Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([O:12]CC)=[O:11])[N:5]=[CH:4][C:3]=1[NH:15][C@@H:16]1[CH2:21][C@@H:20]2[CH2:22][C@@H:18]([C:19]2([CH3:24])[CH3:23])[C@H:17]1[CH3:25].[CH3:26][S-:27].[Na+].O1CCOCC1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:26][S:27][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([OH:12])=[O:11])[N:5]=[CH:4][C:3]=1[NH:15][C@@H:16]1[CH2:21][C@@H:20]2[CH2:22][C@@H:18]([C:19]2([CH3:24])[CH3:23])[C@H:17]1[CH3:25]
Reactant: C[S-]
Reactant: CCOC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CSc1c(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)cnn(CC(=O)O)c1=O
Yield: 90.2 %

Procedure:
Ethyl 2-{5-bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetate (220 mg, 0.533 mmol) and sodium thiomethoxide (112 mg, 1.60 mmol) in toluene (22 mL) were stirred at 80° C. for 3 hours. After cooling, the reaction solution was stirred with 1,4-dioxane (6 mL) and 1 M aqueous sodium hydroxide (1.59 mL) at room temperature for 4 hours. After completion of the reaction, the reaction solution was mixed with toluene and extracted with 1 M aqueous sodium hydroxide twice. The resulting aqueous layer was acidified to pH 1 with 1 M hydrochloric acid and extracted with ethyl acetate twice, and the extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the desired product (169 mg, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[CH2:23][NH:24][CH2:25][CH2:26][OH:27])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:35]([Si:39](Cl)([CH3:41])[CH3:40])([CH3:38])([CH3:37])[CH3:36].O>C1COCC1>[Si:39]([O:27][CH2:26][CH2:25][NH:24][CH2:23][C@H:10]1[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:41])[CH3:40]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNCCO)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNCCO[Si](C)(C)C(C)(C)C)C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a solution (13.2 mL) of tert-butyl (6R,7R)-7-(3,4-dichlorophenyl)-6-{[(2-hydroxyethyl)amino]methyl}-1,4-oxazepane-4-carboxylate (1.65 g) and triethylamine (0.605 mL) in THF was added, under ice-cooling, tert-butylchlorodimethylsilane (654 mg), and the mixture was stirred at room temperature overnight. Then, tert-butylchlorodimethylsilane (654 mg) and triethylamine (0.605 mL) were added, and the mixture was stirred at 50° C. for 1 hr. Distilled water was added, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (1.96 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]([F:15])([F:14])[F:13])=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+]>O1CCCC1.O>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]([F:15])([F:13])[F:14])[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(C(F)(F)F)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(C(F)(F)F)c1C(=O)O
Yield: 80.1 %

Procedure:
A solution of 5-methyl-3-trifluoromethylisoxazole-4-carboxylic acid ethyl ester (2.0 g) and sodium hydroxide (1.1 g) in tetrahydrofuran/water (20 ml/20 ml) was heated at reflux for 18 hours. The tetrahydrofuran was removed in vacuo and the aqueous residue washed with ethyl acetate (50 ml), acidified to pH2 with conc. hydrochloric acid and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50 ml), separated, dried over magnesium sulphate, filtered and concentrated in vacuo to afford the title compound as a peach-coloured solid (1.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Br:17]>C1(C)C(C)=CC=CC=1>[Cl-:8].[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Br:17]
Reactant: ClCSc1ccccc1Br
Reactant: Nc1ccccn1
Solvent: Cc1ccccc1C
Product: Nc1cccc[n+]1CSc1ccccc1Br
Product: [Cl-]
Yield: 81.5 %

