Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:11]3[O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[N:9]=[CH:10][C:3]=12.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[CH:36]=[CH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O>[CH2:35]([S:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:11]3[O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[N:9]=[CH:10][C:3]=12)[CH:36]=[CH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: BrCC=Cc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ncc3c(S)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2ncc3c(SCC=Cc4ccccc4)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.17 h

Procedure:
A suspension of 4-mercapto-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (1.0 g) and potassium carbonate (0.37 g) in N,N-dimethylformamide was stirred for 10 minutes and then cinnamyl bromide (0.53 g) was added. After stirring for 3 hr. at 40° C. the solution was filtered and 100 ml chloroform was added. The solution was extracted with water. The chloroform layer was dried, filtered and taken to dryness on a rotary evaporator. The residue was purified on a column of silica gel using chloroform as the eluant. The fractions containing the product were pooled and taken to dryness in vacuo. The residue was dissolved in chloroform, filtered through a Millipore filter in vacuo and evaporated in vacuo, to give the product 4-cinnamylthio-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine as a glass.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:16]2[N:17]=[CH:18][N:19]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=2)[CH2:13][CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([C:14]#[N:15])[CH:7]=[CH:6][C:5]1=2.Br[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43].C(=O)(O)[O-].[Na+]>O1CCCC1>[C:14]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([C:16]1[N:17]=[CH:18][N:19]([C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=1)([O:3][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:13][CH2:12][CH2:11]2)#[N:15]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccc2c(c1)CCCC2(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC1(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CCCc2cc(C#N)ccc21

Procedure:
1.9 mmol of sodium hydride (60% dispersion in oil) are added in portions to a solution of 1.3 mmol of 5-hydroxy-5-(1-trityl-1H-imidazol-4-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile in 10 ml of tetrahydrofuran, and the mixture is stirred under reflux for 1 hour. 3.0 mmol of ethyl bromoacetate [105-36-2] are added and the reaction mixture is stirred under reflux for 8-16 hours. The reaction mixture is cooled and poured into saturated sodium bicarbonate solution and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with water and brine, dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of its Rf by flash chromatography (SiO2 60F).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.C(N(C(C)C)CC)(C)C.[CH:29]([C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([C:42]([F:45])([F:44])[F:43])[C:39]=1[O:40][CH3:41])[C:34](Cl)=[O:35])=[O:30]>ClCCl>[CH:29]([C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([C:42]([F:43])([F:45])[F:44])[C:39]=1[O:40][CH3:41])[C:34]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:35])=[O:30]
Reactant: COc1c(C=O)cc(C(=O)Cl)cc1C(F)(F)F
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C=O)cc(C(=O)N2CSc3ccccc32)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (1.55 g) and 37% formalin (1.0 mL) in the same manner as in Example 1 was dissolved in dichloromethane (15 mL), and diisopropylethylamine (2.7 mL) and 3-formyl-4-methoxy-5-trifluoromethylbenzoyl chloride (2.42 g) were added to the solution, and then the mixture was stirred at room temperature for 14 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the title compound (1.44 g) as a yellow oily substance.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1)(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reaction time: 1.5 h
Yield: 102 %

Procedure:
A mixture of N-Boc-4-piperidinemethanol (1.0 g, 4.51 mmol), Et3N (1.30 mL, 9.01 mmol) in CH2Cl2 (20 mL) at 0° C. was treated dropwise with methanesulfonyl chloride (0.39 mL, 4.96 mmol). The reaction mixture was stirred at 0° C. to 5° C. for 1.5 h, was diluted with CH2Cl2 (100 mL) and washed with 1M NaH2PO4 (50 mL×2) and brine (25 mL). The CH2Cl2 layer was dried over Na2SO4, filtered, and the filtrate was concentrated to a brown oil, which solidified upon cooling to give 1.35 g (100%) of 1,1-dimethylethyl 4-{[(methylsulfonyl)oxy]methyl}-1-piperidinecarboxylate as a brown solid, which was used without further purification. 1H NMR (400 MHz, CDCl3): δ 4.20-4.10 (m, 2H), 4.04 (d, 2H, J=6.5 Hz), 2.99 (s, 3H), 2.75-2.60 (m, 2H), 1.95-1.85 (m, 1H), 1.75-1.65 (m, 2H), 1.43 (s, 9H), 1.30-1.10 (m, 2H).
