Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([CH2:12][OH:13])[CH2:6]2.Br>>[OH:13][CH2:12][CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([OH:2])[CH:4]=2)[CH2:8]1
Reactant: COc1ccc2c(c1)CC(CO)C2
Agent: Br
Product: OCC1Cc2ccc(O)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
Combine (5-Methoxy-indan-2-yl)-methanol (117.0 mg, 0.65 mmol), and 48% HBr(aq). After the reaction refluxes for 30 minutes, cool to room temperature and extract the product with ethyl acetate. Wash with brine and dry over Na2SO4. After concentrating the organic layer under reduced pressure, flash chromatograph using 2/1 Hexanes/Ethyl acetate eluent to afford 67.3 mg, 0.41 mmol (63% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 2.6-2.8 (3H, m), 2.9-3.1 (2H, m), 3.6-3.8 (2H, m), 6.6-6.8 (2H, m), 7.0-7.1 (1H, m); TLC 1:1 Hexanes:Ethyl acetate Rf:=0.3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.CC[N:16](CC)CC.N>C1COCC1>[NH2:16][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([Cl:1])[N:3]=[C:4]([S:12][CH3:13])[N:5]=1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CCN(CC)CC
Agent: N
Solvent: C1CCOC1
Product: CSc1nc(N)c([N+](=O)[O-])c(Cl)n1
Temperature: 0 °C

Procedure:
To a solution of 4,6-dichloro-2-(methylthio)-5-nitropyrimidine (327 mg, 1.36 mmol) in THF (5.4 mL) at −10° C. was added Et3N (474 μL, 3.40 mmol) followed by a solution of NH3 (2.0 M in MeOH, 750 μL, 1.5 mmol). The mixture was stirred while warming to 0° C. for 1.5 h (LC/MS indicated consumption of starting materials). The reaction mixture was taken forward without work-up.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=2)=[CH:10][O:9][N:8]=1.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:26][CH2:25][C:24]([F:28])([F:27])[F:23])=[O:20])=[CH:16][N:15]=2)=[CH:10][O:9][N:8]=1
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccccn2)nc1
Reactant: NCC(F)(F)F
Product: O=C(NCC(F)(F)F)c1ccc(OCc2conc2-c2ccccn2)nc1
Yield: 65 %

Procedure:
As described for example 358 g, 6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) was converted using 2,2,2-trifluoroethylamine instead of 4-aminotetrahydropyran to the title compound (83 mg, 65%) which was obtained as a white solid. MS: m/e=379.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]2[C:11]([C:22]3[N:23](S(C)(=O)=O)[CH2:24][N:25]=[CH:26][CH:27]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:13](=[O:14])[N:6]12)=[O:4].[C:32]1([OH:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[H-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]2[C:11]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([O:38][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:23]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:13](=[O:14])[N:6]12)=[O:4]
Reactant: COC(=O)C1CCCn2c(C3=CC=NCN3S(C)(=O)=O)c(-c3ccc(F)cc3)c(=O)n21
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CCCn2c(-c3ccnc(Oc4ccccc4)n3)c(-c3ccc(F)cc3)c(=O)n21
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of 2-(4fluorophenyl)-1-(3-methanesulfonyl-pyrimidin-4-yl)-3-oxo-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid methyl ester, 21, (0.033 g, 0.074 mmol) in THF (3 mL) is added phenol and NaH (0.009 g, 0.22 mmol). The reaction mixture is stirred at room temperature for 1 hour. The reaction is quenched by the addition of 1 N HCl (20 mL) and the solution is extracted with ethyl acetate (3×25 mL). The organic phases are combined, washed with brine, dried, and concentrated in vacuo to afford the crude product which is purified over silica (hexanes/ethyl acetate 1:3) to afford 0.012 g (35% yield) of the desired product as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.64 (d, J=4.6 Hz 1 H), 7.59-7.63 (m, 2 H), 7.40-7.45 (m, 3 H), 7.28-7.30 (m, 1 H), 7.18 (d, J=8.4 Hz, 2 H), 7.03-7.08 (m, 2 H), 4.50-4.56 (m, 1 H), 3.99-4.04 (m, 1 H), 3.86 (s, 1 H), 3.01-3.10 (m, 1 H), 2.33-2.41 (m, 1 H), 1.86 (brs, 2 H), 1.64 (brs, 3 H); ESI/MS: 461 (M+H).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[CH3:14][NH2:15]>>[OH:1][C:3]1([CH2:2][NH:15][CH3:14])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CCOC(=O)N1CCC2(CC1)CO2
Reactant: CN
Product: CCOC(=O)N1CCC(O)(CNC)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.2 g (28 mmol) of ethyl 6-aza-1-oxaspiro[2,5]-octane-6-carboxylate are added dropwise to 30 ml of methylamine solution (25% in water) and the mixture is stirred overnight at room temperature. It is then concentrated and recrystallized from petroleum ether (hygroscopic crystals).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)(=[O:35])=[O:34]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccccc4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2-chlorobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:9]2[C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[C:18]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31]OS(C)(=O)=O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:18]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][N:10]1[C:9]2[C:8]([O:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=[C:2]1[CH3:1])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CS(=O)(=O)OCCOCCOC(=O)c1ccccc1
Reactant: Cc1cc2ncnc(Oc3ccccc3)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2ncnc(Oc3ccccc3)c2n1CCOCCOC(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 21 h
Yield: 93.2 %

