Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:9][N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]=2)[N:3]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C:27]1[C:28]([C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)=[N:29][C:30]2[N:31]([N:33]=[C:34]([CH3:36])[N:35]=2)[CH:32]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.C(N(CC)CC)C>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C:27]1[C:28]([C:37]2[CH:38]=[CH:39][C:40]([CH2:41][N:16]3[CH2:17][CH2:18][CH:13]([C:11]4[N:12]=[C:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=5)[NH:9][N:10]=4)[CH2:14][CH2:15]3)=[CH:43][CH:44]=2)=[N:29][C:30]2[N:31]([N:33]=[C:34]([CH3:36])[N:35]=2)[CH:32]=1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccc(F)cc3F)cn2n1
Reactant: Cc1cccc(-c2nc(C3CCNCC3)n[nH]2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2nc(C3CCN(Cc4ccc(-c5nc6nc(C)nn6cc5-c5ccc(F)cc5F)cc4)CC3)n[nH]2)n1
Reaction time: 1 h

Procedure:
180 mg (0.57 mmol) 2-Methyl-6-(5-piperidine-4-yl-2H-[1,2,4]triazole-3-yl)-pyridine×2HCl are dissolved in 4.8 mL NMP. After addition of 0.19 mL triethylamine the reaction mixture is stirred for one hour. 200 mg (0.57 mmol) 4-[6-(2,4-Difluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-benzaldehyde and 0.06 mL acetic acid are added. The reaction mixture is stirred over night at room temperature. 133 mg (0.63 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 5 hours. The reaction mixture is treated with saturated NaHCO3. The precipitate is filtered off, washed with water and dried. After chromatography of the precipitate on silica gel (dichloromethane/methanol) 99.7 mg (28.7%) of the desired product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C:9]2=[O:17])[CH:5]=[CH:6][CH:7]=1.[CH:18](OCC)(OCC)[O:19][CH2:20][CH3:21].C([O-])([O-])[O-]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[CH:18][O:19][CH2:20][CH3:21])[C:9]2=[O:17])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: O=C1Cc2ccccc2N1c1cccc(Cl)c1
Agent: [O-]C([O-])[O-]
Solvent: CCOCC
Product: CCOC=C1C(=O)N(c2cccc(Cl)c2)c2ccccc21
Reaction time: 2 h
Yield: 140.1 %

Procedure:
1-(3-Chlorophenyl)-2(1H, 3H)-indolone (2.4 g, 0.01 mole) and triethyl orthoformate (8.3 ml, 0.05 mole) were combined and heated at 150°±10° for 18 hours. An additional 20 ml of the orthoformate were added and heating continued 2 hours. The reaction mixture was cooled to 25°, diluted with ether, washed with H2O and then brine, dried over MgSO4, concentrated in vacuo to oily solids, and triturated with pentane to yield solids (4.2 g). The solids were chromatographed on silica gel (7.5×15 cm) with 4:1 hexane:ethyl acetate as eluant to yield purified title product, 0.5 g; m.p. 132°-134°; m/e 310/299.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:18]3[CH2:27][CH2:26][C:21]4(OCC[O:22]4)[CH2:20][CH2:19]3)[C:12]3[S:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:4]([F:28])[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(#N)C.CC(C)=O>O>[ClH:1].[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:18]3[CH2:19][CH2:20][C:21](=[O:22])[CH2:26][CH2:27]3)[C:12]3[S:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:4]([F:28])[CH:3]=1
Reactant: Fc1cc(-c2nc(N3CCC4(CC3)OCCO4)c3sccc3n2)c(F)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Solvent: CC(C)=O
Product: Cl
Product: O=C1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 140 %

Procedure:
A mixture of 451 mg of 8-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]-1,4-dioxa-8-azaspiro[4.5]decane, 20 mg of p-toluenesulfonic acid monohydrate and 8 ml of acetonitrile-acetone (1:1) was stirred for 5 hours heated to reflux. The reaction mixture was allowed to cool to room temperature and was added to 200 ml of water. After the precipitate was filtered and washed with water, it was dried at 50° C. under reduced pressure. The obtained solid was dissolved in 12 ml of THF and added 2 ml of 4M HCl-dioxane solution. The resultant was concentrated under reduced pressure to give a solid. This solid washed with acetonitrile-ether to give 310 mg of 1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperidine-4-one hydrochloride.
Reaction SMILES: [CH3:1][CH:2]1[C:4]2([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:3]1[C:10]([O:12]CC)=[O:11].C1(C(OCC)=O)C2(CCCCC2)C1>>[CH3:1][CH:2]1[C:4]2([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:3]1[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C1C(C)C12CCCCC2
Agent: CCOC(=O)C1CC12CCCCC2
Product: CC1C(C(=O)O)C12CCCCC2

