Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([CH:11]=[N:12]O)=[CH:9][CH:8]=2)=[C:4]([Cl:18])[CH:3]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=2)=[C:4]([Cl:18])[CH:3]=1
Reactant: ON=Cc1ccc(Oc2ccc(Br)cc2Cl)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NCc1ccc(Oc2ccc(Br)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
18 mg (0.06 mmol) of 4-(4-bromo-2-chloro-phenoxy)-benzaldehyde-oxime was dissolved in 2 mL methanol, then 37 mg (0.15 mmol) of nickel(II)chloride hexahydrate and 21 mg (0.56 mmol) of sodium borohydride were slowly added. The reaction mixture was stirred overnight at RT and then purified by chromatography (reversed phase).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]5[CH:29]=[CH:28][C:27]([N:30](C)[C:31](=O)OC(C)(C)C)=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl.C(N(CC)CC)C>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]5[CH:25]=[CH:26][C:27]([NH:30][CH3:31])=[CH:28][CH:29]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(N(C)C(=O)OC(C)(C)C)cc5)cn34)ccnc2c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CNc1ccc(-c2ccc3nnc(COc4ccnc5cc(OC)ccc45)n3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl 4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl(methyl)carbamate (0.067 g, 0.13 mmol) was dissolved in MeOH (1.7 mL) and to the solution was added concentrated HCl (0.50 ml, 6.0 mmol). The reaction mixture was stirred at room temperature overnight. Upon completion, the crude mixture was concentrated in vacuo. The solid that remained after concentration was dissolved in MeOH and to the solution was added triethylamine (0.23 ml, 1.6 mmol). The reaction was allowed to stir for 1 h. The crude mixture was concentrated in vacuo. The compound was purified using via flash chromatography, eluting with 5-8% MeOH/NH4OH in DCM to yield 4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-N-methylbenzenamine as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH2:10][C:11]#[N:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH2:10][C:11]#[N:12])[N:3]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1cc(Cl)nc(SCC#N)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Nc2cc(C)nc(SCC#N)n2)cc1

Procedure:
A stirred mixture of 15.0 g. (0.075 mole) of (4-chloro-6methyl-2-pyrimidinylthio)aceto nitrile, 10.0g. (0.075 mole) p-anisidine and 7.5 g. (0.075 mole) of sodium carbonate in 150 ml of ethanol was heated under reflux for five hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The oily residue was dissolved in ethyl acetate. Dilution of the ethyl acetate solution with petroleum ether and cooling in ice yielded a precipitate. This solid was collected and recrystallized from a mixture of benzene-petroleum ether to afford 7.2 g. of product, m.p. 128°-131°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C:28](Cl)=[O:29].C(=O)(O)[O-].[Na+]>O1CCOCC1>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:28]([C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)=[O:29])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a mixture of 3-nitroaniline (2.07 g) and triethylamine (2.3 ml) in 1,4-dioxane (40 ml) was added 2-naphthoyl chloride (3.00 g) and the mixture was stirred at room temperature for 30 minutes. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate three times. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give N-(3-nitrophenyl)-2-naphthalenecarboxamide (3.02 g).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH2:23]([S:26](Cl)(=[O:28])=[O:27])[CH2:24][CH3:25]>ClCCl>[C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH:16][S:26]([CH2:23][CH2:24][CH3:25])(=[O:28])=[O:27])=[CH:12][C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc2oc(-c3ccccc3)nc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc2oc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.5 %

Procedure:
