Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)=[O:2].[CH:4]1([N:10]=[C:11]=[N:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>C(Cl)Cl>[CH:13]1([NH:12][C:11](=[O:2])[NH:10][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=CO
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
In this example, 11.7 g (0.2534 mole) of formic acid was added to a stirred slurry containing 26.1 (0.1267 mole) of dicyclohexyl carbodiimide in 300 ml of methylene chloride at about -10° C. A precipitate of dicyclohexyl urea formed. The mixture was then stirred at 0° to 3° C. for 20 minutes and then a solution containing 24.6 g (0.0756 mole) of N-(2-[4-(4-trifluoromethylphenoxy)-phenoxy]propyl)-N-methylformamide and 0.1267 mole of 4-dimethylaminopyridine in 125 ml of methylene chloride was slowly added over a 2-hour period. The mixture was allowed to warm to room temperature and stirred at room temperature overnight (about 12 hours). Thin layer chromatographic analysis of a sample showed complete reaction. The mixture was then filtered and the filter cake washed with methylene chloride. The combined filtrate and washing was washed with 200 ml aqueous 5% by weight hydrochloric acid, then with 200 ml of water and then dried over magnesium sulfate and filtered. The filtrate was evaporated under vacuum affording a semi-oil product. The semi-oil product was treated with ethyl ether and then filtered. The filtrate was evaporated under vacuum affording an oil which was then chromatographed on 300 g of silica gel sequentially eluting with pet (i.e., petroleum ether); 80:20 volume pet:ethyl ether; 60:40 volume pet:ethyl ether; ethyl ether and 96% ethyl ether in methanol affording the title compound as an oil contaminated with water and methanol. The oil was then dissolved in methylene chloride and the resulting solution then washed with water, then with 100 ml of a saturated aqueous solution of sodium bicarbonate and then dried over magnesium sulfate and filtered. The filtrate was evaporated under vacuum affording 10.3 g of the title compound as a clear oil. Elemental analysis: Calculated: C-61.19%, H-5.13%, N-3.96%; Found: C-62.56%, H-5.31%, N-4.05%.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:11][C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[N:27]=[CH:26][N:25]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=4[NH:38][C:39]([C@@H:41]4[CH2:44][CH2:43][NH:42]4)=[O:40])[CH:23]=3)[C:15]=2[N:16]=1)(=[O:10])[CH3:9].[CH:45](=O)[CH:46]([CH3:48])[CH3:47]>>[C:8]([NH:11][C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[N:27]=[CH:26][N:25]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][C:29]=4[NH:38][C:39]([C@@H:41]4[CH2:44][CH2:43][N:42]4[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:40])[CH:23]=3)[C:15]=2[N:16]=1)(=[O:10])[CH3:9]
Reactant: CC(C)C=O
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@@H]4CCN4)ncn3)cccc2s1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@@H]4CCN4CC(C)C)ncn3)cccc2s1

Procedure:
The title compound was prepared by reacting (2S)-N-(2-(6-(2-acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)azetidine-2-carboxamide trifluoroacetic acid salt [Example 37(c)] with isobutyraldehyde (Aldrich) under the conditions of Example 3(d). MS (ESI, pos. ion.) m/z: 585 (M+1). Mp: 174.4-174.9° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]#[N:11].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:22])[C:20]=1F)[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:16]([C:15]1[CH:14]=[C:13]([F:12])[C:20]([N:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]#[N:11])[C:5]2=[O:9])=[C:19]([F:22])[CH:18]=1)#[N:17]
Reactant: N#Cc1cc(F)c(F)c(F)c1
Reactant: COc1cc[nH]c(=O)c1C#N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccn(-c2c(F)cc(C#N)cc2F)c(=O)c1C#N
Temperature: 50 °C
Reaction time: 5 h
Yield: 43.1 %

