Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([F:9])=[N:7][CH:8]=1)[CH3:2].[O:10]1CCC[CH2:11]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:11]=[O:10])[C:6]([F:9])=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(F)nc1
Reactant: C1CCOC1
Product: CCc1cnc(F)c(C=O)c1
Reaction time: 0.5 h

Procedure:
A solution of diisopropylainine (1.01 mL, 7.19 mmol) in tetrahydrofuran (20 mL) was treated in ice-bath with n-butyllithiuin (2.5M, 2.9 mL, 7.19 mmol) and stirred for 30 min. The resulting solution was reacted at −78° C. with 5-ethyl-2-fluoropyridine (2-b, 0.75 g, 5.99 mmol), stirred for 4 h, and treated with N,N-dimethylforninamide (482 mg, 6.59 mmol). The reaction mixture was quenched with acetic acid (1 mL), partitioned between ethyl acetate and water. The organic layer was washed with 0.5N—HCl and then with brine, separated, dried (MgSO4) and concentrated in vacuo. Chromatography (30% ethyl acetate in hexanes) afforded the desired compound (2-f); 1H NMR (500 MHz, CDCl3) δ10.3 (s, 1H), 8.29 (d, 1H, J=2.0 Hz), 8.12 (dd, 1H, J=9.0, 2.5 Hz), 2.73 (q, 2H, J =7.8 Hz), 1.29 (t, 3H, J=7.5 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[CH:18]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[C:21]([SH:27])=[CH:20][CH:19]=1>>[C:24]([C:22]1[CH:23]=[CH:18][CH:19]=[CH:20][C:21]=1[S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)([OH:26])=[O:25]
Reactant: O=C(O)c1ccccc1S
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Product: O=C1CCc2cc(OCCCCSc3ccccc3C(=O)O)ccc2N1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril and 2-thiobenzoic acid.
Reaction SMILES: C([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([N:20]1[C:31]3[C:23](=[C:24]4[C:28](=[C:29]([OH:32])[CH:30]=3)[NH:27][C:26]([C:33]([F:36])([F:35])[F:34])=[C:25]4[C:37]([O:39][CH3:40])=[O:38])[C@H:22]([CH2:41][Cl:42])[CH2:21]1)=[O:19])=[CH:12]2)=O)(C)(C)C.Cl.[CH3:44][N:45]([CH3:50])[CH2:46]C(O)=O>>[Cl:42][CH2:41][C@H:22]1[C:23]2=[C:24]3[C:28](=[C:29]([OH:32])[CH:30]=[C:31]2[N:20]([C:18]([C:13]2[NH:14][C:15]4[C:11]([CH:12]=2)=[CH:10][C:9]([NH:8][C:6]([CH2:44][N:45]([CH3:50])[CH3:46])=[O:5])=[CH:17][CH:16]=4)=[O:19])[CH2:21]1)[NH:27][C:26]([C:33]([F:34])([F:36])[F:35])=[C:25]3[C:37]([O:39][CH3:40])=[O:38]
Reactant: CN(C)CC(=O)O
Reactant: COC(=O)c1c(C(F)(F)F)[nH]c2c(O)cc3c(c12)[C@H](CCl)CN3C(=O)c1cc2cc(NC(=O)OC(C)(C)C)ccc2[nH]1
Agent: Cl
Product: COC(=O)c1c(C(F)(F)F)[nH]c2c(O)cc3c(c12)[C@H](CCl)CN3C(=O)c1cc2cc(NC(=O)CN(C)C)ccc2[nH]1

Procedure:
Methyl (1S)-1-chloromethyl-3-[5 (dimethylaminomethylcarbonyl)amino-1H-indol-2-ylcarbonyl]-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate was prepared from 12.1 mg (20 μmol) of methyl (1S)-3-[5-(t-butoxycarbonyl)amino-1H-indol-2-ylcarbonyl]-1-chloromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate and 2.8 mg (20 μmol) of N, N-dimethylglycine hydrochloride in the same manner as in Example 6 in a yield of 7.8 mg (66%).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.O.[Cl:16][CH2:17][C:18]([CH3:20])=[CH2:19]>ClCCl>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([C:18]([CH3:20])([CH3:19])[CH2:17][Cl:16])[CH:8]=1
Reactant: COc1ccc(Br)cc1
Reactant: C=C(C)CCl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Br)cc1C(C)(C)CCl

