Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)=[O:9].[C:24]1([CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[OH:1][CH:2]([CH2:3][N:34]1[CH2:35][CH2:36][N:31]([CH:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:32][CH2:33]1)[CH2:4][O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)=[O:9]
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC1CO1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Product: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC(O)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 91.4 %

Procedure:
Using the procedure of Example 28 of Step C, 3.08 g of 2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl)benzamide of Step B of Example 28, and 5.2 g of 1-(diphenylmethyl)piperazine were reacted to obtain after chromatography over silica (eluant:chloroform/ethyl acetate 7:3), 5.12 g of 2-[2-hydroxy-3-[4-(diphenylmethyl)-1-piperazinyl]propoxy]-N-(1H-indol-4-yl)benzamide, and then 3.22 g of its neutral oxalate from 4.36 g of base melting at 170° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([CH2:19]O)[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.O=S(Cl)[Cl:25]>C(Cl)Cl>[Cl:25][CH2:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:21])[F:1])[CH:4]=1)[CH:18]=[CH:17]2
Reactant: OCc1cccc2ccc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1cccc(-c2ccc3cccc(CCl)c3n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a solution of (2-(3-(trifluoromethyl)phenyl)quinolin-8-yl)methanol (0.67 g, 2.2 mmol) in CH2Cl2 (20 ml) was added SOCl2 (0.32 ml, 4.4 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 2 h, and then concentrated. The residue was purified by column chromatography (1:15 ethylacetate in pentane) to give the product as a white solid (0.668 g, 94% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[C:15]1([NH:21][CH2:22][CH2:23][C:24]#[N:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:11]([O:10][C:8]([C:7]1[C:2]([N:21]([CH2:22][CH2:23][C:24]#[N:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3][C:4]([S:13][CH3:14])=[N:5][CH:6]=1)=[O:9])[CH3:12]
Reactant: N#CCCNc1ccccc1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Product: CCOC(=O)c1cnc(SC)nc1N(CCC#N)c1ccccc1

Procedure:
The title compound was prepared from ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (3.7 g, 15.8 mmol) and 3-phenylamino-propionitrile (2.3 g, 15.8 mmol) according to the procedure outlined in Example 1 (B). The product was purified chromatographically (silica, EtOAc/hexanes 1:20-1:2, v/v). A white solid was obtained (3.5 g, 65%). 1H NMR (300 MHz, CDCl3) δ (ppm): 8.32 (s, 1H), 7.34(m, 2H), 7.20 (m, 1H), 7.13 (m, 2H), 4.32 (t, J=7.1 Hz, 2H), 3.56 (q, J=7.1 Hz, 2H), 2.75 (t, J=7.1 Hz, 2H), 2.55 (s, 3H), 1.00 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:33]=[CH:32][C:23]([O:24][CH2:25][C:26](N(OC)C)=[O:27])=[C:22]([CH3:34])[CH:21]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36]([Mg]Cl)([CH3:38])[CH3:37]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:33]=[CH:32][C:23]([O:24][CH2:25][C:26](=[O:27])[CH:36]([CH3:38])[CH3:37])=[C:22]([CH3:34])[CH:21]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Mg]Cl
Reactant: CCC(CC)(c1ccc(OCC(=O)N(C)OC)c(C)c1)c1ccc(OCc2ccccc2)c(C)c1
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(=O)C(C)C)c(C)c1)c1ccc(OCc2ccccc2)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
To a 0° C. solution of 2-{4-[1-(4-benzyloxy-3-methyl-phenyl)-1-ethyl-propyl]-2-methyl-phenoxy}-N-methoxy-N-methyl-acetamide (2.36 g, 4.98 mmol) in THF (50 mL) is added 2.0 M iPrMgCl (3.0 mL, 5.98 mmol). The reaction is stirred at 0° C. for 30 m, then at RT for 1 h. It is quenched with satd NH4Cl (20 mL), diluted with H2O (50 mL), extracted with EtOAc (2×100 mL), washed with 0.1 M HCl (50 mL), H2O (50 mL); MgSO4 dried, concentrated and purified to give the title compound (1.01 g, 2.21 mmol, 44%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:9][O:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([Br:25])=[CH:22][CH:23]=3)[CH:18]=[CH:17][C:16]=2[O:26][CH3:27])[C:4]1=[O:28].[C:29]([O:33][C:34]([NH:36][C@@H:37]([CH2:41][CH3:42])[C:38](O)=[O:39])=[O:35])([CH3:32])([CH3:31])[CH3:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Br:25][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[C:15]([CH2:14][N:5]1[C:4](=[O:28])[C@@H:3]([NH:2][C:38](=[O:39])[C@@H:37]([NH:36][C:34](=[O:35])[O:33][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:41][CH3:42])[CH2:9][O:8][C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]1=3)=[C:16]([O:26][CH3:27])[CH:17]=[CH:18]2
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](N)COc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1COc2ccccc2N(Cc2c(OC)ccc3cc(Br)ccc23)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
A mixture of (S)-3-amino-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride (348 mg, 750 μmol), (S)-2-(tert-butoxycarbonylamino)butanoic acid (168 mg, 825 μmol), DIEA (519 μL, 3.00 mmol), and HBTU (313 mg, 825 μmol) in DMF (2.5 mL) was stirred at RT for 30 min. The mixture was diluted with EtOAc, washed with sat. NaHCO3, H2O, and brine brine, then dried over Na2SO4, and filtered. The filtrate was concentrated to give a residue that was purified by silica gel chromatography to provide tert-butyl (S)-1-((S)-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxobutan-2-ylcarbamate (431 mg, 94%) as a white solid. MS m/z 634/636 (MNa)+
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[CH:4][CH:3]=1.[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[CH:22]=[CH:21][N:20]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:18]=2[N:19]=1.FC(F)(F)C(O)=O>C(O)C(F)(F)F>[Cl:13][C:14]1[N:15]=[C:16]([NH:1][C:2]2[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[CH:4][CH:3]=2)[C:17]2[CH:22]=[CH:21][N:20]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:24])=[O:25])[C:18]=2[N:19]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: NC(=O)c1c(N)ccc(F)c1F
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc(F)c(F)c4C(N)=O)nc(Cl)nc32)cc1
Reaction time: 8 h
Yield: 55 %

