Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([C:16]([OH:18])=[O:17])=[CH:11][CH:10]=[CH:9]2.[CH2:19](O)[CH3:20]>>[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=[CH:9]2
Reactant: CCO
Reactant: O=C(O)c1cccc2cc(O)ccc12
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cccc2cc(O)ccc12
Temperature: 25 °C
Yield: 87 %

Procedure:
Thionyl chloride (2.3 mL, 31.9 mmol) was slowly added to a solution of 6-hydroxy-1-naphthoic acid (3 g, 15.9 mmol) in ethanol (140 mL) and stirred under N2. After addition, the reaction mixture was heated at reflux under nitrogen for 6 days. The reaction mixture was cooled to room temperature and concentrated to give the crude product as an oil. The oil was carefully partitioned between 5% NaHCO3 and EtOAc. The organic phase was separated and washed with brine, dried over MgSO4, filtered and the filtrate was concentrated to give 3 g (87%) of the product as a red amorphous solid. 1H NMR (400 MHz, DMSO-d6): δ 9.92 (s, 1H), 8.57 (m, 1 H), 7.92 (d, J=8 Hz, 1 H), 7.85 (d, J=7 Hz, 1 H), 7.45 (t, J=8, 1H), 7.20-7.18 (m, 2 H), 4.38-4.33 (m, 2 H), 1.34 (t, J=7 Hz, 3 H).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[F:8][C:9]([F:16])([F:15])[C:10](=[O:14])[CH2:11][C:12]#[N:13]>C(OCC)C>[F:8][C:9]([F:16])([F:15])[C:10]([O:14][CH3:1])=[CH:11][C:12]#[N:13]
Reactant: N#CCC(=O)C(F)(F)F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=CC#N)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(Trimethylsilyl)diazomethane (21 mL, 2M in diethyl ether) was added dropwise to a solution of 4,4,4-trifluoro-3-oxobutanenitrile (3.79 g, 26 mmol) in anhydrous diethyl ether (25 mL) previously cooled to 0° C. The resulting mixture was allowed to slowly warm to room temperature and stirred overnight. The solvent was removed under reduced pressure to give 4,4,4-trifluoro-3-methoxybut-2-enenitrile, which was directly used in the next step without further purification. 1H NMR (300 MHz, CDCl3) d 5.00 (s, 1H), 4.16 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[C:6]([I:8])[CH:7]=1.[CH2:10](Cl)Cl.CO>>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH3:10])[CH:5]=[C:6]([I:8])[CH:7]=1
Reactant: Oc1ncc(I)cc1Cl
Reactant: ClCCl
Solvent: CO
Product: Cn1cc(I)cc(Cl)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Step 23.2 using 3-chloro-5-iodo-pyridin-2-ol. tR: 3.30 min (HPLC 1); tR: 0.71 min (LC-MS 2); ESI-MS: 270 [M+H]+ (LC-MS 2); Rf=0.79 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][CH2:12]O)[CH:7]=[CH:8][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]N1C(=O)CCC1=O>C(Cl)Cl>[Br:35][CH2:12][CH2:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:15])([F:14])[F:1])[CH:5]=1
Reactant: OCCCc1cccc(OC(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)Oc1cccc(CCCBr)c1
Reaction time: 3 h
Yield: 87.4 %

Procedure:
Compound 58-2 (3.15 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (4.13 g) and N-bromosuccinimide (2.79 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.54 g) as a yellow oil.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:13]([OH:26])[CH2:14][N:15]([CH2:24][CH3:25])[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][C@@H:12]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C@H:13]([OH:26])[CH2:14][N:15]([CH2:24][CH3:25])[NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18]
Reactant: [H][H]
Reactant: CCN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCN(C[C@@H](O)[C@@H](N)Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 100 %

Procedure:
A solution of tert-butyl 2-((2R,3S)-3-{[(benzyloxy)carbonyl]amino}-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate (3.11 g, 6.8 mmol) in methanol (50 mL) was added to 10% Pd/C (0.32 g) and stirred in a hydrogen atmosphere (@ ambient pressure) for 5 h. The reaction was filtered through Celite and the filtrate concentrated under reduced pressure to yield tert-butyl 2-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate (2.2 g) as an oil. MS (ESI+) for C17H29N3O3 m/z 324.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[S:14]1[CH2:18][C:17](=[O:19])[NH:16][C:15]1=[O:20].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:18]2[S:14][C:15](=[O:20])[NH:16][C:17]2=[O:19])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: O=C1CSC(=O)N1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(C=C2SC(=O)NC2=O)cc1[N+](=O)[O-]
Yield: 88.4 %

