Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(O)=O.[CH2:12]=[CH:13][CH2:14][CH3:15]>>[C:1]([O:8][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5]
Reactant: C=CCC
Reactant: CC(=O)CCC(=O)O
Solvent: O=CO
Product: CCCCOC(=O)CCC(C)=O
Temperature: 100 °C

Procedure:
A 5 cc autoclave is charged with 2 cc of an aqueous solution containing 0.5 mmoles of levulinic acid and 2 mmoles of formic acid. 15 wt. % ZSM-5 zeolite is added as a catalyst. The reactor is pressurized to 0.69 MPa with 1-butene and heated to 100° C. for 4 hours while maintaining a constant pressure of 1-butene. After cooling, the organic phase is separated. A mixture of butyl formate and butyl levulinate is formed as product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[C:12]3[CH:18]=[C:17]([C:19]([OH:21])=O)[O:16][C:13]3=[N:14][CH:15]=2)=[CH:5][CH:4]=1.[Br:24][C:25]1[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.CN(C)C(Cl)=[N+](C)C>CN(C=O)C>[Br:24][C:25]1[C:26]([NH:31][C:19]([C:17]2[O:16][C:13]3=[N:14][CH:15]=[C:10]([CH2:9][O:8][CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=4)[CH:11]=[C:12]3[CH:18]=2)=[O:21])=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ncccc1Br
Reactant: COc1ccc(COCc2cnc3oc(C(=O)O)cc3c2)cc1
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc(COCc2cnc3oc(C(=O)Nc4ncccc4Br)cc3c2)cc1
Temperature: 70 °C

Procedure:
In an oven-dried sealed tube, a mixture of 5-(((4-methoxybenzyl)-oxy)methyl)furo[2,3-b]pyridine-2-carboxylic acid (2.0 g, 6.4 mmol), 3-bromo-2-amino pyridine (3.31 g, 19.2 mmol), N-methyl morpholine (1.93 g, 19.2 mmol) and N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate (3.58 g, 12.8 mmol) in DMF (20 mL) was heated to 70° C. for 5 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 40% ethyl acetate in petroleum ether to give the title compound. MS: m/z=468.5 (M+1).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1>>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1)[CH:11]=[CH:10]2
Reactant: OCCC1CCNCC1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Product: OCCC1CCN(c2ccc3cc(Cl)ccc3n2)CC1

Procedure:
The process is performed as described in Example 4 (step 4.1). Starting with 2 g (10.10 mmol) of 2,6-dichloroquinoline and 1.44 g (11.10 mmol) of 2-(4-piperidyl)ethanol, and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, 2.54 g of pure product are obtained in the form of a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([NH:7][C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C@@:28]([OH:43])([CH2:37][N:38]1[CH:42]=[N:41][CH:40]=[N:39]1)[C@@H:29]([CH3:36])[CH2:30][CH:31]([CH2:34]O)[CH2:32][OH:33].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([NH:7][C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[O:33][CH2:32][C@H:31]([CH2:30][C@H:29]([CH3:36])[C@:28]([C:22]4[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=4[F:20])([OH:43])[CH2:37][N:38]4[CH:42]=[N:41][CH:40]=[N:39]4)[CH2:34][O:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(NC(=O)c2ccc(C=O)cc2)cc1
Reactant: C[C@@H](CC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@@H](C[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(C#N)cc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as described in Example 1(2), a reaction was carried out using 4′-cyano-4-formylbenzanilide (78 mg, 0.31 mmol) obtained in Example 2(1), (4S,5R)-5-(2,4-difluorophenyl)-2-(hydroxymethyl)-4-methyl-6-(1H-1,2,4-triazol-1-yl)-1,5-hexanediol (disclosed in Japanese Patent Application Publication No. Hei-11-80135: 100 mg, 0.29 mmol) and p-toluenesulfonic acid monohydrate (99 mg, 0.52 mmol) and the reaction mixture was treated using a similar procedure to that described in Example 1(2) to give the trans isomer of the title compound (100 mg, yield 59%) as a white solid and the cis isomer (23 mg, yield 14%) as a colorless oil. The trans isomer was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: II.C1[O:14][CH:6]([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)OC1.[Cl-].[Li+].[Cl:17]/[CH:18]=[CH:19]\[CH2:20]Cl>C1COCC1.[Cu]Cl>[Cl:17]/[CH:18]=[CH:19]\[CH2:20][C:10]1[CH:9]=[CH:8][C:7]([CH:6]=[O:14])=[CH:12][CH:11]=1
Reactant: Cl/C=C\CCl
Reactant: Brc1ccc(C2OCCO2)cc1
Agent: Cl[Cu]
Agent: II
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=Cc1ccc(C/C=C\Cl)cc1
Reaction time: 1 h

