Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]3[CH:11]=[CH:12][C:13]([OH:15])=[N:14][C:9]=3[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.[H-].[Na+].IC.[C:25]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]3[CH:11]=[CH:12][C:13](=[O:15])[N:14]([CH3:25])[C:9]=3[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1
Reactant: Nc1ncc2c3ccc(O)nc3n(C3CCCC3)c2n1
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1c(=O)ccc2c3cnc(N)nc3n(C3CCCC3)c21
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
Compound 272 (100 mg, 0.37 mmol) was dissolved in dry DMF (1 mL). Sodium hydride, 60% dispersion in oil (16.0 mg, 0.4 mmol) was added and the reaction stirred at 60° C. for 20 minutes. Iodomethane (26.5 μl, 423 μmol) was the added and the reaction stirred at 60° C. for 2 hr. The solution was allowed to cool and added to water (10 mLl) and aqueous K2CO3 (saturated, 2 mL), and extracted with ethyl acetate (2×30 mL), and dichloromethane+10% methanol (2×30 mLl). The combined organics were dried (MgSO4) and evaporated to give an orange solid. Silica gel chromatography (gradient elution hexanes+2.5% TEA/0-70% ethyl acetate+2.5% TEA) afforded compound 273 as a white solid, 64 mg (61%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:17])[O:11][CH2:10][CH2:9][C@H:8]2[N:5]1[C:6](=[O:16])[C@@H:7]2[C:12]([OH:15])([CH3:14])[CH3:13].S(OC)(O[CH3:22])(=O)=O.C(O)(=O)C>CN(C)C=O>[CH3:3][C:4]1([CH3:17])[O:11][CH2:10][CH2:9][C@H:8]2[N:5]1[C:6](=[O:16])[C@@H:7]2[C:12]([O:15][CH3:22])([CH3:13])[CH3:14]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(O)[C@H]1C(=O)N2[C@@H]1CCOC2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(C)(C)[C@H]1C(=O)N2[C@@H]1CCOC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (38.1 mg, 50% in mineral oil) in N,N-dimethylformamide (1.14 ml) was added dropwise a solution of (6R, 7S)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-1-aza-3-oxabicyclo[4.2.0]-octan-8-one (84.6 mg) in N,N-dimethylformamide (25.4 ml) at 0° C. After stirring for 30 minutes at 0° C., thereto was added a solution of dimethyl sulfate (75.13 μl) in N,N-dimethylformamide (0.676 ml), and the resultant mixture was stirred for 3 hours at 0° C. and for additional 1.5 hours at ambient temperature. Acetic acid (0.046 ml) was added to the mixture, and the solvent was distilled off in vacuo. The residue was diluted with ethyl acetate (20 ml) and then washed with an aqueous sodium chloride, 10% aqueous sodium bicarbonate, and a saturated aqueous sodium chloride in turn. The aqueous washings were extracted with ethyl acetate, and this extract was washed with an aqueous sodium chloride. The combined extracts were dried over magnesium sulfate, filtered and evaporated in vacuo. The residue (92.9 mg) was chromatographed on silica gel (2.5 g) eluting with a mixture of ethyl acetate and methylene chloride (1:100 to 1:3) to give (6R, 7S)-2,2-dimethyl-7-(1-methoxy-1-methylethyl)-1-aza-3-oxabicyclo[4.2.0]-octan-8-one (69.1 mg) as a pale yellow solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C@@H:8]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]2[OH:10])[CH:6]=[N:5][C:4]=1[C:17](=[N:19]O)[NH2:18].CO.N1C=CC=CC=1.[C:29](=S)=[S:30]>>[CH:6]1[N:7]([C@@H:8]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]2[OH:10])[C:3]2[C:4](=[C:17]([NH2:18])[NH:19][C:29]([N:2]=2)=[S:30])[N:5]=1
Reactant: NC(=NO)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N
Reactant: S=C=S
