Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(O[NH:16][S:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:45]=[CH:46][CH:47]=1)[CH2:24][C:25]1[C:26](=[O:44])[O:27][C:28]2[CH:36]=[C:35]([O:37][C:38](=[O:42])[N:39]([CH3:41])[CH3:40])[C:34]([Cl:43])=[CH:33][C:29]=2[C:30]=1[CH2:31][F:32])(=[O:19])=[O:18])=O)(C)(C)C.C(=O)([O-])O.[Na+]>>[NH2:16][S:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:45]=[CH:46][CH:47]=1)[CH2:24][C:25]1[C:26](=[O:44])[O:27][C:28]2[CH:36]=[C:35]([O:37][C:38](=[O:42])[N:39]([CH3:40])[CH3:41])[C:34]([Cl:43])=[CH:33][C:29]=2[C:30]=1[CH2:31][F:32])(=[O:18])=[O:19]
Reactant: CN(C)C(=O)Oc1cc2oc(=O)c(Cc3cccc(NS(=O)(=O)NOC(=O)OC(C)(C)C)c3)c(CF)c2cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)Oc1cc2oc(=O)c(Cc3cccc(NS(N)(=O)=O)c3)c(CF)c2cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
Trifluoroacetic acid (0.1 mL) was added to a solution of dimethylcarbamic acid 3-{3-((tert-butoxycarbonyloxy)aminosulfonyl)aminobenzyl}-6-chloro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester (compound 1j-1-3-1F-other) (23 mg, 0.039 mmol) in anhydrous dichlromethane (1.0 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then poured into saturated sodium hydrogen carbonate and extracted with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate. A crude solid was then obtained by vacuum concentration, and purified by preparative TLC (ethyl acetate:hexane=1:1) to yield the title compound (19 mg, 100%) as a pale yellow powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13].C(OCC)C>C1(C)C=CC=CC=1.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.[Cu]I>[CH3:15][Si:14]([C:12]#[C:13][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1)([CH3:17])[CH3:16]
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C[Si](C)(C)C#Cc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 60.5 %

Procedure:
To a solution of 4-bromobenzenesulfonamide (4.51 g, 19.1 mmole) in toluene (900 mL) at 75° C. was added ethynyl(trimethyl)silane (4 g, 40 mmole), Pd(PPh3)4 (1.3 g, 1.1 mmole), CuI (0.46 g, 2.42 mmole) and TEA (5.7 g, 56 mmole) and the mixture was allowed to cool to room temperature while stirring. Additional Pd(PPh3)4 (1 g, 0.9 mmole) was added and the mixture was stirred at room temperature. After 5 days, ethyl ether was added and the mixture was washed with 10% HCl, H2O, sat. aqueous NH4Cl, dried over Na2SO4 and concentrated in vacuo to give 2.93 g (61% yield) of the product: ESHRMS m/z 271.0935 (M+NH4, C11H15NO2SSiNH4, Calc'd 271.0937).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>C(Cl)Cl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N1CCC(O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N1CCC(OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
1-Isopropyl-4-hydroxypiperidine (1 g, 6.98 mmol), DCM (10 ml) and triethylamine (1.08 ml, 7.68 mmol) were cooled to 0-5° C. and mesyl chloride (0.54 ml, 6.98 mmol) was added dropwise under N2. The reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with sat. NaHCO3 (20 ml) and the aqueous phase extracted with DCM (2×5 ml). The combined organic extracts were dried over MgSO4, filtered, washed with DCM and concentrated in vacuo to give the title compound (1.55 g, 100%) as a pale yellow oil.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH2:18][C:19]#[N:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl>O1CCCC1.C(O)C.[Ni]>[Si:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH2:18][CH2:19][NH2:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2c1ccn2CC#N
Agent: [Ni]
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc2c1ccn2CCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a solution of (4-{[tert-butyl(dimethyl)silyl]oxy}-1H-indol-1-yl)acetonitrile (259 mg, 0.904 mmol) in tetrahydrofuran (20 mL) are added a 2.0M hydrochloric acid in ethanol (1 mL) and active Raney-nickel (manufactured by Kawaken Fine Chemicals Co., Ltd., about 1 mL), and the mixture is vigorously stirred under hydrogen atmosphere under pressure (0.5 Pa) at room temperature for 1 hour. To the mixture is further added active Raney-nickel (about 1.5 mL), and the mixture is vigorously stirred under the same conditions for 4 hours. The catalyst is removed by filtration through celite, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by silica gel column (ammonia-chloroform:methanol=100:1→50:1→30:1) to give the title compound as pale brown oil (207 mg, yield: 79%).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].CB1OB(C)OB(C)O1.[CH2:16](Cl)Cl.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([F:31])([F:30])([F:29])([F:28])[F:27])=[CH:22][C:21]=1Br>C(COC)OC.CCOCC.Cl[Pd]Cl.O>[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([F:31])([F:30])([F:29])([F:28])[F:27])=[CH:22][C:21]=1[CH3:16]
Reactant: ClCCl
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1Br
Agent: Cl[Pd]Cl
Agent: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCOCC
Product: Cc1cc(S(F)(F)(F)(F)F)ccc1N
Temperature: 70 °C
Yield: 1724.8 %

