Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12])([CH3:4])([CH3:3])[CH3:2].O1CCC[CH2:15]1.[H-].[Na+].CI>ClCCl>[C:1]([O:5][C:6](=[O:13])[N:7]([CH3:15])[CH2:8][CH2:9][CH2:10][C:11]#[CH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: C#CCCCNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CI
Product: C#CCCCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 500 mL round bottom flask was charged with pent-4-ynyl-carbamic acid tert-butyl ester (5.0 g, 27.3 mmol) and tetrahydrofuran (138 mL) and the resulting mixture cooled with an ice/water bath. Sodium hydride (830 mg, 32.9 mmol) was added in 3 portions and the resulting mixture stirred at room temperature for 20 minutes. Methyl iodide (8.6 mL, 138.1 mmol) was slowly added and the resulting mixture stirred for 72 h. The resulting mixture was diluted with dichlormethane (350 mL), washed with 1N HCl (100 mL), 1N, NaOH (100 mL), and water (100 mL). The organic layer was washed with MgSO4, filtered, then concentrated in vacuo to yield methyl-pent-4-ynyl-carbamic acid tert-butyl ester. 1H NMR (300 MHz, CDCl3) δ 3.31 (t, J=7.0 Hz, 2H), 2.86 (s, 3H), 2.17-2.24 (m, 2H), 1.96 (s, 1H), 1.72-1.79 (m, 2H), and 1.46 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(N(CC)CC)C.Cl[CH2:21][C:22](Cl)=[O:23].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]2[O:12][CH2:21][C:22](=[O:23])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Reactant: O=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1COc2cc([N+](=O)[O-])c(Cl)cc2N1
Yield: 52.5 %

Procedure:
Using 2-amino-4-chloro-5-nitrophenol (3.0 g, 15 mmol), triethylamine (2.7 mL, mmol) and chloroacetyl chloride (2.0 g, 17 mmol) in THF (100 mL) followed by sodium hydride (1.3 g of a 60% suspension in oil, 30 mmol) to yield the title compound as an orange solid (1.8 g, 54%). δH (DMSO-d6) 4.74 (2H, s), 7.07 (1H, s), 7.77 (1H, s), 11.29 (1H, br s).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=2)[C:28]([NH:30][CH3:31])=[O:29])[C:21]([Cl:35])=[CH:20][N:19]=1>>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=2)[C:28]([NH:30][CH3:31])=[O:29])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CNC(=O)c1cccc(Nc2nc(Cl)ncc2Cl)c1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: CNC(=O)c1cccc(Nc2nc(Nc3ccc4c(c3)CCN(CCOC)CC4)ncc2Cl)c1
Yield: 38 %

Procedure:
In an analogous procedure to Example 651, part c, 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 3-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide were combined to yield 3-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide (29.56 mg, 38% yield) as a beige amorphous solid. 1H-NMR (CDCl3) δ 8.07 (s, 1H), 7.97 (s, 1H), 7.75 (m, 1H), 7.52 (m, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.22 (m, 1H), 6.97 (t, J=7.9 Hz, 1H), 5.99 (br s, 1H), 3.54 (m, 2H), 3.35 (s, 3H), 2.90 (m, 5H), 2.81 (m, 1H), 2.74 (m, 6H). LC/MS (ESI+)=481 (M+H). MP=102.5° C. dec.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH2:13][C:14](=O)[CH3:15])[N:7]=1)=[O:5])[CH3:2].Cl.[Cl:18][C:19]1[CH:20]=[C:21]([NH:25]N)[CH:22]=[CH:23][CH:24]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:22]3[C:21](=[CH:20][C:19]([Cl:18])=[CH:24][CH:23]=3)[NH:25][C:14]=2[CH3:15])[N:7]=1)=[O:5])[CH3:2]
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)c1cccc(SCC(C)=O)n1
Agent: Cl
Product: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)n1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 6-(2-oxo-propylsulfanyl)-pyridine-2-carboxylic acid ethyl ester and (3-chloro-phenyl)-hydrazine hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[O:15])=[N:11][N:10]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>CN(C=O)C.N1C=CC=CC=1>[C:29]([N:26]1[CH2:27][CH2:28][N:23]([C:20]2[N:19]=[CH:18][C:17]([NH:16][C:14]([C:12]3[O:13][C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[N:10][N:11]=3)=[O:15])=[CH:22][CH:21]=2)[CH2:24][CH2:25]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1nnc(Nc2ccccc2F)o1
Reactant: O=C(Cl)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(N2CCN(C(=O)c3ccccc3)CC2)nc1)c1nnc(Nc2ccccc2F)o1
Reaction time: 18 h
Yield: 68.4 %