Procedure:
The title compound was prepared as described in Example 1B substituting the product from Example 18A for the product from Example 1A. MS m/z 186 (M+NH4)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:24](I)[CH3:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH2:15]1)[CH2:24][CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)CN1CCC(CNC(=O)OC(C)(C)C)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(CN(CC)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl [4-(tert-butoxycarbonylamino-methyl)-piperidin-1-yl]-acetate (1.86 g) is dissolved in N,N-dimethylformamide (10 ml), and thereto are added sodium hydride (63%) (1.19 g) and ethyl iodide (6.0 ml), and the mixture is stirred at room temperature for 2 hours. The reaction mixture is made weak basic with a 10% aqueous citric acid solution and a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give ethyl {4-[(tert-butoxycarbonyl-ethyl-amino)-methyl]-piperidine-1-yl}-acetate (905 mg). MS (m/z): 329 [M+H]+
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:15]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C@@H:14]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]=[C:12]1[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:15]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C@@H:14]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:13]1
Reactant: CC(C)(C)OC(=O)[C@H]1CC(O)CN(C(=O)OCc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)[C@H]1CC(=O)CN(C(=O)OCc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Temperature: 78 °C
Reaction time: 0.75 h
Yield: 99.6 %

Procedure:
To an oven-dried 5 mL conical vial equipped with a magnetic stir bar and under a nitrogen gas atmosphere was placed oxalyl chloride (0.080 mL, 0.92 mmol) and methylene chloride (0.7 mL). The solution was cooled to 78° C. prior to the dropwise addition of dimethyl sulfoxide (0.080 mL, 1.13 mmol) in methylene chloride (0.3 mL). After stirring the solution for 45 min, a solution of 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-hydroxypiperidine-1,2,3-tricarboxylate (266 mg, 0.567 mmol) in methylene chloride (1 mL) was added dropwise and the solution was allowed to gradually warm to ca. 0° C. over 1.5 h. The reaction mixture was cooled to 78° C. prior to the dropwise addition of triethylamine (0.240 mL, 1.72 mmol) and stirring was continued for 3 h with gradual warming to ca. 0° C. The reaction was quenched by the dropwise addition of 5% citric acid (2 mL) and diluted with methylene chloride (15 mL). The organic layer was washed with brine (2×5 mL), dried (NaSO4), and concentrated in-vacuo to afford 264 mg (100%) of the desired ketone as a sticky yellow oil. LCMS (ESI): 490 (M+Na+)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[N:12]O)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH2:12])[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1C(=NO)CO2
Agent: [Pd]
Solvent: CCO
Product: COc1cccc2c1C(N)CO2
Reaction time: 18 h
Yield: 64.4 %

Procedure:
A mixture of the above described 4-methoxy-benzofuran-3-one oxime (6.15 g, 34.3 mmol) in ethanol (500 mL) with 10% palladium on carbon (6.15 g) was hydrogenated at 23° C. and atmospheric pressure for 18 h. Filtered the catalyst off, washed with ethanol, evaporated the filtrate totally and dried in high vacuum to give the title compound as a light yellow oil (3.65 g, 64%); MS: m/e=166.2 (M+H−).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]2[C:11]3=[N:12][CH:13]=[N:14][C:15]([NH2:16])=[C:10]3[CH:9]=[N:8]2)[CH2:2]1.[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][CH2:26][C:27](O)=[O:28])[CH:21]=[C:22]([Cl:24])[CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[NH2:16][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:7]([CH:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:27](=[O:28])[CH2:26][NH:25][C:20]4[CH:19]=[C:18]([Cl:17])[CH:23]=[C:22]([Cl:24])[CH:21]=4)[CH2:2]3)[N:8]=[CH:9][C:10]=12
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Reactant: Nc1ncnc2c1cnn2C1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2c1cnn2C1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 50 °C
Yield: 6.8 %

