Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1)#N.CC(C[AlH]CC(C)C)C.C[OH:24].Cl>ClCCl.C1(C)C=CC=CC=1>[CH3:13][O:12][C:11]1[C:5]2[O:4][C:3]([CH:1]=[O:24])=[CH:7][C:6]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc2cc(C#N)oc12
Reactant: CO
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cccc2cc(C=O)oc12
Reaction time: 1 h

Procedure:
2-Cyano-7-methoxybenzofuran (0.736 g) was dissolved in dichloromethane (10 ml), and a 1.02N DIBAL solution (5.4 ml) in toluene was added thereto at −4 to −30° C., followed by stirring for one hour. Methanol and dilute hydrochloric acid were added to the mixture, and the solvent was distilled off. The obtained residue was purified by column chromatography (hexane/ethyl acetate=10/1) to give Compound IIad-a (0.371 g, 50%) as an oily substance.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.Cl[C:34]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:35]>>[CH2:37]([O:36][C:34](=[O:35])[NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:32])[F:30])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1)[CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CCCCCOC(=O)Cl
Agent: Cl
Product: CCCCCOC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)-phenyl)urea hydrochloride and pentyl chloroformate by using the same method as in Example 107.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[C-:13]#[N:14].[Na+]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.C1C=CC=CC=1.O>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH2:2][C:13]#[N:14])=[CH:4][CH:5]=1
Reactant: [C-]#N
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1ccc(CC#N)cc1
Yield: 60.1 %

Procedure:
A mixture of methyl 4-(bromomethyl)benzoate (10.09 g, 44.05 mmol), sodium cyanide (6.42 g, 131 mmol) and cetyltrimethylammonium bromide (1.59 g, 4.36 mmol) in benzene/water (2:1, 187.5 mL) was heated at reflux for 5 h then extracted with CH2Cl2 3×50 mL). The organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. Purification of the crude material by chromatography on silica gel (35% EtOAc/hexanes) gave 4-cyanomethyl-benzoic acid methyl ester as a colourless solid (4.64 g, 60%). 1H NMR (CDCl3) δ3.82 (s, 2H), 3.93 (s, 3H), 7.42 (d, 2H, J=9 Hz), 8.06 (d, 2H, J=9 Hz).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[CH:21]=[C:20]([CH2:22][N:23]3[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]3)[C:19]=2[CH:30]=1.[CH3:31][Si:32]([CH3:35])([CH3:34])Cl>CCCCCC.O1CCCC1>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[CH:21]=[C:20]([CH2:22][N:23]3[CH2:28][CH2:27][C:26]([O:29][Si:32]([CH3:35])([CH3:34])[CH3:31])=[CH:25][CH2:24]3)[C:19]=2[CH:30]=1
Reactant: C[Si](C)(C)Cl
Reactant: COc1ccc2c(c1)C(CN1CCC(=O)CC1)=C2
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CN1CC=C(O[Si](C)(C)C)CC1)=C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
17.4 ml of n-butyllithium in hexane are added at 0°-5° to a solution of 2.81 g of diisopropylamine in 30 ml of dry tetrahydrofuran. The whole is stirred at room temperature for 30 minutes, is again cooled to -15° and a solution of 6.13 g (25 mmol) of 1-[(5-methoxybenzocyclobuten-1-yl)methyl]-piperidin-4-one in 30 ml of tetrahydrofuran is added. After 15 minutes, a solution of 3.05 g (28 mmol) of trimethylchlorosilane in 15 ml of tetrahydrofuran is added dropwise. The whole is stirred overnight at room temperature, filtered and concentrated to dryness by evaporation in vacuo. 1-[(5-methoxybenzocyclobuten-1-yl)methyl]-4-trimethylsilyloxy-1,2,5,6-tetrahydro-pyridine is thus obtained in the form of a light-yellow oil.
Reaction SMILES: [CH2:1]([C:3]1([CH:13]=[N:14][S:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1)[CH3:2].C(C1(C#N)CCC2(OCCO2)CC1)C.C1(CC2(C=NS(C(C)(C)C)=O)CCC3(OCCO3)CC2)CC1.[F:57][CH2:58][S:59]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)(=[O:61])=[O:60].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[C:62]1([S:59]([CH:58]([F:57])[CH:13]([NH:14][S:15]([C:17]([CH3:19])([CH3:18])[CH3:20])=[O:16])[C:3]2([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]3([O:7][CH2:8][CH2:9][O:10]3)[CH2:11][CH2:12]2)(=[O:61])=[O:60])[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: O=S(=O)(CF)c1ccccc1
Reactant: CCC1(C=NS(=O)C(C)(C)C)CCC2(CC1)OCCO2
Agent: CC(C)(C)S(=O)N=CC1(CC2CC2)CCC2(CC1)OCCO2
Agent: CCC1(C#N)CCC2(CC1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: CCC1(C(NS(=O)C(C)(C)C)C(F)S(=O)(=O)c2ccccc2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a solution of 1.70 g (5.64 mmol) of 2-methyl-propane-2-sulfinic acid 1-(8-ethyl-1,4-dioxa-spiro[4.5]dec-8-yl)methylideneamide (prepared from 8-ethyl-1,4-dioxa-spiro[4.5]decane-8-carbonitrile using the protocol described for the synthesis of 19) and 982 mg (5.64 mmol) of fluoromethyl-phenyl sulfone in 60 mL of abs. tetrahydrofuran were added at −78° C. 5.92 mL (5.92 mmol) of a 1M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran. The mixture was stirred for 1 h at −78° C. before being quenched by addition of saturated aqueous ammonium chloride solution and extracted twice with 100 mL of ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered, and concentrated in vacuo to give 2.65 g of the crude title compound. Rt=0.91 min (Method P). Detected mass: 476.4 (M+H+)
Reaction SMILES: [C:1]([CH:6]=[CH:7][C:8]1[N:12]([CH3:13])[C:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:10][C:9]=1[CH3:24])([O:3][CH2:4][CH3:5])=[O:2].N(C([O-])=O)=NC([O-])=O.[K+].[K+].C(O)(=O)C>CO>[C:1]([CH2:6][CH2:7][C:8]1[N:12]([CH3:13])[C:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:10][C:9]=1[CH3:24])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C=Cc1c(C)nc(SCc2ccc(OC)cc2)n1C
Agent: O=C([O-])N=NC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CCc1c(C)nc(SCc2ccc(OC)cc2)n1C

