Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([CH3:35])[CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:8]=[C:7]([C:17]2[C:18]([C:25]3[CH:30]=[C:29]([CH2:31]C)[CH:28]=[C:27]([O:33]C)[CH:26]=3)=[N:19][N:20]([CH2:22][C:23]#[N:24])[CH:21]=2)[CH:6]=1.B(F)(F)F.CSC>ClCCl>[OH:1][C@@H:2]([CH3:35])[CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:8]=[C:7]([C:17]2[C:18]([C:25]3[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([OH:33])[CH:26]=3)=[N:19][N:20]([CH2:22][C:23]#[N:24])[CH:21]=2)[CH:6]=1
Reactant: CCc1cc(OC)cc(-c2nn(CC#N)cc2-c2cc(NC[C@H](C)O)nc(-c3cccnc3)n2)c1
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Product: Cc1cc(O)cc(-c2nn(CC#N)cc2-c2cc(NC[C@H](C)O)nc(-c3cccnc3)n2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.5 %

Procedure:
To anhydrous dichloromethane (5 mL) was added [4-[6-(2(S)-hydroxypropylamino)-2-pyridin-3-yl-pyrimidin-4-yl]-3-(3-methoxy-5-ethylphenyl)pyrazol-1-yl]acetonitrile (150 mg, 0.33 mmol) and boron trifluoride-dimethylsulfide (344 μL, 3.27 mmol) under nitrogen atmosphere. The reaction mixture was stirred for 12 hours at room temperature under nitrogen atmosphere. After completion of the demethylation, the solvent was removed by vacuum distillation, and the reaction mixture was dissolved, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated through vacuum distillation. Column chromatography gave the title compound (64.89 mg, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[N:12]([CH2:15]O)[C:11](=[O:17])[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][Cl:20])[C:11](=[O:17])[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(Cl)Cl
Reactant: O=c1on(-c2ccc(Cl)c(Cl)c2)c(=O)n1CO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=c1on(-c2ccc(Cl)c(Cl)c2)c(=O)n1CCl

Procedure:
2-(3,4-Dichlorophenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione (0.03 mole) dissolved in chloroform (40 ml) and thionyl chloride (0.06 mole) dissolved in chloroform (10 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the reaction mixture is stripped of solvent under reduced pressure, leaving a residue. This residue is dissolved in toluene, and the toluene solution is stripped of solvent and unreacted starting materials to yield the desired product 2-(3,4-dichloropheny)-4-chloromethyl-1,2,4-oxadiazolidin-3,5-dione as the residue.
Reaction SMILES: C[O:2][C:3](=[O:44])[CH:4]=[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12](S(C1C=CC=CC=1)(=O)=O)[CH:11]=[C:10]2[C:25]1[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:28]=[C:27]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:26]=1[O:39][CH2:40][CH:41]([F:43])[F:42])[CH3:6].[OH-].[Na+]>CO.O1CCOCC1.Cl>[C:35]([C:27]1[C:26]([O:39][CH2:40][CH:41]([F:43])[F:42])=[C:25]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]([CH3:6])=[CH:4][C:3]([OH:44])=[O:2])[CH:8]=3)[NH:12][CH:11]=2)[CH:30]=[C:29]([C:31]([CH3:33])([CH3:34])[CH3:32])[CH:28]=1)([CH3:36])([CH3:37])[CH3:38]
Reactant: COC(=O)C=C(C)c1ccc2c(c1)c(-c1cc(C(C)(C)C)cc(C(C)(C)C)c1OCC(F)F)cn2S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(=CC(=O)O)c1ccc2[nH]cc(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3OCC(F)F)c2c1

