Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)#[N:7].[OH-].[K+]>C(O)C.O>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:2][CH2:3][CH2:4][OH:5])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)#[N:7]
Reactant: OCCCBr
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(-c2ccc(OCCCO)cc2)cc1
Temperature: 25 °C

Procedure:
3-Bromo-1-propanol (5.6 g, 0.04 mol) and 4-cyano-4'-hydroxybiphenyl (6.0 g, 0.02 mol) were dissolved in ethanol (300 ml) and agitated at room temperature. To this solution was gradually dropwise added a solution of KOH (10 g) dissolved in water (20 ml), over 30 minutes, followed by stirring for 40 hours, distilling off about 200 ml of ethanol under reduced pressure, adding water (500 ml) to deposit solids, adding toluene (300 ml) to the mixture system, filtering off insoluble matter, washing the toluene solution twice with 2N-NaOH, then three times with water, drying over anhydrous sodium sulfate, distilling off toluene, and recrystallizing the resulting crystals from methanol to obtain 4-cyano-4'-(3-hydroxypropoxy)biphenyl. Yield: 2 g (28%). C-N: 109.0°-110.7° C. N-I: 113.6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[O:12]=[C:7]1[C:8]2[C:3](=[C:2]([NH:1][C:13](=[O:15])[CH3:14])[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][NH:6]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2c1CCNC2=O
Product: CC(=O)Nc1cccc2c1CCNC2=O
Temperature: 0 °C
Yield: 56 %

Procedure:
To 1.0 g (6.17 mmol) of 5-amino-3,4-dihydro-1(2H)-isoquinolinone was added 3 ml of acetic anhydride and the solution was warmed on a steam bath for one hour. It was poured into ice water and heated on a steam bath until all material dissolved. The solution was allowed to cool, the solid was collected, washed with water, and dried to give 0.7 g (56%) of product; mp 244°-246°.
Reaction SMILES: [OH-].[Li+].[CH:3]1([O:6][C:7]2[N:8]=[CH:9][C:10]([C:13]([O:15]C)=[O:14])=[N:11][CH:12]=2)[CH2:5][CH2:4]1.Cl>O1CCCC1.O>[CH:3]1([O:6][C:7]2[N:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=2)[CH2:4][CH2:5]1
Reactant: COC(=O)c1cnc(OC2CC2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(OC2CC2)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
Lithium hydroxide (264 mg, 6.28 mmol) is added to a solution of methyl 5-(cyclopropoxy)pyrazine-2-carboxylate (610 mg, 3.14 mmol) in tetrahydrofuran (10 mL) and water (0.5 mL). The reaction mixture is stirred for 1 hour at 50° C., cooled to ambient temperature, diluted with water, brought to pH=2 by slow addition of 1 M HCl, and extracted with dichloromethane (4 times). The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (550 mg, 97%). ES/MS (m/e): 181.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:6]=[CH:5]2.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21].C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)(C)C>[N:15]1([CH2:14][CH2:13][O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]=[C:2]([C:26]2[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=2)[C:20]#[N:21])[CH:11]=[CH:10]3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Brc1ccc2cc(OCCN3CCCC3)ccc2c1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: N#Cc1cccc(-c2ccc3cc(OCCN4CCCC4)ccc3c2)c1
Temperature: 85 °C

