Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[CH:16]=[C:15]([C:17](=[O:25])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[S:14][C:12]=3[N:13]=2)[CH2:3][CH2:2]1.[BH4-].[Na+].C(OCC)(=O)C>C(O)C>[O:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[CH:16]=[C:15]([CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[OH:25])[S:14][C:12]=3[N:13]=2)[CH2:5][CH2:6]1
Reactant: O=C(c1cc2cnc(NC3CCOCC3)nc2s1)c1ccccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OC(c1cc2cnc(NC3CCOCC3)nc2s1)c1ccccc1F
Reaction time: 8 h
Yield: 46.4 %

Procedure:
To a solution of 2-(tetrahydropyran-4-ylamino)-6-(2-fluorobenzoyl)thieno[2,3-d]pyrimidine (300 mg) in ethanol (30 mL) was added sodium borohydride (0.4 g) at room temperature and stirred overnight. Ethyl acetate (50 mL) was added to the reaction mixture. The organic layer was separated, washed with brine, dried, and evaporated. Purification by preparative TLC (silica gel, 50% EtOAc/hexanes) gave 140 mg of the alcohol. MS: 360.2 (M+H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:8]=1)=O.[OH:27][CH2:28][CH2:29][NH:30][NH2:31]>CO>[OH:27][CH2:28][CH2:29][N:30]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:31]1
Reactant: NNCCO
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(N3CCOCC3)cc2)ccc1=O
Solvent: CO
Product: O=c1ccn(-c2ccc(N3CCOCC3)cc2)nc1-c1ccnn1CCO
Yield: 7.3 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-morpholin-4-ylphenyl)pyridazin-4(1H)-one (476 mg, 1.34 mmol) in 20 mL of methanol, 2-hydroxyethylhydrazine (414 mg, 5.36 mmol) was added, the resulting mixture was refluxed for 4 hours, and then concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1 M acetic acid aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (36 mg, 7.3% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3): δ 3.20-3.22 (4H, m), 3.87-3.89 (4H, m), 4.03-4.05 (2H, m), 4.33-4.36 (2H, m), 6.69 (1H, d, J=7.6 Hz), 6.98 (2H, dd, J=6.8, 2.0 Hz), 7.34 (1H, d, J=2.4 Hz), 7.51-7.53 (3H, m), 8.14 (1H, d, J=7.6 Hz); LCMS (mobile phase: from 95% water and 5% CH3CN to 5% water and 95% CH3CN in 6 min, finally under these conditions for 0.5 min.) purity is >95%, Rt=2.770 min; MS Calcd.: 367, MS Found: 368 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([NH:8]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:5][C@@H:4]1[OH:28]>CO>[NH2:8][C@H:6]1[CH2:5][C@H:4]([OH:28])[C@H:3]([CH2:2][OH:1])[CH2:7]1
Reactant: OC[C@@H]1C[C@@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@@H]1O
Solvent: CO
Product: N[C@@H]1C[C@@H](CO)[C@@H](O)C1
Temperature: 35 °C
Yield: 84.1 %