To a solution of 2-phenylbenzo[d]oxazol-5-amine (100 mg, 0.48 mmol) in dichloromethane (2 mL) at room temperature was added pyridine (83 μL, 0.95 mmol) followed by propane-1-sulfonyl chloride (61 μL, 0.52 mmol). The resulting solution was then stirred at room temperature for 16 h. Dichloromethane was added and the organic layer was washed with saturated aqueous copper sulfate solution. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting insoluble solid was washed with saturated aqueous NaHCO3 to afford 37.2 mg (25%) of the title compound (LCMS RT=6.25 min, MH+ 317.0)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:36])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[CH:25][CH:24]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[F:33][C:31]([F:32])([F:34])[C:30]([NH:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][C:20](=[O:36])[C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:15][CH:16]=2)=[CH:28][CH:27]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)CCc3ccc(NC(=O)C(F)(F)F)cc3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCc1ccc(NC(=O)C(F)(F)F)cc1)c1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A suspension of 4-(4-{3-[4-(2,2,2-trifluoroacetylamino)phenyl]propionyl}-phenyl)piperazine-1-carboxylic acid tert-butyl ester (2.5 g, 4.95 mmol) in dichloromethane (10 mL) and trifluoroacetic acid (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and diluted with water. The resultant white solid was collected, washed with water, dried in vacuo to give the title compound (1.93 g, 96%). The product was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[I-].[Mg+2].[I-].[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[CH:18]1[C:22](=[O:23])[CH:21]=[CH:20][C:19]1=[O:24]>>[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[CH:18]1[C:19](=[O:24])[CH:20]2[CH:21]([CH:5]3[O:1][CH:2]2[CH:3]=[CH:4]3)[C:22]1=[O:23]
Reactant: Cc1cc(C)c(C2C(=O)C=CC2=O)c(C)c1
Reactant: c1ccoc1
Agent: [I-]
Agent: [Mg+2]
Product: Cc1cc(C)c(C2C(=O)C3C4C=CC(O4)C3C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Furan (214 ml, 3.15 mol) and magnesium iodide (7.0 g, 0.025 mol) are added to 2-(2,4,6-trimethylphenyl)cyclopent-4-ene-1,3-dione (27.0 g, 0.126 mol) and the mixture is stirred at room temperature for 4 days. The reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-(2,4,6-trimethylphenyl)-10-oxatricyclo[5.2.1.02,6]dec-8-en-3,5-dione.
Reaction SMILES: [CH:1]([C:4]1[CH:35]=[CH:34][CH:33]=[CH:32][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:21](=[O:22])[CH2:20][C:19](=[O:23])[NH:18][C:17]3[C:24]4[C:29]([CH:30]=[CH:31][C:16]2=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:11][CH:10]=1)=[O:7])=[CH:2][CH3:3]>CO.O1CCCC1.[C].[Pd]>[CH2:1]([C:4]1[CH:35]=[CH:34][CH:33]=[CH:32][C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:21](=[O:22])[CH2:20][C:19](=[O:23])[NH:18][C:17]3[C:24]4[C:29]([CH:30]=[CH:31][C:16]2=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:13][CH:14]=1)=[O:7])[CH2:2][CH3:3]
Reactant: CC=Cc1ccccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1ccccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reaction time: 16 h
Yield: 46.5 %

Procedure:
5-[4-(2-Propenylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.065 mmol) was dissolved in a mixture of methanol (0.3 mL) and tetrahydrofuran (0.3 mL), the atmosphere was substituted with argon, then the solution was added with 10% palladiumcarbon (3 mg), and the mixture was stirred for 16 hours under a hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered through Celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/1) to give the title compound (14 mg, yield 46%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])([O:3]C(C)(C)C)=O.[CH2:17]([NH:24][CH2:25]C(OCC)=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[CH2:17]([N:24]1[CH2:25][C:1](=[O:3])[NH:8][C@@H:9]([CH2:10][CH2:11][S:12][CH3:13])[C:14]1=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CSCC[C@@H]1NC(=O)CN(Cc2ccccc2)C1=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
