Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)=O.C([NH:18][C:19]([NH2:21])=[NH:20])(=O)C>C(#N)C>[NH2:21][C:19]1[NH:18][CH:2]=[C:3]([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[N:20]=1
Reactant: CC(=O)NC(=N)N
Reactant: COC(=O)c1ccc(C(=O)CBr)cc1
Solvent: CC#N
Product: COC(=O)c1ccc(-c2c[nH]c(N)n2)cc1

Procedure:
At room temperature, methyl 4-bromoacetylbenzoate (1.37 g) and acetylguanidine (1.62 g) were suspended in acetonitrile, followed by heating under reflux for 16 hours. The solvent was then distilled off under reduced pressure. Water was added to the residue. The insoluble matter so precipitated was collected by filtration, followed by washing with ethanol, whereby methyl 4-[2-aminoimidazol-4-yl]benzoate was obtained. The resulting product was dissolved in a mixed solvent of dioxane (10 ml) and 1N hydrochloric acid (10 ml), followed by heating under reflux for 8 hours. The residue obtained by distilling off the solvent was solidified by tetrahydrofuran and then collected by filtration, whereby the title compound (500 mg, 39%) was obtained.
Reaction SMILES: [NH:1](/[C:8](=[C:17]1\[C:18](=[O:30])[NH:19][C:20]2[C:25]\1=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)/[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl>N.[Ni]>[NH:1](/[C:8](=[C:17]1\[C:18](=[O:30])[NH:19][C:20]2[C:25]\1=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)/[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OC)/C(=C(/Nc1ccccc1)c1cccc(C#N)c1)C(=O)N2
Agent: [Ni]
Agent: N
Solvent: ClCCl
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccccc1)c1cccc(CN)c1)C(=O)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.8 g of 3-(Z)-[1-anilino-1-(3-cyanophenyl)-methylidene]-5,6-dimethoxy-2-indolinone are dissolved in 50 ml of methanolic ammonia and 30 ml of methylene chloride are added. After the addition of 500 mg of Raney nickel the mixture is hydrogenated for 2 hours at ambient temperature at a pressure of 50 psi. After the end of the reaction the catalyst is filtered off and the filtrate is concentrated by evaporation. The residue is separated over a silica gel column with methylene chloride/methanol (5:1) as eluant. The product is suspended in 3 ml of dioxane, 0.4 ml of 1N hydrochloric acid are added and the solution formed is concentrated by evaporation after 10 minutes' stirring at ambient temperature. The residue thus obtained is triturated with ether, suction filtered and dried in vacuo at 80° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.C(=O)([O-])N.[C:26]([N:37]=[C:38]=[O:39])(=[O:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[C:26]([NH:37][C:38](=[O:39])[O:1][CH2:2][C:3]1[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:9])[CH3:10])[N:7]=1)(=[O:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCC(=O)N=C=O
Reactant: CCn1c(CO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Agent: NC(=O)[O-]
Product: CCCCCCCCCC(=O)NC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1CC
Yield: 88.8 %

Procedure:
The compound 19 (240 mg, 0.695 mmol) was converted to the carbamate with decanoyl isocyanate (205 mg, 1.04 mmol) in the same manner as the example 66 to give the compound 83 (335 mg, 92%) as crystals. Mp. 102-103° C. Rf 0.28 (1:2 EtOAc - hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([N:13]=[C:14]=[O:15])=[N:10][C:9]=2[CH3:16])=[CH:4][C:3]=1[S:17]([CH3:20])(=[O:19])=[O:18].ClC1C=CC(C2SC(N)=NC=2C)=CC=1S(C)(=O)=O.[C:39]([Si:43]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[O:44][CH:45]1[CH2:48][NH:47][CH2:46]1)([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH:13][C:14]([N:47]3[CH2:46][CH:45]([O:44][Si:43]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)[C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[CH2:48]3)=[O:15])=[N:10][C:9]=2[CH3:16])=[CH:4][C:3]=1[S:17]([CH3:20])(=[O:18])=[O:19]
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Reactant: Cc1nc(N=C=O)sc1-c1ccc(Cl)c(S(C)(=O)=O)c1
Agent: Cc1nc(N)sc1-c1ccc(Cl)c(S(C)(=O)=O)c1
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)sc1-c1ccc(Cl)c(S(C)(=O)=O)c1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 5-(4-chloro-3-methanesulfonyl-phenyl)-2-isocyanato-4-methyl-thiazole [prepared by the same procedure as example 88a replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) in this example with 5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 83)] (0.2 g, 0.61 mmol) in DMF is treated with 3-(tert-butyl-diphenyl-silanyloxy)-azetidine (162b) (0.25 g, 0.8 mmol) and the reaction mixture is heated to 120° C. After 30 minutes, the reaction is complete. The product is purified by chromatography on silica eluting with ethyl acetate-hexane (1:2) to give the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18](O)=[O:19])=[N:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH2:21][CH2:22][C:23]([CH3:29])([OH:28])[C:24]([F:27])([F:26])[F:25]>>[NH2:1][C:2]1[C:3]([C:18]([NH:21][CH2:22][C:23]([OH:28])([CH3:29])[C:24]([F:27])([F:26])[F:25])=[O:19])=[N:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: CC(O)(CN)C(F)(F)F
Reactant: Cn1cc(-c2nc(C(=O)O)c(N)cc2C(F)(F)F)cn1
Product: Cn1cc(-c2nc(C(=O)NCC(C)(O)C(F)(F)F)c(N)cc2C(F)(F)F)cn1

