Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].C1C=C2N=NN(O)C2=CC=1.O.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[CH3:55][NH:56][CH2:57][CH2:58][CH2:59][N:60]1[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1>CN(C=O)C.CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:56]([CH3:55])[CH2:57][CH2:58][CH2:59][N:60]4[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CNCCCN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N(C)CCCN3CCCCC3)cn2)c1O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61.2 %

Procedure:
Combined 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (70 mg, 0.219 mmol), HOBT hydrate (50.2 mg, 0.328 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (62.8 mg, 0.328 mmol) in DMF (1 mL), and added triethylamine (0.092 mL, 0.656 mmol), then stirred at ambient temperature for 5 minutes and N-methyl-3-(piperidin-1-yl)propan-1-amine (0.085 mL, 0.437 mmol) was added. The reaction was stirred at 50° C. for 3 hours. The crude reaction was then cooled to ambient temperature and diluted with DMSO (1 mL) and purified via preparative HPLC (25-45% acetonitrile in water, with trifluoroacetic acid) to give the title compound (61.5 mg, 0.134 mmol, 61.4%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30-1.49 (m, 1 H) 1.68 (br. s., 3 H) 1.82 (br. s., 2 H) 1.93-2.07 (m, 2 H) 2.43 (s, 3 H) 2.88-3.15 (m, 7 H) 3.31-3.43 (m, 1 H) 3.45-3.58 (m, 3 H) 7.65-7.87 (m, 3 H) 8.04-8.67 (m, 4 H) 9.35 (br. s., 1 H). ESI-MS m/z [M+H]+ 459.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:6][C:7]=1[N+:8]([O-])=O.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:8][C:7]1[S:6][C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCOC(=O)c1cc(OC)c([N+](=O)[O-])s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(OC)c(N)s1
Temperature: 50 °C

Procedure:
A mixture of ethyl 4-methoxy-5-nitrothiophene-2-carboxylate (Int. 68) (300 mg, 1.297 mmol) (prepared as described in Step 4 hereabove reported), and ammonium chloride (139 mg, 2.59 mmol) in EtOH/water=2/1 (18 ml) was heated at 50° C. until complete dissolution. Iron powder (435 mg, 7.78 mmol) was added, and the reaction was heated at 80° C. for 2 hours. The mixture was filtered and the filtrate was concentrated under vacuum; the residue was portioned between brine and EtOAc and the organic phase was dried over sodium sulfate. The solvent was removed to afford ethyl 5-amino-4-methoxythiophene-2-carboxylate (Int. 69) in a mixture with approximately 30% of corresponding methyl ester (261 mg, 1.297 mmol, MS/ESI+201.9 [MH]+). This intermediate was used as such in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH2:17])[C:6](=[O:16])[NH:7]2.Cl.N[OH:20].O>C(O)CCC>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[N:17][OH:20])[C:6](=[O:16])[NH:7]2
Reactant: NO
Reactant: Nc1nc2c(Cl)cc(C(F)(F)F)cc2[nH]c1=O
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: O=c1[nH]c2cc(C(F)(F)F)cc(Cl)c2[nH]c1=NO
Temperature: 25 °C
Yield: 68.8 %

