Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:4]2[C:5]([N:7]([C:10]3([C:16]#[N:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:8](=[O:9])[C:3]=12)=[O:6].S(=O)(=O)(O)[OH:23].O>C(Cl)Cl>[Cl:1][C:2]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:4]2[C:5]([N:7]([C:10]3([C:16]([NH2:17])=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)[C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc2c(c1Cl)C(=O)N(C1(C#N)CCCCC1)C2=O
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2c(c1Cl)C(=O)N(C1(C(N)=O)CCCCC1)C2=O
Reaction time: 4 h
Yield: 62 %

Procedure:
A solution of about 4.35 g (14.4 mmol) of 3-chloro-N-(1-cyanocyclohexyl)-4-methylphthalimide in about 50 ml methylene chloride is added to concentrated sulfuric acid and water at less than 10° C. with rapid stirring. The reaction mixture is stirred very vigorously at ambient temperatures for 4 hours (reaction complete by thin layer chromatography), poured over crushed ice and extracted with about 450 ml methylene chloride. The organic extracts are combined and concentrated in vacuo to give a white fluffy precipitate. The precipitate is filtered and air dried to give the title product, 2.86 g (62% yield), mp 192°-208° C., identified by infrared and NMR analysis.
Reaction SMILES: [C:1]1(=[O:30])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[C:13]([O:21][CH:22]([CH3:24])[CH3:23])[CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:25])[C:3]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]12.[OH-].[NH4+:32].O>CN(C)C1C=CN=CC=1.O1CCCC1>[C:1]1(=[O:30])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[C:13]([O:21][CH:22]([CH3:24])[CH3:23])[CH:12]=2)[CH2:7][C:8]([NH2:32])=[O:9])[C:4](=[O:25])[C:3]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]12
Reactant: [NH4+]
Reactant: CC(C)Oc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC(C)C
Agent: CN(C)c1ccncc1
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C(CC(N)=O)N2C(=O)c3ccccc3C2=O)cc1OC(C)C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
A solution of 3-phthalimido-3-(3,4-diisopropoxyphenyl)propionic acid (1.0 g, 2.4 mmol), 1,1 carbonyldiimidazole (0.43 g, 2.6 mmol), and 4-dimethylaminopyridine (trace) in tetrahydrofuran (18 mL) was stirred for 1.5 hours at room temperature. To the solution was added ammonium hydroxide (0.24 mL, 3.7 mmol, 28-30%) and stirring was continued for 2 hours. The tetrahydrofuran was removed in vacuo leaving an oil. To the oil was added 2 mL of water and the mixture was stirred at room temperature overnight. The resulting slurry was filtered, the solid was washed with water, air dried, and dried in vacuo (60° C.,<1 mm) to afford 0.87 g (88%) of 3-phthalimido-3-(3,4-diisopropoxyphenyl)propionamide as a white solid: mp 153-154.5° C.; 1H NMR (DMSO-d6) δ 7.92-7.78 (m, 4H), 7.55 (s, 1H), 7.03(s, 1H), 6.93-6.77 (m, 3H), 5.71-5.56 (m, 1H), 4.514.33 (m, 2H), 3.25-3.06 (m, 2H), 1.31-1.08 (m, 12H); 13C NMR (DMSO-d6)δ 171.7, 168.3, 148.9, 133.9, 132.1, 131.9, 123.3, 120.9, 117.7, 72.2, 72.1, 51.5, 37.9, 22.2; Anal. Calcd. for C23H26N2O5. Theoretical: C, 67.30; H, 6.38; N, 6.82. Found: C, 67.01; H, 6.35; N, 6.69.
Reaction SMILES: [CH:1]([NH:3][C:4]1[N:9]=[C:8]([C:10](=[N:37][O:38][CH3:39])[C:11]([NH:13][CH:14]2[C:35](=[O:36])[N:16]3[C:17]([C:22]([O:24]CC4C=CC([N+]([O-])=O)=CC=4)=[O:23])=[C:18]([Cl:21])[CH2:19][S:20][C@H:15]23)=[O:12])[CH:7]=[CH:6][CH:5]=1)=[O:2].CO>[Pd].O1CCCC1>[CH:1]([NH:3][C:4]1[N:9]=[C:8]([C:10](=[N:37][O:38][CH3:39])[C:11]([NH:13][CH:14]2[C:35](=[O:36])[N:16]3[C:17]([C:22]([OH:24])=[O:23])=[C:18]([Cl:21])[CH2:19][S:20][C@H:15]23)=[O:12])[CH:7]=[CH:6][CH:5]=1)=[O:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1cccc(NC=O)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1cccc(NC=O)n1
Reaction time: 4 h
Yield: 62.2 %

