Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[C:17]1(O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[C:13]([O:12][C:10]([N:4]1[C@H:3]([CH2:2][O:1][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7][O:6][C:5]1([CH3:8])[CH3:9])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1[C@H](CO)COC1(C)C
Reactant: Oc1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H](COc2ccccc2)COC1(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a stirred solution of tert-butyl (R)-4-(hydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate (400 mg; CAS 108149-63-9) in THF (20 ml) were added phenol (197 mg), triphenylphosphine (573 mg) and di-tert-butyl azodicarboxylate (488 mg). The resulting yellow solution was stirred at 70° C. for 18 h overnight, then concentrated in vacuo. The crude product was purified by column chromatography (SiO2; gradient: heptane/EtOAc 100:0->70:30) to give (R)-2,2-dimethyl-4-phenoxymethyl-oxazolidine-3-carboxylic acid tert-butyl ester (336 mg, 63%) as a colourless viscous oil. MS (ISP): 308.3 ([M+H]+)).
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=1)=[O:7])(C)(C)C.Cl>ClCCl.O1CCOCC1>[OH:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:23]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1cccc(O)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CCCN1C(=O)COc1cccc(O)c1
Reaction time: 72 h
Yield: 96.8 %

Procedure:
To a solution of 120 mg (0.37 mmol) (R)-1-[(3-hydroxy-phenoxy)-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 1 ml dichloromethane were added 5 ml of a 4 N solution of hydrochloric acid in dioxane. After 3 d, the solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 95 mg (97%) of the title compound as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]2[S:15][CH:14]=[N:13][CH:12]=2)[CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]2[S:15][CH:14]=[N:13][CH:12]=2)[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(O)c(-c2cncs2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(O)c(-c2cncs2)c1

Procedure:
4-Nitro-2-thiazol-5-ylphenol (100 mg, 0.4 mmol) in methanol (5 mL) was hydrogenated in the presence of 10% Pd/C (80 mg) for 16 h. The reaction mixture was filtered through a Celite pad. The filtrate was concentrated in vacuo to afford the title compound, which was used directly in the next step without purification. 1H-NMR (CD3OD, 400 MHz): δ=7.18 (d, J=8.8 Hz, 1H), 7.39 (dd, J=2.4, 8.8 h z, 1H), 7.91 (d, J=2.8 Hz, 1H), 8.91 (s, 1H), 9.97 (s, 1H). MS (ES+): m/z 193.14 [MH+]. HPLC: tR=0.48 min (ZQ2000, polar—5 min).
Reaction SMILES: [Cl:1][C@:2]12[C@@H:22]([Cl:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([O:26][CH2:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17]O)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:37])[CH:4]=[CH:5][C:6](=[O:36])[CH:7]=1.[Cl-:38].[Li+]>CN(C)C=O.O>[Cl:1][C@:2]12[C@@H:22]([Cl:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([O:26][CH2:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][Cl:38])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:37])[CH:4]=[CH:5][C:6](=[O:36])[CH:7]=1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCC(=O)c4ccccc4)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](Cl)[C@@]12Cl
Reactant: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCC(=O)c4ccccc4)[C@](O)(C(=O)CCl)[C@@]3(C)C[C@H](Cl)[C@@]12Cl

