Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.Cl.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH:5]([N:18]2[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:24])[CH2:19]2)[CH2:4][CH2:3]1
Reactant: COc1ccc(C2(O)CCC(=O)CC2)cn1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
4-Hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexanone, as prepared in Step B of this example, (300 mg, 1.36 mmol) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide HCl salt, as prepared in Step D of this example, (460 mg, 1.36 mmol) in DCM (5 mL) were treated with TEA (1 mL, 7.12 mmol) for 10 min followed by NaBH(OAc)3 (860 mg, 4.07 mmol) for another 4 hours at room temperature. The reaction was quenched with saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted 3 times with chloroform and IPA “cocktail” (˜3:1, v/v). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford two title compounds as white solids: a less polar isomer, and a more polar isomer.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:22][CH2:21]3)[C:18]([C:23]3([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)=[N:17][N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.O1CCOCC1>CO.[OH-].[Pd+2].[OH-]>[CH:20]1([N:19]2[C:18]([C:23]3([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH2:24][CH2:25][CH2:26]3)=[N:17][N:16]=[C:15]2[C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH2:22][CH2:21]1
Reactant: c1ccc(COc2ccc(-c3nnc(C4(c5cccs5)CCC4)n3C3CC3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Oc1ccc(-c2nnc(C3(c4cccs4)CCC3)n2C2CC2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-[4-(Benzyloxy)phenyl]-4-cyclopropyl-5-[1-(2-thienyl)cyclobutyl]-4H-1,2,4-triazole was dissolved in methanol (4 ml) and 1,4-dioxane (3 ml) and, after palladium hydroxide (236 mg) was added thereto, the whole was stirred under a hydrogen atmosphere of 1 atm at room temperature for 15 hours. After filtration through celite, the filtrate was purified by silica gel chromatography (chloroform:methanol=99:1 to 95:5) and the resulting crystals were washed with diisopropyl ether to obtain 32 mg of 4-{4-cyclopropyl-5-[1-(2-thienyl)cyclobutyl]-4H-1,2,4-triazol-3-yl}phenol (white crystals).
Reaction SMILES: C([O:9][CH2:10][CH:11]([CH2:23][O:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[O:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])(=O)C1C=CC=CC=1.[CH3:35][C:36](=[CH2:38])[CH3:37].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:36]([CH:10]([CH:11]([CH2:23][O:24][S:25]([C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)(=[O:26])=[O:27])[O:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=1)(=[O:15])=[O:14])[OH:9])([CH3:37])([CH3:35])[CH3:38]
Reactant: C=C(C)C
Reactant: Cc1ccc(S(=O)(=O)OCC(COC(=O)c2ccccc2)OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(OS(=O)(=O)c2ccc(C)cc2)C(O)C(C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of 13.8 g (34.5 mmol) of (-)-1,2-di-p-toluene-sulfonyl glycerol (see Formula (I) in Scheme 2) in 100 ml of dry methylenechloride is added to 100 ml of liquid isobutylene taken in a pressure bottle at -78° C. Concentrated sulfuric acid (0.2 ml) is added to the above reaction mixture, the contents are stirred, and the mixture is then allowed to warm to room temperature and stirred for 16 hours. The pressure is gradually released, and the solution is neutralized with aqueous sodium bicarbonate solution. The organic layer is separated, washed with water, and dried over Na2SO4. The solvent is removed on a rotary evaporator and the crude product is dried under reduced pressure. Recrystallization from absolute ethanol affords white crystals of (+)-t-butyl-2,3-di-p-toluenesulfonyl glycerol (see Formula (J) in Scheme 2), m.p. 70°-71° C. [α]D2 +3.44 (c, 5.9, CHCl3). 1H NMR (CDCl3)δ7.8 (m, 4H); 7.3 (m, 4H); 4.5 (m, 1H); 4.15 (d, 2H); 3.35 (d, 2H); 2.45 (s, 6H); 1.1 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]4([CH2:22][CH2:21][C:20]5[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=5[CH2:18][CH2:17]4)[C:14](=O)[C:13]=3[CH:28]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C[Si]([N:33]=[C:34]=[N:35][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]4([CH2:22][CH2:21][C:20]5[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=5[CH2:18][CH2:17]4)[C:14](=[N:35][C:34]#[N:33])[C:13]=3[CH:28]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1c2cc(-c3cc(F)cc(Cl)c3)ccc2OC12CCc1ccccc1CC2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1c2cc(-c3cc(F)cc(Cl)c3)ccc2OC12CCc1ccccc1CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5′-(3-chloro-5-fluorophenyl)-5,6,8,9-tetrahydro-3′H-spiro[benzo[7]annulene-7,2′-benzofuran]-3′-one (0.0607 g, 0.155 mmol) in CH2Cl2 (5 mL) was added 0.7 mL of 1.0 M TiCl4 in CH2Cl2 at room temperature. After 1 h, 0.28 mL of bis(trimethylsilyl)carbodiimide was added to the red solution. The resulting mixture was then stirred at room temperature for 18 h. The mixture was quenched with ice, diluted with CH2Cl2, and dried over Na2SO4. After the solvent was removed under reduced pressure, the crude product was directly used in the next step without further purification.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:18]=[CH:17][C:8]2[C:9]([C:12](=[NH:16])OCC)=[N:10][O:11][C:7]=2[CH:6]=1)([O-:4])=[O:3].[NH3:19]>C(O)C>[C:12]([C:9]1[C:8]2[CH:17]=[CH:18][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][C:7]=2[O:11][N:10]=1)(=[NH:16])[NH2:19]
Reactant: CCOC(=N)c1noc2cc([N+](=O)[O-])ccc12
Reactant: N
Agent: Cl
Solvent: CCO
Product: N=C(N)c1noc2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In ethanol (100 ml) was dissolved ethyl 6-nitro- 1,2-benzisoxazole-3-formimidate hydrochloride (2.0 g) and the mixture was saturated with ammonia by passing through thereto ammonia gas under stirring at room temperature. The mixture was allowed to stand at room temperature overnight and then ethanol was distilled off under a reduced pressure. The crystalline residue was washed with ether and dissolved in water. The solution was neutralized with sodium bicarbonate and extracted with ether. The extract was distilled to remove ether to give the desired compound (1.2 g), which was recrystallized from chloroform. m.p. 182° to 185°C.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)=[O:9].[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(O)C>[CH:24]1([NH:30][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]2[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=2[C:8]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)=[O:9])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCCCC1
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC1CO1
Solvent: CCO
Product: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC(O)CNC1CCCCC1

