Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[C:24]([CH:29]=[O:30])=[CH:23][N:22]=1>C1COCC1>[F:10][C:8]([F:9])([F:11])[C:6]1[C:7]([CH:29]([C:24]2[C:25]([O:27][CH3:28])=[N:26][C:21]([Cl:20])=[N:22][CH:23]=2)[OH:30])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: FC(F)(F)c1cc(Cl)ncn1
Reactant: COc1nc(Cl)ncc1C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1nc(Cl)ncc1C(O)c1c(Cl)ncnc1C(F)(F)F
Reaction time: 0.17 h
Yield: 9.6 %

Procedure:
4-Chloro-6-trifluoromethylpyrimidine (1.10 g, 6.02 mmol) in THF (15 ml) was added to a solution of lithium diisopropyl amide (LDA) (prepared from n-BuLi (3.7 ml, 5.9 mmol, 1.6M in hexanes) added to diisopropylamine (820 ul, 591 mg, 5.84 mmol) in THF (30 ml) at -78° C., allowing to warm to room temperature for 30 minutes, and re-cooling to -78° C.) at -78° C. The solution turned brown and was stirred for 10 minutes. Then 2-chloro-4-methoxypyrimidine-5-carboxaldehyde (0.96 g, 5.56 mmol) in THF (25 ml) was added dropwise and allowed to stir at -78° C. for 1 hour. The solution was quenched at -78° C. with 30% aqueous HOAc, diluted with water and extracted with EtOAc (3 times). The combined extracts were washed with brine (sat.), dried (MgSO4), filtered and concentrated in vacuo to give 1.61 g of crude product. Preparative radial chromatography (SiO2 ; hexane/EtOAc gradient elution) gave 190 mg (21% based on 530 mg of recovered starting material) of 1-(4-trifluoromethyl-6-chloropyrimidin-5-yl)-1-(2-chloro-4-methoxypyrimidin-5-yl)methanol.
Reaction SMILES: C(OC([N:6]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:13]([O:15][CH:16]=[CH2:17])=[O:14])[CH2:7]1)=O)=C.[ClH:18]>C(Cl)Cl>[ClH:18].[CH:16]([O:15][C:13](=[O:14])[O:12][CH2:11][CH:8]1[CH2:9][CH2:10][NH:6][CH2:7]1)=[CH2:17]
Reactant: C=COC(=O)OCC1CCN(C(=O)OC=C)C1
Agent: Cl
Solvent: ClCCl
Product: C=COC(=O)OCC1CCNC1
Yield: 99 %

Procedure:
3-Vinyloxycarbonyloxymethyl-pyrrolidine-1-carboxylic acid vinyl ester (335 mg, 1.39 mmol) was dissolved in CH2Cl2 (10 mL), and HCl(g) was passed through the solution for 2 minutes then the solution was concentrated in vacuo. The residue was dissolved in MeOH (10 mL) and heated to reflux for 15 minutes then concentrated in vacuo to give a colourless oil (284 mg, 99%). 1H NMR (CD3OD) δ 1.78-1.91 (m, 1H), 2.17-2.28 (m, 1H), 2.79 (m, 1H), 3.09 (dd, 1H, J=12, 7.8 Hz), 3.25-3.51 (m, 3H), 4.19-4.33 (m, 2H), 4.62 (dd, 1H, J=6.2, 2.0 Hz), 4.89 (m, 1H), 7.11 (dd, 1H, J=14, 6.0 Hz).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH3:41])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]3[CH2:26][CH2:25]3)=[CH:18][C:17]=2[S:27]CCC(OCC(CC)CCCC)=O)=O)[O:10][N:9]=1)(=[O:3])[CH3:2].[O-]CC.[Na+].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C1COCC1>[CH:24]1([CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]3[N:15]=[C:13]([C:11]4[O:10][N:9]=[C:8]([O:7][CH2:6][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:41])[CH:12]=4)[S:27][C:17]=3[CH:18]=2)[CH2:26][CH2:25]1
Reactant: CCCCC(CC)COC(=O)CCSc1cc(OCC2CC2)ccc1NC(=O)c1cc(OC[C@H](C)NC(C)=O)no1
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)COc1cc(-c2nc3ccc(OCC4CC4)cc3s2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.7 %