Procedure:
6-Methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine (299.9 mg) and 2-{2-[(methylsulfonyl)oxy]ethoxy}ethyl benzoate (464.1 mg) were dissolved in N,N-dimethylformamide (7 mL), potassium carbonate (431 mg) was added, and the mixture was stirred at 60° C. for 21 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→20:80) to give the title compound (517.8 mg) as a yellow oil.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:17][S:18]([C:21]2[CH:22]=[C:23]([CH:27]=[CH:28][C:29](Cl)=[O:30])[CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=1>O1CCCC1>[OH:3][NH:2][C:29](=[O:30])[CH:28]=[CH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([S:18](=[O:20])(=[O:19])[NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=2)[CH:22]=1
Reactant: COc1cccc(NS(=O)(=O)c2cccc(C=CC(=O)Cl)c2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(NS(=O)(=O)c2cccc(C=CC(=O)NO)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.39 g, 5.7 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-(3-methoxy-phenylsulfamoyl)-phenyl]-acryloyl chloride (6i) (0.40 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-acetonitrile affording the title compound (0.15 g, 39%) as a lightly pink crystals. M.p. 137° C. 1H NMR (DMSC-d6, HMDSC) δ: 3.65 (3H, s); 6.38-6.78 (4H, m); 6.98-7.27 (1H, m); 7.34-8.03 (5H, m); 9.14 (1H, br s); 10.30 (1H, s); 10.83 (1H, br s). HPLC analysis on Symmetry C8 column: impurities 5% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 40:60; sample concentration 0.5 mg/ml; flow rate 1.2 ml/min; detector UV 254 nm). Anal. Calcd for C16H16N2O5S containing 1% of inorganic impurities, %: C 54.67, H 4.50, N 8.09. Found, %: C 54.61, H 4.58, N 7.96.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:14]O.S(Cl)(Cl)=O>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([O:7][CH3:14])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cc(I)cc([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(I)cc([N+](=O)[O-])c1

Procedure:
To a stirred solution of 3-iodo-5-nitrobenzoic acid (15.1 g, 0.049 mol) in methanol (151 mL, 3.73 mol) was added thionyl chloride (15.1 mL, 0.205 mol) dropwise at 0° C. The mixture was heated to reflux for 2 hours. The solvent was removed in vacuo. The residue was purified by flash chromatography (0-100% EtOAc/hexane) to afford an white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]1[O:4][CH2:3]1.[CH3:9][C:10]([NH2:21])([CH3:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>>[OH:4][CH:2]([CH2:1][O:5][CH2:6][CH:7]=[CH2:8])[CH2:3][NH:21][C:10]([CH3:20])([CH3:9])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: C=CCOCC1CO1
Product: C=CCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 26.9 %

