Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][CH2:9][CH:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[O:11][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][O:18]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: C1=COCCC1
Reactant: CC(C)(C)[Si](C)(C)OCC(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(OC1CCCCO1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of 2-(tert-butyldimethylsilanyloxy)-1-phenylethanol (0.73 g, 2.9 mmol) and 3,4-dihydro-2H pyran (486 mg, 5.78 mmol) in dichloromethane (30 ml) was added p-toluenesulfonic acid monohydrate (50 mg). The mixture was stirred at room temperature for 12 hours and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=3/1) to give tert-butyldimethyl[2-phenyl-2-(tetrahydropyran-2-yl-oxy)ethoxy]silane (0.86 g, 2.9 mmol, >99%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C)=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.O.[OH-].[K+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: CC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 95 %

Procedure:
To a solution of N-(4-bromo-2-nitrophenyl)acetamide obtained in step H above (1.0 eq) in MeOH and water was added KOH (1.5 eq) at room temperature and stirred for 5 hrs. Water was added to the reaction mixture and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired 4-bromo-2-nitroaniline. (Yield=95%)
Reaction SMILES: [CH2:1]([CH:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH2:15][NH:16]C(OC(C)(C)C)=O)[C:4]([NH2:6])=[O:5])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([CH:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH2:15][NH2:16])[C:4]([NH2:6])=[O:5])[CH3:2]
Reactant: CCC(Oc1ccc(Cl)cc1CNC(=O)OC(C)(C)C)C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(Oc1ccc(Cl)cc1CN)C(N)=O

Procedure:
Ethyl-(2-t-butoxycarbonylaminomethyl-4-chlorophenoxy)-acetamide from Step F was dissolved in 2:1 methylene chloride/TFA (3 ml) and after 15 min the solvent was evaporated in vacuo. The residue was dissolved in water and the solution was washed with methylene chloride (twice). The aqueous layer was then basified with saturated sodium carbonate solution and NaCl was added to saturation. The mixture was extracted with ethyl acetate, and the organic layer was dried (Na2SO4) and evaporated in vacuo to give the title compound as a crystalline solid:
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([O:13]CC)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].C(O)CO.Cl>O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cnn(C(C)(C)C)c(=O)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1c(O)cnn(C(C)(C)C)c1=O
Yield: 88.2 %

Procedure:
The resulting 2-tert.-butyl-5-ethoxy-4-methyl-3(2H)-pyridazinone (1.7 g) and potassium hydroxide (6.0 g) were added to 30 ml of ethyleneglycol, and the mixture was stirred under reflux for 3 hours. The reaction mixture was poured into 200 ml of water and added with 30 ml of 6N-hydrochloric acid. The crystals thus precipitated was collected by filtration. After drying, the crystals were washed with hot hexane to give 1.3 g of 2-tert.-butyl-5-hydroxy-4-methyl-3(2H)-pyridazinone. The melting point and the result of NMR analysis of this product were identical with those of the product obtained by the Method A.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:19][C:18]([F:20])([F:21])[C:15]1[CH:16]=[CH:17][C:12]([CH2:11][O:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)=[CH:13][CH:14]=1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: OCc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1

Procedure:
4-Hydroxymethyl-phenol (1 g, 8.06 mmol), 1-Chloromethyl-4-trifluoromethyl-benzene (1.57 g, 8.06 mmol), and cesium carbonate (5.26 g, 16.12 mmol) were refluxed in acetonitrile for 20 h, cooled, filtered, and concentrated to give the title compound. MS m/z 265 (M−H2O+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([OH:25])=O)[CH2:17]1.Cl.O[NH:32][C:33](=[NH:35])[CH3:34].ClCCl.O>CN(C=O)C>[CH3:34][C:33]1[N:35]=[C:23]([C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[CH:18]2[CH2:19][CH2:20][N:16]([CH2:15][CH2:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C:2]3=[O:1])[CH2:17]2)[O:25][N:32]=1
Reactant: CC(=N)NO
Reactant: O=C(O)c1ccccc1C1CCN(CCc2ccccc2N2CCCCC2=O)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: Cc1noc(-c2ccccc2C2CCN(CCc3ccccc3N3CCCCC3=O)C2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6 %

