Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([Li])CCC.CCCCCC.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[C:31](Cl)=[O:32]>O1CCCC1>[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[C:31]([C:7]1[C:2]([Cl:1])=[CH:3][C:4]([CH3:9])=[CH:5][C:6]=1[Cl:8])=[O:32]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: Cc1cc(Cl)cc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(Cl)c(C(=O)c2ccc3ccccc3c2)c(Cl)c1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a cold (-60° C.) stirred solution of 3,5-dichlorotoluene (2.5 g, 15.5 mmol) in 30 ml of dry tetrahydrofuran under a nitrogen atmosphere, a 2.6 M solution of n-butyllithium in hexane (6.3 ml, 16.3 mmol) was added slowly over 15 minutes. The reaction mixture was stirred for an additional 30 minutes at -60° C. and then treated dropwise with a solution of 2-naphthoyl chloride (2.95 g, 15.5 mmol) in 15 ml of dry tetrahydrofuran over 15 minutes. The reaction mixture was stirred for 4 hours at -60° C. and then quenched with 4 ml of saturated NH4Cl solution. The mixture was permitted to come to room temperature at which point it was diluted with 20 ml of water and 20 ml of ether. The layers were separated and the aqueous layer further extracted with ether. The combined extracts were washed with brine, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to give 4.76 g of crude product. This material was chromatographed on silica gel (20:1 hexane:ethyl acetate) to give 1.71 g of pure product.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([NH:15][C@@H:16]([CH3:20])[C:17](O)=[O:18])=[O:14])=[CH:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH2:29]([N:31](CC)[CH2:32]C)C.Cl.CNC.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([NH:15][C@@H:16]([CH3:20])[C:17]([N:31]([CH3:32])[CH3:29])=[O:18])=[O:14])=[CH:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:7]3=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CCN(CC)CC
Reactant: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12)C(=O)O
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12)C(=O)N(C)C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of (S)-2-(2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)propanoic acid (253 mg, 0.63 mmol), triethylamine (0.44 mL, 3.13 mmol), and dimethylamine hydrochloride (102 mg, 1.25 mmol) in DMF (5 mL) at room temperature was added PyBOP (358 mg, 0.69 mmol). The reaction mixture was stirred overnight then diluted with EtOAc (50 mL) and washed with water (4×25 mL). The organic extracts were combined and dried (Na2SO4) then evaporated under vacuum. The crude residue was purified by SiO2 chromatography (24 g, hexanes:EtOAc, 3:7) to give 190 mg (70%) of (S)-2-cyclopropyl-N-(1-(dimethylamino)-1-oxopropan-2-yl)-5-((2-(trimethyl-silyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide as a colorless viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH2:11])[N:10]=1)[C:5]([NH2:7])=O.CSC.Cl.[OH-].[Na+]>C1COCC1>[NH2:7][CH2:5][C:4]1[CH:8]=[C:9]([NH2:11])[N:10]=[C:2]([NH2:1])[CH:3]=1
Reactant: NC(=O)c1cc(N)nc(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CSC
Product: NCc1cc(N)nc(N)c1
Yield: 36.5 %

Procedure:
To a refluxing suspension of 0.5 g (3.29 mmol) 2,6-diamino-isonicotinamide in 3 ml THF was added dropwise 0.455 ml (4.8 mmol) boran-dimethylsulfide-complex and the mixture was refluxed for 4 d. After cooling to room temperature 0.548 ml 6N HCl was added and the mixture was neutralized with 2N NaOH. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica eluting with DCM:MeOH:NH3aq. 100:100:1 to yield 166 mg (36%) of the title compound as yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([C:16]#[N:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.BrC1N=C(NCC2CC(C#N)CCO2)C=CC=1.[Cl:35][C:36]1[C:37](B(O)O)=[CH:38][C:39]([F:42])=[N:40][CH:41]=1.C(Cl)Cl>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].COCCOC>[Cl:35][C:36]1[C:37]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3([C:16]#[N:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:7]=2)=[CH:38][C:39]([F:42])=[N:40][CH:41]=1
Reactant: N#CC1(CNc2cccc(Br)n2)CCOCC1
Reactant: OB(O)c1cc(F)ncc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#CC1CCOC(CNc2cccc(Br)n2)C1
Solvent: ClCCl
Solvent: COCCOC
Product: N#CC1(CNc2cccc(-c3cc(F)ncc3Cl)n2)CCOCC1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
A mixture of 4-((6-bromopyridin-2-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate S, 410 mg, 1.384 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (362.2 mg, 2.07 mmol), PdCl2(dppf).CH2Cl2 adduct (113 mg, 0.14 mmol), DME (5 Ml) and 2 M aqueous Na2CO2 (1.75 Ml, 3.5 mmol) was sealed and stirred at 110° C. for 20 min using microwave reactor. After cooling to room temperature the mixture was extracted with EtOAc (35 Ml), filtered and concentrated in vacuo. The crude material was purified by column chromatography [silica gel, 24 g, EtOAc/hexane=5/100 to 50/50] to provide 4-((5′-chloro-2′-fluoro-2,4′-bipyridin-6-ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrile (360 mg, 75% yield). LCMS (m/z): 347 [M+H]+; retention time=0.814 min.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.[CH3:29][N:30]([CH3:34])[CH2:31][C:32]#[CH:33].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:27][C:19]1[CH:18]=[C:17]([C@@H:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:33]#[C:32][CH2:31][N:30]([CH3:34])[CH3:29])=[CH:7][N:6]=2)=[O:28])[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: C#CCN(C)C
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC#Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.6 %

