Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH3-][C:2]#[N:3].[Na+].[CH3:5][O:6][C:7]1[C:8](N)=[CH:9][C:10]2[CH:16]([CH3:17])[CH2:15][N:14]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:13][CH2:12][C:11]=2[N:24]=1.C=O.[C:28]([O-])([O-])=O.[K+].[K+]>CC#N.CC(O)=O>[CH3:5][O:6][C:7]1[C:8]([N:3]([CH3:2])[CH3:28])=[CH:9][C:10]2[CH:16]([CH3:17])[CH2:15][N:14]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:13][CH2:12][C:11]=2[N:24]=1
Reactant: O=C([O-])[O-]
Reactant: [BH3-]C#N
Reactant: COc1nc2c(cc1N)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: C=O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1nc2c(cc1N(C)C)C(C)CN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
NaBH3CN (63.0 mg, 990 μmol) was added portionwise at room temperature to a solution of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (100 mg, 330 μmol) and HCHO (37% in H2O, 2.31 mmol) in MeCN (1 ml). The mixture was stirred at room temperature for 15 min before slow addition of HOAc (0.2 ml). The reaction was stirred at room temperature for an additional 3 h and was basified with aq. K2CO3 and extracted with DCM. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to provide 94.0 mg (86%) of 2-methoxy-N,N,5-trimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. MS (ESI) m/z 332. 2-Methoxy-N,N,5-trimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (35.0 mg, 106 μmol) was treated under basic condition (K2CO3/MeOH/H2O), as described above, to provide 17 mg (68%) of 2-methoxy-N,N,5-trimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. MS (ESI) m/z 236.
Reaction SMILES: [Br:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]1=[O:11].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[Br-:1].[CH2:7]([N:4]1[CH2:5][CH2:6][CH:2]([P+:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:3]1=[O:11])[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)CN1CCC(Br)C1=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CN1CCC([P+](c2ccccc2)(c2ccccc2)c2ccccc2)C1=O
Product: [Br-]
Temperature: 25 °C

Procedure:
2.74 g (12.4 mmol) rac-3-Bromo-1-isobutyl-pyrrolidine-2-one were dissolved in 12 ml THF, and 3.43 g (13.1 mmol) triphenylphosphine were added. The mixture was then refluxed for 3 days under argon atmosphere. After cooling to room temperature, the suspension was filtered with suction, the white crystals were washed with ice-cold THF and then dried under high vacuum.
Reaction SMILES: [OH-:1].[Na+].[NH2:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][NH2:9].[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20])([O-:12])=[O:11]>O.O1CCCC1.C(Cl)Cl>[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([NH:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N+:10]([O-:12])=[O:11])(=[O:20])=[O:1])(=[O:21])=[O:20])([O-:12])=[O:11]
Reactant: [OH-]
Reactant: NCCNCCN
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCNCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
8.4 g of NaOH are dissolved in 100 ml of H2O at 0° C. and 9.2 g of diethylenetriamine are added, followed dropwise, at 0° C., to a solution of 41.5 g of 2-nitrophenylsulphonic acid chloride dissolved in 100 ml of tetrahydrofuran. The reaction medium is taken up in CH2Cl2 and the organic phase is washed with H2O and then dried over magnesium sulphate. After evaporating the solvent, 37.5 g of crystals are obtained.
