Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:33]=[CH:32][C:16]([O:17][C:18]([CH:20]([NH:24]C(=O)OC(C)(C)C)[CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:15][CH:14]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][CH:20]([CH:21]([CH3:23])[CH3:22])[C:18]([O:17][C:16]1[CH:32]=[CH:33][C:13]([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:14][CH:15]=1)=[O:19]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)Oc1ccc(C2(c3ccccc3)CCCCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(N)C(=O)Oc1ccc(C2(c3ccccc3)CCCCC2)cc1

Procedure:
To a stirred solution at room temperature of tert-butyl 1-((4-(1-phenylcyclohexyl)phenoxy)carbonyl)-2-methylpropylcarbamate (142 mg, 0.31 mmol) in dry DCM (3 mL) was added TFA (300 μL), which caused gas evolution. Stirring was continued. After 1 h the reaction mixture was concentrated in vacuo to afford 96 mg (0.21 mmol; 67%) of colourless oil. LC-MS purity (UV/MS): 92/97%, Rt 5.45 min, M+1: 352.49. 1H NMR (400 MHz, CDCl3): 11.12 (br s), 7.76 (br s), 7.29 (d, 2H, J=8.8Hz), 7.27 (d, 4H, J=4.8 Hz), 7.13-7.16 (m, 1H), 6.95 (d, 2H, J=8.8 Hz), 6.16(d, 1H, J=4.0 Hz), 2.40-2.48 (m, 1H), 2.18-2.33 (m, 4H), 1.50-1.58 (m, 6H), 1.05-1.08 (m, 6H).
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][O:8][C:9]([CH:11](P(OCC)(OCC)=O)[F:12])=[O:10].[CH2:21]([C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:36][CH3:37])=[C:30]([C:33](=O)[CH3:34])[CH:31]=2)[O:26][C:25]([CH3:39])([CH3:38])[CH:24]=1)[CH3:22]>C1COCC1>[CH2:21]([C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:36][CH3:37])=[C:30](/[C:33](/[CH3:34])=[C:11](/[F:12])\[C:9]([O:8][CH2:7][CH3:6])=[O:10])[CH:31]=2)[O:26][C:25]([CH3:39])([CH3:38])[CH:24]=1)[CH3:22]
Reactant: CCC1=CC(C)(C)Oc2cc(OC)c(C(C)=O)cc21
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OC)OC(C)(C)C=C2CC
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
To a solution of n-butyllithium (2.5 M in hexanes, 1.3 mL, 3.28 mmol) in THF (5 mL) at 0° C. was slowly added triethyl-2-fluoro-2-phosphonoacetate (700 mg, 2.89 mmol). The solution was stirred for 10 min at −40° C. The mixture was cooled to −78° C., and a solution of 1-(4-ethyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-ethanone (Compound 53, 222 mg, 0.97 mmol) in THF (5 mL) was added by cannula. After stirring at 0° C. for 4 h, the reaction mixture was quenched with water. The product was extracted with ethyl acetate and the combined extracts were washed with water and brine, and dried over Na2SO4. The solution was filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 10% ethyl acetate in hexane) to produce the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10](Cl)=[CH:9][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:7][C:6]=12.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][NH2:33])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][NH:33][C:10]2[N:5]3[N:4]=[CH:3][C:2]([Br:1])=[C:6]3[N:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Clc1ccccc1-c1cc(Cl)n2ncc(Br)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(-c3ccccc3Cl)nc3c(Br)cnn23)CC1
Temperature: 75 °C
Yield: 101.2 %

