Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[OH:22])=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][C:27]1=C=O.[O:35]1CCC[CH2:36]1>>[CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[O:22][C:36]([N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)=[O:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2ccc(N3C(=O)c4cccnc4C3O)nc2n1
Reactant: CN1CCN(Cl)C(=C=O)C1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc2ccc(N3C(=O)c4cccnc4C3OC(=O)N3CCN(C)CC3)nc2n1
Temperature: 0 °C

Procedure:
Following the procedure of Example 9 but starting with a suspension of 6-(7-methyl-1,8-naphthyridin-2-yl)-7-hydroxy-5-oxo-pyrrolo[3,4-b]pyridine (2.7 g.) in anhydrous tetrahydrofuran (27 cc.), sodium hydride (50% dispersion in mineral oil) (0.885 g.) and 1chloro-carbonyl-4-methylpiperazine (3 g.) dissolved in anhydrous tetrahydrofuran (30 cc.), a reaction mixture is obtained which is poured into ice-water (210 cc.). The mixture is extracted with methylene chloride (3 × 400 cc.). The combined extracts are dried over potassium carbonate and are concentrated to dryness. A residue weighing 4.9 g. is thus obtained and is triturated with diisopropyl ether (60 cc.). The precipitate which appears is filtered off. The resulting product (3.6 g.) is dissolved in methylene chloride (72 cc.), and the solution is passed through a column of silica gel (36 g.). Elution is carried out successively with methylene chloride (3 × 500 cc.), a mixture (3 × 500 cc.) of methylene chloride and ethyl acetate (50--50 by volume), pure ethyl acetate (3 × 500 cc.) and a mixture (4 × 500 cc.) of ethyl acetate and methanol (90-10 by volume). The last four eluates are concentrated to dryness and the residue obtained is recrystallised from acetonitrile (58 cc.). 6-(7-Methyl-1,8-naphthyridin-2-yl)-7-(4-methylpiperazin-1-yl)carbonyloxy-5-oxo-pyrrolo[3,4-b]pyridine (1.12 g.), melting at 226° C., is thus obtained.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:13])([CH3:12])[N:3]=1.[CH2:14]([C:16]1[CH:17]=[N+:18]([O-])[CH:19]=[CH:20][CH:21]=1)[CH3:15].C(OCC)(=[O:25])C>C(Cl)Cl>[CH2:14]([C:16]1[CH:21]=[CH:20][C:19]([N:3]2[C:2](=[O:25])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][C:4]2([CH3:13])[CH3:12])=[N:18][CH:17]=1)[CH3:15]
Reactant: CCOC(C)=O
Reactant: CCc1ccc[n+]([O-])c1
Reactant: CC1(C)N=C(Cl)c2ccccc2O1
Solvent: ClCCl
Product: CCc1ccc(N2C(=O)c3ccccc3OC2(C)C)nc1
Yield: 33 %

Procedure:
A solution of 172 mg (0.87 mmol) of 4-chloro-2,2-dimethyl-(2H)-1,3-benzoxazine (K. Wachi and A. Terada, Chem. Pharm. Bull, 1980, 28, 465-472) and 215 mg (1.75 mmol) of 3-ethylpyridine N-oxide (S. Hibino and E. Sugino, J. Heterocycl Chem., 1990, 27, 175) in 1.6 mL of methylene chloride was heated to reflux for 9 h with stirring. After cooling the reaction, 30 mL ethyl acetate was added and the mixture was washed in succession with 10 mL saturated sodium bicarbonate and 10 mL of saturated aqueous sodium chloride. The organic solution was dried (sodium sulfate), decanted, and evaporated to give a yellow liquid. Flash column chromatography on 17 g of silica gel, eluting with 100 mL of 5% ethyl acetate/hexane and 500 mL of 7% ethyl acetate/hexane furnished 84 mg (33% yield) of 3-(5-ethyl-2-pyridinyl)-2,2-dimethyl-2,3-dihydro-(4H)-1,3-benzoxazin-4-one as a colorless syrup.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]O)[CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)[CH:20]=1
Reactant: OCc1cccnc1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(OCc3cccnc3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 103.6 %

