Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[C@@:10]([CH2:14][OH:15])([CH2:11]2)[C@@H:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:24].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([N:8]1[CH2:13][CH:12]2[C@@:10]([C:14]([OH:24])=[O:15])([CH2:11]2)[C@@H:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@]12CC1CN(Cc1ccccc1)[C@H]2c1ccccc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)[C@@]12CC1CN(Cc1ccccc1)[C@H]2c1ccccc1
Yield: 62 %

Procedure:
To a stirred solution of racemic Intermediate 38, one enantiomer being ((1S,2S)-3-benzyl-2-phenyl-3-aza-bicyclo[3.1.0]hex-1-yl)-methanol (0.69 g, 2.5 mmol) in acetone (20 mL) was added Jones Reagent (3 mL) dropwise with stirring. Additional acetone (50 mL) was added and the material was triturated then filtered to remove the solid. The filtrate was concentrated and partitioned between water of pH=6 and methylene chloride. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound (0.45 g, 62% yield).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(I)cc1)N1CCOCC1
Reaction time: 2 h
Yield: 81.2 %

Procedure:
A mixture of 4-iodobenzoyl chloride (500 mg), morpholine (163 mg) and triethylamine (380 mg) in CH2Cl2 (20 ml) is stirred 2 h before washing with H2O (20 ml) and brine (20 ml). The organic layer is dried over MgSO4 and the solvent is evaporated to obtain 482 mg of (4-iodo-phenyl)-morpholin-4-yl-methanone, yellowish semisolid, MS (ESI) 318.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[N+]=[N-])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>ClCCCl>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:28][CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C(=[N+]=[N-])c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: ClCCCl
Product: CCOC(=O)C(OC1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1

Procedure:
To a solution of diazophenylacetic acid ethyl ester (2.55 g) in 1,2-dichloroethane is added 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (5.4 g). The flask is evacuated and filled with argon. Rhodium(II) acetate-dimer (60 mg) is added to the reaction mixture. Evolution of nitrogen occurs until the end of the reaction (about 1 hour). The solvent is removed under reduced pressure. The residue is purified by chromatography (gradient heptane/ethyl acetate from 95/5 to 80/20) to give 4-(ethoxy-carbonylphenylmethoxy)piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=1>C(Cl)Cl>[F:26][C:27]([F:37])([F:36])[C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:6]/[C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:30][CH:29]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Yield: 71.1 %

Procedure:
To a solution of (carbethoxymethylene)triphenylphosphorane (55.3 g, 159 mmol) in 150 mL DCM, alpha,alpha,alpha-trifluoro-p-tolualdehyde (25.00 g, 144 mmol) in 75 mL DCM was added. The reaction is exothermic. The mixture was heated at reflux for 90 minutes. After removing the solvent, hexane was added to the resulting residue. A precipitate appeared and was filtered through filter paper. The collected solid was subjected to a silica gel chromatography with 100% hexane as the eluant to afford a white solid ((E)-ethyl 3-(4-(trifluoromethyl)phenyl)acrylate(25.0 g, yield=71%). LCMS (API-ES) m/z (%): 245.1 (100%, M++H); 1H NMR (400 MHz, CD3OD) δ ppm 1.35 (t, J=7.14 Hz, 3H) 4.28 (q, J=7.04 Hz, 2H) 6.68 (d, J=1 6.04 Hz, 1H) 7.70-7.77 (m, 3H) 7.80-7.84 (m, 2H).
Reaction SMILES: [N:1]1([CH2:10][CH2:11][OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[N:1]1([CH2:10][CH2:11][O:12][C:14]2[CH:46]=[CH:45][C:17]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]3=[O:44])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: OCCN1CCc2ccccc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=C1SC(Cc2ccc(OCCN3CCc4ccccc43)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 59 %

Procedure:
A procedure similar to that described in Preparation was repeated, except that 240 mg of 2-(indolin-1-yl)-ethanol (prepared as described in Preparation 9), 690 mg of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.37 ml of tributylphosphine, 370 mg of 1,1'-(azodicarbonyl)dipiperidine and 5 ml of anhydrous tetrahydrofuran were used, to give 530 mg of the title compound having Rf=0.88 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[CH:13]=1>C1(C)C=CC=CC=1>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][C:10](=[O:11])[NH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH:13]=1
Reactant: OCc1cccnc1
Reactant: COc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)OCc2cccnc2)cc1
Temperature: 100 °C