Procedure:
The title compound was prepared from 3-amino-6-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoro methyl)picolinic acid and 3-amino-1,1,1-trifluoro-2-methylpropan-2-ol analogously to Example 4 1H NMR (400 MHz, Methanol-d4) δ 7.97 (1H, s), 7.85 (1H, s), 7.60 (1H, s), 3.97 (3H, s), 3.77 (1H, m), 3.56 (1H, m), 1.37 (3H, s)
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]3[C:18](=[O:21])[NH:19][S:20][C:5]2=3)[CH2:3][CH2:2]1.Cl.Cl.[CH3:24][C:25]1([NH2:29])[CH2:28][NH:27][CH2:26]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]4[CH2:28][C:25]([NH2:29])([CH3:24])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]3[C:18](=[O:21])[NH:19][S:20][C:5]2=3)[CH2:2][CH2:3]1
Reactant: O=c1[nH]sc2c1c(=O)c1cc(F)c(F)c(F)c1n2C1CC1
Reactant: CC1(N)CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1(N)CN(c2c(F)cc3c(=O)c4c(=O)[nH]sc4n(C4CC4)c3c2F)C1
Yield: 74.3 %

Procedure:
A mixture of 250 mg (0.8 mmol) of 9-cyclopropyl-6,7,8-trifluoro-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-dione, 255 mg (1.6 mmol) of 3-methyl-3-aminoazetidine dihydrochloride and 0.6 ml of triethylamine in 10 ml of pyridine is kept refluxing for 2 hours, the mixture is evaporated under vacuum, a mixture of ethanol with water is added, the resulting mixture is filtered and the product is washed. 0.225 g of 9-cyclopropyl-6,8-difluoro-7-(3-amino-3-methyl-1-azetidinyl)-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-dione, melting point 294°-300° C., is thereby obtained.
Reaction SMILES: B(F)(F)F.CCOCC.[OH:10][C:11]1[C:20]([CH3:21])=[C:19]2[C:14]([CH:15]=[C:16]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17](=[O:22])[O:18]2)=[C:13]([O:34][CH3:35])[CH:12]=1.ClC(Cl)(Cl)C(=N)O[C@H:40]1[C@@H:45]2[O:46][C:47](=[O:49])[O:48][C@@H:44]2[C@@H:43]([O:50][CH3:51])[C:42]([CH3:53])([CH3:52])[O:41]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:35][O:34][C:13]1[CH:12]=[C:11]([O:10][C@H:40]2[C@@H:45]3[O:46][C:47](=[O:49])[O:48][C@@H:44]3[C@@H:43]([O:50][CH3:51])[C:42]([CH3:53])([CH3:52])[O:41]2)[C:20]([CH3:21])=[C:19]2[C:14]=1[CH:15]=[C:16]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:17](=[O:22])[O:18]2
Reactant: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](OC(=N)C(Cl)(Cl)Cl)OC1(C)C
Reactant: COc1cc(O)c(C)c2oc(=O)c(NC(=O)OCc3ccccc3)cc12
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1cc(O[C@@H]2OC(C)(C)[C@H](OC)[C@H]3OC(=O)O[C@@H]23)c(C)c2oc(=O)c(NC(=O)OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.5 %