Procedure:
A mixture of 5-[2-(carbethoxy)ethenyl]-1,4-dimethyl-2-(4-methoxybenzylthio)imidazole (600 mg, 1.7 mmole) and potassium azodicarboxylate (29 g, 0.17 mole) in methanol (50 ml) was stirred and treated with acetic acid (7 g, 0.12 mole). The mixture was concentrated in vacuo, partitioned between methylene chloride and 5% aqueous sodium carbonate, and the organic phase was concentrated in vacuo. The residue was chromatographed on silica gel eluted with ethyl acetate to give 5-[2-(carbethoxy)ethyl]-1,4-dimethyl-2-(4-methoxybenzylthio)imidazole (mp 63° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16](=O)[CH3:17])=[CH:11][C:10]=1[CH3:19])([CH3:7])[CH3:6])[CH3:2].ICC[C:24]#[C:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][CH2:17][C:24]#[C:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=2)=[CH:11][C:10]=1[CH3:19])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(SC(C)=O)cc1C
Reactant: FC(F)(F)c1ccc(C#CCCI)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(SCCC#Cc2ccc(C(F)(F)F)cc2)cc1C

Procedure:
In analogy to the procedure described in example 1D], 2-(4-acetylsulfanyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 1C]) was reacted with 1-(4-iodo-but-1-ynyl)-4-trifluoromethyl-benzene (example 2E]) to give the title compound as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH:16]([C:19]1([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:21][CH2:20]1)[CH:17]=O>C(O)(C)C.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:16]([C:19]4([C:22]5[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=5)[CH2:20][CH2:21]4)=[CH:17][N:14]=3)[N:13]=2)=[CH:6][CH:7]=1
Reactant: Nc1ncc(-c2ccc(F)cc2)nn1
Reactant: COc1ccc(C2(C(Cl)C=O)CC2)cc1
Solvent: CC(C)O
Solvent: CO
Product: COc1ccc(C2(c3cnc4ncc(-c5ccc(F)cc5)nn34)CC2)cc1
Temperature: 90 °C

Procedure:
A mixture of 6-(4-fluorophenyl)-1,2,4-triazin-3-amine (20.1 mg, 0.106 mmol) and chloro[1-(4-methoxyphenyl)cyclopropyl]acetaldehyde (53 mg, 0.24 mmol) in isopropyl alcohol (0.6 mL) was heated to 90° C. overnight. After cooling, the mixture was diluted with methanol and was purified by mass-guided RP-HPLC to afford the desired product. LCMS: (M+H)=361.1.
Reaction SMILES: C(OC([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([C:19]1[NH:20][C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:22]2[C:27]=1[CH:26]=[CH:25][C:24]([Cl:28])=[CH:23]2)=[O:18])=O)C1C=CC=CC=1.Br.C(OCC)C>C(O)(=O)C>[CH3:11][NH:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([C:19]1[NH:20][C:21]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:22]2[C:27]=1[CH:26]=[CH:25][C:24]([Cl:28])=[CH:23]2)=[O:18]
Reactant: O=C(CNCCCNC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CNCCCNC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Reaction time: 2 h

