Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH3:22])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[OH-].[K+].[CH3:25][C@@H:26]([CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>C(O)C>[CH3:25][C@@H:26]([CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH3:22])=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)=[N:4][CH:3]=1
Reactant: CCCc1ccc(-c2ccc(-c3ncc(O)cn3)cc2)cc1
Reactant: CC[C@H](C)CCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1ccc(-c2ccc(-c3ncc(OCCCCC[C@@H](C)CC)cn3)cc2)cc1
Yield: 62.8 %

Procedure:
5-Hydroxy-2(4'-propyl-biphenyl-4-yl)pyrimidine (10 g, 0.034 mol) was dissolved in ethanol (100 ml), followed by adding KOH (2.1 g, 0.037 mol), refluxing the mixture, dropwise adding (S)-6-methyloctyl bromide (7.7 g, 0.037 mol) over about 15 minutes, further refluxing the mixture for 5 hours, distilling off ethanol (80 ml), dissolving the residue in toluene (100 ml), transferring the solution into a separating funnel, sufficiently washing it with a 2N-NaOH aqueous solution, washing it with water until the washing water became neutral, drying the resulting organic layer over anhydrous magnesium sulfate, distilling off toluene and recrystallizing the residue from ethanol (200 ml) to obtain (S)-5-(6'-methyloctyloxy)-2(4'-propylbiphenyl-4-yl)pyrimidine (8.9 g). This product was a liquid crystal and exhibited the following phase transition points (also see Table 1): ##STR86##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH2:32][CH2:33][CH3:34])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[C:31]([NH:30][C:26]1[CH:25]=[C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][NH:14][C:11]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[O:13])[CH2:19][CH2:20]2)[CH:29]=[CH:28][CH:27]=1)(=[O:35])[CH2:32][CH2:33][CH3:34]
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CC3)CC2)c1

Procedure:
Example 69 was prepared from 1-(4-chlorophenyl) cyclopropanecarboxylic acid and N{3-[1-(3-amino propyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.45 (s, 1H), 7.36–7.34 (m, 5H), 7.24 (t, 1H, J=8.0 Hz), 6.94 (d, 1H, J=7.6 Hz), 5.69 (br s, 1H), 3.25 (dd, 2H, J=6.8, 12.8 Hz), 2.87 (d, 2H, J=11.6 Hz), 2.44 (m, 1H), 2.35 (t, 2H, J=7.2 Hz), 2.29 (t, 2H, J=6.8 Hz), 1.95 (t, 2H, J=11.2 Hz), 1.80–1.74 (m, 4H), 1.63–1.59 (m, 6H), 1.03–1.00 (m, 5H); ESMS m/e: 482.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH3:33][N:34]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:33]#[N:34])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)c2cc(C#N)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg), zinc cyanide (50 mg), tetrakis(triphenylphosphine)palladium(0) (35 mg) and 1-methyl-2-pyrrolidone (3 ml) was stirred at 100° C. for 2 hrs. under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with a mixture of ethyl acetate and THF. The organic layer was washed with aqueous ammonia, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure, and the obtained crystals were washed with a mixture of ethyl acetate and diethyl ether to give the title compound (210 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:18]1([CH2:21][C@@H:22]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[NH2:23])[CH2:20][CH2:19]1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([NH:23][C@H:22]([C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[CH2:21][CH:18]1[CH2:20][CH2:19]1)=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@@H](CC1CC1)C(=O)OCc1ccccc1
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC1CC1)C(=O)OCc1ccccc1

Procedure:
N-(tert-Butoxycarbonyl)-D-leucine (540 mg, 2.32 mmol) and benzyl 3-cyclopropyl-L-alaninate hydrochloride (Example 3A, 490 mg, 1.93 mmol) are reacted by general procedure 6. The crude product is purified by preparative HPLC, (method 16), resulting in a quantitive yield of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[Br:12]Br>ClCCl.Br.BrBr>[Br:12][CH:9]([CH3:10])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:11]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(Cl)cc1
Agent: Br
Solvent: ClCCl
Product: CC(Br)C(=O)c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
A stirred solution of p-chloropropiophenone (2.0 g, 11.9 mmol) in dichloromethane (35 mL) was treated with one drop of 48% HBr and one drop of bromine. When the color had discharged, bromine (608 μL, 1.90 gm, 11.9 mmol) was added dropwise. The solution was stirred until 15 min after the color had fully discharged, then the mixture was concentrated under reduced pressure to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(Cl)Cl>[NH:6]1[C:7]2[C:3](=[C:2]([O:1][CH2:13][CH2:12][Cl:11])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: OCCCl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: ClCCOc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 50.1 %

