Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1.[Li]CCCC.[B:15](OCC)([O:19]CC)[O:16]CC>O1CCCC1>[CH2:8]([C:5]1[N:6]=[CH:7][C:2]([B:15]([OH:19])[OH:16])=[CH:3][CH:4]=1)[CH3:9]
Reactant: CCc1ccc(Br)cn1
Reactant: CCOB(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(B(O)O)cn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Into a 500-mL 3-necked round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed 5-bromo-2-ethylpyridine (3 g, 16.12 mmol, 1.00 equiv) and tetrahydrofuran (200 mL). To the resulting mixture was then added n-BuLi (8.4 mL, 2.5 M) dropwise with stirring at −78° C. The resulting solution was stirred for 30 min at −78° C. in an ethanol/N2 bath. To the resulting mixture was then added triethyl borate (4.7 g, 32.19 mmol, 2.00 equiv) dropwise with stirring at −78° C. The resulting solution was allowed to react, with stirring, overnight at room temperature. The reaction was then quenched by the addition of methanol (20 mL) and water (0.5 mL). The resulting mixture was then concentrated under vacuum. The resulting solution was diluted with methanol (10 mL). The resulting residue (10 mL) was purified by Flash-Prep-HPLC (reversed column) with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, A:water with trifluoroacetic acid (0.05%); B: MeCN=1/100 increasing to A:water with trifluoroacetic acid (0.05%); B: MeCN=20/100 within 25 min; Detector, UV 254 nm to yield of (6-ethylpyridin-3-yl)boronic acid as a white solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:16][CH2:17]CC1CCC(=O)CC1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(P(N(C)C)(N(C)C)=[O:30])C.C(C(OC)=O)#N>C1COCC1>[CH3:17][O:16][C:9]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:30]
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: O=C1CCC(CCOCc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: COC(=O)C#N
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1CCCCC1
Temperature: 0 °C

Procedure:
A solution of LDA (33 ml, 1.5 M in Et2O) in THF (50 mL) at −78° C. was treated with 4-(2-benzyloxy-ethyl)-cyclohexanone (9.5 g, 40.2 mmol). The mixture was warmed to 0° C. over 30 min. before re-cooling to −78° C. and adding HMPA (7 mL). Methyl cyanoformate (CNCO2Me, 4.1 mL, 85 mmol) was added and the mixture was stirred for 15 m before aqueous quench and work-up. The product was purified by chromatography on SiO2 with 10% EtOAc:Hx. 5-(2-Benzyloxy-ethyl)-2-oxo-) cyclohexanecarboxylic acid methyl ester was isolated, 5.8 g (49%).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH2:18][NH:19][S:20]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][C:31](Cl)=[O:32])[CH:26]=[CH:27][CH:28]=3)(=[O:22])=[O:21])=[CH:17][C:12]=2[O:11][CH2:10]1>O1CCCC1>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH2:18][NH:19][S:20]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][C:31]([NH:2][OH:3])=[O:32])[CH:26]=[CH:27][CH:28]=3)(=[O:22])=[O:21])=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: NO
Reactant: O=C(Cl)C=Cc1cccc(S(=O)(=O)NCc2ccc3c(c2)OCO3)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1cccc(S(=O)(=O)NCc2ccc3c(c2)OCO3)c1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.37 g, 5.40 mmol) in tetrahydrofuran (6 ml) a saturated NaHCO3 solution (4.5 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-{3-[(benzo[1,3]dioxol-5-ylmethyl)-sulfamoyl]-phenyl}-acryloyl chloride (0.41 g) in tetrahydrofuran (4 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was crystallised from ethyl acetate and washed with diethyl ether affording the title compound (0.14 g, 35%). M.p. 163° C. 1H NMR (DMSO-d6, HMDSO) δ: 3.92 (2H, d, J=6.4 Hz); 5.92 (2H, s); 6.49 (1H, d, J=16.0 Hz); 6.67 (3H, s); 7.34-7.89 (5H, m); 8.12 (1H, t, J=6.4 Hz); 9.07 (1H, br s); 10.78 (1H, br s). HPLC analysis on Symmetry C8 column: impurities 3.5% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 30:70; sample concentration 0.25 mg/ml; flow rate 1.2 ml/min; detector UV 254 nm). Anal. Calcd for C17H16N2O6S, %: C, 54.25; H, 4.28; N, 7.44. Found, %: C, 54.19; H, 4.20; N, 7.33.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([Cl:19])=[N:5][CH:6]=[CH:7][C:8]=1[NH:9][CH2:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[F:18].[N:20]([O-])=O.[Na+].[OH-].[NH4+]>C(O)C>[Cl:19][C:4]1[C:3]2[N:2]=[N:20][N:9]([CH2:10][C:11]3[C:12]([F:18])=[CH:13][CH:14]=[CH:15][C:16]=3[F:17])[C:8]=2[CH:7]=[CH:6][N:5]=1
Reactant: O=N[O-]
Reactant: Nc1c(NCc2c(F)cccc2F)ccnc1Cl
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: Fc1cccc(F)c1Cn1nnc2c(Cl)nccc21
Temperature: 5 °C
Reaction time: 0.58 h

