Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:7]=2[CH:8]=1)(O)=[O:2].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.C[N:26](C=O)C>>[NH2:26][C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:7]=2[CH:8]=1)=[O:2]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A dry reaction flask equipped with a magnetic stirring bar, nitrogen inlet and rubber septum was charged with 2-carboxy-5-nitrobenzofuran (0.414 g, 2 mmol) and CH2Cl2 (100 mL). To this was added DMF (0.1 mL) followed by a slow addition of oxaloyl chloride (0.519 mL, 6 mmol) over the period of 5 minutes at 0° C. The reaction mixture was further stirred for 30 minutes by the time the formation of a clear solution was observed. The resulting clear solution was concentrated under a reduced pressure and dried under high vacuum for 30 minutes. The resulting residue was suspended in EtOAc (25 mL), cooled to 10° C., to it was added NH4OH (30% solution, 25 mL) and stirred at room temperature for 24 h. The organic phase was separated and dried over anhydrous sodium sulfate and solvent was removed to give 2-aminocarbonyl-5-nitrobenzofuran. 1H NMR (DMSO-d6): δ 8.75 (d, 1H, J=2.7 Hz), 8.28 (m, 2H), 7.86 (d, 1H, J=9.0 Hz), 7.83 (bs, 1H), 7.72 (s, 1H); LCMS: purity: 93%, MS (m/e): 206 (M+).
Reaction SMILES: O1CCCC1.[CH:6]([C@H:9]1[CH2:13][O:12][C:11](=[O:14])[NH:10]1)([CH3:8])[CH3:7].[C:15](Cl)(=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19]>O>[CH:6]([C@H:9]1[CH2:13][O:12][C:11](=[O:14])[N:10]1[C:15](=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19])([CH3:8])[CH3:7]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: C=CCCC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran (2 L) solution of 108 g of (S)-4-isopropyl-oxazolidin-2-one was cooled in a dry ice bath at −70° C., 345 mL of 2.66 M n-butyllithium-hexane solution was added thereto, and the reaction liquid was stirred at −70° C. for 30 minutes. Next, 102 mL of 4-pentenoyl chloride was added thereto at −70° C., the reaction liquid was stirred for 30 minutes, and water was added thereto to stop the reaction. This was extracted with ethyl acetate, the organic layer was washed with aqueous saturated sodium deuteride solution, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure to obtain a crude product of the entitled compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:15][C:16]1[CH:21]=[C:20]([NH:22][CH:23]([CH3:25])[CH3:24])[C:19]([C:26]2[O:27][C:28](S(C)(=O)=O)=[N:29][N:30]=2)=[CH:18][N:17]=1>O1CCOCC1>[Cl:15][C:16]1[N:17]=[CH:18][C:19]([C:26]2[O:27][C:28]([NH:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)=[N:29][N:30]=2)=[C:20]([NH:22][CH:23]([CH3:25])[CH3:24])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(C)Nc1cc(Cl)ncc1-c1nnc(S(C)(=O)=O)o1
Solvent: C1COCCO1
Product: CC(C)Nc1cc(Cl)ncc1-c1nnc(NC2CCN(C(=O)OC(C)(C)C)CC2)o1
Temperature: 90 °C

Procedure:
tert-butyl 4-aminopiperidine-1-carboxylate (8 mmol, 5 equiv.) was added to a stirred solution of 2-chloro-N-isopropyl-5-(5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl)pyridin-4-amine (44) (500 mg, 1.7 mmol) in Dioxan (5 mL) and heated at 90° C. for 4 h. The reaction mass was concentrated under reduced pressure. The crude material obtained was purified by column chromatography through silica gel and MeOH: DCM as eluent to afford the desired compound, tert-butyl 4-((5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)piperidine-1-carboxylate. LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 2.049 min; LCMS (ES-API), m/z 437.2 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:5])[CH3:4].[H-].[K+].C(S([C:16]1[O:17][CH:18]=[C:19]([CH3:21])[N:20]=1)=O)CCCCC.CCOCC>CN(P(N(C)C)(N(C)C)=O)C>[CH3:1][N:2]([C:16]1[O:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:3](=[O:5])[CH3:4]
Reactant: CCCCCCS(=O)c1nc(C)co1
