Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:23])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:22])/[CH2:9][CH2:10][C:11](=[O:21])[CH:12]([CH3:20])[CH2:13][S:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].N1C=CC=CC=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)Cl>[C:30]([O:1][CH2:2]/[CH:3]=[C:4](/[CH3:23])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:22])/[CH2:9][CH2:10][C:11](=[O:21])[CH:12]([CH3:20])[CH2:13][S:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CSCC(C)C(=O)CC/C(C)=C/CC/C(C)=C\CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CSCC(C)C(=O)CC/C(C)=C/CC/C(C)=C\COC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 300 mg (0.00088 mol) of methyl [[(6E, 10Z)-12-hydroxy-2,6,10-trimethyl-3-oxo-6,10-dodecadienyl]thio]acetate in 5 ml of methylene chloride is treated with 0.5 ml of pyridine and 0.4 ml of acetic anhydride. The solution is stirred at room temperature for 18 hours under argon. After removing the solvent the residue is taken up three times in toluene and freed from solvent each time on a rotary evaporator. The residue is chromatographed on silica gel with ether. There is obtained (2Z,6E)-12-[[(methoxycarbonyl)methyl]thio]-3,7,11-trimethyl-10-oxo-2,6-dodecadienyl acetate which exhibits the following bands in the IR spectrum: 1710 cm-1, 1657 cm-1, 1552 cm-1, 1445 cm-1, 1375 cm-1, 1290 cm-1, 1235 cm-1.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:11]=[CH:10][C:9]([S:12][C:13]#N)=[CH:8][C:5]=1[C:6]#[N:7].CI.O>C(O)C>[F:3][C:4]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#CSc1ccc(F)c(C#N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CI
Product: CSc1ccc(F)c(C#N)c1
Yield: 91.7 %

Procedure:
To a suspension of sodium borohydride (90%, 0.41 g (9.76 mmol)) in ethanol (10 ml), 2-fluoro-5-(thiocyanato)benzonitrile (0.29 g (1.63 mmol)) was added with stirring under cooling with ice. To the resulting mixture, after one hour's stirring at room temperature, methyl iodide (0.11 ml (1.71 mmol)) was added and the resulting mixture was stirred overnight at room temperature. Then, the reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (3:7) as eluent, to give 0.25 g (92%) of 2-fluoro-5-(methylthio)benzonitrile as pale yellow-white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]([C:19]2[CH:27]=[CH:26]C=C3[C:20]=2[CH2:21][O:22]C3=O)[C:9](=[O:18])[C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].[O-]CC.[Na+].C(O)C.[C:45]([O:49][CH2:50][CH3:51])(=[O:48])[CH2:46][CH3:47]>>[OH:22][C:21]1[C:20]2[C:46]([C:45]([O:49][CH2:50][CH3:51])=[O:48])=[CH:47][CH:26]=[CH:27][C:19]=2[N:8]([CH2:7][C:6]2[CH:29]=[CH:30][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9](=[O:18])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(CN(C(=O)C(=O)c2ccccc2)c2cccc3c2COC3=O)cc1
Reactant: CCOC(=O)CC
Agent: CC[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cccc2c1c(O)c(-c1ccccc1)c(=O)n2Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
A mixture of N-(4-methoxybenzyl)-2-oxo-N-(1-oxo-1,3-dihydroisobenzofuran-4-yl)-2-phenylacetamide (4.7 g, 11.7 mmol) and anhydrous Na2SO4 (16.6 g, 117 mmol) in anhydrous ethyl propionate (120 mL) was cooled to 0° C. Then a solution of sodium ethoxide in ethanol (sodium (673 mg, 29.2 mmol) in anhydrous ethanol (70 mL)) was added dropwise. After the addition, the mixture was stirred at room temperature for 18 hr. The mixture was quenched with water (100 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (250 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give product (4.02 g, yield 80%). LC-MS (ESI) m/z: 430 (M+1)+. 1H-NMR (400 MHz, DMSO-d) δ (ppm): 1.23-1.26 (t, J=6.8 Hz, 3H), 3.69 (s, 3H), 4.21-4.23 (m, 2H), 5.46 (s, 1H), 6.86-6.88 (d, J=7.6 Hz, 2H), 7.11-7.18 (m, 3H), 7.36-7.55 (m, 7H), 10.59 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]4[CH2:21][O:20]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]([OH:20])[CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]c(-c3ccc(OCC4CO4)cc3)nc2c1
Reactant: C1CCNC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: OC(COc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1)CN1CCCC1
Temperature: 85 °C
Yield: 24 %