Procedure:
A solution of 9,11β-dichloro-17,21-dihydroxy-16α-(2-oxo-2-phenylethoxy)pregna-1,4-diene-3,20-dione, 21-methanesulfonate (1 mmole) in 20 ml of dimethylformamide is heated at 80°C for 3 hours with 1 g of lithium chloride, cooled, diluted with water and filtered to give the title compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:12][C:13]([C:15]1([NH:20][C:21]([CH:23]2[CH2:27][CH:26]([OH:28])[CH2:25][CH:24]2[C:29]([OH:31])=O)=[O:22])[CH2:17][CH:16]1[CH:18]=[CH2:19])=[O:14])[CH3:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][NH:57][CH2:58][CH2:59][CH2:60][CH2:61][CH:62]=[CH2:63].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:10]([O:12][C:13]([C:15]1([NH:20][C:21]([CH:23]2[CH2:27][CH:26]([OH:28])[CH2:25][CH:24]2[C:29](=[O:31])[N:57]([CH2:58][CH2:59][CH2:60][CH2:61][CH:62]=[CH2:63])[CH3:56])=[O:22])[CH2:17][CH:16]1[CH:18]=[CH2:19])=[O:14])[CH3:11]
Reactant: C=CCCCCNC
Reactant: C=CC1CC1(NC(=O)C1CC(O)CC1C(=O)O)C(=O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
The crude compound 10b (5.5 mol) was dissolved in DCM (50 mL) and DMF (14 mL) followed by addition of HATU (2.09 g, 5.5 mmol), N-methyl-N-hex-5-enylamin (678 mg, 6.0 mmol) and DIPEA (3.08 mL, 17.5 mmol) at room temperature. The reaction was stirred at ambient temperature for 1 h. LC/MS analysis showed complete conversion of the starting materials and the reaction mixture was concentrated in vacuo. The residue was redissolved in EtOAc (100 mL) and the organic phase washed with 0.1 M HCl (aq), K2CO3 (aq) and brine, dried (MgSO4) and filtered. Removal of the solvent in vacuo gave an oil which was purified by flash chromatography (Silica, EtOAc:MeOH) to afford the title compound (1.65 g, 74%). TLC (Silica): MeOH:EtOAc 5:95, Rf=0.5; LC/MS >95%, m/z (ESI+)=407 (MH+).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[N:20]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccncc1
Reactant: COc1cccc(CNc2cccn3nc(Cl)nc23)c1
Product: COc1cccc(CNc2cccn3nc(Nc4ccncc4)nc23)c1

Procedure:
N(8)-(3-Methoxy-benzyl)-N(2)-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methoxy-benzyl)-amine (99.9 mg, 0.346 mmol) and 4-aminopyridine (36.47 mg, 0.3875 mmol) in a manner analogous to Example 2d. Product was isolated as an off-white foam (3.63 mg, 3%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.02 (s, 1H), 8.32 (m, 2H), 8.00 (d, J=6.7 Hz, 1H), 7.69 (m, 2H), 7.23 (t, J=16.4, 8.2 Hz, 1H), 6.97 (s, 2H), 6.79 (m, 2H), 6.67 (m, 1H), 6.34 (d, J=8.0 Hz, 1H), 4.50 (d, J=6.1 Hz, 2H), 3.72 (s, 3H). MS=347 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:35])[CH2:24][CH2:25][CH2:26][C:27](=[O:34])[N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:18][C:17]=2[CH2:36][CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])=[CH:5][CH:4]=1>C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:35])[CH2:24][CH2:25][CH2:26][C:27](=[O:34])[N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[CH:18][C:17]=2[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:5][CH:4]=1
Reactant: COc1ccc(/C=C/CCCCOc2ccc(NC(=O)CCCC(=O)N3CCOCC3)cc2CCC(=O)OC(C)(C)C)cc1
Solvent: O=CO
Product: COc1ccc(/C=C/CCCCOc2ccc(NC(=O)CCCC(=O)N3CCOCC3)cc2CCC(=O)O)cc1
Reaction time: 5 h
Yield: 62.9 %

Procedure:
The butyl ester (70 mg; prepared in reference example 6) was dissolved in formic acid (5 ml). The solution was stirred for 5 hr. at room temperature. The reaction solution was evaporated to remove formic acid. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=10:1) to give the title compound (40 mg) of the present invention, having the following physical data.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](/[C:17](=[CH:25]\[CH:26]([CH3:28])[CH3:27])/[C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CS(C)=O.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](/[C:17](=[CH:25]\[CH:26]([CH3:28])[CH3:27])/[C:18]([CH3:23])([CH3:24])[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)/C(=C/C(C)C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)/C=C(\c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)C(=O)O
Reaction time: 8 h
Yield: 188.2 %

Procedure:
(E)-Methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhex-3-enoate (121 mg, 0.29 mmol) was dissolved in MeOH (10 mL) and DMSO (10 mL) and treated with 1 M NaOH (10 mL) at 100° C. After stirring overnight, the MeOH was removed in vacuo, the residue acidified with sat KH2PO4 to pH 4-5 and extracted with EtOAc×3. The organic layer was dried with MgSO4, filtered, concentrated in vacuo to give 200 mg (94% yield) of (E)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhex-3-enoic acid. MS found: (M+H)+=367.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:17])([CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1.Cl.[O:37]1CCOCC1>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]([OH:37])([CH3:15])[CH3:16])([CH3:17])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1
Reactant: CC(C)=CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reactant: C1COCCO1
Agent: Cl
Product: CC(C)(O)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21

