Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[C:16]([N:21]2[CH:25]=[C:24]([C:26]([OH:28])=O)[N:23]=[CH:22]2)[CH:17]=[CH:18][C:19]=1[Cl:20].N.O>CN(C=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([N:21]2[CH:25]=[C:24]([C:26]([NH2:3])=[O:28])[N:23]=[CH:22]2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cn(-c2ccc(Cl)c(Cl)c2)cn1
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cn(-c2ccc(Cl)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Carbonyldiimidazole (0.49 g, 3 mmol) was added to a stirred suspension of 1-(3,4-dichloro-phenyl)-1H-imidazole-4-carboxylic acid (0.64 g, 2.5 mmol) in DMF (10 ml). After 1 h at 60° C., the reaction mixture was cooled to rt, aqueous ammonia (25%, 20 ml) was added and stirring was continued for 12 h. Then H2O (100 ml) was added and the precipitated product was filtered. Recrystallisation from EtOH afforded the title compound as off-white crystals. Mp. 244-245° C. (EtOH), MS: m/e=255 (M+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:15]2[CH2:17][CH2:16]2)[N:3]=1.[Br:18][C:19]1[N:20]=[CH:21][NH:22][CH:23]=1>>[Br:18][C:19]1[N:20]=[CH:21][N:22]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=3)[CH:5]=[C:4]([CH:15]3[CH2:17][CH2:16]3)[N:3]=2)[CH:23]=1
Reactant: Brc1c[nH]cn1
Reactant: Clc1ccc(-c2cc(C3CC3)nc(Cl)n2)cc1
Product: Clc1ccc(-c2cc(C3CC3)nc(-n3cnc(Br)c3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-cyclopropyl-pyrimidine (example A.13) (0.80 g, 3.0 mmol) and commercially available 4-bromo-imidazole (0.66 g, 4.50 mmol) according to the general procedure IVa. Obtained as a white solid (0.71 g, 63%). MS (ISP) 375.1 [(M+H)+].
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17](B(O)O)=[CH:18]4)=[CH:13][C:12]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:32][C:33]1[CH:42]=[C:41](I)[CH:40]=[CH:39][C:34]=1[C:35]([O:37][CH3:38])=[O:36]>>[OH:32][C:33]1[CH:42]=[C:41]([C:17]2[CH:16]=[CH:15][C:14]3[C:19](=[CH:20][C:11]([C:1]45[CH2:2][CH:3]6[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]6)[CH2:10]4)[CH2:8]5)=[C:12]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:13]=3)[CH:18]=2)[CH:40]=[CH:39][C:34]=1[C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: OB(O)c1ccc2cc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)cc2c1
Product: COC(=O)c1ccc(-c2ccc3cc(OCc4ccccc4)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1O
Yield: 36.2 %