Procedure:
To a solution of 6-bromo-2-[4-(oxiran-2-ylmethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (119 mg, 0.35 mmol) in DMF (8 ml), pyrrolidine (144 μl, 1.73 mmol) was added. The mixture was heated at 85° C. for 10 h. 5% Aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic phase was filtered and concentrated. Purification by flash chromatography on silica using methylene chloride/methanol/ammonia as eluent afforded the title compound (35 mg, 24%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.[CH3:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:15]=1[CH:16]=O.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>CS(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]=[C:16]([C:15]3[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:14]=3[CH3:13])[NH:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: Cc1cccc(C)c1C=O
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2nc(-c3c(C)cccc3C)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3,4-diaminobenzoic acid methyl ester (5.2 g) and 2,6-dimethylbenzaldehyde (4.2 g) in DMSO (50 mL) was added Yb(OTf)3 (3.9 g). The mixture was stirred at room temperature for 18 h. The mixture was partioned between water and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated to give 2-(2,6-dimethylphenyl)-3H-benzoimidazole-5-carboxylic acid methyl ester as a red solid; MS (ESI)m/z 281 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([OH:32])=[O:31].C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:27]4[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=4)[C:30]([OH:32])=[O:31])[CH2:21][CH2:20]3)=[CH:17][CH:18]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCNCC3)cc2)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCN(c4cccc(C(=O)O)c4)CC3)cc2)c1

Procedure:
3-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperidin-1-yl}-benzoic acid was synthesized from N-(3-tert-butyl-phenyl)-4-piperidin-4-yl-benzamide and 3-bromo-benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C29H32N2O3 (m/e) 456, obsd 457 (M+H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:24]O.[Br:30]C(Cl)(Cl)C(Cl)(Cl)Br>C(OCC)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:24][Br:30]
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: OCc1cc(Cl)cc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Clc1cc(Cl)cc(CBr)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A solution of triphenylphosphine (8.1 g) in diethyl ether (100 cm3) was added to a stirred solution of 3,5-dichlorobenzyl alcohol (5 g) and 1,2-dibromotetrachloroethane (9.9 g) in diethyl ether whilst maintaining the reaction temperature below 5° C. When the addition was complete the reaction mixture was allowed to warm to the ambient temperature (ca. 25° C.), and the mixture stirred for a further 2 hours. The precipitated solid was removed by filtration, and the filtrate concentrated by evaporation of the solvent to give 3,5-dichlorobenzyl bromide (6.8 g).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[C:6]=1[F:21])C.[AlH4-].[Li+]>O1CCCC1>[F:21][C:6]1[C:5]([CH2:4][OH:3])=[C:10]([F:11])[CH:9]=[CH:8][C:7]=1[NH:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])=[O:14]
Reactant: CCOC(=O)c1c(F)ccc(NS(=O)(=O)c2cccs2)c1F
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccc(F)c(CO)c1F)c1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2,6-difluoro-3-(thiophene-2-sulfonylamino)-benzoic acid ethyl ester (510, 1.6 g, 3.5 mmol) in tetrahydrofuran (25.0 mL) was added lithium tetrahydroaluminate (1.00 M in tetrahydrofuran, 8.08 mL, 8.08 mmol) under an atmosphere of nitrogen at room temperature. The reaction was stirred at room temperature for 8 hours, followed by addition of 10 g of NaSO4.10H2O. After 12 hours, the reaction was filtered, concentrated and purified with silica gel column chromatography eluting with 5% methanol in methylene chloride to give a white solid (511, 300.0 mg, 21.0%).
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.P(=O)(O)(O)O.CO>O.S(N(C1C=C(C(O)=O)C(N(S(=O)(=O)N)C2C=CC=CC=2)=CC=1C(O)=O)C1C=CC=CC=1)(=O)(=O)N.C(N(CC)S(C1C=CC(NC2C=C(C(O)=O)C(NC3C=CC(S(=O)(=O)N(CC)CC)=CC=3)=CC=2C(O)=O)=CC=1)(=O)=O)C>[CH3:1][C:2]1[CH:28]=[CH:27][C:5]2[NH:6][C:7]3[C:8]([C:9](=[O:10])[C:4]=2[CH:3]=1)=[CH:12][C:13]1[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[C:16](=[O:18])[C:14]=1[CH:15]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Agent: CCN(CC)S(=O)(=O)c1ccc(Nc2cc(C(=O)O)c(Nc3ccc(S(=O)(=O)N(CC)CC)cc3)cc2C(=O)O)cc1
Agent: NS(=O)(=O)N(c1ccccc1)c1cc(C(=O)O)c(N(c2ccccc2)S(N)(=O)=O)cc1C(=O)O
Agent: O=P(O)(O)O
Solvent: CO
Solvent: O
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Temperature: 92 °C
Reaction time: 0.08 h
Yield: 103.7 %

