Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[N:10]=2)=[CH:6][CH:5]=1)([O-])=O>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[N:10]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(NCCCO)n2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Yield: 74.4 %

Procedure:
A solution of 8.66 g (29.8 mmol) 3-[4-(4-Nitro-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in a mixture of 173 ml THF and 173 ml methanol was hydrogenated over 3.46 g of 10% palladium on charcoal for 8 h. The catalyst was filtered off and the filtrate evaporated. The obtained oil was treated with a small amount of THF and the precipitate removed by filtration. Evaporation of the filtrate gave an oil that was purified by chromatography on silica (dichloromethane/ethanol 95:5) to give 5.77 g (74%) of 3-[4-(4-Amino-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol as colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:5][C:4]=1[F:21])#[CH:2].Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][N:24]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([C:2]#[C:1][C:3]2[CH:20]=[CH:19][C:6]([O:7][CH2:8][C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:5][C:4]=2[F:21])=[N:24][CH:25]=1)[CH3:31]
Reactant: C#Cc1ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc1F
Reactant: CCOc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOc1ccc(C#Cc2ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc2F)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
Under nitrogen, a mixture of tert-butyl [(1S)-2-(4-ethynyl-3-fluorophenoxy)-1-methylethyl]carbamate (9.36 g), 2-bromo-5-ethoxypyridine (5.86 g), bis(triphenylphosphine)palladium(II) dichloride (2.04 g), cuprous iodide (0.552 g), triethylamine (6.06 mL), and toluene (20 mL) was stirred at 100° C. overnight. The precipitate was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (7.00 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:4]=2[CH:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.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[N:7]=[CH:6][C:5]2[C:8]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)=[N:9][N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:4]=2[CH:3]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1cc2c(cn1)c(I)nn2C1CCCCO1
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: Cn1cc(-c2nn(C3CCCCO3)c3cc(Cl)ncc23)cn1
Temperature: 85 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
A mixture of 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (120 mg, 0.33 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.50 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol) and cesium carbonate (320 mg, 0.99 mmol) in 1,4-dioxane (1 mL) and water (0.12 mL) was degassed and sealed. It was stirred at 85° C. for 3 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.10 g). LCMS (M+H)+=318.1.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].ClN1C(=[O:19])CCC1=O>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:19])[NH:8]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: O=C1Cc2c(cccc2[N+](=O)[O-])N1
Temperature: 70 °C

Procedure:
A mixture of 4-nitroindole (12.2 g, 75.2 mmol) and N-chlorosuccinimide (6.07 g, 30.1 mmol) in CHCl3 (500 mL) was heated at reflux for 30 h, then concentrated to dryness under reduced pressure. The residue was dissolved in AcOH (200 mL) and the resulting solution was warmed to 70° C., then 85% H3PO4 (80 mL) was added over 2 min. The mixture was heated to reflux for 90 min then cooled on ice. The cooled mixture was adjusted to pH 6 by addition of 10 N NaOH (450 mL), followed by aqueous NaHCO3, keeping the temperature below 30° C. The mixture was extracted with EtOAc (3×1 L) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was partially purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 0:100, and then triturated with MeOH to give the title compound. MS: m/z=179 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)=[CH:4][CH:3]=1.CC(=O)CC.Cl[CH2:24][C:25]1[N:26]=[C:27](/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=2)[O:28][CH:29]=1.[I-].[K+]>>[N:12]1([CH2:11][CH2:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:24][C:25]3[N:26]=[C:27](/[CH:30]=[CH:31]/[C:32]4[CH:33]=[CH:34][C:35]([O:38][C:39]([F:42])([F:40])[F:41])=[CH:36][CH:37]=4)[O:28][CH:29]=3)=[CH:3][CH:4]=2)=[O:17])[CH:16]=[CH:15][N:14]=[N:13]1
