Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CN(P(N(C)C)(N(C)C)=O)C.[CH2:24]([O:26][C:27](=[O:32])[CH2:28][CH2:29][CH:30]=[CH2:31])[CH3:25].I[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=1>C1COCC1.CCOCC>[CH2:24]([O:26][C:27](=[O:32])[CH:28]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:43])([F:44])[F:45])[CH:37]=1)[CH2:29][CH:30]=[CH2:31])[CH3:25]
Reactant: FC(F)(F)c1cccc(CCI)c1
Reactant: C=CCCC(=O)OCC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCC(CCc1cccc(C(F)(F)F)c1)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
To a 100-mL three-neck round-bottomed flask equipped with a thermometer, addition funnel, and nitrogen inlet was added diisopropylamine (2.4 mL, 17.2 mmol) in THF (4 mL). The solution was cooled to −78° C., then a solution of n-BuLi (2.5 M in hexanes, 6.9 mL) was added slowly, followed by HMPA (3.1 mL, 18.0 mmol) and the reaction was stirred at this temperature for 30 min. A solution of ethylpent-4-enoate (2.0 g, 15.6 mmol) in THF (15.6 mL) was added dropwise, then the mixture was stirred for 45 min. To this mixture was added a solution of 1-(2-iodoethyl)-3-trifluoromethylbenzene (35a) (1.37 g, 4.58 mmol) in THF (2 mL) and the resulting mixture was allowed to warm to room temperature overnight. The mixture was diluted with ether (500 mL), washed with water (2×250 mL), and brine (2×250 mL), dried over Na2SO4, filtered, and evaporated. The residue was purified by flash chromatography to provide 2-[2-(3-trifluoromethylphenyl)ethyl]pent-4-enoic acid ethyl ester (529 mg, 39%) as a colorless oil: ESI MS m/z 301 [C16H19F3O2+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[C:3]=1[CH:9]=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[C:3]=1/[CH:9]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=CC1=C(Cl)C2CCC1C2
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/C1=C(Cl)C2CCC1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of 167a (9.0 g, 57.7 mmol) in methylene chloride (250 mL) was added ethyl 2-(triphenyl-λ5-phosphanylidene)acetate (20 g, 57.7 mmol). The mixture was stirred at room temperature overnight. It was then evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:100 ethyl acetate/petroleum ether to afford 167b as a yellow oil (6.0 g, 46%). MS: [M+H]+ 227.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[C@H:9]([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([O:19][C:20]([NH:22]O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:1]([O:5][C:6]([N:8]([CH3:14])[C@H:9]([CH3:13])[C:10]([O:12][NH:22][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NO
Reactant: C[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Product: C[C@H](C(=O)ONC(=O)OC(C)(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino (2R)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanoate is prepared from (2R)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanoic acid and N-tert-butoxycarbonyl hydroxylamine according to Scheme 6. The compound exists as rotomers and is reported as such. (0.95 g, 60%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.81-7.95 (1H, m), 4.60-5.04 (1H, m), 2.85-2.93 (3H, m), 1.40-1.54 (18H, m), 1.22-1.33 (3H, m).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[NH:4][CH2:3][CH2:2]1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:4]1[C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH2:2][CH2:3]1
Reactant: O=C1NCCOc2ccccc21
Reactant: BrCCCCCBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2OCCN1CCCCCBr
Reaction time: 1 h
Yield: 65 %

