Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([NH:13][C:14]3[CH:23]=[C:22]4[C:17]([CH2:18][CH2:19][CH2:20][N:21]4C(=O)C(F)(F)F)=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+]>O.CO>[NH:21]1[C:22]2[C:17](=[CH:16][CH:15]=[C:14]([NH:13][C:11](=[O:12])[C:10]3[CH:30]=[CH:31][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8][CH:9]=3)[CH:23]=2)[CH2:18][CH2:19][CH2:20]1
Reactant: O=C(Nc1ccc2c(c1)N(C(=O)C(F)(F)F)CCC2)c1ccc(-c2ccccc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc2c(c1)NCCC2)c1ccc(-c2ccccc2)nc1

Procedure:
6-Phenyl-N-(1-trifluoroacetyl-1,2,3,4-tetrahydroquinolin-7-yl)nicotinamide (Example 25) (155 mg, 0.364 mmol) and potassium carbonate (252 mg, 1.82 mmol) in water (2 ml) and methanol (8 ml) was stirred at ambient temperature for 40 mins. The resulting suspension was filtered and the solid was washed with water then dried in vacuo to give the title compound as a white solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 9.11 (m, 1H), 8.22 (dd, 1H), 8.03 (m, 2H), 7.82 (d, 1H), 7.75 (br, 1H), 7.48 (m, 3H), 7.06 (d, 1H), 6.91 (d, 1H), 6.62 (dd, 1H), 3.95 (br, 1H), 3.30 (m, 2H), 2.73 (t, 2H), 1.93 (m, 2H).
Reaction SMILES: C1C2C(COC([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[C:23]3[NH:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][C:27]([Br:34])=[CH:28][CH:29]=4)[N:24]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CC#N.O>[Br:34][C:27]1[CH:26]=[C:25]2[C:30]([C:31](=[O:33])[NH:32][C:23]([CH:19]3[CH2:20][CH2:21][CH2:22][NH:18]3)=[N:24]2)=[CH:29][CH:28]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCCC1c1nc2cc(Br)ccc2c(=O)[nH]1
Solvent: C1CCNCC1
Solvent: O
Solvent: CC#N
Product: O=c1[nH]c(C2CCCN2)nc2cc(Br)ccc12
Yield: 53 %

Procedure:
A solution of (9H-fluoren-9-yl)methyl-2-(7-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate (305 mg, 1.04 mmol) and piperidine (2 mL) in CH3CN was stirred at room temperature for 2 h. The mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give 162 mg of the desired product. MS (ESI): 294, 296 (MH+)
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[NH:5][NH:4][C:3]1=[O:8].C1C=CC=CC=1.CN(C)C=O.CC(C)([O-])C.[K+].[CH:26]([C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29])=[CH2:27]>CN(C)C=O>[O:29]=[C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:26][CH2:27][N:4]1[C:3](=[O:8])[N:2]([CH3:1])[C:6](=[O:7])[NH:5]1
Reactant: Cn1c(=O)[nH][nH]c1=O
Reactant: C=CC(=O)CCCCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCCCCC(=O)CCn1[nH]c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 47453.9 %

Procedure:
A solution of 4-methyl-1,2,4-triazolidine-3,5-dione (16 g; 0.14 mmole) in dry 1:1 benzene-dimethylformamide (100 ml) was heated under reflux, with stirring under nitrogen, and potassium t-butoxide (17.62 g), was added. The resultant suspension was heated under reflux for 2 hr. and then n-pentyl vinyl ketone (12,568; 0.10 mole) in dry dimethylformamide (10 ml) added dropwise. After 2 days the mixture was allowed to cool to room temperature and partitioned between 5 M HCl (200 ml) and ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (5×70 ml) and the combined organic layers washed with water (2×100 ml) and brine (100 ml) and dried (Na2SO4). Evaporation in vacuo gave an oil. Recrystallisation from ethyl acetate - 60/80 petroleum ether gave 2-(3'-oxo-octyl)-4-methyl-1,2,4-triazolidine-3,5-dione (16.03 g; 66%). m.pt., 75°-76°
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=O.ClC(OCC(C)C)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[N:20]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C(N(CC)CC)C>[NH2:18][C:19]1[N:20]=[C:21]([NH:25][C:7](=[O:9])[CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(N)n1
Reactant: COCCOCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCOCC(=O)Nc1cccc(N)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4.9 ml of (2-methoxyethoxy)-acetic acid is dissolved in 500 ml of tetrahydrofuran. 9.7 ml of triethylamine and 5.6 ml of isobutyl chloroformate are added at 0° C., and it is stirred for 30 minutes at 0° C. 3.96 g of 2,6-diaminopyridine is added, and it is stirred for another 4 hours at room temperature. The reaction mixture is mixed with semi-saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic solution is washed with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation, and after purification by chromatography on silica gel, 5.04 g of the title compound is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S:21]1[CH2:27][C:25](=[O:26])[NH:24][C:22]1=[S:23].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:14]=[C:27]3[S:21][C:22](=[S:23])[NH:24][C:25]3=[O:26])[CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(COc2cccc(C=O)c2)cc1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(COc2cccc(C=C3SC(=S)NC3=O)c2)cc1

