Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH2:22][CH:21]([CH2:23][F:24])[O:20][C:7]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:6]1)[C:2]#[C:3][CH3:4].[ClH:25].O1CCOCC1>ClCCl.C(=O)(O)[O-].[Na+]>[ClH:25].[CH2:1]([N:5]1[CH2:22][CH:21]([CH2:23][F:24])[O:20][C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCN1CC(CF)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC#CCN1CC(CF)OC2(CCNCC2)C1
Reaction time: 2 h
Yield: 98 %

Procedure:
Tert-butyl 8-but-2-ynyl-10-(fluoromethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (23.0 mg, 0.0676 mmol) was dissolved in dichloromethane (2 mL) and treated with HCl in dioxane (1.69 mL of 4 M, 6.76 mmol). The reaction mixture was stirred for 2 h, then diluted with dichloromethane (10 mL) and 1:1 saturated sodium bicarbonate/1 M NaOH (10 mL). The organic layer was separated, dried over Na2SO4, and concentrated to yield 8-but-2-ynyl-10-(fluoromethyl)-11-oxa-3,8-diazaspiro[5.5]undecane hydrochloride (16.0 mg, 0.0666 mmol, 98%). ESI-MS m/z calc. 240.2. Found 241.5 (M+1)+; Retention time: 0.22 minutes (3 min run).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:36])/[C:6](/[NH:15][C:16](=[O:35])[C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:33])[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[CH:19][C:18]=1[Cl:34])=[CH:7]/[C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[CH3:14]>CO.O1CCCC1>[Cl:34][C:18]1[CH:19]=[C:20]([C:23](=[O:33])[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[CH:21]=[CH:22][C:17]=1[C:16]([NH:15]/[C:6](=[CH:7]\[C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[CH3:14])/[C:5]([OH:36])=[O:4])=[O:35]
Reactant: COC(=O)/C(=C/c1sc(C)nc1C)NC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C)c(/C=C(\NC(=O)c2ccc(C(=O)CCc3cccc(O)c3)cc2Cl)C(=O)O)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.5 %

Procedure:
An aqueous 1N solution of sodium hydroxide (0.6 mL, 0.6 mmol) was added to a solution of (Z)-2-[[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid methyl ester (Example 227; 95 mg, 0.19 mmol) in methanol/tetrahydrofuran (1:1; 2.4 mL). The solution was stirred at room temperature for 6 h and the solvent was evaporated. Water (5 mL) was added and the mixture was extracted with diethyl ether. The organic extract was discarded and the aqueous layer was acidified with 1N hydrochloric acid solution (0.6 mL) and stirred for 30 min at room temperature. The resulting precipitate was filtered off, washed with water, dried and crystallized from tetrahydrofuran/methanol/water to furnish (Z)-2-[[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid (65 mg, 71% yield) as a colorless solid.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]3[C:14](=[O:17])[O:15][CH2:16][C:12]=3[CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:20][C:21]1[CH:28]=[C:27]([CH2:29][CH:30]=O)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>>[Br:20][C:21]1[CH:28]=[C:27]([CH2:29][CH2:30][N:5]2[CH2:6][CH2:7][N:2]([CH2:8][CH2:9][C:10]3[CH:11]=[C:12]4[C:13](=[CH:18][CH:19]=3)[C:14](=[O:17])[O:15][CH2:16]4)[CH2:3][CH2:4]2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: N#Cc1ccc(CC=O)cc1Br
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Agent: Cl
Product: N#Cc1ccc(CCN2CCN(CCc3ccc4c(c3)COC4=O)CC2)cc1Br

Procedure:
2-Bromo-4-[2-[4-[2-(1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-bromo-4-(2-oxoethyl)benzonitrile. LC-MS (IE, m/z): 456.0 [M+1]+. (0.099 μM)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[C:11](Cl)(Cl)=[S:12].[OH-].[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]2[O:9][C:11](=[S:12])[O:8][C:6]=2[CH:7]=1
Reactant: Oc1cc(Br)cc(F)c1O
Reactant: S=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Fc1cc(Br)cc2oc(=S)oc12
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
5-Bromo-3-fluorobenzene-1,2-diol (2.0 g, 9.7 mmol, prepared according to Lu, Hejun; Tang, Peng Cho; Chen, Yiqian; Wang, Shenglan; Wang, Hua; Zhang, Lei; Li, Jun, WO 2011140936 A1) was dissolved in chloroform (25 mL), treated with thiophosgene (1.2 g, 11 mmol) and cooled to 0-5° C. Sodium hydroxide (10% aqueous, 8.9 g, 22 mmol) was added dropwise with vigorous stirring over 30 min. After 1 h, the chloroform was removed under vacuum and the pH was adjusted to 2 by addition of 6 M HCl. The solid that was formed was taken up in ethyl acetate (120 mL), washed with saturated NaCl (30 mL), dried (Na2SO4) and evaporated. The material was purified by flash chromatography using a 0-30% ethyl acetate-hexane gradient to give the title compound as a tan solid (1.5 g, 62%): mp 41-42° C.; 1H NMR (400 MHz, CDCl3) δ 7.35-7.30 (m, 1H), 7.29 (d, J=1.6 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −128.93; EIMS m/z 248/250.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.C(N)(N)=[O:10].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:10])=[C:4]([CH3:8])[CH:3]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: NC(N)=O
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc[n+]1[O-]
Temperature: 0 °C
Yield: 100.5 %