Procedure:
A mixture of Cs2CO3 (794 g, 2.7 mol), dimethoxyethane (2 l), water (300 ml) and trimethylboroxine (50 percent solution in THF, 225 g, 0.9 mol) was heated to 70° C., PdCl2 (dppf)×CH2Cl2 (37 g, 45 mmol) was added, and a solution of 4-amino-3-bromophenylsulfur pentafluoride (270 g, 0.9 mol) in dimethoxyethane (400 ml) was added dropwise over the course of 2 h while the reaction mixture was heated to reflux. It was subsequently heated under reflux for a further 3 h and then cooled to room temperature, diluted with MTB ether (500 ml), filtered through a silica gel column (14×7 cm, 70-200 μm) and washed with MTB ether (2500 ml). The filtrate was evaporated in vacuo. 490 g of a black, semicrystalline mass was obtained and was subjected to a steam distillation. A total of 5.5 l of condensate was collected, from which the crystals of the product separated out. The condensate was extracted 3× with MTB ether, and the combined organic phases were dried over Na2SO4 and evaporated in vacuo. 4-Amino-3-methylphenylsulfur pentafluoride (181 g, 76%) was obtained as colorless crystals, m.p. 65-66° C.,
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([C@H:13]3[CH2:18][CH2:17][C@H:16]([O:19][CH3:20])[CH2:15][CH2:14]3)[C:9](=[O:12])[CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]([C:35]([O:38][Si](C)(C)C)([CH3:37])[CH3:36])=[N:33][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[OH:38][C:35]([C:32]1[N:33]=[CH:34][C:29]([C:2]2[N:7]=[C:6]3[N:8]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH3:20])[CH2:15][CH2:14]4)[C:9](=[O:12])[CH2:10][NH:11][C:5]3=[N:4][CH:3]=2)=[CH:30][CH:31]=1)([CH3:37])[CH3:36]
Reactant: CC(C)(O[Si](C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CO[C@H]1CC[C@H](N2C(=O)CNc3ncc(Br)nc32)CC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CO[C@H]1CC[C@H](N2C(=O)CNc3ncc(-c4ccc(C(C)(C)O)nc4)nc32)CC1
Temperature: 70 °C

Procedure:
7-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (Alternate Approach). Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (1 equiv) and trans-4-methoxycyclohexanamine hydrochloride (1.5 equiv), NMP and DIPEA were combined and heated to 127° C. and maintained at that temperature for 18 h. Upon reaction completion, the mixture was cooled to 35° C. over 4 h. The solution was transferred to a mixture of ethyl acetate and 5% brine. The aqueous layer was removed and the organic layer was washed successively with 5% brine and water. The organic layer was concentrated by vacuum distillation to a low volume, cooled to ambient temperature and the solids were collected by vacuum filtration. The solids were washed with MTBE and the product was dried in a vacuum oven to give 41% yield of ethyl 2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino)acetate. A mixture of ethyl 2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino) acetate (1 equiv), water and 85% phosphoric acid (3:1) was heated to 80° C. over 1 h. Heating was maintained for 18 h to effect reaction completion. Upon reaction completion, the mixture was cooled to 25° C. and filtered to give a crude product as tan solid. The resulting solids were washed with water, slurried in water and filtered. The solids were washed with water until the pH of the filtrate was between 4 and 8. The resulting material was dried under vacuum to give 89% yield of 7-bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. 7-Bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-(trimethylsilyloxy)propan-2-yl)pyridine (1 equiv), sodium carbonate (3 equiv) and PdCl2(AmPhos)2 (0.003 equiv) were combined in isopropanol and heated at 70° C. for 1.5 h. Standard work-up and purification afforded the protected compound in 93% yield. Deprotection using standard conditions for removal of a trimethylsilyl-group and isolation gave the title compound.
Reaction SMILES: B([C:4]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:5]=1[O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])(O)O.[Cl:17][C:18]1[CH:19]=[C:20]([S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1I>CO>[Cl:17][C:18]1[CH:19]=[C:20]([S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1[C:4]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:5]=1[O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9]
Reactant: CN(C)S(=O)(=O)c1ccc(I)c(Cl)c1
Reactant: C[C@H](Oc1ccc(Cl)cc1B(O)O)C(=O)O
Solvent: CO
Product: C[C@H](Oc1ccc(Cl)cc1-c1ccc(S(=O)(=O)N(C)C)cc1Cl)C(=O)O

