Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=O)[C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[CH:18][C:17]=2[O:25][CH3:26])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCOCC1>[NH2:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([O:25][CH3:26])[C:16]=1[CH2:15][NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1
Reactant: COc1cccc([N+](=O)[O-])c1C(=O)NC1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1cccc(N)c1CNC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C

Procedure:
Into a flame dried flask, N-(1-benzyl-piperidin-4-yl)-2-methoxy-6-nitrobenzamide (1.0 g, 2.8 mmol) and lithium aluminium hydride (0.31 g, 8.45 mmol) were combined. To the mixture was added anhydrous 1,4-dioxane (15 mL). The mixture was slowly brought to reflux over 1 h and stirred at reflux for 16 h. The reaction mixture was cooled to 0° C. and excess lithium aluminium hydride destroyed by dropwise addition of methanol, followed by careful addition of 20% potassium hydroxide. The aluminum salts were filtered, the filtrate concentrated and used as is for the next reaction.
Reaction SMILES: CO[C:3](=[O:20])[C@@H:4]([N:6]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:7][CH:8]=[O:9])[CH3:5].[NH2:21][C@H:22]([CH2:34]O)[CH2:23][CH2:24][N:25]1[CH2:32][CH2:31][C:28]2([CH2:30][CH2:29]2)[C@H:27]([OH:33])[CH2:26]1>C1(C)C=CC=CC=1>[CH2:13]([O:12][C:10]([N:6]1[C@@H:4]([CH3:5])[C:3](=[O:20])[N:21]2[C@@H:22]([CH2:23][CH2:24][N:25]3[CH2:32][CH2:31][C:28]4([CH2:29][CH2:30]4)[C@H:27]([OH:33])[CH2:26]3)[CH2:34][O:9][CH:8]2[CH2:7]1)=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N[C@H](CO)CCN1CCC2(CC2)[C@H](O)C1
Reactant: COC(=O)[C@H](C)N(CC=O)C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H]1C(=O)N2C(CN1C(=O)OCc1ccccc1)OC[C@@H]2CCN1CCC2(CC2)[C@H](O)C1
Yield: 84.3 %

Procedure:
A solution of (S)-2-[benzyloxycarbonyl-(2-oxo-ethyl)-amino]-propionic acid methyl ester (intermediate 1; 570 mg, 2.04 mmol) and (S)-6-((S)-3-amino-4-hydroxy-butyl)-6-aza-spiro[2.5]octan-4-ol (445 mg, 2.04 mmol) in toluene (6 mL) was heated at reflux for 16 h, then the reaction mixture was concentrated. Chromatography (SiO2; DCM→DCM/MeOH/25% aq. ammonia solution 90:10:0.25) produced the title compound (763 mg, 84%) as a 70:30 mixture of (R)- and (S)-epimers. White foam, MS (ISP)=446.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:21]([NH2:23])=[O:22])=[C:12]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]([C:21]([NH2:23])=[O:22])=[C:12]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[NH:13][CH:14]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CCNC(=O)Nc1[nH]cc(-c2ccc([N+](=O)[O-])cc2)c1C(N)=O
Agent: [Pd]
Solvent: CO
Product: CCNC(=O)Nc1[nH]cc(-c2ccc(N)cc2)c1C(N)=O
Yield: 53.8 %

Procedure:
0.115 g (0.362 mmol) of 4-(4-nitrophenyl)-2-(3-ethylureido)-1H-pyrrole-3-carboxamide is added at a temperature in the region of 25° C. to a suspension of 0.067 g (0.0636 mmol) of 10% palladium on carbon in 15 cm3 of methanol. After hydrogenating for 2.5 hours in an autoclave under 2 bar of hydrogen, at a temperature in the region of 25° C., the reaction mixture is filtered, the catalyst is rinsed with three times 5 cm3 of methanol and then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give 0.056 g of 4-(4-aminophenyl)-2-(3-ethylureido)-1H-pyrrole-3-carboxamide, in the form of an orange solid; ES+: m/z=289 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccccc3)c12
Product: Cc1csc2nc(-n3cccn3)nc(NCc3ccccc3)c12