Procedure:
A mixture of 1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (620 mg, 2.2 mmol), 2-((3,5-dichlorophenyl)amino)acetic acid (475 mg, 2.2 mmol, 1 eq), HBTU (822 mg, 2.2 mmol, 1 eq) and DIPEA (560 mg, 4.4 mmol, 2.0 eq) in THF (10 mL) was heated to 50° C. for 16 h. The mixture was concentrated in vacuo and purified by silica gel column with EA in PE (20% to 100%, v/v) to give the title product (63 mg, yield: 7%). 1H NMR (400 MHz, DMSO-d6) δ: 8.21 (d, 1H), 8.11 (d, 1H), 7.85-7.65 (m, 2H), 6.76 (s, 1H), 6.73 (s, 1H), 6.60 (d, 1H), 6.32 (t, 1H), 4.76-4.71 (m 0.5H), 4.61-4.54 (m, 1H), 4.48 (d, 0.5H), 4.19 (d, 0.5H), 4.11-4.08 (m, 1H), 4.02-3.94 (m, 1.5H), 3.86-3.81 (m, 0.5H), 3.17-3.09 (m, 1H), 2.95-2.90 (m, 0.5H), 2.20-2.12 (m, 1H), 2.08-2.05 (m, 1H), 1.89-1.82 (m, 1H), 1.72-1.51 (m, 1H). ESI-MS: 420.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Br[CH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])O.[Na+]>ClCCl>[NH2:1][C:2]1[CH:3]=[C:4]([S:8][CH2:17][C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(S)c1
Reactant: COC(=O)c1sccc1CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1sccc1CSc1cccc(N)c1
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of 3-aminothiophenol (2.3 g, 18.7 mmol) and triethylamine (3.12 ml, 22.4 mmol) in dichloromethane (30 ml) was slowly added methyl 3-bromomethylthiophene-2-carboxylate (6.24 g, 22.4 mmol) under ice-cooling, followed by stirring for 30 minutes. After the reaction was completed, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (hexane/ethyl acetate=7/1) to give oily methyl 3-(3-aminophenylthiomethyl)thiophene-2-carboxylate (4.82 g, 92%).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13].CO>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: COc1cccc(CNS(C)(=O)=O)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)NCc1cccc(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.6 %

Procedure:
A solution of BBr3 (1.0 M in CH2Cl2, 111 mL, 111 mmol) was slowly added to a solution of N-(3-methoxy-benzyl)-methanesulfonamide (12.000 g, 55.7 mmol) in CH2Cl2 (200 mL) at 0° C. The reaction was warmed to room temperature and was stirred for 4 h. Methanol (100 mL) was cautiously added and the solution was concentrated in vacuo. Flash chromatography (1:1 hexanes:EtOAc) provided N-(3-hydroxy-benzyl)-methanesulfonamide (11.50 g). 1H NMR (400 MHz, CDCl3) δ 7.20 (m, 1H), 6.84 (m, 2H), 6.77 (m, 1H), 4.83 (bs, 1H), 4.24 (s, 2H), 2.86 (s, 3H); MS 201 (M+).
Reaction SMILES: [C:1]([O:14][CH2:15][CH3:16])(=[O:13])[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:17](Cl)(=O)[C:18]1C=CC(C(Cl)=O)=CC=1.[CH2:29](O)[CH2:30]CC>C1(C)C=CC=CC=1>[C:6]([O:8][CH2:9][CH2:10][CH2:29][CH3:30])(=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([C:1]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])=[CH:3][CH:4]=1
Reactant: CCCCO
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)c1ccc(C(=O)OCC)cc1
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1ccc(C(=O)OCCCC)cc1
Yield: 75 %

Procedure:
This compound was prepared by the procedure described for diethyl terephthalate. Typical reagent levels were as follows: terephthaloyl chloride (40.6 g, 0.20 mole), 1-butanol (29.6g, 0.40 mole), and 100 ml of toluene. Product yield was 75% and was used without further purification.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[C:12]([OH:20])[CH:13]=[CH:14][CH:15]=3)[C:10](=[O:21])[C:9]=2[C:8](Br)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25]>CO.[Cu]Cl.S([O-])([O-])(=O)=O.[Cu+2]>[CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[C:12]([OH:20])[CH:13]=[CH:14][CH:15]=3)[C:10](=[O:21])[C:9]=2[C:8]([NH:27][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccc(Br)c2c1C(=O)c1cccc(O)c1C2=O
Reactant: CC(C)CN
Agent: Cl[Cu]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: CC(C)CNc1ccc(NC(C)C)c2c1C(=O)c1c(O)cccc1C2=O

