Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1cc(OC2CCCCO2)cc(C)c1Br
Yield: 77.3 %

Procedure:
A solution of 4-bromo-3,5-dimethylphenol (10.5 g, 52.2 mmol), 3,4-dihydro-2H-pyran (8.83 g, 105 mmol) and pyridinium p-toluenesulfonate (2.64 g, 10.5 mmol) in dichloromethane (160 mL) was stirred at room temperature for 80 hrs. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-20% ethyl acetate/hexane) to give the title compound (11.5 g, yield 77%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](OCC)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:5][CH2:4][C:3]1[C:2]([CH3:1])=[N:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cccnc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ncccc1CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of ethyl 2-methylnicotinate (1.50 g, 9.09 mmol) in THF (65 mL) at 0° C. was added LAH (9.1 mL of a 1.0 M solution in THF; 9.1 mmol). The mixture was stirred at ambient temperature for 18 h and then quenched by the sequential addition of ethyl acetate (0.1 mL), water (0.1 mL), 15% aqueous NaOH (0.1 mL) and water (0.28 mL). The solids were removed by filtration through celite and the filtrate solvents were removed under reduced pressure. 3-Hydroxymethyl-2-methylpyridine was obtained as an oil (TLC: Rf = 0.40 (5:95 MeOH:CH2Cl2)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:24])[CH2:15][C:16]2[C:21]([Br:22])=[CH:20][N:19]=[C:18]([Cl:23])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][Mg]Br.[NH4+].[Cl-]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([OH:24])([CH3:25])[CH2:15][C:16]2[C:21]([Br:22])=[CH:20][N:19]=[C:18]([Cl:23])[CH:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2cc(Cl)ncc2Br)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(C)(O)Cc2cc(Cl)ncc2Br)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[2-(5-bromo-2-chloro-pyridin-4-yl)-acetyl]-piperidine-1-carboxylic acid tert-butyl ester (9.80 g) in tetrahydrofuran (6 mL) is added drop wise to an ice cooled solution of methyl magnesium bromide (1.4 M in toluene/tetrahydrofuran 75:25.74 mL). The reaction mixture is stirred for 30 min, warmed to room temperature and stirred for 1 h. The mixture is poured onto aqueous NH4Cl solution and extracted with ethyl acetate. The combined extracts are dried over MgSO4 and concentrated in vacuo. Toluene is added to the residue and evaporated several times. Since the residue still contains a considerable amount of starting material, it is again treated with the Grignard reagent following the procedure described above. The crude product is purified by preparative HPLC (column: Waters X-Bridge C18; mobile phase: water+0.125% NH4OH/methanol 90:10→100:0) to give the title compound. LC (method 4): tR=1.33 min; Mass spectrum (ESI+): m/z=433, 435 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1(=[O:18])[O:17][CH2:16][CH2:15][CH2:14]1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([CH:14]1[CH2:15][CH2:16][O:17][C:13]1=[O:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCO1
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C1OCCC1Cc1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
A solution of diisopropylamine (63.0 mL) in THF was treated dropwise with butyl lithium (268 mL of 1.6M solution in hexanes) at −10° C. Upon completion of the addition, the reaction mixture was cooled to −70° C. and then treated dropwise with γ-butyrolactone (33.0 mL) keeping the speed of the addition at such a rate that the temperature of the mixture remained below −60° C. After stirring for additional 30 min at −70° C., the mixture was treated dropwise with benzyl bromide (51.0 mL) again keeping the speed of the addition at such a rate that the temperature of the mixture remained below −60° C. After completion of the addition, the stirring of the reaction mixture was continued at −70° C. for 2 h. Then the mixture was warmed-up to 0° C. and quenched by addition of a small amount of water. The solvents were removed in vacuum and the residue was redissolved in dichloromethane, washed with 10% aqueous hydrochloric acid, then with water, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and distilled in vacuum to give 26.0 g (34%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH:10]1[C:14]([C:15]2[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=2)[NH2:18])=[N:13][N:12]=[N:11]1>CO.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:15]([C:14]3[NH:13][N:12]=[N:11][N:10]=3)[CH:16]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Solvent: CO
Solvent: O
Product: Fc1cnc(Cl)nc1Nc1cccc(-c2nnn[nH]2)c1