Procedure:
Dry Mg (1.15 g) under dry N2 in a flask is covered with THF (10 ml) and a crystal of I2 added. 5 ml of a solution of 4-bromobenzaldehyde ethylene acetal (10.0 g) in THF (40 ml) is added and kept until it becomes warm, when it is cooled to 15°, and the remainder of the acetal added over 15 minutes, then stirred for an additional 1 hour. A mixture of ground lithium chloride (0.35 g) and copper (I) chloride (0.70 g) dissolved in THF is prepared, treated with Z-1,3-dichloropropene (8.0 g) produced by spinning band distillation of commercially available 1,3-dichloropropene comprising a mixture of the E and Z isomers and cooled to -20°. The above Grignard solution (under moisture excluding conditions) is then added to this solution during 5 minutes, and allowed to warm to 20° with stirring for 16 hours. Saturated aqueous ammonium chloride is added and the organic layer evaporated under reduced pressure to a small residue, which is dissolved in THF (100 ml), cooled to -10°, treated with 3N HCl (50 ml), then stirred at 20° for 1 hour. The product is partitioned between ether and water, and the ether layer washed with saturated aqueous NaHCO3, H2O, saturated aqueous NaCl, dried (MgSO4) and the residue chromatographed on florisil. The fraction eluted by 15 % diethyl ether in petroleum ether bp 60°-80° C. is collected and purified by preparative HPLC. Yield 1.12 g (14%) nD20 1.5655.
Reaction SMILES: [CH2:1]([C:4]1[N:13]=[C:12]2[C:7]([C:8](O)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:8]1[CH:9]=[CH:10][N:11]=[C:12]2[C:7]=1[CH:6]=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[N:13]2
Reactant: CCCc1ccc2c(O)ccnc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCc1ccc2c(Cl)ccnc2n1
Yield: 86 %

Procedure:
The product from Example 2f (145 mg, 0.76 mmol) was reacted with POCl3 4 mL following the procedure from Example 1d giving the title compound as a solid (135 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[NH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][NH:25][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:22]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCOCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCOCCO)ccc21
Yield: 63 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide (72 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (92 mg), 2-(2-aminoethoxy)-ethanol (30 mg), HBTU (116 mg), and DIEA (67 uL). LC/MS: m/z 446.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.38 (bs, 1H), 8.47 (t, 1H), 8.08 (s, 1H), 7.93 (s, 1H), 7.84-7.58 (m, 2H), 7.48 (d, 1H), 7.40 (d, 1H), 4.63 (t, 1H), 3.64 (s, 3H), 3.56 (t, 2H), 3.51 (t, 2H), 3.49-3.41 (m, 4H).
Reaction SMILES: [CH2:1]([C:4]1([CH:19]=[CH:20][C:21](OC)=[O:22])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH2:1]([C:4]1([CH:19]=[CH:20][CH2:21][OH:22])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)[CH:2]=[CH2:3]
Reactant: C=CCC1(C=CC(=O)OC)c2ccccc2CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC1(C=CCO)c2ccccc2CCc2ccccc21
Temperature: 0 °C
Reaction time: 20 h
Yield: 89.2 %