Procedure:
Following the basic procedure of Example 7(f), by reacting 5.52 g (13.4 mmol) of 7-(1-adamantyl)-6-benzyloxy-2-naphthylboronic acid with 2.46 g (8.8 mmol) of methyl 2-hydroxy-4-iodobenzoate, 1.65 g (36%) of the expected compound was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:4].[CH3:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH3:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([N:5]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3](=[O:4])[CH2:2][NH:1][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=2)=[O:31])=[CH:11][CH:10]=1
Reactant: COc1ccc(N(CC(=O)OC(C)(C)C)C(=O)CN)cc1
Reactant: Cc1cccc(N=C=O)c1
Product: COc1ccc(N(CC(=O)OC(C)(C)C)C(=O)CNC(=O)Nc2cccc(C)c2)cc1
Yield: 17.7 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with tert-butyl 2-[2-amino-N-(4-methoxyphenyl)acetamido]acetate (6.6 g) and 3-methylphenyl isocyanate (3 g), and after recrystallisation in acetonitrile, tert-butyl 2-{N-(4-methoxyphenyl)-2-[3-(3-methylphenyl)ureido]acetamido}-acetate (1.7 g), m.p. 158° C., is obtained.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[F:22][C:23]1[CH:24]=[C:25]([C:29]2[S:33][C:32]([CH3:34])=[N:31][C:30]=2[C:35](O)=[O:36])[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:24]=[C:25]([C:29]2[S:33][C:32]([CH3:34])=[N:31][C:30]=2[C:35]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:36])[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(3-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[C:31]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1>>[C:31]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:36]=[CH:35][CH:34]=[C:33]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20][C:19]3=[O:29])[CH:32]=1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Product: O=C(O)c1cnn(-c2nc3ccc(-c4cccc(-c5ccccc5)c4)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (product from Example 69, step B) and biphenyl-3-boronic acid. MS (ESI): mass calcd. for C24H16N4O3, 408.1; m/z found, 409.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.01 (s, 1H), 12.92 (s, 1H), 9.00 (s, 1H), 8.44 (s, 1H), 8.32-8.25 (m, 2H), 8.01 (s, 1H), 7.83-7.77 (m, 4H), 7.72 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.53-7.48 (m, 2H), 7.43-7.40 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C@H:6]1[CH2:9][C@H:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1)[CH3:5].[Li+].[CH3:20]C([N-]C(C)C)C.CCCCCC.IC>C1COCC1.O>[CH3:1][O:2][C:3](=[O:18])[C:4]([C@H:6]1[CH2:7][C@H:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:9]1)([CH3:20])[CH3:5]
Reactant: COC(=O)C(C)[C@H]1C[C@H](OCc2ccccc2)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: COC(=O)C(C)(C)[C@H]1C[C@H](OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of trans-2-(3-benzyloxy-cyclobutyl)-propionic acid methyl ester (94 mg, 0.38 mmol) in THF (1 mL) is added 1.09M LDA in THF and hexane (1.51 mL, 1.65 mmol) at −78° C. under nitrogen, and stirred at −78° C. for 30 minutes. To the mixture, iodomethane (232 uL, 3.76 mmol) is added, and stirred at −78° C. for 30 minutes. The temperature is slowly warmed to room temperature for 3 hours. To the mixture, H2O is added and extracted with AcOEt. The organic layer is dried over MgSO4 and concentrated under reduced pressure to give trans-2-(3-benzyloxy-cyclobutyl)-2-methyl-propionic acid methyl ester (70 mg, 70%); ESI-MS m/z 263 [M+1]+, retention time 2.17 min (condition A).
Reaction SMILES: [O:1]=[C:2]([CH2:13][CH3:14])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].CC1(C)[O:21][C:20](=O)[CH:19]=[C:18]([CH3:23])O1.C(C1(C)OC(=O)C=C(C)O1)C>>[CH2:13]([C:2]1[O:1][C:18]([CH3:23])=[CH:19][C:20](=[O:21])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:14]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: CCC(=O)CC(=O)Nc1ccccc1
Agent: CCC1(C)OC(=O)C=C(C)O1
Product: CCc1oc(C)cc(=O)c1C(=O)Nc1ccccc1
Yield: 49 %

Procedure:
The title compound was prepared from 3-oxo-N-phenylvaleramide (m.p. 84.0°-85.5° C.) and 2,2,6-trimethyl-4H-1,3-dioxin-4-one, instead of 2-ethyl-2,6-dimethyl-4H-1,3-dioxin-4-one in Example 15, as the raw materials in a similar way to the method described in Example 15. (Yield: 49%) m.p.: 154.5°-156° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]>C(OCC)(=O)C.O=[Pt]=O>[OH:10][CH:3]([C:2]([F:1])([F:11])[F:12])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(O)C(F)(F)F
Yield: 75.6 %

Procedure:
A solution of 19.31 g of ethyl trifluoroacetoacetate (Fairfield Chemical) in 50 ml of ethyl acetate was hydrogenated at 3 atmospheres on a Parr shaker over (0.5 g) PtO2 as a catalyst. The volatiles were removed and the residue distilled under high vacuum to afford 14.75 g (76%) of the title compound as a low melting solid. bp=47°-49° C. at 0.1 mm of Hg, mp (uncorrected)=about 25° C.
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[O:16][C:15]3[C:10](=[C:11]([Cl:18])[CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:20])[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:36](=[O:39])([O-])[O-:37].[K+].[K+]>O>[Cl:18][C:11]1[C:10]2[C:9](=[O:19])[C:8]3[CH:7]=[CH:6][C:5]4[O:20][CH:2]([C:36]([OH:37])=[O:39])[CH2:1][C:4]=4[C:17]=3[O:16][C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(O)ccc2c(=O)c3c(Cl)cccc3oc12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)C1Cc2c(ccc3c(=O)c4c(Cl)cccc4oc23)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.3 %

