Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].O.[C:34]([O-:37])([O-])=[O:35].[K+].[K+]>C1COCC1.CC(OC)(C)C>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:34]([O:37][C:3]([CH3:4])([CH3:26])[CH3:2])=[O:35])[CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
First 50 ml of a 55% by weight solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-piperazine in THF and then 25 ml water were added to a suspension of 7.4 9 K2CO3 in 150 ml THF. A solution of 12.2 g tert. butoxycarbonyl anhydride in 50 ml THF was added to this receiving solution, and the mixture was stirred for 12 hours at room temperature. After reduction of the reaction mixture in a vacuum, the residue was taken up in 300 ml MTBE, and the organic phase was washed, in succession, twice with 100 ml portions of water, once with 50 ml of a 15% by weight aqueous tartaric acid solution and another four times with 100 ml portions of water, and then dried over sodium sulfate/SiO2. After filtering out the drying agent, the filtrate was reduced in a vacuum, and the residue was taken up in 20 ml MTBE. After heating to 60° C., 120 ml ligroin was added, and the volume was then reduced by approximately 100 ml by vacuum distillation. After another addition of 100 ml ligroin, the mixture was left to stand for 3 days to precipitate. The precipitated solid was filtered out, washed three times more with 30 ml portions of ligroin and dried at 60° C. in a vacuum. 82.0 g of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl]-4-(tert.butoxycarbonyl)piperazine were obtained as a solid, melting point 155-156° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[C:7]([OH:23])=[C:8]([C:20](=[O:22])[CH3:21])[CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1.Cl>N1C=CC=CC=1>[C:20]([C:8]1[C:7]2[O:23][C:1](=[O:2])[NH:5][C:6]=2[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(N)c1O
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)c1cc(OCc2ccccc2)cc2[nH]c(=O)oc12
Temperature: 50 °C

Procedure:
At 20 to 40° C. 52 g (0.53 mol) phosgene are piped into a solution of 121 g (0.47 mol) 1-(3-amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone in 800 mL pyridine. The reaction mixture is heated to 50° C. for 2 hours, then poured onto ice and acidified with conc. hydrochloric acid. A reddish-brown solid is isolated which is repeatedly recrystallised from ethanol with the addition of activated charcoal.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([NH:8][C:9](=[O:18])[C:10]([CH3:17])([CH3:16])[CH:11]([OH:15])[CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1.I[CH3:22]>CN(C)C(=O)C.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][C:9](=[O:18])[C:10]([CH3:16])([CH3:17])[CH:11]([O:15][CH3:22])[CH:12]([CH3:13])[CH3:14])=[CH:19][CH:20]=1
Reactant: CI
Reactant: CC(C)C(O)C(C)(C)C(=O)Nc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(C(C)C)C(C)(C)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 44.7 %

Procedure:
To a stirred suspension of sodium hydride (0.25 g of a 60% dispersion in mineral oil, 5.1 mmol) in N,N-dimethylacetamide is added dropwise a solution of 4′-chloro-3-hydroxy-2,2,4-trimethylvaleranilide (1.5 g, 5.6 mmol) in N,N-dimethylacetamide. After stirring for 40 minutes at room temperature, iodomethane (1.58 g, 11.1 mmol) is added. The reaction mixture is stirred at room temperature for 18 hours, diluted with water, and extracted with ether. The combined organic extracts are washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a semisolid. Flash column chromatography of the semi-solid using silica gel and an ethyl acetate/hexanes solution (1:10) gives the title product as a white solid (0.71 g, mp 103-107° C.) which is identified by 1H NMR spectral analysis.