Procedure:
In 20 ml of dimethylformamide (DMF) was dissolved 100 mg of 2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one, and the solution then ice-cooled. Then, to the resulting solution were added 0.251 ml (3 equivalents) of 1,5-dibromopentane and 29.4 mg (1.2 equivalent) of a 60% sodium hydride oil dispersion, and the mixture was stirred for one hour with ice-cooling. The reaction solution was poured into a citric acid aqueous solution and extracted with ethyl acetate, and the ethyl acetate phase was washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was then concentrated and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (8:2)) to give 124 mg (yield: 65.0%) of the title compound.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH2:32]([NH2:34])[CH3:33].[BH4-].[Na+]>ClCCl.CO>[CH2:32]([NH:34][CH2:27][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]2)[CH:26]=[CH:25][CH:24]=1)[CH3:33]
Reactant: CCN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (20 mg, 0.045 mmol) in dichloromethane (0.5 mL) and methanol (0.5 mL) was added ethylamine (130 uL, 0.27 mmol). This mixture was stirred for 1 h at room temperature, and then sodium borohydride (10 mg, 0.27 mmol) was added. The reaction was stirred at ambient temperature overnight, and the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (13.2 mg, 63%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:3]=1[CH3:27].[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[C:36]3[NH:42][CH2:41][C:40]4([CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[C:37]3=[N:38][CH:39]=2)[CH2:30][CH2:29]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([N:42]1[C:36]3[C:37](=[N:38][CH:39]=[C:34]([N:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)[CH:35]=3)[C:40]3([CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[CH2:41]1)=[C:3]([CH3:27])[C:4]([N:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:18][CH2:19]1)=[N:5]2
Reactant: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)piperazine-1-carboxylate (690.0 mg, 1.70 mmol) and 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] in toluene to give tert-butyl 4-(5,7-difluoro-3-methyl-4-(6′-(4-morpholinyl)-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-1′(2′H)-yl)-2-quinolinyl)-1-piperazinecarboxylate. 1H NMR (400 MHz, chloroform-d) δ ppm 7.56 (1H, d, J=2.3 Hz), 7.35 (1H, ddd, J=9.8, 2.4, 1.1 Hz), 6.75 (1H, ddd, J=11.8, 8.9, 2.5 Hz), 5.66 (1H, d, J=2.3 Hz), 4.05-4.22 (2H, m), 3.80-3.98 (2H, m), 3.71-3.79 (4H, m), 3.48-3.71 (6H, m), 3.24-3.44 (4H, m), 2.89-3.06 (4H, m), 2.26-2.43 (2H, m), 2.25 (3H, s), 1.64-1.87 (3H, m), 1.51 (9H, s). Mass Spectrum (ESI) m/e=637.5 (M+1).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]=1[OH:28])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:24]([C:20]1[CH:21]=[C:22]([C:4]2[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=2)[C:8]#[N:9])[CH:23]=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:19]=1[OH:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(-c2ccc(C#N)c(C#N)c2)cc(C(C)(C)C)c1O
Reaction time: 72 h

Procedure:
To a stirred solution of 4-nitrophthalonitrile (8 g, 0.05 mol) was added 2,6 di-tert-butylphenol (11.44 g, 0.06 mol), potassium carbonate (9 g, 0.07 mol) and DMF (50 ml), producing a deep red colour. The reaction mixture was stirred under a nitrogen atmosphere for 72 h. Water (300 ml) was added and the mixture extracted with ethyl acetate (3×100 ml), the organic layer was further washed with water (3×75 ml) and dried over MgSO4. Evaporation of the solvent under reduced pressure yielded the crude product. Recrystallisation from ethanol yielded the pure product 4-(3,5-di-tert-butyl-4-hydroxyphenyl)phthlonitrile (1) as colourless, prismatic crystals (18.70 g, 81.70%), m.p. 209-210° C.; IR (KBr) 3416 (OH), 2231 (CN) cm- 1; (Found C, 79.55%; H, 7.50%; N, 8.20%. C22H24N2O requires C, 79.47%; H, 7.28%; N, 8.43%.); MS (EI) m/e 332 (M+); δH (200 MHz, solvent CDCl3): 1.51 (18H, s), 5.55 (1H, s), 7.39 (2H, s), 7.75-8.00 (3H, m).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]([NH:12][CH3:13])=[O:11])[CH:4]=1.[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][C:18]=1Cl>>[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][C:18]=1[NH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]([NH:12][CH3:13])=[O:11])[CH:4]=1
Reactant: COC(=O)c1cccnc1Cl
Reactant: CNC(=O)Nc1cc(CN)ccn1
Product: CNC(=O)Nc1cc(CNc2ncccc2C(=O)OC)ccn1
Temperature: 120 °C
Yield: 62.8 %

Procedure:
A mixture of 1-(4-aminomethyl-pyridin-2-yl)-3-methyl-urea (3.8 g, 21.1 mmol) and 2-chloro-nicotinic acid methyl ester [Mann et al. J. Chem. Soc.; 1952; 2057, 2060] (1.78 g, 10.4 mmol) was heated for 1 hour at 120° C. The crude product was purified by chromatography on silica gel (Gradient elution: 100% CH2Cl2 to 93% CH2Cl2/7% MeOH) to give 2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-nicotinic acid methyl ester (2.06 g); Mp. 145-146° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32](Cl)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:16]=[C:17]([F:24])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32]([C:4]3[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=3)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:16]=[C:17]([F:24])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: Cc1cc(C)cc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(C)cc(-c2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 37.7 %

Procedure:
3,5-Dimethylbenzeneboronic acid (39 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (22 mg, 38%) after purification by flash chromatography on silica gel (% EtOAc in hexane=30%˜100%).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1)[CH3:9].[C:20](=O)=[O:21].C([Li])CCC.CCCCCC.CN(C)C=O.[Cl-].[NH4+]>O1CCCC1.CC(C)=O>[CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[CH:20]=[O:21])[CH3:9]
Reactant: O=C=O
Reactant: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(C=O)c1
Yield: 76.9 %

