Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[C:9](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:4]1=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:32][CH2:33][CH2:34][CH2:35][CH2:36]Br.O>CN(C)C=O>[Br:32][CH2:33][CH2:34][CH2:35][CH2:36][O:23][C:20]1[CH:19]=[CH:18][C:17](/[CH:16]=[CH:15]/[C:9]2[N:10]([CH3:14])[C:11]3[C:12](=[O:13])[N:3]([CH2:1][CH3:2])[C:4](=[O:5])[N:6]([CH2:24][CH3:25])[C:7]=3[N:8]=2)=[CH:22][CH:21]=1
Reactant: BrCCCCBr
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(O)cc3)n2C)n(CC)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCCCCBr)cc3)n2C)n(CC)c1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 60.6 %

Procedure:
Compound 175 (200 mg, 0.59 mmol) obtained in Reference Example 114 was dissolved in 4 ml of dimethylformamide. To the solution were added 163 mg (1.18 mmol) of potassium carbonate and 0.56 ml (1.18 mmol) of 1,4-dibromobutane, and the mixture was stirred at 50° C. for 4 hours. Water was added thereto under ice cooling to dissolve potassium carbonate and the deposited crystals were collected by filtration. The obtained crude crystals were recrystallized from hexane/ethyl acetate to give 170 mg (yield 61%) of Compound 177 as pale yellow grains.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([CH3:14])=[CH2:13])[N:7]=1>[Pd].CO>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[N:7]=1
Reactant: C=C(C)c1cccc(C2OCCO2)n1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cccc(C2OCCO2)n1

Procedure:
A suspension of 0.60 g of 2-[1,3]dioxolan-2-yl-6-isopropenylpyridine (3.15 mmol) and 0.10 g of 10% palladium on carbon, in 7 ml of methanol is stirred vigorously under a low hydrogen pressure for 4 hours at room temperature. The solid is removed by filtration on celite and then the methanol is evaporated off. The title product is isolated by chromatography on a silica column (eluent: chloroform/ethyl acetate; 97:3). 0.40 g of a pale yellow oil is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:17])[CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:20]I.O>CN(C)C=O>[CH3:20][O:17][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH3:16]
Reactant: CI
Reactant: COc1cccc(C(O)CC2CCCN2C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(C(CC2CCCN2C)OC)c1
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
1.0 g of 1-(3-methoxyphenyl)-2-(1-methyl-2-pyrrolidinyl)-ethanol dissolved in 15 ml of dimethyl formamide is added dropwise within 5 minutes, with stirring and exclusion of moisture, to a suspenion of 0.25 g of 80 p.c. sodium hydride. Stirring is effected for 30 minutes and a solution of 0.85 g methyl iodide in 10 ml of dimethyl formamide is added drop by drop. The mixture is kept at 60° for 2 hours, treated with water and extracted with diethyl ether. The etheral phase is concentrated. There are obtained 0.7 g of the title compound as oily mixture of diastereoisomers.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:26])[NH:24][NH2:25]>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:26])[NH:24][N:25]=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: NNC(=O)Nc1ccccc1F
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccccc1F

Procedure:
ninhydrin, 4-(2-fluorophenyl)-semicarbazide hydrochloride
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-])=O)=[C:7]([CH:9]=1)[NH2:8])[CH3:2].[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C(O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([NH2:10])=[C:7]([NH2:8])[CH:9]=1)[CH3:2]
Reactant: CCc1ccc([N+](=O)[O-])c(N)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCc1ccc(N)c(N)c1
Yield: 85.4 %

