Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH2:10]O.P(Br)(Br)[Br:13].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:9][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:10][Br:13]
Reactant: COc1cccc(Cl)c1CO
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cccc(Cl)c1CBr
Temperature: -10 °C

Procedure:
[2-Chloro-6-(methyloxy)phenyl]methanol (0.224 g, 1.30 mmol) in dry dichloromethane (4.5 ml) under nitrogen was stirred and cooled to −10° C. A solution of phosphorus tribromide (0.357 g, 1.32 mmol, Aldrich) in dry dichloromethane (4.5 ml) was added dropwise over about 40 min. The reaction temperature was slowly allowed to warm to 5° C. over about six hours then cooled to 0° C. and saturated aqueous sodium bicarbonate (5 ml) was added. The layers were separated and the aqueous phase further extracted with chloroform. The combined organic extract was dried with magnesium sulphate, filtered and solvent evaporated in vacuo to give the title compound as a slightly yellow solid (0.232 g); LCMS: (System 4) tRET=3.07 min (no MH+ detected).
Reaction SMILES: [NH2:1][C@H:2]([CH2:24][CH3:25])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)=[O:4].C(N(CC)CC)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH3:23][C:20]1([CH3:22])[CH2:19][C:18]2[C:13]([O:12][C:9]3[N:8]=[CH:7][C:6]([N:5]4[C:3](=[O:4])[C@@H:2]([CH2:24][CH3:25])[NH:1][C:34]4=[O:36])=[CH:11][CH:10]=3)=[CH:14][CH:15]=[CH:16][C:17]=2[O:21]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@@H](N)C(=O)Nc1ccc(Oc2cccc3c2CC(C)(C)O3)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3cccc4c3CC(C)(C)O4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
((2R)-2-amino-N-{6-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}butanamide) (Intermediate 209, 10 mg, 0.029 mmol) was dissolved in dry dichloromethane (1 ml). The reaction mixture was cooled down in an ice bath. Triethylamine (0.024 ml, 0.176 mmol) was added at 0° C. Then 0.5 ml of a solution of triphosgene in dry dichloromethane (4.78 mg, 0.016 mmol in 0.5 ml) was added dropwise. The reaction mixture was stirred under argon during 20 min at 0° C. A saturated aqueous solution of NaHCO3 was added (3 ml). The aqueous layer was extracted with dichloromethane 4 times (4×4 mL). Combined organic layers were dried over Na2SO4 and evaporated. the residue was purified by flash chromatography (Companion system) on silica gel using a 4 g silica cartridge and cyclohexane/ethyl acetate from 100:0 to 60:40 as eluents affording the title compound (7 mg).
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:17][CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[C:19]1([C:18]2[NH:17][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:2]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: NCc1cccc2ccccc12
Reactant: CCOC(=O)C(=NO)C(=O)c1ccccc1
Product: CCOC(=O)c1nc(-c2cccc3ccccc23)[nH]c1-c1ccccc1
Yield: 41.3 %

Procedure:
Ethyl 2-hydroxyimino-3-phenyl-3-oxopropionate (10.0 g) and 1-aminomethylnaphthalene (7.8 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 2-(1-naphthyl)-5-phenylimidazole-4-carboxylate (6.4 g). 6.0 g therefrom was dissolved in ethyl alcohol (120 ml) and 1 M sodium hydroxide solution (45 ml) was added. The mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 2-(1-naphthyl)-5-phenylimidazole-4carboxyic acid (4.1 g), melting point 172° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:14]1
Reactant: COc1ccc2nccc(N3CCC(O)C3)c2n1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2nccc(N3CCC(OS(C)(=O)=O)C3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
1-(6-Methoxy-[1,5]naphthyridin-4-yl)-pyrrolidin-3-ol (7.67 g, 31.3 mmole), triethylamine (8.73 mL, 63 mmole) and catalytic amount of 4-dimethylaminopyridine dissolved in DCM (100 mL) and cooled to 0° C. The solution was degassed with argon. Methanesulfonyl chloride (2.9 mL, 37.6 mmole) was added dropwise over 30 minutes. The reaction was stirred under argon for 30 minutes at 0° C. and then stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo. The residue was purified on column chromatography (silica, 1-5% MeOH in chloroform). The solvent was removed in vacuo to afford the title compound as a white solid (7.0 g, 69%): LC-MS (ES) m/z 324 (M+H)+.
Reaction SMILES: CS([O:5][CH:6]([C:8]([F:11])([F:10])[F:9])[CH3:7])(=O)=O.[N+]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([O-])=O>>[F:9][C:8]([F:11])([F:10])[CH:6]([O:5][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[CH3:7]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(OS(C)(=O)=O)C(F)(F)F
Product: CC(Oc1ccc(O)cc1)C(F)(F)F

