Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].O1CCCOO1.[C:12]([OH:15])(=[O:14])[CH3:13].I.[C]=O>>[C:1]([O:4][CH2:5][O:15][C:12](=[O:14])[CH3:13])(=[O:3])[CH3:2]
Reactant: COC(C)=O
Reactant: CC(=O)O
Agent: C1COOOC1
Agent: I
Agent: [C]=O
Product: CC(=O)OCOC(C)=O
Temperature: 200 °C
Reaction time: 16 h

Procedure:
A 1-liter, magnetically stirred autoclave was charged with 0.001 mol of Rh(CO)2Cl, sealed and flushed with nitrogen followed by carbon monoxide. The autoclave was then charged with 1 mol of methyl acetate, 1 mol of trioxane, 0.5 mol of acetic acid and 0.056 mol of hydrogen iodide. The autoclave was sealed, pressured to 1000 psig with carbon monoxide, and rapidly heated to 200° C. After 16 hours at 200° C., the reaction was terminated, the autoclave was opened and the reaction mixture analyzed by nuclear magnetic resonance spectroscopy, infrared spectroscopy and gas-liquid chromatography. The conversion of methyl acetate was 49% and the yield of methylene bis-acetate, ##STR9## based on converted methyl acetate, was 28%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=O)[C:9]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[CH2:8]2)(=[O:3])[CH3:2].N1CCCC1.C(O)(=O)C>C1(C)C=CC=CC=1.CCOC(C)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11]([C:10]3[C:9]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:8]2)[CH2:15][CH2:16][C:17](=[O:19])[CH:18]=3)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CCCCC1(CCC(C)=O)Cc2cc(NC(C)=O)ccc2C1=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCNC1
Product: CCCCC12CCC(=O)C=C1c1ccc(NC(C)=O)cc1C2
Temperature: 90 °C

Procedure:
A solution of 5-(acetylamino)-2-butyl-2-(3-oxobutyl)-1-indanone (9.8 g, 31.1 mmol) in toluene (300 mL) was treated with pyrrolidine (2.6 mL, 31 mmol) and acetic acid (1.8 mL, 31 mmol). The mixture was stirred under a N2 atmosphere and heated in an oil bath at 90° C. for two hours. After cooling, the mixture was diluted with EtOAc (500 mL), washed with water, 5% NaHCO3, water, and brine, dried over MgSO4, filtered, and concentrated under vacuum to an orange-brown foam (7.0 g). 1H NMR of the crude product showed 7-(acetylamino)-9a-butyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one along with 14–17% of a by-product identified as 9a-butyl-4-methyl-8,9,9a,10-tetrahydro-7H-indeno[1,2-g]quinolin-7-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([O:14][CH3:15])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2(N(C)C)CC=CC=C2C2C=CC=CC=2)CCCCC1>[CH3:15][O:14][C:4]1[CH:3]=[C:2]([N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)[CH:7]=[CH:6][C:5]=1[C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: COc1cc(Br)ccc1C#C[Si](C)(C)C
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: CN(C)C1(P(C2CCCCC2)C2CCCCC2)CC=CC=C1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C)CC2)ccc1C#C[Si](C)(C)C
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A solution of [(4-bromo-2-methoxyphenyl)ethynyl](trimethyl)silane (1.426 g, 5.035 mmol) in dry THF (25 mL) was degassed and backfilled with argon for three times. Pd2(dba)3 (230.5 mg, 0.252 mmol) and 2-dicyclohexylphosphino-2-(N,N′-dimethylamino)biphenyl (79.3 mg, 0.201 mmol) were added under argon atmosphere and the mixture was degassed and backfilled with argon for three times. Then 1 M LiHMDS in THF (12.1 mL, 12.084 mmol) and N-methylpiperazine (1.34 mL, 1.21 g, 12.083 mmol) were added by a syringe and the mixture was degassed and backfilled with Argon for three times. The reaction mixture was heated to reflux for 1 h. After cooling to room temperature the reaction mixture was filtered on a pad of celite washing with THF (200 mL). The filtrate was evaporated under vacuum and the black oil so obtained was purified by chromatography on silica gel (DCM/MeOH 9/1) to afford the title compound as a brownish solid (1.042 g, 68.4%).