Procedure:
3-{1-Benzenesulfonyl-3-[3,5-di-tert-butyl-2-(2,2-difluro-ethoxy)-phenyl]-1H-indol-5-yl}-but-2-enoic acid methyl ester (493 mg, 0.79 mmol) was dissolved in methanol (4 mL)/dioxane (8 mL) and treated with 1N NaOH (5.5 mL) at 60° C. for 4 h. Diluted with 1N HCl (25 mL) and extracted with ethyl acetate (3×25 mL). The combined organic portions were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to provide crude material. The material was purified using radial chromatography by elution with hexane/ethyl acetate gradient to provide 158 mg (43%) of a lightyellow solid. Mp. 135-145° C. 1H NMR (250 MHz, CDCl3): δ 8.40 (bs, 1H), 7.92 (s, 1H), 7.47 (m, 3H), 7.39 (m, 2H), 6.26 (d, J=1.1), 5.49 (tt, 1H, J=55.3, J=4.3), 3.69 (td, 2H, J=14.0, J=4.0), 2.68 (d, 3H, J=1.0), 1.50 (s, 9H), 1.37 (s, 9H). MS [EI−] 468 (M−H)+. Analytical (C28H33NO3): Calculated C, 71.62; H, 7.08; N, 2.98. Found: C, 69.95; H, 7.38; N, 2.70.
Reaction SMILES: [O:1]1[C:5]2([CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][OH:12])[CH2:6]2)[O:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[O:1]1[C:5]2([CH2:9][CH2:8][CH:7]([CH2:10][CH:11]=[O:12])[CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OCCC1CCC2(C1)OCCO2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCC1CCC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a solution of 2-(1,4-dioxa-spiro[4.4]non-7-yl)-ethanol (7 g, 40.6 mmol) in dichloromethane (400 mL) was added Dess-Martin periodinane (43 g, 101.6 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 2 h and then quenched with a saturated aqueous sodium bicarbonate solution (100 mL). The mixture was extracted with dichloromethane (2×100 mL), washed with a saturated aqueous sodium bicarbonate solution (3×200 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was diluted with n-hexane (400 mL) and filtered. The filtrate was concentrated in vacuo to afford (1,4-dioxa-spiro[4.4]non-7-yl)-acetaldehyde (5.5 g, 79%) as a light yellow solid: LC/MS m/e calcd for C9H14O3 [M+H]+ 171.21.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:33](=[O:34])[CH:32]=[N:31][C:30]5[CH:35]=[CH:36][C:37]([O:39][CH3:40])=[N:38][C:29]4=5)[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:41].C(O)C>C(O)C>[ClH:41].[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:33](=[O:34])[CH:32]=[N:31][C:30]5[CH:35]=[CH:36][C:37]([O:39][CH3:40])=[N:38][C:29]4=5)[CH2:22][CH2:21]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2n1
Agent: Cl
Solvent: CCO
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2n1
Reaction time: 3 h

Procedure:
To a solution of 0.14 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(6-methoxy-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamate in 3.0 mL of ethanol, 3 mL of a 6.0 mol/L hydrogen chloride/ethanol solution was added at room temperature. The mixture was stirred at the same temperature for 3 hours, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the resultant residue, and the solid was filtered off to obtain 0.11 g of 4-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-6-methoxypyrido(2,3-b)pyrazin-3(4H)-one hydrochloride as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>O1CCOCC1.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]2[C@@H:16]([OH:17])[CH2:15][CH2:14][CH2:13][NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2ncccc2O)cc1OC
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc([C@@H]2NCCC[C@@H]2O)cc1OC

Procedure:
2-(3,4-Dimethoxyphenyl)-3-pyridinol (10.0 g, 43.2 mmoles, described in Example 3) is dissolved in p-dioxane (60 ml) containing 0.1 ml of 12.5N sodium hydroxide. The solution is hydrogenated for 17 hours with Raney nickel catalyst (1.5 g) at 1750 p.s.i. and 140° C. The mixture is filtered and the filtrate is evaporated. The residue is subjected to chromatography on alumina (Woelm, basic activity I) using first chloroform as eluant and then a 1:10 methanol-chloroform solvent combination. The eluates are evaporated, dissolved in acetone and maleic acid is added. The precipitate is crystallized from isopropanol-hexane to give the title compound as the maleate salt, mp 180°-181° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([C:8]3=O)[CH2:6]1)[CH2:12]2)=[O:4].C([O-])=O.[NH4+:19]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH:8]3[NH2:19])[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: COC(=O)C12CC3CC(C1)C(=O)C(C3)C2
Reactant: [NH4+]
Agent: [Pd]
Agent: O=C[O-]
Solvent: CO
Product: COC(=O)C12CC3CC(C1)C(N)C(C3)C2
Temperature: 25 °C
Yield: 76.6 %

