Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[Br-].[CH3:11][C:12]1[N:17]=[C:16]([Zn+])[CH:15]=[CH:14][CH:13]=1.C1COCC1>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].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(OCC)(=O)C>[CH3:11][C:12]1[N:17]=[C:16]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CSc1nccc(I)n1
Reactant: Cc1cccc([Zn+])n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1nccc(-c2cccc(C)n2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
4-Iodo-2-methylsulfanyl-pyrimidine (1 g, 3.97 mmol) was dissolved in dry and degassed THF (9 ml). Pd(dba)2 (114 mg, 0.20 mmol) and tri(2-furyl)phosphine (50 mg, 0.20 mmol) were added. The mixture was cooled at 0° C. and then a 0.5 M solution of 6-methyl-2-pyridylzinc bromide in THF (13 ml, 6.5 mmol) was slowly added dropwise. After stirring the mixture at room temperature for 3 hours, ethyl acetate was added and the mixture was washed with water. The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography DCM-MeOH—NH4OH (20-0.1-0.1) to give 785 mg of the title compound (90% yield).
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:33][CH3:34])[C:8]2[N:13]=[C:12]3[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]3=[CH:10][C:9]=2[CH2:19][N:20]([CH2:23][C:24]2[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26]([F:32])[CH:25]=2)[C:21]#[N:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+].[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C=O)C>[CH:1]1([CH2:6][N:7]([CH2:33][CH3:34])[C:8]2[N:13]=[C:12]3[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]3=[CH:10][C:9]=2[CH2:19][N:20]([CH2:23][C:24]2[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26]([F:32])[CH:25]=2)[C:21]2[NH:39][N:38]=[N:37][N:22]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCN(CC1CCCC1)c1nc2c(cc1CN(C#N)Cc1cc(F)c(F)c(F)c1)c(C)nn2C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC1CCCC1)c1nc2c(cc1CN(Cc1cc(F)c(F)c(F)c1)c1nnn[nH]1)c(C)nn2C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a stirred suspension of [6-(cyclopentylmethyl-ethyl-amino)-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-ylmethyl-(3,4,5-trifluoro-benzyl)-cyanamide (0.280 g, 0.590 mmol) and ammonium chloride (0.160 g, 2.95 mmol) in dry DMF (10 mL) was added sodium azide (0.195 g, 2.95 mmol) and the reaction mixture was heated at 100° C. overnight. After the reaction mixture was cooled to RT, ice water was added, and this mixture was stirred for 30 min, and then extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and evaporated to yield the product as oil (90%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@@H:9]([OH:12])[C@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1O.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[F:38])[C@H:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: Oc1ccccc1F
Reactant: CCOC(=O)N1CC[C@@H](O)[C@H](c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)N1CC[C@H](Oc2ccccc2F)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 6.23 g of trans-1-ethoxycarbonyl-3-phenyl-4-piperidinol, 7.21 g of triphenylphosphine, 3.08 g of 2-fluorophenol and 250 ml of benzene is added dropwise, at 4° C. under nitrogen, a solution of 4.79 g of diethyl azodicarboxylate in 250 ml of benzene. After the addition is complete, the mixture is stirred at room temperature overnight and is processed according to the procedure of Example 75 to give product as a gum.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:31])=O>CC#N>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:31])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Br)(Br)Br
Reactant: CCCCOC(=O)c1nc(O)c2ccc(Oc3c(C)cccc3C)cc2c1O
Solvent: CC#N
Product: CCCCOC(=O)c1nc(Br)c2ccc(Oc3c(C)cccc3C)cc2c1O
Yield: 36 %

