Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5](Br)[C:3]=1N.CB1OB(C)OB(C)O1.[C:23](=O)([O-])[O-].[K+].[K+].O.C[N:31]([CH:33]=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>[CH3:23][C:2]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[C:5]([CH3:3])[C:33]=1[NH2:31]
Reactant: O=C([O-])[O-]
Reactant: Nc1c(Br)cc(C(F)(F)F)cc1Br
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: O
Product: Cc1cc(C(F)(F)F)cc(C)c1N
Temperature: 90 °C

Procedure:
A mixture of 2,6-dibromo-4-trifluoromethyl aniline (1.00 g, 3.14 mmol), trimethylboroxin (1.16 ml, 1.04 g, 8.33 mmol), potassium carbonate (1.15 g, 8.33 mmol) and catalytic amount (10%) Pd(PPh3)4 in DMF (5 ml) was heated to 90° C. for 14 h. Water (10 ml) was added. The mixture was extracted with ethyl acetate (3×20 ml). The combined EtOAc layers were washed with brine and dried over sodium sulfate. The titled compound was obtained as a colorless oil after a flash column using EtOAc:hexane (1:9) as the elute. 1H NMR (CDCl3, 500 MHz): δ 7.28 (s, 1H), 7.22 (s, 1H), 3.88 (br s, 2H), 2.21 (s, 6H).
Reaction SMILES: COC1C=CC(C[NH:8][CH2:9][C:10]2[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])=CC=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>CC#N.O>[CH3:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[N:12]=[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:28])[F:29])[C:10]([CH2:9][NH2:8])=[CH:19]2
Reactant: COc1ccc(CNCc2cc3cccc(C)c3nc2-c2ccccc2C(F)(F)F)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: Cc1cccc2cc(CN)c(-c3ccccc3C(F)(F)F)nc12

Procedure:
Prepared according to Procedure G using N-(4-methoxybenzyl)(8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methanamine (1.1427 g, 2.62 mmol, 1 eq) and ammonium cerium(iv) nitrate (3.59 g, 6.55 mmol, 2.5 eq) in CH3CN—H2O (2:1, 12 mL). After purification, (8-methyl-2-(2-(trifluoromethyl)phenyl)quino-lin-3-yl)methanamine was obtained as brown syrup. 1H NMR (DMSO-d6) δ ppm 8.47 (1 H, s), 7.91 (1 H, d, J=7.4 Hz), 7.84 (1 H, d, J=7.4 Hz), 7.67-7.81 (2 H, m), 7.47-7.62 (3 H, m), 3.46-3.70 (2 H, m), 2.61 (3 H, s), 1.86 (2 H, br. s.). Mass Spectrum (ESI) m/e=317.0 (M+1).
Reaction SMILES: COC(=O)[NH:4][C@:5]1([C:9](=[O:27])[NH:10][C:11]2[S:12][C:13]([CH3:26])=[C:14]([CH3:25])[C:15]=2[C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:7][C@@H:6]1[CH3:8].N1CCCCC1.C(O)(=O)C>CN(C=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[C:15]3[C:14]([CH3:25])=[C:13]([CH3:26])[S:12][C:11]=3[NH:10][C:9](=[O:27])[C@:5]3([CH2:7][C@@H:6]3[CH3:8])[N:4]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)N[C@]1(C(=O)Nc2sc(C)c(C)c2C(=O)c2ccc(Cl)cc2)C[C@@H]1C
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@]1(C[C@@H]1C)C(=O)N2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.3 %

