Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][N:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(N(CC)CC)C.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:18]1([S:24]([N:6]2[C:7]3=[N:8][CH:9]=[CH:10][C:2]([Cl:1])=[C:3]3[CH:4]=[CH:5]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1ccnc2[nH]ccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)ccnc21
Reaction time: 8 h
Yield: 82.9 %

Procedure:
A stirred suspension of 4-chloro-7-azaindole (1.00 g, 6.55 mmol) in dichloromethane (DCM) (50 ml) was treated with 4-(dimethylamino)pyridine (80.0 mg, 0.66 mmol), triethylamine (1.36 ml, 9.83 mmol) and benzenesulfonyl chloride (0.93 ml, 7.21 mmol) at ambient temperature. The mixture was left to stand overnight and then diluted with DCM and washed with 1M aqueous HCl solution, saturated sodium hydrogen carbonate solution, water, and brine, dried with sodium sulfate and concentrated under vacuum to give crude product. Trituration (diethyl ether) afforded 1.59 g (83%) of 1-benzenesulfonyl-4-chloro-1H-pyrrolo[2,3-b]pyridine. LCMS (Method B, ESI): RT=4.48 min, m+H=293.3; 1H NMR (400 MHz, CDCl3) δ: 8.31 (d, 1H), 8.18 (m, 2H), 7.78 (m, 1H), 7.62-7.56 (m, 1H), 7.52-7.45 (m, 2H), 7.20 (m, 1H), 6.72 (m, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]1([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][C:35]([F:38])([F:37])[F:36])[C:24]=2[CH2:39]O)[CH2:22][CH2:21]1.C(Br)(Br)(Br)[Br:42]>ClCCl>[Br:42][CH2:39][C:24]1[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][C:35]([F:38])([F:37])[F:36])=[N:26][O:27][C:23]=1[CH:20]1[CH2:22][CH2:21]1
Reactant: OCc1c(-c2ccccc2OC(F)(F)F)noc1C1CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)Oc1ccccc1-c1noc(C2CC2)c1CBr
Temperature: 25 °C
Reaction time: 15 h
Yield: 88 %

Procedure:
Triphenylphosphine (1.1 equiv., 51.5 mmoles, 13.5 g) is added in small portions to a 0° C. solution of [5-Cyclopropyl-3-(2-trifluoromethoxy-phenyl)-isoxazol-4-yl]-methanol and carbon tetrabromide (1.1 equiv, 51.5 mmoles, 17.1 g) in dichloromethane (187.1 mL). The reaction mixture is stirred at ambient temperature for 15 h and concentrated under reduced pressure. The crude residue is purified via silica gel chromatography eluting with 5:1 hexanes/ethyl acetate) to afford the title compound (15 g, 88%) as a white powder.
Reaction SMILES: [CH3:1][O:2]C(=O)CCBr.[CH3:8][Si:9]([CH3:39])([CH3:38])[CH2:10][CH2:11][O:12][CH2:13][N:14]1[C:18]([C:19]2[CH:37]=[CH:36][C:22]([O:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29]([CH2:33][CH2:34]O)[N:28]=[CH:27]4)=[CH:21][CH:20]=2)=[CH:17][CH:16]=[N:15]1>>[CH3:39][Si:9]([CH3:38])([CH3:8])[CH2:10][CH2:11][O:12][CH2:13][N:14]1[C:18]([C:19]2[CH:20]=[CH:21][C:22]([O:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29]([CH2:33][CH2:34][CH2:1][OH:2])[N:28]=[CH:27]4)=[CH:36][CH:37]=2)=[CH:17][CH:16]=[N:15]1
Reactant: C[Si](C)(C)CCOCn1nccc1-c1ccc(Oc2ccc3c(cnn3CCO)c2)cc1
Reactant: COC(=O)CCBr
Product: C[Si](C)(C)CCOCn1nccc1-c1ccc(Oc2ccc3c(cnn3CCCO)c2)cc1

