Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:16])[CH:14]=[O:15])[CH:7]=[CH:6]2.[N+]1([O-:23])C=CC=CC=1.C(O)(=O)C.C(OO)(=O)C>C(OCC)(=O)C>[CH3:16][C@H:13]([C:14]([OH:23])=[O:15])[C:8]1[CH:7]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=2[CH:9]=1
Reactant: COc1ccc2cc([C@H](C)C=O)ccc2c1
Reactant: [O-][n+]1ccccc1
Agent: CC(=O)OO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Yield: 80.3 %

Procedure:
To a stirred solution of 2.00 g (9.3 mmol) of (S)-2-(6-methoxy-2-naphthyl)propionaldehyde in ethyl acetate (10 mL) cooled in a wet-ice bath (ca. 2° C.) was added concurrently 0.89 g (9.3 mmol) of pyridine N-oxide and 0.56 g (9.3 mmol) of acetic acid. To this solution was then added slowly dropwise 5.8 mL (14.0 mmol) of a 20.4 weight percent solution of peracetic acid in ethyl acetate, at a rate slow enough such that the reaction temperature did not exceed 10° C. (ca. 15 minutes). After the initial exotherm, the temperature returned to 2° C., and the reaction was maintained at this temperature for an additional 4 hours. The reaction solution was transferred into a separatory funnel, was diluted with ethyl acetate (15 mL), and was washed with a 0.1N aqueous solution of sodium thiosulfate (Na2S2 O3, 25 mL). The ethyl acetate layer was further washed with water (10 mL), and the combined water washes were back-extracted with ethyl acetate (10 mL). The combined ethyl acetate layers were extracted with two portions of a 5% aqueous solution of potassium hydroxide (KOH, 65 mL then 25 mL). The combined KOH solutions of potassium naproxenate were acidified to pH=1 with a 5% aqueous solution of hydrochloric acid, precipitating the naproxen acid. The mixture was cooled in a wet-ice bath, and then was vacuum filtered through a #1 Whatman filter. The filter cake was washed with cold water (20 mL) and the white solid thus obtained was dried in a vacuum oven 18 hours at 55° C. (25 mm Hg), giving 1.72 g (80.0%) of naproxen.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH:15]([N:18]=[C:19]=[O:20])([CH3:17])[CH3:16]>>[CH:15]([NH:18][C:19]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:3][CH2:2]1)=[O:20])([CH3:17])[CH3:16]
Reactant: CC(C)N=C=O
Reactant: Nc1ccc(CC2CCNCC2)cc1
Product: CC(C)NC(=O)N1CCC(Cc2ccc(N)cc2)CC1
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
A solution of 4-(piperidin-4-ylmethyl)-phenylamine (0.57 g, 3 mmol) in dicholoromethane (20 mL) was cooled in an ice bath under nitrogen atmosphere. Isopropyl isocyanate (0.28 g, 3.3 mmol) was added dropwise to the solution and stirred at ice bath temperature for 30 minutes. The reaction mixture was quenched with water and extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried, and solvents removed in vacua. The crude product was chromatographed on silica gel, eluting with 2% methanol/dichloromethane containing 0.01% ammonium hydroxide, to give 4-(1-isopropylaminocarbonylpiperidin-4-ylmethyl)-phenylamine (0.66 g, 80%) as a gum.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][O:12][C:13]1[CH:30]=[CH:29][C:28]2[C@@H:27]3[C@H:18]([C@@H:19]4[C@@:23]([CH2:25][CH2:26]3)([CH3:24])[C:22](=[O:31])[CH2:21][CH2:20]4)[C@H:17]([CH3:32])[CH2:16][C:15]=2[CH:14]=1.I[CH3:34].[Cl-].[NH4+]>O1CCCC1>[CH3:11][O:12][C:13]1[CH:30]=[CH:29][C:28]2[C@@H:27]3[C@H:18]([C@@H:19]4[C@@:23]([CH2:25][CH2:26]3)([CH3:24])[C:22](=[O:31])[C@@H:21]([CH3:34])[CH2:20]4)[C@H:17]([CH3:32])[CH2:16][C:15]=2[CH:14]=1
Reactant: CI
Reactant: COc1ccc2c(c1)C[C@@H](C)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@H]12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C[C@@H](C)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@@H](C)C[C@H]12
Reaction time: 0.75 h

