Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:30])[C@@H:13]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:14][CH:15]([OH:18])[CH2:16][OH:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:31]1(C)[CH:36]=CC(S(O)(=O)=O)=C[CH:32]=1.COC(OC)(C)C>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:30])[C@@H:13]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:14][CH:15]2[CH2:16][O:17][C:31]([CH3:36])([CH3:32])[O:18]2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(O)CO)NC(=O)OCc2ccccc2)CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC2COC(C)(C)O2)NC(=O)OCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 755 mg 4-((S)-2-Benzyloxycarbonylamino-4,5-dihydroxy-pentanoyl)-piperazine-1-carboxylic acid ethyl ester in 10 ml dichloromethane were added 10 mg p-toluenesulfonic acid and 10 ml 2,2-dimethoxypropane and the solution stirred for 1 h. The reaction mixture was concentrated, the residue dissolved in dichloromethane and washed with saturated aqueous NaHCO3 and brine. The crude product obtained after evaporation of the solvent was directly used in the next reaction step. Yield: 612 mg.
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[C:14]([Cl:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Cl:15][C:14]1[C:8]2[C:9](=[N:10][N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=3)([C:3]#[N:4])[CH3:18])[N:7]=2)[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: COc1cc(Cl)c2nn(CC(C)(N)C#N)nc2c1
Product: COc1cc(Cl)c2nn(CC(C)(C#N)NC(=S)c3ccc(C(F)(F)F)cc3)nc2c1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(4-chloro-6-methoxy-2H-benzotriazol-2-yl)-2-methylpropionitrile (50 mg, described in Example 42) and 4-trifluoromethylthiobenzoyl chloride (0.04 mL), the title compound was isolated as a white solid (45 mg, 51%). MS (ES): M/Z [M+H]=470. 1H NMR: (400 MHz, DICHLOROMETHANE-d2): 1.86 (s, 3H), 3.88 (s, 3H), 5.11 (d, J=13.9 Hz, 1H), 5.36 (d, J=13.9 Hz, 1H), 7.05 (d, J=2.1 Hz, 1H), 7.20 (d, J=2.0 Hz, 1H), 7.72 (s, 1H), 7.79 (d, J=8.2 Hz, 2H) and 7.92 (d, J=8.6 Hz, 2H). 19F NMR (376 MHz, DICHLOROMETHANE-d2): −42.8 (s, 3F).
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([O:18]C)(=[O:17])[CH:15]=[CH2:16].[OH-].[K+].Cl>CC#N.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O>[C:8]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:16][CH2:15][C:14]([OH:18])=[O:17])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=CC(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(O)CCP(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 92.2 %