Procedure:
A round bottomed flask was charged with 9H-fluoren-9-yl)methyl-(1R,2S)-1-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-ylcarbamoyl)-2-methylcyclopropylcarbamate (225 mg, 0.385 mmol) and a stir bar. DMF (16 mL, 0.02 M) was added, followed by piperidine (4 mL, 40.4 mmol), and the solution was stirred at room temperature 15 min. The solution was washed with water, extracted twice with ethyl acetate, washed with brine, and concentrated before being taken up in ethanol (25 mL). Acetic acid (12.5 mL, 218 mmol) was added, and the solution was stirred at 90° C. 3 h before being concentrated with celite and purified by column chromatography to give (1R,2S)-5′-(4-chlorophenyl)-2,6′,7′-trimethylspiro[cyclopropane-1,3′-thieno[2,3-e][1,4]diazepin]-2′(1′H)-one (Compound 218) as a light yellow amorphous solid (96 mg). LRMS (M+H)+: 345 m/z.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:16]1([C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C2CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CC1)N1CCNCC1
Temperature: 25 °C

Procedure:
1-Tertbutoxycarbonyl-4-(cyclopropanecarbonyl) piperazine (254 mg, 1 mmol) was dissolved in dichloromethane, and then trifluoroacetic acid (1.5 mL) was added. The reaction mixture was stirred at room temperature until completed, and then washed with saturated sodium bicarbonate solution for three times. The organic phases were concentrated. N-(cyclopropanecarbonyl) piperazine was obtained for use.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[S:4].[CH3:6][O:7][C:8]([N:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:16]=2)[C@@:12]([C:30](=O)[CH2:31]Br)([CH3:29])[CH2:11]1)=[O:9]>CO>[CH3:6][O:7][C:8]([N:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH:16]=2)[C@:12]([CH3:29])([C:30]2[N:5]=[C:3]([NH:2][CH3:1])[S:4][CH:31]=2)[CH2:11]1)=[O:9]
Reactant: COC(=O)N1C[C@H](c2ccc(OC)c(OC3CCCC3)c2)[C@](C)(C(=O)CBr)C1
Reactant: CNC(N)=S
Solvent: CO
Product: CNc1nc([C@]2(C)CN(C(=O)OC)C[C@@H]2c2ccc(OC)c(OC3CCCC3)c2)cs1
Temperature: 70 °C

Procedure:
To a solution of 1-methyl-2-thiourea (0.038 g, 0.418 mmol) in methanol (1 mL), at 50° C., was added a solution of (3S,4R)-3-(2-bromoethanoyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-pyrrolidine-1-carboxylic acid methyl ester (0.19 g, 0.42 mmol) in methanol (1 mL). The temperature was raised to 70° C. and refluxed for 2 hours. The reaction mixture then was concentrated under reduced pressure and dissolved in acetonitrile-water (CH3CN—H2O) (1 mL) for purification by HPLC on a C18 column (Luna 10 μ, C18, 250×10 mm). Gradient elution of 50-100% acetonitrile-water (0.05% TFA) yielded the named product as a white powder after lyophilization (91 mg, 49%).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4]1[O:5][C:6]2[C:7](=[C:9]([C:13]([O-:15])=O)[CH:10]=[CH:11][CH:12]=2)[N:8]=1)[CH3:2].[Li+].Cl.Cl.[NH2:21][C@H:22]1[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1>>[N:24]12[CH2:23][C@@H:22]([NH:21][C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:6]4[O:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:16][CH3:17])=[N:8][C:7]=34)=[O:15])[CH:27]([CH2:28][CH2:29]1)[CH2:26][CH2:25]2
Reactant: CCN(CC)c1nc2c(C(=O)[O-])cccc2o1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: Cl
Agent: [Li+]
Product: CCN(CC)c1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1