Procedure:
2-(1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}pyrrolidin-3-yl)benzoic acid a6-6 (0.31 g, 0.79 mmol, 1 eq) is dissolved in DMF and N,N′-carbonyldiimidazole (140 mg, 0.87 mmol, 1.1 eq) is added. The mixture is stirred at room temperature for 30 min, N-hydroxyacetamidine hydrochloride (95 mg, 0.87 mmol, 1.1 eq) is added and stirring is pursued for 4 hours. Another 1.1 eq of N,N′-carbonyldiimidazole and 1.1 eq of N-hydroxyacetamidine hydrochloride are added and the reaction mixture is stirred at reflux overnight. Dichloromethane and water are added and the organic layer is subsequently washed with water, HCl 1N, aqueous saturated NaHCO3 and brine. The organic layer is dried over MgSO4, evaporated and purified by preparative basic LC/MS (gradient: H2O/acetonitrile/NH4HCO3 0.5% w/v from 85/5/10 to 5/95/0 in 6.5 minutes) to afford 19 mg of 1-[2-(2-{3-[2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]pyrrolidin-1-yl}ethyl)phenyl]piperidin-2-one 11.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH2:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=2)[C:22]#[N:23])[S:14][N:13]=1)[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH:35]1[CH2:38][CH:37]([C:39]([O:41]C)=[O:40])[CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:14][N:13]=[C:12]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH2:10][N:35]4[CH2:38][CH:37]([C:39]([OH:41])=[O:40])[CH2:36]4)[CH:7]=[CH:6][CH:5]=3)[N:16]=2)[CH:18]=[CH:19][C:20]=1[CH2:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: CCc1c(CC=O)cccc1-c1nsc(-c2ccc(CC(C)C)c(C#N)c2)n1
Reactant: COC(=O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1c(CCN2CC(C(=O)O)C2)cccc1-c1nsc(-c2ccc(CC(C)C)c(C#N)c2)n1
Reaction time: 0.5 h
Yield: 17.9 %