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[C:12]([Cu])#[N:13].Cl>CN(C=O)C.O>[C:12]([CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])#[N:13]
Reactant: O=C(CCBr)c1ccccc1
Reactant: N#C[Cu]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCC(=O)c1ccccc1
Temperature: 80 °C

Procedure:
Based on Kulkarni, N. R. Ayyangar, Tetrahedron, 1994, 50, 1243–1260. ]: A mixture of 3-bromopropiophenone (10.65 g, 50 mmol), CuCN (5.82 g, 65 mmol) in DMF (35 mL) was heated under reflux for 6 h. After cooling the mixture to ambient temperature FeCl3 (5 g) in H2O (30 mL)/HCl conc (10 mL) was added and heated to 80° C. for another 20 min. After cooling to room temperature and extraction with ether further purification occurred by destination under reduced pressure (bp.: 140° C., 10 torr). The ketone could be obtained as slightly yellow, low melting (42° C.) solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:17][N:16]([C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH2:26][NH:25][CH2:24][CH2:23]4)=[O:19])[CH2:15]2)[CH2:10][CH2:9]1)=[O:7].[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.O>[CH2:30]([N:25]1[CH2:24][CH2:23][C:22]2[C:27](=[CH:28][CH:29]=[C:20]([C:18]([N:16]3[CH2:17][CH:14]([N:11]4[CH2:12][CH2:13][N:8]([C:6]([C:2]5[S:1][CH:5]=[CH:4][N:3]=5)=[O:7])[CH2:9][CH2:10]4)[CH2:15]3)=[O:19])[CH:21]=2)[CH2:26]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(c1ccc2c(c1)CCNC2)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc2c(c1)CCN(Cc1ccccc1)C2)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A solution of Cpd 916 (50 mg, 0.121 mmol) and benzaldehyde 23a (0.014 mL, 0.134 mmol) in CH2Cl2 (2 mL) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (38.6 mg, 0.182 mmol) was added and the mixture was stirred overnight. The resulting mixture was combined with CH2Cl2 and H2O, and pH of the water layer was adjusted to pH˜8 with 1N aqueous NaOH. The organic solution was dried over Na2SO4 and concentrated. Purification the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc) gave Cpd 680 (38.6 mg). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J=3.2 Hz, 1H), 7.55 (d, J=3.2 Hz, 1H), 7.32-7.44 (m, 6H), 7.3 (d, J=8.1 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 4.33-4.63 (m, 2H), 3.99-4.34 (m, 4H), 3.75-3.98 (m, 2H), 3.70 (s, 2H), 3.65 (s, 2H), 3.16-3.30 (m, 1H), 2.93 (t, J=5.7 Hz, 2H), 2.76 (t, J=5.7 Hz, 2H), 2.37-2.60 (m, 4H). MS m/z (M+H+) 502.0.
Reaction SMILES: [O:1]=[C:2]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28]CC)=[O:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:17])([CH3:16])[C:11]([O:13]CC)=[O:12].[OH-].[K+]>>[O:1]=[C:2]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH3:32])([CH3:31])[C:26]([OH:28])=[O:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:17])([CH3:16])[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)C(C)(C)CCCCCCCC(=O)CCCCCCCC(C)(C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Product: CC(C)(CCCCCCCC(=O)CCCCCCCC(C)(C)C(=O)O)C(=O)O