Procedure:
A reaction mixture containing 2,4-dichloro-5-fluoro-pyrimindine (1.2 equivalents) and 3-(tetrazol-5-yl)aniline (1 equivalents) in methanol:water (1:1; v/v) was heated at 60° C. for 24 h. Upon dilution with water and acidification, the solid formed was filtered, washed with water, dried and analyzed to give 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine (R926853). Alternatively this reaction can be achieved by treating 2,4-dichloro-5-fluoropyrimidine (1 equivalent) with 3-(tetrazol-5-yl)aniline (3 equivalents) in methanol:water (1:1; v/v) at 60° C. for 2-3 hours or at room temperature for 24 h to give 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine. 1H NMR (DMSO-d6): δ 10.25 (s, 1H), 8.43 (s, 1H), 8.37 (d, 1H, J=3.6 Hz), 7.90 (dd, 1H, J=0.9 and 9 Hz), 7.75 (d, 1H, J=7.5 Hz), 7.61 (t, 1H, J=7.8 Hz); LCMS: purity: 90%; MS (m/e): 292 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][CH:5]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:24]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:24])=[N:6][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)nc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)nc1
Yield: 34.1 %

Procedure:
To a solution of 6-methyl-nicotinic acid methyl ester (0.54 g, 3.57 mmol) in carbon tetrachloride (10 mL) was added 2,2′-azobis(2-methyl-proprionitrile) (0.030 g, 0.18 mmol) and N-bromosuccinimide (0.703 g, 3.95 mmol). The solution was stirred at reflux for 12 hours, cooled and concentrated in vacuo. Flash chromatography on silica gel provided the title compound (0.28 g).
Reaction SMILES: Cl.[OH:2][C:3]1[C:12]([OH:13])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C[CH2:15][O:16]CC>[C-]#N.[Zn+2].[C-]#N>[OH:2][C:3]1[C:12]([OH:13])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:15]=[O:16]
Reactant: Oc1cc2ccccc2cc1O
Reactant: CCOCC
Agent: Cl
Agent: [C-]#N
Agent: [Zn+2]
Product: O=Cc1c(O)c(O)cc2ccccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A stream of HCl gas was passed through a stirred, cooled (0° C.) mixture of 2,3-dihydroxynaphthalene (6 g, 37.4 mmol) and zinc cyanide (6.6 g, 56.1 mmol) in dry Et2O (28 mL) for 20 min. An insoluble yellow oil was generated. Stirring was continued for 1 h at 0° C., then at room temperature for 1 h. The yellow brown oil was separated and washed with Et2O. Water (120 mL) was added and the mixture was heated at 60° C. for 10 min. The yellow solid generated was filtered and washed with water to give product (5.48 g, containing 20% starting material). MS (APCI) m/z 187 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:25]1[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:19]([N:25]4[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]4)=[O:21])=[CH:22][CH:23]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)N2CCS(=O)(=O)CC2)cn1
Yield: 87 %