Procedure:
Sulfuric acid (2 mL, 0.033 mol) was added dropwise under argon to 4-bromoanisole (14.6 mL, 0.117 mol). The mixture was warmed to 40–43° C. (warm water bath) and 3-chloro-2-methyl propene was added dropwise in 4 equal portions over 2 hrs. After 2 hrs at 40–43° C. the solution was diluted with dichloromethane and washed successively with water, saturated aqueous NaHCO3, water and brine, dried (Mg2SO4), filtered and evaporated. The residue was crystallized from hexanes to give 14.1 g of 4-bromo-2-(2-chloro-1,1-dimethyl-ethyl)-1-methoxy-benzene. The mother liquor was further purified on silica gel (10% ethyl acetate in hexane) to afford additional 4.8 g of product. 58% yield. 1H NMR (300 MHz; CDCl3): δ 1.43 (s, 6 H), 3.82 (s, 3 H), 3.93 (s, 2 H), 6.75 (dd, J=2.4 Hz and 7.2 Hz, 1 H), 7.32 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:31])=[C:4]([S:9]([N:12]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:39][NH:40][O:41][CH3:42]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([OH:31])=[C:4]([S:9]([N:12]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([N:40]([O:41][CH3:42])[CH3:39])=[O:28])=[CH:24][CH:23]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Temperature: 25 °C
Yield: 65.2 %

Procedure:
To a suspension of 4-((3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxyphenylsulfonamido)methyl)benzoic acid (0.726 g, 1.5 mmol) in DCM (20 mL) at rt was added oxalyl chloride (0.394 mL, 4.50 mmol) and a few drops of DMF. The mixture was stirred at rt to give a yellow solution. The reaction mixture was concentrated and the residue was dissolved in DCM. At 0° C., a mixture of N,O-dimethylhydroxylamine hydrochloride (0.439 g, 4.50 mmol) and TEA (1.045 mL, 7.50 mmol) were added. The resulting mixture was stirred at rt for 1 h. The mixture was diluted with DCM and washed with water and brine. The organic extract was dried, concentrated and purified by flash column chromatography (ISCO system, eluting with DCM/EtOAc) to give the desired product (0.516 g, 62%) as a light yellow solid. MS (ESI): 527.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10](/[N:17]=[CH:18]/[N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.NC1[CH:43]=[CH:42][C:26]([O:27][CH2:28][C@@H:29]2[CH2:33][C@@H:32]([OH:34])[CH2:31][N:30]2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[C:25]([O:44][CH3:45])[CH:24]=1>C1(O)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([C:21]4[CH:43]=[CH:42][C:26]([O:27][CH2:28][C@@H:29]5[CH2:33][C@@H:32]([OH:34])[CH2:31][N:30]5[C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])=[C:25]([O:44][CH3:45])[CH:24]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(N)ccc1OC[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Solvent: Oc1ccccc1
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Yield: 41.8 %

Procedure:
Methyl 5-(4-chlorophenyl)-3-{[(E)-(dimethylamino)methylidene]amino}-2-thiophenecarboxylate (857 mg, 2.66 mmol) was mixed with tert-butyl (2S,4R)-2-[(4-amino-2-methoxyphenoxy)methyl]4-hydroxypyrrolidine-1-carboxylate (900 mg) in phenol (1.0 g) at 120° C. for 15 min. Workup and purification of the reaction mixture provided 650 mg of tert-butyl (2S,4R)-2-({4-[6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl]-2-methoxyphenoxy}methyl)-4-hydroxypyrrolidine-1-carboxylate. A portion of this material (105 mg, 0.179 mmol) was dissolved in a 1:1 mixture of dichloromethane and trifluoroacetic acid. The mixture was stirred at room temperature for 10 min and was then concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with a saturated solution of NaHCO3, brine, dried (Na2SO4) and concentrated to provide the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.[OH2:19]>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1)=[O:19]
Reactant: O
Reactant: Nc1ccc(CSc2nc3ccccc3[nH]2)cn1
Product: Nc1ccc(CS(=O)c2nc3ccccc3[nH]2)cn1

