Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1cccc2[nH]ccc12
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)cccc21

Procedure:
4-Bromo-1-(benzenesulfonyl)-1H-indole was prepared from 4-bromoindole and phenylsulfonyl chloride according to Method 4 to afford 3.1 g (91%) of a light purple solid: 1HNMR (CDCl3) δ 7.94 (d, J=8 Hz, 1H), 7.89-7.84 (m, 2H), 7.62 (d, 4 Hz, 1H), 7.57-7.51 (m, 1H), 7.46-7.37 (m, 3H), 7.19-7.13 (m, 1H), 6.72 (dd, J=1, 4 Hz, 1H); MS (ESI) 419.9+421.9 (M+H)+; Purity (HPLC) >95%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[C:10]([O:14][C:15]([NH:17][C:18](=[N:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])SC)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CN(C=O)C.O.C([O-])(=O)C.[Ag+]>[C:25]([O:24][C:22]([NH:21][C:18]([NH:17][C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])=[N:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: NCc1cccc(O)c1
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(=NCc1cccc(O)c1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
3-hydroxybenzylamine, prepared as above (1.23 g) and N,N'-bis(tert-butoxycarbonyl)-S-methylisothiourea (2.90 g) were combined in 100 mL DMF, and silver acetate (2.9 g) was added in three portions over 30 min with mechanical stirring. The mixture became thick and a yellow color developed. After 1 hr, the mixture was diluted with 300 mL water, and the solids collected by filtration, re-suspended in dichloromethane, filtered to remove silver salts, and chromatographed on silica gel with 10% ethyl acetate in dichloromethane. Recrystallization provided the title compound as a white solid, mp 169°-172° C. (dec) (2.2 g, 61%).
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:10][NH:9][CH2:8][C@H:7]2[OH:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:13]([CH3:17])([CH3:16])[C:14]#[CH:15].CCN(CC)CC>[Cu]I.C1COCC1>[CH3:16][C:13]([N:9]1[CH2:10][C@@H:6]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C@H:7]([OH:11])[CH2:8]1)([C:14]#[CH:15])[CH3:17]
Reactant: O[C@@H]1CNC[C@H]1N1CCCC1
Reactant: C#CC(C)(C)Cl
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CC(C)(C)N1C[C@@H](O)[C@H](N2CCCC2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 45 %

Procedure:
A mixture of (3R,4R)-4-(pyrrolidin-1-yl)pyrrolidin-3-ol (Lexicon Pharma, 1.56 g, 10.0 mmol) and 3-chloro-3-methyl-1-butyne (GFS Chmeical, Inc., 1.36 g, 13.2 mmol), THF (15 mL) and Et3N (13.3 mmol) was treated with CuI (77 mg, 0.78 mmol). An exothermic reaction ensued with concomitant formation of a precipitate. After stirring at RT for 15 h, the mixture was concentrated in vacuo and partitioned between EtOAc and saturated aqueous NaHCO3 solution. The aqueous phase was extracted twice with EtOAc and the combined EtOAc phases were dried (MgSO4) and concentrated to give a light brown solid (1.0 g, 45%). 1H NMR (CDCl3) δ 4.20 (br s, 1H), 3.13-3.04 (m, 1H), 2.95 (dd, 1H, J=10.1, 6.6 Hz), 2.77 (dd, 1H, J=10.1, 2.6 Hz), 2.64 (m, 3H), 2.61 (m, 2H), 2.55-2.46 (m, 1H), 2.26 (s, 1H), 1.85-1.74 (m, 4H), 1.38 (s, 3H), 1.36 (s, 3H); MS(ESI+): m/z 223.29 (M+H)+.
Reaction SMILES: [C:1]1([C@H:7]([CH3:13])[CH2:8][NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:15]([CH:19]([CH3:21])[CH3:20])[C:16](O)=[O:17]>>[CH:19]([C@@H:15]1[S:11][C:10]([NH:9][CH2:8][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:13])=[N:12][C:16]1=[O:17])([CH3:21])[CH3:20]
Reactant: C[C@H](CNC(N)=S)c1ccccc1
Reactant: CC(C)C(Br)C(=O)O
Product: CC(C)[C@@H]1SC(NC[C@@H](C)c2ccccc2)=NC1=O

Procedure:
Synthesis was performed from N-[(2S)-2-phenylpropyl]thiourea and 2-bromo-3-methylbutyric acid according to Method D3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=1I>>[C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[C:18][C:22]1[CH:23]=[C:24]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=[CH:26][C:21]=1[Cl:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(Cl)c(I)c1
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)COc1ccc(C#N)cc1C#Cc1cc(S(C)(=O)=O)ccc1Cl
Yield: 74 %

