Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:34]=[CH:33][C:29]([C:30]([O-:32])=[O:31])=[C:28]([O:35][CH3:36])[CH:27]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[C:28]([O:35][CH3:36])[CH:27]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCC(NC(=O)c4ccc(C(=O)[O-])c(OC)c4)C3)nc3scnc23)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Nc2nc(N3CCC(NC(=O)c4ccc(C(=O)O)c(OC)c4)C3)nc3scnc23)cc1OC
Reaction time: 16 h
Yield: 38.9 %

Procedure:
To a stirred solution of 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)-2-methoxybenzoate (80 mg, 0.14 mmol) in 5 mL of THF and 5 mL of methanol was added a solution of 1N NaOH (5 mL) at room temperature. After the addition, the reaction was stirred at this temperature for 16 hours. The solvent was evaporated and the residue was diluted with water and adjusted to pH=2 by HCl (aq.). The suspension was filtered and dried. The crude was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 20% acetonitrile/80% water (0.1% TFA V/V) initially, and then proceed to 55% acetonitrile/45% water (0.1% TFA V/V) in a linear fashion after just 9 min) to give 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)-2-methoxybenzoic acid (30 mg, 39%) as white solid. 1H NMR (300 MHz, DMSO): δ 9.66 (s, 1H), 8.83 (s, 1H), 8.74-8.72 (m, 1H), 7.88 (brs, 1H), 7.66 (d, 1H, J=7.8 Hz), 7.50-7.46 (m, 3H), 6.91 (d, 1H, J=8.7 Hz), 4.59 (brs, 1H), 3.87 (s, 4H), 3.76-3.72 (m, 8H), 2.27 (brs, 1H), 2.09 (brs, 1H). LC-MS: 550.8 [M+H]+, tR=1.38 min. HPLC: 98.09% at 214 nm, 96.40% at 254 nm, tR=4.64 min.
Reaction SMILES: [Br:1][C:2]1[N:3](COC)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.Cl>CO>[Br:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: COCn1cc([N+](=O)[O-])nc1Br
Agent: Cl
Solvent: CO
Product: O=[N+]([O-])c1c[nH]c(Br)n1
Reaction time: 1 h
Yield: 66 %

Procedure:
Solution of 2-bromo-1-methoxymethyl-4-nitroimidazole (11.17 g), methanol (10 ml) and 5N hydrochloric acid (60 ml) was stirred under refluxing condition for 2.5 hours. After being let to stand the reaction mixture at a room temperature for 24 hours, the mixture was stirred for 1 hour under ice-cooling condition, the precipitated crystals were collected by filtration, and dried at 50° C. under a reduced pressure for 24 hours, there was obtained 2-bromo-4-nitroimidazole (6.0 g, yield: 66.0%) of white powdery product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:19])CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([F:19])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Br)cc2)CCC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC1(c2ccc(Br)cc2)CCC1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 64.1 %

Procedure:
To a solution of 5.66 g of 1-(4-bromophenyl)-cyclobutanol (24.92 mmol, described in example S2-A) in 70 ml DCM were added 4.23 g of (diethylamino)sulfur trifluoride (95%, 24.92 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 35 min, then sat. NaHCO3-solution was added and the resulting mixture was extracted with DCM. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give a residue which was purified by flash column chromatography (100% pentane) to give 1-bromo-4-(1-fluoro-cyclobutyl)-benzene (3.66 g, 64%) as a colourless liquid.
Reaction SMILES: [C:1]([Si:8]([CH3:16])([CH3:15])[O:9][Si:10]([CH3:14])([CH3:13])[CH:11]=[CH2:12])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C=C[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:1]([Si:8]([CH3:15])([CH3:16])[O:9][Si:10]([CH3:13])([CH3:14])/[CH:11]=[CH:12]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C=C[Si](C)(C)O[Si](C)(C)C#CCCCCC
Reactant: C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCC#C[Si](C)(C)O[Si](C)(C)/C=C/c1ccccc1