Procedure:
2.5 g of 2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl)-benzamide in 20 ml of ethanol was refluxed for 2 hours with 1.86 ml of cyclohexylamine and the solvent was eliminated under reduced pressure. The residue was chromatographed over silica (eluent:chloroform-methanol 9-1) to obtain 1.97 g of 2-[3-(cyclohexylamino)-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamide
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[NH2:19])[CH:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>CCOCC>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][C:10]=2[NH:19][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH:7]=1
Reactant: Nc1cc(C(F)(F)F)ccc1Oc1cncc(Cl)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)Nc2cc(C(F)(F)F)ccc2Oc2cncc(Cl)c2)cc1

Procedure:
Using the method of Example 17.4, 4-(3-chloro-5-pyridyloxy)-3-aminobenzotrifluoride (0.41 g) and 4-methoxybenzenesulfonyl chloride ((0.30 g ) were combined to provide the title compound (0.236 g) as a crystalline solid following flash chromatography and trituration with ether.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2Cl)=[N:13][C:12]([Cl:17])=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.[CH3:18][N:19]([CH3:27])[C@H:20]1[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]1>>[Cl:17][C:12]1[N:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5])=[C:15]2[NH:26][C@H:23]1[CH2:24][CH2:25][C@H:20]([N:19]([CH3:27])[CH3:18])[CH2:21][CH2:22]1
Reactant: O=C(c1cnc2ccc(Cl)nc2c1Cl)C1CC1
Reactant: CN(C)[C@H]1CC[C@H](N)CC1
Product: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Cl)nc23)CC1

