Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:9]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[C:7]([NH:8][S:22]([C:19]2[CH:18]=[CH:17][C:16]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:21][CH:20]=2)(=[O:24])=[O:23])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccnc1Br
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1cccnc1Br)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-bromo-3-aminopyridine (0.69 g, 3.98 mmol) in dry pyridine (15 mL) was added a solution of 4-phenoxy-benzenesulfonyl chloride (1.03 g, 3.98 mmol) in pyridine (3 mL) at 0 C. The resulting mixture was allowed to warm to room temperature and stirred until TCL showed the completion of the reaction. The reaction mixture was diluted with EtOAc and washed with aqueous HCl solution. After the pyridine was neutralized, the organics were washed with water, brine and dried over anhydrous Na2SO4. The filtration (Celite) and concentration under vacuo gave a crude material, which was purified by silica column (30% EtOAc/hexanes). MS: 405, 407 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].[OH-].[K+].Br[C:10]([CH3:24])([CH3:23])[C:11]([NH:13][C:14]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[O:16][N:15]=1)=[O:12]>C(O)C>[C:19]([C:17]1[O:16][N:15]=[C:14]([NH:13][C:11](=[O:12])[C:10]([CH3:23])([S:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH3:24])[CH:18]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Sc1cccs1
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)on1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(Sc1cccs1)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
To a stirred solution of 0.16 mL (1.7 mmol) of thiophene-2-thiol in ethanol (5 mL) were added 102 mg (1.8 mmol) of KOH pellets, followed by 460 mg (1.6 mmol) 2-bromo-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-propionamide (prepared as described in step 1, method C). The reaction mixture was heated to reflux for 18 h. The reaction was cooled to room temperature. The solid (KBr) was separated by filtration and rinsed with ethanol (15 mL). The filtrate was concentrated under reduced pressure and the residue purified by column chromatography (silica, eluent: heptanes, 0-10% ethyl acetate) to yield 504 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-2-(thiophen-2-ylsulfanyl)-propionamide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](/[C:10](/[C:20]3[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=3)=[C:11](/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)\[CH2:12][CH3:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Li+].[OH-].Cl>C1COCC1.CCO.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6](/[C:10](/[C:20]3[CH:21]=[CH:22][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:24][CH:25]=3)=[C:11](/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)\[CH2:12][CH3:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccccc2)c2ccc3[nH]ncc3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2[nH]ncc2c1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of (E)-ethyl 3-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylate (2.5 g, 5.9 mmol; Compound 1) in THF-EtOH (1:1, 59 mL), an aqueous solution of LiOH (2.8 g, 118 mmol; dissolved in a minimum amount of water) was added at room temperature. The resulting mixture was stirred overnight. The reaction was monitored by LCMS. Upon completion, 1N aqueous HCl was added until pH was 3. Then, the mixture was diluted with water and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water, washed with brine, dried over sodium sulfate, filtered, and concentrated to give the crude product. This crude material was purified on a silica gel column eluted with 0-20% methanol in dichloromethane affording the title compound as a pale yellow solid (1.9 g). 1H NMR (300 MHz, DMSO-d6): δ 13.11 (s, 1H), 12.30 (br, 1H), 8.08 (s, 1H), 7.65 (s, 1H), 7.53 (d, 1H), 7.43 (d, 1H), 7.37 (d, 2H), 7.29-7.11 (m, 6H), 6.88 (d, 2H), 6.37 (d, 1H), 2.44 (q, 2H), 0.87 (t, 3H); LCMS: 395 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23](I)[CH:22]=2)=[O:18].[C:39](=O)([O-])[O-:40].[Na+].[Na+].C([SiH](CC)CC)C.[C]=O>CN(C)C=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([CH:39]=[O:40])[CH:22]=2)=[O:18]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc3ccc(I)cc32)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc3ccc(C=O)cc32)cc1
