Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[O:15][C:16]([CH:30]([CH3:32])[CH3:31])=[C:17]([CH2:19][CH2:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[O:22])[N:18]=1.[Cl-].[NH4+]>C1COCC1>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[O:15][C:16]([CH:30]([CH3:32])[CH3:31])=[C:17]([CH2:19][CH2:20][CH:21]([C:23]2[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=2)[OH:22])[N:18]=1
Reactant: CC(C)c1oc(-c2ccccc2Cl)nc1CCC(=O)c1ccc(O)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)c1oc(-c2ccccc2Cl)nc1CCC(O)c1ccc(O)cc1
Reaction time: 1 h
Yield: 91 %

Procedure:
Lithium aluminum hydride (25 mg, 0.659 mmol) was suspended in THF (5 mL). To the suspension was added 4-[3-[2-(2-chlorophenyl)-5-isopropyl-4-oxazolyl]propionyl]-phenol (240 mg, 0.65 mmol) for 3 minutes under chilling with ice. The mixture was stirred for one hour under cooling with ice, and further stirred for one hour at room temperature. To this was added saturated aqueous ammonium chloride solution under cooling with ice. The mixture was then filtered over celite. After addition of water and ethyl acetate, the organic layer was collected, washed with water, dried over anhydrous sodium sulfate, and filtered. The ethyl acetate was distilled off under reduced pressure, to give 220 mg of the desired compound as pale yellow oil residue (yield 91%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:29](=[O:30])[N:12]2[C:13]([C:26]([OH:28])=[O:27])=[C:14]([CH2:17][S:18][C:19]3[S:20][C:21]([CH2:24][NH2:25])=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8].[OH-].[Na+:32].O.[Na+].O[CH2:36][S:37]([O-:40])(=[O:39])=[O:38]>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:29](=[O:30])[N:12]2[C:13]([C:26]([O-:28])=[O:27])=[C:14]([CH2:17][S:18][C:19]3[S:20][C:21]([CH2:24][NH:25][CH2:36][S:37]([OH:40])(=[O:39])=[O:38])=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8].[Na+:32].[Na+:32].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:29](=[O:30])[N:12]2[C:13]([C:26]([O-:28])=[O:27])=[C:14]([CH2:17][S:18][C:19]3[S:20][C:21]([CH2:24][NH:25][CH2:36][S:37]([OH:40])(=[O:39])=[O:38])=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: NCc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)[C@H]3SC2)s1
Reactant: O=S(=O)([O-])CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)[O-])=C(CSc3nnc(CNCS(=O)(=O)O)s3)CS[C@H]12
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a suspension of 7-{2-(2-thienyl)acetamido}-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.39 g.) in water (27 ml.) was added 1 N aqueous sodium hydroxide solution (3 ml.) to dissolve. After hydroxymethanesulfonic acid sodium salt hydrate (456 mg.) was added to the resultant solution, the solution was stirred at room temperature for 4.5 hours, was lyophilized to give di-sodium 7-(2-thienyl)acetamido-3-(5-sulfomethylaminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate m.p. 112° to 120° C. (dec.).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[N:5]1([NH:10][CH:11]2[CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19](C)C=3O2)[CH2:9][CH2:8][N:7]=[CH:6]1.N1(NC2CC3C=CC=C(C)C=3O2)CCN=C1.NCCNC(=S)NC1C=CC2CCOC=2C=1C>CO>[N:5]1([NH:10][C:11]2[CH:15]=[CH:14][C:16]3[CH2:2][CH2:1][O:4][C:17]=3[C:18]=2[CH3:19])[CH2:9][CH2:8][N:7]=[CH:6]1
Reactant: CC(=O)O
Reactant: Cc1cccc2c1OC(NN1C=NCC1)C2
Agent: Cc1c(NC(=S)NCCN)ccc2c1OCC2
Solvent: CO
Product: Cc1c(NN2C=NCC2)ccc2c1OCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(2-Imidazolinylamino-7-methyl-2,3-dihydrobenzofuran hemiacetate. The above crude 6-[N'-(2-aminoethyl)thioureido]-7-methyl-2,3-dihydrobenzofuran is dissolved in 3 mL of methanol and treated with 0.25 g of mercuric acetate, forming a black color. The reaction mixture is stirred overnight at room temperature. The reaction mixture is filtered through celite, concentrated, and purified by silica gel chromatography to provide 0.131 g of 6-(2-imida zolinylamino)-7-methyl-2,3-dihydrobenzofuran as the hemiacerate salt.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)N>>[N:31]1[CH:32]=[CH:33][C:28]([N:26]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:29][CH:30]=1
Reactant: NNc1ccncc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccncc1
Yield: 16 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 4-hydrazinopyridine according to the method described for Example 1 in 16% yield. MS: M=400.2 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][CH:19]([CH2:24][CH3:25])[CH2:20][C:21](O)=[O:22].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:21](=[O:22])[CH2:20][CH:19]([CH3:18])[CH2:24][CH3:25])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: CCC(C)CC(=O)O
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Product: CCC(C)CC(=O)Nc1cccc(-n2ncc3c(N)ncnc32)c1
Reaction time: 0.17 h
Yield: 56.3 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (40 mg, 1.1 eq, 0.18 mmol) was added to a solution 3-methylpentanoic acid (20 μl, 1.0 eq, 0.16 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27 mg, 1.1 eq, 0.18 mmol), 1-hydroxybenzotriazole (22 mg, 1.0 eq, 0.17 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 48 hours, after which methanol (1 ml) was added, and the solvents were removed in vacuo. The residue was purified by mass direct preparative HPLC to yield the title compound as a white solid (28 mg, 0.09 mmol, 54%). LCMS: [M+H]+=325, Rt=1.67 min, 100% purity.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12]([CH3:15])(=[O:14])=[O:13].[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[F-].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CO.C1(C)C=CC=CC=1>[CH3:25][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Cl)c(S(C)(=O)=O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2C)c(S(C)(=O)=O)c1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
In a schlenk flushed with Argon were added methyl 4-chloro-3-(methylsulfonyl)benzoate (124.34 mg; 0.50 mmol; 1 eq.), o-tolylboronic acid (84.97 mg; 0.62 mmol; 1.25 eq.), palladium(II) acetate (22.45 mg; 0.10 mmol; 0.20 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (82.11 mg; 0.20 mmol; 0.40 eq.), potassium fluoride (87.14 mg; 1.50 mmol; 3 eq.), toluene (2.49 mL), MeOH (2.49 mL) and water (5.40 μl). The reaction was degassed with Ar and heated under reflux for 2 hours. Then, it was cooled down to RT. The solvents were evaporated and the crude mixture was dissolved in EtOAc, washed with water and brine and dried over MgSO4. The resulting crude product was purified by flash chromatography (c-hex/EtOAc 9:1 to 5:5), affording the title compound as a light yellow oil (135 mg; 88%). 1H NMR (DMSO-d6, 300 MHz) δ 8.89 (d, J=1.77 Hz, 1H), 8.32 (dd, J=1.77, 7.90 Hz, 1H), 7.43-7.19 (m, 5H), 4 (s, 3H), 2.76 (s, 3H), 2.09 (s, 3H). LC/MS (Method B): 305.1 (M+H)+. HPLC (max plot) 99.2%; Rt 4.51 min.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[N:14]2.[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].CC([O-])(C)C.[Na+]>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[C:24]([O:23][C:21]([N:28]1[CH2:33][CH2:32][N:31]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[N:14]3)[CH2:30][CH2:29]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: COc1ccc2c(Br)cccc2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2n1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 65.8 %