Procedure:
A hydrogenation reactor was purged with argon and charged with 5% palladium on carbon (50% water wet, 80 g, 20 mol %) and the reactor sealed. Using vacuum, a solution of (1S,2S,4R)-2-(hydroxymethyl)-4-(tritylamino)cyclopentanol (400 g, 1.07 mol) in methanol (2.7 L) was added to the reactor. The reactor was purged with argon, charged to 35 to 45 psi hydrogen and heated to 35° C. for 72 h. The reaction mixture was filtered through a pad of diatomaceous earth, washed with methanol (32 L) and concentrated under reduced pressure to ˜1 L volume. Precipitated triphenyl methane was filtered from the mixture and the filtrate further concentrated to give an amber oil. The crude material was purified by silica-gel chromatography. The column was performed as follows. A 15 cm diameter glass column was loaded with a slurry of silica gel (1.6 kg) in methylene chloride. The amber oil was adsorbed onto silica gel (200 g) and loaded on the column. The polarity was gradually increased from 100% methylene chloride to 50% methylene chloride/methanol. The pure fractions were combined and concentrated under reduced pressure to afford the title compound (118 g) as a waxy yellow solid. 1H NMR (300 MHz, CD3OD, δ): 4.35-4.32 (m, 1H), 3.76-3.70 (m, 1H), 3.64-3.56 (m, 2H), 2.34-2.26 (m, 1H), 2.10-2.03 (m, 1H), 1.93-1.82 (m, 1H) and 1.63-1.46 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([O:16]C)=O)[CH2:3]1.[NH2:18][CH2:19][CH2:20][OH:21]>CO>[OH:21][CH2:20][CH2:19][NH:18][C:14]([CH:4]1[CH2:3][C:2](=[O:1])[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5]1)=[O:16]
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Reactant: NCCO
Solvent: CO
Product: O=C(NCCO)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
A mixture of 46.7 g (0.2 mole) of methyl 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate [J. Org. Chem., 26, 1519 (1961)], 36.7 g (0.6 mole) of 2-aminoethanol and 500 ml methanol was refluxed overnight. The reaction was cooled to room temperature and the solvent removed at reduced pressure. The residue was taken up in dichloromethane and extracted 3×100 ml 1N sodium hydroxide. The aqueous layer was taken to pH 5, extracted 3×150 ml dichloromethane, then taken to pH 8 and again extracted 3×150 ml dichloromethane. The aqueous layer was concentrated at reduced pressure and the resulting slurry stirred in dichloromethane. The salts were filtered off. The combined organic layers were dried over magnesium sulfate, the solvent removed at reduced pressure to Yield 47.9 g of N-(2-hydroxyethyl)-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide as an oil. This was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[N:22]=[C:21]3[C:15]([N:16]([CH3:29])[C:17](=[O:28])[CH2:18][CH2:19][N:20]3[CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:14][N:13]=2)[O:9][CH:10]=1)=[O:5])C.O.[OH-].[Li+]>C1COCC1.O.CO>[CH:23]1([N:20]2[CH2:19][CH2:18][C:17](=[O:28])[N:16]([CH3:29])[C:15]3[C:21]2=[N:22][C:12]([NH:11][C:8]2[O:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[N:13][CH:14]=3)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCOC(=O)c1coc(Nc2ncc3c(n2)N(C2CCCC2)CCC(=O)N3C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3nc(C(=O)O)co3)ncc21
Yield: 60.4 %

Procedure:
Ethyl2-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-1,3-oxazole-4-carboxylate (Intermediate 151; 160 mg, 0.40 mmol) was dissolved in THF (1 mL) and water (0.5 mL). Lithium hydroxide monohydrate (84 mg, 2.0 mmol) was added and a few drops of methanol and the mixture stirred at room temperature overnight. The mixture was neutralised with 2N HCl(aqu) and concentrated. The residue was taken up in MeOH/Water and absorbed onto an SCX column, washed with methanol/water and eluted with ammonia in methanol. Product containing fractions were concentrated, the residue taken-up in DCM, dried (MgSO4) and concentrated to give the title compound as a white solid (90 mg, 60%).
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Cl[CH2:10][C:11]#[N:12]>CCCCCCC>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][CH2:10][C:11]#[N:12]
Reactant: N#CCCl
Reactant: OCC(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCCC
Product: N#CCOCC(F)(F)F
Temperature: 25 °C

