Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[O:11]1[C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:25][C@@H:24]([CH2:26][OH:27])[O:23][C:22]3=[O:28])=[CH:20][C:15]=2[O:14][CH2:13][CH2:12]1>C(Cl)Cl>[O:11]1[C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:25][C@@H:24]([CH:26]=[O:27])[O:23][C:22]3=[O:28])=[CH:20][C:15]=2[O:14][CH2:13][CH2:12]1
Reactant: O=C1O[C@H](CO)CN1c1ccc2c(c1)OCCO2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C[C@@H]1CN(c2ccc3c(c2)OCCO3)C(=O)O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of oxalyl chloride (0.229 mL, 2.71 mmol) in DCM (5 mL) was cooled to −78° C. and DMSO (0.395 mL, 5.572 mmol) was added dropwise. The mixture was stirred for 10 min at that temperature and a suspension of (S)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-hydroxymethyl-oxazolidin-2-one (400 mg, 1.59 mmol) in DCM (6 mL) was then added dropwise within 1 min. Stirring was continued for 20 min. TEA (0.665 mL, 4.78 mmol) was added and the mixture was stirred for 5 min, and then allowed to warm to 0° C. The mixture was filtered through Celite and concentrated with a bath temperature below 30° C. The residue was partitioned between water and EA and the org. layer was washed with brine, dried over Na2SO4 and concentrated with a bath temperature below 30° C. The highly unstable intermediate was used immediately in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:15][CH2:14][C:13]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.O1CCOCC1.Cl.C(=O)([O-])O.[Na+]>O.C(OCC)(=O)C.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:15][CH2:14][C:13]([C:20]3[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=3)([C:16]([F:17])([F:18])[F:19])[CH2:12]2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: O=[N+]([O-])c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: Nc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Temperature: 25 °C
Yield: 70.7 %

Procedure:
To the solution of 1-(3-bromo-4-nitrophenyl)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (1.10 g) in the mixed solvent of 1,4-dioxane and ethanol was added stannous chloride dihydrate (2.05 g) and a small amount of concentrated hydrochloric acid, and the mixture was then stirred 4 hours at 90° C. The mixture was cooled to room temperature and then poured into the mixed solution of ethyl acetate and water, which was then neutralized with sodium hydrogen carbonate with vigorous stirring. After filtration of precipitate through Celite, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer was combined, which was then washed with brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield 2-bromo-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-pyrrolidin-1-yl]aniline (0.73 g). 1H-NMR (CDCl3) δ: 2.44-2.54 (1H, m), 2.75-2.83 (1H, m), 3.32-3.50 (2H, m), 3.56-3.76 (3H, m), 3.92 (1H, d), 6.46 (1H, dd), 6.70-6.78 (2H, m), 7.29 (2H, br s), 7.37 (1H, t).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]1[C:18]2([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=[O:25])[CH2:17][CH2:16][CH2:15][CH2:14]1.[C:26](=O)([O:29]C)[O:27][CH3:28].CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[O:25]=[C:19]1[CH:20]([C:26]([O:27][CH3:28])=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][C:18]21[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2
Reactant: O=C1CCCCCC12CCCCC2
Reactant: COC(=O)OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C1CCCCC2(CCCCC2)C1=O
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (1.130 mL, 7.93 mmol) in THF (10 mL) was treated with n-butyllithium (3.17 mL, 7.93 mmol) at −78° C., and the reaction was stirred at this temperature for 30 minutes. The above solution was then transferred via cannula into a solution of the product from Example 16A (1.1 g, 6.10 mmol) in THF (10 mL) at −78° C., and the resulting mixture was stirred at this temperature for 30 minutes. Dimethyl carbonate (5.14 mL, 61.0 mmol) was added, the cold bath was removed, and HMPA (1.062 mL, 6.10 mmol) was then added. The resulting mixture was stirred at ambient temperature for 16 hours. It was quenched with HCl (1N) and diluted with ether (200 mL), then the organic layer was separated, washed with H2O and brine, dried with MgSO4, and concentrated under reduced pressure. The residue was chromatographed on silica gel (95:5 hexane-EtOAc, eluant) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 3.88 (dd, J=11.87, 3.05 Hz, 1 H), 3.68 (s, 3 H), 2.06-2.16 (m, 1 H), 1.92-2.04 (m, 2 H), 1.59-1.90 (m, 5 H), 1.29-1.51 (m, 8 H), 0.98-1.16 (m, 2 H). MS (DCI+) m/z 239 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:17]=3[S:16](=[O:27])(=[O:26])[CH2:15][CH2:14]2)[CH:3]=1.[O:28]1[CH2:31][C:30]([CH2:34][NH2:35])([CH2:32][NH2:33])[CH2:29]1>>[NH2:33][CH2:32][C:30]1([CH2:34][NH:35][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:17]=4[S:16](=[O:26])(=[O:27])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:31][O:28][CH2:29]1
Reactant: COc1ccc2c(c1)S(=O)(=O)CCN(c1cc(Cl)c3cc(Cl)ccc3n1)C2
Reactant: NCC1(CN)COC1
Product: COc1ccc2c(c1)S(=O)(=O)CCN(c1cc(NCC3(CN)COC3)c3cc(Cl)ccc3n1)C2