Procedure:
To a solution of 5-{3-[2-ethyl-3-(2-oxoethyl)phenyl]-1,2,4-thiadiazol-5-yl}-2-(2-methylpropyl)benzonitrile (D62) (110 mg) in dichloromethane (DCM) (15 mL) was added sodium acetate (25.5 mg), hydrogen chloride-methyl 3-azetidinecarboxylate (1:1) (45.0 mg) and 5 drops of acetic acid. After stirring for 30 min, sodium triacetoxyborohydride (90 mg) was added and the reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 mL), the organic phase was washed with water, dried over sodium sulphate and concentrated. The residue was dissolved in isopropanol/water (10 mL, 1:1), 0.5M sodium hydroxide (2.82 mL) was added. The reaction solution was stirred at room temperature overnight. The isopropanol was removed in vacuo and the residue was acidified to pH=3-4. The resulting solution was extracted with ethyl acetate (2*15 mL), and the combined organic phases were dried over sodium sulphate, concentrated and purified by Mass Directed AutoPrep to afford 1-[2-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,2,4-thiadiazol-3-yl}-2-ethylphenyl)ethyl]-3-azetidinecarboxylic acid (E30) (24 mg) as a TFA salt. δH (DMSO-d6, 400 MHz): 0.86 (6H, d), 1.06 (3H, t), 1.92 (1H, m), 2.70 (2H, d), 2.84 (4H, m), 3.34 (2H, m), 3.55 (1H, m), 4.21 (4H, m), 7.29 (1H, t), 7.38 (1H, d), 7.63 (1H, d), 7.69 (1H, dd), 8.26 (1H, dd), 8.46 (1H, d). δF (DMSO-d6, 376 MHz): −73.6. MS (ES): C27H30N4O2S requires 474. found 475.1 (M+H+).
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][O:5]C[CH2:3]1.[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH:20]1[CH2:23][CH2:22][CH2:21]1)[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.N1CC(O)C1>C(Cl)Cl.CN(C=O)C.C([O-])(O)=O.[Na+]>[CH:20]1([C@H:16]([NH:15][C:13](=[O:14])[O:12][C:8]([CH3:9])([CH3:10])[CH3:11])[C:17]([N:2]2[CH2:7][CH:6]([OH:5])[CH2:3]2)=[O:19])[CH2:23][CH2:22][CH2:21]1
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CC(O)C1)C1CCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
NMM (4.26 mL, 38.8 mmol) was added to a mixture of (S)-2-(tert-butoxycarbonylamino)-2-cyclobutylacetic acid (4.04 g, 17.6 mmol), which is commercially available, in DCM (45 mL) and DMF (14 mL). The mixture was cooled to 0° C. and TBTU (5.66 g, 17.6 mmol) was added. After 10 min was azetidin-3-ol hydrochloride (2.40 g, 21.9 mmol) added. The resultant mixture was stirred at rt over night. The mixture was washed with NaHCO3 (8% aq., 30 mL). A second wash with NaHCO3 (8% aq., 30 mL) resulted in an emulsion. The emulsion was diluted with DCM (50 mL) and NaHCO3 (8% aq., 30 mL), mixed well and left to separate. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was co-evaporated with toluene to give the title compound (4.10 g, 82%) as a solid. The obtained crude product was used without further purification. 1H NMR (400 MHz, CD3OD) δ 1.44 (9H), 1.76-2.09 (6H), 2.51-2.65 (1H), 3.67-3.82 (1H), 3.97-4.27 (3H), 4.45-4.69 (2H). Expected Number of protons: 24. OH- and NH-protons are exchanged with CD3OD.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][C:17]=1[C:26]([OH:28])=[O:27].C(N(CC)CC)C>CC(C)=O>[OH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:6][CH:7]=2)(=[O:24])=[O:23])=[CH:18][C:17]=1[C:26]([OH:28])=[O:27]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1O
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: N#CC=CS(=O)(=O)c1ccc(NS(=O)(=O)c2ccc(O)c(C(=O)O)c2)cc1

Procedure:
is prepared by dissolving 10.4 grams (0.05 mol) of 3-(4-aminobenzenesulfonyl)acrylonitrile and 14 g (0.05 mol + 15% excess) of 4-hydroxy-3-carboxybenzenesulfonyl chloride in 200 ml acetone, cooling in an ice bath and slowly adding thereto 8 ml (0.055 mol) of triethylamine diluted with 25 ml acetone. After filtration and evaporation of the acetone the remaining semi-solid is dissolved in dimethylformamide, dispersed in water and the emulsion extracted with chloroform. After work-up the above sulfonamide is recovered.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[C:30]4[O:29][CH2:28][O:27][C:26]=4[CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:32]>ClCCl>[ClH:32].[O:27]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:19]3[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C@H:11]4[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]4)[CH2:17][CH2:18]3)[C:30]=2[O:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reaction time: 4 h

