Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[CH2:2]([O:9][C:10]1[C:15](=[O:16])[CH:14]=[CH:13]O[C:11]=1[CH3:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[CH2:2]([O:9][CH:10]1[C:15](=[O:16])[CH:14]=[CH:13][N:1]=[C:11]1[CH3:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: N
Solvent: CCO
Product: CC1=NC=CC(=O)C1OCc1ccccc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
28% aqueous ammonia (100 ml) and 30 ml of ethanol were added to 3-benzyloxy-2-methyl-4-pyrone (40.6 g, 0.188 mol). The mixture was stirred at room temperature for 5 days. The reaction mixture was concentrated under the reduced pressure. The precipitate was filtered, and was then washed with a minor amount of ethyl acetate to give 32.2 g of 3-benzyloxy-2-methyl-4-pyridone as a light yellow crystal. The same compound was also obtained from the filtrate (5.6 g, yield 93%).
Reaction SMILES: [N:1]1[C:10]2C(=C[CH:7]=[CH:8][CH:9]=2)C=CC=1.[Br-:11].[CH3:12][O:13][N:14]=[C:15]([C:23]1[CH:28]=[CH:27][C:26](C)=[CH:25][CH:24]=1)[CH2:16][N+:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[Br-:11].[CH3:12][O:13][N:14]=[C:15]([C:23]1[CH:24]=[CH:25][C:26]([N:1]2[CH2:7][CH2:8][CH2:9][CH2:10]2)=[CH:27][CH:28]=1)[CH2:16][N+:17]1[C:18]2[C:19](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc2ncccc2c1
Reactant: CON=C(C[n+]1ccccc1)c1ccc(C)cc1
Agent: [Br-]
Solvent: CC(C)=O
Product: CON=C(C[n+]1cccc2ccccc21)c1ccc(N2CCCC2)cc1
Yield: 61 %

Procedure:
A solution of quinoline (149 μl, 1.26 mmol) and (8) (486 mg, 1.64 mmol) was refluxed in acetone (4 mL) for 5 days. A dark red solid was separated by filtration in 61% yield: mp 178-180° C.; 1H NMR 400 MHz (DMSO-d6) δ 1.90 (s, 4H), 3.15 (s, 4H), 3.99 (s, 3H), 6.39 (m, 4H), 7.36 (d, 2H, J=7.3 Hz), 8.05 (t, 1H, J=7.0 Hz), 8.18 (m, 1H), 8.30 (m, 2H), 8.46 (d, 1H, J=8.1 Hz), 9.29 (d, 1H, J=8.1 Hz), 9.65 (d, 1H, J=5.1 Hz); FABHRMS: found M+, 346.1920 (calcd for C22H24ON3: M+, 346.1914).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][C:21]=1[CH3:28])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:30]>C(Cl)Cl>[Br:30][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:21]([CH3:28])[CH:22]=1
Reactant: BrP(Br)Br
Reactant: Cc1cc(CO)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: ClCCl
Product: Cc1cc(CBr)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a stirred solution of [4-[(tert-butyl(diphenyl)silyl)oxymethyl]-3-methyl-phenyl]methanol (0.3 g, 0.76 mmol) in DCM (30 mL) is added phosphorus tribromide (0.072 mL, 0.76 mmol) at 0° C. and the reaction mixture is stirred for 1 hour. The reaction mixture is diluted with dichloromethane (50 mL), washed with aqueous sodium bicarbonate solution, dried over magnesium sulphate, and concentrated under vacuum to give the title compound as a light yellow liquid (0.3 g, crude). ESI/MS m/z 438.1 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([CH:10]=[CH:11][N:12]=3)[CH2:8]1)[C:4]([OH:6])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[NH:36]1[CH2:39][CH:38]([C:40]#[N:41])[CH2:37]1.CN1CCOCC1>CN(C=O)C>[CH3:1][CH:2]([CH3:20])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([CH:10]=[CH:11][N:12]=3)[CH2:8]1)[C:4]([N:36]1[CH2:39][CH:38]([C:40]#[N:41])[CH2:37]1)=[O:6]
Reactant: CC(C)[C@H](C(=O)O)N1Cc2ccnc3[nH]cc(c23)C1=O
Reactant: N#CC1CNC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC(C)[C@H](C(=O)N1CC(C#N)C1)N1Cc2ccnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
(R)-3-Methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoic acid (80 mg, 0.29 mmol), HOBt (54 mg, 0.35 mmol) and EDC (84 mg, 0.44 mmol) were combined in DMF (2 mL). Azetidine-3-carbonitrile HCl salt (52 mg, 0.44 mmol) and N-methylmorpholine (130 μL, 1.17 mmol) were added, and the solution was stirred at room temperature for 2 h. Purification by preparative HPLC (10-45% AcCN/water with 0.035% TFA) followed by purification by silica gel chromatography (8% MeOH/DCM) gave the title compound as a white solid (28 mg, 28%). 1H NMR (500 MHz, DMSO-d6) δ 0.90 (dd, J=6.5, 2.0 Hz, 3H), 1.06 (dd, J=6.5, 2.0 Hz, 3H), 2.42-2.51 (m, 1H), 3.61-3.75 (m, 1H), 4.15-4.68 (m, 4H), 4.95-5.21 (m, 3H), 7.09 (t, J=5.0 Hz, 1H), 7.81 (d, J=12.5 Hz, 1H), 8.27 (t, J=5.0 Hz, 1H). [M+H] calc'd for C18H19N5O2, 338; found, 338.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:34])[CH2:13][NH:14][C:15](=[O:33])[CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[N:22]=[CH:21]2.[CH2:35](N(CC)CC)C.C=O.[BH3-]C#N.[Na+]>CO>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:34])[CH2:13][NH:14][C:15](=[O:33])[CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH:27]1[CH2:32][CH2:31][N:30]([CH3:35])[CH2:29][CH2:28]1)[N:22]=[CH:21]2
