Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([N:19]3[CH2:24][CH2:23][N:22](C(OC4C=CC=CC=4)=O)[CH2:21][CH2:20]3)=[N:11]2)(=O)=O)C=CC=CC=1.[OH-].[K+].Cl>C(O)C>[N:19]1([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:11]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: O=C(Oc1ccccc1)N1CCN(c2nn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc2c(N3CCNCC3)n[nH]c2c1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
To a suspension of 1-benzenesulfonyl-3-(1-phenoxycarbonyl-4-piperazinyl)-1H-indazole (31.3 g, 67.7 mmol) in ethanol (500 ml) was added 50% KOH (aq.) (100 g of KOH in 100 g H2O) at room temperature. The reaction mixture was warmed to reflux for 6.5 hours and cooled to room temperature. After adjusting the pH to about two using HCl (con., 120 ml), the volatiles were removed under reduced pressure. The remaining residue was diluted with water and removed via filtration. The aqueous filtrate was washed with EtOAc and basified to pH=8 using 50% NaOH (aq.). The product was extracted into 10:1 dichloromethane/isopropylalcohol. The combined organics were dried (MgSO4), filtered, and concentrated to give 13.0 g of desired 3-piperazin-1-yl-1H-indazole as a brown solid which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][CH2:20][OH:21].CCN(C(C)C)C(C)C>CN(C=O)C>[N:8]1([C:4]2[N:3]=[C:2]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]3[CH2:19][CH2:20][OH:21])[CH:7]=[CH:6][N:5]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: Clc1ccnc(-n2ccnc2)n1
Reactant: OCCC1CCCCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: OCCC1CCCCN1c1ccnc(-n2ccnc2)n1
Temperature: 80 °C
Yield: 46.1 %

Procedure:
The above synthesis may be carried out as follows: To DMF (100 ml) was added 4-chloro-2-imidazol-1-ylpyrimidine (0.50 g, 2.77 mmol), 2-piperidineethanol (0.359 g, 2.77 mmol), and Hünig's base (0.536 g, 4.15 mmol). After heating at 80° C. for 5 hours, the solvent was removed in vacuo and the residue was chromatographed (CH2Cl2/MeOH, 19/1) to give 349 mg (46%) of 1-[(1H-imidazol-1-yl)pyrimidin-4-yl]piperidine-2-ethanol (the compound of formula (XVI)), (1H NMR (CDCl3) δ8.54 (s, 2), 8.11 (d, 1), 7.82 (t, 1), 7.11 (d, 1), 6.44 (d, 1), 3.60 (m, 2), 3.03 (m, 1), 1.77 (m); MS: 2.74 (M+H)+). To a solution of 1-[(1H-imidazol-1-yl)pyrimidin-4-yl]piperidine-2-ethanol (25 mg, 0.092 mmol) dissolved in DMF (5 ml) was added NaH (60% dispersion in oil, 5.5 mg, 0.14 mmol) followed by piperonyl chloride (17 mg, 0.10 mmol) and t-butyl ammonium chloride. After stirring for 16 hours at 80° C., the solvent was removed in vacuo and the residue was partitioned with saturated NH4Cl and CH2Cl2. The organic layer was separated, dried (MgSO4), the solvent removed in vacuo, and the residue chromatographed (CH2Cl2/MeOH, 19/1) to give 13 mg (35%) of 4-[2-[[(1,3-benzodioxol-5-yl)methoxy]ethyl]piperidin -1-yl]-2-(1H-imidazol-1-yl)pyrimidine (the compound of formula (Icc)); 1H NMR (CDCl3) δ8.52 (s, 1), 8.05 (d, 1), 7.80 (s, 1), 7.09 (s, 1), 6.73 (m, 3), 6.45 (d, 1), 5.93 (s, 2), 4.30 (s, 2), 3.45 (m, 2),2.95 (m, 1), 1.55 (m); MS: 408.7 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1[C:17]2[CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]([CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=O)[C:11]=2[CH:10]=[CH:9][CH:8]=1>O1CCOCC1>[CH:7]1[C:17]2[CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]([CH2:22][CH2:23][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CC1c2ccccc2CCc2ccccc21)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: c1ccc2c(c1)CCc1ccccc1C2CCN1CCCC1