Procedure:
As in reaction conditions of Example XIX Step 2, to 2.48 mL of toluene, the 0.013 g carbonylchlorohydridebis(tricyclohexylphosphine)ruthenium(II) was added, and the reaction was carried out between the 1-(1-heptynyl)-1,1,3,3-tetramethyl-3-vinyldisiloxane obtained in Step 1 and 0.56 g styrene. Product was separated under the purification conditions of Example XII. The product, 1-(1-heptynyl)-1,1,3,3-tetramethyl-3-[(E)-styryl]disiloxane was obtained with a total yield of 85% pure product in the form of an oily liquid, light yellow in color.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:20].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C)C=O>[C:2]([CH:3]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])([OH:20])=[O:1]
Reactant: COC(=O)CCCC=CC1C2CCC(C2)C1CO
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCC=CC1C2CCC(C2)C1C(=O)O
Temperature: 20 °C
Reaction time: 9 h
Yield: 65 %

Procedure:
A solution of 25.0 g (0.1 mole) of methyl 6-(3-hydroxymethyl-bicyclo[2.2.1]hept-2-yl)-hex-5-enoate in 60 ml of absolute dimethylformamide is added to 132.0 g (0.35 mole) of pyridinium dichromate in 200 ml of absolute dimethylformamide at 20° C. The reaction mixture is stirred at 20° C. for 9 hours, left to stand for 14 hours and then poured into 1.9 liters of water and extracted with diethyl ether. After drying over Na2SO4, the mixture is evaporated in vacuo and the residue is chromatographed on silica gel, using methylene chloride/methanol (95:5) to give 17.3 g of methyl 6-(3-carboxy-bicyclo-[2.2.1]hept-2-yl)-hex-5-enoate (yield: 65%)
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:14][CH2:15]Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[C:17]([NH:25][CH:26]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:27][P:28]([CH2:31][C:32]([N:34]1[CH2:48][CH2:47][CH2:46][C@H:35]1[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])=[O:33])([OH:30])=[O:29])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.C(OCC)(=O)C>[C:17]([NH:25][CH:26]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:27][P:28]([CH2:31][C:32]([N:34]1[CH2:48][CH2:47][CH2:46][C@H:35]1[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:37])=[O:33])([O:30][CH2:15][O:14][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:29])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(NC(Cc1ccccc1)CP(=O)(O)CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCOP(=O)(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)CC(Cc1ccccc1)NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
An equimolar mixture of triethylamine and chloromethyl pivalate are added to a solution of (S)-1-[[[2-(benzoylamino)-3-phenylpropyl]hydroxyphosphinyl]acetyl]-L-proline, phenylmethyl ester, prepared, for example, as set forth in Example 1(g), in dimethylformamide under argon. The mixture is stirred for several hours at room temperature, diluted with ethyl acetate, washed with water, brine, dried (MgSO4), and evaporated. Thecrude product is chromatographed to give (S)-1-[[[2-(benzoylamino)-3-phenylpropyl][(2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]acetyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:12][C:11]([C:13](O)=[O:14])=[C:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:21]=[N+:22]=[N-:23].[Na+]>CC(C)=O.O.C(N(CC)CC)C.ClC(OCC)=O>[C:1]([O:5][C:6]([C:8]1[S:12][C:11]([C:13]([N:21]=[N+:22]=[N-:23])=[O:14])=[C:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)c1cc(OC(C)(C)C)c(C(=O)O)s1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)c1cc(OC(C)(C)C)c(C(=O)N=[N+]=[N-])s1
Reaction time: 0.25 h
Yield: 99882.2 %

