Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[CH:4][C:3]=1[CH3:12].[O:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[C:18](O)=[O:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[O:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[C:18]([O:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[C:3]([CH3:12])[CH:4]=1)=[O:19]
Reactant: O=C(O)[C@H]1CCCO1
Reactant: Cc1cc(O)cc([N+](=O)[O-])c1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(OC(=O)C2CCCO2)cc([N+](=O)[O-])c1N

Procedure:
0.84 g (5.00 mmol) 4-amino-3-methyl-5-nitro-phenol, 0.58 g (5.00 mmol) (R)-tetrahydro-furan-2-carboxylic acid, 1.77 g (5.50 mmol) TBTU and 1.92 mL (11.00 mmol) DIPEA in 10.0 mL DMF were stirred overnight at RT. The reaction mixture was poured onto ice water and extracted with ethyl acetate. The organic phase was separated off, dried and evaporated down i.vac. The residue was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with an aqueous 1M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:12]([CH3:21])[C:11]([CH:22]2[O:27][CH2:26][CH2:25][NH:24][CH2:23]2)=[N:10]1.C(N(CC)CC)C.[CH:35]([S:38](Cl)(=[O:40])=[O:39])([CH3:37])[CH3:36]>ClCCl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]2[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[Cl:2])[N:10]=[C:11]([CH:22]3[O:27][CH2:26][CH2:25][N:24]([S:38]([CH:35]([CH3:37])[CH3:36])(=[O:40])=[O:39])[CH2:23]3)[C:12]=2[CH3:21])=[CH:19][CH:18]=1
Reactant: Cc1c(C2CNCCO2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C2CN(S(=O)(=O)C(C)C)CCO2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
To a stirred suspension of 2-[1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazol-3-yl]-morpholine hydrochloride 5A-2 (75 mg, 0.18 mmol) and triethylamine (49 μL, 0.36 mmol) in dichloromethane (0.5 ml) was added isopropylsulfonyl chloride (0.22 μL 0.2 mmol) dropwise. After stirring for 18 h, the reaction was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica, 40–50% ethyl acetate/hexanes) to give the title compound 6A-1 as a colorless foam (49 mg).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O.[OH-].[Na+]>O>[C:1]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([Cl:18])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(c1ccccc1)c1cc[n+]([O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(c1ccccc1)c1ccnc(Cl)c1

Procedure:
A mixture of 2.5 g 4-benzoylpyridine N-oxide m.p. 127°-30° C. (obtained according to T. KATO et. al., Yakugaku Zasshi 86, 1022-26, 1966), and 6 ml phosphorus oxychloride is refluxed for 2 hrs. After cooling, the reaction mixture is very slowly added to ice:water, basified (10N NaOH) and extracted with methylene chloride. The organic layer is washed with water, dried and solvent removed in a rotary evaporator. Yield: 2.4 g of title product, identical with that described in Ex. 4.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:12]=1>CC(C)=O>[C:17]([C:13]1[CH:12]=[C:11]([NH:10][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH:16]=[CH:15][N:14]=1)([O:19][CH3:20])=[O:18]
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)c1cc(N)ccn1
Solvent: CC(C)=O
Product: COC(=O)c1cc(NC(=O)Nc2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
146 mg of phenyl isocyanate was added to a solution of 186 mg (1.2 mmol) of methyl 4-aminopicolate in 4 ml of dry acetone. The resulting mixture was agitated at room temperature overnight. Solvent was then evaporated off and the residue chromatographed in a conventional manner using silica gel (solvent:CHCl3 :acetone=4:1 volume). Fractions were collected and solvent removed by distillation. The residue was recrystallized from methanol to give the desired product having a melting point of 206°-208° C. (decompd.) in an amount of 261 mg (yiled 78.6%).
Reaction SMILES: C([C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([O:17][CH3:18])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])(O)=O.S(Cl)(Cl)=O.C[N:24](C)C=O>C1(C)C=CC=CC=1>[NH2:24][C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([O:17][CH3:18])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(OC)c([N+](=O)[O-])c1C(=O)O
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OC)c([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 2-carboxy-4-methoxy-3-nitrobenzoate (3.43 g, Reference Example 10) was dissolved in toluene (20 ml) was treated with thionyl chloride (1.5 ml) then with dimethylformamide (0.015 ml). The resulting solution was stirred at reflux for 1 hour then cooled to room temperature and then evaporated. The residue was dissolved in acetone (20 ml) and added to a solution of sodium azide (1.3 g) in water (20 ml) cooled in an ice bath. The mixture was stirred for 1 hour then diluted with water. The resulting precipitate was collected by filtration. This solid was dissolved in a mixture of t-butanol and water (20 ml, 9:1) and gradually warmed to reflux and held at this temperature for 1 hour. The solution was cooled to room temperature and then evaporated. The residue was subjected to flash chromatography on silica to give the title compound (1.8 g). M+H 227. NMR ((CD3)2SO): δ 3.82 (s, 3H), 3.90(s, 3H), 6.53(d, J=8 Hz, 1H), 7.1(bs, 2H), 7.96(d, J=8 Hz, 1H).
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=O)=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][NH2:28])[CH3:24].[ClH:31]>ClCCl.C(O)C>[ClH:31].[ClH:31].[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][NH:28][C:17](=[O:19])[C:16]1[CH:21]=[CH:22][C:13]([C:3]2[C:4]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[NH:1][N:2]=2)=[CH:14][CH:15]=1)[CH3:24]
Reactant: CCN(CC)CCN
Reactant: COC(=O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCN(CC)CCNC(=O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reaction time: 16 h