Procedure:
A mixture of 28.5 g of lithium aluminum hydride and 300 ml of dry dioxane, stirred under argon, is treated dropwise over a period of 1.25 hours with a solution of 230 g of 1-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)acetyl]-pyrrolidine in 700 ml of dry dioxane, whereby the mixture is heated to boiling under reflux. 10 minutes after completion of the addition, the mixture is cooled to about 10°-15° and excess lithium aluminum hydride is destroyed by the cautious addition of 200 ml of ethyl acetate, the temperature rising to about 40°. The mixture is subsequently cooled to about 10° and hydrolyzed by the slow dropwise addition of about 250 ml of water while cooling well. The mixture is suction filtered while back-washing with about 200 ml of chloroform and the filtrate is evaporated in vacuo. The residual brown oil is taken up in 1 l of ether and extracted successively with 300 ml of 2N hydrochloric acid, 150 ml of 2N hydrochloric acid and twice with 100 ml of water each time. The acid-aqueous phase is made basic with about 100 ml of 28 percent sodium hydroxide while cooling with ice and extracted successively with 500 ml of hexane and twice with 300 ml of hexane each time. The organic extracts are washed twice with 250 ml of saturated sodium chloride solution each time and twice with 250 ml of distilled water each time, dried over magnesium aluminum in the presence of a spatula tip of active carbon and evaporated in vacuo. After drying the residue at 40° in a high vacuum, there is obtained 1-[2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)ethyl]pyrrolidine as a light yellow oil which crystallizes slowly; m.p. 51°-53°. By distillation of the crude base under argon over a Hickmann head at 163°-165°/0.09 Torr there is obtained pure material of melting point 53.5°-54°.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:2].[CH3:16][NH:17][CH3:18].O.[BH4-].[Na+]>CO>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:17]([CH3:18])[CH3:16])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CNC
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(OCC)c1ccc(CN(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A solution of 4-(diethoxymethyl)benzaldehyde (6.8 g, 32.69 mmol) and dimethylamine in 33 wt. % solution in water (9.25 g, 98 mmol) in methanol (200 mL) was stirred at room temperature for overnight. Sodium borohydride (1.85 g, 49 mmol) was added by portions with ice cooling. After the addition, the mixture was stirred at room temperature for 4 hr. The mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 ml×3). The extract was dried over anhydrous sodium sulfate and concentrated to give crude title compound (7.0 g, yield 90%), which was used in the next step without further purification. LC-MS (ESI) m/z: 238 (M+1)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[Br:14]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][Br:14])=[CH:11][CH:12]=1
Reactant: Cc1ccc(-c2ccccn2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccccn2)cc1

Procedure:
4-(2-Pyridyl)toluene, 2 mL (1.98 g, 11.7 mmol), N-bromosuccinimide (NBS), 2.5 g (14.0 mmol), and α,α′-azobis(isobutyronitrile)(AIBN), 23 mg (0.14 mmol) were suspended in 35 mL tetrachloromethane, and refluxed for 24 hours. The product was filtered, and the solvent removed from the filtrate by rotary evaporation. Equal amounts of chloroform and water were added and the product extracted. The chloroform layer was separated and dried, and the solvent removed. 4-(2-Pyridyl)benzyl bromide, 2 g, was obtained as a sticky yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([N+]([O-])=O)[CH:12]=[CH:11][C:10]=2[Cl:18])=[C:4]([CH3:19])[N:3]=1.N([O-])=O.[Na+].[CH3:24][SH:25]>[Cu]>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([S:25][CH3:24])[CH:12]=[CH:11][C:10]=2[Cl:18])=[C:4]([CH3:19])[N:3]=1
Reactant: CS
Reactant: Cc1nc(N)nc(N)c1-c1cc([N+](=O)[O-])ccc1Cl
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Product: CSc1ccc(Cl)c(-c2c(C)nc(N)nc2N)c1

Procedure:
This compound was prepared in a similar manner to the compound of Example 54 by reaction of the diazonium salt with methanethiol in the presence of copper powder, mp. 194°-198° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.[CH:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])=[CH:15][CH:14]=1>>[CH3:2][O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:25](=[O:26])[CH2:24][NH:23][C:21]([O:20][CH2:19][C:16]2[CH:15]=[CH:14][CH:13]=[CH:18][CH:17]=2)=[O:22])[CH:6]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: Cl
Product: COC(=O)c1cccc(NC(=O)CNC(=O)OCc2ccccc2)c1
Yield: 91.1 %