Procedure:
The title compound was prepared by the method of Example 85 using 1.0 g (3.9 mmole) of 5-[(1H-benzimidazol-2-ylthio)methyl]-2-pyridinamine (see Example 110) instead of 6-[(1H-benzimidazol-2-ylthio)methyl]-2-pyridinamine. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis. Analysis. Calc'd. for C13H12N4SO*¼ H2O: C, 56.40; H, 4.55; N, 20.24; S, 11.58. Found: C, 56.35; H, 4.46; N, 20.25; S, 11.66.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][N:10]=1.[NH:19]1[CH2:29][CH2:28][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20]1>C1COCC1>[CH2:26]([O:25][C:23]([CH:22]1[CH2:28][CH2:29][N:19]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH2:20][CH2:21]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ncnc2ccccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2ncnc3ccccc23)CC1
Yield: 92.1 %

Procedure:
Triethylamine (12.7 mL, 91.1 mmol) was added to a solution of 4-chloro-quinazoline (5.00 g, 30.4 mmol) and ethyl isonipecotate (4.78 g, 30.4 mmol) in THF (80 mL) at ambient temperature. After being refluxed for 12 hours, the mixture was concentrated in vacuo, and the resulting residue was partitioned between DCM and aqueous 0.1 M NaOH. The separated DCM layer was dried (Na2SO4), filtered, and concentrated in vacuo. The resulting solids were suspended in Et2O and filtered to give 1-quinazolin-4-yl-piperidine-4-carboxylic acid ethyl ester (8.0 g, 28.0 mmol). This material was dissolved in EtOH (50 mL) and THF (50 mL) followed by the addition of NaOH (3.73 g, 93.4 mmol) in H2O (50 mL). After being stirred for 12 hours, the mixture was neutralized with 1.0N HCl (93.5 mL) and concentrated in vacuo. After the volatile organics are removed, a white precipitate forms in the resulting aqueous solution. The solid was filtered off and air-dried to give 1-quinazolin-4-yl-piperidine-4-carboxylic acid (6.5 g). 1H NMR (DMSO-d6, 400 MHz) δ 12.28 (bs, 1H), 8.57 (s, 1H), 7.91 (m, 1H), 7.75 (m, 2H), 7.49 (m, 1H), 4.13 (m, 2H), 3.22 (m, 2H), 2.57 (m, 1H), 1.93 (m, 2H), 1.72 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21](COCC[Si](C)(C)C)[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[Cl:38])[CH:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][NH:30][C:26]1[CH:25]=[C:24]([C:23]2[C:18]3[C:19](=[N:20][C:15]([NH:14][CH:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)=[N:16][CH:17]=3)[NH:21][N:22]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(NCc5ccccc5Cl)c4)nn(COCC[Si](C)(C)C)c3n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC(Nc2ncc3c(-c4cccc(NCc5ccccc5Cl)c4)n[nH]c3n2)CC1
Reaction time: 4 h

Procedure:
To a stirred solution of {4-[3-[3-(2-chloro-benzylamino)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (110 mg, 0.162 mmol) in dichloromethane (3 mL) was added TFA (3 mL) at room temperature. The resulting mixture was stirred for another four hours at this temperature. The solvent was evaporated under reduced pressure and the residue was treated with saturated aqueous NaHCO3 (5 mL) and extracted with EtOAc (30 mL). The organic phase was washed with brine (5 mL) and dried to give crude product. It was purified by prep-HPLC to give N-{3-[3-(2-chloro-benzylamino)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-cyclohexane-1,4-diamine as solid. (Yield 15 mg, 21%).
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:22](=[O:27])C(Cl)(Cl)Cl)[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:28].[OH-].[Na+]>O1CCCC1>[C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:22]([OH:27])=[O:28])[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)n2c1COCC2)c1ccccc1
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@@H](NC(=O)c1cc(C(=O)O)n2c1COCC2)c1ccccc1
Yield: 84 %

Procedure:
To a solution of 6-(2,2,2-trichloro-acetyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide (Comp. No. 10a) (9.8 g, 22.8 mmol) in tetrahydrofuran (160 ml) was added water (160 ml) and sodium hydroxide (4.5 g, 114 mmol) and the mixture was stirred at reflux until complete conversion according to LC/MS (ca. 60 min). Approximately half of the solvents were evaporated in vacuo and the mixture was acidified with excess hydrochloric acid. The forming precipitate was filtered off, washed once with water and dried in vacuo to give 6.29 g (84%) of 8-((R)-1-phenyl-propylcarbamoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylic acid as white solid. LC/MS (method 4): Rt=1.14 min; m/z=329.26 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:9][CH2:10][CH:11]([NH:14][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCC(NS(C)(=O)=O)CC1
Reaction time: 0.67 h