Procedure:
5-[(2-Fluorophenyl)amino]-N-(6-piperazin-1-ylpyridin-3-yl)-1,3,4-oxadiazole-2-carboxamide (intermediate 41, 150 mg, 0.39 mmol), was stirred in DMF (4 mL) and pyridine (1 mL). Benzoyl chloride (60 mg, 0.43 mmol) was added and the reaction stirred for 18 h. Water (20 mL) was added and the reaction mixture thoroughly mixed. The resulting precipitate was filtered, washed with water (2×10 mL) then ether (2×10 mL) and dried in vacuo to give the title compound (130 mg) as a pale purple solid:
Reaction SMILES: C([O:5][C:6](=[O:36])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:35])[CH2:13][CH2:14][S:15][C:16](=[O:34])[C@H:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH2:18])(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][C@@H:17]([C:16]([S:15][CH2:14][CH2:13][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:36])=[O:5])=[O:35])=[O:34])[NH2:18])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CCSC(=O)[C@@H](N)Cc1ccccc1C(=O)c1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1C(=O)c1ccccc1)C(=O)SCCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 3 h

Procedure:
The product of Example 17, N-(2-benzoylphenylalanylthiopropanoy L-proline-t-butyl ester, 1.25 g, was suspended in 4 ml anisole and with 8 ml trifluoroacetic acid for 1 hour at room temperature with stirring. In view of the fact that some starting material was later recovered, the reaction time should be increased. Trifluoroacetic acid was removed with a rotary evaporator under high vacuum. The residue was dissolved in 1 ml THF and chromatographed on a 2.2 cm×99 cm column of Sephadex LH-20 eluted with THF. Fractions of about 5.3 ml were collected. The product was eluted in fractions 41-43. The combined fractions 41-43 were evaporated to dryness, dissolved in a small amount of isopropanol and rechromatographed on a 1.2 cm×95 cm LH-20 column, eluted with isopropanol. Fractions of about 2.05 ml were collected. Fractions 48-50 contained 78 mg of the desired compound as an oil. Side fractions 46-47 and 51-53 were saved for rechromatography. The oil was dissolved in a small volume of THF in a vial, then the THF was evaporated under a stream of N2 . The vial was then placed in a round bottom flask connected to a rotary evaporator. After 3 hr under high vacuum, a stable, dry foam was obtained.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2([CH3:12])[CH2:11][CH2:10]2)=[N:5][N:4]=[C:3]1[SH:13].[CH3:14]O.CI>[OH-].[Na+]>[NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2([CH3:12])[CH2:10][CH2:11]2)=[N:5][N:4]=[C:3]1[S:13][CH3:14]
Reactant: CC1(c2nnc(S)n(N)c2=O)CC1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Product: CSc1nnc(C2(C)CC2)c(=O)n1N
Reaction time: 6 h
Yield: 82.3 %

Procedure:
198 g of compound obtained according to (b) is dissolved in 500 ml of 2 N NaOH, and 500 ml of methanol and 150 g of methyl iodide are added. The reaction mixture is stirred at 20° to 30° C. for 6 hours. The crystals which have formed are filtered off with suction, washed and dried to yield 174.5 g of final product (dried in vacuo at 40° C.); white crystals; melting point 115° to 116° C.; yield 82.3% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Br[CH2:39][CH2:40][F:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:39][CH2:40][F:41])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: FCCBr
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: COc1ccc(CC2c3cc(OCCF)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 1-bromo-2-fluoro-ethane
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[CH:8][CH:7]=1
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Reactant: Oc1ccc(-c2nnco2)cc1
Product: Fc1ccc(N2CCN(CCCOc3ccc(-c4nnco4)cc3)CC2)cc1
Yield: 66 %

