Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[F:11][C:12]([F:25])([F:24])[C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15](OCC)=[O:16].CC[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[C:15]([OH:16])[C:14]2[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=2[C:12]([F:11])([F:24])[F:25])[C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccccc1C(F)(F)F
Reactant: N#CCc1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC(=C(O)c1ccccc1C(F)(F)F)c1ccc(Cl)cc1
Yield: 50.9 %

Procedure:
5.8 g of 4-chlorobenzyl cyanide, 10 g of ethyl 2-trifluoromethylbenzoate and 2.9 g of sodium ethylate were added to 100 ml of toluene and then reacted for 8 hours under reflux. The reaction mixture was returned to room temperature and extracted by an addition of 200 ml of water. The aqueous phase was adjusted to pH 6 to 7 with 6N hydrochloric acid and then extracted by an addition of 400 ml of methylene chloride. The organic layer was washed with water and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 6.3 g of the desired product. The NMR spectrum data of this product were the same as in Reference Preparation Example 3.
Reaction SMILES: [C:1](=[S:3])=S.[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[N:14]=[C:13]2[CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)=[CH:7][CH:6]=1.[C:35]1([CH2:41][N:42]2[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[N:44]=[C:43]2[CH2:51][CH:52]2[CH2:57][CH2:56][N:55]([CH2:58][CH2:59][NH2:60])[CH2:54][CH2:53]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[N:14]=[C:13]2[CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][CH2:27]2)=[CH:7][CH:6]=1.[N:60]([CH2:59][CH2:58][N:55]1[CH2:56][CH2:57][CH:52]([CH2:51][C:43]2[N:42]([CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[N:44]=2)[CH2:53][CH2:54]1)=[C:1]=[S:3]
Reactant: S=C=S
Reactant: NCCN1CCC(Cc2nc3ccccc3n2Cc2ccccc2)CC1
Agent: Cc1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3cccnc32)cc1
Solvent: C1CCOC1
Product: S=C=NCCN1CCC(Cc2nc3ccccc3n2Cc2ccccc2)CC1
Yield: 89 %

Procedure:
To a stirred and cooled (-10° C.) mixture of 20.8 parts of carbon disulfide, 9 parts of N,N'-methanetetraylbis[cyclohexanamine] and 135 parts of tetrahydrofuran was added dropwise a solution of 15 parts of 4-[[1-(phenylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidineethanamine in tetrahydrofuran at a temperature below -10° C. The reaction mixture was allowed to reach room temperature and the solvent was evaporated. The residue was crystallized from acetonitrile. The precipitate was filtered off and the filtrate was evaporated, yielding 15 parts (89%) of 2-[[1-(2-isothiocyanatoethyl)4-piperidinyl]methyl]-1-(phenylmethyl)-1H-benzimidazole (395).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:8][C:6]1[CH:7]=[C:2]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-n2cccn2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 106.8 %

Procedure:
To a solution of 5-fluoro-2-nitrotoluene (1.27 g, 8.20 mmol) and pyrazole (1.3 g, 19.3 mmol) in dimethylformamide (32 mL) was added potassium carbonate (1.3 g, 9.7 mmol), and the mixture was heated to 100° C. overnight. The reaction was cooled, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with 10% aqueous lithium chloride, water and saturated sodium chloride, then dried over sodium sulfate and concentrated on a rotary evaporator to give 1-(3-methyl-4-nitrophenyl)-1H-pyrazole (1.78 g, 100%). This material was dissolved in ethanol (50 mL) and, after addition of 5% palladium on carbon (100 mg), the reaction was stirred under a balloon of hydrogen overnight. The mixture was filtered through Celite and washed with ethanol. The solvent was removed on a rotary evaporator to give 2-methyl-4-(1H-pyrazol-1-yl)aniline. A portion of this material (52 mg, 0.30 mmol) was added to a solution of 4-(4-phenylquinazolin-2-ylamino)benzoyl chloride (110 mg, 0.30 mmol) and Hunig's base (157 μL, 0.90 mmol) in tetrahydrofuran (2 mL) and the reaction was allowed to stir at rt overnight. The mixture was concentrated on a rotary evaporator and purified by flash column chromatography to give N-[2-methyl-4-(1H-pyrazol-1-yl)phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide (90 mg, 60%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.30 (s, 1H), 9.80 (s, 1H), 8.50 (d, 1H), 8.20 (d, 2H), 8.02 (d, 2H), 7.86 (m, 3H), 7.80 (m, 3H), 7.75 (d, 1H), 7.70 (dd, 1H), 7.64 (t, 3H), 7.50 (d, 1H), 7.42 (m, 1H), 6.58 (t, 1H), 2.30 (s, 3H). MS (EI) for C31H24N6O: 497.4 (MH+).
Reaction SMILES: N1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.O1C2C=CC=CC=2N=[CH:12]1.S1C2C=CC=CC=2N=C1>>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:12]=[CH:2][CH:3]=1
Reactant: c1ccc2nccnc2c1
Reactant: c1ccc2ocnc2c1
Agent: c1ccc2scnc2c1
Product: c1ccc2ncccc2c1