Procedure:
Diphenylphosphine (2.00 mL, 11.5 mmol) was dissolved in degassed CH3CN (20 mL). Methyl acrylate (3.80 mL, 42.5 mmol) and a few drops of benzyltrimethylammonium hydroxide (40 wt. % in MeOH) were added, and the resulting solution was stirred under Ar(g). The reaction was monitored by TLC and after the introduction of additional drops of base (after 2 h) the reaction was found to be complete after 4 h. The solution was then concentrated under reduced pressure; the resulting oil was dissolved in CH2Cl2 (100 mL) and concentrated again. The resulting oil was then dissolved in MeOH (10 mL) and an aqueous solution of KOH (4.00 g, 71.4 mmol in 10 mL of H2O) was added. The mixture was stirred under Ar(g). After 1 h, the reaction was found to be complete, and the solution was diluted with H2O (200 mL) and acidified to pH 2 with 2M HCl. The suspension was then extracted with CH2Cl2 (2×150 mL), and the organic layers were combined, dried over Na2SO4(s) and concentrated under reduced pressure. The solid residue was purified by silica gel flash chromatography, eluting with 2% MeOH/CH2Cl2, to give the acid 1d as a white solid (2.74 g, 10.6 mmol, 92% yield).
Reaction SMILES: [CH2:1]([NH:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH3:21])[CH:19]=O.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C1COCC1.CO>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:18]([CH3:21])[CH3:19]
Reactant: CC(C)C=O
Reactant: c1ccc(CNOCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CN(Cc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of II (1 eq.), 2-methylpropanal (1 eq.) and BH3(pyridine) (1 eq.) in THF:MeOH (1:3) was added PPTS (1 eq.). The reaction mixture was stirred at rt for 12 h and afforded, after aqueous workup and purification by column chromatography, III as a colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[CH:6]2.B(Br)(Br)Br.[OH-].[Na+]>C(Cl)CCl.C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[CH:6]2
Reactant: COc1ccc2[nH]ncc2c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClCCl
Product: Oc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
5-Methoxyindazole (1.7 g, 11.5 mmol), (Tetrahedron, 1994, 50, 3529), was dissolved in ethylene chloride (35 ml) and cooled in an ice/water bath. Boron tribromide (57.4 ml of a 1M olution in methylene chloride, 57.4 mmol) was added over 10 minutes and then the mixture allowed to warm to ambient temperature. The mixture was stirred for 2 hours and then re-cooled in an ice/water bath. 2N Sodium hydroxide was slowly added until pH 8. The precipitated solid was filtered off and dried under vacuum at 60° C. overnight. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 5-hydroxyindazole (1.0 g, 65%) as a brown solid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[N+:19]([C:22]1[CH:23]=[C:24]([CH2:28][C:29](O)=[O:30])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Product: O=C(Cc1cccc([N+](=O)[O-])c1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(3-nitrophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.28 (t, J=1.9 Hz, 1H), 8.17 (ddd, J=8.2, 2.3, 1.2 Hz, 1H), 8.03-8.05 (m, 1H), 7.97-8.01 (m, 1H), 7.91 (td, J=7.5, 1.3 Hz, 1H), 7.84 (d, J=7.7 Hz, 1H), 7.68 (t, J=7.9 Hz, 1H), 3.88 (s, 2H), 3.81-3.83 (m, 4H), 3.09-3.11 (m, 4H); MS (ESI−) M/Z 408 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].Cl[N:14]1C(=O)CC[C:15]1=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:6]2[C:5]([CH2:12][N:14]([CH3:15])[C:7]2=[O:8])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc(Br)ccc1C
Solvent: CCOC(C)=O
Product: CN1Cc2ccc(Br)cc2C1=O
Yield: 10.1 %

Procedure:
Methyl 5-bromo-2-methylbenzoate (3 g) in ethyl acetate (100 mL) was treated with N-chlorosuccinimide (1.749 g). The mixture was stirred and heated under reflux whilst being irradiated with a halogen lamp for 5 h. The reaction mixture was cooled and washed with 10% aqueous sodium metabisufite (100 mL) and water. The organic phase was dried over magnesium sulfate and concentrated to an oil. The crude product was treated with 8M methylamine in ethanol (20 mL) and the resulting mixture heated under reflux for 30 min. After cooling, the solution was concentrated to an oil, and the mixture purified on silica gel eluting with ethyl acetate to afford the sub-titled compound (0.300 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=O)[CH3:10].[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:18]([O:17][C:15](=[O:16])[C:14]([C:12]#[N:13])=[C:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1])[CH3:10])[CH3:19]
Reactant: CC(=O)c1cccc(Cl)c1Cl
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=C(C)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2′,3′-dichloroacetophenone (50 mmol), ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate in petroleum ether.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2[CH3:30]>>[CH3:30][N:25]1[CH:24]=[N:23][C:22]2[C:26]1=[N:27][CH:28]=[N:29][C:21]=2[NH:19][CH2:18][CH:15]1[CH2:14][CH2:13][N:12]([S:9]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:10])=[O:11])[CH2:17][CH2:16]1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Reactant: Cn1cnc2c(Cl)ncnc21
Product: Cn1cnc2c(NCC3CCN(S(=O)(=O)CCc4ccccc4)CC3)ncnc21

Procedure:
EXAMPLE 84 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 6-chloro-9-methyl-9H-purine (6-chloro-9-methyl-9H-purine prepared according to G. B. Eilon, J. Org. Chem., 27:2478–2491(1962): MS (m+1)=415.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.Cl.[CH2:11]([O:13][C:14](=[O:20])[C@H:15]([CH:17]([CH3:19])[CH3:18])[NH2:16])[CH3:12].C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH2:11]([O:13][C:14]([C@@H:15]([NH:16][CH2:8][C:5]1[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH:17]([CH3:19])[CH3:18])=[O:20])[CH3:12]
Reactant: O=Cc1ccc(Br)nc1
Reactant: CCOC(=O)[C@@H](N)C(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: CCOC(=O)[C@@H](NCc1ccc(Br)nc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.5 %

