Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[BH4-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH:18](O)[C:19]1[C:20]2[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:21]=2[O:22][C:23]=1[CH3:24].[OH-].[Na+]>C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][C:19]1[C:20]2[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:21]=2[O:22][C:23]=1[CH3:24]
Reactant: COC(=O)c1ccc2oc(C)c(C(O)c3ccc(Cl)cc3Cl)c2c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2oc(C)c(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Trifluoroacetic acid (50 ml) was ice-cooled and sodium borohydride (873 mg, 23.1 mmol) was gradually added over 20 min under a nitrogen atmosphere at 5-7° C. Thereto was dropwise added a solution of 3-((2,4-dichlorophenyl)hydroxymethyl)-5-(methoxycarbonyl)-2-methylbenzo[b]furan in methylene chloride over 20 min, and the mixture was stirred at room temperature for 45 min. After the completion of the reaction, the reaction mixture was poured into ice water and a 25% aqueous sodium hydroxide solution was added to make an alkali solution. The solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The crystalline residue was purified by silica gel column chromatography to give the objective compound (0.58 g, 72% in 2 steps) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N:24]5[CH2:32][C:31]6[C:26](=[CH:27][C:28]([CH3:33])=[CH:29][CH:30]=6)[C:25]5=[O:34])[C:19]=4[CH3:35])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][CH2:44][O:45][Si](C(C)(C)C)(C)C>CN(C=O)C>[OH:45][CH2:44][CH2:43][O:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N:24]5[CH2:32][C:31]6[C:26](=[CH:27][C:28]([CH3:33])=[CH:29][CH:30]=6)[C:25]5=[O:34])[C:19]=4[CH3:35])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Cc1ccc2c(c1)C(=O)N(c1cccc(-c3ccc(C(N)=O)c4[nH]c5cc(O)ccc5c34)c1C)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C(=O)N(c1cccc(-c3ccc(C(N)=O)c4[nH]c5cc(OCCO)ccc5c34)c1C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
A mixture of 7-hydroxy-4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 40-2, 30 mg, 0.065 mmol) and potassium carbonate (36 mg, 0.260 mmol) in DMF (1.0 mL) was stirred at rt for 30 min, then was treated with (2-bromoethoxy)(tert-butyl)dimethylsilane (62.2 mg, 0.260 mmol) and heated at 90° C. for 4 h. The mixture was filtered, the filtrate was treated with hydrogen chloride (4 M in dioxane, 1 mL) and the solution was stirred at rt overnight. The solution was concentrated under vacuum and the residue was purified by preparative HPLC to provide 7-(2-hydroxyethoxy)-4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide as an off-white solid (16.5 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 11.39 (1H, s), 8.17 (1H, br. s.), 7.94 (1 H, d, J=7.9 Hz), 7.53-7.65 (3H, m), 7.49 (3H, t, J=7.8 Hz), 7.27-7.39 (2H, m), 6.99 (1H, d, J=7.7 Hz), 6.92 (1H, d, J=8.8 Hz), 6.59 (1H, dd, J=8.8, 2.4 Hz), 4.75-4.98 (3H, m), 3.95-4.07 (2H, m), 3.69-3.80 (2H, m), 2.44 (3H, s). Mass spectrum m/z 506.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]3[CH2:13][C:14]([CH3:19])([CH3:18])[CH2:15][C:16](=[O:17])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:20]([Mg]Cl)=[CH2:21].[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]3[CH2:13][C:14]([CH3:19])([CH3:18])[CH2:15][C:16]([CH:20]=[CH2:21])([OH:17])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)c2cc(-c3cccc(Br)c3)sc2C1
Reactant: C=C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC1(O)CC(C)(C)Cc2sc(-c3cccc(Br)c3)cc21
Temperature: -30 °C
Reaction time: 18 h
Yield: 118.4 %

Procedure:
2-(3-Bromophenyl)-6,6-dimethyl-6,7-dihydrobenzo[b]thiophen-4(5H)-one (0.36 g, 1.0 mmol) was dissolved in anhydrous THF (10 mL) and the solution was cooled to −30° C. under a nitrogen atmosphere. Vinyl magnesium chloride (2.8 mL, 1.6 M solution in THF, 5.4 mmol) was added to the ketone portion-wise whilst maintaining the temperature at −30° C. Upon completion of the addition, the reaction was allowed to warm to 25° C. and then stirred for 18 hr. Monitoring of the reaction by LC/MS indicated starting material was still present so further vinyl magnesium chloride (2.8 mL, 1.6 M solution in THF, 5.4 mmol) was added. After 2 hr the solution was treated with saturated aqueous ammonium chloride solution. The product was extracted into ethyl acetate (×3) and this was back extracted with water and saturated brine. The organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo to afford the title compound (0.43 g, quant.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18].[CH:19]1[CH:20]=[CH:21][N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[NH:25][CH2:24][C:23]=12.C(N(CC)C(C)C)(C)C>S(Cl)(Cl)=O.ClCCl>[CH:19]1[CH:20]=[CH:21][N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]([C:8]([C:6]3[CH:5]=[CH:4][C:3]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[O:17][CH3:18])=[C:2]([CH3:1])[CH:7]=3)=[O:10])[CH2:24][C:23]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
The (2-methyl-2′-methoxy-[1,1′-biphenyl]4-yl)carboxylic acid of Step B (0.50 g, 2.06 mmol) was suspended in thionyl chloride (3 mL) and the mixture heated at reflux for 30 minutes. After cooling, the thionyl chloride was removed in vacuo. The residue was dissolved in toluene and concentrated in vacuo to give the crude acid chloride as a brown oil. The acid chloride was then dissolved in dichloromethane (5 mL) and slowly added to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.57 g, 3.10 mmol) and N,N-diisopropylethyl amine (0.79 mL, 4.53 mmol) in dichloromethane (15 mL). After stirring for 1 hour, the reaction was quenched with water. The organic layer was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification by flash chromatography using a solvent gradient of 5 to 15% ethyl acetate in hexane yielded a white foam which crystallized upon sonication in ethanol/hexane to give 0.42 g of the desired title product as a white solid, m.p. 133–135° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1.[CH3:19][C:20]1[S:29][C:28]2[NH:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]=[C:23](N)[C:22]=2[CH:21]=1.CN1CCCC1=O>C(OCC)(=O)C.O>[CH3:19][C:20]1[S:29][C:28]2[NH:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]=[C:23]([N:17]3[CH2:16][CH2:15][NH:14][C@@H:13]([CH2:12][CH2:11][C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=4)[CH2:18]3)[C:22]=2[CH:21]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: c1ccc2cc(CC[C@H]3CNCCN3)ccc2c1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.2 %

Procedure:
Combine (S)-2-(2-naphthalen-2-yl-ethyl)-piperazine (854 mg, 3.72 mmol), 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (895 mg, 3.72 mmol) and 1-methyl-2-pyrrolidinone (8 mL). Heat at reflux. After 5 h, cool to ambient temperature and dilute with ethyl acetate and water. Extract with ethyl acetate. Wash the extracts with water and brine, dry over sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (2.5%) as the eluent to give 576 mg (34%) of the title compound: mass spectrum (ion spray): m/z=453 (M+1), 451 (M−1). HR-MS calculated for C28H29N4S: 453.2113. Found 453.2116. HPLC: Symmetry C18 column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile. Retention time 5.7 min; 100% pure.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](I)[CH3:23].[H-].[Na+].Cl>CN(C=O)C.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:22][CH3:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: COC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)OC)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To 82 mg (0.28 mmol) of 1-benzyloxycarbonyl-4-(methoxycarbonylamino)piperidine from Step A and 0.045 mL (0.56 mmol) of ethyl iodide in 4 mL of DMF under nitrogen was added 22 mg (0.56 mmol) of 60% sodium hydride in mineral oil. The reaction was stirred at rt for 1 h and was then poured into water containing 1 mL of 2 N hydrochloric acid and extracted twice with ether. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC eluting with 50% ethyl acetate in hexanes to afford 87 mg of title compound.