Procedure:
The title compound was prepared by the method of example 144 step (i) using the product from example 151 step (iv), the product from example 148 step (ii) and methanol as solvent. Yield (0.08 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.Cl.[CH3:33][NH:34][O:35][CH3:36]>C(Cl)(Cl)Cl.O>[CH3:36][O:35][N:34]([CH3:33])[C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1]
Reactant: CNOC
Reactant: Cc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: CON(C)C(=O)c1ccccc1C
Temperature: 25 °C
Yield: 50 %

Procedure:
2-Methylbenzoic acid (1.00 g, 7.34 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.69 g, 8.81 mmol) in chloroform (10 mL) stirred with N,N-diisopropylethylamine (1.50 mL, 8.81 mmol) for 10 minutes under cooling with ice and then stirred with N,O-dimethylhydroxylamine hydrochloride (860 mg, 8.81 mmol) and N,N-diisopropylethylamine (1.50 mL, 8.81 mmol) for one day while the temperature was gradually raised to room temperature. After addition of water, the reaction mixture was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound as a pale yellow oil (658 mg, yield 50%).
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1.[F-].[Cs+].C(N(CC)CC)C>CC(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C.O>[F:12][C:11]1[C:2]([C:18]2[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=2)=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]=[C:8]([CH3:13])[CH:7]=[CH:6]2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc2ccc(Br)c(F)c2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1ccc2ccc(-c3cnn(C)c3)c(F)c2n1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
A solution of 7-bromo-8-fluoro-2-methylquinoline (0.15 g, 0.63 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.26 g, 1.25 mmol), PdCl2(dppf)*dcm (0.051 g, 0.063 mmol), CsF (0.247 g, 1.62 mmol) and triethylamine (0.13 mL, 0.94 mmol) in IPA (3 mL) was heated at 100° C. in a sealed tube for 6 hours. After cooling to ambient temperature, water (10 mL) and ethyl acetate (20 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ethyl acetate) to give 8-fluoro-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)quinoline (0.132 g, 87.6%) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH2:11])=[N:7]1)[CH3:2].[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([Cl:13])=[CH:15][CH:16]=2)=[N:7]1)[CH3:2]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cn1ccc(N)n1
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc(NC(=O)c2ccc(Cl)cc2)n1

Procedure:
59.1 Using general method A, with THF instead of DMF as solvent, (3-amino-pyrazol-1-yl)-acetic acid ethyl ester (example 57.1) was coupled with 4-chlorobenzoic acid to give [3-(4-chloro-benzoylamino)-pyrazol-1-yl]-acetic acid ethyl ester. Off-white solid. MS 308.3 ([M+H]+)
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][C@H:13]([C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=1[CH:24]1[CH2:29][CH2:28][N:27]([C:30](OC(C)(C)C)=[O:31])[CH2:26][CH2:25]1)[CH2:14][CH3:15])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl.[C:47]([N:51]1[CH2:55][C@@H:54]([C:56]2[CH:61]=[CH:60][C:59]([F:62])=[CH:58][C:57]=2[F:63])[C@H:53](C(O)=O)[CH2:52]1)([CH3:50])([CH3:49])[CH3:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCOC(C)=O.C(Cl)Cl.O>[C:47]([N:51]1[CH2:55][C@@H:54]([C:56]2[CH:61]=[CH:60][C:59]([F:62])=[CH:58][C:57]=2[F:63])[C@H:53]([C:30]([N:27]2[CH2:28][CH2:29][CH:24]([C:17]3[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:16]=3[C@@H:13]([NH:12][C:10](=[O:11])[O:9][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:14][CH3:15])[CH2:25][CH2:26]2)=[O:31])[CH2:52]1)([CH3:50])([CH3:48])[CH3:49]
Reactant: CC[C@H](NC(=O)OCc1ccccc1)c1cc(C)c(C)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)N1C[C@@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC[C@H](NC(=O)OCc1ccccc1)c1cc(C)c(C)cc1C1CCN(C(=O)[C@@H]2CN(C(C)(C)C)C[C@H]2c2ccc(F)cc2F)CC1
Reaction time: 18 h