Procedure:
To a mixture of trans-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.06 g, 2.46 mmol,) in dichloromethane (15 ml) was added at room temperature hydrochloric acid solution (4M in dioxane, 6.15 ml, 24.6 mmol,) and the mixture was allowed to stir for 4 h, the solvent was evaporated, diisopropyl ether (15 ml) were added and the mixture was allowed to stir for 10 min at room temperature. The precipitate was collected by filtration, washed with diisopropyl ether and dried to yield the title compound as a white solid (0.954, 100%), MS m/z=330.23 [(M)+].
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1.[CH3:18][C:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][C@H:32]2[C:40](Cl)=[O:41])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])[CH3:20]>ClCCl>[CH3:21][C:19]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][C@H:32]2[C:40]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)=[O:41])(=[O:30])=[O:29])=[CH:26][CH:27]=1)([CH3:18])[CH3:20]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2c3ccccc3C[C@H]2C(=O)Cl)cc1
Reactant: NCc1cccc(O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(S(=O)(=O)N2c3ccccc3C[C@H]2C(=O)NCc2cccc(O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
54 mg (0.53 mmol) of triethylamine are added to a suspension of 42.26 mg (0.265 mmol) of 3-(aminomethyl)phenol hydrochloride in 8 ml of dichloromethane at ambient temperature, then a solution of 100 mg (0.265 mmol) of 1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-(2S)-1H-indole-2-carbonyl chloride in 2 ml of dichloromethane is added over 10 minutes. This is left to agitate at ambient temperature for 1 hour. The reaction medium is washed with water, dried on magnesium sulfate, the solvents are evaporated and the evaporation residue is purified by silica column chromatography eluting with the help of a toluene/ethyl acetate mixture (8/2; v/v). The expected product is obtained in the form of a white solid with a yield of 51%.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([N:17]2[C@@:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)([CH3:22])[C@@:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)([CH3:30])[N:19]=[C:18]2[C:38]2[CH:39]=[N:40][C:41]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:42][C:43]=2[O:44][CH2:45][CH3:46])=[O:16])[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[CH2:51]([N:53]=C=O)[CH3:52]>ClCCl>[CH2:51]([NH:53][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]([N:17]2[C@@:21]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)([CH3:22])[C@@:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)([CH3:30])[N:19]=[C:18]2[C:38]2[CH:39]=[N:40][C:41]([C:47]([CH3:50])([CH3:48])[CH3:49])=[CH:42][C:43]=2[O:44][CH2:45][CH3:46])=[O:16])[CH2:12][CH2:13]1)=[O:7])[CH3:52]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)N1CCC(NC(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
A mixture of (4S,5R)-2-(6-tert-butyl -4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carboxylic acid piperidin-4-yl amide (51.2 mg, 0.082 mmole, example 205) and ethyl isocyanate (12.0 mg, 0.169 mmole, Aldrich) in dichloromethane (4 mL) was stirred at room temperature for 2 h before concentrated to dryness. The residue was purified by flash column chromatography (silica gel, eluting with a gradient of 1-10% methanol in dichloromethane) to give the title compound (44.6 mg, 78% yield). HR-MS (ES, m/z) calculated for C37H47Cl2N6O3 [(M+H)+] 693.3081, observed 693.3081.
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:8]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([Cl:17])=[CH:9]2)[C:7]1([CH3:19])[CH3:18])=[O:5])C.[OH-].[K+]>C(O)C.O>[Cl:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2([C:7]([CH3:18])([CH3:19])[CH:6]2[C:4]([OH:5])=[O:3])[CH:9]=1
Reactant: CCOC(=O)C1C(C)(C)C12C=C(Cl)c1ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)C(C(=O)O)C12C=C(Cl)c1ccccc12
Yield: 86.2 %