Procedure:
A mixture of 4-allyl-8-chloro-3-hydroxy-9-oxo-9H-xanthene (15 g), m-chloroperbenzoic acid (14 g) and chloroform (1,000 ml) was stirred at room temperature for 5 hours and left to stand overnight. To the mixture, potassium carbonate (20 g) and water (500 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (2,000 ml) and, to the stirred solution, a mixture of chromium trioxide (15 g), water (90 ml) and concentrated sulfuric acid (26 g) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 8.0 g of 7-chloro-1,2-dihydro-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid. m.p. 283°-286° C. This compound produced a mass spectrum having a molecular ion peak at m/e 316.
Reaction SMILES: C(OC([N:8]1[C:12]2=[C:13](Cl)[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])=[C:11]2[C:10]([CH3:26])=[CH:9]1)=O)(C)(C)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31]>C(OCC)C>[Cl:27][C:28]1[CH:29]=[C:30]([NH:31][C:13]2[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:18])=[C:11]3[C:10]([CH3:26])=[CH:9][NH:8][C:12]=23)[CH:32]=[CH:33][CH:34]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)N3CCCCC3)c12
Solvent: CCOCC
Product: Cc1c[nH]c2c(Nc3cccc(Cl)c3)ncc(C(=O)N3CCCCC3)c12

Procedure:
Prepared in a similar manner to Example 4(d) from 7-chloro-3-methyl-4-(1-piperidin-1-yl-methanoyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (90 mg) and using 3-chloroaniline (50 ul) instead of 3-bromoaniline and heating for 15 rather than 30 minutes. Isolated by MDAP rather than trituration with diethyl ether to give the title compound (67 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:5][N:4]=1.[OH-].[NH4+].[CH:19](O)=[O:20]>>[CH:19]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:5][N:4]=1)=[O:20]
Reactant: COC(=O)CCCCc1ccc(CN)nc1
Reactant: O=CO
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)CCCCc1ccc(CNC=O)nc1

Procedure:
2-Aminomethyl-5-(4-methoxycarbonylbutyl)pyridine (0.20 g) is heated at 90° in 0.6 ml of formic acid for 18 hours. The mixture is cooled to 0°, made basic with saturated ammonium hydroxide solution and extracted with methylene chloride (4×15 ml). Drying, filtration and evaporation of the extracts yields 2-(N-formylaminomethyl)-5-(4-methoxycarbonylbutyl)pyridine as an oil (IR 1720, 1675 cm-1) which is redissolved in 1 ml of toluene and heated at 90° for 18 hours with phosphorus oxychloride (0.166 g). Evaporation of excess phosphorus oxychloride with toluene, basification at 0° with saturated ammonium hydroxide solution, extraction with methylene chloride (4×15 ml) and drying over sodium sulfate yields an oil which is chromatographed (silica gel, ethyl acetate) to yield 6-(4-methoxycarbonylbutyl)-imidazo[1,5-a]pyridine; Rf=0.26; NMR (CDCl3) 3.58 (s, 3H), 6.45 (d, 1H), 7.25 (d, 1H), 7.38 (s, 1H), 7.62 (s, 1H), 7.94 (s, 1H); IR (CH2Cl2) 1730 cm-1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:17])=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O.O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:17])=[C:13]([CH:14]=1)[CH:15]=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1CO
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(OCc2ccccc2)cc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of (5-(benzyloxy)-2-methylphenyl)methanol (280 mg) in DMSO (5.0 ml) was added 2-iodoxybenzoic acid (343 mg), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (250 mg) as a pale-yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:13][S:12][C:11](=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=3[CH3:22])[N:10]2[CH3:23])=[CH:5][C:4]=1[S:25](=[O:34])(=[O:33])[N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29]>C(O)(=O)C>[BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:23])[C:11](=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=3[CH3:22])[S:12][CH:13]=2)=[CH:5][C:4]=1[S:25](=[O:34])(=[O:33])[N:26]([CH2:27][CH2:28][CH3:29])[CH2:30][CH2:31][CH3:32]
Reactant: CCCN(CCC)S(=O)(=O)c1cc(C2(O)CSC(=Nc3cccc(C)c3C)N2C)ccc1Cl
Agent: Br
Solvent: CC(=O)O
Product: CCCN(CCC)S(=O)(=O)c1cc(-c2csc(=Nc3cccc(C)c3C)n2C)ccc1Cl