Procedure:
The preparation is carried out as described in Example 1, using 4-(1,3,4-oxadiazol-2-yl)-phenol and 1-(3-chloropropyl)-4-(4-fluorophenyl)-piperazine. The crude product is recrystallized from toluene and subsequently from ethanol, and a product of melting point 157°-158° C. is obtained (yield: 66%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].[CH3:12][Li].[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]([OH:5])[CH3:12]
Reactant: [Li]C
Reactant: COc1cccc(F)c1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc(F)c1C(C)O
Reaction time: 1 h

Procedure:
To a solution of 2-fluoro-6-methoxybenzaldehyde (0.5 g) in tetrahydrofuran (10 mL) was added methyllithium (1.15 mol/L diethyl ether solution, 3.4 mL) at −78° C., and the mixture was stirred at the same temperature for 1 hour. Then the mixture was stirred at room temperature for 30minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.45 g).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23]>C1COCC1>[CH:1]([NH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23])=[O:2]
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: O=CO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(NC=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To formic acid (75 mL) was added dropwise acetic anhydride (50 mL) at room temperature, and the mixture was stirred at room temperature for 40 min. A mixture of methyl 4-amino-3-methoxybenzoate (25 g) in THF (100 mL) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Ice water (700 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration. The solid was washed with water (400 mL) to give the title compound (25.8 g).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][S:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)[CH:30]=2)=[O:28])[C:14]=1[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]>ClCCl>[CH3:12][C:13]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][S:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)[CH:30]=2)(=[O:9])=[O:28])[C:14]=1[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc(CS(=O)c2cccc(OCc3ccc4ccccc4n3)c2)c1C(=O)OCC(C)C
Solvent: ClCCl
Product: Cc1cccc(CS(=O)(=O)c2cccc(OCc3ccc4ccccc4n3)c2)c1C(=O)OCC(C)C
Reaction time: 8 h

Procedure:
m-Chloroperbenzoic acid (<86%, 62 mg, 0.31 mmol) is added to a solution of isobutyl 2-methyl-6-[3-(quinolin-2-ylmethoxy)-phenylsulfanylmethyl]-benzoate (73 mg, 0.16 mmol, example 85) in dichloromethane (1 mL) and the reaction is stirred overnight. The reaction is partitioned between ethyl acetate and sodium bicarbonate and the organic phase is washed with additional bicarbonate solution, dried over magnesium sulfate, concentrated and purified by column chromatography (silica, 30% ethyl acetate in hexanes) to provide the title compound. MS (ESI) 504 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.C([O-])(O)=O.[Na+].Cl.Cl[CH2:17][CH2:18][N:19]([CH3:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[K+]>CCO>[CH2:20]([N:19]([CH2:18][CH2:17][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH3:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc2c(c1)CNC2
Reactant: CN(CCCl)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCO
Product: CN(CCN1Cc2ccccc2C1)Cc1ccccc1

Procedure:
A solution of 1,3-dihydroisoindole [Bornstein, J.; Shield, J. E.; Boisselle, A. P. Organic Synthesis, Collective Vol 5; John Wiley & Son, Inc; New York, 1973, 406-408](2.30 g, 19.3 mmol), NaHCO3 (5.59 g, 66.6 mmol), and N-(2-chloroethyl)-N-methylbenzenemethanamine hydrochloride (4.25 g, 19.3 mmol) in anhydrous EtOH was refluxed overnight under an atmosphere of N2. The black, opaque mixture was filtered and the solids were washed with EtOH. The filtrate was concentrated to give a black slurry. The slurry was dissolved into a 1.0 N KOH solution (25 mL) and was extracted with EtOAc (3×10 mL). The combined organic layers were washed with a 5% NaHCO3 solution (10 mL), H2O (10 mL), and brine (10 mL) and then dried over MgSO4. The filtrate was concentrated in vacuo and purified by medium pressure column chromatography [silica gel, NH4OH:EtOH:CHCl3 (1:4:95)] to give the title compound as a black oil (2.22 g). The proton NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:13])[NH:8]3.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33].O>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:13])[N:8]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Reactant: Cc1nc2cccc3[nH]c(=O)c1n23
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2cccc3n(CCCCCCN4C(=O)c5ccccc5C4=O)c(=O)c1n23
Yield: 28.7 %

