Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([S:7]([NH:10][C:11]2[C:19]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=3[F:28])=[C:18]([F:29])[C:14]3[N:15]=[CH:16][S:17][C:13]=3[CH:12]=2)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C[N+]1([O-])CC[O:34]CC1.[OH2:38]>C1COCC1.[Os](=O)(=O)(=O)=O>[OH:38][CH:2]([CH2:3][OH:34])[CH2:1][C:4]1([S:7]([NH:10][C:11]2[C:19]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=3[F:28])=[C:18]([F:29])[C:14]3[N:15]=[CH:16][S:17][C:13]=3[CH:12]=2)(=[O:9])=[O:8])[CH2:6][CH2:5]1
Reactant: C=CCC1(S(=O)(=O)Nc2cc3scnc3c(F)c2Nc2ccc(I)cc2F)CC1
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc2scnc2c(F)c1Nc1ccc(I)cc1F)C1(CC(O)CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
To a solution of 1-allyl-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazol-6-yl)cyclopropane-1-sulfonamide (50 mg, 0.09 mmol) in THF (5 mL) was added N-methylmorpholine-N-oxide (11 mg, 0.09 mmol) followed by osmium tetraoxide (3 mg, 0.01 mmol) and water (0.5 mL). The resultant was stirred at room temperature overnight. The mixture was concentrated and then diluted with ethyl acetate. The organic layer was washed with water, saturated NaHCO3 (aq.) and brine sequentially, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel to give the product as white solid (20 mg, 37.7% yield). 1H NMR (400 MHz, CDCl3): δ 8.68 (s, 1H), 7.98 (s, 1H), 7.90 (d, 1H), 7.75 (d, 1H), 7.45 (m, 1H), 6.81 (s, 1H), 6.66 (s, 1H), 4.42-4.28 (m, 2H), 4.21-4.12 (m, 1H), 3.76-3.62 (m, 1H), 3.60-3.50 (m, 1H), 2.62-2.50 (m, 2H), 0.92-0.80 (m, 4H). MS APCI (+) m/z: 582.5 [M+H].
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][CH2:26][N:27]1[C:31](=[O:32])[CH2:30][S:29][C:28]1=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH2:25][CH2:26][N:27]3[C:31](=[O:32])[CH2:30][S:29][C:28]3=[O:33])[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][CH:10]=3)[C:22]=12
Reactant: O=C1CSC(=O)N1CCBr
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2CCN1C(=O)CSC1=O
Temperature: 80 °C
Reaction time: 10 h
Yield: 42.4 %

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (800 mg, 2.64 mmol, 1.00 equiv) in N,N-dimethylformamide (25 mL), 3-(2-bromoethyl)-1,3-thiazolidine-2,4-dione (890 mg, 3.97 mmol, 1.50 equiv) and cesium carbonate (1.72 g, 5.26 mmol, 2.00 equiv). The resulting solution was stirred for 10 h at 80° C. in an oil bath. The reaction mixture was cooled with a water bath, diluted with 150 mL of ethyl acetate and washed with brine and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100/1) to give 500 mg (42%) of 3-[2-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-1,3-thiazolidine-2,4-dione as a light yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[Cl:9][C:10]1[C:18]([Cl:19])=[CH:17][C:16]([S:20](Cl)(=[O:22])=[O:21])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>C(Cl)Cl>[Cl:9][C:10]1[C:18]([Cl:19])=[CH:17][C:16]([S:20]([N:4]2[CH2:5][C@H:6]([CH3:8])[CH2:7][C@H:2]([CH3:1])[CH2:3]2)(=[O:22])=[O:21])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: C[C@@H]1CNC[C@H](C)C1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc(Cl)c1Cl
Solvent: ClCCl
Product: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2cc(Cl)c(Cl)c(C(=O)O)c2)C1

Procedure:
To cis-3,5-dimethylpiperidine (374 mg.; 3.3 m moles) in 3 ml. of methylene chloride is added 192 mg. (0.66 m moles) of 2,3-dichloro-5-chlorosulfonylbenzoic acid and the mixture heated to reflux for 1.5 hrs. The solvent is removed under reduced pressure, and the residue is partitioned between 25 ml. of 1N sodium hydroxide solution and diethyl ether. The aqueous layer is separated, acidified with 6N hydrochloric acid and the resulting precipitated product filtered and dried, 230 mg., m.p. 235°-238° C. Recrystallization from acetonitrile gave the purified product, m.p. 244°-245° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:20]=2)[CH:4]=1.I[CH:33]([CH3:35])[CH3:34]>CN(C=O)C.CCOC(C)=O>[CH:33]([N:29]1[CH2:30][CH2:31][CH:26]([N:24]2[CH:25]=[C:21]([C:19]3[CH:20]=[C:15]([C:5]4[CH:4]=[C:3]([NH:2][CH3:1])[N:8]=[C:7]([C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=5)[CH:6]=4)[CH:16]=[N:17][CH:18]=3)[CH:22]=[N:23]2)[CH2:27][CH2:28]1)([CH3:35])[CH3:34]
