Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([NH2:14])[C:6]([NH2:13])=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].C([O:21][C:22](=O)[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:38][C:34]1[CH:33]=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:21])[NH:13][C:6]4[CH:7]=[C:8]([C:9]([F:12])([F:11])[F:10])[C:3]([C:2]([F:15])([F:16])[F:1])=[CH:4][C:5]=4[N:14]=3)[CH:31]=[CH:30][CH:29]=2)[CH:37]=[CH:36][N:35]=1
Reactant: Nc1cc(C(F)(F)F)c(C(F)(F)F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(C(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from 4,5-bis-trifluoromethyl-benzene-1,2-diamine [CAS-No. 30454-92-3] (244 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) in toluene (10 ml) under reflux conditions for 2 h according to the general procedure M and subsequent treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (304 mg, 66%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH2:4][N:3]1[CH:13]1[CH2:18][CH2:17][N:16](C(OCC2C=CC=CC=2)=O)[CH2:15][CH2:14]1.[H][H]>C(O)C.[Pd]>[NH:16]1[CH2:15][CH2:14][CH:13]([N:3]2[CH2:4][CH:5]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[NH:6][C:2]2=[O:1])[CH2:18][CH2:17]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CCC(N2CC(c3ccncc3)NC2=O)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C1NC(c2ccncc2)CN1C1CCNCC1
Reaction time: 16 h

Procedure:
A solution of benzyl 4-(2-oxo-4-pyridin-4-ylimidazolidin-1-yl)piperidine-1-carboxylate (55 mg, 0.145 mmol) in ethanol (15 mL) was hydrogenated at 1 atm hydrogen over palladium on carbon (50 mg). After 16 h, the reaction was filtered and concentrated to give the title product. MS 247.2 (M+1)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[CH:30]=[C:31]([S:35]([NH:38][C:39]([CH3:43])([CH3:42])[CH2:40][OH:41])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[OH:41][CH2:40][C:39]([NH:38][S:35]([C:31]1[CH:30]=[C:29]([NH:28][C:25]([C:24]2[CH:23]=[N:22][N:15]3[C:16]([C:18]([F:19])([F:21])[F:20])=[CH:17][C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:11])[F:10])=[C:2]([CH3:1])[CH:3]=4)=[N:13][C:14]=23)=[O:26])[CH:34]=[CH:33][CH:32]=1)(=[O:37])=[O:36])([CH3:43])[CH3:42]
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)NC(C)(C)CO)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Yellow solid. MS (ISP) 614.2 [(M−H−]; mp 230° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=C[CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][NH:5]2.[H-].[Na+].[Cl:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:17]=1[CH2:18]Br.C[N:27](C=O)C>>[Br:1][C:2]1[CH:11]=[N:27][C:9]2[NH:8][C:7](=[O:12])[CH2:6][N:5]([CH2:18][C:17]3[C:20]([F:25])=[CH:21][CH:22]=[C:23]([F:24])[C:16]=3[Cl:15])[C:4]=2[CH:3]=1
Reactant: Fc1ccc(F)c(CBr)c1Cl
Reactant: O=C1CNc2cc(Br)ccc2N1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: O=C1CN(Cc2c(F)ccc(F)c2Cl)c2cc(Br)cnc2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71 %

Procedure:
To a solution of 6-bromo-3,4-dihydro-1H-quinoxalin-2-one (228 mg, 1.00 mmol) in DMF (10 mL) was added NaH (40 mg of a 60% dispersion in mineral oil, 1.00 mmol) and the resulting mixture sonicated for 5 minutes. After stirring at room temperature for 20 minutes, 2-chloro-3,6-difluorobenzylbromide (242 mg, 1.00 mmol) was added and the mixture was stirred for 20 minutes. Solvent was reduced 90% and the residue was triturated with ether (3×1 mL) and water (2×2 mL) to give the title compound (275 mg, 71%). m.p. 214-216° C. (dec); LCMS: m/z=388/390/392 (M+H+); 1H-NMR (DMSO-d6, 400 MHz) δ 7.73 (s, 1H), 7.47-7.42 (m, 1H), 7.35 (s, 1H), 7.32-7.26 (m, 1H), 7.11 (s, 1H), 5.24, (s, 2H), 4.01 (s, 2H).
