Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[O:27][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(Oc3cccc(Cl)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-chloro-phenol to give [1-(3-chloro-phenoxy)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 367(MH+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[CH2:6][C:7]#[N:8].O1CCCC1.[CH2:19](Br)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[CH2:19]([CH:6]([C:7]#[N:8])[C:5]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:4]=1[Cl:3])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCCc1ccccc1
Reactant: N#CCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(CCc1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Sodium hydride (0.13 mole as a 50% dispersion in mineral oil) is washed with 100 ml. of dry n-hexane to remove the mineral oil, then blanketed with dry nitrogen and suspended in 250 ml. of freshly distilled tetrahydrofuran. To this sodium hydride suspension is added dropwise at room temperature a solution of 2,4-dichlorobenzyl cyanide (25g., 0.13 mole) dissolved in 100 ml. of tetrahydrofuran. When the addition is completed, the temperature is maintained at 30° C. for an additional 0.5 hours. A solution of phenethylbromide (26g., 0.14 mole) is then added dropwise and the resultant reaction mixture is stirred at 40° C. overnight under nitrogen. The reaction mixture is poured into 1 liter of water and extracted with (3 × 200 ml.) of ether. The combined ether extracts are washed with water, dilute hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated and the crude product distilled (144°-56°/0.03 mm) to give 26.6g. (70.5%) of product, which is identified by nmr.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH:9]([OH:18])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=2)[N:3]=1.[C:19]1([CH3:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>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].[Pd](Cl)Cl>[OH:18][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=1)[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2](/[CH:4]=[CH:8]/[CH:9]([OH:18])[CH2:10][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:19][CH3:25])[N:3]=1
Reactant: OCc1cccc(C(O)Cc2cccc(Br)n2)c1
Reactant: Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCCCCCCCC(O)/C=C/c1cccc(CC(O)c2cccc(CO)c2)n1

Procedure:
Under the conditions of example 24D, 96 mg of 2-bromo-6[(2RS)-2-hydroxy-2-(3-hydroxymethylphenyl)-ethyl]-pyridine and 160 mg of (1E)-1-(tri-n-butylstannyl)-1-undecen-(3RS)-3-ol in 1 ml of toluene is reacted in the presence of 1,1'-bis-(diphenylphosphino)-ferrocene-palladium(II) chloride as catalyst and worked up. The crude product is chromatographed on silica gel with hexane/0-25% ethyl acetate. 20 mg of the title compound is obtained as wine-red oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[CH2:16]([N:15]1[C:5]2[C:4]3[CH:3]=[C:2]([C:22]4[CH:23]=[CH:24][S:20][CH:21]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=[CH:14]1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Reactant: OB(O)c1ccsc1
Product: CC(C)Cn1cnc2c(N)nc3ccc(-c4ccsc4)cc3c21

Procedure:
8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and thiophene-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from isopropanol followed by chromatography on silica gel (7% methanol in CH2Cl2) afforded 1-isobutyl-8-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 235-236° C.
Reaction SMILES: [OH:1][C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH:14]2[O:16][CH2:15]2)[N:3]=1.[NH2:17][CH2:18][CH2:19][C:20]1[NH:21][C:22]2[CH:28]=[C:27]([C:29]3[CH:30]([CH3:36])[CH2:31][C:32](=[O:35])[NH:33][N:34]=3)[CH:26]=[CH:25][C:23]=2[N:24]=1>>[OH:1][C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:17][CH2:18][CH2:19][C:20]2[NH:21][C:22]3[CH:28]=[C:27]([C:29]4[CH:30]([CH3:36])[CH2:31][C:32](=[O:35])[NH:33][N:34]=4)[CH:26]=[CH:25][C:23]=3[N:24]=2)[N:3]=1
Reactant: CC1CC(=O)NN=C1c1ccc2nc(CCN)[nH]c2c1
Reactant: OC1=Nc2cccc(OCC3CO3)c2CC1
Product: CC1CC(=O)NN=C1c1ccc2nc(CCNCC(O)COc3cccc4c3CCC(O)=N4)[nH]c2c1