Reactant: CC(C)I
Reactant: CNc1cc(-c2cncc(-c3cnn(C4CCNCC4)c3)c2)cc(-c2ccccn2)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNc1cc(-c2cncc(-c3cnn(C4CCN(C(C)C)CC4)c3)c2)cc(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of Methyl-[5″-(1-piperidin-4-yl-1H-pyrazol-4-yl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (Example 2.183) (1 eq, 0.122 mmol, 50 mg) in DMF (3 ml) cooled at 0° C. is added 2-iodopropane (7 eq, 0.854 mmol, 0.084 ml) and the reaction is stirred at room temperature for 5 hours. The reaction mixture is dissolved in EtOAc and washed with water. The combined organic extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is purified by reverse phase column chromatography (Isolute™ C18, 0-20% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 454.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][S:5]([N:8]([CH3:11])[O:9][CH3:10])(=[O:7])=[O:6].Cl[S:13]([NH:16][C:17](=[O:25])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:15])=[O:14].Cl>CCCCCC.C1COCC1>[CH3:11][N:8]([O:9][CH3:10])[S:5]([N:4]([S:13]([NH:16][C:17](=[O:25])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:14])=[O:15])[CH3:3])(=[O:7])=[O:6]
Reactant: CNS(=O)(=O)N(C)OC
Reactant: O=C(NS(=O)(=O)Cl)Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CON(C)S(=O)(=O)N(C)S(=O)(=O)NC(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
1.15 g (28.8 mmol) of 60% sodium hydride was washed with n-hexane, and dry THF was added, and the mixture was cooled with ice. To this mixture, a THF solution containing 2 g (13 mmol) of N,N'-dimethyl-N'-methoxysulfamide was dropwise added. After stirring the mixture for 10 minutes, a dry THF solution containing 3.21 g (13.6 mmol) of phenyl N-chlorosulfonylcarbamate was dropwise added thereto. The mixture was stirred at room temperature for 7 hours. The reaction mixture was poured into 500 ml of ice water containing 3.5 g of 35% hydrochloric acid and extracted three times with diethyl ether. The diethyl ether layer was washed sequentially with water and a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4.3 g of phenyl N-[(N-(N-methyl N-methoxyaminosulfonyl)-N-methylamino)sulfonyl]carbamate as slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[C:23]1[CH:28]=[CH:27][N:26]=[N:25][CH:24]=1>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][N:26]=[N:25][CH:24]=1
Reactant: Brc1ccnnc1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc(Cl)c(-c2ccnnc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
[2-Chloro-5-(trifluoromethyl)phenyl]boronic acid (0.410 g, 1.83 mmol), caesium carbonate (1.1 g, 3.38 mmol) and 4-bromopyridazine hydrobromide (Preparation 20, 0.35 g, 1.46 mmol) were dissolved in 1,4-dioxane (3.5 mL) and water (1 mL). The mixture was heated to 80° C. under nitrogen then palladium tetrakis triphenylphosphine (0.085 g, 0.074 mmol) was added. The reaction was stirred for three hours before it was left to cool to room temperature. The mixture was subsequently filtered through Arbocel®, then diluted in ethyl acetate (15 mL) and washed twice with a saturated solution of aqueous brine (15 mL). The organic layer was collected, dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (ISCO™, 0-50% ethyl acetate in heptane gradient elution, 12 g SiO2) to give title compound as a green solid (0.23 g, 61%).