Procedure:
At about 50° C., 26.4 g (0.40 mole) of 85% potassium hydroxide are solubilized in 100 g (1.0 mole) of 2,2,2-trifluoroethanol. After cooling at 25° C. 37.8 g (0.50 mole) of chloroacetonitrile are added dropwise to this solution. The temperature rises slowly to 40° C. and a precipitate appears. The reaction mixture is then brought gradually to 60° C.; after the addition of 300 ml of heptane, it is then brought to reflux. The whole of the vapour is condensed by means of a Dean and Stark apparatus. The lower phase of the condensate is separated after settling has taken place and distilled at atmospheric pressure. Yld: 19.6 g (28%), b.p. 125°-140° C.
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[NH:6][N:5]=1)=[O:2].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20].O>N1C=CC=CC=1>[CH3:17][N:18]([CH3:22])[C:19]([N:6]1[C:7]2[C:12](=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:9][CH:8]=2)[C:4]([NH:3][CH:1]=[O:2])=[N:5]1)=[O:20]
Reactant: CN(C)C(=O)Cl
Reactant: O=CNc1n[nH]c2ccc(C(F)(F)F)cc12
Solvent: c1ccncc1
Solvent: O
Product: CN(C)C(=O)n1nc(NC=O)c2cc(C(F)(F)F)ccc21
Yield: 57 %

Procedure:
0.2 mol of 3-formylamino-5-trifluoromethylindazole and 0.05 mol of dimethylcarbamic acid chloride in 20 ml of pyridine are heated for 4 hours to 50° C. After cooling, 150 ml of water are allowed to run in and the reaction product which has crystallized out is isolated by filtration. Recrystallization from ethanol gives 3formylamino-5-trifluoromethylindazole-1-carboxylic acid dimethylamide (melting point: 198°-200° C; 57% of theory).
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].Cl[C:7](Cl)([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(#N)C>[S:1]([N:5]=[C:7]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:3])(=[O:2])[NH2:4]
Reactant: NS(N)(=O)=O
Reactant: ClC(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Product: NS(=O)(=O)N=C(Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of sulfamide (100.9 mg, 1.05 mmol) in anhydrous acetonitrile (3.3 mL) is slowly added dichlorodiphenoxymethane (269.1 mg, 1.00 mmol) at 0° C. The reaction mixture is stirred at room temperature overnight before removal of the solvent. The residue is purified by chromatography to provide diphenyl sulfamoylcarbonimidate (280.2 mg, 96% yield) as a white solid product; HPLC-MS calculated for C13H12N2O4S (M+H+) 293.1, found 293.1.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][NH:8][C:7](=O)[CH2:6]1)=[O:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:12].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][NH:8][C:7](=[S:12])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CNC(=O)C1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)C1CNC(=S)C1

Procedure:
10 g of 4-methoxycarbonyl-pyrrolidine-2-one II (prepared as described in P. L. Paytash, E. Sparrow and I. C. Gathe, J. Am. Chem. Soc. 72, 1415 (1950)) were dissolved in 170 ml of absolute toluene under the influence of heat. 16.7 g of P4S10 ×4 pyridine (Riedel de Haen, Hanover, West Germany) and 42 g of kieselguhr (as a filtration aid) were then added in succession. The mixture was subsequently warmed at 90°-100° C. for 3 hours, while stirring and under nitrogen as an inert gas. The solid was then filtered off with suction and the residue on the filter was rinsed with hot toluene. The filtrate was concentrated in vacuo.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: OB(O)c1cccnc1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(-c2cccnc2)nc(N2CCOCC2)n1
Yield: 61 %

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) and 3-pyridinylboronic acid, as in Example 47, gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(3-pyridinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole in 61% yield: mp (CH2Cl2/MeOH) 208-210° C.; 1H NMR (DMSO-d6) δ 9.59 (dd, J=2.2, 0.7 Hz, 1H), 8.85 (dd, J=4.8, 1.7 Hz, 1H), 8.75 (dt, J=8.0, 1.9 Hz, 1H), 8.35 (dd, J=8.4, 0.4 Hz, 1H), 7.83 (t, Jjw=52.6 Hz, 1H), 7.66 (ddd, J=8.0, 4.8, 0.8 Hz, 1H), 7.50 (t, J=8.3 Hz, 1H), 7.02 (d, J=7.8 Hz, 1H), 4.09 (t, J=7.8 Hz, 2H), 4.00 (s, 3H), 3.94 (m, 2H), 3.78 (m, 4H); Anal. Calcd. for C21H19F2N7O40.3H2O: C, 56.7; H, 4.4; N, 22.0. Found: C, 56.6; H, 4.0; N, 22.1%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1Cl.[OH-].[K+].[F:14][C:15]([F:20])([F:19])[CH:16]([OH:18])[CH3:17]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1[O:18][CH:16]([CH3:17])[C:15]([F:20])([F:19])[F:14]
Reactant: CC(O)C(F)(F)F
Reactant: O=C(O)c1ccc(Br)c(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(Oc1nc(C(=O)O)ccc1Br)C(F)(F)F
Reaction time: 0.25 h
Yield: 104.1 %

