Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2([C:10]3[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][O:3]1.[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:20][C:21]1[C:22]([N:28]2[CH2:29][CH2:30][N:31]([C:14]([C:13]3[CH:12]=[CH:11][C:10]([C:7]4([N:6]5[CH2:5][CH2:4][O:3][C:2]5=[O:1])[CH2:8][CH2:9]4)=[CH:19][CH:18]=3)=[O:16])[CH2:32][CH2:33]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: COC(=O)c1ccc(C2(N3CCOC3=O)CC2)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(C4(N5CCOC5=O)CC4)cc3)CC2)c(C)c1
Yield: 67 %

Procedure:
Using methyl 4-[1-(2-oxooxazolidin-3-yl)cyclopropyl]benzoate (52 mg) described in Preparation Example 69 and 1-(3,5-dimethylpyridin-2-yl)piperazine (38 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (56 mg) was obtained.
Reaction SMILES: Cl.NO.C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.C[O-].[Na+].O=C1N[C@H]2CS[C@@H](CCCCCC3[O:49][N:48]=[C:47]([CH2:50][CH2:51][CH2:52][CH2:53][N:54]4[C:58]5[CH:59]=[C:60]([CH3:63])[CH:61]=[CH:62][C:57]=5[O:56][C:55]4=[O:64])[N:46]=3)[C@H]2N1>CO.C(O)C>[OH:49][N:48]=[C:47]([NH2:46])[CH2:50][CH2:51][CH2:52][CH2:53][N:54]1[C:58]2[CH:59]=[C:60]([CH3:63])[CH:61]=[CH:62][C:57]=2[O:56][C:55]1=[O:64]
Reactant: Cc1ccc2oc(=O)n(CCCCc3noc(CCCCC[C@@H]4SC[C@@H]5NC(=O)N[C@@H]54)n3)c2c1
Agent: C[O-]
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCO
Product: Cc1ccc2oc(=O)n(CCCCC(N)=NO)c2c1
Yield: 51.7 %

Procedure:
A solution of hydroxylamine hydrochloride salt (345 mg, 5.00 mmol) and phenolphthalein (1 crystal) in anhydrous methanol (5 ml) was stirred at reflux under an nitrogen atmosphere. Sodium methoxide was added portion-wise until a pink solution persisted (approximately 350 mg was used). The hot solution was filtered directly into a solution of compound 2 (115 mg, 0.50 mmol) in anhydrous ethanol (5 ml). The reaction mixture was stirred at reflux under a nitrogen atmosphere for 6 h. The reaction mixture was cooled, concentrated in vacuo and purified by silica gel chromatography eluting with 19:1 dichloromethane/methanol to give a brown solid (68 mg, 52%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[N:22]2.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[N:22]2
Reactant: Oc1cccc2ncccc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3cccc4ncccc34)c2cc1OC
Temperature: 170 °C
Reaction time: 0.17 h
Yield: 63.3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (50 mg) and commercially available 5-hydroxyquinoline (50 mg) were mixed and stirred at 170° C. for 10 minutes. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with anhydrous sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by thin layer chromatography on silica gel eluting first with hexane/ethyl acetate (1/1) and then with chloroform/methanol (50/1) to obtain 47 mg of the title compound (yield: 64%).
