Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.B(O)(O)[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[S:21][CH:20]=1>>[S:21]1[CH:20]=[C:19]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]1=2
Reactant: OB(O)c1csc2ccccc12
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: c1ccc2c(-c3csc4ccccc34)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and thianaphthene-3-boronic acid to give (1-benzo[b]thiophen-3-yl-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 343(MH+).
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])(=O)=O.[CH2:16]([N:23]1[CH:28]2[CH:29]([C:31]#[N:32])[CH2:30][C:24]1([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:25](O)[CH2:26][CH2:27]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[CH2:16]([N:23]1[C@@H:28]2[C@@H:29]([C:31]#[N:32])[CH2:30][C@@:24]1([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@H:25]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH2:26][CH2:27]2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: N#CC1CC2(c3ccccc3)C(O)CCC1N2Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H]2[C@@H](C#N)C[C@]1(c1ccccc1)N2Cc1ccccc1
Reaction time: 0.25 h

Procedure:
t-Butyldimethylsilyl trifluoromethanesulphonate (23 ml, 76 mmol) was added dropwise to a stirred solution of (1R*,2R*5S*,6S*)-8-benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 41; 31 g), triethylamine (18 ml, 243 mmol) in dichloromethane (100 ml) at room temperature over 30 minutes. The reaction mixture was stirred for 15 minutes, quenched with saturated aqueous NaHCO3 and extracted into diethyl ether (3×100 ml). The combined organic extracts were washed with water, brine, dried (Na2SO4) and concentrated to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:23])=[C:8]([C:10]2[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:13]=[C:12]([C:19](OC)=[O:20])[CH:11]=2)[CH:9]=1)[CH3:2].CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:23])=[C:8]([C:10]2[CH:15]=[C:14]([CH:16]([CH3:17])[CH3:18])[N:13]=[C:12]([CH:19]=[O:20])[CH:11]=2)[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(F)c(-c2cc(C(=O)OC)nc(C(C)C)c2)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(-c2cc(C=O)nc(C(C)C)c2)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
A solution of methyl 4-(5-ethoxy-2-fluoro-phenyl)-6-isopropyl-pyridine-2-carboxylate (which may be prepared as described in Description 115) (0.72 g, 2.27 mmol) in THF (20 mL) was cooled to −78° C. under nitrogen and was treated dropwise with 1M DIBAL in toluene (4.54 mL, 4.54 mmol) over 10 minutes. The mixture was stirred at −78° C. for 2 hrs. The mixture was quenched with satd. aq. NH4Cl solution (5 ml) and the mixture was allowed to reach room temperature and stirred for 30 mins. Celite was added to the mixture and the mixture was stirred for 10 minutes and then filtered through Celite and concentrated to give 4-(5-ethoxy-2-fluoro-phenyl)-6-isopropyl-pyridine-2-carbaldehyde (D116) (0.57 g);
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][CH2:10][CH2:11][CH3:12])[N:3]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].CCN(C(C)C)C(C)C>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:15]([CH3:14])[O:16][CH3:17])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][CH3:12])[N:3]=1
Reactant: CNOC
Reactant: CCCNc1nc(N)nc(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCCNc1nc(N)nc(N(C)OC)n1
Temperature: 100 °C
Yield: 88.4 %

Procedure:
A mixture of 6-amino-2-chloro-4-n-propylamino-[1,3,5]triazine (XXXVIII) (5 g, 26.65 mmol), N,O-dimethylhydroxylamine hydrochloride (13 g, 133.24 mmol) and DIPEA (27.5 g, 213.2 mmol) in EtOH (100 mL) was heated at 100° C. for 16 h, after which time the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (400 mL), which was washed with water (200 mL) and then with a brine solution (200 mL) and finally dried over Na2SO4. The solvent was removed under reduced pressure to yield N-(6-amino-4-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXXIX) as a white solid (5 g, 89% yield). LCMS (ESI) m/z=213 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10](C(C)(C)C)=[CH:9][CH:8]=1)([CH3:4])[CH3:3].[C:17](C1C=C(Br)C=CC=1)([CH3:20])([CH3:19])[CH3:18]>>[CH3:4][Si:2]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cccc(Br)c1
Reactant: CC(C)(C)c1ccc(C#C[Si](C)(C)C)cc1
Product: CC(C)(C)c1cccc(C#C[Si](C)(C)C)c1

