Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[I-].[Na+].Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>O.C(O)C>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: OCCCCCCCl
Reactant: O=Cc1ccc(O)cc1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=Cc1ccc(OCCCCCCO)cc1
Yield: 90.9 %

Procedure:
To a solution of 40 g (1 mole) of sodium hydroxide in 60 ml of water and 400 ml of ethanol were added 122.12 g (1 mole) of 4-hydroxybenzaldehyde, 30 g of sodium iodide and 136.62 g (1 mole) of 1-chloro-6-hydroxyhexane. The mixture was heated at reflux for 24 hours under a nitrogen atmosphere. After cooling, the mixture was filtered and the solvent was removed under reduced pressure. Water (400 ml) was added to the residue and the mixture was extracted twice with 400 ml of ethyl acetate. The ethyl acetate layers were extracted twice with 200 ml of 5% aq. sodium hydroxide, and once with 200 ml of brine, dried over magnesium sulfate, and the solvent was evaporated. A brown oil (202 g, 91%) was obtained, which crystallized slowly.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:17]O)[C:11]([CH3:16])=[N:12][C:13]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.[Cl:19]C1C=C(C2C(OC)=NC(C)=C(C=2)C=O)C=CC=1.[BH4-].[Na+]>CO>[Cl:19][CH2:17][C:10]1[C:11]([CH3:16])=[N:12][C:13]([O:14][CH3:15])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:9]=1
Reactant: COc1nc(C)c(CO)cc1-c1cccc(Cl)c1
Reactant: COc1nc(C)c(C=O)cc1-c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C)c(CCl)cc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
(5-(3-Chlorophenyl)-6-methoxy-2-methylpyridin-3-yl)methanol. To a solution of 5-(3-chlorophenyl)-6-methoxy-2-methylnicotinaldehyde (350 mg, 1.34 mmol) in methanol (3 mL) was added sodium borohydride (52 mg, 1.3 mmol). The solution was stirred at room temperature for 20 minutes then concentrated under reduced pressure. Purification (FCC, SiO2, 0-50%, EtOAc/hexanes) afforded the title compound (322 mg, 91%). [M+H]=264.06.
Reaction SMILES: [C:1]1([C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:8][CH:9]2[N:12]([CH:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])Cl)[C:11](=[O:25])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:38]1([P:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C>[C:1]1([C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:8][CH:9]2[N:12]([C:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])=[P:44]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:11](=[O:25])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(OCc1ccccc1)C(Cl)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C(N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
A solution of 4-(triphenylmethylthio)-1-(benzyloxycarbonylchloromethyl)azetidin-2-one (850 mg), triphenylphosphine (640 mg) and 2,6-butidine (210 μl) in DMF (50 ml) was heated at 80° C. under nitrogen for 24 hours. The reaction was then cooled, diluted with ice water and extracted with ethyl acetate (2×100 ml). The ethyl acetate extracts were washed with water and brine, dried (Na2SO4) and evaporated. The residue was flash chromatographed with a solvent gradient of 15 to 60% ethyl acetate/hexane to afford recovered starting material (500 mg) and then 4-(triphenylmethylthio)-1-[(benzyloxycarbonyl)triphenylphosphoranylidenemethyl]azetidin-2-one (650 mg) as a white foam, Rf =0.20 (30% ethyl acetate/hexane).
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[C:8]([CH3:15])=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].[H][H]>[Ni].N>[CH3:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[C:8]([CH3:15])=[CH:7][C:3]=1[CH2:4][CH2:5][NH2:6]
Reactant: [H][H]
Reactant: COc1c(C)cc(CC#N)c(C)c1OC
Agent: [Ni]
Agent: N
Product: COc1c(C)cc(CCN)c(C)c1OC

Procedure:
A mixture of 18.3 g (0.0865 mole) of the nitrile, 1.6 g of Raney nickel catalyst and 170 ml of saturated anhydrous methanolic ammonia is hydrogenated at 50°, 100 p.s.i. of hydrogen gas until hydrogen uptake stopped (about 6 hours). Removal of the catalyst by filtration followed by evaporation gives the 2-(2,5-dimethyl-3,4-dimethoxyphenyl)ethylamine which can be used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:3]=1.[H][H]>[Ni].C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]2[CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[CH:3]=1
Reactant: [H][H]
Reactant: Cc1cn(-c2cc(Cl)ccc2[N+](=O)[O-])c(C2CCCCC2)n1
Agent: [Ni]
Solvent: CCO
Product: Cc1cn(-c2cc(Cl)ccc2N)c(C2CCCCC2)n1

