Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[S:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]2)=[S:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: COc1nc(C)c(C)cc1NC(=S)Oc1ccccc1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=S)Nc3cc(C)c(C)nc3OC)CC2)c1
Yield: 69 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9]O.P(Br)(Br)[Br:12]>COCCOC.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][Br:12]
Reactant: BrP(Br)Br
Reactant: OCc1cc(F)ccc1Br
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(Br)c(CBr)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-bromo-5-fluorophenyl)methanol (11, 4.10 g, 20.0 mmol) in dry DME (40 mL) at 0° C. was added a solution of PBr3 (3.25 g, 12.0 mmol) in dry DME (40 mL) dropwise. The mixture was then slowly warmed up to RT and stirred at for another 3 h. The mixture was diluted with water (100 mL), and extracted with 1:1 petroleum-ether-EtOAc (100 mL×2). The combined extracts were washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated to give 1-bromo-2-(bromomethyl)-4-fluorobenzene (12).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])=[CH:9][C:10]2[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.C1C=C(C2C=CC=C([OH:36])C=2)C(O)=CC=1>O1CCOCC1>[OH:1][C:2]1([OH:36])[CH:7]=[CH:6][C:5]([C:8]([CH3:17])=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH2:3]1
Reactant: Oc1cccc(-c2ccccc2O)c1
Reactant: CC(=Cc1ccc(O)cc1)c1ccc(O)cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(=Cc1ccccc1)C1=CCC(O)(O)C=C1
Temperature: 19 °C
Reaction time: 1.17 h

Procedure:
Trimellitic anhydride chloride (10.53 grams, 0.05 mole) and anhydrous 1,4-dioxane (400 milliliters) are added to a reactor and maintained under a nitrogen atmosphere with stirring to provide a solution. The resultant solution is cooled in an ice bath to 12° C., then a solution of 4,4'-dihydroxy-alpha-methylstilbene (5.66 grams, 0.05 hydroxyl equivalent), anhydrous 1,4-dioxane (50 milliliters) and pyridine (0.05 mole, 3.96 grams) is added dropwise to the reactor from a pressure equalizing addition funnel at a rate so as to maintain the temperature at 10°-12° C. The 4,4'-dihydroxy-alpha-methylstilbene used contains 98.8 area percent of the diphenol and 1.2 area percent of a single dimeric component as determined by high pressure liquid chromatographic analysis (uv detector set at 254 nm). After 70 minutes, addition of the solution is completed. After and additional 11 minutes, the ice bath cooling the reactor exterior is removed and the product slurry is allowed to warm to 19° C. over the next 236 minutes. The product slurry is filtered under a nitrogen atmosphere through a bed of diatomaceous earth with washing of the filter cake using anhydrous 1,4-dioxane (250 milliliters). The clear filtrate is concentrated to approximately 100 milliliters total volume via removal of 1,4-dioxane by rotary evaporation at 90° C. under vaccuum. The resultant slurry of crystalline product is held under a nitrogen atmosphere for 24 hours followed by filtration to recover the solid product. After drying in a vacuum oven at 100° C. and 1 mm Hg the product is recovered at a constant weight of 9.3 grams of light yellow colored powder. During the drying process, a minor amount of pyridine hydrochloride sublimed out of the product. Fourier transform infrared spectrophotometric analysis of a potassium chloride pellet of the product demonstrated the presence of anhydride carbonyl group absorbances (1868 and 1782 (with 1815 as a shoulder) cm-1) and the ester carbonyl group absorbance (1742 cm-1). Proton magnetic resonance spectroscopy additionally confirms the product structure.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16](Br)[C:11]=2[N:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[C:37]4=[N:38][CH:39]=[CH:40][CH:41]=[C:36]4[N:35]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:34]3=[O:50])=[CH:29][CH:28]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>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>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([C:27]3[CH:32]=[CH:31][C:30]([N:33]4[C:37]5=[N:38][CH:39]=[CH:40][CH:41]=[C:36]5[N:35]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:48])([CH3:47])[CH3:49])[C:34]4=[O:50])=[CH:29][CH:28]=3)[C:11]=2[N:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2c(Br)cccc2n1Cc1ccccc1
Reactant: CC1(C)OB(c2ccc(-n3c(=O)n(COCC[Si](C)(C)C)c4cccnc43)cc2)OC1(C)C
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: O
Solvent: C1CCOC1
Product: Cc1nc2c(-c3ccc(-n4c(=O)n(COCC[Si](C)(C)C)c5cccnc54)cc3)cccc2n1Cc1ccccc1
Temperature: 100 °C
Yield: 53.5 %