Procedure:
An adaptation of the method of Harsanyi et al., Liebigs Ann. Chem. 190 (1973), was used. A mixture of 5-chloro-7-trifluoromethyl-3-aminoquinoxalin-2(1H)-one (35 mg, 0.13 mmol) and hydroxylamine hydrochloride (20 mg, 0.29 mmol; Aldrich Co.) in 2 mL of 1-butanol was heated to reflux. The resulting suspension was stirred under reflux for 12 h. The resulting suspension was cool to 25° C., and added H2O (5 mL). A pale yellow precipitate appeared. The mixture was vacuum filtered and the solid was washed with EtOH (5×2 mL) and dried in vacuum at 60° C. overnight to yield 25 mg (69%) of 5-chloro-7-trifluoromethyl-3-(hydroxyimino)-1,4-dihydroquinoxalin-2-one (tentatively named as this since the regiochemistry is not sure) as a pale yellow solid of a new compound: mp dec.>235° C. 1H NMR (300 MHz, DMSO-d6) δ 11.199 (br s, 1H, NH), 10.932 (br s, 1H, NOH), 10.411 (br s, 1H, NH), 7.604 (s, 1H, H-7), 7.317 (s, 1H, H-5). LRMS: 279 (M+, 100%), 249 (50%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13](=[O:16])[CH2:14]Cl)[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([CH2:14][N:28]2[CH2:27][CH2:26][N:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][CH3:17])[CH2:30][CH2:29]2)=[O:16])[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCc1cc(NC(=O)CCl)c(OC)nc1C
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1cc(NC(=O)CN2CCN(c3ccccc3OC)CC2)c(OC)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
After N-(5-ethyl-2-methoxy-6-metylpyridine-3-yl)chloroacetamide(0.10 g, 0.43 mmol) and 1-(2-methoxyphenyl)piperazine(0.0091 g, 0.47 mmol) were dissolved into tetrahydrofuran(5 ml) and was added DBU(0.060 g, 0.43 mmol), the reaction mixtures were stirred at room temperature for 2 hours. After the product of reaction were concentrated, separated by column chromatography to obtain 0.12 g of the titled compound.
Reaction SMILES: N1C2NC=CC=2C=NC=1.[Cl:10][C:11]1[C:12]2[C:19](I)=[CH:18][N:17]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)[C:13]=2[N:14]=[CH:15][N:16]=1.[O:34]([C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C(#N)C>[Cl:10][C:11]1[C:12]2[C:19]([C:44]3[CH:45]=[CH:46][C:41]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:42][CH:43]=3)=[CH:18][N:17]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: CN1CCC(N2CCC(n3cc(I)c4c(Cl)ncnc43)CC2)CC1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ncc2cc[nH]c2n1
Solvent: COCCOC
Solvent: CC#N
Solvent: O
Product: CN1CCC(N2CCC(n3cc(-c4ccc(Oc5ccccc5)cc4)c4c(Cl)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
1H NMR (DMSO-d6, 400 MHz) 8.62(s, 1H), 8.16(s, 1H), 4.66-4.58(m, 1H), 3.17(s, 1H), 3.02-3.00(d, 2H, J=8 Hz), 2.84-2.82 (d, 2H, J=8 Hz), 2.33-2.26(m, 2H), 2.17 (s, 3H), 2.08-2.04(m, 2H), 1.95-1.85 (m, 4H), 1.91-1.88(d, 2H, J=12 Hz), 1.49-1.45(m, 2H); Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 3.505 min. 4-chloro-5-(4-phenoxyphenyl)-7-1-(1-methyl-4-piperidinyl)-4-piperidinyl]-7H-pyrrolo[2,3-d]pyrimidine A mixture of 4-chloro-5-iodo-7-[ 1-(1-methyl-4-piperidinyl)-4-piperidinyl]-7H-pyrrolo[2,3-d]pyrimidine (0.390 g, 0.845 mmol), 4-phenoxyphenyl boronic acid (0.199 g, 0.93 mmol), tetrakis(triphenylphosphine)pallidium (0.058 g, 0.051 mmol), and sodium carbonate (0.215 g, 2.03 mmol) were heated in a mixture of ethylene glycol dimethyl ether (20 mL) and water (10 mL) at 80° C. for 7 hours under a nitrogen atmosphere. Reaction solution was allowed to cool to room temperature, and the organic layer was removed under reduced pressure. Ethyl acetate was added, the layers were partitioned and the aqueous layer was extracted with ethyl acetate (250 mL). The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica using 10% methanol in dichloromethane, then 20% methanol in dichloromethane as eluent to give 0.241 g (51%) of 4-chloro-5-(4-phenoxyphenyl)-7-[1-(1-methyl-4-piperidinyl)-4-piperidinyl]-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]1[C:25]([NH2:26])=[CH:24][NH:23][N:22]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[NH:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]=[C:13]1[C:21]1[C:25]([NH:26][C:4](=[O:6])[C:3]2[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[CH:24][NH:23][N:22]=1
Reactant: O=C(O)c1c(F)cccc1F
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1c[nH]nc1-c1nc2ccccc2[nH]1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.6 %

