Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[NH:11]1[CH2:15][CH2:14][CH:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH2:12]1.CN1CCOCC1.[CH3:32][N:33]([CH3:50])[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]1.C1(N=C=NC2CCCCC2)CCCCC1.C(NC1CCCCC1)(NC1CCCCC1)=O.[OH-].[Na+]>CN(C)C=O.O>[CH3:50][N:33]([CH3:32])[C:34]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:11]2[CH2:15][CH2:14][CH:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH2:12]2)=[O:42])[CH2:36][CH2:35]1
Reactant: c1ccc2c(C3CCNC3)c[nH]c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(CC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1(c2ccccc2)CCC(CC(=O)N2CCC(c3c[nH]c4ccccc34)C2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 40 %

Procedure:
1-hydroxybenzotriazole (810 mg, 6.0 mmole), 3-pyrrolidine-3-yl-1H-indole (558 mg, 3.0 mmole) and N-methylmorpholine (0.666 ml, 6.0 mmole) were added in succession under argon to a solution of (4-dimethylamino-4-phenylcyclohexyl)-acetic acid (897 mg, 3.0 mmole) in dry dimethylformamide (15 ml). The solution was cooled in an ice bath and dicyclohexylcarbodiimide (1.2 g, 6.0 mmole) was added. The reaction mixture was stirred for 4 days at RT, the dicyclohexylurea precipitating out little by little. The reaction mixture was worked up by separating the precipitated urea and adding the filtrate to a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Further urea thereupon precipitated out, which was separated. The aqueous phase was diluted with water (300 ml), 5M sodium hydroxide (7 ml, 35 mmole) was added, and the reaction mixture was kept for 3 days at 5° C. The crude product of 2-(4-dimethylamino-4-phenylcyclo-hexyl)-1-[3-(1H-indol-3-yl)pyrrolidine-1-yl]-ethanone precipitated out as a beige-coloured solid (1.11 g). After chromatographic separation on silica gel (80 g) with methanol 2-(4-dimethylamino-4-phenylcyclohexyl)-1-[3-(1H-indol-3-yl)pyrrolidine-1-yl]-ethanone was isolated in a yield of 40% (521 mg) as a colourless solid with an m.p. of 98°-100° C.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][CH:5]([CH2:7][CH2:8][CH2:9][CH3:10])[O:4][C:3]1=[O:11].[H][H]>[Pd].C(O)C>[CH3:1][C@H:2]1[CH2:6][C@@H:5]([CH2:7][CH2:8][CH2:9][CH3:10])[O:4][C:3]1=[O:11]
Reactant: [H][H]
Reactant: C=C1CC(CCCC)OC1=O
Agent: [Pd]
Solvent: CCO
Product: CCCC[C@@H]1C[C@H](C)C(=O)O1
Temperature: 25 °C
Yield: 10.3 %

Procedure:
3-Methylene-5-butyldihydro-2(3H)-furanone (5.8 g; 0.33 mole) was charged to a reactor with 0.25 g 5% palladium on carbon and 6 mls ethanol. The mixture was stirred at room temperature and hydrogen gas slowly introduced subsurfacely for eight hours. The catalyst was removed by filtering and the solvent evaporated under reduced pressure to yield 5.3 g of cis- 3-methyl-5-butyldihydro-2(3H) furanone (84% assay by GLC; 86.5% yield)
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([N:10]([CH2:18][C:19]2([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:22][CH2:21][CH2:20]2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].[CH2:30]([O:32][C:33](=[O:41])[CH:34](Br)[C:35](OCC)=[O:36])[CH3:31]>C1(C)C=CC=CC=1>[C:13]([O:12][C:11]([N:10]([CH2:18][C:19]1([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:22][CH2:21][CH2:20]1)[C:7]1[N:8]=[N:9][C:4]([CH:1]2[N:2]=[C:35]([OH:36])[CH:34]([C:33]([O:32][CH2:30][CH3:31])=[O:41])[S:3]2)=[CH:5][CH:6]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(C(N)=S)nn1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1SC(c2ccc(N(CC3(c4ncccc4F)CCC3)C(=O)OC(C)(C)C)nn2)N=C1O
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 17.2 %

