Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:13][CH2:14][N:15]1[C:19]2[CH:20]=[C:21]([NH:24][C:25]3[C:30]([CH3:31])=[CH:29][N:28]=[C:27]([NH:32][C:33]4[CH:38]=[C:37]([CH3:39])[C:36]([F:40])=[C:35]([O:41][CH3:42])[CH:34]=4)[N:26]=3)[CH:22]=[CH:23][C:18]=2[O:17][C:16]1=[O:43])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].CC(O)=O>O>[P:1]([OH:8])([OH:3])([O:13][CH2:14][N:15]1[C:19]2[CH:20]=[C:21]([NH:24][C:25]3[C:30]([CH3:31])=[CH:29][N:28]=[C:27]([NH:32][C:33]4[CH:38]=[C:37]([CH3:39])[C:36]([F:40])=[C:35]([O:41][CH3:42])[CH:34]=4)[N:26]=3)[CH:22]=[CH:23][C:18]=2[O:17][C:16]1=[O:43])=[O:2]
Reactant: COc1cc(Nc2ncc(C)c(Nc3ccc4oc(=O)n(COP(=O)(OC(C)(C)C)OC(C)(C)C)c4c3)n2)cc(C)c1F
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Nc2ncc(C)c(Nc3ccc4oc(=O)n(COP(=O)(O)O)c4c3)n2)cc(C)c1F
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To the crude di-tert-butyl (5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl phosphate, was added HOAc (280 mL) and H2O (70 mL), the resultant light brown homogeneous solution was stirred at 65° C. (note: a lighter color ppt was formed between 15-45 min). The reaction was monitored by LC-MS. After 1 h, the mixture was cooled to rt, ppt was collected by filtration, washing with H2O (˜50 mL×2). Product (5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl dihydrogen phosphate was obtained as a light pinkish beige color solid and was used directly in salt formation.
Reaction SMILES: [C:1]([C:3]1[CH:37]=[CH:36][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]2[C:27]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][C:14]3[CH2:15][CH:16]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:17][C:13]=3[CH:12]=2)=[CH:5][CH:4]=1)#[N:2].C([Sn]([N:51]=[N+:52]=[N-:53])(CCCC)CCCC)CCC>>[NH:51]1[C:1]([C:3]2[CH:37]=[CH:36][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]3[C:27]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][C:14]4[CH2:15][CH:16]([CH2:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[O:17][C:13]=4[CH:12]=3)=[CH:5][CH:4]=2)=[N:2][N:53]=[N:52]1
Reactant: N#Cc1ccc(OCCCc2cc3c(cc2OCc2ccccc2)CC(CCc2ccccc2)O3)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Product: c1ccc(CCC2Cc3cc(OCc4ccccc4)c(CCCOc4ccc(-c5nnn[nH]5)cc4)cc3O2)cc1

Procedure:
A mixture of 6-[3-(4-cyanophenoxy)propyl]-5-benzyloxy-2-(2-phenylethyl)-2,3-dihydrobenzofuran E22 (1 gm, 2.0 mmoles) and tri-n-butyl tin azide (2.2 gm; 6.6 mmoles) was heated in an oil bath at 125° C. for 90 minutes. The total mixture was chromatographed on silica gel using 1:1 ethyl acetate in hexane and containing 10% acetic acid to yield 1.2 gm of 6-{3-[4-(1H-tetrazol-5-yl)phenoxy]propyl}-5-benzyloxy-2-(2-phenylethyl)-2,3-dihydrobenzofuran, E23.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[CH2:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.C(O)(=O)[CH2:30][C:31]([OH:33])=[O:32].N1CCCCC1>N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[CH2:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[CH:30][C:31]([OH:33])=[O:32]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccccc1OCc1cccc(OCc2ccc3ccccc3n2)c1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccccc1OCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
2-[3-(Quinolin-2-ylmethoxy)-benzyloxy]-benzaldehyde (110 mg, 0.3 mmol, example 56) is dissolved in pyridine (1 mL). Malonic acid (63 mg, 0.6 mmol) and piperidine (10 μL, 0.1 mmol) are added and the contents are heated to 85° C. for 2 hrs, then at 110° C. for another 2 hrs. The reaction is cooled and placed under a nitrogen stream at 40° C. to remove the pyridine. A small amount of toluene is added and the contents are again placed under a nitrogen stream at 40° C. (repeat). The crude material is purified on silica gel by flash chromatography (silica, 2.5% methanol in dichloromethane) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.33 (d, 1H), 8.21–8.16 (m, 2H), 7.81–7.70 (m, 3H), 7.56–7.50 (m, 2H), 7.37–7.25 (m, 3H), 7.03–6.93 (m, 4H), 6.50 (d, 1H), 5.48 (s, 2H), 5.14 (s, 2H); MS (ion spray) 412 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:28][N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:20]=[CH:21][C:16]([NH:15][CH:14]=[C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:34]5[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[CH:32][CH:33]=5)[CH:3]=4)[C:8](=[O:12])[NH:7][C:6]3=[O:13])=[CH:17][CH:18]=2)[CH2:27][CH2:26]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CN1CCN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(-c5ccc(C#N)cc5)cc43)cc2)CC1
Temperature: 180 °C
Yield: 29.5 %