Procedure:
A solution of N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 6, 486 mg, 1.0 mmol) and 1-dimethylamino-2-propyne (830 mg, 10.0 mmol) in toluene (6 ml) was treated with N,N-diisopropylethylamine (1.5 ml), copper(I) iodide (19.2 mg, 0.10 mmol), and dichlorobis(triphenylphosphine)palladium(II) (36.0 mg, 0.05 mmol). The resulting reaction mixture was stirred at 25° C. for 24 h. At this time, the reaction mixture was concentrated in vacuo. The residue was extracted into methylene chloride from water. The combined organic layers were dried and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 4/1 ethyl acetate/methanol) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-prop-1-ynyl)-pyrazin-2-yl]-propionamide (360 mg, 74%) as a pale brown solid: (ES)+-HRMS m/e calcd for C24H29ClN4O3S (M+H)+ 489.1722, found 489.1725.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[N:20]1([C:25]2[CH:32]=[CH:31][C:30]([CH:33]=[CH2:34])=[CH:29][C:26]=2[CH:27]=O)[CH:24]=[N:23][CH:22]=[N:21]1.N1CCC[C@H]1C(O)=O>CO>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:27]1[C:26]1[CH:29]=[C:30]([CH:33]=[CH2:34])[CH:31]=[CH:32][C:25]=1[N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Reactant: C=Cc1ccc(-n2cncn2)c(C=O)c1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CO
Product: C=Cc1ccc(-n2cncn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Temperature: 60 °C
Yield: 8.8 %

Procedure:
To a solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (100 mg, 0.39 mmol) in MeOH (5 mL) are added crude 2-1,2,4-triazol-1-yl-5-vinyl-benzaldehyde (93 mg, 0.47 mmol) and L-proline (4 mg, 0.04 mmol) at room temperature. The solution is heated to 60° C. for 12 hours, then cooled down and is concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography eluting with 10% MeOH in CH2Cl2 to afford the title compound (15 mg, 9%) as a white solid. LCMS (ESMS): m/z 437.72 (M++1)
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:45]([C:46]3[CH:51]=[CH:50][C:49]([CH:52]([CH2:54][CH3:55])[CH3:53])=[CH:48][CH:47]=3)[C:44](=[O:56])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=2)=[CH:32][C:31]=1[CH3:57])(C(C)(C)C)(C)C>C1COCC1>[CH:52]([C:49]1[CH:48]=[CH:47][C:46]([N:45]2[C:44](=[O:56])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=[C:36]2[C:33]2[CH:34]=[CH:35][C:30]([O:29][CH2:28][CH2:27][OH:26])=[C:31]([CH3:57])[CH:32]=2)=[CH:51][CH:50]=1)([CH2:54][CH3:55])[CH3:53]
Reactant: CCC(C)c1ccc(-n2c(-c3ccc(OCCO[Si](C)(C)C(C)(C)C)c(C)c3)nc3ccccc3c2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(C)c1ccc(-n2c(-c3ccc(OCCO)c(C)c3)nc3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1 M THF solution of TBAF (1.7 mL, 1.70 mmol) was added to a solution of 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3-methylphenyl)-3-(4-sec-butylphenyl)quinazolin-4(3H)-one (0.320 g, 0.59 mmol) in THF (2 mL). The mixture was stirred at room temperature for 1 hour and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 10% to 90% EtOAc in heptane, afforded the title compound, as a white solid (0.175 g, 69%). 1H-NMR (300 MHz, DMSO-d6): δ 8.15-8.18 (m, 1H), 7.80-7.95 (m, 1H), 7.74 (d, J=7.7 Hz, 1H), 7.49-7.64 (m, 1H), 7.01-7.25 (m, 6H), 6.72 (d, J=8.5 Hz, 1H), 4.81 (t, J=5.5 Hz, 1H), 3.80-3.97 (m, 2H), 3.56-3.73 (m, 2H), 2.54-2.67 (m, 1H), 1.99 (s, 3H), 1.32-1.66 (m, 2H), 1.17 (d, J=6.9 Hz, 3H), 0.67 (t, J=7.3 Hz, 3H). MS (APCI) m/z: 429 (M+H)+.
Reaction SMILES: [OH:1][C:2]1(S)[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])[N:5]=[CH:4][NH:3]1.ClCC(O)=[O:17].[OH-].[Na+]>O>[OH:17][C:4]1[N:3]=[C:2]([OH:1])[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])[N:5]=1
Reactant: O=C(O)CCl
Reactant: COCCCC1=CC(O)(S)NC=N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCCc1cc(O)nc(O)n1
Temperature: 120 °C
Yield: 52.9 %