Procedure:
Following the above procedures, 1-trifluoromethylethyl methanesulfonate is reacted with 4-nitrophenol to give 4-(1trifluoromethylethoxy)phenol, which is then reacted with ethyl N-(2-chloroethyl)carbamate to give ethyl N-{2-[4-(1-trifluoromethylethoxy)phenoxy]ethyl}carbamate (compound 29, Table A).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[CH3:29][C:30]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:31]=1[NH2:32].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:30]1([CH3:29])[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:31]=1[NH:32][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1cc(C)c(N)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(C)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 71.4 %

Procedure:
After adding sodium triacetoxyborohydride (7.98 g, 37.6 mmol) to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.00 g, 25.1 mmol), 2,4,6-trimethylaniline (3.56 g, 26.3 mmol) and acetic acid (2.9 mL, 50.2 mmol) in methylene chloride (50 mL), the mixture was stirred at room temperature for 3.5 hours. Saturated aqueous sodium hydrogencarbonate (150 mL) was added to the reaction mixture, which was then stirred until bubbling settled. The organic layer was separated and the aqueous layer was extracted with chloroform (100 mL). The organic layers were combined, washed with saturated brine (100 mL) and dried (Na2SO4), and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (50 g Merck Art. 9385, hexane:ethyl acetate=9: 1) to obtain the title compound as a brown oil (5.71 g) (71% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[N:35]1C=CC(CO)=CC=1>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][CH2:20][C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][N:35]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OCc1ccncc1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)Oc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OCc1ccccn1
Temperature: 100 °C

Procedure:
Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed 4-pyridylmethanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase LC/MS to give 2-pyridylmethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (11 mg, 0.023 mmol). The solid was dissolved in ethyl acetate (2 mL) and 1.0N HCl in ether (0.1 mL) was added slowly. The precipatate was collected through filtration under nitrogen to give 4-pyridylmethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate hydrochloride (12 mg, 0.023 mmol). 1H NMR (DMSO-d6) δ 1.91(m, 2H), 2.16(m, 2H), 3.55 (m, 2H), 3.90 (s, 3H), 4.03 (m, 2H), 4.92 (m, 1H), 5.34 (s, 2H), 7.06 (d, J=8.2 Hz, 1H), 7.16 (s, 1H), 7.73 (m, 1H), 7. 81 (m, 1H), 7.87 (s, 1H), 8.46(s, 1H), 8.76 (d, J=5.6 Hz, 1H), 9.05 (s, 1H). LC/MS: MH+=475.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[CH3:5][CH:6]([CH2:8][CH2:9][CH2:10][C@H:11]([CH2:13][CH2:14][CH2:15][C@H:16]([CH2:18][CH2:19][CH2:20]/[C:21](=[CH:23]/[CH2:24][OH:25])/[CH3:22])[CH3:17])[CH3:12])[CH3:7]>C(O)(=O)C.C(OCC)(=O)C>[C:2](=[O:1])([O:25][CH2:24]/[CH:23]=[C:21](/[CH2:20][CH2:19][CH2:18][C@@H:16]([CH2:15][CH2:14][CH2:13][C@@H:11]([CH2:10][CH2:9][CH2:8][CH:6]([CH3:5])[CH3:7])[CH3:12])[CH3:17])\[CH3:22])[NH2:3]
Reactant: N#C[O-]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C/C(=C\COC(N)=O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.3 %