Reactant: O=C(CCCn1ccnn1)c1ccc(O)cc1
Reactant: FC(F)(F)Oc1ccc(/C=C/c2nc(CCl)co2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(CCCn1ccnn1)c1ccc(OCc2coc(/C=C/c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 116 mg (0.5 mmol) 1-(4-hydroxy-phenyl)-4-[1,2,3]triazol-1-yl-butan-1-one in 10 ml 2-butanone 98 mg (0.3 mmol) cesium carbonate was added and the mixture was stirred at 60° C. for 30 minutes. Then 152 mg (0.5 mmol) 4-chloromethyl-2-[(E)-2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole and 83 mg (0.5 mmol) potassium iodide were added and the mixture was stirred at 60° C. overnight. After removal of all volatiles in vacuo the residue was purified by column chromatography on silica (ethyl acetate) to give 4-[1,2,3]triazol-1-yl-1-(4-{2-[(E)-2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butan-1-one. Yield: 200 mg (81%) white solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](N)=[O:8])=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)O.[CH2:17]([OH:19])[CH3:18]>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:19][CH2:17][CH3:18])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(N)=O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(C#N)cc1
Yield: 75.9 %

Procedure:
p-Cyanobenzamide (73.0 g, 0.5 mol) which has a purity of 99% or more and ethanol (657.0 g) were placed in a 2 l-separable flask, and the mixture was allowed to react at 78° C. for 19 hours while a 95% sulfuric acid (51.6 g) was added thereto with stirring. Gas chromatographic analysis revealed that the reaction mixture contained 66.5 g of ethyl p-cyanobenzoate (yield 76%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][S:9]([O:12][N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]([S:9]([O:12][N:13]1[C:14](=[O:19])[CH2:15][CH2:16][C:17]1=[O:18])(=[O:10])=[O:11])[CH2:23][CH2:22][O:21][CH3:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)ON1C(=O)CCC1=O
Reactant: COCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCN(C(=O)OC(C)(C)C)S(=O)(=O)ON1C(=O)CCC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To a solution of N-(t-butoxycarbonylaminosulfonyloxy)-succinimide (272 mg), 2-methoxyethanol (84.4 mg) and triphenylphosphine (291 mg) in tetrahydrofuran (5 ml) was added diethyl azodicarboxylate (193 mg) under ice-water cooling and the mixture was stirred at 0° C. for 1 hour. After evaporation of solvent, the residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (2:1, 1:1) to give N-(N-t-butoxycarbonyl-N-(2-methoxyethyl)aminosulfonyloxy)succinimide as colorless oil (205 mg).
Reaction SMILES: Cl.Cl.Cl.[C:4]1([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][C:14]([C:20]4[N:21]=[C:22]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[N:23]5[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[C:24]=45)=[CH:15][CH:16]=3)[N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(N(CC)CC)C.CN(C=O)C>[NH2:29][C:25]1[C:24]2[N:23]([C:22]([CH:30]3[CH2:35][CH2:34][N:33]([C:36](=[O:38])[CH3:37])[CH2:32][CH2:31]3)=[N:21][C:20]=2[C:14]2[CH:13]=[C:12]3[C:17]([CH:18]=[CH:19][C:10]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)=[N:11]3)=[CH:16][CH:15]=2)[CH:28]=[CH:27][N:26]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nccn2c(C3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Reaction time: 1 h

Procedure:
