Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Br:16].Cl[Si:18]([CH3:21])([CH3:20])[CH3:19].Cl>C1COCC1>[Br:9][C:10]1[C:11]([Br:16])=[C:12]([Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[CH:14][C:15]=1[Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: Brc1ccccc1Br
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc([Si](C)(C)C)c(Br)c1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
LDA (2 M, 70 mL, 140 mmol) was added dropwise to a solution of 1,2-dibromobenzene (15.0 g, 64 mmol) and chlorotrimethylsilane (20 mL, 153 mmol) in THF (90 mL) at −78° C. The resultant brown suspension was stirred at −78° C. for 30 min and then gradually warmed to room temperature. The reaction mixture was stirred for 18 h and then cooled to −78° C. again and chlorotrimethylsilane (20 mL, 153 mmol) was added. LDA (2M, 70 mL, 140 mmol) was added dropwise and the resultant brown suspension was stirred at −78° C. for 30 mins and then gradually warmed to room temperature. The reaction mixture was stirred for a further 18 h and then hydrolyzed with 1 N HCl (100 mL). The resultant mixture was extracted with diethyl ether (3×200 mL) and the combined organic layers was concentrated to give brown oil, which was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.34 (s, 2H), 0.40 (18H).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@:10]2([NH2:22])[C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:5])C.O[Li].O.Cl>C1COCC1.O.CO>[NH2:22][C@@:10]1([C:12]([OH:14])=[O:13])[C@H:9]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][C@@H:7]2[C@H:11]1[C@H:6]2[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](OCc3ccccc3)[C@@](N)(C(=O)OCc3ccccc3)[C@@H]21
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1OCc1ccccc1)[C@@H]2C(=O)O
Temperature: 23 °C
Yield: 73.2 %

Procedure:
A solution of (1S,2R,3R,5R,6S)-2-amino-3-benzyloxy-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXIV-3) (50 mg, 0.122 mmol) and LiOH.H2O (13 mg, 0.30 mmol) in THF (4 mL), H2O (2 mL) and MeOH (0.4 mL) was stirred at 23° C. for 36 h. The solution was acidified with conc. HCl and evaporated to dryness. The remaining pale yellow solid was suspended in EtOH, filtered, washed with more EtOH and the filtrate was evaporated to dryness. The residue was dissolved in EtOH (1 mL) and propylene oxide (1 mL) and refluxed for 3 min, whereupon the amino acid precipiated. After cooling to 23° C., the product was filtered off, washed with ether and dried to give (1S,2R,3R,5R,6S)-2-amino-3-benzyloxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid (I-10) (26 mg, 72%) as a white solid. 1H-NMR (250 MHz, D2O) □1.57 (1H, t, J=3.5 Hz), 1.97 (2H, m), 2.13 (1H, ddd, J=12.5, 8,3.5 Hz), 2.35 (1H, dd, J=12.5, 7 Hz), 3.73 (1H, dd, J=8, 7 Hz), 4.51 (2H, s), 7.36 (5H, bm); MS[ISN] 290 [(M-H)- ]; mp>250° C.; □D20 -5.69° (c=0.25, H2O).
