Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:13][NH2:14]>C(O)C>[CH3:13][NH:14][CH2:2][C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: BrCc1cnc2ccccc2n1
Reactant: CN
Solvent: CCO
Product: CNCc1cnc2ccccc2n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
The 2-(bromomethyl)quinoxaline (3.0 g, 13.4 mmol) was added portionwise to a stirring solution of methylamine (30%) in ethanol (100 mL) at 0° C. The reaction was stirred at 0° C. for 2 hours, concentrated, and partitioned between 10% aqueous potassium carbonate/ethyl acetate. The organic phase was dried (MgSO4), decolorized (charcoal) and concentrated. Purification was accomplished by eluting the sample through a short silica plug to yield 1.80 g (78%) of a brown oil.
Reaction SMILES: [C:1]([C:3]1[S:7][N:6]=[C:5]([CH3:8])[C:4]=1[CH2:9]O)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>ClCCl>[Br:31][CH2:9][C:4]1[C:5]([CH3:8])=[N:6][S:7][C:3]=1[C:1]#[N:2]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1nsc(C#N)c1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nsc(C#N)c1CBr
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5-Cyano-4-hydroxymethyl-3-methyl-isothiazole (50% purity) (1.14 g, 3.7 mmol) was dissolved in dichloromethane (10 ml) and triphenyl phosphine (1.07 g, 4.0 mmol) and carbon tetrabromide (1.18 g, 3.6 mmol) were added at 0° C. The mixture was stirred at 0° C. for 2 hours, concentrated and the crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane). The colourless oil (0.65 g) consisted of a 1:1 mixture of methyl ester (see Example I14) and product. The mixture was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1.[C:17](OCC)(=[O:21])[C:18]([CH3:20])=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:10]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:16]=[C:18]([CH3:20])[C:17]2=[O:21])=[CH:7][CH:8]=1
Reactant: COc1ccc(Nc2ccccc2N)cc1
Reactant: CCOC(=O)C(C)=O
Product: COc1ccc(-n2c(=O)c(C)nc3ccccc32)cc1

Procedure:
Preparation as in Example 1 but using N-(4-methoxyphenyl)benzene-1,2-diamine and ethyl pyruvate gave the title compound mp 230°-232° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13])=[CH:5][CH:4]=1.[N:15]([O-])=[O:16].[Na+]>C1COCC1.C(OCC)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:14])/[C:10](=[N:15]\[OH:16])/[CH2:11][CH2:12][CH3:13])=[CH:7][CH:8]=1
Reactant: CCCCC(=O)c1ccc(Br)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC/C(=N/O)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.1 %

Procedure:
The conc. HCl (40 mL) was added dropwise to a solution of 1-(4-bromophenyl)pentan-1-one (4.68 g, 19.41 mmol) and sodium nitrite (4.02 g, 58.2 mmol) in THF (80 ml) at 0° C. and allowed to warm to room temperature and stirred 18 hours. The reaction mixture was diluted with diethyl ether and the organic phase washed with sat'd NaHCO3 and brine. Concentration gave (Z)-1-(4-bromophenyl)-2-(hydroxyimino)pentan-1-one 3.1 g (33%) as an oil which was used without further purification.). RT=2.1 min, (Condition 1) LCMS: Anal. Calcd. for C11H12BrN1O2 270.01. found: 270.15 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[O:16][N:15]=[C:14]([CH3:17])[C:13]=2[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:19]1([N:25]=[C:26]=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:25][C:26](=[O:27])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[O:16][N:15]=[C:14]([CH3:17])[C:13]=3[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1noc(NS(=O)(=O)c2ccc(N)cc2)c1C
Reactant: O=C=NC1CCCCC1
Product: Cc1noc(NS(=O)(=O)c2ccc(NC(=O)NC3CCCCC3)cc2)c1C

