Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:17]([OH:18])=[C:16]([Cl:19])[C:15]2[O:14][C:13]3[C:8](=[C:9]([Cl:20])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:21])[C:6]=2[CH:5]=1)[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:37](=[O:40])([O-])[O-:38].[K+].[K+]>O>[Cl:20][C:9]1[C:8]2[C:7](=[O:21])[C:6]3[CH:5]=[C:4]4[CH2:1][CH:2]([C:37]([OH:38])=[O:40])[O:18][C:17]4=[C:16]([Cl:19])[C:15]=3[O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: C=CCc1cc2c(=O)c3c(Cl)cccc3oc2c(Cl)c1O
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)C1Cc2cc3c(=O)c4c(Cl)cccc4oc3c(Cl)c2O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.7 %

Procedure:
A mixture of 2-allyl-4,8-dichloro-3-hydroxy-9-oxo-9H-xanthene (14 g), m-chloroperbenzoic acid (11 g) and chloroform (1,000 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, potassium carbonate (20 g) and water (500 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (2,000 ml) and to the stirred solution, a mixture of chromium trioxide (17 g), water (100 ml) and concentrated sulfuric acid (30 g) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 5.0 g of 6,11-dichloro-2,3-dihydro-5-oxo-5H-furo[3,2-b]xanthene-2-carboxylic acid. m.p. 291°-294° C. This compound showed a mass spectrum having a molecular ion peak at m/e 350.
Reaction SMILES: [CH2:1]([NH+:4]([CH2:8][CH2:9][CH3:10])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[CH3:11][CH2:12][N:13]([C:16]([SH:18])=[S:17])[CH2:14][CH3:15].C(=S)=S.C(N(CCC)CCC)CC.C(NCC)C>>[CH2:12]([N:13]([CH2:14][CH3:15])[C:16](=[S:17])[S-:18])[CH3:11].[CH2:1]([NH+:4]([CH2:8][CH2:9][CH3:10])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCN(CC)C(=S)S
Agent: CCCN(CCC)CCC
Agent: CCC[NH+](CCC)CCC
Solvent: S=C=S
Solvent: CCNCC
Product: CCN(CC)C(=S)[S-]
Temperature: 50 °C

Procedure:
Preparation of tripropylammonium salt of diethyl dithiocarbamate is as follows: 76 grams (1 mole) carbon disulfide and 143 grams (1 mole) tripropylamine are mixed at 10° C. under nitrogen. 80.5 grams (1.1 mole) diethylamine is added slowly and drop wise to the mixture and the mixture is maintained at a temperature below 30° C. Then the mixture is heated to 50° C. for 1 hour. The solution is then stripped out under vacuum to remove the excess amine and for the removal of low volatiles to obtain final product. The acid number (normally below 30) is measured to check the acidity. The product purity (ranging between 85-95%) is measured by LC-MS and NMR.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]([CH3:21])[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[CH3:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC1CNCCC1Cc1ccccc1
Yield: 108.6 %

Procedure:
A solution of 2.7 g of 1-benzyl-4-benzylidene-3-methyl-piperidine and 2 g of 20% palladium hydroxide on carbon in 125 mL of ethanol was shaken 3 days under 55 psi of hydrogen. The catalyst was filtered off and the solution concentrated to give 2 g of a mixture of cis and trans-4-benzyl-3-methyl-piperidine as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[Br:20][C:21]1[CH:22]=[CH:23][C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[C:25]([NH2:27])[CH:26]=1.Cl>O1CCOCC1.CO>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[C:25]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:3]=2[CH3:19])[CH:26]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: Nc1cc(Br)ccc1N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(Br)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 1 using 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (131 mg, 480 μmol), 5-bromo-2-morpholinobenzenamine (124 mg, 480 μmol) and 4.0N hydrochloric acid (0.12 mL, 480 μmol) solution in dioxane in MeOH (1.50 mL) to afford a yellow solid after purification by chromatography on silica gel, eluting with EtOAc-hexane solvent mixture. Mass Spectrum (ESI) m/e=493.0 & 495.0 (M+1).
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[N:19]=[N:20][NH:21][CH:22]=3)=[C:9]([OH:23])[C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:26].C1(N2C=CC(CCCC3N=NNC=3)=C(O)C2=S)C=CC=CC=1>>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[N:19]=[N:20][NH:21][CH:22]=3)=[C:9]([OH:23])[C:8]2=[S:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1c(O)c(CCCCCc2c[nH]nn2)ccn1-c1ccccc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: Oc1c(CCCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Product: Oc1c(CCCCCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Yield: 121.3 %