Procedure:
Following the general method as outlined in Intermediate 79, starting from (4-cyano-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 46) and 1-chloro-2-iodo-4-(methylsulfonyl)benzene (Intermediate 74), the title compound was obtained as a yellow solid in 74% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:23]=[CH:22][C:12]([C:13]([C:15]3[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=3)=[O:14])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]([C:12]2[CH:22]=[CH:23][C:9]([C:8]#[C:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:10][CH:11]=2)=[O:14])=[CH:27][CH:26]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2ccccc2C(=O)c2ccc(C#Cc3ccccc3)cc2)cc1

Procedure:
The phenylethynyl group has two important advantages over the ethynyl group. These are stability towards conditions of aromatic nucleophilic displacement reactions and stability at moderate temperatures (i.e. 150-250° C.). For example, when 4-phenylethynyl-4'-fluorobenzophenone was treated with a slight excess of 3 or 4-aminophenol in the presence of an alkali metal base such as potassium carbonate in a polar aprotic solvent such as N,N-dimethylacetamide (DMAc) at 143° C., 3 or 4-aminophenoxy-4'-phenylethynylbenzophenone was afforded in nearly quantitative yield. However, several attempts to make the 3-aminophenoxy-4'-ethynylbenzophenone from the 4-ethynyl-4'-fluorobenzophenone under similar reaction conditions afforded a mixture of products. In addition, imide model compounds of the phenylethynyl endcapper react at a moderate to fast rate in air at 300° to 350° C. whereas analogous model compounds containing the ethynyl group react at a moderate to fast rate in air at 200° to 250° C. Phenylethynyl containing imide model compounds are reasonably stable at 200° C. (see Example 6) whereas thynyl containing imide model compounds react at 200° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[OH-].[Na+]>ClCCl.O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: OCCc1ccc2ccccc2n1
Reactant: BrCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: BrCCCCCOCCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(2-Hydroxyethyl)quinoline (2.00 g), TAB (200 mg) and 1,5-dibromopentane (8 ml) were dissolved in dichloromethane (6 ml) and 50% aqueous sodium hydroxide (8 ml) added. The mixture was vigorously stirred at room temperature for 24 h, diluted with water (50 ml) and extracted with diethyl ether (2×30 ml). The organic extracts were dried, filtered and evaporated in vacuo to afford an oil, which was purified by FCC eluting with cyclohexane-ether (1:1) and ether, to give the title compound as a yellow oil (2.67 g), t.l.c. (ether) Rf 0.40.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH3:9][S:10]SC>>[CH3:9][S:10][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1
Reactant: CSSC
Reactant: O=Cc1cc(Br)cs1
Product: CSc1csc(C=O)c1

Procedure:
4-bromo-2-thiophenecarboxaldehyde was converted into the 4-lithio derivative (A. L. Johnson, J. Org. Chem. 41, 1976, 1320) of its ethylene acetal and reaction of this organometallic with dimethyl disulphide followed by acid hydrolysis gave 4-methylthio-2-thiophenecarboxaldehyde (R. Noto, L. Lamartina, C. Arnone and D. Spinelli, J. Chem. Soc., Perkin Trans. 2, 1987, 689). Sodium borohydride reduced this aldehyde to the 4-methylthio alcohol (for B.4356), which in turn with one of two equivalents of MCPBA yielded the 4-methylsulphinyl and 4-methylsulphonyl alcohols (for B.4377 and B.4361 respectively). reaction of the above organometallic with naphthalene-2-sulphonyl azide (A. B. Khare and C. E. McKenna, Synthesis, 1991, 405) and sodium pyrophosphate followed by hydrolysis by the method (P. Spagnolo and P. Zamirato, J. Org. Chem., 43, 1978, 3539) for the preparation of other azidothiophene aldehydes gave 4-azido-2-thiophenecarboxaldehyde leading to the alcohol for B.4373.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].F[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH:22]=[CH:21][N:20]=2)=[C:11]([O:34][CH3:35])[CH:10]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH:22]=[CH:21][N:20]=2)=[C:11]([O:34][CH3:35])[CH:10]=1
Reactant: CNCCN(C)C
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Temperature: 140 °C
Yield: 80.5 %