Procedure:
6.6 g of sodium cyanate was added to a solution of 10.0 g of phytol dissolved in 50 ml of acetic acid, in small portions. The resulting mixture was stirred for 6 hours at room temperature. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in 50 ml of ethyl acetate. The solution was washed with 3% aqueous sodium hydrogen-carbonate solution and water in this order and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure. The residue obtained was purified by a column chromatography (eluant: benzene) to obtain 10.0 g (yield: 87%) of oily phytyl carbamate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[N:2].Cl.[CH3:13][C:14]1[C:18]([CH2:19][N:20]2[CH:24]=[C:23]([NH2:25])[CH:22]=[N:21]2)=[C:17]([CH3:26])[O:16][N:15]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:25][C:23]1[CH:22]=[N:21][N:20]([CH2:19][C:18]2[C:14]([CH3:13])=[N:15][O:16][C:17]=2[CH3:26])[CH:24]=1)=[O:8])#[N:2]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(NC(=O)c2cccc(C#N)c2)cn1
Yield: 15 %

Procedure:
Prepared as in Example 4-8 from 3-cyanobenzoic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 15%. MS M+H calculated 322.6. Found 322.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:44][CH2:45][CH:46]([OH:57])[CH2:47][N:48]1[CH2:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49]1>C(Cl)Cl>[OH:57][CH:46]([CH2:47][N:48]1[CH2:49][C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:56]1)[CH2:45][NH:44][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:8]=1
Reactant: NCC(O)CN1Cc2ccccc2C1
Reactant: O=C(O)c1cccc(-c2ccccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC(O)CN1Cc2ccccc2C1)c1cccc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(pyridin-2-yl)benzoic acid (60 mg, 0.30 mmol) in DCM (8 mL) was added EDCI (86 mg, 0.45 mmol), HOBt (61 mg, 0.45 mmol), Et3N (61 mg, 0.6 mmol) and 1-amino-3-(isoindolin-2-yl)propan-2-ol (86 mg, 0.45 mmol). The mixture was stirred at 25° C. for 16 h, washed with water and extracted with DCM. The combined organic extracts were concentrated, and the residue was purified by preparative HPLC purification. (30 mg, 27%) MS (ESI+) e/z: 374.2 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 8.65 (d, J=4.8 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.96-7.92 (m, 3H), 7.62 (dd, J=7.2 Hz, 1H), 7.40-7.35 (m, 6H), 4.70 (s, 4H), 4.29 (br.s, 1H), 3.63-3.30 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([C:10]([OH:12])=O)[CH:3]=1.Br.[Br:14][CH2:15][CH2:16][NH2:17]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:8][CH:9]=1)[C:6](=[O:7])[N:17]([CH2:16][CH2:15][Br:14])[CH:10]2[OH:12]
Reactant: O=Cc1ccc(Cl)cc1C(=O)O
Reactant: NCCBr
Agent: Br
Product: O=C1c2ccc(Cl)cc2C(O)N1CCBr
Yield: 27.8 %

Procedure:
The compound was prepared as described in example 1A, starting from 2.5 g (0.013 mole) of 4-chloro-2-carboxybenzaldehyde (I1 farmaco, Ed. Sci 31, 691, 1976) and 2.76 g (0.013 mole) of 2-bromoethylamine hydrobromide. 1.05 g of the title product were obtained; mp=164°-168 ° C. (n-hexane).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=O)[N:9]=[C:8]([C:19]([F:22])([F:21])[F:20])[CH:7]=1.[NH2:23][CH2:24][CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH2:14][NH:23][CH2:24][CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[N:9]=[C:8]([C:19]([F:22])([F:20])[F:21])[CH:7]=1
Reactant: O=Cc1cccc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CCNCc1cccc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of crude 122 (1.522 g, 4.97 mmol) in MeOH (20 mL) was added a solution of tert-butyl 2-aminoethyl(methyl)carbamate (1.732 g, 9.94 mmol, E. Atherton et al, J. Chem. Soc. C, 1971, 3393-3396) in MeOH (5 mL) followed by acetic acid (1.1 mL, 20 mmol). The reaction was stirred at room temperature for 1 hour then sodium cyanoborohydride (0.625 g, 9.94 mmol) was added and the resulting mixture was stirred for 16 hours. After the usual work-up crude 123 (2.30 g, 4.95 mmol, 100% yield) was obtained as yellow oil. LRMS(ESI): (calc.) 464.5 (found) 465.2 (MH)+, 487.2 (MNa)+.
Reaction SMILES: F[C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl-].[O:10]1[CH2:15][CH2:14][CH:13]([C@H:16]([NH3+:18])[CH3:17])[CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[I:8][C:7]1[C:2]([NH:18][C@@H:16]([CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)[CH3:17])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ncccc1I
Reactant: C[C@@H]([NH3+])C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: C[C@@H](Nc1ncccc1I)C1CCOCC1
Temperature: 125 °C
Reaction time: 48 h
Yield: 34.4 %

