Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:13]([O:14]C2CCCCO2)=[CH:12][C:5]2[CH:6]=[C:7]([C:9](=[O:11])[CH3:10])[O:8][C:4]=2[C:3]=1[CH3:21].OC1C(C)=C(C)C(O)=CC=1C=O.O>Cl.CO>[OH:14][C:13]1[C:2]([CH3:1])=[C:3]([CH3:21])[C:4]2[O:8][C:7]([C:9](=[O:11])[CH3:10])=[CH:6][C:5]=2[CH:12]=1
Reactant: CC(=O)c1cc2cc(OC3CCCCO3)c(C)c(C)c2o1
Agent: Cc1c(O)cc(C=O)c(O)c1C
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(=O)c1cc2cc(O)c(C)c(C)c2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
A mixture of 1-[6,7-dimethyl-5-(tetrahydro-pyran-2-yloxy)-benzofuran-2-yl]-ethanone (1.1 g) (prepared from 2,5-dihydroxy-3,4-dimethyl-benzaldehyde following the procedure of Steps 3, 4 and 5 of Example 13) and conc. HCl (10 drops) in MeOH (20 mL) was stirred at room temperature for 2 h. Water was poured into the mixture and left to precipitate overnight in the refrigerator. The precipitate was collected, washed with hexane and dried to give 1-(5-hydroxy-6,7-dimethyl-benzofuran-2-yl)-ethanone as a light brown solid (490 mg). 1H NMR (CDCl3, 300 MHz) δ: 7.38 (s, 1H), 6.89 (s, 1H), 4.88 (1H, OH), 2.60, 2.50, 2.31 (3s, 9H) ppm. 13C NMR (CDCl3, 75 MHz) δ: 192.76, 155.45, 155.13, 153.72, 130.29, 127.27, 124.75, 117.44, 106.18, 29.30, 15.56, 15.28 ppm. MS (m/z): 205 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH:2]([C:3]1[CH:4]=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH:8]=1)=[O:1]
Reactant: CCOC(=O)c1cc(CO)cc(-c2ccc(C)cc2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)c1cc(C=O)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 5-(hydroxymethyl)-4′-methylbiphenyl-3-carboxylate (400 mg, 1.5 mmol) and manganese(IV) oxide (660 mg, 6.6 mmol) in methylene chloride (14 mL) was stirred at room temperature overnight. The reaction mixture was filtered through Celite and washed with methylene chloride. The filtrate was concentrated to afford the title compound.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4](=O)[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([CH3:14])[CH2:8]2.C1([NH3+])CCCCC1>>[CH3:14][CH:9]1[CH2:8][C:7]2[C:11](=[CH:12][CH:13]=[C:5]([CH2:4][C:3]([OH:16])=[O:2])[CH:6]=2)[CH2:10]1
Reactant: COC(=O)C(=O)c1ccc2c(c1)CC(C)C2
Agent: [NH3+]C1CCCCC1
Product: CC1Cc2ccc(CC(=O)O)cc2C1

Procedure:
α-oxo-2-methyl-5-indanacetic acid methyl ester is reduced in a manner analogous to that described in Example 4. The cyclohexyl-ammonium salt of the title compound has a M.P. of 175°-178°.
Reaction SMILES: S(=O)(O)[O-].[Na+].[CH3:6][CH:7]1[CH2:12][CH:11]([CH3:13])[CH2:10][C:9](=[O:14])[CH2:8]1.[C-:15]#[N:16].[K+]>O>[OH:14][C:9]1([C:15]#[N:16])[CH2:10][CH:11]([CH3:13])[CH2:12][CH:7]([CH3:6])[CH2:8]1
Reactant: CC1CC(=O)CC(C)C1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC1CC(C)CC(O)(C#N)C1
Reaction time: 2 h
Yield: 33.2 %

Procedure:
A solution of 106.8 grams of sodium bisulphite in 130 ml. of water is added dropwise with stirring over 30 minutes to a stirred mixture of 100 grams of 3,5-dimethylcyclohexanone, 67.0 grams of potassium cyanide and 170 ml. of water. The reaction mixture is kept below 40° C. by means of a cold water bath. The reaction mixture is stirred for an additional 2 hours, the organic layer separated and the aqueous layer extracted with 250 ml. of ether three times. The combined organic layer and ether solutions are dried over magnesium sulfate and concentrated at reduced pressure to yield 40.3 grams of 1-hydroxy-3,5-dimethyl-cyclohexanecarbonitrile.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH2:4]1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>C(#N)C>[CH2:12]([NH:19][CH2:2][CH:3]1[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH2:4]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCC1Cc2ccccc2O1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: c1ccc(CNCC2Cc3ccccc3O2)cc1
Yield: 73 %