Procedure:
Compound 7 (1.64 g: 5.12 mmol) was dissolved in tetrahydrofuran (20 ml), and the solution was cooled to −75° C. by use of a mixture of dry ice and acetone solvent under nitrogen atmosphere. n-butyl lithium in n-hexane (1.56 M: 3.3 ml; 5.12 mmol) was slowly added dropwise to the mixture, and the resultant mixture was stirred for 15 minutes. Subsequently, N,N-dimethylformamide (0.56 g; 7.68 mmol) was added dropwise to the mixture, and the resultant mixture was gradually brought to room temperature. Saturated aqueous ammonium chloride solution was added dropwise to the mixture, and the reaction was stopped, followed by extraction with ether (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 1.06 g of the target compound (yield: 76.9%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][CH:12]=[CH:13][N:14]=1)([O-])=O>[Pd].[Ni]>[NH:11]1[CH:12]=[CH:13][N:14]=[C:10]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccccc1-c1ncc[nH]1
Agent: [Ni]
Agent: [Pd]
Product: Nc1ccccc1-c1ncc[nH]1

Procedure:
By catalytic hydrogenation, using palladium on charcoal or Raney Nickel as catalyst, 2-(2-nitro-phenyl)-1H-imidazole, which is commercially obtainable, is converted into 2-(1H-imidazol-2-yl)-phenylaamine (U.S. Pat. No. 6,376,664).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[N:4](COCC[Si](C)(C)C)[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH:29]2[CH2:31][CH2:30]2)[CH:21]=1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NNC(=O)C=4C=3)C=CC=2OC(F)F)CC1.O1CCCC1>O.CO>[Cl:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[NH:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH:29]2[CH2:30][CH2:31]2)[CH:21]=1
Reactant: COc1ccc(-c2c(Cl)c3c(=O)[nH]ncc3n2COCC[Si](C)(C)C)cc1OC1CC1
Agent: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)cc2c(=O)[nH]ncc21
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2[nH]c3cn[nH]c(=O)c3c2Cl)cc1OC1CC1
Yield: 60.6 %

Procedure:
Reaction was carried out in the same manner as in Example 1-(b) except for using 313 mg (0.677 mmol) of 3-chloro-2-(3-cyclopropoxy-4-methoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 42-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained crude solid was dissolved by adding small amounts of tetrahydrofuran and methanol, followed by addition of water, and the solid precipitated by ultrasonic wave treatment was collected by filtration. The obtained solid was washed with water and dried under reduced pressure to obtain 136 mg of the title compound as a white solid. (Yield: 61%)
Reaction SMILES: C(N(CC)CC)C.[F:8][C@@H:9]1[C@@H:14]([OH:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[F:8][C@@H:9]1[C@@H:14]([O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@@H](F)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)[C@@H](F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
Triethylamine (0.95 mL, 6.8 mmol) was added to a 0° C. solution of (3S,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (500.0 mg, 2.28 mmol) and methanesulfonyl chloride (0.27 mL, 3.4 mmol) in dichloromethane (9 mL), and the resulting mixture was warmed to room temperature and stirred overnight. The reaction was quenched with saturated aqueous sodium bicarbonate (10 mL). Additional dichloromethane (10 mL) was added, and the layers were separated. The organic layer was washed with 1M aqueous citric acid (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified directly via column chromatography on silica gel (Biotage 50 g column, gradient elution with 20-30% ethyl acetate in hexanes) to afford tert-butyl (3S,4S)-3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (629 mg, 93%) as a colorless oil that solidified to a white solid upon standing. 1H NMR (300 MHz, CDCl3) δ ppm 1.46 (s, 9H), 1.73-1.87 (m, 1H), 2.15-2.25 (m, 1H), 2.97-3.12 (m, 2H), 3.08 (s, 3H), 3.85-3.95 (m, 1H), 4.39-4.46 (m, 1H), 4.55-4.62 (m, 1H), 4.65-4.78 (m, 1H).
Reaction SMILES: [C:1]1([CH2:9][OH:10])([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl.[OH-].[Na+].Cl>C1(C)C=CC=CC=1>[CH2:11]([O:10][CH2:9][CH:1]1[O:8][CH2:7]1)[CH:13]1[O:15][CH2:14]1.[C:1]1([CH2:9][OH:10])([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCC1CO1
Agent: Cl
Agent: OCC1(CO)CCCCC1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C(OCC1CO1)C1CO1

