Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=4[N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C1COCC1.ClCCl.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>C(N(CC)CC)C>[NH:17]1[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[N:14]=[C:13]1[C:10]1[CH:9]=[CH:8][C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:34]([C:33]3[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=3[C:31]([F:30])([F:41])[F:42])=[O:35])[CH2:3][CH2:2]2)=[N:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: c1ccc2[nH]c(-c3ccc(N4CCNCC4)nc3)nc2c1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(-c3nc4ccccc4[nH]3)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
To the suspension of 2-(6-piperazin-1-ylpyridin-3-yl)-1H-benzoimidazole (0.403 g, 1.440 mmol) in 25 mL of mixture of THF:dichloromethane (1:1) was added 2-trifluoromethylbenzoyl chloride (0.300 g, 1.440 mmol) in the presence of triethylamine (1 mL). The mixture was stirred at room temperature for 1 hour. The solvent was then evaporated and ethyl acetate was added. The suspension was ultrasonicated and filtered. The filtrate was concentrated in vacuo and the residue was subjected to column chromatography. The title compound was obtained as a white solid in 15% yield (0.097 g). 1H NMR (300 MHz, CDCl3) δ 8.71 (s, 1H), 8.24 (dd, J=2.4 and 9.0 Hz, 1H), 7.81 (d, J=7.5 Hz, 1H), 7.74 (t, J=7.5 Hz, 1H), 7.63 (t, J=7.5 Hz, 1H), 7.52-7.48 (m, 2H), 7.51 (d, J=7.5 Hz, 1H), 7.14-7.11 (m, 2H), 6.97 (d, J=9.0 Hz, 1H), 3.78-3.71 (m, 4H), 3.60-3.46 (m, 2H), 3.29-3.11 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 166.8, 159.2, 150.4, 146.8, 136.1, 135.1, 135.1, 133.4, 130.1, 128.0, 127.1, 127.0, 126.1, 126.0, 125.6, 122.4, 116.2, 107.4, 46.6, 44.6, 44.4, 41.4. MS (ES+) m/z 452.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH3:15])=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl>CC(C)=O>[O:26]1[CH2:25][CH:24]1[CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH3:15])=[O:11])=[CH:6][CH:7]=1
Reactant: CCCOC(=O)CCc1ccc(O)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOC(=O)CCc1ccc(OCC2CO2)cc1
Yield: 28.4 %