Temperature: 60 °C
Yield: 92.8 %

Procedure:
In a pressure-proof container, palladium acetate (1.0 mg, 0.0044 mmol), 1,3-bis(diphenylphosphino) propane (1.8 mg, 0.0044 mmol), [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[6-iodo-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone (100 mg, 0.16 mmol), and sodium carbonate (18 mg, 0.17 mmol) were dissolved in anhydrous N,N-dimethylformamide (DMF) (0.22 ml). After triethylsilane (52 μl, 0.33 mmol) was added, the air inside the container was replaced with carbon monoxide. Then, the reaction mixture was heated at 60° C. with stirring under pressure with carbon monoxide (3 atm) for 24 hours. After the reaction mixture was cooled to room temperature, the pressure was released to ambient pressure. The reaction mixture was diluted with ethyl acetate. The sodium carbonate was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=100/5) to give 2-[5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazole-4-carbonyl]-1-(toluene-4-sulfonyl)-1H-indole-6-carbaldehyde as a yellow solid (80 mg, 85%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[C:3]1=[O:16].Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[N:23]=1.C(N(CC)CC)C>CC(O)C>[Br:24][C:22]1[N:23]=[C:18]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([C@H:4]3[C:3](=[O:16])[N:2]([CH3:1])[CH2:7][CH2:6][N:5]3[CH3:8])=[CH:10][CH:11]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: CN1CCN(C)C(c2ccc(N)cc2)C1=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CN1CCN(C)[C@@H](c2ccc(Nc3nc(Br)cn(C)c3=O)cc2)C1=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a single-necked 250 mL round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged (−)-1,4-dimethyl-3-(4-aminophenyl)piperazin-2-one (8.2 g, 37.3 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (10.0 g, 37.3 mmol), and i-PrOH (100 mL). Triethylamine (5.72 mL, 41 mmol, 1.1 eq) was then added and the resulting suspension was heated at 80° C. for 16 hrs. A thick slurry was observed the following day. The reaction was cooled to room temperature then concentrated in vacuo to ˜20 mL total volume. At that point 20 mL of 2M Na2CO3 solution was added followed by 100 mL of water. The mixture was then allowed to slurry for 2 hrs at room temperature. The off-white solid was then collected on a fritted funnel and allowed to air dry for ˜1 hr. The solids were returned to the reaction flask and 100 mL of diethyl ether/hexanes (1:1) was added and the suspension was triturated at room temperature for 1 hr. The white solid was then collected on a fritted funnel, dried on the filter with vacuum for 1 hr, then transferred to a round-bottomed flask and vacuum-dried overnight. White solids were obtained, 12.88 g (85%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C[N+]1([O-])CCOCC1.C(OCC)(=O)C>ClCCl.C(#N)C.CCCCCC.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: OCc1cccc(I)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CC#N
Product: O=Cc1cccc(I)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.7 %

Procedure:
A solution of 3-iodobenzyl alcohol (Aldrich, 4.72 g, 20 mmol) in dichloromethane (50 mL) and acetonitrile (5 mL) was treated sequentially with 4 A molecular sieves powder (5 g), tetra-n-propyl ammoniumperruthenate (0.1 g) and N-methyl morpholine-N-oxide (2.34 g, 40 mmol). After stirring at ambient temperature for 3 h, the reaction mixture was diluted with hexane and subjected to flash column chromatography over silica gel (230-400 mesh) using 6-10% ethyl acetate in hexane as the eluent to afford the title compound (3.7 g, 80%). It was used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Sn](CCCC)(CCCC)CCCC)[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:33]=[C:32]2I>CN(C=O)C.C(Cl)Cl.[Cu]I.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>[Cl:1][C:2]1[N:3]=[C:4]([C:32]2[C:31]3[C:35](=[CH:36][CH:37]=[C:29]([C:23]4[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=4[F:21])[CH:30]=3)[N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:33]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)n1cc(I)c2cc(-c3c(F)cccc3F)ccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(Cl)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cc(-c2cncc(Cl)n2)c2cc(-c3c(F)cccc3F)ccc21