Procedure:
4-Methoxy-3-nitrobenzaldehyde (4.00 g, 22.2 mmol), thiazolidine-2,4-dione (3.10 g, 26.5 mmol), ammonium acetate (3.40 g, 44.1 mmol), acetic acid (8 mL) and benzene (120 mL) were mixed, and, while removing water formed by the reaction, the mixture was refluxed for 8 hours. After allowed to stand for cooling, the precipitated crystals were collected by filtration, washed with benzene and 20% aqueous acetone, and then dried to obtain 5.50 g (88%) of the title compound as yellow powder.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:6][CH:5]=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:26]=[C:25]([C:33](O)=O)[N:24]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[N:26]=[C:25]([C:33]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:6][CH:5]=4)[N:14]=3)[N:24]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1nc(-c2ccc(Cl)c(Cl)c2)cc(C(F)(F)F)n1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)n2)cc1

Procedure:
The title compound was prepared from N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (0.16 g, 0.74 mmol) and 4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.6) (0.17 g, 0.50 mmol) according to the general procedure V. Obtained as a light yellow solid (0.042 g, 16%). MS (ISP) 516.1 [(M+H)+]; mp 302.5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]([C:5]1[C:17]([CH2:18][CH2:19][CH:20](O)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:16]([OH:28])[C:8]2[N:9]=[C:10]([CH3:15])[N:11]([CH2:12][O:13][CH3:14])[C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>>[CH3:1][N:2]([CH3:29])[C:3]([C:5]1[C:17]2[CH2:18][CH2:19][CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:28][C:16]=2[C:8]2[N:9]=[C:10]([CH3:15])[N:11]([CH2:12][O:13][CH3:14])[C:7]=2[CH:6]=1)=[O:4]
Reactant: COCn1c(C)nc2c(O)c(CCC(O)c3ccccc3)c(C(=O)N(C)C)cc21
Agent: [Na+]
Agent: [OH-]
Product: COCn1c(C)nc2c3c(c(C(=O)N(C)C)cc21)CCC(c1ccccc1)O3
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 57.1 %

Procedure:
A suspension of 0.20 g (0.6 mmol) 7-hydroxy-6-(3-hydroxy-3-phenyl-propyl)-3-methoxymethyl-2-methyl-3H-benzoimidazole-5-carboxylic acid dimethylamide in 2 ml 85% ortho-phosphorlc acid was heated to 80° C. After 90 min stirring, the reaction was cooled to room temperature, poured into ice/water and neutralized with 10M sodium hydroxide. The water layer was extracted with dichloromethane, the organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue was crystallized from ethyl acetate/petroleum ether to afford 130 mg (59%) of the title compound as a beige powder. m.p. 213°-215° C.
Reaction SMILES: Br[C:2]1[C:3]([N:25]2[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]2)=[N:4][CH:5]=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=1)=[O:8].[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1>>[OH:30][C@@H:27]1[CH2:28][CH2:29][N:25]([C:3]2[C:2]([C:35]3[CH:36]=[N:31][CH:32]=[N:33][CH:34]=3)=[CH:24][C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:23])([F:22])[C:18]([F:19])([F:20])[F:21])=[CH:14][CH:15]=3)=[O:8])=[CH:5][N:4]=2)[CH2:26]1
Reactant: O=C(Nc1ccc(OC(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(OC(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described infashion to that described in Example 185 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethoxy)phenyl)nicotinamide (Stage 220.1) and pyrimidin-5-ylboronic acid to afford an off-white solid. HPLC (Condition 4) tR=5.17 min, UPLC-MS (Condition 3) tR=0.99 min, m/z=496.4 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.77 (m, 1H) 1.79-1.91 (m, 1H) 2.88 (d, J=11.34 Hz, 1H) 3.21 (m, J=11.10, 4.90 Hz, 2H) 3.32-3.44 (m, 1H) 4.20 (d, J=2.35 Hz, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.85 (d, J=9.38 Hz, 2H) 8.08 (d, J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 8.88 (s, 2H) 9.13-9.34 (m, 1H) 10.16 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)=[O:14]>>[Br:21][C:17]1[CH:16]=[C:15]([C:13](=[O:14])[CH2:12][O:10][C:3]2[CH:4]=[C:5]([CH3:9])[CH:6]=[C:7]([CH3:8])[C:2]=2[CH3:1])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: O=C(CBr)c1cccc(Br)c1
Product: Cc1cc(C)c(C)c(OCC(=O)c2cccc(Br)c2)c1
Yield: 52 %