Procedure:
To a solution of 4-hydroxyindole (4 g, 30 mmol), 2-chloroethanol (4.83 g, 60 mmol), triphenylphosphine (15.7 g, 60 mmol) in anhydrous tetrahydrofuran (40 ml) was slowly added diisopropyl azodicarboxylate (12.1 g, 60 mmol). The reaction was allowed to stir for 2.5 hours at room temperature, then poured into methylene chloride (250 ml), washed with water (3×100 ml) and dried over anhydrous sodium sulfate. This material was filtered and the solvent was removed under vacuum. Chromatography (20% hexanes-ethyl acetate) to remove triphenylphosphine, (20% methylene chloride-hexanes) afforded 2.94 g (50%) of product as a white solid: mp 69.5-72° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23](F)=[O:24])=[O:17])([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23](=[O:24])[NH:7][CH2:8][CH2:9][SH:10])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: NCCS
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCCS
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 50 mL round-bottom flask charged with a solution of sodium bicarbonate (117.0 mg, 1.39 mmol) in 6.8 mL water was added 2-aminoethanethiol hydrochloride (85.0 mg, 0.75 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25e (148.0 mg, 0.78 mmol) in 6.8 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 169.2 mg (91% from 24e) of clean 26e as a pale yellow oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[CH:26]=1)(=O)=O.B([C:32]1[CH:33]=[CH:34][C:35]([O:41][CH3:42])=[C:36]([CH:40]=1)[C:37]([OH:39])=[O:38])(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[O:14][C:10]3[CH:9]=[CH:8][C:7]([C:32]4[CH:33]=[CH:34][C:35]([O:41][CH3:42])=[C:36]([CH:40]=4)[C:37]([OH:39])=[O:38])=[CH:26][C:11]=3[C:12]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:20][CH:19]=1
Reactant: COc1ccc(B(O)O)cc1C(=O)O
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3ccc(OC)c(C(=O)O)c3)cc12
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
To a 150 mL sealed tube was added 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (1.252 g, 3 mmol), 5-borono-2-methoxybenzoic acid (0.882 g, 4.50 mmol), cesium carbonate (1.466 g, 4.50 mmol), tetrakis(triphenyl phosphine)palladium(0) (0.069 g, 0.060 mmol), dioxane (18 mL) and water (3.60 mL). The vial was sealed and heated in an oil bath over night at 85° C. The reaction mixture was then filtered through celite and concentrated in vacuo. Cold 0.5N HCl was then added and the heterogeneous mixture was stirred for 30 minutes. The resulting product, a white solid was filtered, washed with water and dried overnight to give a quantitative yield of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy benzoic acid which was carried on without further purification. LCMS m/z 420.92 (M+H), Rt 2.003 min., 87% purity.
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16](=[CH2:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:24])(=[O:6])=[O:5])([CH3:3])[CH3:2].[Cl:25]N1C(=O)CCC1=O>O1CCCC1>[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16](=[CH:23][Cl:25])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:24])(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=C(c1ccccc1)c1ccc2nc(N)n(S(=O)(=O)C(C)C)c2c1
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=CCl)c3ccccc3)cc21
Temperature: 25 °C
Yield: 34 %