Procedure:
4-Chloro-2-methylpyridine (5.0 g, 39 mmol, 1.0 eq) and hydrogen peroxide-urea adduct (7.37 g, 78.4 mmol, 2.00 eq) were dissolved in THF (196 mL) and cooled to 0° C. Trifluoroacetic anhydride (12 mL, 86.3 mmol, 2.2 eq) was added dropwise over 15 minutes and the reaction was allowed to warm to room temperature. After determination of the completion of the reaction by LCMS (approximately 45 minutes), the reaction was cooled to 0° C. and quenched with a 10% aqueous solution of NaS2O3. The reaction was extracted with EtOAc (3×), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 5.63 g (99%) of the title compound as a white solid.
Reaction SMILES: C[N:2]([C@@:10]1([CH3:15])[CH2:14][CH2:13][NH:12][CH2:11]1)[C:3](=O)OC(C)(C)C.C(N(CC)CC)C.[C:23]([C:25]1[C:30]2[N:31]=[C:32]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[O:33][C:29]=2[C:28](F)=[C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:26]=1[CH3:46])#[N:24]>CS(C)=O>[C:23]([C:25]1[C:30]2[N:31]=[C:32]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[O:33][C:29]=2[C:28]([N:12]2[CH2:13][CH2:14][C@:10]([CH3:15])([NH:2][CH3:3])[CH2:11]2)=[C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:26]=1[CH3:46])#[N:24]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reactant: CN(C(=O)OC(C)(C)C)[C@@]1(C)CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN[C@@]1(C)CCN(c2c(-c3ccccc3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)C1
Temperature: 150 °C
Yield: 21.1 %

Procedure:
A dimethyl sulfoxide (1 ml) solution of tert-butyl methyl[(3S)-3-methylpyrrolidin-3-yl]carbamate (I-348) (318 mg, 1.48 mmol) and triethylamine (241 μl, 1.73 mmol) was added to a dimethyl sulfoxide (6 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (400 mg, 1.24 mmol) stirred in an oil bath at 150° C., followed by stirring in an oil bath at 150° C. for 30 minutes. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→1:2, v/v). The obtained yellow foamy substance was dissolved in dichloromethane (3 ml), and with cooling with ice, trifluoroacetic acid (6 ml) was added, followed by stirring at room temperature for 5 hours. The reaction liquid was concentrated under reduced pressure, then an aqueous saturated sodium hydrogencarbonate solution and water were added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, the residue obtained by concentration was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v), and the obtained eluate was recrystallized from isopropyl ether to obtain the entitled compound (109 mg, 21%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11]3[CH2:12][CH2:13][N:14]4[C:19]([C:10]=3[N:9]([CH3:21])[C:6]2=[CH:7][CH:8]=1)=[CH:18][CH2:17][CH2:16][C:15]4=[O:20].[H][H]>[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11]3[CH2:12][CH2:13][N:14]4[CH:19]([C:10]=3[N:9]([CH3:21])[C:6]2=[CH:7][CH:8]=1)[CH2:18][CH2:17][CH2:16][C:15]4=[O:20]
Reactant: COc1ccc2c(c1)c1c(n2C)C2=CCCC(=O)N2CC1
Reactant: [H][H]
Agent: [Pd]
Product: COc1ccc2c(c1)c1c(n2C)C2CCCC(=O)N2CC1