Procedure:
A resealable tube was charged with 4-methoxyphenylisocyanate (1.00 g, 6.70 mmol), 3-pyridylcarbinol (0.800 g, 7.33 mmol), and toluene (4 mL). The tube was sealed and the mixture was heated at 100° C. for 20 h. The reaction mixture was cooled to room temperature. The resulting white solid was collected by suction filtration and washed with diethyl ether. The solid was dried under vacuum to give (4-methoxyphenyl)-carbamic acid pyridin-3-ylmethyl ester a white solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCOCC1.[NH2:16][CH2:17][CH2:18][O:19][C:20]1[C:30]2[CH2:29][CH2:28][N:27]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[CH2:26][CH2:25][C:24]=2[CH:23]=[CH:22][C:21]=1[Cl:37]>C(Cl)Cl>[C:1]([NH:16][CH2:17][CH2:18][O:19][C:20]1[C:30]2[CH2:29][CH2:28][N:27]([C:31](=[O:36])[C:32]([F:33])([F:35])[F:34])[CH2:26][CH2:25][C:24]=2[CH:23]=[CH:22][C:21]=1[Cl:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Solvent: C1COCCN1
Solvent: ClCCl
Product: O=C(NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccccc1

Procedure:
Combine benzoyl chloride (19.3 mg, 0.137 mmol), PS-morpholine (109 mg, 0.272 mmol), 6-(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (46 mg, 0.137 mmol) in DCM (1.5 mL) and stir at ambient temperature for 16 h. Filter the resin, wash with DCM and concentrate in vacuo. Purify by reverse phase HPLC (10-95% of solvent B in 12.8 min, 25 mL/min; solvent A: water, 0.1% trifluoroacetic acid; solvent B: acetonitrile, 0.1% trifluoroacetic acid; column: YMC SH-341-5, S-5μm, 12 nm, 100×20 mm) to give 6-(2-benzoylamino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[C:11]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19](=O)[C:20]([CH3:24])([CH3:23])[CH:21]=[CH2:22])=[CH:13][CH:12]=1.C[O-].[Na+]>C(#N)C>[C:11]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2([C:20]([CH3:24])([CH3:23])[CH:21]=[CH2:22])[CH2:10][O:9]2)=[CH:15][CH:16]=1
Reactant: C=CC(C)(C)C(=O)COc1ccc(-c2ccccc2)cc1
Reactant: COS(=O)(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CSC
Product: C=CC(C)(C)C1(COc2ccc(-c3ccccc3)cc2)CO1
Reaction time: 96 h
Yield: 80.4 %

Procedure:
A solution of 41.9 ml (0.567 mol) of dimethyl sulphide in 50 ml of acetonitrile was added dropwise to a solution of 49.4 ml (0.518 mol) of dimethyl sulphate in 250 ml of acetonitrile at 25° C., in the course of 2 hours, with external cooling. After the mixture had stood for 4 days at room temperature, 87.4 g (0.31 mol) of 5-(biphenyl-4-yloxy)-3,3-dimethylpent-1-en-4-one, dissolved in 90 ml of acetonitrile, were stirred in in the course of 1 hour. Thereafter, 31.6 g (0.58 mol) of sodium methylate were introduced at 25° C. After the mixture had been stirred for twelve hours at room temperature, the precipitated salt was filtered off, and the filtrate was concentrated. The oily residue was taken up in 500 ml of ethyl acetate, and the solution was washed with twice 500 ml of water and dried over anhydrous sodium sulphate. After the solution had been concentrated in vacuo, 73.4 g (80.4% of theory) of 2-(biphenyl-4-yloxymethyl)-2-(3,3-dimethylprop-1-en-3-yl)-oxirane were obtained as a colorless waxy mass. ##STR23##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:44])[C@@H:5]([NH:36]C(OC(C)(C)C)=O)[CH2:6][NH:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:35])[CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:21][CH2:20]2)[CH2:11]1)=[O:9])[CH3:2].[ClH:45]>C(OCC)(=O)C>[ClH:45].[CH2:1]([O:3][C:4](=[O:44])[C@@H:5]([NH2:36])[CH2:6][NH:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:35])[CH2:17][CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:26])[CH2:23][CH2:24]2)[CH2:11]1)=[O:9])[CH3:2]
Reactant: CCOC(=O)[C@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OCc3ccccc3)CC2)C1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](N)CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OCc3ccccc3)CC2)C1
Temperature: 0 °C

