Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[OH-].[NH4+].S(S([O-])=O)([O-])=[O:16].[Na+].[Na+]>O>[NH2:10][C:4]1[C:5]([C:8]([NH2:9])=[O:16])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=S([O-])S(=O)[O-]
Reactant: N#Cc1ncc(Cl)cc1[N+](=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ncc(Cl)cc1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.6 %

Procedure:
To a suspension of 5-chloro-2-cyano-3-nitropyridine (1.274 mL, 10.9 mmol) in water (22 mL) was added 28% aqueous ammonium hydroxide (3.94 mL, 28.3 mmol), and the reaction was stirred at RT for 20 minutes. Sodium hydrosulfite (2.68 mL, 32.7 mmol) was added, and the reaction mixture was stirred at RT for 70 minutes. The yellow precipitate was collected by vacuum filtration to provide the title compound (1.097 g, 6.39 mmol) as yellow solid. 1H-NMR (400 MHz, DMSO-d6): δ 7.88 (br. s, 1H), δ 7.73 (s, 1H), δ 7.39 (br. s, 1H), δ 7.23 (s, 1H), δ 7.06 (br. s, 2H). LC/MS (ESI+) m/z=172 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8](=[O:13])N(OC)C)[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([Mg]Br)=[CH:25][CH:24]=1>O1CCCC1.[Cl-].[Na+]>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)=[O:13])[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20]
Reactant: CON(C)C(=O)c1ccc(NC(=O)OC(C)(C)C)c(Br)c1
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl N-[2-bromo-4-[methoxy(methyl)carbamoyl]phenyl]carbamate (30 g, 83.52 mmol, 1.00 equip) in tetrahydrofuran (400 mL). To the resulting mixture was then added (4-chlorophenyl)magnesium bromide (250 mL, 3.00 equip, 1 M) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with saturated sodium chloride (200 mL). The resulting solution was extracted with ethyl acetate (400 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting residue was recrystallized from ethyl acetate:petroleum ether in a ratio of 1:20. The solids were collected by filtration. The mother liquor was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) to yield additional tert-butyl N-[2-bromo-4-[(4-chlorophenyl)carbonyl]phenyl]carbamate as a light yellow solid. LCMS (ES, m/z) 410 [M+H]+
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C(OCC)(=O)C.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.O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:6]3[CH:7]=[C:8]([C:11]4[O:12][C:13]([CH3:16])=[N:14][N:15]=4)[CH:9]=[CH:10][C:5]=3[O:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1nnc(-c2ccc3occ(Br)c3c2)o1
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: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2ccc3occ(-c4ccc(F)cc4)c3c2)o1
Yield: 68.7 %

Procedure:
A mixture of 2-(3-bromo-1-benzofuran-5-yl)-5-methyl-1,3,4-oxadiazole (251 mg, 0.900 mmol), (4-fluorophenyl)boronic acid (140 mg, 1.00 mmol), tetrakis(triphenylphosphine)palladium(0) (31.2 mg, 0.0270 mmol), sodium carbonate (212 mg, 2.00 mmol), 1,2-dimethoxyethane (5 mL) and water (1 mL) was heated overnight under reflux under an argon atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) and recrystallized from hexane/ethyl acetate to give the title compound (182 mg, yield 69%) as colorless crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[C:14]12([OH:24])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.N1C=CC=CC=1>O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]([O:24][C:14]12[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2)=[O:12]
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)c1cnc2ccccc2n1
Solvent: O
Solvent: c1ccncc1
Product: O=C(OC12CC3CC(CC(C3)C1)C2)c1cnc2ccccc2n1
Yield: 16.6 %

Procedure:
Prepared from 2-quinoxaloyl chloride (0.84 g, 4.4 mmol), 1-adamantanol (0.60 g, 3.9 mmol), pyridine (10 mL), and water (100 mL) yielding 0.20 g (16%) of (92):
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[S:10]1[CH:14]=[CH:13][N:12]=[C:11]1[CH2:15][C:16](O)=[O:17].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:16](=[O:17])[CH2:15][C:11]2[S:10][CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1nccs1
Reactant: Cc1c(N)cccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Br)cccc1NC(=O)Cc1nccs1
Reaction time: 8 h
Yield: 42.3 %

