Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[C:14]1[S:18][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[N:21]=2)=[C:16]([C:28]([NH2:30])=[O:29])[CH:15]=1.Cl[CH2:32][C:33]1[O:34][C:35]([CH3:38])=[N:36][N:37]=1>CN(C=O)C>[F:3][C:4]1[CH:9]=[C:8]([C:10]([OH:13])([CH3:11])[CH3:12])[CH:7]=[CH:6][C:5]=1[C:14]1[S:18][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27][CH2:32][C:33]3[O:34][C:35]([CH3:38])=[N:36][N:37]=3)[N:21]=2)=[C:16]([C:28]([NH2:30])=[O:29])[CH:15]=1
Reactant: Cc1nnc(CCl)o1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CO)n3)s2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc(COCc2cccc(Nc3sc(-c4ccc(C(C)(C)O)cc4F)cc3C(N)=O)n2)o1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (14 mg, 0.35 mmol) in DMF (1.75 mL) at 0° C. under argon was added 5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-{[6-(hydroxymethyl)pyridin-2-yl]amino}thiophene-3-carboxamide (Example 43) (70 mg, 0.17 mmol) and the mixture was allowed to stir for 10 minutes. 2-(Chloromethyl)-5-methyl-1,3,4-oxadiazole (35 mg, 0.26 mmol) was then added and the reaction was allowed to warm to room temperature overnight. The reaction was then quenched by the addition of water, extracted with ethyl acetate and concentrated in vacuo. The crude residue was reverse phase HPLC (acteonitrile/water with formic acid as a modifier) to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH:10]([CH3:12])[CH3:11])[CH:3]=1.[OH-].[Na+].Cl[CH:16]([F:18])[F:17].Cl>[Br-].C([N+](CC)(CC)CC)C.O.O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([F:18])[F:17])=[C:4]([O:9][CH:10]([CH3:12])[CH3:11])[CH:3]=1
Reactant: FC(F)Cl
Reactant: CC(C)Oc1cc(Br)ccc1O
Agent: CC[N+](CC)(CC)CC
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Oc1cc(Br)ccc1OC(F)F
Temperature: 80 °C
Yield: 31 %

Procedure:
To 21.9 g (94.9 mmol) of 4-bromo-2-isopropoxyphenol obtained in Reference Example 6-(a) were added 2.01 g (9.56 mmol) of tetraethylammonium bromide, 150 ml of 1,4-dioxane, 11.2 g (275 mmol) of sodium hydroxide and 10 ml of water, and the mixture was stirred at 80° C. Then, the mixture was stirred at the same temperature for 1 hour while blowing 40.4 g of chlorodifluoromethane therein. After completion of the reaction, water was added to the reaction mixture, a pH of the mixture was adjusted to 7 with conc. hydrochloric acid, and extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=100:1→25:1 (V/V)), and the obtained crude oil containing the desired compound was applied to distillation under reduced pressure (105 to 110° C./7 Pa) to obtain 8.27 g of the title compound as a colorless oil. (Yield: 31%)
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:23][C:24]1[S:25][C:26]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:27][C:28]=1[CH3:29].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl.CN(C)C=O.O>[CH2:30]([C:26]1[S:25][C:24]([CH3:23])=[C:28]([CH3:29])[C:27]=1[C:9]([C:8]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]=1)=[O:11])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1cc(Cc2ccccc2)sc1C
Reactant: COc1ccc(C(=O)O)cc1C1CCCC1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1C1CCCC1
Reaction time: 1.5 h
Yield: 52.3 %

