Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:15][CH:16]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[CH2:40]([N:47]1[CH:51]=[C:50](B2OC(C)(C)C(C)(C)O2)[CH:49]=[N:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:40]([N:47]1[CH:51]=[C:50]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[CH:13][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[N:15][CH:16]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[CH:49]=[N:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Yield: 48.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (Intermediate 66K) (200 mg, 0.3 mmol) was coupled with 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 15) (103 mg, 0.36 mmol) using sodium carbonate (95 mg, 0.9 mmol) and Pd(dppf)Cl2 (11 mg, 0.015 mmol) in toluene/ethanol/water (4/4/2 mL) to afford 100 mg (47.8% yield) of the titled compound after purification by column (Silica gel 60/120) using 30% ethyl acetate in hexane as eluent. MS: m/z=690.3 (M+1).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:16]=[N:15][C:14]3[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]2=3)C=CC=CC=1.[Cl:31][CH2:32][CH2:33][O:34][CH2:35]Cl>CN(C=O)C>[Cl:31][CH2:32][CH2:33][O:34][CH2:35][N:15]1[C:14]2[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]=2[N:8]=[CH:16]1
Reactant: Nc1nc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Reactant: ClCCOCCl
Solvent: CN(C)C=O
Product: Nc1nc2ncn(COCCCl)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
To a solution of 6 (1.77 g, 4.49 mmol) in DMF (30 mL) was added (2-chloroethoxy)methyl chloride (0.65 g, 5.0 mmol). The reaction mixture was stirred at 25° C. for 8.0 h. The solution was then partitioned between EtOAc (100 mL) and water (100 mL). The EtOAc solution was washed with water (4×100 mL); then it was dried over MgSO4 (s) and filtered. Evaporation under reduced pressure and purification of the residue by use of column chromatography (EtOAc) afforded 7 (1.07 g, 4.39 mmol) in 88%: mp>280° C. (dec.); Rf(hexanes/EtOAc=1:2) 0.20; UV (EtOH) λmax 288 (ε 15,100); 1H NMR (DMSO-d6) δ 3.67 (t, J=6.10 Hz, 2 H, CH2Cl), 3.75 (t, J=6.10 Hz, 2 H, OCH2), 5.62 (s, 2 H, H2C1′), 6.15 (s, 2 H, NH2), 7.58 (s, 1 H, NH), 8.16 (s, 1 H, HC8); 13C NMR (DMSO-d6) δ 43.39 (CH2Cl), 68.50 (OCH2) 74.71 (C1′), 107.71 (C5), 143.87 (C8), 153.15 (C4), 154.37 (C2), 159.12 (C6); MS m/z 243 (M+, Cl-cluster). Anal (C8H10ClN5O2) C, H, N, Cl; calcd (%): 39.43, 4.14, 28.74, 14.56; found (%): 39.38, 4.13, 28.70, 14.45.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[N:8](C)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)=[CH:13][C:12]([Cl:23])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[C:26](=O)([O-])[O-:27].[Na+].[Na+].OCCN1CCNCC1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:26][OH:27])[CH2:18][CH2:17]1)=[CH:13][C:12]([Cl:23])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C)CC2)c2cc(Cl)ccc2n(C)c1=O
Reactant: O=C([O-])[O-]
Agent: OCCN1CCNCC1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N2CCN(CCO)CC2)c2cc(Cl)ccc2[nH]c1=O

Procedure:
A stirred mixture of 6.09 g. of 4,6-dichloro-1,2-dihydro-1-methyl-2-oxo-3-quinolinecarboxylic acid ethyl ester (prepared as in Example 4), 2.12 g. of sodium carbonate, and 2.6 g. of N-2-hydroxyethylpiperazine in 50 ml. of ethanol was heated under reflux for 3 hours. The reaction mixture was filtered under suction and the filtrate taken to dryness in a rotary evaporator. On triturating the residual oil with diethyl ether gave 6.0 g. of product, m.p. 130°-134° C. Recrystallization from ethyl acetate gave 4.4 g. of the title compound, m.p. 135°-138° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.[Br:23][C:24]1[S:25][C:26](Br)=[N:27][N:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>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.O>[Br:23][C:24]1[S:25][C:26]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]=2)=[N:27][N:28]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Brc1nnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2nnc(Br)s2)CC1
Temperature: 100 °C
Yield: 46.2 %

