Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[CH2:8][C@H:4]1[C:5]([OH:7])=O)[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[CH2:44][NH2:45].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[CH2:44][NH:45][C:5](=[O:7])[C@@H:4]1[CH2:8][C:9]([CH3:13])([CH3:12])[C:10](=[O:11])[N:3]1[CH2:1][CH3:2]
Reactant: NCc1ccc(F)cc1Cl
Reactant: CCN1C(=O)C(C)(C)C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN1C(=O)C(C)(C)C[C@H]1C(=O)NCc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
1-ethyl-4,4-dimethyl-5-oxoproline (0.130 g, 0.702 mmol, prepared as described below), 1-Hydroxybenzotriazole (0.161 g, 1.053 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.202 g, 1.053 mmol) were dissolved in dichloromethane (5 ml) and stirred for 15 minutes at room temperature. [(2-chloro-4-fluorophenyl)methyl]amine (0.134 g, 0.842 mmol) and diisopropylethylamine (0.184 ml, 1.053 mmol) were then added to the mixture and stirring continued overnight at room temperature. The mixture was then concentrated in vacuo and the residue partitioned between ethyl acetate and water and extracted with ethyl acetate. The combined organic layers were washed sequentially with 3N citric acid, water, saturated aqueous sodium carbonate, water (×3), and then brine and dried over anhydrous sodium sulfate. Concentration gave a crude solid which was subsequently purified by mass-directed automated HPLC to give N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-4,4-dimethyl-5-oxoprolinamide (0.146 g) as a solid. LC/MS [M+H]+=327/329, retention time=2.35 minutes.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH3:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19]=1[CH:27]=O.N1CCCCC1>C(O)C>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:27][C:19]1[NH:20][C:21]2[C:26]([C:18]=1[CH3:17])=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:5])=[O:4]
Reactant: Cc1c(C=O)[nH]c2ccccc12
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C=C2C(=O)Nc3ccc(S(=O)(=O)N(C)C)cc32)[nH]c2ccccc12
Temperature: 90 °C
Yield: 56.6 %

Procedure:
A mixture of 5-dimethylaminosulfonyl-2-oxindole (96 mg), 3-methylindole-2-carbaldehyde (56 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (30 mg) in ethanol (1 mL) was heated in a sealed tube at 90° C. for overnight. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in oven for overnight to give 76 mg (57% yield) of 3-(3-methyl-1H-indol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (mixture of isomers).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[N:8]=[CH:7][C:6]([CH3:13])=[N:5][C:4]=2[C:3]=1[OH:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+]>CCO>[CH2:15]([O:14][C:3]1[C:2]([Cl:1])=[CH:11][C:10]([Cl:12])=[C:9]2[C:4]=1[N:5]=[C:6]([CH3:13])[CH:7]=[N:8]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cnc2c(Cl)cc(Cl)c(O)c2n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnc2c(Cl)cc(Cl)c(OCc3ccccc3)c2n1
Yield: 46.9 %

