Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:4](SC)=[CH:5][N+:6]([O-:8])=[O:7])=O.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([OH:21])[CH2:19][NH2:20])[CH:13]=1>C(O)C>[OH:21][CH:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH3:11])[CH:13]=1)[CH2:19][NH:20][C:4]([S:2][CH3:1])=[CH:5][N+:6]([O-:8])=[O:7]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: Cc1cccc(C(O)CN)c1
Solvent: CCO
Product: CSC(=C[N+](=O)[O-])NCC(O)c1cccc(C)c1
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
In 50 ml of anhydrous ethanol was suspended 9.3 g of 1-methylsulfinyl-1-methylthio-2-nitroethene, and the resulting suspension was stirred. A solution of 9.3 g of DL-[2-hydroxy-2-(3-methylphenyl)ethyl]amine in 5 ml of ethanol was added thereto dropwise at -10° C. to 0° C. over a period of 30 minutes in a nitrogen atmosphere. After the addition, the resulting mixture was stirred at the same temperature for 1.5 hours, and the crystals deposited were collected by filtration, washed with 10 ml of ethanol, and then dried to obtain 7.0 g (yield 50.8%) of 1-{[2-hydroxy-2-(3-methylphenyl)ethyl]amino}-1-methylthio-2-nitroethene having a melting point of 99°-101° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[O:18]1CCC[CH2:19]1>>[NH2:8][C:4]1[C:3]2[N:9]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:19](=[O:18])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCCNc1c(N)cccc1N
Reactant: C1CCOC1
Product: CCOC(=O)CCCn1c(=O)[nH]c2cccc(N)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
A mixture of ethyl 4-[(2,6-diaminophenyl)amino]butanoate (35.1 g, 0.148 mol), N,N′-carbonyldiimidazole (74.5 g, 0.444 mol) in tetrahydrofuran (600 mL) was stirred at room temperature for 16 hr. The mixture was concentrated, and the residue was washed with ethyl acetate/diisopropyl ether to give the title compound as a colorless powder (26.5 g, 0.101 mol, 68%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28]Cl>CS(C)=O.O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:28][CH2:27][O:26][C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)=[CH:11][CH:10]=1
Reactant: ClCCOc1ccc2ccccc2c1
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(NCCOc2ccc3ccccc3c2)cc1
Temperature: 145 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and p-anisidine (0.45 gm, 0.003 mole) was taken in dry dimethylsulphoxide (DMSO, 40 ml). Now 2-(2-naphthyloxy)-1-chloroethane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 145° C. for 7 hrs. The reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(4-methoxyphenyl)-[2-(naphthalen-2-yloxy) ethyl] amine yellow solid, m.p. 92° C., (yield 0.67 gm, 94%).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[O-]CC.[Na+].[CH2:15]([N:19]([CH2:30][CH2:31][CH2:32][CH3:33])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:16][CH2:17][CH3:18].C(OCC)(=O)C>O1CCCC1>[CH2:15]([N:19]([CH2:30][CH2:31][CH2:32][CH3:33])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH:10][C:4]2[CH2:5][C:6]([CH3:8])([CH3:7])[CH2:9][C:2](=[O:1])[CH:3]=2)=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OC)c1
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)c1ccc(C=CC2=CC(=O)CC(C)(C)C2)c(OC)c1
Temperature: 50 °C
Reaction time: 4.5 h
Yield: 45 %