Procedure:
Compound 107n was prepared likewise Method D starting from 106n (11.63 g, 25.6 mmol) and KOH (4.31 g, 77.0 mmol) to give, after recrystallization from iPr2O/heptane, 107n (7.56 g, 74%) as white crystals. mp=74-77° C. 1H NMR: (CD3OD) δ 2.43 (t, J=7.3 Hz, 4H), 1.57-1.50 (m, 8H), 1.33-1.21 (m, 16H), 1.14 (s, 12H). 13C NMR: δ 214.5, 182.1 (2×), 43.6 (2×), 43.2 (2×), 42.0 (2×), 31.2 (2×), 30.4 (2×), 30.38 (2×), 26.2 (2×), 25.9 (4×), 25.0 (2×). Anal calcd for C23H42O5: C, 69.31; H, 10.62. Found: C, 69.41; H, 10.73.
Reaction SMILES: Cl.[CH:2]12[C:10](=[O:11])[CH:6]([CH2:7][NH:8][CH2:9]1)[CH2:5][O:4][CH2:3]2.C([O-])([O-])=O.[Na+].[Na+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>CCOC(C)=O>[CH2:22]([O:21][C:19]([N:8]1[CH2:7][CH:6]2[C:10](=[O:11])[CH:2]([CH2:3][O:4][CH2:5]2)[CH2:9]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1C2CNCC1COC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1C2COCC1CN(C(=O)OCc1ccccc1)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a stirred mixture of 3-oxa-7-aza-bicyclo[3.3.1]nonan-9-one hydrochloride [CAS #1228600-54-1] (4.80 g, 27 mmol), EtOAc (105 ml) and saturated aqueous Na2CO3 (105 ml) was added benzyl chloroformate (4.60 ml, 32.4 ml) at 0° C. The reaction mixture was stirred for 1 h at 0° C. and then extracted with EtOAc (2×). The organic phases were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. Purification of the residue by normal phase column chromatography, eluting with heptane-EtOAc 1:1, gave the title compound as a colorless oil (5.75 g, 20.68 mmol, 77%): 1H-NMR (400 MHz, DMSO-d6): δ 2.31-2.35 (d, 2H), 2.34 dd, 2H), 3.78 (d, 2H), 4.19 (t, 2H), 4.55 (q, 2H), 5.11 (m, 2H), 7.28-7.38 (m, 5H).
Reaction SMILES: [C:1]([N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)(=[O:3])[CH3:2].Cl[CH2:10][CH2:11][CH2:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1.[I-:24].[Na+]>C(#N)C>[I-:24].[C:1]([N+:4]1[CH:8]=[CH:7][N:6]([CH2:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1ccnc1
Reactant: CCOC(=O)c1ccc(CCCCl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(CCCn2cc[n+](C(C)=O)c2)cc1
Temperature: 140 °C
Yield: 93.5 %

Procedure:
To 10 ml of dry acetonitrile were added 1.1 g of 1-acetylimidazole, 2.26 g of ethyl 4-(3-chloropropyl)benzoate and 1.5 g of sodium iodide, and the mixture was heated in a sealed tube for 18 hours at 140° C. under stirring. After cooling, the reaction mixture was filtrated to remove insoluble materials and the filtrate was concentrated under reduced pressure. To the residue was added an adequate amount of dry diethyl ether and the resulting powder was collected by filtration to obtain 3.99 g of 1-acetyl-3-[3-(4-ethoxycarbonylphenyl)propyl]imidazolium iodide. (pale yellow hygroscopic amorphous).
Reaction SMILES: [CH3:1][N:2]1[CH:15]([CH3:16])[CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:28])=[CH2:27])=[CH:22][N:21]=1.O>CN1C(=O)CCC1>[CH3:1][N:2]1[CH:15]([CH3:16])[CH2:14][C:5]2[N:6]([CH2:27][CH:26]([C:23]3[CH:22]=[N:21][C:20]([CH3:19])=[CH:25][CH:24]=3)[CH3:28])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=C(C)c1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)C(C)C3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(C)c2ccc(C)nc2)CC(C)N(C)C1
Temperature: 140 °C

