Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:13][C:14]([F:27])([F:26])[S:15]([O:18]S(C(F)(F)F)(=O)=O)(=[O:17])=[O:16]>N1C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:18][S:15]([C:14]([F:27])([F:13])[F:26])(=[O:16])=[O:17])=[C:10]([C:14]([F:27])([F:26])[F:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(=O)N1CCc2ccccc21
Solvent: c1ccncc1
Product: CC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)c(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 173.8 %

Procedure:
To a solution of the acetylindoline (D11, 1.19 g, 4.9 mmol) in dry pyridine (10 ml) at 0° C. was added trifluoromethanesulphonic anhydride (1.52 g, 5.4 mmol). The mixture was then stirred overnight, while slowly warming to room temperature. The mixture was partially evaporated, the residual liquor was diluted well with water and the precipitate was filtered off. The crude product was dissolved in dichloromethane and the solution was washed with IN hydrochloric acid and brine, dried and evaporated to give the title compound (1.77 g, 96%).
Reaction SMILES: [CH2:1]([N:8]([CH3:30])[C:9](=[O:29])[C@@H:10]([N:18]([CH2:26][CH:27]=[O:28])[C:19]([O:21][C:22]([CH3:25])(C)[CH3:23])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[CH2:33](O)C>C(OCC)(=O)C>[CH2:1]([N:8]([CH3:30])[C:9](=[O:29])[C@@H:10]([N:18]([CH2:26][CH2:27][OH:28])[C:19]([O:21][CH:22]([CH2:25][CH3:33])[CH3:23])=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)N(CC=O)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCC(C)OC(=O)N(CCO)[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1
Reaction time: 16 h

Procedure:
Combine (S)-N-benzyl-N-methyl-2-[N-(t-butoxycarbonyl)-2-oxo-ethylamino]-3-phenyl-propionamide (5.0 mmol) and sodium borohydride (5.0 mmol) in ethanol (20 mL). Stir for 16 hours. Concentrate in vacuo to obtain a residue. Dilute the residue with ethyl acetate and extract with 0.5M hydrochloric acid solution and water. Separate the layers, dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11]C=O)=[CH:7][N:6]=1)=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:26]([O:31][CH3:32])([O:29][CH3:30])OC>CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11][CH:26]([O:29][CH3:30])[O:31][CH3:32])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(OC)OC
Reactant: COC(=O)c1cnc(CC=O)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)c1cnc(CC(OC)OC)cn1
Yield: 78.5 %

Procedure:
A mixture of 5-(2-oxo-ethyl)-pyrazine-2-carboxylic acid methyl ester (prepared as in Example 42, 330 mg, 1.83 mmol), p-toluenesulfonic acid monohydrate (35 mg, 0.184 mmol), trimethyl orthoformate (3 mL, 137 mmol), and methanol (10 mL) was heated under reflux for 90 min. The mixture was concentrated in vacuo to dryness, and the residue was further concentrated in vacuo to dryness from toluene (10 mL). The resulting residue was shaken with methylene chloride (25 mL) and a saturated aqueous sodium bicarbonate solution (10 mL). The aqueous phase was back-extracted with methylene chloride (10 mL). Each extract was washed with a saturated aqueous sodium chloride solution (5 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 5-(2,2-dimethoxy-ethyl)-pyrazine-2-carboxylic acid methyl ester (325 mg, 78%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([OH:25])[C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:26](OC(=N)C(Cl)(Cl)Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl.C(S(O)(=O)=O)(F)(F)F.[Cl-].[Na+].O>[CH2:26]([O:25][CH:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[N:9]=[CH:10]2)[C:18]([CH3:23])([CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)C(C)(C)C(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(C)(C)C(OCc1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 2 h
Yield: 14.7 %

Procedure:
Methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-hydroxy-2,2-dimethylpropanoate (282 mg, 0.82 mmol) was dissolved in 10 mL DCM and benzyl-2,2,2-trichloroacetimidate (0.185 mL, 1.0 mmol) was added followed by 3 drops of CF3SO3H. The reaction was stirred for 2 h. Reaction was incomplete so added more benzyl-2,2,2-trichloroacetimidate (0.185 mL, 1.0 mmol). After 12 h, diluted with brine and extracted with DCM×3. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by SiO2 chromatography eluting with EtOAc/hexane gradient. Obtained 52 mg (15% yield) of methyl 3-(benzyloxy)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoate. MS found: (M+H)+=433.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][O:15][CH2:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][O:26][CH3:27])[CH:21]=[CH:20][C:19]=1[CH:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1.O>COCCOC.C(OCC)C>[CH3:14][O:15][CH2:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][O:26][CH3:27])[CH:21]=[CH:20][C:19]=1[CH:28]1[CH2:33][CH2:32][C:31](=[CH:5][C:3]#[N:4])[CH2:30][CH2:29]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COCOc1ccc(C2CCC(=O)CC2)c(OCOC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOCC
Product: COCOc1ccc(C2CCC(=CC#N)CC2)c(OCOC)c1
Temperature: 0 °C
Reaction time: 17 h
Yield: 65.3 %