Procedure:
A mixture of 3-bromo-2-methylaniline (0.764 mL, 6.20 mmol), 1,3-thiazol-2-ylacetic acid (0.74 g, 5.17 mmol) and DIEA (1.63 mL, 9.30 mmol) in DMF (15 mL) was treated with HATU (2.36 g, 6.20 mmol). After stirring overnight, the mixture was diluted with EtOAc, washed twice with 10% aqueous LiCl followed by brine, and the combined aqueous layers were extracted with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes, to give N-(3-bromo-2-methylphenyl)-2-(thiazol-2-yl)acetamide as a white solid (0.681 g, 42% yield). 1H NMR (400 MHz, chloroform-d) δ 9.84-9.65 (m, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.84 (d, J=3.3 Hz, 1H), 7.42-7.35 (m, 2H), 7.07 (t, J=8.0 Hz, 1H), 4.18 (s, 2H), 2.38 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[CH2:27][CH2:26][N:25]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:24][C:9]=3[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](SC)=[NH:21])=[CH:15][CH:14]=3)[N:12]=2)[CH2:3][CH2:2]1.C(O)CC.[CH2:38]([NH2:40])[CH3:39]>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[CH2:27][CH2:26][N:25]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:24][C:9]=3[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]4[NH:40][CH:38]=[CH:39][N:21]=4)=[CH:15][CH:14]=3)[N:12]=2)[CH2:3][CH2:2]1
Reactant: CCN
Reactant: CSC(=N)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2ncccn2)C3)cc1
Solvent: CCCO
Product: c1cnc(N2CCc3c(nc(-c4ccc(Nc5ncc[nH]5)cc4)nc3N3CCOCC3)C2)nc1
Temperature: 97 °C
Reaction time: 1 h

Procedure:
Methyl 4-(4-morpholino-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenylcarbamimidothioate (0.070 g, 0.00015 mol) in 1-Propanol (5.00 mL, 0.0669 mol) was added Ethanamine, 2,2-diethoxy- (0.0664 mL, 0.000454 mol) heated at 97° C. for 2 hours. At this time, an additional portion of Ethanamine, 2,2-diethoxy- (0.0222 mL, 0.000152 mol) was added to the reaction mixture and stirred for 1 hour at 97° C. After this time, an additional portion of Ethanamine, 2,2-diethoxy- (0.0222 mL, 0.000152 mol) was added to the reaction mixture and heated at 97° C. for 6 hours. The reaction mixture was concentrated and dried in vacuo overnight. The crude product was cooled at 0° C. and then added 10.0 M of Hydrogen chloride in Water (2.00 mL), allowed to warm slowly to room temperature, stirred for 6 hours, then poured into ice, and to the ice solution was added saturated NaHCO3 until the pH was approximately 9. The aqueous solution was extracted three times with 10% MeOH in dichloromethane, dried over Magnesium sulfate, filtered, and concentrated to provide the crude product which was chromatographed through silica gel (4 g, 0-10% MeOH in dichloromethane), and further purified by HPLC. 1-(4-(4-morpholino-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-1H-imidazol-2-amine (tz) 1H NMR (400 MHz, DMSO) δ 8.44 (t, J=6.7, 3H), 8.23 (s, 1H), 7.58 (d, J=8.7, 2H), 6.93 (d, J=1.5, 1H), 6.71 (t, J=4.7, 1H), 6.59 (d, J=1.5, 1H), 5.52 (s, 2H), 4.86 (s, 2H), 4.00 (t, J=5.1, 2H), 3.74 (d, J=4.5, 4H), 3.52 (d, J=4.4, 4H), 2.79 (s, 2H). LC/MS-m/z+456.2 (M+H)+; and N-(4-(4-morpholino-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-1H-imidazol-2-amine (ty) LC/MS-m/z+456.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5]O)[OH:4].[H][H].C(O)CO>O.[Pt]>[CH2:2]([OH:1])[CH:3]([OH:4])[CH3:5].[CH3:5][C:3]([CH2:2][OH:1])=[O:4]
Reactant: OCC(O)CO
Reactant: [H][H]
Agent: [Pt]
Solvent: OCCO
Solvent: O
Product: CC(=O)CO
Product: CC(O)CO