Procedure:
3.2 g 4-Chloro-2-(2-cyclohexyl-4-methyl-imidazol-1-yl)-nitrobenzene, 50 ml ethanol, and 0.5 g Raney-Nickel were heated in a closed vessel with 10 bar hydrogen at 40-45° C. The catalyst was filtered off and the solvent was removed by distillation.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>CN(C)C=O.O>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][N:19]2[C:18](=[O:20])[C:17]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]3[C:15]2=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCc1ccccc1-c1ccccc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1-c1ccccc1
Reaction time: 60 h
Yield: 90.6 %

Procedure:
(2-Phenyl)-phenylmethyl bromide (6 g, 0.0243 mol) and potassium phthalimide (5 g, 0.0270 mol) were mixed together in dimethyl formamide at room temperature, stirred for 60 hrs, diluted with cold water, and the solid isolated by filtration. After washing with water, isopropyl alcohol, and hexane the white solid was vacuum dried to yield 6.9 g of the subtitled compound. Mass spectrum: 313
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH2:2][CH3:3].[N+:11]([O-])([O-:13])=[O:12].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:1][CH2:2][CH3:3])[C:5]=1[OH:10])([O-:13])=[O:12]
Reactant: CCCc1ccccc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1cccc([N+](=O)[O-])c1O
Reaction time: 24 h
Yield: 0 %

Procedure:
2-n-propylphenol (5.00 g, 36.8 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (3.43 g, 40.5 mmol). The addition of sulfuric acid (45 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(3.2 mg, 48%). 1H NMR (CD3COCD3): δ 7.99 (d, 1H), 7.46 dd, 1H), 6.90 (t, 1H), 2.70 (t, 2H), 1.70 (m, 2H), 1.00 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[N:3]=1.O.[NH3:14]>>[NH2:14][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[N:3]=1
Reactant: N
Reactant: Brc1cccc(-n2cccn2)n1
Solvent: O
Product: Nc1cccc(-n2cccn2)n1
Temperature: 25 °C
Yield: 81 %

Procedure:
To a mixture of 2-bromo-6-(1H-pyrazol-1-yl)pyridine (3.0 mmol, 669 mg) and Cu2O (0.01 mmol, 1.0 mg) in glycol in autoclave NH3 was feed. The reaction was maintained under 10 atm of NH3 at 110° C. for 24 h. After cooling to room temperature, water was added and the aqueous phase was extracted with DCM. The combined organic layers were washed with brine and dried over MgSO4. After solvent evaporation, the crude product was purified by column chromatography on silica gel (Hexanes:ethyl acetate=6:1 as eluent) to afford a white solid (388 mg, 81% yield). 1H NMR (400 MHz, CDCl3, ppm): 8.44 (s, 1H), 7.69 (s, 1H), 7.53 (m, 1H), 7.28 (m, 1H), 6.42-6.37 (m, 2H), 4.49 (br, 2H). 13C NMR (100 MHz, CDCl3, ppm): 151.45, 142.72, 140.73, 139.91, 127.58, 125.25, 110.89, 108.23.
Reaction SMILES: [OH:1][C:2]1([C:6]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([O:16][CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH:7]=2)[CH2:5][O:4][CH2:3]1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.OS(O)(=O)=O>[NH:20]1[CH2:19][CH2:18][CH:17]([O:16][C:8]2[CH:7]=[C:6]([C:2]3([OH:1])[CH2:5][O:4][CH2:3]3)[CH:11]=[C:10]([C:12]([F:13])([F:15])[F:14])[N:9]=2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C3(O)COC3)cc(C(F)(F)F)n2)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OC1(c2cc(OC3CCNCC3)nc(C(F)(F)F)c2)COC1
Reaction time: 8 h