Procedure:
To a suspension of 5.20 g (30 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one in 60 ml of DMF was added, while stirring under ice-cooling, 1.44 g (36 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 15 minutes at the same temperature. To the reaction mixture was added a DMF solution (20 ml) of 9.31 g (30 mmol) of N-(6-bromohexyl)phthalimide. The mixture was stirred for 1.5 hour at 110° C. After cooling, the reaction mixture was poured into water, which was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by column chromatography (eluent: ethyl acetate/ethanol=10:1) to give 3.47 g of the desired compound (28.7%, pale brown solid). NMR(200 MHz,CDCl3) δ: 1.33-1.56(4H,m), 1.68(2H,m), 1.85(2H,m), 2.82(3H,s), 3.67(2H,t,J=7.2 Hz), 4.04(2H,t,J=7.2 Hz), 6.78(1H,d,J=7.4 Hz), 7.47(1H,d,J=8.6 Hz), 7.69(1H,dd,J=8.6,7.4 Hz), 7.67-7.76(2H,m), 7.78-7.88(2H,m).
Reaction SMILES: C(OC)(=O)C1C=CC(C(OC)=O)=CC=1.[CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([O:27]C)=[O:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[C:29]([O:31]C)=[O:30].O=[Sb]O[Sb]=O.C(O)(=O)C1C=CC(C(O)=O)=CC=1>C(O)CO>[CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([OH:27])=[O:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[C:29]([OH:31])=[O:30]
Reactant: COC(=O)c1ccc2cc(C(=O)OC)ccc2c1
Agent: COC(=O)c1ccc(C(=O)OC)cc1
Agent: O=C(O)c1ccc(C(=O)O)cc1
Agent: O=[Sb]O[Sb]=O
Solvent: OCCO
Product: O=C(O)c1ccc2cc(C(=O)O)ccc2c1

Procedure:
The ester exchange reaction was carried out according to a conventional method in a mixture of 100 weight % dimethyl terephthalate, 14 weight % dimethyl naphthalene-2,6-dicarboxylate and 80 weight % ethylene glycol. The resulting mixture was mixed with 0.05 weight % antimony trioxide and gradually heated and evacuated. Polymerization was carried out at 280° C. and 0.5 mmHg. Thus, modified polyester containing a terephthalic acid and naphthalene-2,6-dicarboxylic acid unit (90/10, mol ratio) was obtained. The intrinsic viscosity of the resulting modified polyester was 0.7 cc/g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][Br:15]
Reactant: COC(=O)CCCc1ccccc1O
Reactant: BrCCCCCBr
Product: COC(=O)CCCc1ccccc1OCCCCCBr
Yield: 81 %

Procedure:
Using the procedure of example 108, 2-hydroxybenzenebutanoic acid methyl ester was converted into the title compound by alkylation with 1,5-dibromopentane, in 81% yield, as a colorless oil.
Reaction SMILES: [N:1]1([C:6]2[S:7][C:8]([C:12](=[S:14])[NH2:13])=[C:9]([NH2:11])[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.BrBr>>[NH2:13][C:12]1[S:14][N:11]=[C:9]2[N:10]=[C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[S:7][C:8]=12
Reactant: NC(=S)c1sc(N2CCCC2)nc1N
Agent: BrBr
Agent: O=S(=O)(O)O
Product: Nc1snc2nc(N3CCCC3)sc12
Yield: 91 %

