Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:35]C(=O)OC(C)(C)C)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=4)=[CH:22][N:21]=[C:20]4[NH:32][CH:33]=[CH:34][C:19]=34)[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[NH2:35][C@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)=[CH:22][N:21]=[C:20]3[NH:32][CH:33]=[CH:34][C:19]=23)[CH2:14][CH2:13]1)=[O:11]
Reactant: COc1cccc(-c2cnc3[nH]ccc3c2N2CCN(C(=O)[C@@H](Cc3ccc(Cl)cc3)NC(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2cnc3[nH]ccc3c2N2CCN(C(=O)[C@H](N)Cc3ccc(Cl)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
(R)-tert-Butyl 3-(4-chlorophenyl)-1-(4-(5-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (0.021 g, 0.036 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.3 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added dropwise to a stirring solution of 1M HCl in ether. The solid product was filtered, washed with ether, and dried to give (R)-2-amino-3-(4-chlorophenyl)-1-(4-(5-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propan-1-one (0.015 g, 86% yield) as the dihydrochloride salt. MS ESI (+) m/z 491 detected.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][C:10]=2[CH3:22])=[CH:5][C:4]=1[B:23]1[O:27]C(C)(C)C(C)(C)[O:24]1.Cl.I([O-])(=O)(=O)=O.[Na+].C(OCC)(=O)C>O>[C:16]([O:15][C:13]([C:12]1[CH:20]=[CH:21][C:9]([C:6]2[CH:5]=[C:4]([B:23]([OH:27])[OH:24])[C:3]([O:2][CH3:1])=[N:8][CH:7]=2)=[C:10]([CH3:22])[CH:11]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1B(O)O

Procedure:
A solution of tert-butyl 4-[6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-3-methylbenzoate (INTERMEDIATE 31, 16.0 g, 37.6 mmol), HCl (150 mL, 150 mmol), sodium periodate (24.14 g, 113 mmol) and ethyl acetate (150 mL) was stirred rapidly at room temperature for 1 hour, at which time LCMS showed complete boronate ester hydrolysis. The reaction was diluted with some water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated. The crude was purified by silica gel chromatography to give the title compound. LCMS (M+H)+: 343.95. 1H NMR (500 MHz, CDCl3) δ 8.24 (d, 1H), 8.14 (d, 1H), 7.93 (s, 1H) 7.88 (d, 1H), 7.28 (d, 1H), 5.84 (br, 2H) 4.13 (s, 3H), 2.35 (s, 3H), 1.64 (s, 9H).
Reaction SMILES: NC1C=CC=CC=1.[C:8]1([CH3:15])[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:16]([C:19]1[CH:20]=[C:21]([CH3:26])[C:22]([OH:25])=[CH:23][CH:24]=1)([CH3:18])=[CH2:17]>>[OH:14][C:13]1[CH:12]=[CH:11][C:10]([C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=2)([CH3:18])[CH3:17])=[CH:9][C:8]=1[CH3:15]
Reactant: C=C(C)c1ccc(O)c(C)c1
Reactant: Cc1ccccc1O
Solvent: Nc1ccccc1
Product: Cc1cc(C(C)(C)c2ccc(O)c(C)c2)ccc1O