Procedure:
N1,N1,N2-Trimethylethane-1,2-diamine (83 mg, 0.82 mmol) was added to a mixture of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 68, 409 mg, 0.74 mmol), DIPEA (0.259 mL, 1.48 mmol) and DMA (3 mL). The resulting mixture was heated in a microwave at 140° C. for 0.5 h. Part-purification was achieved by ion exchange chromatography, using an SCX column (20 g) and eluting with 0.35 M methanolic ammonia. Appropriate fractions were concentrated in vacuo to provide an orange/brown gum. This gum was triturated with ethanol (15 mL) to give a solid which was collected by filtration and dried under vacuum to give the title compound (275 mg, 80%) as an orange solid; 1H NMR: 2.18 (6H, s), 2.45-2.55 (2H, m), 2.87 (3H, s), 3.25-3.30 (2H, m), 3.97 (3H, s), 6.87 (1H, s), 7.08 (1H, t), 7.18 (1H, t), 7.29 (1H, d), 7.46 (1H, d), 8.03 (1H, s), 8.33 (3H, dd), 8.66 (1H, s), 11.80 (1H, s); m/z: ES+ MH+ 462.34.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[N:17]3)[CH:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.[C:25](Cl)(=[O:27])[CH3:26]>C(Cl)Cl.O>[N:16]1([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C@H:6]3[CH2:5][CH2:4][C@H:3]([CH2:2][NH:1][C:25](=[O:27])[CH3:26])[CH2:8][CH2:7]3)[N:15]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1
Reactant: CC(=O)Cl
Reactant: NC[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
TEA (52 μL, 0.37 mmol) was added, under nitrogen atmosphere, to a solution of trans-(4-aminomethyl-cyclohexyl)-(4-benzotriazol-1-yl-pyrimidin-2-yl)-amine (60 mg, 0.185 mmol) in DCM (3 mL). The mixture was cooled to −78° C. and acetyl chloride (13.2 μL, 0.185 mmol) was added. The reaction mixture was stirred at RT overnight; it was then poured in water and extracted 3 times with a mixture of isopropanol and chloroform. The combined organic extracts were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude residue was purified via preparative TLC to give 10 mg of trans-N-[4-(4-benzotriazol-1-yl-pyrimidin-2-ylamino)-cyclohexylmethyl]-acetamide. 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (1 H, d, J=8.19 Hz), 8.41 (1 H, d, J=5.14 Hz), 8.12 (1 H, d, J=8.19 Hz), 7.57-7.67 (1 H, m), 7.42-7.51 (2 H, m), 7.16-7.24 (0.3 H, m), 5.55-5.64 (0.7 H, m), 5.18-5.43 (1 H, m), 3.80-3.93 (1 H, m), 3.11-3.25 (2 H, m), 2.27 (1 H, s), 2.19-2.35 (2 H, m), 2.00 (2 H, s), 1.85-1.95 (2 H, m), 1.50-1.63 (1 H, m), 1.11-1.37 (4 H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:32]=[CH:31][CH:30]=[C:27]([C:28]#[N:29])[CH:26]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC/C=C/c3cccc(C#N)c3)cc2)CC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C/C=C/c1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 70 °C
Reaction time: 9 h

Procedure:
To a solution of 3-[3-[N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzonitrile (1.00 g) in N,N-dimethylformamide (20 ml) were added potassium carbonate (0.96 g) and ethyl bromoacetate (0.62 ml). The mixture was stirred at 70° C. for 9 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=2/1 as an eluant to give the desired compound (1.31 g, yield quantitative) as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH3:6])[CH2:3][OH:4].CC(C)([O-])C.[Na+].Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1>COCCOC.O>[CH3:1][CH:2]([CH2:5][CH3:6])[CH2:3][O:4][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Reactant: CCC(C)CO
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCC(C)COc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C

Procedure:
To 2-methyl-1-butanol (0.855 mL) in DME (4 mL) was added sodium tert-butoxide (760 mg). The mixture was stirred at room temperature until homogeneous. 2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (500 mg) was added followed by DME (4 mL). The reaction was heated at 110° C. overnight. The mixture was cooled and concentrated in vacuo to give a yellow residue. The residue was taken up in water (30 mL) and extracted with EtOAc (2×30 mL). The organics were separated and washed with brine (30 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a yellow/brown residue. This material was taken on to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1>CN1CCCC1=O.O>[C:34]([O:33][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=3[F:19])=[CH:6][N:5]=2)[CH2:26][CH2:27]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2c(OC)ccc(F)c2F)c(N)n1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1N
Yield: 80 %

Procedure:
A solution of (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone (7.7 g, 23 mmol, Example 165) and 4-amino-1N-Boc-piperidine (6.8 g, 34 mmol, Astatech) in 30 mL of 1-methyl-2-pyrrolidinone was heated at 70° C. for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The dried (Na2SO4) organic solution was evaporated and the residue was chromatographed on silica gel. Elution with 3:2 ethyl acetate/hexane provided 80% yield of 4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester as a colorless solid, mp 114 dec., identical to material prepared in Example 106. Mass Spectrum (LR-ES) M+: 463.
Reaction SMILES: CS(O[CH2:6][CH2:7][NH:8][C:9]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Br:26])[CH:20]=3)[C:17](=[O:27])[O:16][N:15]=2)=[N:12][O:11][N:10]=1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C)C=O>[N:28]([CH2:6][CH2:7][NH:8][C:9]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Br:26])[CH:20]=3)[C:17](=[O:27])[O:16][N:15]=2)=[N:12][O:11][N:10]=1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 50 °C
Yield: 77 %