Procedure:
Boron trifluoride etherate (18.5 μL, 0.15 mmol) was added to 23d (174 mg, 0.49 mmol) and (3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate (621 mg, 1.71 mmol) in anhydrous CH2Cl2 (11.0 mL). After stirring at room temperature for 14 hours, triethylamine (150 μL) was added and the solvent was concentrated. The residue was purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to give 25d as a colorless foam (200 mg, 74%): 1H NMR (CDCl3, 500 MHz) 8.49 (s, 1H), 7.34-7.27 (m, 5H), 6.67 (s, 1H), 6.60 (s, 1H), 5.69 (s, 2H), 5.16 (d, J=5.3 Hz, 1H), 4.89 (t, J=7.8 Hz, 1H), 4.63 (dd, J=7.9, 2.4 Hz, 1H), 3.83 (s, 3H), 3.37 (s, 3H), 3.15 (d, J=8.0 Hz, 1H), 2.16 (s, 3H), 2.16 (s, 3H), 2.12 (s, 3H); 13C NMR (CDCl3, 125 MHz) 158.9, 156.0, 155.2, 154.2, 153.1 (2C), 149.4, 135.7, 128.7 (2C), 128.5, 128.2 (2C), 120.8, 117.4, 106.6, 105.4, 94.6, 94.1, 82.9, 67.4, 60.6, 60.6, 56.1, 56.0, 22.2, 22.0, 7.9; IR (film) νmax 2955, 2924, 2853, 1817, 1713, 1526, 1209, 1105, 1072, 1034, 976, 808 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C28H29NO11, 556.1819; found, 556.1826.
Reaction SMILES: [ClH:1].[O:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:17]([O:19]C)=O)[CH2:3]1.[NH3:21].Cl>C(O)(C)C>[ClH:1].[NH2:21][C:17]([CH2:16][CH2:15][NH:14][CH2:13][CH2:12][CH:4]1[CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[O:2][CH2:3]1)=[O:19]
Reactant: COC(=O)CCNCCC1COc2ccccc2C1
Reactant: N
Agent: Cl
Solvent: CC(C)O
Product: NC(=O)CCNCCC1COc2ccccc2C1
Reaction time: 12 h

Procedure:
3 g (100 mmol) of N-[2-(chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride (example 4) are added to 20 ml of 5.5N methanolic ammonia solution. The mixture is stirred in a bomb tube for 12 hours at 60°. Subsequently, the reaction mixture is concentrated by evaporation, the resulting residue is dissolved in 2N hydrochloric acid, and the acidic solution is extracted with diethyl ether. The acidic aqueous phase is rendered alkaline with 2N sodium hydroxide solution and extracted with diethyl ether. The combined ethereal phases are washed in succession with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated by evaporation, yielding the crude base in the form of an oil. The crude base is dissolved in a small amount of isopropanol. Ethereal hydrochloric acid is added to the isopropanol solution until the mixture gives a weakly acidic reaction. The precipitate is filtered off and recrystallized from isopropanol/diethyl ether, yielding 0.6 g of N-(2-aminocarbonylethyl)-N-[2-(chroman-3-yl)ethyl]amine hydrochloride melting at 220° to 222°.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](=[O:23])(=[O:22])[NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1>CC(C)=O>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:12]([CH2:31][C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])(=[O:23])=[O:22])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COc1ccccc1CNS(=O)(=O)c1ccc(OC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CN(Cc2ccccc2OC)S(=O)(=O)c2ccc(OC(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(N-(2-methoxybenzyl)sulfamoyl)phenyl acetate (example 5-42a) (50 mg, 0.15 mmol) was dissolved in acetone (1.0 mL) followed by the addition of cesium carbonate (97 mg, 0.30 mmol) and methyl 4-(bromomethyl)benzoate (38 mg, 0.17 mmol). The mixture was stirred at room temperature overnight and then the inorganic salts were filtered off. Acetone was removed in vacuo and the residue was re-dissolved in ethyl acetate and washed with water followed by brine. The organic layer was dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography with ethyl acetate/hexanes as the eluent to afford methyl 4-((4-acetoxy-N-(2-methoxybenzyl)phenylsulfonamido)methyl)benzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[C:8]2Cl.[NH2:14][C:15]1[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1.CCOCC>C1(OC)C=CC=CC=1.CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[C:8]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: COc1cccc2c(Cl)nccc12
Reactant: Cc1ccccc1N
Solvent: CCOCC
Solvent: CO
Solvent: COc1ccccc1
Product: COc1cccc2c(Nc3ccccc3C)nccc12
Reaction time: 4 h
Yield: 30.2 %

