Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:10][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[N+:11]([O-])=O.C(N(CC)CC)C.[Cl:21][C:22]([Cl:27])([Cl:26])[C:23](Cl)=[O:24]>CO.C(Cl)Cl.[Ni]>[Cl:21][C:22]([Cl:27])([Cl:26])[C:23]([NH:11][C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:10][C:2]=1[CH3:1])=[O:24]
Reactant: Cc1sc2cnccc2c1[N+](=O)[O-]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: Cc1sc2cnccc2c1NC(=O)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
Methyl-3-nitro-thieno[2,3-c]pyridine (2.05 g, 10.6 mmol) was dissolved in MeOH (250 mL) and added to a suspension of Raney-Nickel (20 g) in MeOH (100 mL). The reaction flask was flushed with H2. After 3 hours at room temperature under a balloon of H2 the reaction mixture was filtered and condensed to provide a yellow solid. This was then dissolved in DCM (100 mL) and triethylamine (1.6 mL, 11.5 mmol) was added. The solution was cooled to 0° C. in an ice bath. Trichloroacetyl chloride (1.3 mL, 11.6 mmol) was added dropwise. The solution was allowed to slowly warm to room temperature and stirred overnight (16 hrs), then concentrated to a yellow paste and partitioned between equal volumes of water and EtOAc (150 mL each). After separation the organic phase was washed with water (2×70 mL) and brine (1×70 mL), dried (MgSO4) and condensed to provide the title compound as a tan solid (1.63 g, 42%). Used without purification.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.N1C2C(=CC(C3C4C(N)=NC=NC=4N(C)C=3)=CC=2)CC1.CN([C:46]([O:50]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[CH2:68][N:69]([CH:73]([CH3:75])[CH3:74])[CH:70]([CH3:72])C>O>[CH3:22][N:14]1[C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH2:21])[C:20]=2[C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:3]([C:46](=[O:50])[CH2:75][C:73]2[N:69]([CH3:68])[CH:70]=[CH:72][CH:74]=2)[CH2:4][CH2:5]3)=[CH:13]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Product: Cn1cccc1CC(=O)N1CCc2cc(-c3cn(C)c4ncnc(N)c34)ccc21
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
A solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (250 mg, 0.739 mmol), 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine.2HCl (250 mg, 0.739 mmol), HATU (281 mg, 0.739 mmol), DIEA (0.516 mL, 2.96 mmol) was stirred at room temperature overnight. The reaction mixture was poured into 20 mL water and stirred for 30 mins. The grey precipitate was filtered, washed with water (10 mL) and dried for an hour at the pump. The residue was adsorbed onto silica and purified by flash chromatography (0-10% MeOH in DCM, 24-g column) to afford 7-methyl-5-{1-[(1-methyl-1H-pyrrol-2-yl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (128 mg, 44.8% yield) as a white solid. LC-MS (ES) m/z=387 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.23 (t, J=8.34 Hz, 2H), 3.54 (s, 3H), 3.73 (s, 3H), 3.86 (s, 2H), 4.25 (t, J=8.59 Hz, 2H), 5.84-5.94 (m, 2H), 5.94-6.32 (m, 2H), 6.68 (t, J=2.15 Hz, 1H), 7.14-7.29 (m, 2H), 7.31 (s, 1H), 8.08-8.20 (m, 2H). An additional crop of material was obtained from crystals observed in the filtrate after standing overnight. The liquid was filtered and the residue washed with water and dried at the pump to yield a second crop of 7-methyl-5-{1-[(1-methyl-1H-pyrrol-2-yl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (65 mg, 22.76% yield) as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10].CON(C)[C:17]([CH:19]1CCCC[CH2:20]1)=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:13][CH2:12][CH2:20][CH2:19][CH2:17]1)=[O:10]
Reactant: Cc1ccc(N)c(C(=O)C2CC2)c1
Reactant: CON(C)C(=O)C1CCCCC1
Product: Cc1ccc(N)c(C(=O)C2CCCCC2)c1
Yield: 75 %