Reaction SMILES: C([C:5](O[SiH](C)C)([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]1[C@@H:19]([CH:20]=[CH:21][CH2:22][C:23]([CH3:30])([O:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:17][C:16]1=[O:31])[C:6]([O:8][CH3:9])=[O:7])CCC.C1C[O:39]CC1.[OH2:41]>CC(O)=O.O>[OH:41][C@H:18]1[C@H:19]([CH:20]=[CH:21][C@@H:22]([OH:39])[C@:23]([CH3:30])([O:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])[C@@H:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:5][C:6]([O:8][CH3:9])=[O:7])[C:16](=[O:31])[CH2:17]1
Reactant: C1CCOC1
Reactant: O
Reactant: CCCCC(C)(CC=C[C@H]1CCC(=O)[C@@H]1CCCCCC(CCCC)(O[SiH](C)C)C(=O)OC)OC
Solvent: CC(=O)O
Product: CCCC[C@@](C)(OC)[C@H](O)C=C[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC

Procedure:
A mixture of (8R,11R,12R,15R,16R)11,15-di-t.butyl-dimethylsilyloxy-16-methyl-16-methoxy-9 -oxo-prost-13-en-1-oic acid, methyl ester (0.045 g, 0.07 mmol) in 0.5 ml of HOAc/H2O)/THF: 3/1/1) was stirred for 48 h at room temperature. After adding more water (5 ml), the mixture was neutralized by addition of an aqueous solution of Na2HPO4, and extracted with Et2O (2×10 ml). The combined organic layers were washed with aqueous NaHCO3, water and then brine, dried (MgSO4) and flash evaporated to afford crude (8R,11R,12R,15R,16R)11,15-Dihydroxy-16-methyl-16-methoxy-9-oxo-prost-13-en-1-oic acid, methyl ester. Final purification was achieved by chromatography on 10 g of silicagel (eluant EtOAc).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([NH:20][C:21]([C:23]1[C:24]([CH3:36])=[N:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)=[N:27][CH:28]=1)=[O:22])[CH:15]=[CH:14]2.C(N(CC)CC)C>C(Cl)Cl>[C:1]([NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([NH:20][C:21]([C:23]1[C:24]([CH3:36])=[N:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)=[N:27][CH:28]=1)=[O:22])[CH:15]=[CH:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc(N)ccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc(NC(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
A solution of benzoyl chloride (0.85 mmol) in anhydrous DCM (2 mL) is added drop-wise to a solution of 4-methyl-2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (5-amino-indol-1-yl)-amide (0.47 mmol) and triethylamine (1.41 mmol) in anhydrous DCM (16 mL) and the mixture is stirred at rt overnight. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc (25 mL), and washed with water (2×20 mL) and brine (10 mL). The organic layer is dried (Na2SO4), filtered and concentrated. The residue is triturated with EtOAc to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-benzoylamino-indol-1-yl)-amide (95 mg, 43%) as a solid. MS: 466 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.99(s, 3H), 6.72(d, H), 7.38-7.48(m, H), 7.48-7.80(m, 6H), 7.83-8.016(m, 3H), 8.07-8.20(m, H), 8.23-8.35(m, 2H), 9.24(s, H), 10.25(br, H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=S)=[CH:15][CH:14]=1>CO.O=[Hg]>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[O:7][C:6]([C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=3)=[N:8][N:9]=2)=[CH:15][CH:14]=1
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: O=[Hg]
Solvent: CO
Product: Oc1ccc(-c2nnc(Nc3ccc(Cl)cc3)o2)cc1
Temperature: 25 °C

Procedure:
Mercury (II) oxide yellow (6.38 g, 29.47 mmol) was suspended in ca. 70 mL of anhydrous methanol. 4-Hydroxybenzoic acid hydrazide (4.48 g, 29.47 mmol) was added to this bright-orange suspension, followed by 4-chlorophenylisothiocyanate (5.0 g, 29.47 mmol). The reaction mixture was brought to reflux and refluxed for 2 hours. The reaction mixture turned pitch-black in color and formed black precipitate. Then it was cooled down to ambient temperature and filtered through a short pad of Celite, then through a short pad of silica gel. Then methanol was removed in vacuo and the resulting grey precipitate was re-crystallized from ca. 40 mL of EtOAc. The formed white precipitate was filtered, washed with a small amount of EtOAc and dried in vacuo to give the title product as a white powder.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[Mg].Br[C:7]1[CH:8]=[C:9]([CH3:14])[CH:10]=[C:11]([CH3:13])[CH:12]=1.[CH2:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C:16]1=[O:24]>C1COCC1.CCOCC>[C:7]1([C:16]2([OH:24])[CH2:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15]2)[CH:8]=[C:9]([CH3:14])[CH:10]=[C:11]([CH3:13])[CH:12]=1