Procedure:
This compound was prepared from 4-amino-N-(3,4-dimethyl-5-isoxazolyl)benzene-sulfonamide and cyclohexyl isocyanate according to the method in Example 110 in 75% crude yield. Further purification was achieved by preparative HPLC (76% recovery), furnishing the pure product as a white solid, m.p. 190°-195° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[Si:42]([O:49][CH2:50][CH2:51][CH2:52]O)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:52][CH2:51][CH2:50][O:49][Si:42]([C:45]([CH3:46])([CH3:48])[CH3:47])([CH3:43])[CH3:44])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCO[Si](C)(C)C(C)(C)C)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate was treated with 3-{[tert-butyl(dimethyl)silyl]oxy}-1-propanol (J. Org. Chem. 1986, 51, 3388-3390)/triphenyl phosphine/diisopropyl azodicarboxylate as described in step a (Example 213) to provide the title compound as solid foam. 1H NMR (DMSO-d6): δ 0.0 (6H, s), 0.78 (3H, d), 0.8 (9H, s), 0.82 (3H, d), 1.2 (1H, dd), 1.4 (1H, quintuplet), 1.8 (2H, quintuplet), 1.9-2.0 (1H, m), 2.38 (1H, dd), 2.6-2.8 (3H, m), 2.9 (1H, d), 2.98 (1H, dd), 3.2-3.3 (2H, m), 3.35-3.45 (1H, m), 3.5-3.6 (3H, m), 3.7 (2H, t), 3.8 (1H, dd), 3.9 (2H, t), 4.8 (1H, dt), 5.0 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.75 (2H, d), 7.0-7.1 (3H, m), 7.18 (1H, d), 7.2 (1H, s), 7.28 (1H, d); MS: 765 (MH+)
Reaction SMILES: [CH3:1][N:2]([S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)(=[O:33])=[O:32])[C:3]1[CH:4]=[C:5]([O:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][N:18]3[CH2:23][CH2:22][S:21][CH2:20][CH2:19]3)[CH2:15][N:16]=1)=[CH:8]2.[OH-].[Na+]>O1CCCC1.C(O)C>[CH3:1][N:2]([S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)(=[O:33])=[O:32])[C:3]1[CH:4]=[C:5]([O:24][CH2:25][C:26]([OH:28])=[O:27])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][N:18]3[CH2:23][CH2:22][S:21][CH2:20][CH2:19]3)[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCOC(=O)COc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCSCC4)S3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(c1cc(OCC(=O)O)cc2cc(C3=NCC(CN4CCSCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.3 %