Procedure:
A third intermediate compound, 2-Methoxy-5-piperazin-1-yl-quinoline, was produced as follows: To an oven-dried flask, under nitrogen, was added Pd(OAc)2 (0.03 g, 0.13 mmol) and 2-(dicyclohexylphosphino)biphenyl (0.045 g, 0.13 mmol). The flask was evacuated and refilled with nitrogen. The following materials were added in the following order: degassed toluene (10 mL), 5-bromo-2-methoxy-quinoline (0.76 g, 3.23 mmol), 1-Boc-piperazine (0.72 g, 3.87 mmol), and NaOtBu (0.43 g, 4.52 mmol). The mixture was stirred at 80° C. for 1.5 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and filtered through celite. The filtrate was concentrated in vaccuo and purified by chromatography on silica gel (10% EtOAc/Hexane) to give 4-(2-methoxy-quinolin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester as a yellowish solid (0.73 g, 66%). 1H NMR (400 MHz, CDCl3) δ: 8.35 (d, 1H), 7.60 (m, 2H), 7.00 (d, 1H), 6.90 (d, 1H), 4.05 (s, 3H), 3.75 (m, 4H), 3.00 (m, 4H), 1.50 (s, 9H).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([C:9](=[O:23])[CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([C:20]([NH2:22])=[O:21])[CH:12]=2)[C@H:6]([C:24](=[O:35])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[F:34])[CH2:5]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][C@@H:4]1[CH2:8][N:7]([C:9](=[O:23])[CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([C:20]([NH2:22])=[O:21])[CH:12]=2)[C@H:6]([C:24](=[O:35])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[F:34])[CH2:5]1
Reactant: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)NCc2cccc(Cl)c2F)N(C(=O)Cc2cn(C(N)=O)c3ccccc23)C1
Agent: [Pd]
Solvent: CO
Product: NC(=O)n1cc(CC(=O)N2C[C@@H](N)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccccc21

