Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([CH2:13][C@@H:14]([NH:30][CH3:31])[CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH2:18][CH2:17]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH:32]1([C:38]([Cl:40])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>ClCCl.O>[CH:7]1([CH2:13][C@@H:14]([N:30]([CH3:31])[C:38]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:39])[CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH2:20][CH2:21]2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1.[ClH:40]
Reactant: CN[C@H](CC1CCCCC1)CN1CCC(c2ccccc2OC)CC1
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1C1CCN(C[C@@H](CC2CCCCC2)N(C)C(=O)C2CCCCC2)CC1
Product: Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 0.080 g of potassium carbonate (0.58 mmol) in 1 ml. of water was added a solution of 0.20 g of {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperidin-1-yl]-ethyl}-methyl-amine (0.58 mmol) in 10 mL of dichloromethane. The resulting mixture was cooled to 0° C. and 0.090 g of cyclohexanecarboxylic acid chloride (0.58 mmol) was added. The reaction was allowed to stir overnight at 0° C., and was then diluted with 5 mL of water and 20 mL of dichloromethane and the phases separated. The aqueous phase was extracted with three additional portions of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride.0.75 hydrate salt of the title compound with isopropanolic HCl to yield 0.195 g (69%) as a white solid; mp=135-137° C.; MS (+) ESI m/z=455 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH3:20])[CH:13]=2)[CH:3]=1.[NH2:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>>[ClH:1].[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([NH:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][C:14]=1[CH3:20]
Reactant: NCC(O)CO
Reactant: COc1ccc(-c2cc(Cl)c3ccccc3n2)cc1C
Product: COc1ccc(-c2cc(NCC(O)CO)c3ccccc3n2)cc1C
Product: Cl

Procedure:
The title compound, m.p. 166-171° C., and MS: m/e=338 (M+), was prepared from 4-chloro-2-(4-methoxy-3-methyl-phenyl)-quinoline and (RS)-3-amino-1,2-propandiol.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=1.C(N(CC)CC)C.O>CS(C)=O>[CH:2]([C:3]1[CH:7]=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=1)=[O:1]
Reactant: O=C(Nc1cc(CO)nn1-c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=Cc1cc(NC(=O)c2ccccc2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.5 %

Procedure:
N-[3-(Hydroxymethyl)-1-phenyl-1H-pyrazol-5-yl]benzamide (384 mg) and triethylamine (2 mL) were dissolved in dimethyl sulfoxide (5 mL), and sulfur trioxide•pyridine complex (417 mg) was added at room temperature. After stirring at room temperature for 18 hr, sulfur trioxide•pyridine complex (417 mg) was further added at room temperature and the mixture was stirred for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with 2-propanol to give the title compound as a pale-yellow powder (yield 303 mg, yield 79%).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:9]=[CH:10][C:3]=12.CCN(CC)CC.[C]=O.[CH3:27][CH2:28][O:29][C:30](C)=[O:31]>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH2:28]([O:29][C:30]([C:2]1[C:3]2[CH:10]=[N:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:4]=2[CH:5]=[N:6][CH:7]=1)=[O:31])[CH3:27]
Reactant: CCOC(C)=O
Reactant: Fc1ccc(-n2ncc3c(Br)cncc32)cc1
Agent: [Fe+2]
Agent: [C]=O
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cncc2c1cnn2-c1ccc(F)cc1
Temperature: 140 °C