Procedure:
quinoxaline; benzoxazole; or benzothiazole.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](O)=[O:12])[CH2:7][CH2:6]1)=[O:4].CO>O1CCCC1>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](CO)CC1
Reaction time: 4 h

Procedure:
To a solution of trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (10.0 g, 53.7 mmol) in tetrahydrofuran (540 ml) was added borane-dimethylsulfide complex (6.80 g, 80.6 mmol) at 0-5° C. The cooling bath was removed after 15 minutes and the mixture was stirred for 4 h. The reaction mixture was quenched with methanol (17.2 g, 537 mmol), stirred for 20 minutes and concentrated in vacuo. The residue was triturated in tert-butyl methyl ether (300 ml) and filtrated over a pad of Decalite. The filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate (300 ml) and 1 M aqueous sodium hydroxide solution (100 ml). The layers were separated. The organic layer was washed with one 100 ml-portion of water. The combined aqueous layers were extracted with one 150-ml portion of ethyl acetate. The combined organic layers were washed with one 50 ml-portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (8.75 g, 94.6%) as colorless oil, which can be used without further purification. MS m/e: 172 (M+)
Reaction SMILES: [CH3:1][CH2:2]N(C(C)C)C(C)C.[C:10]([C:12]1[CH:13]=[CH:14][C:15]([OH:32])=[C:16]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:17]=1)#[N:11].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[C:10]([C:12]1[CH:13]=[CH:14][C:15]2[O:32][C:1](=[CH2:2])[N:18]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH2:20]3)[C:16]=2[CH:17]=1)#[N:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(C#N)ccc2O)CC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: C=C1Oc2ccc(C#N)cc2N1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 116 %

Procedure:
Hünig's base (1 mL, 5.73 mmol) was added to a solution of 1,1-dimethylethyl 4-[(5-cyano-2-hydroxyphenyl)amino]-1-piperidinecarboxylate (D32, 977 mg, 3.08 mmol) in dichloromethane (20 mL) at rt under argon. The reaction was cooled to 0° C. and triphosgene (373 mg, 1.26 mmol) was added. The reaction was then stirred for 30 min at 0° C. and quenched with saturated aqueous NaHCO3 (20 mL) before being partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×) and the combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give a yellow oil. The crude residue was purified via chromatography (silica, Biotage 40+S column, dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) to give 1,1-dimethylethyl 4-(5-cyano-2-methylidene-1,3-benzoxazol-3(2H)-yl)-1-piperidinecarboxylate (D33, 1.22 g, 92% yield, 82% purity by LC-MS) as a yellow oil.
Reaction SMILES: [CH:1]1[C:17]2[C:16]([C:18]([OH:20])=[O:19])=[C:15]3[C:7](=[C:8]4[C:13](=[N:14]3)[CH:12]=[CH:11][CH:10]=[CH:9]4)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[CH3:26]O>>[CH:1]1[C:17]2[C:16]([C:18]([O:20][CH3:26])=[O:19])=[C:15]3[C:7](=[C:8]4[C:13](=[N:14]3)[CH:12]=[CH:11][CH:10]=[CH:9]4)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1c2nc3ccccc3c-2[nH]c2ccccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1c2nc3ccccc3c-2[nH]c2ccccc12