Procedure:
To a slurry of 3-cyclopentyl-p-anisic acid (5.0 g, 22.7 mmol, RN-59216-82-9) in anhydrous methylene chloride (60 mL) was added oxalyl chloride (2.4 mL, 27.2 mmol) and N,N-dimethylformamide (2 drops) at room temperature under nitrogen. After stirring for 1.5 h the reaction mixture was concentrated under reduced pressure. The residue was dissolved in carbon disulfide (32 mL) and the resulting solution was added to 2,3-dimethyl-5-benzylthiophene (5.1 g, 25.0 mmol). At −78° C. under nitrogen, tin(IV) chloride (2.9 mL, 25.0 mmol) was added, and the reaction mixture was then stirred at room temperature for 4 h. The solution was poured onto a mixture of ice and water (200 mL) and extracted with diethyl ether (200 mL). The diethyl ether layer was washed twice with sodium bicarbonate (50 mL) and once with brine (50 mL). Concentration under reduced pressure and chromatography with petroleum ether:ethyl acetate (95:5) gave the title compound as an amber oil (4.8 g, 52%): (DMSO-d6): δ7.61-7.54 (m, 2H), 7.24-7.14 (m, 3H), 7.08-7.02 (m, 3H), 3.87 (s, 3H), 3.84 (s, 2H), 3.42-3.30 (m, 1H), 2.26 (s, 3H), 2.00-1.85 (m, 2H), 1.81 (s, 3H), 1.74-1.58 (m, 4H), 1.48-1.36 (m, 2H); MS(EI): [M+] 404; Anal. Calc. for C26H28O2S: C, 77.19; H, 6.98; N, 0.00. Found: C, 76.26; H, 7.24; N, 0.04.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][C@@H:6]([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][C:11]([Cl:32])=[N:12][C:13]=3[NH:17][CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:5]([OH:33])[C@@H:4]1[OH:34].ClC1N=C2C(N=CN2)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1.C(N(C(C)C)CC)(C)C.[C:69]1([CH2:75][C:76](Cl)=[O:77])[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>C1COCC1>[Cl:32][C:11]1[N:10]=[C:9]2[C:14]([N:15]=[CH:16][N:8]2[C@@H:6]2[CH2:7][C@H:3]([NH:2][C:76](=[O:77])[CH2:75][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C@@H:4]([OH:34])[C@H:5]2[OH:33])=[C:13]([NH:17][CH2:18][CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]=1
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: Clc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (1S,2R,3S,5R)-3-amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol hydrochloride (an intermediate for preparing the compound of Example 22) (100 mg, 0-2 mmol) in dry THF (1 ml) is treated with diisopropylethylamine (0.17 ml, 1 mmol) and phenylacetyl chloride (0.026 ml, 0.2 mmol) and the mixture is stirred at room temperature for 18 hours. The solvent is removed under reduced pressure and the residue is dissolved in dichloromethane (2 ml) and washed with dilute hydrochloric acid (2 ml). The organic layer is separated and evaporated under reduced pressure to afford the title compound (114 mg). LCMS (electrospray): m/z [MH+] 583.27
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=3[Cl:29])=[C:16]([C:30]([O:32]CC)=O)[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=3[Cl:29])=[C:16]([C:30]([N:45]3[CH2:46][CH2:47][CH:42]([C:39]4[CH:38]=[CH:37][C:36]([F:35])=[CH:41][CH:40]=4)[CH2:43][CH2:44]3)=[O:32])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1cc(C(F)(F)F)ccc1Cl
Reactant: Fc1ccc(C2CCNCC2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cnn2c(Nc3cc(C(F)(F)F)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 73 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2-chloro-5-trifluoromethylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (2.87 g, 5.52 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (1.37 g, 7.62 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (2.63 g, 79%) was obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[N+:13]([O-])=O.[H][H]>CO.[Pd]>[CH3:1][NH:2][C:3]1[C:4]([NH2:13])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: [H][H]
Reactant: CNc1ccc2c(c1[N+](=O)[O-])CCCC2
Agent: [Pd]
Solvent: CO
Product: CNc1ccc2c(c1N)CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
To a solution of N-methyl-1-nitro-5,6,7,8-tetrahydronaphthalen-2-amine (crude product from the previous step, 190 mg, 0.918 mmol) in MeOH (20 mL) was added 10% Pd on carbon (98 mg, 0.0918 mmol) under nitrogen, then replaced with hydrogen atmosphere (1 L). The resulting mixture was stirred at room temperature for 16 h. After filtration through Celite, the filtrate was concentrated and the residue was purified by prep-TLC (DCM/MeOH v/v 10:1) to give N2-methyl-5,6,7,8-tetrahydronaphthalene-1,2-diamine as a white solid (100 mg, 61% yield). ESI MS: m/z 177 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH2:7][C:6]2=1)#[N:2].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>>[C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([F:22])[CH:24]=1)[C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH2:7][C:6]2=1)#[N:2]
Reactant: N#Cc1ccc2[nH]c3c(c2c1)CC(NC(=O)C1CC1)CC3
Reactant: Fc1cccc(CBr)c1
Product: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CCC(NC(=O)C2CC2)C1