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 88 %

Procedure:
To 10.0 g of 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide oxime hydrochloride were added 120 ml of methanol and 120 ml of pyridine to form a solution. 60 ml of carbon disulfide was added to the solution, and the resulting mixture was allowed to react in an autoclave at 120° C for 3 hours under autogenous pressure (about 10 kg/cm2). The reaction mixture was concentrated to dryness, and the residue was dissolved in 1N aqueous ammonia. 100 ml of n-butanol and 50 ml of glacial acetic acid were then added to the solution followed by cooling to crystallize the product to obtain 9.01 g of 2-thioadenosine having a melting point of 199° C (with decomposition) in an 88% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[C:4]([F:13])[CH:3]=1.IC1C=C(O)C=CC=1.[CH:22]1([C:27]([OH:44])([C:38]#[C:39][Si](C)(C)C)[CH2:28][C:29]2[O:34][C:33]([CH3:36])([CH3:35])[O:32][C:31](=[O:37])[CH:30]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([C:27]([OH:44])([CH2:28][C:29]2[O:34][C:33]([CH3:35])([CH3:36])[O:32][C:31](=[O:37])[CH:30]=2)[C:38]#[C:39][C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]#[N:12])[CH2:10][CH2:9]3)=[C:4]([F:13])[CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#C[Si](C)(C)C)C2CCCC2)O1
Reactant: N#CC1(c2ccc(Br)cc2F)CC1
Agent: Oc1cccc(I)c1
Product: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C3(C#N)CC3)c(F)c2)C2CCCC2)O1

Procedure:
The desired product was prepared analogously to example F(7), Step 5, substituting 1-(4-bromo-2-fluoro-phenyl)-cyclopropanecarbonitrile (0.96 g, 4.0 mmol), from Step 2 above in place of 3-iodophenol, and 6-(2-cyclopentyl-2-hydroxy-but-3-ynyl)-2,2-dimethyl-[1,3]dioxin-4-one (1.06 g, 4.0 mmol; from Step 4 above) in place of 6-but-3-ynyl-3-chloro-6-cyclopentyl-dihydro-pyran-2,4-dione. Yield: 1.241 g, 73%.
Reaction SMILES: [CH2:1]([C@H:9]([C@H:12]([OH:14])[CH3:13])[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C(OCC)C.O.C1(C)C=CC=CC=1>[CH2:1]([C@H:9]1[CH2:10][O:11][C@H:20]([C:19]2[CH:22]=[CH:23][C:16]([OH:15])=[CH:17][CH:18]=2)[O:14][C@@H:12]1[CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCC[C@@H](CO)[C@@H](C)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCCCCCCC[C@H]1CO[C@H](c2ccc(O)cc2)O[C@@H]1C
Yield: 84.7 %

Procedure:
A mixture of 320 mg of (2S,3R)-2-octyl-1,3-butanediol, 193 mg of p-hydroxybenzaldehyde, 0.1 ml of 1N sulfuric acid and 20 ml of toluene was placed under nitrogen in a round flask having a magnetic stirrer, water separator and condenser. The mixture was heated to reflux for 3 hours while separating water. The cooled reaction mixture was poured into aqueous sodium hydrogen carbonate solution and treated with diethyl ether. The aqueous phase was separated and extracted three times with diethyl ether. The combined organic phases were washed three times with round flask having a magnetic stirrer, water separator and condenser. The mixture was heated to reflux for 3 hours while separating water. The cooled reaction mixture was poured into aqueous sodium hydrogen carbonate solution and treated with diethyl ether. The aqueous phase was separated and extracted three times with diethyl ether. The combined organic phases were washed three times with water, dried over magnesium sulfate, filtered and evaporated. Recrystallization of the yellowish, solid residue (480 mg) from hexane/ethyl acetate (vol. 25:1) gave 410 mg of 4-[(2S,4R,5S)-5-octyl-4-methyl-1,3-dioxan-2-yl]phenol as yellowish crystals with [a]D =+27° (c=1% in chloroform).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.CS(O[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH3:36])=[CH:29][CH:28]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:34]([O:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:32][CH:31]=1)[CH2:35][CH3:36]