Procedure:
To a suspension of quindoline-11-carboxylic acid (2.3 g, 8.77 mmol) from Example 1 in MeOH (50 mL) was added concentrated H2SO4 (1.5 ml, 28 mmol). The resulting solution was refluxed for 8 hours, cooled, and partitioned between benzene (100 mL) and water (50 mL). After adjusting the pH to 9 with a saturated solution of K2CO3, the benzene layer was separated, washed with water, dried and concentrated. Purification by LPLC (EtOAc-hexane 1:3) gave 0.28 g of the title compound as greenish-yellow crystals (from hexane), mp 152-153.5° C. [lit 152.5-154° C. (Degutis, Y. A.; Ezyarskaite, A. B. Khim. Geterotsik. Soedin. 1986, 1375)]; 1H NMR (CDCl3) δ 9.75 (s, 1H), 9.09 (d, J=6.4, 1H), 8.51 (d, J=8.0, 1H), 8.38 (d, J=7.2, 1H), 7.72-7.62 (m, 3H), 7.49 (d, J=8.0, 1H), 7.38 (t, J=8.0, 1H); 13C NMR (CDCl3) δ 168.19, 147.81, 144.43, 143.56, 133.91, 130.50, 130.27, 127.40, 126.18, 125.05, 123.66, 122.23, 121.65, 121.06, 111.19, 109.21, 52.54; MS (EI, m/z) 276 (M+). Acidification of the water layer with HCl gave 1.8 g (78.3%) of recovered starting material.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:15]([O:17][CH:18]=[CH:19][C:20](Cl)=[O:21])[CH3:16]>C(Cl)Cl>[CH2:15]([O:17][CH:18]=[CH:19][C:20]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1)=[O:21])[CH3:16]
Reactant: Nc1ccc(I)cc1
Reactant: CCOC=CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC=CC(=O)Nc1ccc(I)cc1
Reaction time: 5 h
Yield: 55.8 %

Procedure:
To the mixture of 4-iodoaniline (14 g, 64 mmol) and pyridine (10.5 mL, 128 mmol) in methylene chloride (85 mL) was added 3-ethoxy-acryloyl chloride (10 g, 75 mmol). After stirring for 5 hrs, more 3-ethoxy-acryloyl chloride (5 g, 38 mmol) and pyridine (10.5 mL, 64 mmol) was added. After stirring for 2 days, the reaction mixture was washed with water 3×100 mL), dried over MgSO4 and concentrated to give 3-ethoxy-N-(4-iodo-phenyl)-acrylamide as black oil (11.32 g, 56%). LC-MS m/e 318 (MH+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=CC=CC=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:32][CH:31]([C:33](O)=[O:34])[CH2:30]2)=[CH:25][CH:24]=1)=[O:21].C1C2C(=CC=CC=2)CN1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH:9]1([NH:10][C:33]([CH:31]2[CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:20]([N:12]4[CH2:11][C:19]5[CH:18]=[CH:17][N:16]=[CH:15][C:14]=5[CH2:13]4)=[O:21])=[CH:28][CH:27]=3)[CH2:32]2)=[O:34])[CH2:6][CH2:1][CH2:7][CH2:8]1
Reactant: O=C(O)C1CN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)C1
Reactant: NCCCc1ccccc1
Agent: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Product: O=C(NC1CCCC1)C1CN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)C1