Procedure:
A solution of 4.77 g (25.65 mmol) of 6-bromo-3-pyridinecarboxaldehyde, 4.66 g (25.65 mmol) of L-valine ethyl ester hydrochloride and 4.24 g (51.3 mmol) of sodium acetate in 400 ml of methanol is stirred for 30 min together with 25 g of 4A molecular sieve. After adding 3.22 g (51.3 mmol) of sodium cyanoborohydride, the mixture is stirred at room temperature overnight, adjusted to pH=2 with dilute hydrochloric acid, then adjusted to pH 10 with sodium carbonate and filtered with suction through kieselguhr. The solution is diluted with water and washed three times with ethyl acetate; the combined organic phases are washed with sodium chloride solution, and then dried over sodium sulphate and chromatographed on 350 g of silica gel using ethyl acetate/toluene mixtures (1:20→1:10) to give 1.98 g of the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([C:22]([CH3:25])([CH3:24])[CH3:23])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([OH:11])[CH:10]=1.Cl[CH2:28][C:29](Cl)=[O:30].S(=O)(=O)(O)[O-].[Na+]>ClCCl.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>[CH3:26][Si:2]([CH3:1])([C:22]([CH3:23])([CH3:25])[CH3:24])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:29](=[O:30])[CH2:28][O:11][C:9]=2[CH:10]=1
Reactant: COc1ccc(CNc2ccc(CO[Si](C)(C)C(C)(C)C)cc2O)cc1
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccccn1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)COc3cc(CO[Si](C)(C)C(C)(C)C)ccc32)cc1

Procedure:
To a stirred solution of 5-(dimethyl-t-butylsilyl)oxymethyl-2-(4-methoxybenzylamino) phenol in anhydrous dichloromethane, triethylamine and dimethylaminopyridine at 0° C. and under nitrogen atmosphere, chloroacetyl-chloride is added. The mixture is refluxed for 10 h, poured into aqueous sodium bisulfate, extracted with dichloromethane and the product isolated by flash chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:19]([CH2:20]I)[CH2:18][C:17]3[C:22]4[C:9]2=[N:10][CH:11]=[N:12][C:13]=4[CH:14]=[C:15]([O:25][CH3:26])[C:16]=3[O:23][CH3:24])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]([CH3:20])=[CH:18][C:17]3[C:22]4[C:9]2=[N:10][CH:11]=[N:12][C:13]=4[CH:14]=[C:15]([O:25][CH3:26])[C:16]=3[O:23][CH3:24])=[CH:4][CH:3]=1
Reactant: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc2ncnc3c2c(c1OC)C=C(C)N3c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
To a solution of 4-(4-chloro-phenyl)-5-iodomethyl-7,8-dimethoxy-5,6-dihydro-4H-1,3,4-triaza-phenal (0.15 g, 0.31 mmol) (from Example 16, Step F, supra) in toluene (50 mL) was added DBU (0.46 mL, 3.1 mmol) (Fluka). The reaction mixture was heated at 120° C. for 1 hour. The mixture was then diluted with chloroform (100 mL), and washed with H2O. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:1:0.05) as eluent to give the desired 4-(4-chloro-phenyl)-7,8-dimethoxy-5-methyl-4H-1,3,4-triaza-phenalene as a pale yellow solid. (Yield 0.1 g, 91%).
Reaction SMILES: [CH2:1]([N:8]([CH3:30])[CH2:9][CH2:10][C:11]1[N:16]=[C:15]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:18])[C:14]([OH:28])=[C:13]([OH:29])[N:12]=1)C1C=CC=CC=1.C(C1NC=CN=1)(C1NC=CN=1)=[O:32].CC(C)([O-])C.[K+]>[Pd].O1CCOCC1>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:17]([C:15]2[N:16]=[C:11]3[CH2:10][CH2:9][N:8]([CH3:1])[C:30](=[O:32])[N:12]3[C:13](=[O:29])[C:14]=2[OH:28])=[O:18])=[CH:26][CH:25]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CN(CCc1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1)Cc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN1CCc2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C1=O

