6.32 (br s, 1H), 6.10 (m, 1H), 5.12 (d, J=1.8 Hz, 2H), 5.09 (d, J=1.8 Hz, 2H), 4.78 (ddd, J=13.7, 5.8, 1.8 Hz, 1H), 4.47 (d, J=13.7 Hz, 1H), 2.85 (s, 6H). LRMS m/z (M+H) 605.6 found, 605.6 required.
Reaction SMILES: [F:1][C:2]([O:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1I)([F:4])[F:3].C([Li])CCC.CN([CH:22]=[O:23])C>C1COCC1>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([CH:22]=[O:23])=[C:6]([O:5][C:2]([F:4])([F:3])[F:1])[CH:11]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)Oc1cc(Br)ccc1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(Br)cc1OC(F)(F)F
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
5-bromo-2-iodophenyl trifluoromethyl ether (500 mg, 1.37 mmol) was dissolved in 10 mL of anhydrous THF and cooled to −70° C. Then, n-butyllithium (0.55 mL of a 2.5 M solution, 1.37 mmol) was added dropwise over the course of 30 minutes. DMF (0.19 mL, 2.74 mmol) was added and the reaction was stirred for 30 minutes at −70° C. and then allowed to warm to 0° C. and stir for three hours. The reaction was quenched with 5 mL of saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated to provide 4-bromo-2-[(trifluoromethyl)oxy]benzaldehyde (100 mg, 0.37 mmol, 27%) as a yellow solid. 1H NMR (400 MHz, DMSO-D6) □ 10.1 (s, 1H), 7.9 (s, 3H)
Reaction SMILES: [CH2:1]([O:15][CH2:16][CH:17]([CH2:19][OH:20])[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>CN(C=O)C>[CH2:1]([O:15][CH2:16][CH:17]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOCC(O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOCC(O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A mixture of rac-1-O-tetradecylglycerol (57.7 g, 0.2 mol), tert-butyldimethylsilyl chloride (33.2 g, 0.22 mol), imidazole (30.0 g, 0.44 mol), and DMF (300 ml) was stirred at room temperature for 1 day. The solvent was evaporated to dryness in vacuo at 70° C. and the residue was partioned between H2O and diethyl ether (500 ml each). The organic layer was dried over Na2SO4 and then evaporated to dryness. The oily residue was further evaporated by using a high vacuum at 70° C. The crude product, essentially homogeneous by TLC, was used for the next step without further purification (100% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>CCOC(C)=O>[C:12]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:7]=1)(=[O:14])[CH3:13]
Reactant: COC(=O)c1ccc(N)nc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(C)=O)nc1
Temperature: 100 °C

Procedure:
To a mixture of methyl 6-aminopyridine-3-carboxylate (3 g, 19.72 mmol, Aldrich) in 1,4-ioxane (50 mL) was added acetic anhydride (3.72 mL, 39.4 mmol, Aldrich). The resulting mixture was then heated at 85° C. for 3 h and at 100° C. for an additional 3 h. The mixture was then cooled to rt and diluted with EtOAc (400 mL). The mixture was then washed with saturated NaHCO3 solution (2×200 mL), brine (150 mL), dried over MgSO4, and concentrated in vacuo to afford the title compound as a white solid, which was used in the next step without purification. MS (ESI, positive ion) m/z: 195 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][N:25]1C(=O)C2C(=CC=CC=2)C1=O.Cl[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[F:1][C:2]1[C:3]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)=[C:4]([C:5]([N:20]2[CH2:21][CH2:22][CH2:23][C@@H:18]([CH3:17])[C@H:19]2[CH2:24][NH:25][C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1ccc(C(=O)O)c(-n2nccn2)c1F
Product: Cc1ccc(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c(-n2nccn2)c1F

Procedure:
The title compound was prepared following the same general protocol as described in Example A318, using 3-fluoro-4-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione and 2-chloro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 477 [M+1]+.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C1(C)C=CC=CC=1.O>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(Sc2ccccc2)cc1
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCOc1ccc(Sc2ccccc2)cc1
Reaction time: 16 h
Yield: 90 %

Procedure:
A solution was prepared by combining 15 g of (4-hydroxyphenyl) phenyl sulfide which had been synthesized according to the well-known formulation, 11 g of 1-bromohexane, 9 g of potassium carbonate, and 30 g of DMF. The solution was aged at 80° C. for 16 hours. The aged solution was cooled to room temperature, to which 30 g of water was added to quench the reaction. To the solution, 50 g of toluene was added for extraction. The organic layer was separated and washed with sodium hydroxide aqueous solution and water in sequence. On subsequent concentration in vacuum, 16 g of the target compound, (4-hexyloxyphenyl) phenyl sulfide was obtained as oily matter. Yield 90%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]([C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][C:35]=2[CH3:36])[NH2:32])[N:20]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:32][C:31]3[CH:33]=[CH:34][C:35]([CH3:36])=[C:29]([C:21]4[N:20]=[CH:19][C:28]5[C:23]([CH:22]=4)=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:30]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)cc1-c1cc2ccccc2cn1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: Cc1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1-c1cc2ccccc2cn1
Temperature: 25 °C