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH:12]([C:25](O)=[O:26])[CH2:11]2)=[CH:6][CH:5]=1.O[N:30]=[C:31]([CH:33]1[CH2:35][CH2:34]1)[NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:33]1([C:31]2[N:32]=[C:25]([CH:12]3[CH2:11][CH:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:1])[F:28])=[CH:5][CH:6]=4)[CH2:15][N:14]([C:16]([N:18]4[CH2:19][CH2:20][S:21](=[O:24])[CH2:22][CH2:23]4)=[O:17])[CH2:13]3)[O:26][N:30]=2)[CH2:35][CH2:34]1
Reactant: NC(=NO)C1CC1
Reactant: O=C(O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)CC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCS(=O)CC1)N1CC(c2ccc(OC(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
200 mg (0.48 mmol) of the compound from Example 39A and 96 mg (0.96 mmol) of N′-hydroxycyclopropanecarboximidamide were initially charged in 1.8 ml of DMF and reacted with 274 mg (0.72 mmol) of HATU and 0.25 ml (186 mg, 1.44 mmol) of N,N-diisopropylethylamine. The reaction mixture was stirred at RT for 15 minutes and then partitioned between water and ethyl acetate. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in 2.0 ml of DMF and converted in a microwave at 180° C. for 2 minutes. The reaction mixture was purified by means of preparative HPLC. Yield: 25 mg (10% of theory)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([N:16](CC)CC)C.CN>C1COCC1.[Cl-].[Na+].O>[CH3:14][NH:16][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CC
Agent: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cold solution of 4-nitrobenzenesulfonyl chloride (2.7 g, 12 mmol) and triethylamine (27 mmol) in 60 mL of dry THF was added methylamine (8 mL of a 2 M solution in THF, 16 mmol). The mixture was stirred at room temperature overnight. Brine was added and the reaction solution was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to yield 4-nitrobenzenesulfonic acid methylamide as an oil. The crude material was used in the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:30][C:31]1C=[C:39]2[C:34](C(Cl)=C([N+]([O-])=O)C=[N:38]2)=[CH:33][CH:32]=1)C1C=CC=CC=1.NCCCCCO.O(CCN)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]2[NH:38][CH2:39][CH2:34][CH2:33][CH2:32][CH2:31][OH:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Reactant: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1Cl
Agent: NCCCCCO
Agent: NCCOc1ccccc1
Product: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1NCCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A modification of the general method described in Part A of Example 46 was followed using 6-benzyloxy-4-chloro-3-nitroquinoline (10.5 g, 34 mmol), prepared as described in Parts A-D of Example 57, in lieu of 7-benzyloxy-4-chloro-3-nitroquinoline and 5-amino-1-pentanol (3.5 g, 34 mmol) in lieu of 2-phenoxyethylamine. The reaction was heated at reflux for two hours and then allowed to cool to ambient temperature slowly and stirred overnight. An analysis by TLC indicated the presence of starting material, and additional 5-amino-1-pentanol (0.2 equivalent) was added. The reaction was heated at reflux until the reaction was complete as indicated by TLC. Following the work-up, the crude product was purified by column chromatography on silica gel (eluting with 95:5-dichloromethane:methanol) to provide 5.95 g of 5-{[6-(benzyloxy)-3-nitroquinolin-4-yl]amino}pentan-1-ol as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:8]([CH:9]=O)=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>S([O-])([O-])(=O)=O.[Cu+2].C(Cl)Cl>[CH3:13][C:14]([S@:17]([N:19]=[CH:9][C:8]1[CH:7]=[N:6][CH:5]=[CH:4][C:3]=1[C:2]([F:12])([F:11])[F:1])=[O:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cnccc1C(F)(F)F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)N=Cc1cnccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 68 h

Procedure:
To a the solution of 4-(trifluoromethyl)nicotinaldehyde from above was added DCM (10 mL), (R)-2-methylpropane-2-sulfinamide (1.553 g, 12.81 mmol; See Table 1, footnote 1) (AK Scientific) and copper sulfate (4.09 g, 25.6 mmol) (Aldrich, anhydrous). The suspension was stirred at rt under N2 for 68 h. The suspension was then filtered through Celite® brand filter agent, and the solid was washed with DCM (2×20 mL). The filtrates were concentrated and purified by ISCO (40 g, SiO2, 10-50% EtOAc/hexane) to give (R)-2-methyl-N-((4-(trifluoromethyl)pyridin-3-yl)methylene)propane-2-sulfinamide as a light yellow oil.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@@H:18]1[C:23]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[CH:22][C@@H:21]([CH2:29][O:30][CH3:31])[NH:20][CH2:19]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1>C(#N)C>[CH2:1]([O:4][NH:5][C@@H:18]1[C:23]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[CH:22][C@@H:21]([CH2:29][O:30][CH3:31])[NH:20][CH2:19]1)[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN[C@H](COC)C=C1C(=O)N(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC#N
Product: C=CCON[C@H]1CN[C@H](COC)C=C1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a solution of (3R,6S)-3-(N-(allyloxy)-2-nitrophenylsulfonamido)-6-(methoxymethyl)-N,N-dimethyl-1,2,3,6-tetrahydropyridine-4-carboxamide (Intermediate 141, 1.346 g, 2.96 mmol) and potassium carbonate (2.456 g, 17.77 mmol) in acetonitrile (50 mL) was added benzenethiol (1.825 mL, 17.77 mmol) and stirred at rt overnight. The solvent was evaporated then the crude mixture was redissolved in DCM and a little bit MeOH, filtered, loaded onto silica gel. The crude product was purified via flash chromatography (0-20% MeOH/DCM) and dried under high-vacuum to obtain the desired product (0.725 g, 91%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[C:3]=1[C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[CH:30]=[CH:29][C:18]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:17]([CH2:31][OH:32])[CH:16]=2)=[N:7]1)=[O:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:38])[F:40])[C:3]=1[C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[CH:30]=[CH:29][C:18]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:17]([CH:31]=[O:32])[CH:16]=2)=[N:7]1)=[O:5]
Reactant: O=C(OCc1ccccc1)c1ccc(-c2nn(C(=O)c3c(Cl)cccc3C(F)(F)F)c3ccccc23)cc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=Cc1cc(-c2nn(C(=O)c3c(Cl)cccc3C(F)(F)F)c3ccccc23)ccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of benzyl 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-indazol-3-yl)-2-(hydroxymethyl)benzoate (G-3) (0.4 g, 0.71 mmol) in DCM (10 mL) was added Dess-Martin periodinane (0.45 g, 1.07 mmol), and the mixture was stirred at rt for 24 h. The mixture was diluted with H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The resulting crude oil was used in the next step without further purification. LCMS (ESI)′ calc'd for C30H19ClF3N2O4 [M+H]+: 563. found: 563.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].C1(C[N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][O:24][C:25]3[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=3)[CH2:18][CH2:17]2)C=CC=CC=1.[H][H]>[Pd].C(O)C>[C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[NH:16]1[CH2:17][CH2:18][CH:19]([CH2:22][CH2:23][O:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:34][CH:35]=2)[CH2:20][CH2:21]1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(OCCC2CCN(Cc3ccccc3)CC2)cc1
Reactant: O=C(O)/C=C\C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(OCCC2CCNCC2)cc1
Product: O=C(O)CCC(=O)O
Yield: 100 %

Procedure:
A mixture of 4.8 parts of ethyl 4-[2-[1-(phenylmethyl)-4-piperidinyl]ethoxy]benzoate (Z)-2-butenedioate(1:1) and 120 parts of ethanol was hydrogenated at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from 2-propanol, yielding 4.5 parts (100%) of ethyl 4-[2-(4-piperidinyl)ethoxy]benzoate butanedioate(1:1); mp. 146.7° C. (int. 51).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH3:16])=[C:8]2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:55]([NH:62][C:63]([CH:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1)=[O:64])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>CCOC(C)=O.CN(C=O)C>[CH2:55]([NH:62][C:63]([CH:65]1[CH2:70][CH2:69][N:68]([C:17]([C:8]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][CH:20]=3)[C:15]3[C:10]([C:9]=2[CH3:16])=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:19])[CH2:67][CH2:66]1)=[O:64])[C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: Cc1c(C(=O)O)n(Cc2ccc(Cl)cc2)c2ccccc12