Reactant: O=C(COc1ccc2c(cnn2C2CCNCC2)c1)NCC(O)CN1CCc2ccccc2C1
Reactant: CCN(CC)CC
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCC(n2ncc3cc(OCC(=O)NCC(O)CN4CCc5ccccc5C4)ccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-((1-(piperidin-4-yl)-1H-indazol-5-yl)oxy)acetamide (50 mg, 0.108 mmol) in MeOH (5 mL) was added triethylamine (1 mL), HCHO (30%)(0.3 mL), and HOAC (0.4 mL). The mixture was stirred at 25° C. for 30 min, then NaBH3CN (0.4 mg) was added, and the mixture was stirred at 25° C. for an additional 1 h, concentrated under reduced pressure, and purified by prep-HPLC to give N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-((1-(1-methylpiperidin-4-yl)-1H-indazol-5-yl)oxy)acetamide (51.1 mg, yield 99%) as a colorless oil. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.50 (br. s., 2H), 8.00 (s, 1H), 7.70 (d, J=8.78 Hz, 1H), 7.28-7.19 (m, 3H), 7.17-7.11 (m, 2H), 6.94 (dd, J=8.85, 1.82 Hz, 1H), 5.12 (s, 2H), 4.82 (br. s., 2H), 4.24-4.11 (m, 3H), 3.47-3.35 (m, 3H), 3.32 (br. s., 1H), 3.13-2.94 (m, 4H), 2.87 (s, 3H), 2.32-2.07 (m, 4H). LCMS (m/z): 478.3 [M+H]+
Reaction SMILES: [C:1]([C:5]1[CH:40]=[CH:39][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:20][C:19]([Cl:21])=[N:18][CH:17]=3)[C@@H:14]([C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[CH2:13][C@@:12]2([CH2:35][CH:36]([CH3:38])[CH3:37])[C:28]([O:30]C(C)(C)C)=[O:29])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:20][C:19]([Cl:21])=[N:18][CH:17]=3)[C@@H:14]([C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[CH2:13][C@@:12]2([CH2:35][CH:36]([CH3:37])[CH3:38])[C:28]([OH:30])=[O:29])=[O:10])=[CH:39][CH:40]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)C[C@@]1(C(=O)OC(C)(C)C)C[C@H](c2cnccn2)[C@H](c2cnc(Cl)s2)N1C(=O)c1ccc(C(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@]1(C(=O)O)C[C@H](c2cnccn2)[C@H](c2cnc(Cl)s2)N1C(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1, to afford the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[CH3:10][C@H:11]1[NH:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12]1>>[CH2:17]([N:13]1[CH2:14][CH2:15][N:16]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH3:9])[C@H:11]([CH3:10])[CH2:12]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CSc1ccccc1Br
Reactant: C[C@@H]1CN(Cc2ccccc2)CCN1
Product: CSc1ccccc1N1CCN(Cc2ccccc2)C[C@H]1C
Yield: 26 %

Procedure:
(2R)-4-Benzyl-2-methyl-1-(2-methylthiophenyl) piperazine was prepared in 26% yield from ortho-bromothioanisole and (R)-3-methyl-1-benzylpiperazine in a manner similar to Preparation 1A. LRMS (ESI+): 223.2 (M+1)
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:5]=2[CH:6]=1.[C:13]([NH:16][CH2:17][C:18](=O)[CH3:19])(=[O:15])[CH3:14]>C1C=CC=CC=1>[C:13]([NH:16][CH2:17][C:18]1([CH3:19])[C:8]2[NH:9][C:4]3[C:5]([C:7]=2[CH2:10][CH2:11][O:12]1)=[CH:6][CH:1]=[CH:2][CH:3]=3)(=[O:15])[CH3:14]
Reactant: OCCc1c[nH]c2ccccc12
Reactant: CC(=O)CNC(C)=O
Solvent: c1ccccc1
Product: CC(=O)NCC1(C)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tryptophol (3.86 g; II, R2, R3, R4, R5, R6 = H and X1 = OH) and acetamidoacetone (3.0 g), see R. H. Wileg and O. H. Borum, J. Amer. Chem. Soc., 70, 2005 (1948), in 300 ml of dry benzene is stirred and heated to reflux. Water is collected in a Dean-Stark trap. After removal of the water five drops of boron trifluoride-etherate is added and the mixture refluxed 30 min. using the water-separator again. After stirring at room temperature overnight, the reaction mixture is evaporated to dryness. The solid residue is dissolved in chloroform and washed successively with 10% aqueous sodium bicarbonate, water, and brine. The chloroform solution is dried over magnesium sulfate, filtered, and evaporated. The residue is crystallized from benzene to yield 1-(acetamidomethyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, m.p. 100° - 102° C. This product is dried under reduced pressure at 27° C. Spectroscopic and analytical data show that the compound is solvated with one mole of benzene which can be removed completly only by melting. Rf values of the amide and tryptophol are equal.