Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6](=[O:17])[C:7]2[C:12]([C:13](=[O:16])[C:14]=1Cl)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[O:17]=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13](=[O:16])[C:14]([N:28]2[CH2:29][CH2:30][N:25]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:26][CH2:27]2)=[C:5]1[NH:4][C:1](=[O:3])[CH3:2]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(=O)NC1=C(Cl)C(=O)c2ccccc2C1=O
Solvent: CCO
Product: CC(=O)NC1=C(N2CCN(Cc3ccccc3)CC2)C(=O)c2ccccc2C1=O
Yield: 89.7 %

Procedure:
A mixture of 500 mg of 2-acetylamino-3-chloro1,4-naphthoquinone, 880 mg of N-benzylpiperazine and 40 ml of absolute ethanol was heated at reflux for 3 hours, then the solvent was removed. The remainder was passed through a small plug of silica gel and eluted with chloroform. The eluate was concentrated to a solid which was recrystallized from dichloromethane/hexane, giving 700 mg of the desired product, mp 153-155°C.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]([O:8]CC)=O)[C:2]#[CH:3].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[N:19]=[C:20]=[S:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH3:11])[C:13]=1[N:19]1[C:6](=[O:8])[CH2:5][N:4]([CH2:1][C:2]#[CH:3])[C:20]1=[S:21]
Reactant: C#CCNCC(=O)OCC
Reactant: Cc1cccc(C)c1N=C=S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCN1CC(=O)N(c2c(C)cccc2C)C1=S
Temperature: 25 °C
Yield: 48.5 %

Procedure:
A mixture of ethyl N-propargylaminoacetate (14.1 g), 2,6-dimethylphenylisothiocyanate (16.3 g), triethylamine (10.1 g), and methylene chloride (150 mL) was heated at reflux for 3 hours. The reaction mixture was cooled to ambient temperature, washed with 1N HCl (100 mL), then with water. The organic layer was separated, dried over anhydrous magnesium sulfate, then evaporated to dryness. The residual oil was triturated with hexane. The solid w, as collected by filtration. Recrystallization from hexane-EtOAc afforded the title compound (12.5 g) as yellow solid, m.p. 117°-121° C. Anal. Calcd. for. C14H14N2S2O: C, 65.09; H, 5.46; N, 10.84. Found: C, 65.23; H, 5.43; N, 10.88. Mass spectrum (EI, M.+) m/z 258.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Na].Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]=1[S:1][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCOC(=O)CCCBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCCSc1nc2ccccc2[nH]1
Yield: 97.5 %

