Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:26])[CH2:9][CH:10]([OH:25])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[CH3:27]I>CN(C)C=O>[C:3]([O:7][C:8](=[O:26])[CH2:9][CH:10]([O:25][CH3:27])[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)CC(O)CCc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(CCc1ccc(-c2ccccc2)cc1)CC(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 35.2 %

Procedure:
Sodium hydride (60%; 7.0 mg, 0.17 mmol) was added to a stirred solution of 5-biphenyl-4-yl-3-hydroxy-pentanoic acid tert-butyl ester (Intermediate 3, 50 mg, 0.15 mmol) in dimethylformamide (0.5 mL) at 0° C. under nitrogen. After stirring for 5 minutes methyl iodide (14 μL, 0.23 mmol) was added and stirring continued for 12 hours. The volatiles were evaporated under reduced pressure and the residue partitioned between dichloromethane (5 mL) and water (5 mL). The phases were separated and the organic phase dried (MgSO4), then the solvent evaporated. The residue was purified by column chromatography on silica gel (1:8 diethyl ether:cyclohexane) to give the title compound (18 mg, 35%) as a colourless gum. LC/MS: 3.87 min; z/e 358, calcd (M+NH4) 358. 1H NMR (400 MHz: CDCl3): 7.59 (2 H), 7.53 (2 H), 7.42 (2 H), 7.28 (3 H), 3.68 (1 H), 3.40 (3 H), 2.77 (2 H), 2.56 (1 H), 2.38 (1 H), 1.88 (2 H), 1.47 (9 H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:25][C:26](=[O:40])[C:27]([NH:29][C:30]([CH3:39])([CH3:38])[CH2:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[O:28])[CH:17]=[CH:18][C:19]=1[C:20]1[O:24][CH:23]=[N:22][CH:21]=1>ClCCl.C(OCC)(=O)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:25][C:26](=[O:40])[C:27]([NH:29][C:30]([CH3:38])([CH3:39])[CH2:31][C:32]2[CH:33]=[CH:34][N+:35]([O-:6])=[CH:36][CH:37]=2)=[O:28])[CH:17]=[CH:18][C:19]=1[C:20]1[O:24][CH:23]=[N:22][CH:21]=1
Reactant: COc1cc(NC(=O)C(=O)NC(C)(C)Cc2ccncc2)ccc1-c1cnco1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)C(=O)NC(C)(C)Cc2cc[n+]([O-])cc2)ccc1-c1cnco1
Reaction time: 1 h
Yield: 62.1 %

Procedure:
30 mg (0.1 mmol) of 60% 3-chloroperoxybenzoic acid were added to a stirred solution of 20 mg (0.051 mmol) of N-[3-methoxy-4-(5-oxazolyl)phenyl]-N′-[1,1-dimethyl-2-(4-pyridyl)ethyl]oxalamide in 1 ml of dichloromethane. The mixture was stirred for 1 hour then diluted with ethyl acetate, washed with sodium bisulphite solution, sodium bicarbonate solution and brine. The organic solution was dried over magnesium sulphate, evaporated to dryness and the residue triturated with diethyl ether to give 13 mg of N-[3-methoxy-4-(5-oxazolyl)phenyl]-N′-[1,1-dimethyl-2-(1-oxido-4-pyridyl)ethyl]oxalamide as an off-white solid. MS: m/e 411 [M+]+.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].C([O-])(C)(C)C.[K+].[CH2:20]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32]I)[CH2:27][CH2:26]1)[CH2:21][CH2:22][CH2:23][CH3:24]>CCCCCC.O1CCCC1>[F:6][C:7]1[C:8]([F:13])=[CH:9][CH:10]=[CH:11][C:12]=1[CH2:32][CH2:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:26][CH2:27]1
Reactant: Fc1ccccc1F
Reactant: CCCCC[C@H]1CC[C@H](CCI)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC[C@H]1CC[C@H](CCc2cccc(F)c2F)CC1
Reaction time: 0.17 h