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([OH:13])=[CH:10][CH:9]=[CH:8]2)[CH3:2].[CH3:14][O:15]C(Cl)Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([OH:13])=[CH:10][CH:9]=[C:8]2[CH:14]=[O:15])[CH3:2]
Reactant: CCc1cccc2cccc(O)c12
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCc1cccc2c(C=O)ccc(O)c12
Reaction time: 0.17 h

Procedure:
24.0 g of 8-ethyl-1-naphthol was dissolved in 200 ml of dichloromethane, in which 30.6 ml of titanium tetrachloride was gradually dropped under ice-cooling conditions. Thereafter, 20.3 ml of dichloromethyl methyl ether was gradually dropped under ice-cooling condition. After agitation for 10 minutes, 50 ml of water was gradually dropped under ice-cooling conditions. The reaction solution was extracted with ethyl acetate and the organic phase was washed with water. After drying with anhydrous magnesium sulfate, the solvent was distilled off and the resultant crystals were washed with a mixed solvent of chloroform and isopropyl ether (1:1) to obtain 15.9 g of the captioned compound as yellowish brown crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[S:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[CH:15]=2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].C(N(CC)CC)C.[Br:27][CH:28]([CH2:32][CH3:33])[C:29](Br)=[O:30]>C(Cl)Cl>[S:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[CH:15]=[C:11]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:29](=[O:30])[CH:28]([Br:27])[CH2:32][CH3:33])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: CCC(Br)C(=O)Br
Reactant: NC(=O)c1cc(N)ccc1-c1cc2ccccc2s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(Br)C(=O)Nc1ccc(-c2cc3ccccc3s2)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-2-(1-benzothien-2-yl)benzamide (Example 8A, 886 mg) and triethylamine (650 mg) are introduced into DCM (20 ml) at 0° C., and 2-bromobutyryl bromide (1000 mg) is slowly added. The reaction mixture is warmed to RT and then stirred overnight. The reaction mixture is subsequently diluted with DCM (100 ml) and washed with 5% strength potassium bisulfate solution (twice 50 ml), dried (sodium sulfate) and concentrated in a rotary evaporator. The residue is chromatographed on silica gel (eluent cyclohexane-ethyl acetate 10:1 to 1:1). After concentration of the relevant fraction, 607 mg (47% of theory) of product are isolated.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15]O)=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[Br:25]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:25][CH2:15][CH2:14][O:13][C:12]1[CH:17]=[CH:18][C:9]([O:8][CH2:7][C:4]2[CH:5]=[CH:6][C:1]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:2][CH:3]=2)=[CH:10][CH:11]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCOc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCOc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
800 mg of 2-[4-(biphenyl-4-ylmethoxy)phenoxy]ethanol are introduced into 25 ml of dichloromethane under argon, 1.16 g of tetrabromomethane are added, and the mixture is stirred at room temperture for 10 minutes. The mixture is cooled to 0° C. and, after addition of 1.83 g of triphenylphosphine, stirred at 0° C. for one hour and at room temperature for 2 hours. It is concentrated, and the residue is taken up in a little dichloromethane and filtered through silica gel. 480 mg of product are obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](O)=[O:12])=[CH:7][C:6]=1[Cl:16])(=[O:3])[CH3:2].S(Cl)(Cl)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([N:21]=[N+:22]=[N-:23])=[O:12])=[CH:7][C:6]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1Cl