Reactant: CCCOc1ccc(CCCOS(C)(=O)=O)cc1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1ccc(CCCOc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 141 %

Procedure:
Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (401 mg), 3-(4-propoxyphenyl)propyl methanesulfonate (1017 mg) and potassium carbonate (310 mg) were suspended in DMF (15 ml), and the resulting suspension was stirred at 70° C. for 5 hours. The reaction mixture was diluted with ethyl acetate and was washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain methyl 7-[3-(4-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (937 mg) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH:3]=[CH2:4].[N+:7]([CH2:10][CH3:11])([O-])=[O:8].C1(N=C=O)C=CC=CC=1>C(OCC)C>[CH3:11][C:10]1[CH2:4][CH:3]([C:2]([F:6])([F:5])[F:1])[O:8][N:7]=1
Reactant: CC[N+](=O)[O-]
Reactant: C=CC(F)(F)F
Solvent: O=C=Nc1ccccc1
Solvent: CCOCC
Product: CC1=NOC(C(F)(F)F)C1
Temperature: 22 °C
Reaction time: 60 h
Yield: 40 %

Procedure:
To a solution of 3,3,3-trifluoroprop-1-ene (ca. 18 g) in diethyl ether (120 ml) was added subsequently at −78° C. nitroethane (5.74 g, 76.5 mmol), TEA (76 mg, 0.75 mmol) and phenyl isocyanate (18.2 g, 153 mmol), the solution was warmed to 22° C. and stirring was continued for 60 h. The suspension was filtered and the filtrate distilled from bulb to bulb at 75° C./1.0 mbar to give 3-methyl-5-(trifluoromethyl)-4,5-dihydroisoxazole (4.69 g) as a pale yellow liquid. MS: m/z=153 [M]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:27])[N:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:68]=[CH:67][C:39]([O:40][CH2:41][C@H:42]([NH:47][C:48]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]([O:45][CH3:46])=[O:44])=[CH:38][CH:37]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:27][C:4]1[N:3]=[C:2]([C:36]2[CH:68]=[CH:67][C:39]([O:40][CH2:41][C@H:42]([NH:47][C:48]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C:43]([O:45][CH3:46])=[O:44])=[CH:38][CH:37]=2)[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=1
Reactant: Nc1nc(Cl)cc(OC(c2ccc(-c3cccc(F)c3)cc2)C(F)(F)F)n1
Reactant: COC(=O)[C@H](COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)[C@H](COc1ccc(-c2cc(OC(c3ccc(-c4cccc(F)c4)cc3)C(F)(F)F)nc(N)n2)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
4-chloro-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-2-amine (80 mg, 0.20 mmol), (S)-methyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-(tritylamino)propanoate (113 mg, 0.20 mmol), dichlorobis(triphenylphosphine)palladium (2 mg, 0.03 mmol), and Na2CO3 (42 mg, 0.40 mmol) were added to a mixture of ethanol (5 mL) and water (5 mL) in a round-bottom flask. The flask was heated to reflux for 8 hours. The reaction mixture was cooled and solvent was removed. The residue was purified by chromatography to get (2S)-methyl 3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenoxy)-2-(tritylamino)propanoate, which was deprotected by TFA and LiOH respectively to afford 50 mg of (2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenoxy)propanoic acid as the HCl salt. 1H NMR (300 MHz, CD3OD): δ 7.95 (m, 2H), 7.71 (s, 3H), 7.61 (m, 2H), 7.48 (m, 2H), 7.26 (m, 1H), 7.11 (m, 1H), 7.01 (s, 1H), 6.78 (m, 1H), 4.65 (m, 1H), 4.40-4.55 (m, 3H); M+1=543.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)([CH2:16][CH2:17][CH2:18][CH3:19])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:28][OH:29].[K+].[Br-]>>[OH:29][NH:28][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:10])=[O:11])([CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: NO