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:3].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:43](=[NH:45])[NH2:44])[CH:39]=2)[CH:34]=1)(=O)=O>N1C=CC=CC=1>[O:3]([C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:43](=[NH:44])[NH2:45])[CH:39]=2)[CH:34]=1)[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:1]
Reactant: CCCCCCCCCC(=O)O
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
To a solution of 3.0 g of capric acid in 50 ml of anhydrous pyridine, while being cooled in ice, was added 4.4 g of DCC. After stirring for 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture and further stirred overnight at room temperature. The precipitate was separated by filtration and washed with a small volume of pyridine. The filtrate and washings were poured into stirred ethyl ether. The precipitated crystals were collected by filtration, washed with ethyl ether, then with acetone, and recrystallized from a methanol-ether mixture to yield 1.2 g of a white powder of 6-amidino-2-naphthyl caprate methanesulfonate.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([O:22][CH2:23][CH2:24]NC(OC(C)(C)C)=O)[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S(CC2C([C:54](OC)=[O:55])=C(O)C(C3C=COC=3)=CC=2)(=O)=O)C=CC=CC=1.COCCBr>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:22][CH2:23][CH2:24][O:55][CH3:54])[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCNC(=O)OC(C)(C)C
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Agent: COCCBr
Product: COCCOc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 10, starting from methyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 114) and 2-bromoethyl methyl ether.
Reaction SMILES: C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:15][CH:16]([C:18]#[C:19][C:20]12[O:28][C:21]1([CH3:27])[CH2:22][CH2:23][C:24]2([CH3:26])[CH3:25])[CH3:17])(=O)C.[OH-].[Na+]>O>[OH:28][C:21]1([CH3:27])[CH2:22][CH2:23][C:24]([CH3:25])([CH3:26])[C:20]1=[C:19]=[CH:18][CH:16]([OH:15])[CH3:17]
Reactant: CC(=O)OC(C)C#CC12OC1(C)CCC2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)C=C=C1C(C)(C)CCC1(C)O
Reaction time: 10 h
Yield: 72.2 %

Procedure:
To 20 ml of an anhydrous THF suspension containing 644 mg of lithium aluminum hydride was slowly added 20 ml of an anhydrous THF solution containing 2.0 g of 2-acetoxy-4-(1,2-epoxy-2,5,5-trimethylcyclopentyl)but-3-yn under ice-cooling in a nitrogen atmosphere over 10 minutes. After the addition, the mixture was placed under refluxing conditions and stirred for 10 hours. After completion of the reaction, the reaction mixture was cooled, and 0.6 ml of water, 0.6 ml of a 15% sodium hydroxide aqueous solution, and 1.8 ml of water were carefully added thereto in this order, followed by vigorously stirring for 20 minutes. Any insoluble matter was removed by filtration with suction, and the filtrate was concentrated under reduced pressure. The resulting solid was purified by silica gel column chromatography to obtain 1.2 g (yield: 70%) of 4-(2-hydroxy-2,5,5-trimethylcyclopentylidene)but-3-en-2-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:35]1([C:41]([C:43]2[CH:48]=[C:47]([O:49][CH3:50])[C:46]([O:51][CH3:52])=[C:45]([O:53][CH3:54])[CH:44]=2)=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([N:38]2[CH2:39][CH2:40][N:35]([C:41](=[O:42])[C:43]3[CH:48]=[C:47]([O:49][CH3:50])[C:46]([O:51][CH3:52])=[C:45]([O:53][CH3:54])[CH:44]=3)[CH2:36][CH2:37]2)=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCC=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: COc1cc(C(=O)N2CCNCC2)cc(OC)c1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCN(C(=O)CCCC=C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A solution of 6,6-bis-(4-fluoro-phenyl)-hex-5-enoic acid (2.64 g, 8.75 mmol) and CDI (1.42 g, 8.75 mmol) in dry THF (30 ml) was stirred for 1 hr at room temperature under nitrogen. A solution of piperazin-1-yl-(3,4,5,-trimethoxy-phenyl)-methanone (2.45 g, 8.75 mmol) in dry THF (30 ml) was added to above solution and resulting mixture stirred at room temperature overnight. The mixture is diluted with EtOAc (30 ml) and washed with water (2×30 ml) and dried over MgSO4. Evaporation of solvent followed by column chromatography using CH2Cl2:MeOH (15:1) gave the desired product in 49% yield.