Procedure:
Hydrogenation of 9-methoxy-12-methyl-2,3,4,6,7,1 2-hexahydroindolo[2,3-a]quinolizin-4-one with hydrogen in the presence of palladium-on-charcoal and sodium bicarbonate leadsto9-methoxy-12-methyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3a]quinolizin-4-one
Reaction SMILES: [Br:1][C:2]1[C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2[CH2:20][CH2:21][CH2:22][CH2:23][C:15]1=2.O>C(O)(=O)C>[Br:1][C:2]1[C:8]([O:9][CH:10]([CH3:11])[CH3:12])=[CH:7][C:5]([N:6]2[C:17](=[O:18])[C:16]3[CH2:20][CH2:21][CH2:22][CH2:23][C:15]=3[C:14]2=[O:19])=[C:4]([F:13])[CH:3]=1
Reactant: CC(C)Oc1cc(N)c(F)cc1Br
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Br
Temperature: 25 °C
Yield: 51.9 %

Procedure:
4-Bromo-2-fluoro-5-isopropoxyaniline (2.0 g) and 3,4,5,6-tetrahydrophthalic anhydride (1.23 g) were dissolved in acetic acid (10 ml) and refluxed for 3 hours. The resultant mixture was allowed to cool to room temperature and poured into water, followed by extraction with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate and subjected to filtration. The filtrate was concentrated under reduded pressure, and the residue was purified by silica gel chromatography to obtain 1.6 g of N-(4-bromo-2-fluoro-5-isopropoxyphenyl)-3,4,5,6-tetrahydrophthalimide (Compound No. 2). M.P., 116.5°-117.5° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([Br:8])[N:7]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[Br:8][C:6]1[N:7]=[C:2]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:3](=[O:9])[NH:4][CH:5]=1
Reactant: C1COCCN1
Reactant: O=c1[nH]cc(Br)nc1Br
Product: O=c1[nH]cc(Br)nc1N1CCOCC1
Temperature: 25 °C
Yield: 43 %

Procedure:
A solution of 3,5-dibromopyrazin-2(1H)-one (1.0 equiv.) in morpholine (5 equiv.) was heated to 100° C. for 24 h. Cooled to room temperature and filtered off the precipitate. The filtrate was partitioned between water and ethyl acetate. The organic phase was dried with sodium sulfate, filtered and concentrated. The crude material was purified via silica gel column chromatography eluting with ethyl acetate and heptanes (0-50%). The pure fractions were concentrated to yield 5-bromo-3-morpholinopyrazin-2(1H)-one as a white solid in 43% yield. LCMS m/z (M+H)=259.9, Rt=0.41 min.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]([CH2:16][C:15]3[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=3)[C:2]2=[NH:1])=[CH:14][CH:13]=1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: ClCc1ccc(Cl)cc1
Product: N=c1n(Cc2ccc(Cl)cc2)c2ccccc2n1Cc1ccc(Cl)cc1

Procedure:
The title compound was prepared from 2-aminobenzimidazole and 4-chlorobenzyl chloride by Procedure A. The product was isolated by preparative LCMS to give the title compound as the free base (white solid, mp 185-187° C.). MS(ES+) m/z 382 (M+, 100). 1NMR (DMSO-d6) δ 5.08 (br s, 4H), 5.76 (s, 1H), 6.80-6.90 (m, 4H), 7.25-7.42 (m, 8H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([F:7])[F:6])[CH3:2].I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([CH3:20])(=[O:19])=[O:18].CCOC(C)=O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:9])[C:5]([F:7])([F:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([CH3:20])(=[O:19])=[O:18])[CH3:2]
Reactant: CS(=O)(=O)c1ccccc1I
Reactant: CCOC(=O)C(F)(F)Br
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccccc1S(C)(=O)=O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 2.7 %

Procedure:
To a stirred suspension of Cu(0) (496 mg, 78 mmol) in DMSO (2.5 mL) at room temperature under nitrogen atmosphere was added ethylbromodifluoroacetate (0.5 mL, 39 mmol). The reaction mixture was stirred at 35° C. for 30 min. Then the solution was brought to room temperature and 1-iodo-2-methanesulfonylbenzene (1.0 g, 35 mmol), as prepared in the preceding step, was added. The reaction mixture was stirred at 35° C. for 12 h. The reaction mixture was cooled to room temperature and passed through a bed of Celite using EtOAc to rinse. The filtrate was washed with saturated NH4Cl (50 mL) until the blue color dissipated. The organic phase was then washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo to afford 772 mg crude product. The residue was purified by flash column chromatography (20-40% ethyl acetate in hexanes) to yield the desired compound (264 mg, 27%). 1H-NMR (300 MHz, CDCl3) δ 8.18 (d, J=7.6 Hz, 1H), 7.94 (dd, J=7.7 Hz, 1.7 Hz, 1H), 7.76 (pd, J=7.6 Hz, 1.5 Hz, 2H), 4.31 (q, J=7.2 Hz, 2H), 3.15 (s, 3H), 1.29 (t, J=7.1 Hz, 3H). LC/MS (m/z) [M+1]+ 279.3 (calculated for C11H13F2O4S, 279.3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[CH2:14][CH:13]3[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)(O)[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:5][CH:4]=1.[ClH:27].CCOC(C)=O>CCOC(C)=O>[Cl:27][C:15]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[CH:13]2[CH2:12][CH2:11][CH:10]1[CH2:9][N:8]([CH2:7][C:6]1[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:14]2
Reactant: COc1ccc(CN2CC3CCC(C2)C3(O)c2cccc(OC)c2)cc1
Reactant: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(CN2CC3CCC(C2)C3(Cl)c2cccc(OC)c2)cc1