Procedure:
Following general procedure GP-C2, lithium 2-(diethylamino)benzoxazole-4-carboxylate and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl)-2-diethylaminobenzoxazole-4-carboxamide, which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][C:28]([C:34]#[N:35])=[CH:29][CH:30]=4)[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([S:39]([CH3:38])(=[O:41])=[O:40])[C:22]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][C:28]([C:34]#[N:35])=[CH:29][CH:30]=4)[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)c3ccc4ccc(C#N)cc4c3)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(C(=O)c3ccc4ccc(C#N)cc4c3)S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N-[4-[(1-t-Butoxycarbonyl-4-piperidyl)oxy]phenyl]-7-cyano-2-naphthalenecarboxamide obtained in Reference Example 47 (200 mg) was dissolved in 4 ml of DMF, 52 mg of sodium hydride (content 60%) was added to the solution, and the mixture was stirred at room temperature for 20 minutes. While stirring at 0° C., 1 ml dimethylformamide solution of 100 ml methanesulfonyl chloride was added dropwise to the reaction solution, followed by 1 day of stirring at room temperature. The reaction solution was evaporated and ethyl acetate was added to the resulting residue. The mixture was washed with saturated sodium bicarbonate aqueous solution and 10% citric acid aqueous solution in that order, dried over anhydrous sodium sulfate, and then evaporated. The resulting residue was purified by silica gel column chromatography using hexane:ethyl acetate (8:2-7:3) as the eluent to give 143 mg of N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-7-cyano-N-methylsulfonyl-2-naphthalenecarboxamide.
Reaction SMILES: [CH3:1][C:2]([NH:4][CH:5]1[C:15]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=2[C:13]2[C:8](=[CH:9][C:10]([O:25][CH3:26])=[C:11]([O:23][CH3:24])[C:12]=2[O:21][CH3:22])[CH2:7][CH2:6]1)=[O:3].O[CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1>>[CH3:37][N:34]1[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][CH2:28][O:20][C:17]2[CH:18]=[CH:19][C:14]3[C:13]4[C:12]([O:21][CH3:22])=[C:11]([O:23][CH3:24])[C:10]([O:25][CH3:26])=[CH:9][C:8]=4[CH2:7][CH2:6][C@H:5]([NH:4][C:2](=[O:3])[CH3:1])[C:15]=3[CH:16]=2)[CH2:32][CH2:33]1
Reactant: CN1CCN(CCCO)CC1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OCCCN3CCN(C)CC3)cc1[C@@H](NC(C)=O)CC2
Yield: 22 %

Procedure:
Using an analogous procedure to that described for Example 7, N-acetyl-colchicinol was reacted with 4-(3-hydroxypropyl)-1-methylpiperazine to give N-[(5S)-3-(3-(4-methylpiperazin-1-yl)propoxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([S:14][CH2:15][CH3:16])[N:11]=[C:10]([NH2:17])[CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:19][CH:20](OC)OC>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([S:14][CH2:15][CH3:16])[N:11]3[CH:19]=[CH:20][N:17]=[C:10]3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(CBr)OC
Reactant: CCSc1nc(N)cc(-c2ccc(Br)cc2)n1
Solvent: C1CCOC1
Solvent: O
Product: CCSc1nc(-c2ccc(Br)cc2)cc2nccn12
Reaction time: 24 h
Yield: 77.3 %

Procedure:
To a slurry of 6-(4-bromophenyl)-2-(ethylthio)pyrimidin-4-amine (35.00 g, 112.8 mmol) in 20 mL of THF and 200 mL of water was added 2-bromo-1,1-dimethoxyethane (38.14 g, 225.7 mmol) at ambient temperature. The reaction flask was fitted with a condenser and the mixture was allowed to proceed with stirring at reflux overnight. After 24 hours, the reaction mixture was cooled and poured into 400 mL of water. The solid was collected by vacuum filtration. The wet solid was suspended in 500 mL of aqueous saturated sodium bicarbonate and gas evolution was observed. The mixture was stirred at ambient temperature for 10 minutes before it was extracted with DCM (8×500 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was then dried under high vacuum overnight to afford 7-(4-bromophenyl)-5-(ethylthio)imidazo[1,2-c]pyrimidine (31 g, 87.18 mmol, 77.27% yield). MS (apci) m/z=334.0 (M+H).
Reaction SMILES: N1C2C(=CC=C3C=CC=CC3=2)C[CH2:2]1.[C:14]1([N:20]2[C:28]3[C:23](=[C:24]([OH:33])[CH:25]=[C:26]4[CH:32]=[CH:31][CH:30]=[CH:29][C:27]4=3)C(C)(C)C2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O-]S(C(F)(F)F)(=O)=O.NC1C=CC=CC=1>[Pd]>[NH:20]([C:28]1[C:27]2[C:26](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[C:24]([O:33][CH3:2])[CH:23]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc2c3c(ccc2c1)CCN3
Reactant: CC1(C)CN(c2ccccc2)c2c1c(O)cc1ccccc21
Agent: [Pd]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: Nc1ccccc1
Product: COc1cc(Nc2ccccc2)c2ccccc2c1