Reactant: CNC(C)=O
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(=O)N(C)c1nc(C)co1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
N-Methyl-acetamide (1.02 g, 0.0140 m) in HMPA (10 ml) was stirred at 50° C. under nitrogen during the portionwise addition of 50% potassium hydride/oil dispersion (1.12 g, 0.0140 m). After the addition, the mixture was warmed to 100° C. and 2-n-hexylsulphinyl-4-methyloxazole (3.0 g, 0.0139 m) in HMPA (10 ml) was added and the mixture stirred at 100° C. for 5 hours. The mixture was then hydrolysed with water, solvent removed in vacuo and the product isolated by column chromatography on silica using ether. Recrystallisation from diethyl ether/hexane at -20° C. gave the title product as colourless needles, m.p. 27°-29° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[C:23]=3[CH:24]=2)=[CH:8][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[CH2:25]([N:16]1[C:15]2[CH:14]=[CH:13][C:12]([C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:32])=[O:2])=[CH:11][CH:10]=3)=[CH:24][C:23]=2[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)COc1ccc(-c2ccc3c(c2)c2c(n3Cc3ccccc3)CCCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(-c2ccc3c(c2)c2c(n3Cc3ccccc3)CCCC2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 4. Thus, [4-(9-benzyl-6,7,8,9-tetrahydro-5H-carbazol-3-yl)-phenoxy]-acetic acid methyl ester (0.355 g, 0.834 mmol) was reacted with 1N KOH (1.7 ml) in THF/MeOH (6 ml/4 ml) to give the product (0.261 g, 0.634 mmol, 74%) as a pale-yellow solid, mp 176-180° C. 1H NMR (DMSO-d6) δ 1.77-1.86 (m, 4H), 2.65 (t, J=5.3 Hz, 2H), 2.70 (t, J=6.0 Hz, 2H), 4.69 (s, 2H), 5.33 (s, 2H), 6.96 (d, J=8.7 Hz, 2H), 7.03 (d, J=7.3 Hz, 2H), 7.21 (t, J=7.2 Hz, 1H), 7.25-7.30 (m, 3H), 7.39 (d, J=8.6 Hz, 1H), 7.56 (d, J=8.7 Hz, 2H), 7.58 (d, J=1.7 Hz, 1H), 13.00 (broad s, 1H); IR (solid) 3020, 2920, 1740, 1520, 1470, and 1240 cm−1; [ESI(−)], rn/z 410 (M−H)−; Anal. Calcd. for C27H25NO3: C, 78.81; H, 6.12; N, 3.40; Found: C, 78.69; H, 6.21; N, 3.20.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][Br:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (2.30 g, 10.7 mmol) and carbon tetrabromide (4.43 g, 13.4 mmol) in CH2Cl2 (40 mL) is cooled to 0° C. Triphenylphosphine (4.21 g, 16.0 mmol) is added and the reaction is stirred at 25° C. for 1 h. The reaction is concentrated and ether is added to the residue. The mixture is filtered and washed with ether. The filtrate is concentrated and purified by column chromatography (silica, 20% EtOAc/hexane) to provide 4-bromomethyl-piperidine-1-carboxylic acid tert-butyl ester as a crystaline solid upon standing. Mp 48-50° C.; 1H NMR (300 MHz, CDCl3) δ 4.13 (bm, 2H), 3.29 (d, 2H), 2.70 (dd, 2H), 1.85-1.73 (m, 3H), 1.46 (s, 9H), 1.28-1.13 (m, 2H); MS (EI) 277 (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](N2C(C)=CC=CC2=O)=O)=[CH:6][CH:5]=[C:4]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([C:25]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[CH2:20]2)[N:3]=1.CO.[CH2:34]([OH:38])[CH:35](C)[CH3:36].C[O-].[Na+]>O>[CH3:2][C:7]1[N:8]([CH2:9][C:9]2[NH:1][C:2]3=[N:3][C:4]([N:19]4[CH2:24][CH2:23][CH2:22][C@@H:21]([C:25]([N:27]5[CH2:28][CH2:29][CH2:30][CH2:31]5)=[O:26])[CH2:20]4)=[CH:5][CH:6]=[C:7]3[N:8]=2)[C:34](=[O:38])[CH:35]=[CH:36][CH:6]=1
Reactant: Cc1cccc(=O)n1C(=O)Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CC(C)CO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cccc(=O)n1Cc1nc2ccc(N3CCC[C@@H](C(=O)N4CCCC4)C3)nc2[nH]1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Into a vial were added (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-6-methyl-2-oxopyridine-1(2H)-carboxamide (1 equiv) and a solution of methanol and isobutanol (1:1, 1.5 mL). Sodium methoxide (2.0 equiv) was added and the reaction mixture was shaken at 110° C. for 2 h. Water was added and the mixture was extracted with a mixture of methanol/dichloromethane (1:1). The organics were concentrated by Speedvac and the crude material was purified via preparative HPLC to afford the title compound. MS (ES+) (M+H) 421.4; UPLC 1.09 min (Method T).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O.[F-:13].[K+]>C(#N)C>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([F:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(S(=O)(=O)F)cc1