Procedure:
To a solution of 14.1 g of 2-aminopyridine in 180 ml of xylene is added a solution of 24.0 g of o-bromophenyl chloromethyl sulfide in 40 ml of xylene. The mixture is heated at 90°-95° for about 15 hours to give about 27.3 g of the named compound, mp about 199°-201°.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[C:32]([CH:33]([F:44])[C:34]4[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=4)=[C:31]([CH:45]4[CH2:50][CH2:49][C:48]([F:52])([F:51])[CH2:47][CH2:46]4)[C:30]4[CH:29]([OH:53])[CH2:28][C:27]([CH3:55])([CH3:54])[CH2:26][C:25]=4[N:24]=3)[CH2:19][CH2:18]2)=[N:15][CH:16]=1)=[O:5])C.O1CCCC1.[OH-].[Na+].Cl>C(O)C>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[N:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[C:32]([CH:33]([F:44])[C:34]4[CH:35]=[CH:36][C:37]([C:40]([F:41])([F:42])[F:43])=[CH:38][CH:39]=4)=[C:31]([CH:45]4[CH2:46][CH2:47][C:48]([F:52])([F:51])[CH2:49][CH2:50]4)[C:30]4[CH:29]([OH:53])[CH2:28][C:27]([CH3:55])([CH3:54])[CH2:26][C:25]=4[N:24]=3)[CH2:19][CH2:18]2)=[N:13][CH:12]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCCOc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OCCCCC(=O)O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To the crude (−)-2-{1-[5-(4-Ethoxycarbonylbutoxyl)pyrimidin-2-yl]piperidin-4-yl}-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol obtained in Example (23-1), 2 ml of tetrahydrofuran, 2 ml of ethanol and 1 ml (1.00 mmol) of 1 N sodium hydroxide aqueous solution were added, and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, 1 N hydrochloric acid was poured into the reaction solution under ice cooling and the reaction solution was extracted with methylene chloride. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by high performance liquid chromatography [YMC-pack ODS-A; acetonitrile/aqueous solution of 0.1% acetic acid and 0.1% triethylamine=85/15 (V/V)] to provide 63 mg of the title compound as a white solid (yield in two steps: 64%).
Reaction SMILES: CS[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=2>[Ni].C(O)C>[F:15][C:12]([F:13])([F:14])[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][CH:3]=[CH:11]2
Reactant: CSc1cc2cc(C(F)(F)F)ccc2[nH]1
Agent: [Ni]
Solvent: CCO
Product: FC(F)(F)c1ccc2[nH]ccc2c1
Reaction time: 1.5 h

Procedure:
Combine moist Raney nickel (330 g), 2-methylthio-5-trifluoromethyl-1H-indole (33.8 g, 146.2 mmol) and absolute ethanol (850 ml) and stir. After 1.5 hours, filter the mixture through celite and wash the celite with ethanol (500 ml). Evaporate the filtrate to dryness, add toluene (20 ml) and evaporate and dry to give 5-trifluoromethylindole: mp=55-60° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH3:21])S(C)(=O)=O)=[C:12]([N+:22]([O-:24])=[O:23])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>S(=O)(=O)(O)O>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH3:21])=[C:12]([N+:22]([O-:24])=[O:23])[CH:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(c1ccc(S(=O)(=O)c2ccccc2)cc1[N+](=O)[O-])S(C)(=O)=O
Agent: O=S(=O)(O)O
Product: CNc1ccc(S(=O)(=O)c2ccccc2)cc1[N+](=O)[O-]

Procedure:
7.2 g (19.4 mmol) of N-(4-benzenesulphonyl-2-nitro-phenyl)-N-methyl-methanesulphonamide are heated to 130° C. in 70 ml conc. sulphuric acid for 15 minutes. Then the mixture is poured onto ice water, the precipitate formed is suction filtered, washed with water and dried.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:17][S-:18].[Na+]>CN(C=O)C>[CH3:17][S:18][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccc(C(F)(F)F)cc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C(F)(F)F)cc1SC
Yield: 94.6 %

Procedure:
Example 3 is repeated except that 2.53 g (10 mmol) of ethyl 2-chloro-4-(trifluoromethyl)benzoate are reacted with 0.77 g (11 mmol) of sodium thiomethoxide in 15 ml of DMF. 2.5 g of ethyl 2-methylmercapto-4-(trifluoromethyl)benzoate of high purity are obtained. It is therefore not necessary to purify by distillation.
Reaction SMILES: [C:1]([N:4]([C@H:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]([C:32](=[O:41])[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[C@@H:24]([CH3:42])[CH2:23]1)[C:5]1[CH:10]=[CH:9][C:8]([NH:11]C(=O)OCC2C=CC=CC=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>CO.[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([N:4]([C@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([C:32](=[O:41])[C:33]3[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=3)[C@@H:24]([CH3:42])[CH2:23]2)[C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(NC(=O)OCc4ccccc4)cc3)C[C@@H]2C)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(N)cc3)C[C@@H]2C)cc1
Reaction time: 2 h