1-(2-Phenyl-quinolin-7-yl)-3-piperidin-4-yl-imidazo[1,5-a]pyrazin-8-ylamine-tris HCl salt (59.0 mg, 0.1 mmol) was dissolved in triethylamine (1.0 mL) and DMF (0.5 mL). Acetic anhydride (12.0 μL, 0.1 mmol) was added and the reaction was stirred for 1 h. The reaction was concentrated in vacuo and purified by silica gel chromatography (Jones Flashmaster, 2 g/12 mL cartridge, eluting with 2% 7N NH3 in methanol/CH2Cl2). The sample was further purified using MDPS to yield 1-{4-[8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]piperidin-1-yl}ethanone as a pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 1.95 (ddd, 1H, J=22.4, 11.2, 4.0 Hz), 2.03-2.23 (m, 6H), 2.90 (ddd, 1H, J=13.6, 13.6, 2.8 Hz), 3.19-3.32 (m, 2H), 4.01 (bd, 1H, J=13.6 Hz), 4.64 (bd, 1H, J=13.2 Hz), 5.44 (bs, 2H), 7.11 (d, 1H, J=4.8 Hz), 7.24 (d, 1H, J=5.6 Hz), 7.46 (ddd, 1H, J=6.0, 2.4, 0.8 Hz), 7.50-7.54 (m, 2H), 7.86-7.94 (m, 3H), 8.16 (ddd, 2H, J=7.2, 3.6, 1.6 Hz), 8.24 (d, 1H, J=8.4 Hz), 8.38 (s, 1H); MS (ES+): m/z 463 (10) [MH+]; HPLC: tR=2.1 min (OpenLynx, polar—5 min).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]([CH:18]([C:21]1[NH:22][CH:23]=[CH:24][N:25]=1)[CH2:19][CH3:20])[CH3:17].C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:16]([CH:18]([C:21]1[N:22]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH:23]=[CH:24][N:25]=1)[CH2:19][CH3:20])[CH3:17]
Reactant: CCC(CC)c1ncc[nH]1
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1ccc(-n2ccnc2C(CC)CC)c([N+](=O)[O-])c1

Procedure:
Ethyl 4-fluoro-3-nitrobenzoate 9.16 g, 2-(1-ethylpropyl)-1H-imidazole 5.94 g, N,N-diisopropylethylamine 11.2 mL and acetonitrile 86 mL were mixed and heated under reflux for 15 hours in nitrogen atmosphere. From the reaction liquid the solvent was distilled off, and the residue was dissolved in ethyl acetate and rendered weakly alkaline with saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with water and dried over magnesium sulfate. Distilling the solvent off, 13.16 g of the title compound was obtained.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([NH2:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:33][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:25])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCCCCCCN
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCCNC(=O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 87.7 %

Procedure:
Part C, Method 2. To a solution of 5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentanoic acid (2.0 g, 0.0057 mol) in toluene (35 mL) was added heptylamine (1.63 mL, 1.27 g, 0.011 mol) and then boron trifluoride etherate (1.35 mL, 1.56 g, 0.011 mol) and the reaction mixture was stirred at reflux for 120 hours using a Dean-Stark moisture trap. The reaction mixture was cooled, extracted with 0.1N NaOH, 0.1N HCl, and water, and the combined organic extracts were dried over magnesium sulfate and concentrated under vacuum. The residue was chromatographed and worked-up as described in Part C, Method 1, to give 5-(4,5-diphenyl-1H-imidazol-2-ylthio)-N-heptylpentanamide (2.35 g, 0.005 mol) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]2.[N:14]1([CH2:19][CH2:20]O)[CH:18]=[CH:17][N:16]=[CH:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[N:14]1([CH2:19][CH2:20][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[CH3:12])[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]3)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: Cc1cc2c(cc1O)CCCC2=O
Reactant: OCCn1ccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc2c(cc1OCCn1ccnc1)CCCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
Under N2, a solution of 2.08 g (11.8 mmol) of 6-hydroxy-7-methyl-1,2,3,4-tetrahydro-1-naphthalenone in 25 mL of THF was treated with 1.46 g (13.9 mmol) of 2-(1H-1-imidazolyl)-1-ethanol and 3.1 g (11.8 mmol) of triphenylphosphine. The solution was cooled in ice and treated with a solution of 1.9 mL (11.8 mmol) of diethyl azodicarboxylate in 5 mL of THF. The solution was allowed to stir at room temperature overnight. The mixture was diluted with EtOAc and washed twice with H2O, twice with saturated NaHCO3, then with saturated NaCl. Drying over MgSO4 and removal of the solvent under pressure left the crude product. Chromatography on silica gel, eluting with CHCl3/MeOH (95/5) gave the product which was recrystallized from EtOAc/hexane to give 1.05 g (32.9% yield) of the product as a tan solid, mp 118-120° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 271 (M+H+).