Procedure:
50 g of 2-mercaptobenzimidazole are dissolved in 300 ml of ethanol, and a solution of 7.65 g of sodium in 150 ml of ethanol is added at room temperature, with stirring. The mixture is stirred for a few minutes at room temperature and 64.3 g of ethyl 4-bromobutyrate are added rapidly. The reaction mixture is refluxed for 6 hours and then cooled. The solvents are evaporated off to dryness under vacuum, the residue is taken up with water and the crystals obtained are filtered off, washed with water and then with ether and dried to give 85 g of ethyl 4-(benzimidazol-2-yl)mercaptobutanoate in the form of crystals melting at 70°-72° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:29]1[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 90.5 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate (27 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (23 mg, 0.15 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 36 mg of the titled compound (yield, 91%). 1H NMR (300 MHz, CDCl3): δ 3.22-3.30 (m, 4H), 3.75-3.78 (m, 3H), 4.08-4.13 (m, 4H), 6.89-6.96 (m, 3H), 7.19-7.44 (m, 5H), 7.64-7.80 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:3][CH:2]=1.[N:29]1([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27][N:32]3[CH2:33][CH2:34][N:29]([C:35]4[CH:44]=[CH:43][C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36]=4)[CH2:30][CH2:31]3)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:3][CH:2]=1
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C(NCc1ccncc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCc1ccncc1)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(pyridin-4-ylmethyl)-amide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[C:29]([N:39]1[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]1)([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>O1CCCC1>[C:29]([N:39]1[CH2:44][CH2:43][C:42](=[CH:1][CH2:2][CH2:3][CH3:4])[CH2:41][CH2:40]1)([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]
Reactant: [Li]CCCC
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCC=C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Butyl lithium (44 ml of 1.6 M in hexane) was added slowly to a stirred suspension of 27 g of (n-propyl)triphenylphosphonium bromide in 350 ml of tetrahydrofuran and the resulting solution was refluxed for 1 hour. The mixture was cooled in an ice bath and 18 g of N-carbobenzyloxy-4-piperidone was added. After stirring at room temperature of 0.5 hour, the solution was refluxed for 2 hours. The cooled mixture was concentrated under reduced pressure, partitioned between ether and water, and the ether layer was dried (sodium sulfate) and evaporated. The residue was filtered through silica gel with 20% ethyl acetate-hexane to give 10 g of 1-carbobenzoxy-4-(1-butylidene)piperidine as a colorless oil.
Reaction SMILES: [NH:1]([C:30]([O:32][CH2:33][CH:34]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[C@H:2]([C:27]([OH:29])=[O:28])[CH2:3][CH2:4][C:5](=[O:26])[NH:6][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OC(C)C)(C)C.[F:54][C:55]1[C:60](O)=[C:59]([F:62])[C:58]([F:63])=[C:57]([F:64])[C:56]=1[F:65].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[NH:1]([C:30]([O:32][CH2:33][CH:34]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[C@H:2]([C:27]([O:29][C:60]1[C:55]([F:54])=[C:56]([F:65])[C:57]([F:64])=[C:58]([F:63])[C:59]=1[F:62])=[O:28])[CH2:3][CH2:4][C:5](=[O:26])[NH:6][C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: O=C(CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
1.5 g (2.27 mmol) of Fmoc-Gln(Trt)-OH×0.5 diisopropyl ether and 0.46 g (2.5 mmol) of pentafluoro-phenol are dissolved in 35 ml of ethyl acetate, cooled to 0° and, while stirring, 0.52 g (2.5 mmol) of dicyclohexylcarbodiimide is added. The mixture is stirred at 0° for 1 hour and at room temperature for 3 hours, and insoluble material is filtered off and washed with tetrahydrofuran. The filtrate is evaporated to dryness, and the residue is dissolved in 30 ml of tetrahydrofuran. Slow addition of petroleum ether while stirring results in crystallization of Fmoc-Gln(Trt)-OPfp; m.p. 185°-187°, [α]D20 =-16.4° (THF).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:13](=[O:15])[CH3:14])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(F)cc1C(F)(F)F
Product: CC(=O)Nc1ccc(F)cc1C(F)(F)F
Temperature: 0 °C

Procedure:
10.0 g (0.56 mol) 4-fluoro-2-trifluoromethyl-phenylamine were stirred overnight at RT in 40 mL acetic anhydride. The reaction mixture was poured onto 300 g ice water. The precipitate formed was suction filtered, washed with 100 mL water and dried i. vac.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:24])[NH:17][C:16]([CH3:25])=[C:15]1[C:26]([O:28][CH3:29])=[O:27].[CH2:30]1[O:38][CH:31]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[OH:38][CH:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:30][NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:24])[NH:17][C:16]([CH3:25])=[C:15]1[C:26]([O:28][CH3:29])=[O:27]
Reactant: c1ccc(C2CO2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCN
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCNCC(O)c1ccccc1
Reaction time: 48 h
Yield: 19.3 %