Procedure:
A flask was charged with 2,3,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (117 mg, 0.5 mmol) and KOH (392 mg, 7 mmol) in NMP (2 mL) and heated at 140° C. for 10 min. The mixture was cooled to 0° C. and to it was added 2-methyl-5-(prop-1-en-2-yl)pyridine (199 mg, 1.5 mmol) dropwise. The mixture was heated at 140° C. for 2 h. The progress of the reaction was monitored by LCMS (5% conversion). The mixture was cooled to RT, water was added and the mixture filtered and evaporated. The solid obtained was purified by HPLC. 1HNMR (CD3OD, TFA salt) d (ppm): 8.10 (m, 2H), 7.60 (m, 1H), 7.22 (s, 1H), 7.10 (d, 1H), 6.96 (d, 1H), 4.62 (m, 1H), 4.38 (m, 2H), 4.22 (m, 2H), 3.50 (m, 2H), 3.0 (s, 3H), 2.80 (s, 3H), 2.40 (s, 3H), 1.60-1.30 (m, 7H).
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][C@H:19]([O:24]C(=O)C(C)(C)C)[CH2:18][CH2:17]2)C.Cl[CH2:41][C:42]([N:44]([CH3:46])[CH3:45])=O>>[CH3:45][N:44]([CH3:46])[CH2:42][CH2:41][O:10][C:8]1[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:35][CH:34]=1
Reactant: CN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1-c1ccc2c(c1)CC[C@@H](OC(=O)C(C)(C)C)C2
Product: COc1cc(NCCCc2ccc(OCCN(C)C)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 69.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N,N-dimethylacetamide (6.6 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.3 mg) was obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[C:16]2[CH:17]=[CH:18][C:19]([NH2:21])=[CH:20][C:15]=2[CH2:14][CH2:13][O:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:29][CH2:30][CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34].[OH-].[Na+]>C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[C:16]2[CH:17]=[CH:18][C:19]([NH:21][S:33]([CH2:32][CH2:31][CH2:30][Cl:29])(=[O:35])=[O:34])=[CH:20][C:15]=2[CH2:14][CH2:13][O:12]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1OCCc2cc(N)ccc21
Reactant: O=S(=O)(Cl)CCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC[C@@H]1OCCc2cc(NS(=O)(=O)CCCCl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (1S)-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-amine (0.15 g, 0.49 mmol) in ethyl acetate (18 mL), cooled to 0° C., was added triethylamine (0.274 mL, 1.37 mmol) then 3-chloro-1-propanesulfonyl chloride (0.070 mL, 0.576 mmol), and the reaction mixture allowed to warm to room temperature. After stirring for 1 h, the reaction was basified with 1N sodium hydroxide (2.5 mL), and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated in vacuo to yield the title compound as an oil. This crude product was used in the next step without further purification.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH:10]1([O:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:10]1([O:16][CH:17]2[CH2:18][CH2:19][N:20]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[CH2:21][CH2:22]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCC(OC2CCNCC2)CC1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(N2CCC(OC3CCCCC3)CC2)cc1
Yield: 53.9 %

Procedure:
A solution of 4-fluorobenzonitrile (1.50 g), 4-(cyclohexyloxy)piperidine (2.40 g) and potassium carbonate (3.3 g) in DMF (30 ml) was stirred at 90-95° C. for 6 hours. The reaction mixture was poured into water (100 ml) and extracted twice with a mixture of ethyl acetate and n-hexane (80 ml:30 ml). The extracts were combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (200 ml) eluting with a mixture of n-hexane and ethyl acetate (6:1 v/v-5:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give 4-[4-cyclohexyloxypiperidin-1-yl)benzonitrile (1.90 g).
Reaction SMILES: [C:1]([CH2:3][CH:4]([P:9]([OH:12])([OH:11])=[O:10])[S:5]([O-:8])(=[O:7])=[O:6])#[N:2].[H][H]>N.[Rh]>[NH2:2][CH2:1][CH2:3][CH:4]([P:9]([OH:12])([OH:11])=[O:10])[S:5]([OH:8])(=[O:6])=[O:7]
Reactant: [H][H]
Reactant: N#CCC(P(=O)(O)O)S(=O)(=O)[O-]
Agent: [Rh]
Agent: N
Product: NCCC(P(=O)(O)O)S(=O)(=O)O