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(OC(C)(C)C)=O)[C@H:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1.FC(F)(F)C(O)=O.[C:34]([O:38][C:39]([NH:41][C@H:42]([C:49](O)=[O:50])[C:43]([CH3:48])([CH3:47])[C:44]([OH:46])=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:34]([O:38][C:39]([NH:41][C@H:42]([C:49]([N:12]1[CH2:13][C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])=[CH:10][C@H:11]1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:50])[C:43]([CH3:48])([CH3:47])[C:44]([OH:46])=[O:45])=[O:40])([CH3:36])([CH3:37])[CH3:35]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C(C)(C)C(=O)O
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (5-5, 1.00 g, 2.80 mmol, 1 equiv) in a 4:1 mixture of dichloromethane and trifluoroacetic acid (20 mL) was stirred for 30 minutes, then concentrated. The residue was dried via benzene azeotrope (1×50 mL), then dissolved in DMF (30 mL). N-(tert-butoxycarbonyl)-3,3-dimethylaspartic acid (29-3, 1.08 g, 4.20 mmol, 1.50 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 0.805 g, 4.20 mmol, 1.50 equiv), 1-hydroxy-7-azabenzotriazole (0.571 g, 4.20 mmol, 1.50 equiv) and triethylamine (2.73 mL, 19.6 mmol, 7.00 equiv) were added, and the resulting mixture was stirred at 23° C. for 20 hours. The reaction mixture was partitioned between water, acidified to pH 2, and ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography through silica gel (hexane initially, grading to 100% EtOAc) followed by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide (3S)-3-[(tert-butoxycarbonyl)amino]4-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2,2-dimethyl-4-oxobutanoic acid (29-4) as a white foam. 1H NMR (500 M CDCl3) major rotamer: δ 7.28 (m, 5H), 7.05 (m, 3H), 6.40 (s, 1H), 5.89 (br s, 1H), 5.74 (d, 1H, J=10.2 Hz), 5.17 (d, 1H, J=14.2 Hz), 4.93 (ddd, 1H, J=13.9, 4.4, 1.7 Hz), 4.62 (d, 1H, J=10.2 Hz), 1.45 (s, 9H), 1.30 (s, 3H), 1.05 (s, 3H). LRMS m/z (M+H) 501.5 found, 501.2 required.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.[Br:27][CH2:28][C:29](Br)=[O:30].O>C(Cl)Cl>[Br:27][CH2:28][C:29]([N:9]1[CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)=[O:30]
Reactant: c1ccc(CC2Cc3ccccc3CN2)cc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: O
Solvent: CN(C)c1ccccc1
Product: O=C(CBr)N1Cc2ccccc2CC1Cc1ccccc1
Yield: 96.4 %

Procedure:
89 mg of 3-benzyl-1,2,3,4-tetrahydroisoquinoline obtained in Example 1-d) was dissolved in 2 mL of methylene chloride, and 53 mg of N,N-dimethylaniline, 73 mg of bromoacetylbromide were added thereto, followed by stirring under ice-cooling for 30 minutes. After completion of the reaction, water was added thereto, followed by extraction with chloroform. The chloroform layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was removed by evaporation, followed by purification using PLC (hexane:ethyl acetate=1:1) to obtain 120 mg (yield 88%) of 2-(2-bromoacetyl)-3-benzyl-1,2,3,4-tetrahydroisoquinoline as a yellow oily substance. 34 mg of this product was dissolved in 10 mg of aniline, 15 mg of potassium carbonate, and 1 mL of acetonitrile, followed by stirring at 60° C. for 4 hours. After completion of the reaction, the reaction liquid was filtered with ethyl acetate, concentrated under reduced pressure, and purified using PTLC (chloroform:methanol=10:1) to obtain 28 mg (yield 72%) of a title compound as a yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12]O)=[CH:7]2.P(Br)(Br)[Br:15]>CCOCC>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][Br:15])=[CH:7]2
Reactant: OCc1ccc2c(Br)cccc2c1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: BrCc1ccc2c(Br)cccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a stirred suspension of 5-bromo-2-hydroxymethylnaphthalene (7.00 g, 29.5 mmol) in dry Et2O (100 mL) at 0° C. was added PBr3 (8.91 g, 33 mmol) in portions over 20 minutes. The reaction was stirred for an additional 30 minutes at 0° C., diluted with Et2O (100 mL) and quenched with H2O (100 mL) over 20 minutes. The heterogeneous solution was diluted further with H2O (100 mL) and the layers separated. The aqueous phase was extracted with Et2O (1×200 mL) and the combined organic layers were washed with H2O (1×100 mL) and saturated NaCl (1×100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative HPLC (SiO2 : gradient hexane/EtOAc) to give the title compound as a white solid (4.60 g, 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C@@H:9]([S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@@H:10]1[O:15][CH2:14][CH2:13][N:12](CC2C=CC=CC=2)[CH2:11]1.CCN(C(C)C)C(C)C.ClC(OC(Cl)C)=O>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C@@H:9]([S:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C@@H:10]1[O:15][CH2:14][CH2:13][NH:12][CH2:11]1
Reactant: Clc1ccc(Cl)c([C@@H](Sc2ccccc2)[C@H]2CN(Cc3ccccc3)CCO2)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: Clc1ccc(Cl)c([C@@H](Sc2ccccc2)[C@H]2CNCCO2)c1
Yield: 178.5 %

Procedure:
Debenzylation of (2R)-2-((R)-[2,5-dichlorophenyl][phenylthio]methyl)-4-benzylmorpholine (174 mg, 0.39 mmol) with polymer supported Hunig's base (0.20 g, 0.78 mmol) and α-chloroethyl chloroformate (111 mg, 0.78 mmol) following the procedure described in example 1(iv) gave after SCX chromatography the product as an oil (136 mg).