Procedure:
To a pressure flask is added 6-amino-2,3-difluorobenzamide (0.700 g, 4.07 mmol), 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (1.4 g, 4.07 mmol), trifluoroethanol (30 mL) and trifluoracetic acid (1.6 mL, 20.4 mmol). The resulting clear solution was stirred overnight. The next morning all precipitates were collected to afford analytically pure 6-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluorobenzamide as a white solid (1.07 g, 55% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3 H), 6.74 (s, 1 H), 7.41-7.48 (m, 3 H), 7.49-7.60 (m, 1 H), 7.64 (d, J=3.67 Hz, 1 H), 7.82 (s, 1 H), 7.96 (d, J=8.43 Hz, 3 H), 10.13 (s, 1 H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[OH:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([C:27]3[CH:28]=[C:23]([CH2:22][CH2:21][CH2:20][OH:19])[CH:24]=[CH:25][CH:26]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: OCCCc1cccc(B(O)O)c1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: OCCCc1cccc(-c2cc(-c3cccc(Cl)c3)nc3c2CCC3)c1
Yield: 30.4 %

Procedure:
A mixture of 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.070 g, 0.23 mmol), (3-(3-hydroxypropyl)phenyl)boronic acid (0.054 g, 0.30 mmol), 2M Na2CO3 (0.5 mL), and Pd(PPh3)4 (0.013 g, 0.012 mmol) in dioxane (50 mL) was heated at reflux under nitrogen for 2.5 h. After this time, the mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL), dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by silica gel chromatography eluting with 20% ethyl acetate/hexanes to 100% ethyl acetate to afford the free base of title compound (0.028 g, 34%) as a white foam. This material was redissolved in Et2O (20 mL) and 4N HCl in dioxane (0.1 mL) added. The mixture was concentrated, triturated with Et2O, and lyophilized with a water/acetonitrile/methanol mixture to afford the title compound as a white solid. MW=363.88. 1H NMR (DMSO-d6, 300 MHz) δ 8.21 (s, 1H), 8.12-8.08 (m, 1H), 7.92 (s, 1H), 7.58-7.33 (m, 6H), 3.45 (t, J=6.4 Hz, 2H), 3.16-3.01 (m, 4H), 2.74-2.69 (m, 2H), 2.19-2.08 (m, 2H), 1.83-0.83 (m, 2H); APCI MS m/z 364 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].S(Cl)(Cl)=O.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([N+:26]([O-:28])=[O:27])=[C:22]([CH:25]=1)[CH2:23]O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:1]1[CH:6]=[C:5]([C:7]([O:9][CH2:23][C:22]2[CH:25]=[C:18]([CH3:17])[CH:19]=[CH:20][C:21]=2[N+:26]([O-:28])=[O:27])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([O:12][CH2:23][C:22]1[CH:25]=[C:18]([CH3:17])[CH:19]=[CH:20][C:21]=1[N+:26]([O-:28])=[O:27])=[O:11]
Reactant: Cc1ccc([N+](=O)[O-])c(CO)c1
Reactant: O=C(O)c1ccc(C(=O)O)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])c(COC(=O)c2ccc(C(=O)OCc3cc(C)ccc3[N+](=O)[O-])nc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Analogously to Example 1, 5 g of pyridine-2,5-dicarboxylic acid are converted into the acid chloride with 40 ml of thionyl chloride in 30 ml of methylene chloride and this is reacted with 10 g of 5-methyl-2-nitro-benzyl alcohol in 50 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature, sodium bicarbonate solution is then added, the mixture is extracted with methylene chloride and the organic phase is dried, After the solvent has been stripped off, the residue is stirred with ethyl acetate, filtered off with suction and recrystallized twice from methylene chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][C:28]1([CH3:45])[CH2:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][C:30]([CH3:44])([CH3:43])[NH:29]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O.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>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:32]2[CH2:31][C:30]([CH3:44])([CH3:43])[NH:29][C:28]([CH3:45])([CH3:27])[CH:33]=2)[CH:3]=1)=[O:15]