Procedure:
1.07 g (5.0 mmol) of compound 001C, which had been prepared in Step C of Reference Example 1, was dissolved in 11 ml of acetonitrile. To the resultant solution were added 1.64 ml (15.0 mmol) of benzylamine and 2.07 g (15.0 mmol) of potassium carbonate. The resultant mixture was stirred at 80° C. for 8 hours to effect a reaction. To the resultant reaction mixture was added 100 ml of chloroform to obtain a mixture. The obtained mixture was successively washed with 100 ml of water and 100 ml of saturated saline, to thereby form a chloroform layer containing the desired compound 002A, followed by separation of the chloroform layer. The chloroform layer thus separated was dehydrated by means of a Whatman 1PS filter paper and then, concentrated in vacuo to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography. That is, the residue was applied to a column of 50 g of silica gel (Art. 9385, manufactured and sold by E. Merck, Darmstadt, Germany) and eluted with chloroform, to thereby obtain 873 mg of compound 002A as a yellow oily substance (yield: 73%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:15])[C:9]#[C:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]#[C:10][C:11]([O:13][CH3:14])=[O:12])=[O:15])=[CH:6][CH:7]=1
Reactant: COC(=O)C#CC(O)c1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)C#CC(=O)c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
A solution of 7.5 g (36 mmol) of methyl 4-(4-fluorophenyl)-4-hydroxy-2-butynoate in 100 ml of methylene chloride was added dropwise at 0° to a suspension of 89.3 g (1.03 mol) of manganese dioxide in 150 ml of methylene chloride. The reaction mixture was stirred at 0° for 30 minutes filtered over magnesium sulphate and concentrated. Crystallization of the residue from ether/hexane yielded methyl 3-(4-fluorobenzoyl)propiolate of melting point 62°-63°.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH:4]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:5]1[N:6]([CH3:26])[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH3:23])=[C:17]([CH3:24])[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.[Li+].[OH-]>C1COCC1>[C:28]([O:27][CH:4]([C:5]1[N:6]([CH3:26])[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH3:23])=[C:17]([CH3:24])[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]([OH:32])=[O:2])([CH3:31])([CH3:30])[CH3:29]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2cc(C)c(OC)c(C)c2)c2ccccc2c(=O)n1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(C)cc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3ccccc23)cc1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of tert-Butoxy-[4-(4-methoxy-3,5-dimethyl-phenyl)-2-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl]-acetic acid methyl ester (130 mg, 0.3 mmol) in THF (3.0 ml) was added an aqueous LiOH (1N, 1.22 ml). The mixture was stirred at 60° C. overnight. LCMS showed SM was consumed, cooled to RT, removed the solvent, added water, extracted with EA to remove impurity, the aqueous layer was adjusted to pH=6 with 1N HCl, extracted with EA, the organic layer was washed with water and brine, dried over Na2SO4, filtered, concentrated to dryness, gave the desired product. (m=73 mg, Yield: 58%): 1HNMR: (400 MHz, d6-DMSO) δ 1.03 (s, 9H), 2.31 (s, 6H), 3.64 (s, 3H), 3.79 (s, 3H), 5.29 (s, 3H), 6.94 (s, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.24 (s, 1H), 7.49 (m, 2H), 8.46 (d, J=8.0 Hz, 1H). LCMS: (10-80 AB—2MIN-E.M): Rt=1.258, purity=96.0%, M+1=424.
Reaction SMILES: C[C:2]1[CH:23]=[CH:22][C:5]([NH:6][CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][C:12]=2[Cl:21])=[O:9])=[CH:4][CH:3]=1.[CH2:24]=O.[CH2:26]([OH:28])C>O>[CH3:26][O:28][C:2]1[CH:3]=[CH:4][C:5]([N:6]2[CH2:7][C:8](=[O:9])[N:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:20])[NH2:18])=[CH:13][C:12]=3[Cl:21])[CH2:24]2)=[CH:22][CH:23]=1
Reactant: Cc1ccc(NCC(=O)Nc2ccc(S(N)(=O)=O)cc2Cl)cc1
Reactant: C=O
Reactant: CCO
Solvent: O
Product: COc1ccc(N2CC(=O)N(c3ccc(S(N)(=O)=O)cc3Cl)C2)cc1
Temperature: 0 °C

