Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg]I.[CH2:4](N(CC)CC)C.C(O[C:14]([C:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[O:18][N:17]=1)=[O:15])C.Cl>C1(C)C=CC=CC=1>[F:30][C:27]([F:28])([F:29])[C:23]1[CH:22]=[C:21]([C:19]2[O:18][N:17]=[C:16]([C:14](=[O:15])[CH3:4])[CH:20]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)on1
Reactant: CCN(CC)CC
Agent: C[Mg]I
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(-c2cccc(C(F)(F)F)c2)on1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
To a cooled (5-10° C.) solution of 4.6 ml (0.014 mol) methyl magnesium iodide solution (3M in diethyl ether) and 5.8 ml (0.042 mol) triethylamine in 10 ml toluene, a solution of 2.06 g (0.00723 mol) 5-(3-trifluoromethyl-phenyl)-isoxazole-3-carboxylic acid ethyl ester in 20 ml toluene was added dropwise. After the addition was complete, the reaction mixture was stirred at 0-5° C. for 2 h and then treated with 5.6 ml 4N aqueous HCl solution. The mixture was filtered over celite. The aqueous phase was separated and the organic layer was washed with water, 5% aqueous NaHCO3 solution and twice with water. The organic phase was dried over magnesium sulfate and the solvent was evaporated. The residue was dissolved in a mixture of 28 ml MeOH and 0.45 ml 20% aqueous KOH solution. The solution was heated to 45° C. for 30 min, then cooled and acidified to pH 2 by addition of 6N HCl. The solvent was evaporated and the residue was mixed with toluene and aqueous NaHCO3 solution. The mixture was filtered over celite. The organic layer was separated and the solvent was evaporated to yield 0.7 g (0.00274 mol) 1-[5-(3-trifluoromethyl-phenyl)-isoxazol-3-yl]-ethanone.
Reaction SMILES: [NH:1]([C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[NH2:2].N[C:13](N)=[O:14].N>>[N:1]1[N:2]=[C:13]([OH:14])[N:7]2[C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[S:4][C:3]=12
Reactant: NC(N)=O
Reactant: NNc1nc2ccccc2s1
Agent: N
Product: Oc1nnc2sc3ccccc3n12

Procedure:
2-Hydrazinobenzothiazole (100 grams) and urea (100 grams) were fused on an oil bath at about 180° C. for about an hour, by which time the molten material had solidified and evolution of ammonia had ceased. The solid thus obtained, the desired s-triazolo(3,4-b)benzothiazol-3-ol, was recrystallized twice from methanol, m.p., 235° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:35])([CH3:34])[C:13]([N:15]1[CH2:24][C:23]2[NH:22][C:21]3[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([O:31]C)=O)[C:20]=3[C:19](=O)[C:18]=2[CH2:17][CH2:16]1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:37][NH2:38].C(O)(=O)C.O>CC(N(C)C)=O.CCOC(C)=O>[CH3:34][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:35])[C:13](=[O:14])[N:15]1[CH2:24][C:23]2[NH:22][C:21]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:29](=[O:31])[NH:37][N:38]=[C:19]([C:20]=34)[C:18]=2[CH2:17][CH2:16]1
Reactant: NN
Reactant: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCN(C(=O)C(C)(C)NC(=O)OCc1ccccc1)C3
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N1CCC2=C(C1)Nc1cccc3c(=O)[nH]nc2c13
Temperature: 130 °C
Reaction time: 12 h
Yield: 42 %