Procedure:
A solution of tert-butyl 4-{[4-(3-hydroxyoxetan-3-yl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate (0.080 g, 0.17 mmol, from Step 2) in 1,4-dioxane (1.0 mL) was treated with a few drops of water and six drops of concentrated H2SO4 and was stirred overnight. The mixture was made basic with 10 mL of saturated sodium bicarbonate solution and the product was extracted with three portions of DCM. The combined extracts were dried over sodium sulfate, filtered and concentrated to afford crude product, which was used directly in the next step (44 mg, 81%). 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J=1.2 Hz, 1H), 7.18 (s, 1H), 5.22 (tt, J=8.2, 3.9 Hz, 1H), 4.91 (d, J=7.4 Hz, 2H), 4.78 (d, J=7.4 Hz, 2H), 3.10 (dt, J=11.9, 4.3 Hz, 2H), 2.79 (ddd, J=12.5, 9.1, 3.1 Hz, 2H), 2.16-1.98 (m, 2H), 1.70 (dtd, J=12.7, 8.8, 3.8 Hz, 2H). 19F NMR (282 MHz, CDCl3) δ −68.76 (s). LCMS (M+H)+: 319.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9](Cl)[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]([C:10]([F:13])([F:12])[F:11])=[N:17][N:16]=[N:15]2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)C(Cl)=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: FC(F)(F)c1nnnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
Three grams (12.4 mmol) of N-(4-chlorophenyl)-2,2,2-trifluoroacetimidoyl chloride obtained in Example 11, 1.46 g (22.3 mmol) of sodium azide, 0.85 g (6.20 mmol) of triethylamine hydrochloride, and 30 ml of toluene were introduced into a 100 ml flask and reacted at 80° C. for 24.5 hours. After the reaction, the reaction solution was cooled to room temperature and washed with water (20 ml×2). The organic phase was dried over anhydrous magnesium sulfate for 1 hour, filtered, and then subjected to solvent removal by evaporation. The crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 2.84 g of 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-tetrazole as a pale yellow oil (yield: 92.2%).
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[S:26][C:7]2[N:8]=[CH:9][N:10]=[C:11]([N:12]3[CH2:17][CH2:16][CH:15]([NH:18]C(=O)OC(C)(C)C)[CH2:14][CH2:13]3)[C:6]=2[CH:5]=1)[CH3:3]>ClCCl>[ClH:1].[ClH:1].[CH2:2]([C:4]1[S:26][C:7]2[N:8]=[CH:9][N:10]=[C:11]([N:12]3[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]3)[C:6]=2[CH:5]=1)[CH3:3]
Reactant: CCc1cc2c(N3CCC(NC(=O)OC(C)(C)C)CC3)ncnc2s1
Agent: Cl
Solvent: ClCCl
Product: CCc1cc2c(N3CCC(N)CC3)ncnc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Excess hydrogen chloride gas was bubbled into a solution of tert-butyl N-(1-[6-ethylthieno[2,3-d]pyrimidin-4-yl]piperidin-4-yl)carbamate (1 g, 2.76 mmol, 1.00 equiv) in dichloromethane (20 mL). The resulting solution was stirred for 2 h at 0° C. in a water/ice bath. The resulting mixture was concentrated under vacuum to give 650 mg (70%) of 1-[6-ethylthieno[2,3-d]pyrimidin-4-yl]piperidin-4-amine dihydrochloride as a yellow solid. 1H NMR: (400 MHz, CDCl3) δ 8.61 (1H, s), 7.45 (1H, s), 5.70 (1H, s), 4.68-4.65 (2H, d), 3.43-3.37 (3H, t), 2.96-2.91 (2H, q), 2.16-2.13 (2H, d), 1.70-1.64 (2H, t), 1.29-1.26 (3H, t). MS: m/z 263 (M−2HCl+H)+.
Reaction SMILES: [C:1]([N:4]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([O:29]C)=[O:28])=[N:21][CH:22]=2)=[O:16])[C@@H:7]([CH3:33])[CH2:6]1)(=[O:3])[CH3:2].CO.[OH-].[Na+].Cl>O1CCCC1>[C:1]([N:4]([C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([OH:29])=[O:28])=[N:21][CH:22]=2)=[O:16])[C@@H:7]([CH3:33])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)(C)CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)O)nc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}pyridin-2-yl)oxy]-2,2-dimethylbutanoic acid was prepared from methyl 4-[(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}pyridin-2-yl)oxy]-2,2-dimethylbutanoate. methyl 4-[(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}pyridin-2-yl)oxy]-2,2-dimethylbutanoate (0.005 g, 0.0086 mmol) was hydrolyzed to the acid by dissolving in tetrahydrofuran and methanol and sodium hydroxide (1N) was added. The mixture was stirred at room temperature overnight. The mixture was cooled to rt, acidified to pH=5 with 1N HCl to form a white precipitate (0.002 g, 42%). The solid was filtered to give 4-[(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}pyridin-2-yl)oxy]-2,2-dimethylbutanoic acid.
Reaction SMILES: O=[CH:2]C(=C)C.N.[Al].[P].[B].[N:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1>[Zr].C(C(C)=O)C>[N:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[CH3:2]
Reactant: C=C(C)C=O
Reactant: Cc1cncc(C)c1
Agent: [Zr]
Agent: N
Agent: [Al]
Solvent: CCC(C)=O
Product: Cc1cnc(C)c(C)c1