Procedure:
4-Oxo-adamantane-1-carboxylic acid methyl ester (6.5 g, 31.2 mmol) (prepared following J. Org. Chem. 1983, 48, 1101) was dissolved in MeOH (75 ml). To this solution was added 10% Pd—C (1 g) followed by ammonium formate (10 g, 158 mmol). The reaction mixture was heated under reflux for 1 h after which it was cooled to ambient temperature and filtered through hyflo bed. The clear filtrate was concentrated under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The aqueous layer was separated, basified with 10% NaOH solution and extracted with EtOAc. The combined organic layer was dried over anhydrous sodium sulphate and solvent removed under reduced pressure to give 4-aminoadamantane-1-carboxylic acid methyl ester (5 g, 77%). LC-MS (m/z): 210 (M+1). 1H NMR (300 MHz, DMSO-d6): δ 3.6 (s, 3H), 3.2 (d, 1H), 1.4-2.2 (13H, m).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[CH:18]=[C:19]([C:23]3([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:20]=[CH:21][CH:22]=2)=[CH:12][C:11]=1[Cl:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32]I>>[Cl:31][C:11]1[CH:12]=[C:13]([S:16][C:17]2[CH:18]=[C:19]([C:23]3([O:29][CH3:30])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:15][C:10]=1[N:9]([CH3:32])[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: COC1(c2cccc(Sc3ccc(NC(=O)c4ccccc4)c(Cl)c3)c2)CCOCC1
Product: COC1(c2cccc(Sc3ccc(N(C)C(=O)c4ccccc4)c(Cl)c3)c2)CCOCC1
Yield: 86 %

Procedure:
Using a similar procedure to that described in Example 18, 4-[3-(4-benzamido-3-chlorophenylthio)phenyl]-4-methoxytetrahydropyran was reacted with methyl iodide to give 4-[3-(3-chloro-4-(N-methylbenzamido)phenylthio)phenyl]-4-methoxytetrahydropyran in 86% yield as a gum.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7]2.CO>O1CCCC1>[F:1][C:2]([F:14])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH:9]([OH:13])[CH2:8][CH2:7]2
Reactant: O=C1CCc2cc(OC(F)(F)F)ccc21
Solvent: CO
Solvent: C1CCOC1
Product: OC1CCc2cc(OC(F)(F)F)ccc21
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 28.6 %