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
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: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv), 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) in water was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the desired intermediate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:30]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4([NH:41]C(=O)OC(C)(C)C)[CH2:40][CH2:39][CH2:38]4)=[CH:33][CH:32]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]5[CH2:27][CH2:26][O:25][C@H:24]([CH2:28][OH:29])[CH2:23]5)[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:49].O1CCOCC1>C(Cl)Cl>[ClH:49].[ClH:49].[ClH:49].[NH2:41][C:37]1([C:34]2[CH:35]=[CH:36][C:31]([N:30]3[C:11]4=[N:12][C:13]([C:16]5[CH:17]=[C:18]([N:22]6[CH2:27][CH2:26][O:25][C@H:24]([CH2:28][OH:29])[CH2:23]6)[CH:19]=[CH:20][CH:21]=5)=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:32][CH:33]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(N6CCO[C@H](CO)C6)c5)nc43)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ncccc1-c1nc2ccc(-c3cccc(N4CCO[C@H](CO)C4)c3)nc2n1-c1ccc(C2(N)CCC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.3 %

Procedure:
tert-Butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-{3-[(2S)-2-(hydroxymethyl)morpholin-4-yl]phenyl}-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (4.60 mg, 0.00710 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixute and stirred at room temperature for 15 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (3.42 mg, 73.3%) as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]2[NH:18][CH2:19][CH2:20][CH2:21]O)[CH:5]=[CH:6][C:7]=1[Cl:8].S(Cl)([Cl:26])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]2[NH:18][CH2:19][CH2:20][CH2:21][Cl:26])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCCNC1=Nc2ccccc2C1(O)c1ccc(Cl)c(Cl)c1
Reactant: O=S(Cl)Cl
Product: OC1(c2ccc(Cl)c(Cl)c2)C(NCCCCl)=Nc2ccccc21

Procedure:
Reaction of 3-(3,4-dichlorophenyl)-2-(3-hydroxypropylamino)-3H-indol-3-ol with thionylchloride by a procedure analogous to that described in Example 2 gives 3-(3,4-dichlorophenyl-2-(3-chloropropylamino)-3H-indol-3-ol.
Reaction SMILES: [OH:1][C@H:2]([CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:16][CH3:17].[C:24](OC(=O)C)(=[O:26])[CH3:25].O>>[C:24]([O:1][C@H:2]([CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:16][CH3:17])(=[O:26])[CH3:25]
Reactant: COc1cc2c(=O)[nH]cnc2cc1OC[C@H](O)CN1CCCC1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc2c(=O)[nH]cnc2cc1OC[C@@H](CN1CCCC1)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
A mixture of (2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (803 mg, 2.51 mmol) in acetic anhydride (1.2 ml, 12.5 mmol) was stirred at ambient temperature for 1 hour. Water (360 μl, 20 mmol) was added and stirring was continued for 90 minutes. The mixture was partitioned between aqueous sodium hydrogen carbonate and methylene chloride. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The residue was triturated with ether, filtered and dried under vacuum to give (2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (595 mg, 65%).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[N:25]=[CH:24][NH:23][N:22]=1>CN(C=O)C>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][C:21]2[N:25]=[CH:24][NH:23][N:22]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1nc[nH]n1
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(Nc2nc[nH]n2)=C(c2ccccc2)S1(=O)=O
Yield: 3.1 %