Procedure:
Into a solution of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (500 mg), 3-pyridinemethanol (405 mg) and triphenylphosphine (0.98 g) in THF (10 ml) was added at 0° C. diethyl azodicarboxylate (a 40% solution in toluene) (1.62 g), and the resulting mixture was stirred at room temperature for 20 hours. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate) to obtain methyl 7-(3-pyridylmethoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (694 mg) as colorless crystals.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]2[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]=2[C:18]([CH3:37])([CH3:36])[CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Na].[O:39]=[O:40]>ClCCl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]23[O:40][O:39][C:12]2([C:18]([CH3:36])([CH3:37])[CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:13]([CH3:16])([CH3:17])[CH2:14][O:15]3)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCCCCCCOCC(C)(C)C1=C(c2cccc(OC(C)=O)c2)OCC1(C)C
Reactant: O=O
Agent: [Na]
Solvent: ClCCl
Product: CCOC(=O)CCCCCCCCCCOCC(C)(C)C12OOC1(c1cccc(OC(C)=O)c1)OCC2(C)C

Procedure:
5-(3-acetoxyphenyl)-4-(13-ethoxycarbonyl-1,1-dimethyl-3-oxatridecan-1-yl)-3,3-dimethyl-2,3-dihydrofuran (compound (24)) (57.8 mg, 0.112 mmol) and TPP (0.6 mg) were added to dichloromethane (6 mL), and the mixture was irradiated with visible light by a 940 W sodium lamp in an oxygen atmosphere at 0° C. for 30 minutes. The reaction mixture was concentrated, and the concentrate was put into a silica gel column and developed with a mixed solvent of hexane and ethyl acetate (10:1 to 5:1), whereby 1-(3-acetoxyphenyl)-5-(13-ethoxycarbonyl-1,1-dimethyl-3-oxatridecan-1-yl)-4,4-dimethyl-2,6,7-trioxabicyclo[3.2.0]heptane (compound (25)) was obtained as a colorless oil in an amount of 46 mg in a yield of 75.0%.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:8][N:7]=1)=[O:5])C.[Cl-].[Mg+2].[Cl-].[CH:20]1([NH2:23])[CH2:22][CH2:21]1>C(O)C>[CH:20]1([NH:23][C:4]([C:6]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:8][N:7]=2)=[O:5])[CH2:22][CH2:21]1
Reactant: CCOC(=O)c1ccnc(C(=O)OCC)c1
Reactant: NC1CC1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCO
Product: CCOC(=O)c1ccnc(C(=O)NC2CC2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5.5 g (24.64 mmol) of diethylpyridine 2,4-dicarboxylate (Example 50A) were dissolved in 55 ml of ethanol. 0.47 g (4.93 mmol) of magnesium chloride was added, and the mixture was then cooled to 0° C., 8.44 g (147.83 mmol) of cyclopropylamine were slowly added dropwise and the reaction mixture was stirred at 0° C. for 15 min and stirred further at RT for 2 days. The reaction mixture was evaporated. The residue was dissolved in water and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated using a rotary evaporator.
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:15])[CH2:4][C:5](=[O:14])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>P([O-])([O-])([O-])=O>[Cl:1][CH2:2][C@@H:3]([OH:15])[CH2:4][C@@H:5]([OH:14])[CH2:6][C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8]
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CCl
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)CCl
Temperature: 30 °C
Reaction time: 24 h

Procedure:
Large-sized test tubes were charged with 7 mL of said medium B and, after sterilization, inoculated with the bacteria shown in Table 2, respectively. Then, aerobic shake culture was carried out at 30° C. for 1 day. From the resulting culture broth, the cells were harvested by centrifugation and suspended in 0.5 mL of 50 mM phosphate buffer (pH 6.5) containing 0.5% of tert-butyl(5S)-6-chloro-5-hydroxy-3-oxohexanoate and 1.5% of glucose. The suspension was placed in a 10 mL test tube equipped with a stopper and the reaction was carried out under shaking at 30° C. for 20 hours. After completion of the reaction, the reaction mixture was extracted with 0.5 mL of ethyl acetate and the ethyl acetate phase was analyzed by high performance liquid chromatography (column: Nakalai-Tesque's Cosmocil 5CN-R (4.6 mm×250 mm), eluent: 1 mM phosphoric acid/H2O:acetonitrile=5:1, flow rate: 0.7 mL/min., detection: at 210 nm, column temperature: 30° C.) for reaction rate and for the diastereomer ratio of the product tert-butyl(3R,5S)-6-chloro-3,5-dihydroxyhexanoate. The results are shown in Table 2.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)(Cl)Cl.[OH2:30]>ClCCl>[C:17]([O:24][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)(=[O:30])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O
Reactant: COc1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(OC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
4-Hydroxyanisole (1.25 g, 10.1 mmol) was dissolved in anhydrous dichloromethane (10 mL), and triethylamine (4.25 mL, 30.5 mmol) and benzoyl chloride (1.40 mL, 12.1 mmol) were added thereto successively. The reaction mixture was stirred at room temperature for 4 hours. Chloroform (50 mL) and water (50 mL) were added to the reaction mixture and partitioned. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was filtered with hexane (50 mL) to give the titled reference compound (2.24 g) as a colorless solid. (Yield 98%)
Reaction SMILES: C(Cl)Cl.[F:4][C:5]1[CH:6]=[C:7]2[C:25](=[CH:26][CH:27]=1)[O:24][CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[C:28]3[N:29]=[C:13]([CH:14]=[CH:15][N:16]3[N:17]=[CH:18]1)[N:12]1[C@@H:8]2[CH2:9][CH2:10][CH2:11]1.CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CO>[F:4][C:5]1[CH:6]=[C:7]2[C:25](=[CH:26][CH:27]=1)[O:24][CH2:23][CH2:22][N:21]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:20][C:19]1=[C:28]3[N:29]=[C:13]([CH:14]=[CH:15][N:16]3[N:17]=[CH:18]1)[N:12]1[C@@H:8]2[CH2:9][CH2:10][CH2:11]1
Reactant: Fc1ccc2c(c1)[C@H]1CCCN1c1ccn3ncc(c3n1)CNCCO2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCOc2ccc(F)cc2[C@H]2CCCN2c2ccn3ncc(c3n2)C1
Yield: 51 %