Procedure:
A solution of 3-{2-[(2S,4S)-4-azido-2-(3-chloro-2-fluoro-benzylcarbamoyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-indole-1-carboxylic acid amide (80 mg, 0.161 mmol) in MeOH (8 mL) was hydrogenated over Pd/C 10% (8 mg, 10% w/w) at RT (1 atm). The reaction mixture was filtered through a 0.45 microns filter and concentrated under reduced pressure to give the title compound as colorless foam. MS (LC/MS): 472 [M+H]+; tR (HPLC conditions b) 2.94 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][C:10](O)([CH3:12])[CH3:11].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]([CH3:12])([CH3:11])[CH3:9])=[C:4]([OH:8])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)(C)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 84 h

Procedure:
To a solution of 29.5 g (170.3 mmol) of 3-bromophenol in 100 mL of carbon tetrachloride (under a blanket of argon) was added 16.4 g (221.3 mmol) of 2-methyl-2-propanol followed by 20 mL of conc. sulfuric acid. The reaction mixture was allowed to stir at ambient temperature for 3.5 days. The clear, colorless solution turned pink and eventually turned purple in color. The reaction mixture was neutralized with sat. NaHCO3 (aq.) solution and then extracted between water and dichloromethane. The layers were separated and the aqueous phase was washed with dichloromethane. The organic phases were combined and washed with brine, dried over MgSO4, filtered and concentrated in vacuo to a purple oil. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) followed by kugelrohr distillation (85-95° C., 2 mm Hg) gave the title compound as a clear, slightly yellow oil.
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]1([CH3:21])[CH3:20])[CH:2]=[CH2:3].C(O)C>[H][H].[Pd]>[CH3:21][C:5]1([CH3:20])[CH2:6][CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[C:10]([CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH:9]=2)[N:4]1[CH2:1][CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCN1c2ccc(C(C)C(=O)OC)cc2C=CC1(C)C
Agent: [Pd]
Solvent: CCO
Product: CCCN1c2ccc(C(C)C(=O)OC)cc2CCC1(C)C
Yield: 80 %

Procedure:
3.7 g of methyl 2-(1-allyl-1,2-dihydro-2,2-dimethylquinolin-6-yl)propionate (Compound 20) was added to ethanol. Palladium-on-carbon was further added to the solution, and the mixture were reacted with stirring at room temperature for 20 hours under atmospheric pressure in hydrogen atmosphere. After the catalyst was filtered off, the filtrate was concentrated, and then purified by column chromatography on silica gel (ether:hexane=1:4) to give 3.0 g of methyl 2-(1,2,3,4-tetrahydro-2,2-dimethyl-1-propylquinolin-6-yl)propionate (Compound 14).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:15]2[CH2:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([N:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)=[CH:27][CH:26]=4)=[N:22][C:23]=3[C:14]=2[N:13]([CH3:38])[N:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C(OO)=[O:47])C=CC=1.C([O-])(O)=O.[Na+]>>[CH2:1]([NH:8][C:9]([C:11]1[C:15]2[CH2:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([N:31]5[CH2:32][CH2:33][N+:34]([CH3:37])([O-:47])[CH2:35][CH2:36]5)=[CH:29][CH:30]=4)=[N:22][C:23]=3[C:14]=2[N:13]([CH3:38])[N:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(c2ccc(Nc3ncc4c(n3)-c3c(c(C(=O)NCc5ccccc5)nn3C)CC4)cc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1nc(C(=O)NCc2ccccc2)c2c1-c1nc(Nc3ccc(N4CC[N+](C)([O-])CC4)cc3)ncc1CC2
Temperature: 25 °C
Yield: 65.5 %