Procedure:
Reaction of 159d (0.025 g, 0.077 mmol) and P4S10 (0.020 g, 0.046 mmol) under neat conditions as described for synthesis of 162b gave compound 162d (0.019 g, 73%) as a olive green solid. 1H NMR (400 MHz, DMSO) δ 8.55 (d, J=2.9 Hz, 2H), 7.83 (t, J=7.8 Hz, 3H), 7.43 (q, J=7.4 Hz, 2H), 7.32 (t, J=6.6 Hz, 1H), 7.08 (m, 1H), 6.92 (dd, J=31.0, 6.8 Hz, 1H), 6.81 (m, 1H), 4.51 (m, 2H), 4.41 (t, J=7.0 Hz, 2H), 1.89 (m, 4H), 1.32 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 168.37, 155.10, 147.66, 131.04, 130.46, 128.75, 128.05, 125.57, 119.68, 113.69, 111.96, 57.73, 49.73, 29.47, 27.12, 23.04. HRMS (EI) calcd for C18H20N4OS [M]+ 340.135. found 326.1364.
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.Br[CH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[N:18]=[C:17]([Cl:22])[CH:16]=1>>[ClH:21].[Cl:21][C:19]1[CH:20]=[C:15]([CH2:14][O:1][NH2:2])[CH:16]=[C:17]([Cl:22])[N:18]=1
Reactant: Clc1cc(CBr)cc(Cl)n1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: Cl
Product: NOCc1cc(Cl)nc(Cl)c1

Procedure:
Prepared by a similar procedure as described for preparation 18. Starting materials: N-hydroxyphthalimide and 4-bromomethyl-2,6-dichloropyridin (Maybridge). 1H-NMR (DMSO-d6) δ 11.2 (br, 3H), 7.62 (s, 2H), 5.18 (s, 2H).
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[CH:24][C:25](C4C=CC=CC=4)=[N:26]3)=[CH:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:35](O)(=O)[CH3:36].[OH-].[Na+]>CCO>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[C:24]([C:36]4[CH:35]=[CH:3][CH:2]=[CH:1][CH:6]=4)[CH:25]=[N:26]3)=[CH:21][CH:20]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3ccc(-c4ccccc4)nc3c1)n2C1CCCCC1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3cc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Yield: 17 %

Procedure:
Following the same reaction procedure and workup as for Compound 405, 450 mg (0.9 mmol) of the product from the previous step was cyclized with 40 mL acetic acid and saponified with 35 mL EtOH and 7 mL 1M NaOH to produce 70 mg (17% yield) of the title compound.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=[O:17]>C(O)(=O)C.C1COCC1.O>[OH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=[O:17]
Reactant: O=c1ccccn1CCCOC1CCCCO1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=c1ccccn1CCCO
Yield: 98.7 %

Procedure:
A solution of 1-(3-(2-tetrahydropyranyloxy)propyl)-1,2-dihydro-2-pyridone (1.0 g, 4.5 mmol) in acetic acid (8 ml), THF (4 ml) and water (2 ml) was heated at 50° C. for 4 hours. The volatiles were removed by evaporation and the residue azeotroped with toluene to give 1-(3-hydroxypropyl)-1,2-dihydro-2-pyridone (680 mg, 99%) as an off-white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)#[N:2].[CH2:12](I)[CH3:13].[H-].[Na+].[CH3:17][CH2:18]OC(C)=O>CCCCCCC.O.CN(C=O)C>[C:1]([C:3]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)([CH2:12][CH3:13])[CH2:17][CH3:18])#[N:2]
Reactant: N#CCc1ccc(C#N)cc1
Reactant: CCOC(C)=O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C#N)(CC)c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
4-Cyanomethylbenzonitrile (1.02 g, 7.18 mmol) and ethyl iodide (2.25 g, 14.4 mmol) are added to DMF (20.0 mL), and the resulting solution is cooled to 0° C. NaH (576 mg, 14.4 mmol) is added in portions. The mixture is warmed to room temperature and then stirred for 3 hours. Water (100 mL) is added, and the aqueous phase is extracted with EtOAc (4 times with 50.0 mL). The combined organic phases are dried with MgSO4, filtered and concentrated on the rotovaporator. The product is purified by Combi-Flash silica gel chromatography, eluting with mixtures of heptane and EtOAc (100/0 to 70/30), (936 mg, 5.51 mmol, 77%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.77 (t, J=7.42 Hz, 6H) 1.89-2.14 (m, 4H) 7.64 (d, J=8.40 Hz, 2H) 7.92 (d, J=8.59 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1([CH2:15][O:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:26]=2[N:25]=[C:24]([C:27]2[N:31]4[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:30]4=[N:29][N:28]=2)[CH:23]=[CH:22]3)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].I[CH3:40]>CN(C)C=O>[CH3:40][O:1][C:2]1([CH2:15][O:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:26]=2[N:25]=[C:24]([C:27]2[N:31]4[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:30]4=[N:29][N:28]=2)[CH:23]=[CH:22]3)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:4][CH2:3]1
Reactant: Cc1ccn2c(-c3ccc4cccc(OCC5(O)CCN(C(=O)OC(C)(C)C)CC5)c4n3)nnc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(COc2cccc3ccc(-c4nnc5cc(C)ccn45)nc23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.6 %

