Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:16][CH3:17])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[OH:14])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH:27]=[C:28]1[C:34]2[CH:35]=[CH:36][CH:37]=[N:38][C:33]=2[CH2:32][O:31][C:30]2[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:16][CH3:17])[CH2:13][CH2:12][N:11]([CH2:25][CH2:26][CH:27]=[C:28]3[C:34]4[CH:35]=[CH:36][CH:37]=[N:38][C:33]=4[CH2:32][O:31][C:30]4[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]3=4)[CH2:10][C:9]2([CH3:15])[OH:14])=[CH:4][CH:3]=1
Reactant: COC1(c2ccc(Cl)cc2)CCNCC1(C)O
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC1(c2ccc(Cl)cc2)CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1(C)O
Temperature: 25 °C
Reaction time: 40 h
Yield: 37.7 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-4-methoxy-3-methyl-piperidin-3-ol (206 mg, 1.24 mmol) in acetonitrile/water (4:1, 20 mL) was added potassium carbonate (171 mg, 1.24 mmol) followed by 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (417 mg, 1.12 mmol). The mixture was stirred at rt 40 h and concentrated. The product residue was partitioned between ethyl acetate and water and the organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (100% methylene chloride −90% methylene chloride/10% methanol gradient) to afford the titled compound (232 mg, 35%) as an off-white solid.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([CH2:12][CH2:13][CH3:14])[CH2:6][C:7]([O:9]CC)=O)([O-])=O.C([O-])=O.[NH4+].[CH3:19][O:20][C:21]1[CH:44]=[CH:43][C:24]([CH2:25][N:26]2[C:30]3=[N:31][CH:32]=[CH:33][C:34]([CH:35]=O)=[C:29]3[N:28]=[C:27]2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:23][CH:22]=1>CO.CCOCC.[Pd]>[CH3:19][O:20][C:21]1[CH:44]=[CH:43][C:24]([CH2:25][N:26]2[C:30]3=[N:31][CH:32]=[CH:33][C:34]([CH2:35][N:1]4[CH2:4][CH:5]([CH2:12][CH2:13][CH3:14])[CH2:6][C:7]4=[O:9])=[C:29]3[N:28]=[C:27]2[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:23][CH:22]=1
Reactant: CCCC(CC(=O)OCC)C[N+](=O)[O-]
Reactant: COc1ccc(Cn2c(-c3ccccc3)nc3c(C=O)ccnc32)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CO
Product: CCCC1CC(=O)N(Cc2ccnc3c2nc(-c2ccccc2)n3Cc2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
Ethyl 3-(nitromethyl)hexanoate (0.52 g, 1.1 eq, 2.55 mmol) is dissolved in absolute methanol (8 ml). Then 10% Pd/C (0.2 g) and ammonium formate (1 g) are added under vigorous stirring. After 15 min, the mixture is diluted with ether (100 ml) and filtered. The solid on the filter is washed with ether (2×50 ml). A solution of 3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridine-7-carbaldehyde x225 (1 g, 1 eq, 2.9 mmol) in methanol (5 ml) is added immediately. The combined solution is evaporated in the vacuum of a rotary evaporator. The residue is dissolved in methanol (10 ml), CH(OMe)3 (0.5 ml) is added and the obtained solution is stirred at room temperature for 16 h. An excess of NaBH4 (1 g in several small portions) is then added under vigorous stirring for 20 min. The reaction mixture is evaporated in the vacuum of a rotary evaporator. The residue is partitioned between ethyl acetate and water. The organic phase is separated, dried with anhydrous sodium sulfate, and evaporated. The residue is dissolved in acetonitrile (10 ml), and the solution is refluxed for 24 h to complete the cyclization. The solvent is distilled off. The residue is purified by chromatography on silicagel (CCl4/MeCN) to yield 0.79 g of 1-{[3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one x226.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[C:27](O)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH:13][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=3)[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: O=C(O)c1cccnc1
Reactant: COc1c(OCCCN2CCOCC2)ccc2c1N=C(N)N1CCN=C21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(OCCCN2CCOCC2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Step 5, 1.0 g, 2.2 mmol) was dissolved in DMF (15 mL), and nicotinic acid (0.44 g, 3.3 mmol) was added. PyBOP (1.73 g, 3.3 mmol) and diisopropylethylamine (1.6 mL, 8.9 mmol) were subsequently added, and the mixture was stirred at rt overnight. EtOAc was added, and the solids were isolated by vacuum filtration to give the title compound (0.43 g, 40%): HPLC MS RT=1.15 min, MH+=463.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 9.01 (2H, s), 8.04 (1H, d), 7.43 (1H, d), 4.54 (2H, m), 4.34 (2H, br t), 4.23 (2H, m), 4.04 (2H, m), 4.00 (3H, s), 3.65 (2H, br t), 3.52 (2H, m), 3.31 (2H, m), 3.18 (2H, m), 2.25 (2H, m).
Reaction SMILES: [N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].[Mo:10](=[O:13])(=[O:12])=[O:11].O.O.O.O.O.O.O.[O-:21]S([O-])(=O)=O.[Mg+2]>O>[O-:11][Mo:10]([O-:21])(=[O:13])=[O:12].[N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3]
Reactant: O=S(=O)([O-])[O-]
Reactant: O=[Mo](=O)=O
Agent: Nc1nc(N)nc(N)n1
Agent: [Mg+2]
Solvent: O
Product: O=[Mo](=O)([O-])[O-]
Temperature: 105 °C
Yield: 98.03 %