Procedure:
i)—A solution of lithium bis(trimethylsilyl)amide (55.5 mmol) in tetrahydrofuran (96 ml) was cooled to 40° C. A solution of (7α,14β)-3-methoxy-7-methylestra-1,3,5(10)-trien-17-one (Example 4, step ii; 15.0 g) in dry tetrahydrofuran (66 ml) was added dropwise and the reaction mixture was stirred for 45 min. Then, at −30° C., iodomethane (6.3 ml) was added and stirring was continued for 1 h (−30<T −20° C.). The mixture was poured into a saturated aqueous solution of ammonium chloride and the product was extracted into ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure, to give (7α,14β,16β)-3-methoxy-7,16-dimethylestra-1,3,5(10)-trien-17-one (17.33 g). The product was used in the following step without further purification.
Reaction SMILES: [CH2:1]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([O:25][CH2:26][C:27]#[N:28])[CH:19]=[CH:18]2)[CH2:2][CH2:3][CH2:4][CH3:5].[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Br>>[CH2:1]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[C:30]([F:29])([F:39])[F:40])[C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([O:25][CH2:26][C:27]#[N:28])[CH:19]=[CH:18]2)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CCCCCc1c(-c2ccc3cc(OCC#N)ccc3c2)[nH]c2ccccc12
Product: CCCCCc1c(-c2ccc3cc(OCC#N)ccc3c2)n(Cc2ccccc2C(F)(F)F)c2ccccc12

Procedure:
The title compound was prepared as a solid (0.147 g, 34%) from {[6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile using 2-trifluoromethyl benzyl bromide and the procedure from step 4 of Example 2; 1H NMR (DMSO-d6) δ 0.72 (t, J=7.8 Hz, 3H), 1.08-1.29 (m, 4H), 1.51-1.67 (m, 2H), 2.71 (t, J=8.6 Hz, 2H), 5.29 (s, 2H). 5.47 (s, 2H), 6.37 (d, J=8.6 Hz, 1H), 7.08-7.21 (m, 2H), 7.23-7.32 (m, 2H), 7.35-7.45 (m, 2H), 7.48 (t, J=7.8 Hz, 1H), 7.53 (d, J=1.7 Hz, 1H), 7.63-7.75 (m, 2H), 7.83-7.92 (m, 3H); mass spectrum [(+) ESI], m/z 527 (M+H)+.
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[N:16]1([CH2:22][CH2:23][OH:24])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[OH-].[K+]>CN(C=O)C.O>[N:16]1([CH2:22][CH2:23][O:24][C:4]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=2[C:6]#[N:7])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: OCCN1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C(F)(F)F)cc1OCCN1CCOCC1
Temperature: 0 °C

Procedure:
To a solution of 2-nitro-4-trifluoromethyl benzonitrile (0.5 g, 2.3 mmol) and 2-morpholin-4-yl-ethanol (0.37 g, 0.34 ml, 2.8 mmol) in DMF (4 ml) was added dropwise a solution of KOH (0.23 g, 4.1 mmol) in water (1.5 ml). After 10 min the reaction was poured into ice water and the white crystalline product collected by filtration, washed with water and dried (0.5 g, 72%).
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:11]>>[OH:11][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc(C=O)cc1
Product: O=Cc1ccc(O)cc1
Reaction time: 0.25 h