Procedure:
A solution of 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.110 g, 0.33 mmol) and 3-amino-1,2,4-triazole (0.083 g, 0.991 mmol) in DMF (0.5 mL) was heated at 140° C. for 25 mins in a microwave reactor. The residue was purified by preparative HPLC (Column Ace C8 (5u), 0.1M NH4OAc/MeCN, gradient) to give the title compound (0.0036 g, 2.2%); 1H-NMR (500 MHz, CD3CN): δ 7.78 (s, 1H), 7.20-7.40 (m, 5H), 3.74 (t, 2H), 1.84-1.76 (m, 2H), 1.51-1.42 (m, 2H), 0.99 (t, 3H); Mass Spectrum: M+H 348.
Reaction SMILES: C(C1C=C(C=O)C(O)=C(C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)(C)C.Br[C:26]1[C:27]([OH:38])=[C:28]([CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1)[CH:29]=[O:30].[F:39][C:40]([F:55])([F:54])[C:41]1[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[CH:43][C:42]=1B(O)O>>[C:34]([C:32]1[CH:31]=[C:28]([CH:29]=[O:30])[C:27]([OH:38])=[C:26]([C:42]2[CH:43]=[CH:44][C:45]([C:47]([F:50])([F:48])[F:49])=[CH:46][C:41]=2[C:40]([F:39])([F:54])[F:55])[CH:33]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Agent: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-(tert-Butyl)-2-hydroxy-2′,4′-bis(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde was prepared as an orange oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 2,4-bis(trifluoromethyl)phenylboronic acid.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([CH2:15][O:16]C(=O)C)[O:8][CH:7]=[CH:6]1)(=O)C.C[O-].[Na+].CCOC(C)=O>CO>[O:8]1[C@H:9]([CH2:15][OH:16])[C@@H:10]([OH:11])[C@H:5]([OH:4])[CH:6]=[CH:7]1
Reactant: CC(=O)OC[C@H]1OC=C[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OC[C@H]1OC=C[C@@H](O)[C@@H]1O
Reaction time: 0.33 h

Procedure:
The Tri-O-Acetyl-D-Glucal [SM-A] (100 g, 367 mmol) is dissolved in dry MeOH [1.5 L], and then NaOMe (110 mmol, 5.95 g) is added into reaction mixture. Within about 20 minutes, TLC (40% EtOAc/60% hexanes & 100% EtOAc) confirmed de-acetylated glucal. The reaction is quenched with 50WX4 cation exchange resin until pH is near 7.0 by pH strip paper. The mixture is filtered and evaporated to dryness under vacuum to yield syrupy glucal intermediate IntA1 (59 g). Theoretical yield=100 g×(146/272)=53.7 g TLC IntA1Rf=0.1, SiO2, 100% Ethyl Acetate
Reaction SMILES: Cl.Cl.[CH:3]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][N:5]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][C:17]3[C:20]4[CH:28]=[CH:27][C:26]([O:29]C)=[C:25]([O:31]C)[C:21]=4[O:22][C:23](=[O:24])[C:16]=3[CH2:15]1)[CH2:4]2.[BrH:33]>C(O)(=O)C>[BrH:33].[BrH:33].[CH:3]12[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11]1)[CH2:6][N:5]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][C:17]3[C:20]4[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([OH:31])[C:21]=4[O:22][C:23](=[O:24])[C:16]=3[CH2:15]1)[CH2:4]2
Reactant: COc1ccc2c3c(c(=O)oc2c1OC)CN(CCN1CC2CCC(CC2)C1)CC3
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: O=c1oc2c(O)c(O)ccc2c2c1CN(CCN1CC3CCC(CC3)C1)CC2

