Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12]([NH:14][C@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)=[N:11][C:10]([C:20]1[NH:24][C:23](=[O:25])[NH:22][N:21]=1)=[CH:9]2.CC1C=CC=C(C)N=1.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>C(Cl)Cl>[C:34]([N:17]1[CH2:18][CH2:19][C@H:15]([NH:14][C:12]2[C:13]3[C:8](=[CH:7][CH:6]=[CH:5][C:4]=3[O:3][CH3:2])[CH:9]=[C:10]([C:20]3[NH:24][C:23](=[O:25])[NH:22][N:21]=3)[N:11]=2)[CH2:16]1)(=[O:37])[CH:35]=[CH2:36]
Reactant: C=CC(=O)Cl
Reactant: COc1cccc2cc(-c3n[nH]c(=O)[nH]3)nc(N[C@H]3CCNC3)c12
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(OC)c23)C1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 27.1 %

Procedure:
To a mixture of (S)-3-(8-methoxy-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride (120 mg, 0.33 mmol) in DCM (8 mL) was added 2,6-dimethylpyridine (106 mg, 0.99 mmol). The resulting mixture was cooled to −78° C. Acryloyl chloride (120 mg, 1.20 mmol, 10 mg/mL in dry DCM) was added dropwise and the reaction mixture was stirred at −78° C. for 1.5 hours. The reaction was quenched with MeOH (5 mL) and the mixture was concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (34 mg, 27%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (s, 1H), 11.69 (s, 1H), 7.85 (dd, J=7.1, 14.5 Hz, 1H), 7.57-7.51 (m, 1H), 7.43 (d, J=3.3 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.72-6.54 (m, 1H), 6.16 (m, 1H), 5.73-5.61 (m, 1H), 5.21-5.03 (m, 1H), 4.16 (m, 1H), 4.04-3.89 (m, 3H), 3.79 (m, 1H), 3.71-3.61 (m, 1H), 3.44 (m, 1H), 3.24 (m, 1H), 2.42-2.21 (m, 1H), 2.09-1.90 (m, 1H); ESI-MS m/z [M+H]+ 381.
Reaction SMILES: C(OC(=O)N[C@H](CO)[C@H](OCC1C=CC=CC=1)C)(C)(C)C.C(OC(=O)CBr)(C)(C)C.C(OC(=O)C[O:38][CH2:39][C@@H:40]([NH:51][C:52]([C:54](C)(C)C)=[O:53])[C@H:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH3:42])(C)(C)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].ClCCl.O>[CH2:44]([O:43][C@@H:41]([C@@H:40]1[NH:51][C:52](=[O:53])[CH2:54][O:38][CH2:39]1)[CH3:42])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: C[C@@H](OCc1ccccc1)[C@@H](COCC(=O)OC(C)(C)C)NC(=O)C(C)(C)C
Agent: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[C@@H](OCc1ccccc1)[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](OCc1ccccc1)[C@H]1COCC(=O)N1
Reaction time: 3 h

Procedure:
To a solution of ((1R,2R)-2-benzyloxy-1-hydroxymethylpropyl)carbamic acid t-butyl ester (83.1 g, CAS No. 133565-43-2) in toluene (400 mL) was added tetrabutylammonium hydrogen sulfate (24.1 g) in 50% aqueous sodium hydroxide (400 mL). t-Butylbromoacetate (125 mL) was dropwise added to the resultant solution while cooling with ice, and this solution was stirred at the same temperature for 3 hours. Then, water (500 mL) and toluene (500 mL) was added to the solution. The organic layer was separated and washed with brine. The organic layer was then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, to thereby obtain a crude product (122.5 g) containing ((2R,3R)-3-benzyloxy-2-t-butylcarbonylaminobutoxy)acetic acid t-butyl ester. To a solution of the obtained crude product (118g) in dichloromethane (315 mL) was added trifluoroacetic acid (315 mL), and the resultant solution was stirred for 2 hours at room temperature. Solvent was removed by distillation under reduced pressure, and the resultant product was diluted with methanol (350 mL). To the resultant solution was dropwise added thionyl chloride (96.9 mL) while cooling with ice, and then the solution was stirred