Procedure:
A mixture of 6-(2,6-Dimethyl-phenoxy)-1,4-dihydroxy-isoquinoline-3-carboxylic acid butyl ester (4 mmol, 1.53 g), POBr3 (16 mmol, 4.63 g), MeCN (30 mL) was refluxed gently with stirring before it was concentrated in vacuo. The residue was dissolved in CH2Cl2 (100 mL). To the solution was added NaHCO3 (20 g) and then water (100 mL) in small portions with stirring. The mixture was stirred for 1 h at ambient temperature before the organic phase was separated and dried over MgSO4. Concentration and purification of the residue by flash column chromatography on silica gel using CH2Cl2 as the eluent gave the title compound as a yellowish oil (640 mg); MS-(+)-ion: M+1, 79Br/81Br=443.9 and 445.9.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][CH:7]([CH3:9])[CH3:8])=[CH:4][CH:3]=1.C(O)(=O)C.[CH2:16]=[C:17]1[O:21][C:19](=[O:20])[CH2:18]1>O>[CH:7]([N:6]([C:19](=[O:20])[CH2:18][C:17]([CH3:16])=[O:21])[C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:9])[CH3:8]
Reactant: CC(C)Nc1ccc(Cl)cc1
Reactant: C=C1CC(=O)O1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)CC(=O)N(c1ccc(Cl)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 500 ml reaction flask fitted with a condenser, drying tube, magnetic stirrer and therometer was charged with 89.5 g (0.528 mole) of 4-chloro-N-isopropylaniline, 200 ml of glacial acetic acid and 18.5 g (0.58 mole) of mercuric acetate. To the stirred solution there was added dropwise 48.8 g (0.58 mole) of diketene while the reaction temperature was maintained at 30°-5°. The reaction solution was allowed to stir overnight at ambient temperature. The solution was mixed with two liters of water and twice extracted with ether. The organic phase was washed with water and dried over sodium sulfate. After removing the solvent, the liquid residue weighed 134 g (100%). N.M.R. (CDCl3) ∂1.0 and 1.2 (isopropyl, doublet), 1.8 (CH3, enol), 2.1 (CH3, keto), 3.2 (CH2), 4.7-5.2 (CH, isopropyl), 7.1-7.5 (aromatic).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12](C=O)[CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.Cl.C(O)C.[OH-].[Na+]>O>[F:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: O=CN1CCC(c2nsc3cc(F)ccc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Fc1ccc2c(C3CCNCC3)nsc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.5 %

Procedure:
Reflux a solution of 4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinecarboxaldehyde (Tetrahedron Lett., 1993, 34, 6525-6528, 12 g, 0.045 mol), 3N hydrochloric acid and ethanol (100 mL) for 3 hours. Stir at ambient temperature for 16 hours, add water and stir with ice bath chilling while adding sodium hydroxide solution until the mixture was basic. Extract with ethyl acetate, wash the extract with water, dry (MgSO4), filter and concentrate the filtrate to afford an oil which solidified on standing to afford 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (9.2 g). React 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole under conditions as described for Example 11 to afford the title compound (0.25 g, 61% yield), LC/MS (APCI) m/e 510 (MH+), retention time 4.38 min.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([N:19]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[N:10]([CH3:39])[N:9]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([S:26]([N:19]([C:11]2[N:10]([CH3:39])[N:9]=[C:8]([O:7][CH2:6][CH2:5][OH:4])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: COCCOCN(c1c(-c2ccccc2)c(OCCOC(C)=O)nn1C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COCCOCN(c1c(-c2ccccc2)c(OCCO)nn1C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 2-[(5-{{[4-(tert-butyl)phenyl]sulfonyl}[(2-methoxyethoxy)methyl]amino}-1-methyl-4-phenyl-1H-pyrazol-3-yl)oxy]ethyl acetate (Preparation 16) (1.112 g) in solution in methanol (100 ml) was added a solution of potassium carbonate (890 mg) in water (25 ml), at room temperature. The reaction was stirred at room temperature for 1.5 hours, and then overnight. The reaction was stripped down and the residue partitioned between dichloromethane (20 ml) and water (20 ml). The aqueous layer was extracted with dichloromethane (10 ml). The organics were combined and back-washed with brine (10 ml). The solution was dried on magnesium sulfate, filtered and concentrated under reduced pressure to yield the desired product as an off white solid (528 mg)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([NH:9]C(=O)OCC1C=CC=CC=1)([CH3:8])[CH3:7].[H][H]>C(O)C.[Pd]>[CH3:7][C:6]([CH3:8])([C:2]1[O:1][CH:5]=[CH:4][N:3]=1)[NH2:9]
Reactant: CC(C)(NC(=O)OCc1ccccc1)c1ncco1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(N)c1ncco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.3 %

Procedure:
A mixture of benzyl 2-(oxazol-2-yl)propan-2-ylcarbamate (0.63 g, 24 mmol) and palladium 10% on carbon (0.06 g) in ethanol (20 mL) was charged with hydrogen balloon and stirred at room temperature for 2 h. TLC showed the reaction was completed; it was filtered and concentrated to give a yellow oil (0.1 g, 33%); MS: m/e 127.1 [M+H]+. 1H NMR (300 MHz, CDCl3): δ 7.58 (d, 1H, J=0.6 Hz), 7.02 (s, 1H), 2.56 (bs, 4H), 1.59 (s, 6H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:35](=[O:36])[O:37][CH2:38][CH3:39])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: CCOC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CCOC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f13) and commercially ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5](O)=[O:6].O1CCCC1.C(N(CC)CC)C.[CH2:40]([NH:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]>>[CH2:59]([N:58]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:5](=[O:6])[CH2:4][CH2:3][CH:2]([CH:8]1[C:12]2([CH3:27])[CH:11]([CH:16]3[CH:15]([CH2:14][CH2:13]2)[C:20]2([CH3:26])[CH:19]([CH2:24][CH:23]([OH:25])[CH2:22][CH2:21]2)[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)[CH3:1])[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76]
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CCC(C)C1CCC2C3CCC4CC(O)CCC4(C)C3CCC12C
Yield: 93.8 %