Procedure:
9.5 G. of 5-chloro-3-phenylisoindole-1-carboxylic acid {3-[(benzyloxycarbonyl)methylamino]propyl}amide are dissolved in 20 ml. of glacial acetic acid and 30 ml. of a solution of 33% hydrobromic acid in glacial acetic acid are added thereto. The mixture is allowed to stand at room temperature for 2 hours with occasional agitation and it is thereafter poured into 300 ml. of diethyl ether. The separated hydrobromide is removed by filtration under suction, washed with diethyl ether and treated with 200 ml. of 2-N ammonium hydroxide solution. The liberated base is extracted with methylene chloride and the extract washed with water, dried over sodium sulfate and evaporated to dryness. After crystallization of the solid residue from ethanol, there is obtained 5-chloro-3-phenylisoindole-1-carboxylic acid [3-(methylamino)propyl]amide in the form of yellowish crystals having a melting point of 162°-164° C.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][I:14].[SH:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].C([O-])([O-])=O.[K+].[K+].CCCCCC.C(OCC)(=O)C>C(#N)C>[I:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CCS
Reactant: ICCCCCCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CCSCCCCCCCCCCCCI
Yield: 32.2 %

Procedure:
1,12-diiodododecane (2.66 g, 6.3 mmol) was dissolved in 20 mL acetonitrile. Methyl 3-mercaptopropionate (0.76 g, 6.3 mmol) and K2CO3 (1.1 g, 8 mmol) were added and the mixture was allowed to react at room temperature for 20 h. The mixture was acidified with ice-diluted HCl and the solution was extracted twice with ether (20 mL). The combined ether fractions were washed successively with dilute NaHCO3, water and brine, dried (MgSO4 and evaporated under reduced pressure. The product 1 (0.84 g, 32% yield) was isolated by column chromatography (hexane/ethyl acetate 9:1) and recrystallized in MeOH. TLC (hexane/ethyl acetate 9:1) Rf=0.4. Melting point=33° C. 1H-NMR δ1.4 (m, 20H, CH2), 2.52 (t, 2H, C(2)H2), 2.61 (t, 2H, C(5)H2), 2,79 (t, 2H, C(3)H2), 3.20 (t, 2H, C(16)H2), 3.71 (s, 3H, —COO—CH3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH3:12])=[C:6]([CH:9]=1)[CH:7]=O.Cl.[NH2:14]O>C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH3:12])=[C:6]([CH:9]=1)[C:7]#[N:14]
Reactant: NO
Reactant: CCOc1ccc(Br)cc1C=O
Agent: Cl
Solvent: O=CO
Product: CCOc1ccc(Br)cc1C#N
Temperature: 25 °C
Yield: 93.6 %

Procedure:
In formic acid (85.5 ml) was dissolved 5-bromo-2-ethoxybenzaldehyde (17.1 g). To the mixture was added hydroxylamine hydrochloride (7.8 g), and the mixture was refluxed for 7 hours and cooled to room temperature. Under reduced pressure, the solvent was evaporated, and the residue was washed with water and dried to give 5-bromo-2-ethoxybenzonitrile (15.8 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)[N:6]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:15])[F:16])=[CH:9][CH:8]=2)([C:17]2[CH:24]=[CH:23][CH:22]=[C:19]([CH2:20][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:18]=2)[N:6]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C=O)c2)N=C1N
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(CN3CCCC3)c2)N=C1N
Yield: 82.9 %