Procedure:
A solution of 0.21 mol of n-butyllithium in 130 ml of hexane is added to a mixture of 0.25 mol of 1,2-difluorobenzene, 0.20 mol of potassium tert.-butanolate and 200 ml of tetrahydrofuran at -100° C. After the mixture has been stirred for 10 minutes, a mixture of 0.2 mol of 2-(trans-4-pentylcyclohexyl)-ethyl iodide, 0.2 mol of dimethylaminepropyleneurea and 50 ml of tetrahydrofuran is added at -90° C. After the mixture has been stirred at -40° C. for 1 hour, customary working up gives the ethane derivative of boiling point 135° C./0.5 mm Hg, in addition to a little 1,4-di-(2-trans-4-pentylcyclohexyl)-ethyl)-2,3-difluorobenzene as a by-product, of C 64° C. N 106.7° I.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[C:41]([C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1)#[N:42]>O1CCCC1.O>[Cl:3][C:4]1[C:9]([C:10]2[N:14]([S:49]([C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([C:41]#[N:42])[CH:44]=3)(=[O:51])=[O:50])[CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2cccc(C#N)c2)c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution (5 mL) of tert-butyl {[5-(2-chloropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (340 mg) in tetrahydrofuran, 15-crown-5 (330 mg) and 3-cyanobenzenesulfonyl chloride (302 mg) under ice-cooling and the mixture was stirred for 3 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:1) to give the title compound as a pale-yellow oil (yield 490 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[O:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH2:9][N:10]([C:11]3[C:12](=O)[C:13](=[O:18])[C:14]=3[O:15]CC)[C:4]=2[CH:3]=1.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30]>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[O:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH2:9][N:10]([C:11]3[C:14](=[O:15])[C:13](=[O:18])[C:12]=3[NH:30][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])[C:4]=2[CH:3]=1
Reactant: CCOc1c(N2Cc3ccccc3Oc3ccc(Cl)cc32)c(=O)c1=O
Reactant: CN(C)CCN
Solvent: C1COCCO1
Product: CN(C)CCNc1c(N2Cc3ccccc3Oc3ccc(Cl)cc32)c(=O)c1=O
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of the title product of Example 5 (0.73 g), N,N-dimethylethylenediamine (0.225 mL) and dioxane (20 mL) was heated to reflux for 20 minutes. Then, most of the dioxane was removed in vacuo and the residue was stirred in methanol (20 mL) at ambient temperature for 1/2 hour and the precipitated white solid was filtered and discarded. The filtrate was concentrated and the residue was chromatographed on silica gel using 1% each of methanol and triethylamine in ethyl acetate to give the free amine of the title compound as a pale yellow solid. To a solution of this solid in CH2Cl2 (3 mL) was added 7 N HCl in dioxane (1 mL) and the mixture concentrated. To the residue was added excess water and the resulting mixture was freeze dried to give the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22].[H-].[Na+].C(Cl)OC.C1[CH2:34][O:33][CH2:32][CH2:31]1>>[CH2:32]([O:33][CH2:34][O:20][C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:11]([C:10]#[C:9][C:6]3[CH:7]=[CH:8][C:3]([NH:2][CH3:1])=[C:4]([N+:21]([O-:23])=[O:22])[CH:5]=3)[S:12][C:13]=2[CH:19]=1)[CH3:31]
Reactant: CNc1ccc(C#Cc2nc3ccc(O)cc3s2)cc1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Product: CCOCOc1ccc2nc(C#Cc3ccc(NC)c([N+](=O)[O-])c3)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask under Ar containing 2-((4-(methylamino)-3-nitrophenyl)ethynyl)benzo[d]thiazol-6-ol (1 equiv) is added THF (5 vol). To this solution is added NaH (1.3 equiv). The solution is stirred at RT for 30 min. To this solution is added MOM-Cl (1.5 equiv). The reaction is stirred overnight at RT. The reaction is poured onto water (10 vol) and extracted into DCM (10 vol). The organic layer is washed with water (10 vol), dried (MgSO4), filtered and concentrated to dryness. The material is purified using EtOAc:Hexanes as the eluent over silica gel to afford the final product.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH2:15])[CH3:3].C(N(CC)CC)C.[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(Cl)Cl>[CH3:3][N:2]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([CH3:23])=[CH:25][CH:26]=1)[CH3:1]
Reactant: CN(C)CCn1c(N)nc2ccccc21
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2nc3ccccc3n2CCN(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(N,N-Dimethylaminoethyl)-2-aminobenzimidazole (0.40 g, 1.96 mmol) was dissolved in CH2Cl2 (50 mL) and cooled to 0° C., triethylamine (2 mL) was added followed by 4-methybenzoyl chloride (0.26 g, 1.96 mmol). The reaction mixture was stirred at 0° C. for 1 h and at room temperature for an additional 1 h. The volatiles were evaporated and then the residue was purified by column chromatography using CH2Cl2-MeOH (9.8-0.2). The oily material collected (0.2 g) was dissolved in anhydrous ethyl ether and transformed to the hydrochloride salt. MS 322 (M+1). 1H NMR (DMSO): δ 2.48 (s, 3H), 2.81 and 2.86 (2s, 6H), 3.54 (m, 2H), 4.73 (m, 2H), 35 7.34 (m, 4H), 7.52 (2m, 2H), 8.14 (d, 2H), 10.79 (broad s, NH).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9].C([Li])CCC.[CH:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:18].C(O)(=O)C>C1COCC1.CCCCCC>[C:8]([CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:11])[CH:17]([OH:18])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])([OH:10])=[O:9]
Reactant: COC(=O)CCCCCCC=O
Reactant: Cc1ccccc1CC(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COC(=O)CCCCCCC(O)C(C(=O)O)c1ccccc1C
Reaction time: 1.5 h

