Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:44]1[O:48][C:47]([C:49]2[C:54]([F:55])=[CH:53][CH:52]=[CH:51][C:50]=2[F:56])=[N:46][C:45]=1[C:57]#[N:58].[NH2:59][C:60]1[CH:68]=[CH:67][C:63]([C:64]([OH:66])=[O:65])=[CH:62][CH:61]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)CCC.O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:57]([C:45]1[N:46]=[C:47]([C:49]2[C:54]([F:55])=[CH:53][CH:52]=[CH:51][C:50]=2[F:56])[O:48][C:44]=1[NH:59][C:60]1[CH:68]=[CH:67][C:63]([C:64]([OH:66])=[O:65])=[CH:62][CH:61]=1)#[N:58]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: N#Cc1nc(-c2c(F)cccc2F)oc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCCCO
Product: N#Cc1nc(-c2c(F)cccc2F)oc1Nc1ccc(C(=O)O)cc1
Temperature: 140 °C
Yield: 14 %

Procedure:
A solution of tris(dibenzylideneacetone)dipalladium(0) (0.337 g, 0.368 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.213 g, 0.368 mmol) in n-butanol:dioxane (1:1) (5 mL) was stirred at room temperature for 3 minutes. Then 5-bromo-2-(2,6-difluorophenyl)oxazole-4-carbonitrile (1.50 g, 5.262 mmol), 4-aminobenzoic acid (2.165 g, 15.787 mmol) and cesium carbonate (3.429 g, 10.525 mmol) were added and the mixture heated in the microwave for 3 minutes at 140° C. The reaction was diluted with EtOAc and washed with water. The organic phase was passed through an MP-SH cartridge, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by column chromatography using a 20-45% EtOAc:hexane gradient then further purified by trituration of the solid in DCM:hexane (1:1) to afford 4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzoic acid (0.251 g, 0.735 mmol, 14%) as a light yellow solid. 1H NMR (DMSO) δ 7.34 (2H, t), 7.40 (2H, d), 7.66 (1H, m), 7.92 (2H, d), 11.16 (1H, br s), 12.76 (1H, br s). LCMS (3) Rt: 1.53 min; m/z (ES+) 342.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>>[CH:36]1([NH:39][C:25]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)[N:24]=2)=[O:26])[CH2:38][CH2:37]1
Reactant: C[C@@H](c1ccc(-c2cccc(C(=O)O)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: NC1CC1
Product: C[C@@H](c1ccc(-c2cccc(C(=O)NC3CC3)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylic acid and cyclopropylamine following a procedure analogous to that described in Example 203. Mass spectrum (ESI+): m/z=514 [M+H]+.
Reaction SMILES: C[Al](C)C.CCCCCC.[CH3:11][S:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1.[Cl:20][C:21]1[C:22]([N:27]2[C:31]3=[N:32][CH:33]=[N:34][C:35]([O:36][C@@H:37]([CH2:42][O:43][CH2:44][CH3:45])[C:38](OC)=[O:39])=[C:30]3[CH:29]=[N:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1>C1(C)C=CC=CC=1>[Cl:20][C:21]1[C:22]([N:27]2[C:31]3=[N:32][CH:33]=[N:34][C:35]([O:36][C@@H:37]([CH2:42][O:43][CH2:44][CH3:45])[C:38]([NH:19][C:16]4[CH:15]=[CH:14][C:13]([S:12][CH3:11])=[CH:18][N:17]=4)=[O:39])=[C:30]3[CH:29]=[N:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)OC
Reactant: CSc1ccc(N)nc1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(SC)cn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2M Trimethylaluminium in hexane (0.457 mL, 0.91 mmol) was added to 5-(methylthio)pyridin-2-amine (CAS no. 77618-99-6) (0.111 g, 0.79 mmol) in toluene (22 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-methyl 2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-ethoxypropanoate (Intermediate L2) (0.300 g, 0.79 mmol) in toluene (6 mL) was added dropwise at this temperature. After the addition was complete, the solution was allowed to warm to ambient temperature and was then heated at reflux for 16 hours. The mixture was allowed to cool to ambient temperature and left standing for 2 days. The reaction mixture was concentrated, diluted with ethyl acetate (100 mL) then washed with saturated brine (50 mL). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with 0 to 3% MeOH in DCM to afford the product.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[CH:6]([OH:10])[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[C:15](OC(=NC(C)C)NC(C)C)([CH3:18])([CH3:17])[CH3:16]>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[CH:6]([OH:10])[C:7]([O:9][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8])([O-:3])=[O:2]
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Reactant: O=C(O)C(O)c1ccccc1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)C(O)c1ccccc1[N+](=O)[O-]