Procedure:
A mixture of 4-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine (3.5 g, 12 mmol), Et3N (3.5 mL, 25 mmol), Pd[PhCN]2Cl2 (105 mg, 0.273 mmol), and dppf (418 mg, 0.754 mmol) in absolute ethanol (90 mL) was placed in a sealed bomb with stifling and placed under 15 bars of carbon monoxide and warmed to 140° C. for 4 hours. The mixture was then cooled to room temperature, returned to atmospheric pressure and opened. The reaction was monitored by TLC (EtOAc-hexanes 4:6 and EtOAc) indicating the starting material was consumed. The reaction was diluted with water (300 mL) and the solid was collected by filtration washing with water. The filtrate was diluted with water (200 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (2×100 mL). The still moist filter cake was dissolved in EtOAc and combined with the extracted organic layers, dried over magnesium sulfate, treated with activated carbon) and filtered through a pad of diatomaceous earth and a layer of silica gel. The material from the pad was dissolved in dichloromethane and passed through a pad of silica gel eluting with dichloromethane to afford 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid ethyl ester.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:8]1([CH2:14][CH2:15]O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C([O-])(=O)C([O-])=O.[Sn+4].C([O-])(=O)C([O-])=O>[C:1]([O:7][CH2:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)O
Reactant: OCCc1ccccc1
Agent: O=C([O-])C(=O)[O-]
Agent: [Sn+4]
Product: CCCCC(=O)OCCc1ccccc1
Temperature: 170 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A 2-L, 4-neck, round-bottom flask, fitted with a thermometer, mechanical stirrer, nitrogen inlet tube and Liebig condenser/receiving flask, was charged with 612.8 g (6.00 mol, 1.00 equiv) of pentanoic acid, 733.0 g (6.00 mol, 1.00 equiv) of 2-phenylethanol, and 2.50 g (0.2 wt. %) of tin oxalate (Fascat® 2001). The air was removed with three cycles of evacuation/nitrogen-fill using a mechanical vacuum pump (50-100 torr). The rate of stirring was set at ca. 200 rpm, the nitrogen sparge was set at 0.1 scfh, and the reaction mixture was heated to 170° C. After a 1-h hold, 159.3 g of distillate had been collected. It was not possible to get a clean separation; therefore, the organic layer was not returned to the reaction mixture. The temperature was increased to 180, 190, 200 and 210° C. and held for 1 h at each; the amounts of distillate were 21.4, 9.8, 4.9 and 2.2 g, respectively. The acid number was 2.88 mg KOH/g (99.0% conversion). The excess 2-phenylethanol (6.3% by GLC) was removed by vacuum distillation through a 15-cm Vigreux column at 140-165° C. (15-20 torr). The crude product was distilled at 150-155° C. (10 torr, 0.5 scfh nitrogen sweep) to afford 925 g (75%) of 2-phenylethyl pentanoate (99.3% pure by GLC): residual alcohol, 0.3% (GLC); APHA color, 13; acid number, 0.06 mg KOH/g; saponification number, 271 mg KOH/g (theor. 272 mg KOH/g).
Reaction SMILES: [C:1]([O:9][C@H:10]1[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:13]([O:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:11]1O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(F)([F:48])C1C=CC=C(C)C=1)CC)C>C(#N)C>[C:1]([O:9][C@H:10]1[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:13]([O:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:11]1[F:48])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC[C@H]1O[C@H](OC(=O)c2ccccc2)[C@H](O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: CCN(CC)C(F)(F)c1cccc(C)c1
Solvent: CC#N
Product: O=C(OC[C@H]1O[C@H](OC(=O)c2ccccc2)[C@H](F)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 200 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
Into a pressure resistant vessel (200 ml) of the closed type which was made of Teflon and attached with a fiber optic temperature sensor, a stirrer rod, α-D-ribofuranose 1,3,5-tribenzoate (11 mmole; 5.1 g) and 50 ml of acetonitrile were placed. To the resultant mixture, N,N-diethyl-α,α-difluoro(3-methyl)benzylamine (23.2 mmole; 49.5 g) was slowly added under a nitrogen atmosphere. The temperature was then raised to 200° C. at a rate of 20° C./min under stirring, and the reaction was allowed to proceed for 20 minutes. After the reaction was completed, the reaction product was poured into 200 ml of ice water, and the organic layer was separated. The aqueous layer was treated by extraction with 50 ml of acetonitrile. The obtained two organic layers were combined, washed with pure water, dried with magnesium sulfate and then filtered. The obtained organic solution was concentrated using an evaporator, and the concentrated solution was analyzed in accordance with the liquid chromatography. As the result, 2.8 g (the yield: 55%) of 2-deoxy-2-fluoro-α-D-ribofuranose 1,3,5-tribenzoate of the object compound was obtained.
Reaction SMILES: [CH2:1]([NH-:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]=[C:10]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11](O)=[O:12].C(N)C1C=CC=CC=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O.C(N(CC)CC)C>[CH2:1]([NH:8][C:11](=[O:12])[C:10](=[O:9])[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: [NH-]Cc1ccccc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: NCc1ccccc1
Solvent: CN(C)C=O
Product: O=C(CCc1ccccc1)C(=O)NCc1ccccc1

