Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:11][C:10]=1[O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Li+].Cl>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[O:21][CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(OCc2ccccc2)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(CC(=O)O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
To a solution of ethyl 4-benzyloxy-3-methoxyphenylacetate (32 g, 110 mmol), from Step 1, in ethanol (200 mL) and THF (20 mL) was added 200 mL of a 1M aqueous lithium hydroxide solution. The resulting mixture was stirred at ambient temperature for 4 hours and then 1M aqueous hydrochloric acid solution was added to precipitate the product. The solid was filtered, washed with water, taken up in diethyl ether, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a yellow solid. The solid was recrystallized from methylene chloride/petroleum ether (b.p. 30°-60° C.) to give 19 g (58% yield based on ethyl 4-hydroxy-3-methoxyphenylacetic acid) of the title compound as a white solid; 1H NMR (CDCl3) δ 3.57 (s, 2H), 3.88 (s, 3H), 5.14 (s, 2H), 6.74 (dd, 1H, J=8.0, 2.7 Hz), 6.82-6.85 (m, 2H), 7.28-7.45 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:38](=[O:41])[CH2:39][CH3:40])[C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:36]=[CH:35][C:24]([O:25][CH2:26][CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([O:31]C)=[O:30])=[CH:23][CH:22]=3)=[O:20])[C@@H:11]([CH3:37])[CH2:10]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:38](=[O:41])[CH2:39][CH3:40])[C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:22]=[CH:23][C:24]([O:25][CH2:26][CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([OH:31])=[O:30])=[CH:35][CH:36]=3)=[O:20])[C@@H:11]([CH3:37])[CH2:10]2)=[CH:6][CH:7]=1
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)OC)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)O)cc2)c2ccccc21
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Methyl 4-(4-{[(2S,4R)-4-[(4-chlorophenyl)(propionyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2,2-dimethylbutanoate was dissolved in methanol/tetrahydrofuran/water (2/1/1) then sodium hydroxide (3 equivalents) was added and reaction mixture stirred at 40° C. overnight. The mixture was concentrated, the residue acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 4-(4-{[(2S,4R)-4-[(4-chlorophenyl)(propionyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2,2-dimethylbutanoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:9]=1[Cl:10])[C:5]#[N:6].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O.C(N(CC)CC)C>ClCCl>[NH2:1][C:2]1[C:9]([Cl:10])=[C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:17])[CH2:13][CH2:12]2)[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1
Reactant: N#Cc1cc(N)c(Cl)c(N2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C#N)cc(N)c2Cl)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.5 %

Procedure:
(I11C): To the stirred solution of 3-amino-4-chloro-5-(piperazin-1-yl)benzonitrile (1.0 g, 4.22 mmol) in dichloromethane (10 mL) was added BOC2O (0.981 mL, 4.22 mmol) at 0° C., drop wise over a period of 10 minutes followed by triethylamine (0.883 mL, 6.34 mmol). The reaction mixture was allowed to warm to room temperature, stirred it for 1 hour. The reaction mixture was diluted with methylene chloride (100 mL), washed with brine (30 mL), dried over Na2SO4 and concentrated at 45° C. to get tert-butyl 4-(3-amino-2-chloro-5-cyanophenyl)piperazine-1-carboxylate (1.4 g) as a brown solid. The crude material was washed with diethyl ether four times and dried under vacuum to get tert-butyl 4-(3-amino-2-chloro-5-cyanophenyl)piperazine-1-carboxylate (1.4 g) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:12])[CH:4]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Reactant: NCCCCO
Product: O=S(=O)(NCCCCO)c1ccc(Br)c(F)c1

Procedure:
Using a method analogous to that described in Example 1, 4-bromo-3-fluorophenyl sulphonyl chloride was reacted with 4-aminobutanol, and the title compound obtained as a white solid after recrystallisation from ether/petrol. δC (CDCl3, 62.9 MHz): 26.5, 29.4, 43.2, 62.2, 114.5 (d, J 20.5), 115.3 (d, J 25.4), 123.7 (d, 3.9), 134.5, 141.2 (d, 5.9) and 158.9 (d, J 252).
Reaction SMILES: [CH:1]([C:4]1([CH3:22])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:15]=[C:14]3[O:16][CH:17]=[CH:18][C:13]3=[CH:12][C:11]=2[C:19](O)=[O:20])=[N:5]1)([CH3:3])[CH3:2].C(OC(=O)C)(=O)C.N1C=CC=CC=1>C(COC)OC>[CH:1]([C:4]1([CH3:22])[C:8](=[O:9])[N:7]2[C:19](=[O:20])[C:11]3[CH:12]=[C:13]4[CH:18]=[CH:17][O:16][C:14]4=[N:15][C:10]=3[C:6]2=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)C1(C)N=C(c2nc3occc3cc2C(=O)O)NC1=O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: COCCOC
Product: CC(C)C1(C)N=C2c3nc4occc4cc3C(=O)N2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.5 %

