Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4](C)[CH:5]=O.[CH:8]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])OCC.C([O-])([O-])=O.[Na+].[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[CH2:16]([O:15][CH:8]([O:12][CH2:13][CH3:14])[CH:4]([CH3:5])[CH2:3][CH2:2][Cl:1])[CH3:17]
Reactant: CCOC(OCC)OCC
Reactant: CC(C=O)CCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(OCC)C(C)CCCl
Temperature: 45 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
A mixture of 4-chloro-2-methylbutyraldehyde (4.8 g, 0.040 moles), triethyl orthoformate (6.48 g, 0.044 moles), ethyl alcohol (3.0 g), and p-toluenesulfonic acid monohydrate (0.0144 g, 0.000757 moles) was stirred at 45° C. overnight under an argon atmosphere. Next, after cooling to room temperature, Na2CO3 (0.40 g) was added and the mixture was stirred for 15 min. The reaction mixture was filtered and ethyl alcohol and residual triethyl orthoformate were distilled off under reduced pressure. The residue was subjected to fractional vacuum distillation giving 3.2 g of pure 4-chloro-2-methylbutyraldehyde diethyl acetal. NMR (d6-DMSO): 0.85 ppm (d, —CH3, 3H) 1.13 ppm (m, —CH3, 6H), 1.52 ppm (m, —CH—, 1H), 1.87 ppm (m, —CH2CH2Cl, 2H), 3.35-3.75 ppm (bm, —OCH2CH3, 4H, and —CH2Cl, 2H), 4.22 ppm (d, —CH acetal, 1H).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]([NH:29][C:30]2[C:35]([CH:36]([CH3:38])[CH3:37])=CC(O)=[CH:32][C:31]=2[CH:40]([CH3:42])[CH3:41])=[O:28])[CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][N:20]1[CH2:21][CH2:22][N:23]([CH2:26][C:27]([NH:29][C:30]2[C:35]([CH:36]([CH3:37])[CH3:38])=[CH:6][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:32][C:31]=2[CH:40]([CH3:42])[CH3:41])=[O:28])[CH2:24][CH2:25]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1cc(O)cc(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(C(C)C)c(NC(=O)CN2CCN(CCSc3nc4ccccc4o3)CC2)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Acetic anhydride (2 ml) was dropped into a solution of 2-[4-[2-(benzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-(2,6-diisopropyl-4-hydroxyphenyl)acetamide (149 mg, 0.3 mmol) in pyridine (1 ml) with ice cooling and the mixture was stirred at room temperature for 3 hours. The reaction solution was neutralized by adding a saturated aqueous solution of sodium bicarbonate thereto and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (developing solvent, chloroform:methanol=20:1) to provide 166 mg (yield 100%) of the desired compound as colorless needles.
Reaction SMILES: [F:1][C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[CH:17]=1)=[C:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2](=[C:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(F)c2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(=C1CCNCC1)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a solution of tert-butyl 4-(fluoro(3-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)methylene)piperidine-1-carboxylate (600 mg, 1.32 mmol) in CH2Cl2 (10 mL) was added TFA (0.98 mL, 13.26 mmol) dropwise maintaining ice-cooled conditions. The mixture was stirred for 1 h. The TFA was evaporated and the reaction mixture was partitioned between saturated NaHCO3 solution and CH2Cl2. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (340 mg). 1H NMR (500 MHz, CDCl3): δ 2.3 (m, 2H), 2.6 (m, 2H), 2.8 (m, 2H), 2.9 (m, 2H), 7.0 (d, 1H, J=8.5 Hz), 7.1-7.4 (m, 4H), 7.9 (d, 1H, J=2 Hz), 8.4 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH2:13][CH3:14])=[CH:5][C:6]=1[C:7]([O:9]CC)=O.Cl[C:16]1[N:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1>>[O:9]=[C:7]1[N:21]2[CH:20]=[C:19]([C:22]([OH:24])=[O:23])[CH:18]=[CH:17][C:16]2=[N:1][C:2]2[S:3][C:4]([CH2:12][CH2:13][CH3:14])=[CH:5][C:6]1=2
Reactant: CCCc1cc(C(=O)OCC)c(N)s1
Reactant: O=C(O)c1ccc(Cl)nc1
Product: CCCc1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1
Temperature: 180 °C