Procedure:
Crude (2-amino-5-methyl-phenyl)-cyclohexyl-methanone (75%, oil) was prepared in a similar fashion as described for (2-amino-5-methyl-phenyl)-cyclopropyl-methanone using cyclohexanecarboxylic acid methoxy-methyl-amide instead of cyclopropanecarboxylic acid methoxy-methyl-amide.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=O.[C:12]([NH2:20])(=[S:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[C:13]1([C:12]2[S:19][CH:3]=[C:4]([C:6]3[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=3)[N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CBr)c1ccncc1
Reactant: NC(=S)c1ccccc1
Agent: Br
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(-c3ccncc3)cs2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the solution of 4-(bromoacetyl)pyridine hydrobromide (500 mg, 1.8 mmol) in dry DMF (5 mL) was added thiobenzamide (242 mg, 1.8 mmol,) and the resulting reaction was stirred at rt for 12 h. Thereafter, the reaction quenched with saturated aqueous NaHCO3 solution (25 mL) and the mixture extracted with EtOAc (3×25 mL). The combined organic extracts were washed with water (25 mL), dried (Na2SO4), and concentrated. The resulting residue was purified by flash chromatography (SiO2, 100:0-0:100 hexanes-EtOAc) furnished 2-phenyl-4-(pyridin-4-yl)thiazole: LCMS (m/z): 239.0 (MH+), tR=0.64 min.
Reaction SMILES: C([O:3][C:4]([NH:6][C:7](=[O:19])[C:8]([C:17]#[N:18])=[N:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)C.C([O-])(=O)C.[Na+].C(O)(=O)C>O>[C:11]1([N:10]2[C:4](=[O:3])[NH:6][C:7](=[O:19])[C:8]([C:17]#[N:18])=[N:9]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)NC(=O)C(C#N)=NNc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1nn(-c2ccccc2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Intermediate b (21 g, 0.08 mol) and anhydrous sodium acetate (29 g, 0.35 mol) were added to glacial acetic acid (20v/w, 420 mL). The mixture was warmed up to react under reflux for 2 h. After completion of the reaction, the reaction solution was cooled to 0° C. and poured into water (1200 mL). The mixture was stirred for 30 min and filtered by suction. The filtered cake was washed with water and petroleum ether, and dried to produce an orange red solid (12 g) in a yield of 67.8%.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH3:23]I.O>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH3:23])=[O:8])=[CH:19][CH:20]=1)#[N:2]
Reactant: CI
Reactant: COc1ccc(CNC(=O)c2ccc(C#N)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(C)C(=O)c2ccc(C#N)cc2)cc1
Reaction time: 0.25 h

Procedure:
79 mg of 4-cyano-N-(4-methoxybenzyl)benzamide was dissolved in 2.5 ml of tetrahydrofuran, and 24 mg of 60% sodium hydride was added thereto, followed by heating under reflux for 5 minutes in an atmosphere of nitrogen. After cooling, 0.1 ml of methyl iodide was added thereto, followed by stirring for 15 minutes. Thereafter, the reaction was stopped by the addition of 1 ml of distilled water. After the product was extracted with ethyl acetate, the extract was successively washed with 2 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the resulting crude product was purified by TLC (using a 1:1 mixture of ethyl acetate and hexane as the developing solvent) to obtain 72 mg of 4-cyano-N-(4-methoxybenzyl)-N-methylbenzamide.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][S:2]([N:16]1[CH2:15][CH2:14][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH2:18][CH2:17]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methanesulfonyl chloride (2.28 ml) was added dropwise to a solution of 1-(tert-butoxycarbonyl)piperazine (5 g) in methylene chloride (90 ml) containing triethylamine (4.5 ml). The solution was stirred at ambient temperature for 24 hours. The solution was poured onto cooled water and extracted with methylene chloride. The organic phase was separated, washed with brine and dried over magnesium sulphate and evaporated to give tert-butyl 4-(methylsulfonyl)piperazine-1-carboxylate (7 g).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[C:13]([Cl:21])=[C:14]([O:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[Li+].[OH-]>CO.C1COCC1.O>[Cl:21][C:13]1[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:11][C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:32])=[O:3])=[CH:15][C:14]=1[O:16][CH2:17][CH:18]1[CH2:20][CH2:19]1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OCC2CC2)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)CC(C(=O)O)c1cc(OCC2CC2)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.2 %

