Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:15][CH3:16])[CH2:3][O:4][C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)=[O:6].[CH2:17]([O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:17]([O:31][C:32]1[CH:38]=[CH:37][C:35]([N:36]=[CH:11][C:10]2[CH:13]=[CH:14][C:7]([C:5]([O:4][CH2:3][CH:2]([CH3:1])[CH2:15][CH3:16])=[O:6])=[CH:8][CH:9]=2)=[CH:34][CH:33]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCOc1ccc(N)cc1
Reactant: CCC(C)COC(=O)c1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(N=Cc2ccc(C(=O)OCC(C)CC)cc2)cc1

Procedure:
44.3 g of said p-(2-methylbutoxycarbonyl)benzaldehyde, 32 g of p-n-tetradecyloxyaniline, and 0.1 g of p-toluenesulfonic acid were dissolved in toluene. The solution was heated under reflux, and water generated in the dehydrating condensation was removed with a Dean-Stark condenser. After the reaction solution was cooled, the organic layer was washed with water, and the solvent (toluene) was distilled off in vacuum. The solid residue was recrystallized from ethanol to obtain yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[CH:24]([NH2:28])([CH2:26][CH3:27])[CH3:25]>CN1C(=O)CCC1.CCOC(C)=O>[CH:24]([NH:28][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1)([CH2:26][CH3:27])[CH3:25]
Reactant: CCC(C)N
Reactant: Clc1ccc2ncc(Cc3ccc4ncccc4c3)n2n1
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCC(C)Nc1ccc2ncc(Cc3ccc4ncccc4c3)n2n1
Temperature: 180 °C
Reaction time: 29 h

Procedure:
6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-quinoline (Example 14, 70 mg, 0.237 mmol), KF (70 mg, 1.187 mmol) and sec-butylamine (484 μL, 4.75 mmol) were suspended in NMP (1 mL). The RM was stirred at 180° C. for 29 h. The mixture was diluted with EtOAc and washed with 1 M Na2CO3 (×1) and water (×2). The aqueous was further extracted with EtOAc (2×). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (Flashmaster) and then crystallized in Et2O to afford the title compound as a beige solid (tR 4.28 min (conditions 4), MH+ 332.3, 1H-NMR in DMSO-d6: 8.83 (m, 1H); 8.25 (m, 1H); 7.92 (d, 1H); 7.83 (m, 1H); 7.70 (m, 1H); 7.61 (d, 1H); 7.48 (dd, 1H); 7.32 (s, 1H); 6.66 (d, 1H); 6.56 (d, 1H); 4.34 (s, 2H); 3.70 (m, 1H); 1.46 (m, 2H); 1.07 (d, 3H); 0.80 (t, 3H)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([OH:12])=O.[CH3:13][CH2:14][CH2:15][CH:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:20][CH:16]([CH2:17][CH2:18][CH3:19])[CH2:15][CH2:14][CH3:13])=[O:12]
Reactant: CCCC(N)CCC
Reactant: O=C(O)C=Cc1ccccc1F
Product: CCCC(CCC)NC(=O)C=Cc1ccccc1F

Procedure:
Prepared in a similar manner as described in example 4 from 3-(2-fluoro-phenyl)-acrylic acid and 4-heptylamine. MS (M+H, 264.2).
Reaction SMILES: [C:1]1(=[O:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[CH:2]1[C:11]1C=CN=C[CH:12]=1.[C:18]([N:37]1C=C(C=O)[N:39]=[CH:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([N:37]1[CH:12]=[C:11]([CH:2]2[C:1](=[O:17])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:10])[N:39]=[CH:38]1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1c2ccccc2C(=O)C1c1ccncc1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: O=C1c2ccccc2C(=O)C1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 67 %

Procedure:
The condensing of commercially available 1-trityl-1H-imidazole-4-carboxaldehyde (I) with phtalide to form 2-(1-trityl-1H-imidazole-4-yl)indan-1,3-dione (II) is performed under the conditions that are similar to those used for synthesis of 4-(indane-1,3-dionyl)pyridine J. Org. Chem. 1971, vol. 36, p. 1563. surprisingly, the bulky 1-trityl-1H-imidazole-4-carboxaldehyde (I) reacted as expected and produced 2-(1-trityl-1H-imidazole-4-yl)indan-1,3-dione (II) in over 67% yield. Both ethyl acetate and dioxane can be used as reaction media.
Reaction SMILES: [CH3:1][C:2]1([CH:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)[N:17]=3)[NH:12][CH:11]=2)[OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COc1cc(-c2cnc3[nH]cc(C(O)C4(C)CCCCC4)c3n2)cc(OC)c1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCCCC4)c3n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.4 %