Procedure:
Aniline (25 g; 1.39 moles of aniline per mole of p-isopropenyl-o-cresol) was added to 50 g of a mixture of o-cresol and p-isopropenyl-o-cresol (1:1 mole ratio) obtained by the alkali cleavage of 2,2-bis(4'-hydroxy-3'-methylphenyl)-propane. The mixture was stirred at 170° C., and 1.5 g of the catalyst solution prepared in Example 1 (0.0029 mole of catalyst per mole of p-isopropenyl-o-cresol) was added. The reaction was performed for 3 hours. Gas-chromatographic analysis of the resulting reaction mixture showed that 42.7 g (yield 91%) of 2-(4'-hydroxy-3'-methylphenyl)-2-(4'-aminophenyl)-propane having a melting point of 152.5 to 153.5° C. was formed.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[CH:7]=[C:6]([OH:8])[NH:5][N:4]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(OCC)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[N:5]1[C:6]([OH:8])=[CH:7][C:3]([C:2]([F:10])([F:9])[F:1])=[N:4]1
Reactant: Oc1cc(C(F)(F)F)n[nH]1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1cc(C(F)(F)F)nn1C1CCCCO1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
3-(Trifluoromethyl)-1H-pyrazol-5-ol (5.0 g, 0.032 mole) which is known in the art and p-toluene-sulfonic acid monohydrate (0.08 g) were dissolved in ethyl acetate (30 mL) and warmed to 50° C. 3,4-Dihydro-2H-pyran (2.9 g, 0.034 mole) was slowly added over a 10 minute period. After stirring 30 minutes at 50° C., the mixture was cooled and diluted with 100 mL of ethyl acetate. This solution was washed twice with 0.5% hydrochloric acid solution, then dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was treated with 5 mL of ethyl acetate and 20 mL hexanes and filtered to give 1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-ol (5.8 g, 76% yield) as a white solid, mp=129°-130° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][NH:5][C:6]=1[CH3:7].[Cl:11][C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:17]([N:16]([CH2:15][C:14]1[CH:21]=[CH:22][C:23]([Cl:24])=[C:12]([Cl:11])[CH:13]=1)[C:8]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[NH:5][N:4]=1)=[O:10])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCNCc1ccc(Cl)c(Cl)c1
Reactant: Cc1[nH]nc(C(=O)O)c1Cl
Product: CCCCN(Cc1ccc(Cl)c(Cl)c1)C(=O)c1n[nH]c(C)c1Cl
Yield: 47.8 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 168A, 4-chloro-5-methyl-1H-pyrazole-3-carboxylic acid (1.50 g, 9.32 mmol) and N-(3,4-dichlorobenzyl)butan-1-amine (Intermediate 126, 2.16 g, 9.32 mmol) provided the title compound (1.67 g, 48%) as a colorless oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 7.50-7.32 (m, 2H), 7.24-7.06 (m, 1H), 4.79-4.55 (m, 2H), 3.47-3.26 (m, 2H), 2.34-2.19 (m, 3H), 1.71-1.46 (m, 2H), 1.35 (br s, 1H), 1.18 (br s, 1H), 0.93 (d, J=6.4 Hz, 1.5H), 0.81 (d, J=6.8 Hz, 1.5H); MS(ESI+) m/z 376.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[O:20]=[C:21]1[N:25]([CH2:26][CH2:27][NH2:28])[C:24](=[O:29])[CH2:23][S:22]1>>[O:20]=[C:21]1[N:25]([CH2:26][CH2:27][NH:28][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[C:24](=[O:29])[CH2:23][S:22]1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NCCN1C(=O)CSC1=O
Product: CCc1cc(-c2cncc(C(=O)NCCN3C(=O)CSC3=O)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and [2-(2,4-dioxo-thiazolidin-3-yl)-ethyl]-amine to afford the title compound. MS: m/e=401 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12]([C:17](OCC)=[O:18])=[CH:11]3)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12]([CH2:17][OH:18])=[CH:11]3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cc(OCc3ccc(Br)cc3)ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1cc2cc(OCc3ccc(Br)cc3)ccc2[nH]1
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a solution of the ethyl 5-[(4-bromobenzyl)oxy]-1H-indole-2-carboxylate (300 mg, 0.802 mmol) obtained in the above 1) in tetrahydrofuran (4 ml) was added lithium aluminum hydride (60.8 mg, 1.60 mmol) at 0° C., and the mixture was stirred for 1 hour. Ethyl acetate was added to the reaction solution, the mixture was washed with 1N hydrochloric acid and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After the solvent was concentrated under reduced pressure, the resulting residue was purified by alumina column chromatography (developing solvent: ethyl acetate), and converted into powders with isopropyl ether and hexane to obtain the titled compound (219 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[NH2:16])([O-:8])=[O:7]>N1C=CC=CC=1>[NH2:16][C:10]1[CH:11]=[CH:12][C:13]([NH:15][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:14][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
Methanesulfonyl chloride (11.5 g, 0.1 mmol) was added gradually over 3 min to a solution of 2-nitrobenzene-1,4-diamine (15.3 g) in pyridine (70 ml). The temperature of the mixture rose to ca. 70° C. The solution was set aside for 10 min, and then refluxed for 15 min. The pyridine was evaporated under reduced pressure, and the residue was recrystallized from ethanol (with charcoal) to give the product as white solid.
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH2:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[C:10]([CH3:16])[CH:9]=1.[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](Cl)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([O:15][C:11]3[C:10]([CH3:16])=[CH:9][C:8]([NH2:7])=[C:13]([CH3:14])[CH:12]=3)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cc(O)c(C)cc1N
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(N)cc3C)ccnc2cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
Sodium hydride (60 wt %, 1.17 g) was added to dimethyl sulfoxide (25 ml), and the mixture was stirred at 60° C. for 30 min and was then cooled to room temperature. Next, 4-amino-2,5-dimethylphenol (4.00 g) was added thereto, and the mixture was stirred at room temperature for 10 min. 7-(Benzyloxy)-4-chloro-6-methoxyquinoline (4.36 g) was then added thereto. The mixture was stirred for 22 hr before water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue to prepare a suspension. The precipitated crystal was collected by suction filtration to give 3.04 g (yield 52%) of the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:13]2[N:17]([CH3:18])[CH:16]=[N:15][CH:14]=2)=[CH:8][C:7]=1[CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1)[S:27][CH2:28][CH2:29][C:30](O)=[O:31].[NH4+].[OH-]>C1COCC1>[Cl:39][C:35]1[CH:34]=[C:33]([CH:26]2[C:7]3[CH:8]=[C:9]([CH:12]([C:19]4[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=4)[C:13]4[N:17]([CH3:18])[CH:16]=[N:15][CH:14]=4)[CH:10]=[CH:11][C:6]=3[NH:5][C:30](=[O:31])[CH2:29][CH2:28][S:27]2)[CH:38]=[CH:37][CH:36]=1
Reactant: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc(N)c(C(SCCC(=O)O)c2cccc(Cl)c2)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCCC(=O)N2
Yield: 3.5 %

