Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][C@@H:9]1[CH2:26][CH2:27][OH:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29](O)(=O)[CH3:30]>C(OCC)=C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][C@@H:9]1[CH2:26][CH2:27][O:28][CH:29]=[CH2:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccccc23)C[C@@H]1CCO
Reactant: CC(=O)O
Agent: C=COCC
Product: C=COCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-tert-Butoxycarbonyl-2(S)-(2-hydroxyethyl)-4-naphthoylpiperazine (0.50 g, 1.3 mmol) was dissolved in freshly distilled ethyl vinyl ether (20 mL) under argon. To this solution was added mercuric acetate (0.436 g, 1.37 mmol) and the reaction refluxed overnight. The reaction was cooled to room temperature, acetic acid added (0.035 mL, 0.58 mmol) and stirred 2 h. The reaction mixture was extracted with ethyl acetate and 5% aqueous sodium hydroxide, and the organic phase further extracted with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was chromatographed on silica gel with 30% ethyl acetate in hexane. The title compound was obtained as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:41])[CH2:12][N:13]2[CH2:17][C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C@:15]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@@H:14]2[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:6][CH:5]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([C@H:16]2[CH2:17][N:13]([CH2:12][C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:42])=[O:2])=[CH:9][CH:8]=3)=[O:41])[C@@H:14]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C@@:15]2([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[F:35])[C:26]#[N:27])[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(NC(=O)CN2C[C@H](c3cccc(Cl)c3F)[C@@](C#N)(c3ccc(Cl)cc3F)[C@@H]2CC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C[C@@H]1N(CC(=O)Nc2ccc(C(=O)O)cc2)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.4 %

Procedure:
To a solution of rac-4-{2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetylamino}-benzoic acid methyl ester (0.35 g, 0.57 mmol) in tetrahydrofuran (30 mL) was added an aqueous solution (1 N) of NaOH (10 mL, 10 mmol) and methanol (10 mL). The reaction mixture was stirred at room temperature for 24 h, and the “pH” of the solution was adjusted to 5-6 by aqueous HCl solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give rac-4-{2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetylamino}-benzoic acid as a white solid (0.33 g, 96%). HRMS (ES+) m/z Calcd for C31H29Cl2F2N3O3+H [(M+H): 600.1267; Found: 600.1628.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11]Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:13][N:14]=[C:15]([C:21](=[O:23])[CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:9][CH2:10][CH2:11][O:13][N:14]=[C:15]([C:21](=[O:23])[CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCCBr)c1ccccc1
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)C(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.4 %

Procedure:
2-Bromoethyl benzoate (27.5 g.) was added dropwise to a stirred mixture of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer) (15.7 g.), potassium carbonate (20.7 g.) and N,N-dimethylformamide (25 ml.) under ice cooling over 10 minutes, and stirred at ambient temperature for 4 hours. The resultant mixture was filtered and washed with acetone. The filtrate and washings were combined and concentrated in vacuo. After adding water (100 ml.) to the residue, the solution was extracted with methylene chloride three times. The extracts were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give ethyl 2-(2-benzoyloxyethoxyimino)-3-oxobutyrate (syn isomer) (28 g.).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[C:13]([CH2:15][C:16]([NH2:18])=[O:17])#[N:14]>[O-]CC.[Na+]>[NH2:14][C:13]1[N:1]([CH2:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[N:2]=[N:3][C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: N#CCC(N)=O
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Product: COc1ccc(Cn2nnc(C(N)=O)c2N)cc1
Temperature: 25 °C

Procedure:
A mixture of 1-(azidomethyl)-4-methoxybenzene (5 g) and 2-cyanoacetamide (5 g) was added to a solution of sodium ethoxide (made from 1.6 g of sodium in 100 mL of ethanol). The resulting mixture was refluxed for 20 h. It was cooled down to room temperature and solvent was removed under reduced pressure. The remaining solid was dissolved in water (20 mL) and extracted with ethyl acetate (3×50 mL). The extracts were combined, washed with brine and dried over sodium sulfate. Solvent was removed and the residue was crystallized from hot water to give the desired product 5-amino-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide. ESMS calculated for C11H13N5O2 (m/z): 247.1; found (M+H+): 248.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([C:12]2[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][N:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.Br[CH2:20][CH3:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([S:9]([C:12]2[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][N:13]=2)(=[O:11])=[O:10])[CH2:20][CH3:21])=[CH:6][CH:7]=1
Reactant: CCBr
Reactant: O=S(=O)(Cc1ccc(Cl)cc1)c1cc(Br)ccn1
Product: CCC(c1ccc(Cl)cc1)S(=O)(=O)c1cc(Br)ccn1
Yield: 93 %