Procedure:
A 3-L flask equipped with a thermometer and mechanical stirrer was charged with concentrated hydrochloric acid (140 mL), 1N hydrochloric acid (380 mL) and absolute ethanol (1.10L) and cooled to 5° C. in an ice bath. 3-Amino-2-chloro-4-[(2,6-difluorobenzyl) amino]pyridine(40 g, 0.15mol)(from example 1B) was added followed by the addition of sodium nitrite(13.3 g, 0.19 mol). The solution was stirred for 35 minutes at 5° C., ammonium hydroxide was added to pH9, and the solution extracted with chloroform (2×1.00L). The combined organic extracts were dried (sodium sulphate) and concentrated to produce 4-chloro-1-(2,6-difluorobenzyl)-1H-1,2,3- triazolo[4,5-c]pyridine as a damp pink solid in quantitative yield, sufficiently pure for further reaction. A sample was purified by flash column chromatography to give the analytical sample, mp.=133°-139° C. 1H NMR (DMSO-d6): 6.10 (s, 2H, CH2), 7.10-7.65(m, 3H, C-3'H, C-4'H, C-5'H), 7.95 (d, J=5.9 Hz, 1H, C-7H), 8.43 (d, J=5.9 Hz, 1H, C-6H).
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:17]=[CH:18][C:4]1=2)[CH3:2].[CH3:27][N:28](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn]>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([C:27]#[N:28])[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C#N)ccc21
Temperature: 170 °C

Procedure:
Trifluoromethanesulfonic acid 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-yl ester (0.12 g), zinc cyanide (70 mg), tris(dibenzylideneacetone)dipalladium (7 mg), 1,1′-bis(diphenylphosphino) ferrocene (8 mg), and zinc powder (2 mg) were added to DMF (1 ml), and the mixture was heated for 20 minutes at 170° C. (microwave reactor). The reaction liquid was cooled to room temperature, and subjected to celite filtration. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50→0:100). The purified product was condensed under reduced pressure to give the title compound (77 mg) as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:7]=[C:6]([SH:8])[S:5][N:4]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH:26][CH:27]([CH2:32][CH:33]3[O:35][CH2:34]3)[C:28]([O:30]C)=[O:29])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([NH:26][CH:27]([CH2:32][CH:33]([OH:35])[CH2:34][S:8][C:6]3[S:5][N:4]=[C:3]([S:2][CH3:1])[N:7]=3)[C:28]([OH:30])=[O:29])(=[O:24])=[O:25])=[CH:21][CH:22]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: CSc1nsc(S)n1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nc(SC)ns3)C(=O)O)cc2)cc1

Procedure:
Example 38 is prepared from 3-methylmercapto-5-mercapto-1,2,4-thiadiazole and 1d using the procedure described for compound 20.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[CH3:13][O:14][C:15]1[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][C:16]=1[CH:17]=[CH:18][C:19](O)=O>>[CH3:13][O:14][C:15]1[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][C:16]=1/[CH:17]=[CH:18]/[C:19]1[NH:1][C:2]2[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1C
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Product: COc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(C)c(=O)n3C)c(OC)c1C
Yield: 27.7 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 1.0 g (5.88 mmol) of 5,6-diamino-1,3-dimethyluracil and 1.44 g (6.45 mmol) of 2,4-dimethoxy-3-methylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 581 mg (yield 28%) of Compound 94 as pale yellow needles.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.B(F)(F)F.[C:34]1([OH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:19][CH2:20][C:21]([C:37]4[CH:38]=[CH:39][C:34]([OH:40])=[CH:35][CH:36]=4)([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:22][CH2:23]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Oc1ccccc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CC=C(c2ccccc2)CC1
Agent: FB(F)F
Solvent: O
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC(c2ccccc2)(c2ccc(O)cc2)CC1

