Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(O)=O.[Na+].[NH2:6][OH:7].Cl.[Cl:9][C:10]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:11]=1[C:12]([NH:14][C@H:15]([C:33](Cl)=[O:34])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)=[O:13]>C1COCC1.O.C1COCC1>[OH:7][NH:6][C:33](=[O:34])[C@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)[NH:14][C:12](=[O:13])[C:11]1[C:10]([Cl:9])=[CH:39][CH:38]=[CH:37][C:36]=1[Cl:40]
Reactant: COc1cccc(OC)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)Cl)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(OC)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)NO)cc1
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
NaHCO3 (0.21 g) was added to a solution of NH2OH HCl (0.14 g) in THF/water (5 mL each) at 0° C. and the mixture was stirred for ½ h. A solution of N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanyl chloride (0.1 g) in THF (5 mL) was added to the mixture at 0° C. and the mixture was stirred overnight at room temperature. The mixture was partitioned between EtOAc and water. The EtOAc layer was washed successively with 1 N HCl and brine, dried and evaporated. The residue was purified by preparative TLC (silica gel; eluent: CH2Cl2/MeOH 8%) to yield 27 mg of the title compound. ESMS: m/z 489 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9](CC=C)[S:10]([C:13]2[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:14]=2[F:23])(=[O:12])=[O:11])=[CH:5][CH:4]=1.C[N+]1([O-])CC[O:31]CC1.OS([O-])=O.[Na+].[CH3:40][C:41]([CH3:43])=[O:42].O>O=[Os](=O)(=O)=O>[OH:42][CH:41]([CH2:43][OH:31])[CH2:40][N:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:10]([C:13]1[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:14]=1[F:23])(=[O:12])=[O:11]
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCN(c1ccc(OC)cc1)S(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: COc1ccc(N(CC(O)CO)S(=O)(=O)c2c(F)c(F)c(F)c(F)c2F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
To a solution of 4-methoxy-1-(N-(2-propenyl)pentafluorophenylsulfonamido)benzene (101 mg, 0.26 mmol) in acetone:water (8:1, 1 mL) at rt was added N-methylmorpholine N-oxide (34.0 mg, 0.29 mmol) and OsO4 (0.10 mL of 0.16M solution in H2O, 1.60×10-2 mmol). After stirring at rt for 18 h, the reaction mixture was treated with saturated NaHSO3 (5 mL) and allowed to stir at rt. After 1 h, the reaction mixture was poured onto saturated NaHSO3 (5 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (MgSO4) and concentrated. Flash chromatography (1:1, 1:2/hexanes:EtOAc) afforded 90 mg (83%) of product as a white solid, mp 130-131° C. 1H NMR (CDCl3): d, 7.11(m, 2H), 6.85 (m, 2H), 3.78(s, 3H), 3.90-3.65(m, 5H). Anal. Calcd. for C16H13F5NO5S: C, 45.08; H, 3.07; N, 3.29; S, 7.52. Found: C, 45.09; H, 3.33; N, 3.27; S, 7.46.