Procedure:
3.2 mmoles of 2-[(4-chlorophenyl)methylsulfonyl]-4-bromopyridine was contacted with 7.0 mmoles bromoethane using essentially the conditions of Example 4 providing about 93% yield of 2-[1-(4-chlorophenyl)propylsulfonyl]-4-bromopyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>O1CCCC1>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([O:24][C:25]2[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](=[O:32])[NH:1][C:2]3[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=3[NH2:10])=[CH:27][CH:26]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCC(=O)O)cc2)CC1
Reactant: N#Cc1ccc(N)c(N)c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCC(=O)Nc3cc(C#N)ccc3N)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To a solution of 3,4-diaminobenzonitrile (474 mg), 4-(1-tert-butoxycarbonylpiperidin-4-yloxy)phenoxyacetic acid (1.25 g) in tetrahydrofuran (50 ml) was added 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline (1.06 g) with ice-cooling, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was evaporated and to the obtained residue were added chloroform and hexane. The resultant solid was collected by filtration and dried under reduced pressure to give the title compound (1.55 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]([C:11]([OH:13])=[O:12])[NH2:10])[CH:5]=[CH:6][C:7]=1[OH:8].O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[C:26]1([C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N+]=[N-])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCOCC>CN(C)C=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]([C:11]([O:13][CH:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:12])[NH2:10])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: NC(C(=O)O)c1ccc(O)c(O)c1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: NC(C(=O)OC(c1ccccc1)c1ccccc1)c1ccc(O)c(O)c1
Reaction time: 0.17 h

Procedure:
Into a stirred suspension of 1.83 g (10.0 mmol) of α-(3,4-dihydroxyphenyl)glycine and 1.96 g (10.0 mmol) of toluenesulfonic acid monohydrate (97%) in 5 ml of dry dimethylformamide, a solution of freshly prepared diphenyldiazomethane (2.91 g, 15.0 mmoles) in 10 ml of dimethylformamide was dropped at 50° C. and stirring was continued for 10 minutes. The solvent was evaporated in vacuo, the residue was taken up in ice water/ethyl acetate and the pH was brought to 7.5 by addition of dilute sodium hydroxide. The organic layer was separated, washed with sodium bicarbonate solution and brine, dried (sodium sulfate) and evaporated in vacuo to leave a solid which was stirred with ether. Yield (after filtration and drying in vacuo): 1.89 g, melting point 155°-158° C.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1OS(C(F)(F)F)(=O)=O.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=S(=O)(Oc1ccc2ccccc2c1)C(F)(F)F
Reactant: C1CCNCC1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1ccc2cc(N3CCCCC3)ccc2c1
Temperature: 105 °C
Yield: 76.8 %

Procedure:
The method described in this example is representative of method "A". Into a screw-capped test tube were weighed 8.6 mg (0.015 mmol) Pd(dba)2, 12.8 mg (0.023 mmol) DPPF, and 44.3 mg (0.462 mmol) sodium t-butoxide (NaO-t-Bu). The solid materials were suspended in 8 ml of toluene. 2-Naphthyltriflate (85.0 mg, 0.308 mmol) was dissolved in 1 ml of toluene and added to the test tube. The test tube was sealed with a cap containing a polytetrafluoroethylene (PTFE) septum and removed from the dry box. Piperidine (40.0 μl, 0.462 mmol) was added to the test tube by syringe. The reaction mixture was heated at 105° C. for 5 hours. Thin layer chromatography (TLC) of the reaction mixture indicated complete consumption of the naphthyltriflate. The reaction mixture was cooled to room temperature, and the volatile materials were removed by rotary evaporation. Sublimation (120° C., 0.1 torr) of the resulting residue afforded N-(2-naphthyl)piperidine as a white solid (50.0 mg, 77% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]C(C)(C)C.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:20]=[O:21]>C1COCC1>[S:1]1[C:5]([CH:20]([OH:21])[C:19]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:17]([O:16][CH3:15])[CH:18]=2)=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: COc1ccc(C=O)cc1OC
Reactant: c1ccc2sccc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cc3ccccc3s2)cc1OC