Procedure:
To a 5 mL microwave vial was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (247 mg, 0.8 mmol), 2,5-dibromo-1,3,4-thiadiazole (98 mg, 0.4 mmol), K3PO4 (212 mg, 1.0 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), 1,4-dioxane (2 mL), and water (0.4 mL). The mixture was purged with N2 for 10 min, then heated to 100° C. in the microwave for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/Heptane) to afford 64 mg (46%) of tert-butyl 4-(5-bromo-1,3,4-thiadiazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate: MS (M+2)=348.1; 1H NMR (400 MHz, CHLOROFORM-d) δ 6.46 (td, J=3.0, 1.9 Hz, 1H), 4.15 (d, J=3.0 Hz, 2H), 3.64 (t, J=5.6 Hz, 2H), 2.73 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:4]=[C:5]([N:10]2[C:14](=[O:15])[O:13][N:12]=[C:11]2[C:16]2[C:17]([NH:21][CH2:22][CH2:23][NH:24]C(=O)OC(C)(C)C)=[N:18][O:19][N:20]=2)[CH:6]=[CH:7][C:8]=1[F:9]>C(OCC)(=O)C>[ClH:1].[NH2:24][CH2:23][CH2:22][NH:21][C:17]1[C:16]([C:11]2[N:10]([C:5]3[CH:6]=[CH:7][C:8]([F:9])=[C:3]([Br:2])[CH:4]=3)[C:14](=[O:15])[O:13][N:12]=2)=[N:20][O:19][N:18]=1
Reactant: CC(C)(C)OC(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 248.6 %

Procedure:
In a 22 L flask was charged hydrogen chloride (4 N solution in 1,4-dioxane, 4 L, 16 mol). tert-Butyl [2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)ethyl]carbamate (2315 g, 4.77 mol) was added as a solid in portions over 10 min. The slurry was stirred at room temperature and gradually became a thick paste that could not be stirred. After sitting overnight at room temperature, the paste was slurried in ethyl acetate (10 L), filtered, re-slurried in ethyl acetate (5 L), filtered, and dried to a constant weight to afford the desired product as a white solid (combined with other runs, 5 kg starting material charged, 4113 g, 95%). LCMS for C12H11BrFN6O3 (M+H)+: m/z=384.9, 386.9. 1H NMR (400 MHz, DMSO-d6): δ 8.12 (m, 4H), 7.76 (m, 1H), 7.58 (t, J=8.7 Hz, 1H), 6.78 (t, J=6.1 Hz, 1H), 3.51 (dd, J=11.8, 6.1 Hz, 2H), 3.02 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].BrBr.[CH3:14][OH:15]>C(O)(=O)C>[CH3:14][O:15][CH2:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: Cc1[nH]c2ncccc2c1C
Reactant: CO
Agent: BrBr
Solvent: CC(=O)O
Product: COCc1[nH]c2ncccc2c1C