Procedure:
A mixture of 2,6-difluorobenzoic acid (43 mg, 0.28 mmol), 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.25 mmol), EDC (58 mg, 0.30 mmol) and HOBt (40.5 mg, 0.30 mmol) in DMF (10 ml) was stirred at ambient temperature for 24 h. The mixture was reduced in vacuo, water (30 ml) added and the resultant solid collected by filtration, dried in the vacuum oven and purified by flash column chromatography [SiO2, EtOAc-petrol (1:2, 1:1, 3:1)] affording N-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2,6-difluoro-benzamide (20 mg, 24%). (LC/MS: Rt 3.29, [M+H]+ 339.64).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]([C@H:13]2[C@H:18]([C:19]([CH3:21])=[CH2:20])[CH2:17][CH2:16][C:15]([CH3:22])=[CH:14]2)=[C:10]([OH:12])[CH:11]=1.C([Al](CC(C)C)CC(C)C)C(C)C>ClCCl>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([OH:12])[C:9]2[C@@H:13]3[CH:14]=[C:15]([CH3:22])[CH2:16][CH2:17][C@H:18]3[C:19]([CH3:21])([CH3:20])[O:23][C:8]=2[CH:7]=1
Reactant: C=C(C)[C@@H]1CCC(C)=C[C@H]1c1c(O)cc(CCCCC)cc1O
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: ClCCl
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Temperature: 22.5 °C
Reaction time: 8 h

Procedure:
To a nitrogen inerted, stirred solution of cannabidiol (21.2 g, 67.1 mmol) in dichloromethane (370 mL) was added, by syringe pump, commercial tri-isobutylaluminum solution (1 M in hexanes, 6.7 mL, 10 mol %) over 4.5 hours. The temperature of the reaction mixture was maintained at 20-25° C. and the mixture was stirred overnight. Additional charges of triisobutylaluminum solution (1 M in hexanes, 2.67 mL added, 4 mol %) were made over the next day to drive the reaction to >99% conversion by HPLC analysis. The reaction was quenched by addition of water (250 mL), stirred 30 minutes, combined with a slurry of celite in dichloromethane (10.0 g in 70 mL dichloromethane) and then clarified. The reactor and filter cake were rinsed with dichloromethane (50 mL) and the combined filtrates distilled under reduced pressure (25° C. pot temperature, 22 inches of vacuum) to about 50 mL volume. Toluene (106 mL) was added and the solvents again removed under reduced pressure. More toluene (106 mL) was added and removed under reduced pressure and then the dichloromethane-free residue was reconstituted in toluene (100 mL). HPLC analysis showed 95.6% delta-9-tetrahydrocannabinol, 1.1% cis-tetrahydrocannabinol, and no cannabinol. (Sunfire C18 5u, 4.6 mm×150 mm, 1 ml/min, gradient 80% 0.1% TFA/water and 20% 0.05% TFA/acetonitrile to 100% 0.05% TFA/acetonitrile over 15 minutes, delta-9 tetrahydrocannabinol: rt=15.1 min). The yield was estimated at 95%. The solution was stored under nitrogen until needed for preparation of the camphorsulfonate derivative.
Reaction SMILES: [C:1]([Si:5]([CH3:33])([CH3:32])[O:6][C:7]1[CH:8]=[C:9]([CH:13]([O:15][C:16](=[O:31])[NH:17][C:18]2[C:19]([CH3:30])=[N:20][O:21][C:22]=2[C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=2)[CH3:14])[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([O:36][C:37]([C:39]1([C:42]2[CH:47]=[CH:46][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:44][CH:43]=2)[CH2:41][CH2:40]1)=[O:38])[CH3:35]>>[CH2:34]([O:36][C:37]([C:39]1([C:42]2[CH:47]=[CH:46][C:45]([C:26]3[CH:27]=[CH:28][C:23]([C:22]4[O:21][N:20]=[C:19]([CH3:30])[C:18]=4[NH:17][C:16]([O:15][CH:13]([C:9]4[CH:10]=[CH:11][CH:12]=[C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:33])[CH3:32])[CH:8]=4)[CH3:14])=[O:31])=[CH:24][CH:25]=3)=[CH:44][CH:43]=2)[CH2:40][CH2:41]1)=[O:38])[CH3:35]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)c4cccc(O[Si](C)(C)C(C)(C)C)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:3]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:10][CH2:9]2)[CH:3]=1
Reactant: O=C1CCC(c2cc(O)ccn2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3cc(O)ccn3)CC2)C1

Procedure:
The title compound was prepared as a white solid from reductive amination of 4-(4-hydroxy-pyridin-2-yl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=1)[CH2:12][N:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)=[O:8])([CH3:5])[CH3:4].FC(F)(F)C(O)=O>ClCCl>[N:13]1([CH2:12][C:11]2[CH:10]=[C:9]([CH:28]=[CH:27][CH:26]=2)[C:7]([NH:6][C:3]([CH3:5])([CH3:4])[C:2]([F:29])([F:1])[F:30])=[O:8])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C(F)(F)F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(NC(=O)c1cccc(CN2CCNCC2)c1)C(F)(F)F
Reaction time: 2 h
Yield: 99.7 %