Procedure:
Lithocholic acid (81) (7.1 g, 18.8 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) Isobutylchloroformate (2.6 g, 2.6 mL, 18.8 mmol) was added followed by the addition of triethylamine (3.84 g, 5.3 mL, 38 mmol) and dioctadecylamine (9.8 g, 18.77 g). The reaction mixture was brought to ambient temperature and allowed to stir over night. The reaction mixture was concentrated under vacuum, and the residue was dissolved in dichloromethane (250 mL) The organic layer was washed with 5% sodium bicarbonate, 3% aqueous HCl and water. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to afford amide 82 (15.5 g) in 93% yield. This was used as such for the next step.
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].[NH2:16][CH2:17][C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.C(=O)(O)[O-]>CN(C)C(=O)C>[C:18]12([CH2:17][NH:16][CH2:3][C:4]3[N:5]=[C:6]4[C:11](=[N:12][CH:13]=3)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]4[NH2:15])[CH2:25][CH:24]3[CH2:23][CH:22]([CH2:21][CH:20]([CH2:26]3)[CH2:19]1)[CH2:27]2
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: Br
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2nc(CNCC34CC5CC(CC(C5)C3)C4)cnc2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (41.6 mg, 0.124 mmol) in anhydrous N,N dimethylacetamide was added 1-aminomethyl adamantane (35.43 ul, 0.2 mmol). The reaction mixture was stirred at 50° C. overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 12.7 mg product was obtained. Yield: 40%; 1H NMR (500 MHz, DMSO-d6): δ 1.56754–1.67101(m, 13H), 1.96741(s, 2H), 2.71139(s, 2H), 4.49166(s, 2H), 8.89918(s, 1H); ESI-MS: m/z 340 (M++1)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[C:19]([C:22]5[CH:27]=[CH:26][C:25]([CH:28]6[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]6)=[CH:24][CH:23]=5)[CH:20]=4)[NH:15][CH:14]=3)[CH:10]=[N:9]2)[CH:2]=1>C(O)(C(F)(F)F)=O.CO>[NH:31]1[CH2:32][CH2:33][CH:28]([C:25]2[CH:26]=[CH:27][C:22]([C:19]3[CH:20]=[C:21]4[C:13]([C:11]5[CH:10]=[N:9][N:8]([CH2:7][C:3]6[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=6)[CH:12]=5)=[CH:14][NH:15][C:16]4=[N:17][CH:18]=3)=[CH:23][CH:24]=2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccnc6)c5)c4c3)cc2)CC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: c1cncc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCNCC6)cc5)cc34)cn2)c1
Yield: 15.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (120 mg, 0.224 mmol) was deprotected in TFA/methanol (5/5 ml). This afforded 15 mg (12% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.76 (s, 2H), 8.56-8.55 (d, 2H), 8.36-8.34 (m, 2H), 8.02 (s, 1H), 7.95-7.91 (m, 1H), 7.75-7.72 (m, 3H), 7.45-7.42 (m, 2H), 5.66 (s, 2H), 3.56-3.51 (d, 2H), 3.22-3.14 (t, 2H), 3.10-2.99 (m, 1H), 2.16-2.11 (d, 2H), 2.03-1.93 (td, 2H). MS: m/z=435.2 (M+1), HPLC: 97.0% in method A.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:27][CH3:28])[C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=1.Br[CH2:46][CH2:47][CH2:48][OH:49].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:44][C:2]([F:1])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:38]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:27][CH3:28])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:46][CH2:47][CH2:48][OH:49])=[CH:12][N:13]=1
Reactant: OCCCBr
Reactant: CCN(CC1CCCCC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC1CCCCC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCO)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexylmethyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-ol (250 mg) and 3-bromo-1-propanol (43 μl) are dissolved in N,N-dimethylformamide (1 ml) and thereto is added potassium carbonate (65 mg) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated brine, and the mixture is separated and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:1) to give 3-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexylmethyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-propan-1-ol (150 g). MS (m/z): 693 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].O[N:12]=[C:13]([NH2:15])[CH3:14]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:4]2[O:5][N:15]=[C:13]([CH3:14])[N:12]=2)=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CC(N)=NO
Solvent: c1ccncc1
Product: Cc1noc(-c2cccnc2Cl)n1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 2-chloro nicotinoyl chloride (1.0 eq.) and N′-hydroxy ethanimidamide (1.1 eq) in pyridine (0.6 M) was stirred at 100° C. for 4 h and then concentrated. The residue was purified by flash chromatography (Hexane:EtOAc, 70:30) to afforded the title compound.
Reaction SMILES: Cl[C:2]1[C:3]([O:25]C)=[CH:4][C:5]([O:23]C)=[C:6]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[C:11]([C:20]([OH:22])=[O:21])[N:10]=[N:9]2)[CH:7]=1.C(O)(=O)C.C(OC(=O)C)(=O)C.O>I>[OH:23][C:5]1[CH:4]=[C:3]([OH:25])[CH:2]=[CH:7][C:6]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[C:11]([C:20]([OH:22])=[O:21])[N:10]=[N:9]1
Reactant: COc1cc(OC)c(-n2nnc(C(=O)O)c2-c2ccc(F)cc2)cc1Cl
Agent: I
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1nnn(-c2ccc(O)cc2O)c1-c1ccc(F)cc1

