Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[O:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>CN(C=O)C>[N:35]1([CH2:34][CH2:33][O:25][C:22]2[CH:21]=[CH:20][C:19]([O:18][C:10]3[C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[S:13][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:24][CH:23]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: ClCCN1CCCCC1
Reactant: COc1cccc(-c2sc3ccccc3c2Oc2ccc(O)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2sc3ccccc3c2Oc2ccc(OCCN3CCCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(3-methoxyphenyl)-3-(4-hydroxyphenoxy)benzo[b]thiophene (3.27 g, 9.40 mmol) in 200 mL of anhydrous DMF was added finely ground anhydrous K2CO3 (13.0 g, 94 mmol) and 2-chloroethylpiperidine (2.40 g, 14.1 mmol). The resulting solution was stirred under N2 at room temperature for 16 h. The reaction was then partitioned between EtOAc and H2O. The layers were separated and the organic was washed several times with H2O. The organic was dried (Na2SO4) and concentrated in vacuo to an oil that was chromatographed (SiO2, 0-5% CH3OH/CHCl3) to provide 3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(3-methoxyphenyl)benzo[b]thiophene as a brown oil. This material was treated with Et2O.HCl to provide 2.0 g (43%) 3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(3-methoxyphenyl)benzo[b]thiophene hydrochloride as a white solid.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:16]([N:18]1[CH2:22][CH2:21][CH:20]2[N:23]([C:27](=[O:32])[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:24][CH:25]([OH:26])[CH:19]12)=[O:17])[C:12]([CH3:15])([CH3:14])[CH3:13])C1C=CC=CC=1>CO>[CH:29]([NH:28][C:27]([N:23]1[CH2:24][CH:25]([OH:26])[CH:19]2[N:18]([C:16](=[O:17])[CH:11]([NH2:10])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:22][CH2:21][CH:20]12)=[O:32])([CH3:31])[CH3:30]
Reactant: CC(C)NC(=O)N1CC(O)C2C1CCN2C(=O)C(NC(=O)OCc1ccccc1)C(C)(C)C
Solvent: CO
Product: CC(C)NC(=O)N1CC(O)C2C1CCN2C(=O)C(N)C(C)(C)C
Reaction time: 2 h
Yield: 119.8 %

Procedure:
A mixture containing 55 (7.2 g, 15.6 mmol) and 10% Pd-on-carbon (wet, 1.7 g, 1.5 mmol) in MeOH (200 mL) were stirred vigorously under an atmosphere of H2. After 2 h, the was removed by filtration and the filtrate was diluted with toluene and concentrated in vacuo to afford 6.1 g of 56 as an off-white-colored foam which was used without further purification. Mass spectrum, m/z [326.7] (M+H)+.
Reaction SMILES: O[CH:2]1[C:7]2[CH:8]=[C:9]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])[S:10][C:6]=2[S:5](=[O:20])(=[O:19])[N:4]([CH2:21][CH2:22][O:23][CH3:24])[CH2:3]1.C1C=CC(OC(Cl)=S)=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:24][O:23][CH2:22][CH2:21][N:4]1[CH:3]=[CH:2][C:7]2[CH:8]=[C:9]([S:11]([NH:14][C:15]([CH3:16])([CH3:18])[CH3:17])(=[O:12])=[O:13])[S:10][C:6]=2[S:5]1(=[O:20])=[O:19]
Reactant: COCCN1CC(O)c2cc(S(=O)(=O)NC(C)(C)C)sc2S1(=O)=O
Agent: CN(C)c1ccncc1
Agent: S=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: COCCN1C=Cc2cc(S(=O)(=O)NC(C)(C)C)sc2S1(=O)=O
Yield: 54.6 %

Procedure:
The product from Step G (4.11 g, 10.31 mmol) and 4-dimethylaminopyridine (2.52 g, 20.6 mmol) were combined in dichloromethane (50 mL) and the mixture was cooled by means of an ice bath. Phenyl chlorothionoformate (2.1 mL, 15.5 mmol) was added rapidly to the mixture and the cooling bath removed. After three hours the mixture was washed with 2N HCl (15 mL), water (15 mL), saturated aqueous sodium chloride (20 mL), dried (MgSO4) and evaporated to a residue which was purified by column chromatography (silica, hexane/ethyl acetate) to provide the desired product (2.14 g, 39%) as an oil. This oil was heated under vacuum (200° C./5 mm Hg) for approximately 5 minutes (until no more condensate collected) and then purified by column chromatography (silica, hexane/ethyl acetate) to provide the desired product (1.48 g, 97%) which was used in the next step.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([CH3:13])[C:7]([CH3:15])([CH3:14])[CH2:6]1.[C:17]([OH:21])(=[O:20])[CH:18]=[CH2:19]>C1(C)C(C)=CC=CC=1.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[C:17]([O:21][CH2:16][CH:2]([OH:1])[CH2:3][O:4][CH:5]1[CH2:6][C:7]([CH3:14])([CH3:15])[N:8]([CH3:13])[C:9]([CH3:12])([CH3:11])[CH2:10]1)(=[O:20])[CH:18]=[CH2:19]
Reactant: C=CC(=O)O
Reactant: CN1C(C)(C)CC(OCC2CO2)CC1(C)C
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: Cc1ccccc1C
Product: C=CC(=O)OCC(O)COC1CC(C)(C)N(C)C(C)(C)C1
Temperature: 0 °C
Yield: 43 %