Procedure:
To 720 g of polyphosphoric acid (117%) heated at 92° C. were added 1.6 g of 2,5-di(sulfamoylanilino)terephthalic acid followed by 8 g of 2,5-di[4-(N,N-diethylsulfamoyl)anilino]terephthalic acid. The mixture was stirred for five minutes, after which 160 g of 2,5-di(4-methylanilino)terephthalic acid were added over a period of approximately 65 minutes, the temperature being maintained below 105° C. by adjustment of the addition rate. The reaction mixture was held at 105° C. for five hours and then cooled to 92° C. To this mixture was added 105.8 g of phosphoric acid (75%) dropwise over a period of approximately 30 minutes. The resultant melt was allowed to stir for 15 minutes at 90° C. and then poured slowly into 1120 g of methanol, the temperature being maintained below reflux using a water bath. The slurry was allowed to cool to room temperature and stand for 16 hours. The pigment slurry was heated at reflux for one hour, cooled below 65° C., diluted with water, collected by filtration, and washed with water until free of acid. The resultant presscake was reslurried in water and heated to 45° C. After the slurry was acidified to pH 2.6, an emulsion of 4.7 g of an anionic surfactant, 69.6 g of a petroleum distillate, and 160 g of water was added, and the slurry was stirred for three hours. The resultant slurry was collected by filtration and washed with water. The wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 150 g of 2,9-dimethylquinacridone as a magenta pigment.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH:11]([CH3:13])[CH3:12])=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1>C1C=CC=CC=1.O=[Mn]=O>[Cl:1][C:2]1[C:3]([O:10][CH:11]([CH3:13])[CH3:12])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH:8]=[O:9]
Reactant: CC(C)Oc1c(Cl)cccc1CO
Agent: O=[Mn]=O
Solvent: c1ccccc1
Product: CC(C)Oc1c(Cl)cccc1C=O
Reaction time: 48 h
Yield: 31.5 %

Procedure:
MnO2 (4.86 g, 56.0 mmol) was added to a stirring solution of (3-chloro-2-isopropoxyphenyl)methanol (1.60 g, 8.00 mmol) in benzene (75 mL), under N2. After stirring for 48 h, the solution was filtered over diatomaceous earth, the pad was rinsed with CH2Cl2 (100 mL), and the solution was concentrated to a yellow oil. Purification by column chromatography (silica gel hexanes/EtOAc, 98:2) gave the title compound (0.50 g, 31%) as a clear oil: 1H NMR (300 MHz, DMSO-d6) δ 10.28 (s, 1H), 7.84 (dd, J=7.8, 1.5 Hz, 1H), 7.72 (dd, J=7.8, 1.5 Hz, 1H), 7.31 (t, J=8.1 Hz, 1H), 4.53-4.48 (m, 1H), 1.32 (d, J=6.0 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[C:5]([CH3:13])=[N:6][C:7]=1[C:8](OCC)=[O:9].[NH2:23][CH2:24][C:25]([OH:27])=[O:26].[O-]CC.[Na+].Cl>CN(C=O)C.O>[OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[C:5]([CH3:13])=[N:6][C:7]=1[C:8]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:9]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C)c2c(-c3ccccc3)noc2c1O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2onc(-c3ccccc3)c12
Temperature: 25 °C
Yield: 77.5 %