Procedure:
5-Methoxy-1-chloroisoquinoline (1.5 g, 0.00777 mol) and o-toluidine (0.835 gm, 0.00777 mol) were mixed in anisole (10 ml) and heated with stirring in an oil-bath at 140° for four hours. After cooling the mixture was dissolved in methanol and ether was added to precipitate a tacky solid. The solvent was decanted off and the precipitate washed with more ether. The insoluble residue was equilibrated between N. HCl and ether, the aqueous acid solution filtered and basified with saturated aqueous Na2CO3 to precipitate a buff solid which was collected, washed with water and dried (0.77 g). This material was crystallised from diethyl ether to give the title compound (0.62 g) as fluffy, light-buff needles, m.p. 111°-112°.
Reaction SMILES: [CH2:1]([N:7]1[C:12](=[O:13])[CH:11]2[CH:9]([C:10]2([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)[CH2:14][C:15]([F:18])([F:17])[F:16])[C:8]1=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl-].[Ca+2].[Cl-]>C(O)C.O.[Fe]>[CH2:1]([N:7]1[C:8](=[O:28])[CH:9]2[CH:11]([C:10]2([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=2)[CH2:14][C:15]([F:16])([F:17])[F:18])[C:12]1=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1C(=O)C2C(C1=O)C2(CC(F)(F)F)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCCCCCN1C(=O)C2C(C1=O)C2(CC(F)(F)F)c1cccc(N)c1
Temperature: 25 °C
Yield: 102.5 %

Procedure:
3-Hexyl-6-(3-nitrophenyl)-6-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (Preparation 103, 178 mg, 0.45 mmol) was dissolved in ethanol (15 ml). Iron powder (225 mg, 4.0 mmol) was added at room temperature followed by calcium chloride (50 mg, 0.45 mmol), dissolved in water (2 ml). The vigorously stirred mixture was heated under reflux for 2 h then cooled to room temperature and filtered through a pad of silica. The solvent was removed in vacuo and the filtrate was dissolved in dichloromethane and filtered through a Whatman anotop 10 plus™ cartridge. The organic mixture was concentrated in vacuo to give the product as a brown gum (170 mg, 100%).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([O:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2C(OC(C)(C)C)=O)[CH:7]=[N:8][C:9]=1[Cl:10])[CH:2]=[CH2:3].[ClH:25].O.CO>CCOCC>[ClH:10].[ClH:25].[CH2:1]([C:4]1[CH:5]=[C:6]([O:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)[CH:7]=[N:8][C:9]=1[Cl:10])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: C=CCc1cc(OC[C@H]2CCCN2)cnc1Cl