Procedure:
A mixture of the product from Example 37B (35 mg, 0.11 mmol), 3-cyanophenylboronic acid (22 mg, 0.15 mmol), PdCl2(PPh3)2 (4.2 mg, 6 μmol), and isopropanol (0.5 mL) was treated with 2 M aqueous sodium carbonate (80 μL) and heated at 85° C. overnight. The mixture was cooled to room temperature and partitioned between 2 M aqueous NaOH and dichloromethane. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were filtered through diatomaceous earth, concentrated, and chromatographed through silica with a gradient of 0%/50%/50% to 10%/40%/50% methanol/ethyl acetate/dichloromethane followed by 8% methanol/dichloromethane to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.86 (m, 4H), 2.73 (m, 4H), 3.01 (t, 2H), 4.28 (t, 2H), 7.22 (dd, 1H), 7.31 (d, 1H), 7.65 (t, 1H), 7.70 (dt, 1H), 7.75 (dd, 1H), 7.85-7.92 (m, 2H), 8.06 (dt, 1H), 8.07-8.13 (m, 2H); MS (ESI) m/z 343 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[CH:6]=1)[CH3:2].[N:19]([Si](C)(C)C)=[N+:20]=[N-:21].Cl[Sn](Cl)(Cl)Cl>CO>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([N:19]=[N+:20]=[N-:21])[O:14][CH2:15][CH2:16][OH:17])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(OCC2OCCO2)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CO
Product: CCOC(=O)c1cccc(OCC(N=[N+]=[N-])OCCO)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-([1,3]-dioxolan-2-ylmethoxy)-benzoic acid ethyl ester (2.02 g, 8 mmol) and azidotrimethylsilane (1.17 ml, 8.8 mmol) was added SnCl4 (60 μl) at room temperature under nitrogen. After 2 hr, 2% aqueous methanol (10 ml) was added to the reaction mixture and the reaction was stirred at room temperature for 30 minutes. All the solvents were evaporated under reduced pressure. The residue was co-evaporated with ethanol (2×10 ml). The residue was purified by column chromatography (3×20 cm). The product was eluted with 0 to 1% methanol in DCM. The title compound was obtained as a colourless oil (2.01 g, 85.1%). APCI-MS, m/z 267.90 (M−N2+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=O.[CH3:9][C:10]1([CH3:17])[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[CH3:9][C:10]1([CH3:17])[C:14](=[O:15])[CH:13]=[C:12]([CH:16]=[CH:7][C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)[O:11]1
Reactant: Cn1cccc1C=O
Reactant: CC1=CC(=O)C(C)(C)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cccc1C=CC1=CC(=O)C(C)(C)O1
Temperature: 70 °C
Yield: 64.6 %

Procedure:
To a solution of 1-methyl-2-pyrrolecarboxaldehyde (1.4 g, 12.7 mM) and 2,2,5-trimethyl-3(2H)-furanone (2.0 g, 15.9 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.6 mL, 1.6 mM). The reaction solution was heated at 70° C. for 48 hours. After the reaction solution was cooled to 0° C., saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a brown solid. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to give orange crystals (1.8 g, 65% yield), m.p. 98.5°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:17][O:18][C:19]3[C:24]([F:25])=[CH:23][C:22]([CH2:26][CH2:27][C:28](OCC)=[O:29])=[CH:21][C:20]=3[F:33])=[C:10]([C:13]([F:16])([F:15])[F:14])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([CH2:17][O:18][C:19]3[C:20]([F:33])=[CH:21][C:22]([CH2:26][CH2:27][CH2:28][OH:29])=[CH:23][C:24]=3[F:25])=[C:10]([C:13]([F:16])([F:14])[F:15])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(-c3ccc(Cl)cc3)csc2C(F)(F)F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCc1cc(F)c(OCc2c(-c3ccc(Cl)cc3)csc2C(F)(F)F)c(F)c1
Temperature: 0 °C