Procedure:
The titled compound AA is synthesized from intermediate Y-1 and 3-bromo-propionic acid methyl ester according to the procedure described for the synthesis of intermediate Y.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.S(=O)(=O)(O)O.[BH4-].[Na+]>C(O)(C)C>[CH2:17]([NH:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)c(N)c1
Reactant: O=Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc(C(=O)c2ccccc2)c(NCc2ccccc2)c1
Reaction time: 6 h

Procedure:
To a mixture of 21.1 g. of 2-amino-4-methylbenzophenone, 58.4 g. of benzaldehyde and 35 ml. of isopropanol is added dropwise 5.5 ml. of 46% sulfuric acid while maintaining at temperature of 20°-25° C. There is then slowly added 2.7 g. of sodium borohydride while maintaining 20°-25° C. Thereafter three additional separate and alternate additions of 5.5 mls. of 46% sulfuric acid and 2.7 g. of sodium borohydride are effected while maintaining 20°-25° C. and controlling the foaming caused by the borohydride additions. After stirring for 6 hours there is added with cooling 58 g. of sodium bisulfite in 200 ml. of water followed by the addition of 100 ml. of toluene and stirring for 1.5 hours. The toluene layer is separated, washed twice with water and distilled to remove toluene and benzaldehyde. The cooled residue is treated with heptane which is flashed off and the residue cooled to obtain crystals of 2-benzylamino-4-methylbenzophenone.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:16]=[C:15]([CH3:30])[C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][CH3:14])=[CH:7][CH:6]=1.CN(CCN(C)C)C.[Li]CCCC.CN([CH:47]=[O:48])C>CCOCC>[CH3:30][C:15]1[CH:16]=[C:17]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:21]([CH3:23])[CH3:22])[CH:24]([CH3:26])[CH3:25])[CH:18]=[C:2]([CH3:1])[C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][CH3:14])=[C:7]([CH:6]=1)[CH:47]=[O:48]
Reactant: CN(C)C=O
Reactant: COCOc1ccc(Cc2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: COCOc1ccc(Cc2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-triisopropylsilanyloxybenzyl)-methoxymethoxybenzene (2.0 g, 4.66 mmol) in ether was added TMEDA (1.05 mL, 6.99 mmol), followed by nBuLi (2.5 M in THF, 2.8 mL) at −20° C. The reaction mixture was warmed up to 0° C. and stirred for 1 h DMF (0.72 mL, 9.32 mmol) was then added and after stirring at 0° C. for 2 h, the reaction mixture was quenched with a saturated solution of NH4Cl and diluted with EtOAc. The water layer was extracted with EtOAc and the combined organic extracts were dried (MgSO4), filtered and concentrated to give the crude product 5-(2,6-dimethyl-4-triisopropylsilanyloxybenzyl)-2-methoxymethoxy-benzaldehyde (2.1 g, 98%): 1H NMR (300 MHz, d6-DMSO): δ 10.33 (s, 1H), 7.24 (m, 3H), 6.58 (s, 2H), 5.31 (s, 2H), 3.91 (s, 2H), 3.33 (s, 6H), 1.23 (m, 3H), 1.06 (m, 18H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:9); Rf=0.55.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:19]1[CH:20]=[C:21]([O:25][CH2:26][C@@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2[CH3:32])[CH:22]=[N:23][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:19]2[CH:20]=[C:21]([O:25][CH2:26][C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[CH3:32])[CH:22]=[N:23][CH:24]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1CCC[C@H]1COc1cncc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 50.6 %