Temperature: 100 °C
Yield: 35.1 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-6-(tributylstannyl)pyrazine (177 mg, 0.439 mmol) and tert-butyl 5-(2,6-difluorophenyl)-3-iodo-1H-indole-1-carboxylate (200 mg, 0.439 mmol) in DMF (2.5 mL) followed by CuI (18 mg, 0.044 mmol) and Pd(PPh3)4 (50.8 mg, 0.044 mmol). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 40 min, and then the mixture was diluted with DCM. The organic layer was separated, washed with water (20 mL×4), dried over Na2SO4, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 0-5% EtOAc in Hexanes) to give tert-butyl 3-(6-chloropyrazin-2-yl)-5-(2,6-difluorophenyl)-1H-indole-1-carboxylate (68.0 mg, 0.154 mmol, 35.0% yield) as a white solid. MS (ESI, pos. ion) m/z: 442 (M+1).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:9]1[CH:21]=[C:20]([CH3:22])[C:12]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([CH3:23])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].[CH3:28]I>CN(C)C=O>[F:1][C:2]([F:24])([F:25])[C:3]([C:9]1[CH:21]=[C:20]([CH3:22])[C:12]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([CH3:23])[CH:10]=1)([O:8][CH3:28])[C:4]([F:6])([F:5])[F:7]
Reactant: CI
Reactant: CCOC(=O)COc1c(C)cc(C(O)(C(F)(F)F)C(F)(F)F)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(C)cc(C(OC)(C(F)(F)F)C(F)(F)F)cc1C
Reaction time: 1 h

Procedure:
To ethyl 2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylphenoxy]acetate (6.0 g=16 mmol) in 60 ml dry dimethylformamide add sodium hydride dispersion in mineral oil (0.85 g=18 mmol). Stir 1 hour and add methyl iodide (3.0 g=21 mmol). Let stir 2 hours and partition between water and ether. Wash the ether layer with water, dry and concentrate. Recrystallize from ether-hexane to obtain ethyl 2-[4-(hexafluoro-2-methoxy-2-propyl)-2,6-dimethylphenoxy]acetate, m.p. 97°-98° C.
Reaction SMILES: [Li]CCCC.CCCCCC.[O:12]1[CH2:17][CH2:16][O:15][C:14]2=[CH:18][S:19][CH:20]=[C:13]12.CN(C)CCN(C)C.[CH2:29]([Sn:33](Cl)([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH3:32]>O1CCCC1>[CH2:38]([Sn:33]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:34][CH2:35][CH2:36][CH3:37])[C:18]1[S:19][CH:20]=[C:13]2[C:14]=1[O:15][CH2:16][CH2:17][O:12]2)[CH2:39][CH2:40][CH3:41]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1scc2c1OCCO2
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1scc2c1OCCO2
Temperature: 35 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
1.5M n-BuLi in hexane (53 mL, 80 mmol) was added in small portions to a solution of 2,3-dihydrothieno[3,4-b][1,4]dioxine (10.00 g, 80 mmol) and tetramethylethylenediamine (12.0 mL, 80 mmol) in tetrahydrofuran (100 mL) stirred under argon and cooled in a dry ice/acetone bath. The reaction mixture was heated to 35° C., stirred at this temperature for 1 hour, and then cooled in a dry ice/acetone bath. Tributylstannyl chloride (20.3 mL), 75 mmol was then added, the mixture was allowed to warm up, and it was left at room temperature for 16 hours. The volatiles were removed under reduced pressure. The residue was diluted with toluene (100 mL) and chromatographed using a column filled with silica gel (500 mL) washed with 2% triethylamine in hexane (500 mL) to give tributyl(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)stannane (12.17 g, 40%) of high purity. 1H NMR (400 MHz, CDCl3): δ 6.57 (s, 1H, thiophene), 4.15 (m, 4H, OCH2CH2O), 1.53 (m, 6H, Bu), 1.32 (quintet, J=7.3 Hz, 6H, Bu), 1.09 (m, 6H, Bu), 0.88 (t, J=7.3 Hz, 9H, Bu).