Procedure:
α-(2-benzo[b]thienyl)-3,4-dimethoxybenzyl alcohol was prepared in the same manner as described in Example 40A. Reaction of benzo[b]-thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 m, 97 mmoles, 5.7 ml) and 3,4-dimethoxybenzaldehyde (8.9 mmoles, 1.5 g) in THF (20 ml) yielded, after flash chromatography using 30% ethyl aceteate/hexanes, 2.25 g (≈100%) of a white gummy solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]([CH2:17]Br)[C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[F-:20].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]([CH2:17][F:20])[C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: CC(C)(C)OC(=O)CN(CBr)C(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN(CF)C(=O)c1ccccc1
Yield: 90 %

Procedure:
Bromomethylbenzoyl-glycine t-butyl ester was fluorinated in 90% yield using tetrabutylammonium fluoride in acetonitrile. NMR (CHCl3) δ 7.84 (d, 2H, Ar-2,6, J=8.3Hz), 7.44 (d, 2H, Ar-3,5, J=7.9Hz), 6.66 (1H, NH), 5.44 (d, 2H, CH2F, J=47Hz), 4.15 (d, 2H, CH2 gly, J=5.0Hz), 1.51 (9H, Bu).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:13]=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([SH:11])[N:5]2[N:4]=1.CC(O[CH2:18][C:19]1[CH2:28][S:27][C@@H:22]2[C@H:23]([NH2:26])[C:24](=[O:25])[N:21]2[C:20]=1[C:29]([OH:31])=[O:30])=O.O.N>C(#N)C>[NH2:26][CH:23]1[C:24](=[O:25])[N:21]2[C:20]([C:29]([OH:31])=[O:30])=[C:19]([CH2:18][S:11][C:10]3[N:5]4[N:4]=[C:3]([CH2:2][OH:1])[N:13]=[C:6]4[N:7]=[C:8]([CH3:12])[CH:9]=3)[CH2:28][S:27][C@H:22]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1cc(S)n2nc(CO)nc2n1
Agent: N
Solvent: O
Solvent: CC#N
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n2nc(CO)nc2n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
In 130 ml of acetonitrile were suspended 11.08 g of 2- hydroxymethyl-7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine and 15.38 g of 7-aminocephalosporanic acid, and 24.6 ml of boron trifluoride-ethy: ether complex was added thereto and the mixture was stirred at 50° C. for 2 hours. After the reaction mixture was ice-cooled, 300 ml of water was added thereto and pH thereof was adjusted to 2 with conc. aqueous ammonia. The precipitated crystals were collected by filtration, washed with water and with acetone, and then dried to obtain 18.5 of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[C:19]([Cl:21])[C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:8]2=[O:18])=[C:4]([Cl:22])[CH:3]=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Cl:22][C:4]1[CH:3]=[C:2]([NH:1][S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH:20]=[C:19]([Cl:21])[C:5]=1[CH2:6][CH:7]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[C:8]1=[O:18]
Reactant: Nc1cc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=C1C(Cc2c(Cl)cc(NS(=O)(=O)c3ccccc3)cc2Cl)CCN1C1CCCCC1
Yield: 65.2 %

Procedure:
Using the procedure to synthesize Example 250 and using reagents 3-(4-amino-2,6-dichlorobenzyl)-1-cyclohexylpyrrolidin-2-one (250 mg, 0.73 mmol) and benzene sulfonyl chloride (0.19 mL, 1.5 mmol) affords 229 mg (65%) of the title compound. Mass spectrum (apci) m/z=481.1 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(-c2cccc3nc(N)nn23)c1
Reactant: COc1cccc(Br)c1
Product: COc1cccc(Nc2nc3cccc(-c4cccc(S(C)(=O)=O)c4)n3n2)c1
Yield: 75.3 %