Procedure:
The product of stage a) (15g) was dissolved in ethanol (200 ml) and treated with paraformaldehyde (2.5g) in water (400 ml). The mixture was refluxed for 3 hours, cooled in ice/water and filtered to yield the title product (5 g), m.p. 221°-223°
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:16][O:17][C:18](=[O:26])[CH2:19][O:20][C:21]([CH3:25])([CH3:24])[C:22]#[CH:23]>C(N(CC)CC)C.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.[Cu]I>[CH3:16][O:17][C:18](=[O:26])[CH2:19][O:20][C:21]([CH3:24])([CH3:25])[C:22]#[C:23][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1Br
Reactant: C#CC(C)(C)OCC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)COC(C)(C)C#Cc1cc(-c2ccc(Cl)cc2)ccc1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 3-bromo-4′-chloro-4-methylbiphenyl (12.6 g, 44.7 mmol) and (1,1-dimethylprop-2-ynyloxy)acetic acid methyl ester (prepared according to WO2001/066544) (8.4 g, 53.8 mmol) in triethylamine (70 ml) is added bis(triphenylphosphine)palladium(II) dichloride (0.63 g, 0.9 mmol) and copper(I) iodide (0.34 g, 1.8 mmol). The reaction mixture is degassed and flushed with nitrogen (×3), then stirred under nitrogen at 80° C. for one hour. The cooled mixture is filtered through diatomaceous earth to remove the catalyst, and the filtrate evaporated in vacuo. The residue is resubjected to the same reaction conditions (8.4 g 1,1-dimethylprop-2-ynyloxy)acetic acid methyl ester, 0.63 g bis(triphenylphosphine)-palladium(II) dichloride, 0.34 g copper(I) iodide in 70 ml triethylamine under nitrogen) and stirred at 80° C. for one hour. The cooled mixture is filtered through diatomaceous earth, then concentrated in vacuo and purified by flash chromatography (hexane/ethyl acetate 3:1) to afford [3-(4′-chloro-4-methylbiphenyl-3-yl)-1,1-dimethylprop-2-ynyloxy]acetic acid methyl ester (6.70 g) as an oil.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[C:9](OC(=O)C)(=[O:11])[CH3:10]>C(O)(=O)C>[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:1]([OH:2])[C:3]=1[OH:4])(=[O:11])[CH3:10]
Reactant: Oc1ccccc1O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)c1cccc(O)c1O
Temperature: 110 °C

Procedure:
In the solution of 220 g(2 mol) of catechol in 500 ml of acetic acid, 102 g(1 mol) of acetic anhydride was drop-added for one hour while agitating the solution at 110° C. The mixture was maintained at 110° C. for two hours, and diethylene glycol dibutyl ether was distilled under vacuum. 1 Liter of toluene was added to the reaction mixture and cooled to 0° C. and then the unreacted excess hydroquinone was filtered and collected (recovered amount: 110 g, recycled without any purification process). A desired mono acetyl catechol was obtained by evaporating the residue in vacuum. (Yield: 149.0 g(98%). mp: oil. 1H-NMR(200 MHz, CDCl3, ppm) 2.33(s, 3H), 5.81 (br, 1H), 6.83-7.18 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[S:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[S:14].C(O)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[NH4+]>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[C:18]1[S:12][C:13](=[S:14])[NH:15][C:16]1=[O:17]
Reactant: COc1ccc(F)c(C=O)c1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(F)c(C=C2SC(=S)NC2=O)c1
Temperature: 120 °C
Reaction time: 12 h
Yield: 91.5 %