Procedure:
A process comprising reacting methacrolein with ammonia in a gas phase in the presence of a catalyst which comprises silicon and an element such as zirconium, aluminium and/or phosphorus (see JP-A-8-245589), and a process comprising reacting methacrolein and methyl ethyl ketone with ammonia in a gas phase in the presence of an oxide catalyst comprising silicon, phosphorus and/or boron (see JP-A-8-259537). However, the main product of the former process is 3,5-lutidine, while 2,3,5-collidine is obtained in a yield of only 16.5%. In the latter process, 2,3,5-collidine is obtained in a yield of 15 to 37%.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH:16]2[CH2:21][CH2:20][N:19](C(OCC3C=CC=CC=3)=O)[CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:7])[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[CH2:12][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COC1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)COC1CCN(C2CCNCC2)CC1
Reaction time: 2 h

Procedure:
A suspension of 3.08 g (7.12 mmol) benzyl 4-tert-butoxycarbonylmethoxy-[1,4′]bipiperidinyl-1′-carboxylate and 300 mg 10% Pd/C in 60 mL MeOH was hydrogenated for 2 h at 50° C. and 3447 hPa hydrogen pressure. The catalyst was removed by suction filtering and the filtrate was evaporated to dryness. The product was reacted further without purification.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](O)=[O:34].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.O.C(#N)C.CO>[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)=[O:34]
Reactant: O=C(O)c1ccco1
Reactant: O=C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CC[NH+](CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: CO
Product: O=C1CCN(C(=O)c2ccco2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-piperidone hydrochloride monohydrate (0.23 g, 1.48 mmol) was dissolved in DCM (5 ml), and to this was added MP-Carbonate resin (0.58 g). This was stirred at room temperature for 2 h. Separately, 2-furoic acid (0.2 g, 1.78 mmol), N N-4-dimethylaminopyridine (cat.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.85 g, 4.44 mmol) and TEA (0.15 ml) were dissolved in DCM (5 ml) and stirred at room temperature for 2 h. The 2 reaction mixtures were then combined and stirred at room temperature for 18 h. The resulting solution was then filtered and washed with HCl (1M), NaHCO3 then brine. The organic layers were combined and dried over MgSO4 and evaporated to dryness, to yield a yellow oil. 250 mg, (86%), LCMS tr=1.99 min (50% MeOH and 50% water at 0.5 ml/min), m/z M+H 194.16, HPLC tr=1.85 min (Isocratic 90% acetonitrile and 10% water at 1.0 ml/min), 97.09%, 1HNMR (CDCl3, 270 MHz) δ 2.53 (4H, t, J=6.5 Hz, CH2), 4.02 (4H, m, CH2), 9.49 (1H, q, J=1.7 Hz, ArH), 7.07 (1H, dd, J=0.7, 3.5 Hz, ArH), 7.48 (1H, q, J=1.0 Hz, ArH).
Reaction SMILES: C[Mg]Br.ClC1C=CC([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:14]=[C:13](CCC=O)[CH:12]=2)=CC=1>CCOCC>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([N:15]2[CH:11]=[CH:12][CH:13]=[N:14]2)=[CH:21][CH:20]=1
Reactant: COc1ccc(-n2nc(CCC=O)cc2-c2ccc(Cl)cc2)cc1
Agent: C[Mg]Br
Solvent: CCOCC
Product: COc1ccc(-n2cccn2)cc1
Reaction time: 1 h
Yield: 162.6 %