Procedure:
11 parts of 2-pyrrolidino-4-amino-5-thiocarbamoyl-thiazole in 70 parts of sulfuric acid are oxidized with 0.5 part of bromine by the method described in Example 1(b). 10 parts of 3-amino-5-pyrrolidino-thiazolo-(4,5-c)-isothiazole (91% of theory) of melting point 270°-273° C. are obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Br:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1>C(Cl)Cl>[Br:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.2 %

Procedure:
A solution of triphenylphosphine (168 mg, 0.64 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (114 mg, 0.64 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 72, 200 mg, 0.53 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 25 min. The reaction mixture was then treated with 2-aminopyridine (110 mg, 1.17 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (175 mg, 73%) as a white foam: mp 99-101° C.; FAB-HRMS m/e calcd for C20H23BrN2O3S (M+H)+ 451.0692, found 451.0689.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.S(Cl)([Cl:16])=O>>[CH3:1][N:2]=[C:3]([Cl:16])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Product: CN=C(Cl)c1ccc([N+](=O)[O-])cc1
Yield: 25.9 %

Procedure:
N-Methyl 4-nitrobenzamide (30.0 g, 167 mmole) and thionyl chloride (256 g, 2.15 mole) were heated at reflux for five hours. The excess thionyl chloride was removed at ~15 mm Hg. Xylene was added to the reaction and distilled under reduced pressure to yield a solid which was recrystallized from petroleum ether to yield 8.6 g of the title compound as a light yellow solid, m.p. 67°-73° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([NH2:10])=[C:4]2[CH:3]=[N:2]1.C1C(=O)N([I:18])C(=O)C1.C([O-])(O)=O.[Na+]>CN(C=O)C>[I:18][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:10])[NH:1][N:2]=1
Reactant: Nc1ncnc2[nH]ncc12
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2[nH]nc(I)c12
Temperature: 60 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (3.0 g, 22.20 mmol, 1.0 eq) in DMF (30 mL), NIS (6.7 g, 24.42 mmol, 1.1 eq) was added at room temperature. The reaction mixture was stirred overnight at 60° C. The reaction mixture was cooled to room temperature and 10% aq. NaHCO3 (150 mL) was added to the reaction mixture. The solid was filtered and re-crystallization from DMF solvent to give 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4.0 g, 69% in yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:19]2[CH:20]=[C:21]([CH:33]=[CH:34][CH:35]=2)[C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29](Cl)=[CH:28][CH:27]=2)=[O:23])=[N:6][C:7]=1[C:8]1[NH:12][C:11]([C@H:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[N:10][N:9]=1.[ClH:36]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:19]2[CH:20]=[C:21]([CH:33]=[CH:34][CH:35]=2)[C:22]([NH:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([Cl:36])[CH:31]=2)=[O:23])=[N:6][C:7]=1[C:8]1[NH:12][C:11]([C@H:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[N:10][N:9]=1
Reactant: Nc1ncc(-c2cccc(C(=O)NCc3ccc(Cl)cc3)c2)nc1-c1nnc([C@H]2CCCNC2)[nH]1
Reactant: Cl
Product: Nc1ncc(-c2cccc(C(=O)NCc3cccc(Cl)c3)c2)nc1-c1nnc([C@H]2CCCNC2)[nH]1

Procedure:
3-(5-amino-6-{5-[(3S)-piperidin-3-yl]-4H-1,2,4-triazol-3-yl}pyrazin-2-yl)-N-[(4-chlorophenyl)methyl]benzamide): 1H NMR (400 MHz; DMSO-d6): 9.3 (t, 1H); 8.9 (m, 2H); 8.67 (s, 1H); 8.4 (d, 1H); 7.8 (d, 1H); 7.7 (m, NH); 7.6 (t, 1H); 7.2 (m, 4H); 4.5 (d, 2H); 3.6 (d, 1H); 3.4-3.1 (m, 3H); 3.0 (m, 1H); 2.1 (m, 1H); 1.8 (m, 3H); MS (EI) for C25H25N8OCl HCl: 489 (MH+).