Procedure:
A mixture of 6,8-dichloro-3-methylquinoxalin-5-ol (150 mg, 0.655 mmol), benzyl bromide (0.20 mL, 1.68 mmol), KOH (0.09 g) and EtOH (10 mL) was heated under reflux for 16 h, cooled, and concentrated. Dichloromethane (20 mL) was added and the mixture washed with H2O (5 mL×2), dried and concentrated. The residue was purified via SiO2-gel chromatography (dichloromethane/MeOH, 1:0-150:1) to give 8-benzyloxy-5,7-dichloro-2-methylquinoxaline (98 mg, 47%).—1H NMR (CDCl3): δ 8.82 (s, 1H), 7.81 (s, 1H), 7.58 (m, 2H), 7.38 (m, 2H), 5.45 (s, 2H), 2.85 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:25])[F:24])(=[O:16])=[O:15])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH2:10][OH:11].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:25])([F:26])[F:24])(=[O:16])=[O:15])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2C(F)(F)F)c1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
Sulfur trioxide pyridine complex (1.12 mg, 7.0 mmol) was added to a solution of 3-[5-methyl-3-(2-trifluoromethylphenylsulfonyloxy)phenoxy]propanol (700 mg, 1.8 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.7 mL, 5.5 mmol), and anhydrous dimethyl sulfoxide (0.4 mL, 5.6 mmol) in anhydrous dichloromethane (20 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (50 mL). The mixture was extracted into dichloromethane (3×50 mL), then the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a colorless oil (595 mg, 85%). 1H-NMR (300 MHz, CDCl3) δ 9.84 (s, 1 H), 8.13 (d, J=7.5 Hz, 1 H), 7.99 (d, J=7.5 Hz, 1 H), 7.80 (t, J=7.6 Hz, 1 H), 7.70 (t, J=7.3 Hz, 1 H), 6.62 (s, 1 H), 6.51 (s, 1 H), 6.45 (s, 1 H), 4.21 (t, J=6.0 Hz, 2 H), 2.87 (t, J=6.0 Hz, 2 H), 2.25 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[OH:12].[Cl:13][C:14]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:15]=1[NH2:16]>>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH:16][C:15]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=1[Cl:13])=[O:7]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1O
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Product: O=C(Nc1ccc([N+](=O)[O-])cc1Cl)c1cc(Cl)cc(Cl)c1O

Procedure:
This material was prepared according to the method of Example 1 using 3,5-dichlorosalicylic acid and 2-chloro-4-nitroaniline, with reagents and solvents employed in similar molar ratios. 1HNMR (500 MHz, DMSO-d6): δ 7.85 (m, 1H, H4), 7.98 (m, 1H, H5), 8.29 (m, 1H, H5′), 8.04 (m, 1H, H6), 8.44 (m, 1H, H3′), 8.55 (m, 1H, H6′).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](Cl)=[O:8].[C:11]1([C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH2:19][CH:20]([OH:26])[CH2:21]3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([O:26][CH:20]1[CH2:19][C:18]2[C:22](=[CH:23][CH:24]=[CH:25][C:17]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:21]1)=[O:8]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: OC1Cc2cccc(-c3ccccc3)c2C1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)C(C(=O)OC2Cc3cccc(-c4ccccc4)c3C2)C1(C)C
Yield: 63.2 %

Procedure:
In a manner similar to Example 12A, the reaction of 1.09 g (0.007 mole) of 2,2,3,3-tetramethylcyclopropanecarbonyl chloride and 1.5 g (0.007 mole) of (+)-4-phenyl-2-indanol (EE≥95%) in the presence of 0.7 g (0.009 mole) of pyridine and 20 ml of toluene gave 1.48 g of (+)-4-phenyl-2-indanyl 2,2,3,3-tetramethylcyclopropanecarboxylate, EE≥95%. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][C:12]#N.[OH-:20].[Na+].[OH2:22]>C(O)CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][C:12]([OH:22])=[O:20]
Reactant: O
Reactant: [OH-]
Reactant: COc1ccccc1CC(CC#N)c1ccccc1
Agent: [Na+]
Solvent: OCCO
Product: COc1ccccc1CC(CC(=O)O)c1ccccc1
Yield: 77 %