Procedure:
[5-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(3-methoxyphenyl)-amine was prepared from 5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100 mg, 0.35 mmol) and 1-bromo-3-methoxy benzene (52 μL, 0.42 mmol) in a manner analogous to Example 77 to yield [5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(3-methoxyphenyl)-amine (104 mg, 75%) as a yellow powder following purification on a 12 g Isco silica gel column using 0-5% methanol in dichloromethane as an eluent. MP=180° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.66 (s, 1H), 8.62 (m, 1H), 8.40 (d, J=8.0 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.87 (t, J=16.1 Hz, 8.0 Hz, 1H), 7.68 (m, 2H), 7.32 (m, 2H), 7.25 (d, J=8.6 Hz, 1H), 7.15 (t, J=16.5 Hz, 8.0 Hz, 1H), 6.45 (dd, J=8.0 Hz, 2.7 Hz, 1H), 3.69 (s, 3H), 3.33 (s, 3H). MS=395 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CS(O)(=O)=O.[C@H:25]12[CH2:31][C@H:28]([NH:29][CH2:30]1)[C:27](=[O:32])[O:26]2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.CN(C)C=O.C(N(CC)CC)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:29]3[CH2:30][C@@H:25]4[CH2:31][C@H:28]3[C:27](=[O:32])[O:26]4)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C1O[C@@H]2CN[C@H]1C2
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Agent: CS(=O)(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1O[C@H]2C[C@@H]1N(C(=O)C1(c3ccc(Cl)cc3)CC1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
1-(4-chlorophenyl)cyclopropanecarboxylic acid (8.58 g) and dimethylformamide (136 mg) were suspended in toluene (20 mL). The mixture was cooled down to room temperature then a solution of oxalyl chloride (5.25 g) in toluene (6.7 mL) was dropped within 10 min. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 3 h. At 0-5° C., (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-one methanesulfonate (CAS #: 769167-53-5; 8 g) and tetrahydrofuran (13.2 mL) were added to the reaction mixture, followed by a dropwise addition of triethylamine (14.5 g). The mixture was stirred at 22° C. for 16 hr. An aqueous solution of citric acid (10%, 30 mL) was added and the phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was crystallized in a mixture of dichloromethane, ethyl acetate and heptane to yield 10.6 g (95%) of the title compound as a white solid. MS (ESI): m/z=292.07 [M+H]+.
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]([CH3:20])([OH:19])[C:9]([F:18])([F:17])[C:10](O)([OH:15])[C:11]([F:14])([F:13])[F:12])(=[O:5])[C:2]([CH3:4])=[CH2:3].Cl>C(Cl)Cl>[C:1]([O:6][CH2:7][C:8]([OH:19])([CH3:20])[C:9]([F:17])([F:18])[CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCC(C)(O)C(F)(F)C(O)(O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: C=C(C)C(=O)OCC(C)(O)C(F)(F)C(O)C(F)(F)F
Reaction time: 24 h
Yield: 91.1 %

Procedure:
To a mixture of 30.8 g of 2-methyl-3,3,5,5,5-pentafluoro-2,4,4-trihydroxypentyl methacrylate obtained in Example 1 and 300 g of methylene chloride was added 8.7 g of borane-t-butylamine complex, followed by 24 hours of stirring. Dilute hydrochloric acid was added to stop the reaction. Through conventional aqueous work-up and purification by silica gel column chromatography, 26.6 g of the target compound was obtained (yield 91%).
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([C:29]([O:31][CH3:32])=[O:30])=[CH:11][C:12]([Cl:28])=[C:13]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:12]([Cl:28])=[CH:11][C:10]=1[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)c1cc(Cl)c(N2CCN(C(=O)OC(C)(C)C)CC2)cc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c(N2CCNCC2)cc1N
Yield: 119.1 %

Procedure:
A solution of tert-butyl 4-(5-(tert-butoxycarbonylamino)-2-chloro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (130 mg, 0.277 mmol) and TFA (0.4 mL, 5.19 mmol) in DCM (0.4 mL) was stirred at RT for one hour. Solvent was evaporated in vacuo to give 89 mg of methyl 2-amino-5-chloro-4-(piperazin-1-yl)benzoate. HPLC/MS showed MS (ESI+) (m/z) 270 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1)#[N:2].[CH:11]([N:14]=[C:15]=S)([CH3:13])[CH3:12].CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:15]([NH:14][CH:11]([CH3:13])[CH3:12])=[N:10][C:5]=2[CH:4]=1)#[N:2]
Reactant: CC(C)N=C=S
Reactant: N#Cc1ccc(N)c(N)c1
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2cc(C#N)ccc2[nH]1
Yield: 40 %