Procedure:
A 25.0 gm (0.13 mole) portion of p-toluenesulfonyl chloride was dissolved in 100 ml of acetonitrile and combined in a 250 ml round bottom flask with 25.0 ml of water containing 1.5 gm (0.196 mole) of potassium fluoride. This mixture was stirred and heated under reflux for one hour. Acetonitrile was then removed under reduced pressure in a rotary evaporator. This resulted in crystallization of p-toluenesulfonyl fluoride which was removed by filtration, washed twice with water, and dried, giving 20.7 gm (91% yield) of product with mp 41°-41.2° C; (literature is 41°-42° C; W. Davies and J. H. Dick, J. Chem. Soc., 2104, 1931). The NMR and IR spectra were in agreement with the assigned structure.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[C:19]4[CH:35]=[CH:36][CH:37]=[CH:38][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:39][NH:40][CH2:41][CH2:42][CH2:43][CH3:44]>C(N(CC)CC)C>[CH2:41]([N:40]([CH3:39])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[C:19]4[CH:35]=[CH:36][CH:37]=[CH:38][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCCCNC
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccccc2C(F)(F)F)C3)cc1
Solvent: CCN(CC)CC
Product: CCCCN(C)CCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccccc2C(F)(F)F)C3)cc1

Procedure:
This was synthesized by using 4-(6-(2-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, N-methylbutan-1-amine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=80-82° C.; 1H NMR 400 MHz (DMSO-d6) δ 9.54 (s, 1 H); 8.38-8.35 (m, 2 H), 7.82-7.75 (m, 3 H), 7.58 (t, 1 H), 7.51-7.40 (m, 3 H), 7.27 (d, J=8.0 Hz, 1 H), 7.17 (d, J=8.4 Hz, 2 H), 6.76 (d, J=7.6 Hz, 1 H), 4.64 (t, J=8 Hz, 1 H), 3.19-3.12 (m, 2 H), 2.68-2.65 (m, 2 H), 2.55-2.51 (m, 2), 2.37-2.33 (m, 2 H), 2.21 (s, 3 H), 1.40-1.36 (m, 2 H), 1.30-1.23 (m, 2 H), 0.88 (t, J=7.2 Hz, 3 H). LCMS m/e 531 (M+H).
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[C:23][CH3:24])=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:17]=2)=[O:14])=[CH:5][CH:4]=1.C[Si](I)(C)C.CO>C(Cl)(Cl)Cl>[O:2]=[C:3]1[NH:8][CH:7]=[C:6]([CH2:9][NH:10][C:11]2[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[C:23][CH3:24])=[C:18]([C:25]([F:28])([F:26])[F:27])[CH:17]=2)=[O:14])[CH:5]=[CH:4]1
Reactant: CC#Cc1ccc(NC(=O)c2ccccc2NCc2ccc(OC)nc2)cc1C(F)(F)F
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC#Cc1ccc(NC(=O)c2ccccc2NCc2ccc(=O)[nH]c2)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 2-[[6-methoxy-3-pyridinyl]methyl]amino-N-[4-(1-propynyl)-3-(trifluoromethyl)-phenyl]benzamide (step 4.1; 1.10 g, 2.5 mmol) and trimethylsilyl iodide (Fluka, Buchs, Switzerland; 1.0 mL, 7.5 mmol) in chloroform (30 mL) is stirred at 60° C. for 16 hours under an argon atmosphere. The cooled mixture is then treated with methanol (2 mL) and stirred at room temperature for 10 minutes. The solvent is evaporated under reduced pressure and the residue is treated with an aqueous solution of ammonia (100 mL of 5%) and extracted with ethyl acetate (3×100 mL). The combined extracts are washed with saturated aqueous sodium chloride (50 mL), dried (MgSO4), filtered and the solvent is evaporated under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent ethyl acetate and recrystallised from hot ethyl acetate hexane to give the title compound as a colourless crystalline solid; m.p. 208–212° C.