Reaction SMILES: N1([CH2:5][CH2:6][CH2:7][N:8]2[C:16]([O:17][CH3:18])=[N:15][C:14]3[C:9]2=[N:10][C:11]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:12][C:13]=3[NH2:19])CCC1.F[C:26](F)(F)[C:27]([OH:29])=[O:28].C(OC1N[C:39](N)=[C:40]2[C:44](N=1)=[N:43][C:42](OC)=N2)CCC.BrCCCCBr.N1CCCC1>>[CH:27]([OH:29])=[O:28].[CH2:21]([O:20][C:11]1[N:10]=[C:9]2[C:14]([N:15]=[C:16]([O:17][CH3:18])[N:8]2[CH2:7][CH2:6][CH2:5][CH2:26][N:43]2[CH2:42][CH2:39][CH2:40][CH2:44]2)=[C:13]([NH2:19])[N:12]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN3CCC3)c2n1
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: C1CCNC1
Solvent: BrCCCCBr
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCN3CCCC3)c2n1
Product: O=CO

Procedure:
Prepared similarly to Intermediate 20 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate, 1,4-dibromobutane and pyrrolidine but with mass directed autopreparation using Method D.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([CH:21]=O)[CH:12]=1.C([O:25][C:26](=O)[C:27](=[O:38])[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)C>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:21]([C:13]4[CH:12]=[N:11][C:20]5[C:15]([CH:14]=4)=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:28]([C:29]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[NH:31][CH:30]=4)=[C:27]([OH:38])[C:26]3=[O:25])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: CCOC(=O)C(=O)Cc1c[nH]c2ccccc12
Reactant: O=Cc1cnc2ccccc2c1
Solvent: CCO
Product: O=C1C(O)=C(c2c[nH]c3ccccc23)C(c2cnc3ccccc3c2)N1c1ccc2[nH]cnc2c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1H-Benzoimidazol-5-ylamine (1 mmol) and Quinoline-3-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 3-(1H-Indol-3-yl)-2-oxo-propionic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11]1[O:15][C:14]([C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:30][CH2:29][CH:28]([CH2:31][C:32]([O:34]C)=[O:33])[CH2:27][CH2:26]3)=[N:23][CH:24]=2)=[O:17])=[N:13][N:12]=1.[OH-].[Li+].[ClH:38]>CO.C1COCC1>[ClH:38].[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11]1[O:15][C:14]([C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:26][CH2:27][CH:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][CH2:30]3)=[N:23][CH:24]=2)=[O:17])=[N:13][N:12]=1
Reactant: COC(=O)CC1CCN(c2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cn2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC1CCN(c2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cn2)CC1
Temperature: 45 °C
Yield: 87 %

Procedure:
Methyl (1-{5-[({5-[(2,4,5-trifluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)-amino]pyridin-2-yl}piperidin-4-yl)acetate (Example 319, 216 mg, 0.44 mmol) was suspended in a mixture of MeOH (4 ml) and THF (8 mL). Lithium hydroxide (4.4 mL of a 1M aqueous solution) was added. The resulting clear solution was heated at 45° C. for 15 minutes then cooled and acidified to pH ˜2 with dropwise addition of concentrated aqueous HCl. Volatile material was removed by evaporation and the residue was washed with water then dried to give the title compound (182 mg, 87%) as a solid; 1H NMR δ 1.16-1.45 (2H, m), 1.76-1.93 (2H, m), 1.98-2.13 (1H, m), 2.28 (2H, d), 3.12 (2H, t), 4.28 (2H, d), 7.25-7.41 (1H, m), 7.70-7.88 (1H, m), 8.13-8.32 (2H, m), 8.55 (1H, d), 11.16 (1H, s), 11.29 (1H, s); MS m/e MH+ 477.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[C:19]1([N:25]2[C:29]([C:30]([F:33])([F:32])[F:31])=[C:28]([C:34](Cl)=[O:35])[CH:27]=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:34]([C:28]4[CH:27]=[N:26][N:25]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[C:29]=4[C:30]([F:32])([F:33])[F:31])=[O:35])[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: O=C(Cl)c1cnn(-c2ccccc2)c1C(F)(F)F
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1cnn(-c2ccccc2)c1C(F)(F)F