Procedure:
A mixture of tert-butyl 4-hydroxy-4-((2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)piperidine-1-carboxylate (50 mg, 0.10 mmol) and sodium hydride (18 mg, 0.82 mmol) in dimethylformamide (1 mL) was stirred at ambient temperature for 15 minutes. Iodomethane (0.051 mL, 0.82 mmol) was added and the solution was stirred at ambient temperature overnight. The reaction was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed twice with saturated aqueous ammonium carbonate. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with hexanes and further purified by preparative thin layer chromatography with 1:9 methanol/dichloromethane to provide 25 mg (46%) of desired product.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:16]=[C:17]([Cl:28])[C:18]([S:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.C1COCC1.O[Li].O>O>[CH2:21]([S:20][C:18]1[C:17]([Cl:28])=[CH:16][C:14]2[NH:15][C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)=[N:12][C:13]=2[CH:19]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(SCc4ccccc4)c(Cl)cc3[nH]2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2nc3cc(SCc4ccccc4)c(Cl)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 79.8 %

Procedure:
To a mixture of 1-(5-benzylsulfanyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (57.0 mg, 0.127 mmol), THF (2 mL), and water (0.67 mL) was added LiOH.H2O (27.0 mg, 0.654 mmol). The mixture was stirred for 18 h at 23° C. The reaction mixture was concentrated under reduced pressure, water (3 mL) was added and the mixture acidified to pH=3 with 1M HCl. The resulting white precipitate was filtered and dried to yield the titled compound (39.0 mg, 80%). MS (ESI/CI): mass calcd. for C18H13ClN4O2S, 384.0; m/z found, 385.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 8.86 (s, 1H), 8.29 (s, 1H), 7.67 (s, 1H), 7.53 (s, 1H), 7.39 (d, J=7.4 Hz, 2H), 7.31 (t, J=7.4 Hz, 2H), 7.25 (t, J=7.1 Hz, 1H), 4.29 (s, 2H).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC(=O)[N:14]=[C:15]([NH:55]C(OC(C)(C)C)=O)[NH:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([CH2:28][S:29][C:30]2[N:31]([C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=3)[C:32]([C:35]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([O:45][CH3:46])[CH:39]=3)([CH3:37])[CH3:36])=[CH:33][N:34]=2)=[C:23]([F:54])[CH:22]=1)(C)(C)C>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([O-:7])=[O:2].[NH2:55][C:15]([NH:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([CH2:28][S:29][C:30]2[N:31]([C:47]3[CH:48]=[CH:49][C:50]([F:53])=[CH:51][CH:52]=3)[C:32]([C:35]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([O:45][CH3:46])[CH:39]=3)([CH3:37])[CH3:36])=[CH:33][N:34]=2)=[C:23]([F:54])[CH:22]=1)=[NH2+:14]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Solvent: ClCCl
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCNC(N)=[NH2+])cc3F)n2-c2ccc(F)cc2)ccc1Cl
Product: O=C([O-])C(F)(F)F
Yield: 45 %