Procedure:
A mixture of 2-amino-5-propyl-3-thiophenecarboxylic acid, ethyl ester, 7.4 g (0.035 mol) and 6-chloro-3-pyridinecarboxylic acid (Aldrich Chemical Company), 6.4 g (0.041 mol) is heated in an oil bath at 180° C. for two hours. The mixture is cooled, extracted with hot chloroform and the residue is dissolved in hot pyridine, cooled and 0.45 g of 4-oxo-2-propyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid is collected; mp 250°-254° C. after recrystallization from pyridine.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH:6]12[CH2:14][CH2:13][CH:10]([CH2:11][CH2:12]1)[CH2:9][NH:8][CH2:7]2.C(N(CC)CC)C>C(OCC)C>[O:4]=[C:1]([N:8]1[CH2:9][CH:10]2[CH2:13][CH2:14][CH:6]([CH2:12][CH2:11]2)[CH2:7]1)[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: C1CC2CCC1CNC2
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(=O)N1CC2CCC(CC2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of acryloyl chloride (4.05 ml, 0.05 mole) in 50 ml of ethyl ether was added with stirring to a cold mixture of 3-azabicyclo[3.2.2]nonane (6.26 g, 0.05 mole) and triethylamine (15.3 ml, 0.11 mole) in 250 ml of ethyl ether. The ice bath was removed and the reaction was allowed to warm to room temperature and stirred for 72 hours. The resulting white material was filtered and washed well with ethyl ether and ethyl acetate. The solvent was removed on a rotary evaporator and the residue taken up in ethyl ether, hexane added and the solution chilled. The remaining small amount of insoluble material was filtered and the solvent evaporated, leaving the product as an oil. The structure was confirmed by NMR.
Reaction SMILES: [CH2:1]([C:3](=[CH2:6])[CH:4]=[O:5])[CH3:2].[SH:7][C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11]>C1COCC1.CCOCC>[C:10]([C:9]1[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=1[S:7][CH2:6][CH:3]([CH2:1][CH3:2])[CH:4]=[O:5])(=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(c1ccccc1)c1ccccc1S
Reactant: C=C(C=O)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(C=O)CSc1ccccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.6 %