Reaction SMILES: [Cl:1][C:2]1[CH:46]=[CH:45][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:8]2[CH2:35][C:36]([CH2:43][CH3:44])([CH2:41][CH3:42])[C:37]([O:39]C)=[O:38])=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:28](=[O:34])[CH2:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[C:8]2[CH2:35][C:36]([CH2:41][CH3:42])([CH2:43][CH3:44])[C:37]([OH:39])=[O:38])=[CH:45][CH:46]=1
Reactant: CCC(CC)(Cc1c(C(=O)CC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(Cc1c(C(=O)CC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)O
Temperature: 70 °C

Procedure:
The compound from Step E was hydrolysed using THF (2.5 mL), MeOH (0.6 mL) and NaOH (1N, 1.5 mL). The solution was heated at 70° C. for 2 weeks. The reaction was neutralized by addition of Na4OAc buffer (20 mL of 25% w/v) and extracted with EtOAc (3×30 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (eluant: EtOAc-hexane-HOAc (250:750:1)) to give the title compound.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([C:27]([CH3:29])([CH3:28])[CH3:30])=[CH:32][CH:33]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)cc1

Procedure:
The title compound, yellow solid (110 mg, 90%), MS (ISP) m/z=487.5 [(M+H)+], mp 180° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-tert-butyl-benzoic acid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][C:30](=[O:32])[CH3:31])=[CH:28][C:22]=2[S:21](=[O:34])(=[O:33])[N:20]=1.[OH-].[Na+:36]>O>[C:30]([NH:29][C:27]1[CH:26]=[CH:25][C:23]2[NH:24][C:19]([C:3]3[C:4](=[O:18])[C@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2]=3[O-:1])=[N:20][S:21](=[O:33])(=[O:34])[C:22]=2[CH:28]=1)(=[O:32])[CH3:31].[Na+:36]
Reactant: CC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3[C@@](C)(CCC(C)C)C1=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C([O-])c3ccccc3[C@@](C)(CCC(C)C)C1=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 993 %

Procedure:
A suspension of the product of Example 44A (0.046 g) in water (1 mL) was treated with 0.997N sodium hydroxide solution (0.090 mL, 0.090 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.45 g, 99%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.45 m, 1 H) 0.69 m, 6 H) 0.80 m, 1 H) 1.27 m, 1 H) 1.37 (m, 3H) 1.72 m, 1 H) 2.06 m, 3 H) 2.15 m, 1 H) 7.23 m, 1 H) 7.32 m, 1 H) 7.46 (m, 2 H) 7.65 m, 1 H) 8.03 m, 2 H) 10.13 m, 1 H) 15.44 m, 1 H). MS (ESI−) m/z 480 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>C(O)C.[Pd]>[N:11]1([C:4]2[CH:5]=[CH:6][C:7]([NH2:8])=[C:2]([CH3:1])[CH:3]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: Cc1cc(-n2cncn2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(-n2cncn2)ccc1N
Reaction time: 5 h
Yield: 99.6 %

Procedure:
A mixture of 1-(3-methyl-4-nitrophenyl)-1,2,4-triazole (D61, 1.0 g), 10% Pd/C (200 mg) in ethanol (50 ml) was hydrogenated at ambient temperature and pressure for 5 hours. The reaction mixture was filtered through kieselguhr and the filtrate evaporated to leave the title compound (0.85 g, 98%) which was used directly in the next stage.