Procedure:
Using the method of Example 15, supra, allyl glycidyl ether (119 μL, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 79 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 294 (M+1, 0.1), 278 (0.9), 222 (1.5), 172 (100), 163 (11), 121 (20); 1H-NMR (CDCl3) δ7.04 2H, di J=8.6), 6.79 (2H, d, J=8.6), 5.85 (1H, ddd, J=22.2, 10.5 and 5.7), 5.23 (1H, dd, J=17.3 and 1.5), 5.14 (1H, dd, J=10.3 and 1.5), 3.96 (2H, d, J=5.7), 3.74 (4H, m), 3.43 (2H, d, J=5.7), 2.83 (1H, broad s), 2.77 (1H, dd, J=11.7 and 4.1), 2.62 (5H, m), 1.02 (3H, s), 1.01 (3H, s); 13C-NMR (CDCl3) δ158.0, 134.5, 131.3, 129.9, 117.0, 113.3, 72.8, 72.2, 69.0, 55.0, 53.3, 46.3, 44.5, 26.6, 26.4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][NH:6][C:7](=[O:12])[C:8]([F:11])([F:10])[F:9].[N:17]([O-])=O.[Na+].Cl[Sn]Cl.O>Cl>[Cl:16][C:15]1[CH:14]=[CH:13][C:4]([CH2:5][NH:6][C:7](=[O:12])[C:8]([F:9])([F:10])[F:11])=[CH:3][C:2]=1[NH:1][NH2:17]
Reactant: Nc1cc(CNC(=O)C(F)(F)F)ccc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(CNC(=O)C(F)(F)F)ccc1Cl
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 15385.3 %

Procedure:
To a cold solution of N-(3-amino-4-chlorobenzyl)-2,2,2-trifluoroacetamide (0.500 g, 0.017 mmol) in 6N HCl (50.0 mL), aqueous solution of NaNO2 (1.29 g, 0.018 mmol) was added at 0° C. and the reaction mass was stirred at 0-5° C. for 30 min. The reaction mass was added to a solution of SnCl2.H2O (22.18 g, 0.98 mmol) in 6N HCl at 0-5° C. and further continued stirring for 5-6 h at same temperature. The reaction mass was cooled, basified and extracted with DCM. The organic layer was separated, dried and concentrated to afford 0.700 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 4.22 (br s, 2H), 4.29 (d, J=6.0 Hz, 2H), 6.42-6.67 (m, 2H), 7.14-7.16 (m, 2H), 9.98 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:10])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[CH3:11][N:12]([CH3:15])[CH:13]=O>C(OCC)C>[F:1][C:2]1[C:3]([N:10]=[CH:11][N:12]([CH3:15])[CH3:13])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CSc1ncc(F)c(N)n1
Reactant: CN(C)C=O
Solvent: CCOCC
Product: CSc1ncc(F)c(N=CN(C)C)n1
Reaction time: 4 h
Yield: 84 %

Procedure:
To a solution of 5-fluoro-2-methylsulfanylpyrimidin-4-ylamine (7.5 g, 47.1 mmol) in N,N-dimethylformamide (DMF; 18 mL) was added DMF-dimethylacetal (DMF-DMA; 8.42 g, 70.7 mmol), and the resulting solution was stirred under nitrogen (N2) for 4 h. The homogeneous solution was diluted with diethyl ether (Et2O; 500 mL), washed with H2O (5×100 mL), and the organic phase was dried over Na2SO4, filtered, and concentrated to a white solid. Recrystallization from hexane afforded N′-(5-fluoro-2-methylsulfanylpyrimidin-4-yl)-N,N-dimethylformamidine (8.47 g, 84%) as white needles: mp 75-77° C.; 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.12 (d, J=3.1 Hz, 1H), 3.19 (s, 3H), 3.18 (s, 3H), 2.53 (s, 3H); CIMS m/z 214 ([M]+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[F:32][C:33]([F:39])([F:38])[S:34](Cl)(=[O:36])=[O:35].CN(C1C=CC=CN=1)C>C(Cl)(Cl)Cl>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([C:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9][N:8]([S:34]([C:33]([F:39])([F:38])[F:32])(=[O:36])=[O:35])[CH2:7][CH2:6]2)(=[O:13])=[O:12])=[CH:19][CH:18]=1)[C:22]#[C:23][CH3:24]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(S(=O)(=O)C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.3 %