Procedure:
To a solution of 3,5-bis(trifluoromethyl)phenylboronic acid (0.55 g, 2.0 mmol, Lancaster Chem Co.) and 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (300 mg, 1.1 mmol) in toluene (5.0 mL) was added Pd(0) (25 mg) and Na2CO3 (1 mL of a 2M solution), and the mixture was heated at reflux. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel to afford 225 mg of the title compound. MS (CI/NH3) m/z 405 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.8 (m, 3H), 2.08 (m, 1H), 2.36 (m, 1H), 2.54 (s, 3H), 2.78 (m, 1H), 3.17 (m, 1H), 4.10 (m, 2H), 7.42 (m, 1H), 7.92 (s, 1H), 8.00 (s, 2H), 8.42 (m, 1H), 7.92 (s, 1H), 8.00 (s, 2H), 8.42 (m, 1H), 8.48 (m, 1H).
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])=[CH:4][NH:3][CH2:2]1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:21]([N:3]1[CH2:2][CH2:1][C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])=[CH:4]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCOC(=O)C1=CNCCc2c1[nH]c1ccccc21
Product: CCCOC(=O)C1=CN(C(=O)c2ccccc2)CCc2c1[nH]c1ccccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using n-propyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (compound of step A) and benzoyl chloride; 1H-NMR (CDCl3): δ 10.55 (1H, br s), 8.07 (1H, s), 7.52-7.58 (4H, m), 7.47 (2H, m), 7.33 (1H, d), 7.21 (1H, m), 7.12 (1H, m), 4.23 (2H, t), 4.13 (2H, m), 3.28 (2H, m), 1.56 (2H, m), 1.40 (3H, t); MS (ES): 375 (MH+).
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:20][O-].[Na+].CO.CI>O>[CH3:20][S:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCS
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CI
Product: CCCCCCCCCCCCCCCCCCSC
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
In a 200 ml flask equipped with a stirrer and a calcium chloride dryer tube were charged 5.7 g of 1-octadecanthiol, 1.2 g of sodium methoxide and 30 ml of methanol, and the mixture was refluxed for 10 minutes. Then, 3.0 g of methyl iodide was added dropwise to the mixture and reflux was further contented for 30 minutes. The resulting mixture was poured into 200 ml of distilled water, and the resulting precipitate was collected by filtration under reduced pressure to obtain 6.0 g of methyloctadecylsulfide.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5][CH2:6][C:7](OC)=[O:8].[BH4-].[Li+].CO>CCOCC.Cl>[Si:12]([O:11][C@@H:4]([CH2:5][CH2:6][CH2:7][OH:8])[CH2:3][OH:2])([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)CC[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)[Si](O[C@H](CO)CCCO)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 94.5 %

Procedure:
Compound 5 (0.8 g, 1.8 mmol) was dissolved in dry Et2O (8.5 mL) and the solution was cooled to 0° C., afterward lithium borohydride (0.12 g, 5.4 mmol) and dry methanol (0.22 mL, 5.4 mmol) were sequentially added. The resulting suspension was stirred at 23° C. for 24 h, then a few drops of 6 N HCl were added and the salts were filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by flash-chromatography (1:1 EtOAc/Hex) to furnish 0.61 g (93%) of 6a as a colourless oil: [α]D20=−15.6 (c 3.1, CHCl3); 1H NMR (CDCl3) δ 7.70-7.65 (m, 4H), 7.44-7.32 (m, 6H), 3.82-3.77 (m, 1H), 3.53-3.48 (m, 2H), 3.45-3.41 (m, 2H), 1.65-1.47 (m, 4H), 1.05 (s, 9H); 13C NMR (CDCl3) δ 135.9, 135.7, 133.8, 133.7, 130.1, 129.8, 127.7, 127.6, 73.6, 65.7, 62.7, 29.7, 28.0, 27.0, 19.3.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5]([CH2:13][S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)C.O1CCOCC1.[OH-].[Na+].O>C(O)C>[CH2:15]([S:14][CH2:13][CH:5]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:4]([OH:22])=[O:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(CSCc1ccccc1)CC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C(CSCc1ccccc1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.1 %