Procedure:
Prepare the title compound from cyclopropanecarboxylic acid(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)amide (3.00 g, 10.7 mmol) and 3-fluorobenzyl bromide (2.2 g, 11.8 mmol) by essentially following procedures as described in Example 1 to obtain 1.4 g (34%) of a beige solid. mp: 207-209° C.; MS (ES): m/z 388 (M+1); HPLC: Rt=2.28 min (100%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]([O:13][CH3:14])=[CH:11][N:10]=[C:9]([CH2:15][OH:16])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(OCC)C.ClCCl.[O-2].[O-2].[Mn+4]>[CH:1]1([O:6][C:7]2[C:12]([O:13][CH3:14])=[CH:11][N:10]=[C:9]([CH:15]=[O:16])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cnc(CO)cc1OC1CCCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cnc(C=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 90 h
Yield: 83.3 %

Procedure:
Manganese dioxide (6.0 g) is added to a solution of 4-cyclopentyloxy-2-hydroxymethyl-5-methoxypyridine (2.0 g) in diethyl ether (80 mL) and dichloromethane (10 mL) and the mixture stirred at room temperature for 90 hours. After filtering the filter pad is washed with dichloromethane and the combined filtrate and washings are evaporated to give a white solid. The solid is dried under high vacuum to give 4-cyclopentyloxy-5-methoxypyridine-2-carboxaldehyde (1.65 g). [1Hnmr in D6-DMSO shifts relative to Me4Si:—1.55–1.79, 6H, m; 1.97, 2H, m; 3.96, 3H, s; 5.03, 1H, m; 7.45, 1H, s; 8.41, 1H, s; 9.83, 1H, s.].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:8][CH2:7][CH:3]2[CH2:4][CH2:5][CH2:6][O:1][CH2:2]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: OCC1CCCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCCOC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (tetrahydropyran-3-yl)-methanol (Matrix, 1.67 g, 14.4 mmol) in 15 mL of CH2Cl2 and 15 mL of pyridine was added p-toluenesulfonyl chloride (2.9 g, 15.1 mmol) in portions over 10 minutes. The mixture stirred at ambient temperature for 18 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous phase was extracted three 5 mL of portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 70% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 288 (M+NH4)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH:12]=[CH:13][CH3:14]>>[CH2:1]([NH:8][CH2:14][CH2:13][CH:12]=[CH:11][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC=CCCBr
Product: CC=CCCNCc1ccccc1

Procedure:
Reaction of benzylamine with 5-bromopent-2-ene gives 5-benzylamino-2-pentene, which can be condensed with the half-ester of malonic acid, as described in Section XXVIII. Subsequent diazo transfer and cycloaddition, according to Section XXVIII, provides ethyl 3-benzyloxycarbonyl-7-methyl-2-oxo-3-azabicyclo[4.1.0]heptane-1-carboxylate. Processing of this compound as in Section XXXVIII provides the desired trisubstituted compound.
Reaction SMILES: [CH2:1]([O:6][C:7](=O)[CH:8]([NH:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:9])[CH2:2][CH2:3][CH:4]=[CH2:5].N1C=CC=CC=1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH3:9][C:8]1[N:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:4]2[CH2:3][CH2:2][CH2:1][O:6][C:7]=12
Reactant: C=CCCCOC(=O)C(C)NC(=O)C(=O)OCC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2c(c(C)n1)OCCC2
Temperature: 15 °C

Procedure:
Pent-4-en-1-yl2-(2-ethoxy-2-oxoacetamido)propanoate (1.05 g, 1 eq) and DCM (15 mL) were added to a vessel with stirring. Pyridine (0.39 g, 1.2 eq) was then added and the mixture was cooled to 15° C. Tf2O (1.7 g, 1.5 eq) was added to the mixture over 15 min and the mixture was warmed to ambient temperature to stir for 1.5 h. The reaction was quenched by the addition of DCM and 20 wt % aqueous NaOAc to form a biphasic mixture. The layers were separated and the organic layer was washed with water. The organic layer was then concentrated under reduced pressure to provide the title compound as yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.62 (s, 1H), 4.32 (q, J=7.12 Hz, 2H), 4.16-4.25 (m, 2H), 2.70 (t, J=6.44 Hz, 2H), 2.37 (s, 3H), 1.86-2.03 (m, 2H), 1.31 (t, J=7.12 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ ppm 165.15, 152.44, 147.98, 137.72, 128.73, 124.80, 66.85, 61.09, 23.98, 21.06, 18.98, 14.11; HRMS (M+H) m/z, calcd for C12H16NO3, 222.1130; found, 222.1133.
Reaction SMILES: [C:1]([C:3]1[C:12](=[O:13])[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]([C:14]([O:16][CH2:17]C)=[O:15])[C:4]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)#[N:2].[H-].[Na+]>CO>[C:1]([C:3]1[C:12](=[O:13])[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]([C:14]([O:16][CH3:17])=[O:15])[C:4]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)#[N:2]
Reactant: CCOC(=O)c1c(NCc2ccccn2)c(C#N)c(=O)n2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(NCc2ccccn2)c(C#N)c(=O)n2ccccc12
Yield: 88.9 %