Procedure:
The procedure of Example 8 was followed except that the reaction of p-aminobenzaldehyde with sulphuric acid in 40% aqueous solution was effected at 120° C. for 15 minutes, to obtain 2.6 g (0.021 mol) of p-hydroxybenzaldehyde, accompanied with formation of tarry materials in large quantities. The yield of p-hydroxybenzaldehyde so obtained was 53%, based on the weight of p-aminobenzaldehyde used.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:19])(=[O:18])[C:7]1[CH:17]=[C:14]([O:15][CH3:16])[C:12]([OH:13])=[C:9]([O:10][CH3:11])[CH:8]=1.[CH3:20]O>>[OH:13][C:12]1[C:14]([O:15][CH3:16])=[CH:17][C:7]([C:6]([O:19][CH3:20])=[O:18])=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CO
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(OC)c(O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Concentrated sulphuric acid (3 mL), was added dropwise to a solution of 81 (20.24 g, 102.1 mmol) in refluxing methanol (70 mL). The reaction mixture was heated at reflux for a further 5 hours and then cooled to room temperature and concentrated to a third of its original volume. The concentrate was poured onto crushed ice (c. 150 mL) and allowed to stand for 30 minutes. The aqueous mixture was extracted with ethyl acetate (3×100 mL) and the combined organic phase washed with distilled water (3×100 mL), brine (3×100 mL) and dried over anhydrous MgSO4. Removal of ecxess solvent under reduced pressure afforded the product as a yellow solid, 121 (18.39 g, 86.7 mmol; 1H NMR (270 MHz, CDCl3) δ 3.9 (s, 3H), 3.95 (s, 3H), 3.975 (s, 3H), 6.1 (s, 1H), 7.3 (s, 2H); 13C NMR (67.8 MHz, CDCl3) δ 166.9, 146.6, 139.2, 121.0, 106.6, 56.4, 52.1.
Reaction SMILES: [CH3:1][CH:2]([NH:10][NH2:11])[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.C([O:14][C:15](=O)[CH:16]([CH3:20])[C:17]([CH3:19])=O)C>C(O)C>[CH3:19][C:17]1[NH:11][N:10]([CH:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=2)[C:15](=[O:14])[C:16]=1[CH3:20]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: Cc1ccc(C(C)NN)cc1
Solvent: CCO
Product: Cc1ccc(C(C)n2[nH]c(C)c(C)c2=O)cc1

Procedure:
30 g of α-methyl-4-methylbenzylhydrazine in ethanol were added to a solution of 28.8 g (0.2 mol) of α-methylacetoacetic acid ethyl ester in 40 ml of ethanol under N2 gas; during the addition, the temperature rose to 70° C. After completion of the addition, the reaction mixture was heated for 2 hours under reflux.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5][CH2:4]2)[CH2:2]1.[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]>C(Cl)Cl>[F:20][C:19]([F:22])([F:21])[C:17]([OH:23])=[O:18].[CH2:2]1[C:3]2([CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]2)[CH2:1]1
Reactant: CC(C)(C)OC(=O)NC1CCC2(CC1)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC2(CC1)CC2
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Compound 7-3 (1.5 g, 6.7 mmol) was dissolved in 15 mL of DCM and TFA (2.5 mL) was added and stirred for 1 hour to give Compound 7-4 (1.6 g, 99.8% yield).
Reaction SMILES: OC([C:5]1[S:9][C:8]([NH:10]C(=O)OC(C)(C)C)=[N:7][C:6]=1[CH2:18][CH2:19][O:20][CH:21]1[CH2:26]COC[CH2:22]1)(C)C.Cl.[OH-].[Na+]>O1CCCC1>[CH3:26][C:21]1([CH3:22])[C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH2:18][CH2:19][O:20]1
Reactant: CC(C)(C)OC(=O)Nc1nc(CCOC2CCOCC2)c(C(C)(C)O)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)OCCc2nc(N)sc21
Temperature: 25 °C
Yield: 51.3 %

