Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:11][C@@H:12]4[N:18]([CH:19]=3)[C:17](=[O:20])[C:16]3[CH:21]=[C:22]([O:83][CH3:84])[C:23]([O:25][CH2:26][CH2:27][CH2:28][O:29][C:30]5[C:80]([O:81][CH3:82])=[CH:79][C:33]6[C:34](=[O:78])[N:35]7[CH:41]=[C:40]([C:42]8[CH:47]=[CH:46][C:45]([NH:48][C:49](=[O:77])[C@@H:50]([NH:52][C:53](=[O:76])[C@@H:54]([NH:58]C(=O)OCC9C%10C=CC=CC=%10C%10C9=CC=CC=%10)[CH:55]([CH3:57])[CH3:56])[CH3:51])=[CH:44][CH:43]=8)[CH2:39][C@H:36]7[CH:37]=[N:38][C:32]=6[CH:31]=5)=[CH:24][C:15]=3[N:14]=[CH:13]4)=[CH:9][C:4]=2[O:3][CH2:2]1.N1CCCCC1>CN(C=O)C>[NH2:58][C@@H:54]([CH:55]([CH3:57])[CH3:56])[C:53]([NH:52][C@@H:50]([CH3:51])[C:49]([NH:48][C:45]1[CH:44]=[CH:43][C:42]([C:40]2[CH2:39][C@@H:36]3[N:35]([CH:41]=2)[C:34](=[O:78])[C:33]2[CH:79]=[C:80]([O:81][CH3:82])[C:30]([O:29][CH2:28][CH2:27][CH2:26][O:25][C:23]4[C:22]([O:83][CH3:84])=[CH:21][C:16]5[C:17](=[O:20])[N:18]6[CH:19]=[C:10]([C:8]7[CH:7]=[CH:6][C:5]8[O:1][CH2:2][O:3][C:4]=8[CH:9]=7)[CH2:11][C@H:12]6[CH:13]=[N:14][C:15]=5[CH:24]=4)=[CH:31][C:32]=2[N:38]=[CH:37]3)=[CH:47][CH:46]=1)=[O:77])=[O:76]
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc5c(c4)OCO5)C[C@H]1C=N3)N=C[C@@H]1CC(c3ccc(NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OCC4c5ccccc5-c5ccccc54)C(C)C)cc3)=CN1C2=O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc5c(c4)OCO5)C[C@H]1C=N3)N=C[C@@H]1CC(c3ccc(NC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)cc3)=CN1C2=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The imine 35 (82 mg, 0.07 mmol, 1 equiv.) was dissolved in DMF (1 mL) before piperidine (0.2 mL, 2 mmol, excess) was added slowly. This solution was left to stir at room temperature for 20 minutes until LC/MS analysis showed complete consumption of starting material. The reaction mixture was diluted with CH2Cl2 (50 mL), washed with water (50 mL×4), dried with MgSO4, filtered and the solvent removed in vacuo. The product 33 was used without further purification in the next step. LC/MS (1.15 min (ES+) m/z (relative intensity) 910.60 ([M+H]+, 58).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:34]=[CH:33][C:10]3[N:11]=[C:12]([C@@H:14]4[CH2:17][C@H:16]([N:18]5[CH2:25][C@@H:24]6[C@@H:20]([N:21](C(OC(C)(C)C)=O)[CH2:22][CH2:23]6)[CH2:19]5)[CH2:15]4)[S:13][C:9]=3[CH:8]=2)[CH:4]=[N:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH:21]1[CH2:22][CH2:23][C@@H:24]2[CH2:25][N:18]([C@@H:16]3[CH2:17][C@H:14]([C:12]4[S:13][C:9]5[CH:8]=[C:7]([C:5]6[CH:4]=[N:3][CH:2]=[N:1][CH:6]=6)[CH:34]=[CH:33][C:10]=5[N:11]=4)[CH2:15]3)[CH2:19][C@H:20]12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN([C@H]3C[C@@H](c4nc5ccc(-c6cncnc6)cc5s4)C3)C[C@@H]21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ncc(-c2ccc3nc([C@H]4C[C@@H](N5C[C@H]6CCN[C@H]6C5)C4)sc3c2)cn1
Reaction time: 2 h