Procedure:
To a solution of Example 139 (40 mg, 0.078 mmol) in dioxane (3 mL) was added a solution of 6N aqueous hydrochloric acid (3 mL). The mixture was heated at 65 C for 3 hours, and the solvent removed in vacuo. The resultant residue was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/0.1% trifluoroacetic acid in water over 8 minutes (10 minutes run time) at a flow rate of 40 mL/min to provide the title (6 mg, 14%). MS (ESI) m/z=532 (M−H)+. 1H NMR (500 MHz, DMSO-d6): δ 0.60 (dq, J=12.8, 3.7 Hz, 1H), 0.91 (s, 6H), 0.98 (dq, J=12.8, 4.3 Hz, 1H), 1.59 (s, 3H), 2.09 (m, 1H), 2.26 (dq, J=12.8, 4.3 Hz, 1H), 3.07 (s, 3H), 7.56 (m, 3H), 7.74 (m, 3H), 8.16 (d, J=7.9 Hz, 1H), 10.22 (s, 1H), 13.77 (s, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:23]=[C:18]3[N:17]([CH2:30][CH3:31])[C:16]2=[O:32])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[CH2:30]([N:17]1[C:18]2[C:19](=[N:20][CH:21]=[C:22]([O:24][CH2:25][C:26]([F:28])([F:27])[F:29])[CH:23]=2)[N:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[C:16]1=[O:32])[CH3:31]
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(OCC(F)(F)F)cc21
Agent: [Pd]
Solvent: CCO
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(OCC(F)(F)F)cc21
Reaction time: 8 h

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-ethyl-6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (305 mg) and 10% Pd—C (36.6 mg) in EtOH (10 mL) was hydrogenated under balloon pressure at room temperature overnight. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 1-ethyl-3-(4-hydroxyphenyl)-6-(2,2,2-trifluoroethoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one as colorless solid. To a solution of this product and 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (149 mg) in DMF (5 mL), sodium hydride (33.1 mg) was added at 100° C. and the mixture was heated at 180° C. for 30 min under microwave irradiation. The mixture was quenched with water at room temperature and extracted with AcOEt. The organic layer was separated, washed with sat. NaHCO3 aq. and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 15%-50% AcOEt in hexane) to give 1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (262 mg) as colorless solid. The solid was crystallized from AcOEt-hexane.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH:11]=[CH:12][C:13]3[N:14]=[C:15]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH2:17][N:16]4[CH:24]=3)[N:10]=[C:6]2[C:5]([CH3:25])=[N:4][CH:3]=1>CO.[Pd]>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH2:17][N:16]4[CH:24]=3)[N:10]=[C:6]2[C:5]([CH3:25])=[N:4][CH:3]=1
Reactant: Cc1ncc(C)n2nc(C=Cc3cn4c(n3)-c3ccccc3C4)nc12
Agent: [Pd]
Solvent: CO
Product: Cc1ncc(C)n2nc(CCc3cn4c(n3)-c3ccccc3C4)nc12
Reaction time: 8 h
Yield: 36.2 %

Procedure:
To a solution of 2-[-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-5H-imidazo[2,1-a]isoindole (139 mg, 0.423 mmol) in methanol (100 mL) was added 10% palladium on carbon (27 mg). A current of hydrogen gas was bubbled through, and the reaction was kept under an atmosphere of hydrogen overnight with stirring. After filtration the organics were evaporated onto silica gel (2 g). Chromatography (gradient elution; A:B 100:0 to 0:100, where A is ethyl acetate and B is 10% MeOH in ethyl acetate) afforded the title compound as a white solid (50.6 mg, 36%). 1H NMR (500 MHz, CDCl3): δ 7.86-7.82 (m, 2H), 7.46-7.42 (m, 2H), 7.33 (t, J=7.5 Hz, 1H), 7.02 (s, 1H), 4.84 (s, 2H), 3.44 (dd, J=8.9, 6.6 Hz, 2H), 3.33 (dd, J=8.9, 6.6 Hz, 2H), 2.91 (s, 3H), 2.73 (s, 3H). LC-MS: m/z=331.0 (MH+), tR=0.74 minutes.
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:36][C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[CH:39]=[C:40]([C:48]1[CH:53]=[CH:52][C:51]([CH2:54][N:55]3[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]3)=[CH:50][CH:49]=1)[NH:41][C:42]2=[O:47]>C(Cl)Cl>[C:1]([N:58]1[CH2:59][CH2:60][N:55]([CH2:54][C:51]2[CH:50]=[CH:49][C:48]([C:40]3[NH:41][C:42](=[O:47])[C:43]4[C:38]([CH:39]=3)=[C:37]([CH3:36])[CH:46]=[CH:45][CH:44]=4)=[CH:53][CH:52]=2)[CH2:56][CH2:57]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: Cc1cccc2c(=O)[nH]c(-c3ccc(CN4CCNCC4)cc3)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(Cc2ccc(-c3cc4c(C)cccc4c(=O)[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7.8 %