Reactant: O=C(NCc1ccccc1)C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)N2CCC(C(=O)NCc3ccccc3)CC2)n(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The following was added to sequentially to DMF (3 mL): 1-(4-chlorobenzyl)-3-methyl-1H-indole-2-carboxylic acid (90 mg, 0.315 mmol), DIPEA (0.170 mL, 0.945 mmol), and HATU (144 mg, 0.378 mmol). This was allowed to stir for 30 min at rt, after which time the crude N-benzylpiperidine-4-carboxamide (˜70 mg, 0.315 mmol) was added. The reaction was stirred at rt for 17 h, at which time the reaction was diluted with 1:1 EtOAc:diethyl ether and washed with 10% aq. sodium carbonate (2×), dried over magnesium sulfate, and concentrated. The residue was purified via silica gel flash chromatography (20 g silica, 50% EtOAc/Hexanes) to afford the title compound as an oil. Yield: (77 mg, 0.153 mmol, 51%) 1H NMR (400 MHz, CDCl3) 7.59, 7.34-7.14, 7.03, 5.73, 5.57, 5.43-5.32, 4.76, 4.43, 3.77-3.64, 3.10, 2.80, 2.19-1.52
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH2:16][CH:15]([NH:19][CH2:20][C@H:21]([OH:34])[C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:23]=3)[CH2:14][C:13]=2[CH:35]=1)(C)(C)C.FC(F)(F)C(O)=O.[Cl:44]CCl>>[ClH:44].[OH:34][C@H:21]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:23]=1)[CH2:20][NH:19][CH:15]1[CH2:14][C:13]2[CH:35]=[C:9]([O:8][CH2:7][C:6]([OH:36])=[O:5])[CH:10]=[CH:11][C:12]=2[CH2:18][CH2:17][CH2:16]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)COc1ccc2c(c1)CC(NC[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1)CCC2
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCCc3ccc(OCC(=O)O)cc3C2)ccc1O
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under nitrogen, to a solution of 2-[8-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylaminophenyl)ethylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid tert-butyl ester (257 mg) in dichloromethane (5 ml) was added trifluoroacetic acid (1 ml) at 5° C., and the mixture was stirred at room temperature for 3 hours. The resulting mixture was evaporated in vacuo. The residue was treated with 4N hydrogen chloride in 1,4-dioxane to give 2-[8-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylaminophenyl)-ethylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-acetic acid hydrochloride (247 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:31])[C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18](SCCO)[CH:17]=2)=[C:4]([O:32][CH3:33])[CH:3]=1.O[O:35][S:36]([O-:38])=O.[K+].[NH4+].[Cl-].[CH3:42][CH2:43][O:44]C(C)=O>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:31])[C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[C:18]([S:36]([CH2:42][CH2:43][OH:44])(=[O:38])=[O:35])[CH:17]=2)=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCCO)cc(C(F)(F)F)c1
Reactant: O=S([O-])OO
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)CCO)c1
Temperature: 25 °C
Reaction time: 3.25 h

Procedure:
To an ice-cold solution of N-[4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-3-(2-hydroxy-ethylsulfanyl)-N-methyl-5-trifluoromethyl-benzamide (0.1 g, 208 μmol, example 216) in MeOH (4 mL) and water (0.5 mL) was added Oxone® (320 mg, 520 μmol) and the white suspension was stirred at room temperature for 3.25 hours. The white suspension was poured on saturated aqueous NH4Cl solution and EtOAc. The two layers were separated and the aqueous layer was extracted twice with EtOAc. The organic layers were washed once with aqueous sodium thiosulfate 10% solution and once with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 5 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless foam (0.069 g; 64%). MS (ESI): m/z=513.11 [M+H]+.