Procedure:
The hydrogenation of 2-cyano-1-phosphonoethanesulfonate is carried out using the hydrogenation technique of Freifelder (J. Am. Chem. Soc., 82, 2386 (1960)). The cyano compound (2.15 g; 0.01 mole) is placed in 20 ml of 10% methanolic ammonia. Rhodium on alumina (5%) catalyst (0.5 g) is added, and the mixture is hydrogenated at 40 PSI on a Parr apparatus for several hours (until uptake of hydrogen is complete). The catalyst is filtered off, and the filtrate is evaporated dry. The product is purified by dissolving the residue in water, adding ethanol to give a precipitate, and collecting the solids by filtration. Further purification is accomplished by again recrystallizing from water/ethanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([O:17][CH2:18][C@@H:19]3[CH2:22][CH2:21][N:20]3C(OC(C)(C)C)=O)[CH:16]=2)[O:8][N:7]=1.[ClH:31]>CO.CCOCC>[ClH:31].[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([O:17][CH2:18][C@@H:19]3[CH2:22][CH2:21][NH:20]3)[CH:16]=2)[O:8][N:7]=1
Reactant: COC(=O)CCc1cc(-c2cncc(OC[C@@H]3CCN3C(=O)OC(C)(C)C)c2)on1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)CCc1cc(-c2cncc(OC[C@@H]3CCN3)c2)on1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
To a solution of 3-[5-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]-3-isoxazolyl]propionic acid methyl ester (100 mg, 0.24 mmol) in MeOH (34 mL) was added at 0° C. 2M anhydrous HCl in ether (12 mL). The reaction mixture was stirred at 0° C. for 7 h, then concentrated in vacuo. The residue was purified by HPLC to give the hydrochloride (90 mg). 1H NMR (CD3OD, 400 MHz) δ 8.70 (s, 1H), 8.46 (s, 1H), 7.93 (d, 1H, J=1.6 Hz), 6.93 (s, 1H), 4.92 (s, 1H), 4.49 (m, 2H), 4.10 (m, 2H), 3.69 (s, 3H), 3.04 (t, 2H, J=7.2 Hz), 2.80 (t, 2H, J=7.2 Hz), 2.70 (m, 2H). 13C NMR (CDCl3, 100 MHz) δ 174.3, 165.8, 164.6, 158.5, 134.0, 133.1, 129.5, 128.5, 105.8, 70.1, 60.3, 52.5, 45.1, 32.7, 22.6, 22.0.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5].[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[C:9]1([C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[S:1][CH2:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(CS)C(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O