Procedure:
Into a 25-mL 2-necked round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 3-(4-[[4-(4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl]methoxy]-3,5-difluorophenyl)propanoate (60 mg, 0.12 mmol, 1.00 equiv), tetrahydrofuran (3.0 mL). This was followed by the addition of a solution of LiAlH4 (11.3 mg, 0.30 mmol, 2.51 equiv) in tetrahydrofuran (3.0 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at 25° C. The reaction progress was monitored by LCMS/TLC (ethyl acetate/petroleum ether=1:6). The reaction was then quenched by the addition of 5 mL of water and 2 mL 2N HCl. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a TLC-Plate with ethyl acetate/petroleum ether (1:1.5). This resulted in 0.041 g (75%) of 3-(4-[[4-(4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl]methoxy]-3,5-difluorophenyl)propan-1-ol as a white solid. 1H NMR (CD3OD, 300 Hz): 7.70 (s, 1H), 7.49 (d, J=8.6 Hz, 2H), 7.43 (d, J=8.7 Hz, 2H), 6.80 (d, J=9.3 Hz, 2H), 5.09 (s, 2H), 3.57 (t, J=6.3 Hz, 2H), 2.65 (t, J=7.5 Hz, 2H), 1.76-1.86 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C21H16C1F5O2S, 485.0 (M+Na). found 485.2.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH2:15][CH3:16])[C:9]=1[CH2:17][C:18]([OH:20])=[O:19])[CH3:7].[CH3:21]O>>[CH2:6]([C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH2:15][CH3:16])[C:9]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH3:7]
Reactant: CO
Reactant: CCc1cc(C)cc(CC)c1CC(=O)O
Agent: O=S(=O)(O)O
Product: CCc1cc(C)cc(CC)c1CC(=O)OC

Procedure:
1 ml of concentrated sulfuric acid is added to 18.0 g (87.3 mmol) of 2,6-diethyl-4-methylphenylacetic acid and 300 ml of absolute methanol, and the mixture is heated at reflux for 4 h. After cooling, the mixture is extracted with ethyl acetate, the extracts are washed with water in sodium carbonate solution and dried (magnesium sulfate) and the solvent is distilled off. This gives 18.37 g of (95%) of the desired product as a colorless oil.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[P:43](Cl)([O:48][CH2:49][CH3:50])([O:45][CH2:46][CH3:47])=[O:44]>ClCCl>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][P:43]([O:48][CH2:49][CH3:50])([O:45][CH2:46][CH3:47])=[O:44])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2nn3c(NCCCCN)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: CCOP(=O)(Cl)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(NCCCCNc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(OC)cc3)nn12)OCC
Yield: 81 %

Procedure:
To a cold (0° C.) solution of N-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine (21 mg, 0.04 mmol) in dichloromethane (3 mL) was added triethylamine (0.1 mL), and diethyl chlorophosphate (0.1 mL of a stock solution prepared from 0.1 mL of diethyl chlorophosphate in 3 mL of dichloromethane). The resultant solution was stirred for 3 hours at 0° C. and then quenched by the addition of saturated aqueous sodium bicarbonate. The organic layer was washed with brine. The aqueous layer was extracted with dichloromethane and the combined organics were dried over sodium sulfate. Filtration and concentration followed by flash chromatography (5% methanol in dichloromethane) provided diethyl 4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butylamidophosphate (22 mg, 81%) as a yellow solid. 1H NMR (CDCl3): δ 7.98 (d, 1 H), 7.76 (d, 1 H), 7.55 (d, 2 H), 7.28 (m, 1 H), 6.96 (d, 2 H), 6.31 (d, 1 H), 6.06 (m, 1 H), 5.97 (d, 1 H), 5.11 (d, 1 H), 4.34 (m, 1 H), 4.09–3.98 (m, 4 H), 3.86 (s, 3 H), 3.37 (m, 2 H), 2.95 (m, 2 H), 2.64 (m, 1 H), 2.11–1.48 (m, 12 H), 1.31–1.27 (m, 6 H); MS m/z 608 (M+1).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=3[Cl:29])=[C:19]([F:30])[C:15]3[N:16]=[CH:17][S:18][C:14]=3[CH:13]=2)=[O:11])[CH2:4][O:3]1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:19]([F:30])[C:15]2[N:16]=[CH:17][S:18][C:14]=2[CH:13]=1)=[O:11]
Reactant: CC1(C)OCC(CONC(=O)c2cc3scnc3c(F)c2Nc2ccc(Br)cc2Cl)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NOCC(O)CO)c1cc2scnc2c(F)c1Nc1ccc(Br)cc1Cl
Yield: 76.4 %

