Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][C@H:9]([NH2:13])[C:10]([OH:12])=[O:11].S(OC)(O[CH3:17])=O.[Cl:20][Si](C)(C)C>CO>[ClH:20].[NH2:13][C@@H:9]([CH2:8][CH2:7][CH2:6][CH:2]([O:3][CH3:4])[O:1][CH3:5])[C:10]([O:12][CH3:17])=[O:11]
Reactant: N[C@@H](CCCC1OCCO1)C(=O)O
Reactant: C[Si](C)(C)Cl
Reactant: COS(=O)OC
Solvent: CO
Product: COC(=O)[C@@H](N)CCCC(OC)OC
Product: Cl
Temperature: 41 °C
Reaction time: 8 h

Procedure:
To a 250 mL, 3 neck flask equipped with a mechanical agitator, thermocouple, heating mantle, condenser, nitrogen inlet and vent, 5-(1,3-dioxolan-2-yl)-(S)-2-amino-pentanoic acid (100 g), methanol (1200 mL) and dimethyl sulfite (44.8 mL) were charged. Chlorotrimethyl silane (168 mL) was added to the resulting slurry and the reaction mixture was heated at 40 to 42° C. for about 8 hours, followed by stirring at ambient temperature for eight hours to afford a solution of (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester hydrochloride salt (in-process quantitation 100.9 g, 93 M %). Potassium bicarbonate (208.6 g) as slurried in methanol (400 mL) contained in a 5-L three neck flask and the reaction mixture containing the hydrochloride salt of (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester, was neutralized by adding it to the potassium bicarbonate slurry (over 1.5 hours) maintaining the pH of mixture above 6.9. The solvent of the resulting slurry was replaced with n-butyl acetate by vacuum distillation (50 to 60 mmHg and 30 to 40° C.) maintaining a pot volume of about 2 L. After 2.25 L of n-butyl acetate was distilled, methanol (1.25 L) was added to the distillation vessel and the distillation was continued, maintaining a pot volume of NLT 2 L, until the water content of the slurry supernatant was <0.05 wt % and the methanol level was <5 relative area %. Hexane (1.5 L) was charged to the resulting slurry and it was then cooled to −5° C. After stirring the mixture for 1 hour, it was filtered and the filter-cake was washed with hexane (2×100 mL). The resulting hazy filtrate was polish filtered to afford a clear filtrate. The clear filtrate was warmed to 20 to 25° C. and a methanolic (1333 mL) solution of oxalic acid dihydrate (33.3 g) was added slowly over about 2 hours. The resulting slurry of (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester oxalic acid salt (2:1) was agitated for 18 hours at ambient temperature and the product was collected on a filter. The product wet-cake was washed with acetonitrile (4×100 mL) and dried under vacuum at 45° C. to afford 103.2 g (78 M %) of (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester oxalic acid salt (2:1) having a free base potency of 84 wt % (vs. lab standard, theo.=82 wt %) and an HPLC AP of 100.
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C([Li])CCC.[CH3:16][N:17]([CH3:37])[CH2:18][CH2:19][C:20]1([CH:35]=O)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][CH2:23][C:22]2[CH:31]=[CH:32][CH:33]=[CH:34][C:21]1=2>C1COCC1.CCCCCC.C(OCC)C>[S:4]1[CH2:5][CH2:6][CH2:7][S:8][C:3]1=[CH:35][C:20]1([CH2:19][CH2:18][N:17]([CH3:37])[CH3:16])[C:21]2[CH:34]=[CH:33][CH:32]=[CH:31][C:22]=2[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]1=2
Reactant: C[Si](C)(C)C1SCCCS1
Reactant: CN(C)CCC1(C=O)c2ccccc2CCc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CN(C)CCC1(C=C2SCCCS2)c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-trimethylsilyl-1,3-dithiane (2.5 mL, 12.8 mmol) in 10 mL of THF stirred at −78° C. and maintained under a nitrogen atmosphere was added butyllithium (5.1 mL of a 2.5M solution in hexane; 12.8 mmol) dropwise. The mixture was stirred in the cold for 20 minutes and then treated with 5-(2-dimethylamino-ethyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-carbaldehyde (102), 3.1 g in 20 mL of THF; 10.6 mmol) added dropwise. The solution was stirred for 1.5 hours at −78° C., warmed to ambient temperature and stirred an additional 1.5 hours. The solution was diluted with ethyl ether and quenched with saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride (1×), saturated aqueous sodium bicarbonate (1×), and brine (1×), dried the over sodium sulfate, filtered, and evaporated to dryness. The resulting oil was purified by chromatography on silica gel (95:5 of methylene chloride:methanol). The product fractions were evaporated to dryness to yield the title product as an oil.