Procedure:
To an ice bath cooled solution of 9.76 g (0.116 mole) of 2-ethylacrolein in 40 mL of dry THF was added 24.6 g (0.116 mole) of 2-mercaptobenzophenone in 40 mL of THF followed by 13 g (0.128 mole) of triethylanine. The reaction mixture was stirred at room temperature for 3 days, diluted with ether, and was washed successively with dilute HCl, brine, and 1 M potassium carbonate. The ether layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by HPLC (10% EtOAc-hexane) to give 22 g (64%) of 11 in the second fraction. An attempt to further purifiy this material by kugelronr distillation at 0.5 torr (160-190° C.) gave a fraction (12.2 g) which contained starting material indicating a reversed reaction during distillation. This material was dissolved in ether (100 mL) and was washed with 50 mL of 1 M potassium carbonate three times to give 6.0 g of a syrup which was purified by HPLC (10% EtOAc-hexane) to give 5.6 g of pure 11.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[O:5][CH:6]([CH3:10])[C:7]([OH:9])=O.[N+]([O-])(O)=O.[O:18]([CH2:22][CH2:23][NH2:24])[N+:19]([O-:21])=[O:20].C(OC(C)C)(C)C>>[O:18]([CH2:22][CH2:23][NH:24][C:7](=[O:9])[CH:6]([O:5][C:4]1[CH:11]=[CH:12][CH:13]=[C:2]([Cl:1])[CH:3]=1)[CH3:10])[N+:19]([O-:21])=[O:20]
Reactant: NCCO[N+](=O)[O-]
Reactant: CC(Oc1cccc(Cl)c1)C(=O)O
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: CC(Oc1cccc(Cl)c1)C(=O)NCCO[N+](=O)[O-]
Yield: 56.8 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.71 g of 2-(3-chlorophenoxy)propionic acid and 0.6 g of 2-nitroxyethylamine nitrate, 0.58 g of the title compound was obtained as colorless acicular prisms (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.C(N(CC)CC)C.Cl[C:30]([O:32][CH3:33])=[O:31]>ClCCl>[F:11][C:10]([F:13])([F:12])[C:6]1[CH:5]=[C:4]([CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:2][NH:1][C:30](=[O:31])[O:32][CH3:33])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(CN)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCC(NC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
Of the compound from Example 101A, 500 mg (1.64 mmol) were introduced in dichloromethane together with 320 μl (2.30 mmol) of triethylamine, with ice cooling, and 152 μl (1.97 mmol) of methyl chloroformate were added. The ice bath was removed and the mixture was stirred for a further 1 h. The solvent was removed on a rotary evaporator and the residue was purified by preparative HPLC [Method 20]. The product fractions were combined and freed from the solvents on a rotary evaporator, and the residue was dried in an HV. This gave 428 mg (72% of theory) of the title compound.
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.[CH2:40]([O:42]C(=O)CN1CCC2C(=CC(N)=CC=2)C1)[CH3:41]>>[CH2:40]([O:42][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:41]
Reactant: CCOC(=O)CN1CCc2ccc(N)cc2C1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that (7-amino-3,4-dihydro-1H-isoquinolin-2-yl)-acetic acid ethyl ester was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (DMSO-d6) 9.90 (1H, brs), 7.54-7.42 (3H, m), 7.28-7.11 (4H, m), 4.78 (2H, m), 4.33 (2H, m), 4.09 (2H, m), 3.39 (3H, m), 3.00 (3H, m), 1.65-1.21 (6H, m), 1.12-1.04 (13H, m). The product was further characterised as the hydrochloride salt. Found: C, 47.05; H, 5.34; N, 7.72%; C33H41N5O5.HCl.3.4CH2Cl2 requires: C, 47.14; H, 5.48; N, 7.55%.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:19](=[O:26])[C:20](=[O:25])[C:21]=4OCC)=[CH:13][CH:12]=3)=[C:9]([CH2:27][CH3:28])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33]>C(O)C>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:19](=[O:26])[C:20](=[O:25])[C:21]=4[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[C:30]([CH3:29])[CH:31]=4)=[CH:13][CH:12]=3)=[C:9]([CH2:27][CH3:28])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOc1c(Nc2ccc(-c3c(CC)sc4ncnc(N)c34)cc2)c(=O)c1=O
Reactant: Cc1cccc(N)c1
Solvent: CCO
Product: CCc1sc2ncnc(N)c2c1-c1ccc(Nc2c(Nc3cccc(C)c3)c(=O)c2=O)cc1
Yield: 2.6 %

Procedure:
A mixture of Example 344A (0.027 g, 0.068 mol) and 3-methylaniline (0.073 mL, 0.68 mmol) in ethanol (2 mL) was stirred at reflux for 48 hours and concentrated. The residue was purified by silica gel chromatography with 5% methanol/dichloromethane to provide 8 mg of the desired product. MS (ESI(+)) m/e 346 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.17 (t, J=7.46 Hz, 3H); 2.32 (s, 3H); 2.66 (q, J=7.12 Hz, 2H); 6.80-7.00 (m, 2H); 7.20-7.50 (m, 4H); 7.67 (d, J=8.48 Hz, 2H); 8.28 (s, 1H); 10.11 (s, 1H); 10.30 (s, 1H).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17]CC2C=CC=CC=2)=[C:12]([CH2:25][CH3:26])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([OH:17])=[C:12]([CH2:25][CH3:26])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1cc(OC(=O)c2ccccc2)cc(C)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc(OC(=O)c2ccccc2)cc(C)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
Then, 8.4 g of crude 4-benzyloxy-3-ethyl-5-methylphenyl benzoate was dissolved in 100 ml of ethyl acetate, which was put into a reaction vessel, and the air in the vessel was replaced with nitrogen gas. Then, 0.5 g of 10% palladium on carbon was added, and the nitrogen gas in the vessel was replaced with hydrogen gas, followed by vigorous stirring at room temperature for 24 hours. The hydrogen gas in the vessel was replaced with nitrogen gas, after which the reaction mixture was filtered through cerite and the filtrate was concentrated under reduced pressure, which afforded 5.9 g of crude 3-ethyl-4-hydroxy-5-methylphenyl benzoate (95% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12](NCC(OCC=C)=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH:25]CC)C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:23][NH2:25])[CH2:13][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCNCC
Reactant: C=CCOC(=O)CN[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN)CC1
Reaction time: 0.08 h