Procedure:
3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (300 mg, 0.875 mmoles) (prepared as described in Preparative Example 129) was dissolved in anhydrous 1,4-dioxane (6.8 mL). 4-(aminomethyl)piperidine-1-carboxylic acid tert-butyl ester (225 mg, 1.05 mmoles) and diisopropyl ethylamine (0.3055 mL, 1.75 mmoles) were added and the mixture was heated at 75° C. for 24 h. The solution was evaporated to dryness and the residue was chromatographed on a silica gel column (15×5 cm) using dichloromethane as the eluant to give 4-{[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester (461.2 mg, 100%): FABMS: m/z 520.1 (MH+); HRFABMS: m/z 520.1111 (MH+). Calcd. for C23H28N5O2BrCl: m/z 520.1115; δH (CDCl3) 1.30 (2H, m, CH2), 1.51 (9H, s, —COOC(CH3)3), 1.85 (2H, d, CH2), 1.95 (1H, m, CH), 2.76 (2H, m, CH2), 3.40 (2H, m, CH2), 6.37 (1H, s, H6), 6.55 (1H, m, NH), 7.42 (2H, m, Ar—H), 7.52 (1H, m, Ar—H), 7.76 (1H, m, Ar—H) and 8.07 ppm (1H, s, H2); δC (CDCl3) CH3: 28.5, 28.5, 28.5; CH2: 29.1, 29.1, 43.5, 43.5, 47.9; CH: 36.3, 87.5, 127.2, 130.2, 130.3, 131.6, 143.9; C: 79.7, 83.3, 132.1, 138.6, 145.4, 146.3, 154.7, 158.1.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN1CCN(C)CC1

Procedure:
Using 3.9 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138) and 24 ml of 1-methylpiperazine, a reaction similar to that conducted in Example 142 was carried out. As a result, 2.24 g of N-(trans-4-methylcyclohexyl)-4-[2-(4-methylpiperazinyl)ethoxy]-3-methoxycinnamamide (a compound of the present invention) was obtained as light-brownish white crystal, which had the following physioche mical properties:
Reaction SMILES: N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:13][O:14][C:15]([CH2:17][C:18]1[CH2:19][S:20][C@@H:21]2[C@H:41]([NH:42]C(=O)COC3C=CC=CC=3)[C:40](=[O:53])[N:22]2[C:23]=1[C:24]([O:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:16].P([O-])(O)(O)=O.[K+]>C(Cl)Cl.CO>[CH3:13][O:14][C:15]([CH2:17][C:18]1[CH2:19][S:20][C@@H:21]2[C@H:41]([NH2:42])[C:40](=[O:53])[N:22]2[C:23]=1[C:24]([O:26][CH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:25])=[O:16]
Reactant: COC(=O)CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 3 h

Procedure:
4.4 ml of pyridine and 44 ml of an 8% strength suspension of phosphorus pentachloride in methylene chloride are added to a solution, which has been cooled to -17°, of 3.10 g (5.42 mmols) of diphenylmethyl 3-methoxycarbonylmethyl-7β-phenoxyacetylamino-3-cephem-4-carboxylate in 110 ml of methylene chloride and the mixture is then stirred for 3 hours in an ice bath. After cooling to -30°, 27 ml of absolute methanol are added and the residue mixture is stirred for 1 hour at -10°, for 1 hour at 0° and for 1 hour at room temperature. The pH is adjusted to 2.5 by adding a 0.5 M solution of potassium dihydrogen phosphate, the mixture is stirred for a further 0.5 hour and, for working up, the organic phase is separated off, the aqueous phase is subsequently extracted with twice 50 ml of methylene chloride and the combined methylene chloride phases are extracted by shaking with a saturated solution of sodium chloride, dried over sodium sulphate and evaporated. Chromatography of the crude product over 100 g of silica gel and elution with toluene and 20-30% of ethyl acetate gives amorphous diphenylmethyl 3-methoxycarbonylmethyl-7β-amino-3-cephem-4-carboxylate, which according to thin layer chromatography is a single compound and which is characterised in the form of the crystalline toluenesulphonate; melting point 157°- 158° (decomposition); Rf 0.45 (on silica gel, with ethyl acetate); UV spectrum (in ethanol): λmax =257 nm; IR spectrum (in Nujol): bands at 2.87, 5.57, 5.72, 5.79 and 6.12μ.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][S:4]/[C:3]/1=[N:8]\[N:9]=[CH:10]\[C:11]1[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=1.[S:17]([O:22]C)([O:20][CH3:21])(=[O:19])=[O:18]>CC(C)=O>[CH3:21][O:20][S:17]([O-:22])(=[O:19])=[O:18].[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][S:4]/[C:3]/1=[N:8]\[N:9]=[CH:10]\[C:11]1[N:15]([CH3:21])[CH:14]=[CH:13][N+:12]=1[CH3:16]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cs/c(=N\N=C\c2nccn2C)n1C
Solvent: CC(C)=O
Product: COS(=O)(=O)[O-]
Product: Cc1cs/c(=N\N=C\c2n(C)cc[n+]2C)n1C