Procedure:
To a solution of ethyl ({7-[methyl(pyridin-2-ylsulfonyl)amino]-2-[5-(thiomorpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-5-yl}oxy)acetate (275 mg) in tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (0.70 mL), and the mixture was stirred overnight at room temperature. The organic solvent was evaporated under reduced pressure, and the residue was neutralized with 1N hydrochloric acid. The mixture was extracted with a mixed solvent of tetrahydrofuran-ethyl acetate, and the combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (137 mg, yield 53%) as colorless crystals. melting point 132-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]2)(O)[CH3:9])=[N:6][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]2)=[CH2:9])=[N:4][CH:3]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(C)(O)c2ncc(Cl)cn2)CC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(c1ncc(Cl)cn1)[C@H]1CC[C@H](C(=O)OC)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of methyl trans-4-[1-(5-chloropyrimidin-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate (54 mg, 0.18 mmol) and triethylamine (36 mg, 0.36 mmol) in dichloromethane (2 mL) was added in portions methanesulfonyl chloride (22 mg, 0.2 mmol) at 0° C. for 10 minutes. The mixture was stirred for 3 hours at 0° C. followed by dilution with brine and extraction with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (ethyl acetate/petroleum ether) to give methyl trans-4-[1-(5-chloropyrimidin-2-yl)ethenyl]cyclohexanecarboxylate. MS ESI calc'd for C14H18ClN2O2 [M+H]+ 281. found 281. 1H NMR: (400 MHz, CDCl3) δ 8.64 (s, 2H), 6.37 (s, 1H), 5.47 (s, 1H), 3.68 (s, 3H), 2.99-2.96 (m, 1H), 2.37-2.34 (m, 1H), 2.08-1.96 (m, 4H), 1.66-1.60 (m, 2H), 1.34-1.25 (m, 2H).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[OH:9][C:10]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:11]=1[CH:12]=O>O.CO>[OH:9][C:10]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:11]=1[CH:12]=[N:7][OH:8]
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(O)c(C=NO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
A solution of 68.0 g (0.83 mol) of sodium acetate and 68.0 g (0.98 mol) of hydroxylamine hydrochloride in 300 ml of water is added dropwise to a solution of 80.5 g (0.45 mol) of 2-hydroxy-5-methoxycarbonylbenzaldehyde in 300 ml of methanol and the mixture is stirred at 25° C. for 2 hours. The product which has precipitated is filtered off with suction, washed with water and dried in vacuo over phosphorus pentoxide to give 70.4 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([C@H:12]1[N:20]([C:21](=[O:40])[C@@H:22]([NH:26][C:27](=[O:39])[C@@H:28]([N:30](C)[C:31](=O)OC(C)(C)C)[CH3:29])[CH:23]([CH3:25])[CH3:24])[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([C@H:12]1[N:20]([C:21](=[O:40])[C@@H:22]([NH:26][C:27](=[O:39])[C@@H:28]([NH:30][CH3:31])[CH3:29])[CH:23]([CH3:25])[CH3:24])[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)[C@@H]2Cc3cccnc3N2C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1cc(C)ccc1F)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
In a 50 mL round-bottomed flask, tert-butyl (S)-1-((S)-1-((S)-2-(2-fluoro-5-methylphenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (49 mg, 88.2 μmol, Eq: 1.00) was combined with DCM (3 mL) to give a colorless solution. TFA (1.00 mL, 13.0 mmol, Eq: 147) was added. The reaction was stirred at rt for 1 h and then concentrated in vacuo. The residue taken up in DCM, washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated in vacuo to give (S)-1-[(S)-3-Methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (2-fluoro-5-methyl-phenyl)-amide as a white foam (37 mg), m/z=456 (M+H).
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@@H:29]([O:30]C(=O)C)[C@H:28]([O:34]C(=O)C)[C@@H:27]([CH2:38][O:39]C(=O)C)[O:26][C@H:9]1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=O)C>CO>[O:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[C@@H:9]1[O:26][C@H:27]([CH2:38][OH:39])[C@@H:28]([OH:34])[C@H:29]([OH:30])[C@H:8]1[OH:7]
Reactant: COc1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
Sodium methoxide (28% methanol solution; 0.12 mL) was added to a solution of 2-(4-methoxybenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.11 g) in methanol (4 mL) and the mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 2-(4-methoxybenzyl)phenyl β-D-glucopyranoside (65 mg).
Reaction SMILES: [OH:1][C:2]1([C:18]([O:20]C)=[O:19])[C:11]2[C:6](=[C:7]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=[C:9]([Cl:12])[CH:10]=2)[O:5][CH2:4][CH2:3]1.[OH-].[K+].O>C(O)(C)C>[OH:1][C:2]1([C:18]([OH:20])=[O:19])[C:11]2[C:6](=[C:7]([O:13][C:14]([F:17])([F:15])[F:16])[CH:8]=[C:9]([Cl:12])[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: COC(=O)C1(O)CCOc2c(OC(F)(F)F)cc(Cl)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)C1(O)CCOc2c(OC(F)(F)F)cc(Cl)cc21

Procedure:
A solution of 4-hydroxy-6-chloro-8-trifluoromethoxychroman-4-yl carboxylic acid, methyl ester in iso-propanol (50 mL) was added to KOH/H2O (20%, 60 mL) and the mixture was refluxed overnight. The resultant solution was partially concentrated, and the remainder was acidified with H2SO4 (10%). The very turbid mixture was extracted with ether (3×), and the combined organic phase was dried (Na2SO4) and concentrated. The crude product was purified via prep-HPLC (CH3CN:0.1M ammonium acetate (30:60)). The fractions of interest were partly concentrated and extracted with ether. The combined organic layers were washed with water, dried (Na2SO4), and concentrated, yielding 0.24 g (10% over steps (vi)-(ix)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:32][C:31]2[CH:30]=[CH:29][C:28]([N:25]3[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]3)=[CH:34][CH:33]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Product: CN1CCN(c2ccc(NC(=O)c3cc([N+](=O)[O-])c(Sc4c(Cl)cncc4Cl)s3)cc2)CC1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 4-(4-methylpiperazin-1-yl)aniline (19.0 mg, 0.12 mmol). The title compound was obtained as a solid (10.0 mg, 19% yield). MS m/z: 524.00, 526.00 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:18])[N:8]3[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17].C(N(CC)CC)C.[F:26][C:27]([F:35])([F:34])[C:28]([F:33])([F:32])[C:29](O)=[O:30]>C(#N)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:18])[N:8]3[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:29](=[O:30])[C:28]([F:33])([F:32])[C:27]([F:35])([F:34])[F:26]
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: Cc1nc2cccc3n(CCCCN)c(=O)c1n23
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc2cccc3n(CCCCNC(=O)C(F)(F)C(F)(F)F)c(=O)c1n23
Temperature: 25 °C