Procedure:
A mixture of 2-benzylsulfanylmethyl-3-cyclohexyl-propionic acid ethyl ester (0.230 g), dioxane (10 mL), sodium hydroxide (1N, 3 mL), water (2 mL) and ethanol (4 mL) was stirred for 20 hours at room temperature. The solvents were evaporated and the residue dissolved in water (50 mL). The aqueous solution was washed twice with ether and then acidified to pH2. The product was extracted from the aqueous solution with ethyl acetate and the extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure to give acid 2-benzylsulfanylmethyl-3-cyclohexyl-propionic acid (0.210 g).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[CH:10][CH:9]=1)([CH3:4])[CH3:3].[C:22](OC)(=[O:27])[CH2:23][C:24]([CH3:26])=[O:25].[H-].[Na+].C([Li])CCC>C1COCC1>[CH3:4][C:2]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]2([CH:17]([CH3:18])[CH3:19])[CH2:26][C:24]([OH:25])=[CH:23][C:22](=[O:27])[O:20]2)=[CH:12][CH:13]=1)([CH3:3])[CH3:1]
Reactant: CC(C)C(=O)CCc1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1(CCc2ccc(NC(=O)OC(C)(C)C)cc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared from [4-(4-methyl-3-oxo-pentyl)-phenyl]-carbamic acid 1,1-dimethylethyl ester obtained in Example PPPPP (2.1 g, 7.2 mmol), methyl acetoacetate (2.1 g, 18.1 mmol), 60% NaH (0.80 g, 20 mmol), and n-butyllithium (14 mL of 1.5M, 21 mmol) in THF as described in General Method 6. The product was carried on crude to the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1([NH2:19])[CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[C:22](=[O:40])[N:23]([C:28]2[CH:29]=[C:30]([CH:35]=[C:36]([F:39])[C:37]=2[CH3:38])[C:31]([O:33][CH3:34])=[O:32])[CH:24]=[C:25]([Br:27])[N:26]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1([NH:19][C:21]2[C:22](=[O:40])[N:23]([C:28]3[CH:29]=[C:30]([CH:35]=[C:36]([F:39])[C:37]=3[CH3:38])[C:31]([O:33][CH3:34])=[O:32])[CH:24]=[C:25]([Br:27])[N:26]=2)[CH2:18][CH2:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1(c2cc(F)ccc2OCc2ccccc2)CC1
Reactant: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(Br)c2=O)c1
Product: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(NC3(c4cc(F)ccc4OCc4ccccc4)CC3)c2=O)c1

Procedure:
The subtitle compound was prepared from 1-(2-(benzyloxy)-5-fluorophenyl)cyclopropanamine (Example 278a) and methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-5-fluoro-4-methylbenzoate (Example 252g) using a similar method to that described for Example 268d.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Br[C:27]1[CH:28]=[C:29]([C:33]2[CH:38]=[C:37]([NH:39][CH:40]3[CH2:42][CH2:41]3)[N:36]=[C:35]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)[CH:34]=2)[CH:30]=[N:31][CH:32]=1>COCCOC.C(Cl)Cl>[CH:40]1([NH:39][C:37]2[N:36]=[C:35]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)[CH:34]=[C:33]([C:29]3[CH:30]=[N:31][CH:32]=[C:27]([C:14]4[CH:15]=[CH:16][C:11]([CH2:10][N:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)=[CH:12][CH:13]=4)[CH:28]=3)[CH:38]=2)[CH2:42][CH2:41]1
Reactant: Brc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1
Reactant: CC(C)N1CCN(Cc2ccc(B(O)O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)N1CCN(Cc2ccc(-c3cncc(-c4cc(NC5CC5)nc(-c5ccccn5)c4)c3)cc2)CC1