Procedure:
A solution of methyl 2-(2-(((benzyloxy)carbonyl)amino)-2-methylpropanoyl)-5-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate (0.11 g) and hydrazine hydrate (1.0 mL) in DMA (1.5 mL) was heated at 130° C. for 1.5 h, acetic acid (2.0 mL) was added and the mixture was stirred at 130° C. for another 12 hours. The reaction mixture was cooled to room temperature, then water (15 mL) and EtOAc (50 mL) were added. The organic phase was separated and then washed with aqueous NaHCO3 (2×10 ml) and brine (20 ml), dried over Na2SO4, filtered, the organic phase was concentrated in vacuum to give the crude product, which was purified by Pre-HPLC to afford benzyl (2-methyl-1-oxo-1-(3-oxo-10,11-dihydro-2H-phthalazino[8,1-bc][1,7]naphthyridin-9(3H,7H,8H)-yl)propan-2-yl)carbamate (46 mg, 42%) as a yellow solid. 1H NMR (DMSO-d6) δ 11.8 (s, 1H), 10.6 (s, 1H), 8.4 (s, 1H), 7.65 (t, 1H, J=7.8 Hz), 7.49 (d, 1H, J=7.8 Hz), 7.25-7.35 (m, 6H), 4.90-4.91 (m, 2H), 4.34-4.40 (m, 2H), 3.83-3.89 (m 2H), 2.32-2.34 (m, 2H), and 1.40 (s, 6H). MS (ESI) m/e [M+1]+460.0.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[S:24][C:23]([C:25](OCC)=[O:26])=[N:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[Si:1]([O:18][CH2:19][C:20]1[S:24][C:23]([CH2:25][OH:26])=[N:22][N:21]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1nnc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)s1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)[Si](OCc1nnc(CO)s1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of ethyl 5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1,3,4-thiadiazole-2-carboxylate (998 mg) in methanol (12 ml) was added sodium borohydride (177 mg), and the mixture was stirred at 0° C. for 1 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the title compound (738 mg, yield 82%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[CH:4][C:3]=1[CH3:17].C([C:21]#[N:22])(C)=O.CC(N(C)C)=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.[Cu]I.[C-]#N.[C-]#N.[Zn+2]>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:21]#[N:22])=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C)c1Br
Reactant: CC(=O)C#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C#N)cc(C)c1Br
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
Trifluoro-methanesulfonic acid 4-bromo-3,5-dimethyl-phenyl ester (79.8 g, 0.24 mol) and AcCN (500 mL) were added to a 3 necked, 2.0 L round bottom flask equipped with mechanical stirrer, nitrogen inlet adapter, heating mantle and thermocouple. To the resulting solution were then added Pd(PPh3)4 (27.7 g, 0.024 mol), CuI (9.2 g, 0.048 mol) and Zn(CN)2 (79.8 g, 0.24 mol). The resulting mixture was stirred for 45 minutes at 50° C., DMAc (150 mL) was added and the temperature was increased to 80-88° C. and the mixture aged at this temperature overnight. The resulting mixture was cooled to ambient temperature, diluted with EtOAc (200 mL), and filtered with STAND SUPER-CEL 815520. The SUPER-CEL cake was rinsed with EtOAc (200 mL×6). The EtOAc solutions were combined and quenched with a 4:1:4 mixture of saturated NH4Cl: concentrated NH4OH:H2O (240 mL:60 mL:240 mL). The layers were separated and the organic layer was rinsed once with water (500 mL) and once with brine (500 mL), then concentrated to dryness in vacuo to yield a red thick oil. The title compound was crystallized from EtOAc (135 mL) and heptane (500 mL) to yield white-yellowish crystal.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:18]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:11][CH2:12][C:13]([F:17])([F:16])[CH:14]=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].[NH4+].[Cl-]>ClCCl.C(O)C>[Si:1]([O:8][CH2:9][C@@H:10]([N:18]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])=[CH:24][CH:23]=1)(=[O:20])=[O:21])[CH2:11][CH2:12][C:13]([F:16])([F:17])[CH2:14][OH:15])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCCCCN([C@@H](CCC(F)(F)C=O)CO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Product: CCCCCN([C@@H](CCC(F)(F)CO)CO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a stirred solution of the material from Step 6 (1.17 g, 1.833 mmol) in dichloromethane (22 mL) and ethanol (14 mL) was added sodium borohydride (347 mg, 9.17 mmol). The reaction mixture was stirred at room temperature for 2 hours, poured into saturated aqueous NH4Cl and extracted with dichloromethane (2×). The combined organics were washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using EtOAc-hexanes to afford 625 mg of the title compound. LCMS (M+Na)=660.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[NH2:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=1>C(#N)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]2[N:16]=[C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]3[CH:2]=2)=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: O=C(C=Cc1ccc([N+](=O)[O-])cc1)CBr
Reactant: Cc1ccnc(N)c1
Solvent: CC#N
Product: Cc1ccn2cc(C=Cc3ccc([N+](=O)[O-])cc3)nc2c1
Yield: 55.8 %