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added sodium hydride (40 mg, 0.95 mmol, 60% dispersion in mineral oil). After washing the sodium hydride with petroleum ether (2×20 ml), the excess solvent was removed under reduced pressure. 1,2-Dimethoxyethane (10 ml) was added and the stirred suspension cooled to 0° C. Diethyl cyanomethylphosphonate (102 μl, 0.95 mmol) was added dropwise. The reaction mixture was allowed to warm slowly to room temperature over 2 hr. 4-[(2,4-Bis(methoxymethoxy)phenyl)]cyclohexanone (200 mg, 0.68 mmol) was then added as a solution in 1,2-dimethoxyethane (10 ml) and the reaction mixture stirred for 17 hr at room temperature. The reaction mixture was poured into a separating funnel containing water (50 ml) and diethyl ether (50 ml). The layers were separated and the aqueous phase extracted with diethyl ether (2×20 ml). The combined organic layers were washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo, to give an oil. Purification via flash column chromatography (SiO2, ethyl acetate/petroleum ether, 1:2, v/v) afforded the title compound (141 mg, 66%) as a pale yellow oil. δH(CD3OD) 1.57-1.70 (2H, m), 2.02-2.25 (2H, m), 2.34-2.49 (2H, m), 2.60 (1H, m), 3.03 (1H, m), 3.24 (1H, m), 3.47 (3H, s), 3.52 (3H, s), 5.17 (2H, s), 5.23(2H, s), 5.33 (1H, s), 6.66 and 6.69 (1H, d), 6.83 (1H, d), 7.09 (1H, d
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:21][C:11]3=[N:12][C:13]4[C:18]([C:19](=[O:20])[N:10]3[C:8]=2[CH:9]=1)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH3:2].[Cl:22][C:23]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>>[Cl:22][C:23]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:24]=1[C:25]([N:21]1[C:11]2=[N:12][C:13]3[C:18]([C:19](=[O:20])[N:10]2[C:8]2[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=[CH:6][C:7]1=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:26]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCOc1ccc2[nH]c3nc4ccccc4c(=O)n3c2c1
Product: CCOc1ccc2c(c1)n1c(=O)c3ccccc3nc1n2C(=O)c1ccc(Cl)cc1Cl

Procedure:
6-(2,4-Dichlorobenzoyl)-9-ethoxybenzimidazo[2,1-b]-quinazolin-12(6H)one is prepared with 9-ethoxybenzimidazo[2,1-b]-quinazolin-12(6H)one and 2,4-dichlorobenzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([CH:8](O)[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]C(Br)(Br)C(C(Br)(Br)Br)=O>C(Cl)Cl>[Br:33][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:13])[CH2:9][CH2:10][CH3:11]
Reactant: CCCC(O)c1cccc(Cl)c1F
Reactant: O=C(C(Br)(Br)Br)C(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCC(Br)c1cccc(Cl)c1F
Reaction time: 0.25 h
Yield: 164.6 %

Procedure:
To a solution of 1-(3-chloro-2-fluorophenyl)butan-1-ol (CAS [1340262-68-1], 1.42 g, 7 mmol) in methylene chloride (35 mL) at RT was added triphenylphosphine (2.76 g, 10.5 mmol). After stirring for 15 min, 1,1,1,3,3,3-hexabromoacetone (1.86 g, 3.5 mmol) was added and stirred for 16 h. The reaction mixture was concentrated and the residue was purified by MPLC (100% hexanes) to yield 1.53 g of 1-(1-bromobutyl)-3-chloro-2-fluorobenzene as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:11][C:12]([CH:15]=[CH:16][CH2:17][CH2:18][CH3:19])=[CH:13][CH:14]=2)=[C:6]([F:20])[C:5]=1[F:21])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:13][CH:14]=2)=[C:6]([F:20])[C:5]=1[F:21])[CH3:2]
Reactant: CCCC=Cc1ccc(-c2ccc(OCC)c(F)c2F)[se]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCc1ccc(-c2ccc(OCC)c(F)c2F)[se]1