Procedure:
To a solution of 2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)ethyl methanesulfonate (2.13 kg, 4.6 mol, containing also some of the corresponding bromo-compound) in dimethylformamide (4 L) stirring in a 22 L flask was added sodium azide (380 g, 5.84 mol). The reaction was heated at 50° C. for 6 h, poured into ice/water (8 L), and extracted with 1:1 ethyl acetate:heptane (20 L). The organic layer was washed with water (5 L) and brine (5 L), and the solvents removed in vacuo to afford the desired product (1464 g, 77%) as a tan solid. LCMS for C12H8BrFN8O3Na (M+Na)+: m/z=433.0, 435.0. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (dd, J=6.2, 2.5 Hz, 1 H), 7.72 (m, 1H), 7.58 (t, J=8.7 Hz, 1 H), 6.75 (t, J=5.7 Hz, 1 H), 3.54 (t, J=5.3 Hz, 2 H), 3.45 (dd, J=11.1, 5.2 Hz, 2 H).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:35])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:17]([CH2:26][NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]=1)[CH3:4].[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[CH2:3]([O:5][C:6](=[O:35])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:17]([CH2:26][N:27]([C:36](=[O:38])[CH3:37])[CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]=1)[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2cc3ccccc3nc2CNCc2ccccc2)c1
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc3ccccc3nc2CN(Cc2ccccc2)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 5, Step 5, using the following starting materials: {3-[2-(benzylamino-methyl)-quinolin-3-yl]-4-methoxy-phenyl}-acetic acid ethyl ester, dihydrochloride and acetic anhydride.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[C:1]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1nccc2ccccc12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc(-c2nccc3ccccc23)cc1
Reaction time: 8 h
Yield: 43 %

Procedure:
In a 100 ml-three-necked flask, 3.04 g (24.9 mmole) of phenylboronic acid (made by Tokyo Kasei), 4.0 g of (25.0 mmole) of 1-chloroisoquinoline, 25 ml of toluene, 12.5 ml of ethanol and 25 ml of 2M-sodium carbonate aqueous solution were placed and stirred at room temperature under nitrogen stream, and 0.98 g (0.85 mmole) of tetrakis(triphenylphosphine)palladium (0) was added thereto. Thereafter, reflux under stirring was performed for 8 hours under nitrogen stream. After completion of the reaction, the reaction product was cooled and extracted by addition of cold water and toluene. The organic layer was washed with saline water and dried on magnesium sulfate, followed by removal of the solvent under a reduced pressure to provide dry solid. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to obtain 2.20 g (yield=43.0%) of 1-phenylisoquinoline. FIG. 7 shows a 1H-NMR spectrum of a solution of the compound in heavy chloroform.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([NH:25][CH3:26])[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])=[C:11]2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[F:36][C:37]([F:55])([F:54])[C:38]1[CH:39]=[C:40]([C:48]([CH3:53])([CH3:52])[C:49](Cl)=[O:50])[CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([N:25]([CH3:26])[C:49](=[O:50])[C:48]([C:40]3[CH:39]=[C:38]([C:37]([F:55])([F:54])[F:36])[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=3)([CH3:53])[CH3:52])[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])=[C:11]2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1cnc2c(cnn2Cc2ccccc2)c1-c1ccc(F)cc1C
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)ccc1-c1c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cnc2c1cnn2Cc1ccccc1
Temperature: 40 °C
Yield: 83 %

Procedure:
To a solution of [1-benzyl-4-(4-fluoro-2-methyl-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-methyl-amine (2.125 g, 6.13 mmol) in CH2Cl2 (30 mL) was added iPr2NEt (2.14 mL, 12.3 mmol) and 2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (described in J. Org. Chem, 2006, 71, 2000-2008, 2.93 g, 9.20 mmol). The reaction mixture was heated at 40° C. for 2 hours, diluted with CH2Cl2 (100 mL), and washed with H2O. The organic phase was dried over Na2SO4, concentrated under vacuo, and column chromatography (SiO2, EtOAc/Heptane 1/4) afforded 3.2 g (83%) of the title compound as a white foam. ES-MS m/e: 629.2 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[NH:17][C:16]2=[O:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]1(B(O)O)[CH2:27][CH2:26]1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]([CH:25]3[CH2:27][CH2:26]3)[C:16]2=[O:24])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)C1CC1
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=c1n(-c2ccc(OCc3ccccc3)cc2)c2ncccc2n1C1CC1
Temperature: 140 °C
Yield: 35.5 %

Procedure:
The mixture of 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg), cyclopropylboronic acid (731 mg), TEA (1976 μl), pyridine (1835 μl), copper(II) acetate (1030 mg) and THF (4727 μl) was heated at 140° C. for 30 min under microwave irradiation. The solid was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-30% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-1-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (120 mg) as white crystals.