Reaction SMILES: C(OCC[N:11]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:12]1)C1C=CC=CC=1.[C:22](O)(=[O:24])[CH3:23]>C1COCC1.[Pd]>[C:16]1([C:13]2[CH:14]=[C:15]([CH2:23][CH2:22][OH:24])[NH:11][N:12]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(COCCn2ccc(-c3ccccc3)n2)cc1
Reactant: CC(=O)O
Agent: [Pd]
Solvent: C1CCOC1
Product: OCCc1cc(-c2ccccc2)n[nH]1
Reaction time: 96 h

Procedure:
5-(2-(Benzyloxy)ethyl-3-phenyl-1H-pyrazole (2.1 g, 7.54 mmol) was dissolved in acetic acid (10 mL) and THF (10 mL). Palladium on carbon (0.080 g, 0.754 mmol) was added and the reaction was stirred for 4 days under hydrogen atmosphere on the Parr shaker at 55 psi. After this time, the reaction was filtered through celite and washed with EtOAc. The solvents were evaporated. The reaction progress was checked by TLC and shown to be ˜50-60% complete. The reaction was set up on the Parr shaker again. After three more days on the Parr shaker, the reaction was stopped. The reaction was filtered through celite and the solvents removed. The reaction was extracted (70 mL each of H2O and EtOAc). The aqueous layer was extracted again with EtOAc (70 mL). The combined organic layer was dried and concentrated, and the residue was purified by column chromatography to give the title compound (665 mg) as a white solid. LCMS m/z=189.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.68-2.82 (m, 2H), 3.60-3.71 (m, 2H), 4.73-4.81 (m, 1H), 6.48 (s, 1H), 7.20-7.49 (m, 3H), 7.55-7.96 (m, 2H), 12.53 (s, 1H).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].C([O:20][C@H:21]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[C@@H:23]([CH2:24][CH2:25][C@:26]3([CH3:49])[C@@H:35]2[CH2:34][CH2:33][C@H:32]2[C@@:27]3([CH3:48])[CH2:28][CH2:29][C@@:30]3([CH:46]=O)[CH2:42][CH2:41][C:40]([CH:43]([CH3:45])[CH3:44])=[C:31]32)[C:22]1([CH3:51])[CH3:50])(=O)C>CN(C)C=O.O1CCCC1>[OH:20][C@H:21]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[C@@H:23]([CH2:24][CH2:25][C@:26]3([CH3:49])[C@@H:35]2[CH2:34][CH2:33][C@H:32]2[C@@:27]3([CH3:48])[CH2:28][CH2:29][C@@:30]3(/[CH:46]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:42][CH2:41][C:40]([CH:43]([CH3:44])[CH3:45])=[C:31]32)[C:22]1([CH3:50])[CH3:51]
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)CC[C@]5(C=O)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/[C@]12CCC(C(C)C)=C1[C@H]1CC[C@@H]3[C@@]4(C)CC[C@H](O)C(C)(C)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a suspension of ethyl 2-(diethoxyphosphoryl)acetate (7.80 g, 34.8 mmol) in anhydrous N,N-Dimethylformamide (DMF) (20 ml) and Tetrahydrofuran (THF) (10 ml) stirred under nitrogen at 0° C. was added NaH (1.288 g, 32.2 mmol) dropwise during 5 min and stirred for 10 mins. The solution was warmed to rt and stirred for 30 mins before (3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-formyl-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (4.2 g, 8.70 mmol) was added to above mixture. After sitting overnight, the reaction was quenched by water and washed with saturated NaHCO3, water and brine. The organic fraction was dried over sodium sulfate, filtered and concentrated to give a residue, which was purified on a silica gel column (petrol ether/EtOAc=10:1) to obtain the pure product (E)-ethyl 3-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)acrylate (3.1 g, 69%) as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.01-6.84 (m, 2H), 5.64 (d, J=16.1 Hz, 1H), 4.20 (q, J=7.3 Hz, 2H), 3.26-3.07 (m, 3H), 2.40-2.11 (m, 5H), 2.08-1.91 (m, 2H), 1.89-0.61 (m, 43H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:15][CH:16]=O)[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:18][NH2:19]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:15][CH2:16][NH:19][CH3:18])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN
Reactant: COc1cccc(C2(CC=O)C=CCCC2)c1
Solvent: CO
Product: CNCCC1(c2cccc(OC)c2)C=CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 g of 1-(m-methoxyphenyl)-2-cyclohexene-1-acetaldehyde is dissolved in 10 ml of methanol, and after treatment with 10 ml of methylamine, the mixture is stirred at room temperature overnight with a magnetic stirrer in a bomb tube. After evaporation of the solvent, the residue is dissolved in ethanol. Then, the solution is treated with 0.5 g of sodium borohydride, stirred at room temperature for 2 hours. The solvent is removed by evaporation, and the residue is taken up with 3 N hydrochloric acid. The aqueous phase is extracted with ether and made alkaline by the addition of concentrated ammonia, whereupon the resulting rac. 1-(m-methoxyphenyl)-N-methyl-2-cyclohexene-1-ethylamine is taken up in methylene chloride. The hydrochloride of this compound melts at 177°-179° C.