Procedure:
A saturated solution of hydrogen chloride in EtOAc (10.0 mL) was added to a solution of 111 (830 mg, 1.7 mmol) in DCM (5.0 mL) at ambient temperature. After 30 min the volatiles were evaporated in vacuo. The above residue was resuspended in DCM (10.0 mL) and to this stirred solution was added DIEA (886 μL, 5.1 mmol), (3S,4R)-1-tert-butyl4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid 80 (542 mg, 1.7 mmol), and HATU (710 mg, 1.87 mmol). After approximately 18 h, the reaction mixture was poured into water and extracted three times with DCM. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and the filtrate concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0%-10% methanol [containing 10% v/v ammonium hydroxide]/DCM as eluent) afforded 112 as a colorless oil.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]([NH2:11])([CH3:10])[CH3:9]>>[CH3:9][CH:8]([N:11]=[C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:10]
Reactant: CC(C)N
Reactant: O=C1CCCCC1
Product: CC(C)N=C1CCCCC1
Reaction time: 8 h

Procedure:
To a mixture of 600 g. cyclohexanone and 1 l. isopropylamine are added 500 g. Linde Type 3A molecular sieves. The mixture is allowed to stand overnight at room temperature, after which the isopropylamine is removed in vacuo at room temperature. The oily residue is 1-methyl-N-(cyclohexylidene)-ethylamine.
Reaction SMILES: C[Si](C)(C)[C:3]1[CH:4]=[C:5]([N:22]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:6]=[C:7]([N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:8]=1.[Br:37]N1C(=O)CCC1=O>CN(C)C=O>[Br:37][C:3]1[CH:4]=[C:5]([N:22]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:6]=[C:7]([N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:8]=1
Reactant: C[Si](C)(C)c1cc(-n2c3ccccc3c3ccccc32)cc(-n2c3ccccc3c3ccccc32)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Brc1cc(-n2c3ccccc3c3ccccc32)cc(-n2c3ccccc3c3ccccc32)c1

Procedure:
1 g of 9,9′-(5-(trimethylsilyl)-1,3-phenylene)bis(9H-carbazole) and 0.40 g of N-bromosuccinimide were dissolved in 20 mL of dimethylformamide, and then the reaction was carried out at room temperature. After completion of the reaction, the reaction mixture was extracted with dichloromethane and distilled water, and the solvent was dried. The resulting solid was filtered and purified, yielding 9,9′-(5-bromo-1,3-phenylene)bis(9H-carbazole) as an intermediate.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OC1[CH:23]([N:24]2[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH2:25]2)[C:22]2=[CH:31][CH:19]([O:20][C:21]2=[O:32])[CH:18]2[CH:14]([O:15][C:16](=[O:34])[CH:17]2[CH3:33])[CH2:13][C:12]2(C)[CH:10]1[O:11]2.O>N1C=CC=CC=1>[C:5]([O:4][CH:1]1[CH:23]([N:24]2[CH2:25][CH2:26][CH:27]([CH3:30])[CH2:28][CH2:29]2)[C:22]2=[CH:31][CH:19]([O:20][C:21]2=[O:32])[CH:18]2[CH:14]([O:15][C:16](=[O:34])[CH:17]2[CH3:33])[CH2:13][C:12]2([CH3:10])[CH:2]1[O:11]2)(=[O:7])[CH3:6]
Reactant: CC1CCN(C2C3=CC(OC3=O)C3C(CC4(C)OC4C2O)OC(=O)C3C)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC1C(N2CCC(C)CC2)C2=CC(OC2=O)C2C(CC3(C)OC13)OC(=O)C2C
Reaction time: 20 h
Yield: 36.9 %

Procedure:
Acetic anhydride (150 μmol; 15 μl) is added to a solution of the compound of Example 9 (100 μmol; 40 mg) in pyridine (0.5 ml). The solution obtained is stirred for 20 hours then the reaction mass is poured into water. The aqueous phase is extracted twice with ethyl acetate and the organic phase obtained is washed with water then with a solution of sodium chloride. The organic phase is dried over magnesium sulphate, filtered then evaporated. The residue is eluted on silica with a mixture of isopropyl acetate and dichloromethane (20/80). 16 mg of product is obtained in the form of a white powder.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[Br:12]Br>[Fe]>[Br:12][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[C:3]([CH:4]=1)[NH2:9]
Reactant: Cc1cccc([N+](=O)[O-])c1C
Reactant: BrBr
Agent: [Fe]
Product: Cc1cc(Br)cc(N)c1C
Temperature: 0 °C
Yield: 40.7 %