Procedure:
To a solution of N-[(R)-1-{3-(1-benzyloxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-(tert-butoxycarbonyl)amino-β-alanine ethyl ester (5.98 g) in ethyl acetate (60 ml) was added a solution of 4N HCl in ethyl acetate (24.2 ml) under stirring at 0° C. After stirring at ambient temperature for 2 hours, the resulting precipitates were collected by filtration to give N-[(R)-1-{3-(1-benzyloxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-amino-β-alanine ethyl ester hydrochloride (3.41 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11]1[CH:23]=[CH:22][C:14]([O:15][CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=1.[Na]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11]2[CH:23]=[CH:22][C:14]([O:15][CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COC(=O)C(C)Oc1ccc(CCl)cc1
Agent: [Na]
Solvent: CCO
Product: COC(=O)C(C)Oc1ccc(COc2ccc(Cl)cc2)cc1
Yield: 77.9 %

Procedure:
5.7 gm (0.044 mol) of 4-chloro-phenol and 10 gm (0.044 mol) of methyl 2-(4-chloromethyl-phenoxy)-propionate were added to a solution of 1.01 gm of sodium in 80 ml of ethanol, and the resulting mixture was refluxed for 6 hours, while stirring. Thereafter, the solvent was removed in vacuo, the residue was admixed with water, and the aqueous mixture was extracted with ether. The ethereal extract solution was washed with 1 N potassium hydroxide and then with water, dried and evaporated, leaving 11 gm of an oily residue which was purified by passing it through a silicagel column with benzene as the flow agent. The initially oily product crystallized upon standing and then had a melting point of 76° C.; it was identified to be the compound of the formula ##STR18##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)c(Br)c1
Yield: 87.1 %

Procedure:
Combine 2-bromo-4-fluoro-1-methyl-benzene (15 g, 79.3 mmol), N-bromosuccinimide (18.08 g, 101.6 mmol), and 2,2-azobisisobutyronitrile (3.9 g, 23.8 mmol) in carbon tetrachloride (150 mL) in a round bottom flask fitted with a reflux condensor. Heat the mixture at reflux for 21 h. Cool the mixture and remove the solvent under reduced pressure. Suspend the crude mixture in DCM and wash with water. Wash the organics with aqueous saturated sodium chloride and dry over sodium sulfate. Filter and remove the solvent under reduced pressure to obtain the crude product. Purify by column chromatography (1% ethyl acetate in hexane→10% ethyl acetate in hexanes) to give the title compound as an oily white solid (18.5 g, 87%). GCMS m/z 268 [M]+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][C:13]([CH3:22])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH2:15])(=[O:11])[CH3:10].[C:23]1([C:33](Cl)=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:23]1([C:33](=[O:34])[CH2:10][C:9]([O:12][C:13]([CH3:22])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH2:15])=[O:11])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: C=CC(C)(CCC=C(C)C)OC(C)=O
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)c1cccc2ccccc12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (96.3 mL of a 2.0M solution, 0.193 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is cooled to -78° C. 3,7-dimethyl-1,6-octadien-3-yl acetate (17.81 g, 0.091 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min. before being treated with a solution of 1-naphthoyl chloride (16.82 g, 0.086 mol) dissolved in THF (25 mL) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (53 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an oil. The oil is purified by column chromatography (elution with 2% ethyl acetate/petroleum ether) to yield a colorless oil having 1H and 13C NMR spectra consistent with the desired product.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:16][CH2:17][Cl:18])[C:5]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].[CH2:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][CH2:2][CH2:3][N:4]([CH2:16][CH2:17][Cl:18])[C:5]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:6]=1[C:7]([O:9][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:8]
Reactant: OCc1ccccc1
Reactant: Cc1cc(C)c(N(CCCl)CCCl)c(C(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C)c(N(CCCl)CCCl)c(C(=O)OCc2ccccc2)c1
Reaction time: 17 h
Yield: 91.5 %