Procedure:
t-Butyl 6-carbamothioylpyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (1.0 g, 2.4 mmol), diethylbromomalonate (2 mL, 12 mmol), and toluene were added to a round bottom flask, heated to 90° C., and stirred for 40 min. The reaction was concentrated and purified using reverse phase chromatography to yield 219 mg of ethyl 2-(6-(t-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-hydroxy-2,5-dihydrothiazole-5-carboxylate as an off-white solid.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[OH-].[Li+].O.[CH3:19][N:20]([CH:22]=O)C>C1COCC1>[N:20]1([C:2]2[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH2:22][CH2:4][CH2:3][CH2:2][CH2:12][CH2:19]1
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CN(C)C=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCCCCC2)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
A mixture of ethyl 4-fluoro-3-nitrobenzoate (Chontech 01072; 500 mg; 2.35 mmol; 1 eq.) and hexamethyleneimine (Fluka 52660; 697.89 mg; 7.04 mmol; 3 eq.) in DMF (2 mL) was stirred at 60° C. for 4 hours. The reaction mixture was then partitioned between ethyl acetate and aq. NH4Cl. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give a yellow solid. The latter was taken up in THF (5 mL) and lithium hydroxide (280.86 mg; 11.73 mmol; 5 eq.) then water (5 mL) were added. The reaction mixture was stirred at room temperature for 16 hours then the solvent was evaporated and the residue was diluted with water. After acidification to pH 5 with AcOH, the resulting precipitate was filtered and dried under high vacuum to afford the title compound (534 mg, 86%) as a yellow solid.
Reaction SMILES: C([N:8]1[CH2:13][C@@H:12]([O:14][CH3:15])[CH2:11][C@H:10]([C:16]([O:18][CH3:19])=[O:17])[C@H:9]1[C:20]([O:22]CC1C=CC=CC=1)=[O:21])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:15][O:14][C@@H:12]1[CH2:13][NH:8][C@H:9]([C:20]([OH:22])=[O:21])[C@@H:10]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]1
Reactant: COC(=O)[C@H]1C[C@H](OC)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](OC)CN[C@@H]1C(=O)O

Procedure:
A solution of 2-benzyl 3-methyl (2S,3S,5S)-1-benzyl-5-methoxypiperidine-2,3-dicarboxylate (30.0 mg, 0.0000755 mol) in 2 mL of MeOH was hydrogenated in the presence of 10% Pd/C, under a balloon pressure of hydrogen, for 1 h. The catalyst was filtered off and the filtration was concentrated to dry. The residue was used directly in next step (16 mg, 97.6%). MS (ESI): (M+H)+=218.0.
Reaction SMILES: [CH3:1][SiH:2]([CH3:11])[O:3][Si:4]([CH3:10])([CH3:9])[O:5][SiH:6]([CH3:8])[CH3:7].[CH3:12][NH:13][C:14](=[O:16])[CH3:15]>[Pt].C1(C)C=CC=CC=1>[CH3:12][N:13]([Si:2]([CH3:11])([CH3:1])[O:3][Si:4]([CH3:9])([CH3:10])[O:5][SiH:6]([CH3:7])[CH3:8])[C:14](=[O:16])[CH3:15]
Reactant: CNC(C)=O
Reactant: C[SiH](C)O[Si](C)(C)O[SiH](C)C
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CC(=O)N(C)[Si](C)(C)O[Si](C)(C)O[SiH](C)C
Temperature: 100 °C

Procedure:
To a 1000 ml 3-necked flask was added 208.5 grams (1 mole) purified 1,1,3,3,5,5-hexamethyltrisiloxane prepared in Example 1, 153.3 grams (2.1 moles) of N-methylacetamide, 173.2 grams of toluene and about 120 ppm of platinum containing catalyst (as Pt) prepared in accordance with the teaching of U.S. Pat. No. 3,220,970 to Lamoreaux (hereinafter Lamoreaux catalyst). To the flask was attached a mechanical stirrer, a thermometer and a reflux condenser. The reaction mixture was heated at 100° C. for 20 hours and thereafter heated at 130° C. for 24 hours. At the end of the 44 hour period, analysis by infrared spectroscopy showed no Si--H present in the reaction mixture. The solvent was removed by distillation and the residue filtered through Celite R to give 317.5 grams (90.6% theoretical) of 1,5-bits (N-methylacetamido)-1,1,3,3,5,5-hexamethyltrisiloxane.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:9]=[CH:8][S:7][C:6]=12.C[Mg]Br.O1CCCC1.[Br:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH:25]=[O:26])[CH:24]=1>>[Br:18][C:19]1[CH:24]=[C:23]([CH:25]([OH:26])[C:2]2[N:3]=[CH:4][N:5]3[CH:9]=[CH:8][S:7][C:6]=23)[CH:22]=[N:21][CH:20]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: Ic1ncn2ccsc12
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: OC(c1cncc(Br)c1)c1ncn2ccsc12
Yield: 89.3 %