Procedure:
The 3-[4-(t-butyl)benzyloxy]benzaldehyde (2 g, 7.5 mmol) was coupled to rhodanine (1.19 g, 9 mmol) by reacting the two in the presence of sodium acetate (2.42 g, 29 mmol) and acetic acid. The mixutre was heated to reflux and then refluxed overnight.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH:23][C:9](=[O:11])[CH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)c(F)c1
Reactant: NCc1cccc(F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Cc1ccc(-c2ccccc2)c(F)c1)NCc1cccc(F)c1
Reaction time: 8 h

Procedure:
(2-Fluoro-biphenyl-4-yl)-acetic acid (0.12 gm, 0.5 mmole), 3-fluorobenzylamine (0.0.8 ml, 0.6 mmole), PyBOP (0.34 gm, 0.6 mmole), and DIEA (0.22 ml, 1.3 mmole) was dissolved in DMF stirred overnight, the reaction mixture was then poured into water, solid was collected by filtration, re-crystallized using water-methanol. (0.140 gm, 83%); H1-NMR INOVA-500 (DMSO d6) δ 3.580 (s, 2H), 4.316 (d, J=5.5 Hz, 2H), 7.037-7.110 (m, 3H), 7.210-7.247 (m, 2H), 7.343-7.372 (m, 2H), 7.457-7.501 (m, 3H), 7.544 (d, J=8.0 Hz, 2H), 8.660 (t, J=6.0 Hz, 1H). MS (m/z) 338.1 (M+H)+.
Reaction SMILES: [CH:1]1[N:10]2[C:4]([S:5][C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[C:8](=O)[CH2:9]2)=[CH:3][CH:2]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:8]2[C:7]3[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=3[S:5][C:4]3=[CH:3][CH:2]=[CH:1][N:10]3[CH:9]=2)[CH2:19][CH2:18]1
Reactant: O=C1Cn2cccc2Sc2ccccc21
Reactant: CN1CCNCC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Product: CN1CCN(C2=Cn3cccc3Sc3ccccc32)CC1
Reaction time: 3 h
Yield: 34.5 %

Procedure:
A solution of 9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepin-9-one (0.24 g, 1.11 mmol), N-methylpiperazine (0.55 mL, 0.50 g, 4.99 mmol) and trimethylsilyl triflate (0.55 mL, 0.68 g, 3.05 mmol) was heated at 120° C. under stirring, after a few minutes further 0.55 mL of N-methylpiperazine were added and the reaction was kept for 3 hours at 120° C. After that time water was added and was extracted with dichloromethane. The organic layer was dried over sodium sulphate, filtered and evaporated to give the crude product that was purified by means of a flash chromatography (20% methanol in ethyl acetate) to afford 0.114 g of the pure title compound as a yellowish solid (84% yield).
Reaction SMILES: [CH:1]([C:4]1[O:5][CH:6]=[CH:7][C:8]=1[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21]Br)=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:3])[CH3:2].[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24].O.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31]>CS(C)=O>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[CH:1]([C:4]1[O:5][CH:6]=[CH:7][C:8]=1[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][NH:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CC(C)c1occc1S(=O)(=O)c1ccc(OCCCBr)cc1
Agent: O=C(O)C(=O)O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1occc1S(=O)(=O)c1ccc(OCCCNC(C)(C)C)cc1
Reaction time: 24 h