Procedure:
5-Bromo-6-chloropicolinic acid (5 g, 21.1 mmol; CAN 959958-25-9) was dissolved in DMSO (100 mL) to give a colorless solution. To this solution potassium hydroxide (4.75 g, 84.6 mmol) was added. The reaction mixture turned into a white suspension which was stirred for 15 min. Then 1,1,1-trifluoropropan-2-ol (2.41 g, 1.92 mL, 21.1 mmol) was added. The mixture was stirred for 1 d at ambient temp., poured onto ice-water/1N HCl (200 mL) and extracted with EtOAc (2×400 mL). The organic layers were washed with ice-water/brine (200 mL), combined and dried over Na2SO4 and concentrated in vacuo to give the title compound (6.9 g, quant.) as orange solid. MS (EI): m/e=312.3 [M−H]−.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](I)=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[CH3:18][N:19]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][CH:24]=[CH:25]2)=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:18][N:19]1[C:27]([C:13]2[N:8]3[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]3=[N:15][C:14]=2[CH3:16])=[C:26]2[C:21]([CH:22]=[CH:23][CH:24]=[CH:25]2)=[N:20]1
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cn1cc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)nn2c(-c3c4ccccc4nn3C)c(C)nc12
Temperature: 100 °C
Yield: 28.1 %

Procedure:
8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (300 mg, 0.87 mmol), 2-methyl-2H-indazole (ref. J. Org. Chem. 2003, 68, 4093-4095, 230 mg, 1.76 mmol) and cesium carbonate (570 mg, 1.75 mmol) stirred in DMF (5 ml) and degassed by bubbling a stream of nitrogen through the mixture. PdCl2(PPh3)2 added and the mixture heated to 100° C. overnight. The mixture is added to water and extracted twice with ether. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by chromatography using a hexane-ethyl acetate gradient (100% hexane to 50% ethyl acetate in hexane) to give the title compound (85 mg, 28% yield).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][C@@H:15]3[O:20][CH3:21])([CH3:13])[C:11](=O)[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[C:23]1([CH3:34])[CH:28]=[CH:27][C:26]([S:29]([NH:32][NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(O)C.C(O)(=O)C.O.CCCCCC>[CH3:21][O:20][C@H:15]1[CH2:14][C@@:12]2([CH3:13])[C@@H:8]([CH2:9][CH2:10][C:11]2=[N:33][NH:32][S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:34])=[CH:24][CH:25]=2)(=[O:30])=[O:31])[C@H:7]2[C@H:16]1[C:17]1[CH:18]=[CH:19][C:2]([OH:1])=[CH:3][C:4]=1[CH2:5][CH2:6]2
Reactant: CO[C@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2CCc3cc(O)ccc3[C@H]21
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CCO
Solvent: CCCCCC
Solvent: O
Product: CO[C@H]1C[C@]2(C)C(=NNS(=O)(=O)c3ccc(C)cc3)CC[C@H]2[C@@H]2CCc3cc(O)ccc3[C@H]21