Procedure:
375 g (1.65 mol of (4-(2,3-epoxypropoxy)-1,2,2,6,6-pentamethylpiperidine (=A1a) in 1.5 l of xylene are introduced under argon into a 2.5 l sulfonation flask fitted with magnetic stirrer, thermometer and condenser. 108 g (1.5 mol) of acrylic acid and 27.8 g (75 mmol) of ethyltriphenylphosphonium bromide are added. The reactants are allowed to react at 70° C. for 18 hours. The cooled product is poured into ice water, and the organic phase is separated off, washed twice with 1N sodium hydroxide solution, dried and evaporated. The residue is distilled over a short Vigreux column. 193 g (43%) of the title product are obtained as a clear liquid of boiling point 119°-125° C. (0.06 mm Hg).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([CH3:23])[N:11]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C>C1COCC1.O.O.[OH-].[Li+]>[CH2:16]([N:11]1[C:12]2[C:8](=[C:7]([O:6][CH2:5][C:4]([OH:24])=[O:3])[CH:15]=[CH:14][CH:13]=2)[CH:9]=[C:10]1[CH3:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)COc1cccc2c1cc(C)n2Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(OCC(=O)O)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1-benzyl-2-methyl-1H-indol-4-yloxy)-acetic acid ethyl ester (4) (0.80 g, 2.48 mmole) in THF:H2O (4:1, 10 mL), lithium hydroxide monohydrate was added (0.118 g, 4.96 mmole). The mixture was stirred at room temperature for 1 h. THF was evaporated and then crushed ice was added to the aqueous mixture; the resulting solid was collected by filtration to afford intermediate (5) as a solid. Yield: 0.67 g, 92% 1H NMR: 05-038-055
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2([OH:28])[CH2:27][CH2:26]2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O>[NH:20]1[CH:24]=[C:23]([C:25]2([OH:28])[CH2:27][CH2:26]2)[N:22]=[CH:21]1
Reactant: OC1(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CC1
Solvent: O=CO
Product: OC1(c2c[nH]cn2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 0.1 %