Procedure:
Prepare the benzylamide of 2-oxo-4-phenylbutyric acid by dissolving 3.0 g of this acid, 2.4 ml of benzylamine, and 4.7 ml of diphenylphosphorylazide in 60 ml of cold dimethylformamide and adding dropwise 2.6 ml of triethylamine in DMF, holding the temperature at about -10° C. for 2.5 hours. Store overnight at room temperature, strip off the DMF in vacuo, and partition the residue between water and ethyl acetate. Chromatograph the contents of the organic layer on silica gel, eluting with ethyl acetate:hexane 1:4. Evaporate the solvent from the product fractions to obtain 2.2 g of crystalline N-benzyl-2-oxo-4-phenylbutyramide. Couple 1.26 g of this with 0.19 g of L-Ala-L-Pro using 0.125 g of sodium cyanoborohydride in ethanol in the manner described in Example 44. Purify the crude product by gel filtration (LH-20) to obtain the mixture of diastereoisomers of N-(1-benzylaminocarbonyl-3-phenylpropyl)-L-alanyl-L-proline. The nmr spectrum (CDCl3) shows a doublet at 1.1 ppm (3H) a close pair of singlets at 7.3 (10H), and complex absorption at 1.6-2.3 (6H), 2.3-2.9 (2H), 2.9-3.8 (4H) and 4.0-4.6 (3H). The mass spectrum of silylated material shows prominent peaks at m/e=509 (monosilyl derivative) and 581 (disilyl derivative).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11]2[O:15][N:14]=[CH:13][C:12]=2[C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([S:24][CH3:25])[CH:18]=2)[CH2:10][CH2:9]1.Cl>ClCCl>[C:13]([CH:12]([C:11]([CH:8]1[CH2:9][CH2:10]1)=[O:15])[C:16]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([S:24][CH3:25])[CH:18]=1)=[O:26])#[N:14]
Reactant: CSc1cc(C(=O)c2cnoc2C2CC2)ccc1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1cc(C(=O)C(C#N)C(=O)C2CC2)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
Triethylamine (0.5 g) was added to a solution of 5-cyclopropyl-4-(4-methyl-3-methylsulphenylbenzoyl)isoxazole (0.66 g) in dichloromethane. The mixture was stirred at room temperature overnight. Further triethylamine (0.2 g) was added and the mixture was stirred for a further 24 hours. Hydrochloric acid (2M) was added and the layers were separated. The organic layer was washed with aqueous sodium chloride solution, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give 2-cyano-3-cyclopropyl-1-(4-methyl-3-methylsulphenylphenyl)propan-1,3-dione (COMPOUND 665, 0.12 g) as an orange gum which solidified, m.p. 64.7°-67.9° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][N:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH:22]=1.[Cl:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][C:42]=1[OH:43]>>[Cl:36][C:37]1[CH:38]=[C:39]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:27][CH2:28]3)[CH:22]=2)[CH:40]=[CH:41][C:42]=1[OH:43]
Reactant: OB(O)c1ccc(O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5ccc(O)c(Cl)c5)cc34)cn2)CC1
Yield: 105.4 %