Procedure:
To a solution of 3.00 g of 3-cyano-1-ethoxycarbonyl-2-(2-pyridylmethylamino)-4H-quinolizin-4-one in 1000 ml of abs. methanol was added 40 mg of sodium hydride and the reaction mixture was heated under reflux for 3 hours. After cooling, the precipitated crystals were collected by filtration to give 2.56 g of 3-cyano-1-methoxycarbonyl-2-(2-pyridylmethylamino)-4H-quinolizin-4-one.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:50])[NH:6][C:7]1[N:8]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH2:41][CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)[CH:35]=2)[N:9]=[C:10]([C:12]([CH3:33])([CH3:32])[CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=1.[CH3:53][C@H:54]1[CH2:59][CH2:58][CH2:57][CH2:56][N:55]1[C:60]1[N:64]2[CH:65]=[C:66]([O:69][C@H:70]3[C:79]4[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=4)[C@@H:73]([NH2:80])[CH2:72][CH2:71]3)[CH:67]=[CH:68][C:63]2=[N:62][N:61]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Si:15]([O:14][CH2:13][C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:80][C@@H:73]2[C:74]3[C:79](=[CH:78][CH:77]=[CH:76][CH:75]=3)[C@H:70]([O:69][C:66]3[CH:67]=[CH:68][C:63]4[N:64]([C:60]([N:55]5[CH2:56][CH2:57][CH2:58][CH2:59][C@@H:54]5[CH3:53])=[N:61][N:62]=4)[CH:65]=3)[CH2:71][CH2:72]2)=[O:50])[N:8]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH2:41][CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)[CH:35]=2)[N:9]=1)([CH3:33])[CH3:32])([C:28]([CH3:29])([CH3:31])[CH3:30])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)nn4-c4cccc(OCCOC5CCCCO5)c4)c4ccccc43)cn12
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
A solution of Intermediate 153f (377 mg, 0.48 mmol) in 1,4-dioxane (4.8 mL) was treated with Intermediate 81d (164 mg, 0.43 mmol) and DIPEA (0.095 mL, 0.54 mmol) and the mixture was stirred at 70° C. for 30 mins then at 50° C. for 64 h then at 70° C. for 22 h. The cooled solution was concentrated in vacuo, and the residue was partitioned between DCM and water. The phases were separated and the aqueous layer was extracted with DCM (×2). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to a brown gum. The gum was purified by FCC, using 0-7% MeOH in DCM to give the title compound as a brown glass (320 mg, 72%). LCMS (Method 3): Rt 5.66 min, m/z 1017.7 [MH+].
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]#N)=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)[CH2:3][CH2:2]1.C(O)=[O:27]>[Ni]>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH:14]=[O:27])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)[CH2:3][CH2:2]1
Reactant: CCOc1ccc(Cc2nc3cc(C#N)ccc3n2CC2CC2)cc1
Reactant: O=CO
Agent: [Ni]
Product: CCOc1ccc(Cc2nc3cc(C=O)ccc3n2CC2CC2)cc1
Temperature: 90 °C
Yield: 82 %

Procedure:
To a solution of 1-(cyclopropylmethyl)-2-(4-ethoxybenzyl)-1H-benzimidazole-5-carbonitrile (0.049 g, 0.149 mmol) in 50% aqueous formic acid (1 mL) was added a catalytic amount of Raney nickel (50% suspension in water) and the resulting mixture was heated at 90° C. for 6 hours. The mixture was filtered through a short pad of diatomaceous earth and washed with EtOAc. The solvent was evaporated in vacuo and the residue was taken up into EtOAc (5 mL). The organic phase was washed with 1 N NaOH (2×2 mL) and brine (2 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (40% EtOAc/hexanes) to provide the title compound (0.041 g, 82%) as a white solid. 1H NMR (acetone-d6): δ 10.16 (s, 1H), 8.29 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 4.44 (s, 2H), 4.24 (d, J=6.4 Hz, 2H) 4.07 (q, J=6.8 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H), 1.27–1.14 (m, 1H), 0.58–0.49 (m, 2H), 0.48–0.38 (m, 2H). MS (ESI) (M+H)+=335.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[I-].[Na+].[CH2:17]([O:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Br)[CH3:18]>CC(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:23][CH2:22][CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:25]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1cccc(Br)c1
Temperature: 80 °C