Procedure:
As described for example 98b, 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (69 mg, 0.2 mmol) was converted, using thiomorpholine-S,S-dioxide instead of 2,2,2-trifluoroethylamine, to the title compound (80 mg, 87%) which was obtained as a white solid. MS: m/e=462.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12]O>OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(Cl)cc1
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of 2-(4-chlorophenyl)acetic acid (20.0 g, 117 mmol) in dry methanol (235 mL) was treated with 5 drops of concentrated H2SO4 (cat.) at room temperature. The mixture was stirred overnight to completion, and then concentrated in vacuo to about 40 milliliters. The concentrate was partitioned between ether and half saturated NaHCO3 solution. The aqueous portion was back-extracted once with ether, and the organics were combined. The organic portion washed with water, then brine, dried over MgSO4, and concentrated in vacuo. The material was placed under high vacuum for one hour to afford the pure methyl 2-(4-chlorophenyl)acetate as a pale yellow oil (19.8 g, 92%). 1H NMR (CDCl3, 400 MHz) δ 7.30 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 3.70 (s, 3H), 3.60 (2, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH2:12][C:13]([OH:15])=[O:14]>>[C:13]([CH2:12][NH:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)([OH:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCC(=O)O
Product: O=C(O)CNc1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 1-fluoro-4-nitrobenzene and glycine
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([F:15])[CH2:9]1)=O)(C)(C)C.O1CCOCC1.[ClH:22]>>[F:15][CH:10]1[C:11](=[O:14])[CH2:12][CH2:13][NH:8][CH2:9]1.[ClH:22]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CCNCC1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Fluoro-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.7 g, 12.4 mmol) was dissolved in dioxane/HCl (100 mL, 0.12 M) and stirred at ambient temperature for 2 hours. Volatiles were then removed in vacuo to afford 3-fluoro-piperidin-4-one as an HCl salt, which was carried on without further purification (1.7 g, 92% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (br. s., 1H), 8.77 (br. s., 1H), 6.36 (br. s., 2H), 4.41-4.53 (d, J=48 Hz, 1H), 3.37 (t, J=9.85 Hz, 1H), 3.21 (m, 1H), 3.08 (m, 1H), 2.93 (m, 1H), 1.94 (m, 1H), 1.77 (m, 1H).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]>O.[O-][Mo]([O-])(=O)=O>[O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)[C@@H](O)C=O
Agent: O=[Mo](=O)([O-])[O-]
Solvent: O
Product: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Temperature: 78 °C
Yield: 54 %

Procedure:
The resin-supported molybdate obtained above (10 g) was added to a mixture of 6-deoxy-L-talose (10 g) in water (40 ml). The reaction mixture was stirred at 78° C. (inside the reactor). After cooling to rt the mixture was filtered, the filtrate passed through a column of IRA 400 resin (5 g, OH form, d=1 cm, l=5 cm) two times and concentrated. The residue was dissolved in isopropanol (40 ml) and directly evaporated. Isobutanol (50 ml) was added and the mixture was heated to reflux for 10 min. and allowed to cool. Crystallization spontaneously occurs or it was promoted by adding seed crystals. After 6 h at room temperature the suspension was filtered to give L-fucose (5.4 g, 54%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.O=P(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].O>N1C=CC=CC=1.[Cl-].[Na+].O.Cl.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:9]#[N:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: NC(=O)c1nc(Br)cnc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 57.4 %

Procedure:
3-Amino-6-bromopyrazine-2-carboxamide (1.5 g, 7 mmol) was dissolved in pyridine (15 mL). The solution was then cooled in an ice bath and POCl3 (2 mL) was drop wise added. The resulting mixture was stirred at room temperature for 2.5 h. The solvent was removed and the residue was quenched by the careful addition of ice cooled Na2CO3 (5 mmol). Ethyl acetate was added (45 mL) and the organic layer was separated, washed with brine (5 mL), HCl (0.1 M aqueous solution, 1 mL) and water (5 mmol), dried with K2CO3 and concentrated. The crude matherial was triturated with hexane, and the resulting tan solid was filtered to provide 0.8 g (58% yield) of the title compound: 1H NMR (400 MHz; DMSO-d6): 8.42 (s, 1H); 7.60 (br s, NH); MS (EI) for C5H3BrN4: 199 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[C:17]1([S:23]([N:4]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:10]3[C:2]([Br:1])=[CH:3]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1c[nH]c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2cccnc21

Procedure:
3-Bromo-1H-pyrrolo[2,3-b]pyridine (3, 280 mg, 1.4 mmol) was dissolved in acetone (15 mL) and potassium carbonate (220 mg, 1.6 mmol) was added, followed by benzenesulfonyl chloride (0.2 mL, 1.6 mmol). The reaction mixture was heated to reflux overnight, filtered and concentrated under reduced pressure. The resulting solid was purified by flash chromatography (5%-20% ethyl acetate:hexanes) to provide the desired product, 4, (300 mg, 47%). MS(ESI) [M+H+]+=455.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][N:2]=1.[C:7]1([CH2:13]C(O)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>OS(O)(=O)=O.O.[N+]([O-])([O-])=O.[Ag+]>[CH2:13]([C:5]1[CH:4]=[CH:3][N:2]=[N:1][CH:6]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: c1ccnnc1
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: c1ccc(Cc2ccnnc2)cc1
Temperature: 80 °C
Yield: 21.4 %