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6-dichloroquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 3-13) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 503, 1H NMR (400 MHz, CD3OD) δ ppm 8.23 (s, 1 H), 7.88 (d, J=8.59 Hz, 1 H), 7.73 (d, J=8.84 Hz, 1 H), 7.65-7.51 (m, 2 H), 7.21 (dd, J=8.34, 2.78 Hz, 1 H), 6.30 (s, 1 H), 5.26 (brs, 2 H), 4.76-4.60 (m, 6 H), 4.56 (brs, 1 H), 3.91 (s, 2 H), 3.85 (s, 3 H), 3.69 (brs, 2 H), 3.52 (s, 2 H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@:10]1([CH2:34][O:35]S(C)(=O)=O)[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:40]([O-])(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[Na+]>CN(C=O)C>[CH2:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@:10]1([CH2:34][O:35][C:40](=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Reactant: CS(=O)(=O)OC[C@]12CO[C@@H]([C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)O1)[C@@H]2OCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@]2(COC(=O)c3ccccc3)CO[C@@H]1[C@@H]2OCc1ccccc1)c1ccccc1
Temperature: 90 °C
Yield: 88 %

Procedure:
(1S,3R,4R,7S)-7-Benzyloxy-1-methanesulfonyloxymethyl-3-(6-N-benzoyl-adenine-9-yl)-2,5-dioxabicyclo-[2.2.1]heptane (5D) (11.5 g.; 20.8 mmol) was dissolved in anh. DMF (450 mL). Sodium benzoate (5.40 g.; 37.4 mmol) was added and the mixture was heated to 90° C. for 7 h. The solution was cooled to rt., filtered, evaporated and coevaporated with AcCN. The residue was redissolved in dichloromethane (150 mL) and a saturated aqueous solution of NaHCO3 (150 mL) was added. The phases were separated and the organic phase was washed with a saturated aqueous solution of NaHCO3 (2×100 mL) and brine (100 mL), dried (Na2SO4) and evaporated to give 12.5 g. of a yellowish solid. Recrystallization from EtOH:H2O (1250 mL; 1:1 v/v) gave 28 in 88% yield (10.63 g.). δH (DMSO-d6): 11.2 (1H, br s), 8.72 (1H, s), 8.48 (1H, s), 8.06 (2H, m), 7.94 (2H, m), 7.66 (2H, m), 7.54 (4H, m), 7.36-7.26 (5H, m), 6.11 (1H, s), 4.97 (1H, s), 4.82 (2H, s), 4.77 (1H, s), 4.75 (1H, d, J=12.4 Hz), 4.69 (1H, d, J=11.9 Hz), 4.19 (1H, d, J=8.0 Hz), 4.07 (1H, d, J=7.9 Hz). δc (DMSO-d6): 165.3, 150.5, 141.9, 137.7, 133.7, 132.5, 129.3, 129.1, 128.9, 128.6, 128.5, 128.3, 127.7, 127.6, 125.7, 85.9, 85.3, 77.9, 77.1, 72.0, 71.3, 60.6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24][OH:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24][O:25][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(CO)c2c1cc([N+](=O)[O-])c1ccccc21
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)c2c1cc([N+](=O)[O-])c1ccccc21
Temperature: 20 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
A stirred solution of 3-(tert-butyloxycarbonyl)-1-(hydroxymethyl)-5-nitro-1,2-dihydro-3H-benz[e]indole (12) (450 mg, 1.31 mmol) in pyridine (1.3 mL) was treated dropwise at -5° C. with methanesulfonyl chloride (0.121 mL, 1.57 mmol) and then stirred at 20° C. for 2 h. The mixture was diluted with water then cooled and the resulting solid collected, washed with water and dried. This product was dissolved in CH2Cl2 and the solution was filtered through a short column of silica gel, eluting with further CH2Cl2. The resulting product was triturated with iPr2O/petroleum ether to give 3-(tert-butyloxycarbonyl)-1-[(methanesulfonyloxy)methyl]-5-nitro-1,2-dihydro-3H-benz[e]indole (494 mg, 89%), mp 147° C. (dec.). 1H NMR [(CD3)2SO] δ 8.75 (br s, 1 H, H-4), 8.32 (d, J=8.5 Hz, 1 H, H-6), 8.12 (d, J=8.2 Hz, 1 H, H-9), 7.77-7.63 (m, 2 H, H-7, 8), 4.54 (dd, J=10.0, 3.7 Hz, 1 H, H-2), 4.43 (dd, J=10.0, 6.4 Hz, 1 H, H-2), 4.42-4.33 (m, 1 H, H-1), 4.25 (t, J=10.3 Hz, 1 H, CHHO), 4.14 (dd, J=11.4, 2.5 Hz, 1 H, CHHO), 3.11 (s, 3 H, SO2CH3), 1.56 (s, 9 H, C(CH3)3). Anal. Calculated for C19H22N2O7S: C, 54.0; H, 5.3; N, 6.6; S, 7.6. Found: C, 54.3; H, 5.4; N, 6.9; S, 7.4%.
Reaction SMILES: C([SiH](CC)CC)C.[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13]([C:20](=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][NH:15]2)([O-:10])=[O:9]>C(O)(C(F)(F)F)=O>[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:14][NH:15]2)([O-:10])=[O:9]
Reactant: CCOC(=O)C(=O)c1c[nH]c2cccc([N+](=O)[O-])c12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC1CNc2cccc([N+](=O)[O-])c21
Reaction time: 3 h