Reaction SMILES: [CH:1]1([C:6]2[CH:36]=[CH:35][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[C:21]([CH2:29][C:30]([O:32]CC)=[O:31])([C:24]([O:26]CC)=[O:25])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:37]([F:40])([F:39])[F:38])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+:42]>C(O)(C)C>[C:30]([CH2:29][C:21]1([C:24]([O-:26])=[O:25])[C:16]2[NH:17][C:18]3[CH:19]=[CH:20][C:12]([O:11][CH2:10][C:9]4[CH:35]=[CH:36][C:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[C:7]([C:37]([F:38])([F:39])[F:40])[CH:8]=4)=[CH:13][C:14]=3[C:15]=2[CH2:23][CH2:22]1)([O-:32])=[O:31].[Na+:42].[Na+:42]
Reactant: CCOC(=O)CC1(C(=O)OCC)CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C([O-])CC1(C(=O)[O-])CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Temperature: 100 °C
Yield: 74.3 %

Procedure:
In a 500 mL flask was placed ethyl 7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-3-(2-ethoxy-2-oxoethyl)-1,2,3,4-tetrahydrocyclopenta[b]indole-3-carboxylate (24.1 g, 43.2 mmol) in isopropanol (275 mL). Sodium hydroxide solution (20%, 129.5 mL, 130 mmol) was added and the mixture was heated at 100° C. (bath) for 2.5 h. The mixture was cooled, filtered, washed with isopropanol, and dried overnight under vacuum at 40° C. to give the title compound (17.5 g). LCMS m/z=502.6 [M−2Na+3H]+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:9]=3[C:8]=2[CH:7]=[C:6]([CH3:18])[CH:5]=1.Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[CH2:22]>CN(C=O)C>[Br:3][C:4]1[C:12]2[N:11]([CH2:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH2:20])[C:10]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:9]=3[C:8]=2[CH:7]=[C:6]([CH3:18])[CH:5]=1
Reactant: Cc1cc(Br)c2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=C(CBr)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(Cn1c2c(c3cc(C)cc(Br)c31)CN(C)CC2)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (49.8 mg, 21.67 mmol) was charged in DMF (3 mL) and cooled to 0° C. 6-Bromo-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 0.83 mmol) was added and stirred at 0° C. for 5 min. 1-(3-Bromoprop-1-en-2-yl)-4-fluorobenzene (195.25 mg, 0.917 mmol) dissolved in DMF (1 mL) was added at 0° C. and stirred at RT for 2 h. Ice was added and the resultant solid obtained was filtered. The product was purified on silica using 0-7% MeOH:DCM as eluent. Yield: 85 mg.