Procedure:
2.30 g (6.22 mmol) of 2-(4-ethoxy-2,3-difluorophenyl)-5-pent-1-enylselenophene are hydrogenated in 25 ml of ethyl acetate, in the presence of Pd/C (5% of Pd) at atmospheric pressure and RT. The reaction soln. is filtered and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane:EtOAc=5:1→2:1). The further purification is carried out by recrystallisation from n-heptane. 2-(4-Ethoxy-2,3-difluorophenyl)-5-pentylselenophene is obtained as a colourless solid (m.p. 66° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[CH2:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Li+].CC([N-]C(C)C)C.[CH3:21][O:22][CH2:23][CH2:24]Br.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O>[CH2:1]([O:3][C:4]([C:6]1([CH2:24][CH2:23][O:22][CH3:21])[CH2:11][CH2:10][C:9](=[CH2:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=C1CCC(C(=O)OCC)CC1
Reactant: COCCBr
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCC(CCOC)(C(=O)OCC)CC1
Reaction time: 3 h

Procedure:
A solution of 5 g (30 mmol) 4-methylene-cyclohexanecarboxylic acid ethyl ester (commercially available) in 19 mL THF was added to 59 mmol LDA in 75 mL THF at −5° C. and stirred for 3 h. 8.2 g (59 mmol) 2-bromoethyl methyl ether in 10 mL THF was added and the mixture was allowed to stir to room temperature and stirred additionally over night. Water and 2M Na2CO3 aq. was added and the mixture was evaporated to dryness. The residue was taken up in ethyl acetate washed with water and brine, dried with MgSO4, filtered and evaporated. The residue was purified by flash column chromatography over silica eluting with a gradient formed from hexane and ethyl acetate to yield after evaporation of the product containing fractions 4.98 g (74%) of the title compound as yellow liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.[Cu](I)I>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([O-:3])=[O:2]
Reactant: Brc1ccccn1
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1Nc1ccccn1
Temperature: 160 °C
Yield: 26.9 %

Procedure:
Under the atmosphere of nitrogen gas, 15.0 g (109 mmol) of 2-nitroaniline, 17.2 g (109 mmol) of 2-bromopyridine, 2.06 g (10.9 mmol) of copper iodide and 30 g (218 mmol) of potassium carbonate were stirred with heating at the temperature of 160° C. for 9 hours. The reacted solution was cooled down to room temperature, diluted with ethyl acetate and filtered. After concentrating the filtrate, it was refined with silicagel column chromatography, and 6.30 g of 2-nitro-N-pyridyl aniline was obtained (yield: 27%).
Reaction SMILES: [CH3:1][CH:2]([C:14](=O)[CH3:15])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>C(OCC)C>[CH2:6]([NH:5][C:3](=[O:4])[C:2]([CH3:1])=[C:14]([NH2:17])[CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)C(C)C(=O)NCCc1ccccc1
Reactant: N
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CC(N)=C(C)C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of 2-methyl-3-oxo-N-phenethyl-butyramide of Example 1d (1.10 g, 5.00 mmol) in diethyl ether (300 mL) was saturated with gaseous ammonia for 3 h while cooled in an ice bath. Anhydrous aluminum chloride (99.99% purity, 0.667 g, 5.00 mmol) was then added in small portions and the reaction was allowed to stir at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure to give 3-amino-2-methyl-but-2-enoic acid phenethyl-amide (0.97 g, 85% conversion by NMR) as a white solid which was used without purification for the next synthetic step.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11]3[C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:14]=4[N:13]([CH3:20])[C:12]=3[C:21]([OH:23])=O)=[C:6]([F:24])[CH:5]=2)[CH2:3][CH2:2]1.[CH:25]([O:27][CH2:28][CH2:29][O:30][NH2:31])=[CH2:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[CH:25]([O:27][CH2:28][CH2:29][O:30][NH:31][C:21]([C:12]1[N:13]([CH3:20])[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[C:11]=1[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][C:6]=1[F:24])=[O:23])=[CH2:26]
Reactant: Cn1c(C(=O)O)c(Nc2ccc(C3CC3)cc2F)c2cnccc21
Reactant: C=COCCON
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)c1c(Nc2ccc(C3CC3)cc2F)c2cnccc2n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.1 %