Procedure:
A mixture of 9 g (0.04 mole) of n-propyl 3-(4-hydroxyphenyl)propionate, 10 g (0.08 mole) of K2CO3 and 12 mL (0.15 mole) of epichlorohydrin in 150 mL of acetone was stirred and heated to reflux for 20 hours. The reaction medium was then filtered and evaporated under reduced pressure. The resulting oil was taken up in 100 mL toluene and washed consecutively with 50 mL water 2×50 mL of 1N NaOH and 2×50 mL of water. The toluene phase was then dried over MgSO4 and evaporated under reduced pressure to provide 3 g (30%) of a clear oil which was used directly in the next step without additional purification. The IR and NMR spectra of the reaction product were consistent with the assigned structure.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:11]2[C:15]([CH3:17])([CH3:16])[O:14][C:13](=[O:18])[NH:12]2)[CH:7]=[CH:8][C:9]=1[F:10].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21]>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([CH:11]2[C:15]([CH3:16])([CH3:17])[O:14][C:13](=[O:18])[N:12]2[C:20]([O:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[O:21])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CC1(C)OC(=O)NC1c1ccc(F)c(F)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
Into a stirred suspension of sodium hydride (60% suspension in paraffin 203 mg, 1.4 eq.) in THF (20 mL) at 0° C., a solution of 4-(3,4-difluorophenyl)-5,5-dimethyl-2-oxo-oxazolidine (870 mg, 3.622 mmol) in THF (5 mL) was added followed by stirring for 30 minutes. This suspension was added to a solution of 4-nitrophenyl chloroformate (950 mg, 4.71 mmol) in THF (20 mL) at −78° C. under argon and the stirring was continued for 2 h. It was slowly warmed to room temperature and after 4 h the solvent was evaporated. The residue was mixed with dichloromethane (150 mL), washed with 0.05 N sodium hydroxide (3×10 mL), and dried (sodium sulfate). The solvent was evaporated and the residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (9:1) as the eluent to give the product as a white powder (860 mg, 59% yield).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([O:32][CH2:33][C:34]2[CH:39]=[CH:38]C=[CH:36][CH:35]=2)[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]4=[O:31])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:40]1C=CC(CCl)=CC=1>CN(C=O)C>[N:40]1[CH:36]=[CH:35][C:34]([CH2:33][O:32][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]4=[O:31])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=[CH:39][CH:38]=1
Reactant: ClCc1ccncc1
Reactant: O=C1c2ccccc2CN1C1CCN(c2ccc(C(OCc3ccccc3)c3ccccc3)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2CN1C1CCN(c2ccc(C(OCc3ccncc3)c3ccccc3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a suspension of sodium hydride (55.3 mg, 1.38 mmol) in DMF (5 mL) at 0° C. was added dropwise a solution of Example 293 Part A compound (500 mg, 1.26 mmol) in DMF (8 mL). The reaction was stirred at 0° C. for 30 min. A solution of 4-picolyl chloride (175 mg, 1.38 mmol) in DMF (1 mL) was added dropwise to the reaction at 0° C. The reaction was stirred at 0° C. for 1 h then warmed to RT overnight. The reaction was quenched with saturated ammonium chloride solution (2 mL). Ethyl acetate (200 mL) was added to the reaction, and the organic layer was washed with water (2×100 mL), brine (2×100 mL) and dried over MgSO4. Purification was performed by flash chromatography on silica gel (100 g), loaded and eluted with 70% EtOAc in hexane. Pure fractions were combined and evaporated to give title compound (320 mg, 52%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].[F:18][C:19]1[C:24]([NH:25][NH2:26])=[C:23]([F:27])[C:22]([F:28])=[C:21]([F:29])[C:20]=1[F:30]>C(O)C>[F:18][C:19]1[C:24]([NH:25][N:26]=[CH:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[CH:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[C:5]([CH3:8])=[C:4]2[CH3:9])=[C:23]([F:27])[C:22]([F:28])=[C:21]([F:29])[C:20]=1[F:30]
Reactant: NNc1c(F)c(F)c(F)c(F)c1F
Reactant: CC1=C(C)C(c2ccccc2C=O)C(C)=C1C
Solvent: CCO
Product: CC1=C(C)C(c2ccccc2C=NNc2c(F)c(F)c(F)c(F)c2F)C(C)=C1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a solution of 2-(2,3,4,5-tetramethylcyclopentadienyl)benzaldehyde (10.0 mmol) in ethanol (60.0 mL) was added dropwise pentafluorophenylhydrazine (11.0 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature for 2 hrs. The solvent was distilled off under reduced pressure and the residue was recrystallized from hexane to give 2-(2,3,4,5-tetramethylcyclopentadienyl)benzaldehyde pentafluorophenylhydrazone (4.00 g, yield 97.0%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH:12]([CH:19]1[O:24][CH2:23][C:22](=O)[NH:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C.COCCO[AlH2-]OCCOC.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[NH:21]1[CH2:22][CH2:23][O:24][CH:19]([CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][OH:3])[CH2:20]1
Reactant: CCOC(=O)c1ccccc1OC(c1ccccc1)C1CNC(=O)CO1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: OCc1ccccc1OC(c1ccccc1)C1CNCCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51 %