Procedure:
A mixture of 4-bromo-1-(4-nitrophenyl)but-1-en-3-one (5.7 g) and 2-amino-4-methylpyridine (6.8 g) in acetonitrile (50 ml) was stirred under reflux for 1.5 hours. The precipitate was collected by filtration and washed with acetonitrile to give 2-[2-(4-nitrophenyl)vinyl]-7-methylimidazo[1,2-a]pyridine (3.29 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[F:8].[C:10](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(S)cc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CSc1ccc(F)c(Cl)c1
Reaction time: 8 h
Yield: 101.6 %

Procedure:
To a stirred mixture of 3-chloro-4-fluorobenzenethiol (65 g, 0.403 mol) and potassium carbonate (54 g, 0.39 mol) in DMF (450 mL) was added drop wise CH3I (24.96 mL, 0.442 mol) at room temperature, and the mixture was stirred overnight. The reaction mixture was diluted with water (200 mL) and extracted with ethyl ether (150 mL×3), the combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to give (3-chloro-4-fluorophenyl)(methyl)sulfane (70 g, 98%) as a yellow liquid. To a solution of (3-chloro-4-fluorophenyl)(methyl)sulfane (66 g, 0.37 mol) in dichloromethane (1600 mL) was added 3-chloroperoxybenzoic acid (85% purity, 157 g, 0.77 mol) in portions, and the mixture was stirred at room temperature for 2 h. Then the mixture was washed with saturated aqueous sodium sulfite (600 mL). The organic phases were separated and sequentially washed with saturated aqueous sodium bicarbonate (250 mL×2) and water (250 mL), dried over Na2SO4 and evaporated under reduced pressure to give a yellow solid. The crude product was re-crystallized from ether (200 mL) to give the title compound (39.45 g, 51%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:11]=1[N+:22]([O-])=O)([O-])=O.[BH4-].[Na+].Cl>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:11]=1[NH2:22]
Reactant: O=[N+]([O-])c1cc(-c2ccccc2)ccc1-c1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: Nc1cc(-c2ccccc2)ccc1-c1ccc(-c2ccccc2)cc1N
Temperature: 0 °C
Yield: 84.8 %

Procedure:
16.6 g (42 mmol) of 3′,2″-dinitro-p-quaterphenyl and 1.99 g of Pd/C (10%) are suspended in 200 ml of methanol, and 8.4 g (222 mmol) of sodium borohydride are added in portions with stirring at 0° C. After stirring for 2 hours, the clear solution is neutralised with dilute HCl. The solvent is then removed, and the residue is washed intensively with water and recrystallised from dioxane. The precipitate is filtered and dried in vacuo, giving 11 g (35.6 mmol) of a crystalline solid. The overall yield is 78%.
Reaction SMILES: [OH-].[Na+].O.NN.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([C:13](=O)[CH3:14])[CH:12]=1>C(O)COCCOCCO>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([CH2:13][CH3:14])[CH:12]=1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: CCc1cc(Br)ccc1O
Temperature: 170 °C
Yield: 89.5 %

Procedure:
Sodium hydroxide (1.4 g, 35 mmol) and hydrazine monohydrate (2.04 mL, 42 mmol) were added to a solution of 5′-bromo-2′-hydroxyacetophenone (3 g, 14 mmol) dissolved in triethylene glycol (17 mL). The reaction mixture was heated to 170° C. for 24 h and then partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by flash silica gel chromatography (0% to 10% EtOAc in hexanes) to give the title compound (2.52 g, 90%). 1H NMR (CDCl3): δ 1.22 (t, 3H, J=7.5 Hz), 2.60 (q, 2H, J=7.5 Hz), 6.64 (d, 1H, J=8.5 Hz), 7.17 (dd, 1H, J=8.5, 2.5 Hz), 7.24 (d, 1H, J=2.5 Hz).
Reaction SMILES: [N+]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=[O:7])([O-])=O.NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.[C:56]([O:59]C1C=CC=CC=1C(Cl)=O)(=[O:58])[CH3:57].C(N(CC)CC)C>O1CCCC1>[C:56]([O:59][C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=2)=[N:13][CH:12]=1)[CH3:10])=[O:7])(=[O:58])[CH3:57]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3[N+](=O)[O-])nn2)cc(OC)c1OC
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3OC(C)=O)nn2)cc(OC)c1OC
Yield: 95 %