Procedure:
(2S)-1-(1,3,2-Dioxaborolan-2-yloxy)-3-methyl-1,1-diphenylbutan-2-amine (33 mg, 0.1 mmol) obtained in a similar manner to the method of European Journal of Organic Chemistry, 1999, p. 1775 (Eur. J. Org. Chem. 1999, 1775) was suspended in tetrahydrofuran (5 mL), and then thereto was added borane dimethylsulfide complex (10 mol/L, 0.1 mL, 1 mmol) at room temperature. The mixture was stirred at the same temperature for 20 minutes, and then thereto was added in divided portions 5-trifluoromethoxyindan-1-one (0.217 g, 1 mmol) obtained in a similar manner to the method of U.S. Pat. No. 6,159,996 over 1 hour, and the mixture was stirred at room temperature overnight. The mixture was cooled to 5° C., and then thereto was added methanol (2 mL). The mixture was stirred at the same temperature for 1 hour, and then the reaction solution was concentrated, and then thereto was added chloroform. The chloroform solution was poured into saturated aqueous ammonium chloride solution, and extracted with chloroform three times, and the organic layer was washed with saturated brine. The resultant was dried over magnesium sulfate, and then concentrated. To the resulting residue were added diethyl ether and hexane, and the generated white solid was filtered off. The filtrate was concentrated to give a crude 5-(trifluoromethoxy)indan-1-ol (62.5 mg). The resultant was used in the next step without further purification.
Reaction SMILES: C(O)(=O)C.CC(O)C.[CH3:9][N:10]([CH3:23])[C:11]1[C:16]([N+:17]([O-])=O)=[C:15]([O:20][CH2:21][CH3:22])[N:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>O.[Fe].CC(C)=O>[NH2:17][C:16]1[C:11]([N:10]([CH3:9])[CH3:23])=[N:12][CH:13]=[N:14][C:15]=1[O:20][CH2:21][CH3:22]
Reactant: CCOc1ncnc(N(C)C)c1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Solvent: CC(C)=O
Product: CCOc1ncnc(N(C)C)c1N
Temperature: 80 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A mixture of 3 g of iron dust, 0.3 g of acetic acid and 2.5 ml of water was refluxed with heating for 30 minutes, allowed to cool at 80° C. and mixed with 10 ml of 2-propanol and gradually 2.33 g of 4-dimethylamino-6-ethoxy-5-nitropyrimidine. The resultant mixture was stirred at the same temperature for 1 hour, allowed to cool at 40° C., mixed with solution of 0.9 g of potassium carbonate in 1.5 ml of water and stirred for further 1 hour. Acetone was added to the mixture, which was filtered through Celite. The filtrate was concentrated in vacuo, and the residue was mixed with water and shaken with ether. The organic layer was washed with water and saturated saline in order, dried over anhydrous sodium sulfate and the solvent evaporated to give 1.80 g of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[N+:15]([O-:17])=[O:16])=[O:4].C(N(CC)CC)C.[O:25](C(OC(C)(C)C)=O)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=O.O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:25])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[N+:15]([O-:17])=[O:16])=[O:4]
Reactant: COC(=O)c1cc2cc(C)cc([N+](=O)[O-])c2[nH]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc2cc(C)cc([N+](=O)[O-])c2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
5-Methyl-7-nitro-1H-indole-2-carboxylic acid methyl ester (24.0 g, 100 mmol) prepared in Preparation 15 was dissolved in dichloromethane (500 mL), to which were added triethylamine (84 mL, 601 mmol) and 4-(dimethylamino)pyridine (600 mg, 5 mmol). (BOC)2O (43.7 g, 200 mmol) dissolved in dichloromethane (100 mL) was added in drops thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added. The reaction mixture was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (34.0 g, Yield 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](OCl)(=[O:14])[CH2:11][CH2:12][CH3:13]>>[C:10]([O:9][C:3]1[C:2]([Cl:1])=[CH:7][NH:6][C:5](=[O:8])[CH:4]=1)(=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: CCCC(=O)OCl
Product: CCCC(=O)Oc1cc(=O)[nH]cc1Cl
Yield: 12.8 %

Procedure:
The general procedure of Example 3 was followed using 2.00 g of 5-chloro-4-hydroxy-2-pyridone and 2.20 g of butanoyloxy chloride, thereby producing 0.38 g of the title compound in a yield of 13%.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.[CH:9]([O:11][CH2:12][CH3:13])=[CH2:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[CH2:9]([O:11][CH:12]([O:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)[CH3:13])[CH3:10]
Reactant: C=COCC
Reactant: OCc1c[nH]cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(C)OCc1c[nH]cn1
Reaction time: 2 h