Procedure:
Melaminium octamolybdate having a 2/1 molybdate/melamine molar ratio was prepared by the following procedure. 10.00 grams of melamine, 22.83 grams of molybdenum trioxide, 39.09 grams of epsom salt (MgSO4.7H2O) and 300 milliliters of water were added to a 500 milliliter round-bottom flask fitted with a water-cooled condenser. The mixture was refluxed at about 105° C. for 2 hours while being stirred continuously, cooled to room temperature and filtered. A white crystalline product was recovered. The recovered product was washed with water and vacuum dried at 100° C. for 11/2 hours. The product was identified by infrared and x-ray diffraction analyses to be melaminium octamolybdate. 32.88 grams of the product were recovered, representing a yield of 98.03 percent of the theoretical yield.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[F:21][C:22]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[C:23]=1[C:24](O)=O>>[F:18][C:17]([F:19])([F:20])[C:4]1[C:3]([C:1]#[N:2])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:12][C:13]1[N:16]=[C:24]([C:23]2[C:22]([F:21])=[CH:30][C:29]([F:31])=[CH:28][C:27]=2[F:32])[O:15][N:14]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1c(F)cc(F)cc1F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3c(F)cc(F)cc3F)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 2,4,6-trifluorobenzoic acid: MS (ES) m/z 423 (M+1).
Reaction SMILES: [C:1]1([CH:7]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:17])CO2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:26]N(C=O)C>>[CH2:18]([N:25]1[CH:26]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:12]2[N:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]1=[O:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1COC(c2ccccc2)c2ncccc21
Reactant: NCc1ccccc1
Reactant: CN(C)C=O
Product: O=c1c2cccnc2c(-c2ccccc2)cn1Cc1ccccc1
Yield: 51 %

Procedure:
To a solution of 8-phenylpyrano [3,4-b]pyridin-5-one (100 mg, 0.45 mmoles) in 5 ml DMF was added benzylamine (0,006 ml, 0.54 mmoles) under nitrogen. The reaction mixture was heated overnight to 80° C., cooled and concentrated under vacuum to give 253 mg of crude product. The crude product was chromatographed eluting with 1:1 EtOAc/Hexanes to give 72 mg (51% yield) of the desired 6-benzyl-8-phenyl-1,6-naphthyridin-5-one as a white solid. Characteristic analytical data are as follows: mp 166°-167° C.; 1H NMR (CDCl3, 300 MHz) δ5.31 (s, 2H), 7.28-7.58 (m, 12H) 8.82 (dd, 1H, J=8.2, 1.8 Hz) 8.98 (dd, 1H, J=4.6, 2.0 Hz); 13C NMR (75 MHz, CDCl3) δ161.88, 154.10, 151.84, 137.00, 136.29, 135.06, 134.24, 130.02, 129.02, 128.40, 128.19,128.12, 127.77, 122.06, 121.09,120.99, 52.00; mass spectrum (CI) , m/e 312; exact mass calcd. for C21H16N2O 312.1263, found 312.1259.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21].O>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:19]([O:11][C:6]1([CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[CH2:7][CH2:8][CH2:9][CH2:10]1)(=[O:22])[CH:20]=[CH2:21]
Reactant: C=CC(=O)Cl
Reactant: OC1(C2CCCO2)CCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1(C2CCCO2)CCCC1
Reaction time: 1 h
Yield: 80 %