Procedure:
Using the same general procedure as described for Compound 21, but using 3-tert-butyl-bromobenzene, (Compound 24) the title compound was synthesized as a colorless oil. PMR (CDCl3): & 0.36 (9H, s), 1.40 (9H, s), 7.32 (1H, m), 7.37-7.47 (2H, m), 7.61 (1H, m).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O[N: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)(=O)C1C=CC=CC=1>C1COCC1.CCOCC.[Cl-].[Cl-].[Zn+2]>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([N:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(OC(=O)c2ccccc2)CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
To a solution of the product of Step A (0.32 g; 1.01 mmol) in anhydrous THF (2 ml) 2 M iPrMgCl in THF (0.56 ml; 1.11 mmol) was added at −15° C. under N2, followed 1.27 M solution of anhydrous ZnCl2 in THF (0.41 ml; 0.52 mmol), after stirring for 1 h at 0° C. The resulting mixture was stirred for 30 min on ice-bath under N2 and the solution of the product of Step B (0.16 g; 0.51 mmol) and CuCl2 (2.5 mol %) in anhydrous THF (10 ml) was added. The resulting mixture was allowed to warm up to room temperature and stirred for additional 10 min. This was diluted to 20 ml with Et2O and washed with 5% NaHCO3, H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane/EtOAc 9:1) to give the title compound (0.06 g; 31%), as a creamy syrup. 1H-NMR (CDCl3) 7.07 (d, 2H, J=8.6 Hz); 6.84 (d, 2H, J=8.6 Hz); 3.55 (t, 4H, J=5 Hz); 3.06 (t, 4H, J=5 Hz); 2.51 (t, 2H, J=7.94 Hz); 1.55-1.38 (m, 11H); 1.26 (m, 10H); 0.86 (t, 3H, J=6.93 Hz).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1>>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:30]2[CH:29]=[CH:28][N:27]=[C:26]([O:25][CH3:24])[CH:31]=2)[N:7]=3)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Reactant: COc1cc(B(O)O)ccn1
Product: COc1cc(-c2ccc3nc(NC(=O)c4ccc(C(C)(C)O)cc4)sc3n2)ccn1
Yield: 37 %

Procedure:
The titled compound (yield=37%, yellow solid) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 1D (Example 1) and 2-methoxypyridin-4-ylboronic acid were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (s, 6H) 3.93 (s, 3H) 7.54 (s, 1H) 7.67 (d, J=8.59 Hz, 2H) 7.75 (dd, J=5.43, 1.39 Hz, 1H) 8.11 (d, J=8.59 Hz, 2H) 8.25 (d, J=1.52 Hz, 2H) 8.31 (d, J=5.31 Hz, 1H) 13.07 (br. s., 1H); ESI-MS: m/z 421.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([N:23]([CH3:39])[C:24]([NH:26][C:27]2[C:32]([Cl:33])=[C:31]([O:34][CH3:35])[CH:30]=[C:29]([O:36][CH3:37])[C:28]=2[Cl:38])=[O:25])[CH:18]=1.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42].C1COCC1>CO>[Cl:38][C:28]1[C:29]([O:36][CH3:37])=[CH:30][C:31]([O:34][CH3:35])=[C:32]([Cl:33])[C:27]=1[NH:26][C:24](=[O:25])[N:23]([C:19]1[N:20]=[CH:21][N:22]=[C:17]([NH:16][C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH2:13]3)=[CH:7][C:2]=2[NH:1][C:40](=[O:43])[CH:41]=[CH2:42])[CH:18]=1)[CH3:39]
Reactant: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4c(Cl)c(OC)cc(OC)c4Cl)ncn3)c(N)c2)CC1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Product: C=CC(=O)Nc1cc(N2CCN(CC)CC2)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Reaction time: 1 h
Yield: 7 %