Procedure:
To a stirred solution of (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (Altech, 1.24 g, 5.79 mmol) in methylene chloride (50 mL) at 0° C., triethylamine (202 mg, 6.95 mmol) and methansulfonylchloride (Aldrich, 796 mg, 6.95 mmol) were added successively and the mixture was stirred for 40 minutes. The solvent was removed and the residue was washed with water to give a white solid, which was directly used for the next step.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([C:9](C(O)=O)=[O:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.O.[NH3:15]>C(O)C>[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[NH:2][CH3:1])(=[O:10])[NH2:15]
Reactant: N
Reactant: CNc1ccccc1C(=O)C(=O)O
Solvent: CCO
Solvent: O
Product: CNc1ccccc1C(N)=O
Temperature: 80 °C
Yield: 84.8 %

Procedure:
10.0 g of N-methylisatic acid are added gradually to 140 ml of water at a room temperature and 9.6 g of aqueous ammonia are added dropwise thereto. The mixture is warmed to a temperature of 80° C. during 45 minutes and ethanol is added thereto until the reaction mixture becomes colorless. Then, the reaction mixture is cooled to a room temperature and the precipitated crystals are collected by filtration to obtain 7.11 g of 2-carbamoyl-N-methylaniline as colorless crystal.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1.S(OC)(O[CH3:19])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:14][C:3]1[C:2]([O:1][CH3:19])=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=1
Reactant: O=C1CCCCc2cc(O)c(O)cc21
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2c(cc1O)C(=O)CCCC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A mixture of 2,3-dihydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (1.0 g), dimethyl sulfate (0.65 g), anhydrous potassium carbonate (0.86 g) and acetone (20 ml) is stirred at 50° C. for two hours. After cooling, the reaction mixture is subjected to filtration, and the filtrate is concentrated under reduced pressure. To the concentrate is added water, which is extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to afford 3-hydroxy-2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (0.67 g), which is recrystallized from ethyl acetate-hexane to give colorless needles, m.p. 115°-116° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]([C:6]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[Br-:20].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:20][C:11]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:3]2[CH2:4][CH2:5][O:1][N:2]=2)[C:12]=1[CH3:13]
Reactant: [Br-]
Reactant: Cc1cccc(N)c1C1=NOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(Br)ccc(N)c1C1=NOCC1

Procedure:
30 g (170 mmol) of 2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline are dissolved in 400 ml of acetonitrile, and 94 g (0.68 mol) of potassium carbonate are added. At temperatures <30° C., 84 g (174 mmol) of tetrabutylammonium tribromide are then added a little at a time, with vigorous stirring. For work-up, the solid is filtered off with suction and the solution is diluted with methylene chloride and extracted with water. The solvent is stripped off and the residue is then taken up again in methyl tert-butyl ether and washed twice with water. The organic phase is dried and concentrated.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[C:12]=1[Cl:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[CH:25]1[O:27][CH2:26]1>CO>[CH2:1]([N:8]([CH2:26][CH:25]([OH:27])[C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[Br:22])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[C:12]=1[Cl:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CCNCc2ccccc2)c(Cl)c1OC
Reactant: Brc1ccccc1C1CO1
Solvent: CO
Product: COc1ccc(CCN(Cc2ccccc2)CC(O)c2ccccc2Br)c(Cl)c1OC

Procedure:
Similarly 2.71 g of N-benzyl-2-chloro-3,4-dimethoxyphenethylamine and 2.33 g (0.015 mol) of o-bromostyrene oxide are reacted in methanol to give N-benzyl-N-[2-(2-chloro-3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(2-bromophenyl)ethylamine. The latter is converted to its hydrochloride, which is dissolved in 90 ml of methanol and hydrogenated over 1 g of 10% palladium-on-carbon in 10 ml of ethyl acetate at room temperature for six hours. The reaction mixture is filtered and evaporated in vacuo to leave N-[2-(2-chloro-3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(2-bromophenyl)ethylamine hydrochloride.
Reaction SMILES: [NH2:1][C:2]([CH2:21][OH:22])([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)[CH2:3][OH:4].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>CCOC(C)=O.O>[CH2:27]([O:26][C:24]([NH:1][C:2]([CH2:3][OH:4])([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:12]=1)[CH2:21][OH:22])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCc1ccc(CCC(CO)(CO)NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 119.8 %