Procedure:
A second preferred synthesis method suitable for the synthesis of benzoindoline compounds, e.g., N-phenyl-3,3-dimethyl-4-hydroxy-benzoindoline 9, is also shown in FIG. 1. In this method, the 3-methoxynapthalene-1-triflate 2 is derivatized with a primary amine, e.g., aniline, using a palladium catalyzed triflate coupling reaction to give a secondary amine, e.g., 1-anilino-3-methoxynapthalene 5. The secondary amine 5 is acetylated using an acid chloride, e.g., an haloacetylchloride, to give a disubstituted amide, e.g., 1-amido-3-methoxynapthalene 6. The tertiary amide 6 is cyclized using a Lewis-acid-catalyzed Friedel-Crafts cyclization procedure to give compound 7, e.g., using AlCl3. Compound 7 is than reduced, e.g., using LAH, to give Compound 8. Subsequent methoxy group deprotection by a boron tribromide deprotection procedure gives the benzoindoline, e.g., N-phenyl-3,3-dimethyl-4-hydroxy-benzoindoline 9. An example of this synthesis is provided in Example 2 below.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][CH2:8][C@@H:7]1[C:12]([OH:14])=O.[NH2:18][CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:20]([OH:24])[C:21]([NH2:23])=[O:22].O[NH-].O=[N-]>>[NH2:23][C:21](=[O:22])[C:20](=[O:24])[CH:19]([NH:18][C:12]([C@H:7]1[CH2:8][CH2:9][C:10](=[O:11])[N:6]1[CH2:5][C:4]1[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=1)=[O:14])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1cccc(F)c1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1cccc(F)c1

Procedure:
Coupling of (R)-1-(3-fluoro-benzyl)-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([NH2:11])=[CH:4][N:3]=1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1>CC(O)=O.CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([N:11]=[C:18]([C:15]3[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=3)[N:8]2[CH2:9][CH3:10])=[CH:4][N:3]=1
Reactant: O=Cc1ccncc1
Reactant: CCNc1nc(Cl)ncc1N
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: CCn1c(-c2ccncc2)nc2cnc(Cl)nc21
Temperature: 140 °C
Yield: 15.4 %