Procedure:
2-[(5-Oxo-morpholin-2-yl)-phenyl-methoxy]-benzoic acid ethyl ester (0.66 g) was taken up in 10 mL toluene, and cooled to 0 C for the addition of Red-Al (2.8 mL, 5 equiv). The mixture was allowed to warm to room temperature. After 12 h, 2 mL 2 N NaOH was added, and the mixture was stirred at room temperature for 30 min, extracted with toluene (2×5 mL). The organics were combined, dried over MgSO4, filtered and concentrated. The residual oil was taken up in DCM, and pumped onto silica, and purified by MPLC in DCM/MeOH+0.1 NH4OH. Fractions containing the desired compound were combined and concentrated. 0.287 g of [2-(Morpholin-2-yl-phenyl-methoxy)-phenyl]-methanol as a pale yellow oil (51% yield, M+1=300.1).
Reaction SMILES: C(OC(CC[N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([N+]([O-])=O)=[CH:14][CH:15]=2)[CH2:10]1)=O)(C)C>CO.[C].[Pd]>[CH2:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][CH2:18][NH:9]1
Reactant: CC(C)OC(=O)CCN1CCc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CO
Product: c1ccc2c(c1)CCNC2
Yield: 78 %

Procedure:
The suspension (60 ml) in methanol of 1.58 g of 2-(2-(isopropyloxycarbonyl)ethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline and 1.0 g of palladium-carbon (10%) was stirred for one day, and the catalyst was separated by filtration. The filtrate was concentrated under reduced pressure to obtain 1.11 g of 7-amino-2-(isopropyloxycarbonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline (yield: 78%).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH2:28])=[N:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)[C:13](=[O:29])[CH:12]1[CH2:30][O:31][CH3:32])=[O:10])C1C=CC=CC=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:64][C:65]1[S:69][C:68]([O:70][CH2:71]C(O)=O)=[CH:67][CH:66]=1>CN(C=O)C>[NH2:28][C:22]1[C:21]2[C:26](=[CH:27][C:18]([CH2:17][N:14]3[CH2:15][CH2:16][N:11]([C:9](=[O:10])[CH2:71][O:70][C:68]4[S:69][C:65]([Cl:64])=[CH:66][CH:67]=4)[C@@H:12]([CH2:30][O:31][CH3:32])[C:13]3=[O:29])=[CH:19][CH:20]=2)[N:25]=[CH:24][N:23]=1
Reactant: O=C(O)COc1ccc(Cl)s1
Reactant: COCC1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)COc1ccc(Cl)s1
Reaction time: 16 h

Procedure:
To a solution of 4-(4-amino-quinazoline-7-ylmethyl)-2-methoxymethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester, EXAMPLE 75, (0.69 g, 2.29 mmol) in 9 mL of DMF is added N,N-diisopropylethyl amine (0.89 g, 6.87 mmol), TBTU (0.76 g, 2.36 mmol), and 5-chloro-2-thienyloxyacetic acid, EXAMPLE 24, (0.40 g, 2.08 mmol). The solution is stirred for 16 hours. After this time the solution is concentrated. The crude material is purified by RP-HPLC eluting with a gradient of 10% CH3CN/H2O (0.1% TFA) to 80% CH3CN/H2O (0.1% TFA). The product fractions are lyophilized to give product as a white solid (1.0 g, 1.57 mmol). 1H NMR (d6-DMSO, 300 MHz) δ9.70 (bs, 2H), 8.78 (s, 1H), 8.29 (m, 1H), 7.55 (m, 2H), 6.72 (m, 1H), 6.22 (m, 1H), 4.80 (m, 4H), 3.78 (m, 4H), 3.59 (m, 3H), 3.31 and 3.2 (s, 3H rotational isomers).MS (ion spray) M+H=476. Elemental Analysis: C21H22ClN5O4S.1.4CF3CO2H cal: C=45.03%, H=3.68%, N=11.04%; found C=44.98%, H=3.71%, N=11.02%.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:22][CH2:21][CH2:20][NH:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:23]([O:40][C:41]1[CH:50]=[CH:49][CH:48]=[C:47]2[C:42]=1[CH2:43][CH2:44][CH:45]1[O:51][CH:46]12)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)(=O)C.O>O1CCCC1>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:22][CH2:21][CH2:20][N:19]3[CH:46]3[C:47]4[C:42](=[C:41]([O:40][Si:23]([C:36]([CH3:38])([CH3:37])[CH3:39])([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:50]=[CH:49][CH:48]=4)[CH2:43][CH2:44][CH:45]3[OH:51])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc(C3CCCN3)oc2-c2ccccc2)cc1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC1OC21)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](Oc1cccc2c1CCC(O)C2N1CCCC1c1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Reaction time: 120 h
Yield: 30 %