Procedure:
Benzyl chloride (1.527 mL) was added to a solution of 4-bromo-2-methyl-1H-benzimidazole (1.40 g) and sodium hydride (0.531 g) in DMF (10 mL) at 0° C. The mixture was stirred at room temperature under a dry atmosphere for 1 h. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 5%-50% EtOAc in hexane) to give 1-benzyl-4-bromo-2-methyl-1H-benzo[d]imidazole (1.88 g) as tan oil. The mixture of 1-benzyl-4-bromo-2-methyl-1H-benzo[d]imidazole (496 mg), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (700 mg), Pd(Ph3P)4 (87 mg), sodium carbonate (476 mg) and THF (18 mL)-water (0.90 mL) was heated at 100° C. for 1 h under microwave irradiation. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10%-50% EtOAc in hexane) to give 3-[4-(1-benzyl-2-methyl-1H-benzimidazol-4-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (450 mg) as white crystals.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:35])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]1)[CH:5]=2.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[NH:25]1[CH2:26][CH2:27][CH:22]([CH2:21][CH2:20][O:19][C:6]2[CH:5]=[C:4]3[C:9]([C:10]([C:11]4[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=4)=[C:2]([Br:1])[C:3]3=[O:35])=[CH:8][CH:7]=2)[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(OCCC3CCNCC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of t-Butyl 4-(2-(2-bromo-3-(3,5-difluorophenyl)-1-oxo-1H-inden-6-yloxy)ethyl)piperidine-1-carboxylate (700 mg, 1.4 mmol) obtained in Step 1 in CH2Cl2 was added TFA (20 eq, 27 mmol). The solution was stirred for 1 h at room temperature and diluted with CH2Cl2. The mixture was basicified to with 3N aq. NaOH. The organic layer was washed with H2O and brine, dried over MgSO4, and concentrated to obtain the title compound (99%).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH2:7][C:8](=[O:10])[CH3:9])[O:4][N:3]=1.C(O[CH:16](N(C)C)[N:17]([CH3:19])[CH3:18])(C)(C)C>>[CH3:16][N:17]([CH3:19])[CH:18]=[C:7]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[N:6]=1)[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)Cc1nc(C)no1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CC(=O)C(=CN(C)C)c1nc(C)no1

Procedure:
1-(3-Methyl-[1,2,4]oxadiazol-5-yl)-propan-2-one (224 mg, 1.6 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 28a) to give crude title compound (313 mg) as a yellow oil which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:7]2.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1>CCOC(C)=O>[Cl:18][C:17]1[C:12]([C:6]2[N:7]=[C:8]3[C:3]([C:2]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:22][N:21]=4)=[CH:11][CH:10]=[N:9]3)=[CH:4][CH:5]=2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: Clc1cccnc1-c1ccc2c(Cl)ccnc2n1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(Nc2ccnc3nc(-c4ncccc4Cl)ccc23)nc1