Procedure:
To a solution of Example 3D (4.6 g, 11 mmol) in tetrahydrofuran was added conc. HCl (6.9 mL). The reaction mixture was refluxed overnight and then cooled to room temperature. The mixture was basified with 5N NaOH (17 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® IT280™ (SiO2, 0-10% methanol in dichloromethane to afford 1.04 g (51%) of the title compound. MS (ESI+) m/z 185 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([C:16](=[NH:19])[NH:17][OH:18])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.[OH-].[Na+].[CH3:29]OS(OC)(=O)=O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:11]=[CH:12][C:13]([C:16](=[NH:19])[NH:17][O:18][CH3:29])=[CH:14][CH:15]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: COS(=O)(=O)OC
Reactant: N=C(NO)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CONC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
100 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-hydroxycarbamimidoyl)benzamide was cooled to 0° C. in 1.5 mL of Dioxane. 5 mL of 2N NaOH was slowly added followed by dropwise addition of 33 μL of dimethylsulfate. The ice bath was removed and reaction was stirred at room temperature for 1 hour. The reaction was subsequently evaporated and extracted with water twice in Ethyl Acetate, dried with Magnesium Sulfate, filtered and concentrated to yield pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-methoxycarbamimidoyl)benzamide. MS (Q1) 381 (M)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[N:27]=[C:26]([CH:28]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:29]([OH:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:24][CH:23]=1>>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([CH:28]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:29]([OH:33])[CH:30]([CH3:32])[CH3:31])[N:27]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(C)C(O)C(c1cccc(Br)n1)N1CCOCC1
Product: CC(C)C(O)C(c1cccc(Nc2sc(-c3ccc(C(C)(C)O)cc3F)cc2C(N)=O)n1)N1CCOCC1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.510 mmol) and 1-(6-bromopyridin-2-yl)-3-methyl-1-morpholin-4-ylbutan-2-ol (168 mg, 0.51 mmol) as starting materials.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:21][CH:20]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH2:40]([S:44](Cl)(=[O:46])=[O:45])[CH2:41][CH2:42][CH3:43]>ClCCl>[N:28]1([CH2:27][CH2:26][O:25][C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:16]3[N:17]=[C:13]4[CH:12]=[CH:11][CH:10]=[C:9]([C:5]5[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=5)[CH2:2][NH:1][S:44]([CH2:40][CH2:41][CH2:42][CH3:43])(=[O:46])=[O:45])[N:14]4[N:15]=3)=[CH:20][CH:21]=2)[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CCCCS(=O)(=O)Cl
Reactant: NCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)NCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of [5-(3-aminomethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.03 g, 0.070 mmol) in dichloromethane (1 ml) was added triethylamine (13 μl, 0.091 mmol) followed by butanesulfonyl chloride (11 μl, 0.084 mmol). The mixture was stirred for 18 hours at room temperature, then filtered and concentrated in vacuo. The product was purified by preparatory HPLC to provide the desired product. LCMS RT: 2.66 min, MI: 549, Method: 2; 1H NMR (DMSO, 300 MHz): 9.43 (s, 1H), 8.18 (s, 1H), 8.03 (d, 1H), 7.65 (m, 6H), 7.16 (d, 1H), 6.90 (d, 2H), 4.27 (d, 2H), 4.05 (t, 2H), 2.93 (t, 2H), 2.70 (s, 4H), 2.45 (dd, 2H), 1.74 (s, 4H), 1.59 (m, 2H), 1.28 (m, 2H), 0.82 (m, 3H).
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[CH2:2][O:3][CH2:4][C:5]([O-:7])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.Cl.[OH:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[NH:34][OH:35].C(N(CC)CC)C.OS([O-])(=O)=O.[K+]>C1COCC1.O.C(Cl)Cl>[OH:35][N:34]([C:25]1[CH:26]=[CH:27][C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24]=1[OH:23])[C:5](=[O:7])[CH2:4][O:3][CH2:2][C:1]([O:9][CH3:10])=[O:8]
Reactant: ONc1ccc2ccccc2c1O
Reactant: COC(=O)COCC(=O)[O-]
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)COCC(=O)N(O)c1ccc2ccccc2c1O
Reaction time: 1 h
Yield: 68.8 %