Procedure:
A methanolic solution of 2-{2-[benzyl(methyl)amino]ethyl}-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide prepared as described in Step 4 was stirred under H2 atmosphere in the presence of catalytic 10% Pd/C for 2 hours. The reaction mixture was filtered through celite to remove the catalyst then concentrated under reduced pressure. MS (ES) C17H17FN4O3 requires 320. Found: 321 (M+H+). The crude organic product was treated with carbonyl diimidazole (1.5 equivalents) and potassium tert-butoxide in refluxing dioxane for 1 hour. Title compound was purified by RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant). Lyophilization of appropriate fractions gave title compound as a white solid.
Reaction SMILES: C(OC([NH:11][C:12]12[CH2:18][C:15]([C:19]([OH:21])=[O:20])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=O)C1C=CC=CC=1.CO.Cl.[H][H]>[Pd].CO.C(OCC)(=O)C>[NH2:11][C:12]12[CH2:18][C:15]([C:19]([OH:21])=[O:20])([CH2:14][CH2:13]1)[CH2:16][CH2:17]2
Reactant: O=C(NC12CCC(C(=O)O)(CC1)C2)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: NC12CCC(C(=O)O)(CC1)C2
Yield: 99.9 %

Procedure:
A 2-L Parr bottle was charged with 4-(benzyloxycarbonylamino)bicyclo[2.2.1]heptane-1-carboxylic acid (105 g, 363 mmol), methanol (500 mL), 0.8 N hydrochloric acid (500 mL), and 10% palladium on carbon (38.6 g, 18.15 mmol, 50% wet with water). The reaction mixture was reacted on a Parr shaker under 30 gpsi hydrogen for 10 h when TLC analysis (10% methanol/ethyl acetate) indicated a complete reaction. The catalyst was removed by filtration through a short plug of celite and the plug was washed thoroughly with water (4×100 mL). The filtrate was concentrated to provide 4-aminobicyclo[2.2.1]heptane-1-carboxylic acid (56.3 g, 100%) as a wet white solid which was used in the next step without any further purification; MS (ESI) m/z 156.2 [M+1]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]3[C:22](=[N:23][CH:24]=2)[N:21]([C:25]([NH:27]C(=O)C2C=CC=CC=2)=[O:26])[CH2:20][CH2:19][CH2:18]3)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]3[C:22](=[N:23][CH:24]=2)[N:21]([C:25]([NH2:27])=[O:26])[CH2:20][CH2:19][CH2:18]3)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(=O)N1CCCc2cc(-c3cncc(OCc4ccccc4)c3)cnc21)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=O)N1CCCc2cc(-c3cncc(OCc4ccccc4)c3)cnc21
Temperature: 25 °C
Yield: 40.1 %

Procedure:
To a mixture of N-[6-(5-benzyloxy-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carbonyl]-benzamide (620 mg, 1.3 mmol) in EtOH (23 ml) is added potassium carbonate (276 mg, 2.0 mmol). The resultant mixture is heated at reflux for 15 min. After cooling to rt, the solid is removed by filtration and the filtrate is concentrated under vacuum. The residue is dissolved in DCM, washed with water and brine, and is dried (Na2SO4). The solvent is evaporated and the crude product is purified by silica gel column to afford 6-(5-benzyloxy-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (188 mg).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[CH:7][C:2]([N:28]5[C@H:27]([CH3:26])[CH2:31][O:30][C:29]5=[O:32])=[N:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(Br)cn2)CC1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(N3C(=O)OC[C@H]3C)cn2)CC1
Yield: 16.9 %

Procedure:
Using (5-bromopyrazin-2-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (175 mg) described in Preparation Example 243 and (R)-4-methyloxazolidin-2-one (53 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (31 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:13]([O-])=O)[CH:6]=[C:5]1[C:16]1[S:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:20]=1.O1CCCC1.O.NN>O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.C(O)C>[NH2:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[N:4]([CH2:3][O:2][CH3:1])[C:5]([C:16]1[S:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:20]=1)=[CH:6]2
Reactant: CCOC(=O)c1cnc(-c2cc3cccc([N+](=O)[O-])c3n2COC)s1
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(-c2cc3cccc(N)c3n2COC)s1
Yield: 97.4 %