Procedure:
A mixture of methyl 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl]benzoate (2.2 g, Example 7) and N,N-diethylethylenediamine (7 ml) was boiled under reflux for 5 hours. The mixture was cooled and stood for 16 hours at ambient temperature. Petroleum ether, b.p. 60-80° C. (50 ml) was added and then decanted off to leave a gum which was further treated with petroleum ether as above and the residual gum dissolved in dichloromethane and purified by flash column chromatography on silica using dichloromethane/IMS/triethylamine (25:2:1) as the mobile phase to give a solid which was dissolved in ethanol (70 ml) and then dry hydrogen chloride gas was passed through the solution. The precipated solid was collected by filtration, washed with ethanol and dried to give N-(2-diethylaminoethyl)-4-(1,4-dihydroindeno[1,2-c]-pyrazol-3-yl)- benzamide dihydrochloride, m.p.230° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])=[C:8]([CH:19]=1)[O:9][CH2:10][CH:11]([OH:18])[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)([O-:3])=[O:2].[C:27](Cl)(=[O:29])[CH3:28]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:20]([F:26])([F:25])[C:21]([F:22])([F:23])[F:24])=[C:8]([CH:19]=1)[O:9][CH2:10][CH:11]([O:18][C:27](=[O:29])[CH3:28])[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)([O-:3])=[O:2]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OCC(O)CN2CCCC2)c1
Solvent: ClCCl
Product: CC(=O)OC(COc1cc([N+](=O)[O-])ccc1C(F)(F)C(F)(F)F)CN1CCCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Dissolved 1-(5-nitro-2-pentafluoroethyl-phenoxy)-3-pyrrolidin-1-yl-propan-2-ol (3.5 g) in CH2Cl2 (15 ml) added TEA (2.55 ml) and cooled to 0° C. Acetyl chloride (781.3 μl) was added dropwise, forming a suspension. The mixture was warmed to RT and stirred for 1.5 h. Additional acetyl chloride (200 μl) was added and the mix was stirred for another h. The mixture was diluted with CH2Cl2 and washed with sat. NaHCO3. The organic layer was removed, washed with brine and back extracted with CH2Cl2. Dried the combined organic layers over Na2SO4, filtered and concentrated in vacuo. The residue was purified over silica gel column (5:94.5:0.5 MeOH:CH2Cl2:NH4OH) to provide acetic acid 2-(5-nitro-2-pentafluoroethyl-phenoxy)-1-pyrrolidin-1-ylmethyl-ethyl ester as a yellow brown oil.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[CH:22][CH:21]=[C:20]([F:31])[C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][NH:17][C:14]2=[N:15][CH:16]=1)=[O:9].[C:32](Cl)(=[O:34])[CH3:33].C[N+]([O-])=O>C(Cl)Cl>[C:32]([C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([NH:10][C:8](=[O:9])[C:7]3[C:20]([F:31])=[CH:21][CH:22]=[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])[C:6]=3[F:5])[CH:12]=2)[NH:17][CH:18]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(C)=O)c3c2)c1F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 64 %