Procedure:
To a stirred solution of 4.0 g. of 1-isopropylsulfonyl-2-amino-6-(α-methylenebenzyl)benzimidazole (from U.S. Pat. No. 4,118,742) in 100 ml. of tetrahydrofuran was added in one portion 1.56 g. of N-chlorosuccinimide. The reaction mixture was heated at reflux for two and one-half hours, and then cooled to room temperature. The reaction solvent was removed by evaporation under reduced pressure to provide the crude product as a gum. The gum was suspended in water, and then was extracted into chloroform. The chloroform extracts were combined, washed with fresh water, dried, and the solvent was removed by evaporation under reduced pressure. The product thus formed was dissolved in 50 ml. of diethyl ether, and after concentrating the volume of the mixture to about 25 ml., a white crystalline product precipitated and was identified as 1.5 g. of trans-1-isopropylsulfonyl-2-amino-6-(α-chloromethylenebenzyl)benzimidazole. M.P. 180°-181° C. Yield 34%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.C([O-])([O-])=O.[K+].[K+].[CH3:18][C:19]1[N:24]=[C:23]([CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:26][CH2:25][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:18])[N:24]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: Cc1cccc(CO)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc(COc2ccc([N+](=O)[O-])cc2Cl)n1
Temperature: 65 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a solution of 2-chloro-1-fluoro-4-nitro-benzene (8.75 g, 50 mmol) in dry acetone (100 ml) was added 10.0 g of K2CO3 and 6.15 g of 6-methyl-2-pyridylmethanol (50 mmol). The reaction mixture was then stirred at 65° C. overnight. Filtration and concentration gave a solid which was recrystallized to give the desired product as a white solid (9.5 g).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:6][N:7]=1.NC(N)=[S:13].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.[OH-].[Na+]>[SH:13][C:2]1[C:3]2[N:4]([CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Clc1nccn2ccnc12
Reactant: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Sc1nccn2ccnc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To 3.10 g(0.02 mol) of 8-chloroimidazo[1,2-a]pyrazine in 70 ml of ethanol was added 1.52 g (0.02 mol) of thiourea and the mixture was refluxed. After 3 hours, the reaction mixture was cooled to 0° C. The thiouronium salt was collected by filtration, dried and suspended in 80 ml of water. To this was added 3.46 g (33 mmol) of sodium carbonate. The reaction mixture was stirred for 15 minutes and then diluted with 30 ml of 5% sodium hydroxide solution. The aqueous solution was washed with 50 ml of chloroform, made acidic with acetic acid and then extracted with 2×50 ml of chloroform. The organic extracts were dried (Na2SO4), filtered, and concentrated to yield the crystalline product.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:19])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([Cl:18])[N:6]=2.[O:20]1[CH2:25][CH2:24][N:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:18][C:7]1[N:6]=[C:5]2[C:10]([N:11]=[C:3]([CH2:2][N:29]3[CH2:30][CH2:31][CH:26]([N:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)[CH2:27][CH2:28]3)[N:4]2[CH3:19])=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=1
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: Cn1c(CBr)nc2c(N3CCOCC3)nc(Cl)nc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(CN2CCC(N3CCOCC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a solution of 4-(8-(bromomethyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (935 mg, 2.7 mmol) in DCM (30 mL) was added 4-morpholino-piperidine (505 mg, 2.97 mmol) and DIEA (0.70 mL). The resulting mixture was stirred at room temperature for 18 hours. The mixture was then poured onto water and the layers were separated. The aqueous layer was extracted with three times with DCM. The combined organic extracts were washed with water, dried over Na2SO4, filtered and concentrated. The crude product was then purified by flash chromatography (0-30% gradient MeOH in DCM) to give the title compound as a white solid (95%). LCMS: M+H+=436.2.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][CH2:12][OH:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CN(C)C=O>[OH:13][CH2:12][CH2:11][CH:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:10]=2[O:9][CH2:8]1
Reactant: OCCc1coc2c(O)cccc12
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1OCC2CCO
Temperature: 25 °C
Reaction time: 21 h
Yield: 74 %

Procedure:
7-hydroxy-3-(2-hydroxyethyl)benzofuran (7.01 g) was dissolved in dimethylformamide (100 ml), and potassium carbonate (5.76 g) and methyl bromoacetate (4.74 ml) were added to the resultant solution, and the mixture was stirred at room temperature for 21 hours. The reaction solution was filtered with Celite, and the filtrate was concentrated. Ethyl acetate (300 ml) was added to the residue, and then the mixture was washed with water and saturated brine, and dried over sodium sulfate. After sodium sulfate was filtered off, the filtrate was concentrated, and the residue was dissolved in methanol (100 ml). 5% Pd/C (1.0 g), and acetic acid (5 ml) were added to the resultant solution, and the mixture was stirred at room temperature for 23 hours under a hydrogen atmosphere. The reaction solution was filtered with Celite, and the filtrate was concentrated. Ethyl acetate (300 ml) was added to the residue, and the mixture was washed with water and saturated brine, and dried over sodium sulfate. After sodium sulfate was filtered off, the filtrate was concentrated, and the residue was purified by flash column chromatography using silica gel (elution solvent:hexane/ethyl acetate=1/2) to obtain the object compound (7.80 g, yield 74%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28]2)=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:31][CH2:30][C@@H:29]([O:32][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:28]2)=[CH:25][CH:26]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(N3CC[C@@H](O)C3)cc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(N3CC[C@@H](OS(C)(=O)=O)C3)cc2)C1
Reaction time: 0.33 h
Yield: 101.7 %

Procedure:
To a solution of (S)-1,4-di(t-butoxycarbonyl)-2-(4-((R)-3-hydroxy pyrrolidino)phenyl)piperazine (733 mg, 1.64 mmol) and triethylamine (0.34 mL, 2.46 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.152 mL, 1.97 mmol) at 0° C. After stirring for 20 min, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford (S)-1,4-di(t-butoxycarbonyl)-2-(4-((R)-3-(methansulfonyloxy)pyrrolidin-1-yl) phenyl)piperazine (877 mg, quant.) as a brown solid.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[N:16]=[CH:15][N:14]=[C:13]2O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:32])=O>CN(C)C=O>[C:1]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[N:16]=[CH:15][N:14]=[C:13]2[Cl:32])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CN1CCC(COc2cc3ncnc(O)c3cc2OC(=O)c2ccccc2)CC1
Solvent: CN(C)C=O
Product: CN1CCC(COc2cc3ncnc(Cl)c3cc2OC(=O)c2ccccc2)CC1
Yield: 94 %