for 1 hour at room temperature. Solvent was removed by distillation under reduced pressure, and the resultant product was diluted with methanol (315 mL). To the resultant solution was then dropwise added sodium methoxide (165 mL, 28% methanol solution) while cooling with ice. Solvent was removed by distillation under reduced pressure, and the resultant product was diluted with ethyl acetate and water. The organic layer was partitioned and successively washed with 1 N hydrochloric acid and brine. The organic layer was then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the resulting product was purified by silica gel column chromatography (ethyl acetate), to thereby obtain the titled compound (61.57 g). The physical properties of the compound were as follows.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[S:14][CH3:15])=[CH:11][C:10]([Cl:16])=[CH:9][CH:8]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[Cl:16][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]([CH2:4][CH2:3][OH:2])=[C:13]2[S:14][CH3:15]
Reactant: COC(=O)Cc1[nH]c2ccc(Cl)cc2c1SC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CSc1c(CCO)[nH]c2ccc(Cl)cc12
Reaction time: 0.25 h

Procedure:
To a solution of (5-chloro-3-methylsulfanyl-1H-indol-2-yl)-acetic acid methyl ester (0.252 g, 0.93 mmole) in ether (10 ml) was added 0.93 ml of a 1M solution of lithium aluminum hydride in ether at room temperature. The reaction mixture was stirred for 15 minutes, after which time sodium sulfate decahydrate (1 g) was cautiously added. The reaction mixture was stirred for an hour at room temperature, filtered, and the filtrate evaporated to dryness. The crude alcohol was purified by column chromatography (silica gel) using 7:3 hexane:ethyl acetate as the eluting solvent. The pure 2-(5-chloro-3-methylsulfanyl-1H-indol-2-yl)-ethanol was isolated as a pale solid (0.191 g, 84% yield).
Reaction SMILES: Cl.[C:2]1([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:25][CH2:26][C:27]1([CH2:41][CH3:42])[C:32]2[CH:33]=[C:34]([O:39][CH3:40])[C:35]([O:37][CH3:38])=[CH:36][C:31]=2[CH2:30][CH2:29][O:28]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:51]([OH:58])(=[O:57])/[CH:52]=[CH:53]/[C:54]([OH:56])=[O:55]>CN(C)C=O.C(O)C>[C:51]([OH:58])(=[O:57])/[CH:52]=[CH:53]/[C:54]([OH:56])=[O:55].[CH2:41]([C:27]1([CH2:26][CH2:25][N:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][CH:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:17][CH2:16]2)[C:32]2[CH:33]=[C:34]([O:39][CH3:40])[C:35]([O:37][CH3:38])=[CH:36][C:31]=2[CH2:30][CH2:29][O:28]1)[CH3:42]
Reactant: CCC1(CCCl)OCCc2cc(OC)c(OC)cc21
Reactant: c1ccc(C(CCCN2CCNCC2)c2ccccc2)cc1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCC1(CCN2CCN(CCCC(c3ccccc3)c3ccccc3)CC2)OCCc2cc(OC)c(OC)cc21
Temperature: 100 °C
Yield: 26.4 %

Procedure:
A mixture of 8 g of 1-(4,4-diphenylbutyl)piperazine hydrochloride, 8.4 g of known 1-(2-chloroethyl)-1-ethyl-3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran, 5,6 g of potassium carbonate and 1 g of potassium iodide in 100 ml of dimethylformamide was heated at 100° C. for 3 h. After hydrolysis the mixture was extracted twice with ethyl acetate, dried and concentrated. The difumarate salt was prepared by adding 14.6 g of fumaric acid to a solution of the free base in ethanol, to give 4.2 g (35.6%) of 1-[2-(1-ethyl-3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran-1-yl)ethyl]-4-(4,4-diphenylbutyl)piperazine (E)-2-butenedioate (1:2) salt. mp 207.8° C.