Procedure:
10 Parts 1-isopropylamino-4-bromo-5-hydroxy-anthraquinone, 50 parts isobutylamine, 0.1 part each of copper(I) chloride and basic copper sulphate are boiled under reflux (appr. 70°) until only small amounts of starting material can be detected (appr. 2 hours are required). The mixture is diluted with 50 parts methanol, the precipitated needles are filtered off with suction in the cold, washed with methanol and hot water. It is also possible to filter off with suction without previous dilution with methanol. The 1-isopropylamino-5-hydroxy-4-isobutylamino-anthraquinone so obtained is sulphonated as follows:
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][O:6][C:7]=1[N:8]=[CH:9]OCC)#[N:2].[NH2:13][CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1>C(O)C>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH:14]1[NH:13][C:1]1[C:3]2[N:4]=[CH:5][O:6][C:7]=2[N:8]=[CH:9][N:2]=1
Reactant: NC1Cc2ccccc2C1
Reactant: CCOC=Nc1ocnc1C#N
Solvent: CCO
Product: c1ccc2c(c1)CC(Nc1ncnc3ocnc13)C2
Yield: 14.7 %

Procedure:
4-cyano-5-ethoxymethyleneaminooxazole (240 mg, 1.5 mmol) (see, J. Am. Chem. Soc., 88, 3829 (1966), Bull. Chem. Soc. JAPAN, 43, 187 (1970), Bull. Chem. Soc. JAPAN, 43, 3909 (1970)) and 2-aminoindan (580 mg, 4.4 mmol) in dry ethanol (2 ml) were heated to reflux for 6.5 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (methylene chloride:ethyl acetate=1:4) to obtain the title compound (56 mg, 0.22 mmol) having the following physical properties:
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].C1O[CH:7]1[CH3:8].COC1C=CC(O)=CC=1.[C:19]([O-:32])(=[O:31])CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.O=C=[N:58]C1CC(C)(C)CC(C)(CN=C=O)C1>>[C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[NH2:58][C:19]([O:32][CH2:7][CH3:8])=[O:31]
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: CC1CO1
Reactant: CCCCCCCCCCCC(=O)[O-]
Agent: C=CC(=O)O
Agent: CCCC[Sn+2]CCCC
Agent: COc1ccc(O)cc1
Product: CCOC(N)=O

Procedure:
1,517 Grams of an addition product of acrylic acid with propylene oxide [BLENMAR AP-550 of Nippon Oil and Fats Co. Ltd.; a compound of the formula (vii) wherein R4 is H, R5 is CH3 and h is 10], 1.00 g of hydroquinone monomethyl ether, 0.52 g of di-n-butyltin dilaurate and 222 g of isophorone diisocyanate were charged to a 4-liter four-necked flask equipped with a stirrer, a thermoregulator, a thermometer and a condenser, allowed to react with one another at 40 to 50° C. for 30 minutes and then the reaction was further continued at 80 to 90° C. to produce the third urethane acrylate [a compound of the formula (3) wherein R4 is H, R5 is CH3, A3 is an isophorone group, h is 10 ad j is 2].
Reaction SMILES: [N:1]([C@:4]12[CH2:30][CH2:29][C@@H:28]([C:31]([CH3:33])=[CH2:32])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:27])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C:13](=[O:26])[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)=C=O.[ClH:34]>O1CCOCC1>[Cl-:34].[CH3:22][C@:19]12[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:27])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:24])([CH3:25])[C:13](=[O:26])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C@@H:6]1[C@H:5]1[C@H:28]([C:31]([CH3:33])=[CH2:32])[CH2:29][CH2:30][C@:4]1([NH3+:1])[CH2:21][CH2:20]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N=C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: Cl
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2([NH3+])CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: [Cl-]
Reaction time: 0.17 h
Yield: 72 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)octadecahydro-1H-cyclopenta[a]chrysen-9(5bH)-one (2.1 g, 4.65 mmol) in dioxane (30 mL) at RT was added 7 mL conc. HCl over a period of 5 minutes. The clear solution was stirred for 10 minutes, forming a slightly turbid mixture. Stirring continued for a total of 6 hours and the reaction mixture turned into a 2-layer mixture. All the volatile solvents were removed under high vacuum. The dried, crude material was dissolved into DCM (15 mL), poured over a short bed (˜1″ thick) of silica gel type-H, washed with 500 mL, 20% ethyl acetate in hexanes, followed by a 2:1 mixture of DCM:Ethyl acetate (0.5 L). Upon concentration, a pale gum was obtained. The material was dried under high vacuum to give 1.55 gm (72% yield). MS: m/e 426.40 M+, 4.11 min (method 11). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.24 (br. s., 3H), 4.83 (br. s., 1H), 4.66 (br. s., 1H), 2.62-2.17 (m, 4H), 2.16-1.78 (m, 5H), 1.77-1.31 (m, 17H), 1.30-1.16 (m, 5H), 1.09 (s, 3H), 1.03 (s, 3H), 0.99 (br. s., 3H), 0.93 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[C:11]([CH3:19])[N:10]=1.OC1C([N+]([O-])=O)=C(O)C=C(C)N=1.OC1C([N+]([O-])=O)=C(O)C(C)=C(C)N=1.Cl.[CH2:46]([O:53][CH2:54][CH2:55][NH2:56])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C)C=O>[CH2:46]([O:53][CH2:54][CH2:55][NH:56][C:13]1[CH:12]=[C:11]([CH3:19])[N:10]=[C:9]([Cl:8])[C:14]=1[N+:15]([O-:17])=[O:16])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: NCCOCc1ccccc1
Agent: Cc1cc(O)c([N+](=O)[O-])c(O)n1
Agent: Cc1nc(O)c([N+](=O)[O-])c(O)c1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(NCCOCc2ccccc2)c([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C
Reaction time: 23 h
Yield: 25.2 %