Procedure:
To a solution of 1-(6-(2-amino-4-(4-ethylpiperazin-1-yl)phenylamino)pyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylurea (280 mg, purity: 90%, 0.44 mmol) in THE (30 mL) was added a solution of acryloyl chloride in THF (20 mg/mL, 2 mL, 0.44 mmol) at −10° C., and the resulting mixture was stirred for 1 hour at this temperature. MeOH (1 mL) was added to quench the reaction. The mixture was concentrated and the residue was purified by prep-HPLC and prep-TLC to obtain the title compound (20 mg, yield: 7%). 1H NMR (400 MHz, CDCl3) δ 1.31 (t, 3H), 2.65 (q, 2H), 2.62-2.68 (m, 4H), 3.27 (s, 3H), 3.36-3.38 (m, 4H), 3.91 (s, 6H), 5.76 (d, 1H), 5.90 (s, 1H), 6.24 (dd, 1H), 6.41 (d, 1H), 6.52 (s, 1H), 6.74 (dd, 1H), 7.07 (br s, 1H), 7.23 (d, 1H), 7.72 (br s, 1H), 7.98 (br s, 1H), 8.37 (s, 1H), 12.52 (s, 1H); MS (ESI): 629 [M+H]+.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:29]([O:33][C:34](=[O:46])[NH:35][CH2:36][CH2:37][CH:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:46])[NH:35][CH2:36][CH2:37][CH:38]([NH:45][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CS(=O)(=O)c1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1
Reactant: CC(C)(C)OC(=O)NCCC(N)c1ccccc1
Product: CC(C)(C)OC(=O)NCCC(Nc1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1)c1ccccc1

Procedure:
(3-{4-[6-(2-Morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyrimidin-2-ylamino}-3-phenyl-propyl)-carbamic acid tert-butyl ester was prepared from [3-(2-methane sulfonyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 11 supra) and (3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester (from Example 2 supra) by following the method in Example 61.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:19])([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:17])=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:20]([OH:23])(=[O:22])=[O:21])[CH:8]=2)[N:3]=1.[CH2:24]1[S:29](=[O:31])(=[O:30])[O:28][CH2:27][CH2:26][CH2:25]1.S1(CCCC1)(=O)=O>C(OCC)C>[CH3:1][CH:2]1[C:10]([CH3:19])([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:16])=[O:17])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:20]([OH:23])(=[O:21])=[O:22])[CH:8]=2)[N:3]1[CH2:27][CH2:26][CH2:25][CH2:24][S:29]([OH:31])(=[O:30])=[O:28]
Reactant: CC1=Nc2ccc(S(=O)(=O)O)cc2C1(C)CCCCS(=O)(=O)O
Reactant: O=S1(=O)CCCCO1
Solvent: CCOCC
Solvent: O=S1(=O)CCCC1
Product: CC1N(CCCCS(=O)(=O)O)c2ccc(S(=O)(=O)O)cc2C1(C)CCCCS(=O)(=O)O
Temperature: 140 °C
Yield: 86.8 %

Procedure:
To 2,3-dimethyl-3-(4-sulfobutyl)-5-sulfo-3H-indole (10 g) was added butane sultone (30 g) and the mixture heated to 140° C. overnight. On cooling to room temperature, sulfolan (20 ml) was added and the mixture poured into diethyl ether (500 ml). The resultant precipitate was removed by filtration and dried to give the desired product (12 g).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13](=[O:24])[N:14]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:15]4=[N:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)(Cl)Cl.CO.[OH-].[OH-].[Pd+2]>[CH2:8]([C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:24])[N:14]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:15]3=[N:16]2)=[CH:11][CH:10]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1c2ccc(C#Cc3ccccc3)cc2nc2n1CCCCC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1c2ccc(CCc3ccccc3)cc2nc2n1CCCCC2
Yield: 39.3 %