Procedure:
The title compound was prepared by mixing the product of Example 38B with 1:1 mixture of TFA and dichloromethane. After 2 hours, the solvent was removed under reduced pressure, the residue was basified with saturated sodium bicarbonate and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (0.5% ammonium hydroxide and 5% methanol in dichloromethane) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 9.19-9.26 (s, 1H) 9.01 (s, 2H) 8.09 (d, J=8.54 Hz, 1H) 8.05 (d, J=1.53 Hz, 1H) 7.65 (dd, J=8.54, 1.83 Hz, 1H) 3.81-3.92 (m, 1H) 3.60-3.71 (m, 1H) 3.03-3.12 (m, 1H) 2.95-3.03 (m, 1H) 2.87-2.95 (m, 1H) 2.72-2.79 (m, 1H) 2.64-2.71 (m, 2H) 2.50-2.62 (m, 3H) 2.32-2.46 (m, 3H) 1.91-2.00 (m, 1H) 1.57-1.67 (m, 1H). MS: (M+H)+=378.
Reaction SMILES: [CH:1]1[C:7]([NH2:8])=[N:6][C:4](=[S:5])[NH:3][C:2]=1[Cl:9].[OH-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:19]Cl)[CH:14]=1>C(O)C>[CH:18]1[C:13]([Cl:12])=[CH:14][C:15]([CH2:19][S:5][C:4]2[N:3]=[C:2]([Cl:9])[CH:1]=[C:7]([NH2:8])[N:6]=2)=[N:16][CH:17]=1
Reactant: ClCc1cc(Cl)ccn1
Reactant: Nc1cc(Cl)[nH]c(=S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(Cl)nc(SCc2cc(Cl)ccn2)n1
Temperature: 50 °C

Procedure:
4-Amino-6-chloro-2-thio-pyrimidine (Cpd #110; 614 mg, 2.38 mmol) in ethanol (1.5 ml) is treated with 3.25 M NaOH (1.47 ml, 4.8 mmol) and the mixture is warmed to 50° C. 4-chloro-2-chloromethyl pyridine is added and the solution is stirred warm for 1 hour. The reaction mixture is cooled and concentrated in vacuo, and the resultant solid is filtered and washed with water followed by cold ethanol, mp 195° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([F:14])=[C:9]([O:15]CC1C=CC=CC=1)[CH:8]=2)=[O:4]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([F:14])=[C:9]([OH:15])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2cc(F)c(OCc3ccccc3)cc2[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2cc(F)c(O)cc2[nH]1
Yield: 77.8 %

Procedure:
A solution of 20.2 g (0.067 mol) 6-benzyloxy-5-fluoro-1H-indole-2-carboxylic acid methyl ester in 800 ml ethyl acetate was treated with 2 g (10%) Pd/C and hydrogenated at 1 bar for 2 h. After filtration and evaporation the residue was re-crystallized from ethyl acetate. The crystals were filtered off washed with diethyl ether and dried at 40° C. under vacuum to yield 10.9 g (74%) of the title compound as white crystals. MS (m/e): 208.1 (MH−, 100%).
Reaction SMILES: FC(F)(F)C(O)=O.[Si]([O:15][CH2:16][C:17]([CH3:59])([CH3:58])[CH2:18][N:19]1[CH:28]=[C:27]([S:29][CH:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:43]3[CH:48]=[C:47]([C:49](=[O:54])[NH:50][CH:51]4[CH2:53][CH2:52]4)[CH:46]=[C:45]([F:55])[C:44]=3[CH3:56])[CH:25]=2)[C:20]1=[O:57])(C(C)(C)C)(C)C.C1(C)C=CC=CC=1.C(OCC)C>C(Cl)Cl>[CH:51]1([NH:50][C:49](=[O:54])[C:47]2[CH:48]=[C:43]([C:24]3[CH:25]=[C:26]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:57])[N:19]([CH2:18][C:17]([CH3:59])([CH3:58])[CH2:16][OH:15])[CH:28]=[C:27]4[S:29][CH:30]3[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]3)[C:44]([CH3:56])=[C:45]([F:55])[CH:46]=2)[CH2:52][CH2:53]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(SC3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(SC3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
Trifluoroacetic Acid (1 mL) was added to a solution of tert-butyl 4-({2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl}sulfanyl)piperidine-1-carboxylate (Example 58d, 0.123 g) in DCM (3 mL). The reaction was stirred at room temperature for 30 min. Toluene (5 mL) was added and the volatiles were removed under reduced pressure. The residue was dissolved in MeOH (1 mL)/DMF (1 mL) and purified by preparative HPLC (Xbridge column using a 95-5% gradient of 0.2% aqueous ammonia in acetonitrile) and after solvent removal, the residue was triturated with diethyl ether. This was dissolved in methanol and purified by preparative HPLC (Sunfire C18 column using a 95-30% gradient of 0.1% aqueous formic acid in methanol run over 16 min). The relevant fractions were lyophilized before the solid was dissolved in methanol and passed through a Stratospheres PL-HCO3 cartridge. The solvent was removed from the resulting filtrate under reduced pressure to give, after trituration with diethyl ether, the title compound (0.035 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[C:16]([CH3:24])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])=[C:16]([CH3:24])[CH:15]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Cc1cc(Cl)ccc1S(=O)(=O)Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(Cl)cc2C)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (9.4 mg) with purity >90%. LCMS (pos) m/z 375.2.
Reaction SMILES: [N:1]1([NH:7][C:8]([C:10]2[C:14]([NH2:15])=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[N:11]=2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:30](OC(OCC)OCC)C>C1(C)C=CC=CC=1.O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[N:11]=[C:10]3[C:8](=[O:9])[N:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:30]=[N:15][C:14]=23)=[CH:21][CH:20]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1c(C(=O)NN2CCOCC2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2ncn1N1CCOCC1
Temperature: 25 °C

