Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])C.[N:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1>>[C:36]([CH2:35][CH2:34][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:45]3[CH:46]=[CH:47][N:42]=[CH:43][CH:44]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[O:41])([OH:38])=[O:37]
Reactant: OB(O)c1ccncc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccncc2)c1

Procedure:
The title compound was prepared according to the general procedure described in Steps 3 and 4 of Method F starting from 4-[3-[6-(3-bromo-5-dimethylcarbamoyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester and pyridine-4-boronic acid. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH2:13]([CH2:15][NH2:16])[OH:14].Cl>O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:16][CH2:15][CH2:13][OH:14])=[O:4]
Reactant: NCCO
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cl
Solvent: O
Product: Nc1ccccc1C(=O)NCCO
Yield: 71.4 %

Procedure:
A round-bottomed flask was charged with isatoic anhydride (5.0 g, 0.030 mol) and 40 mL water. Ethanolamine (2.21 mL, 0.036 mol) was added slowly to the reaction mixture. The reaction mixture was acidified with 1N HCl and extracted with EtOAc. The aqueous layer was basified with 6N NaOH and extracted with EtOAc. The EtOac layer was dried over Na2SO4, filtered, and concentrated to dryness to afford 2-amino-N-(2-hydroxyethyl)benzamide (3.86 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:25]([F:28])([F:27])[F:26])[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([CH3:24])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:63][CH2:64][CH2:65][C:66]1[CH:67]=[CH:68][C:69]2[C:73]([CH3:75])([CH3:74])[O:72][B:71]([OH:76])[C:70]=2[CH:77]=1>CN(C=O)C.O>[Cl:9][C:6]1[CH:5]=[C:4]([C:10]2([C:25]([F:28])([F:26])[F:27])[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:63][CH2:64][CH2:65][C:66]4[CH:67]=[CH:68][C:69]5[C:73]([CH3:74])([CH3:75])[O:72][B:71]([OH:76])[C:70]=5[CH:77]=4)=[O:21])=[C:17]([CH3:24])[CH:16]=3)[CH2:11]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: CC1(C)OB(O)c2cc(CCN)ccc21
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCCc1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.9 %

Procedure:
To a solution of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (390 mg, 0.9 mmol) and HATU (513 mg, 1.35 mmol) in DMF (18 mL), DIPEA (350 mg, 2.7 mmol) was added. The reaction mixture was stirred at rt for 10 min and crude 6-(2-aminoethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (1 mmol) was added. The reaction mixture was continued to stir overnight. Water was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the final title compound 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]-oxaborol-6-yl)ethyl)-2-methylbenzamide (280 mg; yield 50.2%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.44 (t, J=6.0 Hz, 1H), 7.83 (d, J=6.5 Hz, 2H), 7.55-7.59 (m, 3H), 7.36-7.37 (m, 3H), 4.36 (d, J=18.5 Hz, 1 H), 4.34 (d, J=18.5 Hz, 1 H), 3.51 (q, J=7.5 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.23 (s, 3 H), 1.45 (s, 6H) ppm;
Reaction SMILES: [Br:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[OH-].[K+]>C(O)C>[Br:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]2[C:4]([CH:3]=1)=[N+:10]([O-:12])[O:11][N:6]=2
Reactant: Nc1cc(Cl)c(Br)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: [O-][n+]1onc2cc(Cl)c(Br)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