Procedure:
4-(2'-Methoxyphenyl)-3-phenylbutanenitrile (60.1 g, 239 mmol), from Step 4, was dissolved in 340 mL of ethylene glycol. Sodium hydroxide (67.5 g, 1.69 mol) and 135 mL of water were added and the reaction mixture was heated at reflux temperature for 24 h. The solvent was removed in vacuo and 1 L of water plus 1 L of methylene chloride were added to the residue. The layers were separated and the organic layer discarded. The aqueuous layer was acidified with concentrated aqueous hydrochloric acid and extracted with 3 L of ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 49.8 g (77% yield) of the title compound as an oil; 1H NMR (CDCl3)δ2.6-2.7 (m, 2H), 2.9 (d, 2H), 3.4-3.5 (m, 1H), 3.77 (s, 3H), 6.56 (t, 1H), 6.73 (dd, 1H), 6.80 (d, 1H), 7.0-7.4 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][NH:12][C:11]=3[C:10](=[O:17])[N:9]2[C:18]2[CH:19]=[C:20]([CH3:28])[C:21]3[N:22]([C:24]([CH3:27])=[N:25][N:26]=3)[CH:23]=2)=[CH:4][CH:3]=1.I[CH:30]1[CH2:33][O:32][CH2:31]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:30]4[CH2:33][O:32][CH2:31]4)[C:11]=3[C:10](=[O:17])[N:9]2[C:18]2[CH:19]=[C:20]([CH3:28])[C:21]3[N:22]([C:24]([CH3:27])=[N:25][N:26]=3)[CH:23]=2)=[CH:4][CH:3]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:11](=[N:12][N:13]([CH:30]4[CH2:33][O:32][CH2:31]4)[C:14]=3[CH3:16])[C:10](=[O:17])[N:9]2[C:18]2[CH:19]=[C:20]([CH3:28])[C:21]3[N:22]([C:24]([CH3:27])=[N:25][N:26]=3)[CH:23]=2)=[CH:4][CH:3]=1
Reactant: Cc1n[nH]c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Reactant: IC1COC1
Product: Cc1cc(N2C(=O)c3nn(C4COC4)c(C)c3C2c2ccc(Cl)cc2)cn2c(C)nnc12
Product: Cc1nn(C2COC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared using an analogous procedure to that described in Example 134 using 4-(4-chlorophenyl)-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 98) (200 mg, 0.509 mmol) and stirring the reaction mixture for 30 min at 80° C. after addition of 3-iodooxetane. Purification of the crude product afforded 50 mg of a 4-(4-chlorophenyl)-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-methyl-1-(oxetan-3-yl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 137) and 31 mg of a 4-(4-chlorophenyl)-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-methyl-2-(oxetan-3-yl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one (title compound). tR: 0.79 min (LC-MS 2); ESI-MS: 449.1 [M+H]+ (LC-MS 2); Rf=0.40 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.05 (s, 3H) 2.43 (s, 3H) 2.61 (s, 3H) 4.85-5.00 (m, 4H) 5.60-5.70 (m, 1H) 6.49 (s, 1H) 7.25-7.38 (m, 5H) 8.45 (s, 1H).
Reaction SMILES: [CH3:1][NH2:2].[CH:3]1([CH2:6][O:7][C:8]2[C:29]([Cl:30])=[CH:28][C:11]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3/[C:20](=[N:25]\[O:26][CH3:27])/[C:21]([O:23]C)=O)=[CH:10][C:9]=2[Cl:31])[CH2:5][CH2:4]1>CN(C=O)C.CO.O>[CH:3]1([CH2:6][O:7][C:8]2[C:29]([Cl:30])=[CH:28][C:11]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3/[C:20](=[N:25]\[O:26][CH3:27])/[C:21]([NH:2][CH3:1])=[O:23])=[CH:10][C:9]=2[Cl:31])[CH2:5][CH2:4]1
Reactant: CO/N=C(/C(=O)OC)c1ccccc1COc1cc(Cl)c(OCC2CC2)c(Cl)c1
Reactant: CN
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cc(Cl)c(OCC2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 40% aqueous solution of methylamine (0.8 ml) is added to a solution of methyl (E)-2-[2-(4-cyclopropylmethoxy-3,5-dichlorophenoxymethyl)-phenyl]-2-methoxyiminoacetate (compound nr.2; 0.88 g; 2 mmoles) in DMF (2 ml) and methanol (4 ml). The mixture is kept under stirring for 2 hours at room temperature, diluted with water (40 ml) and an extraction is effected with ethyl acetate (3×25 ml). The organic phases are joined, washed with water (2×20 ml), dried with sodium sulfate and concentrated at reduced pressure. 0.8 g of the product (thick oil) are obtained, which do not require further purification.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)=[O:4].[CH3:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>C(OCC)C>[Br-:1].[CH3:12][NH+:13]1[CH:17]=[CH:16][N:15]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=2)=[O:4])[CH2:14]1
Reactant: Cc1cccc(C(=O)CBr)c1
Reactant: Cn1ccnc1
Solvent: CCOCC
Product: Cc1cccc(C(=O)CN2C=C[NH+](C)C2)c1
Product: [Br-]
Yield: 24.4 %