Procedure:
To a solution of 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (350 mg, 0.90 mmol) in chloroform (10 ml) was added triethylamine (182 mg, 1.81 mmol), trifluoromethanesulfonyl chloride (0.125 ml, 1.17 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 245 mg (56%) of the product as a solid. HR-MS: m/z Calculated for C18H20F3NO7S2 484.0706; Found 484.0700.
Reaction SMILES: CC([N:5]([CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:14]=[C:15]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)[C:16]2[C:22](=[O:23])[NH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:5][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:14]=[C:15]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)[C:16]2[C:22](=[O:23])[NH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: Cc1cccc(Nc2nc(NCCCN(C(=O)[O-])C(C)(C)C)nc3cc[nH]c(=O)c23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Nc2nc(NCCCN)nc3cc[nH]c(=O)c23)c1
Reaction time: 1 h
Yield: 133.6 %

Procedure:
1,1-dimethylethyl[3-({4-[(3-methylphenyl)amino]-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl}amino)propyl]carbamate (245 mg, 0.577 mmol) was dissolved into dichloromethane (3 mL) and TFA (1 mL) was added. The reaction mixture was stirred for 1 h and concentrated. The residue was further dried under high vacuum to afford the product as a TFA salt (250 mg).
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[C:10]([C:14]3[CH:18]=[N:17][N:16]([CH3:19])[N:15]=3)[CH:11]=[CH:12][CH:13]=2)OC1.Br[C:22]1[N:26]2[N:27]=[CH:28][C:29]([C:31]([F:34])([F:33])[F:32])=[N:30][C:25]2=[N:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:19][N:16]1[N:15]=[C:14]([C:10]2[CH:9]=[C:8]([C:22]3[N:26]4[N:27]=[CH:28][C:29]([C:31]([F:32])([F:33])[F:34])=[N:30][C:25]4=[N:24][CH:23]=3)[CH:13]=[CH:12][CH:11]=2)[CH:18]=[N:17]1
Reactant: Cn1ncc(-c2cccc(B3OCC(C)(C)CO3)c2)n1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
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: COCCOC
Product: Cn1ncc(-c2cccc(-c3cnc4nc(C(F)(F)F)cnn34)c2)n1
Yield: 33.7 %

Procedure:
This reaction was carried out as described in Example 37, step e, using 4-[3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)phenyl]-2-methyl-2H-[1,2,3]triazole (190 mg, 0.7 mmol), 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.156 g, 0.585 mmol), 2 M Na2CO3 (0.70 ml) and tetrakis(triphenylphosphine)palladium(0) (0.034 g) in 1,2-dimethoxyethane (2 ml). The crude residue was purified by flash chromatography (silica gel, 50% Et2O/toluene) and crystallized from toluene to yield the title compound (68 mg, 34%): 1H NMR (400 MHz, CDCl3) δ 4.28 (3H, s), 7.63 (1H, t, J 7.8 Hz), 7.87 (1H, dt, J 7.8, 1.4 Hz), 7.91 (1H, s), 8.05-8.09 (1H, m), 8.52 (1H, t, J 1.4 Hz), 8.68 (1H, s), 8.85 (1H, s); MS (ES+) m/z 346 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=O)[CH:3]=[CH:2]1.[N:12]1[C:21]2[CH:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][N:22]([CH:20]2[C:21]3[N:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH2:17][CH2:18][CH2:19]2)[CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: CC(C)(C)OC(=O)NCCCCNC1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCCCN(Cc1cccc2cc[nH]c12)C1CCCc2cccnc21
Yield: 35 %