Reaction SMILES: [NH2:1][CH:2]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)[C:3]([N:5]([CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][N:13]=[CH:12]2)=[O:4].[CH2:36]([NH:43][C:44](=[O:54])[NH:45][C@H:46]([CH2:51][CH:52]=[CH2:53])[CH2:47][C:48](O)=[O:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[C:32]([O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH:2]([NH:1][C:48](=[O:49])[CH2:47][CH:46]([NH:45][C:44]([NH:43][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:54])[CH2:51][CH:52]=[CH2:53])[C:3](=[O:4])[N:5]([CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][N:13]=[CH:12]3)=[CH:26][CH:27]=1)([CH3:33])([CH3:35])[CH3:34]
Reactant: C=CC[C@H](CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(CN(Cc1cccc2cn[nH]c12)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CCC(CC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2cn[nH]c12)CC(OCC)OCC)NC(=O)NCc1ccccc1
Reaction time: 0.67 h

Procedure:
To a solution of 2-Amino-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-N-(1H-indazol-7-ylmethyl)-propionamide in CH2Cl2 (50 mL) was added a solution of (3R)-3-(3-Benzyl-ureido)-hex-5-enoic acid (1.6 g, 6.1 mmol), EDCI (1.17 g, 1.2 eq), HOBt (0.93 g, 1.2 eq), DIEA (2.13 mL, 12.2 mmol) in CH2Cl2 (100 mL) stirred for 40 min. The reaction mixture was stirred at room temperature for 14 h, and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The crude compound was used next step without further purification. MS ESI 727 (M+H), 749 (M+Na)
Reaction SMILES: [OH-:1].[Na+].OO.[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][C@H:15]([C:17]1[N:21]([CH3:22])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:32])([F:31])[F:30])=[N:19][N:18]=1)[CH3:16])[C:9]#[N:10].O>C(O)C.C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][C@H:15]([C:17]1[N:21]([CH3:22])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:30])([F:32])[F:31])=[N:19][N:18]=1)[CH3:16])[C:9]([NH2:10])=[O:1]
Reactant: [OH-]
Reactant: C[C@H](Oc1ccc(C#N)cc1Cl)c1nnc(-c2ccccc2C(F)(F)F)n1C
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: C[C@H](Oc1ccc(C(N)=O)cc1Cl)c1nnc(-c2ccccc2C(F)(F)F)n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 1M aqueous sodium hydroxide solution (0.74 ml) and a 30% aqueous hydrogen peroxide solution (0.56 ml) were added to a solution of 3-chloro-4-[(1S)-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy}benzonitrile (200 mg) in ethanol (6 ml) at 0° C., followed by stirring at room temperature for 3 hours. The reaction solution was added to a mixture of water and chloroform, followed by separation operation, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was washed with diisopropylether, to obtain, as a colorless solid, 3-chloro-4-[(1S)-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy}benzamide (135 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: Cc1cccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)c1
Reactant: NN
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc5c(N)n[nH]c5c4)nc(N)n3)C2)c1
Temperature: 150 °C
Yield: 83.3 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(3-methylphenyl)-3-piperidinecarboxamide (90 mg, 0.209 mmol), 3 mL of EtOH, Hunig's base (0.11 ml, 0.627 mmol), and hydrazine anhydrous (0.026 ml, 0.836 mmol) were added, and the yellow mixture was heated at 150° C. for 150 minutes in microwave. The solution turned black. LCMS showed mainly product with 10% of remaining starting material. The black solids were filtered and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH, and purified by HPLC (CH3CN/H2O w/0.1% HCO2H) to afford a formic acid salt of the title compound (77 mg) as a light yellow solid. LC-MS (ES) m/z=443 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.52 (m, 1H), 1.84 (m, 2H), 2.07 (m, 1H), 2.27 (s, 3H), 3.50 (m, 1H), 4.48 (m, 2H), 4.75 (m, 1H), 4.90-5.13 (m, 1H), 6.87 (s, 1H), 6.94-7.08 (m, 1H), 7.13-7.26 (m, 1H), 7.41 (m, 6H), 7.75 (s, 1H), 7.83-8.00 (m, 1H), 10.00 (s, 1H), 12.07 (s, 2H).