Procedure:
To a stirred solution of acetic acid (0.005 mL, 0.068 mmol) in CH2Cl2 (5 mL) was added TBTU (22 mg, 0.068 mmol) and N,N-diisopropylethylamine (0.036 mL, 0.20 mmol) and the reaction stirred for 10 min at RT. 5-Methyl-3-(4-piperazin-1-ylmethylphenyl)-2H-isoquinolin-1-one (23 mg, 0.068 mmol) was then added and the reaction stirred for 2 h at RT. The reaction mixture was concentrated in vacuo and purified by reverse phase preparative HPLC-MS to afford 3-[4-(4-acetyl-piperazine-1-ylmethyl)-phenyl]-5-methyl-2H-isoquinolin-1-one as a white solid (2 mg, 9%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][N:6]1C(=O)C2C(=CC=CC=2)C1=O.[CH:18]([NH2:21])([CH3:20])[CH3:19]>>[NH2:6][O:5][CH2:4][C:3]([NH:21][CH:18]([CH3:20])[CH3:19])=[O:2]
Reactant: CC(C)N
Reactant: COC(=O)CON1C(=O)c2ccccc2C1=O
Product: CC(C)NC(=O)CON

Procedure:
Using (1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-acetic acid methyl ester obtained in Step A of Example 19 and isopropylamine as an amine, synthesis was performed according to the procedure described in Step A of Example 20 to give 2-aminooxy-N-isopropyl-acetamide.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.Br[C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:32]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)=[O:20]>>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][N:11]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([CH:32]=3)[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)=[O:20])[CH2:10][CH2:9][C:7]=2[N:8]=1
Reactant: CSc1ncc2c(n1)CCNC2
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cncc(Br)c1
Product: CSc1ncc2c(n1)CCN(c1cncc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2

Procedure:
In a manner similar to that described for Example 138, 2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine and 5-bromo-N-(3-(trifluoromethyl)phenyl)nicotinamide were converted to the title compound.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].[CH:53]1([NH2:59])[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1.[C:60]([O:64][C:65]([N:67]1[CH2:73][CH2:72][C:71]2[C:74]([S:79][CH2:80][C:81]3[CH:82]=[N:83][C:84](Cl)=[CH:85][CH:86]=3)=[C:75]([Cl:78])[CH:76]=[CH:77][C:70]=2[CH2:69][CH2:68]1)=[O:66])([CH3:63])([CH3:62])[CH3:61]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:60]([O:64][C:65]([N:67]1[CH2:73][CH2:72][C:71]2[C:74]([S:79][CH2:80][C:81]3[CH:82]=[N:83][C:84]([NH:59][CH:53]4[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]4)=[CH:85][CH:86]=3)=[C:75]([Cl:78])[CH:76]=[CH:77][C:70]=2[CH2:69][CH2:68]1)=[O:66])([CH3:63])([CH3:61])[CH3:62]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Cl)nc3)c2CC1
Reactant: NC1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(NC4CCCCC4)nc3)c2CC1
Temperature: 95 °C
Yield: 33.2 %