Procedure:
Triethylsilane (80 mL, 493 mmol) was added dropwise to a solution of ethyl (4-nitro-1H-indol-3-yl)(oxo)acetate from Step A (6.46 g, 24.6 mmol) in TFA (100 mL). After 3 h, the reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 99:1, to give the racemic product. The enantiomers were resolved by HPLC, utilizing a Chiralcel OD column and eluting with hexane:i-PrOH—70:30. The first major peak to elute was ethyl (4-nitro-2,3-dihydro-1H-indol-3-yl)acetate, enantiomer A, and the second major peak to elute was ethyl (4-nitro-2,3-dihydro-1H-indol-3-yl)acetate, enantiomer B, the title compound. MS: m/z=251 (M+1).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)[CH3:8]>>[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:10]=1)[CH3:8]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: Brc1cccs1
Product: CCc1ccc(-c2cccs2)cc1

Procedure:
2-Bromothiophene and 4-ethylphenylboronic acid were treated in a manner similar to Reference Example 20-(1) to give the target compound.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1.Cl>C1COCC1>[CH:2]([CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1)=[O:1]
Reactant: NC(=O)c1ccc(CCC2OCCO2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: NC(=O)c1ccc(CCC=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a stirred solution of 4-(2-(1,3-dioxolan-2-yl)ethyl)benzamide (0.50 g, 2.26 mmol) in THF (22 mL) was added 1 N HCl solution (20 mL) at room temperature. The mixture was heated at 80? 90? for 1 h and cooled to room temperature. After saturation with NaCl, the reaction mixture was extracted repeatedly with CHCl3 (5×20 mL). The combined CHCl3 solution was dried (anhydrous Na2SO4), filtered, and evaporated under reduced pressure to give 0.40 g (98%) of 4-(2-formylethyl)benzamide as a solid which was used to the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 9.82 (t, 1H), 7.74 (m, 2H), 7.27 (m, 2H), 6.14 (br s, 1H), 6.03 (br s, 1 H), 3.01 (m, 2H), 2.81 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27]Br>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:12]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:27][CH2:26]2)=[O:18])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: BrCCBr
Reactant: CCOC(=O)CC(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)Nc2ccc([N+](=O)[O-])cc2)CC1
Yield: 14.6 %