Procedure:
A solution of tert-butyl-2-carboxy-3-tert-butoxy-5-thiophenecarboxylate (3 g, 0.01 mmol) in dry acetone (100 ml) was treated, at 0° C., with triethylamine (1.7 ml, 0.012 mmol) added dropwise. The mixture was stirred for 15 minutes and ethyl chloroformate (1.25 ml, 0.013 mmol) added dropwise, at 0° C. After 30 minutes, sodium azide (1.1 g, 0.017 mmol) in water (5 ml) was slowly added, at 0° C. After 4 hours, stirring at ambient temperature, the reaction mixture was filtered and the solvent evaporated. The oily residue was dissolved in CH2Cl2, and the solution washed (2×) with water, dried over MgSO4 and the solvent evaporated to give title compound (3.25 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:28])=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:16]([O:23][CH2:24][C:25](O)=[O:26])=[CH:15][CH:14]=2)[N:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][C:2]1[NH:3][C:4]([CH3:28])=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:16]([O:23][CH2:24][CH2:25][OH:26])=[CH:15][CH:14]=2)[N:8]=1
Reactant: Cc1cc(-c2cccc(-c3ccc(OCC(=O)O)c4c3CCCC4)n2)c(C)[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(-c3ccc(OCCO)c4c3CCCC4)n2)c(C)[nH]1

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and nitrogen (N2) inlet were added 100 mg (0.27 mmol) 2-(2,5-dimethylpyrrolyl)-6-[4-carboxymethoxy-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridine (from Example 1), 20 mL dry tetrahydrofuran, and 0.6 mL (0.53 mmol) of a 1 M solution of lithium aluminum hydride in tetrahydrofuran. The reaction was refluxed 16 hour, cooled, and quenched with 1 N hydrochloric acid. The mixture was adjusted to pH 10 with 1 N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue of 118 mg (100%), an oil, was used directly in the following step. 1H-NMR (δ, CDCl3): 1.69 (m, 2H), 1.78 (m, 2H), 2.16 (s, 6H), 2.7-2.9 (m, 4H), 3.95 (m, 2H), 4.08 (m, 2H), 5.885 (s, 2H), 6.73 (d, J=8, 1H), 7.13 (d, J=8, 1H), 7.20 (d, J=8, 1H), 7.35 (d, J=8, 1H), 7.83 (t, J=8, 1H); MS (%): 363 (parent+1, 100).
Reaction SMILES: [C:1]([O:4][C@H:5]([C:7]#[C:8]/[CH:9]=C/C1C=CC=CC=1)[CH3:6])(=[O:3])[CH3:2].[O:17]=[O+][O-].CSC>CO>[C:1]([O:4][C@H:5]([C:7]#[C:8][CH:9]=[O:17])[CH3:6])(=[O:3])[CH3:2]
Reactant: O=[O+][O-]
Reactant: CC(=O)O[C@@H](C)C#C/C=C/c1ccccc1
Solvent: CSC
Solvent: CO
Product: CC(=O)O[C@@H](C)C#CC=O
Temperature: 23 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of 8 (392 mg, 1.83 mmol) in methanol (4.6 mL) was treated with O3 for 3 min at −78° C. After removing excess O3, the reaction was quenched by slow addition of methylsulfide (1.35 mL, 18.3 mmol) at −78° C. The resulting mixture was stirred for 1 h at −78° C. and for 1 h at 23° C., and then concentrated in vacuo. Purification of the residue via flash chromatography (silica gel 16 mL; 5→15% EtOAc in hexanes) afforded aldehyde 9 (208 mg, 81%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:5]1[N:4]=[N:3][C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(Cl)nn1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccccc2)nn1
Yield: 74 %