Procedure:
Heat a mixture of 5-chloro-2-(3-chloropyridin-2-yl)-[1,8]naphthyridine (82.5 mg, 0.3 mmol) and 2-amino-5-trifluoromethylpyridine (97.2 mg, 0.6 mmol) at 180° C. for 2.0 hours. Cool the mixture, dilute with EtOAc/1.0 N aq. NaOH (5.0 mL each), and separate the organic layer, extract the aq. layer with EtOAc (2×5 mL) and dry the combined organic layers with MgSO4. Filter the dried extract and concentrate under vacuum to afford crude product. Purify by column chromatography using EtOAc to 2% MeOH/EtOAc as eluents to afford title compound as a yellow solid. 1H NMR (400 MHZ, DMSO-D6) δ 10.2 (s, 1H), 9.07 (d, 1H, J=1.9 Hz), 8.93 (d, 1H, J=1.2 Hz), 8.68 (m, 2H), 8.47 (s, 1H), 8.08 (m, 2H), 7.96 (d, 1H, J=2.2 Hz), 7.56 (dd, 1H), 7.46 (d, 1H, J=2.2 Hz). MS=402.22 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([O:10][Si](C(C)C)(C(C)C)C(C)C)[C:7]([CH3:21])=[CH:6][C:3]=1[CH:4]=O.Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH:31]([CH3:33])[CH3:32])[C:24]=1[CH3:34]>>[CH3:21][C:7]1[CH:6]=[C:3]([CH2:4][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH:31]([CH3:32])[CH3:33])[C:24]=2[CH3:34])[C:2]([CH3:1])=[CH:9][C:8]=1[OH:10]
Reactant: COc1ccc(Br)c(C)c1C(C)C
Reactant: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)c(C)cc1C=O
Product: COc1ccc(Cc2cc(C)c(O)cc2C)c(C)c1C(C)C

Procedure:
Intermediate 2,5-dimethyl-4-(4′-methoxy-2′-methyl-3′-iso-propyl-benzyl) phenol was prepared from 2,5-dimethyl-4-triisopropylsilanyloxy-benzaldehyde and 1-bromo-4-methoxy-2-methyl-3-iso-propylbenzene according to the procedure described in Chiellini et al., Bioorg. Med. Chem. Lett. 10:2607 (2000) and transformed into the title compound by the procedure described for the synthesis of compound 7: 1H NMR (300 MHz, DMSO-d6): δ 6.93 (s, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.64 (s, 1H), 4.09 (d, J=9.9 Hz, 2H), 3.79 (s, 2H), 3.77 (s, 3H), 3.34 (m, 1H), 2.22 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.31 (d, J=7.2 Hz, 6H); LC-MS m/z=391 [C21H29O5P−H]−.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[CH:16][C:15]=2[Cl:33])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].[NH3:34]>O1CCOCC1>[NH2:34][C:9]1[N:8]=[C:7]([S:11][CH3:12])[N:6]=[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:24][CH2:25]3)=[CH:16][C:15]=2[Cl:33])[C:4]=1[C:1](=[O:3])[NH2:2]
Reactant: N
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2Cl)n1
Solvent: C1COCCO1
Product: CSc1nc(N)c(C(N)=O)c(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2Cl)n1

Procedure:
A solution of the product of Example 59A (450 mg, 0.88 mmol) and 25% ammonia solution (1 mL) in dioxane (10 mL) was heated in a sealed tube at 100° C. for 16 hours. After cooling and concentration, the residue was purified by flash chromatography on silica gel eluting with 30:1 dichloromethane:methanol to give the title compound. MS: 493 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CS(O[CH2:14][CH2:15][CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:17]1([CH:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:15][CH2:14][O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc(OCCC(c2ccccc2)c2ccccc2)cc1
Yield: 103.5 %