Reaction SMILES: [F:1][C:2]1([F:23])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C:14](=[CH2:16])[S:13]/[C:12]/3=[N:17]\[C:18](=[O:22])[O:19][CH2:20][CH3:21])=[CH:10][C:4]=2[O:3]1.C[O-].[Na+]>CO>[F:23][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:15]=[C:14]([CH3:16])[S:13]/[C:12]/3=[N:17]\[C:18](=[O:22])[O:19][CH2:20][CH3:21])=[CH:10][C:4]=2[O:3]1
Reactant: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)/C(=N/C(=O)OCC)S1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)/N=c1\sc(C)cn1-c1ccc2c(c1)OC(F)(F)O2

Procedure:
A solution of Example 2 (0.35 g, 1.023 mmol) and sodium methoxide (25% wt/wt, 5.11 mmol) in methanol (10 mL) was heated to 50° C. for 2 hours. The mixture was concentrated to dryness under reduced pressure, taken up in DCM (100 mL), washed with water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography using DCM as eluant to provide the titled compound. 1H NMR (CDCl3) δ ppm 1.31 (3H), 2.2 (3H), 4.27 (2H), 6.65 (1H), 7.05-7.25 (3H); MS (ESI) 343 (M+H).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:8][C:9]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:4][CH2:5][CH3:6].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>CN(C=O)C>[CH2:3]([C:7]1[N:11]([CH2:24][C:23]2[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)[C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:9]=2[N:8]=1)[CH2:4][CH2:5][CH3:6]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCCCc1nc2cccc(C)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2c(C)cccc2n1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
To a slurry of NaH (60%, 0.21 g. 5.3 mmol) in DMF was added with stirring a solution of 2-butyl-4-methyl-benzimidazole (1 g. 5.3 mmol) in DMF (20 mL under nitrogen atmosphere. After the gas evolution was complete, the reaction mixture was cooled in ice and a solution of 4-nitrobenzyl bromide (1.5 g, 5.3 mmol) in DMF (5 mL) was added with stirring. The reaction mixture was allowed to warm up slowly to room temperature and stirred for 16 hours. DMF was distilled under reduced pressure and the residue was taken up in EtOAc, and the solution was washed with water. It was dried over MgSO4 and evaporated to give a solid which was chromatographed (CH2Cl2 /EtOAc 4/1-EtOAc) to give 1.5 g of a solid, MP 115°-116° C.
Reaction SMILES: [CH2:1]([Si:3]([CH2:18][CH3:19])([CH2:16][CH3:17])[O:4][CH2:5][C:6]1([CH2:12][CH2:13][CH2:14][OH:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2].[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:15][CH2:14][CH2:13][CH2:12][C:6]1([CH2:5][O:4][Si:3]([CH2:1][CH3:2])([CH2:16][CH3:17])[CH2:18][CH3:19])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CC[Si](CC)(CC)OCC1(CCCO)CCCCC1
Solvent: c1ccncc1
Product: CC[Si](CC)(CC)OCC1(CCCOC(C)=O)CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3-[1-(triethylsiloxymethyl)cyclohexyl]propan-1-ol (410 mg) were added acetic anhydride (3 mL) and pyridine (3 mL) at room temperature. The solution was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was distilled with toluene azeotropically to give the title compound (480 mg). This product was subjected to the subsequent step without further pirification.
Reaction SMILES: [H-].[K+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[C:19]([NH2:20])=[C:18]([S:21]([CH2:23][CH3:24])=[O:22])[C:17]([C:25]#[N:26])=[N:16]1.[CH3:27][S:28][CH2:29][CH2:30]Cl.[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[C:19]([NH:20][CH2:30][CH2:29][S:28][CH3:27])=[C:18]([S:21]([CH2:23][CH3:24])=[O:22])[C:17]([C:25]#[N:26])=[N:16]1