Procedure:
A solution of 3-(phenylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]-quinazolin-12(6H)-one (50 mg, 0.16 mmol) and Pd(OH)2/C in CHCl3 (10 mL) and MeOH (10 mL) was stirred under H2 (1 atm) at room temperature for 8 h. The reaction mixture was filtered and the filter cake was washed with water. The combined filtrate was extracted with ethyl acetate (3×20 mL) and dried over Na2SO4. After filtration and concentration, the residue was purified by preparative HPLC to give 20 mg of the desired product. MS (ESI): 319 (MH+); 1H NMR (300 MHz, CDCl3) δ 7.99-7.97 (d, J=8.10 Hz, 1H), 7.40 (s, 1H), 7.38-7.33 (d, J=8.22 Hz, 1H), 7.29-7.17 (m, 5H), 4.32-4.29 (t, J=4.98 Hz, 2H), 3.06-2.91 (m, 6H), 1.75 (broad, 4H), 1.68 (broad, 2H). mGluR5 PAM EC50: ++.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]1([Mg]Cl)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(OCC)C>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[OH:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Cl[Mg]C1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzaldehyde (4.5 g, 24.32 mmol) in THF (40 ml) was immersed in an ice/methanol bath, followed by the dropwise addition of cyclohexylmagnesium chloride (2M) in diethylether (18.24 ml, 36.5 mmol) at −1° C. to +2° C. The reaction was allowed to warm up to room temperature and the reaction was stopped after 1 hr. The reaction mixture was quenched with saturated aqueous NH4Cl solution before dilution with ethyl acetate. The organic phase was separated and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product which was purified by flash chromatography (normal phase, n-heptane (isom. mixture)/ethyl acetate 4:1) to obtain the title compound as yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:21])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=2)[N:10]=1.Cl[C:23]1[C:28]([C:29]#[N:30])=[CH:27][CH:26]=[CH:25][N:24]=1.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:21])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:23]3[N:24]=[CH:25][CH:26]=[CH:27][C:28]=3[C:29]#[N:30])=[CH:15][CH:14]=2)[N:10]=1
Reactant: N#Cc1cccnc1Cl
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2ncccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a mixture of [4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]phenyl]methanol (4.14 g), 2-chloro-3-cyanopyridine (1.91 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60%, oil, 0.66 g) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (4.65 g, 87%) of 2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]nicotinonitrile from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 135-136° C.
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[NH:7]1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9](O)=[O:10]>CC#N>[Cl:4][C:3]([Cl:6])([Cl:5])[C@@H:2]1[N:7]2[CH2:14][CH2:13][CH2:12][C@H:8]2[C:9](=[O:10])[O:1]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=CC(Cl)(Cl)Cl
Solvent: CC#N
Product: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@H]12
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 81.6 %