Procedure:
To a reaction vessel containing 7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (518 mg, 2 mmol), 3-(isoquinolin-3-yl)-4-methylaniline (470 mg, 2 mmol), pTSA (144 mg, 0.6 mmol) is added isopropanol (7 ml). The vessel is purged with nitrogen, sealed. The reaction vessel is placed in a microwave reactor and irradiated for 30 minutes at 130° C. The reaction mixture is cooled to room temperature and diluted with ethyl acetate. It is washed with saturated aqueous NaHCO3, water and brine, dried over anhydrous MgSO4 and concentrated. The residue is subjected to silica gel flash chromatography (2% methanol in dichloromethane) to afford 7-Benzyl-N-(3-(isoquinolin-3-yl)-4-methylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine as a brown solid. LC-MS m/z: 458.2 (M+1).
Reaction SMILES: [C:1](Cl)(=O)[CH3:2].[Br:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[C:11]2[NH:16][NH2:17].CC1N2C=CC3C(C2=NN=1)=CC=CC=3Cl>>[CH3:1][C:2]1[N:10]2[CH:9]=[CH:8][C:7]3[C:12]([C:11]2=[N:16][N:17]=1)=[CH:13][CH:14]=[CH:15][C:6]=3[Br:5]
Reactant: NNc1nccc2c(Br)cccc12
Reactant: CC(=O)Cl
Agent: Cc1nnc2c3cccc(Cl)c3ccn12
Product: Cc1nnc2c3cccc(Br)c3ccn12

Procedure:
3-Methyl-7-bromo-s-triazolo-[3,4-a]-isoquinoline was prepared from acetyl chloride and 5-bromo-1-hydrazinoisoquinoline by a method generally similarto that described below for the preparation of 3-methyl-7-chloro-s-triazolo-[3,4-a]-isoquinoline. Yield, 78.5%; m.p. 203°-204°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:9][CH2:10][N:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:4][CH:3]=1.[C:24]([NH:26][C:27](=[N:35][CH2:36][CH2:37][S:38][CH2:39][C:40]1[N:41]=[C:42]([NH:45][C:46]([NH2:48])=[NH:47])[S:43][CH:44]=1)OC1C=CC=CC=1)#[N:25]>C(OCC)(=O)C.CO>[C:24]([NH:26][C:27]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:17])=[N:35][CH2:36][CH2:37][S:38][CH2:39][C:40]1[N:41]=[C:42]([NH:45][C:46]([NH2:48])=[NH:47])[S:43][CH:44]=1)#[N:25]
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Reactant: CN(CCCCN)CCC(c1ccc(F)cc1)c1ccccn1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(CCCCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCC(c1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.8 g (2.5 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,4-butanediamine and 0.95 g (2.5 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography (eluant: methylene chloride/methanol 95+5) analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%])=597 ([M+H]+ 1), 214 (100); IR (KBr): 2162 cm-1 (C≡N).
Reaction SMILES: [C:1]([O:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[NH:2][NH2:3].[N:19]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=1>C(O)C>[OH2:4].[N:19]1[CH:24]=[CH:23][C:22]([CH:25]=[N:3][NH:2][C:1]([O:5][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:4])=[CH:21][CH:20]=1
Reactant: O=Cc1ccncc1
Reactant: NNC(=O)OC(c1ccccc1)c1ccccc1
Solvent: CCO
Product: O
Product: O=C(NN=Cc1ccncc1)OC(c1ccccc1)c1ccccc1
Yield: 185.7 %

Procedure:
To 10.89 gm (0.045 mole) of benzhydryl carbazate in 100 ml of warm ethanol is added 4.82 gm (0.045 mole) of 4-pyridinecarboxaldehyde in 50 ml of ethanol. The mixture is refluxed 4.5 hr and cooled. The solvent is removed in vacuo to give the crude product. Recrystallization of the crude material from ethanol yields 14.6 gm (93%) of the title compound having a melting point of 96.9° C.
Reaction SMILES: C[O:2][C:3](=[O:38])[C@H:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[CH:5]([CH3:7])[CH3:6].CO.[Li+].[OH-].Cl>C1COCC1.O>[CH3:6][CH:5]([CH3:7])[C@@H:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:3]([OH:38])=[O:2]
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)[C@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The compound of example 330 (150 mg, 0.293 mmol) was taken in THF (4 mL) and MeOH (1 mL) and to this reaction mixture, 1 N LiOH (61.58 mg, 1.46 mmol) was added and stirred at room temperature for 2-3 h. After completion of the reaction, the solvent was evaporated and the residue obtained was dissolved in water and acidified with 1 N HCl to obtain the title compound, which was filtered and dried.