Procedure:
A mixture of 1-(1-trityl-1H-imidazol-4-yl)cyclopropanol (2.4 g, 6.55 mol) was treated with a 90% aq. solution of formic acid (50 mL) and the mixture was stirred at RT for 24 h. The mixture was then concentrated in vacuo, diluted in a small volume of MeOH, and the solution was rendered basic with a 7M solution of NH3 in MeOH. The white precipitate was filtered off and the filtrate was concentrated in vacuo. Purification by flash chromatography (SiO2, DCM/MeOH 100:0 to 85:15) afforded the title compound (920 mg). UPLC-MS: MS 125.1 (M+H+).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=3)=[CH:14][CH:15]=2)[O:10][C:9]([C:26]2[N:27]=[CH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:39]>CN(C)C=O>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][CH3:39])[CH:20]=3)=[CH:14][CH:15]=2)[O:10][C:9]([C:26]2[N:27]=[CH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#Cc3cccc(N)c3)ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cccc(C#Cc2ccc3c(=NOC(C)(C)C)cc(-c4cc5ccccc5cn4)oc3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A solution of 7-(3-aminophenylethynyl)-2-(Isoquinolin-3-yl)-chromen-4-one O-tert-butyl oxime (tert-butyl protected oxime of example 29) (127 mg, 0.286 mmol) in dimethylformamide (3 ml) was added to a cold suspension of sodium hydride (60% in mineral oil, 24 mg, 0.608 mmol) in DMF (1 ml). The reaction mixture was stirred for 1 hour at room temperature and cooled to 0° C. Iodomethane (43 μl, 0.690 mmol) was added and the solution was stirred at room temperature for 18 hours. The mixture was poured onto water and extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over sodium sulfate and absorbed over silica gel for purification by flash chromatography (gradient cyclohexane/dichloromethane: 0-45%) to yield 2-Isoquinolin-3-yl-7-{3-methylaminophenylethynyl}-chromen-4-one O-tert-butyl oxime (65 mg, 50%) as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8].[Cl:14][S:15](O)(=[O:17])=[O:16].O.C1COCC1>C(Cl)Cl>[Cl:14][S:15]([C:12]1[C:11]([CH3:13])=[CH:10][C:4]([O:5][CH2:6][C:7]([OH:9])=[O:8])=[CH:3][C:2]=1[CH3:1])(=[O:17])=[O:16]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cc(C)cc(OCC(=O)O)c1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(OCC(=O)O)cc(C)c1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
Referring to FIG. 37, to a solution of 2-(3,5-dimethylphenoxy)acetic acid (13 g, 72 mmol) in DCM (130 mL) was added dropwise a solution of ClSO3H (19.2 g, 166 mmol) in DCM (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h. Water (100 mL) and THF (30 mL) were added and the resulting mixture was stirred for 5 min The two layers were separated and the organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give product as a white solid (6 g, 30% yield); 1H NMR (CDCl3, 300 MHz): δ 6.79 (s, 2H), 4.79 (s, 2H), 2.77 (s, 6H).
Reaction SMILES: [C:1]([CH:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:7]=1)[CH2:4][NH2:5])#[N:2].C[Si]([N:24]=[C:25]=[O:26])(C)C.[Cl-].[NH4+]>O1CCCC1>[C:1]([CH:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[CH:7]=1)[CH2:4][NH:5][C:25]([NH2:24])=[O:26])#[N:2]
Reactant: COc1ccc(C(C#N)CN)cc1OC1CCCC1
Reactant: C[Si](C)(C)N=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(C#N)CNC(N)=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-cyano-2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamine [3-amino-2-(3-cyclopentyloxy-4-methoxyphenyl)propionitrile, 0.17 g, 0.66 mmol] in tetrahydrofuran (5 mL) under an argon atmosphere was added trimethylsilyl isocyanate (0.13 mL, 0.96 mmol). The resulting mixture was stirred overnight at room temperature. Aqueous ammonium chloride was added, the mixture was extracted three times with 5% methanol/methylene chloride, the extract was dried (potassium carbonate) and evaporated. Purification of the residue by flash chromatography, eluting with 4% methanol/methylene chloride, provided the urea as a white solid: m.p. 55°-61° C. (sublimes).
Reaction SMILES: C([O:8][C:9]1[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:22][CH3:23])[CH:10]=1)C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:22][CH3:23])[CH:10]=1