Procedure:
To a solution of 5-allyl-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)6-chloropyridine in Et2O was added hydrogen chloride (4.0 M in 1,4-dioxane) carefully to afford the tittle compound: mp 90-92° C.; 1H NMR (D2O) δ 1.92 (m, 1H), 2.02-2.20 (m, 2H), 2.27 (m, 1H), 3.40 (t, 2H, J=7.0 Hz), 3.49 (d, 2H, J=6.5 Hz), 4.11 (m, 1H), 4.21 (dd, 1H, J=7.5, 10.5 Hz), 4.43 (dd, 1H, J=3.5, 10.5 Hz), 5.10 (dd, 1H, J=1.5, 17.0 Hz), 5.18 (dd, 1H, J=2.0, 10.0 Hz), 6.03 (m, 1H), 7.44 (d, 1H, J=3.0 Hz), 7.98 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/z 253 (M+H)+. Anal. Calcd for C13H17ClN2O.2 HCl.0.8 H2O: C, 45.91; H, 6.11; N, 8.24. Found: C, 45.90; H, 6.36; N, 8.20. [α]25D −11.2 (c 1.4, MeOH).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[C:4]([NH2:21])[N:3]=1.CO.[OH-].[Na+].Cl[CH2:27][C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=1>CN(C)C=O>[CH3:34][C:32]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:27][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C:10]3[CH:9]=[C:8]([C:7]4[C:2]([NH2:1])=[N:3][C:4]([NH2:21])=[CH:5][CH:6]=4)[O:12][N:11]=3)=[CH:15][CH:16]=2)[CH:33]=1
Reactant: Cc1ccnc(CCl)c1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccnc(COc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)cc2)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
To 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (80 mg, 0.28 mmol) described in Manufacturing Example 18-1-1 were added methanol (4 mL) and 1 N aqueous sodium hydroxide solution (0.29 mL), which was then dissolved by irradiating ultrasonic wave. This solution was concentrated under a reduced pressure. To the resulting residue was added 2-chloromethyl-4-methyl-pyridine (50.9 mg, 0.36 mol.) described in Manufacturing Example 11-1-4 and N,N-dimethylformamide (3 mL), which was stirred for 10 minutes at 60° C. The reaction solution was partitioned into water and ethyl acetate. The organic layer was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:2, then ethyl acetate) to obtain the title compound (40 mg, 36.5%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29](O)=[O:30])[CH:22]=2)=[N:8][CH:7]=1)=[O:5])C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:18][CH3:19])[C:9]([C:20](=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:30])[CH:22]=1)=[N:8][CH:7]=[C:6]2[C:4]([OH:3])=[O:5]
Reactant: CCOC(=O)c1cnc(C(=O)c2cccc(OCC(=O)O)c2)c2cc(OC)c(OC)cc12
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)N4CCOCC4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To a solution of 1-(3-carboxymethoxybenzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester (93.3 mg, 0.20 mmol) in 8 ml of methylene chloride was added 10 equivalent of morpholine, 1.2 equivalent of HBTU and 4 equivalent of triethylamine. The mixture was stirred at room temperature overnight. The solvents were evaporated and the residue was extracted with ethyl acetate and water. The organic phase was dried and solvents were evaporated. The residue was dissolved in 4 ml of methanol and aqueous lithium hydroxide was added (0.5N, 1 ml). The mixture was stirred overnight until all starting material disappeared. The reaction was loaded on a preparative HPLC for purification to give 6,7-Dimethoxy-1-[3-(2-morpholin-4-yl-2-oxo-ethoxy)-benzoyl]-isoquinoline-4-carboxylic acid as a fluffy solid (20 mg, 21%). ES-MS calcd for C25H24N2O8 (m/e) 480.5, obsd 481.3 (M+H).
Reaction SMILES: Cl[C:2]1[CH2:3][C:4](=[O:8])[N:5]=[N:6][CH:7]=1.[CH3:9][O:10][C:11]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[O:8]=[C:4]1[NH:5][N:6]=[CH:7][C:2]([C:17]2[CH:18]=[C:13]([CH:14]=[CH:15][CH:16]=2)[C:11]([O:10][CH3:9])=[O:12])=[CH:3]1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: O=C1CC(Cl)=CN=N1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2cn[nH]c(=O)c2)c1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
Dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (85 mg, 0.12 mmol) was added to a mixture of 5-chloropyridazin-3(4H)-one (0.52 g, 4.0 mmol, Maybridge, Cat. No. MO08305), [3-(methoxycarbonyl)phenyl]boronic acid (0.864 g, 4.80 mmol, Aldrich, Cat. No. 591130) and sodium carbonate (0.85 g, 8.0 mmol) in 1,4-dioxane (9 mL) and water (1 mL). The reaction mixture was vacuumed and refilled with nitrogen 3 times. The reaction was stirred at 95° C. overnight. To this reaction mixture was added dioxane (3.0 ml) and water (10 ml) and then filtered, washed with acetonitrile/water, dried to provide the pure product (0.86 g). LCMS (M+H)+: m/z=231.1
Reaction SMILES: [O:1]([CH2:9][C@H:10]1[C@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:25])[O:11]1)[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:1][CH2:9][C@H:10]1[C@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:25])[O:11]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1OC(=O)N2c3ccc(C#N)cc3OC[C@@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: N#Cc1ccc2c(c1)OC[C@H]1[C@H](CO)OC(=O)N21
Yield: 65.2 %

Procedure:
Using compound (3R,3 aS)-3-((t-butyldimethylsiloxy)methyl)-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-7-carbonitrile (0.538 g, 1.494 mmol), tetra-n-butylammonium fluoride (1M, 2.99 ml) as starting materials, preparation following the method as described in Example 1(b) afforded 0.24 g white solid, yield 65.3%.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCCC2)cc1
Solvent: CCO
Product: Nc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 42.5 %

Procedure:
In ethanol (100 ml) was dissolved 1-(4-nitrobenzyl)-pyrrolidine (23.5 g), and to the mixture was added dried 10% palladium on carbon (1.00 g). Under hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 20 hours. The palladium was filtered off, and the filtrate was concentrated. The residue was separated and purified with column chromatography (ethyl acetate/triethylamine=10/1) to give 1-(4-aminobenzyl)pyrrolidine (8.54 g) as orange oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1.[OH:27][CH:28]([CH3:32])[C:29](O)=[O:30]>>[OH:27][CH:28]([CH3:32])[C:29]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1)=[O:30]
Reactant: NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Reactant: CC(O)C(=O)O
Product: CC(O)C(=O)NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1

Procedure:
75 mg (196 μmol) (RS)-6-{[7-(aminomethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]amino}-1,3-benzothiazol-2(3H)-one (prepared according to example 20) were transformed in analogy to example 23 using (RS)-2-hydroxypropanoic acid to give after working up and purification 6.0 mg (6%) of the title compound.