Reaction SMILES: [CH2:1]([O:4][NH:5][C@H:6]1[CH2:11][NH:10][C@H:9]([C:12]([NH2:14])=[O:13])[CH:8]=[C:7]1[CH2:15][O:16][CH3:17])[CH:2]=[CH2:3].C(N(C(C)C)C(C)C)C.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.CCOC(C)=O>[CH2:1]([O:4][N:5]1[C:28](=[O:30])[N:10]2[CH2:11][C@H:6]1[C:7]([CH2:15][O:16][CH3:17])=[CH:8][C@H:9]2[C:12]([NH2:14])=[O:13])[CH:2]=[CH2:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCON[C@H]1CN[C@H](C(N)=O)C=C1COC
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCON1C(=O)N2C[C@H]1C(COC)=C[C@H]2C(N)=O
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a stirred solution of (2S,5R)-5-(allyloxyamino)-4-(methoxymethyl)-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 74, 1.12 g, 4.64 mmol) in acetonitrile (100 mL), N-ethyl-N-isopropylpropan-2-amine (4.04 mL, 3.00 g, 23.21 mmol) was added, then triphosgene (551 mg, 1.86 mmol) in 20 mL acetonitrile was added slowly via syringe pump over 4 h at 0° C. It was stirred from 0° C. to rt overnight. The solution was concentrated to give a residue, which was then taken up in 50 mL EtOAc and washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified on a silica gel column eluting with 0-100% ethyl acetate/hexanes gave a yellow oil (420 mg, 34%).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[N:18]=[C:17]4[N:19]([C:24]5[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=5[F:31])[C:20](=[O:23])[NH:21][CH2:22][C:16]4=[C:15](Cl)[N:14]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C(=O)([O-])[O-].[K+].[K+].[F:40][C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:65])[C:49]2[CH:54]=[CH:53][C:52]([CH3:55])=[C:51](B3OC(C)(C)C(C)(C)O3)[CH:50]=2)=[CH:43][CH:42]=1>O1CCOCC1.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>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[N:14]=[C:15]([C:51]4[CH:50]=[C:49]([CH:54]=[CH:53][C:52]=4[CH3:55])[C:48]([NH:47][C:44]4[CH:45]=[CH:46][C:41]([F:40])=[CH:42][CH:43]=4)=[O:65])[C:16]4[CH2:22][NH:21][C:20](=[O:23])[N:19]([C:24]5[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=5[F:31])[C:17]=4[N:18]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1NCc2c(Cl)nc(N3CCC(N4CCCCC4)CC3)nc2N1c1c(F)cccc1F
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(N2CCC(N3CCCCC3)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 49.6 %

Procedure:
To a solution of compound 7-(1,4′-bipiperidin-1′-yl)-5-chloro-1-(2,6-difluorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (18 mg, 0.04 mmol) in dioxane (1.5 mL)/water (0.5 mL) were added potassium carbonate (34 mg, 0.25 mmol), tetrakis(triphenylphosphine)palladium(0) (2.3 mg, 0.002 mmol) and N-(4-fluorophenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (22 mg, 0.062 mmol). The reaction mixture was bubbled with N2 for 5 mins, then microwaved at 150° C. for 30 mins. The reaction mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH [7]+NH4OH[3]) provided the title compound as a white solid (13 mg, 51%). LC-MS m/z 656 (M+H)+; 1H-NMR (MeOD) δ 1.37 (m, 2H), 1.48 (m, 2H), 1.60 (m, 4H), 1.80 (m, 2H), 2.33 (s, 3H), 2.56 (m, 5H), 2.72 (t, 2H), 4.17 (m, 2H), 4.46 (m, 2H), 7.12 (m, 4H), 7.52 (m, 2H), 7.72 (m, 2H), 7.82 (s, 1H), 7.98 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([S:29][CH2:30][CH3:31])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:28])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)=[CH:13][C:12]=1[N+:25]([O-:27])=[O:26])[CH3:2].[OH:32][C:33]1[C:47]([O:48][CH3:49])=[CH:46][C:36]2[C:37](=[O:45])[N:38]3[CH2:44][CH2:43][CH2:42][C@H:39]3[CH2:40][NH:41][C:35]=2[CH:34]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CC(C)=O.O>[CH2:1]([O:3][CH:4]([S:29][CH2:30][CH3:31])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:28])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][O:32][C:33]2[C:47]([O:48][CH3:49])=[CH:46][C:36]3[C:37](=[O:45])[N:38]4[CH2:44][CH2:43][CH2:42][C@H:39]4[CH2:40][NH:41][C:35]=3[CH:34]=2)=[CH:13][C:12]=1[N+:25]([O-:27])=[O:26])[CH3:2]