Procedure:
To a suspension of 2-nitromandelic acid (0.86 g, 4.4 mmol) in chloroform (10 mL) with stirring is added O-t-butyl-N,N'-diisopropylisourea (2.7 g, 13 mmol). The resulting mixture is stirred overnight, then filtered. The filtrate is concentrated in vacuo, and the residue purified by flash chromatography using EtOAc/chloroform (0%→5%→10%), giving t-butyl 2-nitromandelate (18) as 0.99 g (90%) of a pale brown clear oil.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[CH2:4][CH2:3][O:2]1.[BH4-].[Na+].O>C(O)C>[CH2:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[CH2:4][CH2:3][O:2]1
Reactant: O=C1CCC2(CCOC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1CCC2(CCOC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-oxaspiro[4.5]decan-8-one (46.4 g., 0.3 mole) from Part C above in 1.5 liters of absolute ethanol was stirred under N2 atmosphere while sodium borohydride was added in 1-1.5-g. portions. When the addition was completed the mixture was stirred at room temperature for 4 hours. Then 1445 ml. of water was added and stirring was continued for 30 minutes. Ethanol was removed in vacuo and the aqueous layer was extracted with chloroform to give 43 g. (91%) of a mixture of two isomers by TLC analysis and NMR spectral analysis. H-NMR δ (ppm) 1.02-1.79 (10H, multiplet); 3.24-3.95 (5H, multiplet); mass spectrum m/e 156 (M+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[S:19][C:18]([S:20]([N:23]2[CH:27]=[CH:26][CH:25]=[CH:24]2)(=[O:22])=[O:21])=[CH:17][CH:16]=1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[S:19][C:18]([S:20]([N:23]3[CH:27]=[CH:26][CH:25]=[CH:24]3)(=[O:21])=[O:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=S(=O)(c1ccc(-c2ccc(C(F)(F)F)cc2)s1)n1cccc1
Yield: 75 %

Procedure:
N-{5-[4-(trifluoromethyl)phenyl]thiophene-2-sulfonyl}pyrrole was prepared in the same manner as described in Example 32C using 4-trifluoromethylbenzene boronic acid and N-(5-bromothiophene sulfonyl)pyrrole. Purification by column chromatography using 2% ethyl acetate/hexanes gave the pure sulfonamide as a white powder in 75% yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]3[CH:16]=[CH:17][C:18]([F:36])=[C:19]([NH:21][C:22](=[O:35])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[C:24]=4[Cl:34])[CH:20]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.[CH:43]1([C:46](Cl)=[O:47])[CH2:45][CH2:44]1>O1CCCC1.C(OCC)(=O)C>[Cl:34][C:24]1[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([NH:21][C:19]1[CH:20]=[C:15]([O:14][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:46]([CH:43]4[CH2:45][CH2:44]4)=[O:47])[S:3][C:4]=3[C:10]=2[N+:11]([O-:13])=[O:12])[CH:16]=[CH:17][C:18]=1[F:36])=[O:35]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4c3[N+](=O)[O-])ccc2F)c1Cl
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3[N+](=O)[O-])ccc2F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
To a solution of N-{5-[(2-amino-7-nitro-1,3-benzothiazol-6-yl)oxy]-2-fluorophenyl}-2-chloro-3-(1-cyano-1-methylethyl)benzamide (150 mg, 0.285 mmol) produced in Example 41(iii) in tetrahydrofuran (8 mL) were added pyridine (160 μL, 2.0 mmol) and cyclopropanecarbonyl chloride (39 μL, 0.428 mmol), and the mixture was stirred at room temperature for 1 hr. Pyridine (160 μL, 2.0 mmol) and cyclopropanecarbonyl chloride (10 μL, 0.11 mmol) were added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with ethyl acetate (50 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=60/40→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/diethyl ether to give the title compound (54 mg, 32%) as a yellow powder.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][C:7](OC)=O)[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(Cl)Cl.[O:24]1CCCC1>>[S:1]1[CH:5]=[C:4]([CH:6]([OH:24])[CH3:7])[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2
Reactant: C1CCOC1
Reactant: COC(=O)Cc1csc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Product: CC(O)c1csc2ccccc12