Procedure:
The title compound was prepared as described in Example 1C, substituting cyclopentylamine for 3-phenylpropan-1-amine and 1-(4-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)phenyl)azetidine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.59 (s, 1H), 8.49 (d, J=5.0 Hz, 1H), 8.13 (s, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.42 (d, J=5.1 Hz, 1H), 7.34-7.27 (m, 2H), 6.41-6.33 (m, 2H), 4.79-4.73 (m, 4H), 4.06-3.94 (m, 1H), 3.92-3.84 (m, 2H), 3.76-3.66 (m, 2H), 3.46-3.33 (m, 1H), 1.86-1.72 (m, 2H), 1.67-1.30 (m, 6H); MS (ESI(+)) m/e 406 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH:14]=3)=[CH:11][C:10]([NH2:26])=[N:9]2)=[CH:4][CH:3]=1.[O:27]=[C:28]1[NH:32][CH2:31][C@@H:30]([C:33](O)=[O:34])[CH2:29]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH2:21][C:22]([F:24])([F:23])[F:25])[CH:14]=3)=[CH:11][C:10]([NH:26][C:33]([C@H:30]3[CH2:29][C:28](=[O:27])[NH:32][CH2:31]3)=[O:34])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1cc(-c2cccc(COCC(F)(F)F)c2)n(-c2ccc(F)cc2)n1
Reactant: O=C1C[C@H](C(=O)O)CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C1C[C@H](C(=O)Nc2cc(-c3cccc(COCC(F)(F)F)c3)n(-c3ccc(F)cc3)n2)CN1
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (43 mg) in N,N-dimethylacetamide (0.4 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (17 mg) prepared according to the same procedures as Preparation 5 and WSC.HCl (34 mg) at room temperature, and the mixture was stirred for 0.5 hours. To this reaction mixture was added water, and then the precipitated solid was collected by filtration. This solid was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (26 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=O)[CH3:11].C(Cl)Cl.[N-:16]=[N+:17]=[N-:18].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]([CH3:11])=[N:18][N:17]=[N:16]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)Nc1ccc(I)cc1Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1nnnn1-c1ccc(I)cc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
A suspension of N-(2-chloro-4-iodo-phenyl)-acetamide (2.39 g, 8.09 mmol) in acetonitrile (40 mL) at 25° C. was treated with methylene chloride (5 mL) to obtain a clear solution. The resulting solution was then treated with sodium azide (1.05 g, 16.18 mmol), and the reaction mixture was cooled to 0° C. The reaction mixture was then treated with trifluoromethanesulfonic anhydride (3.42 g, 12.13 mmol), and the resulting reaction mixture was allowed to warm to 25° C. where it was stirred overnight. The reaction mixture was then concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL) and water (50 mL), and the two layers were separated. The aqueous layer was further extracted with ethyl acetate (1×30 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethyl acetate) afforded 1-(2-chloro-4-iodo-phenyl)-5-methyl-1H-tetrazole (1.53 g, 59%) as a white solid: mp 128-130.5° C.; EI-HRMS m/e calcd for C8H6ClIN4 (M+) 319.9327, found 319.9325.
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].[CH2:22]([O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[N:36]=[CH:35][N:34]=[C:33]2Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[N:36]=[CH:35][N:34]=[C:33]2[N:18]1[CH2:19][CH2:20][CH:15]([N:5]2[C:6](=[O:14])[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=3)[N:3]([CH3:2])[C:4]2=[O:21])[CH2:16][CH2:17]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Clc1ncnc2cc(OCc3ccccc3)c(OCc3ccccc3)cc12
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Agent: Br
Product: Cc1ccc2c(c1)c(=O)n(C1CCN(c3ncnc4cc(OCc5ccccc5)c(OCc5ccccc5)cc34)CC1)c(=O)n2C
Yield: 54 %

Procedure:
The procedure similar to that described in Example 61 was repeated, except that 836.0 mg (2.36 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide (Compound v) obtained in Example 41 was used and 6,7-dibenzyloxy-4-chloroquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline. As a result, 786.3 mg (yield: 54%) of Compound 88 was obtained as white crystals.
Reaction SMILES: CO.O=[C:4]([CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1.[C:18]([BH3-])#[N:19].[Na+].C(N(CC)CC)C>Cl>[CH3:18][NH:19][CH:4]([CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1
Reactant: [BH3-]C#N
Reactant: COC(=O)Cc1ccc(CC(C)=O)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CNC(C)Cc1ccc(CC(=O)OC)cc1
Reaction time: 3 h

Procedure:
To 25 mL of methanol 0.59 g of methyl 4-(2-oxopropyl)phenylacetate, prepared above, was added and dissolved. Then with stirring the following were added: 2.0 g-methylamine hydrochloride, 0.3 g sodium cyanoborohydride, and 0.3 mL of triethylamine. After approximately 12 hours an additional 0.1 g of sodium cyanoborohydride was added to the mixture. After 3 hours more, the reaction was diluted with 100 mL of 0.1 M hydrochloric acid, washed with diethylether, and the resulting aqueous phase was basified to a pH of 12 by addition of 5 mL portions of 1 N sodium hydroxide solution. This was extracted three times with 100 mL portions of diethylether, combined extracts washed with brine and dried. The solvents were removed in vacuo to yield 0.44 g of a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C)C=O.[BH4-].[Na+].[CH2:21](Br)[C:22]#C>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:21]#[CH:22])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: C#CCBr
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
5.85 G. of 1-amino-2-nitro-4-thiocyanatobenzene in 20 ml. dimethylformamide is treated under nitrogen with 1.14 g. sodium borohydride at not greater than 30° C. The mixture is stirred for one hour at 15°-20° C, then treated with 5 ml. of propargyl bromide at 20°-25° C. After a further 3 hours, water is added and the crude product extracted with chloroform. The dried chloroform solution is passed through a column of silica gel to remove a little polar material. Pure 1-amino-2-nitro-4-(prop-2-yn-1-ylthio)benzene is obtained from the eluate.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:4])=[O:3]
Reactant: CCOC(=O)CSCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CSCCCCCOS(C)(=O)=O