Procedure:
Following general procedure D, tert-butyl 4-(4-((6-bromo-3-(cyclopropanecarbonyl)quinolin-4-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (54 mg, 0.10 mmol) was reacted with (3-chloro-4-hydroxyphenyl)boronic acid (34 mg, 0.20 mmol) to afford the desired product (62 mg, >99%) as a yellow-brown solid. ESI MS m/z 588 [C32H34ClN5O4+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12]O)[CH:8]=2)[N:3]=1.C1CCN2C(=NCCC2)CC1.C1C=CC(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)=CC=1.O>CN(C=O)C>[N:39]([CH2:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)=[N+:40]=[N-:41]
Reactant: Cc1ccc2cc(CO)ccc2n1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Cc1ccc2cc(CN=[N+]=[N-])ccc2n1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
To a solution of (2-methyl-6-quinolinyl)methanol (100 mg, 0.560 mmol) and DBU (0.152 ml, 1.008 mmol) in DMF (4 ml) was added DPPA (0.205 ml, 0.952 mmol). The reaction mixture was stirred overnight at 23° C. Reaction mixture was poured into water and extracted twice with ethyl acetate. Organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to afford a crude material, which was purified by silicagel chromatography (cyclohexane:ethyl acetate from 100:0 to 0:100) to afford the title compound. HPLC (Method G) Rt=1.048 min; MS (Method F) [M+H]+=199.2
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>CS(C)=O>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=2[CH:14]=1
Reactant: BrCCCCCBr
Reactant: CC1(C)OC(=O)Nc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)OC(=O)Nc2ccc(OCCCCCBr)cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 19.3 gm (0.1 mol) of 6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one in 200 ml of dimethyl sulfoxide is mixed at ambient temperature with 41.5 gm (0.3 mol) of potassium carbonate and 92 gm (0.4 mol) of 1,5-dibromopentane, whereupon the temperature rises to 45° C. After stirring a further two hours, ice water is added, and the resulting mixture is extracted with chloroform. The chloroform phase is washed with water and dried with sodium sulfate, and the chloroform is distilled off. The residue is recrystallized from ethyl acetate/petroleum ether.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2OC(=O)N[C:6]=2[CH:11]=1.N1C=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[CH3:16][CH2:15][CH:14]=[CH:13][CH2:11][CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2]
Reactant: c1ccncc1
Reactant: Nc1ccc2oc(=O)[nH]c2c1
Solvent: O
Product: C=CCCCCC=CCC

Procedure:
A mixture of anti-tricyclo[4.2.2.02,5 ]dec-3,9-diene-endo-7,endo-8-dicarboxylic anhydride (2.02 g., 0.01 mole), 5-aminobenzoxazolin-2-one (1.50 g., 0.01 mole) and pyridine (20 ml.) is heated under reflux for six hours. The cooled solution (25° C.) is diluted with water (200 ml.) and the precipitate is collected by filtration, 2.60 g., m.p. 252°-257° C. Recrystallization from 2-propanol provides N-(5-benzoxazolinyl-2-one)-antitricyclo[4.2.2.02,5 ]dec-3,9-diene-endo-7,endo-8-dicarboximide, m.p. 287.5°-290° C.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=CC(O)=C[CH:5]=1.N[C@H](C(O)=O)CCCCN>>[NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH:4]([CH3:9])[CH3:5]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: NCCCC[C@H](N)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
6.09 (6), Tyr; 0.97 (1), Lys; 2.91 (3),
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([C:15]2[S:19][CH:18]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C=O.O1CCCC1.O>[Br:1][C:18]1[S:19][C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:16][C:17]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1csc(-c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)sc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
N-Bromosuccinimide (360 mg, 2.02 mmol) was added to a solution of methyl 5-phenylthiophene-3-carboxylate (11b) (440 mg, 2.02 mmol) in a mixture of N,N-dimethylformamide (4 mL) and tetrahydrofuran (4 mL). The reaction mixture was stirred at room temperature for 1 hour. N-Bromosuccinimide (72 mg, 0.40 mmol) was added and the stirring was maintained for 1 hour. The mixture was poured in water (10 mL) and extracted with dichloromethane (2×15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to provide the desired product (11c) (390 mg, 1.3 mmol, 65%).
Reaction SMILES: [CH:1]([Sn](CCCC)(CCCC)CCCC)=[CH2:2].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:46]1[CH:47]=[CH:48][C:49]([NH2:52])=[N:50][CH:51]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([C:46]1[CH:47]=[CH:48][C:49]([NH2:52])=[N:50][CH:51]=1)=[CH2:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=Cc1ccc(N)nc1
Yield: 74 %