Reactant: O=C1Cc2ccccc2C1
Reactant: Cc1cc(C)cc(Br)c1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C)cc(C2(O)Cc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A suspension of anhydrous cerium chloride (43.88 g, 178.1 mmol) in THF (250 mL) was stirred at room temperature for 2 hours under nitrogen. A solution of 3,5-m-xylenylmagnesium bromide (178 mmol, prepared from magnesium (4.33 g, 178.1 mmol) and 5-bromo-m-xylene (24.2 mL, 178.1 mmol) in ether (60 mL) was added at 0° C. and stirred for 3.5 h. A solution of 2-indanone (14.21 g, 107.7 mmol) in THF (20 mL) was added at the same temperature. After stirring at 0° C. for 3 h, the mixture was allowed to warm to room temperature and kept at ambient temperature for 12 h. It was then treated with 5% aqueous hydrochloric solution. The solution was extracted with diethyl ether (4*200 mL). All etheral layers were combined, washed with water (100 mL), dried over anhydrous magnesium sulphate and concentrated to give the crude product. 2-Indanone was distilled out at 80° C. (0.3 mm Hg). The residue was washed with pentane (50 mL) to yield 21.57 g of 2-(3,5-xylenyl)-2-indanol in solid form.
Reaction SMILES: [CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:27]#[N:28])=[CH:22][CH:23]=[C:24]([CH3:26])[CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:33].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[C:21]([C:27]#[N:28])=[CH:22][CH:23]=[C:24]([CH3:26])[CH:25]=4)=[CH:18][CH:19]=3)[C:8](=[O:12])[N:9]([CH2:31][C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[O:33])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4cc(C)ccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4cc(C)ccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-5-methylbiphenyl-2-carbonitrile (2 g), 2-bromo-1-(4-methoxyphenyl)ethanone (1.4 g) and N,N-dimethylformamide (19 mL) was added 60% sodium hydride (0.3 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.2 g, 80%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH:23][CH2:24][CH2:25][CH:26]=[CH2:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[CH2:16]([N:23]([CH2:24][CH2:25][CH:26]=[CH2:27])[C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH:14]=[CH2:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=CCCNCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: C=CCCN(Cc1ccccc1)C(=O)[C@H](CC=C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.5 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (400 mg, 1.86 mmol), N-benzylbut-3-en-1-amine (449 mg, 2.79 mmol) in DMF (5 mL) was added EDC (410 mg, 2.14 mmol), HOBt (370 mg, 2.42 mmol) and followed by TEA (0.259 mL, 1.858 mmol). The reaction was stirred at rt for 3 days. The reaction was diluted with EtOAc and washed with water (2×), 1 M aqueous KHSO4 (2×), saturated aqueous NaHCO3 (2×) and saturated aqueous NaCl. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-60% EtOAc/Hex to give (S)-tert-butyl 1-(benzyl(but-3-enyl)amino)-1-oxopent-4-en-2-ylcarbamate (270 mg, 0.753 mmol, 40.5% yield). Anal. Calcd. for C21H30N2O3 m/z 358.4. found: 359.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.43-7.13 (m, 5H), 5.85-5.62 (m, 2H), 5.40-5.27 (m, 1H), 5.19-4.97 (m, 3H), 4.87 and 4.37 (d, J=14.9 Hz, 1H), 4.76-4.51 (m, 2H), 3.59-3.22 (m, 3H), 2.39 (ddq, J=25.6, 21.3, 7.1 Hz, 4H), 1.44 and 1.42 (s, 9H).