Procedure:
A mixture of 0.00282 mol of 2-isopropyl-3-[4-(3-bromopropyloxy)benzenesulphonyl]furan and 0.013 mol of tert-butylamine in 7 ml of dimethylsulphoxide was stirred at room-temperature for 24 hours. After that, the mixture was poured into water, distilled in the presence of ethyl acetate, dried on sodium sulphate, filtered and concentrated. The residue so obtained was purified on a silica column using a methanol/ethyl acetate 2/8 mixture as eluent. The oily base so provided was then treated with an ethereal solution of oxalic acid and the precipitate was recrystallized from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: C1CCNCC1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.45 minutes; C22H22Cl2N4O2 (445.35); mass spectrum: (M−H)−=444/446/448 (chlorine isotope).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[C:3]=1F.[NH2:13][C:14]1[CH:18]=[CH:17][N:16]([CH2:19][CH3:20])[N:15]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([OH:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[C:3]=1[O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]=[C:22]2[NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH2:19][CH3:20])[N:15]=1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: CCn1ccc(N)n1
Reactant: CS(=O)(=O)c1cccc(F)c1F
Product: CCn1ccc(Nc2ncnc3ccc(Oc4c(F)cccc4S(C)(=O)=O)cc23)n1

Procedure:
The compound of Example 96 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 1,2-difluoro-3-methanesulfonylbenzene, 3-amino-1-ethyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[N:12][C:11]([NH:14][NH2:15])=[N:10][CH:9]=1.[CH:16]([O-])([O-])OCC>CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([CH:16]=[N:15][N:14]=2)[N:13]=1
Reactant: CCOC([O-])[O-]
Reactant: NNc1ncc(-c2ccccc2F)nn1
Solvent: CCCCCC
Product: Fc1ccccc1-c1cnc2nncn2n1

Procedure:
A mixture of 3.8 g. of 6-(o-fluorophenyl)-3-hydrazino-1,2,4-triazine and 40 ml. of ethyl orthoformate is refluxed for 4 hours, cooled and poured into hexane. The solid is separated and washed with ethanol, giving the desired product as a yellow solid, m.p. 193°-196° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@:9]1([CH2:22][OH:23])[CH3:21])=O)(C)(C)C.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25].C(Cl)Cl>>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[Si:14]([O:13][C@@H:10]1[CH2:11][CH2:12][NH:8][C@@:9]1([CH2:22][OH:23])[CH3:21])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@]1(C)CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCN[C@]1(C)CO

Procedure:
(2R,3R)-3-(tert-Butyldimethyl-silanyloxy)-2-hydroxymethyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (58B) (269 mg, 0.78 mmol) was stirred in 17% TFA/CH2Cl2 (6 mL) for 30 min. The reaction was concentrated to provide a brown oil (334 mg). LC/MS m/z 246 [M+H]+
Reaction SMILES: [Br:1][C:2]1[C:19](=[O:20])[NH:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[C:3]=1[OH:21].[NH4+].[Cl-].[CH2:24](Cl)Cl>>[Br:1][C:2]1[C:19]([O:20][CH3:24])=[N:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[C:3]=1[OH:21]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c(=O)c(Br)c(O)c2CC1
Agent: [Cl-]
Agent: [NH4+]
Product: COc1nc2c(c(O)c1Br)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.17 h
Yield: 67 %

Procedure:
NBS (0.668 mmol, 119 mg) was added in one portion to a stirred solution of tert-butyl 4-hydroxy-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (0.607 mmol, 170 mg) in DCM (3 ml) at room temperature. After 3 h of stirring, the reaction was quenched with sat. aq. NaHCO3 and extracted with DCM. The organic layer was dried, concentrated in vacuo and purified purified by column chromatography to provide 180 mg (83%) of tert-butyl 3-bromo-4-hydroxy-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate. Ag2CO3 (0.42 mmol, 116 mg) was added to a solution of tert-butyl 3-bromo-4-hydroxy-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (75.0 mg, 0.21 mmol) in DCM (1.5 ml) at room temperature. After 10 min of stirring, Mel (0.23 mmol, 15 μl) was added. After 5 h of stirring, sat. aq. NH4Cl was added and the mixture was extracted with DCM. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to provide 52 mg (67%) of tert-butyl 3-bromo-4-hydroxy-2-methoxy-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate. The correct regioselectivity was confirmed by NOESY. 1H-NMR (CDCl3) δ 13.21 (1H), 3.85 (3H), 3.65 (2H), 3.55 (2H), 3.05 (2H), 2.85 (2H), 1.49 (9H) ppm. To a solution of tert-butyl 3-bromo-4-hydroxy-2-methoxy-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (51 mg, 0.137 mmol) was added HC1 (2 N in Et2O, 3 ml) at room temperature. After 10 h of stirring, the reaction was quenched with sat. aq. NaHCO3 and extracted with DCM. The organic layer was dried and concentrated in vacuo to provide 33 mg (89%) of 3-bromo-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-4-ol. 1H-NMR (CDCl3) δ 12.02 (br s, 1H), 9.21 (br s, 1H), 3.79 (3H), 3.25 (m, 2H), 3.15 (m, 2H), 3.06 (m, 2H), 2.92 (m, 2H) ppm.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=O)[CH3:2].O.O.[NH2:12][NH2:13]>O>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[N:12][NH2:13])[CH3:2])[CH:5]=1
Reactant: CC(=O)c1cccnc1
Reactant: NN
Solvent: O
Product: CC(=NN)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
To 3-acetylpyridine (6.1 g, 52 mmol) in industrial methylated spirits (50 ml) was added dropwise hydrazine hydrate monohydrate (3.11 ml, 0.1 mol). The reaction mixture was refluxed for 4 h, before cooling to room temperature and stirring for 16 h. Water (25 ml) was added and the volatile organics were removed in vacuo. The predominantly aqueous residual liquor was extracted with ethyl acetate, and the combined organic extracts were dried (Na2SO4) and concentrated to give a yellow oil (5.4 g, 80%) which was taken forward without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11](O)=[O:12])[N:10]=1)=[O:5])[CH3:2].C1COCC1>CO>[OH:12][CH2:11][C:9]1[N:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:7][CH:8]=1
Reactant: CCOC(=O)c1nc(C(=O)O)cs1
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(CO)cs1
Yield: 51.6 %