Procedure:
In 15 ml of tetrahydrofuran, 1.5 g (10.85 mmol) of isophorone was dissolved, and 3.4 g of sodium ethoxide (20% solution in ethanol) (10.0 mmol) was added thereto. To this mixture, 2.6 g (9.87 mmol) of 4-dibutylamino-2-methoxybenzaldehyde in tetrahydrofuran was added dropwise with heating at 50° C., and the mixture was stirred for 4.5 hours. To the mixture, 100 ml of ethyl acetate was added. Washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 1.7 g of a reddish orange oily matter (yield: 45.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[C:22]([C:24]1[CH:25]=[C:26]([CH3:33])[C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1)#[N:23]>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:15])[F:16])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30](=[O:31])[C:27]3[C:26]([CH3:33])=[CH:25][C:24]([C:22]#[N:23])=[CH:29][N:28]=3)[CH:3]=[CH:4][C:5]=2[F:21])([CH2:19][F:20])[N:9]=1
Reactant: NC1=N[C@](CF)(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)O1
Reactant: Cc1cc(C#N)cnc1C(=O)O
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-2) and 5-cyano-3-methylpicolinic acid [S. Badiger et al. WO2011009943 (2011)] following General Procedure G yielded the title compound as a light yellow solid. MS: m/z=454.4 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:20]/[N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(CCc2ccccn2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(CCc2ccccn2)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
To an acetic acid (30 mL) solution of 4-(2-pyridin-2-yl-ethyl)benzaldehyde (2.57 g, 12.2 mmol) described in Manufacturing Example 93-1-5 were added nitromethane (7.45 g, 122 mmol) and ammonium acetate (1.88 g, 24.4 mmol) under nitrogen atmosphere at room temperature, which was stirred for 3 hours at 120° C. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporation under a reduced pressure to obtain the title compound (2.83 g, 91%) as a raw product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH2:13]1[CH:21]2[N:16]([CH2:17][CH2:18][C:19](=O)[CH2:20]2)[CH2:15][CH2:14]1>>[CH2:13]1[CH:21]2[N:16]([CH2:17][CH:18]=[C:19]([C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[NH:9][CH:8]=3)[CH2:20]2)[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=C1CCN2CCCC2C1
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1

Procedure:
The 5-nitro-1H-indole (4.48 g, 27.6 mmol) and 7-octahydroindolizinone (5.0 g, 35.9 mmol) were converted to product by the procedure of Preparation IV to yield 2.99 g. (38.5%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:13]C)=[CH:8][CH:9]=2)[CH2:4]1.C(OCC)C.[BrH:20]>C(O)(C)C>[BrH:20].[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([OH:13])=[CH:8][CH:9]=2)[CH2:4]1
Reactant: COc1ccc2c(c1)CC(N)CC2
Agent: Br
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: NC1CCc2ccc(O)cc2C1

Procedure:
A suspension of the compound obtained in step (b) (6.6 g) in 48% hydrobromic acid (80 ml) is refluxed for 2 hours. The obtained solution is evaporated to dryness and the residue is twice taken up in absolute ethanol and concentrated to dryness. An oily product is thus obtained which is dissolved in hot isopropanol (20 ml). Ethyl ether (30 ml) is added thereto and a crystalline precipitate of 2-amino-7-hydroxytetralin hydrobromide (6.8 g) is obtained. M.p. 171°-173° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.Br[CH2:13][CH:14]=[CH2:15]>>[CH2:15]([N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11])[CH:14]=[CH2:13]
Reactant: O=C1COc2ccccc2N1
Reactant: C=CCBr
Product: C=CCN1C(=O)COc2ccccc21