The title compound was prepared according to the procedure described in Example 2, Step A, except using Boc-L-methionine (10.0 g, 40.0 mmol), ethyl N-benzylglycinate (7.75 g, 40.0 mmol), HOBT (5.41 g, 40.0 mmol) and EDC.HCl (7.68 g, 40.00 mmol) in dimethylformamide. Upon completion of the reaction, the dimethylformamide was removed in vacuo and the crude product partitioned between ethyl acetate and water. The organic phase was washed with water and saturated sodium chloride solution, then dried over sodium sulfate. The solvent was removed in vacuo and the residue taken up in methylene chloride (200 mL). Trifluoroacetic acid (100 mL) was added and the reaction stirred at 20° C. for 2 h. The volatiles were removed in vacuo and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The title compound was obtained as a white solid (9.08 g). NMR (CHCl3, 300 MHz) δ 7.4-7.2 (6H, m); 4.60 (2H, AB q, J=13 Hz); 4.24 (1H, m); 3.85 (2H, AB q, J=18 Hz); 2.63 (2H, t, J=7Hz); 2.3-2.1 (2H, m); 2.1 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[O:13]([C:20]1[CH:21]=[C:22]([CH2:26][C:27](Cl)=[O:28])[CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[O:13]([C:20]1[CH:21]=[C:22]([CH2:26][C:27]([NH:1][C:2]2[N:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:28])[CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cccnc1N
Reactant: O=C(Cl)Cc1cccc(Oc2ccccc2)c1
Solvent: c1ccncc1
Product: CCOC(=O)c1cccnc1NC(=O)Cc1cccc(Oc2ccccc2)c1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
Ethyl 2-aminonicotinate (121, Example 4) (367.3 mg, 2.238 mmol) was added to 3-phenoxyphenylacetyl chloride (1.0 g, 4.4 mmol) in a 10 mL round-bottom flask. A stir bar and pyridine (2.0 mL, distilled) were added and the mixture heated to reflux (130° C., oil bath) under nitrogen with stirring for 3 h, then cooled to room temperature. The reaction mixture was quenched with water (10 mL) and extracted with chloroform (3×15 mL). The combined organic extracts were washed with sat. NaHCO3 (3×10 mL) and water (3×10 mL), dried (MgSO4), and rota-evaporated to dryness, leaving a dark residue. This residue was chromatographed on silica gel (24 g, Mallinckrodt, grade 62; mesh 60-200) and eluted with hexanes-EtOAc (1:4, 300 mL). The desired fractions were collected (Rf =0.52) and rota-evaporated to dryness, leaving an orange oil. This oil eventually precipitated out as a wet orange mass. Crystallization from ethanol afforded the title compound as yellow flakes, 224 mg (26.5%), mp 90°-1° C.; 1H NMR (CDCl3): δ1.39 (t, J=6.8, 3, CH3CH2), 3.83 (s, 2, benzylic), 4.35 (q, J=6.8, 2, CH3CH2O), 7.10 (m, 9, phenyl), 8.29 (dd, J1 =1.5, J2 =7.8, 1, py), 8.59 (dd, J1 =1.5, J2 =4.8, 1, py), 10.81 (s, 1, NH); IR (KBr): 3441, 3168, 1723, 1668, 1660, 1549, 1490, 1436, 1409, 1307, 1246, 1211, 1143, 1027, 980, 775, 700; HPLC: 100%; LRMS: 377 (10), 376 (M+, 45), 211 (15), 210 (100), 183 (10), 167 (15), 166 (25), 147 (35), 121 (10), 94 (35), 89 (30), 77 (15), 51 (10), 39 (10); HRMS Calcd: 376.1423. Found: 376.1419.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[C:21]([N:27]3[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]3)[CH:22]=2)=[O:10])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COc1ccc(NC(=O)c2ccc(Br)nc2)cc1N1CCN(C)CC1
Reaction time: 18 h

Procedure:
2-Bromo-5-pyridinecarboxylic acid (0.34 g; 1.68 mmol) was heated at reflux in thionyl chloride (8 ml) for 1 hour, cooled, evaporated in vacuo and the residue azeotroped with toluene. The orange residue was redissolved in CH2Cl2 (6 ml) and treated with dry triethylamine (0.24 ml;1.68 mmol) and 4-methoxy-3-(4-methyl-1-piperazinyl)benzenamine (0.372 g;1.68 mmol). The solution was stirred under Ar (18 hours), evaporated in vacuo and partitioned satd. K2CO3 (aq)/EtOAc. The organic phases were combined, dried over Na2SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 3%MeOH/CHCl3 to yield the title compound as brown crystals after trituration with acetone/Et2O (0.13 g;19%).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:31][CH2:32][C:33]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[O:34])=[CH:15][N:16]3[CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][C:21]=3[O:29][CH3:30])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:41]1([S:47]([NH2:50])(=[O:49])=[O:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:31][CH2:32][C:33]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[O:34])=[CH:15][N:16]3[CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH:50][S:47]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)(=[O:49])=[O:48])=[O:26])=[CH:22][C:21]=3[O:29][CH3:30])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Cn1cc(CCC(=O)N2CCOCC2)c2ccc(C(=O)NCC3CCCC3)cc21
Reactant: NS(=O)(=O)c1ccccc1
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2)ccc1Cn1cc(CCC(=O)N2CCOCC2)c2ccc(C(=O)NCC3CCCC3)cc21

Procedure:
Using a similar procedure to the described in Example 2, but starting from 4-[6-(N-cyclopentylmethylcarbamoyl)-3-[2-(morpholinocarbonyl)ethyl]indol-1-ylmethyl]-3-methoxybenzoic acid and phenylsulfonamide, the title compound was obtained as a white solid (69%); mp 244°-245°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:34][C@@H:33]([CH3:35])[N:11]2[C:12]3[CH:13]=[C:14]([N:19]=C(C4C=CC=CC=4)C4C=CC=CC=4)[CH:15]=[CH:16][C:17]=3[CH2:18][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].CO.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:34][C@@H:33]([CH3:35])[N:11]2[C:12]3[CH:13]=[C:14]([NH2:19])[CH:15]=[CH:16][C:17]=3[CH2:18][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(N=C(c4ccccc4)c4ccccc4)cc3N21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(N)cc3N21
Temperature: 60 °C

Procedure:
A mixture of (4R,10aR)-7-(benzhydrylidene-amino)-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester (3.35 g, 7.2 mmol), ammonium formiate (6.8 g, 107 mmol) and palladium on carbon (1.5 g, 5%) in methanol (35 mL) was heated to 60° C. for 1 h. After cooling the mixture was diluted with dichloromethane (100 mL) and filtered. The filtrate was washed with water (100 mL), the water phase was extracted with dichloromethane, and organic phases were pooled and dried with MgSO4. The solvents were removed in vacuo and the residue was purified by chromatography on silica gel with ethylacetate/n-hexane (1:1). The title product was isolated as yellow foam (1.15 g, 53%); ISP-MS: m/e=304.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:13]3[O:17][N:16]=[C:15]([CH3:18])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1I.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[N:36]=[C:37]([NH:40][C:41](=[O:43])[CH3:42])[S:38][CH:39]=3)=[CH:31][CH:30]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:13]3[O:17][N:16]=[C:15]([CH3:18])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[C:29]1[CH:30]=[CH:31][C:32]([C:35]2[N:36]=[C:37]([NH:40][C:41](=[O:43])[CH3:42])[S:38][CH:39]=2)=[CH:33][CH:34]=1
Reactant: CC(=O)Nc1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cs1
Reactant: Cc1cc(-c2c(O)c3cc(I)c(Cl)cc3[nH]c2=O)on1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1nc(-c2ccc(-c3cc4c(O)c(-c5cc(C)no5)c(=O)[nH]c4cc3Cl)cc2)cs1
Temperature: 80 °C
Yield: 84.9 %

Procedure:
To a solution of 7-chloro-4-hydroxy-6-iodo-3-(3-methylisoxazol-5-yl)quinolin-2(1H)-one (Intermediate 99) (125 mg, 0.311 mmol) in 1,4-dioxane (4 mL) and water (2 mL) were added N-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-yl)acetamide (Intermediate 31) (118 mg, 0.342 mmol), cesium carbonate (152 mg, 0.466 mmol) and tetrakis(triphenylphosphine)palladium (3.59 mg, 3.11 μmol). The reaction mixture was heated at 80° C. for 16 h. After cooling the reaction mixture was filtered, evaporated to dryness. The resulting residue was acidified with HCl 1N. The precipitate was filtered and dried to give the title compound N-(4-(4-(7-chloro-4-hydroxy-3-(3-methylisoxazol-5-yl)-2-oxo-1,2-dihydro quinolin-6-yl)phenyl)thiazol-2-yl)acetamide (130 mg, 0.264 mmol, 85% yield) as a grey solid. LCMS: (M+H)+=493; Rt=2.37 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][C@H:12]([CH2:14][C:15]([OH:17])=[O:16])[O:11][N:10]=2)=[CH:5][CH:4]=1)#[N:2].[C:18](OC(=N)N(C(C)C)C(C)C)([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl.Cl[Cu]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:13][C@H:12]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[O:11][N:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(C2=NO[C@@H](CC(=O)O)C2)cc1
Reactant: CC(C)N(C(=N)OC(C)(C)C)C(C)C
Agent: Cl[Cu]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H]1CC(c2ccc(C#N)cc2)=NO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
To a suspension of [3-(4-cyanophenyl)isoxazolin-5(R)-yl]acetic acid(500 mg, 2.17 mmol) in CH2Cl2 (20 ml) cooled in an ice-water bath was added a 1.6M solution of O-tert-butyl-N, N-diisopropylisourea, cat. CuCl(4 ml). The resulting mixture was stirred at rt for 48 hrs and then filted. The fitrate was concentrated and the residue dissolved in EtOAc. The EtOAc solution was washed with brine and then dried over Na2SO4. After concentration, the residue was chromatographed with a mixture of EtOAc and hexane to afford 600 mg of the product as a white solid(96%). 1H NMR(300 MHz, CDCl3) δ1.48(s, 9H), 2.60(dd, 1H), 2.60(dd, 1H), 3.16(dd, 1H), 3.52(dd, 1H), 5.169m, 1H0, 7.70(d, 2H), 7.78(d, 2H); MS(ESI) Calc. for (M−1)+: 285. Found: 285.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][C:14]([C:23](=[O:25])[CH3:24])=[CH:15][CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:3][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][C:14]([CH:23]([OH:25])[CH3:24])=[CH:15][CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:1]
Reactant: CC(=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Temperature: 60 °C
Yield: 83.6 %

Procedure:
To a solution of 1-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethan-1-one (500 mg, 1.48 mmol) in THF (50 mL) was added LiAlH4 (0.282 g, 7.37 mmol). The mixture was heated at 60° C. for 1 h. After cooling to room temperature, the reaction was quenched with a piece of ice cube. The solid was filtered off and washed with ethyl acetate (3×10 mL). The combined filtrate was concentrated to give the crude product, which was purified by silica gel chromatography using 2% MeOH in DCM as eluant to give the desired product (420 mg, 83% yield) as a white solid. LCMS m/z [M+H]+ 340.3
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)=O.[N+:7]([C:10]1[CH:28]=[CH:27][C:13]([CH2:14][O:15][C:16]([N:18]2[CH2:26][C@H:24]([OH:25])[CH2:23][C@H:19]2[C:20]([OH:22])=[O:21])=[O:17])=[CH:12][CH:11]=1)([O-:9])=[O:8]>ClCCl>[OH:25][C@H:24]1[CH2:26][N:18]([C:16]([O:15][CH2:14][C:13]2[CH:27]=[CH:28][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=2)=[O:17])[C@H:19]([C:20]([O:22][CH3:1])=[O:21])[CH2:23]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methanol (94.5 ml) and dichloromethane (945 ml) under ice cooling are dropwise added thionyl chloride (18.7 ml) and after 5 minutes stirring N-p-nitrobenzyloxycarbonyl-L-hydroxyproline (1: 72.4 g), and the mixture is stirred overnight at room temperature. The reaction mixture is concentrated in vacuum to give crude (2S,4R)-4-hydroxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (86.5 g) as pale yellow oil. This product can be used in the next step without further purification. IR ν (CHCl3) cm-1 : 3450, 1742, 1703, 1605. 1HNMR δ (CDCl3) ppm: 1.77(1H, s), 2.05 to 2.45(2H, m), 3.55 to 3.8(2H, m), 3.66, 3.76(3H, 2s), 4.49 to 4.62(2H, m), 5.06 to 5.35(2H, m), 7.43 to 7.56(2H, m), 8.22(2H, d, J=8.2 Hz).