Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6](=[O:35])([O:10][CH:11]([O:13][C:14](=[O:34])[CH2:15][CH2:16][CH:17]([P:26]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27])[P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])[CH3:12])SCC>C(Cl)Cl>[CH2:21]([O:20][P:18]([CH:17]([P:26]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27])[CH2:16][CH2:15][C:14]([O:13][CH:11]([O:10][C:6]([Cl:4])=[O:35])[CH3:12])=[O:34])([O:23][CH2:24][CH3:25])=[O:19])[CH3:22]
Reactant: CCOP(=O)(OCC)C(CCC(=O)OC(C)OC(=O)SCC)P(=O)(OCC)OCC
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(CCC(=O)OC(C)OC(=O)Cl)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sulfuryl chloride (78 μL, 0.96 mmol) was added drop-wise to a solution of 23 (237 mg, 0.48 mmol) in 10 mL of CH2Cl2 cooled to 0° C. The solution was stirred for 2 h. The solvent was removed under reduced pressure to afford chloroformate 24 and which was used for the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N+:19]([O-])=O)[C:12]([OH:18])=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl>CO.[Rh]>[NH2:19][C:11]1[C:12]([OH:18])=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)cc([N+](=O)[O-])c1O
Agent: [Rh]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1cc(OCc2ccccc2)cc(N)c1O

Procedure:
69.5 g (242 mmol) 1-(5-benzyloxy-2-hydroxy-3-nitrophenyl)-ethanone are dissolved in 1.4 L methanol and hydrogenated in the presence of 14 g rhodium on charcoal (10%) as catalyst at 3 bar and ambient temperature. Then the catalyst is filtered off and the filtrate is evaporated down. The residue is reacted further without additional purification. Yield: 60.0 g (96%), Rf value=0.45 (dichloromethane on silica gel).
Reaction SMILES: C[O-].[Na+:3].[NH2:4][C:5]([NH2:7])=[S:6].C([O:10][C:11](=O)[CH:12]([NH:18][C:19](=[O:30])[C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH3:28])=[C:22]([CH3:29])[CH:21]=1)[C:13](OCC)=[O:14])C>C(O)C>[OH:10][C:11]1[C:12]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH3:28])=[C:22]([CH3:29])[CH:21]=2)=[C:13]([OH:14])[N:7]=[C:5]([S-:6])[N:4]=1.[Na+:3]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(NC(=O)c1cc(C)c(OC)c(C)c1)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1c(C)cc(C(=O)Nc2c(O)nc([S-])nc2O)cc1C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
1.5 equivalents of sodium methoxide (30% solution in methanol) were added to 20.6 g of thiourea in 900 ml of absolute ethanol. 91 g of 2-(4-methoxy-3,5-dimethyl-benzoylamino)-malonic acid diethyl ester were added in small portions, and then the mixture was stirred at 60° C. for 3 h. Then the mixture was cooled to room temperature, and the precipitate was filtered off with suction, washed with 100 ml ethanol and 100 ml diethyl ether and dried in vacuo. 78.2 g of the crude title compound were obtained.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]=1)=[O:7].[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>O1CCOCC1>[ClH:3].[Cl:3][C:4]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]([C:31]([CH:28]2[CH2:30][CH2:29]2)=[O:32])[CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[CH:10]=1)=[O:7]
Reactant: O=C(Cl)C1CC1
Reactant: CN1CCC(Nc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCC(N(C(=O)C2CC2)c2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CC1
Temperature: 106 °C
Yield: 172.8 %