Procedure:
A solution of methyl benz[b]thiophen-3-ylacetate (69 g) in dry tetrahydrofuran (100 ml) was added dropwise to a suspension of lithium aluminium hydride (10 g) in dry tetrahydrofuran (500 ml) at room temperature followed by reflux for 1 h. Hydrolysis with water, filtration and removal of solvent gave an oil which was applied to a 5 silica gel column (eluent: methylene chloride) giving 34.5 g of benzo[b]thiophen-3-ylethanol as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Br:19]N1C(=O)CCC1=O>ClCCl>[NH2:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([S:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:10]=2)[C:5]([Br:19])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccn2nc(SCc3ccccc3)nc12
Solvent: ClCCl
Product: Nc1ccc(Br)n2nc(SCc3ccccc3)nc12

Procedure:
8-Amino-2-benzylthio[1,2,4]triazolo[1,5-a]pyridine (25.6 g, 0.1 mol), N-bromosuccinimide (17.8 g, 0.1 mol) and 2 L of dichloromethane were combined with stirring for an hour. The solution was washed with dilute aqueous sodium bisulfite and then with water and the volatiles were removed by evaporation under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 25 percent ethyl acetate in hexane. The product fractions were concentrated by evaporation under reduced pressure and the solid residue obtained was extracted with ether and dried to obtain 17.5 g (52 percent of theory) of the title compound as a light tan powder melting at 125°-126° C.
Reaction SMILES: [Br-].[CH2:2]([N+:6]1[CH:10]=[CH:9][N:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:7]=1)[CH:3]([CH3:5])[CH3:4].[OH2:15]>>[OH-:15].[CH2:2]([N+:6]1[CH:10]=[CH:9][N:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:7]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: O
Agent: *CC*
Agent: CC(C)Cn1cc[n+](CC(C)C)c1
Agent: [Br-]
Product: [OH-]
Reaction time: 8 h

Procedure:
The 1,3-diisobutylimidazolium bromide product was dissolved in deionized water (10 mL water/1 mmol salt) in a polyethylene plastic bottle. To the solution, Bio-Rad AG 1-X8 ion-exchange resin (1.1 g resin/mmol salt) was added and the slurry-like mixture was gently stirred overnight. The exchange solution was filtered and a small aliquot of the filtrate was titrated with 0.1N HCl to indicate the exchange yielded 89% of the desired 1,3-diisobutylimidazolium hydroxide product.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([N:11]1[C:23]2[CH:22]=[CH:21][C:20]([CH:24]=O)=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[C:15]([CH:26]=O)[CH:16]=2)[CH3:10]>C1(C)C=CC=CC=1.C1COCC1>[C:1]1([NH:7][N:8]=[CH:24][C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[N:11]([CH2:9][CH3:10])[C:12]2[CH:13]=[CH:14][C:15]([CH:26]=[N:8][NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:16][C:17]3=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: CCn1c2ccc(C=O)cc2c2cc(C=O)ccc21
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCn1c2ccc(C=NNc3ccccc3)cc2c2cc(C=NNc3ccccc3)ccc21
Temperature: 25 °C