Procedure:
o-Tolylacetic acid (4.56 g.) in THF (50 ml.) was treated at 5°-10° C. under argon with a 1.6M solution (36.0 ml.) of butyllithium in hexane. After 1 hour the solution obtained was added dropwise to a solution of methyl 7-formylheptanoate (5.68 g.) in dry THF (50 ml.) at -30 ° to -50° C. during 30 minutes. The mixture was stirred for 1.5 hours at the same temperature. Acetic acid (3.5 ml. ) was then added carefully and the mixture was evaporated. The residue was partitioned between ether (100 ml.) and saturated sodium bicarbonate solution (50 ml.). The aqueous layer was acidified to pH 4 (HCl) and extracted thoroughly with ether. The combined extracts were washed with water, dried (MgSO4) and evaporated. The residual oil was purified by medium pressure liquid chromatography on silica (190 g.), eluting with 30% v/v ethyl acetate/hexane, to give methyl 9-carboxy-8-hydroxy-9-o-tolylnonanoate (A) as an oil (1.94 g., single diastereoisomer);NMR : 1-1.7 (10H,m), 2.1-2.5 (5H,m), 3.6 (3H,s), 3.8-4.3 (2H,m), 6.7 (2H,br s), 7.2 (4H,s); m/e (chemical ionisation): 323 (M+ +H), 340 (M+ +NH4).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[S:4].[CH3:12][NH:13][NH2:14]>CCOCC>[CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([N:13]([CH3:12])[NH2:14])=[S:4]
Reactant: CN(C(=S)Cl)c1ccccc1
Reactant: CNN
Solvent: CCOCC
Product: CN(N)C(=S)N(C)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of N-methyl-N-phenylthiocarbamyl chloride 79.6 g (0.43 m) in 250 ml dry ether, a solution of 39.5 g (0.86 m) methylhydrazine in 100 ml of dry ether was added dropwise with stirring below 10° C. The reaction temperature was allowed to increase to room temperature and filtered. The filtrate was evaporated to low volume and diluted with ~300 ml hexane. After stirring for a few hours the hexane layer was decanted. The hexane immiscible layer was reevacuated to remove organic solvents, giving the desired product, 70.0 g as a thick orange liquid.
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[CH:10]=[C:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:32][CH2:33][NH:34][C:35](=[O:37])[CH3:36])=[CH:24]1>>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[C:10]([CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:24]2[NH:23][C:31]3[C:26]([C:25]=2[CH2:32][CH2:33][NH:34][C:35](=[O:37])[CH3:36])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=C(O)C(Cc2ccccc2)O1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)NCCc1c[nH]c2ccccc12
Product: CC(=O)NCCc1c(C(C2=C(O)C(Cc3ccccc3)OC2=O)c2ccccc2)[nH]c2ccccc12