Procedure:
To a solution of 2.44 g (10.0 mmol) of 3-methyl-1-[4-(amino)butan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one and 1.81 ml (13.0 mmol) of triethylamine in 100 ml of acetonitrile was added, while stirring at room temperature, 2.31 g (12.0 mmol) of ethyl ester of pentafluoropropionic acid. The mixture was stirred for 14 hours at the same temperature. The solvent was distilled off. To the residue was added methylene chloride. The mixture was washed with water, which was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent:ethyl acetate), and recrystallized from ethyl acetate—hexane to afford 1.53 g (39.1%, a colorless crystals) of the desired compound.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:16]=[C:15]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[OH-].[Na+].Cl>CO>[CH3:13][N:9]([CH2:10][CH2:11][CH3:12])[C:7](=[O:8])[C:6]1[CH:5]=[C:4]([CH:16]=[C:15]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH:14]=1)[C:3]([OH:22])=[O:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(-c2nccs2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(-c2nccs2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve N-Methyl-N-propyl-5-thiazol-2-yl-isophthalamic acid methyl ester (150 mg, 0.47 mmol) in methanol (6 mL). Add dropwise 2 N NaOH (0.3 mL) and stir overnight at room temperature. Acidify the mixture to about pH=6 by 5 N HCl and concentrate to near dryness. Dilute with ethyl acetate (20 mL) and wash the organic layer with saturated aqueous sodium chloride solution, dry (magnesium sulfate) and concentrate to give the title compound as an oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][CH:21]=2)[N:11]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][NH:16]3)=[C:12]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([NH2:26])=[O:25])=[CH:27][CH:28]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: NC(=O)c1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Product: NC(=O)c1ccc(Nc2nc(N[C@H]3CC[C@H](N)CC3)nc3[nH]cnc23)cc1

Procedure:
800 mg of trans-1,4-diaminocyclohexane are heated to its melting point (70° C.) and 289 mg of the product obtained in stage 1 above are added. 147 mg of the expected product are thus obtained.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[C:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:5][N:4]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[F:29]>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:4]2[CH:5]=[C:6]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:7]([CH2:9][O:10][CH3:11])=[CH:8][C:3]2=[O:2])=[C:23]([F:29])[CH:24]=1
Reactant: Fc1cc(Cl)ccc1CBr
Reactant: COCc1cc(OC)ncc1-c1ccc(OC)cc1
Product: COCc1cc(=O)n(Cc2ccc(Cl)cc2F)cc1-c1ccc(OC)cc1
Yield: 0.8 %

Procedure:
According to Scheme 31 Step 4: The title compound was prepared from 2-methoxy-4-(methoxymethyl)-5-(4-methoxyphenyl)pyridine (1 eq, 0.66 mmol, 0.17 g) and 1-(bromomethyl)-4-chloro-2-fluorobenzene (1.5 eq, 0.98 mmol, 0.22 g) according to the procedure described for Example 6 Step 2. Reaction conditions: 12 hours at 80° C. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/MeOH 98/2 as the eluent to afford 1-(4-chloro-2-fluorobenzyl)-4-(methoxymethyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (5 μmol, 2 mg, 1%) as yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:8]=O)=[C:5]([CH3:7])[N:6]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:17][C:18](=[O:20])[CH3:19])C=CC=CC=1.O>CS(C)=O>[CH3:1][C:2]1[S:3][C:4]([CH:8]=[CH:17][C:18](=[O:20])[CH3:19])=[C:5]([CH3:7])[N:6]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nc(C)c(C=O)s1
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)C=Cc1sc(C)nc1C
Yield: 81.8 %