4-Bromo-5-chloro-2-nitroaniline (13.3 g, 53 mmol) was dissolved in 250 mL ethanol, treated with potassium hydroxide (10 g, 88%, 160 mmol) and heated at 60° C. for 2 h. The mixture was cooled to 0-5° C. and treated with dropwise with commercial bleach solution (320 g, 5%, 210 mmol). The cooling was removed and the mixture was stirred for 2 h at 20° C. The mixture was diluted with 1.5 liter of water and the precipitated product was collected by filtration and washed well with water. The wet product was taken up in 250 mL ethyl acetate, washed twice with 50 mL water, 50 mL saturated NaCl, dried (Na2SO4) and evaporated. The residue was chromatographed on silica with a 0-40% ethyl acetate-hexane gradient to give the title compound (5.0 g, 38%): mp 123-125° C. 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.68 (s, 1H); EIMS m/z 248.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([N:15]3[C:24]4[N:20]([C:21]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)=[N:22][N:23]=4)[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:31][N:32](C=O)C>[C-]#N.[Zn+2].[C-]#N>[N:28]1[CH:29]=[CH:30][C:25]([C:21]2[N:20]3[C:24]([N:15]([CH:13]([C:10]4[N:11]=[N:12][N:8]([C:4]5[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=5)[C:31]#[N:32])[N:9]=4)[CH3:14])[CH2:16][CH2:17][CH2:18][CH2:19]3)=[N:23][N:22]=2)=[CH:26][CH:27]=1
Reactant: CN(C)C=O
Reactant: CC(c1nnn(-c2cccc(I)c2)n1)N1CCCCn2c(-c3ccncc3)nnc21
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(c1nnn(-c2cccc(C#N)c2)n1)N1CCCCn2c(-c3ccncc3)nnc21

Procedure:
The title compound is prepared from 8-{1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-ethyl}-3-pyridin-4-yl-5,6,7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene (1 mmol), zinc cyanide (1.1 mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL) at 80° C. overnight.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N:15]([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.I(C1C=CC=CC=1C(O)=O)(=O)=O>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([N:15]([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH:18]=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1cccc(CO)c1OCc1ccccc1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C)c1cccc(C=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [2-(benzyloxy)-3-(dimethylamino)phenyl]methanol (3.6 g, 13.99 mmol, 1.00 equiv) and DMSO (50 mL). This was followed by the addition of 2-iodoxybenzoic acid (4.31 g, 15.39 mmol, 1.10 equiv) in several batches. The resulting solution was stirred for 2 h at 25° C. The resulting solution was diluted with 200 mL of ethyl acetate. The resulting mixture was washed with 4×50 mL of water. The solids were filtered out. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 3.4 g (95%) of 2-(benzyloxy)-3-(dimethylamino)benzaldehyde as yellow oil. MS (ESI) m/z 256 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.Cl.[C@H:13]12[CH2:19][C@H:16]([NH:17][CH2:18]1)[CH2:15][N:14]2[C:20]([C@@:22]1([CH2:36][CH:37]([F:39])[F:38])[CH2:26][CH2:25][C@@H:24]([NH:27][C@@H:28]2[C@H:33]([O:34][CH3:35])[CH2:32][O:31][CH2:30][CH2:29]2)[CH2:23]1)=[O:21].C(N(CC)CC)C>CS(C)=O.O1CCOCC1>[F:39][CH:37]([F:38])[CH2:36][C@:22]1([C:20]([N:14]2[CH2:15][C@@H:16]3[CH2:19][C@H:13]2[CH2:18][N:17]3[C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)=[O:21])[CH2:26][CH2:25][C@@H:24]([NH:27][C@@H:28]2[C@H:33]([O:34][CH3:35])[CH2:32][O:31][CH2:30][CH2:29]2)[CH2:23]1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@](CC(F)F)(C(=O)N2C[C@@H]3C[C@H]2CN3)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@](CC(F)F)(C(=O)N2C[C@@H]3C[C@H]2CN3c2nccc(C(F)(F)F)n2)C1