Procedure:
To a suspension of 2-fluoro-5-methoxybenzaldehyde (5.00 g, 32.46 mmol) and rhodanine (4.31 g, 32.46 mmol) in dry toluene (1000 mL) was added ammonium acetate (50 mg) and acetic acid (2 mL). The resulting suspension was allowed to stir at 120° C. for 12 h under Dean-Stark apparatus before being allowed to cool and filtered. Resultant solid was washed with hexane and allowed to dry in vacuo to give an orange crystalline solid (8.00 g, 91%); δH (300 MHz, CDCl3) 7.50 (1H, s, CH═C); 7.31 (1H, t, Ar), 7.20-7.11 (1H, m Ar), 6.95-6.89 (1H, m, Ar), 3.80 (3H, s, OCH3).
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([NH:6][C:7](=[O:18])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:39])([CH3:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(O)C>[N:13]1([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([NH:6][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:38])([CH3:39])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:20][CH:19]=2)=[O:18])[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=C(CCCCCn1ccnc1)Nc1ccc(O)cc1
Reactant: CCOC(=O)C(C)(C)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)CCCCOc1ccc(NC(=O)CCCCCn2ccnc2)cc1
Reaction time: 0.5 h

Procedure:
To 20 ml of ethanol were added 1.37 g of p-hydroxy-6-(1-imidazolyl)hexaneanilide and 0.69 g of anhydrous potassium carbonate and the mixture was stirred for 30 minutes with heating under reflux. After cooling, 1.26 g of ethyl 6-bromo-2,2-dimethylhexanoate was added thereto and the mixture was reacted overnight with heating under reflux. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the resulting residue followed by extracting with chloroform. After the chloroform layer was successively washed with a 1N aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution, it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the resulting residue was subjected to silica gel column chromatography. The product was eluted out using a chloroform-methanol liquid mixture (50:1 in a volume ratio). The solvent was removed by distillation under reduced pressure. The resulting crystals were recrystallized from a solvent mixture of n-hexane-ethylacetate to obtain ethyl 6-[p-[6-(1-imidazolyl)hexanamido]phenoxy]-2,2-dimethylhexanoate as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:16])[CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([NH:24][C:25]1([C:40](O)=[O:41])[CH2:30][CH2:29][N:28]([C:31]2[C:32]3[CH:39]=[CH:38][NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH2:27][CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CC(N(C)C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:16][C:40]([C:25]2([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:26][CH2:27][N:28]([C:31]3[C:32]4[CH:39]=[CH:38][NH:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:29][CH2:30]2)=[O:41])[CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: CCN(CC)CC[C@H](N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCN(CC)CC[C@H](NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
(S)-1-(4-Chlorophenyl)-N3,N3-diethylpropane-1,3-diamine (Intermediate 60) (119 mg, 0.49 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (179 mg, 0.49 mmol) and DIPEA (0.259 mL, 1.48 mmol) in DMA (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (207 mg, 0.54 mmol) was added and the resulting solution was stirred at 50° C. for 2 hours. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 10% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness to afford (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-(diethylamino)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (189 mg, 65.5%) as a colourless gum. (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-(diethylamino)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (189 mg, 0.33 mmol) was dissolved in DCM (5.00 mL) and TFA (1 mL) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness to afford crude product which was triturated with diethyl ether to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-(diethylamino)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (70.0 mg, 29.3%) as a white foam.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:27]=[CH:26][C:10]2[C:11]3[C:12](=[CH:23][NH:24][CH:25]=3)[CH2:13][N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:9]=2[CH:8]=1.[C:28](=O)([O-])[O-:29].[Na+].[Na+]>C(Cl)Cl.CN(C)C=O>[Cl:6][C:7]1[CH:27]=[CH:26][C:10]2[C:11]3[C:12](=[C:23]([CH:28]=[O:29])[NH:24][CH:25]=3)[CH2:13][N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:9]=2[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1c[nH]cc1-2
Agent: [Na+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1[nH]cc2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Reaction time: 2 h