Procedure:
A suspension of 3-(4-cyclopropyl-2-fluoro-phenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (88 mg, 0.25 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (028 mg, 0.28 mmol), HATU (114 mg, 0.30 mmol) and DIPEA (0.052 ml, 0.30 mmol) in THF (3 ml) was stirred at ambient temperature for 18 hours. On completion of the reaction, the mixture was concentrated in vacuo then re-dissolved in DCM. The solution was washed with saturated aqueous NaHCO3 and brine, dried over magnesium sulphate then concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM:MeOH, gradient 99:1 to 90:10) to give a yellow solid (34 mg, 33%). LCMS (method B): RT=2.46 min, M+H+=411. 1H NMR (CDCl3): 8.58 (1H, s), 8.41-8.36 (1H, m), 7.30 (1H, d, J=6.08 Hz), 7.26 (1H, d, J=1.99 Hz), 6.87 (1H, dd, J=8.33, 2.02 Hz), 6.47 (1H, dd, J=8.34, 3.82 Hz), 5.85 (1H, s), 4.11 (3H, s), 3.97-3.90 (2H, m), 3.71 (2H, dd, J=5.23, 3.41 Hz), 2.78 (1H, m), 1.22-1.13 (6H, m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[F:18].[C:19]([Si:23](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:22])([CH3:21])[CH3:20].N1C=CN=C1.O>CN(C=O)C>[Si:23]([O:9][CH2:8][C:6]1[N:7]=[C:2]([Cl:1])[C:3]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[F:18])=[CH:4][CH:5]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2Cl)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc2Cl)c1
Reaction time: 14 h
Yield: 252 %

Procedure:
To a solution of (6-chloro-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol (3.00 g) and tert-butylchlorodiphenylsilane (1.53 g) in DMF (7.0 mL) was added imidazole (1.53 g) at room temperature, and the mixture was stirred for 14 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (7.10 g) as a pale-yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH3:1][Mg]Br.[NH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13](=[O:15])[CH3:14])=[C:7]([O:16][CH3:17])[CH:6]=1.[Cl-].[NH4+]>O1CCCC1.O>[NH2:4][C:5]1[CH:6]=[C:7]([O:16][CH3:17])[C:8]([C:13]([OH:15])([CH3:1])[CH3:14])=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: C[Mg]Br
Reactant: COc1cc(N)cc(OC)c1C(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N)cc(OC)c1C(C)(C)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.2 %

Procedure:
To a solution of methyl magnesium bromide (3M in ether, 16.8 mL, 50.5 mmol) in anhydrous tetrahydrofuran (20 mL), cooled in an ice bath, was added 1-(4-amino-2,6-dimethoxy-phenyl)-ethanone (2.19 g, 11.2 mmol-dissolved in 65 mL anhydrous tetrahydrofuran), maintaining the reaction temperature below 10° C. After stirring 4 hours at room temperature, 10% ammonium chloride (20 mL) was added, maintaining the temperature of the reaction below 20° C. (with the use of an ice bath) during the addition. The mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried using anhydrous sodium sulfate, filtered and concentrated to yield 2-(4-Amino-2,6-dimethoxy-phenyl)-propan-2-ol (2.23 g, 94%) as a pale yellow solid.
Reaction SMILES: C(O[C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])CCC.[C:18]([C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[CH2:23][NH2:24])#[N:19]>O1CCCC1>[CH3:15][C:11]([NH:10][C:9]1[C:8](=[O:16])[C:7](=[O:17])[C:6]=1[NH:24][CH2:23][C:22]1[CH:21]=[C:20]([CH:27]=[C:26]([CH3:28])[CH:25]=1)[C:18]#[N:19])([CH3:14])[CH2:12][CH3:13]
Reactant: Cc1cc(C#N)cc(CN)c1
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Solvent: C1CCOC1
Product: CCC(C)(C)Nc1c(NCc2cc(C)cc(C#N)c2)c(=O)c1=O
Reaction time: 48 h
Yield: 67 %