Procedure:
A mixture of 4-nitrobenzyl 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer) (1.43 g.), 10% palladium on carbon (0.8 g.), methanol (30 ml.) and tetrahydrofuran (60 ml.) was subjected to catalytic reduction at ambient temperature under ordinary pressure for 4 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. An aqueous solution of sodium bicarbonate and ethyl acetate were added to the residue, and the aqueous layer was separated. The aqueous layer was adjusted to pH 6, washed with ethyl acetate, and then adjusted to pH 1 to 2. The aqueous layer was extracted with ethyl acetate. The ethyl acetate extract was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. Diethyl ether (30 ml.) was added to the residue, stirred for one hour, and then precipitates were collected by filtration to give 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer) (680 mg.), brownish yellow powder, mp. 200° to 204° C. (dec.).
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:50][O:51][CH3:52])[C:27]([NH:29][CH:30]2[C:48](=[O:49])[N:32]3[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]4[S:43][C:42]([CH3:44])=[N:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)=O>O.C(N(CC)CC)C>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:50][O:51][CH3:52])[C:27]([NH:29][CH:30]2[C:48](=[O:49])[N:32]3[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]4[S:43][C:42]([CH3:44])=[N:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)c1csc(N)n1
Temperature: 57 °C
Yield: 28.7 %

Procedure:
A mixture of 1.4 g of the product of Example 1 and 5 ml of 50% aqueous formic acid was heated at 57° C. for 15 minutes and 5 ml of water were added. The mixture was cooled to room temperature and was vacuum filtered. The product was washed with ethanol and ether to obtain 0.687 g of raw product which was dissolved in 7 ml of water and 0.2 ml of triethylamine. The mixture was vacuum filtered and the filter was rinsed. The filtrate was acidified with 0.2 ml of 50% aqueous formic acid and the mixture was stirred and vacuum filtered. The product was washed with alcohol and ether to obtain 0.275 g of 7-[{2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl}amino]-3-[(2-methyl-1,3,4-thiadiazol-5-yl)-thiomethyl]-ceph-3-eme-4-carboxylic acid with a syn configuration.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:28][NH2:29])[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[Cl:39][C:40]1[C:41]([F:49])=[N:42][C:43]([F:48])=[C:44]([F:47])[C:45]=1F>C(#N)C.CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([NH:13][C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:28][NH:29][C:45]3[C:44]([F:47])=[C:43]([F:48])[N:42]=[C:41]([F:49])[C:40]=3[Cl:39])[CH2:20][CH2:21]2)=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:8]=1
Reactant: Fc1nc(F)c(Cl)c(F)c1F
Reactant: NCc1ccccc1N1CCN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC#N
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2ccccc2CNc2c(F)c(F)nc(F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
4-(2-Aminomethyl-phenyl)piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)amide (50 mg, 0.11 mmol, prepared in Example 26b) was dissolved in 500 μL of acetonitrile. Then, triethylamine (20 μL, 0.14 mmol) was added, followed by 3-chloro-2,4,5,6-tetrafluoropyridine (17 μL, 0.15 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was diluted to 2 mL in volume with methanol and the mixture was purified by reverse phase HPLC to give 15 mg of the product as a white solid. 1H NMR (CDCl3) δ 7.88 (s, 2H), 7.52 (s, 1H), 7.31-7.38 (m, 2H), 7.15-7.22 (m, 2H), 6.70 (s, 1H), 5.88 (br t, 1H), 4.85 (dd, 2H), 3.71 (m, 4H), 3.02 (t, 4H) ppm.
Reaction SMILES: C(OC(=O)[NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21]([C@H:23]2[N:27]3[C:28](=[O:38])[C:29]([NH:33][CH:34]4[CH2:37][CH2:36][CH2:35]4)=[N:30][C:31]([Cl:32])=[C:26]3[CH2:25][CH2:24]2)=[O:22])=[CH:15][CH:14]=1)=[NH:12])C1C=CC=CC=1.Cl.[H][H]>CO.O1CCOCC1.[Pd]>[ClH:32].[C:11]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][NH:20][C:21]([C@H:23]2[N:27]3[C:28](=[O:38])[C:29]([NH:33][CH:34]4[CH2:37][CH2:36][CH2:35]4)=[N:30][C:31]([Cl:32])=[C:26]3[CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:18]=1)(=[NH:10])[NH2:12]
Reactant: [H][H]
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(CNC(=O)[C@@H]2CCc3c(Cl)nc(NC4CCC4)c(=O)n32)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N=C(N)c1ccc(CNC(=O)[C@@H]2CCc3c(Cl)nc(NC4CCC4)c(=O)n32)cc1
Yield: 165.4 %