Procedure:
In a three-liter three-neck glass reaction flask, equipped with a thermometer, stirrer, condenser and dropping funnel were placed cyclohexane dimethanol, toluene and the catalyst. Epichlorohydrin was then added gradually through the dropping funnel to the mixture at such a rate that the temperature varied from 70° to 90° C., with external cooling being applied to the flask. Sodium hydroxide was then added which dehydrohalogenated the chlorohydrin intermediate and neutralized the formed hydrochloric acid. After removal of salt, the mixture was dried and filtered to yield pure diglycidyl ether of cyclohexane dimethanol. The weight per epoxide of the reaction product was 158 to 168, with a viscosity of 60 to 70 centipoise.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1>CO.CS(C)=O.O.C1(C)C=CC=CC=1>[C:7]([C:6]1[CH:5]=[C:4]([CH:12]=[CH:11][CH:10]=1)[O:3][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1)([OH:9])=[O:8]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=C(O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
A solution of potassium hydroxide (1.32 g; 85% pellets) in dry methanol (25 ml) was treated at room temperature with metahydroxybenzoic acid (1.38 g) to give a solution. This was stirred for 30 minutes and then coevaporated with added toluene to give a white solid. The solid was dispersed in dry dimethylsulphoxide (10 ml). Anhydrous potassium carbonate (0.5 g) and 2-chloro-5-trifluoromethylpyridine (1.82 g) were added, and the solution stirred. After 64 hours, water (100 ml) was added. The mixture was extracted with chloroform, filtered and brought to pH 1 with concentrated hydrochloric acid. The solid which precipitated was washed with water and dried to give 2-(3-carboxyphenoxy)-5-trifluoromethylpyridine (2.4 g) (m.p. 146° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:22][C@H:21]([CH3:23])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]3[O:12][C:13](=[O:15])[CH3:14])[C:6]=2[CH:24]=1.[Br:25]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+].C(Cl)(Cl)Cl>C1COCC1>[Br:25][C:8]1[N:7]([C@@H:10]2[O:22][C@H:21]([CH3:23])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]2[O:12][C:13](=[O:15])[CH3:14])[C:6]2[CH:24]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:9]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cnc2ccc(Cl)cc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2ccc(Cl)cc21
Temperature: 0 °C

Procedure:
To a refluxing solution of 0.76 g (2.2 mmol) of 6-chloro-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole in 30 mL of THF was added 0.77 g (4.3 mmol) of N-bromosuccinimide. The resultant mixture was further refluxed for 15 min. The reaction mixture was then poured into an ice-cooled mixture of 20 mL sat. NaHCO3 solution and 20 mL CHCl3. The CHCl3 layer was separated and was further washed with sat. NaHCO3. After drying (MgSO4) and solvent removal, a crude product was obtained which was purified by flash column chromatography on silica with EtOAc/hexane (2:3) as the eluent. This gave 0.73 g (79%) of the title compound as an oil. 1H NMR (DMSO-d6) δ1.42 (d, 3H, CH3), 2 (s, 3H, COCH3), 2.1 (s, 3H, COCH3), 4.2 (quintet, 1H, CH), 5.2 (t, 1H, CH), 5.6 (t, 1H, CH), 6.1 (d, 1H, CH), 7.3 (d, 1H, aromatic), 7.6 (d, 1H, aromatic), 7.82 (s, 1H, aromatic).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[C:23]4[CH:24]=[N:25][C:26]([N+:29]([O-])=O)=[C:27](O)[C:22]=4[O:21][CH:20]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([C:39]([C@H:42]([OH:44])[CH3:43])=[N:40][N:41]=2)[N:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>Cl.[Fe].CCO.C1COCC1>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([C:39]([C@@H:42]([O:44][C:27]3[C:22]4[O:21][CH:20]=[C:19]([C:17]5[CH:16]=[N:15][N:14]([CH:11]6[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]6)[CH:18]=5)[C:23]=4[CH:24]=[N:25][C:26]=3[NH2:29])[CH3:43])=[N:40][N:41]=2)[N:38]=1
Reactant: C[C@@H](O)c1nnc2ccc(Cl)nn12
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3coc4c(O)c([N+](=O)[O-])ncc34)cn2)CC1
Agent: [Fe]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@H](Oc1c(N)ncc2c(-c3cnn(C4CCNCC4)c3)coc12)c1nnc2ccc(Cl)nn12
Temperature: 40 °C

Procedure:
To a mixture of 4-[4-(7-hydroxy-6-nitrofuro[3,2-c]pyridin-3-yl)pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (50.0 mg, 0.116 mmol), (R)-1-(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethanol (46.2 mg, 0.233 mmol), triphenylphosphine (122 mg, 0.466 mmol) and THF (5 mL) under nitrogen at rt was added diisopropyl azodicarboxylate (0.09 mL, 0.466 mmol) dropwise. The solution was heated to 40° C. overnight. The solvent was removed in vacuo, and EtOH (8 mL), iron powder (60 mg, 1 mmol) and conc. HCl (8 drops) were added. The mixture was heated to 75° C. for 2 h. The material was loaded into a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The filtrate was concentrated in vacuo to afford the title compound as a dark orange solid, and was used in the next step without further purification.