Procedure:
1.40 g (5.95 mmol) of (2Z)-3,4-dimethyl-2-{(2E)-[(1-methyl-1H-imidazol-2-yl)methylidene]hydrazono}-2,3-dihydro-1,3-thiazole from Step 1 and 7.58 9 (59.50 mmol) [sic] of dimethyl sulfate in acetone were heated at reflux for 2 hours. After the solvent was removed, the precipitate was suction-filtered off, washed with ethyl acetate and dried under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:10][C:11]2[N:12]([C:14](=O)[NH:15][N:16]=2)[N:13]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:14]1[N:12]2[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[CH:10][C:11]2=[N:16][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Product: Clc1ccc(-c2cc3nnc(Cl)n3nc2-c2ccccc2Cl)cc1
Temperature: 130 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
A suspension of 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (1.0 g, 2.8 mmol) in phosphorus oxychloride (10 mL) was stirred at 130° C. for 6 h. Analysis by HPLC/MS indicated the starting material had been consumed. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with CH2Cl2, the resulting solution washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure to afford 1.1 g (100%) of the title compound as an off-white solid. HPLC/MS (method A): retention time=3.52 min, (M+H)+=375.0.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+]>>[CH3:1][C:2]1[CH:11]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CC(=O)Nc1cc(C)nc2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1cc(C)nc2c1CCCC2
Yield: 78.6 %

Procedure:
Reaction of N-(2-methyl-quinolin-4-yl)acetamide (136 mg, 0.679 mmol) using the general procedure for small scale hydrogenations (workup with NaOH in place of saturated NaHCO3) provided N-(2-methyl-5,6,7,8-tetrahydroquinolin-4-yl) acetamide (109 mg, 78%): 1H NMR δ 1.83-1.90 (m, 4H), 2.21 (s, 3H), 2.47 (s, 3H), 2.46-2.2.53 (m, 2H), 2.84-2.87 (m, 2H), 7.18 (br s, 1H), 7.82 (br s, 1H); 13C NMR δ 22.7,22.8,23.5,24.6,25.3, 33.1, 112.3,117.3, 143.7, 156.4, 157.3, 169.0; MS m/z: 205 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](Cl)(=[O:11])[CH3:10].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:9][C:10]1[NH:1][C:2]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][N:3]=2.[C:9]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1)(=[O:11])[CH3:10]
Reactant: Cc1cccnc1N
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ncccc1C
Product: Cc1cc2cccnc2[nH]1

Procedure:
2-methyl-7-azaindole was prepared in two steps. First, 2-amino-3-picoline was reacted with acetyl chloride in toluene in the presence of pyridine to produce 2-acetamido-3-picoline in 65% yield. Second, pyrolysis of 2-acetamido-3-picoline in N-methylaniline in the presence of NaH at 280° C. was performed to produce 2-methyl-7-azaindole (FIG. 18) in 23% yield. This compound was characterized by NMR spectroscopy.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:12]([O-])([OH:14])=[O:13]>>[N+:12]([C:6]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][NH:1][CH2:2][CH2:3][C:4]=2[CH:5]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)CCCCN2
Product: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Reaction time: 1 h