Procedure:
Vinyltributyltin (13 mL, 44.6 mmol), palladium(II) acetate (0.45 g, 2.1 mmol), triethylamine (12.4 mL, 89.1 mmol) and tri-(o-tolyl)phosphine (3.69 g, 12.15 mmol) were added to a solution of 5-bromopyridin-2-amine (7.0 g, 40.5 mmol) in acetonitrile (70 mL) and the reaction mixture refluxed for 18 hours. The reaction mixture was washed with 2M sodium carbonate solution (80 mL), the organics separated, dried over magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using methanol:dichloromethane 3:97 to yield 3.6 g of product. This residue was dissolved in dichloromethane and washed with aqueous solutions of potassium fluoride and then sodium hydrogencarbonate. The organic solution was dried over magnesium sulphate, filtered and concentrated in vacuo to yield 1.9 g of final product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[CH:30][NH:31]2)=[CH:27][CH:26]=1>>[NH:31]1[C:32]2[C:28](=[CH:27][CH:26]=[C:25]([O:24][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:33]=2)[CH:29]=[CH:30]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Oc1ccc2cc[nH]c2c1
Product: COc1cc2c(Oc3ccc4cc[nH]c4c3)ncnc2cc1OCCCN1CCOCC1
Yield: 60.5 %

Procedure:
Using an analogous procedure to that described for Example 120, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (200 mg, 0.59 mmol), (prepared as described for the starting material in Example 1), was reacted with 6-hydroxyindole (95 mg, 0.71 mmol) to give 4-(indol-6-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (155 mg, 60%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:14][C:13]3[C:12](=O)[NH:11][CH:10]=[N:9][C:8]=3[CH:7]=2)=[CH:2]1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:23])=O>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:14][C:13]3[C:12]([Cl:23])=[N:11][CH:10]=[N:9][C:8]=3[CH:7]=2)=[CH:2]1
Reactant: O=c1[nH]cnc2cc(-c3ccsc3)sc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ncnc2cc(-c3ccsc3)sc12
Temperature: 25 °C
Yield: 81 %

Procedure:
A solution of 6-(3-thienyl)-3H-thieno[3,2-d]pyrimid-4-one (218, 74 mg, 0.32 mmol) in phosphorus oxychloride (2 mL) under N2 was heated at reflux for 1 hour. The resulting solution was allowed to cool to room temperature, poured into a saturated aqueous solution of sodium bicarbonate to neutralize and then extracted with ethyl acetate. The organic layer was washed with water followed by saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to yield 6-(3-thienyl)-4-chlorothieno[3,2-d]pyrimidine (65 mg, 81% yield) as a yellow solid.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([O:16][CH:17]1[C:23]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=2[N:21]([C:29](=[O:48])[C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:45])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH3:44])=[CH:32][C:31]=2[O:46][CH3:47])[CH2:20][CH2:19][CH2:18]1)=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=O)(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[NH2:8][C@H:9]([C:14]([O:16][CH:17]1[C:23]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=2[N:21]([C:29](=[O:48])[C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:45])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH3:44])=[CH:32][C:31]=2[O:46][CH3:47])[CH2:20][CH2:19][CH2:18]1)=[O:15])[CH2:10][CH2:11][S:12][CH3:13]
Reactant: COc1cc(NC(=O)c2ccccc2C)ccc1C(=O)N1CCCC(OC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COc1cc(NC(=O)c2ccccc2C)ccc1C(=O)N1CCCC(OC(=O)[C@@H](N)CCSC)c2cc(Cl)ccc21

Procedure:
A uniform solution of 1.27 g of 5-(N-tert-butoxycarbonyl-L-methionyloxy)-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo-azepine, 2.5 ml of trifluoroacetic acid and 0.6 ml of anisole was stirred at room temperature for 2 hours. The most part of trifluoroacetic acid was removed by distillation under reduced pressure. To the residue was added a 0.2N aqueous sodium hydroxide solution to make the residue alkaline. The mixture was subjected to extraction with dichloromethane. The dichloromethane layer was water-washed, then dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (elutant: ethyl acetate) to obtain 0.34 g of an isomer A and 0.35 g of an isomer B both of 5-(L-methionyloxy)-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetra-hydro-1H-benzoazepine.