Temperature: 100 °C
Yield: 58 %

Procedure:
Prepared as described in example 24 using 2-chloro-4-(trifluoromethyl)pyrimidine in place of 4-chloro-6-(trifluoromethyl)pyrimidine and modifying step 9 as follows. The HCl salt of 1,5-anhydro-2,3-dideoxy-3-{[(1R,3S)-3-{[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-(2,2-difluoroethyl)cyclopentyl]amino}-4-O-methyl-D-erythro-pentitol (175 mg, 0.41 mmol) was placed in flask with 1,4-dioxane dioxane (3 ml). Triethylamine (0.2 ml, 1.43 mmol) was added as well as 2-chloro-4-(trifluoromethyl)pyrimidine (237 mg, 1.30 mmol). DMSO (0.3 ml) was added for solubility and the reaction was heated to 100° C. for 14.5 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organics were washed with brine, dried over MgSO4, concentrated under reduced pressure and purified with the Biotage (0-100% methanol/ethyl acetate 15 column volumes) to give 1,5-anhydro-2,3-dideoxy-3-{[(1R,3S)-3-(2,2-difluoroethyl)-3-({(1S,4S)-5-[4-(trifluoromethyl)pyrimidin-2-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}carbonyl)cyclopentyl]amino}-4-O-methyl-D-erythro-pentitol as a brown foam (126 mg, 58%). LC/MS (M+H)=534.2504 exp, 534.2452 obs; 1H NMR (400 MHz, CDCl3) δ ppm 8.48-8.45 (1H), 6.79-6.78 (1H), 5.96-5.58 (1H), 5.10-4.71 (2H), 4.07-4.01 (1H), 3.93-3.87 (1H), 3.69-3.55 (4H) 3.39-3.32 (4H), 3.30-3.21 (3H), 2.77-2.66 (1H), 2.52-2.40 (1H), 2.23-1.82 (7H), 1.70-1.39 (5H)
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:11]=[C:10]([C:12]([C:14]2[CH:23]=[C:22]([CH3:24])[C:17]3[NH:18][C:19](=[O:21])[O:20][C:16]=3[CH:15]=2)=[O:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].I[CH3:26]>CN(C=O)C>[CH3:26][N:18]1[C:17]2[C:22]([CH3:24])=[CH:23][C:14]([C:12]([C:10]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:3])[CH:11]=3)=[O:13])=[CH:15][C:16]=2[O:20][C:19]1=[O:21]
Reactant: Cc1cc(C(=O)c2ccc(C#N)c(F)c2)cc2oc(=O)[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2ccc(C#N)c(F)c2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.190 g (4.30 mmol) sodium hydride (55%, suspension in mineral oil) were added to 1.15 g (3.88 mmol) 2-fluoro-4-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-benzonitrile in 5.0 mL DMF at RT. The reaction mixture was stirred for 30 min at RT. Then 0.320 mL (5.00 mmol) iodomethane were added and the mixture was stirred for 1 h at RT. Then another 0.1 mL iodomethane were added and stirring was continued at RT. Ice water was added to the reaction mixture and the precipitate formed was suction filtered. The residue was purified by flash chromatography. The fractions containing the product were combined, evaporated down, triturated with diethyl ether, suction filtered and again washed with diethyl ether. The residue was dried i. vac.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)[CH2:10][OH:11])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)[CH:10]=[O:11])=[CH:4][CH:3]=1
Reactant: OCC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Yield: 55.9 %

Procedure:
Following the general procedure of Example 6, 0.21 g (0.67 mmole) of 3,3-bis(4-fluorophenyl)-2-(1H-tetrazol-1-yl)-2-propenol was treated with 288 mg (1.33 mmoles) of pyridinium chlorochromate in 10 mL of methylene chloride and there was thereby produced 117 mg (56%) of the title compound after crystallization from ethyl acetate-hexanes; m.p. 160.7°-161.4° C.