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]([CH:15]=[O:16])=[CH:7][CH:6]=1.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([NH:22][CH2:17][CH:2]([OH:1])[CH2:3][O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]([CH:15]=[O:16])=[CH:7][CH:6]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: O=Cc1ccc(OCC2CO2)c2c1CCCC2
Reactant: CC(C)(C)N
Product: CC(C)(C)NCC(O)COc1ccc(C=O)c2c1CCCC2
Temperature: 45 °C

Procedure:
To 4-(2,3-epoxypropoxy)-5,6,7,8-tetrahydronaphthaldehyde (2.4 gms) is added tert.-butylamine (15 ml.). The resulting solution is heated at 45° C. for 15 hours. The excess tert.-butylamine is removed at reduced pressure (20 mm). To the residue is added 30 ml. 6N hydrochloric acid, and the resulting mixture is refluxed for three hours. The acidic mixture i poured into a saturated solution of sodium carbonate which is heated on a steam bath with nitrogen bubbling through it. The basic mixture is extracted with chloroform, which is dried over anhydrous sodium sulfate, filtered and concentrated to give 2.3 g of 4-(3-tert.butylamino-2-hydroxypropoxy)-5,6,7,8-tetrahydronapthaldehyde as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:8](=[O:21])[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[C:31]2[C:26](=[CH:27][C:28]([OH:32])=[CH:29][CH:30]=2)[N:25]([CH3:33])[N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:22][C:23]1[C:31]2[C:26](=[CH:27][C:28]([O:32][C:2]3[C:11]4[CH2:10][N:9]([CH2:12][C:13]5[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=5)[C:8](=[O:21])[NH:7][C:6]=4[N:5]=[CH:4][CH:3]=3)=[CH:29][CH:30]=2)[N:25]([CH3:33])[N:24]=1
Reactant: COc1ccc(CN2Cc3c(Cl)ccnc3NC2=O)cc1
Reactant: Cn1nc(N)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2Cc3c(Oc4ccc5c(N)nn(C)c5c4)ccnc3NC2=O)cc1
Temperature: 130 °C
Yield: 70.4 %

Procedure:
Suspended 5-chloro-3-(4-methoxy-benzyl)-3,4-dihydro-1h-pyrido[2,3-d]pyrimidin-2-one (400.00 mg; 1.32 mmol; 1.00 eq.), 3-amino-1-methyl-1h-indazol-6-ol (268.61 mg; 1.65 mmol; 1.25 eq.) and cesium carbonate (858.15 mg; 2.63 mmol; 2.00 eq.) in DMF (4.00 ml). Heated in a microwave at 130° C. for 90 min. The reaction was concentrated, redissolved in DMSO (20 mL) and filtered through celite. Purified filtrate via prep HPLC to afford 400 mg (56%) of compound 276 as a tan solid. LC-MS (M+H=431, obsd.=431)
Reaction SMILES: [Na].[N+:2]([CH3:5])([O-:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([O:20][CH3:21])[C:15]=1[O:16][CH2:17][O:18][CH3:19])[CH:11]=[O:12].C(O)(=O)C>CO.O.C(OCC)C>[CH3:21][O:20][C:14]1[CH:13]=[C:10]([CH:11]([OH:12])[CH2:5][N+:2]([O-:4])=[O:3])[CH:9]=[C:8]([O:7][CH3:6])[C:15]=1[O:16][CH2:17][O:18][CH3:19]
Reactant: COCOc1c(OC)cc(C=O)cc1OC
Reactant: C[N+](=O)[O-]
Agent: [Na]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: COCOc1c(OC)cc(C(O)C[N+](=O)[O-])cc1OC
Reaction time: 3 h
Yield: 3.3 %

Procedure:
To a dissolved solution of sodium (2.54 g, 0.111 mol) in anhydrous methanol (70 ml) was added nitromethane (7.07 g, 0.116 mol) at room temperature. A solution of 3,5-dimethoxy-4-(methoxymethoxy)benzaldehyde (23.8 g, 0.1053 mol) in methanol (70 ml) was added dropwise, and the resulting mixture was stirred for 3 hours. After completion of a reaction, diethyl ether (500 ml) was added and precipitated crystals were collected by filtration. The crystals were suspended in diethyl ether (500 ml). At 0°C., acetic acid (6.4 g, 0.107 mol) was added, followed by stirring for 12 hours. After insoluble matter was filtered off, the filtrate was concentrated. The resulting crystals were washed with hexane, whereby the title compound (15.42 g) was obtained as pale yellow crystals. The filtered-off insoluble matter was dissolved in water, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was removed, whereby the title compound (1.0 g) was obtained additionally.