Reactant: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCCBr)cc1[N+](=O)[O-]
Reactant: COc1cc2c(cc1O)NC[C@@H]1CCCN1C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCCOc2cc3c(cc2OC)C(=O)N2CCC[C@H]2CN3)cc1[N+](=O)[O-]

Procedure:
A solution of (2S)-N-[4-(4-bromobutoxy)-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula I (535 mg, 1 mmol), 8-hydroxy-7-methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrol[2,1-c][1,4]benzodiazepine-5-one (248 mg, 1 mmol) of the formula II and K2CO3 (414 mg, 3 mmol) in dry acetone (20 mL) was refluxed for 48 h. After the completion of reaction as indicated by TLC, EtOAc, the reaction mixture was poured on to the water and then extracted with ethylacetate. Evaporation of the organic layer gave the crude product, which was further purified by column chromatography on silica gel eluting with EtOAc:hexane (8:2) gave the pure (2S)-N-{4-[4-(7-Methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one-8-yloxy)butoxy]-5-methoxy-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal III.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11](=[O:14])[NH:12][CH2:13][C:3]=12.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1>>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[N:10]1[C:4]2[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([C:29]3[CH:28]=[C:27]([NH:30][C:31]([C:33]4[CH:37]=[CH:36][S:35][CH:34]=4)=[O:32])[CH:26]=[CH:25][C:24]=3[CH3:23])[C:3]=2[CH2:13][NH:12][C:11]1=[O:14]
Reactant: CSc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Product: CSc1nc(-c2cc(NC(=O)c3ccsc3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2

Procedure:
The title compound was prepared from 5-Chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one by following the procedures in Example 1d except using N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-thiophenecarboxamide for the Suzuki cross-coupling reaction. LC-MS m/z 524 (M+H)+, 2.21 min (ret. time). xdb
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13](S(C3C=CC(Cl)=CC=3)(=O)=O)[CH2:12][C:11]3[CH:24]=[N:25][NH:26][C:10]=3[CH2:9]2)=[CH:4][CH:3]=1.ClC1C=CC(C2CC(=O)CCN2[C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])=CC=1.O.NN.N1CCC(=O)CC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:13]([C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])[CH2:12][C:11]3[CH:24]=[N:25][NH:26][C:10]=3[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1Cc2cn[nH]c2CC1c1ccc(Cl)cc1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C(c2ccc(Cl)cc2)C1
Agent: NN
Agent: O=C1CCNCC1
Solvent: O
Product: O=C(OCc1ccccc1)N1Cc2cn[nH]c2CC1c1ccc(Cl)cc1

Procedure:
6-(4-Chlorophenyl)-5-(4-chlorophenylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (Enantiomers A and B) Benzyl 2-(4-chlorophenyl)-4-oxopiperidine-1-carboxylate, 67, was formylated and treated with hydrazine hydrate as described for compounds 50 and 51 in Example 1 to give benzyl 6-(4-chlorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate which was then deprotected and sulfonylated as described for compound 84 in Example 7. The enantiomers were separated by HPLC using Method [2].