Procedure:
Solid 3-bromophenol (10.0 g, 58 mmol) was added portion wise to a stirred suspension of K2CO3 in acetone (100 mL) at room temperature. see FIG. 1. Sodium iodide (NaI, 1.0 g) was added, followed by ethyl-4-bromobutyrate (9.2 mL, 64 mmol). The reaction mixture was heated at 80° C. overnight, cooled to room temperature, diluted with water and extracted with ethylacetate to give ethyl 4-(3-bromophenoxy)butanoate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=2)=[CH:4][CH:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: ClCc1coc(-c2ccc(Br)cc2)n1
Solvent: C1CCOC1
Product: Brc1ccc(-c2nc(CN3CCCC3)co2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
2-(4-Bromo-phenyl)-4-chloromethyl-oxazole (See Intermediate 1) (0.321 g, 1.18 mmol), and pyrrolidine (0.639 g, 9.0 mmol) are dissolved in 20 mL tetrahydrofuran and stirred at ambient temperature for 1.5 hours. The reaction is concentrated to an oil and redissolved in diethyl ether which is washed with aqueous sodium bicarbonate, water, separated and dried over sodium sulfate, filtered and concentrated to a dark oil. The oil is purified by flash silica gel chromatography (2% 2M NH3 in MeOH/dichloromethane) to give 0.185 g of the titled compound. MS (m/e) (81Br): 309.1 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH2:9]Cl)=[CH:4][N:3]=1.C(N(CC)CC)C.O>C(O)C.[Ni].CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: ClCc1cnc(Cl)cc1Cl
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: Cc1cnc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,4-Dichloro-5-chloromethyl-pyridine (1.43 g, 7.28 mmol) is dissolved in ethanol (14 ml). After addition of triethyl amine (737 mg, 7.28 mmol), Raney nickel (143 mg) is added. The reaction vessel is connected to a balloon filled with H2. After 3 hours of very vigorous magnetically stirring at RT, NMR analysis of a reaction aliquot indicated complete conversion of the starting material. The reaction mixture is diluted with EtOAc and poured into water.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:23])[C@H:15]([CH2:19][CH:20]1[CH2:22][CH2:21]1)/[CH:16]=[CH:17]/[CH3:18])C1C=CC=CC=1.OO.O.[OH-].[Li+].S(S([O-])=O)([O-])(=O)=[O:30].[Na+].[Na+].Cl>O1CCCC1.O>[CH:20]1([CH2:19][C@H:15](/[CH:16]=[CH:17]/[CH3:18])[C:14]([OH:23])=[O:30])[CH2:21][CH2:22]1
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: C/C=C/[C@@H](CC1CC1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C/C=C/[C@@H](CC1CC1)C(=O)O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 78 %

Procedure:
A solution of (S)-4-benzyl-3-((E)-(R)-2-cyclopropylmethyl-pent-3-enoyl)-oxazolidin-2-one (3.50 g, 10.92 mmol) in tetrahydrofuran (75 mL) was cooled to 0° C. before addition of a 30% aqueous solution of hydrogen peroxide (5.8 mL, 56 mmol) and a solution of lithium hydroxide monohydrate (950 mg, 22.6 mmol) in water (37 mL). The reaction was stirred at 0° C. for 2.5 h. The reaction mixture was treated with an aqueous solution of sodium metabisulphite and stirred for 10 minutes before acidifying to pH 1 with hydrochloric acid (2 M). The mixture was extracted with ethyl acetate (3×50 mL). The extract was dried over anhydrous sodium sulfate, filtered and evaporated to give a colourless oil. The oil was purified by silica gel chromatography using iso-hexanes/ethyl acetate 7:3 to yield the title compound (1.32 g, 78%) as a colourless oil and as a mixture of 2.5:1 E/Z isomers. 1H NMR (300 MHz, CDCl3) δ 0.02-0.15 (m, 1.96H), 0.39-0.52 (m, 1.96H), 0.65-0.81 (m, 0.98H), 1.47-1.63 (m, 1.96H), 1.71 (d, J=6.7 Hz, 2.94H), 3.06-3.17 (m, 0.98H), 3.45-3.56 (m, 0.28H), 5.40-5.56 (m, 0.98H), 5.57-5.72 (m, 0.98H), 10.5-12.0 (bs, LCMS (m/z) 153.1 [M−H], Tr=1.91 min.