Procedure:
Dissolved methyl 3-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-propenoate (6.00 g, 0.0188 mol) in 80 mL of dry THF. Cooled to 0° C. under a nitrogen atmosphere, and added lithium aluminum hydride (18.8 mL of 1.0M in THF, 0.018 mol) via syringe. Warmed slowly to room temperature and stirred for 20 hours. Recooled to 0° C., and carefully added 0.8 mL water, 0.8 mL of 1N NaOH, and then 2.5 mL of water in sequence. Stirred at room temperature for 1 hour, and filtered through celite. Washed filtrate with saturated NH4Cl, dried with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 1:4 ethyl acetate:hexane then 1:2 ethyl acetate:hexane. Combined appropriate fractions, and evaporated to give 4.87 g (89% yield) of 3-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-prop-2-en-1-ol as a colorless oil.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl-].[Li+].Br[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.[CH3:19][N:20]1[C:24]([CH:25]=[O:26])=[CH:23][N:22]=[CH:21]1>C1COCC1>[CH3:19][N:20]1[C:24]([CH:25]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[OH:26])=[CH:23][N:22]=[CH:21]1
Reactant: Cn1cncc1C=O
Reactant: FC(F)(F)c1cc(Br)ccn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cncc1C(O)c1ccnc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of isopropylmagnesium chloride/lithium chloride complex (1.3 M in THF, 10.6 mL, 13.8 mmol) was added dropwise by syringe to a solution of 4-bromo-2-(trifluoromethyl)pyridine (3.12 g, 13.8 mmol) in dry THF (50 mL) at 0° C. After 30 minutes, a solution of 1-methyl-1H-imidazole-5-carbaldehyde (1.38 g, 12.5 mmol) in THF (28.5 mL) was added to the Grignard solution by syringe at 0° C. The reaction mixture was warmed to room temperature over 2 hours after which it was quenched with saturated aqueous ammonium chloride solution. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate and washed with saturated aqueous NaCl solution. The organic phase was dried (MgSO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-10% MeOH-DCM) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:21]([CH:23]2[CH2:27][CH2:26][C@@H:25]([N:28]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:24]2)[OH:22])=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:21]([CH:23]2[CH2:27][CH2:26][C@@H:25]([N:28]([CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:24]2)=[O:22])=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:19])[CH3:20])([CH:15]([CH3:16])[CH3:17])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(O)C3CC[C@@H](N(Cc4ccccc4)Cc4ccccc4)C3)c(Cl)cnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(=O)C3CC[C@@H](N(Cc4ccccc4)Cc4ccccc4)C3)c(Cl)cnc21
Temperature: 5 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
A solution of (5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3R)-3-(dibenzylamino)cyclopentyl)methanol (1.14 g, 1.89 mmol) in DCM (50 mL) was cooled to about 0° C. Dess-Martin periodinane (2.41 g, 5.68 mmol) was added and the reaction mixture was stirred at about 0-10° C. for about 3 h. The mixture was quenched by a drop-wise addition of aqueous sodium sulfite (1 M, 20 mL), and the organic solvent was removed under reduced pressure. The aqueous layer was extracted with EtOAc (2×25 mL), and the combined organic extracts were washed with aqueous NaOH (1 N, 3×20 mL), brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-20% EtOAc in heptane to yield (5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3R)-3-(dibenzylamino)cyclopentyl)methanone (0.68 g, 60%) as a yellow amorphous solid: LC/MS (Table 2, Method a) Rt=1.65 min; MS m/z: 442 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1)=[O:12])=[O:4].O.[OH-].[Li+]>C1COCC1>[C:13]1([C:11]([N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C@H:5]2[C:3]([OH:4])=[O:2])=[O:12])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1
Reactant: COC(=O)[C@@H]1CCCCN1C(=O)c1nccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCCCN1C(=O)c1nccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of (S)-1-(isoquinoline-1-carbonyl)-2-piperidinecarboxylic acid methyl ester (1.05 g, 3.52 mmol) in THF (20 ml) at room temperature was treated with water (10 ml). Lithium hydroxide (84 mg, 3.51 mmol) was then added and the resulting mixture was stirred at room temperature for 16 hrs. The resulting mixture was concentrated to remove the organic solvent. The resulting solution was then washed with diethyl ether and the remaining aqueous layer was made acid with 2 N HCl. The resulting solution was extracted with ethyl acetate and the organic layer was separated, dried (Na2SO4), filtered and concentrated to reveal a white solid (902 mg, 90%): 1H NMR (400 MHz, d4-MeOH) δ 1.20-2.52 (6H, m), 3.10-3.39 (2H, m), 4.10-4.90 (1H, m), 7.68-8.55 (5H, m).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:44])[C@@H:19]([CH:20]=[CH:21][C:22](=[O:24])[OH:23])[C@H:18]1[C:25]([O:27][C@H:28]([C:42]#[N:43])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]=1)=[O:26].[C:45]([CH:47](O)[C:48](Cl)([Cl:50])[Cl:49])#[N:46]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:44])[C@@H:19](/[CH:20]=[CH:21]\[C:22](=[O:23])[O:24][C:47]([C:45]#[N:46])=[C:48]([Cl:50])[Cl:49])[C@H:18]1[C:25]([O:27][C@H:28]([C:42]#[N:43])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]=1)=[O:26]
Reactant: N#CC(O)C(Cl)(Cl)Cl
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C=CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OC(C#N)=C(Cl)Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
140 mg of 4-dimethylaminopyridine and then 1.76 g of dicyclohexylcarbodiimide were added at 0° C. to a mixture of 3.36 g (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[3-oxo-3-hydroxy-1-propenyl]-cyclopropane-carboxylate, 1.7 g of chloral cyanohydrin and 16 ml of methylene chloride and the mixture was stirred at 20° C. for 21/2 hours and was then evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with an 85-15 cyclohexane-ethyl acetate mixture to obtain 1.65 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-(2,2-dichloro-1-cyanovinyloxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+40° (c=0.3% in chloroform).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]([CH:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:11][CH2:12][NH:13][OH:14])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O-:25][C:26]#[N:27].[Na+].[OH-].[Na+]>O>[CH3:1][C:2]1[C:3]([N:9]([CH:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:11][CH2:12][N:13]([OH:14])[C:26]([NH2:27])=[O:25])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N(CCCNO)C2CCCc3cccnc32)c(C)c1
Reactant: N#C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cnc(N(CCCN(O)C(N)=O)C2CCCc3cccnc32)c(C)c1