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc(C=CC(=O)N=[N+]=[N-])cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
24.0 g (0.1 mol) of 4-acetoxy-3-chloro-cinnamic acid are suspended in 90 ml of benzene and 14.6 ml (0.2 mol) of thionyl chloride are added. The reaction mixture is heated to the boil for half an hour under a reflux condenser and thereafter the solvent and excess thionyl chloride are removed by distillation under reduced pressure. The residual crude 4-acetoxy-3-chloro-cinnamic acid chloride is dissolved in 100 ml of absolute 1,2-dimethoxyethane, 19.5 g (0.3 mol) of sodium azide are added and thereafter the mixture is stirred for 48 hours at room temperature. The inorganic salts are then filtered off and the filtrate is concentrated under reduced pressure at 30° C. Hereupon, colourless crystals separate out. The crystallisation is completed by adding ether. 4-Acetoxy-3-chloro-cinnamic acid azide of melting point 102°-103° C (decomposition) is thus obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1/[CH:17]=[CH:18]/[C:19]1[C:27]2[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=2)[N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[N:20]=1>>[N:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1/[CH:17]=[CH:18]/[C:19]1[C:27]2[C:22](=[CH:23][C:24](/[CH:28]=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:25][CH:26]=2)[N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[N:20]=1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2cnccn2)c2ccc(C=O)cc21
Reactant: O=C1Cc2ccccc2N1
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2cnccn2)c2ccc(/C=C3/C(=O)Nc4ccccc43)cc21

Procedure:
The title compound was synthesized according to the method of Example A19, utilizing indolin-2-one (10.0 mg, 0.075 mmol) and (E)-3-(2-(pyrazin-2-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (28 mg, 0.074 mmol). The crude mixture was concentrated under reduced pressure and purified by prepTLC (SiO2 2% MeOH/DCM) to provide the title compound to as a yellow material (20 mg, 55%); MS ESI 496.3 [M+H]+, calcd for [C28H29N5O2Si+H]+ 496.6.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Br)=[CH:5][CH:4]=1.[C-:13]#[N:14].[K+]>C(O)C.O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:13]#[N:14])=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 1.75 h
Yield: 101.3 %

Procedure:
A stirred solution of 250.0 grams (1.05 moles) of 4-trifluoromethylphenylmethyl bromide in 1000 mL of ethanol was heated to about 80° C., and a solution of 109.0 grams (1.67 moles) of potassium cyanide in about 275 mL of water was added. Upon completion of addition, the reaction mixture was stirred at 80° C. for about 1.75 hours. After this time the reaction mixture was cooled to ambient temperature and extracted with three portions of diethyl ether. The combined extracts were washed with two portions of water and one portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding about 197 grams of 4-trifluoromethylphenylacetonitrile.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:5]([C:12]1[CH:21]=[CH:20][C:15]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[Na+].[CH3:30][CH2:31][O:32][C:33]([CH2:35]Br)=[O:34]>O1CCCC1>[CH2:31]([O:32][C:33](=[O:34])[CH2:35][O:19][CH2:18][CH2:17][O:16][C:15]1[CH:14]=[CH:13][C:12]([C:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[C:4]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:3][CH2:2][Cl:1])=[CH:21][CH:20]=1)[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: OCCOc1ccc(C(=C(CCCl)c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COCCOc1ccc(C(=C(CCCl)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethanol (Compound II) (0.3 g, 0.79 mmol) was dissolved in tetrahydrofuran (5 ml) under a nitrogen atmosphere. Sodium hydride (0.058 g, 1.21 mmol) was added in THF (5 ml) to the solution and the mixture was stirred at room temperature for an hour. Then the mixture was cooled to 0° C., ethyl bromo acetate (0.4 g, 2.38 mmol) was added and the stirring was continued for 5 hours at 0-5° C. The mixture