Procedure:
A solution of pyridazine (2.2 g, 27.5 mmol) and 2-phenylacetic acid (18.7 g, 137.5 mmol), AgNO3 (1.4 g, 8.25 mmol) in 2N H2SO4 (27.7 ml) was heated to 60-70° C. under stirring, then, a solution of (NH4)2S2O8 (18.6 g, 82.5 mmol) in 80 ml of water was added within 20 minutes, After heating to 70-90° C. for 1.5 hour, the reaction solution was cooled to room temperature and extracted with DCM (2×100 ml), the combined organic layers were washed with 2NH. SO4 (3×70 ml), then, the combined aqueous layer was made alkaline with 50% NaOH and extracted with DCM (3×80 ml), dried over Na2SO4 and concentrated to get the crude product, which was purified by column chromatography on silica gel (petroleum Ether: EtOAc=2:1) to afford 4-benzylpyridazine (1.0 g, yield: 22%). 1H NMR (CDCl3 400 MHz): δ9.09 (s, 1H), 9.06 (d, J=5.2 Hz, 1H), 7.40-7.28 (m, 3H), 7.25-7.20 (m, 1H), 7.18 (d, J=7.2 Hz, 2H), 4.0 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: c1ccc2[nH]cnc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Product: Brc1ccc(Cn2cnc3ccccc32)cc1
Temperature: 139 °C
Yield: 41.5 %

Procedure:
1-Bromo-4-(bromomethyl)benzene (2.50 g, 10 mmol), 1H-benzo[d]imidazole (1.181 g, 10.0 mmol), potassium hydroxide (0.561 g, 10.0 mmol), potassium carbonate (1.382 g, 10.0 mmol) and tetrabutylammonium bromide (0.161 g, 0.5 mmol) was mixed in xylenes (60 mL). The reaction mixture was heated at 139° C. overnight. The hot reaction mixture was filtered and washed with hot xylenes. The solvent was evaporated and the residue was purified by flash column chromatography using dichloromethane/methanol (95:5 to 80:20) as mobile phase to give 1-(4-Bromobenzyl)-1H-benzo[d]imidazole (1.193 g, 42%). 1H NMR (CDCl3) δ 5.31 (s, 2H), 7.05 (m, 2H), 7.28 (m, 3H), 7.46 (m, 2H), 7.82 (m, 1H), 7.95 (s, 1H).
Reaction SMILES: [C:1]([CH2:4][S:5][CH:6]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][CH2:11][N:10]=1)[C:7]#[N:8])(O)=[O:2].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[C:7]([C:6]1[S:5][CH2:4][C:1](=[O:2])[N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[C:9]=12)#[N:8]
Reactant: COc1cc2c(cc1OC)C(C(C#N)SCC(=O)O)=NCC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)C1=C(C#N)SCC(=O)N1CC2
Reaction time: 48 h

Procedure:
To a pyridine solution of 3.2 g. of α-(carboxymethyl-mercapto)-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile 2.1 g. of dicyclohexyl-carbodiimide are added. The reaction mixture is allowed to stand at room temperature for two days. The solvent is evaporated in vacuo and the residue is recrystallized from butanol. 1.9 g. of 1-cyano-9,10-dimethoxy-3,4,6,7-tetrahydro-1,4-thiazino[3,4-a]isoquinoline-4-one are obtained, melting at 186° to 187° C. after recrystallization from butanol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)([O-])=O.[H][H]>[Ni].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCO2
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1ccc2c(c1)CCO2
Yield: 97 %