Procedure:
To a suspension of 6-bromo-4-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-4H-isoquinoline-1,3-dione (221 mg, 0.5 mmol) in N,N-dimethylformamide (5 mL) is added 4-cyanophenylboronic acid (88 mg, 0.6 mmol), followed by 300 □L of 2M aqueous cesium carbonate and tetrakis triphenylphosphine palladium (30 mg, 0.06 mmol). The reaction mixture is subjected to microwave heating at 180° C. for 300 seconds. The reaction mixture is then diluted with N,N-dimethylformamide and purified by C18 reverse phase HPLC. The pure fractions were combined and concentrated to yield 4-(4-{[4-(4-Methyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dioxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-benzonitrile (68.4 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[S:5][CH:6]=1.C[CH2:15][O:16]CC.C([Li])CCC.CN(C=O)C>CCCCCC>[CH2:9]([O:8][CH:7]([O:11][CH2:12][CH3:13])[C:4]1[S:5][CH:6]=[C:2]([CH:15]=[O:16])[CH:3]=1)[CH3:10]
Reactant: CCOC(OCC)c1cc(Br)cs1
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(OCC)c1cc(C=O)cs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
A solution of 4-bromo-2-(diethoxymethyl)thiophene (500 mg, 0.002 mol) in ether (5 mL, 0.05 mol) was cooled at −78° C. To this solution, 2.5 M n-butyllithium in hexane (0.83 mL) was added dropwise. The reaction was stirred at −78° C. for 1 hour. To the reaction was added DMF (0.4 g, 0.006 mol) at −78° C. and the mixture was stirred for 30 minutes. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography to yield the 5-(diethoxymethyl)thiophene-3-carbaldehyde as an oil (170 mg, 42.0%). By 1H NMR two different regioisomers of aldehydes were formed and were not separated; (note: NMR shifts are for the major isomer only) 1H NMR (400 MHz, CDCl3): δ 9.85 (s, 1H), 8.05, 7.7 (s, 1H), 7.45, 7.15 (s, 1H), 5.7 (s, 1H), 3.65 (m, 2H), 1.25 (m, 2H).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:9]=[N:8][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH2:16][N:15]([CH2:20][C:21]([OH:23])=O)[CH2:14][CH2:13]3)=[CH:6][CH:5]=1.F[P-](F)(F)(F)(F)F.[N:31]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:35]2[CH:36]=[CH:37][CH:38]=CC=2N=N1.O>C(Cl)Cl>[CH:35]1([N:31]2[CH2:17][CH2:16][N:15]([C:21](=[O:23])[CH2:20][N:15]3[CH2:14][CH2:13][C:12]4[C:17](=[CH:18][CH:19]=[C:10]([C:7]5[N:8]=[N:9][C:4]([CH3:3])=[CH:5][CH:6]=5)[CH:11]=4)[CH2:16]3)[CH2:14][CH2:13]2)[CH2:36][CH2:37][CH2:38]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Cc1ccc(-c2ccc3c(c2)CCN(CC(=O)O)C3)nn1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)CCN(CC(=O)N2CCN(C4CCC4)CC2)C3)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of [6-(6-methyl-pyridazin-3-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-acetic acid dihydrochloride (313 mg, 0.88 mmol) and 1-cyclobutyl-piperazine bistrifluoroacetate (356 mg, 0.97 mmol, 1.1 eq.) in DCM (10.0 ml) are added BOP (467 mg, 1.06 mmol, 1.2 eq.) and TEA (267 mg, 2.64 mmol, 3.0 eq.). The mixture is stirred at rt for 2 hr. Water (10.0 ml) is added to quench the reaction, and the organic layer is collected, dried over sodium sulfate, and concentrated. The residue is purified by PTLC (EtOAc/4% TEA) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.85 (1H, s), 7.78 (1H, dd), 7.72 (1H, d), 7.36 (1H, d), 7.15 (1H, d), 3.75 (2H, s), 3.65 (4H, m), 3.39 (2H, s), 2.99 (2H, t), 2.82 (2H, t), 2.74 (3H, s), 2.68 (1H, m), 2.28 (4H, m), 1.64-2.08 (6H, m); MS (+VE) m/z 406.2 (M++1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].[CH3:12][C:13]([CH3:16])([O-])[CH3:14].[K+]>CS(C)=O>[CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([O:6][C:3]1[C:16]2[C:13](=[CH:14][CH:9]=[CH:10][CH:11]=2)[CH:12]=[CH:5][CH:4]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)[O-]
Reactant: CNCC[C@H](O)c1cccs1
Agent: [K+]
Solvent: CS(C)=O
Product: CNCC[C@H](Oc1cccc2ccccc12)c1cccs1