Procedure:
A mixture of 3.07 g (10.0 mmol) of 2-amino-2-hydroxymethyl-4-(4-(octyl)phenyl)butanol and 3.00 g (30.0 mmol) of KHCO3 in 200 mL of EtOAc and 150 mL of H2O was treated with 1.50 mL (10.0 mmol) of benzyl chloroformate, then stirred at rt for 2 h. The organic layer of the reaction mixture was separated, dried over MgSO4 and concentrated to afford 5.29 g of the title compound: 1H NMR (500 Mhz) δ0.88 (t, J=6.5, 3H), 1.22-1.34 (12H), 1.55-1.60 (m, 2H), 1.87-1.91 (m, 2H), 2.53-2.59 (4H), 3.23 (br s, 2H), 3.67 (dd, J=6.5, 11.5, 1H), 3.90 (dd, J=6.5, 11.5, 1H), 5.08 (s, 2H), 5.30 (s, 1H), 7.05-7.09 (4H), 7.32-7.36 (5H); HPLC A 5.34 min.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1([C:43]2[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=2)[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[F:37])[C:24]([O:26]CC)=[O:25])[C:13]2[C:8](=[CH:9][C:10]([OH:42])=[CH:11][CH:12]=2)[S:7][CH2:6]1)[CH3:4].Cl>O.C(O)C>[CH2:3]([C:5]1([C:43]2[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=2)[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([F:41])([F:40])[C:36]([F:38])([F:37])[F:39])[C:24]([OH:26])=[O:25])[C:13]2[C:8](=[CH:9][C:10]([OH:42])=[CH:11][CH:12]=2)[S:7][CH2:6]1)[CH3:4]
Reactant: CCOC(=O)C(CCCCCCCCC1c2ccc(O)cc2SCC1(CC)c1ccc(O)cc1)CCCCCCC(F)(F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Yield: 89.9 %

Procedure:
A solution of sodium hydroxide (325 mg) in water (4 ml) was added to a solution of ethyl 10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)decanoate (558 mg, 0.81 mmol) in ethanol (8 ml). The reaction mixture was heated under reflux for 12 hours. Dilute hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=2/1) to give 10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(7,7,8,8,8-pentafluoro-octyl)decanoic acid (480 mg, Yield 89%).
Reaction SMILES: O[C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6](OC)[C:5](OC)=[C:4](OC)[CH:3]=1.CO[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.CC([O-])(C)C.[K+]>C(O)C>[C:22]1([CH:23]=[CH:9][C:8]([C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])[CH:25]=[CH:26][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COc1cc(O)c(C(C)=O)c(OC)c1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(C=Cc1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 143.6 %

Procedure:
To a solution of 1-(6-hydroxy-2,3,4,-Trimethoxyphenyl)ethanone 5 (2.26 g, 10 mmol), 4-methoxybenzaldehyde (1.63 g, 12 mmol) and t-BuOK (2.11 g, 22 mmol) in ethanol (30 mL) was refluxed for 4 h. The reaction mixture was poured onto crushed ice (100 g). The resulting precipitate was filtered and washed with water. The residue was air-dried at room temperature. The crude product was recrystallized from ethyl acetate to afford chalcone as orange crystals (2.99 g, 87%): 1H NMR (CDCl3, 200 M Hz) δ 11.75 (br s, 1H), 7.84 (s, 2H), 7.60 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 6.29 (s 1H), 3.93 (s 3H), 3.90 (s, 3 M), 3.85 (s, 3H), 3.84 (s, 3H); 13C NMR (CDCl3, 50 M Hz) δ 192.7 (s), 162.6 (s), 161.5 (s), 159.9 (s), 154.9 (s), 143.3 (d), 135.2 (s), 130.1 (d, 2C), 128.0 (s), 124.0 (d), 114.4 (d, 2C), 108.7 (s), 96.5 (d), 61.8 (q), 61.2 (q), 56.0 (q), 55.3 (q).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[CH:37]1[C:46]2CCCCC=2C=[CH:39][C:38]=1C(=O)C.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][C:3]4[CH2:39][CH2:38][CH2:37][CH2:46][C:2]=4[CH:7]=2)[CH:17]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(=O)c1ccc2c(c1)CCCC2
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc5c(c4)CCCC5)ccc3c1)n2C1CCCCC1
Yield: 60 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in Ethanol (506 μL, 0.64 mmol) to produce the title compound (65 mg, 60% yield).