Procedure:
Combine 2-chloro-4-fluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamide dihydrochloride (Example 1, 48 mg, 0.134 mmol), dioxane (1 mL) and cyclopropylcarbonyl chloride (0.013 mL, 0.148 mmol). Shake and heat (106° C.) in a J-Kem® Reaction Block for 2 hr. Load onto a SCX column (Varian) and elute with 2 M ammonia methanol to give the free base of the title compound (54 mg, 93%). Following a salt formation method similar to that described in Example 1 gives the title compound as a white solid (47 mg): mp 133–6° C.; mass spectrum (freebase, ion spray): m/z=430.1 (M+1), 1H NMR (freebase, CDCl3): 8.31 (bs, N—H), 7.76 (dd, J=6.0 Hz, 8.6 Hz, 1H), 7.61–7.56 (m, 2H), 7.38 (t, J=8.0 Hz, 1H), 7.19 (dd, J=2.4 Hz, 8.3 Hz, 1H), 7.09 (td, J=2.4 Hz, 8.2 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H), 4.62–4.53 (m, 1H), 2.80 (bd, J=11.5 Hz, 2H), 2.20 (s, 3H), 2.05 (td, J=2.2 Hz, 12.1 Hz, 2H), 1.83–1.69 (bm, 2H), 1.59–1.37 (bm, 2H), 1.21–1.13 (m, 1H), 0.99–0.89 (bm, 2H), 0.56 (bd, J=7.4 Hz, 2H). Analysis calc'd for C23H26Cl2FN3O2.0.8H2O: C, 57.46; H, 5.79; N, 8.74. Found: C, 57.16; H, 5.73; N, 8.70.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11](O)=[CH:10][N:9]=1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:1][C@@H:2]2[CH2:6][CH2:5][NH:4][CH2:3]2)=[CH:10][N:9]=1
Reactant: O[C@H]1CCNC1
Reactant: Oc1ccc(Cl)nc1
Product: Clc1ccc(O[C@@H]2CCNC2)cn1

Procedure:
By the procedure of Example 2, employing the appropriate 3-(S)-hydroxypyrrolidine in place of 3-hydroxypyrrolidine and 2-chloro-5-hydroxypyridine in place of 3-hydroxypyridine, 2-chloro-5-(3-(R)-pyrrolidinyloxy)-pyridine was produced as a clear oil: 1H NMR (300 MHz, CD3OD) δ 8.10 (1H, s), 7.50 (1H, dd, J=2.3, 8.8 Hz), 7.40 (1H, d, J=8.8 Hz), 5.28 (1H, s), 3.63-3.31 (4H, m), 2.34 (2H, m).
Reaction SMILES: [CH3:1]I.[CH2:3]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C@H:25]([OH:53])[CH2:26][O:27][CH2:28][C:29]([O:32][C:33]([F:52])([F:51])[C:34]([F:50])([F:49])[O:35][C:36]([F:48])([F:47])[C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40])([F:31])[F:30])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H-].[Na+]>CN(C)C=O.O>[CH2:3]([C:11]1[CH:16]=[N:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C@H:25]([O:53][CH3:1])[CH2:26][O:27][CH2:28][C:29]([O:32][C:33]([F:52])([F:51])[C:34]([F:49])([F:50])[O:35][C:36]([F:47])([F:48])[C:37]([F:45])([F:46])[C:38]([F:43])([F:44])[C:39]([F:40])([F:41])[F:42])([F:30])[F:31])=[CH:21][CH:22]=2)=[N:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CI
Reactant: CCCCCCCCc1cnc(-c2ccc(OC[C@H](O)COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCc1cnc(-c2ccc(OC[C@@H](COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OC)cc2)nc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Methyl iodide (1.1 g, 7.76 mmol) was added to a solution of 5-octyl-2-[4-((R)-2-hydroxy-3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2,-difluoroethoxy)propoxy)phenyl]pyrimidine (Example 4, 1.5 g, 1.94 mmol) and sodium hydride (116 mg, 60 weight percent in oil, 2.91 mmol) in dimethyl formamide (10 ml). The resulting mixture was stirred at room temperature for 10 hours, was diluted with 50 ml of water, and was extracted with three 50 ml aliquots of diethyl ether. The organic extracts were dried (over MgSO4), filtered, and concentrated. The resulting product was then recrystallized from methanol at -30° C. to give a white smectic material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][CH:14]([C:16]1[N:17](C(OC(C)(C)C)=O)[CH2:18][C:19]([C:27]([O:29][CH3:30])=[O:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=1)[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][CH:14]([C:16]2[NH:17][CH2:18][C:19]([C:27]([O:29][CH3:30])=[O:28])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:20]=2)[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: COC(=O)C1(c2ccccc2)CN(C(=O)OC(C)(C)C)C(C(C)N)=N1
Product: COC(=O)C1(c2ccccc2)CNC(C(C)NC(=O)Cc2cc(F)cc(F)c2)=N1