Procedure:
2-Bis(2'-chloroethyl)amino-3,5-dimethylbenzoic acid (1.0 g, 3.45 mmol), benzyl alcohol (0.75 g, 6.90 mmol), 1,3-dicyclohexylcarbodiimide (0.82 g, 3.975 mmol), and 4-dimethylaminopyridine (0.50 g, 4.03 mmol) were dissolved in 25 mL dichloromethane at room temperature to form a reaction mixture. The mixture was stirred for 17 hours, diluted with hexanes (10 mL), cooled in the freezer for 20 minutes, and then filtered, It was then concentrated and then subjected to flash chromatographic purification (silica gel, 5% to 10% ethyl acetate in hexanes) to afford the product as a white oil (1.20 g, 92%). 1H NMR (300 MHz, CDCl3): 7.4 (m, 5H), 7.33 (d, J=2.1 Hz, 1H), 7.17 (d, J=2.1 Hz, 1H), 5.32 (s, 2H), 3.46 (m, 4H), 3.30 (br m, 4H), 2.33 (s, 3H), 2.29 (s, 3H). ESMS calcd (C20H23Cl2NO3): 379.1; found: 380.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH:15][S:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:18])([F:30])[F:31])[CH:21]=3)(=[O:28])=[O:27])[CH:12]=[CH:11][CH:10]=2)=[CH:16][CH:17]=1
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: O=S(=O)(Nc1cccc(COCc2ccc(F)cc2)n1)c1cccc(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.058 g) and 3-(trifluoromethyl)-benzenesulfonyl chloride (0.067 g) as a light yellow gum (0.08g). MS (ESI−): 439.1 ([M−H]−)
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[CH3:41])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.CCN(C(C)C)C(C)C>C1COCC1>[F:47][C:2]([F:1])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[CH3:41])=[CH:24][N:23]=[C:22]([N:49]4[CH2:54][CH2:53][O:52][CH2:51][CH2:50]4)[N:21]=3)[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Cc1cc(C(=O)O)ccc1-c1nc(C)c(-c2cnc(S(C)(=O)=O)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)O)ccc1-c1nc(C)c(-c2cnc(N3CCOCC3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-4-methyl-1,3-thiazol-2-yl}-3-methylbenzoic acid (INTERMEDIATE 54, 200 mg, 0.280 mmol) in THF (5 mL) was added morpholine (73.1 mg, 0.840 mmol) and DIEA (0.244 mL, 1.399 mmol). It was stirred at 60° C. for 15 minutes to see complete conversion by LCMS. The solvent was evaporated and the residue was purified on reverse phase HPLC, eluting with 10%-100% acetonitrile in water to give the title compound as a white solid. LCMS (M+H)+: 728.1. 1H NMR (CDCl3, 500 MHz): δ 8.33 (s, 1H), 8.08 (s, 1H), 8.02 (d, J=8.5 Hz, 1H), 7.92 (s, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.77 (s, 2H), 5.75 (d, J=8.5 Hz, 1H), 4.77 (d, J=17.0 Hz, 1H), 4.36 (m, 1H), 4.086 (d, J=17.0 Hz, 1H), 3.92 (m, 4H), 3.85 (m, 4H), 2.71 (s, 3H), 2.44 (s, 3H), 0.78 (d, J=7.0 Hz, 3H). RTA IC50: 82 nM.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[Mg].C[O:12][B:13](OC)[O:14]C>C1COCC1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([B:13]([OH:14])[OH:12])=[CH:3][CH:4]=1)=[CH2:7]
Reactant: C=Cc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: [Mg]
Solvent: C1CCOC1
Product: C=Cc1ccc(B(O)O)cc1
Yield: 93.3 %

