Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.[H-].[Na+].Cl.Cl[CH2:15][C:16]1[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=1.O>CN(C)C=O>[CH3:22][C:21]1[C:16]([CH2:15][S:1][C:2]2[NH:3][C:4]3[C:5]([N:10]=2)=[N:6][CH:7]=[CH:8][CH:9]=3)=[N:17][CH:18]=[C:19]([CH3:25])[C:20]=1[O:23][CH3:24]
Reactant: COc1c(C)cnc(CCl)c1C
Reactant: Sc1nc2ncccc2[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C)cnc(CSc2nc3ncccc3[nH]2)c1C
Reaction time: 0.5 h

Procedure:
1.5 Grams of 2-mercaptoimidazo[4,5-b]pyridine was dissolved in 50 ml of dimethylformamide, to this solution was added, under ice-cooled condition, 0.88 g of 60% sodium hydride (in oil), and the mixture was stirred at the same temperature for 30 minutes. Then, to this reaction mixture was added 2.2 g of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride and the whole mixture was heated at 70° to 80° C. under stirring condition for 3 hours. After the reaction was completed, dimethylformamide was removed by evaporation, and to the residue thus obtained was added water, and then extracted with chloroform. The chloroform extract was washed with water, and dried with anhydrous magnesium sulfate. Chloroform was removed by evaporation, then the residue thus obtained was recrystallized from ethanol to obtain 1.3 g of 2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylthio]-imidazo[4,5-b]pyridine in the form of white powdery crystals. Melting point: 186°-188° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C.C1(C)C=CC=CC=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:19][C:14](=[O:16])[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Temperature: 25 °C

Procedure:
In 15 mL of ethyl acetate was suspended 5.0 g (18.73 mmol) of N-benzyloxycarbonyl-L-aspartic acid (compound B′). This solution was stirred at room temperature in a nitrogen atmosphere. Thereto was added dropwise 1.76 g of acetyl chloride (98%, 22.48 mmol). The mixture was stirred at 60° C. for 2 hours. After completion of the reaction, 50 mL of toluene and 6 mL of dimethylformamide were added to the reaction mixture. The resultant mixture was heated to 90 to 103° C. to remove 20 mL of volatile ingredients including the ethyl acetate and the excess acetyl chloride by azeotropic distillation. The N-benzyloxycarbonyl-L-aspartic anhydride (compound 1) thus yielded was subjected to the subsequent step without being taken out. To the reaction mixture was added dropwise 2.0 g (18.69 mmol) of benzylamine at 44 to 54° C. Thereafter, a Dean Stark condenser was attached to the reactor, and the reaction mixture was heated with refluxing and stirring for 30 minutes. After the reaction mixture was cooled, 0.36 g (18.95 mmol) of p-toluenesulfonic acid monohydrate was added thereto and this mixture was heated at 110° C. with refluxing for 8 hours to conduct azeotropic dehydration (reaction yield, 80%; optical purity, 94%ee). The resultant reaction mixture was cooled and then, while being kept at 70° C., subjected twice to washing with 10 mL of saturated aqueous sodium hydrogen carbonate solution and then once to washing with 10 mL of saturated aqueous sodium chloride solution, followed by liquid separation each time. Subsequently, the organic layer obtained was heated with refluxing for 30 minutes to conduct azeotropic dehydration and then cooled to cause crystallization. Crystals began to separate out at 65° C. The organic layer was stirred for 1 hour with cooling to 20° C. and then further stirred at 10° C. or lower for 30 minutes. The crystals formed were isolated by filtration, washed with 20 mL of toluene, and then vacuum-dried to obtain 4.64 g of white crystals (13.73 mmol; isolation yield, 71.1%). The solid obtained was ascertained to be (3S)-1-benzyl-3-benzyloxycarbonylaminopyrrolidine-2,5-dione (compound 2′) by 1H-NMR spectroscopy. Analysis by HPLC revealed that this reaction product had a chemical purity of 100% and an optical purity of 100%ee.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:21]=[CH:20][C:16]([CH2:17][C:18]#[N:19])=[CH:15][CH:14]=2)[CH2:5][CH2:4]1)=O.[N:22]([C:24]1[C:25]([NH2:32])=[N:26][C:27]([NH2:31])=[N:28][C:29]=1[NH2:30])=O.C(OCC[O-])C.[Na+].[OH-].[Na+]>C(OCCO)C.CCOCC>[N:6]1([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]3[N:22]=[C:24]4[C:25](=[N:32][C:18]=3[NH2:19])[N:26]=[C:27]([NH2:31])[N:28]=[C:29]4[NH2:30])=[CH:20][CH:21]=2)[CH2:5][CH2:4][NH:3][CH2:8][CH2:7]1