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.CN.[CH2:10]([C:12]1[N:13]=[C:14]([C:17]2[CH:22]=[C:21]([NH:23][C:24]([NH:26][CH2:27][CH3:28])=[O:25])[N:20]=[CH:19][C:18]=2[C:29]2[CH:30]=[N:31][CH:32]=[C:33]([C:35](O)=[O:36])[CH:34]=2)[S:15][CH:16]=1)[CH3:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO.CN(C=O)C>[CH2:27]([NH:26][C:24]([NH:23][C:21]1[N:20]=[CH:19][C:18]([C:29]2[CH:30]=[N:31][CH:32]=[C:33]([C:35]([NH:3][CH3:1])=[O:36])[CH:34]=2)=[C:17]([C:14]2[S:15][CH:16]=[C:12]([CH2:10][CH3:11])[N:13]=2)[CH:22]=1)=[O:25])[CH3:28]
Reactant: CCNC(=O)Nc1cc(-c2nc(CC)cs2)c(-c2cncc(C(=O)O)c2)cn1
Reactant: CCN(CC)CC
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: CCNC(=O)Nc1cc(-c2nc(CC)cs2)c(-c2cncc(C(=O)NC)c2)cn1
Reaction time: 0.17 h

Procedure:
Triethylamine (30.6 mg, 0.30 mmol) and methanamine (0.075 mL, 0.15 mmol), (2M soln in methanol) were added to a solution of 4′-(4-ethylthiazol-2-yl)-6′-(3-ethylureido)-3,3′-bipyridine-5-carboxylic acid (Example 99, 60 mg, 0.15 mmol) in DMF (1.5 mL). The solution was stirred for 10 minutes and then 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (57.4 mg, 0.15 mmol) was added. The resulting light yellow solution was stirred at room temperature for one hour. A small aliquat was withdrawn and analyzed by LCMS. Since the reaction was not complete, one more equivalent of methylamine solution and HATU were added. The analysis and addition of methylamine and HATU was repeated 3-4 times, however, the reaction did not go to completion. It was then diluted with water and extracted with ethylacetate 2-3 times. The extract was washed with water (3 times), brine and dried over magnesium sulfate, then concentrated to give the title compound as an off-white solid, which was triturated with acetonitrile and lyophilized to remove excess solvent (15 mg). MS (ES) MH+: 411 for C20H22N6O2S; NMR: 1.08 (t, 3H); 1.11 (t, 3H); 2.64 (q, 2H); 2.79 (d, 3H); 3.17-3.22 (m, 2H); 7.40 (s, 1H); 7.66 (s, 1H); 8.12 (d, 1H); 8.16 (s, 1H); 8.28 (s, 1H); 8.55 (s, 1H); 8.68 (s, 1H); 8.99 (d, 1H); 9.02 (s, 1H); 9.44 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1)[CH3:2].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C([O-])([O-])=O.[K+].[K+]>>[CH2:12]([O:10][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCBr
Reactant: CCc1cc(C)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCCCOc1cc(C)cc(CC)c1

Procedure:
Quantities: 3-ethyl-5-methylphenol (5.0 g, 0.036 mol), 1-bromodecane (11.05 g, 0.05 mol), K2CO3 (30.0 g, 0.2 mol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[C:5]([Cl:25])=[CH:4][N:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH2:34]>O1CCOCC1>[Cl:25][C:5]1[C:6]([CH:8]([S:17][C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=[CH:7][C:2]([NH:34][CH2:33][CH2:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)=[N:3][CH:4]=1
Reactant: NCCc1ccccn1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Solvent: C1COCCO1
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(NCCc3ccccn3)ncc2Cl)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
A 1,4-dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (150 mg, 0.36 mmol) obtained in Example 54 and 2-pyridin-2-ylethylamine (400 μl) was stirred at 120° C. for 5 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (126 mg, 70%) as an oil.