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Si:13]([N:20]1[C@@H:23]([CH2:24][C:25]([S:30][CH3:31])([S:28][CH3:29])[S:26][CH3:27])[CH2:22][C:21]1=[O:32])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[C:33](N1C=CN=C1)(=[O:35])[CH3:34]>O1CCCC1>[Si:13]([N:20]1[C@H:23]([CH2:24][C:25]([S:28][CH3:29])([S:26][CH3:27])[S:30][CH3:31])[C@@H:22]([C:33](=[O:35])[CH3:34])[C:21]1=[O:32])([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:15])[CH3:14]
Reactant: CC(=O)n1ccnc1
Reactant: CSC(C[C@H]1CC(=O)N1[Si](C)(C)C(C)(C)C)(SC)SC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSC(C[C@@H]1[C@@H](C(C)=O)C(=O)N1[Si](C)(C)C(C)(C)C)(SC)SC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (2.43 ml of 2.4 m solution, 5.84 mmol) is added by syringe to a solution of diisopropylamine (591 mg, 5.84 mmol) in 25 ml of freshly distilled tetrahydrofuran at -78° C. The resulting solution is stirred at -78° C. for 15 minutes prior to the addition of a solution of (4R)-1-(t-butyldimethylsilyl)-4-[2,2,2-tri(methylthio)ethyl]azetidin-2-one (1.00 g, 2.85 mmol) in tetrahydrofuran (5 ml). This solution is stirred at -78° C. for 15 minutes, then added via a Teflon tube to a mixture of N-acetylimidazole (642 mg, 5.84 mmol) in 25 ml of THF at -78° C. The resulting yellow reaction mixture is stirred at -78° C. for 10 minutes, then quenched by addition of saturated aqueous ammonium chloride solution. The mixture is diluted with ether (200 ml) and washed with 2.5 N hydrochloric acid solution (50 ml), water (50 ml) and brine (50 ml) and dried over magnesium sulfate. Removal of solvents in vacuo gives a yellow oil which is chromatographed on silica gel (30% ether in petroleum ether) to yield (3S, 4R)-1-(t-butyldimethylsilyl)-3-(1-oxoethyl)-4-[2,2,2-tri(methylthio)ethyl]azetidin-2-one. n.m.r. (CDCl3) δ4.42(m,l), δ4.32 (d,l) δ2.35(m,2), δ2.32(s,3), δ2.2(s,9), δ0.98(s,9), δ0.3(2s,6).
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Cl:12][C:13]1[C:21]([I:22])=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][N:14]=1.CCN(C(C)C)C(C)C.[F:32][C:33]([F:43])([F:42])[O:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.CCCCCC>[Cl:12][C:13]1[C:21]([I:22])=[CH:20][C:16]([C:17]([NH:39][C:38]2[CH:40]=[CH:41][C:35]([O:34][C:33]([F:32])([F:42])[F:43])=[CH:36][CH:37]=2)=[O:19])=[CH:15][N:14]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1cnc(Cl)c(I)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(I)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DMF (0.014 mL, 0.176 mmol) and oxalyl chloride (2.316 mL, 26.5 mmol) were added to a solution of 6-chloro-5-iodonicotinic acid (5 g, 17.64 mmol) in DCM (80 mL) and the RM was stirred for 2 h at RT under a nitrogen atmosphere. The solvent was evaporated off under reduced pressure and the residue was dissolved in THF (60 mL). DIPEA (9.24 mL, 52.9 mmol) was added and the mixture was cooled down to 5° C., treated dropwise with a solution of 4-(trifluoro methoxy)aniline (2.62 mL, 19.40 mmol) in DCM (20 mL) and stirred at 5° C. for 30 min and at RT for 1 h. The solvent was off under reduced pressure and the residue was treated with aq. 10% citric acid (70 mL) and extracted with EtOAc. The combined extracts were washed with sat. aq. Na2CO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product was suspended in n-hexane, and filtered to afford the title compound as a beige solid. UPLC-MS (Condition 3) tR=1.22 min, 440.9/442.9 [M−H]−.
