Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][NH:4][C:3]1=[S:8].C(O)(=O)C.C(O)(=O)C.[OH:17][C:18]1[C:19]([CH2:28]O)=[CH:20][C:21]2[O:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:27]=1>>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][N:4]=[C:3]1[S:8][CH2:28][C:19]1[C:18]([OH:17])=[CH:27][C:22]2[CH2:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=1
Reactant: OCc1cc2c(cc1O)CCCO2
Reactant: Cc1c[nH]c(=S)n1C
Solvent: CC(=O)O
Product: Cc1cnc(SCc2cc3c(cc2O)CCCO3)n1C
Yield: 29.2 %

Procedure:
In a manner analogous to Example 1, 1,5-dimethylimidazole-2-thione (0.80 g, 6.25 mmal) was treated with 6-hydroxy-7-hydroxymethyl-1,2,3,4-tetrahydrobenzopyran diacetate (1.70 g, 6.25 mmal) to afford 7-(((1,5-dimethyl-1H-imidazole-2-yl)thio)methyl)-6-hydroxy-1,2,3,4-tetrahydrobenzopyran (480 mg, 26%) mp 139°-140° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([CH2:13][CH2:14][NH:15][C:16]2[C:17]3[S:24][CH:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][N:12]=1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][C:8]1[S:9][C:10]([CH2:13][CH2:14][NH:15][C:16]2[C:17]3[S:24][CH:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][N:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(CCNc2ncnc3ccsc23)s1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ncc(CCNc2ncnc3ccsc23)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 14.2 (14.5 mmol) in 1,4-dioxane (30 mL) was added anhydrous HCl (20 mL of a 4 N solution in 1,4-dioxane) after stirring at room temperature for 2 hours the reaction was concentrated to dryness, diluted with water and the solution adjusted to pH 8 with saturated sodium bicarbonate. The slurry was extracted several times with EtOAc and the organic layers were combined, dried and concentrated to provide [2-(2-amino-thiazol-5-yl)-ethyl]-thieno[3,2-d]pyrimidin-4-yl-amine (compound 14.3) in 88% yield.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:10]=[CH:11][C:12]([C:24]2[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][CH:29]=2)=[N:13][C:14]=1[C:15]1[N:23]=[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]2[N:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:23]1[C:15]([C:14]2[C:9]([NH2:8])=[N:10][CH:11]=[C:12]([C:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=3)[N:13]=2)=[N:16][N:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=12
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nc4ccccn4n3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(C2=CCNCC2)nc1-c1nc2ccccn2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 273.4 %

Procedure:
Tert-butyl 4-[5-(bis(tert-butoxycarbonyl)amino)-6-([1,2,4]triazolo[1,5-a]pyridin-2-yl)pyrazin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (77 mg, 0.1297 mmol) was dissolved in DCM (1.6 mL) and treated with TFA (400 μL, 5.192 mmol). The mixture was allowed to stir at ambient temperature for 2 hours and the solvent removed in vacuo. The mixture was azeotroped with DCM (3×) and Ether (3×) and dried under vacuum to furnish the product as a yellow solid (104 mg, quantitative yield). MS (ES+) 294.0
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:33])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:31][CH3:32])=[C:16]([CH2:19][N:20]([CH3:30])[C:21]4([C:27]([NH2:29])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:34]=O>>[Cl:1][C:2]1[C:3]([F:33])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:31][CH3:32])=[C:16]([CH2:19][N:20]([CH3:30])[C:21]4([C:27]([NH2:29])=[O:28])[CH2:26][CH2:25][N:24]([CH3:34])[CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCNCC1
Reactant: C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCN(C)CC1

Procedure:
4-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-carboxamide (Example 16) was reacted with paraformaldehyde using an analogous method to that described for the equivalent step in Example 11 to give 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-1-methylpiperidine-4-carboxamide; 1H NMR Spectrum: (DMSO d6) 1.80 (m, 2H); 2.03-2.17 (m, 10H); 2.66 (m, 2H); 3.64 (s, 2H); 3.95 (s, 3H); 7.08 (s, 1H); 7.17 (m, 2H); 7.30 (t, 1H); 7.51 (m, 1H); 7.57 (m, 1H); 8.34 (s, 1H); 8.42 (s, 1H); 9.68 (s, 1H). Mass Spectrum: (M+H)+ 487.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12]COC)[CH:3]=1.[CH2:16]([S-:19])[CH2:17][CH3:18].[K+]>>[OH:12][C:4]1[CH:3]=[C:2]([S:19][CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCC[S-]
Reactant: COCOc1cc(F)ccc1C(=O)OC
Agent: [K+]
Product: CCCSc1ccc(C(=O)OC)c(O)c1
Yield: 55 %