Procedure:
Ethyl 7-hydroxy-4-methyl-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (41 mg, 0.138 mmol) was dissolved in 5 mL of DMF. Glycine (207 mg, 2.75 mmol) and sodium ethoxide (140 mg, 2.06 mmol) were added and the mixture was refluxed for 2 h. The mixture was cooled to room temperature and diluted with 30 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 3. The aqueous phase was extracted with EtOAc and the combined organic layer was dried over MgSO4 and concentrated to give 35 mg of pale yellow solid. The solid was dissolved in saturated NaHCO3 (10 mL) and washed with hexanes and EtOAc. The aqueous phase was acidified to pH 3 with concentrated HCl and extracted with EtOAc. The organic layer was dried and concentrated to give 15 mg of the title compound. MS: (+) m/z 328.39 (M+1).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([F:11])[C:8]2[N:7]([CH3:12])[C:6]3[CH2:13][CH:14]4[NH:18][CH:17]([C:5]=3[C:4]=2[C:3]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15]4.[C:26]1([S:32](C2C=CC=CC=2)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([S:32]([C:2]2[CH:10]=[C:9]([F:11])[C:8]3[N:7]([CH3:12])[C:6]4[CH2:13][CH:14]5[NH:18][CH:17]([C:5]=4[C:4]=3[C:3]=2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15]5)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S(=O)(c1ccccc1)c1ccccc1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)cc(F)c31)C1CCC(C2)N1
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccccc4)cc(F)c31)C1CCC(C2)N1
Yield: 26 %

Procedure:
The product of step C was converted to the phenylsulfone derivative following the procedure of Example 71, step D. The crude product was purified by flash column chromatography (SiO2, 75:25 hexane/ethyl acetate) to give tert-butyl 2-phenylsulfonyl-4-fluoro-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (61 mg, 26%) as an off-white solid: 1H NMR (CDCl3, 300 MHz): δ 7.91-7.99 (m, 3H), 7.43-7.55 (m, 3H), 7.28-7.36 (m, 1H), 5.13-5.31 (m, 1H), 4.58-4.70 (m, 1H), 3.78 (s, 3H), 3.14-3.50 (m, 1H), 2.41 (d, J=19.2 Hz, 1H), 2.12-2.40 (m, 2H), 1.86-1.97 (m, 1H), 1.58-1.68 (m, 1H), 1.38 (br s, 9H).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=O)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][NH:24][C:25]([NH2:27])=[S:26]>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15](=[N:23][NH:24][C:25]([NH2:27])=[S:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(N)=S
Reactant: O=C(c1ccccc1)c1cccc(C(=O)c2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: NC(=S)NN=C(c1ccccc1)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 26 h
Yield: 100 %

Procedure:
p-toluenesulfonic acid (0.026 g, 0.02 mmol) was added to a solution of 1,3 dibenzoylbenzene 2 (2.00 g, 6.98 mmol) in anhydrous methanol (20 mL). After stirring at reflux for 10 min, thiosemicarbazide (0.476 g, 5.235 mmol) was added to the reaction mixture and stirred for 26 h under an inert atmosphere of nitrogen gas. After 26 h, methanol was removed under reduced pressure and 50 mL of water was then added. The products were extracted with ethyl acetate (2×50 mL) and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification using flash chromatography (silica gel, hexanes:ethyl acetate, gradient 90:10 to 52:48) afforded 3-benzoyl benzophenone thiosemicarbazone 3 (0.829 g, 5.235 mmol) as a light yellow solid in a 44% yield. HRMS (ESI) calculated for C21H17N3OSH+ (M+H)+ 360.11651, found 360.11654. The isolated product 3 was 99.3% pure by HPLC at 300 and 320 nm; retention time 7.225 (method: 0-25 min, 50 to 100% acetonitrile, 50 to 0% water). This purified product was submitted for biological testing.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Cl)[CH:27]=1>[I-].[Na+].O>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:27]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccnc2)CCCC1=O
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 79.8 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (500 mg, 2.06 mmol), potassium carbonate (860 mg, 18.8 mmol), and catalytic amount of sodium iodide (ca. 10 mg), was treated with 3-picolyl chloride hydrochloride (500 mg, 3.05 mmol). The reaction was stirred at ambient temperature 19.5 hours. The mixture was poured into H2O (100 mL) and the mixture extracted four times with ethyl acetate. The combined organic layers were washed four times with H2O, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (elution with 5% MeOH in EtOAc) to afford 550 mg (80%) of the 9-[(3-pyridyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a white solid. 1H NMR (CDCl3) δ 8.48 (d, 1H, J=2.9 Hz), 8.43 (br s, 1H), 7.31 (d, 1H, J=7.3 Hz), 7.25-7.09 (m, 5H), 5.29 (s, 2H), 3.97 (s, 3H), 2.80 (t, 2H, J=6.1 Hz), 2.49 (t, 2H, J=6.4 Hz), and 2.20-2.12 (m, 2H). IR (CHCl3, cm−1) 1726, 1656, 1464, 1444, 1434, 1289 and 1119. MS (ES) m/e 335 (M+1).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:11]([OH:13])=O)=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[S:3][C:4]([C:11]([Cl:16])=[O:13])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1sc(Cl)nc1C(F)(F)F
Product: O=C(Cl)c1sc(Cl)nc1C(F)(F)F