Procedure:
A slurry of aluminum trichloride (0.270 g, 2.03 mmol) was added to a slurry of 2,6-difluoro-3-(propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.100 g, 0.254 mmol) in DCM (0.7 mL) at 0° C., and the reaction mixture was allowed to stir at 0° C. for 40 minutes. Acetyl chloride (0.0271 mL, 0.380 mmol) was added, and the mixture was allowed warm to room temperature overnight. CH3NO2 (200 μL) was added, and the reaction mixture was sonicated for 2 minutes, and allowed to stir at room temperature overnight. The reaction mixture was quenched with ice and then partitioned between aqueous sodium bicarbonate and EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified via column chromatography (5% MeOH/EtOAc) to yield N-(3-acetyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (71 mg, 64%) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.98-8.99 (m, 1H), 8.63-8.64 (m, 1H), 8.04 (s, 1H), 7.49-7.54 (m, 1H), 7.15-7.18 (m, 1H), 3.10-3.30 (m, 2H), 2.55 (s, 3H), 1.93-2.00 (m, 2H), 1.09-1.13 (m, 3H); m/z (APCI-pos) M+1=437.1.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH:35]([C:37]1([C:43]([OH:45])=[O:44])[CH2:42][O:41][CH2:40][O:39][CH2:38]1)=[CH2:36].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1.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]>[OH:32][C@@H:28]([CH:29]([CH3:31])[CH3:30])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2](/[CH:36]=[CH:35]/[C:37]4([C:43]([OH:45])=[O:44])[CH2:42][O:41][CH2:40][O:39][CH2:38]4)=[CH:3][CH:4]=3)[N:9]=2)[CH3:13])=[O:16])[NH:18]1)=[O:34])=[O:33]
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Reactant: C=CC1(C(=O)O)COCOC1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/C4(C(=O)O)COCOC4)cc3n2)N1
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (398.4 mg, 0.745 mmol), 5-vinyl-[1,3]dioxane-5-carboxylic acid (117.9 mg, 0.745 mmol), tri(o-tolyl)phosphine (45.3 mg, 0.149 mmol) and triethylamine (0.32 mL, 2.235 mmol) in 1,4-dioxane (15 mL) was degassed by bubbling nitrogen through for 5 minutes then warmed to 50° C. and treated with tris(dibenzylideneacetone)dipalladium(0) (68.2 mg, 0.074 mmol). After stirring at 100° C. for 40 minutes the reaction was cooled to room temperature, filtered through a pad of Celite, which was rinsed with ethyl acetate. The volatiles were removed in vacuo to provide crude title compound as an orange foam that was used without further purification. LCMS (m/z) 612.2 [M+H], Tr=1.70 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:16][CH2:15][N:14](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:13][CH2:12][N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9][N:8](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:7][CH2:6][N:5](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][CH2:3]1.OS(O)(=O)=O.C(O)C>C(OCC)C>[CH3:1][N:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(C)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCO
Product: CN1CCNCCNCCNCCNCC1
Temperature: 100 °C
Reaction time: 72 h
Yield: 51 %

Procedure:
A mixture of 1-methyl-4,7,10,13-tetra(p-toluenesulfonyl)-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 15C (3.6 g, 4.3 mmol) and concentrated H2SO4 (15 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 72 h. To the resulting brown solution, ethanol (30 mL) was added dropwise with stirring at 5° C. followed by ethyl ether (80 ml). The tan solid was filtered and dissolved in H2O (10 ml). The pH of the solution was adjusted to 10 with 10N NaOH and the solution was extracted with 6×CHCl3. The extracts were combined, dried (Na2SO4) and the solvent removed in vacuo. The crude solid was purified by crystallization from cold (-20° C.) CH3CN to give 0.50 g (51% yield) of the product as colorless needles: mp 71.0°-2.5° C.; 1H NMR (CDCl3) δ 1.90 (br s, 4H), 2.22 (s, 3 H), 2.52 (m, 4H), 2.68 (m, 12H), 2.78 (m, 4H); Anal. calcd. for C11H27N5 : C, 57.60; H, 11.86; N, 30.53. Found: C, 57.17; H, 12.13; N, 30.12.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12]C=O)([CH3:11])[CH3:10])=[C:4]([CH3:15])[CH:3]=1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:12])([CH3:10])[CH3:11])=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1cc(F)ccc1CC(C)(C)NC=O
Agent: Cl
Product: Cc1cc(F)ccc1CC(C)(C)N