Procedure:
To a solution of 2-(4,5-diphenyloxazol-2-yl)pyrrolidine (0.66 g) and 5-tert-butyldiphenylsilyloxy-1,2-epoxy-1,2,3,4-tetrahydronaphthalene (0.6 g) in tetrahydrofuran (10 ml) was added Ti[O-CH(CH3)2 ]4 (0.66 ml) at room temperature. After being stirred for 5 days at the same temperature, the mixture was poured into the mixture of ethyl acetate and water. The organic layer was washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-[2-(4,5-diphenyloxazol-2-yl)pyrrolidin-1-yl]-2-hydroxy-5-tert-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (0.31 g). MS (m/z): 691 (M+) IR (Neat): 3300 cm-1NMR (CDCl3, δ): 1.07 (9H, s), 1.7-2.4 (6H, m), 2.6-3.3 (2H, m), 3.4-3.6 (2H, m), 4.1-4.4 (2H, m), 6.28 (1H, d, J=8.0 Hz), 6.75 (1H, t, J=8.0 Hz), 6.88 (1H, d, J=8.0 Hz), 7.3-7.8 (20H, m)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].CCN(CC)CC.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCc1cccc(N)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.1 %

Procedure:
To a stirred solution of tert-butyl 3-aminobenzylcarbamate (Hah, Jung-Mi; Martasek, Pavel; Roman, Linda J.; Silverman, Richard B.; J. Med. Chem.; 2003, 46, 1661-1669) (287 mg, 1.29 mmol) in CH2Cl2 (10 mL) at 0° C. was added Et3N (0.27 mL, 2.0 mmol) and acetyl chloride (0.10 mL, 1.4 mmol) and the resulting solution was warmed up to room temperature slowly. After further stirring of 4 h, the reaction was quenched with saturated aqueous NH4Cl. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic layer was washed with H2O, brine, dried with Na2SO4 and concentrated under reduced pressure. The residue oil was purified by column chromatography (60% EtOAc in hexanes) to provide tert-butyl 3-acetamidobenzylcarbamate (123.1 mg, 36%). N-(3-(aminomethyl)phenyl)acetamide was then generated by removal of the Boc protecting group by treatment with HCl (in methanol or dioxane) or trifluoroacetic acid in dichloromethane.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)[CH2:6][CH2:5]1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].C1(C)C=CC=CC=1.O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:14]2[C:15]3[C:11](=[C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]4)[CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CN1CCN(c2cccc3[nH]ccc23)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CCN(c2cccc3c2ccn3S(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.5 %

Procedure:
A mixture of 0.2 g (0.79 mmole) 4-(4-methyl-piperazin-1-yl)-1H-indole dihydrochloride, 0.2 g (1.03 mmole) 4-fluorobenzenesulfonyl chloride and 0.025 g tetrabutylammonium hydrogen sulfate in 5 mL 4M sodium hydroxide and 15 mL toluene was stirred at room temperature for 24 hrs. The mixture was diluted with 10 mL water and extracted with 25 mL ethyl acetate. The organic phase was washed with 5 mL water, 5 mL saturated sodium chloride, dried (magnesium sulfate) and concentrated under reduced pressure. The hydrochloride salt was recrystallized from ethyl acetate/ether to provide 0.208 g of 1-(4-fluoro-benzenesulfonyl)-4-(4-methyl-piperazin-1-yl)-1H-indole (32), m.p. 151-152° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)O1.Br[C:33]1[N:34]=[C:35]([C:40]2[S:41][C:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[N:43][N:44]=2)[C:36]([NH2:39])=[N:37][CH:38]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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]>[NH2:39][C:36]1[N:37]=[CH:38][C:33]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([CH:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:19]3)(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[N:34][C:35]=1[C:40]1[S:41][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[N:43][N:44]=1
Reactant: Nc1ncc(Br)nc1-c1nnc(-c2ccccc2)s1
Reactant: CC(C)(C)OC(=O)N1CCCC(S(=O)(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC(S(=O)(=O)c2ccc(-c3cnc(N)c(-c4nnc(-c5ccccc5)s4)n3)cc2)C1
Yield: 99.9 %