Procedure:
In 80 ml of toluene were dissolved 16.8 g of 1-(2-tetrahydrofuranyl)cyclopentanol, 13.1 g of triethylamine, and 0.5 g of 4-(N,N-dimethylamino)pyridine. Then 10.7 g of acrylic chloride was added to the solution at 50° C., which was stirred at the temperature for one hour. Water, 50 ml, was added to the solution below 30° C., followed by ordinary post-treatment. Vacuum distillation yielded 18.1 g of 1-(2-tetrahydrofuranyl)cyclopentyl acrylate. The two-step yield was 80%.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:29](OCC)=O)=[CH:16][C:15]([F:34])=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].[OH2:35].[NH2:36][NH2:37]>CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:36][NH:37][C:29](=[O:35])[C:17]=4[CH:16]=[C:15]([F:34])[CH:14]=3)[CH:20]2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:9][CH:10]=1)[CH3:3]
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ccc(F)cc1)C(c1ccc(CN(C)C)cc1)N2
Reactant: NN
Reactant: O
Solvent: CO
Product: CN(C)Cc1ccc(C2Nc3cc(F)cc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of ethyl 2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (100 mg) in 85% hydrazine monohydrate (0.5 mL) and methanol (2 mL) was stirred at room temperature overnight. Methanol was removed under reduced pressure. The crude was purified by prep-HPLC to give the title compound (35 mg, yield 37%). LC-MS (ESI) m/z: 433 (M+1)+. 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.12 (s, 3H), 3.35 (s, 2H), 4.21 (d, J=8.0 Hz, 1H), 4.64 (d, J=8.0 Hz, 1H), 6.81-6.85 (m, 3H), 6.99-7.01 (m, 2H), 7.13-7.19 (m, 5H); 19F-NMR (400 MHz, CD3OD) δ (ppm): −105.66 (s), −118.17 (s).
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.C[C:7]([O:9][CH2:10][C:11]1[CH2:20][S:19][C@@H:14]2[C@H:15]([NH2:18])[C:16](=[O:17])[N:13]2[C:12]=1[C:21]([OH:23])=[O:22])=O.[Sb](Cl)(Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>O.CO>[NH2:18][CH:15]1[C:16](=[O:17])[N:13]2[C:12]([C:21]([OH:23])=[O:22])=[C:11]([CH2:10][O:9][CH3:7])[CH2:20][S:19][C@H:14]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 10 °C

Procedure:
To 10 ml of carbon tetrachloride were added 2.72 g of 7-ACA, 15 g of antimony pentachloride and 1.40 g of methanol. The mixture was cooled at 10° C. for 80 min to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. To the reaction mixture was added 150 ml of water. Then, the mixture was adjusted to pH 7.7 with sodium bicarbonate at a temperature of from 0° C. to 5° C. The resulting precipitate was filtered off, and then washed with water. The filtrate was combined with the washings. The resulting mixture was adjusted to pH 3.5 with 36 % hydrochloric acid, and then concentrated by evaporation under reduced pressure so that a precipitate was formed. The precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 10 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.61 g. The yield of the desired product was 25 %.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.[CH2:26]([O:33][C:34]1[CH:48]=[CH:47][C:37]([CH2:38][C@H:39]([NH2:46])[CH2:40][O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OCC)C>CN(C)C=O>[CH2:26]([O:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:38][CH:39]([NH:46][C:12]([CH:11]([NH:10][C:8]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:40][O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[CH:47][CH:48]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: CC(C)(C)OC[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Solvent: CCOCC
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(COC(C)(C)C)Cc1ccc(OCc2ccccc2)cc1
Temperature: 3 °C
Reaction time: 0.67 h