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24](Br)=[O:25].[NH2:27][CH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1>>[CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][N:9]1[CH2:23][C:24]([NH:27][CH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1)=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCc2ccccc21
Reactant: O=C(Br)CBr
Reactant: COc1cc2c(cc1OC)C(Cc1ccccc1)NCC2
Product: COc1cc2c(cc1OC)C(Cc1ccccc1)N(CC(=O)NC1CCc3ccccc31)CC2

Procedure:
prepared by reaction of 1-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and 2-bromoacetyl bromide with 1-amino-indane
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]1N2CN3CN(C2)CN1C3.[OH2:26]>C(O)(=O)C>[C:11]([C:7]1[CH:8]=[C:9]([CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])[CH:16]=[O:26])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O

Procedure:
2,6-di-tert-butylphenol was dissolved in glacial acetic acid. Subsequently, urotropin and water were added, and the reaction mixture heated at not more than 2° C. below the reflux temperature for 4 to 5 hours. The precipitated product was filtered off and washed with water and methanol, and dried on a rotary evaporator. The molar ratios of the reactants used and also the determined yields of 3,5-di-tert-butyl-4-hydroxybenzaldehyde, based on 2,6-di-tert-butylphenol, are shown in Table 4.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH:10][C:11](=[O:15])OCC)=[N:2]1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.O>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH:10][C:11]([N:26]2[CH2:25][CH2:24][N:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[F:16])[CH2:28][CH2:27]2)=[O:15])=[N:2]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1n[nH]c2ccccc12
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1n[nH]c2ccccc12)N1CCN(c2ccccc2F)CC1
Temperature: 100 °C
Yield: 54.2 %

Procedure:
Ethyl 1H-indazol-3-ylcarbamate (81 mg) and 1-(2-fluorophenyl)piperazine (Aldrich Co., 47 mg) were dissolved in dimethylformamide (2 ml), and the mixture was stirred with heating at 100° C. for 11 hr. After allowing to cool, water was added to the reaction mixture, and the precipitated solid was collected by filtration and dried to give 4-(2-fluorophenyl)-1-piperazinecarboxylic acid (1H-indazol-3-yl)amide (48 mg, yield 57%).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[N:7]=[C:8]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])[S:9][CH:10]=1)(=[O:5])[CH3:4]>C(O)(=O)C.O>[C:13]([NH:12][CH2:11][C:8]1[S:9][CH:10]=[C:6]([C:3](=[O:5])[CH2:4][Br:1])[N:7]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)NCc1nc(C(C)=O)cs1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)NCc1nc(C(=O)CBr)cs1
Temperature: 70 °C

Procedure:
Bromine (2.2 g) was added slowly to a solution of 4-acetyl-2-acetylaminomethylthiazole (2.2 g) in acetic acid (20 ml) and water (20 ml), and the mixture was heated at 70° C. for 4 hours. The solvent was removed under reduced pressure to give crude product of 2-acetylaminomethyl-4-bromoacetylthiazole. The above residue was dissolved in ethanol (50 ml). Diaminomethylenethiourea (1.3 g) was added to the solution and the mixture was refluxed for 4 hours. The solvent was removed under reduced pressure. The residue was dissolved in water and then the solution was alkalized with a saturated aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. The filtrate was extracted by ethyl acetate and then the solvent was removed under reduced pressure. The residue and the precipitate were chromatographed on an alumina column eluting with a mixture of chloroform and methanol (10:1). Recrystallization from water afforded 4-(2-acetylaminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole (430 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.CC(O)=O.C(O[C:37]1(O[Si](C)(C)C)[CH2:39][CH2:38]1)C.[NH4+].[Cl-]>CO>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH:37]4[CH2:39][CH2:38]4)[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C5CC5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To a solution of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (30 mg, 0.072 mmol) in MeOH (0.7 mL) was added AcOH (35 mg, 0.58 mmol), (1-ethoxycyclopropoxy)trimethylsilane (37 mg, 0.216 mmol) and a small amount of 4 Å molecular sieves. The mixture was stirred at room temperature for 1 h before the addition of Na(CN)BH3 (14 mg, 0.216 mmol). The resulting mixture was then stirred at 60° C. for 14 h and cooled to room temperature. Saturated aqueous NH4Cl (2 mL) was added and the mixture was extracted with EtOAc (3×3 mL). The combined organic layers were concentrated and purified by preparative RP-HPLC to provide 5-chloro-N2-(4-(1-cyclopropylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; 1H NMR (400 MHz, MeOD-d4) δ 7.97 (s, 1H), 7.84 (d, 1H), 7.50 (s, 1H), 6.93 (d, 1H), 6.29 (s, 1H), 5.33 (s, 1H), 2.80 (m, 1H), 2.58 (s, 2H), 2.28 (s, 3H), 2.24 (s, 3H), 1.96 (m, 1H), 1.80-1.85 (m, 2H), 1.65-1.75 (m, 2H), 0.2-0.7 (m, 6H); ESMS m/z 456.2 (M+H+).