Procedure:
To a solution of 8.6 g (50 mmol, 1.0 eq.) of 2-chloro-N4-ethylpyrimidine-4,5-diamine (I-5) in 200 mL of 2% v/v AcOH/DMA was added 6.0 mL (65 mmol, 1.3 eq.) of 4-pyridine carboxaldehyde. The mixture was heated at 140° C. for 14 h. The mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was purified by preparative HPLC to provide 2.0 g (7.7 mmol, 15%) of 2-chloro-9-ethyl-8-(pyridin-4-yl)-9H-purine (I-6).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21]C)=[CH:18][CH:19]=2)[CH2:14][C:13]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][CH:24]=1.[CH2:31]([SH:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[H-].[Na+]>CN(C)C=O>[CH2:31]([S:37][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=2)[CH2:14][C:13]=1[C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCS
Reactant: COc1ccc(C2=C(CCCCCCCCCCBr)c3ccc(OC)cc3C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCSCCCCCCCCCCC1=C(c2ccc(O)cc2)Cc2cc(O)ccc21
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A solution of 1-(10-bromodecyl)-5-methoxy-2-p-methoxyphenylind-1-ene (0.24 g.) in dimethylformamide (1 ml.) was added to a stirred solution of hexanethiol (0.07 g.) and sodium hydride (0.029 g. of a 50% dispersion in mineral oil from which the oil had been washed with petroleum ether) in dimethylformamide which had been stirred at laboratory temperature under an atmosphere of argon for 15 minutes, and the mixture was heated at 60° C. for 2 hours, cooled and water (5 ml.) was added. The mixture was extracted 3 times with ethyl acetate (5 ml. each time) and the combined extracts were washed with water, dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 1:1 v/v mixture of toluene and petroleum ether (b.p. 60°-80° C.) as eluant. The methoxy groups were removed by treatment with boron tribromide in a similar manner to that described in Example 7, and the residue was purified by chromatography on a silica gel column using a 9:1 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained as an oil 1-(10-hexylthiodecyl)-2-p-hydroxyphenylind-1-en-5-ol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [CH2:1]1[O:8]C(=O)C[O:4][C:2]1=[O:3].[CH3:9][C@@H:10]1[O:17]C(=O)[C@H](C)[O:13][C:11]1=[O:12]>>[C:2]([OH:4])(=[O:3])[CH2:1][OH:8].[C:11]([OH:13])(=[O:12])[CH:10]([CH3:9])[OH:17]
Reactant: C[C@@H]1OC(=O)[C@H](C)OC1=O
Reactant: O=C1COC(=O)CO1
Product: CC(O)C(=O)O
Product: O=C(O)CO

Procedure:
Polymerization and post-treatment were performed in the same manner as in Polymer Preparation Example 1 except that a mixture of 196 g of glycolide and 4 g of L-(-)-lactide (product of Tokyo Kasei Kogyo Co., Ltd.) was used in place of 200 g of glycolide, thereby obtaining a glycolic acid-lactic acid copolymer [Polymer (P-2)]. The same process was conducted repeatedly to prepare a necessary amount of Polymer (P-2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:18]1[O:20][CH2:19]1.C(O)(=O)[C:22]1[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([OH:27])=[O:26])[CH:23]=1.C(OCCCC)(=O)C1C(=CC=CC=1)[C:36]([O:38]CCCC)=[O:37].[N-]=C=O.NC(OCC)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1.[CH2:19]1[O:20][CH2:18]1.[C:25]([OH:27])(=[O:26])[C:24]1[CH:23]=[CH:22][C:30]([C:36]([OH:38])=[O:37])=[CH:29][CH:28]=1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Reactant: CCCCOC(=O)c1ccccc1C(=O)OCCCC
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: CCOC(N)=O
Agent: [N-]=C=O
Solvent: C1CO1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(C(=O)O)cc1
Temperature: 110 °C

Procedure:
In a reaction vessel having a cooler, a stirrer and a nitrogen introducing tube, 343 parts of adduct of bis-phenol A and 2 moles of ethylene oxide, 166 parts of iso-phthalic acid and 2 parts of dibutyl phthalate are put, and reacted for 8 hours at 230° C. under an ordinal pressure, and further reacted for 5 hours under a reduced pressure of from 10 to 15 mmHg (from 1.33 to 1.99 Pa) and then cooled by 110° C. Then 17 parts of isoborondiisocyanate was added in toluene and reacted for 5 hours at 110° C., and the solvent was removed. Thus Urethane-modified Polyester 1 was obtained, which has a weight average molecular weight of 72.000 and a free isocyanate content of 0.7%. Besides, 570 parts of adduct of bis-phenol A and 2 moles of ethylene oxide and 217 parts of terephthalic acid were condensed-polymerized for 6 hours at 230° C. in a manner similar to the above-mentioned. Thus unmodified Polyester 1 with a number average molecular weight of 2.400, a hydroxide group value of 51 and an acid value of 5. In 2,000 parts of ethyl acetate, 200 parts of Urethane-modified Polyester 1 and 800 parts of Polyester 1 were dissolved and mixed to obtain Resin Solution 1. The Tg of the resin component in the Resin Solution 1 was 64° C.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH3:11][C:12]1[N:13]=[CH:14][S:15][C:16]=1[CH3:17]>O>[Cl-:1].[C:5]1([CH:3]([OH:4])[CH2:2][N+:13]2[C:12]([CH3:11])=[C:16]([CH3:17])[S:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1ncsc1C
Reactant: OC(CCl)c1ccccc1
Solvent: O
Product: Cc1sc[n+](CC(O)c2ccccc2)c1C
Product: [Cl-]
Temperature: 135 °C
Reaction time: 28 h