Procedure:
4-Phenyl-3,6-dihydro-2H-pyridine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (200 mg, 0.52 mmol) was treated with a drop of BF3*H3PO4 and phenol (200 mg, 2.1 mmol) at 60° C. for 6 h. Water (10 mL) was added and aqueous phase was extracted dichloromethane (2×10 mL). The combined organic phase was concentrated. 1H nmr indicated full conversion of the starting material. The desired product was isolated after flash chromatography. Yield: 270 mg. LC/MS purity (UV/MS): 96/91%, Rt 7.32 min. M+1: 432.
Reaction SMILES: ClCCl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[C:9](Cl)=[O:10].[NH2:19][C:20]1[N:25]2[N:26]=[CH:27][CH:28]=[C:24]2[N:23]=[C:22]([CH2:29][CH2:30][CH:31]([O:33][Si](C)(C)C)[CH3:32])[CH:21]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[OH:33][CH:31]([CH3:32])[CH2:30][CH2:29][C:22]1[CH:21]=[C:20]([NH:19][C:9](=[O:10])[C:8]2[CH:7]=[C:6]([O:5][CH3:4])[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=2)[N:25]2[N:26]=[CH:27][CH:28]=[C:24]2[N:23]=1
Reactant: CC(CCc1cc(N)n2nccc2n1)O[Si](C)(C)C
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(=O)Nc2cc(CCC(C)O)nc3ccnn23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
A dry dichloromethane solution (5 ml) containing 650 mg of 3,4,5-trimethoxybenzoyl chloride was slowly added dropwise to 5 ml of a pyridine solution containing 520 mg of the crystals obtained in step (7), and stirred at room temperature for 2 hours. After completion of the reaction, a saturated aqueous NaHCO3 solution was added and the reaction mixture was extracted with dichloromethane. The organic layer was collected and washed with a 1N aqueous hydrochloric acid until the pH of the water layer became about 1. The organic layer was allowed to stand for 2 hours, washed with water and a saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-n-hexane to provide 480 mg of the object compound as colorless crystals. Table 2 shows the structure and melting point of the compound obtained.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Br)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[NH3:14]>O1CCOCC1>[N+:11]([C:6]1[CH:7]=[C:8]2[CH2:9][NH:14][CH2:2][CH2:3][N:4]2[N:5]=1)([O-:13])=[O:12]
Reactant: N
Reactant: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc2n(n1)CCNC2
Temperature: 50 °C
Yield: 100 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 125c (4 g, 12.9 mmol) 0.5M ammonia solution in dioxane (200 mL). The resulting mixture was carefully heated to 50° C. overnight. After this time, the reaction mixture was concentrated under reduced pressure, and to the residue was added H2O (50 mL) and EtOAc (50 mL). The aqueous layer was separated and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate. The resulting solution was concentrated under reduced pressure to afford a 100% yield (2.1 g) of crude 125d.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][N:5]2[CH:22]=1.[CH:23](=O)[CH2:24][CH2:25][CH3:26].N1CCCCC1>C(O)C>[CH:23](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[C:4]3[N:5]([CH:22]=[C:2]([CH3:1])[N:3]=3)[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:24][CH2:25][CH3:26]
Reactant: Cc1cn2cccc(OCCCCN3C(=O)CSC3=O)c2n1
Reactant: CCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCOc2cccn3cc(C)nc23)C1=O