Procedure:
Prepared by the method described in Example 19 from 3-[2-(3-azabicyclo[3.2.2]non-3-yl)ethyl]-1,2,3,4-tetrahydro-7,8-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one dihydrochloride (1.3 g, 0.0027 moles) and aqueous 48% hydrobromic acid (25 ml) plus acetic acid cosolvent (25 ml). After washing with a small amount of warm acetic acid, the final product (0.90 g) had mp 310°-313° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:22]=[N:23][N:24]([CH:26]3[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)[CH:25]=2)=[C:6]2[CH:10]=[C:9]([C:11]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:12]=3[CH:13]=[CH:14][N:15]=[CH:16]4)[O:8][C:7]=12.Cl>C(Cl)Cl>[NH:28]1[CH2:27][CH:26]([N:24]2[CH:25]=[C:21]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[C:7]4[O:8][C:9]([C:11]5[CH:20]=[CH:19][CH:18]=[C:17]6[C:12]=5[CH:13]=[CH:14][N:15]=[CH:16]6)=[CH:10][C:6]=34)[CH:22]=[N:23]2)[CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(-c3cnc(N)c4oc(-c5cccc6cnccc56)cc34)cn2)C1
Agent: Cl
Solvent: ClCCl
Product: Nc1ncc(-c2cnn(C3CNC3)c2)c2cc(-c3cccc4cnccc34)oc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 1 %

Procedure:
A solution of tert-butyl 3-{4-[7-amino-2-(isoquinolin-5-yl)furo[2,3-c]pyridin-4-yl]-1H-pyrazol-1-yl}azetidine-1-carboxylate in DCM (10 mL) was treated with HCl (4 M in 1,4-dioxane, 2.57 mL, 10.3 mmol) and stirred at RT for 16 h. The reaction was then concentrated in vacuo to a solid which was purified by MDP to afford 1.3 mg (1%) of the title compound. 1H NMR (400 MHz, CD3OD) δ 9.77 (br. s, 1H), 8.93 (d, J=6.32 Hz, 1H), 8.70 (d, J=7.33 Hz, 2H), 8.59 (d, J=8.34 Hz, 1H), 8.41 (s, 1H), 8.21 (s, 1H), 8.11 (t, J=7.96 Hz, 1H), 7.91 (d, J=4.29 Hz, 2H), 5.58 (s, 1H), 4.63 (dd, 4H); MS (ESI): 383.15 [M+H]+; HPLC tR=0.72 min (TOF: polar—3 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.Cl[C:11]1[C:16]([C:17](OCC)=[O:18])=[CH:15][N:14]=[C:13]2[CH2:22][CH2:23][CH2:24][C:12]=12>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11]([C:12]4[CH2:24][CH2:23][CH2:22][C:13]=4[NH:14][CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CCC2
Reactant: NNc1ccc(Cl)cc1
Solvent: CCCCO
Product: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CCC3

Procedure:
A mixture of 1.1 g of p-chlorophenylhydrazine and 1.9 g of ethyl 4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (Example 2a) in 100 mL of n-butanol is refluxed for 24 hours under nitrogen atmosphere. The precipitate is collected and recrystallized from ethanol to yield 2-p-chlorophenyl-2,3,5,6,7,8-hexahydrocyclopenta[b]pyrazolo[3,4-d]pyridin-3-one, m.p. above 350°, showing IR peaks at 900, 835, 805, 798, 765, and 740 cm-1.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[O:7]([CH2:14][C:15]([NH:17][C@H:18]1[C:21](=[O:22])[N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])[C@H:19]1[C:34]([O:36]C)=[O:35])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1.O>[O:7]([CH2:14][C:15]([NH:17][C@H:18]1[C:21](=[O:22])[N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])[C@H:19]1[C:34]([OH:36])=[O:35])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)[C@H]1[C@@H](NC(=O)COc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C(=O)[C@H](NC(=O)COc3ccccc3)[C@@H]2C(=O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of anhydrous K2CO3 (249 mg, 1.8 mmol) in tetrahydrofuran (8 ml) and water (12 ml) is degassed with argon and then methyl cis-3-phenoxyacetamido-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate (150 mg, 0.35 mmol) is added. The reaction is stirred 1.5 hours at room temperature, the organic solvent is evaporated and the aqueous layer is acidified and extracted with methylene chloride. The dried extracts are evaporated to give a solid which is recrystallized from ethyl acetate-hexane to give pure cis-3-phenoxyacetamido-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylic acid, mp 169°-170° (d).