Reactant: Nc1nc(N)c(N=O)c(N)n1
Reactant: N#CCc1ccc(NCCCN2CCN(C=O)CC2)cc1
Agent: CCOCC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOCCO
Product: Nc1nc(N)c2nc(-c3ccc(NCCCN4CCNCC4)cc3)c(N)nc2n1
Reaction time: 2.5 h
Yield: 64.8 %

Procedure:
A mixture of 4-[3-(4-formyl-1-piperazinyl)propylamino]benzylcyanide (1.15 g, 4.0 mmol), 5-nitroso-2,4,6-triamino-pyrimidine (0.56 g, 3.6 mmol) and 0.2N sodium-(2-ethoxy-ethoxide) in 2-ethoxyethanol (18 ml) was stirred under reflux for 3 hours, then NaOH (0.14 g, 3.5 mmol) was added and stirring under reflux was continued for further 2.5 hours. After cooling the mixture was diluted with 100 ml of ether. The separated precipitate was collected, washed with ether, then with water and dried to afford the title compound (0.92 g) as a yellow powder, yield: 64.8%. The above product was dissolved in a hot solution of L(+)-tartaric. acid (0.75 g, 5 mmol) in water (6 ml) and after cooling the mixture was diluted with methanol (6 ml). The separated crystals were collected, washed with methanol and dried to give the ditartrate of the title compound, mp. 170°-178° C. Yield of the salt formation: 51.9%.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][CH2:6]2.[OH-].[K+].Cl[CH2:14][CH:15]([OH:21])[CH2:16][NH:17][CH:18]([CH3:20])[CH3:19]>>[CH:18]([NH:17][CH2:16][CH:15]([OH:21])[CH2:14][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][CH2:6]2)([CH3:20])[CH3:19]
Reactant: CC(C)NCC(O)CCl
Reactant: Oc1cccc2c1C=CC2
Agent: [K+]
Agent: [OH-]
Product: CC(C)NCC(O)COc1cccc2c1C=CC2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 0.44 g. of 4-hydroxyindene in 4 ml. of an aqueous 10% potassium hydroxide solution there was added 0.65 g. of 1-chloro-2-hydroxy-3-isopropylaminopropane. After stirring the resulting mixture at room temperature for 15 hours, the reaction mixture was extracted with ether, the ether extract was dried with anhydrous sodium carbonate and the ether was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography using acetone as eluent, and 0.23 g. of white crystals of 4-(3-isopropylamino-2-hydroxypropoxy)indene was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]4[CH:17]([C:7]=3[C:6]=2[CH:5]=[C:4]([CH3:18])[CH:3]=1)[CH2:16][CH2:15][CH2:14]4.[H-].[Na+].[O:21]1[CH2:23][CH:22]1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH3:1][C:2]1[C:10]2[N:9]([CH2:23][CH:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[OH:21])[C:8]3[CH2:11][CH2:12][N:13]4[CH:17]([C:7]=3[C:6]=2[CH:5]=[C:4]([CH3:18])[CH:3]=1)[CH2:16][CH2:15][CH2:14]4
Reactant: Cc1cc(C)c2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: c1cc(C2CO2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(c1)c1c(n2CC(O)c2ccncc2)CCN2CCCC12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 18.9 %

Procedure:
8,10-Dimethyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (700 mg, 2.92 mmol) in DMF (20 mL) was stirred at 0° C. for 5 min. NaH (580 mg, 14.60 mmol) was added slowly at 0° C. After 10 min. stirring, 4-(oxiran-2-yl)pyridine (710 mg, 5.87 mmol) was added and the reaction mixture was stirred at RT for 15 h. The reaction mixture was poured in ice-cold water (150 mL) and extracted with EtOAc (3×200 mL). The combined organic layer was washed with water (6×300 mL), dried over anhydrous sodium sulfate and concentrated to obtain semi-solid residue that was washed with hexane (3×20 mL). The residue was suspended in ether (30 mL) stirred for 1 h. The suspension was filtered to give 200 mg of 2-(8,10-dimethyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)-1-(pyridin-4-yl)ethanol. 1H NMR (CD3OD, HCl salt) δ (ppm): 8.79 (d, 2H), 8.03 (d, 2H), 7.13 (s, 1H), 6.82 (s, 1H), 5.22 (dd, 1H), 5.01 (t, 1H), 4.67 (dd, 1H), 4.48 (dd, 1H), 4.79 (m, 1H), 3.64 (t, 2H), 3.4 (m, 3H), 2.9 (m, 1H), 2.73 (s, 3H), 2.37 (s, 3H), 2.22 (m, 3H). Separation by chiral HPLC provided diastereomers II-125a-b.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)(OC(C)(C)C)=O.Br[C:27]1[C:28]([Cl:33])=[N:29][CH:30]=[CH:31][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+].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.CCOC(C)=O.O>[Cl:33][C:28]1[C:27]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][N:9]=[CH:10]3)=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Clc1ncccc1Br