Reactant: COC(=O)c1cc(C(C)C)c(OCc2ccccc2)cc1OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(C(C)C)c(O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
10% Palladium on carbon (80 mg) was added to a suspension of methyl 4-benzyloxy-5-isopropyl-2-methoxybenzoate (624 mg, 1.99 mmol) in methanol (16 ml) and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The mixture was filtered, the catalyst was rinsed with methanol (3×5 ml) and the combined filtrates were evaporated in vacuo to afford methyl 4-hydroxy-5-isopropyl-2-methoxybenzoate (432 mg, 97%) as an off-white solid. 1H NMR (DMSO-d6) 10.18 (1H, br s), 7.52 (1H, s), 6.52 (1H, s), 3.73 (3H, s), 3.71 (3H, s), 3.11 (1H, m), 1.14 (6H, d). MS: [M+Na]+ 247.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][CH:8]=1.Br[C:17]1[CH:18]=[CH:19][C:20]2[O:24][CH2:23][C:22](=O)[C:21]=2[CH:26]=1.Cl>O1CCCC1.O>[Br:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH:14]=[C:15]([C:17]3[CH:26]=[CH:21][C:20]([O:24][CH2:23][CH3:22])=[CH:19][CH:18]=3)[C:9]=2[CH:8]=1
Reactant: CCOc1ccc(Br)cc1
Reactant: O=C1COc2ccc(Br)cc21
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(-c2coc3ccc(Br)cc23)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
4.95 ml (15% solution in n-hexane) of n-butyllithium are added to a solution, cooled to −78° C., of 1.03 ml (7.23 mmol) of 4-bromophenetole in 35 ml of tetrahydrofuran under nitrogen, and the mixture is stirred at −78° C. for one hour. A solution of 1.4 g (6.6 mmol) of 5-bromobenzofuran-3-one is subsequently added dropwise at such a rate that the temperature does not rise above −70° C., stirring is continued at −78° C. for one hour, the reaction mixture is then allowed to come to room temperature stirred at room temperature for a further 15 hours, finally 10 ml of 1N hydrochloric acid are added, and stirring is continued for a further one hour. After addition of 20 ml of water, the tetrahydrofuran is stripped off in vacuo, and the aqueous mixture remaining is extracted three times with 10 ml of diethyl ether each time. After the combined organic phases have been washed with 10 ml of saturated sodium chloride solution and after drying over sodium sulfate, the solvent is stripped off in a rotary evaporator, and the crude product is purified by column chromatography on silica gel (petroleum ether/ethyl acetate 98:2), giving 0.95 g of 5-bromo-3-(4-ethoxyphenyl)-benzofuran as colourless oil; LC/MS: 318 (M+H);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17](O)[CH2:18][N:19]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[S:20]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.C(N(S(F)(F)[F:47])CC)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]([F:47])[CH2:18][N:19]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[S:20]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3
Reactant: COc1cccc(N(CC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Reactant: CCN(CC)S(F)(F)F
Product: COc1cccc(N(CC(F)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
An oven dried 20 ml scintillation vial containing N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-N-(3-methoxyphenyl)-4-nitrobenzenesulfonamide (18.3 mg, 0.027 mmol; see representative procedure 3 above) was purged with N2 and charged with anhydrous dichloromethane (1.5 ml, 0.018 M). The sealed vial was cooled in a dry ice acetone bath before the dropwise addition of diethylaminosulfur trifluoride (DAST, 7 ul, 0.053 mmol). The reaction temperature was maintained at −78° C. for an hour and then slowly warmed to room temperature and stirred overnight. The reaction was quenched with 2.0 ml of saturated NaHCO3 solution and diluted with 6 ml CH2Cl2 and extracted three times. The combined organics were dried over Na2SO4, filtered and condensed. Crude product carried forward. Quantitative yield.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]=1.O>C(O)(=O)C>[NH2:3][C:4]1[C:9]([Br:1])=[CH:8][C:7]([Cl:10])=[CH:6][N:5]=1
Reactant: BrBr
Reactant: Nc1ccc(Cl)cn1
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncc(Cl)cc1Br
Temperature: 25 °C
Yield: 63.8 %