Procedure:
Using a procedure analogous to Example 66-A, methyl 4-fluoro-2-(methoxymethoxy)benzoate and potassium propanethiolate gave the title compound (6.1 g, 55%).
Reaction SMILES: O[CH2:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12].[N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][CH:14]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>C(#N)C>[N:13]1([CH2:2][N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]2=[O:12])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1
Reactant: O=C1Cc2ccccc2N1CO
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: O=C1Cc2ccccc2N1Cn1cnc2ccccc21
Yield: 25 %

Procedure:
A solution of 1-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one a25 (1 eq, 3.06 mmol, 500 mg), benzimidazole (4 eq, 12.26 mmol, 1.45 g) and carbonyldiimidazole (1 eq, 3.06 mmol, 500 mg) in acetonitrile (3 ml) was irradiated in a microwave apparatus (CEM discover) for 10 minutes (100 w). After evaporation of the acetonitrile under reduced pressure, the crude product was purified by preparative HPLC on reverse phase to give 203 mg of 1-(1H-benzimidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one 167 (25%) after recrystallization in diisopropylether.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:7][CH:6]=1)C.[OH-].[Na+].Cl>CCO.O>[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:23])=[O:3])=[CH:6][CH:7]=1)(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCC(=O)Nc1ccc(C(=O)OCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCC(=O)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
(Scheme 3, Compound I) To a solution of 4-decanoylamino-benzoic acid ethyl ester (2.0 g, 6.6 mmol) in EtOH (30 mL) was added NaOH (10 N, 6 mL, 60 mmol). The resulting mixture was stirred at rt for 3 hours, diluted with H2O (30 mL), acidified to pH˜1.0 using HCl (6N). The precipitates were filtered off by filter paper, washed by H2O and hexanes. This compound was obtained as a white solid. (1.8 g, 6.5 mmol, 98% yield). 1H NMR (DMSO-d6) δ 9.91 (br. s, 1H), 7.76 (d, 2H, J=8.7 Hz), 6.50 (d, 2H, J=8.7 Hz), 2.29 (t, 2H, J=7.5 Hz), 1.57 (m, 2H), 1.25 (m, 12H), 0.85 (t, 3H, J=6.9 Hz). Mass Spec: 278.21 (MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[C:9]([F:17])=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=O.[F:18][C:19]([F:29])([F:28])[O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[Br:7][C:8]1[C:9]([F:17])=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH:25][C:24]1[CH:26]=[CH:27][C:21]([O:20][C:19]([F:18])([F:28])[F:29])=[CH:22][CH:23]=1)=[O:13]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1cccc(Br)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of oxalyl chloride (0.657 mL, 7.50 mmol) in DCM (10 mL) and of DMF (0.01 mL) were added to a suspension of 3-bromo-2-fluorobenzoic acid (1.095 g, 5 mmol) in DCM (10 mL) and the RM was stirred for at RT for 2 h. The solvent was evaporated off under reduced pressure. The residue was dissolved in DCE (10 mL), treated dropwise with a solution of 4-(trifluoromethoxy)aniline (0.744 mL, 5.50 mmol) and DIPEA (1.747 mL, 10.00 mmol) and the RM was stirred for at RT for 1 h. The RM was treated with an aq. NaHCO3 and extracted with DCM. The combined extracts were washed with water, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 100 g, n-hexane/EtOAc 2:1) to afford the title compound as beige crystals. UPLC-MS (Condition 2) tR=1.22 min, m/z=375.9/378.0 [M−H−]−.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH2:20]3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]2=[CH:5][N:4]=1>C(Cl)Cl>[NH2:25][C@H:22]1[CH2:21][CH2:20][C@H:19]([CH2:18][N:9]2[C:7]3=[N:8][C:3]([NH:2][CH3:1])=[N:4][CH:5]=[C:6]3[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10]2)[CH2:24][CH2:23]1
Reactant: CNc1ncc2c(-c3ccccc3)nn(C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Solvent: ClCCl
Product: CNc1ncc2c(-c3ccccc3)nn(C[C@H]3CC[C@H](N)CC3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
To a solution of tert-butyl trans-4-((6-(methylamino)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.082 g, 0.19 mmol) in methylene chloride (3 mL) was added trifluoroacidic acid (0.60 mL). The reaction mixture was stirred at room temperature for 2 h, concentrated and basified by a 7.0 M aqueous solution of ammonia to pH 12. After evaporation, the residue was purified by Isco to provide 1-((trans-4-aminocyclohexyl)methyl)-N-methyl-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine (UNC00000545A) (0.051 g, 80%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.94 (s, 1H), 7.94-7.83 (m, 2H), 7.55-7.44 (m, 2H), 7.44-7.36 (m, 1H), 4.16 (d, J=7.5 Hz, 2H), 3.06-2.91 (m, 1H), 2.99 (s, 3H), 2.13-1.93 (m, 3H), 1.78 (d, J=12.7 Hz, 2H), 1.45-1.14 (m, 4H); 13C NMR (100 MHz, CD3OD) δ 162.87, 157.72, 154.93, 145.73, 133.64, 130.01, 129.95, 127.97, 52.28, 51.32, 49.64, 49.43, 49.21, 49.00, 48.79, 48.57, 48.36, 38.38, 31.91, 29.71, 28.52; MS m/z 337.3 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=1
Reactant: Clc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCCc1ccccc1
Product: Clc1cc2c(NCCc3ccccc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-phenethylamino-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][CH:8]([CH2:11][CH2:12][CH3:13])[CH:9]=O.[O-2].[Pr+3].[O-2].[O-2].[Pr+3]>[Pd]>[CH3:7][CH:8]([CH2:11][CH2:12][CH3:13])[CH2:9][CH:2]1[CH2:3][CH2:4][CH2:5][C:1]1=[O:6]
Reactant: O=C1CCCC1
Reactant: CCCC(C)C=O
Agent: [Pd]
Agent: [O-2]
Agent: [Pr+3]
Product: CCCC(C)CC1CCCC1=O
Temperature: 150 °C
Yield: 89 %