Procedure:
A mixture of tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylpiperidine-1-carboxylate (162.0 mg, 0.3590 mmol), 5-bromo-3-(5-phenyl-1,3,4-thiadiazol-2-yl)pyrazin-2-amine (100 mg, 0.2992 mmol), Pd(dppf)Cl2.DCM (24.43 mg, 0.02992 mmol) and Na2CO3 (448.8 μL of 2 M, 0.8976 mmol) in dioxane (2 mL) was irradiated by microwave at 100° C. for 30 minutes. The mixture was diluted with water and the aqueous layer was extracted with EtOAc (×2). The combined organic extracts were washed with brine (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 24 g column, eluting with 0 to 50% EtOAc/Petroleum Ether, loaded in DCM) to give the sub-title product as a yellow solid (173 mg, 100% Yield). 1H NMR (400.0 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.36 (d, 2H), 8.16 (br s, 2H), 8.13 (dd, 2H), 8.01 (d, 2H), 7.64-7.61 (m, 3H), 4.10-3.95 (m, 1H), 3.76 (br d, 1H), 2.99-2.74 (m, 2H), 2.12-2.02 (m, 1H), 1.75-1.59 (m, 2H) and 1.35-1.32 (m, 11H) ppm; LC/MS m/z 579.2 [M+1]+.
Reaction SMILES: C1C2C(=CC=CC=2)C=C1.CCC(C[O:16][C:17](C(N(CC[NH+](C)C)C)=O)([C:24]1[CH:29]=CC=CC=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)CC.[Cl-].[BrH:40].OO>ClCCl.O>[Br:40][C@@H:24]1[CH2:29][C:19]2[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:17]1[OH:16]
Reactant: Br
Reactant: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: C1=Cc2ccccc2C1
Agent: OO
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O[C@@H]1c2ccccc2C[C@H]1Br
Reaction time: 8 h
Yield: 83.9 %

Procedure:
237 ml of water, 173.9 g of indene (92 wt %; 1.38 mol), 2.8 g of Triton X-100 and 262.0 g of hydrogen bromide (47 wt %; 1.52 mol, 1.1 mol/mol indene) were put into a 1000-ml 3-mouthed flask, and emulsified by stirring together with a magnetic stirrer. The emulsion was stirred at 60° C. as 147.2 g of hydrogen peroxide (35 wt %; 1.52 mol, 1.1 mol/mol indene) was added dropwise over 4 hours and 20 minutes. After stirring for 2 hours at the same temperature, stirring was continued at room temperature overnight. 200 ml of dichloromethane was added to the reaction mixture, and after stirring at room temperature for 1 hour it was filtered at decreased pressure. The wet crystals were dried, to obtain 246.1 g of pale yellow crystals of trans-2-bromoindan-1-ol (yield 83.9%; GC purity 97.0%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C@@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([OH:16])=O)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[NH2:24][CH2:25][CH2:26][NH:27][CH2:28][CH:29]([OH:42])[CH2:30][O:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1.C(OC1C=CC2C(=CC=CC=2)N1C(OCC(C)C)=O)C(C)C.C(=O)(O)[O-].[Na+]>CS(C)=O>[NH2:1][C:2]1[C:3]([C:10]([NH:12][CH:13]([C:14](=[O:16])[NH:24][CH2:25][CH2:26][NH:27][CH2:28][CH:29]([OH:42])[CH2:30][O:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: Nc1nc(N)c(C(=O)N[C@@H](Cc2ccccc2)C(=O)O)nc1Cl
Reactant: NCCNCC(O)COc1cccc2ccccc12
Agent: CC(C)COC(=O)N1c2ccccc2C=CC1OCC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1nc(N)c(C(=O)NC(Cc2ccccc2)C(=O)NCCNCC(O)COc2cccc3ccccc23)nc1Cl
Temperature: 75 °C