Procedure:
In 30 ml of N,N-dimethylformamide were dissolved 2 g of dimethyl 4-[2-(2-aminoethoxy)-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and 0.6 g of styrene oxide, and the solution thus formed was allowed to stand for 2 days at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The product was eluted with chloroform-methanol (95:5 v/v). Crude crystals were recrystallized from ethyl acetate to give 500 mg of dimethyl 4-[2-[2-(β-hydroxyphenethylamino)ethoxy]-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[CH2:12][N:11]([C:13](Cl)=[O:14])[CH:10]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]2([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])[C:21]#[N:22])[CH:5]=[CH:6][CH:7]=1.CC1(C)[O:37][C@@H:36]([CH2:38][CH2:39][NH2:40])[CH2:35][O:34]1.C(N(CC)CC)C.Cl>O1CCCC1>[OH:37][C@H:36]([CH2:35][OH:34])[CH2:38][CH2:39][NH:40][C:13]([N:11]1[CH2:12][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])[C:9]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]1[CH2:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:14]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CC(C)(C)CC1N(C(=O)Cl)CC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)CC1N(C(=O)NCC[C@H](O)CO)CC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
To a solution of rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl chloride (0.34 g, 0.7 mmol) in tetrahydrofuran (5 mL) was added 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.1 g, 0.71 mmol) and triethylamine (0.15 mL, 1 mmol). The reaction mixture was stirred at room temperature for 30 min. An aqueous HCl solution (1 N, 5 mL, 5 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solvents were removed and the residue was partitioned between ethyl acetate and NaHCO3 (sat.) solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography (EtOAc) to afford rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.11 g, 28%). HRMS (ES+) m/z Calcd for C27H31Cl2F2N3O3+H [(M+H)+]: 554.1784; Found: 554.1785.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:27]=[CH:26][C:12]([CH2:13][O:14][C:15]([N:17]2[CH2:24][C@H:23]([OH:25])[CH2:22][C@H:18]2[C:19]([NH2:21])=[O:20])=[O:16])=[CH:11][CH:10]=1)([O-:8])=[O:7].C(N(CC)CC)C>O1CCCC1>[N+:6]([C:9]1[CH:27]=[CH:26][C:12]([CH2:13][O:14][C:15]([N:17]2[CH2:24][C@H:23]([O:25][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:22][C@H:18]2[C:19]([NH2:21])=[O:20])=[O:16])=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h

Procedure:
A solution of 1.89 g of methanesulfonyl chloride in 10 ml of dried tetrahydrofuran was added dropwise to a suspension of 2.32 g of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-prolineamide and 1.67 g of triethylamine in 40 ml of dried tetrahydrofuran at room temperature. After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure, and to the residue were added 30 ml of water and 30 ml of diethyl ether. After cooling, the resulting white crystals were separated by filtration, washed successively with cool water and cool diethyl ether and dried under reduced pressure to obtain trans-1-(p-nitrobenzyloxycarbonyl)-4-methanesulfonyloxy-L-prolineamide.
Reaction SMILES: C[O-].[Na+].[CH3:4][SH:5].[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Cl)([O-:8])=[O:7]>CO.O>[CH3:4][S:5][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CSCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.4 %

Procedure:
To a stirred solution of 10.8 g (0.2 mol) of sodium methoxide in 70 ml of methanol at room temperature was added dropwise 12 ml (10.8 g, 0.22 mol) of methyl mercaptan through a gas addition funnel connected to a dry-ice condenser. The resulting mixture was stirred at room temperature for 1 hour and then added dropwise to a stirred solution of 30.0 g (0.175 mole) of o-nitrobenzyl chloride in 120 ml of methanol over 1 hour, while the temperature rose to 40° C. The reaction mixture was then diluted with 300 ml of water, and extracted 3 times with methylene chloride. The methylene chloride extracts were washed with dilute hydrochloric acid, dried, and concentrated to afford 38.6 g (96%) of yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:16][CH2:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[C:23](=O)[CH2:22][CH2:21]3)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([O:16][CH2:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[C:23](=[S:39])[CH2:22][CH2:21]3)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC1(c2cc(F)cc(OCc3ccc4c(c3)CCC(=O)N4C)c2)CCOCC1
Product: COC1(c2cc(F)cc(OCc3ccc4c(c3)CCC(=S)N4C)c2)CCOCC1
Temperature: 90 °C
Yield: 28 %