Procedure:
Prepared analogously to Example 1 from 1-(3,4-dihydro-2-hydroxy-quinolin-5-yloxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32](=[O:44])[C:33]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=1)([CH3:35])[CH3:34])C>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:42][C:39]1[CH:38]=[CH:37][C:36]([C:33]([CH3:35])([CH3:34])[C:32]([O:31][CH3:29])=[O:44])=[CH:41][CH:40]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCOC(=O)C(C)(C)c1ccc(CBr)cc1
Product: COC(=O)C(C)(C)c1ccc(COc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and 2-(4-Bromomethyl-phenyl)-2-methyl-propionic acid ethyl ester as in the procedure of Example 43. MS m/z 570;
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].N1C=CN=C1.[CH2:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CCCCCC>[CH:1]([Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[O:23][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:3])[CH3:2]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CCCCCCO
Agent: c1c[nH]cn1
Solvent: CCCCCC
Product: CCCCCCO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 250 ml, three-necked flask was fitted with a large magnetic, egg-shaped stir bar, a small, pressure-equalizing addition funnel, a thermocouple connected to a THERM-O-WATCH®, a reflux condenser, and an argon inlet. This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon. The flask was charged with 32.46 grams (0.168 mole, 1.01 equivalents) of triisopropylsilyl chloride, 11.69 grams (0.172 mole, 1.03 equivalents) of imidazole, and 100 mls of hexane. 1-Hexanol, 17.03 grams (0.167 mole, 1.00 equivalent), was then added dropwise to the resultant slurry. A very mild exotherm was detected. The total feed time was five minutes. A heavy, white precipitate formed after a few more minutes stirring. The reaction mixture became very hard to stir. Therefore, an additional 25 mls of hexane was added to the reaction. The progress of the reaction was monitored by gas chromatography (GC). An aliquot of the clear supernatant was injected into the GC. The sample at 2.33 hours indicated the conversion to the desired product was 73.0%. The reaction mixture was heated to 40° C. with a heating mantle, controlled by the THERM-O-WATCH®. After stirring overnight at 40° C., the conversion had increased to 87.2%. The temperature was increased to 60° C. After seven hours at 60° C., the conversion was 90.0%. The reaction mixture was heated to reflux overnight, under a blanket of argon. The temperature was decreased to 60° C., and the reaction was analyzed by GC. The conversion was 95.2%. The reaction mixture was held at 60° C. for an additional seven hours, then the reaction mixture was allowed to stir at room temperature over the weekend. The conversion had reached 98.1%. The reaction mixture was transferred to a small, dry, Chemglass pressure filter. The tiltrate was collected in a dry, 500 ml flask. The filter cake was rinsed with additional hexane (2×100 ml). The solvent was removed on the rotary evaporator, with the bath temperature set at 40° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][CH3:13])[C:5]#[N:6].[Br:14]Br>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:14])[C:9]=1[NH:10][CH2:11][CH2:12][CH3:13])[C:5]#[N:6]
Reactant: CCCNc1ccc(C#N)cc1Cl
Reactant: BrBr
Solvent: CO
Product: CCCNc1c(Cl)cc(C#N)cc1Br
Reaction time: 0.5 h

Procedure:
Step AR2. To 3-chloro-4-(propylamino)benzonitrile (365 mg, 1.87 mmol) in MeOH (10 ml) was added bromine (300 mg, 1.87 mmol) in MeOH (2 mL) dropwise. After stirred for 30 minutes, the solvent was removed and crude 3-chloro-5-bromo-4-(propylamino)-benzonitrile was obtained (549 mg, 100%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH:21]=[O:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].[CH3:23][Mg]Br>C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH:21]([OH:22])[CH3:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCC=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCc1nc2cnc3ccccc3c2n1CCCC(C)O

Procedure:
The general method described in Part G of Example 28 was used to react 4-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde (8.5 g, 28.8 mmol) with methylmagnesium bromide (20.6 mL of a 1.4 M solution in toluene/THF, 28.8 mmol) to provide 5-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-ol (3.54 g) as an off-white solid after chromatography on silica gel (elution with 5% methanol in dichloromethane).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)(=[O:34])[CH3:33]
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)NC3CCNCC3)c[nH]c12
Reactant: CC(=O)Cl
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)NC3CCN(C(C)=O)CC3)c[nH]c12

Procedure:
Starting from 4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A184) and acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: C(N=C=NCCCN(C)C)C.[O:12]=[C:13]1[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15][N:14]1[CH2:30][C:31](O)=[O:32].Cl.[F:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[CH2:41][NH:40][CH2:39]2>ClCCl>[F:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[CH2:41][N:40]([C:31](=[O:32])[CH2:30][N:14]1[CH2:15][CH2:16][C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:13]1=[O:12])[CH2:39]2
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Fc1ccc2c(c1)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1Cc2ccc(F)cc2C1
Reaction time: 8 h

Procedure:
A solution of N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.067 mL, 0.381 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.075 g, 0.254 mmol) and 5-fluoroisoindoline hydrochloride (0.044 g, 0.254 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.13-7.40 (m, 11H), 6.88-7.05 (m, 2H), 4.75-4.81 (m, 4H), 4.23 (s, 2H), 3.60 (t, J=6.6 Hz, 2H), 2.85 (t, J=6.6 Hz, 2H); MS (ESI+) m/z 415 (M+H)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[CH3:24][S:25][C:26]1[CH:31]=[CH:30][C:29]([Mg]Br)=[CH:28][CH:27]=1>>[CH3:21][C@@H:17]1[CH2:18][CH2:19][CH2:20][N:16]1[CH2:15][CH2:14][C:12]1[O:13][C:9]2[CH:8]=[CH:7][C:6]([C:4]([C:29]3[CH:30]=[CH:31][C:26]([S:25][CH3:24])=[CH:27][CH:28]=3)=[O:5])=[CH:22][C:10]=2[CH:11]=1
Reactant: CSc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Product: CSc1ccc(C(=O)c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)cc1