Reaction SMILES: [Na].[F:2][C:3]1[C:4]([CH3:18])=[C:5]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[NH:11])[CH:6]=[CH:7][CH:8]=1.C([O:21][CH:22]=[C:23]([C:29](OCC)=O)[C:24]([O:26]CC)=[O:25])C.O.C(=O)(O)[O-].[Na+]>C(#N)C>[F:2][C:3]1[C:4]([CH3:18])=[C:5]([N:9]2[C:22](=[O:21])[C:23]([C:24]([OH:26])=[O:25])=[CH:29][N:11]=[C:10]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(F)cccc1NC(=N)c1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC#N
Product: Cc1c(F)cccc1-n1c(-c2ccccc2)ncc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-(3-fluoro-2-methylphenyl)benzenecarboximidamide sodium salt (1:1) (i.e. the product from Example 5, Step A) (51.0 g, 200 mmol) in acetonitrile (300 mL) was added diethyl ethoxymethylenemalonate (44.04 g, 200 mmol). The reaction was stirred at room temperature for 30 min followed by the addition of water (3.6 mL, 200 mmol). The reaction was then stirred for another 30 min Water (100 mL) was added to the residue, followed by a saturated solution of sodium bicarbonate (300 mL), and the mixture was extracted with ethyl acetate. The aqueous layer was acidified with concentrated hydrochloric acid until the pH was 1-2, and the mixture was extracted with dichloromethane. The organic layer was dried (MgSO4) and concentrated under reduced pressure to provide a solid, which was washed with diethyl ether and dried under reduced pressure to afford the title product as a off-white solid (18 g).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[C:15]1([CH:21]([NH2:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:29][CH:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NC(Cc1ccccc1)c1ccccc1
Solvent: CO
Product: N#CNC(=NC(Cc1ccccc1)c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 56.3 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.60 g, 3.2 mmol) was dissolved in methanol (10 ml), and 1,2-diphenylethylamine (0.69 g, 3.5 mmol) was added. The mixture was stirred at room temperature for 45 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 50 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure to give N-cyano-N'-(1,2-diphenylethyl)-3-pyridinecarboximidamide (0.60 g, 1.8 mmol, yield: 58%) as colorless syrup. Next, to this syrup was added a 5% hydrogen chloride solution in methanol (2.5 ml). The solution was crystallized from methanol-diethyl ether to give N-cyano-N'-(1,2-diphenylethyl)-3-pyridinecarboximidamide hydrochloride as colorless powder.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=O)[O:22][C:21]2=[O:28]>>[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:22])[N:1]([CH:2]1[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=3)[O:5][C:4]([CH3:14])([CH3:15])[CH:3]1[OH:16])[C:21]2=[O:28]
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Product: CC1(C)Oc2ccc(C#N)cc2C(N2C(=O)c3ccc(Cl)cc3C2=O)C1O

Procedure:
Following the procedure in Example 89, using (3S,4R)-4-amino-3-hydroxy-2,2-dimethyl-chroman-6-carbonitrile and 5-chloro-isobenzofuran-1,3-dione as starting materials, the title compound was prepared as a pale yellow solid.
Reaction SMILES: Cl.C(O[C:10]([N:12]([C:14]1[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=1)C)=O)C1C=CC=CC=1>CO.[Pd]>[CH3:10][NH:12][C:14]1[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=1
Reactant: CCOC(=O)COc1ccc(N(C)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)COc1ccc(NC)cc1

Procedure:
1.93 ml (1.93 mmol) of 1N aqueous hydrochloric acid were added to a solution of 600 mg (1.75 mmol) of ethyl 4-(N-benzyloxycarbonyl-N-methylamino)phenoxyacetate (prepared as described in Preparation 16) in 18 ml of methanol, and the mixture was stirred at room temperature for 1.5 hours in the presence of a palladium-on-charcoal catalyst, under an atmosphere of hydrogen. At the end of this time, the catalyst was removed by filtration, and the filtrate was freed from the solvent by distillation under reduced pressure. The resulting residue was mixed with benzene, and the mixture was dehydrated by azeotropic distillation. This operation was repeated again, to give ethyl 4-methylaminophenoxyacetate as a residue. The whole of this residue was dried in vacuo and then dissolved in 2 ml of dimethylformamide. 186 mg (1.75 mmol) of sodium carbonate and 0.12 ml (1.93 mmol) of methyl iodide were added to the solution, and the mixture was stirred at room temperature for 48 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was mixed with ethyl acetate. The resulting organic mixture was washed with a 5% w/v aqueous solution of sodium hydrogencarbonate, with a 5% w/v aqueous solution of sodium thiosulfate and with a saturated aqueous solution of sodium chloride, in that order. The reaction mixture was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by preparative thin layer chromatography, using a 1:1 by volume mixture of hexane and ethyl acetate as the developing solvent, to give 129 mg of the title compound as an oil.