Reactant: CSCCCl
Reactant: CCS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: [Cl-]
Agent: [H-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1NCCSC
Temperature: 20 °C
Reaction time: 0.67 h
Yield: 4.4 %

Procedure:
To a suspension of 35% potassium hydride in oil (1.4 g) in dry N,N-dimethylformamide (DMF) was added a solution of 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-amino-4-(ethylsulfinyl)-1H-pyrazole-3-carbonitrile (5.0 g) in dry DMF at 4° C. and stirred for 40 min. 2-Chloroethyl methyl sulfide (1.39 g) was added at 4° C. and the stirred mixture allowed to warm to 20° C. over 40 minutes, then heated to 50° C. for 4 hours and at 20° C. for 3 days. Ammonium chloride solution and ethyl acetate were added and the organic layer dried (sodium sulfate), evaporated and purified by column chromatography using 80% methyl t-butyl ether in hexane to give 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-[[-2-(methylthio)ethyl]amino]-4-(ethylsulfinyl)-1H-pyrazole-3-carbonitrile (0.26 g), m.p.126-127° C.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[N:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH3:20])=[CH:15][CH:14]=1>>[N:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=3[C:2](=[O:3])[O:4][C:5]2=[O:12])[CH3:20])=[CH:15][CH:14]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CC(O)c1ccncc1
Product: CC(c1ccncc1)n1c(=O)oc(=O)c2ccccc21

Procedure:
Prepared by a similar procedure as described for preparation 7A, starting from isatoic anhydride and (+/−)-1-(4-pyridyl)ethanol (Fluka). 13C-NMR (DMSO-d6) δ 159.0, 149.8, 148.6, 140.6, 136.5, 129.8, 123.6, 121.2, 115.7, 112.9, 53.1, 15.4.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[O:12][C@@H:11]([N:23]2[C:41]3[N:40]=[CH:39][N:38]=[C:27]([O:28][C:29]4[CH:34]=[CH:33][C:32]([N+]([O-])=O)=[CH:31][CH:30]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1(OC2C3N=CN(C=3N=CN=2)[C@@H]2O[C@H](CO[Si](C(C)(C)C)(C)C)[C@@H](O[Si](C(C)(C)C)(C)C)C2)C2C=CC=CC=2N=N1.C([O-])([O-])=O.[Cs+].[Cs+].O[C:90]1[CH:102]=[CH:101][C:100]2C3C(=CC=CC=3)[CH2:93][C:92]=2[CH:91]=1>COCCOC>[Si:16]([O:15][C@@H:14]1[C@@H:13]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[O:12][C@@H:11]([N:23]2[C:41]3[N:40]=[CH:39][N:38]=[C:27]([O:28][C:29]4[CH:34]=[CH:33][C:32]5[C:100]6[C:92](=[CH:91][CH:90]=[CH:102][CH:101]=6)[CH2:93][C:31]=5[CH:30]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(Oc4ccc([N+](=O)[O-])cc4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: Oc1ccc2c(c1)Cc1ccccc1-2
Agent: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(Oc4ccc5c(c4)Cc4ccccc4-5)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 87 %

Procedure:
As described for the synthesis of 3′,5′-bis-O-(tert-butyldimethylsilyl)-O6-(4-nitrophenyl)-2′-deoxyinosine, this fluorenyl derivative was prepared by a reaction between O6-(benzotriazol-1-yl)-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (26) (59.8 mg, 0.100 mmol), Cs2CO3 (65.2 mg, 0.200 mmol) and 2-hydroxyfluorene (20.0 mg, 0.110 mmol) in dry DME (1.0 mL) at 85° C. for 1 h. Chromatographic purification (SiO2, elution with 20% EtOAc in hexanes) afforded 56.0 mg (87% yield) of the title compound as a clear, yellowish gum. Rf (20% EtOAc in hexanes)=0.31. 1H NMR (500 MHz, CDCl1): δ 8.52 (s, 1H, Ar—H), 8.41 (s, 1H, Ar—H), 7.83 (d, 1H, Ar—H, J=8.3), 7.77 (d, 1H, Ar—H, J=7.3), 7.53 (d, 1H, Ar—H, J=7.3), 7.45 (s, 1H, Ar—H), 7.37 (t, 1H, Ar—H, J=7.6), 7.29 (t, 1H, Ar—H, J=7.8), 6.55 (t, 1H, H-1′, J=6.4), 4.66 (m, 1H, H-3′), 4.05 (q, 1H, H-4′, J=3.4), 3.94 (s, 2H, CH2), 3.92 (dd, 1H, H-2′, J=11.2, 4.1), 3.81 (dd, 1H, H-2′, J=11.2, 2.9), 2.67 (app quint, 1H, H-2′, Japp˜6.3), 2.50 (ddd, 1H, H-2′, J=13.2, 6.0, 4.3), 0.94, 0.93 (2 s, 18H, tert-Bu), 0.12 (s, 12H, SiCH3). 