Procedure:
3-Amino-benzoic acid methyl ester hydrochloride (1.88 g, 10.0 mmol) was reacted with N-α-CBZ-glycine (3.14 g, 15.0 mmol) according to the procedure of Example 102, step a to afford the product (3.12 g, 91%). 1H NMR (300MHZ, CDCl3) 10.18 (1H, br s), 8.26 (1H, m), 7.84 (1H, d), 7.65 (1H, d), 7.55 (1H, d), 7.48-7.22 (7H, m), 5.05 (2H, s), 3.85 (3H, s), 3.83 (2H, d).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10](O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10]([Cl:25])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccc(Cl)cc2)c(O)nn1Cc1ccccc1
Product: O=c1cc(-c2ccc(Cl)cc2)c(Cl)nn1Cc1ccccc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A suspension of 2-benzyl-5-(4-chlorophenyl)-6-hydroxypyridazin-3(2H)-one (8.5 g, 27.2 mmol) in phosphorus oxychloride (50 mL) was stirred at 95° C. for 1 h. Analysis by HPLC/MS indicated the starting material had been consumed. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with EtOAc. The resulting EtOAc solution was washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (330 g) eluting with a gradient of EtOAc (0-40%) in hexanes to afford 6.2 g (69%) of the title compound as a white solid. HPLC/MS (method A): retention time=3.80 min, (M+H)+=331.0. 1H NMR (CDCl3, 400 MHz): δ 7.27-7.80(m, 9H), 6.88 (s, 1H), 5.36 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]([F:13])([F:12])[F:11])=[CH2:9])[CH:5]=[C:4]([Cl:14])[CH:3]=1.[CH2:15]([N:22]([CH2:28]OC)[CH2:23][Si](C)(C)C)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([N:22]1[CH2:28][CH2:9][C:8]([C:6]2[CH:5]=[C:4]([Cl:14])[CH:3]=[C:2]([Cl:1])[CH:7]=2)([C:10]([F:11])([F:13])[F:12])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 5 h
Yield: 48.3 %

Procedure:
To a stirred solution of 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (10 g, 41.49 mmol) in DCM (150 mL) was added benzyl-methoxymethyl-trimethylsilanylmethyl-amine (Preparation 29, 39.33 g, 165.97 mmol) at room temperature. Resulting reaction mixture was cooled to 0° C. and TFA (0.32 mL, 0.41) was added slowly and stirred at room temperature for 5 hours. After complete consumption of starting material, reaction mixture was basified by aqueous Na2CO3 and extracted with DCM (3×100 mL). Combined organic layer was dried over Na2SO4, and concentrated under vacuum to afford brown oil (9.5 g, crude). Crude compound was purified by column chromatography using 100-200 mesh silica gel. Desired product was eluted in 2% ethyl acetate in hexane to afford product as brown solid (7.5 g, 48.29%). 1H-NMR (400 MHz, CDCl3) δ: 2.28-2.35 (m, 1H), 2.53-2.60 (m, 1H), 2.69-2.81 (m, 2H), 3.03-3.11 (m, 2H), 3.66 (s, 2H), 7.26-7.35 (m, 8H).
Reaction SMILES: [C:1]12([O:7][C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[C:4]1=[O:12])[CH2:3][CH2:2]2.[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:10]1[CH:9]=[CH:8][C:6]2[O:7][C:1]3([C:4](=[O:12])[C:5]=2[CH:11]=1)[CH2:3][CH2:2]3)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C1c2ccccc2OC12CC2
Product: O=C1c2cc([N+](=O)[O-])ccc2OC12CC2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Spiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (7.0 g.) was added in small portions to fuming nitric acid (70 ml.) previously cooled to -50° C. to -60° C. After stirring for 20 minutes, the reaction mixture was poured into ice-water and the precipitated crystals were collected by filtration, washed with water and recrystallized from ethanol. By the above procedure there was obtained 5-nitrospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one as colorless prisms, m.p. 107°-110° C. Yield 7.3 g. This product was in good agreement with the crystals obtained in Example 18.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH2:17][NH:18][C:19]5[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=5[C:21]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([S:34]([N:18]2[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[C:21]3[C:11]4[CH:10]=[N:9][NH:8][C:12]=4[N:13]=[CH:14][C:15]=3[CH2:16][CH2:17]2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CCNc2ccccc2-4)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(c1ccccc1)N1CCc2cnc3[nH]ncc3c2-c2ccccc21