Procedure:
A solution of TFA (5 mL) and tert-butyl(tert-butoxycarbonylamino)(3-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)propylamino)methylenecarbamate (559 mg, 0.57 mmol) in DCM (1 mL) was stirred 1 h and purified by preparative HPLC (30-100%, CH3CN/H2O with 0.05% TFA) to yield the title compound as a white solid (157 mg, 45%, 2 steps). 1HNMR (400 MHz, CD3CN) δ 7.25-7.10 (m, 2H), 6.88-6.78 (m, 2H), 6.56 (d, J=2.0 Hz, 1H), 6.50 (m, 3H), 6.46-6.30 (m, 2H), 4.04 (t, J=6.1 Hz, 2H), 3.90 (s, 2H), 3.71 (s, 3H), 3.28 (t, J=6.7 Hz, 2H), 2.06-1.98 (m, 2H), 1.48 (s, 6H); MS (EI) m/z 618.4 (MH+).
Reaction SMILES: O1CCCC1.[NH3:6].Cl[C:8]1[C:9]2[C:16]([I:17])=[CH:15][N:14]([C@H:18]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]3)[C:10]=2[N:11]=[CH:12][N:13]=1.C(Cl)(Cl)Cl>O>[NH2:6][C:8]1[C:9]2[C:16]([I:17])=[CH:15][N:14]([C@H:18]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]3)[C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2cc(I)c3c(Cl)ncnc32)C1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](n2cc(I)c3c(N)ncnc32)C1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
Tetrahydrofuran (2.5 ml) and 28% aqueous ammonia (2.5 ml) were added to (S)-tert-butyl 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (400 mg) obtained in Step 1 above. The reaction mixture was stirred at 100° C. for 1.5 hours using a microwave reactor. Chloroform and water were added thereto to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a white, solid compound (382 mg). Physical properties: m/z [M+H]+ 430.3
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[BrH:11]>>[BrH:11].[NH2:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([OH:2])=[CH:4][CH:5]=1
Reactant: COc1ccc(CN)cc1
Agent: Br
Product: NCc1ccc(O)cc1
Yield: 35 %