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: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Clc1ncccc1-c1ccc2[nH]ncc2c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
A single necked round bottom flask equipped with a magnetic stir bar was charged with 1-Boc-indazole-5-boronic acid pinacol ester (3.0 g, 8.7 mmol), 3-bromo-2-chloropyridine (2.0 g, 10.4 mmol), Pd(PPh3)4 (1 g, 0.86 mmol) and 2M aq. Na2CO3 (10 mL, 20 mmol) and 1,4-dioxane under nitrogen atmosphere. The reaction flask was fitted with a reflux condenser containing three-way stopcock equipped with argon filled balloon. The reaction contents were stirred and air was removed from the closed reaction system by vacuum and back filled with argon. Following three cycles of degassing, the reaction mixture was heated at 100° C. (oil-bath) under argon. Initial clear heterogeneous reaction mixture turned to clear biphasic off-yellow solution. After 12 h with no additional change in the proportion of the product, as analyzed by LC/MS, the reaction mixture was cooled to room temperature. Upon concentration of the reaction mixture, EtOAc/water (200 mL/100 mL) was transferred to the concentrate and stirred for 30 min. The organic layer was separated and the aqueous layer extracted with EtOAc (2×75 mL). MgSO4 and Celite® were added to combined organic layers, stirred for 20 min and the contents suction filtered. The filter cake was washed with EtOAc (100 mL) and the combined filtrates concentrated by rotary evaporator under vacuum. The crude concentrate was dissolved in 1% MeOH/CH2Cl2 and absorbed on silica gel (20g) by evaporating the solvent followed by drying. Subsequent purification by flash silica gel column purification of the dry powder (Combiflash® companion System® with RediSep® silica gel column 120 g, 30-70% EtOAc/hexanes eluting solvent) provided 5-(2-chloropyridin-3-yl)-1H-indazole (1.0 g, 50%) as a white crystalline solid after concentration of the desired product fractions. 1H NMR (DMSO-d6): δ 13.2 (s, 1H), 8.41 (dd, 1H, J=1.8 and 4.7 Hz), 8.13 (s, 1H), 7.90 (dd, 1H, J=1.7 and 4.7 Hz), 7.84 (s, 1H), 7.62 (d, 1H, J=8.8 Hz), 7.51 (dd, 1H, J=4.7 and 7.3 Hz), 7.42 (dd, 1H, J=1.4 and 8.5 Hz). LCMS: 95%, MS (m/e) 230 (MH+).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([OH:20])[C:11]1=[CH2:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].[NH4+].[Cl-]>CO>[Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@@H:12]([OH:20])[C:11]1=[CH2:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=C1[C@@H](O)[C@@H]2OC(C)(C)O[C@@H]2[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: C=C1[C@H](O)[C@@H]2OC(C)(C)O[C@@H]2[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a stirred solution of allylic alcohol 11 (4 g, 12.7 mmol) was added dess marline (8.1 g, 19.7 mmol) at 0° C. The mixture was warm to ambient temperature and stirred for 1 hr. The mixture was passed through celite bed and obtained filtrate was concentrated under reduced pressure to give crude allylic ketone, which was proceeded as such in next step without further purification. The crude allylic ketone (3.5 g, 11.1 mmol) was dissolved in anhydrous methanol, cooled the solution at −78° C. Added CeCl3.7H2O (5.8 g, 15.6 mmol) at −78° C. and after 10 minutes stirring NaBH4 (0.54 g, 14.5 mmol) was added at one portion. After 15 min stirring at −78° C., the reaction mixture was allowed to 0° C. then saturated NH4Cl (30 mL) was added and the mixture was allowed to stir for 1 hr. Solvent was removed under reduced temperature and pressure and the residue was extracted with DCM (200 mL×2). The combined DCM extracts were washed with brine (40 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash silica gel column chromatography (5% EtOAc/hexane) to give compound 12 (3.2 g, 80%) as oil. [α]22D −96.878° (c 2.01, CHCl3); 1H NMR (500 MHz, CDCl3) δ 5.26(s, 1H), 5.10 (s, 1H), 4.52 (m, 2, 3- H's, 2H), 4.4 (m, 1H, 1-H′), 3.71 (dd, J=4 & 10 Hz, 1H, 5- Ha), 3.53 (dd, J=4 & 10 Hz, 5- Hb, 1H), 2.57 (br, 1H), 2.29 (d, J=10.5 Hz, D2O exchange, OH), 1.38 (s, 3H), 1.30 (s, 3H), 0.85 (m, 9H), 0.013-0.006 (m, 6H). 