Procedure:
Following General Procedure C above and using 3,5-difluorophenylacetic acid (Aldrich) and 1-tert-butoxycarbonyl-2-(1-aminoethyl)-4-methoxycarbonyl-4-phenyl-2-imidazoline (Example K), the title compound was prepared as a white foam (90%). The reaction was monitored by tlc (Rf=0.39 in 3:2 hexanes/EtOAc) and the product was purified by flash column chromatography.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=1)[N:7]=3.Cl.[NH2:27][C@@H:28]([CH2:32][O:33][CH3:34])[C:29]([OH:31])=[O:30]>>[CH3:34][O:33][CH2:32][C@H:28]([NH:27][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=1)[N:7]=3)[C:29]([OH:31])=[O:30]
Reactant: COC[C@H](N)C(=O)O
Reactant: FC(F)(F)Cn1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: Cl
Product: COC[C@H](Nc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(=O)O

Procedure:
8-bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene and (S)-2-amino-3-methoxypropanoic acid hydrochloride were reacted to form (S)-3-Methoxy-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino}-propionic acid. LCMS: RT=2.89 min, [M+H]+=453
Reaction SMILES: N[C:2]1[C:3]([F:20])=[CH:4][C:5]([F:19])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:9]=2[CH3:18])[CH:7]=1.N(OCCC(C)C)=O.[I:29]I>C(Cl)(Cl)Cl>[F:19][C:5]1[CH:4]=[C:3]([F:20])[C:2]([I:29])=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:9]=1[CH3:18]
Reactant: COC(=O)c1ccc(-c2cc(N)c(F)cc2F)c(C)c1
Reactant: II
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(-c2cc(I)c(F)cc2F)c(C)c1

Procedure:
methyl 5′-amino-2′,4′-difluoro-2-methylbiphenyl-4-carboxylate (500 mg, 1.80 mmol), 3-methylbutyl nitrite (317 mg, 2.71 mmol), iodine (549 mg, 2.16 mmol) and chloroform (15 ml) were refluxed in an oil bath for 5 hours then allowed to cooled to ambient overnight. Reaction crude was purified by flash chromatography (SiO2, Biotage 40+M cartridge) eluted with a EtOAc/hexanes gradient mixture. Related fractions were pooled and concentrated in vacuo to afford the title compound. LCMS (ESI) calc.=387.98; found=388.92 (M+1)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[C:20]([F:22])[CH:21]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:17]=[C:16]([F:15])[CH:21]=[C:20]([F:22])[CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cc(F)cc(F)c1
Reactant: OC1CCN(Cc2ccccc2)CC1
Product: Fc1cc(F)cc(OC2CCN(Cc3ccccc3)CC2)c1

Procedure:
The title compound was prepared from 1-benzyl-4-hydroxypiperidine and 3,5-difluorophenol, using the same method as that described for preparation 43. The crude compound was purified by column chromatography on silica gel, eluting with dichloromethane:methanol, 95:5, to afford the desired product in 63% yield. LRMS APCI m/z 304 [M+H]+
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13]C(=O)C)=[CH:9][CH:8]=1)[CH3:5]>Cl>[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH:4]([CH3:5])[C:3]([OH:17])=[O:2])=[CH:12][CH:11]=1
Reactant: COC(=O)C(C)Oc1ccc(NC(C)=O)cc1
Agent: Cl
Product: CC(Oc1ccc(N)cc1)C(=O)O
Temperature: 10 °C
Yield: 98.1 %

Procedure:
2-(4-Acetylaminophenoxy)-propionic acid methyl ester 8 (320 g, 1.35 mol) in conc. HCl (8 L) was refluxed for 48 hours. Excess conc. HCl was distilled off in vacuum and filtered hot. The mixture was cooled to 10° C., filtered and dried to give pure 9 (240 g, 81.7%) as a brown powder with an m.p between 175-180° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[C@@H:10]([CH3:12])[OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.Cl.[CH3:18][C:19]1[N:24]=[CH:23][C:22]([C:25]2[CH:26]=[N:27][C:28]([C@H:31]([NH2:33])[CH3:32])=[CH:29][CH:30]=2)=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:13](=[O:15])[NH:33][C@@H:31]([C:28]1[N:27]=[CH:26][C:25]([C:22]2[CH:23]=[N:24][C:19]([CH3:18])=[CH:20][CH:21]=2)=[CH:30][CH:29]=1)[CH3:32])[C@H:10]([OH:11])[CH3:12])([CH3:5])([CH3:6])[CH3:7]
Reactant: Cc1ccc(-c2ccc([C@@H](C)N)nc2)cn1
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc([C@@H](C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O)nc2)cn1
Reaction time: 2 h
Yield: 107.7 %