Reaction SMILES: BrBr.[O:3]=[C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:18](=[O:19])[C:17]2[N:16]([CH3:20])[CH:15]=[N:14][C:13]=2[N:12]([CH3:21])[C:10]1=[O:11])[CH3:5].C(=O)(O)[O-].[Na+].[Br:27]C(CCN1C(=O)C2N(C)C=NC=2N(C)C1=O)C(=O)C>CO.O>[Br:27][CH2:5][C:4](=[O:3])[CH2:6][CH2:7][CH2:8][N:9]1[C:18](=[O:19])[C:17]2[N:16]([CH3:20])[CH:15]=[N:14][C:13]=2[N:12]([CH3:21])[C:10]1=[O:11]
Reactant: CC(=O)C(Br)CCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: CC(=O)CCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1cnc2c1c(=O)n(CCCC(=O)CBr)c(=O)n2C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4.93 Grams (0.031 moles) of bromine were added to a solution of 7.3 g (0.0276 moles) of compound (a) in 100 ml of methanol, at 10° C. After stirring for 15 hours at room temperature, the reaction mixture volume was concentrated to 30 ml under reduced pressure, then 60 ml of water, and 3 drops of conc. sulphuric acid were added. The mixture was stirred at room temperature for 4 hours, in order to hydrolyze any dimethylketals formed by reaction with methanol. After dilution with 50 ml of water, the pH of the mixture was adjusted to 8-9, by addition of a 10% sodium bicarbonate aqueous solution, the mixture was extracted with 3×50 ml of methylene chloride, washed with water, dried on anhydrous sodium sulfate, filtered and evaporated under vacuum. 8.3 Grams of compound were obtained, which, by TLC and NMR analysis, showed to be impure by the presence of the 1-(3-bromo-2-keto-5-pentyl)-3,7-dimethylxanthine regioisomer. The crude compound was directly used for the next step.
Reaction SMILES: I[CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C)C=O>[N:14]([CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1Nc2ccccc2CCC1I
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCc2ccccc2NC1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
To a solution of 36.7 g (128 mmol) of 3-Iodo-2,3,4,5-tetrahydro-1H-[1]-benzazapin-2-one in 200 mL of dimethylformamide was added 9.97 g (153 mmol) of sodium azide. After 3 h, the mixture was poured into 800 mL of ice water and the precipitate collected on a filter. After washing the solid successively with water, 3% aqueous sodium bisulfite, and water, the product was dried under vacuum to give 21.5 g (83%) of a tan powder. 1H NMR (300 MHz, CDCl3) d 8.91 (1H, bs), 7.4-7.0 (4H, m), 3.89 (1H, t, J=9 Hz), 2.97 (1H, m), 2.73 (1H, m), 2.52 (1H, m), 2.32 (1H, m).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]=O.[Cl-].[Li+].O>CN1CCN(C)C1=O>[CH2:14]([C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:1]=1[OH:8])[OH:7])[C:10]1[O:9][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)CC1
Reactant: O=Cc1ccco1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: Oc1ccc(O)c(Cc2ccco2)c1
Temperature: 165 °C
Yield: 70.5 %

Procedure:
A mixture of 1,4-cyclohexanedione (5.6 g; 50 mmol), furan-2-carbaldehyde (4.8 g; 50 mmol) and anhydrous lithium chloride (2.1 g; 50 mmol) in 1,3-dimethyl-2-imidazolidinone (20 ml) was heated with stirring over an a oil bath at atmospheric pressure. The temperature of the bath was maintained at 165° C. for 1 h. The cooled reaction mixture was poured into water (300 ml) and extracted with ethyl acetate (2×150 ml). The combined organic layers were washed with water (2×100 ml), dried over magnesium sulphate and filtered. The organic solvent was removed in vacuo. The residue (9.4 g) was purified by flash chromatography using a silica gel column and toluene/ethyl acetate (90:10) as eluent, to give 6.7 g (70%) of 3-furfurylhydroquinone.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[O:3]1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:16].[K+].[K+]>C(#N)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][C:2]1([CH3:14])[C:6](=[O:16])[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[O:3]1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: CC1(C)Cc2cccc([N+](=O)[O-])c2O1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC1(C)Oc2c(cccc2[N+](=O)[O-])C1=O