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([NH2:19])[CH2:16][CH2:17][NH2:18].C>>[C:2]1([C:1]23[CH2:9][CH2:10][CH2:11][C:12](=[O:14])[N:18]2[CH2:17][CH2:16][CH2:15][NH:19]3)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCC(=O)c1ccccc1
Reactant: NCCCN
Product: O=C1CCCC2(c3ccccc3)NCCCN12

Procedure:
19.2 Parts of 4-benzoyl-butyric acid and 9 parts of 1,3-propanediamine are heated for 21/2 hours at 150°-160°. The reaction mixture is cooled to about 60°, extracted with hot ethyl acetate and the solution obtained is clarified over charcoal. On concentrating, the reaction product precipitates and is purified by recrystallisation from ethyl acetate. The melting point of the 9a-phenyl-octahydro-6H-pyrido[1,2-a]pyrimidin -6-one of the formula ##STR34## obtained is 142.5°. The following compound is obtained in an analogous manner:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=CC(NC2C3C(=CC=C(Br)C=3)N=CN=2)=CC=1)[C:2]1[CH:7]=C[CH:5]=[CH:4][CH:3]=1.CN1C([Sn](CCCC)(CCCC)CCCC)=CN=N1.[O:46]1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:9]([O:8][CH2:1][CH3:2])(=[O:46])[CH3:14].[CH3:5][CH2:4][CH2:3][CH:2]([CH3:7])[CH3:1]
Reactant: Brc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Reactant: C1COCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnnn1C
Product: CCCC(C)C
Product: CCOC(C)=O

Procedure:
The (4-benzyloxy-phenyl)-(6-bromoquinazolin-4-yl)-amine (250 mg, 0.62 mmol), 1-methyl-5-(tributylstannyl)-1,2,3-triazole (300 mg, 0.81 mmol) and bis(triphenylphosphine)palladium(II) chloride (catalytic) were dissolved in dioxan (10 ml) and heated at reflux under nitrogen for 48 hr. The solvent was removed from the cooled reaction under vacuum, and the residue was triturated with iso-hexane. The resulting material was dissolved in ethyl acetate, filtered and the filtrate evaporated to dryness. Trituration with ethyl acetate/iso-hexane gave the product (115 mg, 45%) as a beige solid; δH [2H6]-DMSO 9.90 (1H, b, NH), 8.76 (1H, s, 5-H), 8.61 (1H, s, 2-H), 8.10 (2H, m, 7-H, triazole-H), 7.92 (1H, d, 8-H), 7.70 (2H, d, 2′-H, 6′-H), 7.58-7.38 (5H, m, 5×Ph-H), 7.12 (2H, d, 3′-H, 5′H), 5.19 (2H, s, CH2), 4.22 (3H, s, CH3); m/z 409 (M+1)+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([P:19](=[O:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl.CCCCCC>C(Cl)Cl>[Br:8][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]([O:10][CH3:9])=[CH:12][C:13]=1[P:19](=[O:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc(OC)cc(P(=O)(c2ccccc2)c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1cc(OC)c(Br)c(P(=O)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NBS (6.7 g, 37.6 mmol) was added to a solution of (3,5-dimethoxyphenyl)diphenylphosphine oxide (12.3 g, 36.4 mmol) in CH2Cl2 (140 ml) at 0° C. The resulting suspension was stirred at 0° C. for 1 h. Na2CO3 (saturated, 40 ml) was added to quench the reactions. It was stirred at RT for 30 min, the organic layer was separated and the aqueous layer was extracted with CH2Cl2 (40 ml×2). The combined organic layer washed with brine and dried over MgSO4. It was filtered and the solvent was removed to give the crude product as a pale yellow solid (14.3 g, 94% yield). It was sufficiently pure for the next step. The pure sample was obtained by crystallization from CH2Cl2/Hexane (1/15). 1H NMR (300 MHz, CD2Cl2) δ: 7.73-7.67 (m, 4H), 7.62-7.56 (m, 2H), 7.53-7.46 (m, 4H), 6.69 (d, J=3 Hz, 1H), 6.57 (dd, J1=3 Hz, J2=14.1 Hz, 1H), 3.89 (s, 3H), 3.68 (s, 3H). 31P NMR (121.5 MHz, CD2Cl2) δ: 30.72.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.[C:19]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:20][C:21]([CH3:23])=O>>[CH3:23][C:21]1[NH:13][C:14]2=[N:15][NH:16][CH:17]=[C:18]2[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[C:2]([F:12])([F:11])[F:1])[C:20]=1[C:19]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1cc[nH]n1