Procedure:
N-{3-[(3,5-Dimethyl-pyridin-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-hydroxylamine (HBr salt) (138 mg, 0.22 mmol) was dissolved in H2O (2 mL) and treated with sodium cyanate (42 mg, 0.65 mmol) for 3.5 hours. 15% aqueous NaOH solution (0.1 mL) was added and the aqueous was extracted with CH2Cl2 (3×5 mL). The combined organics were then dried (Na2SO4) and concentrated under reduced pressure to afford, after radial chromatographic purification on a silica gel plate (3% NH4OH/CH3CN) N-{3-[(3,5-dimethyl-pyridin-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-N-hydroxyurea (42 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][C:17]=3[Cl:18])[O:10][N:9]=2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[N-:23]=[N+:24]=[N-].[Na+]>C(O)(=O)C.O>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][C:17]=3[Cl:18])[O:10][N:9]=2)=[CH:4][CH:3]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(-c2noc(-c3sccc3Cl)n2)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: [N-]=[N+]=Nc1ccc(-c2noc(-c3sccc3Cl)n2)cc1
Temperature: 2.5 °C
Reaction time: 0.33 h
Yield: 105.4 %

Procedure:
To a mixture of 3-(4-aminophenyl)-5-(3-chloro-thiophen-2-yl)-[1,2,4]-oxadiazole (15.5 mg, 0.05 mmol) in acetic acid (2 mL) and conc. sulfinuric acid (0.3 mL) was added sodium nitrite (3.8 mg, 0.055 mmol) in water (0.5 mL). The mixture was stirred vigorously at 0-5° C. for 20 min, then sodium azide (3.6 mg, 0.055 mmol) in water (0.5 mL) was added. It was stirred at 0-5° C. for 3 h and then poured into ice water (30 mL). The resultant mixture was extracted with ethyl acetate (3×10 mL). The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The crude residue was purified by flash chromatography to yield 16 mg (100%) of the title compound. 1H NMR (CDCl3): 8.18 (d, J=8.7 Hz, 2H), 7.63 (d, J=5.4 Hz, 1H), 7.18 (d, J=8.7 Hz, 1H), 7.16 (d, J=5.4 Hz, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.C([O-])([O-])=O.[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>O1CCOCC1.[Cu]I>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([N:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=[N:10]2)[CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(-c2cn[nH]c2)cc1
Reactant: COc1cccc(I)c1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cccc(-n2cc(-c3ccccc3)cn2)c1
Temperature: 110 °C
Reaction time: 72 h