Procedure:
In analogy to Example 64, step 1, 2H-1,4-benzoxazin-3(4H)-one (15 g) was reacted with 3-bromo-propene to give the title compound (17.4 g) as a colorless oil. MS (m/e)=190.3 [M+H+].
Reaction SMILES: [CH:1]([N:4]([CH:9]([CH3:11])[CH3:10])[C:5](=[O:8])[O:6][CH3:7])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]CCCC.[C:25]1(=[O:29])[CH2:28][CH2:27][CH2:26]1.Cl>C1COCC1.CCOCC>[CH:9]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:8])[O:6][CH2:7][C:25]1([OH:29])[CH2:28][CH2:27][CH2:26]1)([CH3:11])[CH3:10]
Reactant: O=C1CCC1
Reactant: COC(=O)N(C(C)C)C(C)C
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)N(C(=O)OCC1(O)CCC1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
11.148 g (70 mmol) of methyl N,N-diisopropylcarbamate and 12.424 g (105 mmol) of TMEDA in 200 ml of THF are lithiated at -78° C. with 70 mmol of sec. BuLi. After 1 h, 2.453 g (35 mmol) of cyclobutanone are added in portions (about 500 mg every 30 min). The reaction is complete after 3 h (TLC checking) and the reaction mixture is treated in the cold with 100 ml of ether and 120 ml of 2N hydrochloric acid. After warming to room temperature, the phases are separated and the aqueous phase is extracted three times using 50 ml of ether each time. The combined organic phases are then freed from acid with 50 ml of saturated NaHCO3 solution and dried over magnesium sulphate. After the solvent has been stripped off in vacuo, a crude yield of 12.197 g is obtained, chromatographic purification of which on silica gel using ether/petroleum ether (1:1) gives 3.721 g (46.4% of theory) of the title compound as a colorless liquid.
Reaction SMILES: [C:1]1(Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[Cl:19])[NH:15][C:14](=[O:20])[CH:13]=[N+:12]2[O-:21].CO>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[Cl:19])[NH:15][C:14](=[O:20])[C:13]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[N+:12]2[O-:21]
Reactant: Brc1ccccc1
Reactant: O=c1c[n+]([O-])c2cc(Cl)c(Cl)cc2[nH]1
Solvent: C1CCOC1
Solvent: CO
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2[n+]([O-])c1-c1ccccc1
Reaction time: 2 h
Yield: 39 %