Procedure:
Phenylhydrazine (0.2 mole, commercially available from Aldrich, Milwaukee, Wis.) and N-ethyl-3,6-diformylcarbazole (0.1 mole) were dissolved in 100 ml of a 1:1 v/v mixture of toluene and THF in 250 ml 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The solution was refluxed for 2 hours. Thin layer chromatography indicated the disappearance of the starting materials. At the end of the reaction, the mixture was cooled to room temperature. The N-ethyl-3,6-diformylcarbazole bis(N-phenylhydrazone) crystals formed upon standing were filtered off, washed with isopropanol and dried in a vacuum oven at 50° C. for 6 hours. Without further purification, the product was used for the next step.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Cl:13][C:14]1[C:15]([N:20]2[C:24]3=[N:25][CH:26]=[N:27][C:28]([O:29][C@@H:30]([CH2:35][O:36][C@H:37]([CH3:41])[CH2:38][O:39][CH3:40])[C:31](OC)=[O:32])=[C:23]3[CH:22]=[N:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[Cl:13][C:14]1[C:15]([N:20]2[C:24]3=[N:25][CH:26]=[N:27][C:28]([O:29][C@@H:30]([CH2:35][O:36][C@H:37]([CH3:41])[CH2:38][O:39][CH3:40])[C:31]([NH:12][C:9]4[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=4)=[O:32])=[C:23]3[CH:22]=[N:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc(N)nc1
Reactant: COC[C@@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)OC
Agent: C[Al](C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC[C@@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(C)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47.4 %

Procedure:
Trimethylaluminium (0.334 mL, 0.67 mmol) was added to 5-methylpyridin-2-amine (69.1 mg, 0.64 mmol) in toluene (8 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-Methyl 2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-((R)-1-methoxypropan-2-yloxy)propanoate (Intermediate Y8) (245 mg, 0.58 mmol) in toluene (2 mL) was added and the reaction was allowed to warm to room temperature and then heated at reflux for 24 hours. The reaction mixture was allowed to cool and neutralised with citric acid (1M, aq) and then diluted with water (50 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (50 mL). The combined organics were dried (MgSO4), filtered and evaporated. The crude product was purified by preparative HPLC (Phenomenex Gemini C 18 110A (axia) column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents to afford the product (137 mg, 47.4%). 1H NMR (400 MHz, DMSO) δ 1.10 (d, 3H), 2.26 (s, 3H), 3.23-3.42 (m, 5H), 3.76-3.85 (m, 1H), 4.10-4.16 (m, 2H), 5.95-6.00 (m, 1H), 7.55-7.60 (m, 1H), 7.68-7.73 (m, 1H), 7.86 (d, 1H), 8.14-8.18 (m, 1H), 8.24-8.29 (m, 1H), 8.54 (s, 2H), 8.62-8.67 (m, 1H), 10.21 (s, 1H) m/z (ESI+) (M+H)+=498.16; HPLC tR=1.84 min.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[S:21](Cl)(=[O:23])=[O:22]>>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[S:21]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[Cl:1])[N:8]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1nc(-c2sccc2Cl)cs1
Product: O=S(=O)(Nc1nc(-c2sccc2Cl)cs1)c1c(Cl)cccc1Cl

Procedure:
The title compound was prepared from 4-(3-chloro-2-thienyl)-1,3-thiazol-2-amine (59 mg) and 2,6-dichlorobenzenesulfonyl chloride (66 mg) as descrbed in the synthetic METHOD B to give a yellow solid (34.5 mg) with purity >90%: MS (pos) m/z 425.3, 427.3; HRMS m/z 423.8730 (calc. of monoisotopic mass for C13 H7 Cl3 N2 O2 S3 gives 423.8735).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[O:17][CH3:18].[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:25]/[S@@:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])/[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: CC(C)(C)[S@](N)=O
Reactant: COc1cc(C(=O)Cc2ccccc2)ccc1F
Solvent: C1CCOC1
Product: COc1cc(/C(Cc2ccccc2)=N/[S@](=O)C(C)(C)C)ccc1F
Temperature: 25 °C
Yield: 65.2 %

Procedure:
To a solution of 1-(4-fluoro-3-methoxyphenyl)-2-phenylethanone (13 g, 53 mmol) dissolved in THF (266 mL) was added (R)-2-methylpropane-2-sulfinamide (7.8 g, 64 mmol) at rt, followed by Ti(OEt)4 (17 mL, 80 mmol). The reaction mixture was heated to reflux for 48 h, then allowed to cool to rt. The reaction mixture was concentrated under reduced pressure and the residue was diluted with Et2O. H2O was added and the solid was filtered and washed with Et2O. The filtrate was washed with H2O, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, eluting with 0-100% EtOAc/hexane) to yield (R,E)-N-(1-(4-fluoro-3-methoxyphenyl)-2-phenylethylidene)-2-methylpropane-2-sulfinamide (12 g, 67% yield). LCMS: RT=3.655 min [M+H] 348.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm); 1H NMR (500 MHz, CDCl3) δ ppm 7.60-7.53 (m, 1H), 7.43-7.36 (m, 1H), 7.29-7.15 (m, 5H), 7.03 (dd, J=11, 8 Hz, 1H), 4.75 (d, J=15 Hz, 1H), 4.54 (d, J=15 Hz, 1H), 3.84 (s, 3H), 1.34 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([NH:26][CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[CH2:34]([NH:41][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([NH:26][CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(Cl)nc1)C2
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(NCc3ccccc3)nc1)C2
Temperature: 100 °C
Yield: 46.6 %