Procedure:
A mixture of 4-bromophenol (1.73 g, 10 mmol), 1-methanesulphonyloxy-3, 3-diphenylpropane (3.05 g, 10 mmol) and anhydrous potassium carbonate (2.07 g, 15 mmol) in acetonitrile (25 mL) is stirred and heated to reflux under nitrogen for 24 h. The reaction mixture is filtered, washed with acetone and the combined filtrate and washings are evaporated to dryness in vacuo. The residue is taken up in Et2O washed with successive portions of 5% aqueous NaOH and H2O, dried (Na2SO4), filtered and concentrated in vacuo to give an oily residue (3.8 g) which crystallizes upon standing: mp 70°-71° C.; 1H NMR (CDCl3) d 7.35-7.16 (m, 12H), 6.70 (d, 2H, J=8.98), 4.22 (t, 1H, J=7.9), 3.85 (t, 2H, J=6.), 2.54 (q, 2H). IR 1592, 1490, 1470, 1291 cm1 ; MS 366-368 (MH+, one Br); Anal. calc'd. for C21 H19Br O: C, 68.86, H, 4.95. Found C, 68.60, 5.18.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22](=[O:29])[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:38])C=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22](=[O:29])[C:23]2[CH:24]=[CH:25][N+:26]([O-:38])=[CH:27][CH:28]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2cc[n+]([O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a solution of 4-tert-butyl-N-(4-chloro-2-isonicotinoylphenyl)benzenesulfonamide (191 g) in dichloromethane (3000 mL) was added m-chloroperbenzoic acid (65%, 146 g) at 0° C., and the mixture was stirred for 30 min. The mixture was warmed to room temperature and stirred for 16 hr. The mixture was cooled to 0° C., 10% aqueous sodium dithionite solution (630 mL) was added, and the mixture was stirred for 30 min and extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (500 mL) and saturated brine (500 mL). The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (NH, chloroform) to give the object 4-tert-butyl-N-[4-chloro-2-(1-oxidoisonicotinoyl)phenyl]benzenesulfonamide (181 g, pale-yellow solid).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33][CH2:34][C:35]=1[C:36]1[S:40][C:39]([CH2:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[N:38][CH:37]=1)[CH:31]([NH:48][C:49](=[O:79])[C:50](=[N:76][O:77][CH3:78])[C:51]1[N:52]=[C:53]([NH:56][C:57]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[S:54][CH:55]=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>C(Cl)Cl>[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33](=[O:9])[CH2:34][C:35]=1[C:36]1[S:40][C:39]([CH2:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[N:38][CH:37]=1)[CH:31]([NH:48][C:49](=[O:79])[C:50](=[N:76][O:77][CH3:78])[C:51]1[N:52]=[C:53]([NH:56][C:57]([C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)([C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[C:70]3[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=3)[S:54][CH:55]=1)[C:30]2=[O:80])=[O:27])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Cc4cccnc4)s3)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Cc4cccnc4)s3)CS(=O)C12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 3 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
A solution of m-chloroperbenzoic acid (1.46 g) in methylene chloride (30 cc) is added dropwise, in the course of 15 minutes, to a solution, cooled to 3° C., of the syn isomer of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-3-[2-(pyridin-3-yl-methyl)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (8.30 g) in methylene chloride (85 cc). The mixture is stirred at 3° C. for 4 hours 30 minutes and then diluted with methylene chloride (100 cc). The organic phase is washed successively with a semi-saturated solution of sodium bicarbonate (150 cc), distilled water (100 cc) and then a saturated solution of sodium chloride (100 cc). It is then dried over anhydrous sodium sulphate; the mixture is filtered and the filtrate is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The residue is purified by chromatography on a column (height=30 cm, diameter=2.5 cm) containing silica gel (0.05-0.2 mm), elution being carried out with ethyl acetate (1.2 liters) and then with a mixture of ethyl acetate and methanol (95/5 by volume) (0.8 liter) and 60 cc fractions being collected. Fractions 19 to 33, containing the pure product, are combined and concentrated under reduced pressure (30 mm Hg; 4 kPa) at 30° C. to give the syn isomer of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-3-[2-(pyridin-3-yl-methyl)-thiazol- 5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene 5-oxide (5 g) in the form of a hard yellow foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH3:15])[CH2:9]2)[N:5]=[C:4]([NH:16][CH3:17])[N:3]=1.[F:18][C:19]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:15][C@H:10]1[O:11][CH2:12][C@@H:13]([CH3:14])[N:8]([C:6]2[N:5]=[C:4]([NH:16][CH3:17])[N:3]=[C:2]([C:25]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([F:18])[CH:26]=3)[CH:7]=2)[CH2:9]1
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C)OC[C@H]2C)n1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
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: O
Solvent: C1COCCO1
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C)OC[C@H]2C)n1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
To a solution of 4-chloro-6-[(2R,5R)-2,5-dimethyl-4-morpholinyl]-N-methyl-2-pyrimidinamine (430 mg, 1.675 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (621 mg, 2.51 mmol) in 1,4-dioxane (2 mL) and water (1.00 mL) in a microwave reaction vessel stirred under nitrogen at room temperature was added Na2CO3 (355 mg, 3.35 mmol) and Pd(Ph3P)4 (194 mg, 0.167 mmol). The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 1 hour. After cooling the reaction to room temperature, the mixture was filtered through a pad of celite, and the filter cake was washed with THF (3×30 mL) and CH3OH (3×30 mL). The filtrate was purified with a silica gel (300-400) column and was eluted with Hex/EtOAc (2:1 to 1:2) to afford the title compound (315 mg) as a light yellow solid. LC-MS (ES) m/z=342 [M+H]+.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:12]=[C:13]2[CH2:19][C:18]3([CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)[O:17][C:14]2=[N:15][CH:16]=1>O1CCCC1>[C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:12]=[C:13]3[CH2:19][C:18]4([CH:24]5[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]5)[CH2:20]4)[O:17][C:14]3=[N:15][CH:16]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)Nc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Reaction time: 12 h
Yield: 86 %