Procedure:
A mixture of 2-ethylhexyl 3-{[2-{[(3-{[(2S)-2-(acetylamino)propyl]oxy}isoxazol-5-yl)carbonyl]amino}-5-(cyclopropylmethoxy)phenyl]sulfanyl}propanoate (935 mg), sodium ethoxide (20% ethanol solution, 1.08 g) and THF (10 mL) was stirred at room temperature for 30 min. To the reaction mixture was added trifluoroacetic acid (0.611 mL) at 0° C., and the obtained mixture was stirred at 70° C. overnight. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (ethyl acetate) to give the title compound as white crystals (71.6 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:5]([CH:9]=[C:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27]C)=[O:25].OC1C2N=NNC=2C=CC=1.CN1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C.O>[C:1]([C:3]1[C:4]2[N:5]([CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:16]([NH:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:18])=[CH:19][CH:20]=3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccn2cc(-c3ccc(C(=O)O)cc3)nc12
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)CCNC(=O)c1ccc(-c2cn3cccc(C#N)c3n2)cc1

Procedure:
4.0 g Of 4-(8-cyanoimidazo[1,2-a]pyridin-2-yl)benzoic acid and 2.14 g of ethyl 3-aminopropionate in 40 ml of DMF are stirred in the presence of 2.28 g of hydroxybenzotriazole, 3.0 g of N-methylmorpholine and 2.9 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide at room temperature for 4 h. After addition of 400 ml of water, the precipitate is filtered off with suction and washed successively with dilute bicarbonate solution and water. Methyl 3-[4-(8-cyanoimidazo[1,2-a]pyridin-2-yl)benzamido]propionate, m.p 201-204° is obtained.
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]([CH2:31][O:32][C:33](=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[O:23][Si](C(C)(C)C)(C)C)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[C:1]([O:20][CH2:21][CH:22]([CH2:31][O:32][C:33](=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[OH:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)COC(=O)CCCCCCC/C=C\CCCCCCCC
Reaction time: 0.5 h

Procedure:
To 1,3-O-dioleoyl-2-O-(t-butyldimethylsilyl)glycerol was added 266 ml of 0.1M tetra-n-butylammonium fluoride-tetrahydrofuran and the reaction was carried out at ambient temperature for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was diluted with methylene chloride, washed with water, dried, and concentrated. The residue was subjected to column chromatography (silica gel/ethyl acetate-n-hexane) to provide 3.97 g (48.0% based on 2-O-t-butyldimethylsilylglycerol) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[O:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23]>COCCO>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:27]2[CH2:28][CH2:29][N:24]([C:22]([CH:18]3[CH2:19][CH2:20][CH2:21][O:17]3)=[O:23])[CH2:25][CH2:26]2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(C1CCCO1)N1CCNCC1
Solvent: COCCO
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.6 %

Procedure:
Sixty grams (0.25 tool) of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 56.8 grams (0.308 tool) of N-(2-tetrahydrofuroyl)piperazine were added to a stirred solution of 500 grams of Methyl Cellosolve® (ethylene glycol monomethyl ether) and 37.9 grams of tricthylaminc. The reaction mixture was heated to and maintained at a temperature of between 115° C. to 120° C. for 8 hours, and then allowed to cool to room temperature overnight. The Methyl Cellosolve® was removed by vacuum distillation, the residue was taken up in 1920 ml of 45° C. distilled water, and the temperature of the solution was readjusted to 45° C. The pH was then adjusted to pH 2.5 with concentrated hydrochloric acid and the solution mixed for 1 hour. The solution was then filtered and the pH adjusted to pH 8.3 with filtered ammonia water (28%). After heating for one hour at 65° C., the solution was cooled to 15° C. and held at a temperature of between 15°C. -20° C. for 16 hours. The resulting crystalline product was filtered, washed with cold water (15° C.) and dried in vacuo at 65° C. to yield 84 grams (87%) of anhydrous base.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:6][CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1>C1COCC1>[OH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-n2ccnc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a mixture of 4-(1H-imidazol-1-yl)benzoic acid methyl ester (prepared as described in U.S. Pat. No. 4,804,662) (1.5 g) in THF (25 ml) at -15° C. was added a solution of 1M LAH/THF (10.4) ml). The mixture was stirred for 1/2 hour and allowed to warm to room temperature. The reaction was quenched by addition of water (0.5 ml), and then diluted with methanol (50 ml) and filtered. Concentration of the filtrate yielded 1.2 g (98%) of 1-(hydroxymethyl)-4-(1H-imidazol-1-yl)-benzene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]3[N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16][C@@H:9]23)[CH:5]=[N:4][C:3]=1[C:24]#[N:25].Cl.[CH:27]1([N:32]2[CH2:37][CH2:36][CH:35]([C:38]3[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=3)[CH2:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:24]([C:3]1[N:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]3[N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16][C@@H:9]23)=[N:7][C:2]=1[NH:42][C:41]1[CH:43]=[CH:44][C:38]([CH:35]2[CH2:36][CH2:37][N:32]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:33][CH2:34]2)=[CH:39][CH:40]=1)#[N:25]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H]1CCCN2c1cnc(C#N)c(Cl)n1
Reactant: Nc1ccc(C2CCN(C3CCCC3)CC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H]1CCCN2c1cnc(C#N)c(Nc2ccc(C3CCN(C4CCCC4)CC3)cc2)n1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 76.3 %