Procedure:
Using 2,3,5-trimethylphenol and 2-bromo-1-(3-bromophenyl)ethanone, the title compound was synthesized in the same manner as in Reference Example 159. Yield 52%. Oily matter.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9].[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH3:13][CH:12]([CH3:14])[CH2:11][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:10])=[O:9]
Reactant: C1CNCCN1
Reactant: CC(C)CS(=O)(=O)c1ccccc1Br
Product: CC(C)CS(=O)(=O)c1ccccc1N1CCNCC1

Procedure:
To a solution of 1-bromo-2-isobutylsulfanyl-benzene (8.0 g, 32.6 mmol, 1.0 eq) in DCM (100 mL) at 0° C. was added CaCO3 (13.05 g, 130.4 mmol, 4.0 eq.) and MCPBA (28.1 g, 81.5 mmol, 2.5 eq.). The mixture was stirred for about 30 minutes and filtered through a pad of celite. The solution was washed with sodium bisulfite (2×) and 5N NaOH (2×). The organic layer was dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (250 g SiO2, linear gradient, 40 mL/min, 10%-40% EtOAC/hexane for about 33 minutes) afforded 1-bromo-2-(2-methyl-propane-1-sulfonyl)-benzene (7.4 g, 26.6 mmol, 82%). GCMS (EI): 276.0. 1-bromo-2-(2-methyl-propane-1-sulfonyl)-benzene was coupled to piperazine in a manner similar to Preparation 1A. LRMS (ESI+): 283.06 (M+1)
Reaction SMILES: C[Si]([N-:5][Si](C)(C)C)(C)C.[Li+].C1COCC1.[C:16]([C:18]1[CH:45]=[CH:44][C:21]([C:22]([NH:24][C:25]2[CH:30]=[C:29]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[CH:28]=[CH:27][C:26]=2[NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:23])=[CH:20][N:19]=1)#[N:17].Cl>>[C:16]([C:18]1[CH:45]=[CH:44][C:21]([C:22]([NH:24][C:25]2[CH:30]=[C:29]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[CH:28]=[CH:27][C:26]=2[NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:23])=[CH:20][N:19]=1)(=[NH:5])[NH2:17]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(C#N)nc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(C(=N)N)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48 %