Procedure:
Benzyl (4-{acetyl[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}phenyl)carbamate was dissolved in MeOH and was added a catalytic amount of Palladium on Carbon (10%). The system was purged by Hydrogen gas, the subjected to 1 atm of H2 for 2 h. The reaction was quenched with air and filtered to give the title compound as a white solid.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]1([O:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2c1CCCC2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc2c1CCCC2
Temperature: 80 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a stirred mixture of 5,6,7,8-tetrahydronaphthalen-1-ol (200 mg, 1.35 mmol) in MeCN (5 mL) was added ethyl bromoacetate (269 mg, 1.62 mmol) and K2CO3 (372 mg, 2.70 mmol). The mixture was stirred at 80° C. for 4 hours. The mixture was filtered, the filtrate concentrated to yield the desired product which used directly for the next step without further purification (300 mg, Yield 95%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][C:12]2=[O:15])=[CH:8][CH:7]=1)=[O:4].C(OCC)(=O)C>[Pd].CN(C)C=O>[OH:15][CH:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:16])([F:17])[F:1])[CH:14]=2)[CH2:10][CH2:11]1
Reactant: O=C1CCc2ccc(NC(=O)C(F)(F)F)cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2c(c1)C(O)CC2)C(F)(F)F
Reaction time: 72 h
Yield: 56.1 %

Procedure:
A mixture of 10% (w/w) palladium on carbon (2.34 g), 6-(trifluoroacetamido)indan-1-one (7.79 g), ethyl acetate (53 ml) and dimethylformamide (11 ml) was hydrogenated at atmospheric pressure for 72 h. The reaction mixture was filtered through diatomaceous earth with ethyl acetate wash and evaporated. The residue was flash chromatographed, eluting with 95:5 methylene chloride:methanol, and triturated with ether to give 1-hydroxy-6-(trifluoroacetamido)indane (4.41 g, 56%) as a colorless solid; mp 123.0°-124.5° C.; MS(EI), m/e=245(M+.).
Reaction SMILES: [OH:1][C@H:2]([CH3:47])[C@H:3]([NH:16][C:17]([C:19]1[NH:20][C:21]([C:24]2[CH:29]=[C:28]([O:30][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])[CH:27]=[C:26]([O:41][C@@H:42]([CH3:46])[CH2:43][O:44][CH3:45])[CH:25]=2)=[CH:22][CH:23]=1)=O)[CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8].CS(O)(=O)=O.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[CH3:45][O:44][CH2:43][C@@H:42]([O:41][C:26]1[CH:25]=[C:24]([C:21]2[NH:20][C:19]([C:17]3[O:1][C@@H:2]([CH3:47])[C@@H:3]([CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:7]([CH3:9])[CH3:8])[CH:10]([CH3:11])[CH3:12])[N:16]=3)=[CH:23][CH:22]=2)[CH:29]=[C:28]([O:30][Si:31]([CH:32]([CH3:34])[CH3:33])([CH:35]([CH3:36])[CH3:37])[CH:38]([CH3:40])[CH3:39])[CH:27]=1)[CH3:46]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)[C@@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C3=N[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)[C@H](C)O3)[nH]2)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
N-{(2R,3R)-3-Hydroxy-1-[(tripropan-2-ylsilyl)oxy]butan-2-yl}-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tripropan-2-ylsilyl)oxy]phenyl)-1H-pyrrole-2-carboxamide (2.52 g, 3.65 mmol) synthesized in Example (110b) was dissolved in tetrahydrofuran (20 mL), and anhydrous methanesulfonic acid (1.05 g, 6.03 mmol) and triethylamine (2.00 mL, 14.35 mmol) were added, followed by stirring at 50° C. for 1 day under nitrogen atmosphere. To the reaction solution, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-30%) to afford the desired compound (2.30 g, yield 94%) as a pale yellow liquid.
Reaction SMILES: [OH:1][CH:2]([C:6]([O:19]/[CH:20]=[CH:21]/[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[H-].[Na+].[CH3:31][C:32]1[CH:37]=[C:36]([CH3:38])[N:35](S(C)(=O)=O)[CH2:34][N:33]=1.Cl>CN(C=O)C.O>[CH3:31][C:32]1[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([O:1][CH:2]([C:6]([O:19]/[CH:20]=[CH:21]/[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([OH:5])=[O:4])[N:33]=1
Reactant: CC1=CC(C)=NCN1S(C)(=O)=O
Reactant: O=C(O)C(O)C(O/C=C/Cc1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(OC(C(=O)O)C(O/C=C/Cc2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.3 %

