Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.C1(CC([NH:16][CH:17]2[C:42](=[O:43])[N:19]3[C:20]([C:26]([O:28][CH:29]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])=[C:21]([CH2:24]O)[CH2:22][S:23][C@H:18]23)=O)C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)[Cl:45].CO>C(Cl)Cl>[NH2:16][CH:17]1[C:42](=[O:43])[N:19]2[C:20]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:21]([CH2:24][Cl:45])[CH2:22][S:23][C@H:18]12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
19.64 ml (0.242 mol) of pyridine are added to a suspension of 50 g (0.0972 mol) of benzhydryl 7-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate in 500 ml of methylene chloride at room temperature. After cooling to -20° C., 40.48 g (0.0972 mol) of phosphorus pentachloride are added and the mixture is stirred at -20° C. for 5 minutes. The mixture is warmed to 0° C. with an icebath and stirred for 10 minutes, and is then warmed to 15° C. with a waterbath and stirred for 1 hour. Thereafter, the mixture is cooled to -70° C. and 720 ml of cold methanol are quickly added The mixture is then stirred at -70° C. for 5 minutes, at 0° C. for 10 minutes and at +15° C. for 25 minutes. The solution is subsequently concentrated to a high degree in vacuo and 1,400 ml of saturated sodium bicarbonate solution are added. The solution is extracted three times with methylene chloride and the organic phase is dried with sodium sulphate and concentrated in vacuo. The crude product is chromatographed on 500 g of silica gel 60 (0.04-0.063 mm) with methylene chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[C:15]([O:17][CH2:18][CH3:19])[C:14]([O:20][CH2:21][CH3:22])=[CH:13][C:5]=1[C:6](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[O:7])[CH3:2]>[Pd].CO>[CH2:1]([O:3][C:4]1[CH:16]=[C:15]([O:17][CH2:18][CH3:19])[C:14]([O:20][CH2:21][CH3:22])=[CH:13][C:5]=1[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])[CH3:2]
Reactant: CCOc1cc(OCC)c(C(=O)/C=C/C(=O)O)cc1OCC
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(OCC)c(C(=O)CCC(=O)O)cc1OCC
Reaction time: 1 h

Procedure:
A mixture of 1.0 part by weight of 3-(2',4',5'-triethoxybenzoyl)-trans-acrylic acid, 50 parts by volume of methanol and 0.2 part by weight of 5% palladium-charcoal is subjected to catalytic reduction at 25°C under atmospheric pressure for 1 hour. After removal of the catalyst by filtration, the filtrate is evaporated and the residue is recrystallized from aqueous ethanol to give 0.85 part by weight of 3-(2',4',5'-triethoxybenzoyl)-propionic acid as pale yellow needles melting at 150°-151°C.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=S.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[N:30][C:31]=3[NH2:33])[N:26]([C@H:34]3[CH2:39][CH2:38][C@@H:37]([N:40]4[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]4)[CH2:36][CH2:35]3)[N:25]=2)=[CH:20][CH:19]=1.[NH2:47][C:48]1[C:53]([OH:54])=[CH:52][CH:51]=[CH:50][C:49]=1[CH3:55].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[NH2:33][C:31]1[N:30]=[CH:29][N:28]=[C:27]2[N:26]([C@H:34]3[CH2:39][CH2:38][C@@H:37]([N:40]4[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]4)[CH2:36][CH2:35]3)[N:25]=[C:24]([C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:1]4[O:54][C:53]5[CH:52]=[CH:51][CH:50]=[C:49]([CH3:55])[C:48]=5[N:47]=4)=[CH:23][CH:22]=3)[C:32]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: Cc1cccc(O)c1N
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1cccc2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)nc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,1′-Thiocarbonyldi-2(1H)-pyridone (0.086 g, 0.369 mmol) was added to a solution of cis-3-(4-aminophenyl) 1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.150 g, 0.369 mmol) in pyridine (7 mL) at 0° C., and the mixture was stirred for 1 h at 0° C. The resulting orange solution was partitioned between dichloromethane (10 mL) and water (10 mL). The organic layer was separated and washed with 0.5 N HCl (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. 2-Amino-m-cresol (0.045 g, 0.369 mmol) was added to a suspension of the resulting orange solid and toluene (10 mL), and the mixture was heated at 80° C. for 1 h. 1,3-Dicyclohexylcarbodiimide (0.114 g, 0.554 mmol) was added and the reaction mixture was heated at 80 C for an additional 18 h. The resulting orange brown solution was cooled to room temperature and concentrated to afford a light brown glassy solid. Purification by preparative HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 20 min at 21 mL/min using a 8μ Hypersil HS C18, 250×21 mm column, tr=8.1-10.3 min.) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-methyl-1,3-benzoxazol-2-amine as an off-white solid (0.024 g, 12%): 1H NMR (DMSO-d6, 400 MHz) δ 10.81 (s, 1H), 8.24 (s, 1H), 7.96 (d, 2H), 7.66 (d, 2H), 7.33 (d, 1H), 7.06 (m, 2H), 4.80 (m, 1H), 3.391 (m, 1H), 2.67-2.10 (m, 18H), 1.71-1.60 (m, 4H); RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=7.57 min., 99%; m/z 538 (MH+).
Reaction SMILES: [C:1]([CH:3]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)#[N:2].[CH2:20]([Cl:29])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1C=CC=CC=1>[ClH:29].[ClH:29].[C:1]([CH:3]([N:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:19]1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)#[N:2]
Reactant: ClCC=Cc1ccccc1
Reactant: COc1ccc(C(C#N)N2CCNCC2)cc1OC
Solvent: c1ccccc1
Product: COc1ccc(C(C#N)N2CCN(CC=Cc3ccccc3)CC2)cc1OC
Product: Cl