13C NMR(125 MHz, CDCl3) 159.01, 115.9, 115.4, 86.85, 84.85, 79.48, 71.63, 57.21, 32.13, 31.54, 30.33, 23.83, 0.015; HR-MS Calcd. For (C16H30O4Si+H)+ 315.1913, found 315.1987.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:20]=[C:19]3[C:13]([CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18]3)=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl>O1CCOCC1.CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:20]=[C:19]3[C:13]([CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(S(C)(=O)=O)cc3)nc2CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CS(=O)(=O)c1ccc(-n2cc3c(n2)CCNCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl 2-[4-(methylsulfonyl)phenyl]-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 32) (10 mg, 0.03 mmol) in dioxan (1 ml) was added 4M hydrochloric acid in dioxan (2 ml). The resulting mixture was stirred at room temperature, under argon, overnight. The reaction mixture was diluted with methanol and then purified by SCX, eluting with methanol and then 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (D38). MS (ES+) m/e 292 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C1(N)CCCCCC1>C(O)(=O)C>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:24]1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: NC1CCCCCC1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1C1CCCCCC1
Yield: 93 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (80 mg, 0.34 mmol), triethyl orthoformate (0.65 ml), cycloheptylamine (0.08 ml, 0.63 mmol), and acetic acid (0.08 ml) were used to give 103 mg (0.32 mmol, 93% yield) of the title compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)O1.Br[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([Br:27])=[CH:20][N:19]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.CCO>[Br:27][C:21]1[CH:22]=[C:23]([N+:24]([O-:26])=[O:25])[C:18]([C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[N:19][CH:20]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
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: CCO
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Br)cnc1-c1ccc(O)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (300 mg, 1.36 mmol), 2,5-dibromo-3-nitropyridine (383 mg, 1.36 mmol), tetrakis(triphenylphosphine)palladium (31 mg, 0.027 mmol), Na2CO3 (4.3 mL, 2 M aqueous), 4.3 mL toluene, and 2.1 mL EtOH was vigorously stirred at 55° C. for 2 h. After cooling to rt, the volatiles were removed under reduced pressure and the residue was purified with silica chromatography (EtOAc in hexane, 5% to 35%) to afford 4-(5-bromo-3-nitropyridin-2-yl)phenol as a yellow wax (285 mg, 71%). MS (ESI) m/z [M+H]+295, 297.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=2)[CH:5]=[C:4]([Br:17])[CH:3]=1.C(OC1C=C(C=CC=1)CN)C1C=CC=CC=1.[C:34]([O:38][C:39]([NH:41][C@H:42]([C:47](O)=[O:48])[CH2:43][CH2:44]SC)=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[Br:17][C:4]1[CH:3]=[C:2]([N:1]2[CH2:44][CH2:43][C@H:42]([NH:41][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[C:47]2=[O:48])[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH:10]=2
Reactant: CC(C)(C)Oc1ccc2cc(Br)cc(N)c2c1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: NCc1cccc(OCc2ccccc2)c1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2cc(Br)cc3ccc(OC(C)(C)C)cc23)C1=O

Procedure:
Following the procedures described in Example 1, Steps J-L, but using 1-amino-3-bromo-7-tert-butoxynaphthalene, as described in Example 46, Step H, in place of 3-benzyloxybenzylamine, and (S)-N-(tert-butoxycarbonyl)methionine in place of (R)-N-(tert-butoxycarbonyl)methionine in Step J, the above-titled compound was obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[C:18]1([CH2:24][O:25][C:26]([NH:28][CH:29]=[CH2:30])=[O:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C12CCCC(CCC1)B12[H]B2(C3CCCC2CCC3)[H]1.[OH-].[Na+].OO>Cl[Pd]Cl.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]>[CH3:17][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:30][CH2:29][NH:28][C:26]([O:25][CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:27])=[CH:3][CH:4]=1)[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(I)cc1
Reactant: C=CNC(=O)OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: OO