Procedure:
Under a nitrogen atmosphere, phenyl isocyanate (0.056 mL, 0.515 mmol) was added to a suspension of 5'-aminospiro[1-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine] (119 mg, 0.514 mmol) in anhydrous tetrahydrofuran (5 mL) and stirred for 12 hours. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography through silica gel, eluting with ammoniated chloroform/methanol (92.5:7.5), to obtain the title compound (155 mg, 0.442 mmol, 86%) as an off-white solid: electrospray MS (m/z, relative intensity) 351 ([MH]+, 100).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.C([Li])CCC.[CH3:17][S:18]SC>C1COCC1.[NH4+].[Cl-]>[Cl:11][C:9]1[C:10]2[C:2]([S:18][CH3:17])=[CH:3][NH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Reactant: CSSC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSc1c[nH]c2ncnc(Cl)c12
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.18 g, 0.77 mmol) in dry THF (2 ml), cooled in a dry ice-acetone bath, was added dropwise n-butyllithium (0.77 ml, 1.9 mmol, 2.5 M in hexanes). The mixture was stirred for 1 hour, then dimethyldisulfide (0.077 mL, 0.77 mmol) suspended in dry THF (1 ml) was added. The solution was stirred for 2.5 hours at −78° C. and then diluted with aqueous NH4Cl. The phases were separated and the water extracted 2 times with ethyl acetate. The combined organic phases were dried over Na2SO4, and concentrated in vacuo to afford 4-chloro-5-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine as an orange solid (150 mg).
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:20]Br)=[CH:14][C:15]=2[N+:17]([O-:19])=[O:18])[C:10]([Br:22])=[C:9]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[O:36]=[C:37]1[CH2:42][NH:41][CH2:40][CH2:39][NH:38]1.[NH4+].[Cl-]>C(Cl)Cl>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:20][N:41]3[CH2:40][CH2:39][NH:38][C:37](=[O:36])[CH2:42]3)=[CH:14][C:15]=2[N+:17]([O-:19])=[O:18])[C:10]([Br:22])=[C:9]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: O=C1CNCCN1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccccc2)c(Br)c2cc(CBr)cc([N+](=O)[O-])c21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccccc2)c(Br)c2cc(CN3CCNC(=O)C3)cc([N+](=O)[O-])c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.9 %

Procedure:
1-BOC-3-bromo-5-bromomethyl-7-nitro-2-phenyl-indole prepared in Step B (1.0 g, 2 mmol) was dissolved in DCM (10 mL). Et3N (560 uL, 4 mmol) was added, 2-oxo-piperazine (300 mg, 3 mmol) was added, and the mixture was stirred for 12 h at room temperature. After completion of the reaction, saturated aqueous NH4Cl solution was added, and the reaction mixture was extracted with DCM. After drying, the solvent was removed under reduced pressure. The residue was purified by column chromatography to give the title compound (825 mg, Yield 78%).