Procedure:
To 3.6 g. of N-(α-cyano-3,4-dimethoxybenzyl)piperazine was added 8 ml. of benzene and then 1.47 g. of soda ash. To the resulting mixture was added 2.53 g. of cinnamyl chloride over a period of about 1 hour while the mixture was heated under reflux with stirring. After dropping, the mixture was further refluxed with stirring for 2 hours. After cooling, the mixture was filtered and the filtrate was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure. To the residue was added ligroin to be allowed to stand to give crystal which was collected by filtration. The product was recrystallized from ligroin to give 3.4 g. of crystal having a melting point of 119° - 123°C. This crystal was dissolved in benzene and the resultant solution was saturated with dry hydrochloric gas to separate crystal which was collected by filtration. Recrystallization from methanol afforded N-(α-cyano-3,4-dimethoxybenzyl)-N'-cinnamyl piperazine dihydrochloride as needles melting at 203° - 204.6°C. (decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:5]=1[O:17][CH3:18])[CH3:2].CON(C)[C:22](=[O:38])[CH:23]([O:36][CH3:37])[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:12]2[O:13][C:14]([C:22](=[O:38])[CH:23]([O:36][CH3:37])[C:24]3[CH:25]=[CH:26][C:27]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[CH:28][CH:29]=3)=[CH:15][CH:16]=2)=[CH:6][C:5]=1[O:17][CH3:18])[CH3:2]
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Reactant: CCOc1c(OC)cc(-c2ccco2)cc1OC
Product: CCOc1c(OC)cc(-c2ccc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)o2)cc1OC
Yield: 58 %

Procedure:
2-(4-Ethoxy-3,5-dimethoxyphenyl)furan was coupled with N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to the procedure for the synthesis of Example 12. Purification by chromatography (EtOAc-hexanes) gave 1-(5-(4-ethoxy-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone as a yellow foam (0.263 g, 58% yield). MS: m/z 482.2 [M+H]+.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH:6]([C:8]1[O:9][C:10](=[O:23])[C:11]2[C:16]([C:17]=1[C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:7]>C(Cl)Cl.C(#N)C>[Br:2][CH:6]([C:8]1[O:9][C:10](=[O:23])[C:11]2[C:16]([C:17]=1[C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:7]
Reactant: BrP(Br)Br
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1cncs1
Solvent: CC#N
Solvent: ClCCl
Product: CC(Br)c1oc(=O)c2ccccc2c1-c1cncs1
Yield: 44.8 %