Procedure:
In order to prepare the amine, 27.0 g (130 mmol) of N-[2-(4-fluoro-2-methylphenyl)-1,1-dimethylethyl]formamide is reacted as described in the method for Example 10(c). White solid. Yield: 15.5 g (55%, hydrochloride); melting point: 277° C.-280° C.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5](O)=[O:6].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]3[N:42]=[C:41]([C:43]4[C:51]5[C:46](=[CH:47][CH:48]=[C:49]([NH2:52])[CH:50]=5)[N:45]([CH:53]5[CH2:58][CH2:57][CH2:56][CH2:55][O:54]5)[N:44]=4)[NH:40][C:39]=3[CH:59]=2)[CH2:30][CH2:29]1>CN(C=O)C>[F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5]([NH:52][C:49]1[CH:50]=[C:51]2[C:46](=[CH:47][CH:48]=1)[N:45]([CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][O:54]1)[N:44]=[C:43]2[C:41]1[NH:42][C:38]2[CH:37]=[CH:36][C:35]([CH2:34][N:31]3[CH2:32][CH2:33][O:28][CH2:29][CH2:30]3)=[CH:59][C:39]=2[N:40]=1)=[O:6]
Reactant: O=C(O)C1CC1(F)F
Reactant: Nc1ccc2c(c1)c(-c1nc3ccc(CN4CCOCC4)cc3[nH]1)nn2C1CCCCO1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2c(c1)c(-c1nc3cc(CN4CCOCC4)ccc3[nH]1)nn2C1CCCCO1)C1CC1(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
2,2-Difluorocyclopropane carboxylic acid (3 mg, 0.024 mmol), HOBt (5 mg, 0.037 mmol), EDC (6.6 mg, 0.035 mmol) and sodium bicarbonate (2 mg, 0.024 mmol) were added to a solution of 3-(6-(morpholinomethyl)-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (10 mg, 0.023 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) yielded the title compound (10 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.62 (s, 1H), 7.75-7.66 (m, 4H), 7.34 (d, 1H, J=8.0 Hz), 5.94 (dd, 1H, J=2.8 and 9.6 Hz), 4.01 (m, 3H), 3.85 (m, 1H), 3.77 (m, 4H), 2.81 (m, 4H), 2.68 (m, 1H), 2.18-2.10 (m, 3H), 1.91-1.83 (m, 3H), 1.71 (m, 2H); ESI-MS [M+H]+: 537.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([S:11](=[O:27])(=[O:26])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[NH2:29][CH2:30][C@@H:31]([C:33]1[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=1)[OH:32]>>[CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][CH:22]([NH:29][CH2:30][C@H:31]([OH:32])[C:33]4[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=4)[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)(=[O:26])=[O:27])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CCOC(=O)c1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from 4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-benzoic acid ethyl ester (which was obtained in Example 235) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 278 as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.32 (t, J=7.1 Hz, 3 H), 1.75–1.90 (m, 2 H), 2.50–2.70 (m, 5 H), 2.91 (s, 3 H), 3.40–3.55 (m, 2 H), 4.32 (q, J=7.1 Hz, 2 H), 4.47 (dd, J=8.1, 4.2 Hz, 1 H), 6.70–6.90 (m, 5 H), 6.99 (dd, J=8.3, 2.0 Hz, 1 H), 7.17 (d, J=2.0 Hz, 1 H), 7.79 (d, J=8.5 Hz, 2 H), 8.07 (d, J=8.5 Hz, 2 H); MS (ES) m/z: 633.3 (MH+); HRMS Calcd. for C29H37N4O8S2 (MH+): 633.2047. Found: 633.2013.
Reaction SMILES: C[O:2][C:3](=[O:29])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C:10]1[C:11]2[C:16]([C:17]3[CH:18]=[C:19]4[O:26][CH2:25][O:24][C:20]4=[CH:21][C:22]=3[CH:23]=1)=[CH:15][C:14]([O:27][CH3:28])=[CH:13][CH:12]=2.N>>[CH2:25]1[O:26][C:19]2[C:20](=[CH:21][C:22]3[CH:23]=[C:10]([CH2:9][N:5]4[CH2:6][CH2:7][CH2:8][C@H:4]4[C:3]([OH:29])=[O:2])[C:11]4[C:16]([C:17]=3[CH:18]=2)=[CH:15][C:14]([O:27][CH3:28])=[CH:13][CH:12]=4)[O:24]1
Reactant: COC(=O)[C@@H]1CCCN1Cc1cc2cc3c(cc2c2cc(OC)ccc12)OCO3
Agent: N
Product: COc1ccc2c(CN3CCC[C@H]3C(=O)O)cc3cc4c(cc3c2c1)OCO4