Reaction SMILES: [CH3:1][C:2]1([O:5][CH2:4]1)[CH3:3].C(N(CC)C(C)C)(C)C.Cl.[CH3:16][N:17]1[C:21]2[N:22]=[C:23]([C:52]#[N:53])[N:24]=[C:25]([C:26]3[CH:27]=[N:28][C:29]([O:36][CH2:37][CH:38]4[CH2:43][CH2:42][N:41]([C:44]([CH:46]5[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]5)=[O:45])[CH2:40][CH2:39]4)=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=3)[C:20]=2[CH:19]=[CH:18]1.CN(C=O)C>CCO.O>[OH:5][C:2]([CH3:4])([CH3:3])[CH2:1][N:49]1[CH2:48][CH2:47][CH:46]([C:44]([N:41]2[CH2:42][CH2:43][CH:38]([CH2:37][O:36][C:29]3[N:28]=[CH:27][C:26]([C:25]4[C:20]5[CH:19]=[CH:18][N:17]([CH3:16])[C:21]=5[N:22]=[C:23]([C:52]#[N:53])[N:24]=4)=[CH:31][C:30]=3[C:32]([F:34])([F:33])[F:35])[CH2:39][CH2:40]2)=[O:45])[CH2:51][CH2:50]1
Reactant: Cn1ccc2c(-c3cnc(OCC4CCN(C(=O)C5CCNCC5)CC4)c(C(F)(F)F)c3)nc(C#N)nc21
Reactant: CC1(C)CO1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc2c(-c3cnc(OCC4CCN(C(=O)C5CCN(CC(C)(C)O)CC5)CC4)c(C(F)(F)F)c3)nc(C#N)nc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Isobutylene oxide (38 μL) and N,N-diisopropylethylamine (73 μL) were added to a solution of 7-methyl-4-[6-{[1-(piperidin-4-yl carbonyl)piperidin-4-yl]methoxy}-5-(trifluoromethyl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile monohydrochloride (120 mg) in EtOH (2.4 mL)-DMF (0.5 mL) at room temperature, and the mixture was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature, and EtAOc and water were added thereto. Extraction was performed on the mixture using EtOAc, and the extract was washed with saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (Hex:CHCl3=70:30 to 20:80), whereby 4-{6-[(1-{[1-(2-hydroxy-2-methylpropyl)piperidin-4-yl]carbonyl}piperidin-4-yl)methoxy]-5-(trifluoromethyl)pyridin-3-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (93 mg) was obtained as a solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:19][C:20]([C@H:22]2[C:31]3[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=3)[CH2:25][CH2:24][N:23]2[C:34]([C@H:36]2[CH2:39][C@H:38]([CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])[CH2:37]2)=[O:35])=[O:21])[CH:12]=[CH:13][C:14]=1[Si:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])O.[Na+]>O.C(#N)C>[F:8][C:9]1[CH:10]=[C:11]([NH:19][C:20]([C@H:22]2[C:31]3[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=3)[CH2:25][CH2:24][N:23]2[C:34]([C@H:36]2[CH2:39][C@H:38]([CH2:40][C:41]([OH:43])=[O:42])[CH2:37]2)=[O:35])=[O:21])[CH:12]=[CH:13][C:14]=1[Si:15]([CH3:16])([CH3:17])[CH3:18]
Reactant: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1ccc([Si](C)(C)C)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@H](CC(=O)O)C1)[C@H]2C(=O)Nc1ccc([Si](C)(C)C)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Cooled TFA (2.0 mL) was added to tert-butyl 2-(trans-3-((R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (90 mg, 0.16 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was neutralized with ice and aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20→90% ethyl acetate/hexane), and then preparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)) to give the title compound (29.8 mg, 0.058 mmol, 36.7%) as a white solid.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=1.[C:25](=[O:47])([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])O.[Na+]>O.C(OCC)(=O)C.C(O)C>[C:27]([O:26][C:25]([O:31][C:32]1[CH:33]=[C:34]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=2)[CH:35]=[CH:36][CH:37]=1)=[O:47])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)Oc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Oc1cccc(-c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
To toluene 24 mL solution of tert-butyl 4-bromo-2-nitrobenzoate 3.0 g were added ethanol 9.0 mL, water 4.5 mL, tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl carbonate 3.8 g, sodium hydrogen carbonate 2.1 g and tetrakis (triphenylphosphine)palladium(0) 0.57 g sequentially, and it was heated and refluxed under nitrogen atmosphere for 6 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added to it. After insoluble matter was filtrated, the organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=3:1] to give tert-butyl 4-(3-(tert-butoxycarbonyl)oxyphenyl)-2-nitrobenzoate 3.6 g of yellow oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:11]=1)[C:8](O)=[O:9].C(N(CC)CC)C.ClC(OCC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1C=CC=CC=1>[F:12][C:2]([F:1])([F:13])[C:3]1[CH:11]=[C:7]([CH2:8][OH:9])[CH:6]=[N:5][CH:4]=1