Procedure:
A mixture of 36.0 g (0.1554 mole) of the acid of Example 15 and 171 g (1.437 mole) of thionyl chloride were held at reflux for 6 hours. Excess thionyl chloride was removed under reduced pressure and the residue (38.1 g, 98%) was reacted as described in Examples 17-29.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:17]2([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[C:9]2=[CH:10][CH:11]=[C:12]([C:13]([F:16])([F:15])[F:14])[N:8]2[CH2:7][CH2:6]1)=[O:4].[ClH:30].O1CCOCC1>C(#N)C>[ClH:30].[CH3:1][NH:2][C:3]([N:5]1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:9]2=[CH:10][CH:11]=[C:12]([C:13]([F:15])([F:16])[F:14])[N:8]2[CH2:7][CH2:6]1)=[O:4]
Reactant: CNC(=O)N1CCn2c(C(F)(F)F)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: CNC(=O)N1CCn2c(C(F)(F)F)ccc2C12CCNCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To tert-butyl 2-(methylcarbamoyl)-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (0.66 g, 1.6 mmol) and acetonitrile (5 mL) was added a solution of HCl in dioxane (5.2 mL of 4.0 M, 21 mmol). The reaction mixture was stirred at room temperature for 60 minutes. The solvent was evaporated under reduced pressure to yield N-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-2-carboxamide hydrochloride as a brown solid (99%). ESI-MS m/z calc. 316.2, found 317.2 (M+1)+; Retention time: 0.77 minutes (3 min run).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1>>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)=[CH:8][CH:9]=2)[N:4]([C:24]2[CH:25]=[C:20]([Cl:19])[N:21]=[CH:22][N:23]=2)[CH:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: COc1ccc(-c2ccc3c(Br)c[nH]c3c2)cc1
Product: COc1ccc(-c2ccc3c(Br)cn(-c4cc(Cl)ncn4)c3c2)cc1

Procedure:
The target compound was prepared as in Example 9 using 3-bromo-6-(4-methoxyphenyl)-1H-indole (500 mg, 1.65 mmol) and 4,6-dichloropyrimidine (247 mg, 1.65 mmol).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:14]([F:15])=[CH:13][N:12]=[C:11]([C:16]([O-:18])=[O:17])[CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1>Cl>[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:14]([F:15])=[CH:13][N:12]=[C:11]([C:16]([OH:18])=[O:17])[CH:10]=3)[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=C([O-])c1cc(-n2cnc(C3CC3)c2)c(F)cn1
Agent: Cl
Product: O=C(O)c1cc(-n2cnc(C3CC3)c2)c(F)cn1
Temperature: 100 °C

Procedure:
4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropicolinate (640 mg, 2.11 mmol) was dissolved in 1N HCl (5 mL) and the reaction was heated to 100° C. overnight. The solvent was removed, CH3CN was added and the solvent removed to afford 4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropicolinic acid which was used in subsequent reactions.
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([O:16]C)[C:9]=2[F:18])[CH2:7][CH2:6]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH:5]1([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([OH:16])[C:9]=2[F:18])[CH2:6][CH2:7]1
Reactant: COc1c(C=O)ccc(C2CC2)c1F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1ccc(C2CC2)c(F)c1O
Reaction time: 2 h
Yield: 90.3 %

Procedure:
Boron tribromide (1 M dichloromethane solution, 18.5 mL) was added at −78 C to a dichloromethane (70 mL) solution of 4-cyclopropyl-3-fluoro-2-methoxybenzaldehyde (1.79 g), and the mixture was stirred at the same temperature as above for 2 hours in a nitrogen atmosphere and then stirred at 0 C for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture at 0 C, and dichloromethane was distilled off under reduced pressure. The obtained residue was subjected to extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.50 g).