Procedure:
1M PBr3 (0.5 ml, 0.50 mmol) in DCM was added drop-wise to of 3-(1-hydroxyethyl)-4-(thiazol-5-yl)-1H-isochromen-1-one (Intermediate B11, 102 mg, 0.372 mmol) in DCM (4 ml) and ACN (2 ml) at RT. Reaction mixture was then concentrated under reduced pressure and straightforward purified on Biotage Silica SNAP 12 g cartridge with a gradient of hexane and EtOAc to give the title compound (56 mg, 45%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[CH:9]=[C:8]([C:18]([O:20]CC)=[O:19])[CH:7]=1>C1C=C2C=CC=C(O)C2=CC=1>[C:2]1([C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]([C:18]([OH:20])=[O:19])[CH:7]=2)[CH:14]=[CH:15][CH:6]=[CH:7][CH:8]=1.[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[CH:9]=[C:8]([C:18]([OH:20])=[O:19])[CH:7]=1
Reactant: CCOC(=O)c1cc(-c2nccs2)c2ccc(OC)cc2c1
Agent: Oc1cccc2ccccc12
Product: COc1ccc2c(-c3ccccc3)cc(C(=O)O)cc2c1
Product: O=C(O)c1cc(-c2nccs2)c2ccc(O)cc2c1

Procedure:
Following the procedure described in Naphthol 1, Step 3, but substituting 1-(2-thiazolyl)-3-carbethoxy-6-methoxynaphthalene from Step 6, for 1-phenyl-3-carboxy-6-methoxynaphthalene, the title product was obtained and used as such for the next step.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.Cl.[CH3:33][O:34][C:35](=[O:39])[CH:36]([CH3:38])[NH2:37]>C(Cl)Cl>[CH2:11]([C:4]1[S:3][C:2]2[NH:1][C:14](=[O:16])[N:37]([CH:36]([CH3:38])[C:35]([O:34][CH3:33])=[O:39])[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH3:12]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C(C)N
Reactant: CCc1cc(C(=O)OC)c(N)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc2c(=O)n(C(C)C(=O)OC)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
To a solution (500 mL) of methyl 2-amino-5-ethylthiophene-3-carboxylate (15 g) in methylene chloride were added triphosgene (10.4 g) and triethylamine (29.4 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture were further added triethylamine (24.8 mL) and DL-alanine methyl ester hydrochloride (22.6 g), and the mixture was further stirred at room temperature for 1 hr, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (500 mL), sodium methoxide (21.9 g) was added, and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with 1N hydrochloric acid and chloroform. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (9.96 g, 44%).
Reaction SMILES: [C:1]1([C:7](=[N:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.FC(F)(F)S(O[CH2:57][CH2:58][C:59]([F:62])([F:61])[F:60])(=O)=O>C1COCC1>[C:1]1([C:7](=[N:14][CH:15]([CH2:57][CH2:58][C:59]([F:62])([F:61])[F:60])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(OCCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: CC(C)(C)OC(=O)C(CCC(F)(F)F)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.6 %

Procedure:
To a stirred solution of tert-butyl 2-((diphenylmethylene)amino)acetate (1 g, 3.39 mmol) in THF (20 ml) cooled to −78° C. under nitrogen atmosphere was added LDA, 2M in THF/heptane/ethylbenzene (2.54 ml, 5.08 mmol) dropwise for 30 mins. To this mixture was then added 3,3,3-trifluoropropyl trifluoromethanesulfonate (1.083 g, 4.40 mmol). The reaction was gradually warmed to rt and stirred for 4 h. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride at 0° C. The reaction mixture was then extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 2% ethyl acetate in hexane to afford tert-butyl 2-((diphenylmethylene)amino)-5,5,5-trifluoropentanoate (800 mg, 2.02 mmol, 60% yield) as a yellow oil. LCMS (ESI) m/e 391.9 [(M+H)+, calcd for C22H24F3NO2, 392.2]; LC/MS retention time (method E): tR=2.49 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[NH:8][N:7]=1)=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1.O>[OH:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[NH:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cc(-c2ccc(O)cc2)[nH]n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2ccc(O)cc2)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a stirred solution of 5-(4-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (5.8 g, 0.018 mole) in a mixture of methanol (50 mL) and THF (180 mL) was added 10% Pd/C (2 g) and the resulting mixture was stirred under an atmosphere of hydrogen for 5 hours. The reaction mixture was then filtered through celite, and the celite was washed with methanol. The filtrate was collected and concentrated under reduced pressure afford 4.05 g (97%) of 5-(4-Benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 233.08 (M+1)+, 97%. To a stirred solution of 5-(4-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (4 g, 0.01724 mol) in a mixture of 1,4-dioxane (88 mL) and H2O (88 mL) was added NaOH (1.57 g, 0.03793 mol) and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was then acidified with concentrated HCl solution. The mixture was concentrated and the resulting precipitate was isolated by filtration and dried to afford 3.1 g (76%) of 5-(4-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid. LCMS: 205.05 (M+1)+, 91.6%.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[CH3:23][NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:23][N:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: CNc1ccccc1
Solvent: Cc1ccccc1
Product: CN(CCn1cnc(-c2cc(C(=O)O)ccn2)c1)c1ccccc1
Temperature: 25 °C
Yield: 41 %