Procedure:
7-[(5-Bromopyridin-3-yl)hydroxymethyl]imidazo[5,1-b]thiazole (2.77 g) was prepared in substantially the same manner as in step a) of Synthesis Example 1, except that 2.50 g of 7-iodoimidazo[5,1-b]thiazole, 12.2 ml of a 0.93 M methylmagnesium bromide/tetrahydrofuran solution, and 2.05 g of 3-bromo-5-formylpyridine were used as the starting materials.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[Mg].[CH2:12]([CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH:19]=[CH:18]1)[CH2:13][CH2:14][CH2:15][CH3:16].Cl>C(OCC)C>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:20]2([OH:23])[CH2:21][CH2:22][C:17]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:18][CH2:19]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCCCC1C=CC(=O)CC1
Reactant: CCCc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCC1=CCC(O)(c2ccc(CCC)cc2)CC1

Procedure:
A solution of 7.1 g of 4-propylbromobenzene in 25 ml of anhydrous diethyl ether was added dropwise under stirring at 15°-20° C. to 1 g of magnesium metal powder, followed by reaction at room temperature for 1 hour so that a Grignard reagent was formed. After 5 g of 4-pentylcyclohexenone were added under stirring at -10° to 0° C. to the thus-formed Grignard reagent, they were reacted at room temperature for additional 1 hour. After the completion of the reaction, diluted hydrochloric acid was added dropwise to the reaction mixture, followed by the extraction of the reaction mixture with diethyl ether. After the extract was washed with saturated NaCl, anhydrous sodium sulfate was added to dry the extract. The diethyl ether was distilled off under reduced pressure, whereby 4-(4-propylphenyl)-4-hydroxy-1-pentylcyclohexene was obtained as a crude reaction product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:11][C:10]([CH3:20])([CH3:19])[C:9]=2[CH:21]=O)=[CH:4][C:3]=1[CH3:23].[Li+].CC([N-]C(C)C)C.C(=NC1CCCCC1)C.[C:41]([OH:46])(=O)[C:42](O)=O>CCOCC.O.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:11][C:10]([CH3:19])([CH3:20])[C:9]=2/[CH:21]=[CH:42]/[CH:41]=[O:46])=[CH:4][C:3]=1[CH3:23]
Reactant: Cc1cc(C2=C(C=O)C(C)(C)CC(N3CCCC3)C2)ccc1F
Reactant: O=C(O)C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: CC=NC1CCCCC1
Agent: O=C([O-])O
Solvent: O
Solvent: CCOCC
Product: Cc1cc(C2=C(/C=C/C=O)C(C)(C)CC(N3CCCC3)C2)ccc1F
Yield: 54.9 %

Procedure:
In a manner similar to Scheme I, 32 (3.80 g, 12.1 mmol) was treated with the LDA-derived anion of ethylidenecyclohexylamine (2.90 g, 23.2 mmol) in anhydrous ether. Workup and purification of the residue by HPLC. using 1% Et3N in 10:l hexanes:EtOAc as eluent provided the dieneimine (2.4 g). The imine and oxalic acid (10 g) in 40 mL H2O was heated at 100° C. for 2 h, cooled, diluted with saturated NaHCO3 and ether. The organic layer was washed with H2O and brine and dried (MgSO4). Removal of volatiles in vacuo provided 2.27 g of gum which was taken forward without further purification.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:22](=[CH:23][CH:24]=1)[C:13]1[N:14]([CH2:18][CH:19](O)[CH3:20])[C:15]([CH3:17])=[CH:16][C:12]=1[CH2:11]2.C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+]>ClCCl.CN(C)C=O.O>[N:32]([CH:19]([CH3:20])[CH2:18][N:14]1[C:15]([CH3:17])=[CH:16][C:12]2[CH2:11][C:10]3[C:22]([C:13]1=2)=[CH:23][CH:24]=[C:8]([O:7][CH3:6])[CH:9]=3)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)Cc1cc(C)n(CC(C)O)c1-2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)Cc1cc(C)n(CC(C)N=[N+]=[N-])c1-2
Yield: 67.6 %