Procedure:
The mixture of 90.60 g of 2,3-dimethylnitrobenzene (3-10) and 1.20 g of iron powder was heated at 75° C., to which 115.00 g of bromine was dropped with stirring, and then the resulting mixture was stirred at the same temperature for 4 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate, and the resulting organic layer was washed with sodium thiosulfate solution and saturated salt water in order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and 400 ml of methanol and 400 ml of concentrated hydrochloric acid were added to the resulting residue, to which 100 g of iron powder was added in a divided form, and thereafter, the resulting mixture was stirred at 70° C. for 30 minutes. The reaction solution was poured into ice water, and the resulting mixture was alkaline with sodium bicarbonate, and thereafter, extracted with ethyl acetate and the resulting organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent; hexane:ethylacetate=9:1) to obtain 48.82 g of 5-bromo-2,3-dimethylaniline (3-11).
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH2:27]([O:34][C:35]([NH:37][C:38]1[N:46]=[CH:45][N:44]=[C:43]2[C:39]=1[N:40]=[CH:41][N:42]2[CH2:47][C:48](O)=[O:49])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:48](=[O:49])[CH2:47][N:42]2[CH:41]=[N:40][C:39]3[C:43]2=[N:44][CH:45]=[N:46][C:38]=3[NH:37][C:35]([O:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:36])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C(O)Cn1cnc2c(NC(=O)OCc3ccccc3)ncnc21
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ncnc2c1ncn2CC(=O)N1CCN(S(=O)(=O)c2nc3ccccc3s2)C(=O)C1)OCc1ccccc1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [6-N-(benzyloxycarbonyl)-adenine-9-yl]-acetic acid as per the procedure of Example 52. 1H-NMR (500 MHz; DMSO-d6) δ 10.81 (brs, 1H), 8.60 (d, 1H), 8.36 (m, 1H), 8.28 (m, 2H), 7.73 (m, 2H), 7.46 (d, 2H), 7.40 (t, 2H), 7.34 (t, 1H), 5.41 (s, 1.21H), 5.29 (s, 0.8H), 5.23 (s, 2H), 4.57 (s, 0.8H), 4.28 (s, 2.4H), 4.09 (m, 2.0H), 3.88 (t, 0.8H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][O:10]COCC[Si](C)(C)C)=[CH:4][N:3]=1.[F:19][C:20]1[CH:21]=[C:22]([C:27]2[N:28]=[C:29]([N:42]3[CH2:47][CH2:46][NH:45][CH2:44][C@H:43]3[CH3:48])[NH:30][C:31]=2[C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[CH:23]=[CH:24][C:25]=1[F:26].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:8][C:7]1[CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=[N:3][C:2]=1[N:45]1[CH2:46][CH2:47][N:42]([C:29]2[NH:30][C:31]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:39])([F:41])[F:40])=[CH:34][CH:33]=3)=[C:27]([C:22]3[CH:23]=[CH:24][C:25]([F:26])=[C:20]([F:19])[CH:21]=3)[N:28]=2)[C@H:43]([CH3:48])[CH2:44]1
Reactant: C[Si](C)(C)CCOCOCc1cnc(Cl)c(Cl)c1
Reactant: C[C@@H]1CNCCN1c1nc(-c2ccc(F)c(F)c2)c(-c2ccc(C(F)(F)F)cc2)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc(-c2ccc(F)c(F)c2)c(-c2ccc(C(F)(F)F)cc2)[nH]1

Procedure:
A mixture of 2,3-dichloro-5-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)pyridine from step (a) above (80 mg, 0.26 mmol), (2R)-1-(4-(3,4-difluorophenyl)-5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)-2-methylpiperazine (100. mg, 0.236 mmol, Example 1(d)), and DIEA (0.082 mL, 0.47 mmol, Aldrich) in NMP (0.7 mL) was subjected to microwave irradiation at 170° C. for 1 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified on silica gel using ISCO Combiflash® system with EtOAc/Hexanes (1:9) as the eluant to give the title compound as a light brown solid. MS (ESI, positive ion) m/z: 694 (M+1).