Reaction SMILES: C(C1C=CC([C:10]2[C:29]3[NH:30][C:26](=[CH:27][CH:28]=3)[C:25](C3C=CC(C(O)=O)=CC=3)=[C:24]3[N:40]=[C:21]([CH:22]=[CH:23]3)[C:20](C3C=CC(C(O)=O)=CC=3)=[C:19]3[NH:50][C:16]([CH:17]=[CH:18]3)=[C:15](C3C=CC(C(O)=O)=CC=3)[C:14]3=[N:60][C:11]=2[CH:12]=[CH:13]3)=CC=1)(O)=O.N1C=CC=CC=1.ClC(OCC(C)C)=O>CS(C)=O>[C:26]12[CH:25]=[C:24]3[N:40]=[C:21]([CH:22]=[CH:23]3)[CH:20]=[C:19]3[NH:50][C:16]([CH:17]=[CH:18]3)=[CH:15][C:14]3=[N:60][C:11]([CH:12]=[CH:13]3)=[CH:10][C:29]([NH:30]1)=[CH:28][CH:27]=2
Reactant: O=C(O)c1ccc(-c2c3nc(c(-c4ccc(C(=O)O)cc4)c4ccc([nH]4)c(-c4ccc(C(=O)O)cc4)c4nc(c(-c5ccc(C(=O)O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Agent: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3

Procedure:
The synthesis was performed in a three-necked flask under nitrogen. 50 mg of mezo-tetra(4-carboxyphenyl)porphine (4CP) was dissolved in 5 ml of dry DMSO, the catalysts, i.e. 120 μl of pyridine and 30 μl of isobutyl chloroformate, were added and after 5 minutes a suspension of 0.5 g Cloisite 30 B in 15 ml of dry DMSO was added. The reaction mixture was mixed at 70° C. for 4 hours. The product obtained was filtered on a Buchner funnel with a sintered glass disc and washed with methanol till the transparent filtrate was obtained and then the product was dried in a vacuum dryer. A green powder was obtained.
Reaction SMILES: [CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:3]1[CH:4]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:14])=O)=[CH:8]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1.[C:50]([O:55][CH2:56][CH3:57])(=[O:54])[C:51]#[C:52][CH3:53].C(P(CCCC)CCCC)CCC>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:3]1[CH:4]=[C:5]([O:15][C:16]([F:17])([F:19])[F:18])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:37][CH:52]([CH2:51][C:50]([O:55][CH2:56][CH3:57])=[O:54])[CH2:53][N:14]=1)=[CH:8]2
Reactant: CN(c1cc(OC(F)(F)F)cc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(OC(F)(F)F)cc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
A mixture of 7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxamide (1.15 g), Lawesson's reagent (1.09 g) and tetrahydrofuran (20 mL) was stirred at 50° C. for 30 min. The reaction mixture was concentrated, and the residue was washed with diisopropyl ether to give pale-yellow crystals. A mixture of the obtained crystals, ethyl but-2-ynoate (710 mg), tributylphosphine (510 mg), toluene (30 mL) and tetrahydrofuran (15 mL) was stirred at 50° C. for 2 hr. ethyl but-2-ynoate (710 mg) and tributylphosphine (510 mg) were added to the mixture, and the mixture was further stirred at room temperature for 2.5 days. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-3:1, volume ratio). The obtained crystals were washed with hexane to give the title compound (600 mg, yield 41%) as pale-yellow crystals. melting point 93-94° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[N:22][N:23]=[C:17]2[CH:16]1[C:32]1[O:36][N:35]=[C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[N:33]=1)=O)(C)(C)C>ClCCl>[Cl:43][C:39]1[CH:38]=[C:37]([C:34]2[N:33]=[C:32]([CH:16]3[NH:15][CH2:20][CH2:19][N:18]4[C:21]([C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)=[N:22][N:23]=[C:17]34)[O:36][N:35]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: COc1ccc(-c2nnc3n2CCN(C(=O)OC(C)(C)C)C3c2nc(-c3cccc(Cl)c3)no2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2nnc3n2CCNC3c2nc(-c3cccc(Cl)c3)no2)cc1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of 8-[3-(3-chloro-phenyl) -[1,2,4]oxadiazol-5-yl]-3-(4-methoxy-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine-7-carboxylic acid tert-butyl ester (72.5 mg, 0.14 mmol) in dichloromethane (1 mL) at 0° C. The reaction mixture was then diluted with dichloromethane, After 15 minutes, the reaction was warmed to room temperature and stirred for an additional hour. washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated. Purification was performed by flash column chromatography on silica gel using 85-90% ethyl acetate in hexanes to 2% ammonia in methanol in dichloromethane followed by trituration with diethyl ether to afford the titled compound (40.6 mg, 69%). 1H NMR (CDCl3) δ (ppm): 8.10 (m, 1H), 8.00 (m, 1H), 7.67 (m, 2H), 7.48 (m, 2H), 7.05 (m, 2H), 7.86 (m, 1H), 4.09 (m, 3H), 3.89 (s, 3H), 3.47 (m, 2H), 3.24 (m, 1H), 2.83 (bs, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Cl:15])[CH:9]=1)(=[O:5])[CH3:4].[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21]Cl.O>O1CCCC1.CN(C)C=O>[C:3]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:10]([Cl:15])[CH:9]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)OCc1ccc(O)c(Cl)c1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOCOc1ccc(COC(C)=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 64.4 %