Procedure:
A suspension of 4-hydroxy-4-mercapto-6-(3-methoxypropyl)pyrimidine (Method 84) (3.9 g, 19.5 mmol) and chloroacetic acid (1.89 g, 19.9 mmol) in water (20 ml) was heated at 120° C. for 24 hours. The mixture was allowed to cool, adjusted to pH7 with sodium hydroxide solution and extracted with EtOAc. The extracts were combined, dried (Na2SO4) and the solvent removed by evaporation to give the title compound (1.9 g, 55%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[CH2:14][N:15]([C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.[Cl:42][C:43]1[CH:44]=[C:45]([CH:50]=[CH:51][C:52]=1[NH:53][C:54](OC1C=CC([N+]([O-])=O)=CC=1)=[O:55])[C:46]([O:48][CH3:49])=[O:47]>C1COCC1>[C:18]([O:17][C:16]([N:15]([CH2:14][CH:9]1[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:13][CH2:12][N:11]([C:54]([NH:53][C:52]2[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][C:43]=2[Cl:42])=[O:55])[CH2:10]1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1F)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)N2CCC(c3ccccc3F)C(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.5 %

Procedure:
To a mixture of 191 mg of tert-butyl {[4-(2-fluorophenyl)piperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate, 0.115 mL of triethylamine, and 3.0 mL of THF was added 175 mg of methyl 3-chloro-4-{[(4-nitrophenoxy)carbonyl]amino}benzoate at room temperature. After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 330 mg of methyl 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]carbonyl}amino)-3-chlorobenzoate as a crude product. ESI+: 674
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[N:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH:21]1[C:33]2[NH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:30]1[C:31]2[N:32]([C:2]3[CH:3]=[C:4]([C:8]4[O:9][C:10]([C:13]5[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=5)=[N:11][N:12]=4)[CH:5]=[CH:6][CH:7]=3)[C:33]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]=2[CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: COc1cccc(-c2nnc(-c3cccc(I)c3)o2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2nnc(-c3cccc(-n4c5ccccc5c5ccccc54)c3)o2)c1
Reaction time: 5 h

Procedure:
To a solution of 2-(3-iodophenyl)-5-(3-methoxyphenyl)-1,3,4-oxadiazole (3.0 g, 7.93 mmol), carbazole (1.5 g, 8.97 mmol), Cu (2.0 g, 31.47 mmol) in DMF (20.0 ml) was added potassium carbonate (4.0 g, 28.94 mmol) under nitrogen and stirring. Heating was started. The reaction was carried out at 150° C. for 5 h. After cooling, the reaction mixture was filtrated. The solid residues were carefully washed with THF. THF was evaporated from the combined filtration solution. Water (150.0 ml) was added, the brown solid product was obtained by filtration. The crude product was purified by silica gel column chromatography using dichloromethane/ethyl acetate (9.5:0.5) as eluent. After evaporating solvent, the white solid was recrystallized from acetone/methanol and finally dried under vacuum. Pure product was obtained as white solid in 3.15 g (95.4%) yield. 1H NMR (400 MHz, CDCl3, δ): 8.34 (m, 1H), 8.27 (m, 1 Hz), 8.18 (m, 2H), 7.78 (m, 2H), 7.71-7.65 (m, 2H), 7.46-7.41 (m, 5H), 7.36-7.31 (m, 2H), 7.09 (m, 1H), 3.89 (s, 3H, OCH3). 13C NMR (100 MHz, CDCl3, δ): 164.85, 163.84, 159.96, 140.60, 138.70, 130.85, 130.32, 130.25, 126.19, 125.84, 125.40, 124.72, 123.55, 120.45, 120.37, 119.39, 118.44, 111.52, 109.55, 55.55. [M]+ calcd for C39H26N4O2, 417.2. found 417.1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[CH:7][N:6]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1ccc(Br)cn1
Product: COc1ccc(-c2ccc(OC)nc2)cc1
Yield: 61.4 %