Procedure:
A small vial (10 ml) was charged with 3-[2-Amino-4-(4-difluoromethoxy-phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-benzaldehyde (69 mg, 192 μmol) and 1,2-dichloroethane (DCE, 1 ml). To this was added one-third of a solution of pyrrolidine (41 mg, 0.576 mmol) in 1,2-dichloroethane (3.00 ml). After stirring overnight at room temperature sodium triacetoxyborohydride (58 mg, 270 μmol) was added followed by 1 drop of glacial acetic acid (˜12 mg), then after another 20 hours 1N sodium hydroxide (1 ml) was added and the mixture extracted with diethyl ether. The ethereal layer was concentrated by rotary evaporation, diluted with methanol and re-concentrated (repeated three times). Finally the oily residue was redissolved in diethylether/hexanes and concentrated, twice then placed under vacuum to give a white foam 66 mg (82%) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (t, J=3.4 Hz, 4H) 2.32 (t, J=6.5 Hz, 4H) 2.93 (s, 3H) 3.44 (s, 2H) 6.62 (br. s., 3H) 7.05 (d, J=8.8 Hz, 2H) 7.08-7.11 (m, 1H) 7.12 (t, J=74.18 Hz, 1H) 7.17 (t, J=7.6 Hz, 1H) 7.25 (t, J=4.6 Hz, 1H) 7.34 (s, 1H) 7.40 (d, J=8.8 Hz, 2H); MS (ES) m/z 413.3 [M−H]−
Reaction SMILES: [CH3:1][O:2][CH2:3][Si](C)(C)C.C([Li])(CC)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][C:22](=O)[CH2:21]2)=[CH:16][CH:15]=1>O1CCCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][C:22](=[CH:3][O:2][CH3:1])[CH2:21]2)=[CH:16][CH:15]=1
Reactant: COC[Si](C)(C)C
Reactant: O=C1CCCC(c2ccc(Cl)cc2)C1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COC=C1CCCC(c2ccc(Cl)cc2)C1
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (methoxymethyl)trimethylsilane (694 mg, 5.75 mmol) in tetrahydrofuran (6.8 mL) at −78° C. was added drop-wise sec-butyllithium (1.4 M, 4.45 mL, 6.23 mmol). The solution was warmed to −25° C., held at that temperature for 30 minutes, then cooled to −78° C. To the reaction was added drop-wise 3-(4-chlorophenyl)cyclohexanone (prepared according to the method of G. A. Whitlock et al., Bioorg. Med. Chem. Lett. 2009, 19, 3118-3121) (1.0 g, 4.8 mmol). The reaction was warmed to −25° C. and stirred for 30 minutes, then allowed to slowly warm to room temperature and stir for 48 hours. The reaction was diluted with tetrahydrofuran (10 mL), quenched with saturated aqueous ammonium chloride solution, and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to provide the crude title compound as a pale yellow oil. Yield: 1.25 g. This material was used directly in the following step. GCMS m/z 236 (M+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:33]=[C:34]([CH2:36][CH2:37][C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[N:35]=3)[C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[C:23](=[O:24])[N:22](COCC[Si](C)(C)C)[CH:21]=[N:20]4)=[CH:15][CH:14]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.C(Cl)Cl.C(O)(C(F)(F)F)=O.O.CCO.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[N:9]([CH:33]=[C:34]([CH2:36][CH2:37][C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[N:35]=3)[C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[C:23](=[O:24])[NH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)=[CH:11][N:12]=2)[CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1cnn(-c2ccc(-c3cnc(N4CCOCC4)c4nc(CCc5ccc6ccccc6n5)cn34)cc2)c1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]cnn1-c1ccc(-c2cnc(N3CCOCC3)c3nc(CCc4ccc5ccccc5n4)cn23)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Compound 84e (89.8 mg, 0.138 mmol) was treated with 5 mL of DCM-TFA-water (30:10:1) and stirred at rt for 14 h. EtOH (1 mL) was added and the mixture was concentrated to a yellow resin (112 mg). The resulting material was taken up in MeOH (20 mL) and CHCl3 (10 mL), treated with DIEA (241 μL, 1.38 mmol), refluxed for 2 h, and then concentrated to give a beige solid. The solid was then purified by flash column chromatography on silica gel (100% EtOAc, followed by 0-30% MeOH-EtOAc) to afford a beige solid that was washed with MeOH (1.5 mL) and dried to give compound 21 as an off-white solid. 1H-NMR (CDCl3—CD3OD (1:1), 400 MHz): δ 8.19 (d, J=8.6 Hz, 1H), 8.05 (d, J=8.6 Hz, 2H), 8.00 (d, J=8.1 Hz, 1H), 7.87 (d, J=9.1 Hz, 1H), 7.81 (s, 1H), 7.72-7.77 (m, 1H), 7.54-7.59 (m, 1H), 7.52 (d, J=9.1 Hz, 2H), 7.38-7.42 (m, 2H), 7.28 (s, 1H), 4.06-4.10 (m, 4H), 3.81-3.85 (m, 4H), 3.38-3.44 (m, 2H), 3.29-3.33 (m, 2H); Mass spectrum (LCMS, ESI pos.): Calcd. for C29H26N8O2, 519.2 (M+H). found 519.4.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([NH2:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[CH3:45][C:33]1[N:32]([CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:26][CH:27]=2)[C:40]2[C:35]([C:34]=1[CH3:44])=[CH:36][C:37]([C:41](=[O:42])[NH:11][CH:9]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:10])=[CH:38][CH:39]=2
Reactant: CC(N)CCc1ccccc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NC(C)CCc3ccccc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-phenylbutan-2-amine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:51]=[CH:50][C:16]2[N:17]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[N:41](COCC[Si](C)(C)C)[N:40]=[CH:39][CH:38]=4)[CH:32]=3)[C:18]([CH2:20][C:21]3([C:26]([O:28][CH3:29])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:19][C:15]=2[CH:14]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH:41]1[C:37]([C:33]2[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=2)[CH2:30][N:17]2[C:16]3[CH:50]=[CH:51][C:13]([O:12][CH2:11][C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)=[CH:14][C:15]=3[N:19]=[C:18]2[CH2:20][C:21]2([C:26]([O:28][CH3:29])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:38][CH:39]=[N:40]1
Reactant: COC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(-c3ccnn3COCC[Si](C)(C)C)c2)CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(-c3ccn[nH]3)c2)CCCC1
Temperature: 70 °C