Procedure:
To a solution of the compound obtained from Step H (50 mg) in methanol (2.0 mL) was added HCl in dioxane (4.0 M, 0.13 mL) and 10% Pd/C (20 mg). This mixture was hydrogenated with a hydrogen ballon for 1.0 h. Removal of Pd/C and solvent gave the desired product as a white solid (34 mg, 82%). 1HNMR (300 MHz, DMSO-d6) δ 9.34 (br, 2H), 9.05 (m, 3H), 7.78 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 5.02 (m 1H), 4.43–4.31 (m, 3H), 3.5 (s, br), 2.90 (m, 2H), 2.21–2.05 (m, 6H), 1.65 (m, 2H). MS m/e 415(M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([O:11]C)=O)=[CH:4][CH:3]=1.[NH2:14][NH:15][C:16]([NH2:18])=[S:17].[OH-].[K+].[CH3:21]I>O.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:11])[NH:18][C:16]([S:17][CH3:21])=[N:15][N:14]=2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: COC(=O)C(=O)c1ccc(F)cc1
Reactant: NNC(N)=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSc1nnc(-c2ccc(F)cc2)c(=O)[nH]1
Temperature: 90 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
A mixture of methyl (4-fluorophenyl)(oxo)acetate (1.1 g, 0.0059 mol), thiosemicarbazide (0.54 g, 0.0059 mol) in water (10 mL) was heated at reflux for 15 min. Then methanol (10 mL) was added, followed by potassium hydroxide (0.43 g, 0.0077 mol). The mixture was stirred at 90° C. overnight. After cooling, methyl iodide (4 mL, 0.06 mol) was added. The mixture was stirred at RT for 30 min. The precipitate formed was collected by filtration, washed with ether, and dried under high vacuum to give the desired product (1.2 g, 77%). Analytical LCMS: (M+H)+=238.1.
Reaction SMILES: [N:1]1(C(N2C=CN=C2)N)C=CN=[CH:2]1.[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:17]=1[NH2:23]>C1COCC1.CCOC(C)=O>[NH2:1][C:2]1[O:22][C:18]2[C:17](=[C:16]([C:15]([O:14][CH3:13])=[O:24])[CH:21]=[CH:20][CH:19]=2)[N:23]=1
Reactant: NC(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1cccc(O)c1N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2oc(N)nc12
Temperature: 25 °C
Yield: 46.7 %