Procedure:
1,2,4,5-Tetrahydro-3H-benzazepine (1 g) (See P. Ruggli et al., Helv. Chim. Acta, 18, 1388, [1935]) was added slowly dropwise to stirred fuming nitric acid (25 ml) at −10° C. Stirring was continued at −10° C. for 1 hour and the reaction mixture was then poured onto ice, the precipitate collected by filtration and dried to give the title compound as the nitrate salt, 1.4 g. This was suspended in water, cooled to 5° C. and neutralised with 5M sodium hydroxide. The precipitate was collected by filtration, recrystallised from water and dried, affording the title compound D1a as a white solid (0.6 g)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21]1[CH2:25][O:24][CH2:23][CH2:22]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[CH:13]([C:14]([C:15]1[CH:11]=[CH:12][C:22]3[C:17](=[CH:9][CH:10]=[C:25]([O:24][CH3:23])[CH:21]=3)[CH:16]=1)=[O:18])[CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCc2cc(OCc3ccccc3)ccc21
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2cc(C(=O)C3Cc4cc(OCc5ccccc5)ccc4C3=O)ccc2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5-Benzyloxyindanone (1.5 g, 6.29 mmol) was treated with NaH (60%, 377 mg) in THF (50 mL), and then Example 168A (1.59 g) was added. The reaction was stirred for 6 hours at room temperature. The precipitates were collected by filtration and dissolved in water, acidified with concentrated HCl, and the resulting precipitates were collected, washed with water and dried to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][CH3:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:8]=2[N:9]=[CH:10][N:11]=1.[C:29](Cl)(=[O:33])[C:30](Cl)=[O:31].[N:35]1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[C:7]2[C:14]([C:29](=[O:33])[C:30]([NH2:35])=[O:31])=[C:13]([CH2:15][CH3:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=3)[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCc1cc2c(OCC(=O)OC)ncnc2n1Cc1cccc(C(F)(F)F)c1
Reactant: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)ncnc2n1Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
To a suspension of 115 mg (0.29 mmol) of [[6-ethyl-7-[[3-(trifluoromethyl)phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester in 3 mL of chloroform was added 0.102 mL of oxalyl chloride followed by 0.094 mL of pyridine. The reaction was stirred for 48 hours at ambient temperature then an additional 0.100 mL of oxalyl chloride and 0.100 mL of pyridine was added. This mixture was stirred and additional 4 days then quenched into solution prepared from 4 mL of water and 2 mL of concentrated ammonium hydroxide. The mixture was partitioned by the addition of 20 mL of ethyl acetate and 10 mL of water. The organic phase was dried with sodium sulfate and concentrated to 108 mg of crude solid. The residue was purified by flash chromatography (7 g of silica, ethyl acetate) to provide 72 mg (53%) of [[5-(aminooxoacetyl)-6-ethyl-7-[[3-(trifluoromethyl)phenyl]-methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a white solid. nmr (500 MHz, CDCl3) δ1.15 (t, J=7.5 Hz, 3H), 2.96 (q, J=7.5 Hz, 2H), 3.78 (s, 3H), 5.07 (s, 2H), 5.57 (s, 2H), 5.68 (br s, 1H), 6.60 (br s, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.54 (s, 1H), 7.55 (d, J=7.8 Hz, 1H), 8.46 (s, 1H)
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH:27]1([CH2:30][N:31]2[CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=[N:32]2)[CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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.O>[CH:27]1([CH2:30][N:31]2[CH:35]=[C:34]([C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]5[CH:17]=[C:16]([N:18]6[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]6)[N:15]=[C:14]([NH2:25])[N:13]=5)[CH2:9]4)=[CH:4][CH:3]=3)[CH:33]=[N:32]2)[CH2:29][CH2:28]1
Reactant: CC1(C)OB(c2cnn(CC3CC3)c2)OC1(C)C
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
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: O
Solvent: C1COCCO1
Solvent: CO
Product: CC1Cc2ccc(-c3cnn(CC4CC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2 (1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.1 mg, 0.029 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling it was diluted with methanol. After filtration the filtrate was purified with RP-HPLC (pH=10) to afford the desired product (5.3 mg). LCMS (M+H)+: m/z=459.3.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]#[N:21])[CH:15]=[CH:16][C:17]=1[Cl:18].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl.[OH-:30].[Na+]>C(OC)(C)(C)C.C(O)(C)C.O>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:19]([C:20]#[N:21])([C:14]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:30])[CH3:28]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: [OH-]
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(Cl)c(Cl)c1
Temperature: -10 °C

Procedure:
Cool a solution of sodium bis(trimethylsilyl)amide (480 lb, 1 M in THF) to about −10° C. and stir. Add a solution of 3,4-dichlorophenylacetonitrile in methyl t-butyl ether (34.5% by weight, 125 lb of solution) at such a rate that the temperature of the reaction mixture does not rise above about 10° C. Combine ethyl bromoacetate (94 lb) and methyl t-butyl ether (about 125 lb) and cool to about −18° C. and then add the solution prepared above over 60-90 minutes. After the reaction is complete, as determined by chromatography, add water (18 gal). Add a 12 M aqueous hydrochloric acid solution until the pH is about 4. If the pH falls below 3, use 20% aqueous sodium hydroxide solution to raise the pH to about 4. Separate the layers and extract the organic layer with brine. Evaporate in vacuo at about 40° C. to give a residue. Combine the residue and isopropanol (about 45 lb) and evaporate in vacuo at about 40° C. to give a residue. Add isopropanol (190 lb), warm to about 35° C, and then cool to about −10° C. to give a solid. Collect the solid by filtration, rinse with cold isopropanol, and centrifuge to give the title compound as a wet cake containing isopropanol.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[Na+].CO>[Pd].C(OCC)(=O)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccccc3)ccc2c1O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reaction time: 15 h
Yield: 77.1 %