Procedure:
Following general procedure I, cyclopropyl(4,6-dichloro-1,5-naphthyridin-3-yl) methanone (243 mg, 0.91 mmol) was reacted with trans-N1,N1-dimethylcyclohexane-1,4-diamine (168 mg, 1.2 mmol) to afford the desired product (150 mg, 44%) as a light yellow solid. 1H NMR (500 MHz, Chloroform-d) δ 10.83 (br s, 1H), 9.20 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 4.98 (br s, 1H), 2.71-2.63 (m, 1H), 2.33 (s, 6H), 2.34-2.29 (m, 2H), 2.28-2.19 (m, 1H), 2.06-1.97 (m, 2H), 1.54-1.33 (m, 4H), 1.31-1.22 (m, 2H), 1.11-1.01 (m, 2H). ESI MS m/z 373 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[N:16]=1>C1(C)C=CC=CC=1.O>[CH2:3]([O:10][CH2:11][CH2:12][O:13][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([Br:14])[N:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: OCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cccc(OCCOCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (900 mg, 60% dispersion in mineral oil, 22.5 mmol) was added portionwise to an ice-cold solution of 2-(benzyloxy)ethanol (3.0 g, 20.0 mmol) in toluene (100 ml), and the solution stirred for 30 minutes. 2,6-Dibromopyridine (4.75 g, 20.0 mmol) was added, and the reaction heated under reflux for 2 hours. The cooled mixture was diluted with water (100 ml), and extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give the title compound as a yellow oil, (quantitative).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].CN(C)C=O.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Br>C(#N)C>[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[C:30]([F:29])([F:39])[F:40])[CH:10]=1)=[O:8]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1ccc(C(=O)c2cn(Cc3ccccc3C(F)(F)F)c3ccccc3c2=O)cc1C

Procedure:
Compound 4kk was prepared following the procedure outlined in Step 3 of Example 1 using 26 mg (0.65 mmol) of sodium hydride (60%), 138.6 mg (0.50 mmol) of 3-(3,4-Dimethyl-benzoyl)-2,3-dihydro-1H-quinolin-4-one 3a, 3 mL of anhydrous dimethylformamide, and 155.4 mg (0.65 mmol) of 2-trifluoromethylbenzylbromide. The crude product was purified by flash chromatography to yield 96 mg of 4kk as a colorless solid: LC-MSD, m/z for C26H20F3NO2, [M+H]+=436.5, [M+2H]+=437.5; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.709 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.32 (d, 6H), 5.60 (s, 2H), 6.92 (m, 1H), 7.17 (t, 2H), 7.39-7.47 (m, 3H), 7.54-7.60 (m, 2H), 7.65 (s, 1H), 7.79 (m, 1H), 8.22 (s, 1H), 8.50 (m, 1H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[Na].[C:6](OC)(=[O:13])[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1>N>[C:6]([NH:1][C:2]([NH2:4])=[O:3])(=[O:13])[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: NC(N)=O
Reactant: COC(=O)c1ccncc1
Agent: N
Agent: [Na]
Product: NC(=O)NC(=O)c1ccncc1

Procedure:
Urea (7.5 g., 0.125 mole) is suspended in liquid ammonia (250 ml.) in a round bottom flask fitted with an acetone/dry-ice condenser. Sodium pellets (2.9 g., 0.125 mole) are added and, after they have dissolved, methyl isonicotinate (12 g., 0.089 mole) is added to the mixture. The ammonia is allowed to evaporate from the mixture overnight. The yellow-tan residue is dissolved in water (150 ml.), the pH of the mixture adjusted to 5.5 with glacial acetic acid, and the precipitate which forms filtered, washed with water and air dired. It is then washed with hexane and triturated with boiling methanol. The white solid (isonicotinic acid) is removed by filtration and the filtrate evaporated to dryness to give the title product as a yellowish solid: m.p. 245°-247° C. Quantitative analysis and infra-red data are consistent with the values expected for the product.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:17]1[N:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[N:18]=1>O1CCCC1>[CH2:1]([NH:8][C:17]1[N:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Clc1cc(Cl)nc(NCc2ccccc2)n1