Procedure:
A mixture of ethyl 2-[1-(methoxymethyl)-7-nitro-1H-indol-2-yl]-1,3-thiazole-5-carboxylate (2.44 g), iron(III) chloride hexahydrate (92 mg), activated carbon (1.0 g), tetrahydrofuran (10 mL) and ethanol (5 mL) was heated under reflux for 20 min. To the reaction mixture was added hydrazine monohydrate (2.05 g) over 15 min while heating under reflux. The reaction mixture was heated under reflux for 5 hr, filtrated, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated brine, dried (MgSO4), and concentrated. Isopropyl ether was added to the obtained residue. The resulting crystals were collected by filtration, washed with isopropyl ether, and dried to give the title compound (2.18 g, yield 97%) as yellow crystals. melting point 188-190° C.
Reaction SMILES: [C-:1]1([CH:6]=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13].[CH3:14][NH2:15].[BH4-].[Na+]>C1COCC1.CO>[CH3:14][NH:15][CH2:6][C-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13]
Reactant: CN
Reactant: O=C[c-]1cccc1
Agent: [Fe+2]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNC[c-]1cccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
A solution of ferrocenecarboxaldehyde (700 mg, 3.27 mmol) and methylamine (2.0M in THF) (5.0 ml, 10.0 mmol) in THF (25 ml) and methanol (30 ml) was stirred at room temperature for 15 h under a nitrogen atmosphere. Sodium borohydride (371 mg, 9.81 mmol) was added to the solution and it was stirred at room temperature for 1 h. The solvent was removed out under reduced pressure and the residue dissolved in chloroform. The chloroform was washed with water, dried over magnesium sulphate. The solvent was removed under reduced pressure to yield a brown oil (647 mg, 86%).
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[C:3]#[CH:4].Cl[C:7]([O:9][CH2:10][CH3:11])=[O:8]>O1CCCC1>[CH2:10]([O:9][C:7](=[O:8])[C:4]#[C:3][CH:2]([CH3:5])[CH3:1])[CH3:11]
Reactant: C#CC(C)C
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methylbut-1-yne (6.32 g), cooled in a dry-ice/acetone bath, in tetrahydrofuran (200 mL) is added 1.6 M N-butyl lithium solution (63.8 mL). After 1 h, ethyl chloroformate (9.33 mL) is added and the reaction mixture is stirred for an additional 1.5 h. The reaction mixture is allowed to warm to room temperature and is quenched with saturated ammonium chloride solution. The reaction is extracted two times with ethyl acetate. The organic layers are combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (11.5 g). 1H NMR (400 MHz, CDCl3) δ 3.75 (s, 3H), 2.8-2.65 (m, 1H), 1.25-1.23 (d, 6H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15]C)[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([I:14])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.Cl>C1COCC1.O>[I:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][CH:3]([O:2][CH3:1])[OH:15])[N:6]=[CH:7]2
Reactant: COC(Cn1ncc2cc(I)ccc21)OC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(O)Cn1ncc2cc(I)ccc21
Temperature: 70 °C
Yield: 83.6 %

Procedure:
To a solution of 1-(2,2-dimethoxyethyl)-5-iodo-1H-indazole (920 mg, 2.77 mmol) in THF (20 mL) at 40° C. was added 2M HCl (20 mL). The solution was heated at 70° C. for 18 h. The reaction mixture was cooled and diluted with H2O (60 mL). The aqueous mixture was extracted with EtOAc (3×50 mL), dried over Na2SO4 and concentrated to yield the title compound (737 mg, 88%) as a light brown solid: ESI MS m/z 318 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][CH2:11][CH:12]1[CH2:14][O:13]1>>[CH2:1]([NH:8][CH2:14][CH:12]([OH:13])[CH2:11][O:10][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COCC1CO1
Product: COCC(O)CNCc1ccccc1

Procedure:
Starting materials: benzyl amine and 2-(methoxymethyl)oxirane