Procedure:
tert-Butyl 4-(3-(1,1,1-trifluoro-2-methylpropan-2-ylcarbamoyl)benzyl)piperazine-1-carboxylate (0.792 mmol, 340 mg) wsa dissolved in dichloromethane (3 mL) and trifluoroacetic acid (7.92 mmol, 0.588 ml, 903 mg) added. After 2 hours stirring, the mixture was taken up in dichloromethane, loaded on to a strong cation exchange column (5 g) and washed with dichloromethane/methanol. Elution of the column with 2M ammonia in methanol gave the title compound (260 mg). MS (ESI) m/z 330.3 [M+H]+
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:47][N:48]1[CH:52]=[CH:51][C:50]([NH:53][C:54]2[C:63]3[C:58](=[CH:59][CH:60]=[C:61]([O:64][C:65]4[N:70]=[CH:69][C:68](O)=[CH:67][CH:66]=4)[CH:62]=3)[N:57]=[CH:56][N:55]=2)=[N:49]1>C(Cl)(Cl)Cl.O1CCCC1>[CH3:47][N:48]1[CH:52]=[CH:51][C:50]([NH:53][C:54]2[C:63]3[C:58](=[CH:59][CH:60]=[C:61]([O:64][C:65]4[N:70]=[CH:69][C:68]([O:1][CH2:2][CH2:3][CH:4]5[CH2:8][CH2:7][CH2:6][N:5]5[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:67][CH:66]=4)[CH:62]=3)[N:57]=[CH:56][N:55]=2)=[N:49]1
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(O)cn4)cc23)n1
Reactant: CC(C)(C)OC(=O)N1CCCC1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(OCCC5CCCN5C(=O)OC(C)(C)C)cn4)cc23)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
Tert-butyl 2-(2-hydroxyethyl)pyrrolidine-1-carboxylate (260 mg, 1.2 mmol), triphenyl phosphine (310 mg, 1.2 mmol) and diethyl azodicarboxylate (0.19 mmol, 1.2 mmol) were added to a tetrahydrofuran solution (6 ml) of 6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol (200 mg, 0.60 mmol) obtained in Example 6, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was diluted with chloroform, the organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=96:4) and amine-type silica gel column chromatography (hexane:ethyl acetate=50:50) to obtain tert-butyl 2-(2-{[6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}ethyl)pyrrolidine-1-carboxylate (290 mg, yield: 90.5%) as a pale yellow amorphous solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](O)=[O:22])=[CH:16][CH:15]=1.C(N(CC)CC)C.[OH-].[Na+]>C(OC(=O)C)(=O)C>[Br:10][C:8]1[CH:7]=[C:4]2[C:3](=[C:2]([Br:1])[CH:9]=1)[O:11][C:21](=[O:22])[C:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)=[CH:5]2
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: O=Cc1cc(Br)cc(Br)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(-c2cc3cc(Br)cc(Br)c3oc2=O)cc1
Temperature: 80 °C