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(CCNC(=O)OCc2ccccc2)cc1
Yield: 35 %

Procedure:
Scheme Va, step A: 2-(4-iodophenyl) propyl isopropylsulfonamide (1.5 g, 4.1 mmol), (phenylmethoxy)-N-vinylcarboxamide (0.87 g, 4.9 mmol, prepared in example 6), 9-BBN dimer (1.3 g, 5.3 mmol), [1,1′bis(diphenylphosphino)-ferrocene] dichloropalladium (II), PdCl2(dppf) (0.17 g, 0.2 mmol), 3N sodium hydroxide (3 mL), and pH=7 buffer: hydrogen peroxide (2:1, 15 mL) were combined in a manner analogous to the procedure described in example 6 to provide the intermediate title compound, N{2-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]ethyl}(phenylmethoxy)carboxamide, (0.6 g, 35%). Electron spray M.S. 417 (M*−H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH3:17])([C:14](O)=[O:15])[N:9]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Br:26][C:27]1[CH:36]=[C:35]2[C:30]([CH:31]=[CH:32][C:33]([C@H:37]([NH2:39])[CH3:38])=[N:34]2)=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.CN(C(ON1C2=NC=CC=C2N=N1)=[N+](C)C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:14](=[O:15])[NH:39][C@@H:37]([C:33]2[CH:32]=[CH:31][C:30]3[C:35](=[CH:36][C:27]([Br:26])=[CH:28][CH:29]=3)[N:34]=2)[CH3:38])([CH3:17])[N:9]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(C)(C(=O)O)N1C(=O)OC(C)(C)C
Reactant: C[C@@H](N)c1ccc2ccc(Br)cc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](NC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C)c1ccc2ccc(Br)cc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
To a solution of 3-methyl-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-methyl ester (1.62 g, 4.52 mmol) in tetrahydrofuran/water/methanol (50 mL, 5:1:1) at 0° C. was added lithium hydroxide hydrate (2.2 g, 52.3 mmol). The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 1 h. The reaction mixture was heated at 40° C. for 19 h then cooled to room temperature and the solvent was evaporated. The residue was partitioned between ethyl acetate and water and the mixture was acidified to pH 5 with hydrochloric acid (1 M). The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The residue was dissolved in toluene and the solvent was evaporated to give 3-methyl-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester as a yellow oil (1.47 g, 95%). LCMS (m/z) 343.1 [M−H], Tr=2.36 min. To a solution of 3-methyl-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester (1.37 g, 4.0 mmol) in dichloromethane (30 mL) at 0° C. was added (R)-1-(7-bromo-quinolin-2-yl)-ethylamine hydrochloride (1.30 g, 4.5 mmol) and N,N-diisopropylethylamine (2.8 mL, 16.0 mmol) followed by (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate (1.81 g, 4.76 mmol). The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 2 h. The reaction mixture was diluted with dichloromethane and washed with water. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were passed through a hydrophobic frit and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with a gradient of iso-hexanes/ethyl acetate 20:1 to 0:1 to afford the title compound (929 mg, 40%) as a yellow foam and as a mixture of diastereoisomers. LCMS (m/z) 577.3, 579.2 [M+H], Tr=3.72 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[C:12](I)[C:11]([O:15][CH2:16][C:17]([CH3:19])=[CH2:18])=[C:10](I)[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].CCCC[SnH](CCCC)CCCC.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]3[O:15][CH2:16][C:17]([CH3:19])([CH3:18])[C:10]=3[CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: C=C(C)COc1c(I)cc(C2(C(=O)OC)CC2)cc1I
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)C1(c2ccc3c(c2)C(C)(C)CO3)CC1
Yield: 60.9 %

Procedure:
To a solution of 1-[3,5-diiodo-4-(2-methyl-allyloxy)-phenyl]-cyclopropane-carboxylic acid methyl ester (3.5 g, 7.0 mmol) in toluene (15 mL) was added Bu3SnH (2.4 g, 8.4 mmol) and AIBN (0.1 g, 0.7 mmol). The mixture was heated at reflux overnight. The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel (Petroleum Ether/EtOAc 20:1) to give 1-(3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-cyclopropanecarboxylic acid methyl ester (1.05 g, 62%). 1H NMR (400 MHz, CDCl3) δ 7.10-7.07 (m, 2 H), 6.71 (d, J=8 Hz, 1 H), 4.23 (s, 2 H), 3.62 (s, 3 H), 1.58-1.54 (m, 2 H), 1.34 (s, 6 H), 1.17-1.12 (m, 2 H).