Procedure:
1.12 g (3 mmol) of 2-hydroxy-3-(3-phenyl-(2E)-propenoxy)-3,3-diphenylpropionic acid were added to a suspension of 432 mg (9 mmol, 50%) of NaH in 20 ml of DMF, and the mixture was stirred at room temperature for 10 minutes. 614 mg (3.3 mmol) of 4,6-dimethyl-1-methylsulfonylpyrimidine were added, and the mixture was stirred for 16 hours, then diluted with 200 ml of water, acidified with 1 N hydrochloric acid and extracted with ether. The ether phase was extracted with 1 N sodium hydroxide solution, the aqueous phase was again acidified, and the product was extracted with ether. The organic phase was dried over magnesium sulfate and filtered, and the solvent was distilled off. The residue was recrystallized from ether/hexane, and 927 mg (65%) of crystalline product were isolated.
Reaction SMILES: [CH2:1]([C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]2([CH3:18])[CH3:17])=O)[CH3:2].[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Mg].C(Cl)C1C=CC=CC=1.[Cl-].[NH4+]>CCOCC>[CH2:1]([C:3]([C:5]1[CH2:6][CH:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]2([CH3:18])[CH3:17])=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClCc1ccccc1
Product: CCC(=Cc1ccccc1)C1=CC=C2C(C1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.1 g of (1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl) ethyl ketone are dissolved in 25 ml of abs. ether and added dropwise at 0° to a benzylmagnesium chloride solution prepared from 0.6 g of magnesium and 4.3 g of benzyl chloride in 30 ml of abs. ether. After stirring at room temperature for 2 hours the reaction mixture is poured into a saturated ammonium chloride solution, extracted with ether, dried over sodium sulphate and evaporated. The thus-obtained oil is dissolved in 100 ml of toluene and, after the addition of 0.5 g of p-tlouenesulphonic acid, boiled at reflux overnight. After cooling the mixture is treated with 10% sodium bicarbonate solution, extracted with ether, dried and evaporated. The residue is purified by filtration over a short column (silica gel, elution agent hexane) and recrystallized from methylene chloride/methanol. There are obtained 3 g of 6-(α-ethylstyryl)-1,2,3,5-tetrahydro-1,1,4,4-tetramethylnaphthalene in colourless crystals, melting point 65°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.Cl[C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][N:22]=1.C(=O)(O)[O-].[Na+]>C(O)CCC>[N+:27]([C:25]1[CH:24]=[CH:23][N:22]=[C:21]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=3)[CH2:3][CH2:2]2)[CH:26]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: CS(=O)(=O)Nc1ccc(OCC2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: CS(=O)(=O)Nc1ccc(OCC2CCN(c3cc([N+](=O)[O-])ccn3)CC2)cc1
Reaction time: 18 h

Procedure:
A mixture of the product of part (v) (0.50 g), 2-chloro-4-nitropyridine (0.28 g) and sodium bicarbonate (1.00 g) in n-butanol (20 ml) was heated under reflux with stirring for 18 hours. The mixture was cooled, filtered, and the residue was washed with ethanol. The combined filtrate and washings were evaporated to give a gum which was chromatographed on silica gel eluting with ether. Earlier fractions gave impurity and the pure product was eluted in the later fractions. The product fractions were combined and evaporated to give the product, (0.21 g), m.p. 183.5°-184.5° (from ethanol).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH3:13])=[N:10]2)=[CH:5][CH:4]=1.[Se](=O)=[O:16]>>[CH3:1][N:2]([CH3:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH:13]=[O:16])=[N:10]2)=[CH:5][CH:4]=1
Reactant: Cc1ccc2ccc(N(C)C)cc2n1
Reactant: O=[Se]=O
Product: CN(C)c1ccc2ccc(C=O)nc2c1
Temperature: 90 °C
Yield: 41.7 %