Procedure:
A solution of 3-butoxy-4-(1,1-dimethyl-propylamino)cyclobut-3-ene-1,2-dione (1.44 g, 6.0 mmol, Example 3) and 3-cyano-5-methylbenzylamine from Example 7, Step 3 (6.0 mmol) and tetrahydrofuran (15 mL) were stirred at room temperature for approximately 20 hours. An additional 7 mL of tetrahydrofuran were added and stirring continued for an additional 48 hours. The solvent was removed and the residue was recrystallized twice from methanol to provide 1.251 g (67%) of the title compound as a white solid: mp 231°-133° C. (softens 229° C.); 1H NMR (DMSO-d6) δ7.78 (m, 1H), 7.62 (m, 2H), 7.51 (s, 1H), 7.41 (s, br, 1H), 4.74 (d, 2H), 2.35 (s, 3H), 1.67 (m, 2H), 1.30 (s, 6H), 0.82 (m, 3H) ppm. IR (KBr): 3290, 2240, 1780, 1670 cm-1 ; MS (m/z) 311 (M+). HPLC indicates a major component (99.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][C:12]([OH:14])=O)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:35])[CH:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[CH:28][CH:29]=2)[CH2:24]1>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][C:12]([NH:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:35])[CH:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[CH:28][CH:29]=3)[CH2:24]2)=[O:14])=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1
Reactant: COc1cc(CC(=O)O)c([N+](=O)[O-])cc1OC
Reactant: COc1ccc2c(c1)CC(N(C)CCCN)CC2
Product: COc1ccc2c(c1)CC(N(C)CCCNC(=O)Cc1cc(OC)c(OC)cc1[N+](=O)[O-])CC2

Procedure:
The title compound here is prepared from 4,5-dimethoxy-2-nitrophenylacetic acid (5.25 g, 0.0217 mol) and 1-amino-3-[N-methyl-N-(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-propane (5.4 g, 0.0217 mol) analogously to Example R(c). Yield: 8.2 g Mp: 116°-118° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2.[CH3:14]C(C)([O-])C.[K+].CI.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[N:8]([CH3:14])[C:7](=[O:13])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)cc(Cl)c2N1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)CCc2cc(Br)cc(Cl)c21
Reaction time: 12 h
Yield: 44.7 %

Procedure:
A solution of 6-bromo-8-chloro-3,4-dihydro-1H-quinolin-2-one (7.0 g, 26.9 mmol) in DMF (100 mL) was treated with potassium tert-butoxide (6.0 g, 53.8 mmol) at 0° C. portionwise. The resulting mixture was stirred at 0° C. for 30 minutes before methyl iodide (5.0 g, 35.0 mmol) was added. After stirred for 12 hours, the reaction mixture was treated with water, extracted with EtOAc, washed with water and brine in sequence, and dried over anhydrous Na2SO4. After removal of solvent under reduced pressure, the crude product (3.3 g, 45%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:25]([F:28])([F:27])[F:26])[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:21][CH2:22]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:25]([F:28])([F:27])[F:26])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-c4ccccc4)C(F)(F)F)nc(N)n3)CC2)CN1
Agent: [Li+]
Agent: [OH-]
Product: Nc1nc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1

Procedure:
Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as an off-white solid as the zwitterionic form.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:12][CH2:13][CH:14]([OH:21])[CH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])=[O:11])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([NH:12][CH2:13][C:14](=[O:21])[CH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])=[O:11])=[CH:6][CH:7]=1
Reactant: CCC(C)(C)CC(O)CNC(=O)CCc1ccc(Br)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCC(C)(C)CC(=O)CNC(=O)CCc1ccc(Br)cc1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-(4-bromophenyl)-N-(2-hydroxy-4,4-dimethylhexyl)propionamide (71.9 g, 202 mmol) in methylene chloride (1 L) was added Dess-Martin periodinane (100 g, 226 mmol). After 1.5 h, saturated sodium bicarbonate (500 mL) and saturated sodium thiosulfate (500 mL) were added and the mixture was stirred for another 10 minutes. The organic layer was separated and treated with another batch of saturated sodium bicarbonate (500 mL) and saturated sodium thiosulfate (500 mL). The organic layer was separated, dried over sodium sulfate, and concentrated to provide 3-(4-bromophenyl)-N-(4,4-dimethyl-2-oxohexyl)propionamide, which was used without further purification.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH2:11][CH2:10]2)(=O)C.[OH-].[Na+]>Cl>[NH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH2:11][CH2:10]2
Reactant: CC(=O)Nc1cccc2c1NC(=O)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc2c1NC(=O)CC2
Temperature: 0 °C
Yield: 0.1 %

Procedure:
8-Acetylamino-3,4-dihydrocarbostyril (11.8 g, 57.8 mols) was suspended in 90 ml of 20% hydrochloric acid and the suspension was stirred while heating under reflux for 1 hours. The reaction mixture was poured into ice water and neutralized with 5 N sodium hydroxide followed by adjusting to pH of about 8. Crystals which precipitated were collected by filtration to give 7.87 g of 8-amino-3,4-dihydrocarbostyril.