Procedure:
A stirred solution of 5-ethyl-2-nitro-aniline [200 mg, Reference Example 30(a)] and tin chloride (2.75 g) in ethanol (5 ml) was heated in a Smith Creator microwave at 140° C. for 10 minutes. The reaction mixture was basified to pH 8 by addition of saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate and then evaporated to give 4-ethyl-phenylene diamine (140 mg) as a pale orange solid, which was used without future purification. MS: 137.2 (M+H)+. HPLC (METHOD H): RT=2.91 minutes. (b) 4-Methoxy-5-methyl-benzene-1,2-diamine
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH2:12]P(=O)(OCC)OCC)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].O>C1COCC1.O1CCOCCOCCOCCOCC1>[CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH:12]=[C:36]2[CH2:37][CH2:38][N:33]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:34][CH2:35]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1cccc(Oc2cccc(C)n2)c1)OCC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)n1
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
Diethyl 3-(6-methylpyridin-2-yloxy)benzylphosphonate (4.7 g, 14 mmol) from Step 3 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.05 mL, 0.28 mmol) were combined in THF (150 mL). Sodium hydride (617 mg, 60% dispersion in mineral oil, 15.4 mmol) was added. The reaction was stirred for 30 min and then a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.07 g, 15.4 mmol) in THF (15 mL) was added. After 16 h, water was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×200 mL) and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-30%, EtOAc:heptane) to afford the title compound (4.4 g, 83% yield) as a thick oil.
Reaction SMILES: C([NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([NH:14]C(=O)C)[C:8]([N+:18]([O-:20])=[O:19])=[C:7]([NH:21]C(=O)C)[C:6]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=O)C.Cl>>[NH2:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([NH2:14])[C:8]([N+:18]([O-:20])=[O:19])=[C:7]([NH2:21])[C:6]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1
Reactant: CC(=O)Nc1c(-c2ccc(C)cc2)c(NC(C)=O)c([N+](=O)[O-])c(NC(C)=O)c1[N+](=O)[O-]
Agent: Cl
Product: Cc1ccc(-c2c(N)c([N+](=O)[O-])c(N)c([N+](=O)[O-])c2N)cc1

Procedure:
2′,4′,6′-triacetamido-3′,5′-bis(nitro)-4-methylbiphenyl (5) is treated with 6N hydrochloric acid to yield 2′,4′,6′-triamino-3′,5′-bis(nitro)-4-methylbiphenyl (6).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:22][CH3:23])[C:9]=3[CH:8]2[S:24][CH2:25][CH2:26][C:27](O)=[O:28])=[CH:4][CH:3]=1.C(Cl)CCl.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37]>C(Cl)Cl>[CH2:36]([N:38]([CH2:39][CH3:40])[C:27](=[O:28])[CH2:26][CH2:25][S:24][CH:8]1[C:9]2[C:10]([O:22][CH3:23])=[C:11]3[C:16](=[C:17]([OH:21])[C:18]=2[C:19](=[O:20])[N:7]1[CH2:6][C:5]1[CH:30]=[CH:31][C:2]([F:1])=[CH:3][CH:4]=1)[N:15]=[CH:14][CH:13]=[CH:12]3)[CH3:37]
Reactant: CCNCC
Reactant: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2SCCC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCN(CC)C(=O)CCSC1c2c(c(O)c3ncccc3c2OC)C(=O)N1Cc1ccc(F)cc1

Procedure:
A solution of 24 (10.7 mg, 0.024 mmol) in CH2Cl2 (0.24 mL) was stirred with EDC (14 mg, 0.73 mmol) and diethyl amine (10 μL, 0.097 mmol) for 1 day at ambient temperature. The product 25 was purified by reverse phase HPLC using 5-95% A. Buffer A contained CH3CN—1% HOAc and B contained H2O—1% HOAc. 1H NMR (300 MHz, CDCl3) δ 0.984 (t, 3H, J=6 Hz), 1.05 (t, 3H, J=7 Hz), 2.23-2.45 (m, 4H) 3.04 (q, 2H, J=7 Hz), 3.29 (q, 2H, J=8 Hz), 4.06 (s, 3H), 4.47 (d, 1H, J=14 Hz), 5.31 (d, 1H, J=15 Hz), 5.50 (s, 1H), 7.05 (t, 2H, J=9 Hz), 7.36-7.44 (m, 2H), 7.55-7.62 (m, 1H), J=9 Hz), 8.95-9.00 (m, 1H); EI MS (m/z) 520.2 [MH+], 1016.9 [2M+Na].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[C:10]([C:14]1[O:18][N:17]=[C:16]([N:19]=[C:20]=[O:21])[CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[C:10]([C:14]1[O:18][N:17]=[C:16]([NH:19][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=2)=[O:21])[CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1cc(N=C=O)no1
Reactant: Nc1ccc(Cl)c(O)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Cl)c(O)c2)no1
Temperature: 70 °C