Procedure:
3,5-Dibromo-2-hydroxybenzaldehyde (30.0 g, 107 mmol) [CAS-Nr. 90-59-5] and 4-methoxyphenylacetic acid (35.7 g, 166 mmol) are heated in 51 ml acetic anhydride and 60 ml triethylamine overnight at reflux. The reaction mixture is cooled down to 80° C. and poured onto 1000 ml 2 M sodium hydroxide under stirring. After 5 min the precipitated product is filtered by vacuum, washed with water and digested two times with 100 ml ethanol. 6,8-Dibromo-3-(4-methoxy-phenyl)-chromen-2-one is obtained as a yellow solid.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][C:20]3[N:21]([N:29]=[CH:30][C:31]=3[CH:32]=[O:33])[C:22]=2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.O1CCCC1>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][C:20]3[N:21]([N:29]=[CH:30][C:31]=3[CH2:32][OH:33])[C:22]=2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1cnn2c(C3CCCCC3)c(-c3ccc(OCc4ccccc4)cc3)cnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cnn2c(C3CCCCC3)c(-c3ccc(OCc4ccccc4)cc3)cnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
To a stirred solution of 4.4 mg (0.115 mmol) of sodium borohydride (NaBH4) in 2 mL of methanol (MeOH) was added a solution of 35 mg (0.104 mmol) of 6-(4-benzyloxy-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidine-3-carbaldehyde in 3 mL of tetrahydrofuran (THF) and the resulting mixture was stirred at rt for 30 min when analysis by TLC indicated complete conversion of starting material to product. The reaction mixture was quenched by the addition of saturated ammonium chloride solution, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give (after lyophilization) 20 mg (47% yield) of [6-(4-benzyloxy-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidin-3-yl]-methanol (479) as a white solid (85% purity) as indicated by 1H NMR (containing small traces of starting material); LC-MS—calcd for C26H27N3O2 [M++H]+: 414.21, found: 414.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.N[C:35]1C(C#N)=C(N2CCC(C3N(CCNC)C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=[CH:37][N:36]=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:35][NH:36][CH3:37])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: CNCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: CNCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-methylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=507, obsd.=507).
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:26])=[CH:10][CH2:11][CH2:12][C:13]([CH3:25])=[CH:14][CH2:15][CH2:16][C:17]([CH3:24])=[CH:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:3]([OH:5])=O.[NH:27]([CH2:31][CH2:32][OH:33])[CH2:28][CH2:29][OH:30]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:26])=[CH:10][CH2:11][CH2:12][C:13]([CH3:25])=[CH:14][CH2:15][CH2:16][C:17]([CH3:24])=[CH:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:3]([N:27]([CH2:31][CH2:32][OH:33])[CH2:28][CH2:29][OH:30])=[O:5]
Reactant: OCCNCCO
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N(CCO)CCO

Procedure:
Starting materials: 2,6,10,14-tetramethyl-18-oxo-2,6,10,14-nonadecatetraenoic acid and diethanolamine
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11]C1CCCC1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.[Si](OCCN)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][NH:11][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCNC1CCCC1
Agent: CC(C)(C)[Si](C)(C)OCCN
Product: CC(C)(C)[Si](C)(C)OCCNCc1ccc(F)cc1
Yield: 35.03 %

Procedure:
This compound was prepared following the same method as described for [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopentyl-amine (8e) from 4-fluorobenzaldehyde (1 g, 8.06 mmol) and 2-(tert-butyl-dimethylsilanyloxy)-ethylamine (8c) (1.8 g, 10.48 mmol). The product was obtained as a light yellow liquid (800 mg, 35.03%).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[C:2]#[C:3][C:4]([OH:6])=[O:5].[CH2:9](O)[CH2:10][CH2:11][CH3:12].S(=O)(=O)(O)O>>[C:2]([C:1]([O:8][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])#[C:3][C:4]([O:6][CH2:9][CH2:10][CH2:11][CH3:12])=[O:5]
Reactant: CCCCO
Reactant: O=C(O)C#CC(=O)O
Agent: O=S(=O)(O)O
Product: CCCCOC(=O)C#CC(=O)OCCCC

Procedure:
First, dibutyl acetylenedicarboxylate was prepared. A mixture of 2-butynedioic acid (5.0 g, 44 mmol), n-butyl alcohol (162 g, 2.19 mol), and sulfuric acid (0.86 g, 9 mmol) was heated at reflux for 6 hours. The mixture was cooled to ambient, washed with 10% aqueous NaHCO3 then with brine, dried (Na2SO4), concentrated, and the resulting crude product distilled under reduced pressure (bp 65-70° C./0.08 mm). Dibutyl acetylenedicarboxylate was obtained as a colorless oil (8.5 g, 86% of theory). 1H NMR (CDCl3): δ 1.90 (t, 6H), 1.38 (m, 4H), 1.65 (m, 4H), 4.20 (t, 4H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([CH:12]1[CH2:17][CH2:16][O:15][C:13]1=[O:14])(=O)[CH3:10]>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH:5][C:9](=[C:12]1[CH2:17][CH2:16][O:15][C:13]1=[O:14])[CH3:10]
Reactant: Nc1cccc(I)c1
Reactant: CC(=O)C1CCOC1=O
Solvent: CCO
Product: CC(Nc1cccc(I)c1)=C1CCOC1=O
Yield: 99.6 %

Procedure:
A solution of 3-iodoaniline (5.0 g, 23 mmol), α-acetyl-γ-butyrolactone (14.6 g, 0.11 mol) in ethanol (100 mL) was heated under reflux for seven days. The mixture was evaporated, and the residue was purified by silica gel column chromatography (10% ethyl acetate/hexane), to give the title compound (7.54 g) as white crystals.