Procedure:
Thionyl chloride (1 ml) was added slowly to a mixture of intermediate (22) (0.00456 mol) in THF (15 ml). The mixture was stirred and refluxed for 2.5 hours, poured out on ice and NH4OH and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (4 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.1; 20–45 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN and diethyl ether. The precipitate was filtered off and dried in vacuo. The residue was recrystallized from CH3CN and diethyl ether. The precipitate was filtered off and dried in vacuo, yielding 0.08 g (3%) of 6-(3-chlorophenyl)-8-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1,3,4,6-tetrahydro-2H-5,1-benzothiazocin-2-one, mp. 199° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:32]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)[C:39](=[O:40])[CH2:38][CH2:37][CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(C(=O)OC)cc3)cc2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(C(=O)OC)cc3)C(=O)CCC3CCCC3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure E using methyl 4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]benzoate and 3-cyclopentylpropanoyl chloride as a colorless oil (71%). 1H NMR (CDCl3, 300 MHz) δ 8.02 (d, J=8.3 Hz, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.54-7.39 (m, 4H), 7.30-7.06 (m, 6H), 4.61 (d, J=11.3 Hz, 2H), 4.48 (d, J=11.7 Hz, 2H), 3.91 (m, 3H), 2.61 (t, J=7.7 Hz, 2H), 2.41 (m, 2H), 1.79-1.66 (m, 4H), 1.65-1.43 (m, 7H), 1.40-1.28 (m, 2H), 1.14-1.00 (m, 2H), 0.92 (t, J=7.3 Hz, 3H). M+ (ESI): 536.4. HPLC, Rt: 6.42 min (Purity: 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:15][C:14]([C:26]([OH:28])=O)=[N:13]2)=[O:10])=[N:6][CH:7]=1.Cl.[CH:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)([CH3:32])[CH3:31].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.CCN(CC)CC>[CH:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:26]([C:14]2[CH:15]=[C:16]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[N:13]=2)=[O:28])[CH2:35][CH2:34]1)([CH3:32])[CH3:31]
Reactant: CC(C)N1CCC(N)CC1
Reactant: COCCOCCOCc1cc(C(=O)O)nn1CC(=O)Nc1ccc(Cl)cn1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOCCOCc1cc(C(=O)NC2CCN(C(C)C)CC2)nn1CC(=O)Nc1ccc(Cl)cn1
Reaction time: 16 h