Procedure:
The mixture of (3aR,7aR)-tert-butyl 4-(6-chloro-5-cyanopyrazin-2-yl)octahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (417) (400 mg, 1.10 mmol), 4-(1-cyclopentylpiperidin-4-yl)aniline hydrochloride (304) (340 mg, 1.21 mmol), fine-powder cesium carbonate (1.08 g, 3.30 mmol), Pd(OAc)2 (74 mg, 0.33 mmol), BINAP (206 mg, 0.33 mmol) in 40 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 1.5 hour. The mixture was cooled to RT, diluted with 150 mL EtOAc, and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 6% MeOH in DCM to isolate (3aR,7aR)-tert-butyl 4-(5-cyano-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)octahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (418) (480 mg, 76%). It was dissolved in 25 mL MeOH and 2 mL DMSO. To it were added fine-powder Cs2CO3 (100 mg) and then 1 mL 30% H2O2. The mixture was stirred at RT for 1 hour, diluted with 10 mL MeCN, stirred for 5 min, and concentrated on rotavap. The residue was diluted with 150 mL EtOAc, washed with water ×2, concentrated in vacuo to give crude (3aR,7aR)-tert-butyl 4-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)octahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (419). It was treated with 1:1 TFA/DCM at RT for 5 min, concentrated in vacuo, and subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate 3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((3aR,7aR)-dihydro-1H-pyrrolo[3,2-b]pyridin-4(2H,5H,6H,7H,7aH)-yl)pyrazine-2-carboxamide (420) as HCl salt. LC-MS (ESI): m/z (M+1) 490.4. UV: λ=263, 272, 303, 334, 370 nm. Proton NMR (CD3OD): δ 7.68 (1H, s), 7.57 (2H, d, J=8.5 Hz), 7.30 (2H, d, J=9.0 Hz), 5.16 (1H, m), 4.21 (1H, m), 3.85 (1H, m), 3.72 (2H, d, J=13.0 Hz), 3.58 (2H, m), 3.42 (1H, m), 3.12 (3H, m), 2.89 (1H, m), 2.35 (1H, m), 2.20 (2H, m), 2.14-1.71 (15H, m) ppm.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13]>N1C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:21][C:18]1[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1I
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(OS(=O)(=O)c2ccccc2I)cc1
Yield: 70.6 %

Procedure:
A solution of 2-iodobenzenesulphonyl chloride (obtained as described in J. Org. Chem. 1977, 42, 3265) (8.28 g) and 4-nitrophenol (3.81 g) in pyridine (50 ml) was heated at 100° C. for 3 hours. Volatile material was removed by evaporation and water (200 ml) was added to the residue. The mixture was extracted with ethyl acetate (2×200 ml) and the combined extracts were washed with 1M hydrochloric acid (2×200 ml) and dried (MgSO4). Solvent was removed by evaporation and the residue was recrystallised from a mixture of ethyl acetate and hexane to give 4-nitrophenyl 2-iodobenzenesulphonate (7.83 g), m.p. 131°-133° C.; mass spectrum (+ve CI): 405 (M+).
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][N:13]2[C:17]3=[N:18][C:19]([C:22](=O)[CH3:23])=[CH:20][N:21]=[C:16]3[N:15]=[N:14]2)=[C:10]([F:25])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[NH2:27][O:28][CH2:29][CH2:30][OH:31]>CO>[OH:31][CH2:30][CH2:29][O:28]/[N:27]=[C:22](/[C:19]1[N:18]=[C:17]2[N:13]([CH2:12][C:11]3[C:2]([F:1])=[C:3]4[C:8](=[CH:9][C:10]=3[F:25])[N:7]=[CH:6][CH:5]=[CH:4]4)[N:14]=[N:15][C:16]2=[N:21][CH:20]=1)\[CH3:23]
Reactant: CC(=O)c1cnc2nnn(Cc3c(F)cc4ncccc4c3F)c2n1
Reactant: NOCCO
Agent: Cl
Solvent: CO
Product: C/C(=N\OCCO)c1cnc2nnn(Cc3c(F)cc4ncccc4c3F)c2n1
Temperature: 50 °C
Yield: 60.1 %