Procedure:
A stirred mixture of (S)-2-(3,5-diamino-6-chloropyrazine-2-carboxamido)-3-phenylpropionic acid (1.8 g.), 1-β-aminoethylamino-3-α-naphthyloxypropan-2-ol (1.43 g.), 2-isobutoxy-1-isobutoxycarbonyl-1,2-dihydroquinoline (1.5 g.) and dimethylsulphoxide (30 ml.) was heated at 75° C. for 18 hours, cooled and poured into ice-water (600 ml.). Aqueous 6% w/v sodium bicarbonate solution (50 ml.) was added, the mixture was filtered and the solid product was washed with diethylether (100 ml.). There was thus obtained as solid product 3,5-diamino-6-chloro-N-{1-[N-β-(2-hydroxy-3-α-naphthyloxypropylamino)ethylcarbamoyl]-2-phenylethyl}pyrazine-2-carboxamide, m.p. 142°-146° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.N1(/[C:13](/[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:14]\[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])C=CC=N1>CC#N>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7]/[C:13](/[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:14]\[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:4]=[N:3]1
Reactant: Cn1cc(N)cn1
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)n1cccn1
Solvent: CC#N
Product: Cn1cc(N/C(=N\C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cn1
Reaction time: 20 h
Yield: 92.1 %

Procedure:
1-methyl-1H-pyrazol-4-amine (11.7 g, 0.12 mol) was added portion-wise to a solution of di-tert-butyl [(Z)-1H-pyrazol-1-ylmethylylidene]biscarbamate (17.5 g, 0.056 mol) in MeCN (100 mL). The mixture was stirred for 20 hrs then filtered to afford the title compound (17.5 g, 91% yield) as a crude solid which was used as is in the next step.
Reaction SMILES: [Na].[CH2:2]([SH:6])[CH2:3][CH2:4][CH3:5].S(C1C=CC(C)=CC=1)(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH2:11]([S:6][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCC/C=C\CCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCS
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCCCC/C=C\CCCCCCCCSCCCC
Reaction time: 8 h

Procedure:
Sodium (1.5 g, 0.05 mol) was added to n-butyl mercaptan (9.02 g, 0.10 mol, Eastman) in a dry three-necked, 250-mL, round-bottom flask equipped with drying tube, magnetic stirrer, stopper, and nitrogen inlet. The reaction mixture was cooled in an ice bath. As the reaction progressed, the mixture began to solidify, so sufficient (ca. 5 mL) mixed xylene was added to effect solution. At the end of 6 hr. evolution of hydrogen was no longer apparent. Oleyl tosylate (16.94 g, 0.04 mol) was added to the solution with stirring. The flask was packed in ice and allowed to warm over 15 hr. The reaction mixture was dissolved in ether and extracted with water, 10% NaHCO3, and saturated NaCl. The ether phase was dried over anhydrous potassium carbonate and filtered, and the ether was removed on a rotary evaporator. Vacuum distillation [165° C. (0.5 torr)-190° C. (0.65 torr)] produced an oil with a faint yellow color and an odor characteristic of mercaptans. Lithium aluminum hydride was added to the oil and it was allowed to sit overnight, then filtered, and redistilled. The product was a faintly yellow oil with a slight mercaptan odor. The yield was 6.6 g (48.4%) collected from 212° C. (2.8 torr) to 223° C. (2.7 torr): NMR δ 0.9-2.3 (m, 38 H, --CH3 and --CH2 --), 2.5 (m, 4 H, --CH2 --S), 5.3 (t, J=4.5 Hz, 2 H, olefinic); IR: 3005 cm-1 (olefinic C--H). Anal. Calcd.: C, 77.57; H, 13.02; S, 9.41. Found: C, 77.53; H, 13.02; S, 9.40.