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.[F:8][C:9]1[CH:10]=[C:11]([C:16](=[O:43])[C:17](=[C:34]2[NH:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[NH:35]2)[C:18]([C:20]2[CH:21]=[C:22]([S:26]([NH:29]C(=N)CO)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=2)=[O:19])[CH:12]=[C:13]([F:15])[CH:14]=1.[Cl-].[NH4+].[N:46]1C=CC=[CH:48][CH:47]=1>>[F:15][C:13]1[CH:12]=[C:11]([C:16](=[O:43])[C:17](=[C:34]2[NH:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[NH:38]2)[C:18]([C:20]2[CH:21]=[C:22]([S:26]([NH:29][CH:6]([CH2:48][CH:47]=[NH:46])[C:5]([OH:4])=[O:7])(=[O:27])=[O:28])[CH:23]=[CH:24][CH:25]=2)=[O:19])[CH:10]=[C:9]([F:8])[CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: N=C(CO)NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Reactant: c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Product: N=CCC(NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (90 mg) was added to a pyridine (5 mL) solution of N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)-2-hydroxyethanimidamide (225 mg), followed by stirring at room temperature for 2 hours. An excess amount of an aqueous saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=80/1) and crystallized from ethyl acetate/n-hexane to obtain 2-[({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)amino]-2-iminoethylacetic acid (150 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:21][C:22]1[CH:23]=[CH:24][C:25]([O:32][CH3:33])=[C:26]([S:28](Cl)(=[O:30])=[O:29])[CH:27]=1>C(Cl)Cl>[CH3:33][O:32][C:25]1[CH:24]=[CH:23][C:22]([Br:21])=[CH:27][C:26]=1[S:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:30])=[O:29]
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Reactant: CCOC(=O)c1cc(N)ccc1Oc1cncc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)c1cc(NS(=O)(=O)c2cc(Br)ccc2OC)ccc1Oc1cncc(Cl)c1
Reaction time: 10 h
Yield: 20.4 %

Procedure:
To a solution of the aniline produced in Example 1 (250 mg, 0.85 mmol) in CH2Cl2 (4 mL) was added 5-bromo-2-methoxybenzenesulfonyl chloride (244,mg, 0.85 mmol). The mixture was stirred for 10 hr. The title compound (94 mg, 20% to) was isolated following column chromatography on silica gel (1:1 hexane/ethyl acetate).