Procedure:
To a stirred solution of Grignard reagent prepared from Mg (240 mg, 10 mmol) and phenyl bromide (10 mmol) in THF (50 mL) solid powdered nitrone 124 (2 mmol) was added in small portions. The mixture was stirred for 2 h, then decomposed with MeOH (50 mL) and evaporated. The crude hydroxylamine derivative 139 was washed with hexane (3×10 mL), suspended in CHCl3 (100 mL) and stirred with MnO2 for 16 h. Solid inorganic material was filtered off, washed with CHCl3 (10×10 mL), and MeOH (10×10 mL). Combined organic filtrate was evaporated. Solid residue was chromatographed on prep. TLC plate, eluent--mixture CHCl3 --MeOH (15:1), to yield of 3-aryl nitrone 126. Yield: 39%; the compound was identical to that prepared in Example 6.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]1[OH:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][C@H:13]1[O:25][S:34]([CH3:33])(=[O:36])=[O:35])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a solution of trans-tert-butyl 4-(benzyloxycarbonylamino)-3-hydroxypiperidine-1-carboxylate (5.0 g, 14.3 mmol) and triethylamine (4.5 g, 43.0 mmol) in dichloromethane (100 mL) was added methanesulfonyl chloride (4.9 g, 43.0 mmol) at 0° C., and the mixture was stirred at 0° C. for 2 hours. The solution was washed with water (150 mL×3) and brine, dried over anhydrous sodium sulfate and filtered, followed by concentration under reduced pressure to give the title compound (6.0 g, crude) as a yellow oil. MS (ES+) C19H28H2O7S requires: 428, found: 329 [M+H−100]+.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]([OH:6])=O.C(N(C(C)C)C(C)C)C.ClC(OCC(C)C)=O.[Cl:24][C:25]1[C:29]([NH:30][CH3:31])=[CH:28][N:27]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[N:26]=1>C(Cl)Cl>[Cl:24][C:25]1[C:29]([N:30]([CH3:31])[C:4](=[O:6])[CH2:3][S:2][CH3:1])=[CH:28][N:27]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[N:26]=1
Reactant: CSCC(=O)O
Reactant: CNc1cn(-c2cccnc2)nc1Cl
Agent: CC(C)COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSCC(=O)N(C)c1cn(-c2cccnc2)nc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
To an ice cold solution of 2-(methylthio)acetic acid (0.092 g, 0.863 mmol) in DCM (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.111 g, 0.863 mmol) followed by isobutyl chloroformate (0.099 ml, 0.767 mmol). Stirring was continued for 10 minutes. Next, the mixed anhydride was added to a solution of 3-chloro-N-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.08 g, 0.383 mmol) in DCM (0.66 mL) and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated and purified using reverse phase C-18 column chromatography (0-100% CH3CN/H2O) to yield the title compound as a pale yellow oil (0.075 g, 66%): 1H NMR (400 MHz, CDCl3) δ 8.95 (d, J=2.5 Hz, 1H), 8.62 (dd, J=4.8, 1.4 Hz, 1H), 8.13 (s, 1H), 8.04 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.50-7.43 (m, 1H), 3.26 (s, 3H), 3.12 (s, 2H), 2.24 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 170.00, 148.61, 140.15, 140.03, 135.68, 126.56, 126.42, 125.33, 124.15, 37.16, 34.94, 16.22; ESIMS m/z 297 ([M+H]+).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[C:20]=1[Cl:26])=[O:17].O>C1COCC1>[Br:25][C:21]1[C:20]([Cl:26])=[C:19]([N:18]2[C:16](=[O:17])[C:15]3[C:14](=[C:30]([F:31])[CH:29]=[CH:28][CH:27]=3)[NH:13][C:2]2=[O:4])[CH:24]=[CH:23][CH:22]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(F)cccc1C(=O)Nc1cccc(Br)c1Cl
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2c(F)cccc2c(=O)n1-c1cccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Triphosgene (453 mg, 1.53 mmol) was added in one portion to a solution of amino-N-(3-bromo-2-chlorophenyl)-3-fluorobenzamide (350 mg, 1.019 mmol) in THF (10 mL) at 0° C. The mixture was stirred at room temperature for 1 h, then was cooled to 0° C. and treated with water until no more gas evolution was observed. The mixture was concentrated and the residue was dissolved in EtOAc, washed sequentially with saturated aqueous NaHCO3, water and brine, and dried and concentrated. The residue was purified by column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient from 0-50%), to provide 3-(3-bromo-2-chlorophenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione as a yellow solid (320 mg, 85% yield). Mass spectrum m/z 369, 371 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 8.54 (br. s., 1H), 7.97 (d, J=8.1 Hz, 1H), 7.77 (dd, J=6.8, 2.6 Hz, 1H), 7.46 (ddd, J=9.8, 8.3, 1.2 Hz, 1H), 7.36-7.29 (m, 2H), 7.24 (td, J=8.0, 4.8 Hz, 1H).
Reaction SMILES: O[CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][N:5](C)[C:6](=O)OC(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:39]N1C(=O)CCC1=O>C(Cl)Cl>[Br:39][CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][NH:5][CH3:6]
Reactant: CN(CCC(O)c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CNCCC(Br)c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 22.4 %