Reaction SMILES: BrCCBr.I[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[CH2:35]([N:42]1[C:50]2[CH:49]=[CH:48][N:47]=[C:46](Br)[C:45]=2[CH:44]=[CH:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O1CCCC1.CNC>O1CCCC1.[Zn].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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:35]([N:42]1[C:50]2[CH:49]=[CH:48][N:47]=[C:46]([CH:6]3[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]3)[C:45]=2[CH:44]=[CH:43]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Brc1nccc2c1ccn2Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Agent: [Pd]
Agent: CNC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC(C)(C)OC(=O)N1CCC(c2nccc3c2ccn3Cc2ccccc2)CC1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
0.16 ml of 1,2-dibromoethane is added at ambient temperature, under argon, to a suspension of 1.35 g of powdered zinc in 10 ml of tetrahydrofuran. The mixture is heated for 5 minutes at 65° C., then brought to ambient temperature, and 0.23 ml of trimethylsilyl is then added. After stirring the mixture for 30 minutes, a solution of 4.5 g of the compound obtained in Step 2 in 8 ml of tetrahydrofuran is slowly added, and then after 45 minutes a solution, prepared ex situ 10 minutes beforehand, of 0.2 g of Pd2(dba)3 and 0.2 g of P(2-furyl)3 in 5 ml of tetrahydrofuran is added by cannulation under argon and, finally, 5.5 g of 1-benzyl-4-bromo-1H-pyrrolo[3,2-c]pyridine in 30 ml of a 1/1 tetrahydrofuran/dimethylamine mixture are added. The reaction mixture is heated at 65° C. for 16 hours and then, after return to ambient temperature, filtered and concentrated in vacuo. Chromatography on silica gel (cyclohexane/ethyl acetate: 50/50) enables the expected product to be isolated.
Reaction SMILES: [OH-:1].[Na+].OO.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]([NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])([C:18]#[N:19])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].Cl>C1COCC1>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]([C:18](=[O:1])[NH2:19])([NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)c2cccc(Cl)c2F)CC1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cccc(Cl)c2F)(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
1 N NaOH (8.60 ml, 8.60 mmol) and a 30% H2O2 solution (4.30 ml) were added to a solution of 4-(3-chloro-2-fluoro-benzoylamino)-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (1.63 g, 4.28 mmol) in THF (8.60 ml) at room temperature, and the mixture was stirred at room temperature for two hours. The reaction mixture was adjusted to pH 6 by adding 2 N HCl and then extracted with ethyl acetate three times. The organic layers were sequentially washed with H2O (×2) and saturated brine, and then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was triturated with H2O, and the solid was collected by filtration. The resulting solid was washed with Et2O and then dried under reduced pressure to give 4-carbamoyl-4-(3-chloro-2-fluoro-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white powder (1.30 g, 76%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:27])[NH:12][C@H:13]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C@@H:14]([CH3:17])[CH2:15][CH3:16])[N:10]=2)[CH2:3]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[Si:20]([O:19][CH2:18][C@@H:13]([NH:12][C:11]([C:9]1[N:10]=[C:6]([N:4]2[CH2:3][CH:2]([O:1][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:5]2)[S:7][CH:8]=1)=[O:27])[C@@H:14]([CH3:17])[CH2:15][CH3:16])([C:23]([CH3:25])([CH3:24])[CH3:26])([CH3:22])[CH3:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@H](C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.7 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(1S,2S)-1-(t-butyldimethylsilyloxymethyl)-2-methylbutylcarbamoyl]-1,3-thiazol-2-yl}azetidine (1.35 g, 3.26 mmol) (obtained as described in Reference Example 38(4)) in methylene chloride (68 ml) were added methanesulfonyl chloride (758 μl, 9.79 mmol) and triethylamine (1.37 ml, 9.79 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:2) as the eluant to afford 1-{4-[(1S,2S)-1-(t-butyldimethylsilyloxymethyl)-2-methylbutylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (1.55 g, yield 97%) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[N:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=1.[CH2:16]([O:23]/[N:24]=[C:25]1\[CH2:26][CH2:27][C:28]2[C:33]\1=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:16]([O:23]/[N:24]=[C:25]1\[CH2:26][CH2:27][C:28]2[C:33]\1=[CH:32][CH:31]=[C:30]([C:2]1[C:3]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[N:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=1)[CH:29]=2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OCCn1cc(Br)c(-c2ccncc2)n1