Procedure:
To a solution of 4-((4-Isopropyl-piperazin-1-yl)methyl)-phenyl boronic acid (Intermediate B3) (3 eq, 0.408 mmol, 0.106 g) in dry DME (1 ml) under an inert atmosphere of argon is added 2M Na2CO3 (6 eq, 0.816 mmol, 0.8 ml) followed by (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopropyl-amine (Example 1.26) (1 eq, 0.136 mmol, 50 mg) and PdCl2dppf (0.1 eq, 0.0136 mmol, 10 mg). The reaction mixture is heated using microwave radiation at 90° C. for 2 hours. The reaction mixture is dissolved in DCM and washed with water. The organic solvent is reduced in vacuo and the residue is purified by reverse phase column chromatography (Isolute™ C18, 0-40% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 505.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:43])([CH3:42])[CH2:6][N:7]([S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][CH3:41])[CH:35]=1)(=[O:33])=[O:32])[CH2:8][C@@H:9]([OH:30])[C@@H:10]([NH:18][C:19](=[O:29])[O:20][C@@H:21]1[C@H:28]2[C@H:24]([O:25][CH2:26][CH2:27]2)[O:23][CH2:22]1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C.Cl[C:54]([O:56][CH3:57])=[O:55]>C1COCC1>[CH2:11]([C@H:10]([NH:18][C:19](=[O:29])[O:20][C@@H:21]1[C@H:28]2[C@H:24]([O:25][CH2:26][CH2:27]2)[O:23][CH2:22]1)[C@H:9]([OH:30])[CH2:8][N:7]([CH2:6][C:5]([CH3:43])([CH3:42])[CH2:4][CH2:3][CH2:2][NH:1][C:54]([O:56][CH3:57])=[O:55])[S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][CH3:41])[CH:35]=1)(=[O:33])=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCN)c1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCNC(=O)OC)c1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
A solution of 50 mg (0.081 mmol) of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-3-((5-amino-2,2-dimethylpentyl)[3-(methylamino)phenyl]sulfonylamino)-1-benzyl-2-hydroxypropyl]carbamate and 17 μL (0.097 mmol) of N,N-diisopropylethylamine in 4 mL of anhydrous THF at 0° C. was treated with 6.9 μL (0.089 mmol) of methyl chloroformate. The solution was allowed to warm to RT with stirring. After 18 hours the solution was concentrated in vacuo and the residue was subjected to flash chromatography (SiO2, 95:5 CH2Cl2/2M NH3 in MeOH) to afford 54 mg (98%) of the desired compound as a white foam. H1-NMR (CDCl3): 7.28 (m, 6H), 6.99 (d, 1H), 6.89 (s, 1H), 6.71 (dd, 1H), 5.54 (d, 1H), 5.30 (d, 1H), 4.93 (m, 2H), 4.17-3.50 (m, 11H), 3.25-2.60 (m, 12H), 1.60-1.12 (m, 6H), 0.89 (s, 3H), 0.81 (s, 3H). MS(ESI): 677(M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]=[C:7]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[CH:6]=[CH:5]2>CS(O)(=O)=O>[CH3:12][C:11]1[CH:10]=[C:9]2[C:4](=[CH:3][C:2]=1[CH3:1])[CH:5]=[CH:6][C:7]1[CH2:13][CH2:14][CH2:15][C:16](=[O:18])[C:8]2=1
Reactant: Cc1cc2ccc(CCCC(=O)O)cc2cc1C
Agent: CS(=O)(=O)O
Product: Cc1cc2ccc3c(c2cc1C)C(=O)CCC3
Temperature: 90 °C