Procedure:
Using the procedure described in Example 1, except that the reaction mixture was heated to 90° C. for 2 hours, 4-[5-fluoro-3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylmethoxy)phenyl]-4-methoxytetrahydropyran was reacted with Lawesson's Reagent to give 4-[5-fluoro-3-(1-methyl-2-thioxo-1,2,3,4-tetrahydroquinolin-6-ylmethoxy)phenyl]-4-methoxytetrahydropyran in 28% yield, m.p. 136°-138° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[N:12]1[C:16]2[C:17](=[O:28])[N:18]([C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=3)[CH2:19][CH2:20][C:15]=2[C:14]([C:29]([F:32])([F:31])[F:30])=[N:13]1.[CH3:34][N:35]1[CH2:39][CH2:38][CH2:37][CH:36]1[CH2:40][CH2:41][NH2:42].O>C(O)CO>[I:27][C:24]1[CH:23]=[CH:22][C:21]([N:18]2[CH2:19][CH2:20][C:15]3[C:14]([C:29]([F:32])([F:30])[F:31])=[N:13][N:12]([C:5]4[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=4[C:3]([NH:42][CH2:41][CH2:40][CH:36]4[CH2:37][CH2:38][CH2:39][N:35]4[CH3:34])=[O:2])[C:16]=3[C:17]2=[O:28])=[CH:26][CH:25]=1
Reactant: CN1CCCC1CCN
Reactant: COC(=O)c1cc(OC)ccc1-n1nc(C(F)(F)F)c2c1C(=O)N(c1ccc(I)cc1)CC2
Solvent: O
Solvent: OCCO
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(I)cc2)CC3)c(C(=O)NCCC2CCCN2C)c1
Temperature: 85 °C
Yield: 32 %