Procedure:
A mixture of 5-amino-2-chlorophenol (1.0 g, 6.97 mmol) and 5-tert-butyl-3 isocyanatoisoxazole (1.16 g, 6.97 mmol) in toluene (40 mL) was heated at 70° C. overnight. It was purified by silica gel chromatography with 0-25% EtOAc/hexane as eluants to afford 1-(5-tert-butylisoxazol-3-yl)-3-(4-chloro-3-hydroxyphenyl)urea as solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.O[C@@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:17]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16]2)=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
Tetrahydrofuran (200 ml) was added to 2,6-dichloropurine (6 g, 31.8 mmol), tert-butyl(3R)-3-hydroxypyrrolidine-1-carboxylate (5.94 g, 31.8 mmol), and triphenylphosphine (9.2 g, 34.9 mmol) and the resulting mixture was made uniform. Diisopropyl azodicarboxylate (6.9 ml, 35 mmol) was added with ice cooling and the resulting mixture was stirred at room temperature for 30 minutes and then heated to reflux for 1 hour. The reaction mixture was cooled, then the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=7:3 to 6:4 to 5:5 to 4:6) to give the title compound (10.5 g, 92%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH2:16])[CH2:11][C:10]([O:14][CH3:15])([O:12][CH3:13])[CH2:9]2)=[CH:4][CH:3]=1.[O:17]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])N1C(OCC)=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([N:16]3[C:18](=[O:17])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:27])[CH2:11][C:10]([O:14][CH3:15])([O:12][CH3:13])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: COC1(OC)CC(N)(c2ccc(Br)cc2)C1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC1(OC)CC(c2ccc(Br)cc2)(N2C(=O)c3ccccc3C2=O)C1
Temperature: 70 °C
Yield: 40.6 %

Procedure:
A mixture of 1-(4-bromophenyl)-3,3-dimethoxycyclobutanamine (0.66 g, 2.306 mmol), ethyl 1,3-dioxoisoindoline-2-carboxylate (0.56 g, 2.55 mmol) and triethylamine (1.3 ml, 9.33 mmol) in CHCl3 (15 ml) was heated at 70° C. for 16 h. The reaction mixture was concentrated to as dry as possible. Methanol (˜5 ml) was added. The solution was concentrated to dryness. Methanol (˜5 ml) was added again and the resulted solid was collected by filtration to afford product as a white solid (0.39 g). 1H NMR (500 MHz, CDCl3): 7.70 (dd, 2H), 7.60 (dd, 2H), 7.44 (dd, 2H), 7.37 (dd, 2H), 3.18 (m, 4H), 3.10 (s, 3H), 3.02 (s, 3H).
Reaction SMILES: C(OC(=O)CC[CH2:7][NH:8][C:9]([NH:11][C:12]1[S:13][C:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([F:28])[CH:19]=2)=[C:15]([CH3:17])[N:16]=1)=[O:10])C.[CH2:30]([O:32][C:33](=[O:39])[CH2:34]CN=C=O)[CH3:31]>>[CH2:30]([O:32][C:33](=[O:39])[CH2:34][CH2:7][NH:8][C:9]([NH:11][C:12]1[S:13][C:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([F:28])[CH:19]=2)=[C:15]([CH3:17])[N:16]=1)=[O:10])[CH3:31]
Reactant: CCOC(=O)CCN=C=O
Reactant: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Product: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1