Procedure:
20 wt % glycerol was hydrogenated at 500 psi hydrogen pressure at 220° C. using 80 g of water as solvent. 0.01 g/ml catalyst of 3% Pt/C catalyzed the reaction in 5 h to give glycerol conversion of 32% with 91% selectivity to 1,2-propylene glycol, 2% to acetol and 7% ethylene glycol and <0.01% other products.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[C:7]([NH:14][C@H:15]([C:23]([OH:25])=O)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[C:7]([NH:14][C@H:15]([C:23]([NH:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)CCNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
Isopentylamine (3.00 ml, manufactured by Wako Pure Chemical Industries, Ltd.) and Boc-L-phenylalanine (7.52 g, manufactured by Peptide Institute, Inc.) were dissolved in dichloromethane (50 ml). To the solution were added, under ice-cooling, HOBT (3.84 g) and WSC (5.44 g). The mixture was stirred for 18 hours at room temperature. The reaction mixture was concentrated, to which was added ethyl acetate (300 ml). The mixture was washed with a 10% aqueous solution of citric acid, a 3% aqueous solution of sodium hydrogen carbonate and a saturated aqueous saline solution. The organic layer was dried over anhydrous sodium sulfate, which was then concentrated to dryness. The concentrate was treated with ether to give N-(Boc-L-phenylalanyl)isopentylamine (7.77 g) (yield 90%). The compound thus obtained (1.00 g) was dissolved in dichloromethane (5 ml), to which was added trifluoroacetic acid (TFA, 5 ml), and the mixture was left standing for one hour at room temperature. The reaction mixture was concentrated, to which was added chloroform, followed by washing with a saturated aqueous solution of sodium hydrogen carbonate, water and a saturated aqueous saline solution, successively. The organic layer was dried over anhydrous sodium sulfate, which was then concentrated to dryness. The residue was dissolved in dichloromethane (26 ml). To the solution were added, under ice-cooling, (2S,3S)-ethyl hydrogen N-Z-aziridine-2,3-dicarboxylate (Compound 1, 965 mg) obtained in Working Example 1, HOBT (445 mg) and WSC (631 mg). The mixture was stirred for 18 hours at room temperature. The reaction mixture was concentrated, to which was added ethyl acetate. The mixture was washed with a 10% aqueous solution of citric acid, water, a saturated aqueous solution of sodium hydrogen carbonate, a 2% aqueous solution of sodium hydrogen carbonate, water and a saturated aqueous saline solution, successively. The organic layer was dried over anhydrous sodium sulfate, which was subjected to a silica gel column chromatography (Kieselgel 60 (Merck A.G.), 200 ml). The column was subjected to elution with eluents prepared by adding methanol to chloroform in sequence. From the fraction of chloroform containing 1% (V/V) methanol, the above-titled compound (Compound 2; 1.15 g) was obtained as a white powdery product (yield 76%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]3[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:12]3=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Li+].[OH-].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]3[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:12]3=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(C)c(F)c3)c(-c3ccc(C)c(F)c3)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)c(F)c2)N(CCCCCCC(=O)O)CCC3)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 7-(2,3-bis(3-fluoro-4-methylphenyl)-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (121 mg, 0.238 mmol) in THF (2 ml) and water (2 ml) was treated with LiOH (45.7 mg, 1.907 mmol) and the resulting mixture was stirred at RT for 18 h. The mixture was acidified to pH 4 with HCl and extracted with DCM. The organic extracts were combined, dried (sodium sulphate), filtered and concentrated in vacuo. The residue was azeotroped with ether to afford the title compound;
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[N+](=CP(=O)(OC)OC)=[N-].[CH3:16][O:17][C:18]1([O:40][CH3:41])[CH2:23][CH2:22][C:21]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:27]=2)([CH:24]=O)[CH2:20][CH2:19]1.C(O)(=O)C>O1CCCC1>[CH3:41][O:40][C:18]1([O:17][CH3:16])[CH2:19][CH2:20][C:21]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39]3)[CH:27]=2)([C:24]#[CH:1])[CH2:22][CH2:23]1
Reactant: COc1ccc(C2(C=O)CCC(OC)(OC)CC2)cc1OC1CCCC1
Reactant: CC(C)(C)[O-]
Agent: COP(=O)(C=[N+]=[N-])OC
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC(OC)(OC)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 31.5 %

Procedure:
To a solution of potassium t-butoxide (0.155 g, 1.38 mmol) in dry tetrahydrofuran (5 mL) under an argon atmosphere at -78° C. was added a solution of dimethyl (diazomethyl)phosphonate (ca. 88% pure, 0.24 g, 1.38 mmol). After 0.25 h, a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexan-1-one dimethyl ketal (0.42 g, 1.15 mmol) in dry tetrahydrofuran (5 mL) was added dropwise and the mixture was allowed to stir at -78° C. under an argon atmosphere for 5 h. Aqueous acetic acid was added, the mixture was concentrated, partitioned between methylene chloride and water and extracted twice. The organic extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 3:1 hexanes/ethyl acetate, provided an oil (0.13 g, 32%).
Reaction SMILES: S[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1C#N.SC1N=C(C)C=C(C)C=1C#[N:15].O[S:23]([OH:26])(=O)=O>>[S:23]1(=[O:26])[C:7]2[CH:6]=[CH:3][CH:2]=[N:9][C:8]=2[CH:10]=[N:15]1
Reactant: Cc1cc(C)c(C#N)c(S)n1
Reactant: Cc1ccc(C#N)c(S)n1
Reactant: O=S(=O)(O)O
Product: O=S1N=Cc2ncccc21