Procedure:
A solution of 5.16 g (0.024 mol) of 1-bromo-2-(3-methylphenyl)-2-oxoethane and 2.15 g (0.026 mol) of 1-methylimidazole in approximately 30 ml of diethyl ether was stirred at room temperature for about 19 hours. The reaction solvent was decanted and the resulting brown residue was washed with diethyl ether. The residue was washed with hot acetonitrile and recrystallized twice from acetonitrile/diethyl ether to afford 1.74 g of 1-methyl-3-[2-(3-methylphenyl)-2-oxoethyl]-1H-imidazolium bromide as white needles. (25% yield) mp=185°-187° C.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH3:17])=[C:6]([CH2:8]P(=O)(OCC)OCC)[N:7]=1)[CH3:2].[H-].[Na+].[CH3:20][O:21][CH2:22][O:23][C:24]1[C:28]([CH:29]=O)=[CH:27][N:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]=1.O>O1CCCC1>[CH2:1]([C:3]1[S:4][C:5]([CH3:17])=[C:6](/[CH:8]=[CH:29]/[C:28]2[C:24]([O:23][CH2:22][O:21][CH3:20])=[N:25][N:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:27]=2)[N:7]=1)[CH3:2]
Reactant: CCOP(=O)(Cc1nc(CC)sc1C)OCC
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCOC)c(C)s1
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a solution of diethyl [(2-ethyl-5-methyl-1,3-thiazol-4-yl)methyl]phosphonate (4.16 g) in tetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 0.66 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (3.48 g) was added to the reaction mixture, and the mixture was heated under reflux for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (5:95-25:75, v/v) to give 2-ethyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-5-methyl-1,3-thiazole as a yellow oil (3.56 g, yield 68%). NMR (CDCl3) δ: 1.38 (3H, t, J=7.6 Hz), 2.45 (3H, s), 2.98 (2H, q, J=7.6 Hz), 3.63 (3H, s), 5.55 (2H, s), 7.09 (1H, d, J=15.8 Hz), 7.14-7.33 (2H, m), 7.35-7.46 (2H, m), 7.55-7.65 (1H, m), 7.82 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9](C)[C@@:10](C1CCCCC1)([CH2:12][C@@H:13]([CH:16]([CH3:18])[CH3:17])[CH:14]=[CH2:15])[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29](S(O)(=O)=O)=[CH:28][CH:27]=1.[C:37](=O)(O)[O-].[Na+]>COC(OC)(C)C>[CH:26]1([CH2:36][C@H:9]2[C@H:10]([CH2:12][C@@H:13]([CH:16]([CH3:17])[CH3:18])[CH:14]=[CH2:15])[O:11][CH2:37][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C=C[C@@H](C[C@](O)(C1CCCCC1)[C@H](C)NC(=O)OC(C)(C)C)C(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)OC
Product: C=C[C@@H](C[C@@H]1OCN(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1)C(C)C

Procedure:
1.0 g (2.83 mmol) of (αS,βS)-β-t-butoxycarbonylamino-α-[(S)-2-isopropyl-3-butenyl]cyclohexylpropanol in 15 ml of 2,2-dimethoxypropane and 30 mg of p-toluenesulphonic acid is stirred at room temperature overnight. Thereafter, the reaction mixture is poured into 2N sodium bicarbonate solution and extracted three times with 150 ml of ether each time. The ether extracts are washed with water, combined, dried and evaporated, whereby there are obtained 1.2 g of t-butyl (4S,5S)-4-(cyclohexylmethyl)-5-[(S)-2-isopropyl-3-butenyl]-3-oxazolidinecarboxylate as an oil, MS: 393 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[CH:12]=[C:11]([C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:17]([F:20])([F:19])[F:18])=[O:14])[N:10]([CH2:31][CH3:32])[C:6]2=[N:7][C:8]=1[CH3:9].[C:33](Cl)(=[O:35])[CH3:34].Cl>N1C=CC=CC=1>[C:33]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]2[CH:12]=[C:11]([C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:17]([F:18])([F:19])[F:20])=[O:14])[N:10]([CH2:31][CH3:32])[C:6]2=[N:7][C:8]=1[CH3:9])(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(CN)c(C)nc21
Agent: Cl
Solvent: c1ccncc1
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(CNC(C)=O)c(C)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.7 %