Procedure:
Under a nitrogen atmosphere, triethylamine (40.4 mL, 290 mmol) was added to a solution of 2,4-dichloro-6-methyl-3-nitropyridine (12.0 g, 58.0 mmol), prepared according to the general method of Part A of Example 1 using 2,4-dihydroxy-6-methyl-3-nitropyridine in lieu of 2,4-dihydroxy-5,6-dimethyl-3-nitropyridine, in anhydrous N,N-dimethylformamide (DMF) (200 mL). To the resulting dark brown solution was added 2-(benzyloxy)ethylamine hydrochloride (11.97 g, 63.76 mmol), and the mixture was stirred at room temperature for 23 hours. The volatiles were then removed under reduced pressure, and the residue was mixed with water and ethyl acetate. The organic layer was washed with water (3×200 mL), aqueous sodium bicarbonate (2×200 mL), and brine (3×250 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a brown oil. The crude product (18.1 g) was purified by column chromatography on silica gel (700 g, eluting with 80:20 hexane:ethyl acetate) to provide an oil which was triturated with 80:20 hexane:ethyl acetate. The resulting crystals were isolated by filtration and dried to provide 4.7 g of [2-(benzyloxy)ethyl]-(2-chloro-6-methyl-3-nitropyridin-4-yl)amine as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21]SCC(C)CC.BrCC1[C:39]2[C:34](=[CH:35][CH:36]=[C:37](C3C=CC=CC=3OC)[CH:38]=2)[NH:33]C(C)(C)C=1.C(=O)([O-])[O-].[K+].[K+].CC(CC)CS>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])([CH3:20])[CH:13]=[C:12]2[CH2:21][NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCC(C)CSCC1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: CCC(C)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
6-(2-Methoxyphenyl)-2,2-dimethyl-4-(2-methylbutylsulfanylmethyl)-1,2-dihydroquinoline 60 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 27 μL of 2-methyl-1-butanethiol reacted to give 4 mg of the title compound as an oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].N1C=CC=CC=1.[SH:15][CH2:16][C:17]#[N:18]>CCOCC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([S:15][CH2:16][C:17]#[N:18])=[O:7]
Reactant: N#CCS
Reactant: O=C(Cl)c1ccco1
Solvent: CCOCC
Solvent: c1ccncc1
Product: N#CCSC(=O)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To an ice cold solution of furoyl chloride (4.0 ml; 0.04 mol) in ether (100 ml) is added dropwise a freshly prepared solution of pyridine (3.24 ml; 0.04 mol) in 1 N mercaptoacetonitrile (40 ml; 0.04 mol). After the addition is completed, the mixture is allowed to stir at room temperature overnight. The reaction mixture is then washed with water, saturated sodium bicarbonate solution, saturated brine, dried over sodium sulfate, and is concentrated in vacuo. The residue (6.0 g) is filtered through a 25 g column of silica gel and eluted with methylene chloride. The methylene chloride eluent is diluted with hexane, cooled and filtered to yield 4.3 g (64%) of title product, an orange solid, melting point 76°-78° C. Recrystallization from methylene chloride-hexane affords 3.7 g product, as a pale orange solid, melting point 77°-78° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=O)=[C:10]([F:18])[CH:9]=1.[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:20][C:21]1[C:22]([N:28]2[CH2:29][CH2:30][N:31]([C:12]([C:11]3[CH:16]=[CH:17][C:8]([CH2:7][N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:19])=[CH:9][C:10]=3[F:18])=[O:14])[CH2:32][CH2:33]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: COC(=O)c1ccc(CN2CCCS2(=O)=O)cc1F
Product: Cc1cnc(N2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 87.8 %

Procedure:
Using methyl 4-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)-2-fluorobenzoate (115 mg) described in Preparation Example 200 and 1-(3,5-dimethylpyridin-2-yl)piperazine (92 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (157 mg) was obtained.