Procedure:
In a manner similar to the procedure described in Example B except that a 100 milliliter three-necked Morton flask was used, 10.0 grams (39.6 mmol) of ethyl 3-[(4-nitrophenyl)amino]-3-oxopropanoate, 13.7 grams (99.1 mmol) of anhydrous potassium carbonate, 40 milliliters of anhydrous dimethylformamide and 3.4 milliliters (40.0 mmol) of 1,2-dibromoethane were reacted for a period of 7 days to give 1.6 grams (5.8 mmol) of ethyl 1-(4-nitrophenylaminocarbonyl)cyclopropanecarboxylate as a pale yellow solid having a melting point of 159.0° C.-161.0° C. The total yield was 15 percent. Recrystallization from methylene chloride-hexane furnished 1.39 grams (5.0 mmol) of 1-(4-nitrophenylaminocarbonyl)cyclopropanecarboxylate as pale yellow needles having a melting point of 159.5° C.-161.0° C. NMR analysis of the product indicated the following:
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH3:33])=[C:17]([C:18]4[CH:23]=[C:22]5[NH:24][C:25](=[O:32])[C:26]6([CH2:31][CH2:30][O:29][CH2:28][CH2:27]6)[C:21]5=[CH:20][CH:19]=4)[C:12]=3[O:11][N:10]=2)=CC=1.FC(F)(F)C(O)=O.O.C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[NH2:8][C:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH3:33])=[C:17]([C:18]3[CH:23]=[C:22]4[NH:24][C:25](=[O:32])[C:26]5([CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)[C:21]4=[CH:20][CH:19]=3)[C:12]=2[O:11][N:10]=1
Reactant: COc1ccc(CNc2noc3c(-c4ccc5c(c4)NC(=O)C54CCOCC4)c(C)ccc23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc2c(N)noc2c1-c1ccc2c(c1)NC(=O)C21CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.8 %

Procedure:
To a solution of 6-(3-(4-methoxybenzylamino)-6-methylbenzo[d]isoxazol-7-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one (example 10, 0.12 g, 0.26 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL) and the solution was stirred at room temperature for 5 hours. Water and solid sodium hydrogen carbonate were added in order to neutralize the trifluoroacetic acid. Ethyl acetate was added and the organic phase was separated, dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (96:4 dichloromethane/methanol) to yield the title compound (38 mg, 44%) as a white solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:45])[CH2:30][CH2:31][N:32]([C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)[C:33](=[O:37])[CH:34]([CH3:36])[CH3:35]>>[CH3:45][N:29]([CH3:28])[CH2:30][CH2:31][N:32]([C:38]1[CH:44]=[CH:43][C:41]([NH:42]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:40][CH:39]=1)[C:33](=[O:37])[CH:34]([CH3:36])[CH3:35]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CC(C)C(=O)N(CCN(C)C)c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)C(=O)C(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(2-dimethylamino-ethyl)-N-isobutyryl-amino)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C31H34N4O4
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[C:17]([CH3:31])=[C:18]([CH:23]=[C:24]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:32](=O)[CH3:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:32][CH3:33])[C:16]2[C:17]([CH3:31])=[C:18]([CH:23]=[C:24]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCOc1cc(NC2CCC(NC(=O)OC(C)(C)C)CC2)c(C)c(C(=O)OC)c1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(c1cc(OCCOC)cc(C(=O)OC)c1C)C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.8 %

Procedure:
To a stirred solution of methyl 3-((4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-5-(2-methoxyethoxy)-2-methylbenzoate (1.60 g, 3.67 mmol) and acetaldehyde (0.48 g, 10.9 mmol) in dichloroethane (20 mL) was added acetic acid (1.3 g, 22 mmol) and the reaction mixture stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (2.33 g. 11.0 mmol) was added at 0° C. and the reaction was stirred at room temperature for 2 h. The reaction was quenched with aqueous sodium bicarbonate, the organic phase separated and the aqueous phase extracted with dichloromethane. The combined organic layers were washed with water, dried, concentrated under reduced pressure, the crude material was purified by column chromatography to afford the title compound (1.6 g, 94%).
Reaction SMILES: C([CH:3]([C:26]([OH:28])=[O:27])[N:4]([C:16](OCC1C=CC=CC=1)=O)[CH2:5][P:6]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:8][CH2:9][CH2:10][CH3:11])=[S:7])C.Br.[CH3:30]COCC>C(O)(=O)C>[CH2:16]([N:4]([CH2:5][P:6]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:8][CH2:9][CH2:10][CH3:11])=[S:7])[CH2:3][C:26]([OH:28])=[O:27])[CH3:30]
Reactant: CCOCC
Reactant: CCCCP(=S)(CCCC)CN(C(=O)OCc1ccccc1)C(CC)C(=O)O
Agent: Br
Solvent: CC(=O)O
Product: CCCCP(=S)(CCCC)CN(CC)CC(=O)O