Procedure:
A mixture of 4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile (2.00 g), 3,4,5-trifluorobenzonitrile (2.93 g), potassium carbonate (3.68 g) and N,N-dimethylformamide (20 mL) was stirred at 50° C. for 5 hr. The reaction mixture was slowly poured into saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added a mixed solvent (10 mL) of isopropyl ether/ethyl acetate=4/1, and the mixture was stirred for 15 min. The precipitate was collected by filtration to give the title compound (1.65 g).
Reaction SMILES: C([O:8][C@@:9]12[CH2:15][O:14][C@@H:13]1[C@H:12]([N:16]1[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18])[O:11][C@@H:10]2[CH2:25][O:26]CC1C=CC=CC=1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[OH:8][C@@:9]12[CH2:15][O:14][C@@H:13]1[C@H:12]([N:16]1[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18])[O:11][C@@H:10]2[CH2:25][OH:26]
Reactant: Cc1cn([C@@H]2O[C@H](COCc3ccccc3)[C@]3(OCc4ccccc4)CO[C@H]23)c(=O)[nH]c1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cn([C@@H]2O[C@H](CO)[C@]3(O)CO[C@H]23)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of nucleoside 28 (180 mg, 0.40 mmol) in ethanol (3 cm3) was added 10% palladium hydroxide over carbon (90 mg). The mixture was degassed several times with argon and placed under a hydrogen atmosphere. The reaction mixture was stirred at room temperature for 6 h, then filtered through celite. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (96:4, v/v) as eluent to give nucleoside 29 as a white solid material (92 mg, 86%). δH (CD3OD) 7.79 (1H, d, J 1.2, 6-H), 5.91 (1H, d, J 2.5, 1′-H), 4.96 (1H, d, J 2.5, 2′-H), 4.92 (1H, d, J 7.4, 1″-Ha), 4.58 (1H, dd, J 0.9, 7.4, 1″-Hb), 3.98 (1H, dd, J 7.3, 12.8, 5′-Ha), 3.87-3.82 (2H, m, 4′-H, 5′-Hb), 3.34 (2H, s, 3′-OH, 5′-OH), 1.87 (3H, d, J 1.3, CH3). δC (CD3OD) 166.5 (C-4), 152.1 (C-2), 140.1 (C-6), 110.1 (C-5), 91.2 (C-2′), 85.1 (C-1′), 84.0 (C-4′), 79.6 (C-3′), 78.6 (C-1″), 61.1 (C-5′), 12.3 (CH3).
Reaction SMILES: C(O[CH:4]([O:8][CH2:9][CH3:10])[O:5]CC)C.C(OC(=O)C)(=O)C.[F:18][C:19]([F:32])([C:28]([F:31])([F:30])[F:29])[C:20](=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=O>>[CH2:9]([O:8][C:4](=[O:5])[C:21](=[CH:22][O:24][CH2:25][CH3:26])[C:20](=[O:27])[C:19]([F:18])([F:32])[C:28]([F:29])([F:30])[F:31])[CH3:10]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)C(F)(F)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)C(F)(F)C(F)(F)F
Temperature: 135 °C
Reaction time: 2 h

Procedure:
A sealable vial was charged with triethylorthoformate (1.07 mL, 6.41 mmol), acetic anhydride (3.22 mL, 34.2 mmol) and ethyl 4,4,5,5,5-pentafluoro-3-oxopentanoate (0.747 mL, 4.27 mmol), and the resulting mixture was capped and stirred at 135° C. After 2 h, the reaction mixture was allowed to cool to room temperature, and the volatiles were removed in vacuo to provide the title compound as a mixture of olefin isomers, which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:5]([N+:17]([O-])=O)=[CH:4][C:3]=1Cl.C([O-])(=O)C.[Na+].[H][H]>[Pd].[Cl-].[Zn+2].[Cl-].CO>[CH2:8]([C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[NH2:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CO
Product: CCCCCCCCCc1ccccc1N

Procedure:
A mixture of 120 parts of 1,2-dichloro-4-nitro-5-nonylbenzene, 2 parts of zinc chloride solution, 83 parts of sodium acetate and 480 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in water and the solution is alkalized with ammonium hydroxide. The product is extracted with 2,2'-oxybispropane. The extract is washed with water, dried, filtered and evaporated. The residue is distilled, yielding 59 parts of 2-nonylbenzenamine; bp. 131°-132° C. at 0.2 mm. pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][N:7]1[CH:16]([CH3:17])[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:26][CH3:27])=[C:12]([O:18]CC3C=CC=CC=3)[CH:13]=2)[CH2:8]1>C1COCC1.CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][N:7]1[CH:16]([CH3:17])[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:26][CH3:27])=[C:12]([OH:18])[CH:13]=2)[CH2:8]1
Reactant: COc1cccc(CN2Cc3cc(OC)c(OCc4ccccc4)cc3CC2C)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cccc(CN2Cc3cc(OC)c(O)cc3CC2C)c1
Yield: 45.9 %