Procedure:
To a mixture of N-Boc-(L)-threonine (0.13 g, 0.61 mmol), (R)-1-(6′-methyl-[3,3′]bipyridinyl-6-yl)-ethylamine dihydrochloride (0.16 g, 0.56 mmol) and HATU (0.23 g, 0.61 mmol) was added THF (1 mL) followed by diisopropylethylamine (0.48 mL, 2.8 mmol). After 2 h, the volatiles were removed under a stream of N2 and the resulting oil was purified by flash chromatography on silica gel (0→5% MeOH/CH2Cl2) yielding 250 mg of {(1S,2R)-2-hydroxy-1-[(R)-1-(6′-methyl-[3,3′]bipyridinyl-6-yl)-ethylcarbamoyl]-propyl}-carbamic acid tert-butyl ester as a tan solid, m/z 415.8 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3([CH3:30])[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH2:13][C@@H:12]1[CH3:31])[CH2:6][CH2:5]2>Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3([CH3:30])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:13][C@@H:12]1[CH3:31])[CH2:6][CH2:5]2
Reactant: C[C@H]1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1C1CCc2cc(Br)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CN(C2(C)CCNCC2)CCN1C1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The intermediate obtained from step E (0.23 g) was dissolved in a solution of 4 N HCl in dioxane (3 mL). After being stirred at room temperature for 2 h, the solution was concentrated to provide the title compound as a trihydrochloride salt (0.23 g). MS calculated for C20H30BrN3: (M+H)+392; found 392.2, 394.2.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH2:35][C:36]1[N:37]=[CH:38][NH:39][CH:40]=1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH2:35][C:36]1[N:37]=[CH:38][NH:39][CH:40]=1)[C:30]([N:32]([CH3:33])[CH3:34])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CN(C)C(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](Cc2c[nH]cn2)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.48 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 77-2 (5.28 mmol, crude form) as starting materials, respectively 0.57 g (Isomer A, colorless powder) and 0.88 g (Isomer B, colorless powder) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [C:1]([C:3](=[N:15][O:16][CH:17]([CH3:19])[CH3:18])[C:4]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)=[N:5][O:6][CH:7]([CH3:9])[CH3:8])#[N:2].O.OO.C(=O)([O-])[O-:24].[K+].[K+]>CS(C)=O>[C:1]([C:3](=[N:15][O:16][CH:17]([CH3:19])[CH3:18])[C:4]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)=[N:5][O:6][CH:7]([CH3:9])[CH3:8])(=[O:24])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)ON=C(C#N)C(=NOC(C)C)n1cncn1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)ON=C(C(N)=O)C(=NOC(C)C)n1cncn1
Temperature: 25 °C
Reaction time: 10 h
Yield: 76.9 %

Procedure:
To 2 ml of a dimethyl sulfoxide solution containing 4.0 g (15.1 mmol) of 1-(2-cyano-1,2-diisopropoxyiminoethyl)-1H-1,2,4-triazole were added, with ice-cooling, 3.5 ml of hydrogen peroxide water and 2.30 g (16.6 mmol) of potassium carbonate, followed by stirring at room temperature for 10 hours. The resulting crystal was washed with water and isopropyl ether in this order, to obtain 3.28 g (yield: 77%) of a title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ncnc3[nH]ccc23)cc1
Temperature: 110 °C