Yield: 93.5 %

Procedure:
A mixture of 37.3 g (0.193 mole) of 2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran, 156.6 g (0.58 mole) of potassium persulfate, and 48.2 g (0.193 mole) of copper(II) sulfate pentahydrate in 500 mL of acetonitrile and 500 mL of water was prepared. This mixture was heated at reflux for one hour with vigorous stirring. The reaction mixture was cooled and then extracted three times with methylene chloride. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure, leaving 37.4 g of 2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran-3-one as a residue. The NMR and IR spectra of the same product from a previous run of this reaction were consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][C:18]#[N:19]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[C:17](=[CH:4]/[C:3]2[CH:6]=[C:7]([F:11])[CH:8]=[C:9]([F:10])[C:2]=2[F:1])/[C:18]#[N:19])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1cc(F)cc(F)c1F
Product: COc1ccc(/C(C#N)=C/c2cc(F)cc(F)c2F)cc1OC
Yield: 84 %

Procedure:
2,3,5-Trifluorobenzaldehyde (320 mg) and 3,4-dimethoxybenzyl cyanide (354 mg) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (536 mg, yield: 84%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[C:6]3([CH3:15])[CH2:13][CH2:12][C:9]([CH3:14])([C:10]=2[CH:11]=1)[CH2:8][CH2:7]3.[C:17](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[C:6]3([CH3:15])[CH2:13][CH2:12][C:9]([CH3:14])([CH2:8][CH2:7]3)[C:10]=2[CH:11]=1
Reactant: CC12CCC(C)(CC1)c1cc(Br)c(O)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc2c(cc1Br)C1(C)CCC2(C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-bromo-1,8-dimethyl-tricyclo[6.2.2.02,7]dodeca-2(7),3,5-trien-4-ol (Compound 3, 0.825 g, 2.94 mmol) in 10 mL of anhydrous acetone was added potassium carbonate (0.128 g, 8.82 mmol) and iodomethane (0.1 mL, 8.82 mmol). The reaction mixture was stirred at 25° C. for 12 hours and filtered. The filtrate was concentrated, and then it was diluted with ether and washed with water and brine. The organic layer was dried over Na2SO4, and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate:hexane (5:95) to yield the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:22][CH2:23][CH2:24][CH2:25]I>CCCCCCC.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[N:10]([CH2:25][CH2:24][CH2:23][Cl:22])[C:9]=2[CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCCI
Reactant: CC(C)(C)c1ccc2c(c1)NC(=O)CO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)c1ccc2c(c1)N(CCCCl)C(=O)CO2
Yield: 49.3 %

Procedure:
6-tert-Butyl-4H-benzo[1,4]oxazin-3-one (81MF2248a) (2.07 g, 10.0 mmol), Cs2CO3 (4.88 g, 15.0 mmol) and 3-chloro-1-iodopropane (2.25 g, 11.0 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) to give the title compound (81MF2248b) (1.39 g, 49%). 1H NMR (CDCl3) δ 7.12 (d, J=2.0 Hz, 1H), 7.03 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 4.54 (s, 2H), 4.14 (t, J=7.2 Hz, 2H), 3.65 (t, J=6.0 Hz, 2H), 2.21-2.14 (m, 2H), 1.32 (s, 9H); 13C NMR (CDCl3) δ 164.8, 146.4, 143.1, 127.9, 120.9, 116.7, 112.2, 67.8, 42.6, 38.9, 34.8, 31.6, 30.2.