Procedure:
Obtained by a procedure analogous to that indicated in Example 1(b), from 4-(4-chloro-3-dipropylsulfamoylphenyl)-3-methyl-2-(2,3-dimethylphenyl-imino)thiazolidin-4-ol hydrobromide by refluxing in glacial acetic acid, subsequently evaporating and crystallizing the viscous residue under water. Colorless crystals from methanol/ether; melting point 210°-212°.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.[C:12]1([CH2:18][C:19]([OH:21])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[NH2:41]/[C:42](=[N:56]\O)/[C@@H:43]1[CH2:48][CH2:47][CH2:46][CH2:45][N:44]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50]>CN(C)C1C=CN=CC=1.ClCCl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[NH2:56]/[C:42](=[N:41]\[O:20][C:19](=[O:21])[CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)/[C@@H:43]1[CH2:48][CH2:47][CH2:46][CH2:45][N:44]1[C:49]([O:51][C:52]([CH3:54])([CH3:53])[CH3:55])=[O:50]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1/C(N)=N/O
Reactant: O=C(O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1/C(N)=N/OC(=O)Cc1ccccc1
Reaction time: 2 h
Yield: 91.3 %

Procedure:
1-Hydroxybenzotriazole hydrate (8.67 g), phenylacetic acid (8.0 g), N-methylmorpholine (14.69 ml), 4-dimethylaminopyridine (3.3 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.29 g) were added to a solution of tert-butyl (Z)-(2S)-2-[amino(hydroxyimino)methyl]-1-piperidinecarboxylate (13.0 g) [see Preparation 4] in dichloromethane (180 ml). The reaction mixture was stirred for 2 hours under an atmosphere of nitrogen, after which time the mixture was diluted with dichloromethane and 1N aqueous citric acid solution. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulphate and the solvent was removed under reduced pressure to afford tert-butyl (Z)-(2S)-2-(amino[(2-phenylacetyl)oxy]iminomethyl)-1-piperidinecarboxylate (17.63 g) as a white solid.
Reaction SMILES: CS[C:3]1[C:4]2[C:5](=[CH:14][S:15][CH:16]=2)[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)(=O)C>[N:17]1([C:3]2[C:4]3[C:5](=[CH:14][S:15][CH:16]=3)[NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCNCC1
Reactant: CSC1=Nc2ccccc2Nc2cscc21
Solvent: CC(=O)O
Product: c1ccc2c(c1)N=C(N1CCCCC1)c1cscc1N2