Procedure:
To a solution of di(1H-imidazole-1-yl)methanamine (2.05 g, 12.26 mmol) in THF (60 mL) was added methyl-2-amino-3-hydroxybenzoate (1.98 g, 12.26 mmol) at room temperature and the resulting reaction mixture was heated to reflux for 17 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL) and washed with H2O (3×100 mL), saturated ammonium chloride (2×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by recrystallization from diethyl ether to afford methyl 2-aminobenzoxazole-4-carboxylate (1.10 g, 50%) as a brown solid. 1H NMR and MS consistent.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:12]1([NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Ic1ccccc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1ccccc1)c1ccccc1

Procedure:
Example 2.1 was repeated, using 14.4 mg of cuprous oxide (0.1 mmoles), 117 mg of Chxn-Py-Al (0.4 mmoles), 472 mg of benzenesulphonamide (3 mmoles), 224 μl of iodobenzene (2 mmoles), 1.04 g of caesium carbonate (3.2 mmoles), 600 mg of ground and activated 3 Å molecular sieve and 1.6 ml of DMF.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:12]([OH:14])=[O:13])=[CH:3]1>[Pd].C(O)(=O)C.C(OCC)(=O)C>[O:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH:4]1[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cc(=O)c2ccccc2o1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)C1CCc2ccccc2O1
Yield: 96.2 %

Procedure:
A mixture of the compound from Example 8 (20.0 g, 105 mmol), and 10% palladium on activated carbon (2.0 g) in acetic acid (200 mL) was placed under hydrogen pressure (60 psig) in a Parr hydrogenation apparatus. After 22.5 hours the mixture was removed from the hydrogen atmosphere and filtered through a pad of Celite. The Celite pad was washed with ethyl acetate (800 mL), and the combined filtrate concentrated to give a brown oil. The oil was dissolved in ethyl acetate (500 mL) and extracted with saturated NaHCO3 (4×125 mL). The aqueous phase was acidified to pH=2 with concentrated HCl and extracted with ethyl acetate (4×100 mL). The combined organic phase was washed with saturated aqueous sodium chloride solution (100 mL), dried (MgSO4), and concentrated to give a colorless solid (18.0 g, 96%). Mp 97.5-99° C.; 1H NMR (300 MHz, DMSO-d6) δ 12.96 (br s, 1H), 7.03 (m, 2H), 6.78 (m, 2H), 4.74 (dd, J=6.4 Hz, J=3.9 Hz, 1H), 2.73 (m, 1H), 2.63 (m, 1H), 2.03 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[C:34]([C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH:39]=O)#[N:35].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([CH2:39][C:38]5[CH:37]=[C:36]([CH:43]=[CH:42][CH:41]=5)[C:34]#[N:35])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: N#Cc1cccc(C=O)c1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(Cc3cccc(C#N)c3)CC2)cc1

Procedure:
3-{4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-ylmethyl}-benzonitrile was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 25) with 3-cyanobenzaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.95-1.99 (m, 2H), 2.23-2.29 (m, 4H), 2.94-2.97 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.62 (s, 2H), 4.78-4.85 (m, 1H), 7.55-7.80 (m, 6H), 8.04-8.07 (m, 2H), 8.38 (s, 1H), 8.56 (s, 1H). Mass spectrum MH+=489.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.C1C=NC(NS(C2C=CC(N)=CC=2)(=O)=O)=NC=1.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39].O>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:38](=[O:39])[O:40][CH2:41][CH3:42])[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1nccc(-c2c[nH]nc2-c2ccc(F)cc2)n1
Reactant: CCOC(=O)Cl
Agent: Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Nc1nccc(-c2c[nH]nc2-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinamine prepared in accordance with Example A-306 (0.26 g, 0.001 mol) in 5 mL of pyridine was added ethyl chloroformate dropwise. After the addition, the clear solution was stirred at room temperature for 6 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was triturated with ether to give 0.15 g of product, ethyl[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]carbamate, as a white solid (46% yield), mp: 163-165° C.; Anal. Calc'd for C16H14FN5O2: C, 58.71; H, 4.31; N, 21.04. Found: C, 59.22; H, 4.51; N, 21.66.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=[N:25]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:28]4[N:24]([CH3:23])[N:25]=[CH:26][CH:27]=4)[CH:3]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3ccnn3C)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (116 mg, 0.56 mmol) and K2CO3 (116 mg, 0.84 mmol) in DME-water (2:1) was added Pd(PPh3)4 (16 mg, 0.014 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(1-methyl-1H-pyrazol-5-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 7.78 (t, 1H), 7.62 (d, 1H), 7.57 (m, 3H), 7.37 (d, 1H), 7.18 (d, 1H), 7.02 (d, 1H), 6.43 (d, 1H), 4.76 (d, 1H), 4.4 (d, 1H), 3.93 (s, 3H), 3.8 (m, 1H), 3.57 (m, 1H), 3.2 (m, 4H), 3.0 (m, 1H), 2.42 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][CH:40]([NH:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]4[C:14]5[NH:13][C:12](=[O:15])[NH:11][C:10]=5[CH:9]=[CH:8][CH:7]=4)[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)cc1OC
Product: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)cc1OC