Procedure:
A mixture of 4-phenyl-1H-pyrazole (775 mg, 5.38 mmol, 1.0 eq), 1-iodo-3-methoxybenzene (1510 mg, 768 μL, 6.45 mmol, 1.2 eq), CuI (21 mg, 0.11 mmol, 0.02 eq), K2CO3 (1561 mg, 11.30 mmol, 2.1 eq) and trans-1,2-cyclohexanediamine (123 mg, 1.08 mmol, 0.20 eq) in dioxane (12 mL) was stirred at a temperature of 110° C. for three days, then cooled to ambient temperature. The solvent was removed under reduced pressure and the residue was purified through column chromatography on silica gel using hexane and ethyl acetate (10:1-5:1-3:1) as an eluent to obtain the desired product, 1-(3-methoxyphenyl)-4-phenyl-1H-pyrazole 5, as a colorless liquid (1.13 g in 84% yield). 1H NMR (DMSO-d6, 400 MHz): δ 3.84 (s, 3H), 6.87-6.90 (m, 1H), 7.25 (t, J=7.2 Hz, 1H), 7.38-7.48 (m, 5H), 7.71 (d, J=7.2 Hz, 2H), 8.20 (s, 1H), 9.01 (s, 1H).
Reaction SMILES: [O:1]=[C:2]([N:15]1[CH2:27][CH2:26][C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH:16]1[C:28]1[CH:33]=[CH:32][C:31]2[O:34][CH2:35][O:36][C:30]=2[CH:29]=1)/[CH:3]=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]([C:9](OC)=[O:10])=[CH:7][CH:6]=1.[NH3:37]>CO>[O:1]=[C:2]([N:15]1[CH2:27][CH2:26][C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH:16]1[C:28]1[CH:33]=[CH:32][C:31]2[O:34][CH2:35][O:36][C:30]=2[CH:29]=1)/[CH:3]=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]([C:9]([NH2:37])=[O:10])=[CH:7][CH:6]=1
Reactant: N
Reactant: COC(=O)c1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Solvent: CO
Product: NC(=O)c1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Temperature: 35 °C
Reaction time: 48 h
Yield: 13 %

Procedure:
Into a solution of Example 28 (0.2 g, 0.4 mmol) in 50 mL of MeOH was bubbled ammonia and the resulting mixture was stirred at 35° C. for two days. The mixture was concentrated in vacuo to give a residue which was washed with 2×30 mL of water. Extraction, drying over MgSO4 and concentration in vacuo gave a residue that was purified via radial chromatography using DCM:MeOH (90:10) as eluting solvent and via preparative chromatography (20×20- cm plate, 0.5 mm, SiO2) using the same eluant. The title compound (0.025 g, 13%) was isolated as white crystals after recrystallization from MeOH:H2O. MP: 183° C.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][NH2:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS([C:15]1[N:20]=[C:19]([C:21]2[C:22]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)=[N:23][N:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=23)[CH:18]=[CH:17][N:16]=1)(=O)=O>O>[N:1]1([CH2:8][CH2:9][NH:10][C:15]2[N:20]=[C:19]([C:21]3[C:22]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=4)=[N:23][N:24]4[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][C:25]=34)[CH:18]=[CH:17][N:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3cccc(Cl)c3)nn3cc(C(F)(F)F)ccc23)n1
Reactant: NCCN1CCCCCC1
Solvent: O
Product: FC(F)(F)c1ccc2c(-c3ccnc(NCCN4CCCCCC4)n3)c(-c3cccc(Cl)c3)nn2c1

Procedure:
2-Azepan-1-ylethylamine (0.04 mL) and 4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl methyl sulfone (0.02 g) were mixed at room temperature and heated with an airgun until a homogenous melt was obtained (2 min). Upon cooling, water was added. The precipitated solid was filtered and dried to give the title compound as a beige solid (0.014 g); 1H NMR (d6-DMSO) δ 9.51(1H, s), 8.49(1H, bs), 8.16(1H, d), 7.70–7.65(2H, m), 7.60–7.50(3H, m), 7.00(1H, bs), 6.36(1H, bs), 2.6(6H, bs), 1.6(8H, bs); m/z 515(M+1)+.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:27])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[CH:12]=1.[C:28]1([CH2:34][C:35]([OH:37])=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:3][O:4][C:5](=[O:27])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:25][CH3:26])[C:35](=[O:37])[CH2:34][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:12]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1
Reactant: O=C(O)Cc1ccccc1
Agent: Cl
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1)C(=O)Cc1ccccc1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester, dihydrochloride and phenyl-acetic acid were reacted as described in Example 8, Step 6 to provide (5-{2-[(N-ethyl-N-phenylacetyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid methyl ester.