Procedure:
To an Ar filled flask containing 5 g (4.33 mmol) of tetrakis(triphenylphosphine) palladium (Aldrich) and 15.92 g (50.96 mmol) of trans-4-t-butoxycarbonylaminocyclohexyl-(allyloxycarbonyl)methylamine was added 220 mL of dry THF. After the solids had dissolved, the solution was stirred for 5 min. and 50 mL (483 mmol) of diethylamine (Aldrich) was added in one portion. The solution was stirred at ambient temperature overnight. The solvents were removed by rotovap, and the residue partitioned between ice-cold 0.5M aq HCl and ethyl acetate. The organic layer was extracted with cold 0.5M aq HCl, and the combined aqueous layers washed with ethyl acetate, basified with aq NaOH and extracted with 3 x ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and solvents removed to give an oil that was chromatographed on 250 g of fine SiO2 using 90:10:1 chloroform-methanol-ammonium hydroxide to give 7.9 g (56%) of the title compound as a colorless semi-solid: NMR (CDCl3) d 0.5-1.5 (m, 4H), 1.8-1.3 (m, 1H), 1.44 (s, 9H), 1.81 (dm, J=10.3, 2H), 2.03 (din, J=10.3, 2H), 2.53 (d, J=6.6, 2H), 3.37 (br s, 1H), 4.44 (br s, 1H).
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([CH3:16])[CH:8]=1.Cl.[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:17])=[CH:8][C:9]=4[CH3:16])=[O:13])[CH2:32][CH2:33]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1
Reactant: Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Agent: Cl
Product: Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Yield: 16.3 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methylbenzoic acid (255 mg) described in Preparation Example 29 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (253 mg) described in Preparation Example 82 and by the reaction and treatment in the same manner as in Example 86, the title compound (74 mg) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([NH2:35])=[O:34]>>[C:33]([CH:28]1[N:27]([CH2:2][C:3]2[NH:8][C:7]([C:9]3[S:10][CH:11]=[CH:12][N:13]=3)=[N:6][CH:5]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[Cl:21])[C:4]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:32][CH2:31][O:30][CH2:29]1)(=[O:34])[NH2:35]
Reactant: NC(=O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(N)=O)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 45 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (2.75 g, 6 mmol) was reacted with morpholine-3-carboxamide (0.78 g, 6 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (1.37 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.Cl.[CH3:15]O>>[CH3:15][O:12][C:11]([C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([OH:1])[CH:10]=2)=[O:13]
Reactant: O=C(O)c1cc2ccc(O)cc2[nH]1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc2ccc(O)cc2[nH]1
Temperature: 90 °C
Yield: 77 %

Procedure:
To a solution of 6-hydroxy-1H-indole-2-carboxylic acid (5.0 g, 28.2 mmol) in MeOH (250 mL) was added concentrated HCl (3 mL) and the reaction mixture was heated (90° C., 3 h). The reaction mixture was cooled (rt) and concentrated in vacuo. The resulting residue was partitioned between EtOAc (50 mL) and H2O (200 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×200 mL). The organic layer was dried, filtered and concentrated in vacuo to provide the title compound as a yellow solid (4.2 g, 77%). MS (ESI): mass calcd. for C10H9NO3, 191.1; m/z found, 192.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=3)[CH:9]=2)=[C:4]([CH3:28])[CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][CH2:36][CH2:37]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:28][C:4]1[CH:3]=[C:2]([O:1][CH2:37][CH2:36][CH2:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=2)[CH:9]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3ccc(O)cc3C)c2)cc1
Reactant: OCCCc1ccccn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCc2cccc(-c3ccc(OCCCc4ccccn4)cc3C)c2)cc1
Temperature: 25 °C
Yield: 56.2 %