Reaction SMILES: [OH-:1].[Na+].[Br:3][C:4]1[N:5]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([CH:35]3[CH2:37][CH2:36]3)=[CH:27][CH:26]=2)[C:6]([S:9][CH2:10][C:11](NC2C=CC(S(=O)(=O)N)=CC=2Cl)=[O:12])=[N:7][N:8]=1.C>C(O)C>[Br:3][C:4]1[N:5]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([CH:35]3[CH2:37][CH2:36]3)=[CH:27][CH:26]=2)[C:6]([S:9][CH2:10][C:11]([OH:1])=[O:12])=[N:7][N:8]=1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CSc2nnc(Br)n2-c2ccc(C3CC3)c3ccccc23)c(Cl)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sodium hydroxide solution (2M aqueous, 33.7 mL, 67 mmol, 2 eq) was added to a suspension of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-N-(2-chloro-4-sulfamoylphenyl)acetamide (prepared by previously published procedures; 20 g, 34 mmol) in ethanol (200 mL) and the mixture heated at reflux for 4 hours. Charcoal (10 g) was added, the mixture stirred at room temperature for 12 hours and the charcoal removed by filtration. The charcoal was washed several times with ethanol and the filtrate then concentrated. Water (200 mL) was added and then concentrated to approx. one third volume, to remove all ethanol. Water (200 mL) and ethyl acetate (250 mL) were added, the mixture stirred vigorously for 15 mins and the organic layer removed. The aqueous layer was cooled to 0° C. and acidified by treatment with HCl (IN) resulting in the formation of a cloudy oily precipitate. The mixture was extracted with ethyl acetate (3×) and the combined organic extracts dried over sodium sulfate and concentrated to give 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid as an off white solid (11.2 g, 82%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][S:5][CH2:4]1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([O:1][CH2:2][CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][S:5][CH2:4]1)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: O=C1CCSCC1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC1CSCCC1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
To an ice-cooled solution of 1.26 g (0.0086 mol) of product from Step C and 1.44 g (0.0142 mol) of triethylamine in 25 ml of methylene chloride was added dropwise 0.75 g (0.0095 mol) of acetyl chloride. The solution was stirred for four hours at 0° C., after which time it was washed with water, a saturated solution of sodium bicarbonate, and water. The organic phase was dried (MgSO4), filtered, and evaporated to give 1.52 g (94%) of product.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[N:17]([CH3:18])[C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1.O.NN>CO>[NH2:3][CH2:12][C:13]1[N:17]([CH3:18])[C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)n1C
Agent: NN
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(CN)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
650 mg of methyl 5-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)methyl]-1-methyl-1H-pyrrole-2-carboxylate was dissolved in 20.0 mL of methanol, and 109 mg of hydrazine monohydrate was added thereto, followed by stirring at room temperature overnight. The reaction liquid was concentrated under reduced pressure, to the obtained residue was added chloroform, and the insolubles were filtered off. Then, the filtrate was concentrated under reduced pressure to obtain 294 mg of methyl 5-(aminomethyl)-1-methyl-1H-pyrrole-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:12]2[C:17]([CH:18]([CH3:20])[CH3:19])=[C:16]([O:21][CH3:22])[N:15]=[C:14]([O:23][CH3:24])[N:13]=2)C#N)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].CN(C=[O:31])C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[C:17]([CH:18]([CH3:20])[CH3:19])=[C:16]([O:21][CH3:22])[N:15]=[C:14]([O:23][CH3:24])[N:13]=2)=[O:31])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COc1nc(OC)c(C(C)C)c(C(C#N)c2cc(Cl)cc(Cl)c2)n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(Cl)cc(Cl)c2)n1