Procedure:
tert-Butyl [3-hydroxy-3-phenylpropyl]methylcarbamate (0.52 g, 1.96 mmol) was dissolved in CH2Cl2 (5 mL) and cooled to 0° C. Triphenylphosphine (1.02 g, 3.9 mmol) was added followed by N-bromosuccinimide (0.59 g, 3.3 mmol) and the mixture was stirred for 45 minutes. The reaction mixture was loaded directly onto silica gel and immediately purified via Isco chromatography (Redisep, silica, gradient 0-30% ethyl acetate in hexane) to afford 100 mg of (3-bromo-3-phenyl-propyl)-methyl-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])O[CH:14]=2)=[CH:5][CH:4]=1.Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])[N:21]([OH:22])[CH:14]=2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(COc2coc(CO)cc2=O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(COc2cn(O)c(CO)cc2=O)cc1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of 39.3 g 5-p-methoxybenzyloxy-2-hydroxymethyl-4-pyrone in 600 ml pyridine, was added 52.2 g hydroxylamine hydrochloride, and the mixture was heated at 70°-75° C. for 2.5 hours. The reaction mixture was concentrated to about 100 ml, 100 ml water was added to the concentrate, and the resulting solution was added under ice cooling to a mixture of 75 ml hydrochloric acid and 225 ml water. After adjusting the pH to 2-2.5, stirring was continued under ice cooling for 30 minutes, and the crystals which separated out were collected by filtration, washed with water and dried, giving 16.6 g of 5-p-methoxybenzyloxy-1-hydroxy-2-hydroxymethyl-4-pyridone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:30])[N:13]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29].[N:31]1([CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(C(C)C)CC)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([S:18]([N:41]2[CH2:40][CH2:39][N:38]([CH2:37][CH2:36][N:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)[CH2:43][CH2:42]2)(=[O:20])=[O:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:30])[N:13]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29]
Reactant: O=C1NCc2c(-c3ccccc3Cl)cc(S(=O)(=O)Cl)cc2N1c1c(Cl)cccc1Cl
Reactant: C1CCN(CCN2CCNCC2)C1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCc2c(-c3ccccc3Cl)cc(S(=O)(=O)N3CCN(CCN4CCCC4)CC3)cc2N1c1c(Cl)cccc1Cl

Procedure:
The 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-{[4-(2-pyrrolidin-1-ylethyl)piperazin-1-yl]sulfonyl}-3,4-dihydroquinazolin-2(1H)-one was prepared from 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-sulfonyl chloride and 1-(2-pyrrolidin-1-ylethyl)piperazine by a procedure analogous to that described in EXAMPLE CCC23, STEP A, except that no diisopropylethylamine was used. Mass spectrum (ESI) 648 (M+1). 1H NMR (500 MHz, CDCl3): selected peaks δ 1.81 (brs, 4H); 2.58 (m, 12H); 3.00 (brs, 4H); 4.35 (dd, J=15.4 Hz, J=1.6 Hz, 1 H); 4.46 (dd, J=15.4 Hz, J=1.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19](=[CH2:22])[CH2:20]O>CC(=O)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH2:20][C:19]([CH3:22])=[CH2:18])[CH:7]=1
Reactant: C=C(C)CO
Reactant: O=[N+]([O-])c1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=C(C)COc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 84 %

Procedure:
A mixture of 30.0 g (0.17 mole) of 5-chloro-2-nitrophenol, 30.49 g (0.221 mole) of potassium carbonate, and 18.47 g (0.204 mole) of 2-methyl-2-propen-1-ol in 200 mL of 2-butanone was heated at 80° C. for approximately 16 hours. During this period the reaction changed color from orange to pale yellow. At the conclusion of this period the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure, leaving 32.50 g of 4-chloro-2-(2-methyl-2-propen-1-yloxy)nitrobenzene as a solid residue, m.p. 47°-49° C.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[C:6]([N:11]=[C:12]=[O:13])(=[O:10])[C:7]([CH3:9])=[CH2:8]>C(Cl)(Cl)Cl.ClCCCl>[C:6]([NH:11][C:12](=[O:13])[O:5][CH2:4][CH:2]1[O:3][CH2:1]1)(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: OCC1CO1
Reactant: C=C(C)C(=O)N=C=O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)OCC1CO1
Yield: 99.9 %

Procedure:
Glycidol (2.13 g; 28.8 mmol) was dissolved in dry chloroform (20 ml) under ice-cooling, and a solution of methacryloyl isocyanate (3.2 g; 28.8 mmol) in 1,2-dichloroethane (20 ml) was dropwise added thereto under nitrogen stream. After completion of the addition, chloroform and 1,2-dichloroethane were evaporated under reduced pressure to give glycidyl N-methacryloylcarbamate (5.33 g) as a viscous, colorless oil. Viscosity, 3260 cp.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=2)[C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3n2-c2cccc(C(F)(F)F)c2)CC1
Yield: 65 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone (example 21), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (65%).