Reaction SMILES: Cl.[F:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH2:21][CH:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[O:19][N:18]=3)[N:14]=[C:13]([CH3:28])[N:12]=2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32].[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>C(Cl)Cl.O>[CH2:33]([NH:35][C:36]([N:25]1[CH2:24][CH2:23][CH:22]([CH:20]2[O:19][N:18]=[C:17]([C:15]3[N:14]=[C:13]([CH3:28])[N:12]=[C:11]([C:9]([NH:8][CH2:7][C:6]4[CH:29]=[CH:30][C:3]([F:2])=[C:4]([O:31][CH3:32])[CH:5]=4)=[O:10])[CH:16]=3)[CH2:21]2)[CH2:27][CH2:26]1)=[O:37])[CH3:34]
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCNCC4)C3)nc(C)n2)ccc1F
Reactant: CCN=C=O
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)N1CCC(C2CC(c3cc(C(=O)NCc4ccc(F)c(OC)c4)nc(C)n3)=NO2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold solution of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide hydrochloride (0.10 g, 0.21 mmol, Preparation #K.1) and TEA (0.065 g, 0.64 mmol, Sd Fine Chem) in DCM (10 mL) was added ethyl isocyanate (0.018 g, 0.25 mmol, Lancaster). The reaction mixture was slowly warmed to RT and stirred for about 2 h. The reaction mixture was diluted with water (20 mL) and the product extracted with DCM (2×20 mL). The combined organic layers were washed with water (1×25 mL) followed by brine (1×50 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude material obtained was purified using silica gel column chromatography eluted in 1% methanol in DCM. Relevant fractions containing the required compound were combined and evaporated to dryness under reduced pressure to afford 6-(5-(1-(ethylcarbamoyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide as an off white solid 60 mg (56%): LC/MS (Table 1, Method c) Rt=1.83 min; MS m/z: 499.2 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=[CH:17][CH:18]=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[C:21]([CH2:24][N+]1C=CC=CC=1)(=O)[NH2:22].CNC>CO>[O:19]=[C:18]1[CH:17]=[C:16]([C:15]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][N:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=23)[CH:24]=[CH:21][NH:22]1
Reactant: O=CC=Cc1c(-c2ccccc2)nn2ccccc12
Reactant: NC(=O)C[n+]1ccccc1
Agent: CNC
Agent: [Cl-]
Solvent: CO
Product: O=c1cc(-c2c(-c3ccccc3)nn3ccccc23)cc[nH]1
Temperature: 200 °C
Yield: 24.8 %

Procedure:
A mixture of 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylaldehyde (cis and trans mixture) (1.15 g) and 1-carbamoylmethylpyridinium chloride (0.80 g), 50% aqueous dimethylamine (0.44 g) and methanol (10 ml) was refluxed for 3 hours. The reaction mixture was evaporated in vacuo and the residue was heated for 10 minutes at 200° C. The resulting mixture was chromatographed on silica gel (80 g) with a mixture of chloroform and methanol (100:1). The fractions containing ton silica gel (80 g) with a mixture of chloroform and methanol (100:1). The fractions containing the object compound were combined and evaporated in vacuo and recrystallized from ethanol to give 3-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.33 g).
Reaction SMILES: CC(C)([O-])C.[Na+].[CH:7]([NH:10][C:11]1[C:12]([NH2:18])=[CH:13][CH:14]=[C:15]([CH3:17])[CH:16]=1)([CH3:9])[CH3:8].Cl[C:20]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:28][CH2:27]2)[N:23]=[C:22]([N:38]([CH3:40])[CH3:39])[CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[CH:7]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[NH:18][C:20]1[CH:21]=[C:22]([N:38]([CH3:40])[CH3:39])[N:23]=[C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:28][CH2:27]2)[N:25]=1)([CH3:9])[CH3:8]
Reactant: Cc1ccc(N)c(NC(C)C)c1
Reactant: CN(C)c1cc(Cl)nc(N2CCN(c3ccccn3)CC2)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: Cc1ccc(Nc2cc(N(C)C)nc(N3CCN(c4ccccn4)CC3)n2)c(NC(C)C)c1
Temperature: 110 °C
Yield: 22.4 %

Procedure:
Sodium tert-butoxide (100 mg, 1.04 mmol) was added to a solution of N2-isopropyl-4-methyl-1,2-benzenediamine (100 mg 0.60 mmol) and N-{6-chloro-2-[4-(2-pyridinyl)-1-piperazinyl]-4-pyrimidinyl}-N,N-dimethylamine (100 mg, 0.30 mmol) in 1,4-dioxane (10 mL). Tris(dibenzylidineacetone)dipalladium (8 mg, 0.008 mmol) and 2,2′-Bis(diphenylphosphino)-1,1′binapthyl (10 mg, 0.016 mmol) were added to this mixture and heated at 110° C. for 10 hours. The resulting mixture was cooled to room temperature, concentrated in vacuo, and purified by preparative thin-layer chromatography [eluent: hexane/EtOAc (1:1)], giving the desired product (30 mg, 23%).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[C:11]([Cl:17])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.CS([Cl:29])(=O)=O>ClCCl.C(OCC)(=O)C>[C:4]([Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][Cl:29])=[C:11]([Cl:17])[CH:10]=1)([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CO)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCl)c(Cl)c1
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl[3-chloro-4-(chloromethyl)phenoxy]dimethylsilane (step 1, 500 mg, 1.83 mmol) in dichloromethane (5 mL) were added triethylamine (0.139 mL, 2.75 mmol) and methane sulfonylchloride (231 mg, 2.02 mmol) at room temperature. The mixture was stirred for 2 h at the same temperature. The mixture was diluted with ethyl acetate (100 mL), and the mixture was washed with water and brine, dried over sodium sulfate and evapolated. The residue was purified by silica gel (40 g) eluting with hexane/ethyl acetate (10/1) to afford 580 mg (quant.) of the title compound as a colorless oil:
Reaction SMILES: C([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Br)C.[CH2:10]([O:17][C:18]([N:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]1[C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[OH:37])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[CH2:10]([O:17][C:18]([N:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]1[C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[O:37][CH2:7][CH2:6][CH2:5][C:4]([OH:9])=[O:3])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CCCBr
Reactant: O=C(OCc1ccccc1)N1CCc2ccccc2C1c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)CCCOc1ccc(F)cc1C1c2ccccc2CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl-4-bromobutyrate (45 μL, 0.30 mmol, 1.50 eq.) was added to a solution of (±)-1-(5-fluoro-2-hydroxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (75 mg, 0.20 mmol, 1.00 eq.) and K2CO3 (83 mg, 0.60 mmol) in DMF (0.7 mL). The mixture was stirred at r.t. for 2 hours. Ethyl-4-bromobutyrate (22 μL, 0.15 mmol, 0.75 eq.) was added again and the mixture was stirred at r.t. for 18 hours. The reaction mixture was diluted with AcOEt and water. The layers were separated and the aq. phase was extracted with AcOEt (2×). The combined org. phases were washed with water and sat. aq. NaCl soln., dried over MgSO4, filtered and concentrated in vacuo. To a solution of the crude ester in THF (0.9 mL), 1M aq. NaOH soln. (0.50 mL) was added. The resulting solution was stirred at r.t. during 62 hours. The org. solvent was removed in vacuo. The residue was diluted with water and 1M aq. HCl soln. (0.8 mL) followed by DCM. The mixture was shaked then the layers were separated and the aq. phase was extracted with DCM (2×). The comb. org. phases were dried over MgSO4, filtered and concentrated in vacuo. The crude mixture, redissolved in DMF (1.2 mL), was purified by prep. HPLC (column: Atlantis, 19×50 mm, 5 um, UV/MS, acidic conditions) and evaporated (genevac) to give the desired acid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:7]1)=[O:5])C.O[Li:23].O>C1COCC1.CO.O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:8]1[CH2:9][CH2:10][CH2:11][CH:6]([C:4]([O-:5])=[O:3])[CH2:7]1)(=[O:13])=[O:14].[Li+:23]
Reactant: CCOC(=O)C1CCCN(S(=O)(=O)c2ccccc2Cl)C1