Procedure:
The ethyl-2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (120 mg, 0.255 mmol) dissolved in 10 mL of MeOH/THF/H2O (10 mL/10 mL/5 mL) and LiOH (30 mg, 1.2 mmol) was added. The reaction mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4, filtered and evaporated under reduced pressure. Purification by column chromatography over silica gel (DCM:MeOH 9:1) gave 2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (89 mg) as a white solid. 1H-NMR (500 MHz, CDCl3): 7.68 (d, 2H), 7.55 (d, 2H), 6.92 (s, 1H), 6.85 (s, 1H), 3.96 (d, 2H), 3.64 (t, 1H), 1.98 (m, 1H), 1.68 (m, 1H), 1.55 (m, 1H), 1.32 (m, 1H), 0.91 (d, 6H), 0.64 (m, 2H), 0.42 (m, 2H);
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](#N)C=C>>[CH2:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:2]=[CH:1]1
Reactant: C=CC#N
Reactant: C=Cc1ccccc1
Product: C1=Cc2ccccc2C1

Procedure:
A terpolymer of a weight ratio of 70:25:5 styrene:acrylonitrile:indene was prepared by emulsion polymerization using the following ingredients:
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([NH:42][CH2:43][CH2:44][S:45][CH3:46])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][NH:42][CH2:43][CH2:44][S:45][CH3:46])=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CSCCNC(=O)CCl
Product: CCN(Cc1ccc(OCCNCCSC)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 6.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-(2-methylsulfanylethyl)acetamide (16 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (1.8 mg) was obtained.
Reaction SMILES: CO[N:3]([C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[C:11]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:10]=1)[CH2:4][C:5](NC)=[O:6].[CH2:33]([Mg]Cl)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O.C(OCC)(=O)C>C1COCC1>[C:34]1([CH2:33][C:5](=[O:6])[CH2:4][NH:3][C:9]2[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)=[C:11]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[N:10]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CNC(=O)CN(OC)c1nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c(=O)n1C
Reactant: Cl[Mg]Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(NCC(=O)Cc2ccccc2)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Reaction time: 2 h

Procedure:
To a solution of 2-(N′-methoxy-N′-methylaminocarbonylmethylamino)-3-methyl-5-naphthalen-2-yl-6-pyridin-4-yl-3H-pyrimidin-4-one (1.46 g, 3.4 mmol) in THF (30 mL) at 0° C. was slowly added benzylmagnesium chloride (Aldrich, 2.5M in THF, 20 mL). After 2 h, water (100 mL) and ethyl acetate (200 mL) were added. The layers were separated. The organic layer was washed with brine (3×80 mL), dried, and evaporated to give the crude product. Column chromatograph purification (silica gel, 1-2% MeOH/CH2Cl2) gave the final product. M+1=491.2.
Reaction SMILES: CS(O)(=O)=O.[CH2:6]1[O:24][C:9]2([CH2:14][CH2:13][C:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([CH2:15]O)[CH2:11][CH2:10]2)[O:8][CH2:7]1.[C-]#[N:26].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:6]1[O:24][C:9]2([CH2:14][CH2:13][C:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:15]#[N:26])[CH2:11][CH2:10]2)[O:8][CH2:7]1
Reactant: OCC1(Cc2ccccc2)CCC2(CC1)OCCO2
Reactant: [C-]#N
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#CC1(Cc2ccccc2)CCC2(CC1)OCCO2