Procedure:
To a solution of 1-(1-((5,7-difluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (3.5 mg, 0.01 mmol) in MeOH (1 mL), 2-(aminooxy)ethanol hydrochloride (intermediate S) (1.6 mg, 0.02 mmol) was added, the solution was heated to 50° C. for overnight. The solvent was removed in vacuo. The residue was diluted with water, treated with aqueous NaHCO3 solution, extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prepared HPLC to give white solid (E)-1-(1-((5,7-difluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-2-hydroxyethyl oxime (2.4 mg, 56%). 1H-NMR (400 MHz, CDCl3) δ ppm 9.38 (s, 1H), 8.98 (d, 1H), 8.42 (d, 1H), 7.64 (d, 1H), 7.48 (m, 1H), 6.18 (s, 2H), 4.45 (m, 2H), 3.98 (m, 2H), 2.36 (s, 3H), 1.96 (m, 1H). LCMS (method B): [MH]+=399.9, tR=2.19 min.
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].[Cl:14][C:15]([Cl:19])=[CH:16][CH2:17]Cl>>[Cl:14][C:15]([Cl:19])=[CH:16][CH2:17][N:5]1[C:6]([CH3:9])=[C:7]([CH3:8])[C:3]([CH:1]=[O:2])=[C:4]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: ClCC=C(Cl)Cl
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Product: COC(=O)c1c(C=O)c(C)c(C)n1CC=C(Cl)Cl

Procedure:
The title compound was prepared as grayish-white crystals in 87.1% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 1,1, 3-trichloro-1-propene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[N:37][OH:38])[C:9]2[CH:36]=[CH:35][C:12]3[N:13]([CH2:17][CH2:18][O:19][C:20]4[CH:34]=[CH:33][C:23]([O:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28]CC)=[O:27])=[CH:22][CH:21]=4)[C:14](=[O:16])[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[N:37][OH:38])[C:9]2[CH:36]=[CH:35][C:12]3[N:13]([CH2:17][CH2:18][O:19][C:20]4[CH:34]=[CH:33][C:23]([O:24][C:25]([CH3:32])([CH3:31])[C:26]([OH:28])=[O:27])=[CH:22][CH:21]=4)[C:14](=[O:16])[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCn2c(=O)sc3cc(C(=NO)c4cccc(Cl)c4)ccc32)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(Oc1ccc(OCCn2c(=O)sc3cc(C(=NO)c4cccc(Cl)c4)ccc32)cc1)C(=O)O
Temperature: 25 °C

Procedure:
To a solution of the compound obtained in Example 37 (0.6 g) in 5 ml of ethanol 95° there is added potassium hydroxide (90 mg) dissolved in 1 ml of ethanol 95°. The reaction mixture is heated at reflux overnight. After cooling to ambient temperature, the solution is acidified using 1N HCl. The precipitate obtained is then filtered and purified on a reverse phase, RP18, eluant MeOH/H2O 6/4, to yield the title compound in the form of a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][NH:9][CH2:8][CH2:7][CH:6]=1)=[O:4].Cl.[CH2:12]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20](Cl)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[CH2:10][N:9]([CH:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13][CH2:12][C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]2=3)[CH2:8][CH2:7][CH:6]=1)=[O:4]
Reactant: COC(=O)C1=CCCNC1
Reactant: ClC1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)C1=CCCN(C2c3ccccc3CCc3ccccc32)C1
Temperature: 90 °C
Yield: 44 %