Procedure:
A 3° C. solution of 106 mg (0.41 mmol) (S)-2-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (Example 1, Step B) and 0.137 mL (0.41 mmol) 4-methylmorpholine in 2 mL N,N-dimethylformamide was treated with 165 mg (0.44 mmol) O-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uranium hexafluorophosphate (Novabiochem, La Jolla, Calif.), and stirred for 30 minutes, at which time a solution of (S)-1-(4-benzyloxy-benzyl)-2-tert-butoxy-ethylamine in 3 mL dimethylformamide was added and the mixture stirred at 3° C. for 40 minutes. The clear solution was poured into 15 mL diethyl ether and washed successively with 15 mL of each of the following: 5% aqueous HCl, brine, saturated aqueous NaHCO3, brine (twice) then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo affording 180 mg of white solid, which was recrystallized from hexane to give 116 mg (51%) of the title compound as a white solid; mp 98-99° C.
Reaction SMILES: [S:1](=[N:4][C:5]([NH2:7])=[O:6])(=[O:3])=[O:2].C(OC(=O)[N:14]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:33]=[CH:32][C:31](N)=[CH:30][CH:29]=1)[CH:20]=[CH:19]2)C)(C)(C)C.[CH2:36]([C:38]1[S:42][C:41](S(N)(=O)=O)=[CH:40][CH:39]=1)[CH3:37]>>[NH2:14][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:29]=[CH:30][C:31]([NH:7][C:5]([NH:4][S:1]([C:41]3[S:42][C:38]([CH2:36][CH3:37])=[CH:39][CH:40]=3)(=[O:3])=[O:2])=[O:6])=[CH:32][CH:33]=1)[CH:20]=[CH:19]2
Reactant: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc(N)cc3)c(=O)c2cc1F
Reactant: NC(=O)N=S(=O)=O
Reactant: CCc1ccc(S(N)(=O)=O)s1
Product: CCc1ccc(S(=O)(=O)NC(=O)Nc2ccc(-n3ccc4cc(N)c(F)cc4c3=O)cc2)s1

Procedure:
An analogous sulfonylurea coupling and de-protection procedure to that described in Example 29 was performed on [2-(4-Amino-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and 5-ethylthiophene-2-sulfonamide to give N-({[4-(6-amino-7-fluoro-1-oxoisoquinolin-2(1H)-yl)phenyl]amino}carbonyl)-5-ethylthiophene-2-sulfonamide. ES-MS (M+H)+=501.1.
Reaction SMILES: CO.[N+:3]([C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][CH:29]=1)[C:9]([NH:11][C:12]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])=[O:10])([O-])=O>[C].[Pd].C(OCC)(=O)C>[NH2:3][C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][CH:29]=1)[C:9]([NH:11][C:12]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])=[O:10]
Reactant: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
2.0 mL of methanol, 2.0 mL of ethyl acetate and 3.0 mg of 5% palladium-carbon were added to 15 mg of 2-(3-nitrobenzamido)-4-phenylbenzoic acid at room temperature and stirred under hydrogen atmosphere at 40° C. for 2 hours. Insoluble were removed by filtration, and the solvent was evaporated under reduced pressure to obtain 5.1 mg of 2-(3-aminobenzamido)-4-phenylbenzoic acid as white solid.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[N:26]=[N:27][C:28](Cl)=[CH:29][CH:30]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.C1COCC1.[Pd]>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[N:26]=[N:27][CH:28]=[CH:29][CH:30]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccc(Cl)nn4)ccc32)n1)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4cccnn4)ccc32)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 9.1 %

Procedure:
2-[(S)-1-phenylethylamino]-4-[5-(6-chloropyridazin-3-yl)-benzimidazol-1-yl]pyrimidine (24.0 mg) was dissolved in 2 mL ethanol and 2 mL THF. Added 10%Pd/C (23.0 mg), fitted the system with a balloon of hydrogen and purged 3 times, and the system was left stirring for 20 h at room temperature. No apparent progress at this point so 1-drop of glacial acetic acid was added and refitted with the balloon and purged. Stirred approximately 20 h longer then filtered off the catalyst, the solvent was removed and the residue purified by preparative thin layer chromatography (1:1 hexanes:acetone then another in 90:10 CH2Cl2:MeOH to yield 2.0 mg of the title compound. 1H NMR (500 MHz, CDCl3, partial): δ 9.20 (dd, J=1.5, 4.9 Hz, 1H); 8.54 (br s, IH); 8.44 (d, J=5.3 Hz, 1H); 8.42 (s, 1H); 8.23 (br s, 1H); 7.97 (dd, J=1.5, 8.5 Hz, 1H); 7.59 (dd, J=4.9, 8.6 Hz, 1H); 7.47 (d, J=7.3 Hz, 2H); 7.42 (t, J=7.5 Hz, 2H); 6.82 (d, J=5.3 Hz, 1H); 1.66 (d, J=6.9 Hz, 3H). Mass spectrum (ESI) 394.4 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:20][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:24]3[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=3)=[CH:3][CH:4]=2)=[N:12][C:11]=1[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1oc(-c2ccc(-c3ccncc3)cc2)nc1CCN1CCCC1
Yield: 82.6 %