Reaction SMILES: [C:1](OC=O)(=[O:3])C.[OH:7][C@@H:8]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][C@H:9]1[CH2:21][N:22]1[CH2:38][CH2:37][C:25]2([N:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:28][NH:27][C:26]2=[O:36])[CH2:24][CH2:23]1>>[CH:1]([O:7][C@@H:8]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][C@H:9]1[CH2:21][N:22]1[CH2:23][CH2:24][C:25]2([N:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:28][NH:27][C:26]2=[O:36])[CH2:37][CH2:38]1)=[O:3]
Reactant: CC(=O)OC=O
Reactant: COc1cc2c(cc1OC)[C@@H](O)[C@H](CN1CCC3(CC1)C(=O)NCN3c1ccccc1)C2
Product: COc1cc2c(cc1OC)[C@@H](OC=O)[C@H](CN1CCC3(CC1)C(=O)NCN3c1ccccc1)C2
Reaction time: 288 h

Procedure:
To 0.11 mole of a stirred formic acid-acetic anhydride mixture (prepared as described in Rec. Trav. Chem., 83, 1287 (1964) is added 0.10 mole of trans-8-[(2,3-dihydro-1-hydroxy-5,6-dimethoxy-1H-inden-2-yl)methyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one. The temperature of the reaction mixture is maintained below 20° C and stirring is continued for 12 days under argon. The reaction mixture is then poured, with stirring, into excess ice-cold aqueous sodium bicarbonate, extracted with ether and the ether extracts dried with anhydrous sodium sulfate. The ether is evaporated and the residue is crystallized from cyclohexane to give the title compound.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([S:7]([F:12])([F:11])([F:10])([F:9])[F:8])[CH:4]=[C:3]([C:13]([OH:15])=O)[CH:2]=1.O=S(Cl)[Cl:18]>>[F:8][S:7]([F:12])([F:11])([F:10])([F:9])[C:5]1[CH:4]=[C:3]([CH:2]=[CH:1][CH:6]=1)[C:13]([Cl:18])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(S(F)(F)(F)(F)F)c1
Product: O=C(Cl)c1cccc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(pentafluorothio)benzoic acid (Apollo Scientific, 0.42 g, 1.7 mmol) and SOCl2 (1.2 mL, 16.9 mmol) was warmed to reflux and was allowed to stir for 2 h. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in toluene (5 mL) and was concentrated under reduced pressure. This dilution with toluene and concentration was repeated two additional times to remove residual thionyl chloride and afford 3-(pentafluoro-λ6-sulfanyl)benzoyl chloride, that was used directly below.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7]([CH3:33])=[CH:8][C:9]([CH3:32])=[C:10]([C:12]2[N:17]=[C:16]([CH:18]=[N:19][C:20]3[C:25]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[CH:29]([CH3:31])[CH3:30])[CH:15]=[CH:14][CH:13]=2)[CH:11]=1)[CH2:2][CH:3]=[CH2:4].[C:34]1([Mg]Br)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:7]([CH3:33])=[CH:8][C:9]([CH3:32])=[C:10]([C:12]2[N:17]=[C:16]([CH:18]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[NH:19][C:20]3[C:25]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[CH:29]([CH3:31])[CH3:30])[CH:15]=[CH:14][CH:13]=2)[CH:11]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCOc1cc(-c2cccc(C=Nc3c(C(C)C)cccc3C(C)C)n2)c(C)cc1C
Reactant: Br[Mg]c1ccccc1
Solvent: Cc1ccccc1