Procedure:
To a 20 mL vial was added methyl 1-((5-(quinolin-2-ylmethoxy)-1-(3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)benzyl)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate (51 mg, 0.08 mmol) and THF (2 mL) followed by treatment with TBAF (0.4 mL, 1 M). The reaction mixture was heated to 70° C. After 24 hours the mixture was cooled to RT and concentrated to dryness. The residue was purified using FCC to provide the title compound. MS (ESI): mass calcd. for C35H33N5O3, 571.68; m/z found 572.2 [M+H]+.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][N:24](C(OCC5C=CC=CC=5)=O)[CH2:23][C@H:22]4[F:37])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][NH:24][CH2:23][C@H:22]4[F:37])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C(OCc1ccccc1)N1CC[C@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)[C@H](F)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: F[C@@H]1CNCC[C@@H]1Oc1cccc2ccc(-c3nnc4ccccn34)nc12
Temperature: 100 °C

Procedure:
Enantiomer 1 of (cis)-benzyl 4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-3-fluoropiperidine-1-carboxylate (0.185 g, 0.372 mmol) was dissolved in dioxane (4.6 mL) and treated with 6 M hydrogen chloride (4.65 mL, 27.9 mmol) and the reaction mixture was heated at 100° C. for 2 hours. The reaction was cooled and carefully neutralized with solid NaHCO3. The resulting aqueous layer (pH 8-9) was extracted four times with methylene chloride and the resulting organic layers were combined and dried over Na2SO4 then concentrated in vacuo. The residue was chromatographed on SiO2 eluting with a gradient of 6% NH4OH in MeOH)/methylene chloride. The desired material was isolated as a colorless film (22 mg). MS APCI (+) m/z 364.1 (M+1) detected.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([O:21][CH3:22])[CH:13]=2)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:22][O:21][C:14]1[CH:13]=[C:12]([O:11][CH2:10][CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:17]=[CH:16][C:15]=1[NH2:18]
Reactant: COc1cc(OCCCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(OCCCN2CCN(C)CC2)ccc1N
Reaction time: 1 h
Yield: 64.7 %

Procedure:
1-methyl-4-(3-{[3-(methyloxy)-4-nitrophenyl]oxy}propyl)piperazine (1.8 g, 5.8 mmol) was dissolved in methanol (75 mL) and cycled through the H-Cube using a Pd/C cartridge. After 60 min of cycling through the system, the solvent was removed under reduced pressure. NMR indicates starting material still present so residue was dissolved in ethanol and 5% platinum on carbon (200 mg) was added and subjected to a H2 balloon for 16 h. At this time the reaction mixture was filtered through celite which was washed with methanol. The solvents were evaporated under reduced pressure to afford 2-(methyloxy)-4-{[3-(4-methyl-1-piperazinyl)propyl]oxy}aniline (1.1 g, 3.75 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83 (d, J=5.68 Hz, 2 H) 2.41-2.51 (m, 3 H overlaying with DMSO peak) 2.51-2.99 (m, 10 H) 3.68 (s, 3 H) 3.83 (t, J=6.23 Hz, 2 H) 6.24 (dd, J=8.42, 2.56 Hz, 1 H) 6.39 (d, J=2.47 Hz 1 H) 6.49 (d, J=8.42 Hz, 1 H). ESIMS (M+H)+=311.