Yield: 28 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride to afford the title compound (28 mg, 28%). 1H-NMR (δ, ppm, DMSO-d6): 6.50 (d, 1H, HPy,5, J=6.0 Hz), 6.92 (d, 1H, Harom, J=8.0 Hz), 7.43 (t, 1H, Harom, J=8.0 Hz), 7.51-7.63 (m, 7H, Harom), 7.81 (d, 1H, HPy,6, J=6.0 Hz), 8.29 (s, 1H, Hpyrrazole), 10.63 (s, 1H, NHamide), 11.19 (s, 1H, NHPy3), 11.39 (s, 1H, NHPy2). HRMS (EI): m/z [M+H] calcd for C23H16N6O3F3: 481.1236; found: 481.1229.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH2:8]CO)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].[O:34]1[CH2:38]CCC1>>[CH3:38][O:34][S:30]([CH2:29][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC(Cc1ccc(C(F)(F)F)cc1)c1ccccc1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: COS(=O)(=O)CCC(Cc1ccc(C(F)(F)F)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-Phenyl-4-(4-trifluoromethylphenyl)butanol (3.65 g, 12.4 mmole) was dissolved in 50 ml of tetrahydrofuran and the resulting solution was cooled to about 0° C. Triethylamine (1.82 ml, 13.0 mmole) was added, followed by the dropwise addition of 1.01 ml (13.0 mmole) of methanesulfonyl chloride over a five minute period. The solution was stirred at room temperature (22° C.) for about 2 hours. The reaction solution was then partitioned between ethyl acetate and water. The resulting organic layer was washed with a saturated brine solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to provide 4.47 g of 3-phenyl-4-(4-trifluoromethylphenyl)butane sulfonic acid methyl ester as a yellow oil. N.M.R. analysis (300 MHz instrument, in CDCl3) provided: δ=1.98-2.25 (broad multiplet, 2H); 2.80 (singlet, 3H); 3.00 (multiplet, 3H); 3.92 and 4.09 (multiplet, 2H); 7.02-7.45 (multiplet, 9H).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(Cl)Cl.CC#N>[C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(c1ccccc1)c1cccc(C(F)(F)F)c1
Reactant: C1CNCCN1
Solvent: O=S(Cl)Cl
Solvent: CC#N
Solvent: ClCCl
Product: FC(F)(F)c1cccc(C(c2ccccc2)N2CCNCC2)c1
Temperature: 40 °C
Yield: 85.1 %

Procedure:
To a solution of phenyl(3-(trifluoromethyl)phenyl)methanol (10.0 g, 39.6 mmol) in CH2Cl2 (20 mL) was added thionyl chloride (5.78 mL, 79.3 mmol) dropwise at rt. After the addition, the reaction was warmed to 40° C. for 18 h. The solvent was evaporated in vacuo and the residue was dried under vacuum pump for 1 h. The residue was dissolved in CH3CN and added to a solution of piperazine (13.7 g, 159 mmol) in CH3CN and heated to 100° C. for 12 h. The solvent was removed in vacuo, the residue dissolved in CH2Cl2 (150 mL) and washed with 1N NaOH (150 mL). The organic layer was dried with K2CO3 or Na2SO4, filtered, and concentrated. The crude product 1-(phenyl(3-(trifluoromethyl)phenyl)-methyl)piperazine (10.8 g, 85.0% yield) an oil was used without further purification or can be purified by ISCO flash chromatography using 0-15% 2N NH3 methanol solution in CH2Cl2. MS (ESI, pos. ion) m/z: 321.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br[CH2:14][C:15]1[C:27]([F:28])=[CH:26][C:18]([C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[O:20])=[C:17]([F:29])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:11])[F:9])[O:12][CH2:14][C:15]1[C:27]([F:28])=[CH:26][C:18]([C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[O:20])=[C:17]([F:29])[CH:16]=1
Reactant: Oc1ccc(C(F)(F)F)c(Cl)c1
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(F)c(COc2ccc(C(F)(F)F)c(Cl)c2)cc1F
Yield: 56.3 %

Procedure:
A solution of 3-chloro-4-(trifluoromethyl)phenol (Preparation 5, 50 mg, 0.26 mmol), 4-(bromomethyl)-2,5-difluoro-N-(methylsulfonyl)benzamide (Preparation 4, 84 mg, 0.26 mmol) and potassium carbonate (71 mg, 0.51 mmol) in dimethyl sulfoxide (5 mL) was stirred at room temperature for 16 hours. A 2M aqueous solution of hydrogen chloride was added to the reaction mixture. The resulting precipitate was filtered, washed with diethyl ether (5 mL) and dried. The material was purified by reverse phase column chromatography (12 g C-18 biotage cartridge; eluents: MeCN+0.1% formic acid, and H2O+0.1% formic acid; Gradient: 30% MeCN, followed by gradient to 100% MeCN, 100% MeCN. Fractions containing product were combined and concentrated in vacuo to afford the title compound as a colourless solid (65 mg, 56%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@@H:6]([N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:7]([CH3:10])[CH2:8][OH:9].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:9][CH2:8][C@@H:7]([CH3:10])[C@H:6]([N:11]([C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])[CH3:19])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)(=[O:30])=[O:29]
Reactant: C[C@H](CO)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](COS(C)(=O)=O)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of tert-butyl ((1S,2S)-1-(furan-2-yl)-3-hydroxy-2-methylpropyl)(methyl)-carbamate (108 mg, 0.40 mmol) in DCM (2 mL) at 0° C. was added triethylamine (81 mg, 0.112 ml, 0.80 mmol, 2 equiv) followed by methanesulfonylchloride (55 mg, 0.037 ml, 0.48 mmol, 1.2 equiv) and the solution was stirred at 0° C. for 1 hour. The solution was diluted with 10 mL DCM and washed with sat. NH4Cl solution, water and brine. After drying over MgSO4 the solution was concentrated in vacuo to give crude product 2.16a (140 mg, 99% yield). 1H NMR (CDCl3, 400 MHz) 7.38 (dd, J=1.76, 0.98 Hz, 1H) 6.35 (dd, J=3.13, 1.96 Hz, 1H) 6.31 (br. s., 1H) 5.29-5.32 (m, 1H) 4.16 (dd, J=9.98, 3.33 Hz, 1H) 3.90 (br. s., 1H) 2.89-2.96 (m, 3H) 2.68-2.75 (m, 3H) 2.55-2.67 (m, 1H) 1.48 (br. s., 9H) 1.11 (d, J=6.65 Hz, 3H)
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16](F)[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CCCCO.CS(C)=O>[CH2:1]([NH:8][C:9]1[N:17]=[C:16]([NH:31][C@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)n1cnc2c(NCc3ccccc3)nc(F)nc21
Reactant: CC[C@@H](N)C(O)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CS(C)=O
Product: CC[C@@H](Nc1nc(NCc2ccccc2)c2ncn(C(C)C)c2n1)C(O)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of benzyl-(2-fluoro-9-isopropyl-9H-purin-6-yl)-amine (40 mg, 1 eq, 0.14 mmol) in n-BuOH/DMSO (5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.12 mL, 4.9 eq, 0.69 mmol) followed by (3RS,4R)-4-amino-2,2-dimethyl-hexan-3-ol (69 mg, 3.4 eq, 0.48 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×50 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with hexane:ether:MeOH (50:50:0→50:50:2) to afford the title compound as a white solid; Yield: 13 mg (23%).(55% de 4R,3S: 45% de 4R,3R). 1H-NMR (d-CDCl3, 250 MHz): δ 1.00-1.04 (m, 12H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 1.56+1.58 (2×d, 6H, J=6.63+6.79 Hz, —CH(CH3)2), 1.63-1.87 (m, 2H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.57 (d, 1H, J=1.42 Hz, —NHCH(CH2CH3) CH(C(CH3)3)OH), 3.73-3.87 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 4.57-4.70 (m, 1H, —CH(CH3)2), 4.77-4.86 (m, 2H, —HNCH2-Bz), 5.22-5.36+5.93-6.09 (2×m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 7.25-7.44 (m, 6H, 5×Bz-H+HNCH2-Bz), 7.53 (s, 1H, —N═CH—N). FABMS m/z (relative intensity): 411 ([M+H]+, 90), 323 (100). Accurate Mass (M+H): Actual: 411.2872, Measured: 411.2860.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:47]=[C:17]2[N:18]([CH2:41][C:42]3([CH3:46])[CH2:45][O:44][CH2:43]3)[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1>C(OCC)(=O)C>[CH3:13][C:14]1[N:47]=[C:17]2[N:18]([CH2:41][C:42]3([CH3:46])[CH2:45][O:44][CH2:43]3)[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]4[NH:3][C:4](=[O:7])[O:5][N:39]=4)=[CH:30][CH:31]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC2(C)COC2)c2nc(C)nn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC2(C)COC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 23.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.67 g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({2-methyl-4-[(3-methyloxetan-3-yl)methyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.3 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.12 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.079 g, 23%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][N:12]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:15][NH:14][C:13]2=[O:25])=[CH:5][CH:4]=1.[N:26]([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[NH2:26][N:14]1[CH2:15][CH:16]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[N:12]([CH2:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:13]1=[O:25]