Procedure:
In the step (iv) of the process of the present invention, the reaction of (S)-(−)-3-methylamino-1-(2-thienyl)propan-1-ol and halonaphthalene is carried out by using a proper base such as potassium tert-butoxide in a suitable amount of DMSO to form (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine (Duloxetine®). The excess amount of halonaphthalene, ranging from about 1.5 to 4 equivalents, can be recovered. The reaction is performed at a temperature ranged from 20° C. to 110° C., preferably from 40° C. to 90° C., for 1 to 24 hours. One embodiment of the present invention is conducted in the presence of excess halonaphthalene and a suitable amount of DMSO to overcome the problems regarding racemization and environmental protection. In one preferred embodiment, DMSO is used in amounts ranging from one to ten times the amount of (S)-(−)-3-methylamino-1-(2-thienyl)propan-1-ol, more preferably from one to five times the amount of (S)-(+3-methylamino-1-(2-thienyl)propan-1-ol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]2[O:19][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[FH:26].C(=O)(O)[O-].[Na+]>C(OCC)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]([F:26])[C@@H:10]1[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@@H]2O[C@H]12
Reactant: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@@H](F)[C@@H]1O
Temperature: 0 °C
Reaction time: 9 h

Procedure:
To a solution of (±)-(1S,2R,3R)-3-tert-butoxycarbonylamino-1,2-epoxy-1,2,3,4-tetrahydro-naphthalene (100 mg) in anhydrous diethyl ether (6 ml) cooled in an ice-bath was added 70% hydrogen fluoride-pyridine (0.24 ml). The mixture was stirred at 0° C. for 9 hours, ice was added and the reaction mixture was neutralized by addition of solid sodium bicarbonate (1.2 g) at 0° C. and extracted with diethyl ether. The organic layer was dried over magnesium sulfate and evaporated to afford the crude title compound as an oil (65 mg). This crude material was purified by chromatography on silica gel (10 g, elution with ethyl acetate:cyclohexane, 2:8) and the resulting material (35 mg) was crystallized from a diethyl ether/pentane mixture to afford the title compound as a white solid, m.p. 98°-99° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[O:35][CH:36]=[C:37]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[N:38]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:37]6[N:38]=[C:34]([CH3:33])[O:35][CH:36]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1nc(C2(N)CC2)co1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5coc(C)n5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.15 g, 0.34 mmol, 1 eq), 1-(2-methyloxazol-4-yl)cyclopropanamine (0.047 g, 0.34 mmol, 1 eq), EDCI.HCl (0.076 g, 0.4 mmol, 1.2 eq), HOBT (0.054 g, 0.4 mmol, 2 eq) and TEA (0.14 ml, 1.02 mmol, 3 eq) were dissolved in dichloromethane and the reaction was stirred at room temperature for 14 h. The reaction was diluted with water and the product was extracted with dichloromethane and purified by preparative HPLC yielding the desired product. Yield: 47 mg (25%) 1H NMR (400 MHz, DMSO-d6): δ 1.12-1.15 (m, 2H), 1.21-1.24 (m, 2H), 2.29 (s, 3H), 2.34 (s, 3H), 2.81-2.82 (d, 3H, J=4.60 Hz), 3.95 (s, 3H), 7.12 (s, 1H), 7.31-7.32 (m, 1H), 7.34-7.40 (t, 2H, J=3.21 Hz), 7.56 (s, 1H), 7.61 (s, 1H), 7.71 (s, 1H), 7.73 (s, 1H), 7.97-8.01 (m, 2H), 8.46-8.48 (m, 1H), 8.67 (s, 1H). LCMS: (ES+) m/z=554.2 (M+H).: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% ACN-98% H2O-10 mM NH4COOH Mphase B: 98% ACN-2% H2O-10 mM NH4COOH
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:39])[CH2:15][CH2:16][CH2:17]C(OC1C=C2C(=CC=1)NC=C2CCC(OC(C)(C)C)=O)=O.[CH:40]([OH:42])=[O:41]>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:39])[CH2:15][CH2:16][CH2:17][C:40]([O:42][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH2:13])=[O:41]
Reactant: O=CO
Reactant: CC(C)(C)OC(=O)CCc1c[nH]c2ccc(OC(=O)CCCC(=O)NCCc3c[nH]c4ccc(O)cc34)cc12
Solvent: ClCCl
Product: NCCc1c[nH]c2ccc(OC(=O)CCCC(=O)NCCc3c[nH]c4ccc(O)cc34)cc12
Reaction time: 1 h