Procedure:
In a similar manner as described for Intermediate 10, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (95 mg, 0.31 mmol), 2-(chlorocarbonyl)phenyl acetate (65 mg, 0.33 mmol), and triethylamine (0.050 mL, 0.36 mmol) in tetrahydrofuran (2 mL) gave 2-{[(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)amino]carbonyl}phenyl acetate (138 mg, 95%) as an off yellow solid. MS m/z 467 (M+1).
Reaction SMILES: [CH2:1]([S:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][CH2:17][CH2:18][OH:19])(=[O:5])=[O:4])[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:27][S:28]([O:19][CH2:18][CH2:17][CH2:16][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([NH:6][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:8]=2)[NH:12][CH:11]=1)(=[O:30])=[O:29]
Reactant: CCS(=O)(=O)Nc1ccc2[nH]cc(CCCO)c2c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1ccc2[nH]cc(CCCOS(C)(=O)=O)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a solution of 3-(5-ethanesulfonylamino-1H-indol-3-yl)propanol (0.59 g, 2.1 mmol) in 20 mL of THF at 0° C. was added triethylamine (0.58 mL, 4.2 mmol) followed by the dropwise addition of methanesulfonyl chloride (0.24 mL, 3.1 mmol). The reaction was stirred for 30 minutes at 0° C. The reaction was poured into a mixture of saturated NaHCO3 and ethyl acetate. The organic phase was separated and the aqueous phase reextracted with three portions of ethyl acetate. The combined organic layers were washed with a saturated NaCl solution, dried over anhydrous K2CO3, filtered, and concentrated in vacuo to yield 3-(5-ethanesulfonylamino-1H-indol-3-yl)propyl methanesulfonate (0.75 g, >99%) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].Cl.C[N:15](C)CCCN=C=NCC.ON1C(=O)CCC1=O.N>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([NH2:15])=[O:6]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Agent: Cl
Agent: N
Agent: O=C1CCC(=O)N1O
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
3,4,5-Trifluorobenzoic acid (1.00 g) was dissolved in N,N-dimethylformamide (15 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.31 g) and N-hydroxysuccinimide (785 mg) were added thereto at 0° C. The mixture was stirred at room temperature for 3 hr. 28% Aqueous ammonia solution (2 mL) was added to the mixture at 0° C. and the mixture was stirred at room temperature for 30 min. Water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane=1:2→3:1) and recrystallized from a mixed solvent of isopropylether and hexane to give the title compound as colorless crystals (yield: 734 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C-]#N.[Na+].C1N2CC[N:14](CC2)[CH2:13]1.ClCCl>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:13]#[N:14])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: N#Cc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
A solution of 5-bromo-2-chloropyrimidine (10 g, 51.8 mmol) in dimethylsulfoxide (26 mL) was added to a mixture of sodium cyanide (2.59 g, 51.8 mmol) and triethylenediamine (1.2 g, 10.4 mmol) in dimethylsulfoxide (14 mL) and water (28 mL). The resulting mixture was stirred for 18 hours at room temperature. The mixture was then diluted with water (130 mL) and extracted with diethyl ether (3×150 mL). The combined organic solutions were dried over sodium sulfate and concentrated in vacuo to give a pale yellow solid. Re-crystallisation of the solid from hot dichloromethane afforded the title product in 99% yield, 9.4 g.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:30]=O>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:30][C:26]1[S:25][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1cccs1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1cccs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Mix carbon tetrabromide (49.8 g, 150 mmol) and methylene chloride (75 mL) and cool to 0° C. Add, by dropwise addition, a solution of triphenylphosphine (78.6 g, 300 mmol) in methylene chloride (75 mL). Stir at 0° C. for 30 minutes. Add, by dropwise addition, a solution of 2-thiophene-carboxaldehyde (8.75 g, 78.8 mmol) in methylene chloride (75 mL). Remove the cooling bath and stir at room temperature until the reaction is complete. Pour onto ethyl ether and water, separate the organic layer and dry (MgSO4). Filter and evaporate the solvent in vacuo. Purify by silica gel chromatography to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](O)=[O:6].ON1C2C=CC=CC=2N=N1.Cl.[CH3:23][NH:24][O:25][CH3:26].C(N(CC)CC)C.CNC(N=C=NCC)CCNC>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([N:24]([O:25][CH3:26])[CH3:23])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1cc(F)cc(F)c1
Agent: CCN=C=NC(CCNC)NC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(F)cc(F)c1
Temperature: 25 °C