Procedure:
To a solution of 39.4 mg (0.0774 mmol) of N-benzyl-1-methyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 17.4 mg (0.0774 mg) of 3-chlorobenzenecarboperoxoic acid were added and the mixture was stirred at room temperature. After 45 minutes an aqueous solution of NaHCO3 was added and the solvent removed. Treatment with methanol and filtration afforded 26.6 mg of the title compound (66% yield).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:12]=[C:13]([C:21]#[N:22])[CH:14]=[C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][C:16]=12.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:17]1[C:16]2=[C:11]([N:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)[N:12]=[C:13]([C:21]#[N:22])[CH:14]=[C:15]2[CH:19]=[C:18]1[CH3:20])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc2cc(C#N)nc(N3CCc4ccccc4C3)c2[nH]1
Product: Cc1cc2cc(C#N)nc(N3CCc4ccccc4C3)c2n1Cc1ccccc1
Yield: 87 %

Procedure:
In accordance with the same procedures as in Example 657, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Step 2 of Example 917 and benzyl bromide, the titled compound was obtained as a white solid. (Yield: 87%)
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([NH:24][NH2:25])[CH2:20][CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S.CC1N(C2CCNCC2)[C:31](=[O:39])[NH:30][C:29]=1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1>[C:40]1([C:29]2[NH:30][C:31](=[O:39])[N:24]([CH:21]3[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:14][CH:12]4[C:13]5[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=5[C:6]5[C:11]4=[CH:10][CH:9]=[CH:8][CH:7]=5)=[O:17])[CH2:19][CH2:20]3)[N:25]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Cc1c(-c2ccccc2)[nH]c(=O)n1C1CCNCC1
Reactant: NNC1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: S
Solvent: C1CCOC1
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC(n2nc(-c3ccccc3)[nH]c2=O)CC1

Procedure:
The solutions of 5.56 g (0.0165 mol) of [1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]-hydrazine in 60 ml of tetrahydrofuran and 3.7 g (0.0177 mol) of N-(ethoxycarbonyl)-benzothionamide in 30 ml of tetrahydrofuran were combined and refluxed for 1 hour, whereupon hydrogen sulphide was released. The solvent was distilled off in vacuo, the oily residue remaining was boiled with a little acetonitrile. The mixture was allowed to cool, then additionally cooled from outside with ice water and the resulting precipitate was suction filtered. 4.0 g (52% of theory) of colourless crystals were obtained, melting point 142° C. and Rf=0.38 (eluant 4).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=3)=[CH2:15])[CH:5]=[CH:4][C:3]1=2.[OH-].[K+].Cl>CO>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[CH2:15])[CH:5]=[CH:4][C:3]1=2
Reactant: C=C(c1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=C(c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 50 °C
Reaction time: 14 h
Yield: 81.9 %

Procedure:
To a suspension of the ester 16 (94 mg, 0.27 mmol) in 75% aqueous methanol (2 mL) was added potassium hydroxide (0.045 g), and the reaction mixture was stirred at 50° C. for 14 h during which time the material dissolved. The solution was cooled to room temperature, acidified with 2N aqueous hydrochloric acid, and then extracted with ether. The combined organic layers were washed with water and brine. The organic solution was then dried over anhydrous MgSO4, filtered and concentrated to afford a white solid. Recrystallization from benzene-hexane afforded the desired acid 48 as a white crystalline solid (0.074 g, 82%): m.p. 201°-204° D. The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
Reaction SMILES: [Si]([O:8][C:9]1[CH:37]=[CH:36][C:12]([C:13]([C:15]2[CH:35]=[CH:34][C:18]([CH2:19][N:20]3[C:24]4[N:25]=[C:26]([S:32][CH3:33])[N:27]([CH2:30][CH3:31])[C:28](=[O:29])[C:23]=4[CH:22]=[CH:21]3)=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>C1COCC1>[CH2:30]([N:27]1[C:28](=[O:29])[C:23]2[CH:22]=[CH:21][N:20]([CH2:19][C:18]3[CH:17]=[CH:16][C:15]([C:13](=[O:14])[C:12]4[CH:36]=[CH:37][C:9]([OH:8])=[CH:10][CH:11]=4)=[CH:35][CH:34]=3)[C:24]=2[N:25]=[C:26]1[S:32][CH3:33])[CH3:31]
Reactant: CCn1c(SC)nc2c(ccn2Cc2ccc(C(=O)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc2)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(SC)nc2c(ccn2Cc2ccc(C(=O)c3ccc(O)cc3)cc2)c1=O
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
In THF (76.8 ml) was dissolved 7-[4-(4-t-butyldimethylsilyloxybenzoyl)benzyl]-3-ethyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4-one (4.10 g) followed by addition of 1M-tetrabutylammonium fluoride-THF (7.68 ml), and the mixture was stirred for 30 minutes. To this reaction mixture was added water and the THF was distilled off. Then, ethyl acetate was added to the residue and the organic layer was separated. The organic layer was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate and the solvent was then distilled off under reduced pressure. The residue was triturated with ether and the resulting powder was collected by filtration, rinsed with ether, methanol and hexane, and dried to provide the title compound as crystalline powder (3.0 g)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11].O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[NH:9][C:10](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(Br)cnc1N
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2cc(Br)cnc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
5-Bromopyridine-2,3-diamine (2.45 g) was dissolved in THF (25 mL) and 1,1′-carbonyldiimidazole (2.54 g, 1.2 eq) was added. The reaction was stirred at room temperature under nitrogen gas overnight. Water was then added to the mixture and the product was collected by filtration. The solid was dried under vacuum delivering product (2.57 g, 92% yield). 1H-NMR (300 MHz, DMSO-d6) δ 11.50 (s, 1H), 11.00 (s, 1H), 7.93 (s, 1H), 7.39 (s, 1H). MS (ES+) m/z 213.1 (M+1).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([CH3:38])=[N:13][C:14]2[CH2:15][CH2:16][N:17](C(OCC3C=CC=CC=3)=O)[CH2:18][C:19]=2[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[ClH:39]>C(Cl)Cl.CO.[Pd]>[ClH:39].[ClH:39].[C:1]([O:5][CH:6]([C:11]1[C:12]([CH3:38])=[N:13][C:14]2[CH2:15][CH2:16][NH:17][CH2:18][C:19]=2[C:20]=1[C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(c1-c1ccc(C)cc1)CN(C(=O)OCc1ccccc1)CC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(c1-c1ccc(C)cc1)CNCC2
Reaction time: 3 h