Procedure:
To a re-sealable vial containing 2-fluoro-3-iodopyridine (2.14 g, 9.60 mmol), (S)- or (R)-1-(tetrahydro-2H-pyran-4-yl)ethanaminium chloride (1.2175 g, 7.35 mmol) and cesium carbonate (7.54 g, 23.14 mmol) was added DMAc (10 mL). The vial was subsequently sealed and placed in a 125° C. bath. After stirring at 125° C. for 48 h, the reaction mixture was cooled to room temperature and partitioned between EtOAc with water. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with a minimal amount of water (2×), dried over Na2SO4, and concentrated to give a heterogeneous brown oil. The oil was diluted with EtOAc/Hexanes (1:3) and filtered. The solids were washed with EtOAc:Hexanes (1:3) and the filtrate was concentrated to give a brown oil. The resultant oil was purified on a Biotage system (40 g, gradient elution 2% EtOAc: 98% Hexanes to 10% EtOAc: 90% Hexanes, then isocratic 10% EtOAc: 90% Hexanes). The product (S)- or (R)-3-iodo-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)pyridin-2-amine (0.84 g, 2.53 mmol, 34.4% yield) was isolated as a clear colorless oil. LRMS (M+H+) m/z: calcd 333.0. found 333.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>[Pd].C(O)(C)C>[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 81.5 °C
Reaction time: 17.5 h
Yield: 85.4 %

Procedure:
5% Palladium on carbon, type 58, 50% paste (0.94 kg, 0.22 moles Pd) was added to a mixture of 4-bromobenzaldehyde (3.34 kg, 17.69 moles), 4-trifluoromethylphenyl boronic acid (3.50 kg, 18.06 moles) and sodium carbonate (3.75 kg, 35.38 moles) in process water (36 L). Isopropanol (36 L) was added and the resultant mixture heated to reflux (80-83° C.) for ca. 2.5 hours. The catalyst was removed from the hot suspension by filtration through celite (1.5 kg). The celite bed was washed with a hot (ca. 70° C.) isopropanol (10 L)/water (10 L) mixture then the combined filtrate and wash were cooled to 23° C., process water (18 L) was added and the mixture stirred at 20-25° C. for ca. 17.5 hours. The solid was collected by filtration, washed with process water (1×27 L, 2×18 L) then dried at 39° C. for 24 hours to give the title compound (3.78 kg, 85%) as a white solid. 1H NMR (CDCl3) δ 7.75 (4H, s), 7.78 (2H, d) 7.98 (2H, d), 10.10 (1H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:34]=[CH:33][C:17]4[O:18][CH2:19][C:20]5[CH:27]=[C:26]([CH2:28][CH2:29][C:30](=[O:32])[CH3:31])[CH:25]=[CH:24][C:21]=5[CH:22](O)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][C:3]=1[F:35].[SH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40]>>[C:39]([CH2:38][CH2:37][S:36][CH:22]1[C:21]2[CH:24]=[CH:25][C:26]([CH2:28][CH2:29][C:30](=[O:32])[CH3:31])=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:33]=[CH:34][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([F:35])[CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:41])=[O:40]
Reactant: CC(=O)CCc1ccc2c(c1)COc1ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc1C2O
Reactant: O=C(O)CCS
Product: CC(=O)CCc1ccc2c(c1)COc1ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc1C2SCCC(=O)O

Procedure:
2-(7-Chloro-6-fluoroquinolin-2-yl)methoxy-11-hydroxy-8-(2-acetylethyl)-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)#[N:2].[CH2:18]([Mg]Br)[CH3:19].C(I)C>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH3:19])#[N:2]
Reactant: N#Cc1ccccc1-c1ccc2[nH]ccc2c1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1c[nH]c2ccc(-c3ccccc3C#N)cc12
Yield: 31.6 %