Procedure:
General procedure e from 30 (100%); white powder; mp 145-146° C.; 1H NMR (400.13 MHz) δ 8.21 (d, J=4 Hz, 1H), 7.77 (s, 1H), 7.72 (d, J=2 Hz, 1H), 7.56 (s, 1H), 7.23 (dd, J=4 Hz, 2 Hz, 1H), 7.10 (s, 1H), 6.04 (s, 2H), 4.05 (s, 2H), 3.96 (s, 3H), 3.16 (m, 1H), 2.36 (m, 2H), 2.14 (m, 2H), 1.81 (m, 2H); MS (DCI/NH3) m/e: 380 (M+H)+. Anal. (C22H21O5N) C, H, N.
Reaction SMILES: [C:1]([N:11]([C:45]([C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])=[N:46]SC)[CH2:12][CH2:13][CH2:14][C@H:15]([C:32]([NH:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[CH3:36])=[O:33])[NH:16][C:17](=[O:31])[CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:59]([NH2:61])[CH3:60]>CN(C=O)C>[C:1]([N:11]([C:45]([C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])=[N:46][NH:61][CH2:59][CH3:60])[CH2:12][CH2:13][CH2:14][C@H:15]([C:32]([NH:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[CH3:36])=[O:33])[NH:16][C:17](=[O:31])[CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: COc1ccc([C@@H](C)NC(=O)[C@@H](CCCN(C(=O)OCc2ccccc2)C(=NSC)C(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Reactant: CCN
Solvent: CN(C)C=O
Product: CCNN=C(C(=O)OCc1ccccc1)N(CCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@H](C)c1ccc(OC)cc1)C(=O)OCc1ccccc1
Yield: 65.6 %

Procedure:
A solution of (R)-N5 -(Cbz)-N5 -[methylthio(Cbz-iminomethyl)]-N2 -(diphenylacetyl)-(R)-N-[1-(4-methoxyphenyl)ethyl]ornithine amide(0.5g; 0.63 mmol; from step (d) above) and ethylamine (70% wt. in water; 0.08 mL; 0.94 mmol) in DMF (10 mL) was stirred for 1 h at room temperature. The DMF was removed in vacuo and the residue dissolved in EtOAc. The EtOAc solution was washed with KHSO4 solution, then 0.5 N NaOH solution and then brine, dried over Na2SO4 and concentrated in vacuo to afford 0.33 g of the sub-title compound. The material was used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:18]=[C:17]([CH2:19][N:20]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21]2)[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=1)[CH3:2].C(=O)([O-])[O-:32].[K+].[K+].OO>CS(C)=O>[CH2:1]([O:3][C:4]1[CH:18]=[C:17]([CH2:19][N:20]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21]2)[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]([NH2:12])=[O:32])=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOc1cc(CN2CCC(c3ccccc3)C2)ccc1Oc1ccc(C#N)cn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CCOc1cc(CN2CCC(c3ccccc3)C2)ccc1Oc1ccc(C(N)=O)cn1

Procedure:
Using a method similar to Example 371, and using (±)-6-[2-Ethoxy-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinonitrile (step 2 above), potassium carbonate (approx. 0.5 equivalent), and 30% hydrogen peroxide solution (aq) (approx. 3 mole equivalents) in dimethylsulfoxide provides the title compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[O:3].[Br:14]Br>C(Cl)(Cl)Cl>[CH:9]1[C:4]([C:2]([CH2:1][Br:14])=[O:3])=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([OH:10])[CH:8]=1
Reactant: BrBr
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(O)c([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
In 50 ml. of chloroform was dissolved 5.4 g. of 4-hydroxy-3-nitroacetophenone and then 5 ml. of chloroform solution of 4.8 g. of bromine was added dropwise to the solution gradually. Thereafter, the mixture was stirred for 15 minutes and concentrated under a reduced pressure to form yellow crystals. By recrystallizing the product from benzene-n-hexane, 6.3 g. of the crystals of α-bromo-4-hydroxy-3-nitroacetophenone melting at 69°-71° C. were obtained.