Procedure:
To a flask containing 4 gms 4-hydroxymethyl imidazole hydrochloride in 30 ml dimethylformamide add 3.1 ml vinylethyl ether and 50 mg paratoluene sulfonic acid. Stir for 11/2 hours until the reaction is complete. Extract from saturated K2CO3 /NaCl with ethylacetate to obtain 1-ethoxy-1-(imidazol-4-yl)methoxy ethane.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:23]3[CH:24]=[N:25][C:26]([C:27](O)=[O:28])=[C:22]3[CH2:21][N:20]([CH3:30])[C:19](=[O:31])[C:18]=2[CH:32]=1.C(=O)=O.N>CN(C)C=O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:23]3[CH:24]=[N:25][C:26]([C:27]([NH2:3])=[O:28])=[C:22]3[CH2:21][N:20]([CH3:30])[C:19](=[O:31])[C:18]=2[CH:32]=1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2ccc(Cl)cc2C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Agent: O=C=O
Solvent: CN(C)C=O
Product: CN1Cc2c(C(N)=O)ncn2-c2ccc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
2.7 g (16.8 mmol) of 1,1'-carbonyldiimidazole were added portionwise to a suspension of 4.7 g (16.0 mmol) of 8-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid in 25 ml of N,N-dimethylformamide. After the CO2 evolution had finished the mixture was heated to 60° for 45 min. Subsequently, the solution was cooled to room temperature and 3.9 ml of conc. aqueous ammonia solution were added dropwise thereto. After stirring for a further 90 minutes the reaction mixture was poured into 90 ml of ice-water and stirred for 1 hr. The white crystals were filtered off under suction and washed with a small amount of water. After drying in a high vacuum there were obtained 3.84 g (83%) of 8-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide of m.p. 275°-277°.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>C1COCC1>[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([N:12]1[C:13]2[C:18](=[CH:17][N:16]=[CH:15][CH:14]=2)[C:10]([C:7]2[CH2:8][CH:9]3[N:4]([CH2:3][CH2:2][CH2:1]3)[CH2:5][CH:6]=2)=[CH:11]1)=[O:33]
Reactant: C1=C(c2c[nH]c3ccncc23)CC2CCCN2C1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1Cl)n1cc(C2=CCN3CCCC3C2)c2cnccc21
Reaction time: 0.17 h
Yield: 56.3 %

Procedure:
To a THF (1 mL) solution of 3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1H-5-azaindole (10 mg, 0.0418 mmol) at RT, 1M NaN(TMS)2 (100 μL, 0.1 mmol) was added and the mixture stirred for 10 mins. 2-chlorobenzoyl chloride (13 μL, 0.103 mmol) was added and the reaction mixture stirred overnight. After dilution with dichloromethane, purification by column chromatography with 2% methanol (2M/NH3) in dichloromethane gave 1-(2-chlorobenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole (8.9 mg, 56.4%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[S:12]1[CH:16]=[C:15]([CH2:17][OH:18])[N:14]=[CH:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[S:12]1[CH:16]=[C:15]([CH2:17][O:18][C:2]2[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=2)[N:14]=[CH:13]1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: OCc1cscn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(OCc2cscn2)cn1
Temperature: 40 °C
Reaction time: 72 h
Yield: 42.2 %