Procedure:
The product from Example 71E and 4-(methylthio)phenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.45 (d, 3H), 1.75 (m, 1H), 1.80 (m, 2H), 2.30 (m, 2H), 2.38 (m, 1H), 2.54 (s, 3H), 3.50 (m, 2H), 3.55 (m, 1H), 3.80 (m, 2H), 6.85 (s, 1H), 7.4 (dd, 2H), 7.7 (bs, 1H), 7.6 (dd, 1H), 7.75 (m, 3H), 8.0 (d, 1H); MS (ESI) m/z 380 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.C([O-])(=O)C.[Na+].[Br:16]Br>C(O)(=O)C>[Br:16][C:8]1[N:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][C:4]2=[N:10][CH:9]=1
Reactant: Cc1cc2nccn2cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc2ncc(Br)n2cn1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 84.7 %

Procedure:
To a solution of 7-methylimidazo[1,2-c]pyrimidine (0.3404 g, 2.56 mmol) in acetic acid (10 ml) was added sodium acetate (0.3132 g, 3.82 mmol), then, dropwise over 7 min, a solution of bromine (66.0 μl, 1.28 mmol) in acetic acid (2 ml). The solution was stirred at room temperature for 20 min, then more bromine (19.7 μl, 0.382 mmol) in acetic acid (0.6 ml) was added over 4 min. The solution was stirred at room temperature for a further 15 min, then partitioned between saturated aqueous NaHCO3 (200 ml) and ethyl acetate (200 ml). The aqueous layer (pH 9) was further extracted with ethyl acetate (200 ml), and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, EtOAc) to afford 0.2298 g (42%) of the title compound: 1H NMR (360 MHz, CDCl3) δ 2.57 (3H, s), 7.29 (1H, s), 7.56 (1H, s), 8.91 (1H, s); MS (ES+) m/z 212/214 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[NH:11][CH:12]=[CH:13][CH:14]=2)=O)=[CH:6][CH:5]=[C:4]([Cl:15])[N:3]=1.O.[NH2:17][NH2:18]>C(O)C>[Cl:15][C:4]1[N:3]=[C:2]2[NH:17][N:18]=[C:8]([C:10]3[NH:11][CH:12]=[CH:13][CH:14]=3)[C:7]2=[CH:6][CH:5]=1
Reactant: NN
Reactant: O=C(c1ccc[nH]1)c1ccc(Cl)nc1Cl
Solvent: CCO
Solvent: O
Product: Clc1ccc2c(-c3ccc[nH]3)n[nH]c2n1
Temperature: 90 °C

Procedure:
A mixture of (2,6-dichloro-pyridin-3-yl)-(1H-pyrrol-2-yl)-methanone (1.8 g) and hydrazine hydrate (0.5 mL) in ethanol (70 mL) was heated at 90° C. for 20 hours. The reaction was concentrated to 40 mL, diluted with water (5 mL) and cooled. The precipitate was collected and dried to give 0.84 g of the titled compound.
Reaction SMILES: [OH:1][CH:2]([C@H:6]1[O:10][C:9]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[O:8][C@H:7]1[CH2:16][O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])CCO.I([O-])(=O)(=O)=O>CC(C)=O.O>[CH:2]([C@H:6]1[O:10][C:9]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[O:8][C@H:7]1[CH2:16][O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:1]
Reactant: CC(C)(C)OC(=O)COC[C@@H]1OC2(CCCCC2)O[C@@H]1C(O)CCO
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)COC[C@@H]1OC2(CCCCC2)O[C@@H]1C=O
Reaction time: 4 h
Yield: 92.2 %