Procedure:
To 400 mg 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-5-[2-(2-methoxy-ethoxy)-ethoxymethyl]-1H-pyrazole-3-carboxylic acid in 5 ml DCM and 0.3 ml NEt3, 217 mg 1-Isopropyl-piperidin-4-ylamine hydrochloride and 250 mg BOP-Cl were added at RT and the mixture was stirred for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[H][H]>C(O)C.[Pt]=O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1
Reactant: [H][H]
Reactant: c1cncc(-c2ncc[nH]2)c1
Agent: O=[Pt]
Solvent: CCO
Product: c1c[nH]c(C2CCCNC2)n1
Yield: 108 %

Procedure:
3-(1H-imidazol-2-yl)pyridine (4.0 g, 0.0275 M) and platinum oxide (0.5 g) in ethyl alcohol (50 ml) and 1 NHCl (50 ml) was reduced at 45 psig of hydrogen for 4 hrs. The reaction mixture was filtered and the filtrate was stripped to dryness and crystallized from MeOH-EtOH to give 3-(1H-imidazol-2-yl)piperidine (4.5 g, 74% yield, mp 295° dec.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([O:20][CH3:21])[CH:12]=2)[CH2:4][CH2:3]1>CCOC(C)=O.CO>[CH3:21][O:20][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:16]=[CH:15][C:14]=1[NH2:17]
Reactant: COc1cc(C#CCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(CCCN2CCN(C)CC2)ccc1N
Reaction time: 8 h
Yield: 58.9 %

Procedure:
1-methyl-4-{3-[3-(methyloxy)-4-nitrophenyl]-2-propyn-1-yl}piperazine (0.309 g, 1.07 mmol) was placed in a 40 mL high vial and dissolved in 10 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/carbon (0.291 g, 0.075 mmol) was added followed quickly by a screw cap septum. The vial was evacuated and filled with N2 six times to remove any oxygen. The vial was then pressurized with H2 (balloon). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to afford the title compound of step B (0.165 mg, 0.63 mmol, 60%). 1H NMR (400 MHz, CDCl3) δ ppm 6.55-6.64 (m, 3H), 3.83 (s, 3H), 3.56 (bs, 2H), 2.47-2.56 (m, 8H), 2.36-2.41 (m, 2H), 2.31 (s, 3H), 1.75-1.83 (m, 1H), 1.53-1.64 (m, 1H), 0.92 (t, J=7.42 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.[CH3:39][O:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][C:42]=1[C:50]([F:53])([F:52])[F:51]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:45](=[O:46])[C:44]2[CH:48]=[CH:49][C:41]([O:40][CH3:39])=[C:42]([C:50]([F:53])([F:52])[F:51])[CH:43]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(C(=O)C4(C)CC4)CC3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.7 %