Procedure:
Into a 25 ml methylene chloride solution of 500 mg (3.38 mmol) of methyl diglycolate and 200 μl (3.38 mmol) of DMF was added 660 μl (7.60 mmol) of oxalyl chloride at 0° C., and the mixture was stirred as such for one hour. The mixture was added to a solution of 3.6 g (17 mmol) of 1-hydroxy-2-naphthylhydroxylamine hydrochloride, 3.5 ml (25 mmol) of triethylamine in THF (25 ml), and water (5 ml), at 0° C., and after stirring at 0° C. for one hour and at room temperature for one hour, the reaction was completed with aqueous KHSO4, and the mixture was extracted with methylene chloride. The organic layer was washed with 4N HCl and with saturated aqueous NaCl, and then dried over anhydrous magnesium sulfate, and after evaporation of the solvent under a reduced pressure, the residue was subjected to silica gel column chromatography to give 710 mg (69%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[N:20]([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[O:12]([C:9]1[CH:10]=[CH:11][C:6]([N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:19])[NH2:20])=[CH:7][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=N[O-]
Reactant: COC(=O)CNc1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CN(N)c1ccc(Oc2ccccc2)cc1
Reaction time: 2 h

Procedure:
N-(4-Phenoxyphenyl)glycine methylester (Intermediate 75, 13.5 g, 0.0525 mol) was dissolved in a mixture of acetic acid (90 ml) and water (5 ml) and the solution was cooled to ~5° C. To this was added a solution of sodium nitrite (3,8 g, 0.55 mol) in water (10 ml) over 15 minutes. Stirring was continued for 2 hours and the reaction was cooled to ~0° C. Zinc dust (13.4 g, 0.2048 mol) was added over 30 minutes and the reaction stirred at 0°-5° C. for 2 hours before being poured into water (200 ml) and extracted with ethyl acetate (2×150 ml). The organic extract was washed with 8% sodium bicarbonate solution until effervescence had ceased, dried (MgSO4) and evaporated to give a brown semi-solid. This was triturated with ether/hexane (1:1) to recover starting material (6.5 g, 48%). The liquors were evaporated and purified by flash column chromatography on silica (Merck 9385; 250 g) eluting with ether-hexane (1:1) to give the title compound (Intermediate 76) as an off white solid (1.25 g, 9%) m.p 71°-73° C.
Reaction SMILES: C([O:8][C@H:9]([C@H:11]([N:24]1[CH:28]=[C:27]([C:29]([NH2:31])=[O:30])[N:26]=[CH:25]1)[CH2:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:10])C1C=CC=CC=1>C(O)C.C1CCCCC=1.[OH-].[Pd+2].[OH-]>[OH:8][C@H:9]([C@H:11]([N:24]1[CH:28]=[C:27]([C:29]([NH2:31])=[O:30])[N:26]=[CH:25]1)[CH2:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:10]
Reactant: C[C@H](OCc1ccccc1)[C@@H](CCc1cccc2ccccc12)n1cnc(C(N)=O)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: C[C@H](O)[C@@H](CCc1cccc2ccccc12)n1cnc(C(N)=O)c1
Yield: 68.3 %