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[C:4]1[CH:5]=[C:6]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][C:32]2[NH:35][N:36]=[C:37]([C:38](O)=[O:39])[C:31]=2[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[F:21][C:3]([F:2])([F:20])[C:4]1[CH:5]=[C:6]([CH:14]2[CH2:19][CH2:18][N:17]([C:38]([C:37]3[C:31]4[CH2:30][N:29]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:34][CH2:33][C:32]=4[NH:35][N:36]=3)=[O:39])[CH2:16][CH2:15]2)[CH:7]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:9]=1
Reactant: FC(F)(F)c1cc(C2CCNCC2)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)O)c2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
To a solution of 4-(3,5-bis(trifluoromethyl)phenyl)piperidine hydrochloride (20, 100 mg, 0.30 mmol), 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (81 mg, 0.30 mmol), and diisopropylethylamine (0.18 mL, 0.90 mmol) in DMF (5.6 mL) was added EDCI (69 mg, 0.36 mmol) and HOBt (49 mg, 0.36 mmol). The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was diluted with H2O (30 mL). The resulting precipitate was collected by filtration to yield tert-butyl 3-(4-(3,5-bis(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (53) as a white solid (142 mg, 86%): 1H NMR (300 MHz, DMSO-d6) δ 12.95 (s, 1H), 8.03-7.97 (m, 2H), 7.95-7.90 (m, 1H), 5.31-5.13 (m, 1H), 4.76-4.58 (m, 1H), 4.52-4.39 (m, 2H), 3.64-3.53 (m, 2H), 3.20-3.03 (m, 2H), 2.87-2.61 (m, 3H), 1.97-1.81 (m, 2H), 1.78-1.58 (m, 2H), 1.41 (s, 9H); ESI MS m/z 547 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([N:8]([CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:7].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)C>[Cl:25][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([Cl:24])[CH:21]=1)[CH2:17][N:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=1)[C:6](=[O:7])[C:5]1[CH:26]=[CH:27][CH:28]=[C:3]([CH2:2][NH:1][CH2:34][C:33]2[CH:36]=[CH:37][C:30]([F:29])=[CH:31][CH:32]=2)[CH:4]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NCc1cccc(C(=O)N(Cc2ccc(F)cc2)Cc2cc(Cl)cc(Cl)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(c1cccc(CNCc2ccc(F)cc2)c1)N(Cc1ccc(F)cc1)Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
To a solution of 3-(aminomethyl)-N-(3,5-dichlorobenzyl)-N-(4-fluorobenzyl)benzamide (0.6 g, 1.44 mmol) in CH2Cl2 (6.0 mL) and 2-propanol (6.0 mL) was added 4-fluorobenzaldehyde (0.16 mL, 1.44 mmol). The resulting mixture was stirred at rt for 1.5 h. The reaction mixture was cooled to ice bath temperature and was added sodium triacetoxyborohydride (0.49 g, 2.30 mmol) under N2 atmosphere. The resulting mixture was stirred at rt for 20 h. To the reaction mixture was added saturated aq NaHCO3 solution and the mixture was stirred for 20 minutes. The mixture was concentrated, and the residue was diluted with ethyl acetate and saturated aq NaHCO3 solution. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica gel (ISCO. condition: 24 g column; eluents: 0-25% of ethyl acetate in CH2Cl2, gradient over 40 minutes) to obtain the desired product as colorless oil (0.47, 63%). 1H NMR (CDCl3): δ 7.55-7.29 (m, 7H), 7.17-7.00 (m, 8H), 4.70-4.63 (m, 2H), 4.43-4.36 (m, 2H), 3.82 (s, 2H), 3.77 (s, 2H); MS (ESI): [M+H]+=524.9.