Reaction SMILES: [Si]([O:8][C:9]1[C:16]([CH2:17][CH2:18][CH3:19])=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[N+:20]([O-:22])=[O:21])(C(C)(C)C)(C)C.[C:23]1([C:29](=O)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[NH2:38][C:39]([NH2:41])=[O:40].Cl>C(O)C>[OH:8][C:9]1[C:16]([CH2:17][CH2:18][CH3:19])=[CH:15][C:12]([CH:13]2[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:41][C:39](=[O:40])[NH:38]2)=[CH:11][C:10]=1[N+:20]([O-:22])=[O:21]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: NC(N)=O
Reactant: CCCc1cc(C=O)cc([N+](=O)[O-])c1O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCCc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 15.8 %

Procedure:
To a solution of 4-(tert-butyldimethylsilyloxy)-3-nitro-5-propylbenzaldehyde (Intermediate 81) (100 mg, 0.31 mmol), 1,2-diphenylethanone (78 mg, 0.40 mmol) and urea (60 mg, 1.0 mmol) in ethanol (5 mL) was added conc. HCl (0.2 mL) and the reaction mixture was refluxed under N2 atmosphere overnight. Reaction was cooled and then purified by prep-HPLC (0.1% TFA as additive). The solution was concentrated under reduced pressure to give Compound 156 as a yellow solid (21 mg, yield 16%). 1H NMR (CD3OD 400 MHz): δ 7.95 (d, J=2.0 Hz, 1H), 7.52 (s, 1H), 7.26 (m, 5H), 7.06-7.03 (m, 3H), 6.89-6.86 (m, 2H), 5.39 (s, 1H), 2.70 (t, J=7.6 Hz, 2H), 1.66-1.59 (m, 2H), 0.93 (t, J=7.2 Hz, 3H). MS (ESI): m/z 430.2 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([Cl:9])[CH:3]=1.C(O[C:13]1(O[Si](C)(C)C)[CH2:15][CH2:14]1)C.[BH4-].[Na+]>CC(O)=O.CO.C1COCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:13]2[CH2:15][CH2:14]2)=[C:4]([Cl:9])[CH:3]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Nc1ccc(Br)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: Clc1cc(Br)ccc1NC1CC1
Temperature: 68 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-chloroaniline (C.A.S. 38762-41-3), (1 g, 4.843 mmol) in AcOH (19 ml) and MeOH (10 mL) was added [(1-ethoxycyclopropyl)oxy]-trimethylsilane (1.199 ml, 5.57 mmol) dropwise at r.t. The reaction mixture was then refluxed at 67-69° C. for 3 h. under a N2 atmosphere. The mixture was then concentrated in vacuo to obtain a crude oil. Into a 200 mL four-necked flask fitted with a reflux condenser, a mechanical stirrer and a thermometer were added NaBH4 (0.366 g, 9.687 mmol) and anhydrous THF (10 mL). After cooling to 5° C., BF3.Et2O complex (1.228 ml, 9.687 mmol) was added dropwise and the mixture stirred under a N2 atmosphere at 5° C. for 1 h. The crude oil dissolved in THF (5 mL), was added dropwise at 5-10° C. over 20 min. After stirring at r.t. for 5 h, at reflux for 2 h. and then removing THF by distillation, the mixture was cooled to r.t. and poured into water. The resulting mixture was extracted with Et2O. The Et2O layer was washed with water and dried (Na2SO4) followed by the removal of Et2O in vacuo. The crude product thus obtained was purified by column chromatography (silica gel; Heptane/AcOEt 99:1 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D34 (0.390 g, 32.6%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([NH2:15])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]3[O:14][C:17](=[O:19])[NH:15][C:10]=3[CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(O)c(N)c2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(c2ccc3oc(=O)[nH]c3c2)CC1