Procedure:
According to Scheme 4 Method B: The title compound was prepared according to Example 1 Step 3 from 5-bromo-2-methoxypyridine (12.1 mmol, 2.30 g) and 4-methoxyphenylboronic acid (18.2 mmol, 2.76 g), then purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2, CH2Cl2/MeOH 100/0 to 95/5), yielding the title compound (1.60 g, 61%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([N:20]1[C@@H:24]([CH2:25]S(C2SC3C=CC=CC=3N=2)(=O)=O)[CH2:23][O:22][C:21]1([CH3:39])[CH3:38])=[O:19])([CH3:16])([CH3:15])[CH3:14].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>O1CCCC1>[C:13]([O:17][C:18]([N:20]1[C@@H:24](/[CH:25]=[CH:11]\[C:8]2([C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH2:23][O:22][C:21]1([CH3:38])[CH3:39])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CS(=O)(=O)c2nc3ccccc3s2)COC1(C)C
Reactant: O=CC1(c2ccc(I)cc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](/C=C\C2(c3ccc(I)cc3)CC2)COC1(C)C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a stirred, cooled (0° C.) solution of 1-(4-iodo-phenyl)-cyclopropanecarbaldehyde (1.6 g) in tetrahydrofurane (40 ml) was added under an argon atmosphere (R)-4-(benzothiazole-2-sulfonylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.9 g) [CAS 1043499-96-2] followed by a 1 M solution of LiHMDS in THF (11.8 ml). After 1 h at 0° C. the cooling bath was removed and stirring was continued overnight. The mixture was quenched by the addition of sat. aqueous NH4Cl (50 ml) and H2O (50 ml) and extracted with EtOAc. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2; gradient: heptane->heptane/EtOAc 2:1) to give (S)-4-{(Z)-2-[1-(4-iodo-phenyl)-cyclopropyl]-vinyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.0 g) as light yellow solid. MS (ISP): 470.3 ([M+H]+).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[CH3:38][S:39]([CH:42]=[CH2:43])(=[O:41])=[O:40]>CC(N(C)C)=O>[CH:26]([O:25][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[S:16][C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH2:5][CH2:4][C@@H:3]4[NH:2][CH2:43][CH2:42][S:39]([CH3:38])(=[O:41])=[O:40])=[N:13][N:14]=2)=[CH:24][C:21]=1[C:22]#[N:23])([CH3:28])[CH3:27]
Reactant: C=CS(C)(=O)=O
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4NCCS(C)(=O)=O)s2)cc1C#N
Temperature: 90 °C
Yield: 31.1 %

