Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][CH2:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.[CH:16]([Sn](CCCC)(CCCC)CCCC)=[CH2:17]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:16]([C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][CH2:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1)=[CH2:17]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=c1[nH]c2cc(Br)ccc2c2c1CCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1ccc2c3c(c(=O)[nH]c2c1)CCC3
Temperature: 110 °C
Yield: 87.8 %

Procedure:
A solution of 2.0 g (7.6 mmol) of 7-bromo-1,2,3,5-tetrahydrocyclopenta[c]quinolin-4-one, 2.6 mL (9.9 mmol) of vinyltributyltin and 0.44 g (0.38 mmol) of tetrakis(triphenylphosphine)palladium is degassed and aerated with nitrogen. After six hours of heating to 110° C., the batch is concentrated by evaporation, and the residue is taken up on silica gel. Column chromatography on silica gel with hexane-ethyl acetate yields 1.41 g of product.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[C:8]2[CH:9]=[C:10]([CH2:13][N:14]3[C:18]([C:19]([O:21]CC)=[O:20])=[C:17]([CH:24]4[CH2:26][CH2:25]4)[N:16]=[C:15]3[CH2:27][CH3:28])[CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[NH:39][N:38]=[N:37][N:36]=1>O.C(O)C>[Br:3][C:4]1[C:8]2[CH:9]=[C:10]([CH2:13][N:14]3[C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH:24]4[CH2:26][CH2:25]4)[N:16]=[C:15]3[CH2:27][CH3:28])[CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[NH:39][N:38]=[N:37][N:36]=1
Reactant: CCOC(=O)c1c(C2CC2)nc(CC)n1Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1nc(C2CC2)c(C(=O)O)n1Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Reaction time: 18 h
Yield: 61.1 %

Procedure:
Potassium hydroxide (1.2 g) in water (5 ml) was added to a suspension of the product of Example 1 (0.5 g) in ethanol (15 ml) and the mixture stirred at 55° for 18 h. The solvent was evaporated and the residue partitioned between water (25 ml) and ether (3×25 ml). The aqueous phase was acidified to pH1 with hydrochloric acid (2N, 15 ml) and extracted with ethyl acetate (3×30 ml). The combined ethyl acetate extracts were washed with brine (50 ml) and dried. The solvent was concentrated in vacuo resulting in the precipitation of a colourless solid which was filtered off and washed with ether (2×5 ml) to give the title compound as a colourless solid (290 mg) m.p. 198°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=2)[CH:34]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J17) (347 mg, 1.0 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (297 mg, 1.0 mmol) according to the general procedure M. Obtained as a light red foam (550 mg, 96%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN(C(C)C)C(C)C.[CH3:55][O:56][CH2:57][C:58]1([NH2:63])[CH2:62][CH2:61][CH2:60][CH2:59]1>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:63][C:58]4([CH2:57][O:56][CH3:55])[CH2:62][CH2:61][CH2:60][CH2:59]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Reactant: COCC1(N)CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCC1(NC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4)c3O)nc2)CCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Combine 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (30 mg, 0.098 mmol), EDCI (28.2 mg, 0.147 mmol), and HOBT hydrate (22.50 mg, 0.147 mmol) in DMF (1 mL) and added Hunig's base (50.6 mg, 0.392 mmol). Then 1-(methoxymethyl)cyclopentanamine (19.0 mg, 0.147 mmol) was added and the reaction mixture was stirred at ambient temperature for 20 h. The reaction mixture was purified using HPLC (45-70% ACN in water, TFA-buffered) to give the title compound as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52-1.80 (m, 6H) 2.00-2.13 (m, 2H) 3.27 (s, 3H) 3.60 (s, 2H) 7.79 (d, J=8.59 Hz, 2H) 7.96-8.78 (m, 6H) 8.79-8.99 (m, 1H) 13.53 (br. s., 1H). MS m/z [M+H]+ 418.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C@@H:9]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)C1C=CC=CC=1.O.[H][H]>C(O)C.[Pd]>[F:29][C:26]([F:27])([F:28])[C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=1)[CH2:15][O:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2OCCN(Cc3ccccc3)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1cc(CO[C@H]2OCCN[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Yield: 79.8 %