Procedure:
To a DCM (0.5 mL) solution of (6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo-[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaene (Example 21, 5 mg, 0.0141 mmol) was added DIEA (2.46 μL, 0.0141 mmol), followed by methanesulfonyl chloride (1.10 μL, 0.0141 mmol). The reaction was stirred at ambient temperature for 1 hour before MeOH (0.1 mL) was added. The reaction was concentrated and purified by reverse-phase column chromatography eluting with 0-80% acetonitrile/H2O to provide the title product (3.1 mg, 50.8% yield). MS (apci) m/z=432.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1.[Cu]I>[N+:9]([C:5]1[CH:6]=[C:7]([C:26]#[C:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:2]([NH2:1])=[N:3][CH:4]=1)([O-:11])=[O:10]
Reactant: Nc1ncc([N+](=O)[O-])cc1Br
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncc([N+](=O)[O-])cc1C#Cc1ccccc1
Reaction time: 12 h

Procedure:
1.83 g 2-amino-3-bromo-5-nitropyridine 0.29 g PdCl2(PPh3)2 and 79 mg CuI were mixed in 36 ml dry tetrahydrofuran (THF) and 3.45 ml triethylamine and 1.12 g phenylacetylene were added. Stirring was continued at room temperature for 12 hrs, then the solvent was removed and the residue purified by flash chromatography on silica in ethyl acetate/heptane eluent. Yield 855 mg.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1NC.Cl[C:16]1[N:17]=[N:18][C:19]([I:22])=[CH:20][CH:21]=1.Cl[C:24]1[N:25]=NC(Cl)=CC=1>>[I:22][C:19]1[N:18]=[N:17][C:16]([NH:25][CH2:24][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:21][CH:20]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CNc1c(-c2ccccc2)noc1C
Reactant: Clc1ccc(I)nn1
Product: Cc1onc(-c2ccccc2)c1CNc1ccc(I)nn1
Yield: 24 %

Procedure:
As described for example 72, (5-methyl-3-phenyl-isoxazol-4-yl)-methylamine (2.0 g, 10.6 mmol) was converted using 3-chloro-6-iodopyridazine (Goodman, A. J.; Stanforth, S. P.; Tarbit, B. Tetrahedron 1999, 55, 15067) instead of 3,6-dichloropyridazine to the title compound (1.0 g, 24%) which was contaminated with ca. 33% of (6-chloro-pyridazin-3-yl)-(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amine (example 72). The product was obtained as a white solid. MS: m/e=393.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH3:18])[C:7](=[O:17])[N:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[C:3]=1[O:21][CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([N:14]1[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][N:8]2[C:4]3[C:3]([O:21][CH2:22][CH:23]4[CH2:26][CH2:25][CH2:24]4)=[C:2]([Br:1])[CH:20]=[CH:19][C:5]=3[N:6]([CH3:18])[C:7]2=[O:17])[CH2:16][CH2:15]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: Cn1c(=O)n(CCN2CCNCC2)c2c(OCC3CCC3)c(Br)ccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(CCn2c(=O)n(C)c3ccc(Br)c(OCC4CCC4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.6 %