Procedure:
Benzylamine (0.53 g, 0.54 ml, 5 mmol) and triethylamine (0.50 g, 0.69 ml, 5 mmol) in tetrahydrofuran (20 ml) were added to 2,4,6-trichloropyrimidine (0.917 g, 5 mmol) in tetrahydrofuran (20 ml) at 0° C. The mixture was stirred for several hours. The precipitate then filtered through celite, then the most of the methanol was removed in vacuo. The residue was purified in silica to provide a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4](S(C2C=CC=CC=2)(=O)=O)[C:3]=1[CH2:20][CH2:21][NH:22][CH:23]([C:25]1[N:26]=[CH:27][N:28]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]=1[CH3:30])[CH3:24].[OH-].[K+]>CS(C)=O.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH2:20][CH2:21][NH:22][CH:23]([C:25]1[N:26]=[CH:27][N:28]([C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:29]=1[CH3:30])[CH3:24]
Reactant: Cc1c(CCNC(C)c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)n(S(=O)(=O)c2ccccc2)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(CCNC(C)c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)[nH]c2ccccc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A mixture of 3-methyl-2-[2-[[1-(5-methyl-1-trityl-1H-imidazol-4-yl)ethyl]amino]ethyl]-1-phenylsulfonylindole (970 mg) and powdered potassium hydroxide (819 mg) in dimethylsulfoxide (10 ml) were stirred at 70° C. for 1 hour. The resultant mixture was diluted with cold water and extracted twice with 30% tetrahydrofuran in ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (eluted with 5% MeOH in chloroform) to give 3-methyl-2-[2-[[1-(5-methyl-1-trityl-1H-imidazol-4-yl)ethyl]amino]ethyl]indole (611.3 mg) as amorphous powder.
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][C:22]3=[O:23])[CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][C:22]3=[O:23])[CH2:19][CH2:20]2)=[O:14])=[CH:32][CH:33]=1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(c1ccc(O)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 25 °C
Yield: 66 %

Procedure:
1-[1-(4-Benzyloxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (4.76 g) is dissolved in methanol (100 ml) and thereto is added 5% palladium-carbon (1 g). The mixture is stirred at room temperature under 1 atm. under hydrogen atmosphere. After the completion of the reaction, the catalyst is filtered off and the filtrate is concentrated. The resultant is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=1:1) and further recrystallized from n-hexane/ethanol to give 1-[1-(4-hydroxybenzoyl)-4-piperidinyl]-3,4-dihydro carbostyril (2.5 g) as white powder, m.p. 182°-183° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][O:15][CH3:16])[C:12](=[O:17])[CH:11]([C:18]([O:20][CH3:21])=[O:19])[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH2:9][C:8]=2[CH:30]=1.[CH2:31](Br)[CH:32]=[CH2:33]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]([O:20][CH3:21])=[O:19])([CH2:33][CH:32]=[CH2:31])[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH2:9][C:8]=2[CH:30]=1
Reactant: COCN1C(=O)C(C(=O)OC)C(c2ccc(OC)cc2)Cc2cc(Cl)ccc21
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1(C(=O)OC)C(=O)N(COC)c2ccc(Cl)cc2CC1c1ccc(OC)cc1
Reaction time: 0.33 h