13C NMR (126 MHz, CDCl1): δ 160.5, 152.5, 152.1, 151.6, 144.7, 143.3, 141.6, 141.1, 139.5, 126.8, 126.5, 124.9, 122.2, 120.5, 120.47, 119.7, 118.7, 88.1, 84.7, 71.9, 62.8, 41.5, 37.0, 25.9, 25.7, 18.4, 18.0, −4.7, −4.8, −5.4, −5.5. FAB HRMS calcd for C35H49N4O4Si2 (M++H) 645.3292. found 645.3303.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:27]([F:28])=[CH:26][C:8]([O:9][C:10]2[CH:24]=[CH:23][C:13]([C:14]([N:16]3[CH2:21][CH2:20][NH:19][C:18](=[O:22])[CH2:17]3)=[O:15])=[CH:12][C:11]=2[F:25])=[C:7]([O:29][CH3:30])[CH:6]=1)[CH3:4].IC.[C:33](OCC)(=O)C>CN(C)C=O.O>[CH2:3]([C:5]1[C:27]([F:28])=[CH:26][C:8]([O:9][C:10]2[CH:24]=[CH:23][C:13]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH3:33])[C:18](=[O:22])[CH2:17]3)=[O:15])=[CH:12][C:11]=2[F:25])=[C:7]([O:29][CH3:30])[CH:6]=1)[CH3:4]
Reactant: CCOC(C)=O
Reactant: CCc1cc(OC)c(Oc2ccc(C(=O)N3CCNC(=O)C3)cc2F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCc1cc(OC)c(Oc2ccc(C(=O)N3CCN(C)C(=O)C3)cc2F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
Sodium hydride (60% in oil, 25 mg, 0.6 mmol) was added to a solution of 4-[4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoy]-piperazin-2-one (which may be prepared in accordance with the experimental described in Example 5, step 1; 200 mg, 0.5 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 15 minutes prior to the addition of iodomethane (0.48 mL, 0.77 mmol). After stirring at room temperature for 1 hour, the reaction mixture was diluted by addition of ethyl acetate (30 mL) and water (30 mL). The two phases were separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic phases were finally washed with a saturated solution of sodium chloride (5×20 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford the title product as a yellow oil (200 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][NH:12][C:13]2[N:18]=[N:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N([Si](C)(C)C)=[N+]=[N-].N(C(OCC)=O)=NC(OCC)=O>ClCCl.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[N:18]3[N:17]=[C:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=4)[CH:15]=[CH:14][C:13]3=[N:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Nc1ccc(-c2ccc(NNC(=O)Cc3ccc(Cl)cc3)nn2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: C[Si](C)(C)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(-c2ccc3nnc(Cc4ccc(Cl)cc4)n3n2)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a round bottom flask was added N-(4-(6-(2-(2-(4-chlorophenyl)acetyl)hydrazinyl)pyridazin-3-yl)phenyl)methanesulfonamide (0.928 mmole), triphenylphosphine (3.25 mmole), azidotrimethylsilane (3.25 mmole), diethyl azodicarboxylate (4.18 mmole), and THF (13 mL). The resulting mixture was stirred at room temperature for 22 hours. The reaction mixture was diluted with dichloromethane and washed with saturated NaHCO3 and brine. The organic extract was dried over Na2SO4 and evaporated in vacuo. The crude product was washed with dichloromethane and methanol. The yellow solid was further purified by recrystallization with DMF and water to yield N-(4-(3-(4-chlorobenzyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)methanesulfonamide.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[C:16]([CH2:17][CH2:18][CH3:19])=[CH:15][C:14]([C:20]([O:29][CH2:30][O:31][CH3:32])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:13][C:12]=2[CH2:33][CH2:34][CH3:35])=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+].O>CO>[I:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[C:16]([CH2:17][CH2:18][CH3:19])=[CH:15][C:14]([C:20]([O:29][CH2:30][O:31][CH3:32])([C:21]([F:22])([F:23])[F:24])[C:25]([F:27])([F:28])[F:26])=[CH:13][C:12]=2[CH2:33][CH2:34][CH3:35])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc(CCC)c1Oc1ccc(I)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc(CCC)c1Oc1ccc(I)c(CO)c1