Procedure:
A solution of 257 g (1.61 mol) of bromine in 380 ml of acetic acid was added dropwise over a period of one hour to a solution of 187 g (1.45 mol) of 2-amino-5-chloropyridine in 1.5 l of acetic acid. The reaction mixture was refluxed for 3 h and then allowed to cool to ambient temperature. 1.9 l of demineralized water were added and the mixture was concentrated in vacuo. The residue was partitioned between 4 l of ethyl acetate and 1.8 l of water. The mixture was basified with 3 l of a 10% by weight aqueous sodium hydroxide solution. The organic layer was separated and washed with brine (2×1.5 l), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was filtered, washed with hexane (2×100 ml) and dried in vacuo to give 192 g of 2-amino-3-bromo-5-chloropyridine. The mother liquor was concentrated in vacuo, filtered, washed with hexane and dried to give further 75 g of the same product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[CH:2]=1.O[C:10]1[C:11]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH2:22])=[O:21])[C:12]=2[N:13]=[N:14][N:15]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:10]2[C:11]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH2:22])=[O:21])[C:12]=3[N:13]=[N:14][N:15]=2)[CH:2]=1
Reactant: NCc1cccnc1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Product: NC(=O)c1cccc2c(NCc3cccnc3)nnnc12

Procedure:
Compound 3 was prepared following general synthetic scheme 7 wherein pyridin-3-ylmethanamine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [281 (M+1)], 1H NMR (400 MHz, DMSO-d): δ 9.38-9.32 (m, 2H), 8.66 (s, 1H), 8.54 (d, 1H), 8.50-8.48 (m, 2H), 8.05 (s, 1H), 7.99 (t, 1H), 7.82 (d, 1H), 7.38-7.35 (m, 1H), 4.93 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH:37]([OH:39])[CH3:38]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH2:36][CH:37]([OH:39])[CH3:38])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCC2=O)c1=O
Reactant: CC(O)CN
Product: CC(O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxo-1-pyrrolidinyl)propyl]-l ,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-amino-2-propanol employing methods similar to those described in Example 202. 1H NMR (400 MHz, CDCl3) δ 10.36 (t, J=5.8 Hz, 1 H), 8.52 (s, 1 H), 7.38 (s, 1 H), 7.16 (dd, J=8.2, 5.5 Hz, 2 H), 7.01 (t, J=8.7 Hz, 2 H), 4.20-4.00 (m, 6 H), 3.60 (m, 1 H), 3.43-3.25 (m, 5 H), 2.39 (m, 2 H), 2.01 (m, 2 H), 1.80 (m, 2 H), 1.25 (d, J=6.4 Hz, 3 H); MS m/z 497 (M+H)+.
Reaction SMILES: [OH-].[Na+].CN(C)[CH:5]=[CH:6][C:7]([C:9]1[S:13][C:12]([N:14]=CN(C)C)=[N:11][C:10]=1[CH3:19])=O.Cl.[CH3:22][C@@H:23]1[CH2:25][C@H:24]1[C:26]([NH2:28])=[NH:27]>COCCO>[CH3:19][C:10]1[N:11]=[C:12]([NH2:14])[S:13][C:9]=1[C:7]1[CH:6]=[CH:5][N:28]=[C:26]([CH:24]2[CH2:25][CH:23]2[CH3:22])[N:27]=1
Reactant: C[C@@H]1C[C@H]1C(=N)N
Reactant: Cc1nc(N=CN(C)C)sc1C(=O)C=CN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: Cc1nc(N)sc1-c1ccnc(C2CC2C)n1
Temperature: 125 °C

Procedure:
Powdered sodium hydroxide (300 mg) is added to a solution of N′-[5-(3-dimethylamino-acryloyl)-4-methyl-thiazol-2-yl]-N,N-dimethyl-formamidine (1 g, prepared as described by S. Wang et al J. Med. Chem. 2004, 47, 1662-1675.) and cis/trans 2-methyl-cyclopropanecarboxamidine hydrochloride (0.61 g, prepared as described in WO 03/087064) in 2-methoxyethanol (3.8 ml) and the mixture heated at 125° C. for 1 hour with stirring. The reaction mixture is cooled, filtered, washing with water to give the title compound. MS: M+H 247 and M−H 245.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:46])[C:20]([CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([O:30][C:31](=[O:45])[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:26][CH2:25]2)=[O:21])=[O:14])=[CH:8][CH:7]=1>Cl.C(#N)C>[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:46])[C:20]([CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([O:30][C:31](=[O:45])[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:28][CH2:29]2)=[O:21])=[O:14])=[CH:8][CH:7]=1)=[O:1]
Reactant: CN(CCCCC(=O)Nc1ccc(C2OCCO2)cc1)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: Cl
Solvent: CC#N
Product: CN(CCCCC(=O)Nc1ccc(C=O)cc1)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 50 °C
Yield: 100 %

Procedure:
A stirred mixture of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-(1,3-dioxolan-2-yl)phenylcarbamoyl)butyl]methylcarbamoyl}ethyl)piperidin-4-yl ester (3.04 g, 4.84 mmol) in aqueous hydrochloric acid (1 M, 10 mL) and acetonitrile (10 mL) was heated at 50° C. for 2 h. The reaction mixture was concentrated under reduced pressure and saturated aqueous sodium bicarbonate solution and DCM were added to the residue. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (2.83 g, 100% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[I:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[I:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:27]
Reactant: O=C(Cl)c1cccc(I)c1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1cccc(I)c1
Yield: 75.2 %

Procedure:
1.21 g (0.0063 mol) of 1-benzyl-4-hydroxypiperidine and 0.874 ml (0.0063 mol) of triethylamine were dissolved in 80 ml of toluene and treated with 1.6 g (0.006 mol) of 3-iodo-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 1.9 g (76%) of 1-benzyl-piperidin-4-yl 3-iodo-benzoate were obtained as yellowish crystals; m.p. 101°-103°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11](I)[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C(OCC)(=O)C>[CH2:11]([O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1)[CH3:12]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOc1cccc(C(C)=O)c1
Temperature: 70 °C
Reaction time: 9 h

Procedure:
3′-Hydroxyacetophenone (200 mg) was dissolved in acetonitrile (4 ml). After adding ethyl iodide (0.2 ml) and potassium carbonate (347 mg), the mixture was stirred at 70° C. for 9 hours. After 9 hours, water and ethyl acetate were added to the reaction mixture followed by separation. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated. The crude product thus obtained was purified by silica gel chromatography (n-hexane:ethyl acetate=8:1) to thereby give 204 mg of 3′-ethoxyacetophenone. The procedure employed for the synthesis of F-12 was repeated but replacing the 3′-methoxyacetophenone by 3′-ethoxyacetophenone to thereby give (±)-N-(1-(3-ethoxyphenyl)ethyl)-2-(2′,5′-dichlorophenylthio)ethylamine (F-63). MS m/z: 369 (M+).