Procedure:
A mixture of 10-[(6-chloropyridin-3-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 117 (0.100 g, 0.219 mmol) and benzylamine (0.12 mL, 1.094 mmol) was heated to 100° C. in a sealed tube for 17 hours. The cooled reaction mixture was then diluted with dichloromethane (10 mL), washed with saturated aqueous sodium bicarbonate solution (10 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a yellow semi-solid. Purification by flash chromatography using a solvent gradient of 1 to 5% methanol in dichloromethane gave a white solid that was triturated with diethyl ether to afford the title compound (0.054 g, 47%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[CH:17]([CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:20]1)=O.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1.CCOC(C)=O>[CH2:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:17][NH:10][C:9]2[CH:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:6][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[CH2:20][CH2:21]1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(-c2ccccc2)cc1NCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.6 %

Procedure:
A suspension of 3-amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.70 g, 3 mmol) and 4-formyl N-Cbz-piperidine (0.74 g, 3 mmol) in THF (1.2 mL) was treated with dibutyltin dichloride (46 mg, 0.15 mol) followed by phenylsilane (0.41 mL, 3.3 mmol). The mixture was stirred for 2 days at room temperature. The solvent was then evaporated and the residue was purified by silica gel column chromatography using CH2Cl2:hexanes:EtOAc as eluent to provide 4-[(2-Methoxycarbonyl-5-phenyl-thiophen-3-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (0.6906 g, 50% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Cl.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:12]=1>CN1CCCC1=O>[NH2:8][C:5]1[N:6]=[N:7][C:2]([N:22]2[CH2:23][CH2:24][CH:19]([C:17]([C:14]3[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=3)=[O:18])[CH2:20][CH2:21]2)=[CH:3][CH:4]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Solvent: CN1CCCC1=O
Product: Nc1ccc(N2CCC(C(=O)c3ccc(F)cc3)CC2)nn1
Yield: 46 %

Procedure:
A stirred mixture of 6-chloropyridazin-3-ylamine (0.95 g, 7.28 mmol) and (4-fluorophenyl)piperidin-4-ylmethanone hydrochloride (3.22 g, 10.92 mmol) was heated at 150° C. in N-methylpyrrolidinone (125 mL) for 24 hours. The solvent was evaporated in vacuo and the residue was treated with 1 N NaOH solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and concentrated. The residue was purified by column chromatography to afford [1-(6-aminopyridazin-3-yl)piperidin-4-yl]-(4-fluorophenyl)methanone in 46% yield (1.00 g, 3.33 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH2:12]Br)=[C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]2=[O:20].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C1COCC1.C(=O)(O)[O-]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH2:12][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]2=[O:20]
Reactant: O=c1c(-c2ccccc2)c(CBr)oc2ccc(Br)cc12
Reactant: C1COCCN1
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: O=c1c(-c2ccccc2)c(CN2CCOCC2)oc2ccc(Br)cc12
Yield: 131.3 %

Procedure:
To a solution of Intermediate 3 (0.30 g, 0.761 mmoles) in THF (2 ml), was added morpholine (0.066 g, 0.761 mmoles) at RT and refluxed for 12 h. The reaction mixture was cooled, diluted with aqueous bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as off-white solid (0.40 g, 79% yield). 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 8.12(d, J=2.2Hz, 1H), 7.98(dd, J=8.8,2.3 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 7.45-7.39(m, 3H), 7.29(d, J=7.0Hz, 2H), 3.50(t, J=4.2Hz, 4H), 3.40(s, 2H), 2.32(br S, 4H).