Procedure:
To a solution of 1.36 g (4.26 mmol) 3-[4-(2-methylimidazo[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 0.38 ml (4.26 mmol) of n-butyraldehyde in 20 ml of ethanol, 0.04 ml (0.4 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=0/1) to yield 1.23 g (77.2%, yellow oily substance) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33]>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:21])([CH3:23])[CH3:22])=[N:9][C:8]=2[C:4]2[C:3]([F:24])=[C:2]([NH:1][S:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[F:25])(=[O:34])=[O:33])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccccc3F)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (0.082 g, 0.239 mmol) and 2-fluorobenzenesulfonyl chloride (0.051 g, 0.263 mmol) the title compound, N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-fluorobenzenesulfonamide was obtained (66 mg, 0.125 mmol, 52.4% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (s, 1H), 7.98 (d, J=5.3 Hz, 1H), 7.63-7.74 (m, 2H), 7.36-7.46 (m, 2H), 7.32 (t, J=7.4 Hz, 2H), 7.20-7.29 (m, 1H), 6.75 (s, 2H), 5.79 (d, J=5.1 Hz, 1H), 1.40 (s, 9H). MS (ES+): 502 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=O)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)NCCc2ccccc2C)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C2=NCCc3c(C)cccc32)cc1

Procedure:
1-(4-Methoxybenzoylamino)-2-(2-methylphenyl)ethane, phosphorus oxychloride and phosphorus pentoxide were reacted in the same way as in step (b) of Example 1 to afford 1-(4-methoxyphenyl)-5-methyl-3,4-dihydroisoquinoline as colorless prisms having a melting point of 83.0° to 83.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:16])[C:13]=2[F:15])[N:8]=[CH:7][C:6]=1[O:17][C:18](=[O:20])[CH3:19])=[O:4].[C:21]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.CO.ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:16][CH3:21])[C:13]=2[F:15])[N:8]=[CH:7][C:6]=1[O:17][C:18](=[O:20])[CH3:19])=[O:4]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1c(OC(C)=O)cnc2ccc(O)c(F)c12
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1c(OC(C)=O)cnc2ccc(OC)c(F)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
Methanol (0.52 mL, 12.72 mmol, 3.0 eq) is added at room temperature to a stirred solution of 3-acetoxy-5-fluoro-6-hydroxy-quinoline-4-carboxylic acid methyl ester (1.18 g, 4.24 mmol, 1.0 eq) in tetrahydrofuran (50 mL), followed by triphenylphosphine (2.22 g, 12.72 mmol, 3.0 eq) and diethyl azodicarboxylate (1.48 g, 12.72 mmol, 3.0 eq). After 3 hours stirring at room temperature, solvent is evaporated to give a crude product that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 30:1, v/v) to afford 3-acetoxy-5-fluoro-6-methoxy-quinoline-4-carboxylic acid methyl ester as a yellow oil (0.81 g, 65% yield).
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7]NCCNC(C2SC=CC=2NC2C=CN=C3NC=CC=23)=O)=[CH:5][CH:4]=1.[NH2:31][CH:32]1[CH2:37][CH2:36][N:35]([C:38]([C:40]2[S:41][CH:42]=[CH:43][C:44]=2[NH:45][C:46]2[CH:51]=[CH:50][N:49]=[C:48]3[NH:52][CH:53]=[CH:54][C:47]=23)=[O:39])[CH2:34][CH2:33]1.C(=O)C1C=CC=CC=1>>[CH2:7]([NH:31][CH:32]1[CH2:37][CH2:36][N:35]([C:38]([C:40]2[S:41][CH:42]=[CH:43][C:44]=2[NH:45][C:46]2[CH:51]=[CH:50][N:49]=[C:48]3[NH:52][CH:53]=[CH:54][C:47]=23)=[O:39])[CH2:34][CH2:33]1)[C:6]1[CH:29]=[CH:30][CH:3]=[CH:4][CH:5]=1
Reactant: NC1CCN(C(=O)c2sccc2Nc2ccnc3[nH]ccc23)CC1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Solvent: O=Cc1ccccc1
Product: O=C(c1sccc1Nc1ccnc2[nH]ccc12)N1CCC(NCc2ccccc2)CC1