Procedure:
2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole (See Example 8) (7.23 g, 21.57 mmol), 4-pyridylboronic acid (3.98 g, 32.35 mmol), [1,1 bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (1:1) (0.616 g, 0.755 mmol), and aqueous sodium carbonate (2M, 40 mL) are dissolved in 200 mL of dioxane and heated to reflux for 1.5 hours. The mixture is concentrated to a dark residue and purified by flash silica gel chromatography (gradient: 3-6% 2M NH3 in MeOH/dichloromethane) to provide the titled compound (5.94 g, 82.5% yield). MS (m/e): 334.2 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([OH:11])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.[H][H]>CO.[Pd]>[BrH:1].[NH2:8][C:6]1[CH:7]=[CH:2][CH:3]=[C:4]([CH:12]([CH3:13])[CH3:14])[C:5]=1[OH:11]
Reactant: [H][H]
Reactant: CC(C)c1cc(Br)cc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CO
Product: Br
Product: CC(C)c1cccc(N)c1O
Temperature: 25 °C
Yield: 40.8 %

Procedure:
4-Bromo-2-isopropyl-6-nitrophenol (63.1 g) was dissolved in methanol (442 ml) and to the solution was added 5% Pd-C (11.0 g, water content: 50%). The mixture was subjected to catalytic reduction for 2.5 hours with bubbling hydrogen at hydrogen pressure of 1 to 2 kg/cm2 with maintaining the external temperature at about 25° C. After completion of the reaction, Pd-C was filtered off and the filtrate was concentrated under reduced pressure at an external temperature of not more than 70° C. Then, the residue was washed with ethyl acetate (200 ml) and dried to obtain 2-amino-6-isopropylphenol hydrobromide (23.0 g, 40.8%). The product was recrystallized from methanoldiethyl ether to obtain colorless plates, m.p. 210°-213° C. (decomp.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][P:56](=[O:63])([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59]>C(Cl)Cl>[CH2:61]([O:60][P:56]([CH2:55][CH2:54][O:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][NH:47][C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:13])([O:57][CH2:58][CH3:59])=[O:63])[CH3:62]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOP(=O)(CCOCCOCCN)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOP(=O)(CCOCCOCCNC(=O)[C@H](C)NC(=O)OC(C)(C)C)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (3.5 eq), followed by diethyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)phosphonate (1.2 eq, from example 5, step 3). The reaction was stirred at room temperature for 2 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give the title product as a colorless viscous oil.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11](=O)[CH2:12]Br)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].C(O)C.CCOCC.[C:23]([NH:26][C:27]([NH2:29])=[S:28])(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:1]([NH:4][CH:5]([C:11]1[N:29]=[C:27]([NH:26][C:23](=[O:25])[CH3:24])[S:28][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(N)=S
Reactant: CCOC(=O)C(NC(C)=O)C(=O)CBr
Solvent: CCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)C(NC(C)=O)c1csc(NC(C)=O)n1

Procedure:
To a solution of 34.6 g. of ethyl α-acetamido-β-oxo-γ-bromobutyrate in a mixture of 50 ml. of ethanol and 20 ml. of ether are added 18.9 g. of N-acetylthiourea and 15 ml. of pyridine. The mixture is heated under reflux for 4 hours, and condensed under reduced pressure. The condensate is extracted with ethyl acetate and the extract is washed with 5% aq. NaHCO3, then with water, and dried. The oily substance which is obtained from the extract by removal of the solvent is purified by silica gel chromatography to give ethyl α-acetamido-2-acetamidothiazol-4-ylacetate. 4.46 g. Melting point: 148.9°-150° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].I[CH2:22][CH2:23][CH3:24]>>[F:1][C:2]1[C:10]2[C:6](=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:8]([CH2:22][CH2:23][CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc2c(F)cccc2c1-c1ccc(OC)cc1
Yield: 4.2 %

Procedure:
Prepared according to Method D step B from 7-fluoro-3-(4-methoxyphenyl)-1H-indazole (0.121 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 1-iodopropane (0.096 mL, 1.0 mmol) to give the title compound (0.006 g).