Procedure:
A solution of methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (100 mg, 0.31 mmol) and N-methylaniline (328 mg, 3.1 mmol) in toluene (5 mL) was heated at 110° C. in a sealed tube for 36 hrs. The solution was concentrated to an oily residue which was dissolved in MeOH (5 mL). To this solution was added 10 N NaOH solution (1 g). The mixture was stirred and refluxed for 1 hr and then cooled to RT. The pH was carefully adjusted to 7 whereupon a precipitate formed. The solid was filtered and dried to give the title compound (41 mg) as an off white solid: 1HNMR (400 MHz, CD3OD): δ 2.79 (3H, s), 3.64 (2H, t, J=4.4 Hz), 4.21 (2H, t, J=4.4 Hz), 6.62 (1H, m), 6.68 (2H, m), 7.18 (2H, m), 7.57 (1H, m), 7.66 (1H, s), 7.84 (1H, s), 8.23 (1H, s), 8.63 (1H, m). [M+H] Calc'd for C18H18N4O2, 323. Found, 323.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[C:4]([CH3:11])[CH:3]=1.O.O.O.[O-:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na+]>C1COCC1>[CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(C#N)c(Oc2ccccc2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
4,6-dimethyl-2-chloro-nicotinonitrile (600 mg, 3.60 mmol) was dissolved in 30 mL of anhydrous THF and then added with sodium phenoxide trihydrate (3.06 g, 18.00 mmol) and stirred at 80° C. overnight. The mixture was extracted with methylene chloride, dried with anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. A silica gel column chromatography (10% EtOAc/Hexane) was performed on the resulting residue and 730 mg (90%) of 4,6-dimethyl-2-phenoxy-nicotinonitrile was obtained in white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:14][CH3:15])[C:10]=1[N+:11]([O-])=O)[C:5]([OH:7])=[O:6].CC(O)=O.[H][H]>CO>[NH2:11][C:10]1[C:9]([O:14][CH3:15])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: [H][H]
Reactant: COc1cc(C(=O)O)cc(F)c1[N+](=O)[O-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)cc(F)c1N

Procedure:
A solution of 3-fluoro-5-methoxy-4-nitrobenzoic acid (obtained above), HOAc (5 mL) and MeOH (5 mL) was hydrogenated using a hydrogen balloon overnight. The solution was then filtered through celite and concentrated to a red solid (590 mg, 66%). [M+H] calc'd for C8H8FNO3, 186; found 186.
Reaction SMILES: [C:1]([C:4]1([CH2:17][C:18]([OH:20])=O)[CH2:16][CH2:15][N:7]2[C:8]3[C:13]([CH:14]=[C:6]2[CH2:5]1)=[CH:12][CH:11]=[CH:10][CH:9]=3)(O)=[O:2].C(=O)([O-])[O-].[NH4+:25].[NH4+]>ClCCl.CO>[NH:25]1[C:18](=[O:20])[CH2:17][C:4]2([CH2:16][CH2:15][N:7]3[C:8]4[C:13]([CH:14]=[C:6]3[CH2:5]2)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:1]1=[O:2]
Reactant: O=C(O)CC1(C(=O)O)CCn2c(cc3ccccc32)C1
Reactant: [NH4+]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Product: O=C1CC2(CCn3c(cc4ccccc43)C2)C(=O)N1
Temperature: 200 °C
Yield: 68.8 %