Reactant: CCCCC(Cc1cccnc1)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: CCCCC(Cc1cccnc1)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 37 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid (0.31 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.13 g of the product isolated. Yield 37%; pale yellowish solid; mp 65° C.; MS: 392.9 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 0.80 (t, J=7.2 Hz, 3H), 1.10-1.25 (m, 2H), 1.25-1.50 (m, 2H), 1.70-2.00 (m, 2H), 3.53 (d, J=14.4 Hz, 1H), 3.62 (d, J=14.4 Hz, 1H), 3.88 (s, 3H), 7.15 (d, J=8.9 Hz, 2H), 7.71 (d, J=8.9 Hz, 2H), 7.90-8.00 (m, 1H), 8.40-8.45 (m, 1H), 8.70-8.85 (m, 2H), 11.0 (brs, 1H); IR (KBr, cm−1): 3064 m, 2958s, 2871 m, 1671 m.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][NH:5][C:4](=[O:8])[C:3]1=[O:9].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C>[CH:10](=[N:1][N:2]1[CH2:7][CH2:6][NH:5][C:4](=[O:8])[C:3]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NN1CCNC(=O)C1=O
Reactant: O=Cc1ccccc1
Solvent: CC(=O)O
Product: O=C1NCCN(N=Cc2ccccc2)C1=O
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
1.3 pts. by wt. of 1-amino-2,3-dioxo-piperazine, 1.3 pts. by wt. of benzaldehyde and 7 pts. by vol. of glacial acetic acid are warmed to 90° for 90 minutes and then left at 5° for 30 minutes. The precipitate is filtered off, washed first with 3 pts. by vol. of glacial acetic acid and then with three times 10 pts. by vol. of ethyl acetate and dried over P2O5. 1.75 pts. by wt. (81.8% ) of 1-benzylideneamino-2,3-dioxo-piperazine of melting point 236°-240° C. are obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]=O.Cl.[C:16]([O:20][C:21](=[O:28])[C@H:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[NH2:23])([CH3:19])([CH3:18])[CH3:17].[Na]>O1CCCC1.C(OCC)(=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][NH:23][C@H:22]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:28])[C:24]([CH3:27])([CH3:25])[CH3:26]
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H](NCCN1C(=O)c2ccccc2C1=O)C(C)(C)C
Temperature: 20 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
A solution of the product of Example 111-1 (46.5 g, 246.0 mmol) in tetrahydrofuran (900 mL) was treated with L-tert-leucine-t-butyl ester hydrochloride salt (66.1 g, 295.2 mmol, 1.2 equivalents) stirred at 20° C. for 2 hours, treated with sodium triacetoxyborohydrodride (78.2 g, 369.0 mmol, 1.5 equivalents) portionwise over 5 minutes (slightly exothermic), stirred at 20° C. for 2 hours, diluted with ethyl acetate (1 L) and washed with water (1 L). The organic layer was washed with water (1 L), 10% NaHCO3 (2×1 L) and brine (1 L). The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound (87 g, 98.2% yield). 1H NMR (CDCl3): δ 7.82 (m, 2 H), 7.70 (m, 2 H), 3.77 (t, 2 H), 2.92 (m, 1 H), 2.73(s, 1H), 2.68(m, 1H), 1.44(s, 9H), 0.86(s, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][C:14]3([C:17](O)=[O:18])[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:20][C:21]1[S:22][C:23]2[CH:29]=[C:28]([O:30][C:31]([F:34])([F:33])[F:32])[CH:27]=[CH:26][C:24]=2[N:25]=1.[CH3:35][NH:36][CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:35][N:36]([CH3:37])[C:17]([C:14]1([NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:20][C:21]4[S:22][C:23]5[CH:29]=[C:28]([O:30][C:31]([F:34])([F:32])[F:33])[CH:27]=[CH:26][C:24]=5[N:25]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:15][CH2:16]1)=[O:18]