Procedure:
A mixture of 0.68 g (1.37 mmole) of 4-benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine and 280 mg of 10% Pd/C in 36 mL of 97:3 ethanol:water was stirred under one atmosphere of hydrogen for 15 hr. The mixture was filtered through Celite, the filter cake was washed generously with ethanol, and the filtrated was concentrated in vacuo. The residue was purified by flash chromatography on 68 g of silica eluting with 1 L of 33:67 hexanes:diethyl ether, then 1 L of 25:75 hexanes:diethyl ether to give 0.443 g (80%) of an oil, which by 1H NMR was pure cis morpholine. 1H NMR (CDCl3, 400 MHz, ppm): δ 1.8 (br s, 1H), 3.10 (dd, J=12.5, 2.9, 1H), 3.24 (td, J=12.2, 3.6, 1H), 3.62 (dd, J=11.3, 2.5, 1H), 4.04 (td, J=11.7, 3, 1H), 4.11 (d, J=2.4, 1H), 4.49 (d, J=13.5, 1H), 4.74 (d, J=2.5, 1H), 4.80 (d, J=13.3, 1H), 7.25-7.40 (m, 5H), 7.40 (s, 2H), 7.68 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([S:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:5]=1)(=O)[CH3:2].Cl.[O:25]([NH2:27])[CH3:26].N1C=CC=CC=1>C(O)C>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[S:15][C:6]1[CH:5]=[C:4]([C:1](=[N:27][O:25][CH3:26])[CH3:2])[CH:14]=[CH:13][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CON
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(C)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Yield: 82.3 %

Procedure:
A mixture of 4'-acetyl-2'-(2,4-difluorophenylthio)methanesulfonanilide (0.9 g), methoxylamine hydrochloride (0.21 g) and pyridine (0.2 g) in ethanol (15 ml) was refluxed for 4 hours. The mixture was concentrated under reduced pressure, and the residue was triturated with water to give a powder. The powder was recrystallized from ethanol to give 2'-(2,4-difluorophenylthio)-4'-[1-(methoxyimino)ethyl]methanesulfonanilide (0.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[C:23]([F:26])([F:25])[F:24])[CH:9]=[CH:8][C:4]=1C(O)=O.[CH2:28]([O:35][C:36]1[CH:62]=[CH:61][C:39]([C:40]([O:42][C:43]2[CH:48]=[CH:47][C:46]([CH2:49][NH:50][CH2:51][C:52]([O:54]C(C)(C)C)=[O:53])=[C:45]([O:59][CH3:60])[CH:44]=2)=[O:41])=[CH:38][CH:37]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].CN([C:66]([O:70]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[CH2:28]([O:35][C:36]1[CH:62]=[CH:61][C:39]([C:40]([O:42][C:43]2[CH:48]=[CH:47][C:46]([CH2:49][N:50]([CH2:51][C:52]([OH:54])=[O:53])[C:66](=[O:70])[C:4]3[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:27])[CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[C:23]([F:24])([F:26])[F:25])=[CH:11][C:3]=3[O:2][CH3:1])=[C:45]([O:59][CH3:60])[CH:44]=2)=[O:41])=[CH:38][CH:37]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CNCC(=O)OC(C)(C)C)c(OC)c2)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)c(OC)c2)c(C(F)(F)F)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)O)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4C(F)(F)F)cc3OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.4 %