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]-amide using (4-Amino-piperidin-1-yl)-[3-(1H-pyrrolo[2,3-b]pyridin-4-ylamino)-thiophen-2-yl]-methanone instead of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide and benzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 432 1H NMR (400 MHz, DMSO-d6) δ ppm 11.33 (1H, s) 8.93 (1H, s) 7.86 (1H, d, J=5.27 Hz) 7.70 (1H, d, J=5.27 Hz) 7.20-7.27 (3H, m) 7.11-7.19 (2H, m) 6.53 (1H, dd, J=3.51, 1.95 Hz) 6.43 (1H, d, J=5.47 Hz) 3.90 (2H, d, J=13.08 Hz) 3.57 (2H, s) 2.91 (2H, t, J=10.84 Hz) 1.63 (2H, d, J=10.35 Hz) 1.04-1.15 (2H, m)
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]1OCCO1.[CH:9](/[CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[CH:10]\[CH2:11][CH3:12].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1.C(N(CC)CC)C>[Br:1][CH2:2][CH2:3][CH:4]1[O:17][CH2:16][CH:13](/[CH:9]=[CH:10]/[CH2:11][CH3:12])[CH2:14][O:15]1
Reactant: CC/C=C/C(CO)CO
Reactant: BrCCC1OCCO1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC/C=C/C1COC(CCBr)OC1

Procedure:
A solution of 14.4 ml of 2-(2-bromoethyl)-dioxolane and 20.6 g of (E)-2-but-1-enyl-1,3-propanediol in 200 ml of toluene was heated to slight boiling overnight with 2.7 ml of 10% aqueous sulfuric acid (v/v) and 8 ml of water. The mixture was treated with 6 ml of triethylamine and the aqueous phase was separated. The organic phase was washed with semi-conc. sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The resulting orange oil (31.3 g) was chromatographed on 400 g of silica gel with hexane/ethyl acetate 2.5% (v/v). 23.4 g of (E)-2-(2-bromoethyl)-5-but-1-enyl-1,3-dioxane (GC purity 97.5%, trans/cis ratio 73:27) were obtained as a yellowish oil.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([NH:11][C@H:12]([C:20]([O:22]C)=O)[C@@H:13]([CH3:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6].O.[NH2:25][NH2:26]>CO.C(OCC)(=O)C>[NH2:1][C@H:2]([C:9]([NH:11][C@H:12]([C:20]([NH:25][NH2:26])=[O:22])[C@@H:13]([CH3:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:10])[CH2:3][O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: NN
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](N)COC(C)(C)C)[C@@H](C)OC(C)(C)C
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)[C@@H](N)COC(C)(C)C)C(=O)NN
Reaction time: 2 h

Procedure:
4.253 g (7.4 mmols) of DPC-Ser(tBu)-Thr(tBu)-OMe in 18 ml of methanol are mixed with 5.55 ml (about 110 mmols) of hydrazine hydrate and left to stand for 10 hours at room temperature and 2 hours at 40°C. The reaction solution is taken up in 450 ml of ethyl acetate and washed 4 times with half-saturated sodium chloride solution. The solution is dried over sodium sulphate, concentrated to about 15 ml, and mixed with about 5 ml of petroleum ether. Overnight 3.17 g of a hydrazide of melting point 132°-134°C crystallise out.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]3=[CH:19][CH:20]=[N:21][N:14]3[CH:13]=[CH:12][C:11]=2[C:10]=1[C:22]([O:24][CH3:25])=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.[OH-].[OH-].[Pd+2]>[C:29]([O:28][C:26]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]3=[CH:19][CH:20]=[N:21][N:14]3[CH2:13][CH2:12][C:11]=2[C:10]=1[C:22]([O:24][CH3:25])=[O:23])=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2c1ccn1nccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2c1CCn1nccc1-2
Yield: 12.2 %

Procedure:
A solution of methyl 8-[bis-(tert-butoxycarbonyl)amino]-pyrazolo[5,1-a]isoquinoline-7-carboxylate (Intermediate 7, 0.36 g) in dioxane was passed through the H-Cube, using a 20% palladium hydroxide on carbon cartridge, eluting at 0.5 mL/minute, at 100° C. and 100 bar. Two fractions were isolated. The first fraction was concentrated in vacuo to give methyl 8-[bis-(tert-butoxycarbonyl)amino]-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carboxylate (0.044 g). The second fraction, containing the starting material was concentrated in vacuo then dissolved in a mixture of acetic acid in dioxane solution (20%, 40 mL) and was passed through the H-Cube®, using a 20% palladium hydroxide on carbon cartridge, eluting at 1 mL/minute, at 95° C. and 100 bar. The eluent was concentrated in vacuo and the residue purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-80% to give a solid which was combined with the earlier product to give a 3:7 mixture of methyl 8-[bis-(tert-butoxycarbonyl)amino]-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carboxylate and methyl 8-tert-butoxycarbonylamino-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carboxylate (0.084 g).