Procedure:
5-(Aminomethyl)-1-ethyl-6-methyl-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (70.0 mg, 0.15 mmol) was initially charged in pyridine (1.7 ml), acetyl chloride (14.4 mg, 0.18 mmol) was added and the mixture was stirred at room temperature for 2 hours. Ice-water was added, the reaction mixture was acidified with 2N HCl and the precipitated product was filtered off. After drying, the product was chromatographed using cyclohexane/ethyl acetate (1/1), which gave 5.00 mg (6.5% of theory) of 5-(acetamidomethyl)-1-ethyl-6-methyl-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide. HPLC-MS: log P=3.16; mass (m/z): 501.1 (M+H)+; 1HNMR (D6-DMSO): δ 1.23 (t, 2H), 2.57 (s, 3H), 3.32 (s, 3H), 4.34 (m, 2H), 4.58 (q, 2H), 6.28-6.30 (m, 1H), 7.30 (s, 1H), 7.70-7.87 (m, 2H), 8.05 (d, 1H), 8.20 (s, 1H), 8.25 (m, 1H), 9.68 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.[NH2:29][NH2:30].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[NH:30][N:29]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C(=O)C(Cc2ccccc2)C(=O)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2n[nH]c(-c3ccc(OC)cc3)c2Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A mixture of the 1,3-diketone obtained in step 1 (1.0 equiv.), hydrazine (3.0 equiv.), conc. HCl aq. (catalytic amount) and ethanol was heated to reflux overnight. Cooled to rt and removed solvent in vacuo. Water and ethyl acetate were added. The organic layer was separated, washed with dil. HCl, brine, dried, filtered and the solvent was concentrated in vacuo to give the product 4-methoxy-1-[5-(4-methoxyphenyl)-4-benzylpyrazol-3-yl]benzene.
Reaction SMILES: N(C[C@@H]1O[CH2:9][C@H:7](S)[CH2:6]1)=[N+]=[N-].C(OC(=O)C)C.CCC[CH2:20][CH2:21][CH3:22].[C:23](#[N:25])[CH3:24]>>[CH3:24][CH2:23][N:25]([CH:7]([CH3:6])[CH3:9])[CH:21]([CH3:20])[CH3:22]
Reactant: CC#N
Reactant: [N-]=[N+]=NC[C@H]1C[C@@H](S)CO1
Reactant: CCCCCC
Solvent: CCOC(C)=O
Product: CCN(C(C)C)C(C)C

Procedure:
The title compound is prepared by the procedure of Example 17 using 0.441 gof product from Example 118 in 10 ml of acetonitrile, 1.8 g of product fromExample 15 in 10 ml of acetonitrile and 0.41 ml of Hunig's base to give 0.747 g of the desired product after chromatography (silica gel: 75% ethylacetate/hexane). IR(KBr): 2101, 1769 and 1708 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([S:9]([F:12])(=[O:11])=[O:10])[C:6]([Cl:13])=[CH:5][C:3]=1[NH2:4].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C(O)(=O)CC.N(OS(=O)(=O)O)=O.[CH2:50]([N:52]([CH2:60][CH2:61][C:62]([O:64][CH2:65][CH2:66][CH2:67][C:68]#[N:69])=[O:63])[C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[CH:54]=1)[CH3:51].S(=O)(=O)(O)[NH2:71]>O.CO>[CH3:59][C:55]1[CH:54]=[C:53]([CH:58]=[CH:57][C:56]=1[N:71]=[N:4][C:3]1[CH:5]=[C:6]([Cl:13])[C:7]([S:9]([F:12])(=[O:11])=[O:10])=[CH:8][C:2]=1[Cl:1])[N:52]([CH2:50][CH3:51])[CH2:60][CH2:61][C:62]([O:64][CH2:65][CH2:66][CH2:67][C:68]#[N:69])=[O:63]
Reactant: NS(=O)(=O)O
Reactant: CCN(CCC(=O)OCCCC#N)c1cccc(C)c1
Reactant: Nc1cc(Cl)c(S(=O)(=O)F)cc1Cl
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: O=NOS(=O)(=O)O
Solvent: CO
Solvent: O
Solvent: CCC(=O)O
Product: CCN(CCC(=O)OCCCC#N)c1ccc(N=Nc2cc(Cl)c(S(=O)(=O)F)cc2Cl)c(C)c1
Reaction time: 0.25 h