Procedure:
A mixture of 208 mg of 1-Bromo-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (0.5 mmol), 49 mg of sodium acetate (0.6 mmol), 50 mg of 10 wt % palladium on charcoal, 10 ml of methanol, and 5 ml of ethyl acetate was stirred under hydrogen at 1 atm for 15 h. Then the mixture was filtered by suction through a pad of celite and was concentrated in vacuo. The residue was partitioned between 2 ml of half concentrated aqueous bicarbonate solution and 8 ml of ethyl acetate. The organic phase was dried over MgSO4. Evaporation in vacuo gave 130 mg of the title compound; 1H NMR (CDCl3): δ=11.89 (bs, 1H), 8.61 (s, 1H), 8.36 (d, 1H), 7.10 to 7.53 (m, 7 H), 4.49 (t, 2 H), 1.87 (m, 2 H), 1.47 (m, 2 H), 0.98 (t, 3 H).
Reaction SMILES: [C:1]([NH:20][C@H:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:22][OH:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[C:38]([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH2:30]([O:23][C@H:22]([CH3:38])[C@@H:21]([C:24]([O:26][CH3:27])=[O:25])[NH:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl N-trityl-L-serinate (136 g, 376 mmol) was dissolved in DMF (230 mL) and added dropwise to a stirred mixture of NaH (60% oil dispersion, 30.0 g, 752 mmol) and benzyl bromide (67.0 mL, 564 mmol) in 700 mL of DMF at 0° C. The resulting white suspension was stirred at 0° C. for 1 hour followed by the addition of saturated aqueous NaHCO3 solution. The reaction mixture was diluted with H2O and extracted repeatedly with Et2O. The combined organic layers were washed successively with H2O and brine, dried over MgSO4 and concentrated under reduced pressure to give 137 g of methyl O-benzyl-N-trityl-L-threoninate as a cloudy oil.
Reaction SMILES: [OH:1][C@:2]([CH3:11])([CH2:9][OH:10])[C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4].CO[C:14](OC)([CH3:16])[CH3:15].O.CC1C=CC(S(O)(=O)=O)=CC=1>>[CH3:8][O:7][N:5]([CH3:6])[C:3]([C@@:2]1([CH3:11])[CH2:9][O:10][C:14]([CH3:16])([CH3:15])[O:1]1)=[O:4]
Reactant: CON(C)C(=O)[C@](C)(O)CO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CON(C)C(=O)[C@@]1(C)COC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
(R)-2,3-dihydroxy-N-methoxy-N,2-dimethylpropanamide (32 g, 196 mmol) was dissolved in 2,2-dimethoxypropane (241 ml, 1961 mmol) and 4-methylbenzenesulfonic acid hydrate (3.73 g, 19.6 mmol) was added and stirred at ambient temperature overnight. The reaction was partitioned between saturated aqueous sodium bicarbonate and CH2Cl2, extracted with CH2Cl2, dried over sodium sulfate, filtered and concentrated to afford (R)-N-methoxy-N,2,2,4-tetramethyl-1,3-dioxolane-4-carboxamide (22.9 g, 113 mmol, 57.5% yield).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.Br[C:13]1[CH:22]=[N:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]>>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([CH2:3][NH:2][C:19]2[CH:20]=[N:21][CH:22]=[CH:13][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:5][CH:6]=1)#[N:9]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(=O)c1ccncc1Br
Agent: Cl
Product: COC(=O)c1ccncc1NCc1ccc(C#N)cc1
Yield: 4 %

Procedure:
The title compound was prepared in 4% yield from 4-(aminomethyl)-benzonitrile hydrochloride and methyl 3-bromoisonicotinate according to the procedure for Preparation 4A. 1H NMR (500 MHz, CDCl3): δ 8.07 (s, 1H), 7.97 (d, 2H, J=5.0 Hz), 7.63-7.70 (m, 3H), 7.46 (d, 2H, J=8.3 Hz), 4.61 (d, 2H, J=6.1 Hz), 3.94 (s, 3H). [M+H] calc'd for C15H13N3O2, 268. found 268.