Procedure:
2.75 g (68.4 mmol) of 60% sodium hydride is added in portions to a solution at 0° C. of 11 g (57 mmol) of (3-chloro-4-hydroxy-phenyl)-methyl acetate diluted in 60 ml of tetrahydrofuran and 60 ml of dimethylformamide. The reaction mixture is stirred at room temperature for 45 minutes and then 7.2 ml (62.7 mmol) of 2-methoxyethoxymethyl chloride is added dropwise. The reaction mixture is stirred at room temperature for 2 hours and then the reaction mixture is treated by adding water and extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated. The raw product is purified by silica column chromatography, eluted with a heptane/ethyl acetate mixture 70/30. 10.6 g (66%) of [3-chloro-4-(2-methoxy-ethoxymethoxy)-phenyl]-methyl acetate is obtained in the form of a colorless oil.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:11])[N:5]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C1(P(=[CH:38][C:39]([O:41][CH3:42])=[O:40])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:42][O:41][C:39](=[O:40])[CH:38]=[CH:2][CH2:3][CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:11])[N:5]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)N1C(=O)CCCCC1CC=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C=CCC1CCCCC(=O)N1C(=O)OC(C)(C)C

Procedure:
Example 209) The crude aldehyde of this Example, part B above, is dissolved in toluene and treated with 1.2 equivalents of methyl (triphenylphosphoranylidene)acetate. The mixture is refluxed for four hours. After cooling, the mixture is concentrated and the residue is triturated with several volumes of pentane to remove the phosphorous salts. The extracts are filtered and stripped of all solvent. The crude residue is then purified by column chromatography to give the title product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)N.[CH2:9]([N:11](CC)CC)[CH3:10].S(OCC)(OCC)(=O)=O.O>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:9][NH2:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCN(CC)CC
Reactant: Nc1cccc(Br)c1
Agent: CCOS(=O)(=O)OCC
Solvent: CCOCC
Solvent: O
Product: NCCc1cccc(Br)c1
Reaction time: 192 h

Procedure:
5 g (29.1 mmol) of 3-bromoaniline in 500 ml of ether are introduced into a round-bottomed flask under a stream of nitrogen. 4.5 ml (32 mmol) of triethylamine and 15.2 ml (117 mmol) of diethyl sulfate are added. The medium is refluxed for 24 hours and then left for 8 days at room temperature. It is then poured into water and extracted with ether. The organic phase is washed with saturated aqueous sodium chloride solution and is then dried over magnesium sulfate, filtered and evaporated. The residue is purified by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (95/5) and 2.5 g (43%) of the expected product are obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[C:19]([CH3:29])[C:20]3[O:24][C:23]([C:25](O)=[O:26])=[CH:22][C:21]=3[CH:28]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30].C(Cl)CCl.Cl.C[O:40][C:41](=[O:44])[CH2:42][NH2:43]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:33][C:2]([CH3:1])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[C:19]([CH3:29])[C:20]3[O:24][C:23]([C:25]([NH:43][CH2:42][C:41]([OH:40])=[O:44])=[O:26])=[CH:22][C:21]=3[CH:28]=2)([CH2:13][CH3:14])[CH2:15][CH3:16])=[CH:8][C:7]=1[CH3:30]
Reactant: COC(=O)CN
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c2oc(C(=O)O)cc2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c2oc(C(=O)NCC(=O)O)cc2c1
Yield: 97.4 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-7-methyl-benzofuran-2-carboxylic acid (360 mg, 0.799 mmol) in CH2Cl2 (10 ml) and DMAP (293 mg, 2.40 mmol), EDC (230 mg, 1.20 mmol), and glycine methyl ester hydrochloride (150 mg, 1.20 mmol) are reacted and hydrolyzed analogous to Example 7 to yield title compound (395 mg, 97%).