Procedure:
To a solution of N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]thiazole-6-carboxamide (490 mg, 0.92 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (0.2 mL, 2.69 mmol). The mixture was stirred for 1 h and neutralized with saturated sodium bicarbonate (aq.). The aqueous layer was extracted by CH2Cl2 (10 mL×2). The combined organic layers were washed by water (10 mL) and brine (10 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 50:1, v/v) to afford the desired product (white solid, 345 mg, 58.6% yield for two steps). 1H NMR (400 MHz, DMSO-d6): δ 11.80 (s, 1H), 9.54 (s, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 7.60 (d, 1H), 7.34 (d, 1H), 6.46 (m, 1H), 4.84 (d, 1H), 4.60 (m, 1H), 3.88 (m, 1H), 3.74 (m, 2H), 3.36 (m, 2H). MS APCI (+) m/z: 491.9 [M+H].
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH2:5][CH:4]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:3]1.[CH3:27][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC.O>C1COCC1>[F:26][C:2]1([F:1])[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH2:5][CH:4]([N:18]([CH3:27])[C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:3]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(NC(=O)OC(C)(C)C)CC(F)(F)C1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2c([N+](=O)[O-])cnn2C)CC(F)(F)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
To a cooled (ice-water bath) solution of tert-butyl 6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate (190 mg, 0.51 mmol) in THF (10 mL) was added lithium hexamethyldisilazide (1M in THF, 0.8 mL, 0.8 mmol) and the mixture stirred for 30 min. Iodomethane (0.06 mL, 1.02 mmol) was added and the mixture stirred at room temperature for 16 hr. Water (2 mL) was added and the mixture extracted with EtOAc (30 mL). The organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-70% EtOAc/isohexane) gave tert-butyl 6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl(methyl)carbamate (180 mg, 90%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.09-7.99 (m, 1H), 4.57-4.38 (m, 1H), 3.85 (s, 3H), 3.84-3.53 (m, 1H), 3.45-3.15 (m, 3H), 2.81 (s, 3H), 2.53-2.29 (m, 2H), 2.16-2.01 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:4][CH:3]=1.NC1C=CC([C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[C:28](=[O:35])[CH2:27][CH2:26][CH2:25]2)=[O:23])=CC=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]([C:22]([N:24]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[C:28](=[O:35])[CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:14]=[CH:13][C:9]=2[C:10]([NH:24][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:29]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Product: Cc1ccc(-c2cc(C(=O)N3CCCC(=O)c4ccccc43)ccc2C(=O)Nc2ccccc2)cc1

Procedure:
Using o-(4-methylphenyl)benzoic acid and 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one as starting materials, the procedure of Reference Example 3 was repeated to obtain 2-(4-methylphenyl)-4-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]benzanilide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[S:26][CH:25]=1)[C:20]([O:22][CH3:23])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[S:26][CH:25]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C(N)c1csc2ccccc12
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1csc2ccccc12

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(benzothiophen-3-yl)acetate (prepared from 2-amino-2-(benzothiophen-3-yl)acetic acid [CAS 95834-94-9] using General Procedure H), the title compound was prepared as a solid (mp 185-186° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.CCOCC>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=[N:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: COc1ccc(N)cc1
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(N=Cc2ccc(O)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methoxy-4-hydroxybenzaldehyde (vanillin, 1 g, 6.57 mmol) was dissolved in methanol (30 ml). To this solution was added p-anisidine (0.810 g, 6.57 mmol) and the resultant reaction solution was stirred overnight under nitrogen at room temperature. The reaction solution was taken to dryness in vacuo with the application of heat. The resultant solid was azeotropically mixed with methanol (2×), ether (1×), and again with methanol (2×) to yield yellow crystals. The crystals were triturated with hot ether to yield the title product: 1H NMR (300 MHz, CDCl3); δ 8.36 (S, 1H) 7.60 (S, 1H), 7.30-7.17 (m, 3H), 7.05-6,91 (m, 3H), 6.10 (S, 1H), 3.97 (S, 3H), 3.83 (S, 3H)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][CH2:12][CH2:13]Br)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[N-:15]=[N+:16]=[N-:17].[Na+]>>[CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][CH2:12][CH2:13][N:15]=[N+:16]=[N-:17])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(CCCCBr)CCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: COC(=O)C1(CCCCN=[N+]=[N-])CCCC1