Procedure:
The compound 8-(phenylsulfonyl)-3,6,7,8-tetrahydropyrazolo[4′,3′:5,6]pyrido[3,4-d][1]benzazepine was prepared using 3-(4-methoxybenzyl)-3,6,7,8-tetrahydropyrazolo[4′,3′:5,6]pyrido[3,4-d][1]benzazepine and phenylsulfonyl chloride as described in the 2 step procedure K. The desired compound was obtained as an off-white solid (0.040 g, 18%); 1H NMR (CDCl3, 400 MHz) δ: 8.52 (s, 1H), 8.29 (m, 2H), 7.73 (m, 2H), 7.67-7.50 (m, 6H), 7.00 (dd, J1=1.2 Hz, J2=8.8 Hz, 2H), 6.51 (dd, J1=J2=8.0 Hz, 2H), 6.20 (dd, J1=J2=8.0 Hz, 1H), 4.20 (m, 1H), 3.65 (m, 1H), 2.70 (m, 2H); LCMS [M+H]: 377
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=3)=[CH:11][C:10]([S:27]([NH:30][CH2:31][CH2:32][C:33]([O:35]C)=[O:34])(=[O:29])=[O:28])=[C:9]2[CH3:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[Li].O>CO.O>[CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:21])([CH3:20])[CH3:22])[CH:16]=[C:15]([C:23]([CH3:25])([CH3:26])[CH3:24])[CH:14]=3)=[CH:11][C:10]([S:27]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])(=[O:28])=[O:29])=[C:9]2[CH3:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCNS(=O)(=O)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n(CC2CCCCC2)c1C
Agent: [Li]O
Solvent: CO
Solvent: O
Product: Cc1c(S(=O)(=O)NCCC(=O)O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
To a solution of compound 38 (400 mg, 0.75 mmol) in a mixture of MeOH (10 mL) and water (3 mL) was added LiOH.H2O (200 mg, 4.60 mmol) and then this mixture was stirred at 60° C. for 4 h, evaporated and acidified to pH˜5 with 3N HCl. The aq. layer was extracted with EA (3×). The combined organic layers were concentrated and purified by CC (PE/EA=2/1) to give compound 39 (345 mg, 79%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz) δ: 0.60-0.66 (2H, m), 0.93-1.02 (3H, m), 1.23-1.38 (3H, m), 1.34 (18H, s), 1.51-1.55 (3H, m), 2.51 (3H, s), 2.64 (2H, t, J=5.4 Hz), 3.23-3.29 (2H, m), 3.70 (2H, d, J=7.2 Hz), 5.45 (1H, m), 6.42 (1H, s), 7.14 (2H, s), 7.40 (1H, s). MS Calcd.: 516; MS Found: 517 (M+1).
Reaction SMILES: [OH-].[Na+].C1C[O:6]CC1.[Br:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([Cl:19])[N:15]=[C:14]2Cl>CC(O)=O>[Br:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([Cl:19])[N:15]=[C:14]2[OH:6]
Reactant: Clc1nc(Cl)c2cccc(Br)c2n1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Oc1nc(Cl)nc2c(Br)cccc12
Reaction time: 0.33 h
Yield: 79 %

Procedure:
To a biphasic mixture of NaOH 1 N aq. (10.79 mL, 10.79 mmol) and 11 mL THF was added 8-bromo-2,4-dichloroquinazoline (407b, 1.50 g, 5.40 mmol) in one portion. The reaction became dark red. After 20 min the reaction was checked by LC/MS and judged complete. The reaction was cooled in an ice/water bath and acidified with AcOH. The reaction was concentrated to ½ volume on rotovap (precipitate observed) and cooled in an ice/water bath. The slurry was filtered and the solid rinsed with 2× water. The orange solid was collected and dried in vacuo to give 8-bromo-2-chloroquinazolin-4-ol (1.10 g, 4.24 mmol, 79% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.49 (1H, br. s.), 8.15 (1H, dd, J=7.8, 1.4 Hz), 8.09 (1H, dd, J=7.9, 1.5 Hz), 7.45 (1H, t, J=7.8 Hz). m/z (ESI, +ve ion) 258.9/260.9 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:33])=[C:16]([NH:21][C:22](=O)[CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:35])[CH3:34])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CCCCCC>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:33])=[C:16]([NH:21][CH2:22][CH2:23][C:24]4[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:35])[CH3:34])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(CC(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Solvent: CCCCCC
Product: COc1ccc(CCNc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 66 %