Procedure:
A solution of 3.0 ml (33 mmol) of phosphorous oxychloride in 20 ml of methylene chloride was added dropwise to a solution of 3.0 g (9.1 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine in 40 ml of dimethylformamide which was cooled to 0°. Stirring at 0° was continued for 2 hr. The mixture was poured into a saturated solution of aqueous sodium carbonate and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. Purification by column chromatography (silica gel, 100 g; eluent, 50% (v/v) ethyl acetate in methylene chloride) gave a light pink solid, mp 270°-274°. Recrystallization from a mixture of ethyl acetate and methylene chloride gave peach colored prisms, mp 276°-277°.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:9][C:10]([C:13]2[CH:18]=[C:17]([C:19](=[O:24])[NH:20][CH:21]3[CH2:23][CH2:22]3)[CH:16]=[CH:15][C:14]=2[CH3:25])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[O:29][CH2:28]C1.C([Li])CCC.CN(C=O)C>CCOC(C)=O>[C:1]([NH:5][C:6]([C:8]1[S:9][C:10]([C:13]2[CH:18]=[C:17]([C:19](=[O:24])[NH:20][CH:21]3[CH2:23][CH2:22]3)[CH:16]=[CH:15][C:14]=2[CH3:25])=[CH:11][C:12]=1[CH:28]=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NC(C)(C)C)s1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc(C=O)c(C(=O)NC(C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In 150 mL round-bottom flask equipped with a stir bar, under N2, was added N-tert-butyl-5-(5-(cyclopropylcarbamoyl)-2-methylphenyl)thiophene-2-carboxamide (1.2 g, 3.4 mmol) followed by anhydrous THF (100 mL). The solution was cooled down to −78° C. and butyllithium, (2.2 ml, 30 mmol) was added dropwise over 5 min. The mixture was stirred at −78° C. for 0.5 hrs and was added DMF (0.780 ml, 10 mmol). The mixture was stirred at −78° C. for 0.5 hr, quenched with saturated solution of NH4Cl and then allowed to warm up to room temperature. The reaction then diluted with EtOAc (100 ml) and the layers were separated and the aqueous layer was extracted with EtOAc (3×50 ml) and the combined organic solution was washed with brine, water and dried over MgSO4. The organic solutions were evaporated under reduced pressure and the crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 5% to 95% MeOH in DCM to provide N-tert-butyl-5-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-formylthiophene-2-carboxamide (1.01 g). MS (ES+): 385 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10].[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.[CH2:21]=[C:22]([CH3:24])[CH3:23].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:5]=1[NH:10][CH:16]([C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([Br:12])[CH:14]=1)[CH2:21][C:22]2([CH3:24])[CH3:23])=[O:11]
Reactant: O=Cc1cccc(Br)c1
Reactant: COC(=O)c1ccccc1N
Reactant: C=C(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cccc2c1NC(c1cccc(Br)c1)CC2(C)C
Temperature: 85 °C
Reaction time: 18 h
Yield: 39.9 %

Procedure:
To a stirred solution of 2-amino-benzoic acid methyl ester (11.3 g, 78.4 mmol) and 3-bromobenzaldehyde (9.2 mL, 78.4 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 85° C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (11.7 g, 40.0%) as a light yellow solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 374.0 & 376.0.
Reaction SMILES: [C:1]([CH:6]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[C:14]2[C:13](=[O:24])[CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]1([C:26]([F:29])([F:28])[F:27])[OH:25])([O:3]CC)=[O:2].O.[OH-].[Li+].Cl>C(O)C.O>[C:1]([CH:6]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[C:14]2[C:13](=[O:24])[CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]1([C:26]([F:28])([F:29])[F:27])[OH:25])([OH:3])=[O:2]
Reactant: CCOC(=O)C1C(c2cccc(C#N)c2)C2=C(CCCC2=O)NC1(O)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1cccc(C2C3=C(CCCC3=O)NC(O)(C(F)(F)F)C2C(=O)O)c1
Temperature: 90 °C
Yield: 84.6 %

Procedure:
A suspension of 3-carboethoxy-2-trifluoromethyl-2-hydroxy-4-(3-cyanophenyl)-4,6,7,8-tetrahydro-5(1H )-quinolone (3.39 g) in ethanol (20 ml) and water (20 ml) was treated with lithium hydroxide monohydrate (0.75 g). The mixture was heated at 90° C. for 1.5 hours, diluted with water, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The combined organic extracts were washed (water and brine), dried, filtered, and evaporated to yield a foam which was purified by chromatography (ethyl acetate and ethyl acetate/methanol, 3:1) to afford 3-carboxy-2-trifluoromethyl-2-hydroxy-4-(3-cyanophenyl)-4,6,7,8-tetrahydro-5(1H)-quinolone (2.67 g ) as a pale yellow foam; MS: m/z=381(m).