Procedure:
Prepared using General Procedures 6 then 8: To a stirred solution of 2-methoxy-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid INT-23 (107 mg, 0.278 mmol), TEA (77 μl, 0.556 mmol) and 4-(((2-(tert-butoxy)-2-oxoethyl)amino)methyl)-3-methoxyphenyl 4-(heptyloxy)benzoate INT-26 (135 mg, 0.278 mmol) in DMF (3 mL) was added HATU (111 mg, 0.292 mmol) and left at room temperature for 2 h. The reaction mixture was diluted with EA (50 mL). The organic phase was washed with brine (2×100 mL) then pre-absorbed onto silica gel and purified by chromatography (EA/isohexanes. The isolated material was taken up into DCM (3 mL) and TFA (2 mL) and stirred at room temperature for 2 h. After stirring for 2 h, the solvent was concentrated and the product was purified by preparative HPLC to afford 21 mg (9.4%) of 2-(N-(4-((4-(heptyloxy)benzoyl)oxy)-2-methoxybenzyl)-2-methoxy-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetic acid 316 as a white powder. LCMS-ESI (m/z) calculated for C42H45F3N2O10: 794; found 795 [M+H]+, tR=10.02 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.75-12.57 (br s, 1H), 10.33 (s, 0.5H), 10.30 (s, 0.5H), 8.12-8.00 (m, 2H), 7.52-7.41 (m, 2H), 7.32 (d, J=8.3 Hz, 0.5H), 7.26-7.03 (m, 6.5H), 6.97 (d, J=2.2 Hz, 0.5H), 6.92-6.85 (m, 1H), 6.81 (dd, J=8.2, 2.1 Hz, 0.5H), 5.00-4.70 (br s, 1H), 4.35 (s, 1H), 4.09 (td, J=6.6, 2.5 Hz, 2H), 3.88-3.83 (m, 5H), 3.82 (s, 2H), 3.77 (s, 3H), 3.70 (s, 1.5H), 3.64 (s, 1.5H), 1.80-1.70 (m, 2H), 1.48-1.24 (m, 8H), 0.93-0.84 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C1C(=O)N(Br)C(=O)C1.[CH2:18]([SH:22])[CH2:19][CH2:20][SH:21]>C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[S:22][CH2:18][CH2:19][CH2:20][S:21]1
Reactant: O=Cc1ccccc1F
Reactant: SCCCS
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Fc1ccccc1C1SCCCS1
Reaction time: 0.75 h
Yield: 78.2 %

Procedure:
To a solution of 2-fluorobenzaldehyde (10.03 g, 80.8 mmol, 1.0 eq.) and NBS (2.16 g, 12.1 mmol, 0.2 eq.) in CH2Cl2 (400 mL) was added 1,3-propanedithiol (9.8 mL, 97.6 mmol, 1.2 eq.). After 0.75 h, the reaction mixture was concentrated in vacuo. The residue was diluted with CH2Cl2 and water, and the layers were separated. The organic layer was dried over Na2SO4, filtered, concentrated in vacuo, and triturated with hexanes to give 2-(2-fluorophenyl)-1,3-dithiane as a white solid (13.55 g, 78% yield).
Reaction SMILES: C(O)C.[Na].[Cl:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13](=[NH:15])[NH2:14])[CH:9]=[CH:10][CH:11]=1.[CH2:16]([N:23]1[CH2:29][CH2:28][C:27](=O)[CH:26]([C:31](OCC)=[O:32])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:16]([N:23]1[CH2:24][CH2:25][C:26]2[C:31](=[O:32])[NH:15][C:13]([CH2:12][C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[CH:7]=3)=[N:14][C:27]=2[CH2:28][CH2:29]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CCC1=O
Reactant: N=C(N)Cc1cccc(Cl)c1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c(Cc2cccc(Cl)c2)nc2c1CCN(Cc1ccccc1)CC2
Yield: 33 %