Procedure:
A mixture of 18.6 g. (0.055 M) of 4-benzyl-4-hydroxymethylcyclohexan-1-one ethylene ketal methanesulfonate (2) (prepared as in Example 2C) and 18 g. of potassium cyanide in 180 ml. of hexamethylphosphoramide is heated for about 17 hours in an oil bath at about 145° C. The resulting gel is allowed to cool, diluted to 800 ml. with water and extracted with benzene. The organic layer is washed with water and brine and evaporated to dryness. The residue is chromatographed on 1 l. of silica gel and eluted with 25% ethyl acetate in Skellysolve B and the fractions found similar by TLC pooled to give 4-benzyl-4-cyanocyclohexan-1-one ethylene ketal (3).
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:19](/[CH:20]=[CH:21]/[C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17][CH2:16][C:15]1=[O:31]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:15](=[O:31])[CH2:16][CH2:17][CH2:18][CH:19]1/[CH:20]=[CH:21]/[CH:22]([OH:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)CCCCCCN1C(=O)CCCC1/C=C/C(=O)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCCCCCN1C(=O)CCCC1/C=C/C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
Sodium borohydride (36 mg, 0.96 mmol), followed by MeOH (0.25 mL), was added to a solution of 7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-heptanoic acid methyl ester (37 mg, 0.096 mmol) in CH2Cl2 (0.75 mL) at 0° C. The mixture was allowed to warm to rt. After 1.5 h at rt, the reaction was quenched with HCl (1.0 M aqueous) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 32 mg (86%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[N:13]O)=[CH:5][CH:4]=1.ClC(Cl)(Cl)C(O)=[O:18]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][NH:13][C:10](=[O:18])[C:11]=2[CH:12]=1
Reactant: COc1ccc2c(c1)C(=NO)CCC2
Reactant: O=C(O)C(Cl)(Cl)Cl
Product: COc1ccc2c(c1)C(=O)NCCC2
Yield: 22.3 %

Procedure:
Following a procedure of Tomita, et. al., J. Chem. Soc. C 1969, 183, 7-methoxytetralone oxime (45.0 g, 0.235 mol) was mixed with solid trichloroacetic acid (150 g), and the resulting suspension heated to ca. 80 C., at which time a violent exotherm ensued, yielding a black solid mixture. The residue was cooled, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, and the combined organic layers were concentrated in vacuo. The residue was purified by chromatography over silica gel to yield 10.0 g (22%) of 8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one. An analytical sample was obtained by recrystallization from CH2Cl2 /hexanes to yield colorless crystals: mp. 99°-101° C. (lit. (see above) 100°-101° C.); 1H NMR(CDCl3) d7.35(brs, 1H), 7.30(d, J=3 Hz, 1H), 7.10(d, J=9 Hz, 1H), 6.95(dd, J=3, 9 Hz, 1H), 3.82(s, 3H), 3.10(q, J=6 Hz, 2H), 2.80(t, J=6 Hz, 2H), 1.98(m, 2H),
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH:36]=[O:37])[CH:25]([C:38]([F:41])([F:40])[F:39])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([OH:6])=[O:37])[CH:25]([C:38]([F:41])([F:39])[F:40])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=P([O-])(O)O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C=O)C(C(F)(F)F)C1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C(=O)O)C(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
A solution of sodium chlorite (219 mg; 2.42 mmol; 5 eq.) and sodium dihydrogenphosphate (233 mg; 1.94 mmol; 4 eq.) in water (1 mL) was added dropwise to a mixture of 2-methyl-2-butene (1 mL) and 4-(2-formyl-phenoxy)-3-trifluoromethyl-piperidine-1-carboxylic acid tert-butyl ester (181 mg; 0.48 mmol; 1 eq.) in 1,4-dioxane (4 mL). The reaction mixture was stirred at room temperature for 1 hour and the 1,4-dioxane concentrated in vacuo. The aqueous solution was diluted with water and the pH made acidic with 0.1M HCl. The mixture was extracted with DCM (2×) and the combined organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (86 mg, 46%) as a white solid. HPLC (max plot) 97.3%, Rt 4.39 min. UPLC/MS: (MS−) 388.3 ([M−H]−).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH2:21][CH2:22][C:23]([OH:25])=O)[N:20]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:26]1([CH2:31][CH2:32][NH2:33])[CH2:30][CH2:29][CH2:28][CH2:27]1.O.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH2:21][CH2:22][C:23]([NH:33][CH2:32][CH2:31][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[N:20]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCN1CCCC1
Reactant: O=C(O)CCc1csc(Nc2ncccc2OCc2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(CCc1csc(Nc2ncccc2OCc2ccccc2)n1)NCCN1CCCC1
Temperature: 0 °C