Procedure:
To a suspension of 6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-furo[2,3-b]-pyridine-5-carboxylic acid (11.7 g, 0.039 mol) in 100 mL dimethoxyethane (DME) is added 7.3 mL acetic anhydride and 3.9 mL pyridine. After stirring 24 hours at room temperature, the solids are filtered and washed with ether and the mother liquor is concentrated by adding xylene to aid removal of pyridine. The residue is triturated with ether to obtain solids which are combined with the first crop to give 11.1 g (100%) of product. Recrystallization from 2:1 ethyl acetatehexane gives an analytical sample mp 193°-205° C.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5]S[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=O)C=1.[S:25]([O-:29])([O-])(=[O:27])=S.[Na+].[Na+].C(N(CC)CC)C.C(OC([O-])=O)(OC(OC(C)(C)C)=O)=O>ClCCl>[O:27]=[S:25]1(=[O:29])[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:2][CH2:3]1
Reactant: O=S([O-])([O-])=S
Reactant: CC(C)(C)OC(=O)N1CCSCC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(=O)[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCS(=O)(=O)CC1
Yield: 91.6 %

Procedure:
tert-Butyl thiomorpholine-4-carboxylate (1.91 g, 9.42 mmol) was dissolved in dichloromethane (50 ml); m-chloroperbenzoic acid (5.0 g, 19 mmol) was gradually added while cooled with ice bath, stirred, and under nitrogen atmosphere; and the reaction mixture was stirred at room temperature for 12 hours. After addition of a saturated aqueous solution of sodium thiosulfate, the reaction mixture was kept stirred for a while; and this was subjected to extraction with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Triethylamine (8.1 ml, 58 mmol) were added to the obtained crystals; and the reaction mixture was stirred at room temperature. tert-Butoxycarbonyl dicarbonate (13.3 ml, 58 mmol) was added thereto; and the reaction mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure; and the obtained crystals were suspended with a solvent mixture of diethyl ether:ethanol=10:1, filtered off, washed with diethyl ether and dried under aeration to yield the title compound as colorless crystals (2.03 g, 8.63 mmol, 91.6%).
Reaction SMILES: [CH2:1]([C:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl-:33].[Ca+2].[Cl-].Cl>C(Cl)Cl>[CH2:1]([C:11]([Cl:33])([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [Cl-]
Reactant: CCCCCCCCCCC(O)(CCCCCCCCCC)CCCCCCCCCC
Agent: Cl
Agent: [Ca+2]
Solvent: ClCCl
Product: CCCCCCCCCCC(Cl)(CCCCCCCCCC)CCCCCCCCCC
Yield: 90 %