Procedure:
To a mixture of 2,5-dichloro-4-fluorosulphonylaniline (2 parts) and an acetic/propionic acid mixture (15 parts, 86/14 vol/vol), stirring at 0-5° C., was added dropwise nitrosylsulphuric acid solution (5 parts). The mixture was stirred at this temperature for a further 15 minutes. The diazo solution was added slowly to a mixture of N-ethyl-N-(2-(3-cyanopropoxycarbonyl)ethyl)-3-toluidine (2.6 parts), methanol (50 parts), water (20 parts) and sulphamic acid (0.5 part), stirring at 0-5° C. After stirring for 3 hours at this temperature, the product was isolated by filtration, washed with water and dried at 50° C. to yield 3-methyl-4-(2,5-dichloro-4-fluorosulphonylphenylazo)-N-ethyl-N-(2-(3-cyanopropoxycarbonyl)ethyl)aniline (2.6 parts). When applied to polyester materials from an aqueous dispersion, the dye (λmax=515 nm) gives bluish-red shades with excellent light fastness and excellent fastness to wet treatments.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](Cl)=[O:7].[Cl:14][C:15]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:16]=1[O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:30]([O-:32])=[O:31])=[C:22]([CH:29]=1)[C:23]([O:25][CH2:26][CH2:27][OH:28])=[O:24].N1C=CC=CC=1>C(Cl)Cl>[Cl:14][C:15]1[CH:36]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:34]=[CH:33][C:16]=1[O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:30]([O-:32])=[O:31])=[C:22]([CH:29]=1)[C:23]([O:25][CH2:26][CH2:27][O:28][C:6](=[O:7])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=1[Cl:1])=[O:24]
Reactant: O=C(OCCO)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(COc1ccc(Cl)cc1Cl)OCCOC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 1.5 %

Procedure:
2,4-Dichlorophenoxyacetyl chloride (5.3 g, 0.25 mole), was added portionwise to a solution of 2-hydroxyethyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate (10 g, 0.25 mole) and pyridine (70 ml). The resulting mixture was heated to 60° C. for 1 hr., cooled and taken into 500 ml CH2Cl2. The methylene chloride solution was washed two times with water, dried and concentrated to 12.5 g of gummy material. The crude gum was chromatographed through silica gel (3:10, ethyl acetate:hexane) to give 2.3 g of pure 2-(2,4-dichlorophenoxyacetoxy)ethyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate; nmr (DMSO) 4.20-4.76 (m, 4H), 5.04 (S, 2H), 6.96-8.42 (m, 9H); ir (CHCl3) 1755, 1770 Cm-1.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:14][CH2:13]1.CC(=O)OCC>C(#N)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:15]1[CH2:16][CH2:17][N:12]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:13][CH2:14]1
Reactant: c1ccc(C2CCNCC2)nc1
Reactant: ClCc1nc2cccnc2s1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: c1ccc(C2CCN(Cc3nc4cccnc4s3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 38A (50 mg, 0.11 mmol), 2-(4-piperidinyl)pyridine (25 mg, 0.13 mmol), and D1 EA (340 μL, 2.1 mmol) were combined in acetonitrile (1 mL) and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was treated with hot methanol. The methanol was filtered and the filter cake washed with cold methanol to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.13 (m, 4H), 3.13 (m, 4H), 3.61 (m, 3H), 7.38 (d, J=4.75 Hz, 1H), 7.76 (dd, J=8.3 Hz, 4.6 Hz, 1H), 7.91 (m, 1H), 8.31 (m, 1H), 8.54 (m, 2H), 8.72 (dd, J=4.6 hz, 1.53 Hz, 1H); (ESI) nil/z 311 (M+H)+.