Procedure:
A solution of 16.7 g. (0.146 mol) methanesulphonyl chloride and 150 ml. methylene chloride is added dropwise at -5° C., within the course of 30 minutes, to a mixture of 30.1 g. (0.146 mol) ethyl 8-hydroxy-3-thiaoctanoate, 200 ml. methylene chloride and 22,2 g. (0.219 mol) anhydrous triethylamine and the reaction mixture then stirred at 0° C. for a further 30 minutes. It is then extracted with ice-cold 2N sulphuric acid and subsequently with ice water, dried with anhydrous sodium sulphate and subsequently evaporated. Yield 38.3 g. (93% of theory) in the form of a colourless oil.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:2]2[CH:6]=[CH:5][N:4]=[C:3]2[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:16][CH:15]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CCOC(=O)Cc1ncc[nH]1
Agent: Cl
Product: CCOC(=O)Cc1nccn1Cc1ccc(Cl)cc1
Yield: 47.9 %

Procedure:
1.07 g of ethyl imidazol-2-ylaceate hydrochloride and 1.69 g of 4-chlorobenzyl bromide were subjected to an alkylation reaction to obtain 0.75 g of ethyl 1-(4-chlorobenzyl)imidazol-2-ylacetate.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[OH:6][CH:7]([CH3:40])[CH2:8][S:9]([C:12]1[CH:13]=[C:14]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[O:24]2)[CH:15]=[C:16]([OH:22])[C:17]=1[O:18][CH2:19][CH2:20][CH3:21])(=[O:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:6][CH:7]([CH3:40])[CH2:8][S:9]([C:12]1[CH:13]=[C:14]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=3)[O:24]2)[CH:15]=[C:16]([O:22][CH2:4][CH2:3][CH2:2][Br:1])[C:17]=1[O:18][CH2:19][CH2:20][CH3:21])(=[O:10])=[O:11]
Reactant: BrCCCBr
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(OCCCBr)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
1,3-Dibromopropane (0.105 mL, 1.0 mol) was added to a solution of trans-2-[3-(2-hydroxypropylsulfonyl)-4-n-propoxy-5-hydroxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (102 mg, 0.20 mmol) in DMF (1 mL) containing potassium carbonate (105 mg, 0.76 mmol). The reaction mixture was heated with stirring under nitrogen at 70° C. for 2 h, cooled, and partitioned between ethyl ether and water. The ethereal layer was separated and the aqueous layer was re-extracted twice with ether. The organic extracts were combined, dried, and evaporated to a residue (143 mg). Purification by preparative TLC (hexane-ethyl acetate; 1:1, v/v) gave the title compound as a colorless foam; Rf 0.5; NMR (CDCl3) δ 1.26 (d, CH2CHOHCH3), 3.66 (t, CH2Br).
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([Si:16]([O:21][CH3:22])([O:19][CH3:20])[O:17][CH3:18])=[CH2:15].C(OOC(C)(C)C)(C)(C)C>C(O)(C)C>[C:8]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:15][CH2:14][Si:16]([O:21][CH3:22])([O:19][CH3:20])[O:17][CH3:18])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=C[Si](OC)(OC)OC
Agent: CC(C)(C)OOC(C)(C)C
Solvent: CC(C)O
Product: CO[Si](CCP(c1ccccc1)c1ccccc1)(OC)OC
Reaction time: 100 h

Procedure:
A solution of 2-(diphenylphosphino)ethyltrimethoxysilane (DPETMS) in isopropanol comprising 12% DPETMS and 88% isopropanol and 2-4 drops titanium acetylacetonate dialkoxide in alcohol was prepared. The DPETMS was synthesized by combining diphenylphosphine and vinyltrimethoxysilane in a borosilicate flask and then exposing to sunlight for 100 hours, or by using t-butylperoxide or azodiisobutryonitrile as catalyst. Excess volatile material was removed in vacuo at 1-2 mmHg pressure and remaining material tested.