Procedure:
To an ice cooled mixture of 3,5 difluoro benzoic acid (2.0 g, 0.012 mol), 1-hydroxy-benzotriazole (HOBT, 2.5 g, 0.018 mol) and N,O-dimethylhydroxylamine HCl (2.35 g, 0.025 mol) in CH2Cl2(100 mL) was added triethylamine (5.0 mL, 0.036 mol) and followed by addition of 1,3-dimethylamino propyl-3-ethylcarbodiimide (EDC, 3.8 g, 0.019 mol). The mixture was allowed to warm to room temperature and continuously stir overnight. The reaction mixture was added EtOAc (300 mL) and then washed by diluted HCl solution, NaHCO3 and NaCl solution. The organic layer was collected and dried with Mg2SO4 and evaporated. The crude product was purified by column (0-50% EtOAc/Heptane) to give the title compound, 2.6 gm colorless oil. (100%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:19][C:17]3[C:18]4[C:9](=[N:10][NH:11][C:12](=[O:20])[C:13]=4[CH:14]=[CH:15][CH:16]=3)[CH:8]2[C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:2]=1>CO.[Pt](=O)=O>[NH:23]1[CH2:24][CH2:25][CH2:26][CH:21]([CH:8]2[C:9]3=[N:10][NH:11][C:12](=[O:20])[C:13]4[CH:14]=[CH:15][CH:16]=[C:17]([C:18]=43)[NH:19][CH:7]2[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:22]1
Reactant: O=c1[nH]nc2c3c(cccc13)NC(c1cccnc1)C2c1cccnc1
Agent: O=[Pt]=O
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1cccnc1)C2C1CCCNC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 3.3 %

Procedure:
A suspension of 8,9-di(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (120 mg, 0.35 mmol) and platinum (IV) oxide (60 mg) in methanol (20 mL) was purged in 20 atm hydrogen and stirred at 50° C. for 24 hr. The mixture was filtered and the filtrate was concentrated to give the crude product. The crude product was purified by prep-HPLC to give 9-(piperidin-3-yl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (4 mg, yield: 4%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ 1.19-1.32 (m, 2H), 1.60-1.65 (m, 2H), 1.94-1.97 (d, J=10.0 Hz, 1H), 2.31-2.43 (m, 2H), 2.82-2.85 (d, J=12.4 Hz, 1H), 3.02-3.05 (d, J=12 Hz, 1H), 3.29-3.32 (dd, J1=2.8 Hz, J2=8.4 Hz, 1H), 4.25-4.26 (d, J=2.8 Hz, 1H), 7.02-7.05 (dd, J1=0.8 Hz, J2=8.8 Hz, 1H), 7.22-7.25 (m, 1H), 7.40-7.53 (m, 3H), 8.25-8.29 (m, 2H); LC-MS (ESI) m/z: 348 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:10])=[CH:4][N:3]=1.C([Li])CCC.[O:16]1[C:20]2([CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)OCC1.Cl.C([O-])(O)=O.[Na+].O>C1COCC1.C(OCC)(=O)C.CCCCCC>[OH:26][C:23]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:10])=[CH:4][N:3]=2)[CH2:24][CH2:25][C:20](=[O:16])[CH2:21][CH2:22]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COCc1ccc(Br)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COCc1ccc(C2(O)CCC(=O)CC2)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-bromo-5-(methoxymethyl)pyridine (2.61 g, 12.9 mmoles) was dissolved in dry THF (40 mL) under nitrogen and cooled to −78° C. n-Butyllithium (6.20 mL, 15.5 mmoles, 2.5 M in hexane) was added dropwise over 10 minutes to form a black solution. After 15 minutes, a solution of 1,4-dioxa-spiro[4.5]decan-8-one (2.21 g, 14.1 mmoles) in THF was added dropwise over 2 minutes and the mixture was gradually warmed to room temperature over 3 hours. TLC (50% ethyl acetate/hexane) and LC/MS indicated complete conversion. Aqueous HCl (14 mL, 6.0 M) was added and the mixture was stirred for 3 hours at room temperature and then neutralized with NaHCO3/H2O. The mixture was extracted 3 times with ethyl acetate and the combined extracts were adsorbed onto silica gel and chromatographed. The column was eluted with a gradient of hexane to 40% ethyl acetate/hexane. Pure fractions were combined and concentrated to provide the title compound as a pale yellow solid, 1.00 g (33%). LC/MS (M+H)+ m/z=236.1.