Reactant: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C([O-])C1CCCN(S(=O)(=O)c2ccccc2Cl)C1
Product: [Li+]
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a solution of 5.7 g 1-(2-chloro-benzenesulfonyl)-piperidine-3-carboxylic acid ethyl ester (17 mmol) in 30 mL THF: methanol:water (2:1:1) was added 1.08 g LiOH H2O (25.7 mmol). The mixture was stirred at room temperature for 5-6 h and all volatiles were evaporated to dryness. The compound was used in the consecutive step without further purification.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][N:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[C:10]1=[O:30].Cl[C:32](OC1C=CC([N+]([O-])=O)=CC=1)=[O:33].Cl.Cl.[O:46]=[C:47]1[NH:55][C:50]2=[N:51][CH:52]=[CH:53][CH:54]=[C:49]2[N:48]1[CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>O1CCCC1>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH2:12][N:11]([C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[C:10](=[O:30])[C@H:9]([NH:8][C:32]([N:59]2[CH2:60][CH2:61][CH:56]([N:48]3[C:49]4[C:50](=[N:51][CH:52]=[CH:53][CH:54]=4)[NH:55][C:47]3=[O:46])[CH2:57][CH2:58]2)=[O:33])[CH2:15][CH2:14]1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(c2ccncc2)C1=O
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(c2ccncc2)C1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
Triethylamine (0.018 mL, 0.132 mmol) was added to a solution of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-pyridin-4-ylazepan-2-one (42 mg, 0.132 mmol) and 4-nitrophenyl chloroformate (27 mg, 0.132 mmol) in tetrahydrofuran (2 mL) at 0° C. After 1 h, 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (38 mg, 0.132 mmol) and triethylamine (0.054 mL, 0.396 mmol) were added and the mixture allowed to warm to ambient temperature. After 18 h, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (2×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/methanol (10% ammonium hydroxide/methanol)] gave the title compound (53 mg). The title compound was converted to the HCl salt with 2M HCl in ether. MS 562.2 (M+1). 1H NMR (500 MHz, CD3OD) δ 8.76 (d, J=7.6 Hz, 2H), 8.11 (d, J=7.3 Hz, 2H), 8.00 (d, J=6.4 Hz, 2H), 7.30 (t, J=7.0 Hz, 1H), 7.27-7.21 (m, 3H), 5.11 (d, J=11.5 Hz, 1H), 4.72-4.65 (m, 1H), 4.60-4.55 (m, 1H), 4.35-4.33 (m, 2H), 4.14 (d, J=16.1 Hz, 1H), 3.42-3.39 (m, 1H), 3.09-3.02 (m, 2H), 2.47-2.44 (m, 1H), 2.37-2.30 (m, 2H), 2.24-2.18 (m, 2H), 2.06-2.03 (m, 1H), 1.91 (br. s, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([S:8](=[O:19])(=[O:18])[N:9]([CH3:17])[CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:6][N:7]=1.C1(C)C=CC=CC=1.[CH3:27][N:28]=[C:29]=[O:30]>C(OCC)(=O)C>[CH3:1][N:2]([C:3]1[S:4][C:5]([S:8](=[O:19])(=[O:18])[N:9]([CH3:17])[CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:6][N:7]=1)[C:29]([NH:28][CH3:27])=[O:30]
Reactant: CNc1nnc(S(=O)(=O)N(C)Cc2cccnc2)s1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CNC(=O)N(C)c1nnc(S(=O)(=O)N(C)Cc2cccnc2)s1

Procedure:
To a solution of 5.7 g. of 2-methylamino-5-[N-methyl-N-(3-pyridylmethyl)sulfamoyl]-1,3,4-thiadiazole (from Preparation 4) in 100 ml. of toluene was added 3 g. of methyl isocyanate. The mixture was heated at reflux for about 5 hours. The mixture was cooled and concentrated in vacuo to yield a semisolid residue. A sample of the semisolid subjected to thin layer chromatography in ethyl acetate showed three spots. The semisolid was chromatographed on a silica gel column using ethyl acetate. The eluate corresponding to the second spot material was collected. The eluate was concentrated to dryness in vacuo, leaving a residue. The residue was recrystallized from ethyl acetate to yield white crystals having a melting point of about 169°-170° C., and weighing about 2.2 g. The product was identified by NMR spectrum and elemental analyses as 1,3-dimethyl-1-[5-[N-methyl-N-(3-pyridylmethylsulfamoyl]-1,3,4-thiadiazol-2-yl]urea.