Procedure:
The neat mixture of 2-chloro-1-phenylethanol (2.34 g, 14.9 mmol) and 4,5-dimethylthiazole (1.69 g, 14.9 mmol) were heated with stirring at 135° C. for 28 hrs. It was cooled to room temperature and water (30 mL) was added to the reaction mixture with stirring, and then was extracted with ether (30 mL). The water layer was treated with actived carbon and evaporated to dryness. It was crystallized from a mixture of acetonitrile and ether to give a racemic product as prisms; 0.39 g (9.7%); mp. 201-203° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C@@H:11]([CH2:23][CH2:24][C:25]([NH:27][NH2:28])=[O:26])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:29](Cl)(Cl)Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:14])=[O:15])[C@@H:11]([CH2:23][CH2:24][C:25]3[O:26][CH:29]=[N:28][N:27]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2[C@@H](CCC(=O)NN)CC[C@H]2c2ccc(F)cc2)cc1
Reactant: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2[C@@H](CCc3nnco3)CC[C@H]2c2ccc(F)cc2)cc1

Procedure:
The title compound, light yellow oil, MS: m/e=416.1 (M+H′) and [α]D2=−80.1° (c=0.2211 in chloroform), was prepared in accordance with the general method of example 127 from (2R,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid hydrazide and triethyl orthoformiate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12.I[CH2:14][CH2:15][CH3:16]>>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:14][CH2:15][CH3:16])[C:7]=12
Reactant: Cc1[nH]c2c(Cl)nccc2c1C
Reactant: CCCI
Product: CCCn1c(C)c(C)c2ccnc(Cl)c21
Yield: 95 %

Procedure:
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and 1-iodopropane, the titled compound was obtained as a white solid. (Yield: 95%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[NH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24].C([O-])([O-])=O.[Na+].[Na+].O>CC#N.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:28]3[CH:29]=[CH:30][C:25]([C:23]([NH2:22])=[O:24])=[CH:26][CH:27]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(C(N)=O)cc3)c3cc(Br)cnc32)cc1
Yield: 79 %

Procedure:
5-Bromo-3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (Intermediate BZ, 483 mg, 1.01 mmol), 4-aminocarbonylphenylboronic acid (196 mg, 1.22 mmol) and dichlorobis(triphenylphosphine)palladium (II) (71 mg, 0.1 mmol) were combined in CH3CN (10 ml) and 1 M Na2CO3 (10 ml) and stirred at 60° C. for 3 hrs. Water was added and the mixture was extracted with DCM and purified by silica gel chromatography using 0-30% EtOAc/Hexanes. The title compound was obtained in 79% yield (373 mg). 1H NMR (CDCl3, 300 MHz): δ 8.51 (d, J=1.2 Hz, 1H), 8.20 (d, J=1.2 Hz, 1H), 8.11 (d, J=5.1 Hz, 2H), 7.96 (s, 1H), 7.93 (d, J=5.0 Hz, 2H), 7.64 (d, J=5.1 Hz, 2H), 7.31 (d, J=4.8 Hz, 2H), 6.1 (bs, 1H), 5.7 (bs, 1H), 2.39 (s, 3H).