Procedure:
A solution of 3-mercapto-2-methylpropanoic acid (1.2 g.) and tritylchloride (2.9 g.) in methylene chloride (50 ml.) is kept at room temperature for 2 hours. The mixture is warmed in a steam bath for 20 minutes and then evaporated to dryness in vacuo and the residue is dissolved in saturated aqueous sodium bicarbonate and the solution is washed with ethyl acetate. The aqueous phase is acidified to pH 3 and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness to give 3-triphenylmethylthio-2-methylpropanoic acid. Rf 0.8 (Silica gel, Benzene/acetic acid 3:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:33][C:34]1([CH3:41])[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1.O>CN(C=O)C>[CH3:33][C:34]1([CH3:41])[CH2:39][CH2:38][CH:37]([NH:40][C:8]([C:6]2[CH:7]=[C:2]([NH2:1])[CH:3]=[CH:4][N:5]=2)=[O:10])[CH2:36][CH2:35]1
Reactant: Nc1ccnc(C(=O)O)c1
Reactant: CC1(C)CCC(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CCC(NC(=O)c2cc(N)ccn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-amino-pyridine-6-carboxylic acid (250 mg, 1.81 mmol) with TBTU (600 mg, 1.87 mmol) and TEA (1 mL, 7.2 mmol) in 4 mL DMF was added 4,4-dimethyl-cyclohexylamine (300 mg, 1.83 mmol) and the mixture stirred at ambient temperature for 1 h. Then the mixture was poured into water at 0° C. and stirred for 5 min. The precipitate was filtered off, washed with water and dried at 55° C.
Reaction SMILES: [Br-].[F:2][C:3]1([F:34])[C:7]([F:9])([F:8])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:14][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:5]=2[O:4]1.C([Li])CCC.[CH2:40]1[O:50][C:43]2([CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]2)[O:42][CH2:41]1>O1CCCC1>[F:34][C:3]1([F:2])[C:7]([F:8])([F:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH:14]=[C:46]3[CH2:47][CH2:48][C:43]4([O:50][CH2:40][CH2:41][O:42]4)[CH2:44][CH2:45]3)[C:5]=2[O:4]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: FC1(F)Oc2c(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cccc2C1(F)F
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: FC1(F)Oc2c(C=C3CCC4(CC3)OCCO4)cccc2C1(F)F

Procedure:
This compound is prepared in a manner analogous to that of Step B of Example 2, using 20.1 grams (0.039 mole) of (2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7ylmethyl)triphenylphosphonium bromide, 15.4 mL (0.0) 39 mole) of n-butyllithium (2.5M in hexanes), and 5.0 grams (0.032 mole) of 1,4-cyclohexanedione mono-ethylene ketal in about 55 mL of dry tetrahydrofuran, yielding 8-(2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmethylene)-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:22]([O:24]C)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CO.[OH-].[Na+]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]2([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(CN2CCC(CNC(=O)OC(C)(C)C)CC2)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCN(CC2(C(=O)O)CCCC2)CC1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a solution of Methyl 1-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]cyclopentanecarboxylate (2.8 g, 8.0 mmol, Step 6) in MeOH (11 mL), 2 N aqueous NaOH solution (6 mL) was added at room temperature (exothermic). The resulting solution was stirred at 70° C. for 4 h, then cooled to 5-10° C. in ice-cold water bath. To the solution, 5 N HCl aq (6 mL) was added dropwise. The resulting solution (pH value was ca.6) was concentrated and to the residue, 2-propanol (40 mL) was added. This solution was concentrated and to the residue, CH3CN (40 mL) was added. The resulting mixture was stirred at room temperature for 2 h and it was filtered through a Celite pad (5.0 g) to remove NaCl. The filtrate was concentrated to give 2.4 g (quant) of the titled compound as white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C:11]([CH3:21])([CH3:20])[N:10]2[N:22]=[CH:23][C:24]([C:25](=[O:34])[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:36].[H-].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C:11]([CH3:21])([CH3:20])[N:10]2[N:22]=[CH:23][C:24]([C:25](=[O:34])[CH:26]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[CH3:36])=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CC(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C(C)C(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
To 0.64 g (1.42 mmol) of 4 dissolved in 10 mL of THF was added 0.177 mL (2.85 mmol) of iodomethane followed by 0.11 g (2.8 mmol) of sodium hydride (60% dispersion in mineral oil). After stirring at room temperature for 2 h, the reaction was quenched by addition of approximately 2 mL of saturated aqueous ammonium chloride. The reaction was then diluted with AcOEt and dried over sodium sulfate. Filtering the solution through a short plug of silica gel and concentrating in vacuo provided the crude product. Purification by flash chromatography eluting with 90% hexanes/ethyl acetate gave 0.42 g (64%) of the title compound as a cream colored powder. MS Calcd.: 463. Found: 464 (M+H).