Procedure:
A mixture of 100 mg of 8-carboxy-6,7,8,9-tetrahydropyrido[1,2-a]indole-8-acetic acid and 69 mg of ammonium carbonate was heated at 200° C. for 1 hour. After cooling and chromatography on silica gel using dichloromethane/methanol (9:1) for the elution there were obtained 64 mg of 7,9-dihydrospiro[pyrido[1,2-a]indole-8(6H),3'-pyrrolidine]-2',5'-dione.
Reaction SMILES: B(F)(F)F.CCOCC.[CH:10]1([CH2:13][C@@H:14]2[O:22][CH2:21][C:17]3=[N:18][O:19][CH2:20][C@@H:16]3[CH2:15]2)[CH2:12][CH2:11]1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1I.C([Li])CCC>C1(C)C=CC=CC=1>[CH:10]1([CH2:13][C@@H:14]2[O:22][CH2:21][C@:17]3([C:27]4[CH:26]=[CH:25][C:24]([F:23])=[CH:29][C:28]=4[F:30])[NH:18][O:19][CH2:20][C@@H:16]3[CH2:15]2)[CH2:11][CH2:12]1
Reactant: C1O[C@@H](CC2CC2)C[C@H]2CON=C12
Reactant: Fc1ccc(I)c(F)c1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1ccc([C@]23CO[C@@H](CC4CC4)C[C@H]2CON3)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Boron trifluoride diethyl etherate (5.4 g, 17.9 mmol) was added drop-wise to a solution of rel-(3aR,5S)-5-(cyclopropylmethyl)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C69) (2.7 g, 14.9 mmol) in toluene (100 mL) at an internal temperature of −72.5° C. The reaction mixture was stirred at −73° C. to −76° C. for 30 minutes, then treated with 2,4-difluoro-1-iodobenzene (98%, 4.3 g, 17.9 mmol) in one portion. While the reaction temperature was maintained below −73° C., n-butyllithium (2.5 M in hexanes, 6.0 mL, 14.9 mmol) was added in a drop-wise manner over 15 minutes. The reaction mixture was stirred at −73° C. to −75° C. for 1.5 hours, then was quenched with saturated aqueous ammonium chloride solution (10 mL) at −74° C. and allowed to warm to room temperature. The resulting mixture was extracted with ethyl acetate (300 mL), and the aqueous layer was extracted with additional ethyl acetate (250 mL and 100 mL); the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 10% ethyl acetate in petroleum ether) afforded the product as a yellow oil. Yield: 1.85 g, 6.25 mmol, 42%. LCMS m/z 296 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.92 (q, J=8.3 Hz, 1H), 6.88 (dt, J=8.2, 2.4 Hz, 1H), 6.80 (dt, J=10.4, 2.4 Hz, 1H), 6.31 (br s, 1H), 4.11 (dd, J=12.8, 1.6 Hz, 1H), 3.80 (d, J=12.8 Hz, 1H), 3.70 (d, J=7.2 Hz, 1H), 3.61-3.67 (m, 1H), 3.52-3.55 (m, 1H), 3.04-3.09 (m, 1H), 1.94 (dd, J=14.0, 6.8 Hz, 1H), 1.59-1.67 (m, 2H), 1.45 (q, J=15.1 Hz, 1H), 1.25 (quintet, J=6.9 Hz, 1H), 0.74-0.85 (m, 1H), 0.45-0.53 (m, 2H), 0.08-0.13 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([C:26]#[N:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[OH-:28].[K+].O>CC(O)(C)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([C:26]([NH2:27])=[O:28])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(Sc2cccc(C3(C#N)CCOCC3)c2)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1nccn1-c1ccc(Sc2cccc(C3(C(N)=O)CCOCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
4-{3-[4-(2-Methyl-imidazol-1-yl)-phenyl sulfanyl]-phenyl}-tetrahydro-pyran-4-carbonitrile (27.35 g) were dissolved in t-BuOH (280 mL) at 50° C. To the solution, KOH (12.28 g) was added and the mixture was stirred overnight. The suspension was cooled to room temperature and water (180 mL) was added. The suspension obtained was filtered and the filtercake was dried at 50° C. to yield 4-{3-[4-(2-Methyl-imidazol-1-yl)-phenyl sulfanyl]-phenyl}tetrahydro-pyran-4-carboxylic acid amide (17.52 g, 55% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[CH:24]=[N:23]2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([S:17](Cl)(=[O:19])=[O:18])[CH:10]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C=O.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[CH:24]=[N:23]2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([S:17]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:19])=[O:18])[CH:10]=1
Reactant: C1CCNCC1
Reactant: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1S(=O)(=O)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1S(=O)(=O)N1CCCCC1
Reaction time: 1 h

Procedure:
To a stirred solution of 2-[3,5-dichloro-4-(3-chlorosulfonyl-4-methoxy-phenoxy)-phenyl]-2H-[1,2,4]triazine-3,5-dione (0.7 g) in dimethylformamide (8 mL) was added piperidine (0.4 mL). After 1 h, the reaction was diluted in diethyl ether, washed with 1N hydrochloric acid, brine, dried (Na2SO4) and concentrated in vacuo to a solid. Recrystallization from diethyl ether/petroleum ether afforded the title compound of Step B, 0.5 g. MS Calc.:527.4 Found:527.0.