Procedure:
3-(4-Methoxy-benzyl)-8-(3-methoxy-phenyl)-3-aza-bicyclo[3.2.1]octan-8-ol (1.48 g, 4.19 mmol) was dissolved in EtOAc (20 mL), charged with 2.5N HCl/EtOAc (6 mL), and azeotroped with MeOH (2×50 mL) to yield the HCl salt. This salt was slurried in CH2Cl2 (20 mL) and pyridine (0.34 mL, 4.19 mmol) then treated with thionyl chloride (0.92 mL, 12.6 mmol) dropwise, causing the dispersion to dissolve. The reaction was judged complete by TLC after 2 h, at which time it was carefully added to 1N NaOH (50 mL) at 0° C., bringing the final pH to 9. The product was extracted with CH2Cl2 (3×20 mL), washed with saturated aqueous NaCl solution (1×50 mL), filtered through a cotton plug and concentrated to brown oil. Flash chromatography provided a white solid (1.31 g, 84%). (TLC 40% EtOAc/hexanes Rf 0.75); 1H NMR (400 MHz, CDCl3) δ 7.23 (m, 3H), 7.04 (d, J=7.5 Hz, 1H), 6.99 (s, 1H), 6.84 (d, J=8.7 Hz, 2H), 6.79 (dd, J=7.9, 2.1 Hz, 1H), 3.78 (s, 6H), 3.53 (br s, 2H), 2.95 (d, J=10.3 Hz, 2H), 2.67 (br s, 2H), 2.65 (m, 2H), 1.79 (d, J=1.0 Hz, 2H), 1.45 (m, 2H); LCMS m/z 372.2 (M+1)+; mp 99–102° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:17]3[C:18]([O:24][CH3:25])=[N:19][CH:20]=[CH:21][C:22]=3[I:23])[NH:14]2)=[CH:10][C:9]=1[O:26][CH3:27])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[I:23][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([O:24][CH3:25])[C:17]=1[C:13]1[NH:14][C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:26][CH3:27])=[C:8]([NH2:7])[CH:16]=2
Reactant: COc1cc2cc(-c3c(I)ccnc3OC)[nH]c2cc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2cc(-c3c(I)ccnc3OC)[nH]c2cc1N
Yield: 84.3 %

Procedure:
A solution of [2-(4-iodo-2-methoxy-pyridin-3-yl)-5-methoxy-1H-indol-6-yl]-carbamic acid tert-butyl ester (250 mg, 0.51 mmol) in CH2Cl2 (5 mL) was added 2,2,2-trifluoroacetic acid (1 mL) at 25° C. The solution was heated to reflux for 3 h and then concentrated in vacuo and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (50/50 hexanes/ethyl acetate) afforded 2-(4-iodo-2-methoxy-pyridin-3-yl)-5-methoxy-1H-indol-6-ylamine (170 mg, 85%) as a white solid. MH+ 395.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[CH:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][C@@H:12]([CH2:22][CH:23]=C)[C:11]1=[O:25])=[O:4].C[N+]1([O-])CC[O:36]CC1.O>CC(C)=O.O=[Os](=O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[CH:8][C:9]=1[N:10]1[CH:15]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:14][CH2:13][C@@H:12]([CH2:22][CH2:23][OH:36])[C:11]1=[O:25])=[O:4]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CC[C@@H]1CCC(C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)OC)C1=O
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@H](CCO)CCC1C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 3-((S)-3-allyl-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (less polar diastereomer from previous step) (200 mg, 0.45 mmol, 1.0 equiv) in acetone (3.0 mL) at 0° C. was added N-methylmorpholine oxide (160 mg, 1.36 mmol, 3 equiv), water (1.0 mL) and OsO4 (230 mg, 0.02 mmol, 0.05 equiv). The reaction mixture was stirred at room temperature for 1 hour. The solution was partitioned between brine and EtOAc. The phases were separated and the organic layer was dried over Na2SO4, and concentrated under vacuum. The residue was dissolved in THF/water (3.0 mL/1.0 mL). To the solution was added NaIO4 (194 mg, 0.9 mmol, 2 equiv), and the resulting mixture was stirred at room temperature for 30 minutes, after which another portion of NaIO4 (0.5 equiv) was added. After stirred at room temperature for 30 minutes, the mixture was partitioned between brine and EtOAc. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was dissolved in EtOH (3.0 ml) and the solution was cooled at 0° C. To the solution was added NaBH4 and the mixture was stirred at 0° C. for 15 minutes. The reaction was quenched by addition of water (2.0 mL) and EtOAc (10.0 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, Heptane/EtOAc 1/1 to give 123 mg of the product (yield 60%). MS: 446 [M+H+]
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:10]2[CH2:13][C:12](=[C:14]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11]2)=[CH:5][CH:4]=1.[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1=[O:40]>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C@@H:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:37]3[CH2:38][CH2:39][NH:34][C:35](=[O:40])[CH2:36]3)=[CH:8][CH:7]=2)[N:10]2[CH2:13][C:12](=[C:14]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11]2)=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CCl)cc2)C1)c1cc(F)cc(F)c1
Reactant: O=C1CNCCN1
Solvent: ClCCl
Product: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CN3CCNC(=O)C3)cc2)C1)c1cc(F)cc(F)c1
Temperature: 20 °C
Reaction time: 96 h
Yield: 39.1 %