Reactant: O=C(O)c1cncc(C(F)(F)F)c1
Agent: CCOC(=O)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: OCc1cncc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(trifluoromethyl)nicotinic acid (1.0 g, 5.23 mmol) and triethylamine (0.802 mL, 5.75 mmol) in benzene was added ethyl chloroformate (0.548 mL, 5.75 mmol) and the reaction was stirred 1 hour at room temperature. The reaction was filtered to remove salts and concentrated to dryness. The residue was taken up in tetrahydrofuran and cooled to −78° C. Lithium aluminum hydride (2M in THF, 2.88 mL, 5.75 mmol) was added dropwise and aged 0.5 hour. Reaction was quenched with water and stirred with 0.5N NaOH for 1 hour. The product was extracted with ethyl acetate (2×), washed brine, dried over sodium sulfate and concentrated to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calc'd for C7H6F3NO: 178.04; found: 178.06.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:22][N:23]([CH3:33])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]([CH3:32])[CH3:31])[CH:25]=1>C(OC(=O)C)(=O)C>[CH3:31][N:30]([CH3:32])[C:26]1[CH:25]=[C:24]([N:23]([CH3:33])[CH3:22])[CH:29]=[CH:28][C:27]=1[C:11]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[CH3:1])[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:17])[O:16]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: Cc1[nH]c2ccccc2c1C(=O)c1ccccc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1[nH]c2ccccc2c1C1(c2ccc(N(C)C)cc2N(C)C)OC(=O)c2ccccc21

Procedure:
A mixture of 8.37 g (0.03 mole) of 2-[(2-methyl-3-indolyl)carbonyl]benzoic acid, prepared as described in part A above, 8.37 g (0.05 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and 10 ml of acetic anhydride was interacted at 50° C. as described in part B of Example 8 above to obtain 3-[2,4-bis(dimethylamino)phenyl]-3-(2-methyl-3-indolyl)phthalide (Formula III: Ro =R1 =R2 =R3 =R6 =Y1 =H; R=R5 =CH3 ; R4 =N(CH3)2). After purification by slurrying in a benzene and ligroin mixture, the collected and dried product melted at 183°-186° C. The product had mass spectrum with a m/e peak at 425 (M+). Both the infrared and nuclear magnetic resonance spectra were consistent with this structure. A toluene solution of the product spotted on a phenolic resin coated paper developed an intense grape-colored image.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1.[H-].[Na+].[F:15][CH2:16][CH2:17]I.O>CN(C=O)C.C(OCC)(=O)C>[F:15][CH2:16][CH2:17][O:12][CH2:11][C:5]1[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(CO)cc(CO)c1
Reactant: FCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(CO)cc(COCCF)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
To a solution of 1 g of 5-methoxy-1,3-benzenedimethanol in 10 ml of DMF there was added 238 mg of sodium hydride (60% oily suspension) at 0° C. After stirring at room temperature for 30 minutes, 1.04 g of 1-fluoro-2-iodoethane was added and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (145 mg) as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:11][C@H:12]([OH:27])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CI.[C:37](=O)(O)[O-].[Na+]>O1CCCC1>[CH2:3]([N:10]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:11][C@H:12]([O:27][CH3:37])[CH2:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)CC1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CO[C@H](CN1CCN(C(=O)OC(C)(C)C)CC1)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
Sodium hydride (333 mg, 8.30 mmol) was dissolved in 50 mL of tetrahydrofuran, added dropwise with a solution of tert-butyl 4-[(2S)-3-(dibenzylamino)-2-hydroxy-propyl]piperazine-1-carboxylate 35a (3.65 g, 8.30 mmol) in tetrahydrofuran in an ice-water bath. The reaction solution was stirred for 10 minutes and warmed up to room temperature. The reaction solution was stirred for 1 hour and cooled down to 0° C. followed by the addition of methyl iodide (1.18 g, 8.30 mmol). The reaction solution was stirred for 12 hours. The resulting solution was added with 10 mL of saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-[(2S)-3-(dibenzylamino)-2-methoxy-propyl]piperazine-1-carboxylate 35b (2.10 g, yield: 56.0%) as a yellow oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH:6](O)[C:7]([OH:9])=[O:8])=[O:4].S(=O)(=O)(O)O.C(O)(=O)C.[S:20]1[CH2:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]1=2>O>[Cl:1][CH2:2][C:3]([NH:5][CH:6]([C:26]1[CH:27]=[CH:28][C:21]2[S:20][CH2:24][CH2:23][C:22]=2[CH:25]=1)[C:7]([OH:9])=[O:8])=[O:4]