Procedure:
4-Cyano-1,2-phenylenediamine (prepared according to the method of Fairley, T. A., et.al. J. Med. Chem. 1993, 36, 1746, 3.7 g, 27.8 mmol), isopropyl isothiocyanate (3.3 g, 32.7 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (16.0 g , 37.8 mmol) and pyridine (200 mL) were used according to general procedure I. The title compound was recrystallized from 1,4-dioxane to provide a tan powder (2.2 g, 40%); m.p. 185-190° C.; 1H NMR (DMSO-d6) δ: 11.0 (br s, 1H, NH), 7.44 (s, 1H, Ar—H), 7.2-7.1 (m, 2H, Ar—H), 6.95 (br s, 1H, NH), 3.88 (m, 1H, CH), 1.16 (d, J=6.5 Hz, 6H, overlapping CH3).
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH2:13]([OH:15])[CH3:14]>>[C:7]1([C:5]2[N:6]=[C:2]3[N:3]([CH:4]=2)[C:5]2[CH2:7][CH2:8][CH2:14][C:13](=[O:15])[C:4]=2[S:1]3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Sc1nc(-c2ccccc2)c[nH]1
Reactant: CCO
Product: O=C1CCCc2c1sc1nc(-c3ccccc3)cn21

Procedure:
2-Mercapto-4-phenylimidazole (10.6 g) and 2-bromo-1,3-cyclohexadione (12.6 g) were placed into absolute ethanol (200 ml) and the reaction mixture was heated to reflux for 16 hours and then cooled to give hydrobromide salt of the desired compound (16.3 g). The hydrobromide salt was neutralized with 10% sodium carbonate solution in an aqueous system to give the titled compound (12.3 g, 76%).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:27][C@@H:28]([C@@H:30]4[CH2:34][C:33](=[O:35])[NH:32][CH2:31]4)[CH3:29])=[N:10][C:11]([C:13]4[CH:21]=[C:20]5[C:16]([C:17]6(OCC[O:23]6)[C:18](=[O:22])[NH:19]5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Cl>CO>[CH:1]1([N:4]2[C:8]3[C:9]([O:27][C@@H:28]([C@@H:30]4[CH2:34][C:33](=[O:35])[NH:32][CH2:31]4)[CH3:29])=[N:10][C:11]([C:13]4[CH:21]=[C:20]5[C:16]([C:17](=[O:23])[C:18](=[O:22])[NH:19]5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C[C@@H](Oc1nc(-c2ccc3c(c2)NC(=O)C32OCCO2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: Cl
Solvent: CO
Product: C[C@@H](Oc1nc(-c2ccc3c(c2)NC(=O)C3=O)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Yield: 27.6 %

Procedure:
Into the solution of 6′-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)spiro[[1,3]dioxolane-2,3′-indolin]-2′-one 3G.26 (20 mg) in MeOH (3 mL) was added aqueous HCl (37%, 1 mL). After reflux for 4 h, the solvent was removed, and extracted with ethyl acetate, washed with saturated sodium bicarbonate and brine. After being dried, the solvent was removed and the residue was dissolved in DCM and the desired product was precipitated out by adding hexane. After filtration and vacuum dry, 6-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)indoline-2,3-dione 3.83 (5 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[CH3:19][C:20]1([CH3:28])[CH2:26][C:25](=[O:27])[O:24][C:22](=[O:23])[CH2:21]1>ClCCl>[CH3:19][C:20]([CH3:28])([CH2:26][C:25](=[O:27])[NH:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1)[CH2:21][C:22]([OH:24])=[O:23]
Reactant: CN(C(=O)Oc1ccc(N)cn1)c1ccccc1
Reactant: CC1(C)CC(=O)OC(=O)C1
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(NC(=O)CC(C)(C)CC(=O)O)cn1)c1ccccc1

Procedure:
A solution of methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (243 mg, 1.00 mmol) and 3,3-dimethylglutaric anhydride (142 mg, 1.00 mmol) in dichloromethane (10 mL) was stirred at room temperature for 48 hours. Evaporation of the solvent yielded the title compound as a thick oil.