Procedure:
A solution of 5-bromo-4-(cyclobutylmethoxy)-1-methyl-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one (40.0 mg, 0.0945 mmol) in methylene chloride (2.0 mL) was treated with N,N-diisopropylethylamine (49.4 μL, 0.283 mmol) followed by the addition of acetyl chloride (10.1 μL, 0.142 mmol), and the resultant reaction mixture was stirred at RT for 1 h. Purification by flash column chromatography (5% MeOH/EtOAc) gave the desired product (46 mg, 94%). LCMS calculated for C21H30BrN4O3 (M+H)+: m/z=465.1, 467.1. found: 465.1, 467.1.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:5]1[C:6]([OH:11])=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]([OH:1])=[C:3]([C:12](=[O:14])[CH3:13])[CH:4]=1
Reactant: BrBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Solvent: ClC(Cl)Cl
Product: CCCc1c(O)c(Br)cc(C(C)=O)c1O
Reaction time: 0.75 h
Yield: 73.2 %

Procedure:
To a cold suspension (7°) of 5 g (0.026 mol) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone in 150 ml of chloroform was added 27 ml (0.027 mol) of 1M bromine in chloroform dropwise. The mixture was stirred at 5° for 45 minutes and solvent was removed in vacuo. The residue was extracted with hot hexane and the hexane extract was boiled down to 50 ml and allowed to crystallize. Filtration gave 5.2 g, melting point 67° (74% yield) of 1-(5-bromo-2,4-dihydroxy-3-propylphenyl)ethanone.
Reaction SMILES: [C:1]1([CH2:9]Br)[C:2]([CH2:7]Br)=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:11][N:12]([NH2:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(N(CC)CC)C>CN(C)C=O.O>[C:16]([O:15][C:13]([N:12]([CH3:11])[N:20]1[CH2:7][C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: BrCc1ccccc1CBr
Reactant: CN(N)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A vigorously stirred solution 13.15 g (0.05 mole) of o-xylylene dibromide and 7.3 g (0.05 mole) of t-butyl 2-methylcarbazate in 25 ml of dimethylformamide was warmed to 50° and 14 ml of triethylamine was added during 5-8 minutes while maintaining the temperature at 50°-60°. After complete addition the reaction mixture was stirred at room temperature for 3 hrs. and diluted with 100 ml of water. After stirring for 1 hr the mixture was extracted with ethyl acetate. The organic phase was separated and dried. Filtration and evaporation gave a gummy solid which was used without further purification. The IR and NMR of the material were consistent with the proposed structure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22]([O:24]C)=O)[CH:2]=1.[NH3:26]>C1COCC1.[OH-].[NH4+]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22](=[O:24])[NH2:26])[CH:2]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccnc1
Reactant: N
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccnc1
Temperature: 35 °C
Yield: 74 %

Procedure:
A solution of the 9-[(3-pyridyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (362 mg, 1.09 mmol) in 15 mL THF and 60 mL concentrated aqueous ammonium hydroxide was treated with a stream of NH3 gas to ensure saturation. The reaction vessel was capped and the mixture heated to 35° C. with stirring until tlc indicated complete consumption of starting material (48 hours). The mixture was neutralized to pH 8 with 5 N aqueous HCl, saturated with solid sodium chloride, and extracted twice with THF. The combined organic layers were concentrated. The resulting foam was taken up in a minimal amount of THF and loaded onto a silica gel column which had been pre equilibrated with EtOAc. Elution with EtOAc afforded 255 mg (74%) of the 9-[(3-pyridyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a yellow solid. 1H NMR (DMSO-d6) δ 10.46 (s, 1H), 8.79 (br s, 1H), 8.43 (d, 1H, J=1.5 Hz), 8.39 (dd, 1H, J=1.4 and 4.9 Hz), 8.35 (br s, 1H), 7.84 (d, 1H, J=7.8 Hz), 7.48-7.22 (m, 6H), 7.13 (d, 1H, J=8.3 Hz), 6.58 (d, 1H, J=7.8 Hz), and 5.73 (s, 2H). IR (KBr, cm−1) 3436, 3198 (br), 1629, 1619, 1599, 1580, 1564, 1547, 1444, 1433, 1329, 1263, and 776. MS (ES) m/e 318 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:11])(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[C:20]1(S)[CH:25]=[CH:24]C=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([C:12]#[N:13])=[C:6]([S:8][C:11]2[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=2)[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccccc2)c1C#N
Reactant: Sc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(Sc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-methanesulfonyl-6-phenyl-pyrimidine-5-carbonitrile, thiophenol and DBU in DME. EI-MS m/e (%): 304 (M+, 76), 303 ([M—H]+, 100).
Reaction SMILES: C[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=1)[C:8]([O-:10])=[O:9].[CH2:26]([S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH3:28].[CH3:33]N1CCOCC1>C(Cl)Cl>[CH3:33][O:10][C:8](=[O:9])[CH:7]([N:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:17][CH:18]=1)[S:29]([CH2:26][CH2:27][CH3:28])(=[O:31])=[O:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: CN1CCOCC1
Reactant: CCCCCCC(NCc1ccc(C(O)CCCCC)cc1)C(=O)[O-]
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCCCC(O)c1ccc(CN(C(CCCCC)C(=O)OC)S(=O)(=O)CCC)cc1
Reaction time: 120 h