Procedure:
A solution of 214 (330 mg, 0.82 mmol) in THF (6 mL) and EtOH (6 mL) was treated with 10% Pd/C (33 mg) and stirred under an atmosphere of hydrogen. The reaction was monitored by TLC. Upon completion, the resultant suspension was filtered through celite, washed with ethyl acetate and then evaporated under reduced pressure. Purification (personal flashmaster: 20 g, hex:EtOAc; 2:1) afforded the title compound (118 mg, 46%) as a pale yellow solid. mp=100-105° C. 1H NMR (270 MHz; CDCl3) 1.12 (3H, d, J=6.7 Hz, CH3CH), 2.49 (1H, dd, J=16.1, 5.8 Hz, CHH), 2.89 (1H, dd, J=16.1, 4.8 Hz, CHH), 3.01-3.12 (1H, m, CHCH3), 3.48-3.74 (4H, m, 2×CH2), 3.78 (3H, s, OCH3), 3.79 (3H, s, OCH3), 5.42 (1H, s, OH), 6.42 (1H, s, CH), 6.63 (1H, s, CH), 6.77-6.81 (1H, m, CH), 6.93-6.96 (2H, m, 2×CH), 7.21 (1H, d, J=8.2 Hz, CH). 13C NMR (67.5 MHz; CDCl3) 15.39 (CH3), 34.68 (CH2), 51.43 (CH2), 52.30 (CH), 55.31 (OCH3), 55.99 (OCH3), 57.07 (CH2), 108.73 (CH), 112.54 (CH), 114.35 (CH), 114.54 (CH), 121.36 (CH), 125.48 (C), 126.56 (C), 129.29 (CH), 141.20 (C), 144.04 (C), 144.92 (C), 159.75 (C). LC/MS (ES+) tr=2.43 min, m/z 314.18 (M++H). HRMS (ES+) calcd. for C19H24NO3 314.1751, found 314.1748.
Reaction SMILES: C1COCC1.Br[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][N:8]=1.Br[C:14]1[C:15]([CH3:35])=[C:16]([C:19]2[N:23]3[N:24]=[C:25]([CH3:33])[CH:26]=[C:27]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:22]3=[N:21][C:20]=2[CH3:34])[S:17][CH:18]=1>CCOC(C)=O.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:29]([CH:28]([C:27]1[C:22]2[N:23]([C:19]([C:16]3[S:17][CH:18]=[C:14]([C:7]4[N:11]([CH3:12])[N:10]=[CH:9][N:8]=4)[C:15]=3[CH3:35])=[C:20]([CH3:34])[N:21]=2)[N:24]=[C:25]([CH3:33])[CH:26]=1)[CH2:31][CH3:32])[CH3:30]
Reactant: Cn1ncnc1Br
Reactant: CCC(CC)c1cc(C)nn2c(-c3scc(Br)c3C)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3scc(-c4ncnn4C)c3C)c(C)nc12
Temperature: 65 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
To a slurry of 0.05 g/mL of Reike® Zn in THF (3.0 mL, 2.29 mmol) is added a solution of 5-bromo-1-methyl-1H-[1,2,4]triazole and THF (2 mL). The solution was heated at 65° C. for 1 hour, cooled to ambient temperature and the excess Zn allowed to settle for 1 hour. The solution was transferred to a flask containing 3-(4-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (example Rupp-152) (0.32 g, 0.70 mmol) and PdCl2(dppf) (0.028 g, 0.038 mmol). The solution is heated at 65° C. overnight, diluted with EtOAc (30 mL), washed with sat. NH4Cl (30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (50%-100% Et2O) to furnish the title compound (0.058 g, 0.15 mmol, 19%). 1H NMR (CDCl3) δ 0.86 (t, J=7.5 Hz, 6H), 1.73-1.92 (m, 4H), 2.11 (s, 3H), 2.47 (s, 3H), 2.49 (s, 3H), 3.27-3.37 (m, 1H), 3.97 (s, 3H), 6.68 (s, 1H), 7.64 (s, 1H), 7.99 (s, 1H). LC/MS (m/z): calcd. for C21H26N6S (M+H)+: 395.2; found: 395.4.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]2=[O:24])(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>C(#N)C>[O:15]=[C:11]1[C:12]2[C:8](=[CH:7][C:6]([N:5]([CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=2)[C:9](=[O:24])[N:10]1[CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18]
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(NS(C)(=O)=O)cc2C1=O
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N(CCN3CCCCC3)S(C)(=O)=O)cc2C1=O
Temperature: 90 °C
Yield: 86 %