Procedure:
0.7 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.16 g of (RS)-1-(6-methoxy-2-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 2.5 ml of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 60 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 60 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 40 ml of anhydrous dimethyl-formamide, treated with 0.58 g of sodium azide and the reaction mixture was heated to 80° for 16 hours while stirring. After cooling, the solution was poured into 70 ml of water and extracted twice with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 0.86 g (68%) of (RS)-1-(2-azido-propyl)-6-methoxy-2-methyl-1,4-dihydro-indeno[1,2-b]pyrrole was obtained as a yellow oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][C@:5]2([C:20]3[CH:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=4)[CH:23]=[CH:24][CH:25]=3)[N:6]=[C:7]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:8][CH2:9][C@@H:4]2[CH2:3]1.Cl[CH2:35][O:36][CH3:37].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:33][O:32][C:28]1[CH:27]=[C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C@:5]34[CH2:19][C@H:2]([O:1][CH2:35][O:36][CH3:37])[CH2:3][C@H:4]3[CH2:9][S:8][C:7]([NH:10][C:11](=[O:18])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:6]4)[CH:21]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1cccc(-c2cccc([C@]34C[C@H](O)C[C@H]3CSC(NC(=O)c3ccccc3)=N4)c2)c1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCO[C@@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cccc(-c3cccc(OC)c3)c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a stirred 0° C. solution of N-((4aR,6R,7aS)-6-hydroxy-7a-(3′-methoxybiphenyl-3-yl)-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl)benzamide (0.087 g, 0.190 mmol) in anhydrous dichloromethane (0.6 mL) is added chloromethoxymethane (0.031 g, 0.379 mmol), followed by diisopropylethylamine (0.049 g, 0.379 mmol). The resulting mixture is stirred at 0° C. for 1 hour, and then is warmed to room temperature over 24 h. The mixture is diluted with dichloromethane, quenched by addition of saturated aqueous solution of sodium bicarbonate, and is extracted three times with dichloromethane. The combined organic layers are washed with water and brine. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by silica gel chromatography eluting with a linear gradient of 0% to 60% ethyl acetate in hexanes over 26 minutes to give the title compound (0.089, 93%). ES/MS m/e: 503 (M+1).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH:25]=[CH:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH2:25][CH:26]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: CCCC=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: C1CCNC1
Product: CCCC(CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)N1CCCC1
Yield: 48 %

Procedure:
N-Cyclopropyl-N-[1-(3-pyrrolidin-1-ylhexanoyl)piperidin-4-yl]-3-trifluoromethylbenzenesulfonamide (43) was prepared by reacting N-cyclopropyl-N-(1-hex-2-enoyl-piperidin-4-yl)-3-trifluoromethyl-benzenesulfonamide (30) (250 mg, 0.56 mmol) and pyrrolidine (2 mL) as described in Example 26 above. The residue was chromatographed over flash silica eluting with ethyl acetate:methanol:ammonia (100:10:1) to give the title compound 43 as a white solid (140 mg, 48%). LC: 98.9%. m/z=516.3, 517.3 (M+H). 1H NMR (400 MHz, CDCl3): (1:1 mixture of rotamers) δ 8.14 (1H, s), 8.05 (1H, d, J=7.5 Hz), 7.86 (1H, d, J=7.5 Hz), 7.70 (1H, t, J=7.5 Hz), 4.75 (1H, d, J=15 Hz), 4.10 (1H, m), 3.97 (1H, d, J=15 Hz), 3.05 (2H, m), 2.65-2.45 (6H, m), 2.35 (1H, m), 1.96 (1H, m), 1.85-1.30 (16H, m), 0.98 (1H, m), 0.92-0.70 (6H, m).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([F:19])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([F:19])[CH:12]=2)[C:8]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: COc1ccc(C(CC2CCCC2)C(=O)O)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103 %