Procedure:
A mixture of 3-chloro-6-methoxy-pyridazine (4.0 g, 27.7 mmol) and phenyl boronic acid (5.1 g, 41.6 mmol) in toluene (160 mL) was degassed and tetrakis(triphenylphosphine)palladium (960 mg, 0.83 mmol) and 2M sodium carbonate (29.3 mL, 58.7 mmol) were added. The mixture was heated to reflux under nitrogen for 6 h, then cooled and the organic phase washed with 2M NaOH (75 mL), dried over magnesium sulphate and solvent removed under reduced pressure to give a solid which was subjected to column chromatography (n-Hex/EtOAc 9:1 to 1:1) to afford the title compound (74% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4].[H-].[Na+].Br[CH2:29][C:30]1[CH:34]=[C:33]([C:35]2[S:36][C:37]([Cl:40])=[CH:38][CH:39]=2)[O:32][N:31]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:17]3)[N:11]([CH2:29][C:30]3[CH:34]=[C:33]([C:35]4[S:36][C:37]([Cl:40])=[CH:38][CH:39]=4)[O:32][N:31]=3)[C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: COC(=O)c1cnc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2c(c1)cc(C(=O)NC1CCN(C(C)C)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
To a solution of 1.2 g 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester in 20 mL DMF, 91 mg sodium hydride (95%) were added at 0° C. Then the reaction mixture was warmed to RT and stirred for 30 min. After cooling again to 0° C., 967 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] were added and the mixture was stirred for 2 h at RT. Then 50 mL of water were added and the precipitate was collected by filtration to yield 630 mg pure product. The filtrate was concentrated under reduced pressure and the residue purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization further 371 mg of product were obtained as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.BrN1C(=O)CCC1=O.C(OB(OCC)OCC)C.B(O)O.Cl[C:33]1[CH:38]=[CH:37][N:36]=[C:35]([NH:39][CH:40]2[CH2:45][C:44]([CH3:47])([CH3:46])[NH:43][C:42]([CH3:49])([CH3:48])[CH2:41]2)[N:34]=1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:37]2[CH:38]=[CH:33][N:34]=[C:35]([NH:39][CH:40]3[CH2:45][C:44]([CH3:47])([CH3:46])[NH:43][C:42]([CH3:49])([CH3:48])[CH2:41]3)[N:36]=2)=[CH:3]1
Reactant: Cn1ccc2ccccc21
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOB(OCC)OCC
Agent: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)c2ccccc21
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 1-Methyl-indole (1.00 g, 3.81 mmol) in 30 ml of THF was added 1-bromo-pyrrolidine-2,5-dione (1.36 g, 3.81 mmol) and the mixture was stirred for 2 hours. The reaction mixture was poured into 200 ml of hexanes and purified by filtration over a short plug of silicagel (Ether/hexanes:1/1). The solution was concentrated close to dryness, redissolved in 25 ml of THF and cooled to −78° C. Tert.-butyllithium (5.08 ml of a 1.5M solution in pentane, 7.62 mmol) was added dropwise and stirred for 15 minutes. Then, triethylborate (0.65 ml, 3.81 mmol) was added in one portion and stirring was continued for 2 hours. The reaction was quenched with 3.5 ml of MeOH and 10 ml of water. The mixture was given into EtOAc and the aqueous layer was extracted with EtOAc. The combined organic phases were dried over sodium sulfate and evaporated to give a green suspension, which was used without further purification. The title compound was prepared analogous to Step C of Method C, starting from this crude boronic acid and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine using bis(triphenylphosphine)palladium(II) dichloride as a catalyst. Yield: 327 mg (48%).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][C:6]([OH:18])([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:7][CH2:8][CH3:9])C.[OH-].[Na+]>CO>[OH:18][C:6]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:19])=[O:3]
Reactant: CCCC(O)(CCc1ccccc1)CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(O)(CCc1ccccc1)CC(=O)O
Reaction time: 8 h