Procedure:
5-(2-cyanophenyl)indole (1.26 mmoles, 630 mg) was dissolved in THF (20 ml) and treated with ethylmagnesium bromide (1.26 mmoles, 0.630ml) and ethyl iodide (3.45 mmoles, 0.54 g) as in Example 24 to yield 98 mg of 5-(2-cyanophenyl)-3-ethylindole. (MS)
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[C:12]([C:16]([NH2:18])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.N1C=CC=CC=1.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH3:15][N:14]1[C:5]2[C:4]3[N:3]=[C:2]([NH:1][C:32](=[O:33])[CH2:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:11]=[CH:10][C:9]=3[CH:8]=[CH:7][C:6]=2[C:12]([C:16]([NH2:18])=[O:17])=[N:13]1
Reactant: Cn1nc(C(N)=O)c2ccc3cnc(N)nc3c21
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cn1nc(C(N)=O)c2ccc3cnc(NC(=O)Cc4ccccc4)nc3c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
0.40 g (1.47 mmol) of 8-amino-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide were suspended in 20 mL of tetrahydrofuran and 5 mL of pyridine and 0.42 mL (3.22 mmol) of phenylacetylchloride were added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated, the residue redissolved with dichloromethane, washed with aqueous NaHCO3 and then with water. After drying over anhydrous Na2SO4 the solvent was removed under reduced pressure and the crude purified by chromatography on a silica gel column (eluant cyclohexane/acetone) giving 0.35 mg of the title compound (60% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=O)[CH:5]=[C:4]([CH3:10])[N:3]=1.[NH2:11][C:12]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[C:13]=1[C:14]([NH2:16])=[O:15].S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:16][C:14](=[O:15])[C:13]3[C:12](=[CH:20][C:19]([F:21])=[CH:18][C:17]=3[F:22])[N:11]=2)[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: NC(=O)c1c(N)cc(F)cc1F
Reactant: Cc1cc(C=O)cc(C)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)n1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a solution of 2,6-dimethyl-pyridine-4-carbaldehyde (0.99 g, 7.32 mmol) and 2-amino-4,6-difluorobenzamide (1.26 g, 7.32 mmol) in N,N-dimethyl acetamide (20 mL) were added sodium hydrogen sulfite (58.5 wt %, 1.59 g, 8.78 mmol) and p-toluenesulfonic acid (0.21 g, 1.09 mmol). The reaction mixture was stirred at 115° C. for 16 hours under nitrogen. After cooling to room temperature, the solvent was evaporated under reduced pressure. Water (50 mL) was added, the precipitated solid was filtered, washed with water, and dried under vacuum, to give 2-(2,6-dimethyl-pyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one as a yellow solid. Yield: 0.63 g (30%).
Reaction SMILES: [C:1]([OH:12])(=O)[CH:2]=[CH:3][CH2:4][CH2:5][CH:6]=[CH:7][CH:8]=[CH:9][CH3:10].CN(C=O)C.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[C:1]([Cl:20])(=[O:12])[CH:2]=[CH:3][CH2:4][CH2:5][CH:6]=[CH:7][CH:8]=[CH:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CC=CC=CCCC=CC(=O)O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC=CC=CCCC=CC(=O)Cl
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
In an atmosphere of nitrogen, a toluene solution of the above-mentioned 2,6,8-decatrienoic acid (7) and DMF (3.7 g, 0.05 mol) were added to a 100 ml capacity flask, followed by cooling to 5° C. Thionyl chloride (11.9 g, 0.10 mol) was added dropwise to this, followed by stirring at 5° C. for 0.5 hour to obtain a toluene solution of 2,6,8-decatrienoic acid chloride (8).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[N:12]=2)[CH:6]=1)[CH3:2].[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:12]=2)[CH:6]=1)[CH3:2]
Reactant: NCCc1ccc(O)cc1
Reactant: CCOC(=O)c1cccc(-c2ccnc(Cl)n2)c1
Product: CCOC(=O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 8c was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 364. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 9.15 (s, 1H) 8.72 (br s, 8.35 (m, 2H) 8.07 (d, 1H) 7.65 (m, 1H) 7.18 (m, 1H) 7.05 (m, 2H) 6.68 (d, 2H) 4.35 (q, 2H) 3.5 (m, 2H) 2.78 (m, 2H) 1.35 (t, 3H).