Procedure:
A mixture of 4-hydroxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-6-yl benzoate (0.215 g, 0.55 mmol), thionyl chloride (2 ml) and dimethylformamide (0.05 ml) were refluxed for 15 minutes. The solvent was evaporated in vacuo to yield 4-chloro-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-6-yl benzoate (0.250 g, 94% yield) as the hydrochloride salt:
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.C([Li])CCC.[Br:17]Br.S([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Br:17][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[NH:1][N:2]=[N:3][N:4]=1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccccc1-c1nnn[nH]1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
To (tetrazol-5-yl)benzene (0.29 g) in THF (10 ml) at -25° C. was slowly added n-butyllithium (2 mL, 2.5M in hexanes) while maintaining the reaction temperature below -15° C. When the addition was over in 10 to 15 minutes, the mixture was aged at -10° C. for 30 minutes. The reaction mixture was cooled to -60° C. and bromine (0.2 mL) was added dropwise. To the reaction mixture was added aqueous 10% sodium sulfite (5 mL). An HPLC assay showed a starting material/products ratio of 3.5/96.5. The product was precipitated by the addition of water (20 mL) and acidification with 2N HCl to pH 2. The mixture was aged at 0° C. for 1 hour and filtered. The yield was 0.427 g (95%).
Reaction SMILES: [CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH2:19][CH2:20][OH:21])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:29]([NH:31][CH3:32])=[O:30])[N:8]([C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.[C:33](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH2:19][CH2:20][OH:21])[S:14]([CH3:17])(=[O:15])=[O:16])=[CH:11][C:10]3[C:6](=[C:7]([C:29]([NH:31][CH3:32])=[O:30])[N:8]([C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:33])=[CH:26][CH:27]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 60.5 %

Procedure:
To a suspension of compound (ii) (3 mg, 0.007 mmol) and potassium carbonate (3 mg, 0.022 mmol) in DMF (0.25 mL) was added iodomethane (3 μL, 0.048 mmol) and the reaction was stirred at 60° C. for 45 min. The mixture was concentrated to dryness and the residue was purified by reverse phase flash column chromatography eluting with ACN/water (5-100%) to afford Compound (55) as a white solid (2 mg, 65%). ESI-MS m/z calculated for [M+H]+: 473.2; found: 473.2; 1H NMR (400 MHz, Acetone) δ 7.86 (d, J=0.5 Hz, 1H), 7.64 (brs, 1H), 7.62-7.56 (m, 2H), 7.42 (s, 1H), 7.14-7.06 (m, 2H), 3.99-3.85 (m, 5H), 3.71-3.62 (m, 2H), 3.59 (t, J=5.2 Hz, 1H), 3.18 (s, 3H), 2.96 (d, J=4.7 Hz, 3H), 2.52-2.42 (m, 1H), 1.91-1.73 (m, 2H), 1.11-0.94 (m, 3H), 0.64-0.53 (m, 1H).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)=[O:5].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[CH3:26][S:27]([NH:2][CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=1)=[O:5])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C)cc(COC(=O)C(N)Cc2c[nH]c3ccccc23)c1
Agent: Cl
Product: Cc1cc(C)cc(COC(=O)C(Cc2c[nH]c3ccccc23)NS(C)(=O)=O)c1

Procedure:
Following the method of Example 18, 3,5-dimethylbenzyl 2-amino-3-(3-indolyl)propionate hydrochloride and methanesulphonylchloride gave the title compound which was recrystallised from ethyl acetate/petroleum ether, m.p. 96°-97° C. 1H NMR (360 MHz, CDCl3) δ8.18 (1H, s), 7.70 (1H, d, J=7 Hz), 7.48 (1H, d, J=7 Hz), 7.37 (1H, t, J=7 Hz), 7.28 (1H, t, J=7 Hz), 7.12 (1H, s), 7.08 (1H, s), 6.98 (2H, s), 5.04 (2H, s), 4.89 (1H, d, J=9.2 Hz), 4.50 (1H, m), 3.32 (2H, d, J=5.7 Hz), 2.72 (3H, s), 2.30 (6H, s). Found: C, 62.6; H, 5.9; N, 6.8. C21H24N2O4S requires C, 63.0; H, 6.0; N, 7.0.