Procedure:
A heavy-walled Pyrex tube was charged with a solution of indole-7-carboxaldehyde (0.50 g, 3.44 mmol) in 1,2-dichloroethane (5 mL). This solution was treated with tert-butyl 4-(5,6,7,8-tetrahydroquinolin-8-ylamino)butylcarbamate, 3, (1.21 g, 3.78 mmol), sodium triacetoxyborohydride (1.46 g, 6.88 mmol) and a catalytic amount of acetic acid (2 drops). The reaction mixture was exposed to microwave irradiation for 10 min at a temperature of 100° C. After the irradiation, the reaction tube was cooled with high-pressure air until the temperature had fallen below 40° C. The crude reaction mixture was poured onto a saturated aqueous solution of sodium bicarbonate. The product was extracted with dichloromethane. The combined organic layers were washed with brine, dried over potassium carbonate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-5% methanol/CH2Cl2) to afford 0.54 g (35% yield) of the desired product 6: 1H NMR (400 MHz, CDCl3) δ 12.87 (bs, 1H), 8.56 (d, J=3.6 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.41-7.37 (m, 2H), 7.10 (dd, J=5.2, 7.6 Hz, 1H), 6.97-6.88 (m, 2H), 6.51-6.49 (m, 1H), 4.26-4.20 (m, 2H), 3.96 (d, J=13.2 Hz, 1H), 3.60 (d, J=13.2 Hz, 1H), 2.92-2.72 (m, 3H), 2.65-2.55 (m, 2H), 2.50-2.40 (m, 1H), 2.29-2.20 (m, 1H), 2.14-2.04 (m, 1H), 1.95-1.68 (m, 2H), 1.47-1.15 (m, 2H), 1.39 (s, 9H); ESI+ MS: m/z (rel intensity) 449.2 (100, [M+H]+) Step b: Preparation of N1-((1H-indol-7-yl)methyl)-N1-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine (B). A solution of tert-butyl 4-(((1H-indol-7-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)butylcarbamate, 6, (0.27 g, 0.60 mmol) in methanol (5 mL) was treated with thionyl chloride (1 mL) at room temperature. The resulting mixture was stirred for 30 min. The reaction mixture was then concentrated and dried under reduced pressure to afford 0.26 g (87% yield) of the desired product, B: 1H NMR (400 MHz, d6-DMSO) δ 11.97 (bs, 1H), 8.44 (d, J=4.8 Hz, 1H), 7.59 (d, J=7.2 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.48-7.40 (m, 1H), 7.35-7.20 (m, 2H), 6.98 (t, J=6.8 Hz, 1H), 6.44 (bs, 1H), 4.90-4.78 (m, 2H), 3.60-3.53 (m, 2H), 3.10-3.00 (m, 2H), 2.80-2.60 (m, 4H), 2.50-2.39 (m, 1H), 2.30-1.40 (m, 7H); ESI+ MS: m/z (rel intensity) 349.2 (100, [M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][NH2:16].[C:17]([CH2:19][C:20](Cl)=[O:21])#[N:18]>O1CCCC1>[NH2:18][C:17]1[N:15]([C:3]2[CH:4]=[C:5]([S:9][CH2:10][C:11]([F:13])([F:14])[F:12])[C:6]([CH3:8])=[CH:7][C:2]=2[F:1])[N:16]=[C:20]([OH:21])[CH:19]=1
Reactant: Cc1cc(F)c(NN)cc1SCC(F)(F)F
Reactant: N#CCC(=O)Cl
Solvent: C1CCOC1
Product: Cc1cc(F)c(-n2nc(O)cc2N)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58.1 %

Procedure:
27.5 g of 2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenylhydrazine was dissolved in 300 mL of tetrahydrofuran, and to this solution, 14 g of cyanoacetyl chloride was added, followed by stirring at room temperature for 5 minutes. Then, the solvent was distilled off under reduced pressure, the residue was dissolved in 300 mL of 1-propanol, and 10.6 g of methanesulfonic acid was added, followed by reflux with heating for 3 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, the reaction solution was neutralized to pH=7 with sodium hydrogen carbonate, and extraction with ethyl acetate was carried out. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane:acetic acid=50:50:1) to obtain 20.2 g of 5-amino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole in the form of brown crystals (melting point: 110-113° C.).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([C:16]1[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:18][O:19][C:20]=1[CH3:21])=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:32]>C(O)(=O)C>[CH2:1]([O:8][CH2:9][C:10]1[NH:12][CH:13]=[C:14]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][O:19][C:20]=2[CH3:21])[N:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CNC(=O)COCc1ccccc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1onc(-c2ccccc2)c1-c1c[nH]c(COCc2ccccc2)n1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
To a refluxing solution of 2-benzyloxy-N-[2-(5-methyl-3-phenyl-isoxazol-4-yl)-2-oxo-ethyl]-acetamide (3.35 g, 9 mmol) in acetic acid (10 mL) was added ammonium acetate (14.2 g, 184 mmol) portionwise over 1.5 h. Then the mixture was heated for a subsequent 2 h under reflux and then allowed to cool down to room temperature overnight. The mixture was then poured onto water and extracted with ethyl acetate. The organic layer was then washed with water and brine, dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 50:50) afforded the title compound (2.36 g, 74%) which was obtained as a light yellow solid. MS: m/e=346.1 [M+H]+.