Reaction SMILES: Cl.[C:2]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([NH:17][CH2:18][CH:19]([O:27][CH3:28])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[CH3:16])=[CH:10][CH:9]=1)(OC)=[O:3].[CH3:29][NH2:30].Cl>CO.[Cl-].[Na+]>[ClH:26].[CH3:29][NH:30][C:2]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([NH:17][CH2:18][CH:19]([O:27][CH3:28])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[CH3:16])=[CH:10][CH:9]=1)=[O:3]
Reactant: COC(=O)COc1ccc(CC(C)NCC(OC)c2cccc(Cl)c2)cc1
Reactant: CN
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CNC(=O)COc1ccc(CC(C)NCC(OC)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-methoxy-2-(3-chlorophenyl)ethanamine hydrochloride (0.63 g, diastereoisomeric ratio 92:8) in methanol was added 5 ml of a 30% aqueous solution of methylamine. This mixture was boiled under reflux for 6 hours during which time 3 further 5 ml portions of the methylamine solution were added. The solution was cooled to room temperature, a further 5 ml of methylamine solution added and the reaction mixture allowed to stand at room temperature overnight. After diluting with saturated sodium chloride solution the mixture was extracted with dichloromethane, washed with saturated sodium chloride solution, dried (magnesium sulphate), filtered and evaporated to give an oil which was converted to its hydrochloride salt by addition of ethereal hydrogen chloride. Recrystallisation from methanol-ethyl acetate gave the title compound, mp 217°-9° C., as single diastereoisomer.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[S:19][C:20]([CH:23]=O)=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:11]([CH3:25])=[CH:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:28]OS(O)(=O)=O>C(#N)C.O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[S:19][C:20]([C:23]#[N:28])=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:11]([CH3:25])=[CH:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(-c3ccc(C=O)s3)cc21
Reactant: NOS(=O)(=O)O
Solvent: O
Solvent: CC#N
Product: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(-c3ccc(C#N)s3)cc21
Temperature: 65 °C
Yield: 43.8 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-6-(5-formyl-2-thienyl)-1,2-dihydro-2,2,4-trimethylquinoline (12 mg, 0.03 mmol) in acetonitrile/water (10 ml/0.5 ml) was added hydroxylamine-O-sulphonic acid (5 mg, 0.04 mmol). The reaction mixture was heated to 65° C. for 1 h. The reaction was quenched with 10% NaOH (5 mL) and extracted with EtOAc (10 mL). The organic layer was washed with water and brine (3×5 mL each), dried (Na2SO4), and concentrated in vacuo to afford the crude product as a yellow oil. The crude product was purified by prep. TLC (20×20 cm, 250 μm, 25% EtOAc:hexane) to afford 5 mg (40%) of 1-tert-butyloxycarbonyl-6-(5-cyano-2-thienyl)-1,2-dihydro-2,2,4-trimethylquinoline as a yellow oil. This product was dissolved in CH2Cl2 (5 mL) and treated with TFA (0.1 ml) at rt with stirring. After 2 h, the reaction was quenched with 10% NaOH (5 mL). The organic layer was washed with water and brine (3×5 mL each), dried (Na2SO4) and concentrated in vacuo to afford the crude product as a yellow oil. The crude product was purified by prep. TLC (20×20 cm, 250 μm, 25% EtOAc:hexane) to afford 2 mg (60%) of Compound 451 as a yellow oil. Data for Compound 451: Rf 0.3 (silica gel, 25% EtOAc:Hex); 1H NMR (400 MHz, CDCl3) 7.52 (d, J=4.0, 1 H), 7.23 (s, 1 H), 7.22 (d, J=7.4, 1 H), 7.07 (d, J=4.0, 1 H), 6.43 (d, J=7.4, 1 H), 5.38 (s, 1 H), 2.02 (s, 3 H), 1.31 (s, 6 H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](Cl)=[O:43])=[CH:37][CH:36]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][C:42]([NH:21][C:18]2[C:17]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:43])=[CH:39][CH:40]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3cccs3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2cccs2)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 44.4 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(thiophen-2-yl)pyrazin-2-amine (7f) (600 mg, 1.59 mmol) and 4-(dimethylamino)pyridine (19.8 mg, 162 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 15 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1). The resulting solid was recrystallized (n-hexane/ethyl acetate) to give Compound 11f (446 mg, 706 μmol, 44.4%) as a colorless solid. Rf=0.26 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.18 (s, 6H), 0.23 (s, 6H), 0.94 (s, 9H), 0.97 (s, 9H), 3.65 (s, 2H), 0.678-6.86 (AA′BB′, 2H), 6.97-7.06 (m, 3H, includes AA′BB′), 7.19-7.27 (AA′BB′, 2H), 7.51 (dd, 1H, J=0.9, 3.7 Hz), 7.69 (dd, 1H, J=0.9, 5.0 Hz), 8.06-8.14 (AA′BB′, 2H), 8.93 (s, 1H), 10.60 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.6 (4C), 17.9, 18.0, 25.50 (3C), 25.54 (3C), 41.9, 119.6 (2C), 120.4 (2C), 127.8, 127.9, 128.0, 128.2 (2C), 128.4, 129.5, 130.5 (2C), 137.3, 140.5, 140.6, 142.5, 148.0, 153.9, 157.0, 170.3; IR (KBr, cm−1) 419, 519, 673, 704, 741, 781, 802, 839, 916, 1169, 1265, 1335, 1362, 1373, 1414, 1439, 1472, 1510, 1605, 1667, 2857, 2887, 2930, 2955, 3221; HRMS (ESI+) m/z 654.2617 ([M+Na]+, C34H45N3NaO3Si2+ requires 654.2612).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[N:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH:4](C(OC)=O)[C:3]1=[O:19]>CC(O)=O.O>[CH3:1][C:2]1([CH3:20])[C:3](=[O:19])[CH2:4][CH2:5][N:6]1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: COC(=O)C1CN(C(=O)c2ccccc2)C(C)(C)C1=O
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)C(=O)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A solution of methyl 5,5-dimethyl-4-oxo-1-(phenylcarbonyl)-3-pyrrolidinecarboxylate (2.5781 g, 9.364 mmol) in 10:1 HOAc-water (50 mL) was heated at 100° C. and stirred for 42 h. The solution was cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (200 mL) and washed with sat. aq. NaHCO3. The organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford crude 2,2-dimethyl-1-(phenylcarbonyl)-3-pyrrolidinone as a light yellow oil. LCMS: (M+H)+: 218.1.
Reaction SMILES: IC.[F:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([OH:14])=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.[C:15](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:14])[CH:9]=[CH:10][N:11]2[CH3:15])=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccnc2cc(F)ccc12
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Iodomethane (11.6 ml) was added to a stirred suspension of 7-fluoro-4-hydroxyquinoline (25 g) and anhydrous potassium carbonate (21.7 g) in dimethylformamide (120 ml) and stirring was continued for 15 hours at room temperature. Further quantities of iodomethane (5.8 ml) and anhydrous potassium carbonate (10.85 g) were added and the mixture stirred for a further 2.5 hours at 40°. The mixture was then cooled to room temperature and poured into water (750 ml). The solid product was collected and crystallised from water to give 7-fluoro-1-methyl-4-quinolone, m.p. 146°-149°.