Procedure:
3-(2-(3-(Benzyloxy)pyridin-2-ylamino)thiazol-4-yl)propanoic acid (40 mg, 0.113 mmol), 2-(pyrrolidin-1-yl)ethanamine (0.0171 mL, 0.135 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (22.4 mg, 0.146 mmol) and 4-methylmorpholine (0.0173 ml, 0.158 mmol) were placed in an 8.5 mL screw-cap vial. The reaction mixture was cooled to 0° C. in an ice bath, and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (33.0 mg, 0.172 mmol) was added as a solid. The mixture was stirred at 0° C. and then allowed to warm to room temp overnight. The reaction mixture was concentrated under high vacuum to remove DMF, and the residue was partitioned between dichloromethane and saturated aqueous NaHCO3 diluted with an equal part of water. The organic phase was washed with once with water, then with brine, and dried by passing through a plug of anhydrous sodium sulfate. The solution was concentrated in vacuo and dried under high vacuum to provide the title compound as a colorless oil. 1H NMR (CDCl3) δ 1.76 (s, 4H), 2.56 (m, 4H), 2.59 (dd, J=5.6, 12.9 Hz, 4H), 3.01-2.94 (m, 4H), 3.37 (dd, J=11.3, 5.5 Hz, 2H), 5.13 (s, 2H), 6.75 (bs, 1H), 6.47 (s, 1H), 6.82 (dd, J=8.2, 5.1 Hz, 2H), 7.10 (dd, J=1.2, 7.9, Hz, 1H), 7.42 (br s, 4H), 7.94 (dd, J=1.2, 5 Hz, 1H), 8.59 (bs, 1H); Mass spectrum (apci) m/z=452.2 (M+H).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27](O)=[O:28])[CH:20]=1>>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:3]3)[CH2:6]2)=[O:28])[CH:20]=1
Reactant: O=C(O)c1ccccc1-c1cccnc1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Product: O=C(c1ccccc1-c1cccnc1)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 2-pyridin-3-yl-benzoic acid. MS (ESI): mass calculated for C26H23N5O, 421.51; m/z found 422.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:28][CH3:29])([C:13]2[CH:18]=[CH:17][C:16](OS(C(F)(F)F)(=O)=O)=[C:15]([CH3:27])[CH:14]=2)[CH2:11][CH3:12])=[CH:6][C:5]=1[CH3:30].[CH3:32][Si:33]([C:36]#[CH:37])([CH3:35])[CH3:34].C(N(CC)CC)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:28][CH3:29])([C:13]2[CH:18]=[CH:17][C:16]([C:37]#[C:36][Si:33]([CH3:35])([CH3:34])[CH3:32])=[C:15]([CH3:27])[CH:14]=2)[CH2:11][CH3:12])=[CH:6][C:5]=1[CH3:30]
Reactant: C#C[Si](C)(C)C
Reactant: CCC(CC)(c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1)c1ccc(C(=O)OC)c(C)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(C#C[Si](C)(C)C)c(C)c1)c1ccc(C(=O)OC)c(C)c1
Temperature: 80 °C
Yield: 81.2 %

Procedure:
4-[1-Ethyl-1-(3-methyl-4-trifluoromethanesulfonyloxy-phenyl)-propyl]-2-methyl-benzoic acid methyl ester (11.20 g, 24.43 mmol) in DMF (100 ml) is added trimethylsilylacetylene (6.90 ml, 48.85 mmol), dichlorobis(triphenylphosphine) palladium (1.71 g, 2.44 mmol) and triethylamine (23.84 ml, 171 mmol) and heated to 80° C. overnight. The reaction mixture is concentrated and filtered through a pad of silica gel eluted with 10% EtOAc/Hexanes. The eluent is concentrated and chromatographed (330 g SiO2, 2% EtOAc/Hexanes) to yield the title compound (8.07 g, 81%) as an orange oil.