Procedure:
A mixture of 126 g (1.5 moles) of cyclopentanone, 50 g (0.5 mole) of 2-methylpentanal and 10 g of a pulverulent catalyst containing 1% by weight of palladium, 94% by weight of alumina and 5% by weight of praseodymium oxide was initially taken in a 300 ml autoclave. The autoclave was flushed with nitrogen and hydrogen at 20° C., after which H2 was forced in to a pressure of 10 bar and the reaction mixture was then heated at 150° C. under a hydrogen pressure of 30 bar until the pressure remained constant. The catalyst was removed, after which the mixture discharged from the autoclave was fractionated. 74.9 g of pure 2-(2-methylpentyl)-cyclopentanone (bp. 125° C./20 mbar) were obtained, corresponding to a selectivity of 89.2%, based on 2-methylpentanal.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([O:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[C:27](OB(O)O)=[C:26]([O:32][CH3:33])[CH:25]=[C:24]([O:34][CH3:35])[CH:23]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(OCC)(=O)C>COCCOC.O>[CH3:35][O:34][C:24]1[CH:25]=[C:26]([O:32][CH3:33])[CH:27]=[C:22]([CH3:21])[C:23]=1[C:2]1[N:7]2[N:8]=[C:9]([O:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C)c(OB(O)O)c(OC)c1
Reactant: COc1nn2c(Br)cccc2c1NC(=O)OC(C)(C)C
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(C)c(-c2cccc3c(NC(=O)OC(C)(C)C)c(OC)nn23)c(OC)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 63.4 %