Procedure:
1-[(2S,3R)-2-benzyloxy-5-(1-naphthyl)-3-pentyl]imidazole-4-carboxamide (obtained in Example 17 or 20) (5.07 g) was dissolved in a mixture of ethanol (300 ml) and cyclohexene (150 ml) and then palladium hydroxide (20% on carbon, 5.0 g) was added. The mixture was heated under reflux for 3 days. After cooling, the catalyst was filtered and washed with ethanol. The combined filtrate and washings were concentrated in vacuo. Flash chromatography (dichloromethane:methanol=10:1) gave 1-[(2S,3R)-2-hydroxy-5-(1-naphthyl)-3-pentyl]imidazole-4-carboxamide (2.71 g, 68.4%) as a foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[SH:11].[OH-].[Na+].Br[CH2:15][CH2:16][Cl:17]>C(O)C.O.C(OCC)(=O)C>[Cl:17][CH2:16][CH2:15][S:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc([N+](=O)[O-])cc1S
Reactant: ClCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc([N+](=O)[O-])cc1SCCCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
To a stirred suspension of 2-amino-5-nitrobenzenethiol (4.11 g, 24.15 mmol) in ethanol (50 mL) and water (10 mL) was added sodium hydroxide (0.966 g, 24.15 mmol). To the resulting solution was added 1-bromo-2-chloroethane (8.04 mL, 97 mmol), and the resulting mixture was stirred at room temperature for 3 hours. The mixture was then diluted with ethyl acetate and washed with saturated sodium carbonate (3×). The organic phase was dried, filtered, and concentrated, giving a dark yellow solid (5.13 g, 91%). 1H NMR (DMSO-d6) δ 8.16 (d, J=2.7 Hz, 1H), 7.97 (dd, J=9.0, 2.7 Hz, 1H), 6.94 (brs, 2H), 6.79 (d, J=9.0 Hz, 1H), 3.68 (t, J=7.2 Hz, 2H), 3.11 (t, J=7.2 Hz, 2H); ESI-MS (m/z, %): 233 (MH+, 100), 216 (79).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=S)[CH3:2].Cl.Cl.[NH2:17][CH:18]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:19]([NH:21][C:22]1([C:32]#[N:33])[CH2:26][CH2:25][N:24]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH2:23]1)=[O:20]>>[CH2:1]([O:3][C:4](=[O:14])[N:5]=[C:6]([NH:17][CH:18]([C:19](=[O:20])[NH:21][C:22]1([C:32]#[N:33])[CH2:26][CH2:25][N:24]([CH:27]([CH2:28][CH3:29])[CH2:30][CH3:31])[CH2:23]1)[CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: CCC(CC)N1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)C1
Reactant: CCOC(=O)NC(=S)N1CCOCC1
Agent: Cl
Product: CCOC(=O)N=C(NC(CC1CCCCC1)C(=O)NC1(C#N)CCN(C(CC)CC)C1)N1CCOCC1

Procedure:
The title compound was prepared starting from (Morpholine-4-carbothioyl)-carbamic acid ethyl ester and 2-amino-N-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 76, step b, MS, m/z 519=M+1.
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4][N:5]([CH3:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:20]([SH:24])[CH2:21][CH2:22][CH3:23].N1C2C(=CC=CC=2)C=CC=1.Cl>N1C=CC=CC=1>[CH2:20]([S:24][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4][N:5]([CH3:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:21][CH2:22][CH3:23]
Reactant: Cn1nc(-c2ccccc2)c(Br)c1-c1ccccc1
Reactant: CCCCS
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: c1ccncc1
Product: CCCCSc1c(-c2ccccc2)nn(C)c1-c1ccccc1
Yield: 97.1 %

Procedure:
A mixture of 4-bromo-1-methyl-3,5-diphenylpyrazole (21 g, 0.0671 mole), copper(1)salt of butanethiol (12.58 g, 0.08 mole), pyridine (10 ml) and quinoline (100 ml) is stirred and heated at 175° C. to 180° C. for 8 hours. The reaction mixture is cooled, poured into dilute hydrochloric acid (500 ml) and extracted with benzene. The benzene layer is separated and stripped in vacuo to give a brown oil. The oil is slurried with petroleum ether (b.p. 40° C. to 60° C.), filtered and the filtrate stripped in vacuo to give a brown syrup 21 g (97%), >95% pure by glc.