Yield: 107.7 %

Procedure:
To a solution of (2-iodo-5-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2,6-dipropylphenoxy) benzaldehyde (25 mg, 0.0404 mmol) in methanol (2.0 mL), sodium borohydride (1.7 mg, 0.445 mmol) was added under ice-cold conditions, and the resultant mixture was stirred for 30 minutes. After completion of the reaction, the reaction solution was added with water under ice-cold conditions and extracted with chloroform. The organic layer was washed with brine and dried over sodium sulfate. (2-Iodo-5-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2,6-dipropylphenoxy) phenyl)methanol (27 mg, yield >100%) was obtained as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:28])[CH2:7][N:8]2[CH2:12][CH2:11][C:10]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:9]2=[O:27])[CH2:2]1.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[C:38]([F:41])([F:40])[F:39])[CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:11][CH2:12][N:8]([CH2:7][C:6]([NH:5][CH:3]3[CH2:4][N:1]([CH2:33][C:32]4[CH:35]=[CH:36][C:37]([C:38]([F:39])([F:40])[F:41])=[C:30]([F:29])[CH:31]=4)[CH2:2]3)=[O:28])[C:9]2=[O:27])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Reactant: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)NC1CN(Cc2ccc(C(F)(F)F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-azetidin-3-yl-2-[3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl]acetamide (0.083 g, 0.215 mmol; Example 239A) in dichloromethane (5 mL) was added 3-fluoro-4-(trifluoromethyl)benzaldehyde (0.062 g, 0.323 mmol), sodium triacetoxyborohydride (0.088 g, 0.323 mmol) and a few drops of acetic acid. The reaction mixture was stirred at ambient temperature for 16 hours. The mixture was then diluted with dichloromethane and washed with saturated aqueous NaHCO3 solution. The separated organic layer was dried over MgSO4, concentrated, and purified by silica gel flash chromatography eluting with 5-10% methanol/dichloromethane. 1H NMR (300 MHz, CDCl3) δ ppm 7.54 (t, J=7.6 Hz, 1H), 7.28-7.33 (m, 4H), 7.12-7.16 (m, 2H), 6.98-7.05 (m, 4H), 6.30-6.37 (m, 1H), 4.40-4.59 (m, 1H), 3.99 (s, 2H), 3.54-3.66 (m, 4H), 3.50 (t, J=6.5 Hz, 2H), 2.77 (t, J=6.4 Hz, 4H); MS (ESI+) m/z 562 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[C:13]1([CH:19]2[CH2:23][CH2:22][CH:21](O)[CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OC(=O)C)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH:22]2[CH2:21][CH2:20][CH:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:23]2)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1
Reactant: COC(=O)c1c[nH]c(=O)c(Br)c1