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a stirred solution of (59) (9.6 g, 26 mmol) in anhydrous DMF (100 ml) under nitrogen atmosphere, was added 60% sodium hydride (1.05 g, 26 mmol). After 10 min., oxygen was bubbled into the reaction mixture for 4 hr. The mixture was partitioned between ether and aqueous saturated ammonium chloride solution. The organic layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was then purified by silica gel column chromatography (eluent, ether:hexanes (1:10)) to afford 7.36 g (80%) of the title compound as a white solid. m.p. 120-121° C.; 1H NMR (200 MHz, CDCl3) δ 1.22 (6H, d, J=7.0 Hz), 2.86 (1H, m), 3.96 (6H, s), 4.09 (3H, s), 7.60-7.74 (3H, m).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[F:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(F)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1c(F)cccc1C=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a suspension of 3-fluoro-2-hydroxybenzaldehyde (5.328 g, 38.02 mmol) and potassium carbonate (7.88 g, 57.03 mmol) in acetone (60 mL) was added dimethyl sulphate (3.96 mL, 41.83 mmol). The resulting suspension was stirred at 60° C. for 2 h before being allowed to cool and then concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL) and water (50 mL). The organic phase was washed with saturated sodium bicarbonate (50 mL) with the resulting organic phase being dried (MgSO4) and the solvent evaporated in vacuo to give a pale yellow oil (6.262 g, 38.02 mmol, 100%). δH (300 MHz, CDCl3) 10.40 (1H, s, CHO), 7.60 (1H, d, Ar), 7.30 (1H), m, Ar), 7.10 (1H, m, Ar), 4.10 (3H, s, OCH3).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Cl:10][C:11]1[C:12]([F:37])=[C:13]([CH:34]=[CH:35][CH:36]=1)[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:32][CH3:33])=[C:22]([O:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:23]=2)[N:18]=[CH:17][N:16]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:6]([O:5][C:3](=[O:4])[CH2:2][N:29]1[CH2:30][CH2:31][CH:26]([O:25][C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][C:21]=2[O:32][CH3:33])[N:18]=[CH:17][N:16]=[C:15]3[NH:14][C:13]2[CH:34]=[CH:35][CH:36]=[C:11]([Cl:10])[C:12]=2[F:37])[CH2:27][CH2:28]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: CC(C)(C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(CC(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Yield: 58 %

Procedure:
Tert-butyl chloroacetate (1.43 ml, 10 mmol) was added dropwise to a mixture of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline (4.02 g, 10 mmol), potassium iodide (1.66 g, 10 mmol) and potassium carbonate (1.66 g, 12 mmol) in dimethylacetamide (50 ml). The mixture was heated at 70° C. for one hour. After evaporation of the solvents under vacuum, the residue was triturated in water. The resulting solid was filtered, washed with water and purified by chromatography on silica gel (eluant: 2% 7N methanolic ammonia in dichloromethane) to give tert-butyl[4-({4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl}oxy)piperidin-1-yl]acetate as a white solid (3.0 g, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.C(NC(C)C)(C)C.[C:20]1([O:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:27](=[O:28])[O:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Oc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 4-methoxy-2-nitroaniline (15.0 g) and diisopropylamine (16.2 ml) in dichloromethane (300 ml) was added dropwise under ice-cooling a solution of phenylchloroformate (16.8 g) in dichloromethane (30 ml). The reaction solution was stirred at room temperature overnight, washed with water and saturated saline and dried over anhydrous MgSO4. The solvent was distilled off. Crystallization of the residue from hexane gave phenyl 4-methoxy-2-nitrophenylcarbamate (12.6 g, 49.1%) as crystals.