Procedure:
Referring to FIG. 21, compound 13a (304.3 mg, 1.63 mmol) was dissolved in m-xylenes (2 mL) and stirred under a nitrogen atmosphere. Selenium dioxide (272.29 mg 2.45 mmol) was added and the yellow-orange mixture was heated to 90° C. for 4 h. The black reaction mixture was filtered through cotton, washing several times with chloroform. The filtrate was directly adsorbed onto silica gel and purified by column chromatography (EtOAc) to afford 14a (136.4 mg, 0.68 mmol, 42%) as a pale yellow oil: 1H NMR (CDCl3,) δ 10.11 (1H, s), 8.11 (1H, d, J=8.0 Hz), 7.74 (1H, d, J=8.4 Hz), 7.73 (1H, d, J=8.0 Hz), 7.31 (1H, dd, J=9.6, 2.8 Hz), 7.23 (1H, d, J=1.6 Hz), 3.15 (6H, s); 13C NMR (CDCl3,) δ 194.5, 153.0, 151.9, 150.2, 136.9, 128.6, 123.1, 119.1, 113.8, 107.0, 40.7; FTIR (neat) 2920, 1705, 1620, 1537, 1508, 1382, 1255, 1155, 1066, 835, 761 cm−1; MS (ESI) m/z calculated for (C12H12N2O+H)+ 201, found, 201; HRMS (ESI) m/z calculated for (C12H12N2O+H)+ 201.1028, found, 201.1055.
Reaction SMILES: C(O)(=O)C.S(=O)(=O)(O)O.[CH3:10][O:11][CH2:12][C:13]([NH:15][C:16]1[C:21]([C:22](=[O:25])[NH:23][CH3:24])=[C:20]([O:26][CH3:27])[C:19]([NH:28][C:29](=O)[CH2:30][O:31][CH3:32])=[C:18]([C:34](=[O:37])[NH:35][CH3:36])[C:17]=1[O:38][CH3:39])=O.[K+].[Br-]>C(OCC)(=O)C.CO>[CH3:32][O:31][CH2:30][C:29]1[N:35]([CH3:36])[C:34](=[O:37])[C:18]2[C:19]([N:28]=1)=[C:20]([O:26][CH3:27])[C:21]1[C:22](=[O:25])[N:23]([CH3:24])[C:13]([CH2:12][O:11][CH3:10])=[N:15][C:16]=1[C:17]=2[O:38][CH3:39]
Reactant: CNC(=O)c1c(NC(=O)COC)c(OC)c(C(=O)NC)c(NC(=O)COC)c1OC
Agent: O=S(=O)(O)O
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COCc1nc2c(OC)c3c(=O)n(C)c(COC)nc3c(OC)c2c(=O)n1C
Temperature: 100 °C

Procedure:
To 100 mL acetic acid and 4 mL concentrated sulfuric acid, was added 1.80 g (4.22 mmol) of 11 and the mixture was heated at 100° C. for 5 hours. After evaporating the solvents down to ca 5 mL, the oily residue was poured over 100 mL of ice water, neutralized with sodium carbonate, and the resulting solution extracted with 3×100 mL portions of chloroform. The combined extracts were evaporated to a small volume, placed on a silica column, and purified by flash chromatography employing ethyl acetate as the eluant. The product fraction was collected and evaporated to dryness. Recrystallization was carried out by redissolving the product in a minimum amount of chloroform followed by addition of hexane: 1.10 g (67%) yield; mp 223°-224° C.; TLC (ethyl acetate/methanol [9:1], Rf =0.22; IR (KBr pellet) 1688, 1614, 1474, 1428, 1375, 1342, 1269, 1097, 1036, 797 cm-1 ; 1H NMR (dimethyl-d6 sulfoxide) δ4.58 (4H, s, methylenes), 3.93, 3.62 and 3.42 (18H, 3×s, N- and O-methyls, no assignments made); mass spectrum (EI mode) m/z 390 (P+). Anal. Calcd for C18H22N4O6. 0.3H2O: C, 54.75; H, 5.74; N, 14.19. Found: C, 54.39; H, 5.63; N, 14.25.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]3[CH:33]=[C:32]4[C:27]([CH2:28][CH2:29][NH:30][CH2:31]4)=[CH:26][CH:25]=3)[N:21]=[C:20]([NH2:34])[N:19]=2)[CH2:14][CH2:13]1>>[CH:1]1([C:7]([N:30]2[CH2:29][CH2:28][C:27]3[C:32](=[CH:33][C:24]([C:22]4[CH:23]=[C:18]([N:15]5[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]5)[N:19]=[C:20]([NH2:34])[N:21]=4)=[CH:25][CH:26]=3)[CH2:31]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)C1CCCCC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)C3CCCCC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from cyclohexanecarboxylic acid (Aldrich, Cat. #101834) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=435.2.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH:16]1([NH:19][C:20]([NH:22][CH3:23])=[S:21])[CH2:18][CH2:17]1>>[BrH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:21][C:20](=[N:19][CH:16]3[CH2:18][CH2:17]3)[N:22]2[CH3:23])=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: CNC(=S)NC1CC1
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Product: Br
Product: CN1C(=NC2CC2)SCC1(O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
4.15 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone were reacted with 1.95 g of 1-cyclopropyl-3-methylthiourea according to the prescription given in Example 23 and the oily precipitate was crystallized with diisopropyl ether. Colorless, crystalline solid body: melting point: 204° C. (decomposition).