Procedure:
The title compound was prepared from 4-((2S)-3-Amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one and Reference Example 73, N-(3,4-dimethoxy-phenyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as a grey solid. 1H NMR (DMSO) δ 1.28 (m, 2H), 1.84 (m, 2H), 2.65(m, 1H), 2.81 (m, 4H), 3.62(s, 3H), 3.64(s, 3H), 3.77(m, 2H), 3.89(m, 2H), 4.03(m, 1H), 4.87(bs, 1H), 6.59 (m, 4H), 6.74(d, 1H, J=8.7 Hz), 6.83(d, 1H, J=8.1 Hz), 6.91 (d, 2H, J=9.0 Hz), 7.45(d, 2H, J=9.0 Hz), 10.57 (bs, 1H), 10.69 (bs, 1H); MS (ES) m/z: 598.1 (MH+); HRMS for C29H35N507S: 598.2296 (MH+)
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([P-:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[K+].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1F>O1CCOCC1>[C:8]1([P:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[P:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc([P-]c2ccccc2)cc1
Reactant: Fc1ccccc1Nc1ccccc1F
Agent: [K+]
Solvent: C1COCCO1
Product: c1ccc(P(c2ccccc2)c2ccccc2Nc2ccccc2P(c2ccccc2)c2ccccc2)cc1

Procedure:
A 100-mL Schlenk flask equipped with a condenser was flashed with nitrogen thoroughly. To this flask was added KPPh2 (20 mL, 0.5 M in THF solution, Aldrich, 10 mmol). THF was removed in vacuo and a solution of di(2-fluorophenyl)amine (1.00 g, 4.88 mmol) in 1,4-dioxane (8 ml) was added with a syringe. The transparent, ruby reaction solution was heated to reflux with stirring. The reaction condition was monitored by 31P{1H} NMR spectroscopy, which revealed the completion of reaction in 2 d. The resulting yellow solution was evaporated to dryness in vacuo. The residue was treated with degassed deionized water (50 mL) and the product was extracted with deoxygenated dichloromethane (15 mL). The dichloromethane solution was separated from the aqueous layer, from which the product was further extracted with dichloromethane (15 mL×3). The combined organic solution was dried over MgSO4 and filtered; All volatiles were removed in vacuo to yield the product as a pale yellow crystalline solid; yield 2.1 g (80.15%). 1H NMR (CDCl3, 300 MHz) δ 7.10-7.23 (m, 24, Ar), 6.69-6.76 (m, 5, Ar and NH). 31P{1H} NMR (CDCl3, 121.5 MHz) δ-19.58. 31P{1H} NMR (Et2O, 121.5 MHz) δ-18.62. 13C NMR (CDCl3, 75 MHz) δ 146.51 (JCP=21.1), 135.78 (JCP=8.0), 134.14, 133.72 (JCP=21.1), 129.64, 128.53 (JCP=12.0), 128.46 (JCP=7.5), 126.34 (JCP=10.1), 121.51, 118.16. Anal. Calcd. for C36H29NP2: C, 80.43; H, 5.44; N, 2.61. Found: C, 80.04; H, 5.56; N, 2.69.