Procedure:
After dissolving tert-butyl N-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)carbamate (300 mg) in 1,2-dimethoxyethane (10 mL) and water (5 mL), 6-methyl-2,4-dimethoxyphenylboric acid (258 mg), tetrakis (triphenylphosphine)palladium (0) complex (203 mg) and barium hydroxide octahydrate (415 mg) were added and the mixture was heated and stirred at 80° C. for 3 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (230 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH:11]=[C:12]([C:18]1[S:19][CH:20]=[C:21]([CH3:23])[N:22]=1)[C:13](=O)[CH2:14][O:15][CH3:16])[C:6]#[N:7].[NH2:24][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][C:27]#[N:28].CC(C)([O-])C.[K+]>C(O)(C)C>[C:6]([C:5]1[CH:8]=[CH:9][C:10]([CH:11]2[C:12]([C:18]3[S:19][CH:20]=[C:21]([CH3:23])[N:22]=3)=[C:13]([CH2:14][O:15][CH3:16])[NH:24][C:25]([C:29]([F:32])([F:31])[F:30])=[C:26]2[C:27]#[N:28])=[C:3]([O:2][CH3:1])[CH:4]=1)#[N:7]
Reactant: COCC(=O)C(=Cc1ccc(C#N)cc1OC)c1nc(C)cs1
Reactant: N#CC=C(N)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COCC1=C(c2nc(C)cs2)C(c2ccc(C#N)cc2OC)C(C#N)=C(C(F)(F)F)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.305 mmol) of the compound from example 14A, 41 mg (0.335 mmol) of 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation in analogy to U.S. Pat. No. 3,635,977 and K. Krespan, J. Org. Chem. 34, 42-45 (1969)] and 5.1 mg (0.05 mmol) of potassium tert-butoxide are dissolved in 4 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator, and the crude material is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 18 mg (13% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:19])=[O:4].[Br:22]N1C(=O)CCC1=O>C(#N)C.CCOC(C)=O>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:22])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:19])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)CC(C)N(C(=O)C(F)(F)F)CC2C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)C(C)C2
Reaction time: 8 h

Procedure:
A solution N-trifluoroacetyl-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.452 g, 1.50 mmol) in acetonitrile (20 mL) was treated with N-bromosuccinimide (0.294 g, 1.65 mmol) and stirred overnight at 20 C. The product mixture was diluted with EtOAc (100 mL), washed with sodium bisulfite (50 mL) and brine (50 mL), dried with Na2SO4 and concentrated. Flash chromatography (20% EtOAc in hexane, silica) resulted in a clear oil. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.32 (s, 1 H), 6.62 (m, 1 H), 4.37 (m, 1 H), 3.87 (s, 3 H), 3.81 (m, 1 H), 3.28−3.10 (m, 3 H), 2.73 (m, 1 H), 1.31 (m, 3 H), 1.25 (m, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:16])=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.[Cl:19][C:20]1[C:21]([CH3:30])=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[C:21]([CH3:30])=[C:22]([S:26]([NH:16][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][O:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:18][CH:17]=3)=[C:14]([CH3:15])[N:13]=2)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Cc1nc(N)ccc1COCc1ccc(F)cc1
Product: Cc1nc(NS(=O)(=O)c2cccc(Cl)c2C)ccc1COCc1ccc(F)cc1

Procedure:
This material was prepared in analogy to example 1 from 5-(4-fluoro-benzyloxymethyl)-6-methyl-pyridin-2-ylamine (0.08 g) and 3-chloro-2-methyl-benzenesulfonyl chloride (0.08 g) as an amorphous light yellow solid (0.067 g). MS (ESI−): 433.1 ([M−H]−)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]3[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=3[F:43])(=[O:35])=[O:34])[C:27]=2[F:44])[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[C:27]([F:44])=[C:28]([NH:32][S:33]([C:36]3[C:37]([F:43])=[CH:38][CH:39]=[CH:40][C:41]=3[F:42])(=[O:34])=[O:35])[CH:29]=[CH:30][CH:31]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(N)n3)s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc(-c2sc(C3CCNCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[5-(2-amino-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate (94 mg, 0.145 mmol) in dichloromethane (2 mL) was added TFA (0.5 mL, 6.49 mmol), and the reaction mixture was stirred for 1 h. the reaction mixture was concentrated and the residue was purified using RP-HPLC. The TFA salt was neutralized to the title compound (56 mg). MS (ESI): 547.1 [M+1]+.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:22])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][O:20][CH3:21])[CH2:14]3)[CH:11]=2)[C:6](=[O:23])[C:5]([C:24]([OH:26])=[O:25])=[CH:4]1)[CH3:2].[CH2:27]=O>C(O)=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:22])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:27])[CH:15]([CH2:19][O:20][CH3:21])[CH2:14]3)[CH:11]=2)[C:6](=[O:23])[C:5]([C:24]([OH:26])=[O:25])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(COC)C3)cc21
Reactant: C=O
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(COC)C3)cc21