Procedure:
1-(5-Chloro-2,4-dimethoxy-phenyl)-5-(4-fluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid (0.29 g, 0.77 mmol) was refluxed in a mixture of hydroiodic acid (5 mL), acetic acid (1 mL) and acetic anhydride (0.5 mL) for 16 hours. When cooled, water (20 mL) was added and the aqueous layer was extracted with EtOAc (2×15 mL). The combined organic layers were washed with saturated sodium thiosulphate solution (2×15 mL) and brine (20 mL), dried with NaSO4 and filtered. After evaporation of the solvent, light brown solids were obtained (0.15 g, 62%). The compound was used in the next synthetic step without further purification.
Reaction SMILES: Cl.[CH:2]1([NH:8][CH:9]2[CH2:11][CH2:10]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][C:20](Br)=[O:21]>C(Cl)Cl.O>[Br:18][CH2:19][C:20]([N:8]([CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[CH:9]1[CH2:11][CH2:10]1)=[O:21]
Reactant: C1CCC(NC2CC2)CC1
Reactant: O=C(Br)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)N(C1CCCCC1)C1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.7 %

Procedure:
To an ice cooled mixture of 1.054 g (6 mmol) of N-cyclohexyl-N-cyclopropylamine hydrochloride, 2.07 g (15 mmol) of potassium carbonate in 15 ml of methylene chloride and 15 ml of water was added 1.2 g (6 mmol) of bromoacetyl bromide. Then the reaction mixture was stirred at RT for 20 h. The organic phase washed with water, dried over sodium sulphate and evaporated to dryness to give 1.33 g of crude compound. Flash chromatography using DCM as eluant afforded 1.12 g of the desiderated compound as colorless oil.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=1.O>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:33]([C:32]1[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:37])[F:38])=[CH:36][CH:35]=1)[OH:34])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Brc1ccccc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: OC(c1ccc(C(F)(F)F)cc1)c1ccccc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (2.44 M, 4.0 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (2.6 g, 9.9 mmol) in THF (100 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 30 minutes. To this solution, 4-trifluoromethylbenzaldehyde (1.6 g, 9.0 mmol) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for two hours, and then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (2.6 g, 82%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:6][CH:5]=1.O>C1C=CC=CC=1>[CH3:18][CH:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][CH:6]=1)[CH2:12][CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: COC(=O)c1ccc(OC(C)CCCC(C)C)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)CCCC(C)Oc1ccc(CO)cc1

Procedure:
42 g of p-[(1,5-dimethylhexyl)oxy]benzoic acid methyl ester is dissolved in 250 ml of benzene and, with stirring, treated dropwise with 50 g of 70% bis(2-methoxy-ethoxy)sodium aluminum hydride. The reaction solution is further stirred at 25°C. for 5 hours and thereafter treated with water. The organic phase is separated off, dried under sodium sulfate, carefully filtered (using a filter aid) and evaporated under reduced pressure. There is obtained a residual of p-[(1,5-dimethylhexyl)oxy]benzyl alcohol; B.P. 180°-182°C/1.0 mmHg.