Procedure:
2,3-dimethylpyrrolo[2,3-b]pyridine 0,5 g (0.0034 mol) was treated in 7 ml acetic acid with an equimolecular amount of bromine and after 5 min a yellow precipitate was formed. The solid was filtred off and treated with 20 ml methanol. The mixture was refluxed for 30 min. and was then evaporated. The residue was partitioned between methylene chloride and bicarbonate solution. The organic layer was separated dried over Na2SO4 and evaporated. The residue was treated with boiling petroleumether (60-80) which was decantated and allowed to cool. The precipitated product was filtred off affording 0,13 g (22%) as white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:9]([C:10](OCC)=[O:11])=[CH:8][C:7]2[CH2:15][C:16]([CH3:19])([CH3:18])[CH2:17][C:6]1=2.[O-]CC.[Na+]>C(O)C>[CH3:18][C:16]1([CH3:19])[CH2:15][C:7]2[CH:8]=[C:9]3[N:5]([CH2:4][CH2:3][NH:2][C:10]3=[O:11])[C:6]=2[CH2:17]1
Reactant: CCOC(=O)c1cc2c(n1CCN)CC(C)(C)C2
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC1(C)Cc2cc3n(c2C1)CCNC3=O
Temperature: 55 °C
Yield: 23.1 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with crude 103d (˜18 mmol), sodium ethoxide (6.2 g, 92 mmol) and ethanol (120 mL). The mixture was stirred at 55° C. over night. After that time, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (200 mL) and water (100 mL). The solution was filtered. The solid was washed with ethyl acetate (15 mL) to give 850 mg of desired product 103e. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to near dryness. The solution was filtered and the solid (1.44 g) was washed with ethyl acetate (15 mL). The combined solids were dried under vacuum a afford 61% yield (2.3 g) of 103e.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:20]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCCl.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH:20]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C2CCCCCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: c1ccc(N2CCNCC2)c(C2CCCCCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of the crude product of 4-(2-cyclooctylphenyl)piperazine-1-carboxylic acid t-butyl ester produced in Example (46c), 1,2-dichloroethane (2 mL) and water (0.2 mL) was added trifluoroacetic acid (0.500 mL, 6.490 mmol), followed by stirring for 5 hours and 30 minutes at room temperature. Aqueous solution of potassium carbonate was added to the mixture to make the mixture basic. Ethyl acetate was then added thereto and extraction was performed three times with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 75 mg of the title compound as a light yellow oil.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][OH:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.F[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]>C1COCC1>[N+:22]([C:13]1[CH:14]=[C:15]([C:18]([F:19])([F:20])[F:21])[CH:16]=[CH:17][C:12]=1[O:10][CH2:9][CH2:8][N:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: OCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1OCCN1CCCC1

Procedure:
To a suspension of NaH (60%, 248 mg, 6.21 mmol) in dry THF was added 2-Pyrrolidin-1-yl-ethanol (0.68 mL, 5.74 mmol). Bubbling was observed. The reaction was stirred for 5 minutes, at which time 1-Fluoro-2-nitro-4-trifluoromethyl-benzene (0.67 mL, 4.79 mmol) was added. The solution turned red, and LCMS indicated completion of the reaction. The reaction was quenched by addition of H2O, and the mixture was extracted with EtOAc, dried with MgSO4, filtered, and concentrated to afford the title compound as an orange oil.
Reaction SMILES: [CH2:1]([CH:4]1[N:10]2[C:11](=[O:14])[O:12][N:13]=[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].B.C(=O)(O)[O-:17].[Na+].OO>O1CCCC1.CO>[OH:17][CH2:3][CH2:2][CH2:1][CH:4]1[N:10]2[C:11](=[O:14])[O:12][N:13]=[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C=CCC1CCCCc2noc(=O)n21
Reactant: O=C([O-])O
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=c1onc2n1C(CCCO)CCCC2
Reaction time: 2 h

Procedure:
A solution of the product of Example 6 (3.0 g, 0.0155 mol) in tetrahydrofuran (44 mL) under nitrogen was treated with a Borane.THF complex (1M, 18.56 mL) and this reaction was stirred for 2 hours. Methanol (2.50 mL) was added before a solution of saturated sodium bicarbonate (2.32 mL) and hydrogen peroxide (30%, 2.32 mL) were added resulting in a white precipitate. The precipitate was filtered off and the solvent was removed from the filtrate under reduced pressure to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([C:26]#[N:27])=[CH:21][C:20]=2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[N:6][C:7]=1[Cl:8].O1CCCC1.[N:34]1([CH2:39][CH2:40][NH2:41])[CH2:38][CH2:37][CH2:36][CH2:35]1.Cl.C(OCC)C>CC#N.C(Cl)Cl>[ClH:8].[Br:1][C:2]1[C:3]([O:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([C:26]#[N:27])=[CH:21][C:20]=2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[N:6][C:7]=1[NH:41][CH2:40][CH2:39][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: NCCN1CCCC1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(Cl)c1Br
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(NCCN2CCCC2)c1Br
Temperature: 75 °C
Yield: 50.6 %