Procedure:
In a mixture of 6 ml of ethanol and 4 ml of glacial acetic acid, 1 g (3.3 mmol) of 3-hydroxy-11β-methoxy-estra-1,3,5(10)-trien-17-one and 0.7 g (3.8 mmol) of toluene-4-sulfonic acid hydrazide are refluxed. After a reaction time of about 5 hours at boiling heat, the reaction mixture is cooled, and the product is isolated in about 100 ml of water by addition in drops. By boiling the crude product in n-hexane, the water that is contained is azeotropically removed.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[N:8]=[CH:7][N:6]=1.[F:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][C:20]=1[C:34]1[CH:35]=[N:36][C:37]([NH2:40])=[N:38][CH:39]=1>>[CH:11]1([C:9]2[N:8]=[CH:7][N:6]=[C:5]([O:4][C:3]3[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=3[C:23]3[CH:22]=[CH:21][C:20]([C:34]4[CH:39]=[N:38][C:37]([NH2:40])=[N:36][CH:35]=4)=[C:19]([F:18])[CH:24]=3)[CH:10]=2)[CH2:13][CH2:12]1
Reactant: Brc1ccccc1Oc1cc(C2CC2)ncn1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3Oc3cc(C4CC4)ncn3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-(2-bromophenoxy)-6-cyclopropylpyrimidine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C23H18FN5O, 399.15; m/z found, 399.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.42 (s, 2H), 7.56-7.50 (m, 2H), 7.48-7.43 (m, 1H), 7.41-7.36 (m, 1H), 7.33-7.23 (m, 3H), 6.99 (s, 1H), 6.86 (s, 2H), 2.09-2.01 (m, 1H), 1.02-0.92 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])[N:4]=1.[C:17]1([C:23]2[N:24]=[C:25]([N:28]3[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29]3)[S:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([C:23]2[N:24]=[C:25]([N:28]3[CH2:32][CH2:31][CH:30]([C:33]([NH:11][C:10]4[CH:12]=[CH:13][CH:14]=[C:8]([C:5]5[N:4]=[C:3]([C:2]([F:15])([F:1])[F:16])[O:7][N:6]=5)[CH:9]=4)=[O:34])[CH2:29]3)[S:26][CH:27]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: O=C(O)C1CCN(c2nc(-c3ccccc3)cs2)C1
Product: O=C(Nc1cccc(-c2noc(C(F)(F)F)n2)c1)C1CCN(c2nc(-c3ccccc3)cs2)C1
Yield: 28 %

Procedure:
This compound was synthesized from 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)aniline and 1-(4-phenylthiazol-2-yl)pyrrolidine-3-carboxylic acid as described for example 37 step 3 (20 mg, yield 28%). 1H NMR (400 MHz, MeOD) δ 8.47 (t, J=1.8 Hz, 1H), 7.88-7.81 (m, 3H), 7.57-7.53 (t, J=7.9 Hz, 1H), 7.39-7.35 (m, 2H), 7.30-7.25 (m, 2H), 6.90 (s, 1H), 3.90-3.86 (m, 1H), 3.82-3.78 (m, 1H), 3.76-3.71 (m, 1H), 3.64-3.58 (m, 1H), 3.47-3.39 (m, 1H), 2.46-2.40 (m, 2H). MS (ESI) m/z: Calculated for C23H18F3N5O2S: 485.11. found: 486.0 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[C:11]([OH:12])=[C:5]2[N:6]=[CH:7][N:8]=[C:9]([SH:10])[C:4]2=[N:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(Cl)(Cl)Cl>O>[CH3:1][N:2]1[C:11]([OH:12])=[C:5]2[N:6]=[CH:7][N:8]=[C:9]([S:10][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:4]2=[N:3]1
Reactant: CCOC(=O)CBr
Reactant: Cn1nc2c(S)ncnc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CSc1ncnc2c(O)n(C)nc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 g of 2-methyl-3-hydroxy-7-mercapto-pyrazolo[4,3-d]pyrimidine and 8.36 g of anhydrous potassium carbonate were dissolved in 100 ml of water, and after an addition of 8.08 g of ethyl bromoacetate, the mixture was stirred at room temperature for 4 hours. After confirming the completion of the reaction by means of thin layer chromatography, the reaction mixture was shaked with chloroform, whereby by-products were extracted to the chloroform layer and thus removed. The aqueous layer was neutralized with 1:1 hydrochloric acid to bring the pH to a level of from 3 to 4. The precipitated crystals were collected by filtration and then washed with water. Then, the crystals were recrystallized from chloroform-acetone.
Reaction SMILES: [H-].[Na+].[C:3]1([C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6])[OH:4].[Cl:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][C:17]=1Cl>O1CCOCC1>[Cl:11][C:12]1[N:13]=[N:14][C:15]2[O:4][C:3]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[O:6][C:16]=2[CH:17]=1
Reactant: Oc1ccccc1O
Reactant: Clc1cc(Cl)c(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1cc2c(nn1)Oc1ccccc1O2
Yield: 69.7 %