Procedure:
Ethyl-3-hydroxy-3-(2-phenylethyl)hexanoate (II, EXAMPLE 1, 200 mmol) is dissolved in methanol (423 ml) and 2M sodium hydroxide (150 ml, 300 mmol) is added. The reaction mixture is stirred at 20-25° overnight. Methanol is removed and the remaining aqueous mixture is acidified with hydrochloric acid (4 M). The desired product is extracted into methyl t-butyl ether and dried over magnesium sulfate. The product is concentrated to give the title compound, TLC Rf=0.10 (ethyl acetate/hexane, 30/70); NMR (CDCl3) 7.43-7.13, 2.77-2.62, 2.06, 1.87-1.76, 1.63-1.57, 1.45-1.31 and 0.93 δ; CMR (CDCl3) 176.9, 141.9, 128.4, 128.3, 125.9, 73.4, 42.7, 41.4, 40.9, 31.9, 17.0 and 14.5 δ; MS (CI, ammonia) m/z (relative intensity) 254 (100), 236 (28), 218 (3), 194 (3), 159 (5).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:9]=1[C:10](OC)=[O:11].O>C(OCC)C>[NH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:9]=1[CH2:10][OH:11]
Reactant: COC(=O)c1c(N)cccc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: Nc1cccc(F)c1CO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
676.3 mg (17.8 mmol) lithium aluminium hydride are placed in 65 ml diethyl ether under an N2 atmosphere and cooled to 0° C. 2.01 g (11.9 mmol) methyl 2-amino-6-fluoro-benzoate, dissolved in 65 ml diethyl ether, are slowly added dropwise thereto and the mixture is stirred for 2 h at 0° C. Then the reaction mixture is combined dropwise at 0° C. with 100 ml dist. H2O. The aqueous phase is extracted twice with 100 ml diethyl ether. The combined organic phases are washed once with 100 ml of a saturated, aqueous NaCl solution, dried with MgSO4 and the solvent is eliminated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:23]C)=[C:6]([CH2:8][CH2:9][NH:10][CH:11]2[CH2:20][CH2:19][CH2:18][C:17]3[N:16]=[C:15](C#N)[CH:14]=[CH:13][C:12]2=3)[CH:7]=1.[C:25](=[O:28])(O)[O-:26].[Na+]>Br.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:23])=[C:6]([CH2:8][CH2:9][NH:10][CH:11]2[CH2:20][CH2:19][CH2:18][C:17]3[N:16]=[C:15]([C:25]([OH:26])=[O:28])[CH:14]=[CH:13][C:12]2=3)[CH:7]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(F)cc1CCNC1CCCc2nc(C#N)ccc21
Agent: Br
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc2c(n1)CCCC2NCCc1cc(F)ccc1O
Temperature: 25 °C

Procedure:
72.8 g (223.73 mmol) of rac-5-{[2-(5-fluoro-2-methoxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carbonitrile were taken up in 360 ml of hydrobromic acid (48% in water) and initially stirred at boiling point for 12 h, then cooled to room temperature and allowed to stand at this temperature overnight. The reaction solution was then diluted with 400 ml of water and adjusted to pH 6 using saturated sodium bicarbonate solution. The crystals formed were filtered off with suction, washed with water and dried under reduced pressure at 50° C. This gave 59 g (178.59 mmol, 80% of theory) of the target compound.
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][OH:26])[C:5]1=[O:29])[CH:2]=[CH2:3].N1C=CN=C1.[C:35]([Si:39](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C>[CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][O:26][Si:39]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 615 mg (1.422 mmol) (3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one (Example 126, Step B) in DMF (4741 μL) at 0° C. was added 1H-imidazole (97 mg, 1.422 mmol) followed by tert-butylchlorodiphenylsilane (473 μL, 1.849 mmol). The mixture was stirred at 0° C. for 15 min and then warmed to room temperature. The mixture was stirred at room temperature for 30 min and then quenched with sat. NH4Cl. The mixture was extracted with EtOAc and the organic layer was washed with water, 1 M LiCl, and sat. aq. NaCl solution. The mixture was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (24 g column; eluent: 0 to 30% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]2[CH:10]3[O:20][CH:13]([CH2:14][C:15]=2[C:16]=1[C:17](O)=[O:18])[CH2:12][CH2:11]3)=[O:5].[CH3:29][NH:30][CH3:31].N>>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]2[CH:10]3[O:20][CH:13]([CH2:14][C:15]=2[C:16]=1[C:17]([N:30]([CH3:31])[CH3:29])=[O:18])[CH2:12][CH2:11]3)=[O:5]
Reactant: CNC
Reactant: O=C(Nc1sc2c(c1C(=O)O)CC1CCC2O1)c1c(F)cccc1C(F)(F)F
Agent: N
Product: CN(C)C(=O)c1c(NC(=O)c2c(F)cccc2C(F)(F)F)sc2c1CC1CCC2O1

Procedure:
The title compound was prepared from the product of Example 4A and dimethylamine according to the procedure described for Example 4B. MS (DCI/NH3) m/z 443 (M+H)+.