Procedure:
To a solution of (1-methyl-cyclohexyl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanol (81 mg, 0.196 mmol) in dichloromethane (6 ml) was added Dess-Martin periodinane (125 mg, 0.295 mmol). The reaction mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was partitioned between dichloromethane and 2:1 saturated aqueous NaHCO3:10% aqueous Na2S2O3. The organic layers were collected, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using 20-50% EtOAc in hexanes as eluant to provide 18 mg (22%) of (1-methyl-cyclohexyl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone as an off white solid. MP 246-247° C., M+H=439.
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[OH:28])=[CH:11][CH:10]=1.Cl[CH2:35][C:36]1[CH:37]=[CH:38][C:39]2[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=2[CH:51]=1>>[F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:17][CH:16]2[O:28][CH2:35][C:36]2[CH:37]=[CH:38][C:39]3[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=3[CH:51]=2)=[CH:11][CH:10]=1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccc(F)cc3F)cc2)C(O)C1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4ccc(F)cc4F)cc3)cc21

Procedure:
Analogously to Method D, 0.600 g of tert-butyl 4-{4-[3-(2,4-difluorophenoxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.391 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a colourless oil. Rf=0.17 (1:2 EtOAc-heptane); Rt=5.80.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]1[S:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][C:15]=1[NH:22][C:23](=[O:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH2:32](O)[C:33]1[CH:41]=[CH:40][C:39]2[O:38][CH2:37][O:36][C:35]=2[CH:34]=1>>[O:38]1[C:39]2[CH:40]=[CH:41][C:33]([CH2:32][O:20][C:19]([C:17]3[S:18][C:14]([CH3:13])=[C:15]([NH:22][C:23](=[O:31])[CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:16]=3)=[O:21])=[CH:34][C:35]=2[O:36][CH2:37]1
Reactant: Cc1sc(C(=O)O)cc1NC(=O)Cc1ccccc1
Reactant: OCc1ccc2c(c1)OCO2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1sc(C(=O)OCc2ccc3c(c2)OCO3)cc1NC(=O)Cc1ccccc1
Yield: 73.3 %

Procedure:
The title compound was prepared according to the procedure described for Example 2 using carbonyldiimidazole (0.26 g, 1.7 mmol), 5-methyl-4-phenylacetylamino-thiophene-2-carboxylic acid from Example 10, Step 1 (0.3 g, 1.1 mmol), and piperonyl alcohol (0.17 g, 1.1 mmol). Acidification of the aqueous workup mixture with dilute hydrochloric acid prior to filtration afforded 0.33 g of 5-methyl-4-phenylacetylamino-thiophene-2-carboxylic acid 1,3-benzodioxol-5-ylmethyl ester. A sample of the product was stirred in 2 M aqueous KHCO3 for several hours, filtered off, rinsed with water, and dried to give product with a mp 191-195° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=O)[CH:10]([CH3:12])[CH3:11].Cl.[NH2:15][OH:16]>N1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[N:15][OH:16])[CH:10]([CH3:12])[CH3:11]
Reactant: NO
Reactant: CC(C)C(=O)c1c(O)cccc1O
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)C(=NO)c1c(O)cccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
1-(2,6-dihydroxyphenyl)-2-methyl-1-propanone (Intermediate 37, 416 mg) was dissolved in pyridine (2.0 ml) and hydroxylamine hydrochloride (209 mg, 3.0 mmol) was added. The reaction mixture was then stirred at room temperature overnight. After night, additional hydroxylamine hydrochloride (64 mg, 0.92 mmol) was added and the mixture was heated at 100° C. for 3 hours. After removal of the volatiles, the crude was treated with water and extracted with ethyl acetate. The gathered organic layers were dried over sodium sulphate, filtered and evaporated to afford the title compound (370 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[N:15][C:16]([CH:19]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])=[CH:17][CH:18]=1)=[S:12])(C)(C)C.Cl>C(O)C>[NH2:7][CH2:8][CH2:9][NH:10][C:11](=[S:12])[C:13]1[CH:18]=[CH:17][C:16]([CH:19]([S:28]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)(=[O:30])=[O:29])[C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])=[N:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCNC(=S)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: Cl
Solvent: CCO
Product: NCCNC(=S)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To an ethanol (3 ml) solution of t-butyl[2-[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridine-3-carbothioyl]amino]ethyl]carbamate (80 mg, 0.137 mmol) was added concentrated hydrochloric acid (2 ml). The resulting mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure. To the residue thus obtained was added ethanol, followed by concentration. This operation was conducted three times to give the title compound (76 mg, 0.137 mmol, quant.) as a 1.75 hydrochloride (yellow powder).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[NH:10][C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][Br:17])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:9]2[N:10]=[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][Br:17])[O:26][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:24][CH:23]=1
Reactant: O=C(CCCCCBr)NC(C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2nc(CCCCCBr)oc2-c2ccc(Cl)cc2)cc1
Temperature: 10 °C
Yield: 87 %