Reaction SMILES: [OH-:1].[Na+].Cl.[NH2:4]O.[CH2:6]([O:8][C:9](=[O:22])[C:10](=[O:21])[CH:11]([CH3:20])[C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=O)[CH3:7].Cl>O.C(OCC)(=O)C>[CH2:6]([O:8][C:9](=[O:22])[C:10](=[O:21])[CH:11]([CH3:20])[C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[N:4][OH:1])[CH3:7]
Reactant: [OH-]
Reactant: CCOC(=O)C(=O)C(C)C(=O)C1CCCCC1
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)C(C)C(=NO)C1CCCCC1
Yield: 56.5 %

Procedure:
Sodium hydroxide (0.99 g, 24.7 mmol) was dissolved in 5.5 mL of water. Hydroxylamine hydrochloride (1.71 g, 24.7 mmol) was added and the reaction mixture was stirred until complete dissolution was achieved. 4-Cyclohexyl-3-methyl-2,4-dioxo-butyric acid ethyl ester (5.15 g, 21.5 mmol) was added and the resulting mixture was stirred at ambient temperature for 16 h. Ethyl acetate (20 mL) and 1M hydrochloric acid (10 mL) was added, and the aqueous layer was extracted with additional ethyl acetate (4×20 mL). The organic layers were combined, dried over MgSO4 and concentrated. The crude oil was purified by chromatography (0-30% EtOAc/hexanes) to give 3.1 g of the title compound. MS: (+) m/z 256.39 (M+1).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:29]([F:30])[CH2:28][C@@:27]2([CH3:31])[CH:7]([C@H:8](O)[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O.C(OCC)(=O)C>N1C=CC=CC=1>[C:1]([O:4][C@H:5]1[C@H:29]([F:30])[CH2:28][C@@:27]2([CH3:31])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2[C@H](O)C[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)C[C@H]1F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)C[C@H]1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
To the solution of the acetate (7) (92 mg, 0.198 mmol) in pyridine (2 ml) was added dropwise phosphorusoxychloride (0.06 ml) at 0° and the mixture was stirred at room temperature for 2 hr. To the reaction mixture were added ice and ethyl acetate. The organic phase was washed with 2N-HCl, saturated NaHCO3 and brine, and dried over MgSO4. The residue obtained upon evaporation of the solvent was purified by column chromatography on silica gel (5 g). Elution with benzene-ethyl acetate (20:1) gave the olefine (8) (90 mg, 98%), mp 116°-119° (MeOH); δ0.68(3H s, 18H3), 0.87(6H, d, J=6 Hz, 26- and 27-H3), 0.93(3H, d, J=6 Hz, 21-H3), 1.06(3H, s, 19-H3), 2.08(3H, s, acetyl), 4.10-5.00(1 H, broad, 2β-H), 4.86(1H, m, 3α-H), and 5.42(1H, m, 6-H); m/z 386.3370(M+ -AcOH). (CH27H43F required M, 386.3347).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([CH:13]=O)=[CH:11][N:12]=1.[NH2:15][C:16]1[C:17]([F:29])=[CH:18][C:19]([F:28])=[C:20]([CH:27]=1)[C:21]([NH:23][CH:24]1[CH2:26][CH2:25]1)=[O:22].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:24]1([NH:23][C:21](=[O:22])[C:20]2[CH:27]=[C:16]([NH:15][CH2:13][C:10]3[S:9][C:8]([NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:12][CH:11]=3)[C:17]([F:29])=[CH:18][C:19]=2[F:28])[CH2:25][CH2:26]1
Reactant: O=Cc1cnc(Nc2ccccn2)s1
Reactant: Nc1cc(C(=O)NC2CC2)c(F)cc1F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CC1)c1cc(NCc2cnc(Nc3ccccn3)s2)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.3 %

Procedure:
A mixture of 2-[pyridin-2-ylamino]-thiazole-5-carbaldehyde (41.0 mg, 0.2 mmol) and 5-amino-N-cyclopropyl-2,4-difluorobenzamide (46.6 mg, 0.22 mmol) in TFA/DCM (1:1, 1 mL) was stirred at RT for 10 min and triethylsilane (0.1 mL) was added. The mixture was stirred for 1 h, then concentrated and the residue was neutralized with NaHCO3 solution and the precipitates occurred. The precipitates were collected, washed with water and dried. The solid was triturated with MeOH and filtered to afford the title compound as a grayish solid (38 mg, 47%). Small amount of solid was boiled in methanol, the mixture was cooled to RT and filtered to afford a white solid. MS m/z 402 (M+H)+. 1H NMR (DMSO-d6) δ 8.23 (d, 1H, J=4.0 Hz), 8.15 (s, 1H), 7.65 (t, 1H, J=7.15 Hz), 7.26 (s, 1H), 7.16 (m, 1H), 7.01 (d, 1H, J=8.75 Hz), 6.95 (m, 1H), 6.89 (t, 1H, J=7.15 Hz), 6.12 (s 1H), 4.43 (m, 2H), 2.79 (m, 1H), 0.69 (m, 2H), 0.51 (m, 2H).