Procedure:
The title compound is prepared by the same procedure as 4-{3-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester (Example 164) by replacing ethyl-4-isocyanatobutyrate with 3-isocyanato-propionic acid ethyl ester.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:23]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=2)[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[CH:20]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.7 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide (example 156) (0.4 g, 0.69 mmol) in dichloromethane (5 mL) was added TFA (5 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as an off-white solid (0.31 g, 90%). MS (ISN) 523.7 [(M−H)−]; mp 237° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)[N:6]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:15])[F:16])=[CH:9][CH:8]=2)([C:17]2[CH:24]=[CH:23][CH:22]=[C:19]([CH2:20][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:18]=2)[N:6]=1
Reactant: C1CCNC1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C=O)c2)N=C1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(CN3CCCC3)c2)N=C1N
Yield: 82.9 %

Procedure:
A small vial (10 ml) was charged with 3-[2-Amino-4-(4-difluoromethoxy-phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-benzaldehyde (69 mg, 192 μmol) and 1,2-dichloroethane (DCE, 1 ml). To this was added one-third of a solution of pyrrolidine (41 mg, 0.576 mmol) in 1,2-dichloroethane (3.00 ml). After stirring overnight at room temperature sodium triacetoxyborohydride (58 mg, 270 μmol) was added followed by 1 drop of glacial acetic acid (˜12 mg), then after another 20 hours 1N sodium hydroxide (1 ml) was added and the mixture extracted with diethyl ether. The ethereal layer was concentrated by rotary evaporation, diluted with methanol and re-concentrated (repeated three times). Finally the oily residue was redissolved in diethylether/hexanes and concentrated, twice then placed under vacuum to give a white foam 66 mg (82%) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (t, J=3.4 Hz, 4H) 2.32 (t, J=6.5 Hz, 4H) 2.93 (s, 3H) 3.44 (s, 2H) 6.62 (br. s., 3H) 7.05 (d, J=8.8 Hz, 2H) 7.08-7.11 (m, 1H) 7.12 (t, J=74.18 Hz, 1H) 7.17 (t, J=7.6 Hz, 1H) 7.25 (t, J=4.6 Hz, 1H) 7.34 (s, 1H) 7.40 (d, J=8.8 Hz, 2H); MS (ES) m/z 413.3 [M−H]−
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:9]([C:11]2[CH:20]=[CH:19][C:14]3[NH:15][C:16]([CH3:18])=[N:17][C:13]=3[CH:12]=2)O)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:23])=O>>[ClH:23].[Cl:1][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=1)[C:11]1[CH:20]=[CH:19][C:14]2[NH:15][C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=1
Reactant: Cc1nc2cc(C(O)c3cccc(F)c3)ccc2[nH]1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: Cc1nc2cc(C(Cl)c3cccc(F)c3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
(b-1) A mixture of 13 parts of α-(3-fluorophenyl)-2-methyl-1H-benzimidazole-5-methanol monohydrochloride and 81 parts of thionyl chloride was stirred overnight at room temperature. The reaction mixture was concentrated to dry, yielding 12 parts (86.8%) of 5-[chloro(3-fluorophenyl)methyl]-2-methyl-1H-benzimidazole monohydrochloride as a residue (int. 45).
Reaction SMILES: [NH+]1C=CC=CC=1.[CH3:7][O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[Cl:24])[C:15]([C:25]([O:27][CH3:28])=[O:26])=[C:14]([CH3:29])[NH:13][C:12]=1[CH3:30])=[O:10].[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[Cl:24][C:18]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH:16]1[C:15]([C:25]([O:27][CH3:28])=[O:26])=[C:14]([CH3:29])[NH:13][C:12]([CH2:30][C:32]2[NH:31][CH:35]=[CH:34][N:33]=2)=[C:11]1[C:9]([O:8][CH3:7])=[O:10]
Reactant: c1c[nH]cn1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1=C(C)NC(Cc2ncc[nH]2)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 51 %