Procedure:
A solution of 4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide (I-10A-1a, 200 mg, 0.46 mmol) and triethylorthoformate (116 microliters, 0.7 mmol) in toluene (2.5 ml) was heated at 100° C. for 0.45 h and at 120° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with H2O, and extracted with EtOAc (2×). The combined organic extracts were washed with 1 M K2CO3 and saturated aqueous brine, dried, and concentrated under vacuum. The crude residue was purified via radial chromatography (1 mm plates, 50% EtOAc/hexanes as eluant) to give the desired product 10A-1 as an amorphous solid: MS 442.1 (M+1)+; 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.53–7.50 (m, 1H), 7.47–7.39 (m, 3H), 7.35–7.28 (m, 4H), 4.25 (bm, 2H), 3.95 (bm, 2H), 3.75 (bm, 2H), 3.00 (bm, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[CH2:13]O.P(Br)(Br)[Br:16].C(=O)(O)[O-].[Na+]>C1COCC1>[Br:16][CH2:13][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][C:4]=1[Cl:12]
Reactant: BrP(Br)Br
Reactant: OCc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(Cl)c(CBr)c(Cl)c1
Temperature: 0 °C
Yield: 162.4 %

Procedure:
Dissolve (2,6-dichloro-4-trifluoromethyl-phenyl)-methanol (7.5 g, 31 mmol) is THF (40 mL) and cool to 0° C. Add PBr3 (5.0 g, 18 mmol) under nitrogen and stir at 0° C. for 30 minutes. Pour into saturated aqueous sodium bicarbonate and extract with methylene chloride. Dry over sodium sulfate, filter and concentrate. Purify over silica gel (hexanes) to obtain 9.0 g (96%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][C:4]([NH:6][C@H:7]([C:10]([NH:12][C@H:13]([C:16]([N:18](CNC(=O)C)[CH2:19][C:20]([OH:22])=[O:21])=[O:17])[CH2:14][SH:15])=[O:11])[CH2:8][OH:9])=[O:5].O>C(O)(=O)C>[CH3:1][N:2]([CH3:28])[CH2:3][C:4]([NH:6][C@H:7]([C:10]([NH:12][C@H:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[CH2:14][SH:15])=[O:11])[CH2:8][OH:9])=[O:5]
Reactant: CC(=O)NCN(CC(=O)O)C(=O)[C@H](CS)NC(=O)[C@H](CO)NC(=O)CN(C)C
Solvent: CC(=O)O
Solvent: O
Product: CN(C)CC(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)NCC(=O)O

Procedure:
A solution of dimethylglycylserinylcysteinyl(Acetomidomethyl)glycine (RP414) (50 mg) and mercuric acetate (75 mg) in 30% acetic acid (2 mL) was stirred at room temperature for 3 h. Distilled water (2 mL) was added and H2S gas was slowly bubbled through the solution for 3 min causing a black precipitate (mercury sulfide). The solution was filtered through a 0.2 micron filter diluted with a further 2 mL of distilled water and lyophilised.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:10]2[C:22](=[O:23])[C:21]3[S:20][C:19]4[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=4[C:13]=3[CH:12]=[N:11]2)[C:7]=1[CH:8]=[O:9].[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)[C:26]1=[O:57].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:24][N:25]1[C:26](=[O:57])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([N:10]3[C:22](=[O:23])[C:21]4[S:20][C:19]5[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=5[C:13]=4[CH:12]=[N:11]3)[C:7]=2[CH:8]=[O:9])=[CH:30]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: O=Cc1c(Br)cncc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cn1cc(-c2cncc(-n3ncc4c5c(sc4c3=O)CCCC5)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 100 °C
Yield: 35 %