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 2, starting from 1-[4-bromobutyl]cyclopentanecarboxylic acid methyl ester and sodium azide.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[CH:20]1([C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])[CH2:22][CH2:21]1.Cl.CN(C)CCCN=C=NCC.C(Cl)Cl.CO>N1C=CC=CC=1.CN(C)C=O>[CH:20]1([C:23]2[CH:24]=[C:25]([NH:26][C:16](=[O:18])[CH2:15][C:3]3[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]4[CH2:10][CH2:11][O:12][CH2:13][CH2:14]4)[N:4]=3)[CH:27]=[CH:28][CH:29]=2)[CH2:22][CH2:21]1
Reactant: Nc1cccc(C2CC2)c1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)Nc2cccc(C3CC3)c2)nc(N2CCOCC2)cc1=O
Yield: 48.2 %

Procedure:
The product is prepared according to the procedure described in example 5, using 200 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 194 mg of 3-cyclopropylaniline (prepared according to Wallace et al. in Tetrahedron Lett. 2002, 43, 6987), and 185 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.12 ml of pyridine and 4 ml of N,N-dimethylformamide. After extractions with ethyl acetate and silica column purification of the residue obtained, eluent: 95/05 CH2Cl2/MeOH, 129 mg of N-(3-cyclopropylphenyl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)(=O)=O.ClC1C=CC(C(C2C=CC(Cl)=CC=2)C(Cl)=O)=CC=1.[CH3:42][CH2:43][O:44][C:45]([C:47]1[CH:48]=[CH:49][C:50]([NH2:53])=[CH:51][CH:52]=1)=[O:46]>C1C=CC=CC=1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:53][C:50]2[CH:49]=[CH:48][C:47]([C:45]([O:44][CH2:43][CH3:42])=[O:46])=[CH:52][CH:51]=2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: O=C(Cl)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: O=S(=O)(Cl)Cl
Product: CCOC(=O)c1ccc(NC(=O)C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Reaction time: 8 h

Procedure:
To a stirred solution of 23.55 g. of bis(p-chlorophenyl)acetic acid in 250 ml. of benzene is added dropwise 33.1 g. of sulfonyl chloride. The mixture is refluxed 5 hours, the solvent is evaporated, and the residue is evaporated from three 250 ml. portions of benzene, giving 26.06 g. of bis(p-chlorophenyl)acetyl chloride as an oil. To this oil is added a solution of 27.7 g. of benzocaine. The mixture is stirred overnight, filtered, washed with 200 ml. each of 10% hydrochloric acid, saturated sodium bicarbonate solution, water, and brine, dried over magnesium sulfate, and evaporated. The residue is crystallized twice from 200 ml. of ethanol, giving 25.76 g. of the desired product as colorless needles, m.p. 171°-172° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][NH:7]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][N:7]1[C:29]([O:30][CH3:31])=[O:32]
Reactant: COC(=O)C1CCNC(Cc2cc(F)cc(F)c2)C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2cc(F)cc(F)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
Methyl 2-(3,5-difluorobenzyl)piperidine-4-carboxylate (7.082 g, 26.30 mmol) was dissolved in DCM (170 mL) and DIPEA (5.50 mL, 31.56 mmol), then methyl carbonochloridate (2.88 mL, 36.58 mmol) was added. The reaction mixture was stirred at room temperature for 3 h, then additional methyl carbonochloridate (0.7 mL, 8.89 mmol) was added. The solution was stirred for 30 min then washed with 0.1 M HCl and satd NaHCO3. The organic phase was dried and concentrated to give dimethyl 2-(3,5-difluorobenzyl)piperidine-1,4-dicarboxylate (8.55 g, 99%). MS m/z 328 (M+H)+