Reactant: OC1CCC(c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(=O)n(C2CCC(c3ccccc3)C2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a suspension of methyl 5-bromo-6-oxo-1,6-dihydropyridine-3-carboxylate (1.6 g, 6.8 mmol), 3-phenylcyclopentanol (1.32 g, 8.15 mmol) and triphenylphosphine (2.7 g, 10.2 mmol) in dry THF (15 mL) was slowly added diethyl azodicarboxylate (1.8 g, 10.2 mmol) at RT. The resulting yellow solution was stirred at room temperature for 17 h. The mixture was diluted in ethylacetate, washed with water, brine, dried over MgSO4, and chromatographed on silica gel using hexanes to 3:1 hexanes:ethylacetate, to afford the title compound. MS m/z: 376 (M+1).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:10][C:11]([F:25])([F:24])[C:12]1[CH:13]=[C:14]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1>C1(C)C=CC=CC=1>[CH2:8]([O:7][C:5](=[O:6])[C:4]([N:21]1[CH2:20][CH2:19][N:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:24])([F:25])[F:10])[CH:13]=2)[CH2:23][CH2:22]1)=[CH:3][CH3:2])[CH3:9]
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)/C=C/CBr
Solvent: Cc1ccccc1
Product: CC=C(C(=O)OCC)N1CCN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
Over a period of 20 minutes 29 g of ethyl 4-bromocrotonate are added to 69 g of 1-(3-trifluoromethylphenyl)-piperazine dissolved in 300 ml of anhydrous toluene. The mixture is then heated at reflux for 1 hour. After cooling, the hydrobromide is filtered with suction and the filtrate is concentrate to dryness in vacuo. In this manner crude 4-(3-trifluoromethylphenyl)piperazin-1-ylbut-2-enoic acid ethyl ester is obtained in theoretical yield.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:3]([NH:5][C:6]1[C:7]([O:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)[CH:11]=1)=[O:4].[S:35]1[CH:39]=[C:38]([CH:40]=O)[N:37]=[CH:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CCOC(C)=O.C(O)(=O)C>[CH3:18][C:14]1[CH:13]=[C:12]([C:10]2[CH:11]=[C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:40][C:38]3[N:37]=[CH:36][S:35][CH:39]=3)[CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:7]([O:19][CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[N:8][CH:9]=2)[CH:17]=[CH:16][N:15]=1
Reactant: O=Cc1cscn1
Reactant: Cc1cc(-c2cnc(OCC(=O)OC(C)(C)C)c(NC(=O)[C@@H](N)Cc3ccccc3)c2)ccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2cnc(OCC(=O)OC(C)(C)C)c(NC(=O)[C@H](Cc3ccccc3)NCc3cscn3)c2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To a flask with tert-butyl 2-(3-((S)-2-amino-3-phenylpropanamido)-5-(2-methylpyridin-4-yl)pyridin-2-yloxy)acetate (78.J) (58 mg, 0.13 mmol) was added thiazole-4-carbaldehyde (15 mg, 0.13 mmol). Dichloromathane was added as the solvent. Then acetic acid, glacial (8 mL, 0.13 mmol) was added followed by sodium triacetoxyborohydride (80 mg, 0.38 mmol). The reaction was stirred at room temperature for 1 hour and worked up with EtOAc and saturated NaHCO3 solution. Reverse phase HPLC purification afforded compound 78 26 mg (37%). 1H NMR (400 MHz, MeOH) δ ppm 8.78-8.96 (m, 2H) 8.45 (d, J=5.48 Hz, 1H) 8.22 (d, J=2.35 Hz, 1H) 7.57 (s, 1H) 7.49 (dd, J=5.48, 1.56 Hz, 1H) 7.36 (d, J=1.96 Hz, 1H) 7.18-7.31 (m, 5H) 4.90 (d, J=3.13 Hz, 2H) 3.87-3.98 (m, 2H) 3.63 (dd, J=8.61, 5.09 Hz, 1H) 3.19 (dd, J=13.89, 4.89 Hz, 1H) 2.92 (dd, J=14.09, 8.61 Hz, 1H) 2.60 (s, 3H) 1.46 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[S:29][C:30]([S:34]([N:37]2[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38]2)(=[O:36])=[O:35])=[C:31]([CH3:33])[N:32]=1>>[OH:42][CH:39]1[CH2:40][CH2:41][N:37]([S:34]([C:30]2[S:29][C:28]([NH:27][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=5)=[N:6][C:7]=34)=[O:13])=[N:32][C:31]=2[CH3:33])(=[O:36])=[O:35])[CH2:38]1
Reactant: Cc1nc(N)sc1S(=O)(=O)N1CCC(O)C1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)N1CCC(O)C1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and (RS)-1-(2-amino-4-methyl-thiazole-5-sulfonyl)-pyrrolidin-3-ol (example B.23) according to general procedure II. Light yellow solid. MS (ISP) 621.0 [(M+H)+]; mp 300° C.