Procedure:
A sealed tube was charged with 116a (80 mg, 0.20 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 101l (96 mg, 0.20 mmol), PdCl2(dppf) (18 mg, 0.02 mmol), K3PO4 (30 mg), and NaOAc (20 mg) in CH3CN (5 mL) and H2O (1 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 10:1 of DCM/MeOH to afford 116b in 35% yield (46 mg). MS: [M+H]+ 651.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([CH:15]([O:29][CH2:30][CH2:31][OH:32])[C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)[CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:40][S:41](Cl)(=[O:43])=[O:42].O>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([CH:15]([O:29][CH2:30][CH2:31][O:32][S:41]([CH3:40])(=[O:43])=[O:42])[C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2c(F)cccc2C(OCCO)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(-c2c(F)cccc2C(OCCOS(C)(=O)=O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Yield: 91.7 %

Procedure:
To a solution of (3R)-tert-butyl 3-((6-fluoro-3′-methylbiphenyl-2-yl)(2-hydroxyethoxy)methyl)piperidine-1-carboxylate (1 g, 2.3 mmol) in dry CH2Cl2 (15 mL) was added Et3N (0.9 g, 9.0 mmol) at ca 0 to −5° C. A solution of MsCl (0.5 g, 4.5 mmol) in anhydrous CH2Cl2 (4 mL) was added dropwise at the same temperature. After addition, the mixture was allowed to warm to rt gradually. TIc showed the starting material had disappeared. Water was added and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were washed with 10% aq citric acid, satd aq NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to give (3R)-tert-butyl 3-((6-fluoro-3′-methylbiphenyl-2-yl)(2-(methanesulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (1.1 g, yield 94%), which was used in the next step without purification.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C@@:3]([CH2:18][S@:19]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)=O)([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].[I-].[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>CC(C)=O>[F:29][C:2]([F:1])([F:28])[C@@:3]([CH2:18][S:19][C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6]
Reactant: COc1ccc(F)cc1C(C)(C)C[C@@](O)(C[S@@](=O)c1ccc(C)cc1)C(F)(F)F
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc(F)cc1C(C)(C)C[C@@](O)(CSc1ccc(C)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 100.5 %

Procedure:
To a suspension of (S)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol (44.2 g, 102 mmol) and sodium iodide (46.0 g, 307 mmol) in 600 mL of anhydrous acetone at −40° C. was added a solution of trifluoroacetic acid anhydride (72.2 mL, 511 mmol) in 200 mL of anhydrous acetone via an addition funnel dropwise over 30 minutes. A greenish brown mixture was formed instantaneously. After 15 minutes, the reaction mixture was quenched with saturated aqueous sodium sulfite (Na2SO3) solution and neutralized with saturated aqueous sodium carbonate (Na2CO3) solution. The brown color disappeared and the crude product was concentrated to remove most of the acetone solvent. The resulting material was diluted with water and extracted three times with ether (one 600 mL portion and two 400 mL portions). The combined organic phases were washed with brine, dried over magnesium sulfate (MgSO4), filtered, and concentrated in vacuo to afford (S)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-p-tolylsulfanylmethylpentan-2-ol as an orange oil (42.7 g, 100%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38]([N:40]3[CH:44]=[CH:43][C:42]([NH:45][C:46](=[O:70])[CH:47]([C:49]4([NH:53][C:54](=[O:69])[CH:55]([NH:63][C:64]([O:66][CH2:67][CH3:68])=[O:65])[CH2:56][C:57]5([F:62])[CH2:61][CH2:60][CH2:59][CH2:58]5)[CH2:52][CH2:51][CH2:50]4)[OH:48])=[N:41]3)=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1>ClCCCl>[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38]([N:40]3[CH:44]=[CH:43][C:42]([NH:45][C:46](=[O:70])[C:47]([C:49]4([NH:53][C:54](=[O:69])[CH:55]([NH:63][C:64]([O:66][CH2:67][CH3:68])=[O:65])[CH2:56][C:57]5([F:62])[CH2:61][CH2:60][CH2:59][CH2:58]5)[CH2:50][CH2:51][CH2:52]4)=[O:48])=[N:41]3)=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)NC(CC1(F)CCCC1)C(=O)NC1(C(O)C(=O)Nc2ccn(C(=O)OCC3c4ccccc4-c4ccccc43)n2)CCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCCl
Product: CCOC(=O)NC(CC1(F)CCCC1)C(=O)NC1(C(=O)C(=O)Nc2ccn(C(=O)OCC3c4ccccc4-c4ccccc43)n2)CCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 12.5 %