Reaction SMILES: C(C#N)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11](Cl)(=[O:18])C1C=CC=CC=1.S(=O)(=O)(O)O.[CH3:25][OH:26]>>[C:25]([O:18][CH3:11])(=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1

Procedure:
For example, when pure benzoyl cyanide (i.e., containing essentially no halide ion or halide ion source, such as benzoyl chloride) is reacted with concentrated sulfuric acid and then esterified by further reaction with methanol, the cyano group is cleaved and methyl benzoate is formed as follows: ##STR2##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7](S(C1C=CC=CC=1)(=O)=O)[CH:6]=[C:5]2[CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@@H:25]([CH3:36])[CH2:24]1.[OH-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@@H:25]([CH3:36])[CH2:24]1
Reactant: C[C@H]1CN(Cc2cn(S(=O)(=O)c3ccccc3)c(=O)c3ccc(Br)cc23)CCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1CN(Cc2c[nH]c(=O)c3ccc(Br)cc23)CCN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
A solution of tert-butyl (2S)-4-{[6-bromo-1-oxo-2-(phenylsulfonyl)-1,2-dihydroisoquinolin-4-yl]methyl}-2-methylpiperazine-1-carboxylate (Example 34a, 3.2 g) dissolved in DMF (20 mL) was treated with sodium hydroxide (0.444 g) in water (20 mL) under nitrogen. The resulting mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with water (20 mL), and extracted with ethyl acetate (25 mL). The organics were dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified (SiO2 chromatography, elution 100% diethyl ether). Pure fractions were evaporated to dryness to afford the subtitle compound (0.780 g) as a solid.
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H](C(O)=O)CC1C=C[C:7]([O:10]P(OCC)(OCC)=O)=[CH:6]C=1.[NH2:29][C@H:30]([C:47]([NH:49][C@H:50]([C:54]([NH:56][C@H:57]([C:62]([NH:64][C@H:65]([C:69]([NH2:71])=[O:70])[CH:66]([CH3:68])[CH3:67])=[O:63])[CH2:58][C:59](=[O:61])[NH2:60])=[O:55])[CH:51]([CH3:53])[CH3:52])=[O:48])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][P:39]([O:44][CH2:45][CH3:46])([O:41][CH2:42][CH3:43])=[O:40])=[CH:34][CH:33]=1.CCN(C(C)C)C(C)C.C(OC(=O)C)(=O)C>CN(C=O)C>[NH:29]([C:7]([CH3:6])=[O:10])[C@H:30]([C:47]([NH:49][C@H:50]([C:54]([NH:56][C@H:57]([C:62]([NH:64][C@H:65]([C:69]([NH2:71])=[O:70])[CH:66]([CH3:68])[CH3:67])=[O:63])[CH2:58][C:59](=[O:61])[NH2:60])=[O:55])[CH:51]([CH3:52])[CH3:53])=[O:48])[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][P:39]([O:44][CH2:45][CH3:46])([O:41][CH2:42][CH3:43])=[O:40])=[CH:36][CH:37]=1
Reactant: CCOP(=O)(OCC)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CCOP(=O)(OCC)Oc1ccc(C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(N)=O)C(C)C)C(C)C)cc1
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(OCC)Oc1ccc(C[C@H](NC(C)=O)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(N)=O)C(C)C)C(C)C)cc1

Procedure:
The title compound was obtained by analogous manner as described in Example 18, but using BocTyr(PO3Et2)OH. The N-acetylation was performed by treatment of crude H—Tyr(PO3Et2)—Val—Asn—Val—NH2 with 1.5 equiv. of DIEA and 5 equiv. of acetic anhydride in DMF for 2 h at 25° C. The final compound was obtained with chromatographic purity (HPLC) of 90.0%. Amino acid ratios: Val 2 (2); Asx 1.17 (1); Tyr 0.87 (1). Peptide content: 83%. FAB mass spectroscopy; m/z 671 [M—H]+. (MW 670.1)