Procedure:
One mole of tri-n-decylcarbinol was added to a mixture of 0.2 liters of methylene chloride and 0.32 moles calcium chloride. Approximately 1.5 moles of HCl gas was slowly bubbled through the solution. The product mixture is then washed with 1 liter of a 10% sodium carbonate solution. The organic layer is dried with magnesium sulfate and the methylene chloride evaporated off to give a 90% yield of tri-n-decylmethylchloride.
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]1[O:24][C@@H:23]([P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[S:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>CO.C(Cl)(=O)C.[Cl-].[NH4+]>[CH2:28]([O:27][P:25]([O:30][CH2:31][CH3:32])([C@H:23]1[S:22][CH2:21][C@H:20]([CH2:19][OH:18])[O:24]1)=[O:26])[CH3:29]
Reactant: CCOP(=O)(OCC)[C@@H]1O[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CS1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)Cl
Product: CCOP(=O)(OCC)[C@@H]1O[C@@H](CO)CS1
Temperature: 0 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
To a solution of cis and trans-5-t-butyldimethylsilyloxymethyl-2-(diethyloxyphosphinoyl)-1,3-oxathiolane (example 25) (4.00 g, 10.8 mmol) in MeOH (30 mL) was added a few drops of acetyl chloride (200 μL) at 0° C. The mixture was stirred at 0° C. for 1 hr. and at room temperature for 18 hr. A few drops of ammonium chloride was added and the solvent was evaporated under reduced pressure. The crude material was purified by several flash chromatography with a mixture of dichloromethane and methanol (96:4) to give 382 mg of the cis isomer, 1.19 g of the trans isomer and 332 mg of the mixture in a total yield of 80% after the first purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][O:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:24])[CH3:23])[NH2:21].C(N(CC)C(C)C)(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:17][O:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:24])[CH3:23])[NH:21][C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
N-tert-butoxycarbonyl L-valine (11.67 g, 53.71 mmol) was dissolved in DMF (50 mL) and the solution cooled to 0° C. (icebath). L-valine methyl ester hydrochloride (9.01 g, 53.7 mmol) was suspended in DMF (25 mL) and N,N-diisopropylethylamine (6.94 g, 53.7 mmol) added. The resulting solution was added to the solution of N-tert-butoxycarbonyl L-valine together with DMF (5 mL). HOBt hydrate (8.23 g, 53.7 mmol) and then EDC hydrochloride (11.33 g, 59.10 mmol) were added in portions together with an additional 30 mL DMF. The reaction mixture was stirred at 0° C. for 2 h 30 min after which the icebath was removed and stirring continued for 22 h 30 min at room temperature. The solvent was evaporated and the residue taken up in EtOAc (250 mL). The solution/suspension was washed with 1 M aqueous H2SO4 (3×100 mL), 7.5% (w/w) K2CO3 solution (3×100 mL) and saturated brine (100 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording a white solid (16.92 g, 95%); δH (200 MHz; d6-DMSO) 7.97 (1H, dd, J 8, NH(Val2)), 6.68 (1H, dd, J 9, NH(Val1)), 4.18 (1H, dd, J 8 and 6, CαH(Val2)), 3.86 (1H, dd, J 9 and 8, CαH(Val1)), 3.61 (3H, s, OCH3), 2.15-1.79 (2H, m, CH(CH3)), 1.37 (9H, s, (CH3)3), 0.91-0.80 (12H, m, CH3); δC (50 MHz, d6-DMSO): 171.7, 171.7, 155.3, 77.9, 59.4, 57.2, 51.5, 30.2, 29.8, 28.0, 19.0, 18.8, 18.1, 18.1
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([OH:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16].[CH:23](O)([CH3:25])[CH3:24].O>CN(C=O)C>[OH:16][C:15]1[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=1[C:13]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(C)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC(=O)c1ccccc1O
Temperature: 50 °C
Reaction time: 4 h
Yield: 53.5 %

Procedure:
CDI (2.34 g, 14.48 mmol) was added to a solution of salicylic acid (2.00 g, 14.48 mmol) in DMF (40 mL). The reaction mixture was stirred at 50° C. for 4 h and isopropyl alcohol (2.80 mL, 36.20 mmol) was dropwise added. The reaction mixture was stirred at 50° C. for 16 h and allowed to reach r.t. It was poured into H2O (50 mL) and extracted with Et2O (2×40 mL). The organic layer was washed with NaHCO3 (20 mL, saturated aqueous solution), dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5% EtOAc/hexanes) to furnish 1.395 g of isopropyl 2-hydroxybenzoate (colourless oil, yield: 54%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[O:12][CH2:13][CH:14]1[CH2:16][CH2:15]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:7][C:6]=1[O:12][CH2:13][CH:14]1[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)c1ccc(O)cc1OCC1CC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)COc1ccc(C(C)(C)C)c(OCC2CC2)c1
Yield: 75.6 %

Procedure:
4-tert-Butyl-3-(cyclopropylmethoxy)phenol (444 mg, 2.0 mmol), sodium hydride (60% in mineral oil) (68 mg, 1.7 mmol) and ethyl bromoacetate (270 II, 2.4 mmol) were treated in the same procedure described in Example 31(c). The crude residue was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and ethyl acetate (19/1 to 9/1) to furnish 463 mg (75% yield) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH2:5]([N:9]=[C:10]=[O:11])[CH2:6][CH2:7][CH3:8]>C1(C)C=CC=CC=1>[CH2:1]([NH:4][C:10]([NH:9][CH2:5][CH2:6][CH2:7][CH3:8])=[O:11])[CH2:2][CH3:3]
Reactant: CCCCN=C=O
Reactant: CCCN
Solvent: Cc1ccccc1
Product: CCCCNC(=O)NCCC
Yield: 96.1 %