Procedure:
treating 2-mercapto-6-methylnicotinonitrile and 2-mercapto-4,6-dimethylnicotinonitrile in concentrated H2SO4 at 100° C. to give pyridinoisothiazolone compounds 3 (R1═H, R2=Me) and 4 (R1═R2=Me), respectively;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([OH:18])=O)=[CH:8][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.Cl.[CH3:55][C:56]1([CH3:78])[CH2:61][CH2:60][CH2:59][N:58]([CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:71]=[CH:70][C:69]([CH:72]3[CH2:77][CH2:76][NH:75][CH2:74][CH2:73]3)=[CH:68][CH:67]=2)[CH2:57]1>CN(C=O)C>[CH3:55][C:56]1([CH3:78])[CH2:61][CH2:60][CH2:59][N:58]([CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:67]=[CH:68][C:69]([CH:72]3[CH2:73][CH2:74][N:75]([C:16]([C:9]4[C:10]5[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=5)[C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:19])=[CH:7][CH:8]=4)=[O:18])[CH2:76][CH2:77]3)=[CH:70][CH:71]=2)[CH2:57]1
Reactant: COC(=O)CCc1ccc(C(=O)O)c2ccccc12
Reactant: CC1(C)CCCN(CCCOc2ccc(C3CCNCC3)cc2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCc1ccc(C(=O)N2CCC(c3ccc(OCCCN4CCCC(C)(C)C4)cc3)CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
A solution of 4-[3-(methyloxy)-3-oxopropyl]-1-naphthalenecarboxylic acid (for example as prepared for Intermediate 6) (0.197 g, 0.76 mmol) in anhydrous DMF (2 ml) was treated with HBTU (0.29 g 0.77 mmol), diisopropylethylamine (0.6 ml, 3.82 mmol), the mixture was stirred at room temperature for 20 minutes, 3,3-dimethyl-1-(3-{[4-(4-piperidinyl)phenyl]oxy}propyl)piperidine dihydrochloride (for example as prepared for Intermediate 4) (250 mg, 0.63 mmol) was added and the mixture stirred at room temperature for 4 h. The mixture was evaporated to dryness and purified on a SCX-2 cartridge (5 g) eluting with MeOH, followed by 2M ammonia solution in methanol to afford the title compound (238 mg). LCMS RT=2.79 min, ES+ve m/z 571.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:37])(=[O:36])=[N:10][C:11](=[O:35])[C:12]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]4[O:30][CH:31]=[CH:32][C:33]=4[CH3:34])=[O:28])[CH:21]=3)[CH:15]=[N:14][CH:13]=2)=[CH:5][CH:4]=1.[N:38]1([CH2:44][CH2:45][O:46][CH2:47][CH2:48][OH:49])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>C1COCC1.CCOC(C)=O>[OH:49][CH2:48][CH2:47][O:46][CH2:45][CH2:44][N:38]1[CH2:43][CH2:42][N:41]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([S:9]([CH3:37])(=[O:36])=[N:10][C:11](=[O:35])[C:12]3[CH:17]=[C:16]([C:18]#[C:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]5[O:30][CH:31]=[CH:32][C:33]=5[CH3:34])=[O:28])[CH:21]=4)[CH:15]=[N:14][CH:13]=3)=[CH:5][CH:4]=2)[CH2:40][CH2:39]1
Reactant: OCCOCCN1CCNCC1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CBr)cc3)c2)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CN4CCN(CCOCCO)CC4)cc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Crude N-{[4-(Bromomethyl)phenyl] (methyl)oxido--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide was dissolved in THF (2 mL). 2-(2-piperazin-1-yl-ethoxy)-ethanol (0.064 g, 0.390 mmol) and TEA (0.054 mL, 0.390 mmol) were then added to the solution and the resulting reaction mixture was allowed to stir for 1 h at rt. The reaction mixture, subsequently, was dissolved in EtOAc and then extracted with H2O (2× mL). The organic layer was dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude product was purified via column chromatography (gradient eluant mixture of MeOH in EtOAc: 0% to 20% MeOH) to afford the title compound (0.064 g, 49% overall for step 1 and 2).
Reaction SMILES: C(N(CC)[C:4]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][N:5]=1)C.[OH2:19]>COCCO>[C:11]1([C:8]2[CH:7]=[CH:6][NH:5][C:4](=[O:19])[CH2:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O
Reactant: CCN(CC)C1=NC=CC(c2ccccc2)=CC1
Solvent: COCCO
Product: O=C1CC=C(c2ccccc2)C=CN1