Procedure:
The procedure of Example 9 was repeated with the following reagents: 4-bromostyrene (9.15 g, 0.05 mol), magnesium turnings (1.46 g, 0.06 mol), THF (40 mL), and trimethylborate (6.24 g, 0.06 mol in 30 mL of THF). After work-up, an off-white solid (6.9 g, 93 percent) was isolated. 1H and 13C NMR spectra were consistent with the following structure. ##STR13##
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=3[C:6]3[C:13]([OH:23])=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15]([CH3:17])=[N:16][C:5]2=3)[CH2:3][CH2:2]1.CCN(CC)CC.[O:31](S(C(F)(F)F)(=O)=O)[S:32]([C:35]([F:38])([F:37])[F:36])(=O)=[O:33]>ClCCl>[CH:1]1([N:4]2[C:12]3[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=3[C:6]3[C:13]([O:23][S:32]([C:35]([F:38])([F:37])[F:36])(=[O:33])=[O:31])=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15]([CH3:17])=[N:16][C:5]2=3)[CH2:3][CH2:2]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1c(C)nc2c(c1O)c1c(n2C2CC2)CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nc2c(c3c(n2C2CC2)CCCC3)c1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94.9 %

Procedure:
An ice cold mixture of ethyl 9-cyclopropyl-4-hydroxy-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-3-carboxylate (1.362 g, 4.33 mmol) in dichloromethane (DCM) (20 ml) was treated with Et3N (0.906 ml, 6.50 mmol) and Tf2O (0.805 ml, 4.77 mmol), and then stirred at 0° C. for 90 min. The mixture was concentrated and purified with column chromatography (0-50% EtOAc/Hexane, 120 g silica gel) to give ethyl 9-cyclopropyl-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-3-carboxylate (1.8341 g, 4.11 mmol, 95% yield) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.39 (q, J=7.2 Hz, 2 H), 3.17-2.98 (m, 1 H), 2.90-2.78 (m, 4 H), 2.75 (s, 3 H), 1.99-1.88 (m, 2 H), 1.88-1.76 (m, 2 H), 1.40 (t, J=7.2 Hz, 3 H), 1.22-1.07 (m, 4 H); LCMS (m/z) ES+=447 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:11])[O:7][CH2:8]2)=[CH:4][C:3]=1[O:12][C:13](=[O:15])[CH3:14].[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[OH:1][C:2]1[C:10]([N+:16]([O-:18])=[O:17])=[C:9]2[C:5]([C:6](=[O:11])[O:7][CH2:8]2)=[CH:4][C:3]=1[O:12][C:13](=[O:15])[CH3:14]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Oc1cc2c(cc1O)COC2=O
Solvent: CC(=O)O
Product: CC(=O)Oc1cc2c(c([N+](=O)[O-])c1O)COC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic acid 6-hydroxy-3-oxo-1,3-dihydro-isobenzofuran-5-yl ester (3.8 g) was mixed with acetic acid (150 ml) followed by addition of 65% nitric acid (2.5 ml). After dissolution the mixture was stirred at room temperature for 2 hours followed by removal of the acetic acid and water in vacuo. The remainder was filtered through silica gel using a mixture of toluene, ethyl acetate and methanol (8:1:1) as eluent. Appropriate fractions were collected and evaporated to dryness.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:10](/[CH:11]=[CH:12]/[CH:13]=[N+](C)C)=[C:4]2[CH:3]=1.C(=O)(O)[O-:26].[K+].O>CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:10](/[CH:11]=[CH:12]/[CH:13]=[O:26])=[C:4]2[CH:3]=1
Reactant: COc1ccc(-c2nn3ccc(Br)cc3c2/C=C/C=[N+](C)C)cc1
Reactant: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2nn3ccc(Br)cc3c2/C=C/C=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (E)-N-(3-(5-bromo-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)allylidene)-N-methylmethanaminium (470 mg, 1.22 mmol) in methanol (5 mL) was added a 15% solution of potassium bicarbonate (5 mL) and the mixture was stirred at room temperature for 1 h. Water was added and methanol was evaporated under reduced pressure. Filtration of the precipitate afforded 322 mg of the title compound. LCMS m/z 357.0, 359.0 (M+H)+, ret. time=2.70 min.