Procedure:
A RBF was charged with methyl 5-chloropyrazine-2-carboxylate (1.239 g, 7.18 mmol, Ark Pharm), thiazol-4-ylmethanol (0.8266 g, 7.18 mmol), cesium carbonate (0.689 ml, 8.61 mmol, Alfa Aesar) and DMF (20.51 ml). The reaction mixture was stirred at 40° C. for 3 days. The reaction mixture was allowed to cool to rt and was diluted with water and extracted with EtOAc. The organic extract was washed with water, satd NaCl, dried over MgSO4, and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and purified by silica gel flash chromatography, eluting with a gradient of 10% to 100% EtOAc in hexane, to provide methyl 5-(thiazol-4-ylmethoxy)pyrazine-2-carboxylate (0.7606 g, 3.03 mmol, 42.2% yield). MS m/z=252.1 [M+H]+. Calculated for C10H9N3O3S: 251.036. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.89 (s, 2H) 5.60 (s, 1H) 7.86 (d, J=1.96 Hz, 1H) 8.46 (d, J=1.37 Hz, 1H) 8.86 (d, J=1.37 Hz, 1H) 9.14 (d, J=1.96 Hz, 1H)
Reaction SMILES: N1CCOCC1.BrC1OC(C=O)=CC=1.[N:15]1([C:21]2[O:25][C:24]([CH:26]=O)=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:33][C:34]#[N:35]>>[CH3:28][O:29][C:30]1[CH:31]=[C:32](/[C:33](=[CH:26]/[C:24]2[O:25][C:21]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:22][CH:23]=2)/[C:34]#[N:35])[CH:36]=[CH:37][C:38]=1[O:39][CH3:40]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc(N2CCOCC2)o1
Agent: O=Cc1ccc(Br)o1
Solvent: C1COCCN1
Product: COc1ccc(/C(C#N)=C/c2ccc(N3CCOCC3)o2)cc1OC
Yield: 39.3 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from morpholine (523 mg) was introduced into 5-bromo-2-furaldehyde (350 mg), to thereby yield 5-morpholin-4-yl-furan-2-carbaldehyde (yield: 138 mg, 38%). The produced 5-morpholin-4-yl-furan-2-carbaldehyde (137 mg) was condensed with 3,4-dimethoxybenzyl cyanide (135 mg) through Method A (production step 2), to thereby yield the target product (yield: 102 mg, 40%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:13]=[C:12]([F:22])[CH:11]=2)=[CH:4][C:3]=1[NH:24][C:25](=[O:41])[C:26]1[CH:31]=[C:30]([N:32]2[CH2:38][CH2:37][CH2:36][N:35]([CH3:39])[CH2:34][CH2:33]2)[CH:29]=[CH:28][C:27]=1[NH2:40].[CH:42](OCC)(OCC)OCC>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH:13]=[C:12]([F:22])[CH:11]=2)=[CH:4][C:3]=1[N:24]1[C:25](=[O:41])[C:26]2[C:27](=[CH:28][CH:29]=[C:30]([N:32]3[CH2:38][CH2:37][CH2:36][N:35]([CH3:39])[CH2:34][CH2:33]3)[CH:31]=2)[N:40]=[CH:42]1
Reactant: CCOC(OCC)OCC
Reactant: CN1CCCN(c2ccc(N)c(C(=O)Nc3cc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)ccc3F)c2)CC1
Product: CN1CCCN(c2ccc3ncn(-c4cc(NC(=O)c5cc(F)cc(N6CCOCC6)c5)ccc4F)c(=O)c3c2)CC1
Yield: 63 %

Procedure:
Using an analogous procedure to that described in Example 18, N-[2-fluoro-5-(3-fluoro-5-morpholinobenzamido)phenyl]-2-amino-5-(4-methylhomopiperazin-1-yl)benzamide was reacted with triethyl orthoformate to give the title compound in 63% yield; NMR Spectrum: (DMSOd6) 1.92 (m, 2H), 2.25 (s, 3H), 2.46 (m, 2H), 2.64 (m, 2H), 3.21 (t, 4H), 3.53 (t, 2H), 3.6 (m, 2H), 3.72 (t, 4H), 6.99 (d, 1H), 7.12 (d, 1H), 7.23 (m, 1H), 7.3 (s, 1H), 7.36 (m, 1H), 7.48 (t, 1H), 7.58 (d, 1H), 7.87 (m, 1H), 7.96 (m, 1H), 8.06 (s, 1H), 10.43 (s, 1H); Mass Spectrum: M+H+575.
Reaction SMILES: NC(N)=O.CN(C)C=O.Br[CH2:11][C:12](=[O:21])[C:13](=[N:19][OH:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>O>[OH:21][C:12]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:19][O:20][CH:11]=1
Reactant: CCOC(=O)C(=NO)C(=O)CBr
Agent: NC(N)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nocc1O
Temperature: 100 °C
Yield: 40 %

Procedure:
144 g of urea were added to 1 liter of a dimethylformamide solution containing 72 g of ethyl 4-bromo-2-hydroxyimino-3-oxobutyrate. The reaction solution was heated for 15 minutes at 100° C. and then cooled, after which water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with dilute aqueous hydrochloric acid and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and a 1:1 by volume mixture of ethyl acetate and hexane was added to the residue, to remove insoluble materials. The solution thus obtained was purified by silica gel chromatography, eluted with a 1:4 by volume mixture of ethyl acetate and hexane, to give 19 g of the title compound, melting at 59°-60° C. (after recrystallization from a mixture of ethyl acetate and hexane).