was allowed to warm up to room temperature and stirring was continued overnight. Then the reaction is quenched with water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate. The organic phase was washed with water, dried with sodium sulphate and evaporated to dryness. The residue was used in the next reaction step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][N-:53][CH2:54][CH:55]([OH:62])[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][N:53]([CH2:54][CH:55]([OH:62])[C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(C[N-]CC(O)c2ccccc2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CC(O)c2ccccc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.4 %

Procedure:
To a solution of 100 mg (0.62 mmol) of 1H-indole-7-carboxylic acid and 200 mg of TBTU (0.62 mmol) in 8 ml DMF, were added 0.53 ml (3.1 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 176 mg (0.62 mmol) of [rac]-(4-tert-butyl-benzyl)-(2-hydroxy-2-phenyl-ethyl)-amide were added. After stirring for 17 h at rt, the reaction mixture was diluted with 80 ml water and extracted with EtOAc (2×). The combined organic phases were washed with brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:4) to give 181 mg white solid (66%). MS (ISP) 427.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]([CH2:12][C:13](O)=[O:14])=[C:4]2[N:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=O.CN>O1CCCC1>[CH3:22][NH:24][C:13](=[O:14])[CH2:12][C:11]1[C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:9][N:5]2[C:6]([CH3:8])=[CH:7][C:2]([CH3:1])=[N:3][C:4]=12
Reactant: Cc1cc(C)n2nc(-c3ccccc3)c(CC(=O)O)c2n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)Cc1c(-c2ccccc2)nn2c(C)cc(C)nc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 3.0 g (0.011 mole) of 5,7-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidine-3-acetic acid and 1.73 g (0.011 mole) of 1,1'-carbonyldiimidazole in 120 ml of anhydrous tetrahydrofuran was stirred at room temperature for 4 hours while a stream of nitrogen was bubbled through the mixture. The clear solution which formed was treated with a solution of monomethylamine in tetrahydrofuran (12.8 ml; 0.033 mole; 2.59M) and the mixture stirred at room temperature for 17 hours under nitrogen.
Reaction SMILES: CN(C)C(=CC=C(C1C=CC=CC=1)C(OCC)=O)C(OCC)=S.F[B-](F)(F)F.[CH3:29][N:30]([CH3:42])[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:32][CH:33]=[N+](C)C.CC[O-].[Na+].[CH3:47][C:48]1[CH:61]=[CH:60][C:51]([CH2:52][S:53][CH2:54][C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:50][CH:49]=1>C(O)C>[CH3:29][N:30]([CH3:42])[C:31](=[CH:32][CH:33]=[C:54]([S:53][CH2:52][C:51]1[CH:60]=[CH:61][C:48]([CH3:47])=[CH:49][CH:50]=1)[C:55]([O:57][CH2:58][CH3:59])=[O:56])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Reactant: CCOC(=O)CSCc1ccc(C)cc1
Agent: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: CC[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: CCOC(=O)C(=CC=C(C(=O)OCC)N(C)C)SCc1ccc(C)cc1
Yield: 66.5 %

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (5.7 g), a 2M ethanolic solution of sodium ethylate (10 cc) and ethyl (4-methylbenzylthio)acetate (4.5 g) in ethanol (50 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (50:50 by volume) as eluent, diethyl 2-dimethylamino-5-(4-methylbenzylthio)-2,4-hexadienedioate (5 g) is obtained in the form of a yellow oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: C([O:8][C:9](=[O:39])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:22][CH:21]=1)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1>[Pd].C(O)C>[C:12]([NH:11][C@H:10]([C:9]([OH:39])=[O:8])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:22][CH:21]=1)([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1)C(=O)O
Reaction time: 23.5 h

Procedure:
A mixture of N-Boc-para-(2'-t butoxycarbonylphenyl)phenylalanine-benzyl ester and 10% Palladium on charcoal (0.030 g) in ethanol 20 mL was hydrogenated at 35 psi for 23.5 hours. The reaction mixture was filtered through celite and evaporated to dryness to give the N-Boc-para-(2'-t butoxycarbonylphenyl)phenylalanine (0.175 g).