Procedure:
To a 1M solution of lithium bis(trimethylsilyl)amide in THF (0.0.76 mL, 0.76 mmol) at 0° C. was added compound 251 (0.10 g, 0.24 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 18 h, cooled to 0° C., treated with 1N HCl (15 mL), stirred for 30 min and concentrated. The residue was diluted with AcOEt and extracted with H2O. The aqueous phase was collected, neutralized with 1N NaOH, extracted with AcOEt, dried over MgSO4, filtered and concentrated. The resulting brown solid was triturated with diethyl ether to give intermediate 252 (50 mg, 48% yield).
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]([CH3:19])[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:8]>CCO>[CH3:3][CH:4]([CH3:19])[CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[OH:8]
Reactant: CC(C)CCC(=O)c1ccc(C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)CCC(O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (2.8 g, 0.074 mol) was added portionwise to a solution of 4-methyl-1-[4-(trifluoromethyl)phenyl]pentan-1-one [Intermediate 1; Step 1] in EtOH (50 mL) cooled in ice. When addition was complete (30 min) the mixture was stirred at RT for 1 h then quenched with NH4Cl solution (50 mL) followed by 2N HCl (20 mL). Extraction with ether (3×50 mL) followed by drying (MgSO4) and concentration of the organic phase gave 4-methyl-1-(4-(trifluoromethyl)phenyl)pentan-1-ol as a colourless oil.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.[NH2:39][CH2:40][C:41]([NH2:43])=[O:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:43][C:41](=[O:42])[CH2:40][NH:39][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCC(N)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: NC(=O)CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 42.9 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.07 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.061 mL, 0.556 mmol), 2-aminoacetamide (6.70 mg, 0.090 mmol), and HATU (39.7 mg, 0.104 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM) to give (R/S)-N-(2-amino-2-oxoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (17.4 mg, 0.030 mmol, 43.2% yield): LCMS=488.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.18 (2 H, d, J=8.35 Hz), 7.66-7.80 (4 H, m), 7.51-7.65 (3 H, m), 5.20 (1 H, s), 3.80-4.02 (2 H, m); HPLC Peak RT=8.1 min (Analytical Method D).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:11])[NH:9][N:10]=[C:4]2[C:3]=1[I:12].C([O-])([O-])=O.[K+].[K+].I[CH2:20][CH:21]([CH3:23])[CH3:22]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:11])[N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:10]=[C:4]2[C:3]=1[I:12]
Reactant: O=c1[nH]nc2c(I)c(Br)ccn12
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1nc2c(I)c(Br)ccn2c1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
To a stirring solution of 7-bromo-8-iodo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (2.0 g, 5.9 mmol) in 20 mL DMF at 20° C. was added K2CO3 (1.6 g, 11.8 mmol), followed by addition of 1-iodo-2-methylpropane (2.2 g, 11.8 mmol). The resulting reaction mixture was stirred at 80° C. for 3 h. Analysis by HPLC/MS indicated that starting material had been entirely consumed. The reaction mixture was brought to room temperature, diluted with water, and extracted with diethyl ether and EtOAc. The combined organic extract was washed with saturated aqueous NaHCO3 solution, then brine, then dried (MgSO4), filtered, and concentrated under reduced pressure to obtain the title compound (2.1 g, 5.3 mmol) as a light tan solid. MS: [M+H]+=396. 1H NMR (CDCl3): δ 7.65 (d, J=1.9 Hz, 1H), 6.68 (d, J=1.8 Hz, 1H), 3.82 (d, J=1.8, 2H), 2.33-2.30 (m, 1H), 0.96 (d, J=1.7 Hz, 6H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:34][C:18]4([CH2:33][C:20]5([CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]>[Pd].CO>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]3[CH2:34][C:18]4([CH2:33][C:20]5([CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:24][CH2:25]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O1)C2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(C4CCN(S(C)(=O)=O)CC4)ncc3O1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A flask charged with 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1″-tert-butoxycarbonyl-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (50 mg), 10% palladium on carbon (5 mg), and methanol (5 mL) is shaken under H2 atmosphere (1 bar) at room temperature for 2 h. The catalyst is separated by filtration and the filtrate is concentrated to give the title compound. LC (method 3): tR=0.93 min; Mass spectrum (ESI+): m/z=492 [M+H]+.
Reaction SMILES: CN(C=O)C.O=[C:7]1[CH2:12][CH2:11][CH:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH3:25])[N:19]=3)=[C:16]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[N:15]=[CH:14]2)[CH2:9][CH2:8]1>CCOCC>[CH:10]1([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH3:25])[N:19]=3)=[C:16]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[N:15]=[CH:14]2)[CH2:9][CH2:8][CH2:7][CH2:12][CH2:11]1
Reactant: COc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCC(=O)CC2)n1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCCCC2)n1
Reaction time: 48 h

Procedure:
The product of the preceding example, DMF (10 mL), the product of example 1 (b) (1.59 g, 5.5 mmol) and KCO3 (0.308 g, 2.23 mmol) were combined and stirred for 2 days, diluted with Et2O and filtered. The filtrate was concentrated under high vacuum to a brown paste. Trituration with Et2O and hexane (1:1, 200 mL) afforded the title compound as a tan solid. Crystallization from EtOAc/hexane (1:4) afforded 0.631 g (39% from the product of example 1(d). ESP+ (Mass Spec) m/z 353 (MH+). mp=207-208.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([Cl:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClN1C(=O)CCC1=O.[CH3:21][S:22][CH3:23].C(N(CC)CC)C>ClCCl>[C:1]([C:5]1[CH:11]=[C:10]([CH2:21][S:22][CH3:23])[C:8]([NH2:9])=[C:7]([Cl:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N)c(Cl)c1
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSCc1cc(C(C)(C)C)cc(Cl)c1N
Temperature: -5 °C
Reaction time: 1 h