Procedure:
Pyridinium perbromide hydrobromide (5.6 g, 17.5 mmol) was added to a stirred ice-cooled solution of 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid dimethylester (5.55 g, 15 mmol) and pyridine (2 g) in methylene dichloride (80ml). The solution was stirred at ice temperature for 40 minutes then washed with ice cold water (1×100 ml). The organic phase was separated and imidazole (6.8 g, 0.1 mol) added followed by anhydrous Na2SO4. After drying for 20 minutes the solution was filtered to remove NaSO4, evaporated and the residue heated on a steam bath for 40 minutes. The residue was then dissolved in EtOAc, washed with water (2×50 ml), dried, evaporated and crystallised from methyl acetate (15 ml) to give the crystalline title compound (3.34 g). This was suspended in isopropyl alcohol/methyl acetate (2:3 v/v)and acidified with ethanolic HCl to give the hydrochloride salt on cooling, m.p. 167°-170° C.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][CH2:24][CH2:25][C@H:26]([OH:30])[C:27]([OH:29])=[O:28])=[O:22])[N:4]=1)#[N:2].[CH3:31]O>OS(O)(=O)=O>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][CH2:24][CH2:25][C@H:26]([OH:30])[C:27]([O:29][CH3:31])=[O:28])=[O:22])[N:4]=1)#[N:2]
Reactant: N#Cc1nc(C(=O)NCC[C@H](O)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H](O)CCNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O

Procedure:
To a solution of (S)-4-(1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)-2-hydroxybutanoic acid (73 mg, 0.18 mmol) in anhydrous MeOH (25 mL) was added concentrated H2SO4 (3 drops). The resulting mixture was heated to reflux for 20 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (0-30% EtOAc/CH2Cl2) to give the title compound in 54 mg. MS: (−) m/z 420.26 (M−1).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:3]1[C:27]#[N:28].Cl.[NH2:30][OH:31].N1C=CC=CC=1>C(O)C>[OH:31][N:30]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:3]1[C:27]#[N:28]
Reactant: N#CC1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: N#CC1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=NO
Temperature: 25 °C
Yield: 75.6 %

Procedure:
1-Oxo-3-phenyl-6-(3-phenyl-propoxy)-1H-indene-2-carbonitrile (293 mg, 0.80 mmol) obtained in Example 11 was dissolved in ethanol (20 mL), and hydroxylamine hydrochloride (167 mg, 2.41 mmol) and pyridine (254 mg, 3.21 mmol) were added thereto, refluxed for 3 hrs, and cooled to RT. The resulting mixture washed with saturated sodium bicarbonate, extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 230 mg of 1-hydroxyimino-3-phenyl-6-(3-phenyl-propoxy)-1H-indene-2-carbonitrile (yield: 75%). Subsequently, 1-hydroxyimino-3-phenyl-6-(3-phenyl-propoxy)-1H-indene-2-carbonitrile (230 mg, 0.60 mmol) thus obtained was dissolved in methanol (20 mL), and 10%-palladium (230 mg) was added thereto. The mixture was stirred for 15 hrs at RT while providing H2 gas thereto using a balloon, filtered through celite, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 90 mg of the titled compound (yield: 41%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[C:18]([N:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27](O)=[O:28])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:11]([O:10][C:8]([C@H:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][C:27]([CH:26]2[CH2:30][CH2:31][CH2:32][N:25]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:28])[CH2:3][CH2:4]1)=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NC1CCC(C(=O)OCc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)N[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.7 %

Procedure:
To a stirred solution of benzyl 4-aminocyclohexanecarboxylate (900 mg, 3.9 mmol), boc-proline (830 mg, 3.9 mmol), HOBt (521 mg, 3.9 mmol), and triethylamine (1.6 ml, 11.6 mmol) in CH2Cl2 (30.0 ml) was added EDC.HCl (1.1 g, 5.8 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat. NaHCO3, 2-M citric acid, and sat. NaHCO3, then dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (6:1, v/v) as eluent to give benzylcis-4-[(1-tert-butoxycarbonyl-2-pyrrolidinyl)carbonylamino]cyclohexanecarboxylate (600 mg, 36%) as an amorphous solid. 1H-NMR (CDCl3) δ1.44 (s, 9H), 1.50-1.90 (m, 12H), 2.20-2.26 (m, 1H), 3.25-3.50 (m, 2H), 3.80-3.90 (m, 1H), 4.10-4.25 (m, 1H), 5.12 (s, 2H), 7.35-7.36 (m, 5H).