Procedure:
To 7.338 g (41.31 mol) of guvacoline hydrochloride (Arzneim. Forsch. 1989, 39(5), 539. ) in dioxane (100 ml) was added 5-chloro-dibenzosuberane (14.933 g, 65.39 mmol), Nal (catalytic, ˜1 g), and triethylamine (17 mL, 122.0 mmol) to give a brown heterogeneous slurry that was heated at 90° C. overnight. The solvent was then concentrated and the resultant sludge was taken up in ethyl acetate and sequentially washed with Na2HPO4 buffer (pH 4), Na2CO3 (saturated aqueous), and brine. The organics were then dried over Na2SO4 and concentrated, resulting in a brown solid which was purified by chromatography on silica gel eluting with 1-5% ethyl acetate/hexanes to give 1-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester as a white solid (9.584 g, 28.74 mmol, 67%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.22 (dt, J=9.28, 2.68 Hz, 2H) 2.41 (t, J=5.56 Hz, 2H) 2.73-2.83 (m, 2H) 2.99-3.05 (m, 2H) 3.65 (s, 3 H) 3.90-4.00 (m, 2H) 4.11 (s, 1H) 6.94-6.99 (m, J=3.98, 3.98, 1.89, 1.77 Hz, 1 H) 7.05-7.11 (m, 4H) 7.13-7.21 (m, 4H).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15])[CH2:2][C:3]#[CH:4].O1CCCC1.[C:21]1([C:27]2[S:28][CH:29]=[C:30](Br)[N:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[C:21]1([C:27]2[S:28][CH:29]=[C:30]([C:4]#[C:3][CH2:2][CH2:1][N:5]3[C:9](=[O:10])[C:8]4[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:6]3=[O:15])[N:31]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Brc1csc(-c2ccccc2)n1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1csc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 55.6 %

Procedure:
To 221 mg of dichlorobis(triphenylphosphine)palladium, 60 mg of copper iodide, and 1.24 g of N-(3-butynyl)phthalimide were added 15 ml of tetrahydrofuran, 1.50 g of the 2-phenyl-4-bromothiazole obtained in the foregoing stage, and 3.8 ml of triethylamine in a nitrogen atmosphere, and the mixture was stirred under reflux for 4 hours. After the stifling, the reaction mixture was cooled to room temperature and the solids were filtered. After concentrating the filtrate, the residue was purified by column chromatography (Wakogel C-200; toluene:ethyl acetate=9:1) to give 1.24 g of a phthalimide compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH:13]=[O:14])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH2:13][OH:14])=[CH:4][CH:3]=1
Reactant: O=Cc1sccc1-c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1sccc1-c1ccc(Cl)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 3-(4-chlorophenyl)thiophene-2-carbaldehyde (5.5 g, 24.70 mmol, 1.00 equiv) in tetrahydrofuran (50 ml). This was followed by the addition of LAH (470 mg, 12.38 mmol, 1.00 equiv) in several batches at −10° C. The resulting solution was stirred for 30 min at −10° C. The reaction was then quenched by the addition of 5 g of sodium sulfate. 10H2O. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (30/1-1/1). This resulted in 5 g (81%) of [3-(4-chlorophenyl)thiophen-2-yl]methanol as a white solid.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:10]([CH3:32])[CH2:11][CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[CH:8][CH:9]=1.[N:33]1[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=1.[H-].[Na+]>CS(C)=O.O1CCCC1>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:10]([CH3:32])[CH2:11][CH:12]=[CH:39][C:36]2[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(C(C)CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=Cc1ccncc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1cccc(C(C)CC=Cc2ccncc2)c1

Procedure:
A mixture of 3-(3-methoxyphenyl)butyl triphenylphosphonium bromide (17.5 g., 35.4 mmoles) in dimethylsulfoxide (50 ml.) is added to 4-pyridine-carboxaldehyde (3.79 g., 35.4 mmoles) in tetrahydrofuran (40 ml.). The resulting mixture is then added dropwise to a slurry of 50% sodium hydride (1.87 g., 39 mmoles) in tetrahydrofuran (20 ml.) under a nitrogen atmosphere at 0°-5° C. and then concentrated under reduced pressure. The concentrate is diluted with water (200 ml.) and then acidified with 6 N HCl. The aqueous acid solution is extracted with benzene (4×50 ml.). It is then made basic and extracted with benzene (3×50 ml.). Evaporation of the combined extracts after drying (MgSO4) affords 4-(3-methoxyphenyl)-1-(4-pyridyl)-1-pentene as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[C:11]([NH2:13])=[O:12])=[CH:5][C:4]=1[NH:20][C:21]1[S:25][N:24]=[C:23]([CH3:26])[CH:22]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:33]>CCO.CS(C)=O>[NH2:13][C:11](=[O:12])[C@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:33])=[C:4]([NH:20][C:21]2[S:25][N:24]=[C:23]([CH3:26])[CH:22]=2)[CH:5]=1)[CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2cc(N[C@H](Cc3cccs3)C(N)=O)ccc2C#N)sn1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cc(Nc2cc(N[C@H](Cc3cccs3)C(N)=O)ccc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)-3-(thiophen-2-yl)propanamide (13 mg, 0.034 mmol) in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL, 0.50 mmol) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was purified by HPLC to give the titled compound (10 mg). MS 402.1 (M+H); UV 224.1, 302.6 nm.