Procedure:
Ethyl N-carbobenzoxy-N-(dibutylthiophosphinylmethyl)-glycine (2 g., 0.0046 mole) was reacted with 36% hydrogen bromide (10 ml) in glacial acetic acid at 0° C. Ether was added and the oily precipitate was isolated by decanting the ether layer. The oil was washed with ether twice, then suspended in benzene and treated with propylene oxide. The solution was concentrated in vacuo to yield ethyl N-(dibutylthiophosphinylmethyl)glycine as an amber oil, ND22 =1.4820.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:25][C:13]([F:12])([F:24])[C:14]1[CH:15]=[CH:16][C:17]([S:20]([O:11][CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: OC1CCC2(CC1)OCCO2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(OC1CCC2(CC1)OCCO2)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-ol (82 mmol, 13.0 g) in CH2Cl2 (80 mL) at 0° C. was added 4-(trifluoromethyl)benzenesulfonyl chloride (90 mmol, 20.0 g), Et3N (123 mmol, 12.4 g) and DMAP (8.19 mmol, 1.0 g). The reaction mixture was stirred at 0° C. and then gradually warmed up to room temperature. After stirring overnight, the reaction mixture was washed with sat. NH4Cl (300 mL). The aq layer was separated and extracted with CH2Cl2 (3×300 mL). The organic layers were combined, dried over MgSO4 and concentrated. Chromatography on silica gel, eluting with EtOAc and hexane, provided the title compound.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[C:13]([OH:15])=O)[C:9](=[O:11])[CH:10]=1.[NH2:30][C:31]1[CH:35]=[CH:34][N:33]([CH2:36][C:37]([CH3:40])([OH:39])[CH3:38])[N:32]=1>>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[C:13]([NH:30][C:31]2[CH:35]=[CH:34][N:33]([CH2:36][C:37]([OH:39])([CH3:38])[CH3:40])[N:32]=2)=[O:15])[C:9](=[O:11])[CH:10]=1
Reactant: O=C(O)C(Cc1c(F)cccc1F)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(Cc2c(F)cccc2F)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Yield: 65 %

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(2,6-difluoro-phenyl)-propionic acid (Intermediate 34) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(2,6-difluoro-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a light yellow solid (571 mg, 65%); ES+-HRMS m/e calcd for C26H23N5O4F4 [M+H+] 546.1759 found 546.1762. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.04 (s, 6H) 3.39-3.58 (m, 2H) 3.88 (s, 2H) 4.66 (s, 1H) 5.70 (dd, J=9.7, 5.6 Hz, 1H) 5.90 (d, J=2.7 Hz, 1H) 6.47 (d, J=2.1 Hz, 1H) 6.96 (t, J=8.0 Hz, 2H) 7.19-7.34 (m, 1H) 7.34-7.41 (m, 2H) 7.42-7.51 (m, 1H) 7.54 (d, J=2.1 Hz, 1H) 8.20 (d, J=2.7 Hz, 1H) 10.67 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][C@@H:8]([NH:18][C:19]([C:21]2([NH:26][C:27]([C:29]3[S:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[CH:30]=3)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[C:9](=[O:17])[NH:10][CH:11]2CCNC[CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1C=O.[OH:46][C:47]([C:49]([F:52])([F:51])[F:50])=[O:48].C1(C[C@@H](NC(C2(NC(C3SC4C=CC=CC=4C=3)=O)CCCC2)=O)C(=O)NC2CCN(CC3C=CC=CN=3)CC2)C=CC=CC=1>>[OH:48][C:47]([C:49]([F:52])([F:51])[F:50])=[O:46].[C:1]1([CH2:7][C@@H:8]([NH:18][C:19]([C:21]2([NH:26][C:27]([C:29]3[S:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[CH:30]=3)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[C:9](=[O:17])[NH:10][CH2:11][CH2:12][CH:41]2[CH2:40][CH2:39][NH:38][CH2:43][CH2:42]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccccn1
Reactant: O=C(NC1(C(=O)N[C@H](Cc2ccccc2)C(=O)NC2CCNCC2)CCCC1)c1cc2ccccc2s1
Agent: O=C(NC1(C(=O)N[C@H](Cc2ccccc2)C(=O)NC2CCN(Cc3ccccn3)CC2)CCCC1)c1cc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1(C(=O)N[C@H](Cc2ccccc2)C(=O)NCCC2CCNCC2)CCCC1)c1cc2ccccc2s1

Procedure:
200 mg (0.31 mmol) of benzo[b]thiophene-2-carboxylic acid {1-[2-phenyl-1(R)-(piperidin-4-ylcarbamoyl)-ethylcarbamoyl]-cyclopentyl}-amide are used for the reaction of reductive amination with pyridine 2-carboxaldehyde (64 mg, 0.6 mmol), to yield, after purification by preparative HPLC according to the method already described in the previous Examples, the desired product benzo[b]thiophene-2-carboxylic acid {1-[2-phenyl-1(R)-(1-pyridin-2-ylmethyl-piperidin-4-ylcarbamoyl)-ethylcarbamoyl]-cyclopentyl}-amide TFA salt (120 mg, 0.16 mmol).