Procedure:
The title compound was prepared from 2-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoic acid methyl ester as obtained in Example 1. The ester (159 mg, 0.278 mmol) was dissolved in ethylene glycol (2 mL) containing 2-(1-methyl-pyrrolidin-2-yl)-ethylamine (400 μL, 2.78 mmol) and heated to 85° C. for 12 h. The reaction was poured into water and extracted with ethyl acetate (3×10 mL). The combined extracts were washed with water (5×10 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by preparative thin layer chromatography to give 2-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-benzamide (60 mg, 32%) as a faint yellow solid. MS (ES+) 668.4 (M+H)+(100%). This material (60 mg, 0.089 mmol) was combined with 2-pyridone (17 mg, 0.18 mmol), anhydrous potassium carbonate (49 mg, 0.36 mmol), copper(I) iodide (3.4 mg, 0.018 mmol), 1,10-phenanthroline (3.2 mg, 0.018 mmol), and dry-degassed dimethylsulfoxide (1.0 mL) and heated to 140° C. for 6 h. The mixture was cooled to ambient temperature and diluted with 6N ammonium hydroxide and ethyl acetate. The phases were separated, and the aqueous phase extracted once with ethyl acetate. The combined organic extracts were washed successively with water (2×) and 3N ammonium hydroxide, dried over sodium sulfate, filtered, and evaporated. The residue was purified by preparative HPLC to give the title compound as a colorless solid. MS (ES+) 635.5 (M+H)+(100%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:25]=[C:24]3[C:20]([CH:21]=[CH:22][N:23]3[CH:26]([CH3:28])[CH3:27])=[C:19]([C:29](=[O:43])[NH:30][CH2:31][C:32]3[C:33](=[O:42])[NH:34][C:35]([CH3:41])=[CH:36][C:37]=3[CH2:38][CH2:39][CH3:40])[CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:41][C:35]1[NH:34][C:33](=[O:42])[C:32]([CH2:31][NH:30][C:29]([C:19]2[C:20]3[CH:21]=[CH:22][N:23]([CH:26]([CH3:27])[CH3:28])[C:24]=3[CH:25]=[C:17]([O:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:18]=2)=[O:43])=[C:37]([CH2:38][CH2:39][CH3:40])[CH:36]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(OCCN2CCN(C(=O)OC(C)(C)C)CC2)cc2c1ccn2C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(OCCN2CCNCC2)cc2c1ccn2C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
To a stirred solution of 4-(2-{1-isopropyl-4-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-pyridin-3-ylmethyl)-carbamoyl]-1H-indol-6-yloxy}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (280 mg, 0.472 mmol; prepared following the procedure of Example xx) in dichloromethane (15 mL) was added TFA (1.5 mL) at room temperature and then stirred for 3 h at room temperature. Reaction mixture was concentrated under reduced pressure, diluted with water (20 mL) and washed the resulting aqueous layer with diethyl ether (2×15 mL). The aqueous layer was basified with (pH˜8) with saturated aqueous NaHCO3 solution and extracted with dichloromethane (3×20 mL). The combined organic layer was washed with brine solution (2×25 mL) and concentrated. Purification by preparative HPLC afforded 1-isopropyl-6-(2-piperazin-1-yl-ethoxy)-1H-indole-4-carboxylic acid (6-methyl-2-oxo-4-propyl-1,2-dihydro-pyridin-3-ylmethyl)-amide (48 mg, 20%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 0.93 (t, 3H), 1.42 (d, 6H, J=6.8 Hz), 1.57 (m, 2H), 2.14 (s, 3H), 2.45-2.2 (m, 4H), 2.68 (t, 2H), 2.75 (t, 4H), 4.15-4.19 (m, 2H), 4.35 (d, 2H), 4.78-4.72 (m, 1H), 5.91 (s, 1H), 6.73 (d, 1H), 7.03 (s, 1H), 7.24 (s, 1H), 7.42 (d, 1H), 8.12 (t, 1H), 11.58 (bs, 1H). LCMS (ES+): m/z=494.57[M+H].
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][NH:21][C:20](=[S:23])[C@H:19]([NH:24][C:25](=[O:31])OC(C)(C)C)[CH2:18][CH2:17]1.[O:32]=[C:33]1[NH:41][C:36]2=[N:37][CH:38]=[CH:39][CH:40]=[C:35]2[N:34]1[CH:42]1[CH2:47][CH2:46][N:45](C(Cl)=O)[CH2:44][CH2:43]1>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][NH:21][C:20](=[S:23])[C@H:19]([NH:24][C:25]([N:45]2[CH2:44][CH2:43][CH:42]([N:34]3[C:35]4[C:36](=[N:37][CH:38]=[CH:39][CH:40]=4)[NH:41][C:33]3=[O:32])[CH2:47][CH2:46]2)=[O:31])[CH2:18][CH2:17]1
Reactant: O=C(Cl)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.5 %

Procedure:
Triethylamine (0.45 mL, 3.25 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-thioxoazepan-3-ylcarbamate (416 mg, 1.62 mmol) and 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carbonyl chloride (466 mg, 1.66 mmol) in dichloromethane (70 mL) and the mixture heated to reflux. After 18 h, the mixture was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography (100% dichloromethane o 95% dichloromethane/methanol) gave the title compound (685 mg). MS 501.0 (M+1).
Reaction SMILES: [C:1]123C(=O)[O:10][C:8](=[O:9])[CH:2]1[CH2:3][CH:4]([CH2:7]2)[CH2:5][CH2:6]3.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH2:13]([O:20][CH:3]1[CH:4]2[CH2:7][CH:1]([CH2:6][CH2:5]2)[CH:2]1[C:8]([OH:10])=[O:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1OC(=O)C23CCC(CC12)C3
Reactant: OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(O)C1C2CCC(C2)C1OCc1ccccc1

Procedure:
33.2 g (0.2 mol) bicyclo[2.2.1]heptane dicarboxylic anhydride and 27 g (0.25 mol) benzyl alcohol were charged to 500 ml chloroform in a 1 L round bottom flask. The system was refluxed for 16 hours with magnetic stirring. The solvent was then removed by rotary evaporator. The solid was then dried and grounded. The product was characterized using FTIR and GC-MS. The yield was quantitative.