Procedure:
To a stirred solution of tert-butyl 2-(5-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (prepared in an analogous manner as previously described in Example 34, Scheme 34, Steps 1, 2, 3) (400 mg, 1.129 mmol) in acetonitrile (10 ml), potassium carbonate (312 mg, 2.257 mmol), and 1-(2-chloroethyl)piperidine hydrochloride (249 mg, 1.354 mmol) were added. The reaction was heated at 90° C. under microwave irradiation for 2 hours. The solid inorganic salts were filtered off and the filtrate was evaporated to dryness. The resulting crude was crystallized from EtOH affording tert-butyl 2-(1,3-dioxo-5-(N-(2-(piperidin-1-yl)ethyl)methylsulfonamido)isoindolin-2-yl)acetate (450 mg, 0.967 mmol, 86% yield, MS/ESI+ 465.9 [MH]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([O:13][CH3:14])[C:10]([OH:12])=O.[NH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>>[C:16]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:10](=[O:12])[CH:9]([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[F:1])[O:13][CH3:14])=[CH:19][CH:18]=1)#[N:15]
Reactant: COC(C(=O)O)c1cc(C)ccc1F
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1cc(C)ccc1F

Procedure:
(RS)-(2-Fluoro-5-methyl-phenyl)-methoxy-acetic acid was reacted with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-5-methyl-phenyl)-2-methoxy-acetamide. Colorless amorphous solid. MS 313.2 ([M+H]+)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1>[C].[Pd]>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[CH3:14])[N:5]=[CH:4][CH:3]=[CH:2]2
Reactant: COc1cc2c(Cl)ccnc2cc1C
Agent: [Pd]
Product: COc1cc2cccnc2cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
4-Chloro-6-methoxy-7-methyl-quinoline (10.8 g) was dissolved in diisopropylethylamine/IMS (7.4 g/100 ml), 5% palladium carbon (0.5 g) was added to the solution, and the mixture was stirred under a hydrogen gas atmosphere at room temperature overnight. The reaction solution was filtered, and the solvent was then removed by distillation under the reduced pressure to give 6-methoxy-7-methyl-quinoline (3 g, yield 33%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][C:13](=O)[CH2:14][O:15][CH2:16][CH3:17])=[C:10]([NH:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(O)C.O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:14][O:15][CH2:16][CH3:17])[N:19]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:28])[CH3:26])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCC(=O)Nc1c(Cl)nc2ccccc2c1NCCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1CCNC(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 70.4 %

Procedure:
To a solution of the hydrochloride salt of tert-butyl 2-({2-chloro-3-[(ethoxyacetyl)amino]quinolin-4-yl}amino)ethylcarbamate (2.50 g, 5.44 mmol) in 9:1 ethanol/water (50 mL) was added a solution of potassium carbonate (1.12 g, 8.16 mmol) in water (5 mL). The solution was heated to 50° C. for five hours. The solution was concentrated under reduced pressure and the residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to a pale yellow solid that was purified by flash chromatography (silica gel, gradient elution from 1:1 to 4:1 ethyl acetate/hexane) to afford the tert-butyl 2-(4-chloro-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate as a white solid (1.55 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9](Cl)(=[O:11])=[O:10].[CH3:13][NH2:14].O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([NH:14][CH3:13])(=[O:11])=[O:10]
Reactant: CN
Reactant: O=S(=O)(Cl)Cc1ccccc1Br
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)Cc1ccccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.3 %