Procedure:
A solution of 3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-propionic acid (400.0 mg, 1.50 mmol) in methylene chloride (5.0 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.82 mL, 1.65 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 10 min and at 25° C. for 30 min. The reaction mixture was then treated with a solution of 2-aminothiazole (331 mg, 3.30 mmol) and N,N-diisopropylethylamine (0.62 mL, 3.60 mmol) in tetrahydrofuran (7.5 mL). This solution was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-N-thiazol-2-yl-propionamide (538.4 mg, 100%) as a white solid: mp 51–53° C.: EI-HRMS m/e calcd for C18H21FN2O2S (M+) 348.1307 found 348.1312.
Reaction SMILES: [CH3:1][N:2]([C@@H:22]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([CH3:34])[CH:25]=1)[CH3:23])[C:3]([N:5]1[CH2:10][CH2:9][N:8]2[C:11](=[O:14])[CH2:12][CH2:13][C@H:7]2[C@@H:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[O:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:45](Cl)(=[O:48])[O:46][CH3:47]>C1COCC1>[CH3:1][N:2]([C@@H:22]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([CH3:34])[CH:25]=1)[CH3:23])[C:3]([N:5]1[CH2:10][CH2:9][N:8]2[C:11](=[O:14])[C:12]([C:45]([O:46][CH3:47])=[O:48])([C:45]([O:46][CH3:47])=[O:48])[CH2:13][C@H:7]2[C@@H:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[O:4]
Reactant: Cc1cc([C@@H](C)N(C)C(=O)N2CCN3C(=O)CC[C@H]3[C@@H]2c2ccccc2C)cc(C(F)(F)F)c1
Reactant: COC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)OC)C[C@H]2[C@H](c3ccccc3C)N(C(=O)N(C)[C@H](C)c3cc(C)cc(C(F)(F)F)c3)CCN2C1=O
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
To a solution of (1S,8aS)-N-methyl-N-((R)-1-(3-methyl-5-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-o-tolylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide (350 mg, 0.74 mmol) in anhydrous THF (20 mL) under N2 atmosphere was added LHMDS (4.43 mL, 1 M in THF, 4.43 mmol) at −60° C. The reaction was stirred for 30 min followed by addition of methyl carbonochloridate (174 mg, 1.85 mmol). After stirring for another 3 h at room temperature. The reaction was quenched with water at 0° C. and then extracted with EtOAc (2×30 mL). The combined organic layers were dried over anhydrous Na2SO4 and then concentrated in high vacuum. The residue was purified by silica gel chromatography (DCM/MeOH=20/1 to 10/1) to give the title compound (200 mg, yield: 46%); m/z (ES+): 590 [M+H]+.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1([C:23]2[N:33]=[C:26]3[C:27]([O:31][CH3:32])=[CH:28][CH:29]=[CH:30][N:25]3[N:24]=2)[CH2:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[CH3:32][O:31][C:27]1[C:26]2[N:25]([N:24]=[C:23]([C:20]3([CH2:19][OH:18])[CH2:22][CH2:21]3)[N:33]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cccn2nc(C3(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC3)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccn2nc(C3(CO)CC3)nc12
Reaction time: 16 h
Yield: 78.8 %

Procedure:
To a solution of 2-(1-((tert-butyldiphenylsilyloxy)methyl)cyclopropyl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (4.5 g, 9.84 mmol) in dry THF (40 ml) was added TBAF (38.38 mmol, 1M in THF) at RT and the mixture was stirred further. After 16 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic phase was dried over anhyd. Na2SO4 and concentrated under reduced pressure. The residue obtained was purified by column chromatography to afford (1-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropyl)methanol (1.7 g, 79%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:34])=[C:11]([CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([O:21][CH2:22][C:23]4[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:24]=4[C:25]([O:27]C)=[O:26])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.Cl>C(O)(C)(C)C.[OH-].[K+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH3:34])=[C:11]([CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([O:21][CH2:22][C:23]4[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:24]=4[C:25]([OH:27])=[O:26])[CH2:16]3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(OCc2nc(-c3ccc(Br)cc3)oc2C)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1cccc(COC2CCCC(OCc3nc(-c4ccc(Br)cc4)oc3C)C2)c1C(=O)O
Reaction time: 48 h

Procedure:
117 mg of 49 were stirred in a mixture of 10 ml of tert-butanol and 1 ml of 10 N aqueous potassium hydroxide solution at 90° C. After two days, the mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, the solvents were removed under reduced pressure and the residue was purified by RP-HPLC. This gave 50 as an amorphous solid. C26H28BrNO5 (514.52), MS(ESI): 514.29, 516.29 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:4]=[CH:3]1.C([Li])CCC.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1>C1COCC1.CCCCCC>[CH:20]1([C:23]([C:3]2[N:2]([CH3:1])[C:14]3[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:7]=[CH:6][C:5]=3[N:4]=2)=[O:24])[CH2:22][CH2:21]1
Reactant: O=C(Cl)C1CC1
Reactant: Cn1cnc2cnc3ccccc3c21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1c(C(=O)C2CC2)nc2cnc3ccccc3c21
Temperature: 25 °C
Yield: 36.5 %

Procedure:
In the same manner as in Ex. 1, to a solution containing 550 mg of 1-methyl-1H-imidazo[4,5-c]quinoline (II-2) in 25 ml of THF and a mixture of 2.2 ml of 1.6M solution of n-butyl lithium in hexane-2 ml of THF was added 0.75 g of cyclopropanecarbonyl chloride. The reaction mixture was gradually warmed to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous ammonia. The organic layer was washed with water and brine, and then dried. The ethyl acetate was removed by evaporation, and the residue was chromatographed on a column of silica gel for purification. The fraction eluted with ethyl acetate was concentrated and the residue was crystallized from n-hexane to give 275 mg (yield: 36%) of the titled compound (Ia-1). This was recrystallized from ethyl acetate n-hexane to give colorless crystals melting at 156°~158° C.