Reactant: OB(O)c1ccc2c(c1)CC/C2=N\OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: OCCn1cc(-c2ccc3c(c2)CC/C3=N\OCc2ccccc2)c(-c2ccncc2)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To 2-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)ethanol (100 mg; Example 4, step 3) in 7 mL acetonitrile and 3 mL water, was added 136 mg (E)-1-(benzyloxyimino)-2,3-dihydro-1H-inden-5-ylboronic acid (product of Example 2, Step 4), and 155 mg potassium carbonate. The mixture was purged with nitrogen and about 43 mg tetrakis(triphenyphosphine)palladium(0) catalyst was added. The mixture was heated at 80° C. After 1 hour, the reaction mixture was filtered through celite, the filter cake washed with ethyl acetate, and filtrate evaporated under vacuum. The residue was purified by chromatography, eluting with a mixture of 8:1 ethyl acetate-methanol to afford 110 mg (69% yield) product as a white solid. 1H NMR (CDCl3) was consistent with the desired structure. LC/MS showed one peak with a M+1 molecular ion of m/z 425.2 by positive ESI.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=1>CN(C=O)C>[NH2:21][C:17]1[N:18]=[C:19]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=3)[CH:3]=[N:2]2)[CH:20]=[CH:15][N:16]=1
Reactant: Nc1nccc(Cl)n1
Reactant: N#Cc1ccc2cn[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2cnn(-c3ccnc(N)n3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1H-indazole-6-carbonitrile (200 mg, 1.40 mmol) in DMF (2 mL), was added NaH (60% oil dispersion) (89.4 mg, 2.24 mmol). The reaction mixture was stirred for 10 min at RT before addition of 4-chloropyrimidin-2-amine (362 mg, 2.79 mmol). The reaction mixture was stirred at RT for 1 hr then heated at 50° C. in a sealed tube for 18 hr. LC-MS (Method B) indicated a mixture of desired product and a regiosiomer by-product [21%, Retention time=1.65 min, m/z=237.4 (M+H)+] and [29%, Retention time=1.43 min, m/z=237.4 (M+H)+]. The reaction was quenched by addition of water (1 mL) and EtOAc (3 mL). The precipitated solid was collected by suction filtration: LC-MS (Method B): Retention time=1.65 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[CH3:16][S:17]([NH2:20])(=[O:19])=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2/[CH:14]=[N:20]/[S:17]([CH3:16])(=[O:19])=[O:18])=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1/C=N/S(C)(=O)=O

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (2 g, 7.5 mmol), methane sulfonamide (0.714 g, 7.5 mmol) and p-toluenesulfonic acid (0.010 g, 0.06 mmol) were combined in toluene. The reaction was heated to reflux for 24 hours with Dean-Stark apparatus in place. Upon cooling, the title compound precipitated from solution and was collected by filtration and used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([O:25]CC)=O)[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][NH:33][CH3:34]>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:33]([CH2:32][CH2:31][N:30]([CH3:35])[CH3:29])[CH3:34])=[O:25])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: CNCCN(C)C
Solvent: CCO
Product: CN(C)CCN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 85 °C
Yield: 154.1 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl)-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (560 mg, 1.42 mmol) in ethanol (2 ml) was treated with N,N,N′-trimethylethylenediamine (900 l, 0.91 mmol) and the resulting mixture was heated at 85° C. in a sealed tube for 4.5 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a system of 95:5:0.5 (dichloromethane:methanol:ammonia) to afford the title compound as a colourless oil (632 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:11])[C:8]=1[O:9][CH3:10])[NH2:5].CCN(C1C=CC=CC=1)CC.Cl[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:24](=[O:25])[O:26][CH:27]([CH3:29])[CH3:28])[CH:6]=[C:7]([Cl:11])[C:8]=1[O:9][CH3:10]
Reactant: COc1c(Cl)cc(N)cc1Cl
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: COc1c(Cl)cc(NC(=O)OC(C)C)cc1Cl
Temperature: 0 °C
Reaction time: 12 h
Yield: 92.1 %

Procedure:
3,5-Dichloro-4-methoxyaniline (1.8 g) and diethylaniline (1.5 g) were dissolved in benzene (20 ml). To the resultant solution was dropwise added isopropyl chloroformate (1.2 g) in 5 minutes under ice-cooling. After being allowed to stand at room temperature for 12 hours, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of benzene and tetrahydrofuran as the eluent to give isopropyl N-(3,5-dichloro-4-methoxyphenyl)carbamate (Compound No. 2) (2.4 g) in a yield of 91.8%. M.P., 107.5°-108° C.