Reactant: CNC
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC3(C(=O)O)CC3)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C1(NC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(OC(F)(F)F)cc4s2)n3C)CC1
Temperature: 0 °C

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (1-dimethylcarbamoyl-cyclopropyl)-amide (48 mg) was prepared by following General Procedure F using 1-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-cyclopropanecarboxylic acid (49 mg), dimethyl amine (0.3 ml, 1.0 M solution in THF), HBTU (38 mg), and DIEA (0.1 ml), with a minor modification of General Procedure F where DIEA was slowly added to the reaction mixture at last while stirring at 0° C. LC/MS: m/z 520 [M+2]. 1H NMR (DMSO-d6, 400 MHz): δ 8.92 (s, 1H), 8.06 (s, 1H), 7.91 (m, 1H), 7.72 (d, 1H), 7.60 (br, 1H), 7.46 (d, 1H), 7.33 (d, 1H), 7.24 (m, 1H), 3.66 (s, 3H), 2.87 (d, 6H), 1.26 (t, 2H), and 1.01 (t, 2H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:41][CH:42]1[CH2:47][CH2:46][N:45]([CH2:48][C:49]2[CH:56]=[CH:55][C:52]([C:53]#[N:54])=[CH:51][CH:50]=2)[CH2:44][CH2:43]1>O>[Br:1][C:2]1[S:3][C:4]([C:7]([NH:41][CH:42]2[CH2:47][CH2:46][N:45]([CH2:48][C:49]3[CH:56]=[CH:55][C:52]([C:53]#[N:54])=[CH:51][CH:50]=3)[CH2:44][CH2:43]2)=[O:9])=[CH:5][N:6]=1
Reactant: N#Cc1ccc(CN2CCC(N)CC2)cc1
Reactant: O=C(O)c1cnc(Br)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CN2CCC(NC(=O)c3cnc(Br)s3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a stirred mixture of 2-bromothiazole-5-carboxylic acid (500 mg, 2.4 mmol) in anhydrous N,N-dimethylormamide (5 mL) was added triethylamine (1.1 mL, 7.92 mmol), HATU (1 g, 2.64 mmol), and 4((4-aminopiperidin-1-yl)methyl)benzonitrile (762 mg, 2.64 mmol). The mixture was stirred at room temperature overnight and then poured into water. The resulting solids were collected by filtration and purified by column chromatography to yield 972 mg (100%) of 2-bromo-N-(1-(4-cyanobenzyl)piperidin-4-yl)thiazole-5-carboxamide as a yellow solid. LCMS (m/z): 406 (MH+).
Reaction SMILES: [CH2:1]([N:8]([CH2:16][CH2:17][CH2:18][C:19]#[N:20])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:21]>ClCCl>[CH2:9]([N:8]([CH2:16][CH2:17][CH2:18][C:19]([NH2:20])=[O:21])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O
Reactant: N#CCCCN(Cc1ccccc1)Cc1ccccc1
Solvent: ClCCl
Product: NC(=O)CCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
By a method analogous to Example 1 dibenzylamine was reacted with 4-bromobutyronitrile to give 4-(N,N-dibenzylamino)butyronitrile, mp. 45°-46° C. b) Hydrogen peroxide (30% w/v; 5.6 ml), tetra-n-butylammonium hydrogensulphate (1.70 g) and 5N aqueous sodium hydroxide (4 ml) were added to a stirred solution of 4-(N,N-dibenzylamino)butyronitrile (2.64 g) in dichloromethane (10 ml) with water cooling. The mixture was stirred vigorously at room temperature for 17 hours and dichloromethane (100 ml) was added. The layers were separated and the organic phase was washed with saturated aqueous sodium chloride (10 ml), dried (Na2SO4) and concentrated in vacuo to give a viscous oil (4.12 g). The product was chromatographed on silica with eluant 20% ethyl acetate/toluene →ethyl acetate and recrystallised from cyclohexane to give the title compound (1.86 g, 66%), m.p. 76°-77° C.