Procedure:
The product (1 g, 6.1 mmol) obtained in Step 1, Raney Ni (0.1 g) and MeOH (10 mL) were used for hydrogenation at room temperature and hydrogen pressure of 50 PSI, until the reaction was finished. The catalyst was removed by filtration, the fitrate was concentrated under vacuum to obtain a product (800 mg, 97.2%).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[C:5]2[N:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[C:20]([CH3:27])[CH:19]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(OCC)(=O)C.O>[CH:10]1([CH2:9][N:6]2[C:7](=[O:8])[C:2]([C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][C:20]=3[CH3:27])=[N:3][C:4]3[CH:16]=[CH:15][CH:14]=[N:13][C:5]2=3)[CH2:12][CH2:11]1
Reactant: O=c1c(Br)nc2cccnc2n1CC1CC1
Reactant: Cc1cc(F)ccc1B(O)O
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1-c1nc2cccnc2n(CC2CC2)c1=O
Yield: 45.3 %

Procedure:
To 200 mg (0.71 mM) of 2-bromo-4-(cyclopropylmethyl)pyrido[2,3-b]pyrazin-3(4H)-one and 25.3 mg (0.036 mM) of bis(triphenylphosphine) palladium(II)chloride in 1 ml of dimethylformamide were added 142.9 mg (0.93 mM) of (4-fluoro-2-methylphenyl)boronic acid, 0.1 ml of ethanol and 715 μl of a 2M aqueous solution of sodium carbonate. The reaction mixture was then refluxed for 20 h under stirring. Water and ethyl acetate were added. The organic layer was separated, washed with water, dried on anhydrous sodium sulfate and the solvent was removed under vacuum. The compound was further purified by silica gel column chromatography, using dichloromethane as eluant, to give, after evaporation, 100 mg of 4-(cyclopropyl methyl)-2-(4-fluoro-2-methylphenyl)pyrido[2,3-b]pyrazin-3(4H)-one as a white solid. (Yield: 45.3%)
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][C:2]1=S.[CH:13]([NH:15][NH2:16])=O>C(O)CCC>[CH:13]1[N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[NH:5][CH2:4][CH2:3][C:2]2=[N:16][N:15]=1
Reactant: S=C1CCNc2ccccc2N1
Reactant: NNC=O
Solvent: CCCCO
Product: c1ccc2c(c1)NCCc1nncn1-2
Yield: 37.3 %

Procedure:
A mixture of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-thione (0.8 g) and 0.80 g of N-formylhydrazine in 8 ml of n-butanol is stirred and refluxed for 18 hours and the solvent removed under vacuum. Ice water is added to the residual solid and the mixture filtered to give 0.312 g of a gray solid, m.p. 162-165° C.
Reaction SMILES: Br.C(OC([NH:12][CH:13]1[C:19](=[O:20])[NH:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[S:15][CH2:14]1)=O)C1C=CC=CC=1.CCOCC>C(O)(=O)C>[NH2:12][CH:13]1[C:19](=[O:20])[NH:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[S:15][CH2:14]1
Reactant: O=C(NC1CSc2ccccc2NC1=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: NC1CSc2ccccc2NC1=O
Temperature: 25 °C

Procedure:
14 ml of a 25% solution of hydrogen bromide in acetic acid was added to 3.0 g of 3-benzyloxycarbonylamino-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and the resulting mixture was stirred at room temperature for an hour. After the addition of ether, the precipitated crystals were separated by filtration to obtain 2.45 g of the hydrobroxide of the desired compound, or 3-amino-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. Its melting point was 290° C. or above.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@@H:20]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][C@H:22]([C:33]([O:35]C)=[O:34])[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1CO>[C:29]([O:28][C:26]([N:24]1[CH2:25][C@@H:20]([N:19]([C:17]([C:8]2[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[N:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[N:6][CH:7]=2)=[O:18])[CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:21][C@@H:22]([C:33]([OH:35])=[O:34])[CH2:23]1)=[O:27])([CH3:30])([CH3:32])[CH3:31]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
1-tert-Butyl 3-methyl (3R*,5S*)-5-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (304 mg) was dissolved in tetrahydrofuran-methanol (1:2, 12 ml), 2 M aqueous sodium hydroxide solution (1.35 ml) was added and the mixture was stirred for 2 hr. The reaction mixture was concentrated under reduced pressure, and diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (287 mg).