Procedure:
A mixture of 2-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid (2 g), boran-THF complex (1.0 M in THF, 45.2 ml) and THF (50 ml) was heated under reflux overnight. After MeOH (2.0 ml) was added to the mixture at the same temperature, the mixture was concentrated in vacuo to dryness. The residue was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (0.96 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:19])[C@H:7]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)[NH2:8])([CH3:4])[CH3:3].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CC#N>[CH3:4][C:2]([O:5][C:6](=[O:19])[C@H:7]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)[NH:8][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC(C)(C)C
Yield: 81.6 %

Procedure:
To a solution of L-tryptophan 1,1-dimethylethyl ester (17.10 g; 65.68 mmol) in CH3CN (150 mL) 2M phosphate. buffer (pH 8; 150 mL) was added. Tert-butyl bromoacetate (10.7 mL; 72.25 mmol) was dropped into the mixture and vigorous mechanical stirring set on. The reaction was monitored by HPLC (Chromatographic method of Example 3, A)). After 23 h the organic layer was separated and concentrated to dryness to give a crude oil (26.62 g), which was purified by flash chromatography (silica gel; n-hexane/ethyl acetate, 8:2 v/v) to give the desired product (20.07 g; 53.59 mmol). Yield 54.5% starting from L-tryptophan.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=3)=[CH:7][N:8]2[C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CN1CC=C(c2c[nH]c3cc(Br)ccc23)CC1
Product: COc1ccc(C(=O)n2cc(C3=CCN(C)CC3)c3ccc(Br)cc32)cc1

Procedure:
(17.4 mg, 48%); from 6-bromo-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4f, 25.0 mg, 0.086 mmol) and 4-methoxybenzoyl chloride (26 uL, 0.17 mmol); HRMS-FAB+ for C22H21O2N2Br, calculated MH+ : 425.08646; found: 425.08292.
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:13]>>[NH2:13][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=1
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: N
Product: Nc1nc2ccccc2nc1Cl

Procedure:
2.1 g (10.4 mmol) of 2,3-dichloroquinoxaline are stirred for 8 hours with 50 ml of 20% ethanolic ammonia in an autoclave at 80°–85° C. and autogenous pressure. The reaction solution is evaporated to dryness in a rotary evaporator, and the crude product is chromatographed over silica gel using toluene/ethyl acetate. The product-containing fractions are collected and evaporated in a rotary evaporator. Yield: 1.18 g (63%)
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:19][F:20])[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]2[CH:14]=[C:15](I)[CH:16]=[CH:17][C:5]=2[O:4]1.[F:21][C:22]([F:30])([F:29])[C:23]([F:28])([F:27])C([O-])=O.[K+].C1(C)C=CC=CC=1>CN(C)C=O>[F:27][C:23]([F:28])([C:15]1[CH:16]=[CH:17][C:5]2[O:4][C:3]([CH2:19][F:20])([CH2:2][F:1])[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]=2[CH:14]=1)[C:22]([F:30])([F:29])[F:21]
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(I)cc21
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21