Procedure:
Ethanol (30 ml) was cooled in an ice bath then sodium (160 mg, 6.70 mmol) was added, with vigorous stirring. Once the sodium was dissolved, 2-(3-chlorophenyl)ethanimidamide (474 mg, 2.81 mmol) and ethyl 1-benzyl-5-oxoazepane-4-carboxylate (876 mg, 2.81 mmol) was added. The reaction mixture was refluxed, under nitrogen, for 17 h. Water (2 ml) was added to quench the reaction then the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic phase was dried over magnesium sulphate and concentrated in vacuo. Trituration of the residue with diethyl ether afforded the title compound as a solid in 33% yield, 361 mg.
Reaction SMILES: CN(C)CCN.[CH:7]1([CH2:13][O:14][N:15]2C(=O)C3=CC=CC=C3C2=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(O)(=O)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])=[C:33]([C:45](=O)[CH2:46][CH3:47])[CH:32]=1>CCO>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])=[C:33]([C:45](=[N:15][O:14][CH2:13][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:46][CH3:47])[CH:32]=1
Reactant: O=C1c2ccccc2C(=O)N1OCC1CCCCC1
Reactant: CCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CN(C)CCN
Solvent: CC(=O)O
Solvent: CCO
Product: CCC(=NOCC1CCCCC1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
N,N-Dimethylethylenediamine (1.53 mL, 13.18 mmol) was added to a solution of N-(cyclohexylmethoxy)phthalimide (2.33 g, 8.99 mmol) in EtOH (30 mL), and the reaction allowed to stir at RT for 2 hours. Glacial acetic acid (5 mL) was then added to adjust the mixture to ca. pH 4 followed by a solution of N-(4-chloro-2-propionylphenyl)trifluoromethanesulfonamide 22 (1.89 g, 5.99 mmol) in EtOH (10 mL), and the reaction stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum, and the residue dissolved in Et2O (50 mL) and washed with water, brine, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by column chromatography (eluting with CH2Cl21PE, 3:4 to 1:3) to afford N-[4-chloro-2-(1-cyclohexylmethoxyiminopropyl)phenyl]trifluoromethanesulfonamide 104 (2.34 g, 91%), as colorless crystals. 1H n.m.r. (400 MHz, CDCl3) δ 12.01, br s, 1H, 7.67, d, J=8.8 Hz, 1H, 7.48, d, J=2.4 Hz, 1H, 7.32, dd, J=2.4 and 8.8 Hz, 1H, 4.02, d, J=6 Hz, 2H, 2.81, q, J=7.6 Hz, 2H, 1.74, m, 6H, 1.27, m, 3H; 1.19, t, J=7.6 Hz, 3H, 1.01, m, 2H. HRMS (M+) 426.0971.
Reaction SMILES: CS(C)=O.[F:5][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][C:19]=1/[CH:20]=[CH:21]/[N+:22]([O-:24])=[O:23])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(O)(=O)C.[BH4-].[Na+]>O>[F:5][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][C:19]=1[CH2:20][CH2:21][N+:22]([O-:24])=[O:23])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccn2)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])CCc1ccc(OCc2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
To a dimethyl sulfoxide (20.0 mL) solution of 2-(3-fluoro-4-((E)-2-nitro-vinyl)-phenoxymethyl)pyridine (1.20 g) described in Manufacturing Example 95-1-2 and acetic acid (1.00 mL) was added sodium borohydride (249 mg, 6.57 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 30 minutes at room temperature. Water was then added dropwise at room temperature while cooling appropriately. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, followed by crystallization with an ethyl acetate-heptane system and filtration to obtain the title compound (614 mg, 50.7%).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:9]=1[NH:10][C:11]1[C:12]([CH3:20])=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:7]#[N:8].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:9]=1[NH:10][C:11]1[C:12]([CH3:20])=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:7]#[N:8]
Reactant: Cc1c(Nc2c(I)cncc2C#N)ccc2[nH]ccc12
Reactant: OB(O)c1cc2ccccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1c(Nc2c(C#N)cncc2-c2cc3ccccc3o2)ccc2[nH]ccc12
Temperature: 80 °C
Yield: 18.1 %