Procedure:
4-(6,7-Dimethyl-2-naphthyl)butanoic acid (6.21 g, 0.026 mole) was added to 40 ml of CH3SO3H. The mixture was heated to 90° C. until all solid material disappeared (about 30 min.). The mixture was poured into ice and then extracted twice with ethylacetate. Combined ethylacetate solution was dried over anhydrous Na2SO4 and then concentrated. After flash chromatography on silica gel, 6,7-Dimethyl-4-oxo-1,2,3,4-tetrahydrophenanthrene was obtained as a pale yellow solid material (4.96 g, 0.022 mole, 85% yield). mp 114.0°-115.0° C., 1H NMR (CDCl3)δ 2.12-2.20 (m,2H), 2.41 (s,3H), 2.47 (s,3H), 2.77 (t, J=6.4 Hz,2H), 3.09 (t, J=6.4 Hz,2H), 7.21 (d, J=8.3 Hz,1H), 7.54 (s,1H), 7.31 (d, J=8.3 Hz,1H), 9.20 (s,1 H), IR (KBr) cm-1 2930, 1669, 1590, 1510, Anal. Calcd. for C16H16O: C, 85.67; H, 7.19. Found: C, 86.00; H, 7.18.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:13][CH:14]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>ClCCl>[Cl:8][C:9]1[N:10]=[N:11][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:25]([C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[C:22]([F:21])([F:32])[F:33])=[O:26])[CH2:19][CH2:20]2)=[CH:13][CH:14]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: Clc1ccc(N2CCNCC2)nn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(Cl)nn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Triethylamine (2.0 mL) was added to an ice cold solution of 3-chloro-6-piperazin-1-ylpyridazine (1.00 g, 6.69 mmol) in dichloromethane (10 mL), followed by the addition of 2-trifluoromethylbenzoyl chloride (2.10 g, 10.03 mmol). The mixture was allowed to warm up to room temperature and then stirred for 30 minutes. The solvent was removed in vacuo and the crude mixture was dissolved in ethyl acetate (15 mL), washed with water and dried over anhydrous Na2SO4. [4-(6-chloropyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone was obtained as a thick liquid after purified by column chromatography in 79% yield (1.96 g). 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J=7.9 Hz, 1H), 7.63-7.50 (m, 2H), 7.32 (d, J=7.3 Hz, 1H), 7.21 (t, J=4.4 Hz, 1H), 6.92 (d, J=9.5 Hz, 1H), 4.20-3.92 (m, 1H), 3.92-3.80 (m, 1H), 3.70-3.55 (m, 4H), 3.30 (t, J=5.3 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 167.6, 158.7, 147.7, 134.2, 134.2, 132.3, 129.5, 129.1, 127.2, 126.8, 126.8, 115.6, 46.3, 45.2, 44.7, 41.2. MS (ES+) m/z 371.1 and 373.1 (M+1).
Reaction SMILES: ClCCl.[OH:4][CH2:5][C:6]1[N:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:9]=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>O>[CH3:32][S:33]([O:4][CH2:5][C:6]1[N:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:9]=[CH:8][CH:7]=1)(=[O:35])=[O:34]
Reactant: CC(C)(C)OC(=O)CCCCc1cccc(CO)n1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCc1cccc(COS(C)(=O)=O)n1
Reaction time: 0.17 h

Procedure:
To a 200 mL round-bottom flask, 50 mL of dichloromethane, 2.78 g of t-butyl 5-(6-hydroxymethylpyridin-2-yl)pentanoate and 2.0 g of diisopropylethylamine were added, and the mixture was stirred at ice temperature for 10 minutes. To the reaction mixture, 0.89 mL of methanesulfonyl chloride was added dropwise, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was partitioned. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and then the solvent was removed. The residue was purified by chromatography on silica gel (n-hexane-ethyl acetate=3:1) to give 2.28 g of t-butyl 5-(6-methane-sulfonyloxymethylpyridin-2-yl)pentanoate as a yellow oil.
Reaction SMILES: [C:1]([C:6]1[N:10]([CH3:11])[C:9]([N+:12]([O-:14])=[O:13])=[N:8][CH:7]=1)(OCC)=[O:2].[Li+].[BH4-].Cl>O1CCCC1>[CH3:11][N:10]1[C:6]([CH2:1][OH:2])=[CH:7][N:8]=[C:9]1[N+:12]([O-:14])=[O:13]
Reactant: CCOC(=O)c1cnc([N+](=O)[O-])n1C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(CO)cnc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 33 %

Procedure:
To 0.2 g. of 5-carbethoxy-1-methyl-2-nitroimidazole in 30 ml. of tetrahydrofuran, 0.044 g. of LiBH4 is gradually added under stirring at room temperature. After stirring for 48 hours, the excess of LiBH4 is decomposed with 10% hydrochloric acid, the reaction mixture is filtered and the filtrated is evaporated to dryness under vacuum. The residue is taken up with acetone. Inorganic salts are filtered off and the solution is evaporated. The oily residue is chromatographed through 7 g. of silica gel, by eluting with chloroform containing from 1% to 3% (v/v) of methanol. After concentration of the portions containing the product, 0.052 g. (33%) of 1-methyl-2-nitro-5-hydroxymethylimidazole is obtained.