Procedure:
Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) was reacted with benzaldehyde and N-[2-(1H-indol-3-yl)-ethyl]-acetamide to give the title compound as a white solid. MS: 481.0 ([M+H]+).
Reaction SMILES: [I:1][CH3:2].[Cl:3][C:4]1[N:5]=[CH:6][N:7]([C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([NH2:19])=[S:18])=[CH:11][C:10]=2[F:20])[CH:8]=1>C(O)C>[IH:1].[Cl:3][C:4]1[N:5]=[CH:6][N:7]([C:9]2[C:10]([F:20])=[CH:11][C:12]([NH:16][C:17]([S:18][CH3:2])=[NH:19])=[CH:13][C:14]=2[F:15])[CH:8]=1
Reactant: CI
Reactant: NC(=S)Nc1cc(F)c(-n2cnc(Cl)c2)c(F)c1
Solvent: CCO
Product: CSC(=N)Nc1cc(F)c(-n2cnc(Cl)c2)c(F)c1
Product: I
Temperature: 60 °C
Yield: 100 %

Procedure:
Step J (5): Iodomethane (0.047 mL, 0.753 mmol) was added to a solution of 1-(4-(4-chloro-1H-imidazol-1-yl)-3,5-difluorophenyl)thiourea (207 mg, 0.717 mmol) in absolute ethanol (4 mL). The resulting mixture was heated at 60° C. for 16 h. After cooling to rt, the reaction was concentrated in vacuo. The residual volatiles were removed in high vacuo to afford methyl 4-(4-chloro-1H-imidazol-1-yl)-3,5-difluorophenylcarbamimidothioate hydroiodide (309 mg, 0.717 mmol, 100% yield). LC-MS (M+11)+ 303.1.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[CH2:4][CH2:5][N:6]([CH2:9][CH3:10])[CH2:7][CH3:8].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>>[BrH:1].[BrH:1].[CH2:7]([N:6]([CH2:9][CH3:10])[CH2:5][CH2:4][C:3]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[CH:2]=1)[CH3:8]
Reactant: CCN(CC)CCC(=O)CBr
Reactant: Nc1ccccn1
Product: Br
Product: CCN(CC)CCc1cn2ccccc2n1

Procedure:
Reaction of 1-bromo-4-diethylaminobutan-2-one and 2-aminopyridine by the procedure of Example 2 yields the title product.
Reaction SMILES: Cl.[CH3:2][C:3]1[O:4][CH:5]=[CH:6][C:7]=1[C@H:8]1[C@H:17]2[CH2:18][CH2:19][N:20]([C:21]([C@H:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]3[NH2:29])=[O:22])[C@H:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9]1.C(N(CC)CC)C.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O>ClCCl>[CH3:2][C:3]1[O:4][CH:5]=[CH:6][C:7]=1[C@H:8]1[C@H:17]2[CH2:18][CH2:19][N:20]([C:21]([C@H:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]3[NH:29][C:37](=[O:44])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:22])[C@H:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9]1
Reactant: Cc1occc1[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1N
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1occc1[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a suspension of (1R,2S)-2-{[(3aR,4R,9bR)-4-(2-methyl-3-furyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexaneamine hydrochloride (201 mg, 0.445 mmol) in dichloromethane (5 ml) were added triethylamine (0.203 ml, 1.47 mmol) and benzoylchloride (0.0568 ml, 0.490 mmol) under ice-cooling. The reaction mixture was stirred overnight at room temperature, water was added, and extracted with dichloromethane. The extract was dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (4:1-3:2, v/v) to give the title compound (176 mg, 82%) as an amorphous form.
Reaction SMILES: [OH-].[Na+:2].[C:3]1([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:15]I.Cl>CO>[O:14]=[C:10]([CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:15])[C:11]([O-:13])=[O:12].[Na+:2]
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)C(=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 81 %