Procedure:
205.76 Grams (3.48 moles) of n-propylamine were charged to a 1-1., round bottom flask equipped with stirrer, thermometer, reflux condenser and addition funnel. 313.7 Grams (3.16 moles) of butyl isocyanate were charged to the addition funnel and added to the flask with stirring at a rate which maintained the contents at about 60°-65° C. Toluene was added to dissolve the solid product for transfer to a stripping vessel. The crude product solution was about 92 area % ureas on a solvent-free basis by gas chromatography. The crude product solution was freed of most of the solvent and lights under vacuum with a rotary evaporator leaving 480.6 g of pale yellow solid melting from 68°-70° C. Infrared analysis showed a clean spectrum in agreement with the proposed structure's functionality. The gas chromatograph showed three, major peaks in a 1:2:1 ratio indicating possible `scrambling` of alkyl groups and a statistically determined ratio of products.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9](Br)[CH:10]=[CH:11][C:12]=1[O:13][C:14]([F:17])([F:16])[F:15].[C:19](=[O:21])=[O:20].Cl>C(OC(C)C)(C)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=1[O:13][C:14]([F:17])([F:16])[F:15])[C:19]([OH:21])=[O:20]
Reactant: O=C=O
Reactant: FC(F)(F)Oc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)OC(C)C
Product: O=C(O)c1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyl lithium (4.4 ml of 2.5M solution in hexanes) in dry diisopropyl ether was treated at −78° C. under an inert atmosphere with 3-chloro4-trifluoromethoxy-bromobenzene (2.96 g) in diisopropyl ether. After 10 minutes, excess carbon dioxide (in the form of pellets) was added and the mixture left to slowly warm to ambient temperature. Ice-water was added and the organic layer run off. The aqueous layer was acidified with dilute hydrochloric acid, extracted (ether), dried (magnesium sulphate) and evaporated to dryness to give 3-chloro-4-trifluoromethoxybenzoic acid (1.51 g) as a white solid, m.p. 110.5-111.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN1CCOCC1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:27]=1[C:28](Cl)=[O:29]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:28](=[O:29])[C:27]3[C:31]([O:35][CH3:36])=[CH:32][CH:33]=[CH:34][C:26]=3[O:25][CH3:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1cccc(OC)c1C(=O)N1CCC(CCO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 74.5 %

Procedure:
3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (2 g, 7.695 mmol) was dissolved in dichloromethane at -78° C. and treated with 4-methylmorpholine (1.8 mL, 16.4 mmol, 2.1 eq.) and 2,6-dimethoxy-benzoyl chloride (1.55 g, 7.73 mmol) in dichloromethane (20 mL). The solution was allowed to warm to 0° C. and stirred for 1.5 hours. The solution was washed with 1N HCl and 5% sodium bicarbonate and the organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (200 g) with a gradient of 50% ethyl acetate in hexane to 6% methanol in dichloromethane to give 2.434 g (75%) of the title compound.
Reaction SMILES: Cl.O1CCOCC1.[CH3:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N:15]1[CH2:19][CH2:18][N:17]([C:20]2[CH:21]=[N:22][N:23](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:24]=2)[C:16]1=[O:44].CO>O1CCOCC1.C(Cl)Cl>[CH3:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N:15]1[CH2:19][CH2:18][N:17]([C:20]2[CH:24]=[N:23][NH:22][CH:21]=2)[C:16]1=[O:44]
Reactant: Cc1ccncc1N1CCN(c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: Cc1ccncc1N1CCN(c2cn[nH]c2)C1=O
Yield: 63.9 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465 mmol) was reacted with 4-bromo-1-trityl-1H-pyrazole (369.3 mg, 0.8465 mmol), 1,4-dioxane (50 mL), copper iodide (16 mg, 0.08465 mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium carbonate (468 mg, 3.3860 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in chloroform) afforded 250 mg of 1-(4-Methyl-pyridin-3-yl)-3-(1-trityl-1H-pyrazol-4-yl)-imidazolidin-2-one (60% yield). Dioxane hydrochloride (10 mL) was added to a stirred solution of 1-(4-methyl-pyridin-3-yl)-3-(1-trityl-1H-pyrazol-4-yl)-imidazolidin-2-one (250 mg, 0.51484 mmol) in dioxane under nitrogen atmosphere at 0° C. The reaction mixture was stirred at room temperature for 2 hours with TLC monitoring (10% MeOH in DCM). The solvent was distilled from the reaction mixture and washed with ether. The precipitate was collected and dried under reduced pressure to afford 80 mg of the product (55% yield).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[S:10][C:9]([C:11]([OH:13])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][C@@H:48]([CH2:62][C:63]1[CH:68]=[C:67]([F:69])[CH:66]=[C:65]([F:70])[CH:64]=1)[C@H:49]([OH:61])[CH2:50][NH:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH3:60])[CH:54]=1>C(Cl)Cl>[F:69][C:67]1[CH:68]=[C:63]([CH:64]=[C:65]([F:70])[CH:66]=1)[CH2:62][C@H:48]([NH:47][C:11]([C:9]1[S:10][C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][CH:8]=1)=[O:13])[C@H:49]([OH:61])[CH2:50][NH:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH3:60])[CH:54]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)O)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc(CS(C)(=O)=O)s2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.1 %