Procedure:
In 1,4-dioxane (30 mL) was suspended 3.49 g (80.0 mmol) of 55% sodium hydride, and to the suspension were added a 1,4-dioxane (30 mL) solution containing 4.40 g (40 mmol) of pyrocatechol, then a 1,4-dioxane (30 mL) solution containing 7.30 g (39.9 mmol) of 3,4,6-trichloropyridazine {described in The Journal of Organic Chemistry, 1963, vol. 28, pp. 218 to 221.}, and the mixture was refluxed for 2 hours. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with 1 mol/L sodium hydroxide and water, and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was recrystallized from methyl isobutyl ketone to obtain 6.15 g (27.8 mmol, Yield: 69.7%) of 3-chloro[1,4]-benzodioxino[2,3-c]pyridazine.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:11].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5][NH:6][C:10](=[O:11])[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCC(F)(F)F)Oc1ccc([N+](=O)[O-])cc1
Temperature: -15 °C
Reaction time: 0.75 h
Yield: 94.6 %

Procedure:
To a solution of 0.35 g (2.75 mmol) of 4,4,4-trifluoro-butylamine (CAS 819-46-5) in 20 ml of dichloromethane, cooled to −15° C., is added dropwise 1.00 g (4.96 mmol) of 4-nitrophenyl chloroformate (CAS 7693-46-1) dissolved in 15 ml of dichloromethane, while maintaining the temperature at −15° C. 0.48 ml (2.75 mmol) of diisopropylethylamine in 10 ml of dichloromethane still at −15° C. is then added. Stirring is continued at −15° C. for 45 minutes, and the temperature of the mixture is then allowed to return to 0° C. over 30 minutes. 20 ml of saturated aqueous sodium hydrogen carbonate solution are then added. The organic phase is separated out by settling and dried over sodium sulfate, and the solvent is partially evaporated off under reduced pressure to a volume of about 8 ml. This solution is chromatographed on a column of 40 g of silica gel, eluting with a mixture of 20% cyclohexane in dichloromethane, to give 0.76 g of 4-nitrophenyl 4,4,4-trifluorobutylcarbamate in the form of a white solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:23][CH2:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([N:31]3[CH2:34][CH:33]([OH:35])[CH2:32]3)[CH2:27][CH2:26]2)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:22])([F:21])[F:20])=[N:8][CH:9]=1)([O-:3])=[O:2].N1C=CC=CC=1.[C:42](OC(=O)C)(=[O:44])[CH3:43]>>[C:42]([O:35][CH:33]1[CH2:34][N:31]([C@H:28]2[CH2:27][CH2:26][C@H:25]([CH2:24][NH:23][C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]([NH:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[O:18][C:19]([F:21])([F:22])[F:20])[N:6]=3)[CH2:30][CH2:29]2)[CH2:32]1)(=[O:44])[CH3:43]
Reactant: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N2CC(O)C2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1CN([C@H]2CC[C@H](CNc3nc(NCc4ccccc4OC(F)(F)F)ncc3[N+](=O)[O-])CC2)C1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
1-(trans-4-{[(5-Nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}cyclohexyl)azetidin-3-ol (25 mg, 0.05 mmol) was dissolved in pyridine (12 μL, 0.15 mmol) and acetic anhydride (14 μL, 0.15 mmol) was added to the solution. The reaction was allowed to stir at 20° C. for 18 h. The volatiles were removed in vacuo and the crude product was purified by flash chromatography on a 12 g SiO2 column, eluting with 90:9:1 CH2Cl2:MeOH:NH4OH as an eluent to afford 5 mg of the title compound, m/z 539.6 [M+1]+