Procedure:
Slurry palladium(II) acetate (434 mg, 1.9 mmol), BINAP (1.2 g, 1.9 mmol), sodium-tert-butoxide (644 mg, 6.7 mmol), cyclohexylamine (1.4 g, 14.4 mmol) and 3-tert-butoxycarbonyl-7-chloro-6-(6-chloro-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (2.1 g, 4.8 mmol) in anhydrous toluene (70 mL). Degas the slurry under house vacuum, then buble nitrogen. Heat the mixture to 95° C. for 16 h under a nitrogen atmosphere. Cool the mixture to room temperature, dilute with EtOAc (50 mL) and filter through Celite®. Concentrate the filtrate to an oil and purify by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 13:7 gradient) to obtain 3-tert-butoxycarbonyl-7-chloro-6-(6-cyclohexylamino-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (800 mg, 33%). MS (ES+) m/z: 502.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH:20][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CC(C)COC(=O)[C@H](C)N
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure BI above, and using 3,5-difluorophenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [Li]CCCC.C1COCC1.[S:11]1[CH:15]=[CH:14][C:13]2[CH:16]=[C:17]3[C:25](=[CH:26][C:12]1=2)[CH:24]=[C:23]1[C:19]([S:20][CH:21]=[CH:22]1)=[CH:18]3.[CH3:27][Sn:28](Cl)([CH3:30])[CH3:29]>O>[CH3:27][Sn:28]([CH3:30])([CH3:29])[C:15]1[S:11][C:12]2[CH:26]=[C:25]3[C:17](=[CH:16][C:13]=2[CH:14]=1)[CH:18]=[C:19]1[S:20][C:21]([Sn:28]([CH3:30])([CH3:29])[CH3:27])=[CH:22][C:23]1=[CH:24]3
Reactant: c1cc2cc3cc4sccc4cc3cc2s1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C[Sn](C)(C)c1cc2cc3cc4sc([Sn](C)(C)C)cc4cc3cc2s1
Temperature: -78 °C
Reaction time: 11 h
Yield: 54 %

Procedure:
Under a nitrogen atmosphere, n-BuLi (1.57N hexane solution, 5.7 ml, 8.9 mmol) was slowly added to an anhydrous THF (80 mL) solution of naphtho[2,3-b:6,7-b′]dithiophene (a compound of formula (2)) (675 mg, 2.8 mmol) at −78° C. The reaction solution was heated and refluxed. After the reaction for 1.5 hours, the reaction solution was cooled to −78° C. To the reaction solution, trimethyltin chloride (2.24 g, 11.2 mmol) was added. After the mixture was stirred at room temperature for 11 hours, and water (100 mL) was added thereto. The resultant mixture was separated into phases. The water layer was extracted with methylene chloride (100 mL×3). The organic layer was dried over anhydrous magnesium sulfate (MgSO4) and concentrated under reduced pressure. The resultant residue was recrystallized with acetone to obtain 2,7-bis(trimethylstannyl)naphtho[2,3-b:6,7-b′]dithiophene (861 mg, yield 54%) as a yellow solid substance.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:59])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=[O:58])[NH:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:28][C:27]=3[C:38]3[CH:43]=[C:42]([C:44](=[O:57])[NH:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:56])([F:55])[F:54])[CH:48]=4)[CH:41]=[CH:40][N:39]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7].[CH3:60]OCCNC>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:60])[C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]([CH3:59])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=[O:58])[NH:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:28][C:27]=3[C:38]3[CH:43]=[C:42]([C:44](=[O:57])[NH:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:54])([F:55])[F:56])[CH:48]=4)[CH:41]=[CH:40][N:39]=3)[CH:19]=2)[CH2:12][CH2:13]1)=[O:7]
Reactant: COCCNC(=O)N1CCN(CCN(C)Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Reactant: CNCCOC
Product: COCCN(C)C(=O)N1CCN(CCN(C)Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1

Procedure:
This compound was prepared according to the procedure described for the synthesis of N-(2-methoxyethyl)-4-(2-(methyl(3-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)benzyl)amino)ethyl)piperazine-1-carboxamide Example 208 substituting 2-methoxy-N-methylethanamine in place of 2-methoxyethanamine LC-MS (ES, m/z): 829 [M+H]+ H-NMR (300 MHz, DMSO, ppm): 12.31 (s, 1H), 9.56 (t, J=3.6 Hz, 1H), 8.93 (d, J=6 Hz, 1H), 8.31 (d, J=6 Hz, 2H), 8.04 (s, 1H), 7.94 (d, J=9 Hz, 1H), 7.84-7.86 (m, 1H), 7.56-7.71 (m, 7H), 7.30 (d, J=9 Hz, 1H), 4.63 (d, J=3 Hz, 2H), 4.26 (s, 2H), 3.45 (t, J=6.6 Hz, 2H), 3.23-3.32 (m, 16H), 3.17 (s, 1H), 3.00 (s, 4H), 2.80 (s, 3H), 2.63 (s, 3H), 1.60-1.74 (m, 6H).