Procedure:
A mixture of 40.0 g (0.29 mole) of 4-methoxybenzylamine (98%, Aldrich) and 150 mL of 48% hydrobromic acid (Baker) was stirred and heated at reflux for 18 hr, then stirred at ambient temperature for 72 hr. The precipitate was collected by filtration, washed with ethyl ether (300 mL) and dried to give 21.0 g (35%) of the title compound as an off-white solid, mp 215°-217° C.
Reaction SMILES: [N:1]1([C:7]2([CH2:13][OH:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15]([O:19][C:20]([NH:22][C@H:23]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:24](O)=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O>CN(C)C=O>[C:15]([O:19][C:20](=[O:21])[NH:22][C@H:23]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:24]([N:10]1[CH2:11][CH2:12][C:7]([CH2:13][OH:14])([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][CH2:9]1)=[O:25])([CH3:18])([CH3:16])[CH3:17]
Reactant: OCC1(N2CCCCC2)CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(CO)(N2CCCCC2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a round bottom flask equipped with a stirring bar is charged [1,4′]bipiperidinyl-4′-yl-methanol, 22, (2.2 g, 11.1 mmol, 1.0 eq.) 2-(R)-tert-butoxycarbonylamino-3-(4-chlorophenyl)-propionic acid (3.648 g, 12.2 mmol), 1-hydroxybenzotriazole (2.552 g, 18.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3.71 g, 18.9 mmol) in anhydrous N,N-dimethylformamide (80 mL). The mixture is cooled to 0° C. and N,N-diisopropyl-ethylamine (4.1 mL, 37.7 mmol) is added. The ice bath is removed and the reaction mixture allowed to stir overnight. The mixture is concentrated under reduced pressure and purified by preparative HPLC to afford 2.83 g (43% yield) of the desired compound as the trifluoroacetic acid salt. 1H NMR (CD3OD, 300 MHz) δ 0.85–2.13 (m, 19H), 2.65–3.82 (m, 8H), 3.90–4.10 (m, 3H), 4.48 (m, 1H), 4.76 (m, 1H), 7.22–7.48 (m, 4H). MS (ESI) m/z 480 (M+H+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[O:31]=[C:32]1[C@H:41]2[N:37]([CH2:38][CH2:39][CH2:40]2)[CH2:36][C:35]2[CH:42]=[C:43](/[CH:46]=[CH:47]/[C:48](O)=[O:49])[CH:44]=[N:45][C:34]=2[NH:33]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>CO>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13])[C:48](=[O:49])/[CH:47]=[CH:46]/[C:43]1[CH:44]=[N:45][C:34]2[NH:33][C:32](=[O:31])[C@H:41]3[N:37]([CH2:38][CH2:39][CH2:40]3)[CH2:36][C:35]=2[CH:42]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN1CCC[C@H]1C(=O)N2
Reactant: CNCc1sc2ccccc2c1C
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Solvent: CO
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN2CCC[C@H]2C(=O)N3)sc2ccccc12
Yield: 62 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (S)-(E)-3-(10-oxo-2,3,4,9,10,10a-hexahydro-1H-3a,8,9-triaza-benzo[f]azulen-6-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.15 g, 62%) was prepared as a tan powder: [α]25D+167.8° (c 1.05, methanol); 1H NMR (300 MHz, DMSO-d6) δ 12.33 (br s, 1H), 11.30 (br s, 1H), 8.84 (s, 1H), 8.33 (s, 1H), 7.89-7.86 (m, 1H), 7.75-7.72 (m, 1H), 7.65-7.55 (m, 1H), 7.42-7.31 (m, 3H), 5.13-4.90 (m, 2H), 4.47-4.22 (m, 2H), 3.61 (br s, 1H), 3.42-3.39 (br s, 4H), 3.17-2.95 (m, 3H), 2.42 (s, 3H), 2.10-1.88 (2H); MS (ESI) m/e 447 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[O:10][CH:7]([O:8][CH3:9])[C@H:6]([OH:11])[C@@H:5]1[OH:12].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO>CN(C)C=O>[CH3:1][O:2][CH2:3][C@H:4]1[O:10][CH:7]([O:8][CH3:9])[C@H:6]([O:11][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:5]1[O:12][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC[C@H]1OC(OC)[C@H](O)[C@@H]1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC[C@H]1OC(OC)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of methyl 5-O-methyl-D-ribofuranoside (Dubois L. et al. Tetrahedron 1993, 49(4), 901-910, 2 g, 11.2 mmol) in dimethylformamide (10 mL) was added dropwise to a suspension of sodium hydride (60% in oil, 2.25 g, 563 mmol) in dimethylformamide (54 mL). After stirring at rt for 45 minutes, a solution of benzyl bromide (4 mL, 33.6 mmol) was added dropwise in dimethylformamide (4 mL). The reaction mixture was stirred at rt overnight, quenched with methanol and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, hexanes/ethyl acetate 70/30 to 50/50) to provide the a anomer (2.86 g, 71%) and the β anomer (0.86 g, 21%); α anomer Rf=0.5, β anomer Rf=0.4 (silica, hexanes/ethyl acetate 50/50).
Reaction SMILES: N1(O[C:11]([N:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C@H:16]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[N:15]=[C:14]2[C:32]2[CH:37]=[C:36]([S:38](=[O:42])(=[O:41])[NH:39][CH3:40])[C:35]([Cl:43])=[CH:34][C:33]=2[O:44][CH2:45][CH3:46])=[O:12])C2C=CC=CC=2N=N1.[N:47]1([C:53](=[O:61])[CH2:54][N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C@H:16]2[C@@H:17]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:13]([C:11]([N:58]3[CH2:59][CH2:60][N:55]([CH2:54][C:53]([N:47]4[CH2:48][CH2:49][O:50][CH2:51][CH2:52]4)=[O:61])[CH2:56][CH2:57]3)=[O:12])[C:14]([C:32]3[C:33]([O:44][CH2:45][CH3:46])=[CH:34][C:35]([Cl:43])=[C:36]([S:38]([NH:39][CH3:40])(=[O:41])=[O:42])[CH:37]=3)=[N:15]2)=[CH:30][CH:29]=1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(Cl)c(S(=O)(=O)NC)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1
Temperature: 40 °C
Yield: 100.4 %

Procedure:
To a solution of (4S,5R)-2-(4-chloro-2-ethoxy-5-methylsulfamoyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carboxylic acid benzotriazol-1-yl ester (9 mg, 0.0124 mmol) in 0.5 mL of dimethylformamide was added a solution of 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (5.3 mg, 0.026 mmol) and diisopropylethylamine (4.53 uL). The resulting mixture was heated to 40° C. for 1 h. The solution was concentrated in vacuo then extracted from 1 mL of water with 1 mL of methylene chloride. The organic extract was applied to a 4 gram silica gel cartridge. The product was eluted using a gradient of methanol in methylene chloride to give 5-{(4S,5R)-4,5-bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-2-chloro-4-ethoxy-N-methyl-benzenesulfonamide (9.69 mg, 97%). LC-MS: 777.3 [(M+H)+].