Reaction SMILES: [Br:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[CH2:4][CH2:5]Br.[F:11][C:12]([F:24])([F:23])[CH2:13][CH2:14][S:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:17])=[O:16].[H-].[Na+].Cl>CS(C)=O>[Br:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[CH2:4][CH2:5][CH:18]([S:15]([CH2:14][CH2:13][C:12]([F:23])([F:24])[F:11])(=[O:17])=[O:16])[C:19]([O:21][CH3:22])=[O:20]
Reactant: FC(F)(Br)C(F)(F)CCBr
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CCC(F)(F)C(F)(F)Br)S(=O)(=O)CCC(F)(F)F
Reaction time: 72 h
Yield: 27.2 %

Procedure:
To a solution of 1.2 g of 1,4-dibromo-1,1,2,2-tetrafluorobutane and 1.0 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 30 ml of dimethyl sulfoxide was added 0.2 g of sodium hydride (60% in oil) at room temperature. The mixture was stirred at the same temperature for 3 days. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.50 g of methyl 6-bromo-5,5,6,6-tetrafluoro-2-(3,3,3-trifluoropropylsulfonyl)hexanoate (hereinafter referred to as the present compound (4)).
Reaction SMILES: B(O)(O)[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:14][CH:13]=1.CC#N.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:14][CH:13]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(-n2cccn2)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(-n3cccn3)cc2)cc1
Temperature: 130 °C
Yield: 56 %

Procedure:
Prepared using General Procedure 16. A stirring mixture of p-tolylboronic acid (391 mg, 2.88 mmol) and 1-(4-bromophenyl)-1H-pyrazole (535 mg, 2.40 mmol) INT-84 in THF (4 mL), MeCN (4 mL) and sodium carbonate (1 M aqueous) (4.8 mL, 4.80 mmol) was de-gassed by bubbling through N2 gas. PdCl2dppf (88 mg, 0.120 mmol) was added and the reaction mixture further de-gassed. The reaction was heated at 130° C. for 30 min in a microwave. The mixture was cooled to room temperature, poured onto water (100 mL) and extracted with EA/THF (2×50/10 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography (EA/hexanes) to afford 315 mg (56%) of 1-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazole INT-85. LCMS-ESI (m/z) calculated for C16H14N2: 234; found 235 [M+H]+, tR=2.60 min (Method 10).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15](S(C3C=CC(C)=CC=3)(=O)=O)[CH:14]=2)[N:10]=[CH:9][C:8]=1[CH2:32][C:33]([NH2:35])=[O:34].Cl>CO.[OH-].[Na+].O>[F:39][C:37]1[CH:36]=[C:4]([CH:3]=[C:2]([F:1])[CH:38]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[N:10]=[CH:9][C:8]=1[CH2:32][C:33]([NH2:35])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)c3cccnc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)Cc1cnc(-c2c[nH]c3ncccc23)cc1NCc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.4 %

Procedure:
10 mg of 4-[(3,5-difluorobenzyl)amino]-6-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}pyridine-3-carboxyamide (the compound of Example 370) was dissolved in 0.5 mL of methanol, to which 0.5 mL of 6 mol/L sodium hydroxide in water was added, and stirred at room temperature for 4 hours. Under ice cooling, hydrochloric acid was added to acidify (about pH 1) the reaction mixture, and washed with chloroform. The aqueous layer was basified (about pH 8) with saturated sodium bicarbonate in water, extracted with chloroform, the extract was washed with water, and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain 2.9 mg (yield 41%) of the title compound as a white solid.