Yield: 89.3 %

Procedure:
To a solution of 1-(3-amino-4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester (2.0 g, 9.6 mmol) in THF (40 mL) was added triphosgene (4.2 g, 14 mmol) at room temperature. The mixture was stirred for 20 minutes at this temperature before water (20 mL) was added dropwise at 0° C. The resulting mixture was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-cyclopropanecarboxylic acid methyl ester (2.0 g, 91%), which was directly used in the next step. 1H NMR (CDCl3, 300 MHz) δ 8.66 (s, 1 H), 7.13-7.12 (m, 2 H), 7.07 (s, 1 H), 3.66 (s, 3 H), 1.68-1.65 (m, 2 H), 1.24-1.20 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:13]([N:15]([CH2:18]C)CC)[CH3:14].CN(C)C=[O:23]>>[C:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:18]([NH:15][CH2:13][CH3:14])=[O:23])[S:3][C:4]=2[CH:10]=1)#[N:12]
Reactant: CCN(CC)CC
Reactant: N#Cc1ccc2nc(N)sc2c1
Reactant: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(C#N)cc2s1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
2-Amino-1,3-benzothiazole-6-carbonitrile is dissolved in a polar aprotic solvent, preferrably dimethylformamide. R3NCO is added, followed by an alkyl amine base, preferably triethylamine and the solution is heated to about 70–90° C., preferably about 80° C., under good agitation. The solution is allowed to stir for about 4–8 hours, preferably about 4 hours, then cooled to room temperature. The solvent is removed in vacuo and the solids are washed well with ether. The product is further purified by column chromatography and after drying in vacuo, the title product is isolated.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:34]=[C:33](Cl)[CH:32]=[CH:31][C:22]=1[CH:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N1CC(OC(C2C=CC(Cl)=CC=2)C2C=CC([Cl:63])=CC=2Cl)C1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH:23]([C:24]2[CH:29]=[CH:28][C:27]([Cl:63])=[CH:26][CH:25]=2)[C:22]2[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=2[C:20]([F:37])([F:36])[F:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2Cl)cc1
Reactant: OC(c1ccccc1)c1ccc(Cl)cc1C(F)(F)F
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Product: FC(F)(F)c1ccccc1C(OC1CN(C(c2ccccc2)c2ccccc2)C1)c1ccc(Cl)cc1

Procedure:
This material was prepared from 1-benzhydryl-3-azetidinol (1) (40.1 mmol) and 2-(trifluoromethyl)-4-chlorobenzhydrol (96) (80.2 mmol) using the procedure described for compound (3) (13.5 g, 66%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Li+].[H][H].Cl[CH2:15]/[CH:16]=[CH:17]\[CH2:18]Cl>O.CN(C)C=O>[CH3:6][O:5][C:3]([C:2]1([C:1]([O:8][CH3:9])=[O:7])[CH2:18][CH:17]=[CH:16][CH2:15]1)=[O:4]
Reactant: COC(=O)CC(=O)OC
Reactant: [H][H]
Reactant: ClC/C=C\CCl
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(C(=O)OC)CC=CC1
Temperature: 0 °C

Procedure:
The dimethyl diester 1 was prepared employing Deprés and Greene's procedure. To a flame dried round-bottomed flask was placed dimethyl malonate (ACROS, 99+%, 26.7 g, 23.1 mL, 200 mmol) and anhydrous dimethylformamid (DMF, 300 mL). The mixture was cooled to 0° C. under an atmosphere of nitrogen while stirring. To this solution was then added lithium hydride (ACROS, 98%, 4.06 g, 500 mmol) powder in one portion. The resulting mixture was allowed to stir at 0° C. until the evolution of hydrogen ceased (˜3 hours). To this heterogeneous mixture was then slowly added cis-1,4-dichloro-2-butene (ACROS, 95%, 30 g, 25.3 mL, 228 mmol). The resulting mixture was allowed to slowly come to room temperature and then allowed to stir for 72 hours (the color of the heterogeneous mixture changed from white to brown overnight). The reaction progress was monitored by TLC (silica gel, 20% ethyl ether/hexanes). The reaction mixture was diluted with 20% ethyl ether/hexanes (500 mL) and the solution poured into cold water (350 mL). The organic phase was separated, washed successively with water (300 mL) and brine (300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a light yellow solid. The crude material was recrystallized from refluxing hexanes (or ethyl ether). The desired dimethyl diester 1 was obtained as white needles in 50% yield. Mp (DSC) 63.48° C.; 1H-NMR (CDCl3, 300 MHz) δ 5.56 (s, 2H), 3.68 (2s, 6H), 2.97 (s, 4H); 13C-NMR (CDCl3, 300 MHz) δ 172.47, 127.64, 58.60, 52.66, 40.78; FT-IR (CH2Cl2) (cm−1) 3061, 2955, 1733, 1624, 1436, 1266, 1076, 975.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@H:23]4[C@H:19]([O:20]C(C)(C)[O:22]4)[C@@H:18]([CH2:26][N:27]([CH3:48])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]5[NH:38][C:37]6[CH:39]=[CH:40][C:41]([C:43]7([CH3:47])[CH2:46][CH2:45][CH2:44]7)=[CH:42][C:36]=6[N:35]=5)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.FC(F)(F)C(O)=O.O.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@@H:16]3[CH2:17][C@H:18]([CH2:26][N:27]([CH3:48])[CH:28]4[CH2:29][CH:30]([CH2:32][CH2:33][C:34]5[NH:38][C:37]6[CH:39]=[CH:40][C:41]([C:43]7([CH3:47])[CH2:44][CH2:45][CH2:46]7)=[CH:42][C:36]=6[N:35]=5)[CH2:31]4)[C@@H:19]([OH:20])[C@H:23]3[OH:22])[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(C6(C)CCC6)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: CN(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C4(C)CCC4)ccc3[nH]2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 3.1 %

Procedure:
N-(2,4-dimethoxybenzyl)-7-((3aS,4R,6R,6aR)-2,2-dimethyl-6-((methyl(3-(2-(5-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (128 mg, 0.17 4 mmol) was dissolved in a mixture of Trifluoroacetic Acid (3.60 ml, 46.7 mmol) and Water (0.4 ml, 20 mmol) which had been pre-cooled at 0° C. in an ice bath. The solution was stirred at 0° C. for 30 minutes, then the ice bath was removed and the mixture was warmed to RT at which this temperature was maintained for a further 2.5 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in 3 ml MeOH and concentrated and the process was repeated twice. The resultant white residue was placed on high vacuum. The crude residue was combined with another batch of crude material (prepared identically, ˜⅓ of the amount used in this reaction), diluted with 5 mL MeOH, treated with 140 mg K2CO3, 10 drops of H2O and allowed to stir at RT till the solution was basic by pH paper. The mixture was filtered and the solids were washed with 15 ml MeOH. The solution was concentrated to an oil that was placed on high vacuum. The crude material was purified by flash chromatography (SiO2, eluting with 10-15% 7N NH3 in CH3OH/CH2Cl2 to yield the desired product as glass/stiff foam (68 mg). 