Procedure:
A solution of methyl 3-{4-[(4′-hydroxy-2′-methylbiphenyl-3-yl)methoxy]phenyl}propanoate (0.602 g, 1.60 mmol), 3-(pyridin-2-yl)propan-1-ol (0.822 g, 6.00 mmol) and triphenylphosphine (1.57 g, 6.00 mmol) in tetrahydrofuran (20 mL) under ice-cooling was stirred and diethyl azodicarboxylate (40% toluene solution, 2.72 mL, 6.00 mmol) was added. The mixture was warmed to room temperature and stirred for 42 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane) and preparative HPLC to give the title compound as a yellow viscous oil (0.446 g, yield 56%).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=O)=O)C=CC=CC=1.C(OC(=O)[N:28]([CH2:37][C:38]1[C:39]([O:45][CH3:46])=[N:40][CH:41]=[C:42]([F:44])[CH:43]=1)[C:29]1[N:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][N:30]=1)(C)(C)C>>[F:44][C:42]1[CH:43]=[C:38]([CH2:37][NH:28][C:29]2[N:30]=[CH:31][C:32]([CH2:35][C:12]3[C:13]4[C:14](=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=4)[NH:10][CH:11]=3)=[CH:33][N:34]=2)[C:39]([O:45][CH3:46])=[N:40][CH:41]=1
Reactant: COc1ncc(F)cc1CN(C(=O)OC(C)(C)C)c1ncc(C=O)cn1
Reactant: COc1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccccc1
Product: COc1cnc2[nH]cc(Cc3cnc(NCc4cc(F)cnc4OC)nc3)c2c1

Procedure:
(5-Fluoro-2-methoxy-pyridin-3-ylmethyl)-[5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine P-1599 is prepared in three steps from 1-benzenesulfonyl-3-iodo-5-methoxy-1H-pyrrolo[2,3-b]pyridine 16 and (5-fluoro-2-methoxy-pyridin-3-ylmethyl)-(5-formyl-pyrimidin-2-yl)-carbamic acid tert-butyl ester 123 as shown in Scheme 13.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:28]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:28][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]#[N:9]
Reactant: N#CCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(Br)c1ccccc1
Reaction time: 5 h

Procedure:
To a solution of benzyl cyanide (4.93 mL, 42.7 mmol) in CCl4 (275 mL) were added dibenzoyl peroxide (517 mg, 2.13 mmol) and N-bromosuccinimide (9.12 g, 51.2 mmol). The reaction mixture was heated to reflux and stirred for 5 hours and concentrated in vacuo to a volume of 100 mL. The solution was partitioned between CHCl3 and saturated NaHCO3 solution, and the aqueous layer was extracted with several portions of CHCl3. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford a yellow oil. Purification was achieved by flash column chromatography on silica gel using a gradient elution of 0-20% EtOAc/hexanes. Collection and concentration of the appropriate fractions yielded the title compound as a pale yellow oil. 1H NMR (400 MHz, d6-DMSO) δ 7.61-7.58 (m, 2H), 7.53-7.45 (m, 3H), 6.59 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([CH2:17]O)=[CH:5]2.[CH3:19][S:20]([C:23]1[C:31]2[C:26](=[CH:27][N:28]=[CH:29][CH:30]=2)[NH:25][N:24]=1)(=[O:22])=[O:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([CH2:17][N:25]1[C:26]3=[CH:27][N:28]=[CH:29][CH:30]=[C:31]3[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])=[N:24]1)=[CH:5]2
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Reactant: CS(=O)(=O)CCn1c(CO)cc2cc(Cl)ccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)CCn1c(Cn2nc(S(C)(=O)=O)c3ccncc32)cc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.9 %

Procedure:
To a solution of [5-chloro-1-(2-methanesulfonyl-ethyl)-1H-indol-2-yl]-methanol (287 mg, 1.0 mmol), 3-methanesulfonyl-1H-pyrazolo[3,4-c]pyridine (197 mg, 1.0 mmol) and PPh3 (786 mg, 3 mmol) in THF (50 mL) was added DIAD (606 mg, 3 mmol) dropwise in an ice-water bath under N2 protection. The mixture then stirred at RT overnight. The reaction was purified by preparative-HPLC to give the title product (13.5 mg, 2.8%).