Procedure:
To a mixture of 5-iodo-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile (200 mg, 0.53 mmol), 2-benzofuranboronic acid (173 mg, 1.07 mmol) and Pd(PPh3)4 (31 mg, 0.027 mmol) in DME (4.0 mL) was added 2.0 M aqueous Na2CO3 (0.8 mL). The resulting mixture was heated at 80° C. for 2 h, cooled to r.t. and filtered. The filtrate was concentrated and purified by HPLC to give 35 mg of 5-(1-benzofuran-2-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile 222 as a yellow solid. MS: 365.2 (M+H); HPLC retention time: 11.4 min.(a).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([S:19][CH2:20][C:21]([OH:23])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.FC(F)(F)C([O-])=O.[NH2:31][C@@H:32]1[C:39](=[O:40])[N:38]2[C@@H:33]1[S:34][CH2:35][C:36](/[CH:44]=[C:45]1/[C:46](=[O:69])[N:47]([CH2:50][C:51]3[CH:56]=[CH:55][N+:54]([CH2:57][C:58](=[O:68])[NH:59][C:60]4[CH:65]=[CH:64][C:63]([OH:66])=[C:62]([F:67])[CH:61]=4)=[CH:53][CH:52]=3)[CH2:48][CH2:49]/1)=[C:37]2[C:41]([OH:43])=[O:42]>CN(C)C(=O)C>[F:67][C:62]1[CH:61]=[C:60]([NH:59][C:58]([CH2:57][N+:54]2[CH:55]=[CH:56][C:51]([CH2:50][N:47]3[CH2:48][CH2:49]/[C:45](=[CH:44]\[C:36]4[CH2:35][S:34][C@H:33]5[N:38]([C:39](=[O:40])[C@H:32]5[NH:31][C:21](=[O:23])[CH2:20][S:19][C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:37]=4[C:41]([O-:43])=[O:42])/[C:46]3=[O:69])=[CH:52][CH:53]=2)=[O:68])[CH:65]=[CH:64][C:63]=1[OH:66]
Reactant: O=C(O)CSc1ccccc1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4cc[n+](CC(=O)Nc5ccc(O)c(F)c5)cc4)C3=O)CS[C@H]12
Agent: O=C([O-])C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CSc5ccccc5)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)c(F)c1