1H NMR (400 MHz, MeOD) δH ppm 8 06 (s, 1H), 7.39 (d, J=7.88 Hz, 1H), 7.23 (s, 1H), 7.21 (dd, J=3.63, 1.76 Hz, 1H), 6.99 (m, 1H), 6.60 (d, J=3.52 Hz, 1H), 4.93 (m, 1H), 4.32 (m, 1H), 3.89 (m, 1H), 3.03 (m, 1H), 2.83 (m, 2H), 2.70 (q, J=8.15 Hz, 1H), 2.52 (m, 1H), 2.40 (m, 4H), 2.27 (m, 2H), 2.18 (d, J=6.22 Hz, 3H), 2.11 (m, 4H), 2.03 (m, 1H), 1.86 (m, 4H), 1.62 (m, 1H), 1.51 (m, 1H), 1.47 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:10]=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:22])[N:9]([CH2:11][C:12]4[CH:13]=[N:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=4)[N:10]=[C:4]3[C:3]=2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:32][CH:31]=1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccncc3)c(Cl)ccn12
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Temperature: 100 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a suspension of 7-chloro-8-(pyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (165 mg, 0.40 mmol), 4-chlorophenylboronic acid (190 mg, 1.20 mmol) in toluene (3.0 mL) and 2.0 M aqueous sodium carbonate (0.66 mL) was added (Ph3P)4Pd (70 mg, 0.06 mmol) in one portion, and the resulting yellow mixture was vigorously stirred under argon in a 100° C. oil bath for 2 h. HPLC/MS analysis indicated that the reaction was complete. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The EtOAc phase was washed with water, then saturated aqueous NaCl twice, dried over Na2SO4, and concentrated under reduced pressure to obtain crude product. The crude product was purified by silica gel (12 g) column chromatography eluting with a gradient of EtOAc (0-100%) in hexanes to provide the title compound as a light yellow foam (160 mg), which was crystallized from hot methanol to afford 60 mg of pure product. The mother liquor was concentrated, and the residue was purified by preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 40% to 80% B over 8 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The resulting residue was dissolved in EtOAc, washed with saturated aqueous Na2CO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford an additional 88 mg of pure title compound as a light yellow powder. HPLC/MS: retention time=2.70 min, [M+H]+=482. 1H NMR (CDCl3, 400 MHz): δ 8.78 (s, 1H), 8.57 (d, J=6.2 Hz, 2H), 7.91 (dd, J=1.8, 7.9 Hz, 1H), 7.86 (d, J=7.0 Hz, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.17 (d, J=6.2 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 6.65 (d, J=7.5 Hz, 1H), 5.25 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](O)=[O:8])=[C:5]([N+:10]([O-:12])=[O:11])[C:4]([CH3:13])=[N:3]1.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:21]>ClCCl.CN(C=O)C>[CH3:1][N:2]1[C:6]([C:7]([NH2:21])=[O:8])=[C:5]([N+:10]([O-:12])=[O:11])[C:4]([CH3:13])=[N:3]1
Reactant: Cc1nn(C)c(C(=O)O)c1[N+](=O)[O-]
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nn(C)c(C(N)=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 51.1 %

Procedure:
To 1,3-dimethyl-4-nitro-1H-pyrazole-5-carboxylic acid (1.08 g, 5.84 mmol) in anhydrous dichloromethane (DCM) (25 mL) and DMF (0.5 mL) was added dropwise oxalyl chloride (0.74 mL, 8.77 mmol, 1.5 eq.) over 10 minutes. The reaction mixture was stirred at RT under N2 for 17 hours. Volatile solvent was evaporated in vacuo, and the crude material dissolved in anhydrous THF (20 mL) and acetone (10 mL). Concentrated aqueous ammonium hydroxide (5.0 mL, 128.4 mmol, 22 eq.) was added slowly, and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was concentrated in vacuo, and the residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium bicarbonate, water and brine, dried (Na2SO4), filtered and concentrated in vacuo. Trituration from ether-heptane afforded the desired product as a white solid (550.0 mg, 51.5%). 1H NMR (DMSO-d6, 500 MHz) δ ppm 8.39 (broad s, 1H), 8.21 (broad s, 1H), 3.77 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]=[C:6]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:16]([C:17]3[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=3[O:29][CH2:30][CH3:31])[C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[CH2:30]([O:29][C:18]1[C:19]([CH:26]([CH3:28])[CH3:27])=[CH:20][C:21]([CH:23]([CH3:24])[CH3:25])=[CH:22][C:17]=1[C:16]1[C:10]2[CH:9]=[C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:32])=[O:3])[S:12][C:11]=2[CH:13]=[CH:14][CH:15]=1)[CH3:31]
Reactant: CCOC(=O)C=C(C)c1cc2c(-c3cc(C(C)C)cc(C(C)C)c3OCC)cccc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1c(-c2cccc3sc(C(C)=CC(=O)O)cc23)cc(C(C)C)cc1C(C)C
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 3-[4-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. 3-[4-(2-Ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic acid was isolated as a white solid. 1H NMR (CDCl3), δ: 7.77 (dd, J=5.9, 3.6 Hz, 1H), 7.51 (s, 1H), 7.43 (m, 2H), 7.17 (d, J=2.2 Hz, 1H), 7.05 (d, J=2.3 Hz, 1H), 6.32 (s, 1H), 3.43 (dt, J=13.8, 6.9 Hz, 1H), 3.33 (m, 2H), 2.93 (dt, J=13.7, 6.9 Hz, 1H), 2.61 (s, 3H),1.29 (m, 12H), 0.85 (t, J=7.4 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6]([O-])(=O)[CH3:7].[Na+].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.O>C(OC(=O)C)(=O)C>[CH3:6][C:7]1[O:4][C:3](=[O:5])[C:2](=[CH:16][C:15]2[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=2)[N:1]=1
Reactant: CC(=O)[O-]
Reactant: NCC(=O)O
Reactant: O=Cc1ccc(F)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC1=NC(=Cc2ccc(F)cc2)C(=O)O1
Reaction time: 2 h
Yield: 78.6 %

Procedure:
With stirring, 7.5 g (0.1 mol) of glycine with 6.2 g (0.075 mol) of anhydrous sodium acetate and 18.6 g (0.15 mol) of p-fluorobenzaldehyde in 60 ml of acetic anhydride are heated to 100° C. After 2 hours, the reaction is cooled and poured into water. The resulting precipitate is filtered off with suction and dried under reduced pressure. 12.1 g (59% of theory) of 2-methyl-4-(4-fluorobenzylidene)-oxazol-5-one of mp. 156° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][N:7]2[C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[C:5]3[CH2:15][N:14]4[CH2:13][CH2:12][CH:11]([C:6]2=3)[CH2:17][CH2:16]4)=[CH:21][CH:20]=1
Reactant: C=Cc1ccc(Cl)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(Cl)cc2)C2CCN(CC2)C1

Procedure:
The coupling of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (226 mg, 1.0 mmol; Example 2B) and 1-chloro-4-vinylbenzene (277 mg, 2.0 mmol; Aldrich) was performed according to the procedure described in Example 114B to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.52-1.66 (m, 2H), 1.80-1.95 (m, 2H), 2.39 (s, 3H), 2.85-3.03 (m, 5H), 3.05-3.19 (m, 2H), 4.15 (s, 2H), 4.32 (t, J=7 Hz, 2H), 6.82-6.96 (m, 3H), 7.06-7.22 (m, 4H); MS (DCI/NH3) m/z 365 (M+H)+.