Reaction SMILES: ClCCl.[OH-].[Na+].[CH2:6]([C:13]#N)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[C:7]1([CH:6]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CCc1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: c1ccc(C2Cc3ccccc3C2)cc1
Reaction time: 48 h
Yield: 115.4 %

Procedure:
To a stirred two phase solution of dichloromethane (1 L) and 15% NaOH (750 mL) were added alpha, alpha,-di-bromo-o-xylene (100 g, 0.38 mol), benzyl cyanide (44.3 g, 0.38 mol) and benzyltriethylammonium chloride (17.2 g, 0.075 mol). The two phase solution was vigorously stirred at ambient temperature for 48 hours, at which time benzyl cyanide (20 g, 0.17 mol), benzyltriethylammonium chloride (9.0 g, 0.039 mol), and 15% NaOH (300 mL) were added. The mixture was stirred for an additional 48 hours. The reaction was poured into water (1 L) and extracted with ether (2.5 L). The organic solution was washed with water (3×1 L), brine (500 mL), dried over magnesium sulfate and the solvents evaporated. Vacuum distillation of the residue gave 42.6 g of 2,3-dihydro-2-phenyl-1H-indene- 2-carbontrile, bp 166°-168° C. (5 mm), Lit. bp 160°-180° C. ( 1 mm), as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:17]1([NH2:20])[CH2:19][CH2:18]1>>[C:1]([C:5]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([NH:20][CH:17]3[CH2:19][CH2:18]3)[CH2:12][CH2:11]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CC(C)(C)c1noc(N2CCC(=O)CC2)n1
Product: CC(C)(C)c1noc(N2CCC(NC3CC3)CC2)n1

Procedure:
The title compound is prepared from 1-(3-tert-butyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-one and cyclopropylamine following a procedure analogous to that described in Intermediate 4. LC (method 8): tR=0.95 min, Mass spectrum (ESI+): m/z=265 [M+H]+.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([C:7]([CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=O)=O)=[CH:3][CH:2]=1.C(O)C.[NH2:23][NH2:24]>C(Cl)(Cl)Cl>[C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([C:7]2[NH:24][N:23]=[C:10]3[C:11]4[C:16]([CH2:17][C:9]=23)=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:3][CH:2]=1
Reactant: NN
Reactant: Cc1ccc(C(=O)C2Cc3ccccc3C2=O)cc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2[nH]nc3c2Cc2ccccc2-3)cc1

Procedure:
To a warm solution of 3.3 g. of the diketone of Step A in 33 ml. of ethanol and 10 ml. of chloroform is added 4 g. of hydrazine and the resulting solution is refluxed for 1 hr. It is then cooled and evaporated to dryness under reduced pressure. The crude solid residue obtained is crystallized from methanol to yield the product 3-(p-tolyl)-4H-indeno[1,2-c]-pyrazole (m.p. 250°-252°C).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].[S:43](Cl)([CH3:46])(=[O:45])=[O:44].[Cl-].[NH4+]>O1CCCC1>[CH3:46][S:43]([N:27]1[C:17]2[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:20]=[C:15]([C:12]3[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=4)[CH2:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[N:14][CH:13]=3)[C:16]=2[CH2:29][CH2:28]1)(=[O:45])=[O:44]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4S(C)(=O)=O)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To tetrahydrofuran solution (2 ml) of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg, 0.185 mmol), 60% sodium hydride (222 mg, 5.56 mmol) was added, followed by stirring at room temperature for 30 minutes. To this, mesyl chloride (430 μl, 5.56 mmol) was added, followed by refluxing for 6 hours. This was cooled to room temperature, followed by addition of saturated aqueous ammonium chloride solution, and passed through Whatman tube. The resulting organic phase was concentrated under reduced pressure, followed by purification by silica gel column chromatography (dichloromethane/methanol=200/1), to obtain [5-(7-methanesulfonyl-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-bis-(4-methoxy-benzyl)-amine (80.2 mg, Yield 70%). To this, trifluoroacetic acid (1 ml) and concentrated sulfuric acid (2 drops) were added, followed by stirring at 40° C. for 3 hours. After concentration of trifluoroacetic acid under reduced pressure, water was added, followed by neutralization with 1M aqueous sodium hydroxide solution. The solid was filtered, followed by purification by silica gel column chromatography (dichloromethane/2M ammonia methanol=30/1), to obtain the desired compound as a yellow solid (14.9 mg, Yield 31%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH:20]2[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:31]>C(Cl)Cl>[ClH:31].[NH:22]1[CH2:23][CH:20]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[CH:11][C:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[CH:19]3)[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC(c2cccc3cc(S(=O)(=O)c4ccccc4)cnc23)C1
Agent: Cl
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)c1cnc2c(C3CNC3)cccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
A solution of tert-butyl 3-(3-(phenylsulfonyl)quinolin-8-yl)azetidine-1-carboxylate (54 mg, 0.13 mmol) in CH2Cl2 (3 ml) was treated with hydrochloric acid (1M in ether, 0.3 ml) at 0° C. and then stirred at room temperature for 16 h. After concentration, the product was washed with EtOAc and dried in vacuo to give the title compound (45 mg, 98%) as a white solid.