Procedure:
A solution of 0.7 g. of 10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in 5 ml. of piperidine is treated with a drop of glacial acetic acid and heated under reflux for 4 days. Excess piperidine is removed under reduced pressure and the oily residue is warmed with dilute acetic acid and filtered. The filtrate is cooled and made alkaline with concentrated ammonium hydroxide to give a yellow solid. Recrystallization from acetone-petroleum ether (30°-60° C.) gives yellow crystals, m.p. 157°-159° C.
Reaction SMILES: [CH:1]([C@H:4]1[N:9]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([CH3:20])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:21]3[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[C:25]([C:32](OC)=[O:33])=[CH:24][C:22]=3[N:23]=[C:5]12)([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH:1]([C@H:4]1[N:9]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[C:13]([CH3:20])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:21]3[CH:27]=[C:26]([S:28]([CH3:31])(=[O:29])=[O:30])[C:25]([CH2:32][OH:33])=[CH:24][C:22]=3[N:23]=[C:5]12)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C)c(C(F)(F)F)n1)[C@@H]3C(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: Cc1cnc(N2CCn3c(nc4cc(CO)c(S(C)(=O)=O)cc43)[C@H]2C(C)C)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
A solution of (R)-methyl 1-isopropyl-2-(5-methyl-4-(trifluoromethyl)pyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (3.5 mg, 0.007 mmol) in dry toluene (3 mL) was cooled to −78° C. A solution of DIBAL-H in toluene (1M, 35 μL, 5 equiv.) was added. The mixture was stirred for 3 h. LC-MS indicated the reaction was complete. The mixture was quenched by sat. NH4Cl solution (200 μL) and methanol (200 μL), before being warmed to r.t. After concentration, the residue was filtered and purified by Gilson to afford 1.53 mg (R)-(1-isopropyl-2-(5-methyl-4-(trifluoromethyl)pyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methanol (46% yield). LC-MS: m/z 484.3 [M+H]+. 1H NMR (CD3OD, 400 MHz): δ 8.52 (s, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 6.05 (d, J=8.0 Hz, 1H), 5.30 (dd, J=14.4 Hz, 4.8 Hz, 1H), 5.12 (s, 2H), 4.51 (dd, J=12.0 Hz, 3.2 Hz, 1H), 4.22 (td, 12.0 Hz, 5.2 Hz, 1H), 3.88 (m, 1H), 3.26 (s, 1H), 2.57 (m, 1H), 2.29 (s, 3H), 1.27 (d, 6.4 Hz, 3H), 1.06 (d, 6.4 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]([NH:11][NH:12][C:13]([N:15]1[CH2:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][C:17]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:16]1=2)=[O:14])[CH2:3][CH2:4]C1C=CC=CN=1.[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][S:37]CCC(NN)=O.ClC1C=CC2OC3C=CC=CC=3CN(C(Cl)=O)C=2C=1>>[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][S:37][CH2:4][CH2:3][C:2]([NH:11][NH:12][C:13]([N:15]1[CH2:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][C:17]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:16]1=2)=[O:14])=[O:1]
Reactant: O=C(CCc1ccccn1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: NNC(=O)CCSCc1ccco1
Agent: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(CCSCc1ccco1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[(2-furanylmethyl)thio]-1-oxopropyl]hydrazide (13) was prepared in the manner 8-chlorodibenz[b,f]oxazepine-10(11H)carboxylic acid, 2-[1-oxo-3-(2-pyridinyl)propyl]hydrazide (6) was prepared, as described above in Example 6, from 3-[(2-furanylmethyl)thio]propanoic acid, hydrazide (12), prepared as described above in Example 12, and 8-chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carbonyl chloride (2), prepared as described above in Example 2, on a 10 mmol scale. The yield was quantitative. Analysis calculated for C22H20N3O4SCl (M.W. 457.94): C, 57.70; H, 4.40; N, 9.18; Cl, 7.74; S, 7.00. Found: C, 57.59; H, 4.36; N, 9.01; Cl, 7.95; S, 7.07.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][C@@H:14]2[CH2:18][C@H:17]([O:19][CH2:20][CH2:21][OH:22])[C@@H:16]([OH:23])[C@H:15]2[OH:24])=[N:4][C:5]([S:9][CH2:10][CH2:11][CH3:12])=[N:6][C:7]=1[Cl:8].[N:25]([O-])=O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:8][C:7]1[C:2]2[N:1]=[N:25][N:13]([C@@H:14]3[CH2:18][C@H:17]([O:19][CH2:20][CH2:21][OH:22])[C@@H:16]([OH:23])[C@H:15]3[OH:24])[C:3]=2[N:4]=[C:5]([S:9][CH2:10][CH2:11][CH3:12])[N:6]=1
Reactant: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@@H](O)[C@H]2O)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCSc1nc(Cl)c2nnn([C@@H]3C[C@H](OCCO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
To a stirring solution of (1S,2S,3R,5S)-3-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (OLACINA; 1.14 g, 3 mmol) in acetic acid (5 mL) was added sodium nitrite (0.23 g, 3.3 mmol) while maintaining the reaction temperature at 20-30° C. The reaction mixture was stirred for 30 minutes. It was then diluted with ethyl acetate (50 mL), washed with water (2×35 mL) and evaporated under reduced pressure. The crude product was triturated in hexane (20 mL) and filtered to give CLTOL as an off-white powder (1.00 g, 86% yield): 98 area % by HPLC; mp 98-107° C.; 13C NMR (CDCl3, 125 MHz) δ13.4, 22.0, 33.5, 33.7, 61.75, 61.77, 71.1, 74.9, 75.4, 82.0, 131.8, 150.7, 152.9, 171.8.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([OH:14])[CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[K+]>C(Cl)Cl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([O:14][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1O)CCN(C(C)=O)C2
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1OCc1ccccc1)CCN(C(C)=O)C2
Reaction time: 16 h

Procedure:
N-Acetyl-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline quarter-hydrate (14.0 g) was dissolved in methylene chloride (200 ml). Benzyl bromide (22.6 ml) was then added, followed by the addition of a solution of potassium hydroxide (4.62 g) in water (200 ml) and then tetra-n-butylammonium bromide (2.04 g). The resulting mixture was stirred vigorously overnight (16 hours). The organic layer was then separated, washed (H2O), dried (MgSO4) and evaporated. Medium pressure chromatography of the residue on silica (Merck "Art.9385") eluting with methylene chloride containing gradually increasing amounts of methanol (0-10%) gave, after collection and evaporation of appropriate fractions, the title compound as a semi-solid which was recrystallised from ethyl acetate to give the pure title compound, 16.84 g, m.p. 125°-6°.