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[CH3:8][C:9]([O:18][OH:19])([C:11]#[C:12][C:13]([CH3:17])([O:15][OH:16])[CH3:14])[CH3:10].S(=O)(=O)(O)O>CCOCC>[O:1]=[C:2]([CH2:4][C:5]([CH3:7])([CH3:6])[O:16][O:15][C:13]([CH3:17])([CH3:14])[C:12]#[C:11][C:9]([CH3:8])([CH3:10])[O:18][O:19][C:5]([CH3:7])([CH3:6])[CH2:4][C:2](=[O:1])[CH3:3])[CH3:3]
Reactant: CC(C)(C#CC(C)(C)OO)OO
Reactant: CC(=O)C=C(C)C
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(=O)CC(C)(C)OOC(C)(C)C#CC(C)(C)OOC(C)(C)CC(C)=O
Temperature: 30 °C
Reaction time: 16 h
Yield: 66.7 %

Procedure:
A mixture of 19.6 g. (0.2 mole) of mesityl oxide, 74.4 g. (0.083 mole) of 2,5-dimethyl-2,5-dihydroperoxy-3-hexyne and 60 ml. of ether was stirred at 0° C. while 1.3 g. of 77% sulfuric acid solution was slowly added. The reaction mixture was allowed to warm slowly to 30° C. and stirred for a total of 16 hours. The organic layer was separated, washed with water, 5% sodium hydroxide solution and again with water to pH 8. The mixture was then subjected to steam distillation in the presence of sodium bicarbonate solution at 20 torr for 2 hours to remove unreacted mesityl oxide and hydroperoxide. The product was taken up in ether, dried over anhydrous magnesium sulfate and the ether removed under reduced pressure leaving 20.52 g. of product (66.7% yield).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][CH2:27][C@@H:28]([C:37]3[CH:42]=[C:41]([O:43]CC4C=CC=CC=4)[CH:40]=[C:39]([O:51]CC4C=CC=CC=4)[CH:38]=3)[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH:20][CH:19]=2)=[CH:11][C:10]=1[C@@H:59]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[CH2:60][CH2:61][N:62]([CH:66]([CH3:68])[CH3:67])[CH:63]([CH3:65])[CH3:64])C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[Si:30]([O:29][C@H:28]([C:37]1[CH:42]=[C:41]([OH:43])[CH:40]=[C:39]([OH:51])[CH:38]=1)[CH2:27][NH:26][CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([C@@H:59]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[CH2:60][CH2:61][N:62]([CH:63]([CH3:65])[CH3:64])[CH:66]([CH3:68])[CH3:67])[CH:11]=2)=[CH:19][CH:20]=1)([C:33]([CH3:36])([CH3:34])[CH3:35])([CH3:32])[CH3:31]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3cc(OCc4ccccc4)cc(OCc4ccccc4)c3)cc2)ccc1OCc1ccccc1)C(C)C
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3cc(O)cc(O)c3)cc2)ccc1O)C(C)C
Temperature: 90 °C

Procedure:
(3R)-3-[2-(benzyloxy)-5-{2-[4-(2-{[(2R)-2-[3,5-bis(benzyloxy)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl]amino}ethyl)phenoxy]ethyl}phenyl]-N,N-diisopropyl-3-phenylpropan-1-amine (Preparation 43, 346 mg, 0.30 mmol) was dissolved in methanol (30 ml) and ammonium formate (380 mg, 6.1 mmol) and 20% palladium hydroxide on carbon (43 mg) added. The stirred reaction was then heated at 90° C. for 2 hours. After cooling to room temperature, mixture was filtered and solvent removed in vacuo. The residue was then taken up in ethyl acetate (50 ml) and saturated aqueous sodium hydrogen carbonate (50 ml). The organics were separated, washed with brine then dried (magnesium sulphate) and the solvent removed in vacuo to yield the title compound as a yellow glass, 174 mg.