Procedure:
To a solution of methyl magnesium bromide (MeMgBr) (2.20 ml, 7.04 mM) in Et2O (15 ml) at 0° C. was added a solution of the aldehyde 11 (1.60 g, 4.69 mM) in Et2O (70 ml) dropwise over a 30 minute period. After stirring for 1 hour the reaction was quenched with a saturated, aqueous NH4Cl solution. The reaction mixture was partitioned between EtOAc and H2O. The EtOAc solution was dried (MgSO4), filtered, and concentrated in vacuo. Chromatography (65 g, Baker 40 gm silica gel) of the residue with Et2O as eluent afforded 20 (1.33 g, 79%) as a clear light yellow oil.
Reaction SMILES: [I:1]I.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:27]([O:34][CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44]O)=[CH:40][CH:39]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C(Cl)Cl>[C:30]([Si:27]([O:34][CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][I:1])=[CH:40][CH:39]=1)([CH3:29])[CH3:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: II
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(CO)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(CI)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
At 0° C., iodine (1.2 eq.) and imidazole (1.2 eq.) were added to a CH2Cl2 solution (0.05 M) of triphenylphosphine (1.2 eq.). The resulting yellow-orange suspension was stirred at 0° C. for 10 min and then at RT for 15 min. Finally, [4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)phenyl]methanol from the previous step (1 eq.) was added over 30 min as a 0.2 M CH2Cl2 solution. After another 10 h of stirring at RT, the volatiles were removed in vacuo. The resulting brown residue was suspended in ether and rapidly passed through a plug of SiO2. Removal of the volatiles in vacuo afforded the title compound as a pink oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([OH:14])=[O:13])=[C:6]2[CH2:15][CH2:16][CH2:17][NH:18]C(OC(C)(C)C)=O.[ClH:26].CCOC(C)=O.CCOCC>ClCCl.O1CCOCC1>[ClH:26].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([OH:14])=[O:13])=[C:6]2[CH2:15][CH2:16][CH2:17][NH2:18]
Reactant: COc1ccc2[nH]c(C(=O)O)c(CCCNC(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccc2[nH]c(C(=O)O)c(CCCN)c2c1
Reaction time: 3.5 h
Yield: 78 %

Procedure:
The above carboxylic acid (27 mg) was suspended in 3 mL of dichloromethane and 0.2 mL of a 4 N solution of HCl in dioxane was added. After 3.5 h, TLC analysis (EtOAc) showed only baseline material thus 5 mL of ether was added and the resulting solid was collected by filtration and dried to yield the title compound (15 mg, 78%); MS, electrospray, 249 (M+H).
Reaction SMILES: C([O:4][CH:5]1[CH2:10][CH:9]2[N:11]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH:6]1[CH2:7][C@H:8]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=O)C.C1CCN2C(=NCCC2)CC1>CO>[OH:4][CH:5]1[CH2:10][CH:9]2[N:11]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH:6]1[CH2:7][C@H:8]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)[C@@H]1CC2C(OC(C)=O)CC1N2C(=O)OCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CCOC(=O)[C@@H]1CC2C(O)CC1N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
A mixture of O7-benzyl O5-ethyl (5R)-2-acetoxy-7-azabicyclo[2.2.1]heptane-5,7-dicarboxylate (0.87 g, 2.4 mmol) and DBU (0.73 g, 4.8 mmol) in methanol (20 mL) was stirred for 12 hours at room temperature. After removal of solvent, the residue was purified by silica gel chromatography to give O7-benzyl O5-ethyl (5R)-2-hydroxy-7-azabicyclo[2.2.1]heptane-5,7-dicarboxylate 151d. Yield: 45%. MS: calc'd (MH +) 306, measured (MH+) 306.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH3:32][C:33]1[N:34]=[C:35]([S:39]([NH2:42])(=[O:41])=[O:40])[S:36][C:37]=1[CH3:38]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:35]3[S:36][C:37]([CH3:38])=[C:33]([CH3:32])[N:34]=3)(=[O:40])=[O:41])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: Cc1nc(S(N)(=O)=O)sc1C
Product: Cc1nc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4ccccc4)c3C)cc2)sc1C

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4,5-dimethyl-1,3-thiazole-2-sulfonamide: 1H-NMR (CDCl3) δ 7.45-7.24 (9H, m), 6.47 (1H, br.s), 3.50-3.42 (2H, m), 2.88-2.82 (2H, m), 2.41 (3H, s), 2.35 (3H, s), 2.31 (3H, s), 2.24 (3H, s).