Procedure:
To a solution of benzyl 3-(1-(tert-butoxy)-2-methoxy-2-oxoethyl)-2-methyl-4-(p-tolyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (intermediate 12) (0.100 g, 0.194 mmol) in CH2Cl2 (2 ml) and methanol (2 ml) was added 10% Pd/C (10.30 mg, 9.68 mmol) followed by HCl (0.024 ml, 0.290 mmol). The mixture was shaken under H2 (50 psi) for 3 h. Celite was added and the mixture was filtered over Celite rinsing with MeOH. Concentration gave a residue which was then dissolved in MeOH and re-filtered then concentrated. The residue was triturated with Et2O and the solids were collected by filtration to give methyl 2-(tert-butoxy)-2-(2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate 2 HCl as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.44 (t, J=8.44 Hz, 2H), 7.24 (dd, J=6.85, 18.34 Hz, 2H), 5.08 (s, 1H), 4.10-4.26 (m, 1H), 3.70-3.85 (m, 4H), 3.57-3.70 (m, 2H), 3.21-3.31 (m, 2H), 2.66 (s, 3H), 2.47 (s, 3H), 0.99 (s, 9H). LCMS (M+H) calcd for C23H31N2O3: 383.21. found: 383.1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](=[NH:14])([NH2:13])=[O:12])(=[O:4])=[O:3].C1([O:21][C:22](=O)[NH:23][C:24]2[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[N:25]=2)C=CC=CC=1.N12CCCN=C1CCCCC2.Cl>C(#N)C.O>[CH3:31][O:30][C:28]1[CH:27]=[C:26]([O:32][CH3:33])[N:25]=[C:24]([NH:23][C:22]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:2]([CH3:1])(=[O:4])=[O:3])(=[NH:13])=[O:12])=[O:21])[N:29]=1
Reactant: CS(=O)(=O)c1ccccc1S(=N)(N)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COc1cc(OC)nc(NC(=O)NS(=N)(=O)c2ccccc2S(C)(=O)=O)n1
Reaction time: 0.75 h
Yield: 68.8 %

Procedure:
To a solution of 62.6 mg (0.267 mmol) of 2-(methylsulfonyl)benzenesulfonimidamide and 73.5 mg (0.21 mmol) of phenyl(4,6-dimethoxypyrimidin-2-yl)carbamate in 1.3 mL of dry acetonitrile was added 0.04 mL (0.27 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. After 45 minutes at room temperature, 1.3 mL of water and 0.65 mL of 5% HCl were added. A solid precipitated out of solution. This material was isolated by filtration, washed with ether to give 60 mg of a white solid; m.p. 135° to 145° C. (d).