Product: CCOC(=O)C1=C(C)Nc2n[nH]cc2C1c1ccccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-trifluoromethylbenzaldehyde, 3-aminopyrazole and ethyl acetoacetate in the same manner as in Example 1.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6](=O)[CH2:5][N:4]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[C:3]1=[O:16].Cl.[NH2:19][OH:20].C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1([CH3:17])[C:6](=[N:19][OH:20])[CH2:5][N:4]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[C:3]1=[O:16]
Reactant: C[C@H](c1ccccc1)N1CC(=O)C(C)(C)C1=O
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@H](c1ccccc1)N1CC(=NO)C(C)(C)C1=O
Yield: 91.1 %

Procedure:
In 100 ml of ethanol was dissolved 11.85 g of 3,3-dimethyl-1-[1-(R)-phenylethyl]-pyrrolidine-2,4-dione. To the solution were added 8 g of hydroxylamine hydrochloride and 45 ml of triethylamine, followed by refluxing for 1 hour. The solvent was removed under reduced pressure, and to the residue was added 300 ml of chloroform. The chloroform solution was washed successively with a 10% citric acid aqueous solution and water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield 11.5 g of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1>C1(C)C=CC=CC=1.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(C)nc(O)c(Cc3cccc(Oc4ccccc4)c3)c2cc1OC
Temperature: 130 °C
Reaction time: 0.75 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (152 mg, 693 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.38 mL, 0.76 mmol) at RT followed by 1-(bromomethyl)-3-phenoxybenzene (191 mg, 726 μmol) and the mixture was stirred at 130° C. for 45 min under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with EtOAc (50 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). Both organic phases were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:3) gave 28 mg of 6,7-dimethoxy-1-methyl-4-(3-phenoxybenzyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (2 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-1-methyl-4-(3-phenoxybenzyl)isoquinolin-3-ol hydrochloride 4 as a brown solid (31 mg, 10% yield).
Reaction SMILES: [C:1]([N:9]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]2[NH:11][C:10]1=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.C(Cl)(Cl)Cl>CN(C)C=O>[C:1]([N:9]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]2[N:11]([CH2:25][CH2:24][CH2:23][CH2:22][Br:21])[C:10]1=[O:18])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC2CCCCC2N1C(=O)c1ccccc1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)N1C(=O)N(CCCCBr)C2CCCCC21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
To a solution of 3-benzoylperhydrobenzimidazol-2-one (2.7 9, 10.0 mmoles) in 50 ml of dimethylformamide was added 60% sodium hydride (400 mg, 10.0 mmoles), and the mixture was stirred at 60° C. for 30 minutes. To this mixture having been cooled to room temperature was further added 1,4-dibromobutane (10.8 g, 50.0 mmoles), and the resulting mixture was stirred at 60° C. for 4 hours. After chloroform was added to the reaction, insolubles were removed by filtration, the filtrate was washed with water, and the solvent was evaporated. The residue thus obtained was purified by chromatography on a silica gel column to give 1.5 g of the title compound as an oil.