Reactant: c1ccc2c(c1)CCS2
Reactant: O=C(CCl)NC(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(CCl)NC(C(=O)O)c1ccc2c(c1)CCS2
Yield: 65.3 %

Procedure:
N-Chloroacetyl-α-hydroxyglycine (6.5 g., 0.038 mole) was added to a cold, stirred mixture of concentrated sulphuric acid (1.5 ml.) and glacial acetic acid (15 ml.) followed, after five minutes, by the dropwise addition of 2,3-dihydrobenzo(b)thiophen (98%, 4.1 g., 0.03 mole). The reaction mixture was stirred at ambient temperature for five hours, then water (75 ml.) was added to the resulting suspension and the mixture thoroughly stirred. Filtration gave a solid which was washed successively with water, diethyl ether and hexane, then dried, to afford DL-α-chloroacetamido-2,3-dihydro-5-benzo(b)thienylacetic acid (5.6 g.), m.p. 173°-175° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]([OH:16])=[O:15])=[C:9]([OH:17])[CH:8]=[CH:7]2)(=[NH:3])[NH2:2].CS([O-])(=O)=O.N1C=CC=CC=1.Cl.[NH2:30][N:31]=[CH:32][NH:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>O>[NH2:30][N:31]=[CH:32][NH:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([O:17][C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[CH:12][CH:13]=[C:4]([C:1](=[NH:2])[NH2:3])[CH:5]=3)[C:10]=2[C:14]([OH:16])=[O:15])=[O:39])=[CH:36][CH:35]=1
Reactant: NN=CNc1ccc(C(=O)Cl)cc1
Reactant: N=C(N)c1ccc2c(C(=O)O)c(O)ccc2c1
Agent: CS(=O)(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: N=C(N)c1ccc2c(C(=O)O)c(OC(=O)c3ccc(NC=NN)cc3)ccc2c1
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To 930 mg of 6-amidino-1-carboxy-2-naphthol.methanesulfonate were added 10 ml of anhydrous pyridine and then 667.5 mg of 4-aminoiminomethylaminobenzoic acid chloride.hydrochloride, followed by stirring for 2 hours under cooling with ice and then 48 hours under cooling with water. The precipitate was collected by filtration and washed with a small amount of pyridine. To the collected precipitated were added 20 ml of warm DMF and then 0.6 ml of methanesulfonic acid. The resulting solution was added dropwise to 600 ml of ether, followed by stirring for 1 hour under cooling with ice. The supernatant liquid was decanted, and 20 ml of methanol was added to the residue. This solution was added dropwise to 450 ml of acetone, followed by stirring for 15 minutes under cooling with ice. Then, the precipitate was collected by filtration and washed with a small amount of acetone to obtain 869 mg of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=2)=[CH:4][CH:3]=1.[CH2:21]([N:23](CC)[CH2:24][CH3:25])[CH3:22].ClC(OCC)=O.C(NCC)C>C(Cl)(Cl)Cl>[CH2:21]([N:23]([CH2:24][CH3:25])[C:18]([C:10]1[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:20])[CH3:22]
Reactant: CCN(CC)CC
Reactant: Cc1ccc(-c2nc(C(=O)O)cc3ccccc23)cc1
Agent: CCOC(=O)Cl
Solvent: CCNCC
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)c1cc2ccccc2c(-c2ccc(C)cc2)n1
Yield: 53.7 %

Procedure:
Operations are carried out as for Example 7, starting from 5 g of 1-(4-methylphenyl) isoquinoline 3-carboxylic acid, 2.18 g of triethylamine, 2.39 g of ethyl chloroformate and 1.83 g of diethylamine in 190 ml of chloroform. 3.25 g of N,N-diethyl 1-(4-methylphenyl) isoquinoline 3-carboxamide melting at 113° C., are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=O)[CH:4]=1)#[N:2].[C:11](=O)([O-])[O-].[K+].[K+].O1CCOCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=[CH2:11])[CH:4]=1)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccnc(C=O)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: C=Cc1cc(C#N)ccn1

Procedure:
A mixture of 4-cyanopyridine-2-carboxaldehyde (0.916 g, 6.93 mmol), methyltriphenylphosphonium bromide (2.48 g, 6.93 mmol), potassium carbonate (1.2 g, 8.66 mmol), 1,4 dioxan (9.5 mL) and water (0.13 mL) was heated under reflux for 5 hours. The mixture was diluted with water (30 mL) and ethyl acetate (70 mL) and the organic layer separated. The aqueous phase was further extracted with ethyl acetate (2×40 mL), the organic fractions combined and dried over magnesium sulphate. After removing the solvent, the residue was purified by silica column chromatography using a Biotage cartridge and eluting with cyclohexane/ethyl acetate (7:3 v/v), then (1:1 v/v). This gave the title compound as an oil.