Procedure:
To a solution of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (3.1 g, 20 mmol) dissolved in DMF (60 ml) are added 4-nitrophenol (4.9 g, 35 mmol) and potassium carbonate (5.3 g, 38 mmol). The resulting solution is heated to 110° C. overnight. After the completion of reaction as indicated by disappearance of starting material, the reaction mixture is cooled to ambient temperature and poured into cold water. The resulting solids are collected by filtration and washed with water (3×100 ml). The crude product is purified by flash column chromatography using hexanes:ethyl acetate (1/1 v/v) as eluent to afford the title compound as a solid: 1H NMR 400 MHz (DMSO-d6) δ 12.34 (bs, 1H), 8.35 (m, 3H), 7.57 (m, 3H), 6.61 (m, 1H); HRMS (MALDI-FTMS) calculated for C12H9N4O3 [MH]+ 257.0669,found 257.0670.
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][N:34]=[C:33]5[NH:37][CH:38]=[CH:39][C:32]=45)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:22])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][C:24]=3[NH:29][CH2:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]4[NH:37][CH:38]=[CH:39][C:32]=34)=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc2C(C)(C)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)CNCc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4,4-dimethyl-7-({2-[(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-amino]-pyridine-3-carbonyl}-amino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.115 g, step A), HCl (4N, 3 mL) and dioxane (4 mL) was stirred at RT for overnight. Sat'd NaHCO3 was added until the bubbling stopped. The aqueous phase was extracted with EtOAc 3 times. The combined organic phases were dried over Na2SO4 and evaporated to yield a light purple oil as a crude product, which was purified by chromatography through silica gel (10 g, 5% MeOH/CHCl3 with 1% NH4OH) to afford N-(4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-[(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-amino]-nicotinamide. The material was further purified via silica gel column chromatography (10 g, 1% to 5% MeOH/CH2Cl2, stepwise gradient) to afford pure title compound.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33][CH2:34][C:35]=1[CH2:36][CH:37]=[O:38])[CH:31]([NH:39][C:40](=[O:79])[C:41](=[N:67][O:68][C:69]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])([CH3:71])[CH3:70])[C:42]1[N:43]=[C:44]([NH:47][C:48]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[S:45][CH:46]=1)[C:30]2=[O:80])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>N1C=CC=CC=1>[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33][CH2:34][C:35]=1[CH:36]=[CH:37][O:38][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH:31]([NH:39][C:40](=[O:79])[C:41](=[N:67][O:68][C:69]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])([CH3:70])[CH3:71])[C:42]1[N:43]=[C:44]([NH:47][C:48]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[S:45][CH:46]=1)[C:30]2=[O:80])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC=O)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C3SC2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 8.3 %

Procedure:
p-Toluenesulphonyl chloride (1.31 g) is added to a solution, cooled to 5° C., of the syn isomer of 2-benzhydryloxycarbonyl-7-{2-[(2-t-butoxycarbonylprop-2-yl)-oxyimino]-2-(2-tritylaminothiazol-4-yl)-acetamido}-3-formylmethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (product 5e) (4.45 g) in pyridine (50 cc). The temperature is left to rise to 20° C. in the course of 30 minutes, the mixture is stirred for 1 hour at 20° C. and poured into iced water (300 cc), the water is decanted and the insoluble pasty product is taken up in ethyl acetate (300 cc). The solution is washed with 1 N hydrochloric acid (100 cc), a saturated solution of sodium bicarbonate (100 cc) and a saturated solution of sodium chloride (100 cc), dried over sodium sulphate and filtered and the filtrate is concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa). The product thus obtained is used as such for the remainder of the synthesis. This product (1 g) is purified by chromatography on a column of silica gel (0.05-0.2) (20 g) (diameter of the column: 1.7 cm), elution being carried out with an 80/20 (by volume) mixture of cyclohexane and ethyl acetate, and 50 cc fractions being collected. Fractions 4 to 12, containing the pure product, are evaporated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. to give a product (5d) (0.43 g), which is a mixture of the E and Z forms (in proportions--determined by NMR--of 75% of the E form and 25% of the Z form), in the form of a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][NH:5][C:6](=[O:8])[CH3:7].[O:13]1[CH2:15][C@H:14]1[CH2:16]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>>[O:13]1[CH2:15][C@H:14]1[CH2:16][O:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][NH:5][C:6](=[O:8])[CH3:7]
Reactant: CC(=O)NCc1ccccc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(=O)NCc1ccccc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A mixture of N-(2-hydroxybenzyl)acetamide (382 mg, 2.31 mmol), (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (599 mg, 2.31 mmol) and Cs2CO3 (901 mg, 2.77 mmol) in DMP (5 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-80% ethyl acetate in petroleum spirit) to give the subtitled compound (333 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[Se](=O)=[O:17]>>[O:3]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:5]=1)[CH:2]=[O:17]
Reactant: O=[Se]=O
Reactant: CC(=O)c1cccc(N2CCCC2=O)c1
Product: O=CC(=O)c1cccc(N2CCCC2=O)c1

Procedure:
1-(3-Acetylphenyl)pyrrolidin-2-one (1.2 g, 5.9 mmol) was reacted with selenium dioxide (0.98 g, 8.9 mmol) using the method described in Example 1 to give crude oxo[3-(2-oxopyrrolidin-1-yl)phenyl]acetaldehyde as a yellow oil: m/z (ES+) 218.