Procedure:
With 175.0 mg (1.08 mmol) 1,1′-carbonyldiimidazole, 182.0 mg (1.08 mmol) 2-(phenylthio)acetic acid and 500.0 mg (0.75 mmol) (E)-(6R,7R)-7-amino-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate trifluoroacetate in 4 ml N,N-dimethylacetamide. The resulting solid was purified by column chromatography on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (1:0, 4:1, 3:1, 2:1). The organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.
Reaction SMILES: CS(OCCCOC1C=CC=C(C2N(C3C=CC=C(Cl)C=3)N=C(C(N3CC(=O)NC3)=O)C=2)C=1)(=O)=O.CN.[CH:38]([OH:40])=[O:39].[Cl:41][C:42]1[CH:43]=[C:44]([N:48]2[C:52]([C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([O:59][CH2:60][CH2:61][CH2:62][N:63](C)[CH3:64])[CH:54]=3)=[CH:51][C:50]([C:66]([N:68]3[CH2:72][C:71](=[O:73])[NH:70][CH2:69]3)=[O:67])=[N:49]2)[CH:45]=[CH:46][CH:47]=1>O1CCCC1>[CH:38]([OH:40])=[O:39].[Cl:41][C:42]1[CH:43]=[C:44]([N:48]2[C:52]([C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([O:59][CH2:60][CH2:61][CH2:62][NH:63][CH3:64])[CH:54]=3)=[CH:51][C:50]([C:66]([N:68]3[CH2:72][C:71](=[O:73])[NH:70][CH2:69]3)=[O:67])=[N:49]2)[CH:45]=[CH:46][CH:47]=1
Reactant: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Agent: CN
Agent: CS(=O)(=O)OCCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Solvent: C1CCOC1
Solvent: O=CO
Product: CNCCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 120A and methylamine without the addition of tetrahydrofuran in analogy to the synthesis of the compound of Example 29. 46 mg (44% of theory) of the title compound are obtained.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@@H:6]1[C:13](=[O:14])[N:12]2[C@@H:7]1[S:8][CH2:9][C:10](/[CH:18]=[C:19]1/[C:20](=[O:43])[N:21]([CH2:24][C:25]3[CH:30]=[CH:29][N+:28]([CH2:31][C:32](=[O:42])[NH:33][C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([F:41])[CH:35]=4)=[CH:27][CH:26]=3)[CH2:22][CH2:23]/1)=[C:11]2[C:15]([O-:17])=[O:16])=[O:4].[SH:44][C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=1.C(N(CC)CC)C>CN(C)C=O>[F:41][C:36]1[CH:35]=[C:34]([NH:33][C:32]([CH2:31][N+:28]2[CH:27]=[CH:26][C:25]([CH2:24][N:21]3[CH2:22][CH2:23]/[C:19](=[CH:18]\[C:10]4[CH2:9][S:8][C@H:7]5[N:12]([C:13](=[O:14])[C@H:6]5[NH:5][C:3](=[O:4])[CH2:2][S:44][C:45]5[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=5)[C:11]=4[C:15]([O-:17])=[O:16])/[C:20]3=[O:43])=[CH:30][CH:29]=2)=[O:42])[CH:39]=[CH:38][C:37]=1[OH:40]
Reactant: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CBr)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)c(F)c1
Reactant: Oc1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CSc5ccc(O)cc5)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)c(F)c1

Procedure:
(E)-(6R,7R)-7-(2-bromo-acetylamino)-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate (see ex. C1a) (300.0 mg, 0.45 mmol) was dissolved in 3 ml N,N-dimethylformamide, then 4-mercaptophenol (58.0 mg, 0.45 mmol), followed by triethylamine (62.7 ml, 0.45 mmol) was added. After 22 h the reaction mixture was poured on diethyl ether and the solid was collected by filtration. The brown solid material was suspended in water: acetonitrile (1:1) and chromatographed on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water: acetonitrile (9:1, 4:1, 3:1). The organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH3:31])(=[O:30])=[O:29])=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][CH:17]=1.FC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1C1C=NC=CC=1>>[F:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH3:31])(=[O:30])=[O:29])=[CH:20][C:19]([C:2]2[N:6]3[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3S(C)(=O)=O)c2)OC1(C)C
Agent: CC1(C)OB(c2ccc(F)c(-c3cccnc3)c2)OC1(C)C
Product: CS(=O)(=O)c1ccccc1-c1cc(-c2cnc3nc(C(F)(F)F)cnn23)ccc1F
Yield: 89 %

Procedure:
This was prepared in 89% yield by a similar procedure to that described in Example 3, step f, except using 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine and 2-(6-fluoro-2′-(methanesulfonyl)biphenyl-3-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane instead of 7-bromo-3-(1-fluoro-1-methylethyl)imidazo[1,2-b][1,2,4]triazine and 3-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pyridine: 1H NMR (360 MHz, CDCl3) δ 2.93 (3H, s), 7.37 (1H, td, J 1.6, 7.5 Hz), 7.47 (1H, dd, J 1.2, 7.4 Hz), 7.69 (1H, td, J 1.5, 7.8 Hz), 7.75 (1H, td, J 1.5, 7.4 Hz), 8.17-8.21 (2H, m), 8.27 (1H, dd, J 1.4, 8.0 Hz), 8.61 (1H, s), 8.78 (1H, s); MS (ES+) m/z 437 [M+H]+. Anal. Found: C, 52.15; H, 2.85; N, 12.74%. Required for C19H12F4N4O2S: C, 52.29; H, 2.77; N, 12.84%.