Procedure:
22 ml (225 mmol, 2.5 eq) chloral was added to a suspension of 10.470 g (90.94 mmol, 1.0 eq) L-proline (102) in 45 ml MeCN at RT, and the obtained solution was stirred for 19.5 h at RT. The solvent was removed at reduced pressure and the residue dissolved and filtered in 100 ml DCM. The filtrate was concentrated, and this process was repeated three more times. 18.141 g (74.20 mmol, 82%) of the product 103 was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:4]2[C:9]([C:10]=1[C:11](O)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN(C)C.[NH2:47][CH2:48][C:49]1[C:50](=[O:58])[NH:51][C:52]([CH3:57])=[CH:53][C:54]=1[O:55][CH3:56]>ClCCl.O>[CH3:56][O:55][C:54]1[CH:53]=[C:52]([CH3:57])[NH:51][C:50](=[O:58])[C:49]=1[CH2:48][NH:47][C:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:2]=1[CH3:1])=[O:12]
Reactant: Cc1c(C(=O)O)c2ccccc2n1C(C)c1ccccc1
Reactant: COc1cc(C)[nH]c(=O)c1CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a solution of 2-methyl-1-(1-phenylethyl)-1H-indole-3-carboxylic acid (66 mg, 0.24 mmol) in anhydrous dichloromethane (5 mL) was added N-hydroxybenzotriazole (38 mg, 0.29 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (55 mg, 0.29 mmol) and trimethylamine (36 mg, 0.36 mmol), and stirred at room temperature for 0.5 hour, 3-(aminomethyl)-4-methoxy-6-methylpyridin-2(1H)-one (40 mg, 0.24 mmol) was added and stirred at room temperature for 16 hours. To the reaction mixture was added water (10 mL), extracted with dichloromethane (10 mL) 2 times, combined and concentrated the organic layers, the residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-phenylethyl)-1H-indole-3-carboxamide as an off-white solid (0.08 g, 52%). LRMS (M+H+) m/z: calcd 429.21. found 429.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:17]1[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]1>CC(O)=O>[CH2:14]([O:13][C:11]([CH2:10][N:8]1[C:17]2[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][C:18]=2[C:7]2[C:2]1=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:12])[CH3:15]
Reactant: O=C1CCC(C(=O)O)CC1
Reactant: CCOC(=O)CN(N)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)Cn1c2c(c3ccccc31)CC(C(=O)O)CC2
Temperature: 70 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
A mixture of ethyl (N-phenyl-hydrazino)-acetate hydrochloric acid salt (2.3 g, 10 mmol) and 4-oxo-cyclohexanecarboxylic acid (1.42 g, 10 mmol) in glacial AcOH (20 ml) is stirred at 70° C. for 1 h. The suspension is allowed to cool to rt, poured onto H2O and stirred for 1 h. The resulting precipitate is filtered, washed with H2O and dried under high vacuum to give pure 9-ethoxycarbonylmethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid as a white solid (2.85 g) in 93% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:5]([F:9])=[CH:6][C:7]=1[Cl:8].[Br:22][CH2:23]/[CH:24]=[CH:25]/[C:26](Cl)=[O:27]>>[Br:22][CH2:23][CH:24]=[CH:25][C:26]([NH:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][N:12]=[C:11]2[NH:10][C:4]1[C:5]([F:9])=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:27]
Reactant: Nc1ccc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2c1
Reactant: O=C(Cl)/C=C/CBr
Product: O=C(C=CCBr)Nc1ccc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2c1

Procedure:
In one particular, 3,4-dichloro-6-fluoroaniline is reacted with 4-chloro-6-nitroquinazoline, so as to produce 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-nitroquinazoline, which is reduced, by means of an ethanolic solution of hydrazine hydrate and Raney®Nickel, so as to produce 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-aminoquinazoline. Then, the 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-aminoquinazoline is reacted with 4-bromocrotonyl chloride, so as to produce 4-bromo-N-{4-[(3,4-dichloro-6-fluorophenyl)amino]quinazoline-6-yl}-2-butenamide, which is then reacted with methylamine, so as to produce N-{4-[(3,4-dichloro-6-fluorophenyl)amino]quinazoline-6-yl}-4-(methylamino)-2-butenamide. The obtained methylamino derivative of the butenamide is reacted with a carbon-11 labeled methyliodide, so as to produce a carbon-11 labeled N-{4-[(3,4-dichloro-6-fluorophenyl)amino]quinazoline-6-yl}-4-(dimethylamino)-2-butenamide (carbon-11 labeled Compound 4).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:32])[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.Cl[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.Cl.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[OH:32][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:3][CH:4]=2)[C:13]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=2[O:11][CH2:10][CH:9]1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(O)cc2)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Yield: 7 %

Procedure:
4-(4-Hydroxyphenyl)-4-hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-4H-benzopyran (310 mg, 0.59 mmol) prepared in Example 15, [1-(2-chloroethyl)]piperidine.HCl (176 mg, 0.9 mmol) and K2CO3 (264 mg, 1.8 mmol) were dissolved in acetone (8 ml) and then refluxed for 62 hours. The reaction solution was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer thus separated was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to remove the organic solvent. The residue was separated by column chromatography (n-hexane:ethyl acetate=1:2) to obtain 83 mg (yield: 7%) of the title compound as a white foam.