Procedure:
4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]-benzonitrile (0.000660 mol), tetrahydrofuran (1 ml), and 1-pyrrolidineethanamine (0.00198 mol) were added to a pressure vessel. The mixture was heated at 75° C. for 16 hours. CH2Cl2 was added, and the mixture was washed with water, dried, filtered and the filtrate was evaporated. Purification using flash column chromatography eluting with 1:9 methanol:methylene chloride produced a solid which was redissolved in CH3CN. HCl/diethylether 1.0M (0.48 ml) was added, and the mixture was cooled in ice. Filtration yielded 0.19 g of 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-[(1-pyrrolidinyl)ethylamino]-2-pyrimidinyl]amino]benzonitrile hydrochloride (1:1) (50.6%); mp. 208–210° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:53]=[N:54][C:55]([CH3:58])=[CH:56][CH:57]=2)[C:47]1=[O:59])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:53]=[N:54][C:55]([CH3:58])=[CH:56][CH:57]=2)[C:47]1=[O:59])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: Cc1ccc(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)cn1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccc(C)nc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.9 %

Procedure:
A solution containing the product from Example 2C (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 83A (0.025 g, 0.082 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.033 mL, 0.189 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (0.014 g, 45% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (s, 9 H), 0.88 (s, 9 H), 1.25 (m, 1 H), 1.54 (m, 2 H), 2.32 (m, 1 H), 2.45 (s, 3 H), 2.63 (m, 2 H), 2.89 (m, 3 H), 3.18 (m, 1 H), 3.50 (s, 3 H), 3.66 (m, 1 H), 3.85 (d, J=9.93 Hz, 1 H), 4.13 (m, 3 H), 4.30 (s, 2 H), 4.55 (d, J=7.35 Hz 1 H), 6.65 (d, J=9.56 Hz, 1 H), 7.07 (m, 5 H), 7.28 (m, 4 H), 7.54 (m, 2 H), 7.86 (m, 5 H), 8.37 (d, J=1.84 Hz, 1 H), 8.63 (d, J=4.41 Hz, 1 H).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)[NH2:3].[C:13](/[C:15](=[CH:21]\OCC)/[C:16]([O:18]CC)=[O:17])#[N:14].C([O-])(=O)C.[Na+].[OH-].[Na+]>CN(C=O)C.O>[O:8]=[C:6]1[C:5]2[C:4](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:2]2[N:3]=[CH:21][C:15]([C:16]([OH:18])=[O:17])=[C:13]2[NH:14]1
Reactant: CCO/C=C(\C#N)C(=O)OCC
Reactant: NNc1ccccc1C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cnn2c1[nH]c(=O)c1ccccc12
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of 2-hydrazinylbenzoic acid hydrochloride (1.05 g, 5.57 mmol), (E)-ethyl 2-cyano-3-ethoxyacrylate (0.9 g, 5.32 mmol) and sodium acetate (0.457 g, 5.57 mmol) in DMF (7 mL) was heated to 140° C. for 2 h then cooled. Water (5 mL) was added and the mixture was stirred at rt for 1 h then filtered. The solid was washed with H2O, EtOH and Et2O then dried. The solid was dissolved in EtOH (10 mL), treated with a 1M solution of sodium hydroxide (23 mL, 23 mmol) and the mixture was heated at 80° C. for 18 hr. The mixture was filtered hot then cooled and acidified with acetic acid and 10% HCl. The precipitated product was filtered, washed with H2O and Et2O, dried well and used without any further purification.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:27][CH3:28])=[O:4].[CH:35]1([CH2:40][CH2:41]O)[CH2:39][CH2:38][CH2:37][CH2:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH:35]1([CH2:40][CH2:41][O:25][C:22]2[CH:21]=[CH:20][C:19]([C@H:17]3[CH2:16][O:15][C:11]4=[CH:12][C:13]5[CH2:14][C@@H:5]([C:3]([OH:2])=[O:4])[N:6]([C@H:26]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)[CH2:27][CH3:28])[CH2:7][C:8]=5[CH:9]=[C:10]4[O:18]3)=[CH:24][CH:23]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: OCCC1CCCC1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2CC1C(=O)OC)OC[C@H](c1ccc(O)cc1)O3
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCCC2CCCC2)cc1)O3
Temperature: 25 °C