Procedure:
A solution of 1,1-dimethylethyl [[(2S,3R) 3-(1,3-dihydroxypropyl)-1,4-dioxaspiro[4,5]dec-2-yl]methoxy]acetate (50 g, 138 mmol) in acetone (350 mL) was treated with a solution of periodate (50 g, 235 mmol, 1.7 eq) in water (1.2 L). The reaction mixture was stirred vigorously under nitrogen and monitored by TLC. After about 4 hours, the reaction was complete by TLC analysis. Acetone was removed under reduced pressure without heating. The reaction mixture was extracted with ethyl acetate (3×500 mL). The combined organic layers were dried and concentrated under reduced pressure without heating to give 40 g of 1,1-dimethylethyl [[(2S,3S) 3-formyl-1,4-dioxaspiro[4,5]dec-2-yl]methoxy]acetate as a clear oil: [α]D=−1.142 (10.147 mg/cc in MeOH); 1H NMR (CDCl3) δ1.38 (m, 2H), 1.42 (s, 9H), 1.61 (m, 8H), 1.73 (m, 2H), 3.52 (dd, 1 H), 3.72 (dd, 1 H), 3.88 (s, 2H), 4.38 (dd, 1 H), 4.52 (m, 1H), 9.62 (s, 1H) ppm.
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: CCN(CC1CCCCC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(O)cn1
Reactant: OCCCBr
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: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[C:19]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[CH:28][C:27]=1[CH:36]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][C:13]3[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:36][C:27]5[CH:28]=[N:29][C:30]6[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=6)[N:26]=5)[CH2:22][CH2:21]4)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2nc3cccc(N4CCNCC4)c3s2)cc1
Reactant: O=Cc1cnc2ccccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(-c2nc3cccc(N4CCN(Cc5cnc6ccccc6n5)CC4)c3s2)cc1
Temperature: 25 °C
Yield: 55 %

Procedure:
The piperazine template (0.075 g, 0.213 mmol) of Example 24 was dissolved in 1,2-dichloroethane (3 mL) and treated with quinoxaline-2-carbaldehyde (0.044 g, 0.277 mmol) and glacial acetic acid (2 drops). Sodium triacetoxyborohydride (0.090 g, 0.426 mmol) was added, and the mixture was stirred at room temperature until the reaction was complete by LCMS analysis. The solvent was removed under reduced pressure, and the resulting residue was purified by RP-HPLC to yield the free base (0.0578 g, 55% yield). MS (ESI) m/z 494.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1.[CH3:23][N:24]([CH3:30])[CH2:25][CH2:26][CH2:27][NH:28][CH3:29]>CC(C)=O>[CH3:23][N:24]([CH3:30])[CH2:25][CH2:26][CH2:27][N:28]([CH3:29])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CNCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CC(C)=O
Product: CN(C)CCCN(C)c1ccc(C=O)cc1
Temperature: 50 °C

Procedure:
10 g of 4-fluorobenzaldehyde, 12 g of K2CO3 and 20 ml of NMP are stirred and heated at 50° C. 13 ml of N,N,N′-trimethyl-1,3-propanediamine are added dropwise to the medium kept stirring and heated at 80° C. for 10 h. After the reaction medium has been cooled to ambient temperature, 100 ml of acetone are added. The precipitate obtained is filtered off, and the filtrate is evaporated to dryness and then dried. 21.85 g of powder are recovered. The analyses indicate that the product is in conformity.
Reaction SMILES: CO.C([N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:31])[C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C@H:12]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([OH:40])[CH:34]=2)[CH2:11]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].O>[F:30][C:27]([F:28])([F:29])[C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=1)[C:16]([N:13]1[CH2:14][CH2:15][NH:10][CH2:11][C@H:12]1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([OH:40])[CH:34]=1)=[O:31]
Reactant: Cc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1O
Temperature: 25 °C
Yield: 94.9 %

Procedure:
Into a mixed solution of methanol (270 l) and water (30 l) were charged (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(3-hydroxy-4-methylbenzyl)piperazine (30.0 kg), ammonium formate (8.8 kg) and 10% palladium on carbon (wet condition: 50%, 1.5 kg). They were allowed to react at an inside temperature of 50 to 55° C. for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, clarified and filtered, and washed with methanol (90 l). Water (480 l) was added dropwise to the combined filtrate and washings at room temperature and crystallization was effected under ice-cooling for 8 hours. Crystals were collected by filtration, washed with water (90 l) and dried under reduced pressure to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-piperazine (23.7 kg, yield 94.8%) in the form of white crystals.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:7]=[C:8]=[S:9])=[CH:4][S:5][CH:6]=1.[F:10][C:11]1[C:12]([NH2:21])=[C:13]([NH2:20])[C:14]([F:19])=[C:15]([F:18])[C:16]=1[F:17]>>[NH2:20][C:13]1[C:14]([F:19])=[C:15]([F:18])[C:16]([F:17])=[C:11]([F:10])[C:12]=1[NH:21][C:8]([NH:7][C:3]1[C:2]([CH3:1])=[CH:6][S:5][CH:4]=1)=[S:9]
Reactant: Cc1cscc1N=C=S
Reactant: Nc1c(N)c(F)c(F)c(F)c1F
Product: Cc1cscc1NC(=S)Nc1c(N)c(F)c(F)c(F)c1F

Procedure:
is obtained analogously to the reaction described in example 1 b) from 4-methyl-3-thienyl isothiocyanate and 3,4,5,6-tetrafluoro-1,2-diaminobenzene. Crystalline solid, m.p.: 286-290° C.