Procedure:
A 1N aqueous solution of sodium hydroxide (20 ml, 20 mmoles) and 40 ml of methanol were added to 1.64 g (10.0 mmoles) of phenylpyruvic acid to form a solution. Then, 2.0 ml of methyl iodide was added, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with 150 ml of ether. The ether layer was dried over magnesium sulfate and concentrated under reduced pressure to give a pale yellowish white solid. To the solid was added 3 ml of a 3N aqueous solution of sodium hydroxide, and the mixture was concentrated under reduced pressure. Ether was added to the resulting semi-solid mixture, and the precipitated sodium 2-oxo-3-phenylbutanoate was isolated as a white solid (1.62 g; yield 81 %) by filtration.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[C:14]1([CH2:20][CH2:21]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O.C(OCC)C>[C:14]1([CH2:20][CH2:21][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(CCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
A solution of diethyl malonate (6.07 ml, 40 mmol) in dimethyl formamide (60 ml) at 0° C. was treated portionwise with sodium hydride (1.6 g, 40 mmol, 60% dispersion in oil) and stirred for 0.25 h. 2-Phenylethyl bromide (5.48 ml, 40 mmol) in dimethylformarnmide (30 ml) was added dropwise. The mixture was warmed to room temperature and stirred for 1 h. The mixture was diluted with diethyl ether (300 ml), washed with water (4×200 ml), saturated brine (100 ml), dried (MgSO4) and evaporated. Flash chromatography on silica, eluting with 1% ethyl acetate in hexane, gave the title compound as a colourless oil (7.55 g, 71%); νmax (CH2Cl2), 1726 cm-1 ;
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][C:19]=1[OH:20])[CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13])([O-:7])=[O:6].[CH2:21](O)[CH3:22]>>[ClH:3].[CH2:21]([NH:13][C@H:12]([C:14]([OH:16])=[O:15])[CH2:11][C:10]1[CH:17]=[CH:18][C:19]([OH:20])=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=1)[CH3:22]
Reactant: O=S(Cl)Cl
Reactant: N[C@@H](Cc1ccc(O)c([N+](=O)[O-])c1)C(=O)O
Reactant: CCO
Product: CCN[C@@H](Cc1ccc(O)c([N+](=O)[O-])c1)C(=O)O
Product: Cl
Yield: 97 %

Procedure:
To a stirring 0° C. solution of 1.07 mL (14.7 mmol) of thionyl chloride in 15 mL of absolute ethanol was added 3-nitro-L-tyrosine (2.00 g, 8.84 mmol). After refluxing for 4 hours, the reaction was cooled and the solvents were removed in vacuo from dichloromethane to afford 2.20 g (97%) of the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=[N:20][NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[O:23])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1.CO.[OH-].[Na+].Cl>O>[OH:1][C:2]1[C:3]([C:18](=[N:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)=[O:23])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([CH3:15])[CH3:16])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(CC(C)C)cc3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(CC(C)C)cc2)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.7 %