Procedure:
To a stirred solution of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 (25 mg, 0.06 mmol) and DIEA (32 mg, 0.24 mmol) in DMA (1 mL) was added (methylsulfonyl)ethene (20 mg, 0.18 mmol). The reaction mixture was heated at 90° C. for 24 h. The solvent was evaporated and the product purified by preparative HPLC to afford 9 mg (31%) of (S)-2-isopropoxy-5-(5-(1-((2-(methylsulfonyl)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)benzonitrile 31 as half-white solid. LCMS-ESI (m/z) calculated for. C24H26N4O3S2: 482.1; found 483.1 [M+H]+, tR=2.49 min.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]([O:30][C:31](=[O:33])[CH3:32])[CH2:19][S:20][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[NH:23][CH:24]=[N:25]4)[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[CH3:41][O:42][C:43](=[O:46])[CH:44]=[CH2:45]>CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH:18]([O:30][C:31](=[O:33])[CH3:32])[CH2:19][S:20][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][N:25]4[CH2:45][CH2:44][C:43]([O:42][CH3:41])=[O:46])[CH2:15][CH2:16]2)=[CH:6][CH:5]=1
Reactant: C=CC(=O)OC
Reactant: CC(=O)OC(CSc1ncnc2nc[nH]c12)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCn1cnc2c(SCC(CN3CCN(C(c4ccc(F)cc4)c4ccc(F)cc4)CC3)OC(C)=O)ncnc21
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To NaH (0.02 mmol, 0.96 mg, 50% suspension in mineral oil) in DMF (5 mL) at 0° C. was added 6-(1-[1-[bis(4-fluorophenyl)methyl]-piperazin-4-yl]-2-acetoxy-3-propanylthio]purine (1.0 g, 1.8 mmol) neat in portions. After stirring about 15 min, methylacrylate (1.8 mmol, 0.16 mL) was added neat at 0° C. The ice bath was removed and the mixture stirred at room temperature for 7 days. The mixture was then heated on a 60° C. oil bath for 24 h. The DMF was removed in vacuo (1 mmHg, 60° C.) and the crude residue was eluted through silica gel using 10% MeOH:CH2Cl2. Pure product was isolated (550 mg, 49.1%) as a glassy solid; mp 55°-58° C. (dec.). DCI/MS (M+1) 625; (300 MHz) 1H NMR (CDCl3) δ: 8.15 (s,1H), 8.05 (s,1H), 7.35 (m,4H), 6.95 (m,4H), 5.3 (m,1H), 4.5 (t,2H,J=6.2 Hz), 4.2 (s,1H), 3.4 and 4.0 (q of q 2H), 3.65 (s,3H), 2.91 (t,2H,J=6.1 Hz), 2.6 (d,2H,J=6.1 Hz), 2.55 and 2.35 (m,8H), 2.0 (s,3H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:6](=O)[CH3:7])[CH3:5].O.[NH2:10][NH2:11]>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:6](=[N:10][NH2:11])[CH3:7])[CH3:5]
Reactant: NN
Reactant: CON=C(C)C(C)=O
Solvent: O
Solvent: CCO
Product: CON=C(C)C(C)=NN
Yield: 29.8 %

Procedure:
3 g (0.026 mol) of butane-2,3-dione mono-(O-methyl oxime) are heated at 60° C. in 20 ml of ethanol with 2.6 g (0.052 mol) of hydrazine hydrate for 1 hour. The reaction mixture is poured onto water and extracted with diethyl ether, the organic phase is dried over sodium sulphate and the solvent is distilled off in vacuo. The residue is stirred with petroleum ether and the crystals are filtered off. 1 g (29.7% of theory) of 3-hydrazono-butan-2-one O-methyl oxime is obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[N:2]1.[F:8][C:9]1[CH:34]=[CH:33][CH:32]=[CH:31][C:10]=1[O:11][C:12]1[CH:13]=[C:14]([NH2:30])[C:15]([NH2:29])=[CH:16][C:17]=1[O:18][C:19]1[CH:20]=[N:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=1>CN(C)C=O>[F:8][C:9]1[CH:34]=[CH:33][CH:32]=[CH:31][C:10]=1[O:11][C:12]1[C:17]([O:18][C:19]2[CH:20]=[N:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)=[CH:16][C:15]2[NH:29][C:6]([C:3]3[CH:4]=[CH:5][NH:1][N:2]=3)=[N:30][C:14]=2[CH:13]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(N)c(N)cc2Oc2ccccc2F)cn1
Reactant: O=Cc1cc[nH]n1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cc[nH]n4)nc3cc2Oc2ccccc2F)cn1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
3.9 mg of 1H-pyrazole-3-carboxaldehyde was added to a dimethylformamide (0.5 ml) solution of 15 mg of 4-(2-fluoro-phenoxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 200, and the reaction liquid was stirred at 90° C. for 30 minutes. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=9/1) to obtain the entitled compound as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[S:12][CH:13]=[CH:14][N:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Li]CCCC.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C>C1COCC1>[S:12]1[CH:13]=[CH:14][N:15]=[C:11]1[CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][C:2]([B:21]([OH:26])[OH:22])=[CH:3][C:4]=2[CH:9]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: c1csc(Cc2ccc3occc3c2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc2cc(Cc3nccs3)ccc2o1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
A solution of 2-(benzofuran-5-ylmethyl)thiazole (0.68 g, 3 mmol) in THF (20 mL) was cooled to −78° C. (under argon), treated with 2.5 M n-BuLi (3.0 equiv, 3.6 mL, in hexanes), and stirred for 2 min, warmed to 0° C. for 30 min, cooled to −78° C., and treated with triisopropyl borate (1 mL, 6 mmol). After 5 min, cooling was removed and the mixture slowly warmed to room temperature and stirred for 2 h. The mixture was diluted with EtOAc, washed 1× with brine, dried over MgSO4 and evaporated to give 5-(thiazol-2-ylmethyl)benzofuran-2-ylboronic acid as a yellow solid. MS (ESI) m/z: Calculated: 259.1; Observed: 260.4 (M++1).