Procedure:
4,5-Bis(4-chlorophenyl)-2-(5-bromopentyl)oxazole is prepared in the following manner: 39.5 g of 1,2-bis(4-chlorophenyl)-2-(6-bromohexanamido)ethanone in 80 cm3 of toluene containing 40 g of phosphorus oxychloride are stirred for 3 hours at 80° C. After evaporation to dryness under vacuum, 100 cm3 of ice-cold water are added. The mixture is extracted with diethyl ether (3 times 120 cm3) and the ethereal solutions are washed successively with water (3 times 50 cm3) and saturated aqueous sodium bicarbonate solution (twice 100 cm3). The organic phase is dried and concentrated to dryness. The solid residue is dissolved in 400 cm3 of hexane, the solution is treated with animal charcoal and filtered through kieselguhr, the filtrate is cooled to 10° C. and the precipate is drained and dried. 33 g (87%) of 4,5-bis(4-chlorophenyl)-2-(5-bromopentyl)oxazole are obtained in the form of white crystals, melting point 98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:20](Cl)(=[O:22])=[O:21])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[Cl:18].[OH-].[NH4+:25]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:20]([NH2:25])(=[O:22])=[O:21])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[Cl:18]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1ccc(Oc2c(Cl)cc(S(=O)(=O)Cl)cc2Cl)c(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(Cl)c(Oc2ccc([N+](=O)[O-])cc2Cl)c(Cl)c1
Reaction time: 4 h
Yield: 94 %

Procedure:
2 m. moles of 3,5-Dichloro-4-(2-Chloro-4-Nitrophenoxy)Benzene-1-Sulfonyl Chloride (932 mg) in 5 ml of dichloromethane was cooled to −78° C. and 2 ml of ammonium hydroxide solution added to it. The reaction was stirred for 4 hours. The solvent was evaporated to give 755 mg (94% yield) of pure 3,5-dichloro-4-(2-chloro-4-nitro phenoxy) benzenesulfonamide.
Reaction SMILES: [N:1]([CH2:4][C:5]([CH2:20][N:21]=[N+]=[N-])([CH3:19])[CH2:6][C:7](=[O:18])[CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[N+]=[N-]>CO.[Pd]>[NH2:21][CH2:20][C:5]([CH2:4][NH2:1])([CH3:19])[CH2:6][C:7](=[O:18])[CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:16])([CH3:17])[CH3:15])([CH3:12])[CH3:13]
Reactant: CC(CN=[N+]=[N-])(CN=[N+]=[N-])CC(=O)CCO[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(CN)(CN)CC(=O)CCO[Si](C)(C)C(C)(C)C
Yield: 95.1 %