Procedure:
4-t-Butyl-2-chloroaniline (30 g) was dissolved in dichloromethane (1.21) and the solution was cooled to -5° C. N-chlorosuccinimide (21.7 g) was added portionwise to the vigorously stirred solution and stirring was continued for 1 h. Dimethyl sulfide (35 ml) was added to the solution (-5° C.) and stirring was continued for a further 1 h. The solution was then cooled to -65° C. and triethylamine (27 ml) was added. This solution was allowed to warm to room temperature overnight. The solution was evaporated to half volume, washed with sodium hydroxide (1N), water and brine successively. The organic solution was dried and evaporated and the residue was purified on silica using hexane to 3% ether in hexane as eluant. This afforded the product (31.2 g) as a red oil. 1H NMR (CDCl3, 250 MHz) δ 1.27 (9H, s, (CH3)3), 1.99 (3H, s, SCH3 ), 3.69 (2H, s, CH2SCH3), 4.38 (2H, br s, NH2), 6.92 (1H, d, J=2.0 Hz, ArH), 7.21 (1H, d, J=2.0 Hz, ArH). MS (CI+) m/z 244 (M+ +1, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[CH2:31]Br>O1CCCC1.CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:10][O:11][CH2:27][C:28]1[CH:29]=[C:30]([CH3:31])[CH:33]=[C:34]([CH3:36])[CH:35]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C)cc(CBr)c1
Reactant: CC(C)(C)OC(=O)NC(CO)C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C)cc(COCC(NC(=O)OC(C)(C)C)C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.9 %

Procedure:
To a solution of 2-t-butoxycarbonylamino-3,3-diphenylpropan-1-ol (1.0 g, Example 1d) in tetrahydrofuran (5 ml) and dimethylformamide (1 ml) was added sodium hydride (0.11 g, 80% suspension in oil) over 15 minutes. After an additional 10 minutes 3,5-dimethylbenzyI bromide (0.73 g) was added and the solution stirred at room temperature for 3 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. After washing the organic phase with saturated brine and drying (MgSO4), the solvent was removed in vacuo and the residue chromatographed on silica gel in ethyl acetate/hexane (1:10) to give 2-t-butoxycarbonylamino-1-((3,5-dimethylphenyl)methyloxy)-3,3-diphenylpropane 0.38 g. 1H NMR (360 MHz, CDCl3) δ7.3-6.9 (13H, m), 4.7 (1H, bd), 4.6 (1H, bt), 4.43 (1H, d, J=16.7 Hz), 4.3 (2H, m), 3.4 (1H, dd), 3.2 (1H, dd, J=9.4 Hz and 2.82 Hz), 2.3 (6H, s), 1.3 (9H, s). m/z (CI+) 446 (M+H).
Reaction SMILES: [CH:1]1([CH2:11][C:12](O)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.[CH3:15][CH:16]1[NH:21][CH:20]([CH3:22])[CH2:19][N:18]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=2)[CH2:17]1.N1(C2C=CC(S(N)(=O)=O)=CC=2)CCNCC1.ClCCC1C2C(=CC=CC=2)C(C)CO1.C1(C[C@H]2COC(=O)N2C(=O)C(C2C=CC=CC=2)C)C=CC=CC=1>>[C@H:1]1([CH2:11][CH2:12][N:21]2[C@@H:16]([CH3:15])[CH2:17][N:18]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=3)[CH2:19][C@H:20]2[CH3:22])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1
Reactant: O=C(O)CC1OCCc2ccccc21
Reactant: CC1CN(c2ccc(C(N)=O)cc2)CC(C)N1
Agent: CC(C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccccc1
Agent: CC1COC(CCCl)c2ccccc21
Agent: NS(=O)(=O)c1ccc(N2CCNCC2)cc1
Product: C[C@@H]1CN(c2ccc(C(N)=O)cc2)C[C@H](C)N1CC[C@@H]1OCCc2ccccc21

Procedure:
Following the general procedure of EXAMPLE 48 and making non-critical variations (-)-isochromanylacetic acid (LXI, EXAMPLE 45, 0.346 g) and 4-(3,5-dimethylpiperazin-1-yl)benzamide [(IV), 0.462 g; prepared from 4-fluorobenzamide (III) and cis-2,6-dimethylpiperazine (II, Aldrich) by the procedure of EXAMPLE 47, Step 1] gives the title compound, mp 206-207°; MS (m/z) 393; IR (mineral oil) 1640, 1607, 1246, 3383, 1402, 1395, 1422, 1112 and 1332 cm-1.