Procedure:
The crude diethyl-(5-phenyl-3H-azepin-2-yl)-amine (12.47 g) is added to water (10.0 mL) and 2-methoxy-ethanol (40.0 mL) and the resulting mixture heated to reflux and stirred 4½ days. The volatiles are removed in vacuo and the residue diluted with dichloromethane and washed with 0.1N HCl (2×200 mL) and saturated aqueous NaHCO3 (2×200 mL). The organic layer is dried over Na2SO4 and concentrated in vacuo to give the crude title compound as a dark brown solid (9.63 g). This material is carried into the next reaction without further purification.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9](/[CH:15]=[CH:16]/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: COC(=O)/C=C/C=C/C=C/c1ccc(OC)c(OC2CCCC2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCCc1ccc(OC)c(OC2CCCC2)c1

Procedure:
To a solution of 0.52 g (1.58 mmol) of methyl 7-(3-cyclopentoxy-4-methoxyphenyl)-2,4,6-E,E,E-heptatrienoate in 100 mL of methanol is added 0.05 g of 5% palladium on carbon black. The suspension is shaken under a 50 psi atmosphere of hydrogen for 16 hours after which time the excess gas is dissociated and the solution is filtered over Celite 545. The mixture is concentrated to dryness followed by liquid chromatography of the crude product over 100 g of silica gel eluting with 7.5% ethyl acetate in hexane. The final product is dried in vacuo and is found to be as analytically pure as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.Cl.[CH3:14][NH:15][O:16][CH3:17].CN(C)CCCN=C=NCC.N1C=CC=CC=1>O1CCCC1>[CH3:17][O:16][N:15]([CH3:14])[C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:12]
Reactant: CNOC
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 107.3 %

Procedure:
In a round-bottomed flask, 5.0 g of indole-6-carboxylic acid, 3.3 g of N,O-dimethylhydroxylamine hydrochloride, 11.9 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 10 ml of pyridine are placed in 150 ml of tetrahydrofuran. The mixture is stirred at ambient temperature for 40 h. The mixture is concentrated, and the residue is taken up in 150 ml of ethyl acetate and 50 ml of water. The organic phase is washed with 50 ml of a 1N solution of sodium hydroxide and 50 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. 6.8 g of compound are obtained.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].OC[C:11]1[C:16]([OH:17])=[C:15]([CH2:18][OH:19])[CH:14]=[C:13](C)[CH:12]=1.SCCC(O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)C1C(=CC=CC=1)O>C(O)(=O)C>[C:1]1([C:14]2[CH:13]=[CH:12][CH:11]=[C:16]([OH:17])[C:15]=2[CH:18]=[O:19])[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[OH:7]
Reactant: Cc1cccc(O)c1
Reactant: Cc1cc(CO)c(O)c(CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)CCS
Solvent: O=Cc1ccccc1O
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(O)c1-c1cccc(O)c1C=O
Reaction time: 8 h

Procedure:
A mixture of 146.0 g m-cresol, 25.2 g 2,6-bis(hydroxymethyl)-p-cresol, 5.0 g 3-mercaptopropionic acid and 1.5 g p-toluene-sulfonic acid monohydrate in 200 ml glacial acetic acid were charged into a 1-L reaction vessel equipped with a paddle stirrer, reflux condenser and a nitrogen inlet tube. The mixture was heated to reflux and maintained at reflux to allow formation of the alternating copolymer. After 8 hours, 146.5 g salicylaldehyde were added over time to the reaction mixture to form substantially m-cresol-salicylaldehyde block segments. Reflux was continued for 8 hours. The reaction mixture was slowly poured into 7 L deionized water to precipitate the resin. Once the solvent had exchanged with water, the product was collected on a filter, slurried once in warm deionized water for about 30 minutes, again collected, rinsed with water and dried in a vacuum oven under about 125 mm Hg and at about 100 to 105° C. About 281 g of a block copolymer resin having a number average molecular weight, Mn, of 1472 Daltons and a Tg of 233° C. were obtained.