Procedure:
(S)-3-(4-Hydroxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (20 mg) was dissolved in DCM and cyclopentane-ethanol (5 eq.), triphenyl phosphine (5 eq.) and DIAD (4.5 eq.) added. The reaction mixture stirred at room temperature and was directly purified over silica (hexanes to 9:1 hexanes EtOAc to 7:3 hexanes EtOAc). This ester was hydrolyzed according to General Procedure AB to give (3S,8S)-3-[4-(2-cyclopentyl-ethoxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid. This acid was coupled with (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester di hydrochloride according to General Procedure L to give (S)-2-{[(3S,8S)-3-[4-(2-cyclopentyl-ethoxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester. This ester was hydrolyzed according to General Procedure B to give the title compound (5 mg). LCMS (m/z): 811.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]4[C:24]([O:26][C:27](=O)[C:20]=4[CH:19]=3)=[O:25])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:29]1([CH:36]=[CH:35][C:33]([OH:34])=[CH:32][CH:31]=1)[OH:30].C(O)(=O)C(O)=O>>[OH:30][C:29]1[C:36]2[C:24](=[O:25])[C:21]3[C:20](=[CH:19][C:18]([C:15]4[CH:14]=[CH:13][C:12]([C@H:9]5[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]5)=[CH:17][CH:16]=4)=[CH:23][CH:22]=3)[C:27](=[O:26])[C:35]=2[C:33]([OH:34])=[CH:32][CH:31]=1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc4c(c3)C(=O)OC4=O)cc2)CC1
Reactant: Oc1ccc(O)cc1
Agent: O=C(O)C(=O)O
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc4c(c3)C(=O)c3c(O)ccc(O)c3C4=O)cc2)CC1

Procedure:
1.2 g of 4'-(trans-4-n-pentylcyclohexyl)-biphenyl-3,4-dicarboxylic acid anhydride, 2.0 g of hydroquinone and 10 g of oxalic acid are heated for 2 hours to 220°. After cooling, the 1,4-dihydroxy-6-[4-(trans-4-n-pentylcyclo-hexyl)-phenyl]-anthraquinone obtained is purified by recrystallization from ethanol.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)[CH3:2].C([Li])CCC.CCCCCC.CN(C)[CH:21]=[O:22].[Cl-].[NH4+]>C(OCC)C>[CH2:1]([C:3]1[CH:7]=[C:6]([CH:21]=[O:22])[S:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccsc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CCc1csc(C=O)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
3-Ethylthiophene (2 g, 17.8 mmol) dissolved in diethyl ether (18 ml) was added with a solution of n-butyl lithium in hexane (1.5 M, 14 ml, 21.4 mmol) at room temperature and refluxed by heating at 60° C. for 15 minutes. The reaction solution was returned to room temperature and added dropwise with dimethylformamide (2 ml, 23.2 mmol) dissolved in diethyl ether. After the reaction solution was stirred for 2 hours at room temperature, the reaction was stopped with saturated aqueous ammonium chloride, and the reaction solution was extracted with chloroform. The collected organic layer was washed with saturated brine, then dried over magnesium sulfate and concentrated under reduced pressure.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([C:35]([O:37][CH3:38])=[O:36])[CH:28]=[C:29]([CH:34]=1)[C:30]([O:32][CH3:33])=[O:31]>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:34]=[C:29]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=[C:27]([CH:26]=1)[C:35]([O:37][CH3:38])=[O:36])#[N:7]
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Reactant: CNCCc1cc(C(=O)OC)cc(C(=O)OC)c1
Product: COC(=O)c1cc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc(C(=O)OC)c1

Procedure:
Reaction of 1f with 2i produced 3ai. MS found M+H=511. The oxalate salt of 3ai was recrystallized from hexane/ethyl acetate; mp 100-103° C.