Procedure:
Pd-black (70 mg) was added to a solution of 5 (1 g, 3.05 mmol) in MeOH (27 mL) under N2. The resulting suspension was thoroughly degassed and H2 introduced. After 18 h the suspension was degassed, N2 introduced, filtered through celite (MeOH as eluant) and the solvent removed to give crude 5,5-bis(aminomethyl)-1-O-tert-butyldimethylsilyl-3-oxo-hexan-1-ol (6) (800 mg, 2.90 mmol). This was dissolved in dioxan: 1M aq. NaOH (2:1, 20 mL) and the resulting solution cooled to 0° C. Boc2O (1.4 g, 6.41 mmol) was added and after 30 min. the resulting mixture warmed to RT. After 3 h the reaction mixture was acidified to pH 4 with 1M KHSO4 (aq.) and partitioned between EtOAc (300 mL) and water (100 mL). The aqueous layer was further extracted with EtOAc (200 mL). The organic fractions were combined, washed with sat. NaHCO3 (aq., 100 mL), brine (100 mL), dried (MgSO4), filtered and the solvent removed. The residue was purified by flash chromatography (EtOAc: hexane, 1:9 to 1:3) to give 5,5-bis(aminomethyl)-1-O-tert-butyldimethylsilyl-N,N-di-tert-butoxycarbonyl-3-oxo-hexan-1-ol(7). (1.04 g, 72% over 2 steps) as a colorless oil; IR (film) 3360 (NH), 1701, (amide I), 1508 (amide II) cm−1; 1H NMR (CDCl3, 400 MHz) δ-0.02 (s, 6H, Si(CH3)2), 0.75 (s, 3H, H-6), Q. 81 (s, 9H, SiC(CH3)3), 1.34 (s, 18H, OC(CH3)3×2), 2.83 (dd, 2H, JH,NH 5.3 Hz, JH,H′ 14.0 Hz, —CHH′N—×2), 3.00 (dd, 2H, JH′,NH 7.9 Hz, JH,H′ 14.1 Hz, —CHH′N—×2), 3.16 (s, 2H, H-4), 3.39 (t, 2H, J 4.9 Hz, H-2), 3.65 (t, 2H, J 4.9 Hz, H-1), 5.30 (br t, 2H, J 6.8 Hz, NH×2); 13C NMR (CDCl3, 100 MHz) 8-5.4 (Si(CH3)2), 18.2 (SiC(CH3)), 18.8 (C-6), 25.7 (SiC(CH3)3), 28.3 (OC(CH3)3×2), 40.2 (C-5), 44.4 (—CH2N—), 62.3, 72.8, 76.3 (C-1, C-2, C-4), 78.7 (OC(CH3)3×2), 156.7 (—NH(CO)O—×2); MS m/z (FAB+): 351 (M+Na+, 3), 329 (M+H+, 45).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=3)[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: Cc1cc(C)cc(N=C=O)c1
Product: COc1cccc2c1ncc1c(=O)n(-c3cc(C)cc(C)c3)c(=O)n(C3CCCC3)c12
Yield: 24.8 %

Procedure:
1-Cyclopentyl-3-(3,5-dimethyl-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (33 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.32 mmol) and 1-isocyanato-3,5-dimethyl-benzene (0.48 mmol) following general procedure C. LCMS: m/z 416 [M+1]+.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:4].[OH-].[K+]>CO.O>[CH2:14]([O:13][C:11]([N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C@H:5]1[C:3]([OH:4])=[O:2])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
To a stirred solution of (S)-piperidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (8.0g, 28.8 mmol) in MeOH (75 mL ) and water (38 mL ) at 0° C. was added powdered KOH (1.78 g, 31.7 mmol). The reaction mixture was allowed to stir for 16 h at room temperature and then the MeOH was removed in vacuo. The residue was diluted with water and washed DCM. The aqueous layer was acidified with 1.0-M HCl and extracted with ethyl acetate three times. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as pale yellow oil (7.6 g, 100%): 1H NMR (400 MHz, CD3OD) δ 1.36–1.61 (2H, m), 1.70–1.85 (3H, m), 2.28–2.40 (1H, m), 3.05–3.26 (1H, m), 4.06–4.14 (1H, m), 4.89–5.26 (4H, m), 7.37–7.48 (5H, m); 13C NMR (100 MHz, CD3OD) δ 20.5, 20.6 (CH2), 24.6, 24.7 (CH2), 26.6 (CH2), 41.8, 41.9 (CH2), 54.5, 54.7 (CH), 67.2, 67.3 (CH2), 127.6 (CH), 127.9 (CH), 128.4 (CH), 136.9 (C), 173.4 (CO).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=[CH2:26])[CH:20]=2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].C(=O)([O-])[OH:33].[Na+].ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]([F:30])([F:31])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:20]=[C:21]([CH:25]3[CH2:26][O:33]3)[CH:22]=[CH:23][CH:24]=2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:6])([F:5])[F:7]
Reactant: C=Cc1cccc(Oc2ccc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc2CCC)c1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(C2CO2)c1
Yield: 78.2 %