Procedure:
In the same manner as described in Example 3 (6) but using ethyl 2,2-bisfluoromethyl-6-iodo-2H-1-benzopyran-4-carboxylate, potassium pentafluoropropionate, cuprous iodide, toluene and N,N-dimethylformamide, ethyl 6-pentafluoroethyl-2,2-bisfluoromethyl-2H-1-benzopyran-4-carboxylate was obtained as an oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.O.[C:14]([OH:18])(=O)[CH:15]=O.O.[NH2:20][NH2:21]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]1=[N:20][NH:21][C:14](=[O:18])[CH:15]=[C:7]1[CH2:6]2
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: NN
Reactant: O=CC(=O)O
Solvent: O
Product: COc1ccc2c(c1)Cc1cc(=O)[nH]nc1-2

Procedure:
By a method similar to that described in Preparation 3, treatment of 5-methoxy-1-indanone with glyoxylic acid hydrate and hydrazine hydrate gave 7-methoxy-[5H]-indeno-[1,2-c]pyridazin-3[2H]-one (m.p. 280°-4°, from concentrated hydrochloric acid); ν(Nujol mull) 3350-2200, 1680, 1610, 1580, 1259 and 1041 cm-1 ; δ(DMSO-d6) 2.80 (4H,s,5,6-H2), 3.73 (3H,s,CH3O), 6.74 (1H,s,4-H) 7.00 (1H, dd,8-H), 7.29 (1H,dd,9-H), 7.55 (1H,dd,10-H), 12.86 (1H,br,NH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][N:3]=1.[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13].[CH3:24][NH:25][C:26]([C:28]1[CH:33]=[C:32]([O:34][C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[C:37]([F:42])[CH:36]=2)[CH:31]=[CH:30][N:29]=1)=[O:27]>ClC(Cl)C>[CH3:24][NH:25][C:26]([C:28]1[CH:33]=[C:32]([O:34][C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:12]([NH:1][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[N:5]=[CH:4][N:3]=3)=[O:13])=[C:37]([F:42])[CH:36]=2)[CH:31]=[CH:30][N:29]=1)=[O:27]
Reactant: Nc1cc(C(F)(F)F)ncn1
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC(Cl)Cl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(F)(F)F)ncn3)c(F)c2)ccn1
Temperature: 60 °C
Yield: 29.7 %

Procedure:
In a 8-mL screw-cap vial, 4-amino-6-trifluoromethylpyrimidine (170 mg, 1.04 mmol) was added to a slurry of 1,1′-carbonyldiimidazole (169 mg, 1.04 mmol) in dichloroethane (0.35 mL). The mixture was heated at 60° C. for 30 hours. 4-(4Amino-3-fluoro-phenoxy)-pyridine-2-carboxylic acid methylamide (170 mg, 1.04 mmol) was then added and the mixture was heated overnight at to 60° C. The solvent was evaporated under reduced pressure, and the solid residue was washed with methanol to give the title product as a white solid (139 mg, yield 30%). 1H NMR (400 MHz, DMSO-d6) δ 10.6 (s, 1 H), 9.7 (s, 1 H), 9.0 (s, 1 H), 8.8 (s, 1 H), 8.5 (d, 1 H), 8.20 (m, 2 H), 7.40 (m, 2 H), 7.18 (d, 1 H), 7.10 (d, 1 H), 2.80 (s, 3 H). LC-MS m/z 451.3 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]3[N:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][CH:14]=3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(Cl)Cl>[C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([CH2:19][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[N:18]=3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc(Nc2ncc(-c3ccccc3)s2)n1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc(-c2cnc(Nc3cccc(CN4CCCCC4)n3)s2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-(5-Phenyl-thiazol-2-ylamino)-pyridine-2-carbaldehyde (6-5, 0.025 g, 0.088 mmol) was dissolved in 1 mL dichloroethane. Piperidine (0.014 mL, 0.14 mmol), acetic acid (0.010 mL) and NaBH(OAc)3 (0.030 g, 0.14 mmol) were added. The reaction was stirred at room temperature for 1 h. The reaction was then diluted with CH2Cl2, washed with water and extracted 1× with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, concentrated. Purification by reverse phase HPLC afforded the titled compound. 1H NMR (CDCl3): δ9.94 (bs, 1H), 7.61 (m, 4H), 7.59 (d, 2H, J=8.0 Hz), 7.41 (t, 2H, J=7.5 Hz), 7.29 (d, 1H, J=7.3 Hz), 7.06 (d, 1H, J=7.4 Hz), 6.77 (d, 1H, J=8.1 Hz), 3.73 (s, 2H), 2.56 (bs, 4H), 1.64 (m, 4H), 1.26 (m, 2H). M+1: 351.1.