Procedure:
To a solution of (2-bromophenyl)methanesulfonyl chloride (2 g, 7 mmol) in THF (15 mL) was added CH3NH2/H2O (25%, 2 g, 20 mmol) at 0° Celsius. The resulting mixture was warmed up to rt, stirred for 16 hours, concentrated to dryness and purified by HPLC to give the title compound (0.8 g, 41%). MS (ESI): mass calcd. for C8H8BrO2S, 262.96; m/z found, 264.0 [M+H]+; 1H NMR (300 MHz, CDCl3) δ 7.65-7.54 (m, 2H), 7.35 (m, 1H), 7.22 (dd, J=7.6, 1.7, 1H), 4.53 (s, 2H), 4.10 (s, 1H), 2.72 (s, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[CH:13]=[N:14][N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=1)=O)C.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.O>[C:17]1([N:15]2[CH:16]=[C:12]([CH2:10][OH:9])[CH:13]=[N:14]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cnn(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.9 %

Procedure:
Lithium aluminum hydride (3.51 g) was suspended in tetrahydrofuran (200 mL), 1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester (20 g) synthesized in Reference Example 16 was added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was ice-cooled, water (7 mL) and aqueous sodium hydroxide solution (1 mol/L, 3.5 mL) were successively added dropwise. After warming to room temperature, the mixture was stirred for 30 min. Anhydrous sodium sulfate was added to the reaction mixture, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Diethyl ether (30 mL) and hexane (30 mL) were added to the residue, and the residue was washed by suspending and filtered. The obtained solid was vacuum dried to give the title compound (14.8 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8](Br)=[CH:9][CH:10]=1)=[O:4].[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.[F-].[Cs+]>CN(C=O)C.O.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[CH:9][CH:10]=1)=[O:4]
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(Br)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(F)cc2)nc1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
Combine 6-bromopyridine-3-carboxylic acid methyl ester (1.03 g, 4.78 mmol), 4-fluorophenylboronic acid (1.88 g, 13.41 mmol), and cesium fluoride (2.55 g, 16.78 mmol) in DMF (25 mL) and water (4 mL) with stirring. Place the hetereogeneous reaction mixture, open to the air, in an oil bath maintained at 80° C. After 5 minutes of heating, add Pd(OAc)2 (150 mg, 0.67 mmol) in one portion. After 17 hours, cool the reaction to room temperature, dilute with ethyl acetate and filter through a short plug of celite with additional ethyl acetate. Wash the organics with water, dry over MgSO4, filter and evaporate. Purification by flash column chromatography yields 6-(4-fluorophenyl)pyridine-3-carboxylic acid methyl ester as a yellow solid. Dissolve the purified ester in THF (0.25M) and add an equal volume of 1M NaOH. Stir vigorously at room temperature for 15 hours. Upon completion, acidify the reaction with conc. HCL and collect the white precipitate by filtration. Drying under vacuum yields 385 mg (37%) of the title compound. MS (m/e): 218.1 (MH+)
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:28]>CO.[Pd].C>[NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:28]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)C(C)C
Reaction time: 3 h

Procedure:
5.66 g (15 mmols) of Z-Val-Leu-OMe are hydrogenated in 75 ml of methanol in the presence of 15 mmols of hydrochloric acid and 850 mg of Pd-charcoal (10%) at room temperature. The hydroen uptake has finished after 3 hours. The catalyst is filtered off and the solution is concentrated to about 15 ml. On addition of ether, the product crystallises out. Melting point 136° - 139°C.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:35]1([N:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)N)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:33][CH:2]([CH3:1])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:36]4[C:35](=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:41]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:22]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc([N+](=O)[O-])c3)CC2)c1
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc([N+](=O)[O-])c4)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(3-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 601.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:4].O.[BH4-].[Na+].Cl>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:12][CH2:13][CH:14]([OH:17])[CH2:15][CH2:16]1)[C:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(O)CC1
Temperature: -25 °C
Reaction time: 2 h

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (1 eq.) is dissolved in THF. Water is added to the reaction mixture and cooled to −25° C. NaBH4 (0.5 eq.) is added portion wise maintaining the temperature below −20° C. The mixture is stirred for 2 h at −25° C., 2N HCl is then added and the solution is warmed to room temperature. The phases are separated and the aqueous layer is washed with EtOAC. The organic phases are combined and washed with brine and dried over Na2SO4 and concentrated to dryness to give 5-(3,3-dimethyl-but-1-ynyl)-3-[(4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester as a 93:7 mixture of isomers. The crude cis/trans mixture is recrystallized in methanol to obtain >99% the trans isomer.