Procedure:
The operation is carried out as described in Example 87, but by stirring the reaction mixture for 4 days at 20° C., starting with 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm3 of dichloromethane, and 0.024 g of piperazin-2-one. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm3 fractions immediately after using this eluent mixture. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.022 g of 1-{(R*)-(4-chlorophenyl)[4-(piperazin-2-on-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam [1H NMR spectrum (400 MHz, CDCl3, δ in ppm): 2.62 (t, J=5.5 Hz, 2H), 2.80 (s, 3H), 3.11 (s, 2H), 3.34 (mt, 2H), 3.51 (s, 2H), 3.85 (mt, 2H), 4.34 (mt, 2H), 4.51 (s, 1H), 5.76 (unresolved complex, 1H), 6.84 (broad t, JHF=9 Hz, 1H), 6.98 (mt, 2H) from 7.20 to 7.40 (mt, 8H)].
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][C:14]=1B(O)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].C(Cl)Cl>[F:11][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[C:18]1[CH:17]=[C:16]([O:19][CH2:20][CH2:21][CH3:22])[CH:15]=[CH:14][C:13]=1[F:12]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: CCCOc1ccc(F)c(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: CCCOc1ccc(F)c(-c2nc(C(=O)O)ccc2F)c1

Procedure:
Method 1 was followed using 6-bromo-5-fluoropicolinic acid (1.0 equiv.) and 2-fluoro-5-propoxyphenylboronic acid (1.5 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give 5-fluoro-6-(2-fluoro-5-propoxyphenyl)picolinic acid. LC/MS=294.2 (M+H), Rt=0.95 min.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([NH:13][C@H:14]([C:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:33]([C:34]#[N:35])=[C:32]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:31]=[C:30]([S:41][CH2:42][C:43]3[N:44]=[C:45]([C:48]4[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=4)[S:46][CH:47]=3)[C:29]=2[C:55]#[N:56])=[CH:24][CH:23]=1)=[O:17])[CH3:15])=[O:12])=O)(C)(C)C.Cl>ClCCl.C(OCC)C>[ClH:54].[NH2:8][CH2:9][CH2:10][C:11]([NH:13][C@H:14]([C:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[C:33]([C:34]#[N:35])=[C:32]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:31]=[C:30]([S:41][CH2:42][C:43]3[N:44]=[C:45]([C:48]4[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=4)[S:46][CH:47]=3)[C:29]=2[C:55]#[N:56])=[CH:26][CH:27]=1)=[O:17])[CH3:15])=[O:12]
Reactant: C[C@H](NC(=O)CCNC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@H](NC(=O)CCN)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
200 mg (0.245 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl N-(tert-butoxycarbonyl)-beta-alanyl-L-alaninate (Example 8A) were dissolved in 2 ml dichloromethane, and 2.45 ml 1M HCl in diethyl ether were added. After 3 hours, 1 ml of a 1N solution of hydrogen chloride in diethyl ether was added and the mixture was stirred at room temperature for a further 2 hours. The precipitated solid was filtered off with suction, washed with diethyl ether and dried under reduced pressure. 155 mg (yield: 82% of theory) of the target compound were obtained.