Procedure:
By using N-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-4-methoxyphenylacetamide, the title compound was synthesized according to Example 2b. Yield: 66%. Melting point: 63-65° C. (Hexane)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24](=[O:34])[C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].[Na+].Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CN(C=O)C.CC(=O)OCC>[CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:24](=[O:34])[C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CNC(=O)c3ccc([N+](=O)[O-])cc3)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc([N+](=O)[O-])cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
Prepared using General Procedure 4: To a stirring solution of 4-((4-nitrobenzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-2 (857 mg, 1.75 mmol) in DMF (7 mL) was added sodium hydride (77.0 mg, 1.92 mmol). After 5 min, tert-butyl 2-bromoacetate (0.30 mL, 2.01 mmol) was added. After stirring at room temperature for 1 h, additional tert-butyl 2-bromoacetate (0.297 mL, 2.01 mmol) and sodium hydride (77.0 mg, 1.92 mmol) were added and the reaction stirred for another 1 h. The reaction mixture was diluted with EA (100 mL) and washed with brine (200 mL). The organic layer was concentrated and purified by chromatography (EA/hexanes) to provide 888 mg (84%) of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-nitrobenzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-3. LCMS-ESI (m/z) calculated for C34H40N2O8: 604; no m/z observed, tR=3.62 min (Method 5).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].CCOCC>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:20]
Reactant: Sc1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)CSc1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 89.8 %

Procedure:
To a solution of thiophenol (1 mL, 9.7 mmol) in DMF (20 mL) is added potassium carbonate (1.51 g, 10.9 mmol) and ethyl bromoacetate (1.17 mL, 10.6 mmol), and the mixture is stirred at RT for 25 min. Et2O is added, and the mixture is washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue is vacuum distilled (130-140° C.) to give 1.71 g of the product 400. 1H NMR (CDCl3) δ 7.41 (d, 2H), 7.33-7.2 (m, 4H), 4.16 (q, 2H), 3.63 (s, 2H), 1.22 (t, 3H); MS: m/z 196 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Br:10]Br>C(Cl)(Cl)Cl>[Br:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[OH:1])[CH:6]=[O:7]
Reactant: BrBr
Reactant: O=Cc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(O)c(Br)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (10.00 g, 82 mmol) in chloroform (170 mL) was added bromine (13.76 g, 86.1 mmol) dropwise as a solution in chloroform (80 mL). Upon completion of addition, the reaction was stirred for 30 mins. at room temperature then warmed to 40° C. for 1 hr. The reaction was diluted with aqu. sat'd NaHCO3 (250 mL) and the layers were separated. The aqueous was extracted with CH2Cl2 (2×250 mL). The organics were combined, dried with MgSO4 and concentrated to afford 7.49 g of 3-bromo-4-hydroxybenzaldehyde which contains 10% of 3,5-dibromo-4-hydroxybenzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1>>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:22][CH3:23])[N:13]=[CH:12][N:11]=[C:10]2[S:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1cccc(S)c1
Product: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Yield: 103.8 %

Procedure:
3-Aminothiophenol (1.42 mL, 13.3 mmol) and 4-chloro-6,7-dimethoxyquinazoline (3.0 g, 13.3 mmol) were reacted using the procedure described in Example 46 to give 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (4.32 g, 13.8 mmol, 100% (wet with H2O)). 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 7.33 (s, 1H), 7.31 (s, 1H), 7.13 (t, 1H), 6.80 (s, 1H), 6.73 (d, 1H), 6.68 (d, 1H), 5.34 (br s, 2H), 3.98 (s, 3H), 3.97 (s, 3H); LC-MS (ESI) m/z 314 (M+H)+.
Reaction SMILES: C(=O)([O-])O.[Na+].[C:6]([OH:10])(=[O:9])[CH2:7][OH:8].CN(C)C=O.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>O>[C:6]([O:10][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)(=[O:9])[CH2:7][OH:8]
Reactant: O=C(O)CO
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COC(=O)CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
Sodium hydrogen carbonate (2.20 g, 26.3 mg) was added to a solution of glycolic acid (2.00 g, 26.3 mmol) in water (2.00 mL), and the mixture was stirred for one hour at room temperature. The solvent was distilled off from the reaction mixture under reduced pressure, and to a dimethylformamide (10.0 mL) solution of the resulting residue, p-methoxybenzyl chloride (4.10 g, 26.3 mmol) was added. The mixture was stirred for 2 hours at room temperature. Water was added to the reaction mixture, and the mixture was subjected to extraction with ethyl acetate. The organic layer thus obtained was washed sequentially with water and saturated brine, and was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Thus, a crude product of the title compound (4.24 g) was obtained.