Procedure:
A solution of 7-methyl-{[4-(1-hydroxy-hexyl)-benzyl]-amino}-heptanoate (82.2 mg, 0.235 mmol), 1-propanesulfonyl chloride (29.1 RL, 0.259 mmol) and 4-methylmorpholine (28.5 μL, 0.259 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 24 h. Additional 1-propanesulfonyl chloride (14.5 μL) and 4-methylmorpholine (14.3 μL) were added, and the reaction was stirred for 5 days. The organic solution was washed consecutively with 5.5% HCl, water, aqueous NaHCO3, and brine. The organic solution was dried (MgSO4), filtered, and concentrated to yield 7-[[(4-(1-hydroxy-hexyl)-benzyl]-(propane-1-sulfonyl)-amino]-heptanoic acid methyl ester which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](=[O:8])[NH:4][C:3]=1[C:9]#[N:10].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:11]([O:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([Br:1])=[CH:7][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1[nH]c(=O)ccc1Br
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: N#Cc1nc(OCc2ccccc2)ccc1Br

Procedure:
A solution of 3-bromo-6-oxo-1,6-dihydropyridine-2-carbonitrile (from Example 15/Step 2) (1.0 eq.), silver carbonate (1.3 eq.), and benzyl bromide (1.2 eq.) in toluene (0.16 M) was stirred in the dark at 50° C. overnight. The solvent was concentrated en vacuo, and the resulting residue was purified by a COMBIFLASH® system (ISCO) using 0-20% ethyl acetate in hexane to give 6-(benzyloxy)-3-bromopicolinonitrile.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([CH3:14])[CH:7]=1)([OH:5])[CH3:4].[H-].[Na+].I[CH3:20].O>CN(C=O)C.C(OCC)(=O)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:3]([O:5][CH3:20])([CH3:4])[C:2]([F:15])([F:16])[F:1])=[CH:7][C:8]=1[CH3:14]
Reactant: CI
Reactant: COc1ccc(C(C)(O)C(F)(F)F)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)(OC)C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1,1,1-trifluoro-2-(4-methoxy-3-methylphenyl)-propane-2-ol (1 g) in DMF (20 ml) were added sodium hydride (60% in mineral oil, 205 mg) and iodomethane (727 mg). After stirring for 5 hours at room temperature, the reaction mixture was ice cooled, then water and ethyl acetate were added to the reaction mixture. The organic layer was separated and washed with brine, and dried over anhydrous magnesium sulfate. After removing the drying agent, the organic layer was concentrated under reduced pressure.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[NH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH:10](OCC)(OCC)OCC.Cl>C(O)(=O)C>[N:5]1([CH2:6][C:7]([OH:9])=[O:8])[CH:10]=[N:3][N:2]=[N:1]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)Cn1cnnn1
Temperature: 55 °C
Reaction time: 6 h
Yield: 28.1 %

Procedure:
The title compound was prepared by a literature procedure* as follows: A mixture of sodium azide (10.5 g, 0.3 mol) and glacial acetic acid (125 ml) was blanketed with nitrogen and heated at 55° C. with stirring. After most of the solids had dissolved (15 min), glycine (18.75 g, 0.25 mol) and triethyl orthoformate (40 g, 0.27 mol) were added to the reaction mixture and heating at 55°-50° C. with stirring under nitrogen continued for 6 h. The reaction mixture was cooled to room temperature, acidified with concentrated hydrochloric acid (25 ml) and evaporated to dryers. The residue was extracted with ethyl acetate (4×100 ml) and the extracts evaporated to give 9.0 g (28%) of the title compound mp 121°-125° C. (lit. mp 125°-127° C.). 1Hmr (DMSO-d6) δ: 5.35 (s, 2H,--CH2 --) and 9.25 ppm (s, 1H, C5 --H).