Procedure:
A 200 mg portion of 1-ethyl-6-fluoro-1,4-dihydro-7-[3-(methoxymethyl)-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid was dissolved in a mixture of 0.6 ml of 37% formaldehyde and 0.75 ml of 90% formic acid, heated on a steam bath for 3 hours and then concentrated in vacuo. The residue was dissolved in 5 ml of water and 1N sodium hydroxide was added to pH 7. The resulting solid was collected, washed with water and dried, giving 180 mg of the desired product, mp 228°-230° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].F[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+].O>C1COCC1.C(OCC)(=O)C>[N+:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCNc1ccccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A mixture of methyl 3-aminopropanoate hydrochloride (15 g, 0.107 mol), 1-fluoro-2-nitrobenzene (14.9 g, 0.107 mol) and K2CO3 (36.6 g, 0.265 mol) in THF (50 mL) was heated at 90° C. and stirred overnight. After cooled to room temperature, water (20 mL) and ethyl acetate (40 mL) were added, and the separated organic layer was dried over Na2SO4, concentrated, and the resulting residue was purified by CombiFlash (PE:EA=4:1) to give methyl 3-((2-nitrophenyl)amino)propanoate (21.4 g, 90%). 1H NMR (300 MHz, CD3OD): δ 2.72 (t, J=6.6 Hz, 2H), 3.64-3.69 (m, 5H), 6.64-6.70 (m, 1H), 7.01-7.04 (m, 1H), 7.46-7.52 (m, 1H), 8.09-8.13 (m, 1H).
Reaction SMILES: [P:1]([O:19][C:20]1[C:40]([CH:41]([CH3:43])[CH3:42])=[CH:39][C:23]2[C:24](=S)[N:25]([C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[CH2:34][CH2:33][CH2:32]4)[C:26](=[O:28])[O:27][C:22]=2[CH:21]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].O.[NH2:45][NH2:46]>C(O)C>[P:1]([O:19][C:20]1[CH:21]=[C:22]([OH:27])[C:23]([C:24]2[N:25]([C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[CH2:34][CH2:33][CH2:32]4)[C:26]([OH:28])=[N:46][N:45]=2)=[CH:39][C:40]=1[CH:41]([CH3:43])[CH3:42])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:2]
Reactant: NN
Reactant: CC(C)c1cc2c(=S)n(-c3ccc4c(c3)CCC4)c(=O)oc2cc1OP(=O)(OCc1ccccc1)OCc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)c1cc(-c2nnc(O)n2-c2ccc3c(c2)CCC3)c(O)cc1OP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
To a stirred solution of 0.52 g (0.84 mmols) of 7 in 15 mL of anhydrous ethanol was added 63 mg (1.27 mmols) of hydrazine hydrate and the mixture stirred at 80° C. for 30 min. The mixture was concentrated and chromatographed on silica gel using 1:1 hexane:ethylacetate to afford 0.16 g of the product 8 as off-white foam.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH:16]=1)[CH:14]=[O:15].[N:18]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O>[C:27]([O:26][C:24]([N:18]1[CH2:23][CH2:22][N:21]([C:9]2[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH:16]=2)[CH:14]=[O:15])[CH2:20][CH2:19]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(O)c(C=O)c2)CC1
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
0.58 g of bis(dibenzylideneacetone)palladium and 0.16 g of tri-tert-butylphosphine are added under nitrogen to 200 ml of toluene, and the resultant solution, which becomes dark red, is stirred at 20° for 30 minutes. 10 g of 5-bromo-2-hydroxybenzaldehyde, 10.2 g of tert-butyl 1-piperazinecarboxylate and 7.2 g of sodium tert-butoxide are then added. The mixture is stirred at 60° for 24 hours and cooled, 800 ml of water are added, and the mixture is extracted with 2×500 ml of ethyl acetate. The organic phases are combined and washed with 300 ml of water, and the solvent is removed at 30° under reduced pressure. The dark-orange oil which remains (11 g) is purified by chromatography (300 g of silica gel; MTB ether/heptane 5:1; 1.5 litres) leaving 7.8 g of pale-yellow crystals (51%), m.p. 84-86°; MS 306 (M+), 250 (100%), 233, 176, 164.