Procedure:
To a suspension of 50% sodium hydride (48 mg; 1 mmole) in dimethylformamide (5 ml) cooled at 0°-5° C. was added dropwise a solution of 7-chloro-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-1-(methoxymethyl)-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (102 mg; 0.25 mmole) in dimethylformamide (1 ml). After stirring at 0°-5° C. for 20 minutes, allyl bromide (360 μl ; 4 mmole) was added dropwise, and the reaction mixture was allowed to stir at 0° C. to room temperature for two hours. Excess sodium hydride was destroyed with water, and the mixture was extracted with ether. The aqueous layer was extracted with ether (two times), and the combined organic layers were dried (magnesium sulfate) and concentrated. The crude residue was triturated with hexane (20 ml) to obtain 93 mg of white, crystalline title compound. [The mother liquor contained additional product].
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([CH:22]=[N:23][N:24]=2)[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([Se]C3C=CC=CC=3)[CH2:9]2)[CH:7]=1.ClN1C(=O)CCC1=O.N12CCCN=C1CCCCC2>ClCCl>[CH3:1][C:2]1[C:3]2[N:4]([CH:22]=[N:23][N:24]=2)[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]=[CH:9]2)[CH:7]=1
Reactant: Cc1cc(N2CCC(O)C([Se]c3ccccc3)C2)nn2cnnc12
Agent: O=C1CCC(=O)N1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1cc(N2C=CC(O)CC2)nn2cnnc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 387 mg of 1-(8-methyl-1,2,4-triazolo-[4,3-b]pyridazin-6-yl)-3-(phenylselenyl)-4-piperidinol in dichloromethane at room temperature was treated with a solution of 147 mg of N-chlorosuccinimide in 3 ml of dichloromethane and stirred at room temperature. A white precipitate formed. After 15 minutes, 305 mg of 1,8-diazabicyclo [5,4,0]undec-7-ene was added and stirring continued at room temperature for 20 hours. This resulted in a very dark-colored solution. The reaction volume was reduced at the rotary evaporator and the solution put directly on a silica gel (20 g) flash chromatography column. After rinsing the material on the column with dichloromethane, it was eluted with 95% dichloromethane/5% ethanol (10% concentrated ammonium hydroxide). The clean fractions were combined to give, on evaporation of the solvent, a tan viscous oil which slowly crystallized to give 1-(8-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)-1,4,5,6-tetrahydro-4-pyridinol melting at about 171°-173° C.
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].C[O:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[N:14][CH:13]=1.O>O1CCOCC1>[CH:5]([NH:8][C:11](=[O:10])[C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[N:14][CH:13]=1)([CH3:7])[CH3:6]
Reactant: COC(=O)c1ccc(/C=C/c2c(-c3ccccc3)noc2C)nc1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2)c1/C=C/c1ccc(C(=O)NC(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 1.25 mL, 2.0 mmol) was added dropwise (exothermic) to a solution of isopropylamine (210 μL, 2.0 mmol) in dioxane (6 mL) and the resulting mixture was stirred at room temperature for 1 h. Then 6-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester (200 mg, 0.62 mmol) was added. The resulting mixture was then heated at 90° C. for 2 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:4) afforded the title compound (170 mg, 78%) which was obtained as a white solid after trituration from diisopropylether/ethyl acetate. MS: m/e=348.3 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[C:12]([CH3:15])[S:11][C:10]2=[NH:16])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[N:26]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]1>C(#N)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([CH3:14])=[C:12]([CH3:15])[S:11]/[C:10]/2=[N:16]\[C:31]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:32])=[CH:7][CH:8]=1
Reactant: O=C(Cl)N1CCCC1
Reactant: Cc1sc(=N)n(-c2ccc(Cl)cc2)c1C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1s/c(=N\C(=O)N2CCCC2)n(-c2ccc(Cl)cc2)c1C
Temperature: 75 °C

Procedure:
To a suspension of 3-(4-chlorophenyl)-4,5-dimethyl-1,3-thiazol-2(3H)-imine hydrochloride (90 mg, 0.33 mmol, Example 160A) in acetonitrile (2.0 mL) containing diisopropylethylamine (102 mg, 0.79 mmol) was added 1-pyrrolidinecarbonyl chloride (53 mg, 39 mmol). The mixture was heated at 75° C. for 18 hours, then concentrated. The residue was dissolved in dichloromethane (10 mL). The organic layer was washed with dilute aqueous ammonium chloride (5 mL) and water (2×5 mL) and the dichloromethane was removed under reduced pressure. The residue was purified on a Waters Symmetry C8 30×100 mm column (flow rate 40 mL/min, 5-95% gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid) to afford the title product.