Procedure:
A solution of 2,4-dimethylthiazole-5-carboxaldehyde (2.0 g) and 1-triphenylphosphoranylidene-2-propanone (8.2 g) in dimethylsulphoxide (140 ml) was stirred at ambient temperature for 24 hr. The solution was poured into water (400 ml) and extracted with dichloromethane. The dried (Na2SO4) organic extract was evaporated and the residue was purified by column chromatography over silica with ethyl acetate/n-hexane (1:1 v/v) elution to give 1-(2,4-dimethyl-5-thiazolyl)but-1-en-3-one (2.1 g). Pmr spectrum (CDCl3 ; δ in ppm): 2.32 (3H,s); 2.49 (3H,s); 2.67 (3H,s); 6.30 (1H,d); 7.60 (1H,d).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].[CH:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+]>CO.ClCCl>[CH2:5]([NH:1][CH2:2][CH2:3][NH2:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCN
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: NCCNCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
60.0 g (998 mmol) of 1,4-diazabutane is dissolved in 750 ml of absolute methanol and cooled to 0° C. At this temperature, the drop-by-drop addition of 20.0 g (188 mmol) of benzaldehyde, dissolved in 100 ml of absolute methanol, is carried out. After a reaction time of 2 hours at 0° C., the addition in portions of a total of 7.13 g (188 mmol) of sodium borohydride is carried out. After 12 hours at 25° C., the reaction solution is suctioned off on diatomaceous earth, and the solvent is drawn off in a vacuum. The remaining oily residue is taken up in 500 ml of dichloromethane and washed three times with 100 ml of water in each case. After the organic phase is dried on sodium sulfate, the solvent is drawn off in a vacuum. The oily residue that is thus obtained is chromatographed on silica gel (eluant: methanol/aqueous ammonia solution 20:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)[CH:7]=[CH:6]2.[Br:23]Br>C(Cl)Cl>[Br:23][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)=[N:9]2
Reactant: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3n2)cc1
Reactant: BrBr
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc3c(Br)c(OC)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of methyl 4-(6-methoxyquinolin-2-yl)benzoate (630 mg, 2.15 mmol) in DCM (9 mL) was added Br2 (0.3 mL, 6.45 mmol). The reaction mixture was stirred at room temperature overnight. Then the mixture was partitioned with brine and DCM. The precipitate was filtered and dried to give the product as a solid (800 mg, 100%). MS (ESI): m/z=373.0 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[C:5]([CH3:13])=[N:4][N:3]=1.[CH2:14](Br)[C:15]#[CH:16].C([O-])([O-])=O.[K+].[K+].CC(C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:16][C:15]#[CH:14])=[CH:9][CH:10]=2)[C:5]([CH3:13])=[N:4][N:3]=1
Reactant: C#CCBr
Reactant: Cc1nnc(Cl)c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: C#CCOc1ccc2c(Cl)nnc(C)c2c1
Temperature: 68 °C
Reaction time: 23 h
Yield: 43.8 %

Procedure:
The mixture of 1-chloro-6-hydroxy-4-methylphthalazine (8) (195 mg, 1.00 mmol), 80% propargyl bromide (1.30 mmol) in toluene (145 μL), K2CO3 (187 mg, 1.35 mmol), and acetone (8 mL) is stirred at 68° C. under argon for 23 h, and then cooled to room temperature. The mixture is concentrated, diluted with H2O (40 mL), and extracted with ethyl acetate (70 mL and 60 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (33% to 56% ethyl acetate/hexane) to give 102 mg (44%) of 11 as alight-yellow solid, mp 178-180° C. IR 2946, 1615, 1378, 1234 cm−1; 1H NMR (DMSO-d6) δ 2.61 (t, J=2.1 Hz, 1H, CH≡C), 2.93 (s, 3H, CH3), 4.91 (d, J=2.1 Hz, 1H, CH≡CCH2), 7.40 (d, J=2.4 Hz, 1H, 5-PhthH), 7.58 (dd, J=9.1, 2.4 Hz, 1H, 7-PhthH), 8.23 ppm (d, J=9.1 Hz, 1H, 8-PhthH).