Reactant: O=N[O-]
Reactant: COc1ccc(CCCN2C(=O)NCC2c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CCCN2C(=O)N(N)CC2c2ccc(OC)cc2)cc1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 109.3 %

Procedure:
To a solution of 1-[3-(4-methoxyphenyl)propyl]-5-[(4-methoxy)-phenyl]-2-imidazolidinone (0.6 g, 1.75 mmol) in acetic acid (15 mL) is added dropwise a solution of NaNO2 (0.12 g, 1.8 mmol) in water (1 mL). The mixture is cooled in an ice bath to 5° C. and zinc dust (0.6 g, 9 mmol) is added in portions (starting with 0.5 g addition) over 50 minutes at less than 12° C. The reaction is stirred for 5 minutes and the ice bath is removed. The reaction temperature rises quickly to about 20° C. and the reaction is maintained below about 32° C. with an ice bath. The reaction is stirred for 70 minutes at 20° C. to 27° C. and any unreacted zinc is removed by filtration. The volume of the filtrate is reduced in vacuo then diluted with dichloromethane (15 mL). To the stirred mixture is added concentrated ammonium hydroxide (2 mL), keeping the temperature below about 32° C. with an ice bath. The organic phase is separated, washed with brine, dried (Na2SO4), and concentrated to afford 0.68 g (quantitative yield) of the desired compound as a colorless oil which is used without further purification.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:38][CH2:39][CH2:40][O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH:10]=[CH:11][CH:12]([CH:14]1[C:18](=[O:19])[C:17]([S:20][CH3:21])=[CH:16][C:15]1([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[O:22][Si:23]([CH3:26])([CH3:25])[CH3:24])O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CS(Cl)(=O)=O.S([O-])(O)(=O)=O.[K+]>ClCCl>[Si:1]([O:8][CH:9]([CH2:38][CH2:39][CH2:40][O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:43])[CH3:44])[CH:10]=[CH:11][CH:12]=[C:14]1[C:18](=[O:19])[C:17]([S:20][CH3:21])=[CH:16][C:15]1([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[O:22][Si:23]([CH3:24])([CH3:25])[CH3:26])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CSC1=CC(CCCCOc2ccccc2)(O[Si](C)(C)C)C(C(O)C=CC(CCCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)C1=O
Agent: CS(=O)(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CSC1=CC(CCCCOc2ccccc2)(O[Si](C)(C)C)C(=CC=CC(CCCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)C1=O
Yield: 66 %

Procedure:
To a solution of 1.00 g of 5-[4,7-bis(t-butyldimethylsilyloxy)-1-hydroxy-2-heptenyl]-2-methylthio-4-(4-phenoxybutyl)-4-trimethylsilyloxy-2-cyclopentenone obtained in Example 62 dissolved in 10 ml of dichloromethane was added under ice-cooling and stirring 497 mg of dimethylaminopyridene, and then 147 μl of methanesulfonyl chloride was added dropwise. The temperature of the mixture was gradually elevated to room temperature, and then stirred for 6 hours. Saturated aqueous potassium hydrogensulfate was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium hydrogencarbonate and with saturated aqueous sodium chloride in the order mentioned, and dried over anhydrous sodium sulfate. After filtration and concentration, the concentrate was subjected to silica gel chromatography to give 644 mg (yield 66%) of low polarity isomer and 255 mg (yield 26%) of high polarity isomer of 5-[4,7-bis(t-butyldimethylsilyloxy)-2-heptenylidene]-2-methylthio-4-(4-phenoxybutyl)-4-trimethylsilyloxy-2-cyclopentenone.