Procedure:
To a solution of 4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propyl-1-(3-vinylphenoxy) benzene (686 mg, 1.52 mmol) in chloroform (10 mL), sodium hydrogen carbonate (510 mg), m-chloroperbenzoic acid (60%) (880 mg) were added at room temperature and the resultant mixture was stirred. After completion of the reaction, the reaction solution was added with an aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and then concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (552 mg, yield 78%) was obtained as a colorless oil.
Reaction SMILES: [C:1]1([CH:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][C:16]=1[Cl:17]>CC(O)C>[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][C:16]=1[Cl:17].[C:1]1([C@@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(N)c1ccccc1
Agent: COC(=O)C(CC(=O)O)c1ccc(Cl)c(Cl)c1
Solvent: CC(C)O
Product: C[C@H](N)c1ccccc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
1.22 g (10.1 mmol) of (−)-1-phenylethylamine, 0.0766 g (0.503 mmol) of 1,8-diazobicyclo[5.4.0]-undeca-7-ene (hereinafter abbreviated as DBU) and 23.9 ml of 2-propanol were added to 2.77 g (10.0 mmol) of (±)-3-(3,4-dichlorophenyl)-3-methoxycarbonylpropionic acid and heated until the internal temperature became 72° C. With this temperature maintained, the solution was stirred in a suspended state for 8 hours, then it was cooled to an internal temperature of 20° C. and further stirred at this temperature for 0.5 hour. The precipitated crystals were filtered out, washed with a small amount of 2-propanol and dried to obtain 3.37 g (84.7% yield) of (+)-3-(3,4-dichlorophenyl)-3-methoxycarbonylpropionic acid·(S)-1-phenylethylamine salt.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=2[OH:25])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12>C(Cl)Cl>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([CH3:18])[CH3:17])[CH:13]=[C:12]([C:12]3[C:11]([OH:25])=[C:10]([N:2]4[N:3]=[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]5=[N:1]4)[CH:15]=[C:14]([C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)([CH3:18])[CH3:17])[CH:13]=3)[C:11]=2[OH:25])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(c1ccccc1)c1ccc(O)c(-n2nc3ccccc3n2)c1
Solvent: ClCCl
Product: CC(C)(c1ccccc1)c1cc(-c2cc(C(C)(C)c3ccccc3)cc(-n3nc4ccccc4n3)c2O)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Anhydrous ferric chloride (2.6 g) was added over a period of 30 minutes to a solution of 2-(2H-benzotriazol-2-yl)-4-cumyl-phenol (2.7 g) in methylene chloride (100 ml) and the resulting mixture stirred at room temperature for 6 hours. After filtering over celite, the filtrate was extracted with dilute hydrochloric acid, washed with water and purified by column chromatography using hexane/ethyl acetate 9:1 v/v mixture as the eluent. Evaporation of the volatiles gave 3,3′bis-(2H-benzotriazol-2-yl)-5,5′-di-cumyl-1,1′-biphenyl-2,2′-diol (COMPOUND 3) as a white powder, m.p. 249-251° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5](=[O:8])[NH:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].[Br:13]N1C(=O)CCC1=O>ClCCl>[Br:13][C:6]1[C:5](=[O:8])[NH:4][C:3]([C:9]([O:11][CH3:12])=[O:10])=[C:2]([CH3:1])[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1[nH]c(=O)cnc1C
Solvent: ClCCl
Product: COC(=O)c1[nH]c(=O)c(Br)nc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 3-methyl-6-oxo-1,6-dihydropyrazine-2-carboxylate (2.0 g, 11.89 mmol) was dissolved in dichloromethane (30 mL) and N-bromosuccinimide (2.12 g, 11.89 mmol) was added. The reaction was allowed to stir at room temperature for 16 h. On completion, the reaction mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The solid was washed with ether to afford methyl 5-bromo-3-methyl-6-oxo-1,6-dihydropyrazine-2-carboxylate (2) as light brown solid. Yield: 1.25 g, 42%; MS (ESI) m/z 247.04 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.92 (brs, 1H), 3.87 (s, 4H), 2.50 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH:10]1([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[OH:9])[CH2:11][CH2:12]1
Reactant: O=C(c1ccc(F)cc1)C1CC1
Agent: [BH4-]
Agent: [Na+]
Product: OC(c1ccc(F)cc1)C1CC1

Procedure:
Reduction of cyclopropyl 4-fluorophenyl ketone by reaction with sodium borohydride gave cyclopropyl-4-fluorophenylcarbinol. Reaction of the cyclopropyl carbinol with hydrogen chloride in acetic acid effected opening of the cyclopropyl ring, chlorination and dehydration to afford 1-chloro-4-(4-fluorophenyl)-3-butene. The chlorobutene was reacted with dimethylamine in ethanol at 100° C. for forty-eight hours to provide N,N-dimethyl-4-(4-fluorophenyl)-3-butenylamine. A solution of 54.4 g. of the butenylamine in 343 ml. of ethanol containing 2.5 g. of Raney Nickel was hydrogenated to provide 47.71 g. of N,N-dimethyl-4-(4-fluorophenyl)butylamine. B.P. 115°-118° C. at 12 torr.