Procedure:
A solution of 3'-chloro-3,3-dimethyl-spiro[cyclopropane-1,1'-indene]-2-carboxylic acid ethyl ester (2.0 g; 0.007 mole) in ethanol (10 ml) is added to a mixture of 50% aqueous potassium hydroxide (1.2 ml) and water (1.2 ml), and the mixture is heated at reflux for 11/2 hours, then cooled down, diluted with water and extracted with ether. The aqueous phase is then made acid with concentrated hydrochloric acid and extracted with ether. The ethereal extract is washed with water, saturated salt solution, dried over magnesium sulfate and is stripped to afford 1.5 g of title product, a read-brown semisolid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][OH:12])=[CH:6][CH:5]=1.[CH3:23]I>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:11][O:12][CH3:23])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[CH:6][CH:5]=1
Reactant: CCCCC(CO)(Cn1cncn1)c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(COC)(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a 100 mL 3 neck flask stirring under nitrogen was charged 0.40 g (0.010 mole) of 60% sodium hydride, prewashed with hexanes, in 30 mL of dimethylformamide. The slurry was cooled to 10° C. and 2.12 g (0.00723 mole) of 2-(4-chlorophenyl)-2-[(1,2,4-triazol-1-yl)methyl]hexan-1-ol in 15 mL of dimethylformamide was added over 15 minutes. The reaction was warmed to room temperature and 1.17 g (0.00812 mole) of methyl iodide was added directly and the reaction was stirred overnight at room temperature. The reaction was quenched with 10 mL water and 100 mL ether. The organic phase was washed with 2×25 mL water, dried, concentrated and gave 1.53 g (69% yield) of product as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[CH:4][C:3]=1[CH2:19][CH2:20][CH2:21][OH:22].N1C=CN=C1.[CH3:28][C:29]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C(Cl)Cl>[C:29]([Si:32]([CH3:34])([CH3:33])[O:22][CH2:21][CH2:20][CH2:19][C:3]1[C:2]([NH2:1])=[C:7]([NH2:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:16])([F:17])[F:18])[CH:4]=1)([CH3:31])([CH3:30])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1cc(-c2ccccc2C(F)(F)F)cc(CCCO)c1N
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCc1cc(-c2ccccc2C(F)(F)F)cc(N)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
3-(4,5-Diamino-2′-trifluoromethyl-biphenyl-3-yl)-propan-1-ol (101 mg, 0.324 mmol, as prepared in the previous step) was placed in an 8 mL vial equipped with a magnetic stir bar, and DCM (2 mL) was added via pipette. Imidazole (1.1 eq., 24.5 mg, 0.356 mmol) and TBSCl (1.1 eq., 53.7 mg, 0.356 mmol) were added sequentially as solids, and the reaction was stirred at RT for 2 h. The reaction was filtered, the precipitate was washed once with DCM (5 mL), and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on a 24-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 1:1, v/v over 30 min, yielding 93.2 mg (68%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 7.69 (d, J=7.8 Hz, 1H), 7.49 (t, J=7.5 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 6.61 (s, 1H), 6.59 (s, 1H), 3.66 (t, J=5.9 Hz, 2H), 3.52 (br. s., 4H), 2.65 (t, J=7.3 Hz, 2H), 1.75-1.87 (m, 2H), 0.91 (s, 9H), 0.07 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][C:3]=1[CH2:29][O:30][C:31]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1CCCCC1.C([Li])(CC)C.[CH2:61]([O:68][CH:69]1[CH:74]([O:75][CH2:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[CH:73]([O:83][CH2:84][C:85]2[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=2)[CH:72]([CH2:91][O:92][CH2:93][C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)[O:71][C:70]1=[O:100])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>C1(C)C=CC=CC=1.O>[CH2:61]([O:68][CH:69]1[CH:74]([O:75][CH2:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[CH:73]([O:83][CH2:84][C:85]2[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=2)[CH:72]([CH2:91][O:92][CH2:93][C:94]2[CH:95]=[CH:96][CH:97]=[CH:98][CH:99]=2)[O:71][C:70]1([C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[CH:4][C:3]=1[CH2:29][O:30][C:31]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[OH:100])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: O=C1OC(COCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Reactant: Brc1cc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]C(C)CC
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Product: OC1(c2cc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)ccc2COC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(COCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
Under a nitrogen stream, to a solution of 2-bromo-1,4-bis(trityloxymethyl)benzene (255.3 mg, 0.36 mmol) in toluene (1.5 ml), a cyclohexane solution of sec-butyllithium (0.99 M, 367 μl, 0.36 mmol) was added dropwise at room temperature and the solution was stirred for 30 minutes. This solution was added dropwise at −78° C. to a solution of 3,4,5-trisbenzyloxy-6-(benzyloxymethyl)tetrahydropyran-2-one (140 mg, 0.26 mmol) in toluene (1.5 ml) and the mixture was stirred at the same temperature for 30 minutes. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:5)) to give the titled compound (242 mg, 80%).