Procedure:
To a solution of acid from step 5 (115 mg, 0.52 mmol) and N,N-diisopropylethylamine (540 μL, 3.12 mmol) in methylene chloride (6.5 mL) was added HBTU (200 mg, 0.52 mmol) and the reaction mixture was stirred for 0.5 h. (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (211 mg, 0.52 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, 1-5% methanol in chloroform) gave the title compound (45 mg): mp 128-131° C.; ESI MS m/z 537 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:45][CH3:46])=[C:6]([C:8]([CH3:44])([CH3:43])[CH2:9][C:10]([OH:42])([C:38]([F:41])([F:40])[F:39])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([C:29]([NH:31][C@@H:32]([C:35]([OH:37])=O)[CH2:33][OH:34])=[O:30])[CH:26]=[CH:27][CH:28]=2)[CH:7]=1.[NH3:47]>>[NH2:47][C:35](=[O:37])[C@H:32]([NH:31][C:29](=[O:30])[C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([N:17]2[C:18]3[C:14](=[C:13]([NH:12][CH2:11][C:10]([OH:42])([C:38]([F:41])([F:40])[F:39])[CH2:9][C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:45][CH3:46])([CH3:44])[CH3:43])[CH:21]=[C:20]([CH3:22])[CH:19]=3)[CH:15]=[N:16]2)[CH:24]=1)[CH2:33][OH:34]
Reactant: N
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N[C@H](CO)C(=O)O)c1)C(F)(F)F
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N[C@H](CO)C(N)=O)c1)C(F)(F)F

Procedure:
Prepared similarly to Example 14 from N-{[3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)phenyl]carbonyl}-D-serine and ammonia.
Reaction SMILES: [C:1]([O:5][CH:6]([CH3:17])[CH2:7][CH2:8][CH2:9][CH:10]1[O:15][CH:14]([OH:16])[CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[CH:18]([Mg]Cl)=[CH2:19].CCOCC.[Cl-].[NH4+]>O1CCCC1>[OH:16][CH:14]([CH2:13][CH2:12][CH2:11][CH:10]([OH:15])[CH2:9][CH2:8][CH2:7][CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:17])[CH:18]=[CH2:19]
Reactant: CC(CCCC1CCCC(O)O1)OC(C)(C)C
Reactant: C=C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC(O)CCCC(O)CCCC(C)OC(C)(C)C

Procedure:
4.5 G. of 6-[4-tertiarybutoxypentyl]-2-tetrahydropyranol produced in Example 120 was dissolved in 200 ml. of tetrahydrofuran and added slowly over a 20 minute period to a solution of 300 ml. of vinyl magnesium chloride in tetrahydrofuran at 0°. After agitation for an additional hour at room temperature, 200 ml. of ether was added which was followed by the addition of 100 ml. of a 20 per cent aqueous solution of ammonium chloride. Extraction with ether yielded a waxy solid, 3,7-dihydroxy-11-tertiarybutoxydodec-1-ene.