Procedure:
To a solution of {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone (200 mg, 0.456 mmol) in THF (2 mL) was added N,N-diisopropyl ethyl amine (117 μl, 0.684 mmol), 4-methoxy-3-(trifluoromethyl)benzoyl chloride (131 mg, 0.547 mmol) and stirred for 4 h at ambient temperature. The reaction mixture was diluted with ethzl acetatec (10 mL) and was washed with an aqueous solution of sodium carbonate (1 M, 10 mL), water (10 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate (20 mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:methanol=50:50:0 to 0:90:10) afforded the title compound (230 mg, 79%) as a colorless oil. MS m/e: 640.3 [M]+.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:6]2[O:28][CH2:27][CH2:26][C:7]=2[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[CH3:29][O:30][CH2:31][CH2:32][C:33](O)=[O:34]>>[CH3:29][O:30][CH2:31][CH2:32][C:33]([NH:25][C@H:22]1[CH2:21][CH2:20][C@H:19]([CH2:18][CH2:17][N:14]2[CH2:13][CH2:12][N:11]([C:8]3[C:7]4[CH2:26][CH2:27][O:28][C:6]=4[C:5]([CH3:4])=[CH:10][N:9]=3)[CH2:16][CH2:15]2)[CH2:24][CH2:23]1)=[O:34]
Reactant: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c2c1OCC2
Reactant: COCCC(=O)O
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3ncc(C)c4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (53 mg, 82%), MS (ISP) m/z=431.6 [(M+H)+], mp 163.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(7-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate G) (68.1 mg, 0.15 mmol) and 3-methoxypropionic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([NH:34][C:35]([NH:37][CH3:38])=[O:36])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:66])(=O)=O)CCCCCCCCCCCCCCC>>[I:66][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([NH:34][C:35]([NH:37][CH3:38])=[O:36])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)NC(=O)NC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCI)NC(=O)NC

Procedure:
3-(3-chloropropylsulfonylamino)-2-(3-methylureido)-1-octadecylcarbamoyloxypropane IIIf1 is allowed to react and worked up by the same procedure as described in (5). m.p. 87°-89° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@@H:10]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][N:8]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:7]1)=[O:5])C.O.[OH-].[Li+].O>C1COCC1>[CH2:20]([N:8]1[CH2:9][C@H:10]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1CNC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@H]1CN(Cc2ccccc2)C[C@H]1C(=O)O
Temperature: 40 °C

Procedure:
To a solution of 2.9 (3R,4R) and (3S,4S)-1-benzyl-4-(tert-butoxycarbonylamino-methyl)-pyrrolidine-3-carboxylic acid ethyl ester (8.0 mmol) in 50 ml THF were added 671 mg lithium hydroxide mono hydrate (16 mmol) and 0.5 ml water. The solution was stirred at 40° C. and the reaction monitored by TLC. After 72 h the solvent was evaporated, the residue dissolved in dichloromethane, washed with water and brine, dried over Mg sulfate, filtered and evaporated. The residue was crystallized from a dichloromethane/hexane mixture.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([O:19][CH3:20])[CH:9]=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:4])=[O:3].[C:21](Cl)(=[O:23])[CH3:22].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][S:2]([NH:5][C:6]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][C:9]([C:21]([CH3:22])=[O:23])=[C:8]([O:19][CH3:20])[CH:7]=1)(=[O:4])=[O:3]
Reactant: CC(=O)Cl
Reactant: COc1ccc(Oc2ccccc2)c(NS(C)(=O)=O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(NS(C)(=O)=O)c(Oc2ccccc2)cc1C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
In 100 ml of anhydrous methylene chloride were dissolved 10 g of 3-methylsulfonylamino-4-phenoxyanisole and 2.81 g of acetyl chloride. Thereto was added 9.1 g of aluminum chloride in 5 minutes with ice-cooling. The mixture was stirred for 1 hour at 20°-25° C. The reaction mixture was introduced into 100 ml of ice water. The resulting organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from isopropyl alcohol to obtain 9.83 g (yield: 86%) of methyl 4-methylsulfonylamino-2-methoxy-5-phenoxyphenyl ketone having a melting point of 108.5-110° C.