Procedure:
Dess-Martin periodinane (47 mg, 0.11 mmol) was added to a solution of alcohol 58-a (0.079 mmol) in anh. DCE (3 ml). The reaction mixture was stirred at room temperature for 90 min and then quenched with 10% aq. Na2S2O3 and aq. NaHCO3 (sat.). The phases were separated and the organic layer was dried (Na2SO4) and concentrated. Purification by flash column chromatography (EtOAc/iso-Hexane, 0:100-40:60) gave the title compound (6.5 mg, 13%). MS m/z 660.1 (M+H)+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:36][CH:37]([N:41]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]2=[O:50])[C:38]([OH:40])=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[CH:28]1([CH2:36][CH:37]([N:41]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]2=[O:50])[C:38]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: O=C(O)C(CC1CCCCCCC1)N1Cc2ccccc2C1=O
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1nccs1)C(CC1CCCCCCC1)N1Cc2ccccc2C1=O
Yield: 87.5 %

Procedure:
BOP coupling of 3-Cyclooctyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Step D; 200 mg; 0.65 mmol) and 2-aminothiazole (70 mg; 0.70 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as outlined in Example 9, Step B) provided after flash chromatography (eluent: 30% ethyl acetate/hexanes) 226 mg (88%) of 3-Cyclooctyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as a white foam: EI-HRMS m/e calcd for C22H27N3O2S (M+) 397.1824, found 397.1825.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=2[F:26])=[CH:14][CH:15]=1)=O)C.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41]C(C3C4N=CC=NC=4C(C4C(Cl)=C(OC)C=C(OC)C=4Cl)=CC=3)=O)=[N:39][CH:40]=2)[CH2:30][CH2:29]1>C(Cl)Cl.CO>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=4[F:26])=[CH:14][CH:15]=3)=[O:3])=[N:39][CH:40]=2)[CH2:30][CH2:29]1
Reactant: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2F)c2nccnc12
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1
Reaction time: 1 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-fluoro-3,5-dimethoxy-phenyl)quinoxaline-5-carboxylic acid ethyl ester (Step 143.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), and stirring the reaction mixture for 1 h at reflux. Title compound: ESI-MS: 517.1 [M+H]+; tR=3.37 min (System 1); TLC: Rf=0.11 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2[N:17]=[C:18]([NH:30][C:31](=[O:33])[CH3:32])[S:19][C:20]=2[CH2:21][NH:22][CH2:23][CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl.O.CO>[C:31]([NH:30][C:18]1[S:19][C:20]([CH2:21][N:22]([CH2:23][CH2:24][C:25]([N:27]([CH3:28])[CH3:29])=[O:26])[CH3:37])=[C:16]([CH2:15][CH2:14][C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:6](=[O:34])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:13][CH:12]=2)[N:17]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(CNCCC(=O)N(C)C)s1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(CN(C)CCC(=O)N(C)C)s1
Reaction time: 12 h
Yield: 87.9 %

Procedure:
To a solution of the compound obtained in Step 1 (100 mg) in dichloromethane (1.5 mL) was added formaline (35%, 87.6 μl). To this suspension was added 0.05 ml of MeOH. Then, sodium triacetoxyborohydride (433 mg) was added, and the mixture was stirred for 12 hrs. To the mixture were added water and 1N NaOH to adjust pH of aquaous phase (ca. pH 8-9). The mixture was extracted with dichloromethane. The organic layer was dried with MgSO4 and concentrated under redused pressure. Resulting oil was purified by silica gel column chromatograph (mixed solvent of CH2Cl2/MeOH 15/1 as an eluent) to give tert-butyl {4-[2-(2-(acetylamino)-5-{[[3-(N,N-dimethylamino)-3-oxopropyl](methyl)amino]methyl}-1,3-thiazol-4-yl)ethyl]phenyl}carbamate as pale yellow oil (90.4 mg).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:15][N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][NH:17]1>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([NH:15][N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][NH:17]1)=[O:9])(=[O:3])[CH3:2]
Reactant: NN1C=CC=CN1
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)O
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)NN1C=CC=CN1
Yield: 19.7 %

Procedure:
Using 2-acetoxy-5-chlorobenzoic acid and 2-aminopyridazine as the raw materials, the same operation as the Example 198(3) gave the title compound.