Procedure:
To methyl 4-[(2-{1-[4-hydroxy-5-(4-isobutylphenyl)-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.129 mmol, 57.7 mg), methanol (2.5 mL) was added, and 1 M aqueous sodium hydroxide (5 eq., 0.643 mL) was added at room temperature. After 15 minutes of stirring at room temperature and 1.5 hours of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (Seq., 0.643 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump, and the residue was further purified by silica gel thin layer chromatography (chloroform/methanol=10/1). After addition of chloroform/n-hexane, the precipitated solid was dried to give the desired product as a yellow solid (25.6 mg, yield 46%).
Reaction SMILES: N12CCC(C[OH:10])(CC1)CC2.FC1C=CC(C#N)=CC=1.[N:20]12[CH2:27][CH2:26][C:23]([CH2:28][O:29][C:30]3[CH:37]=[CH:36][C:33]([C:34]#N)=[CH:32][CH:31]=3)([CH2:24][CH2:25]1)[CH2:22][CH2:21]2>>[N:20]12[CH2:27][CH2:26][C:23]([CH2:28][O:29][C:30]3[CH:37]=[CH:36][C:33]([CH:34]=[O:10])=[CH:32][CH:31]=3)([CH2:24][CH2:25]1)[CH2:22][CH2:21]2
Reactant: N#Cc1ccc(OCC23CCN(CC2)CC3)cc1
Reactant: OCC12CCN(CC1)CC2
Agent: N#Cc1ccc(F)cc1
Product: O=Cc1ccc(OCC23CCN(CC2)CC3)cc1

Procedure:
Synthesized from (1-azabicyclo[2.2.2]oct-4-yl)methanol and 4-fluorobenzonitrile according to an analogous synthetic method to Preparation Example 15, 4-(1-azabicyclo[2.2.2]oct-4-ylmethoxy)benzonitrile (200 mg) was used according to an analogous synthetic method to Preparation Example 16 to provide the title compound (120 mg).
Reaction SMILES: O.[Na+].[Cl-].[CH3:4][O:5][C:6](=[O:25])[CH:7]([CH:12]([C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH2:15][CH3:16])C(OC)=O>CS(C)=O>[CH3:4][O:5][C:6](=[O:25])[CH2:7][CH:12]([C:17](=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(C(=O)c1ccccc1)C(C(=O)OC)C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCC(CC(=O)OC)C(=O)c1ccccc1
Temperature: 150 °C

Procedure:
Water (3 ml, 166 mmol) and NaCl (5.3 g, 90.2 mmol) are added to a solution of 2-(1-benzoyl-pentyl)-malonic acid dimethyl ester (25.0 g, 81.7 mmol) in DMSO (150 mL). The mixture is heated at 150° C. for 6 hours. Water (450 mL) is added and the mixture is extracted with EtOAc (4×150 mL). The combined extracts are washed with brine (300 mL), dried (Na2SO4), and evaporated, to provides 3-Benzoyl-heptanoic acid methyl ester as a light yellow oil. LC-MS (M+1) 249. This compound without further purification is used directly to the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[CH3:30]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:3]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:4][C:5]([F:9])=[C:6]([F:8])[CH:7]=2)=[CH:23][C:22]=1[CH3:30]
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Reactant: Cc1cc(B(O)O)ccc1Cl
Product: Cc1cc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)ccc1Cl

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 4-chloro-3-methylphenylboronic acid (Step 1) to give 4-(4-chloro-3-methylphenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 151.5-152.2° C.; NMR (CDCl3) δ 2.29 (s, 3H), 3.05 (s, 3H), 6.73 (dd, J=2, 8 Hz, 1H), 6.98 (d, J=2 Hz, 2H), 7.16 (d, J=9 Hz, 1H), 7.19-7.32 (m, 4H), 7.82 (d, J=9 Hz, 2H); MS (FAB) m/z 399 (M+Li)+; HRMS calc'd for M+ 392.0449, found 392.0437. Anal. Calc'd for C20H15ClF2O2S: C, 61.15; H, 3.85; F, 9.67. Found: C, 61.04; H, 3.79; F, 9.55.