Product: C=CCCOc1cc(-c2cccc(C(Nc3c(C(C)C)cccc3C(C)C)c3ccccc3)n2)c(C)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In the glovebox, N-((6-(5-(but-3-enyloxy)-2,4-dimethylphenyl)pyridin-2-yl)methylene)-2,6-diisopropylaniline (1.527 g, 3.40 mmol) is dissolved in toluene (40 mL). Phenylmagnesiumbromide (3.0M in ether, 1.36 mL, 4.09 mmol) is added, and the reaction mixture stirred at room temperature for one hour, removed from the glovebox, and quenched by addition of water (60 mL), and ether (80 mL). The aqueous layer is washed with additional ether (40 mL), and the combined organic fractions are washed with brine, dried over magnesium sulfate and filtered. Solvents are removed in vacuo, and the crude product is purified by column chromatography using 10:1 hexanes:ethylacetate (Rf=0.39) to yield 1.27 g (72.0%) of a very pale yellow solid. The structure is assigned by 1H NMR as shown in FIG. 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH:19]=O)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[NH:25]1[CH2:30][CH2:29][CH:28]([CH2:31][OH:32])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][OH:32])[CH2:27][CH2:26]2)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: OCC1CCNCC1
Reactant: O=CCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCCCN1CCC(CO)CC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for step D of example 223 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(3-oxopropyl)thiophene-2-carboxamide (150 mg, 0.37 mmol) and 4-piperidylmethanol (51.0 mg, 0.44 mmol). The title compound was afforded as a solid (30.0 mg, 17% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 8.83 (1H, m), 8.40 (1H, s), 3.38 (1H, m), 3.21 (4H, m), 2.83 (2H, m), 2.28 (2H, m), 1.60 (4H, m), 1.30 (1H, m), 1.00 (2H, m). MS m/z: 503.33, 505.32 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19](=[O:29])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[C:22]([F:28])[CH:21]=1.C[O-].[Na+].Cl>CO.O>[CH3:17][O:18][C:19](=[O:29])[C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:15]/[C:14](=[O:16])[C:13]2[C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:22]([F:28])[CH:21]=1
Reactant: CC(=O)c1cccnc1Nc1ccccc1
Reactant: COC(=O)c1ccc(C=O)c(F)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(/C=C/C(=O)c2cccnc2Nc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.5 %

Procedure:
A mixture of 1-(2-phenylamino-pyridin-3-yl)-ethanone (700 mg, 3.3 mmol) in methanol (16.5 mL) at 25° C. was treated with 3-fluoro-4-formyl-benzoic acid methyl ester (601 mg, 3.3 mmol, calculated from 50% mixture) and sodium methoxide in methanol (4.37M, 1.51 mL, 6.6 mmol). The reaction was stirred at 25° C. for 48 h. At this time, the reaction was diluted with water (50 mL), neutralized with a 2N aqueous hydrochloric acid solution, and extracted with methylene chloride (3×75 mL). The combined organics were dried over sodium sulfate and filtered. Silica gel was added to the filtrate, concentrated in vacuo and dried under high vacuum. Flash Chromatography (40 g silica column, 1% methanol/methylene chloride) afforded 3-fluoro-4-[(E)-3-oxo-3-(2-phenylamino-pyridin-3-yl)-propenyl]-benzoic acid methyl ester (1 g, 80.6%) as a red solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(Cl)Cl.CCN=C=NCCCN(C)C.Cl>>[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:11]([C:8]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]3[C:7]=2[NH:6][CH:5]=[CH:4]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)c1ccc(F)c2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)cc2)C(=O)c2ccc(F)c3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
To a solution of 59 mg (0.33 mmol) of 4-fluoro-1H-indole-7-carboxylic acid and 86 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-amine in 3 ml DCM 63 mg (0.33 mmol) of EDC.HCl were added and the reaction mixture was stirred over night at rt. The product was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 96 mg (72%) product as a colorless viscous oil. MS (ISP) 447.4 (M+H)+.