Procedure:
To a solution of 6b (90 mg, 0.164 mmol) in CH2Cl2 (200 μL) at 0° C., 96% formic acid (400 μL) was added drop wise. After 30 mM the cooling bath was removed and stirring continued at room temperature for another 1 h. Formic acid was removed under a vacuo; residue was dissolved in MeOH (1 mL). The pH of the solution was then adjusted to 8 with 30% aqueous NH3, The alcoholic portion was removed under reduced pressure. 6c was isolated as semi solid (60 mg, 81.66%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[C@@H:3]1[C:10]([O:12][CH:13]1[CH:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][CH:15]([CH3:22])[CH2:14]1)=[O:11].[C:23](=O)([O-])[O-].[K+].[K+]>CO.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[CH3:23][O:8][C:6]1[CH2:7][C@H:2]([CH3:1])[C@@H:3]([C:10]([O:12][C@H:13]2[C@H:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][C@@H:15]([CH3:22])[CH2:14]2)=[O:11])[C:4](=[O:9])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: CC1CCC(C(C)C)C(OC(=O)[C@H]2C(=O)CC(=O)C[C@@H]2C)C1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: [K+]
Solvent: CO
Product: COC1=CC(=O)[C@H](C(=O)O[C@@H]2C[C@H](C)CC[C@H]2C(C)C)[C@@H](C)C1
Temperature: 23 °C
Reaction time: 12 h
Yield: 713.6 %

Procedure:
A solution of (1R,3R,4S)-p-menth-3-yl(1R,2S)-2-methyl-4,6-dioxocyclohexanecarboxylate (2, 24.0 g, 77.8 mmol, 1 equiv) in methanol (300 mL) was treated with camphorsulfonic acid (ca. 800 mg, 3.9 mmol, 0.05 equiv) and the resulting solution was stirred at 23° C. for 12 h. The reaction mixture was neutralized by the addition of solid potassium carbonate (1.08 g, 7.78 mmol, 0.10 equiv) and the resulting suspension was filtered and the filtrate was concentrated. The residue was concentrated from toluene (2×15 mL) and then was purified by flash column chromatography (20% ethyl acetate-hexanes) to afford (1R,3R,4S)-p-menth-3-yl(1R,6S)-4-methoxy-6-methyl-2-oxo-3-cyclohexene-1-carboxylate (4) as a white solid (mp 78°-80° C., 17.9 g, 71%). The regioisomeric enone, (1R,3R,4S)-p-menth-3-yl(1R,6S)-2-methoxy-6-methyl-4-oxo-2-cyclohexene-1-carboxylate (5) was isolated in separate fractions and was resubjected to the reaction conditions to establish the equilibrium mixture of enones, in which the desired product 4 is strongly favored. ##STR16##
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:20])[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[C:21](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(=O)CC>[CH3:21][O:20][C:3]1[C:2](=[O:1])[C:8]([NH:9][S:10]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccccc(=O)c2O)cc1
Agent: [K+]
Solvent: CCC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccccc(NS(=O)(=O)c2ccc(C)cc2)c1=O

Procedure:
A mixture of 2-hydroxy-3-[N-[(4-methylphenyl)sulfonyl]-amino]-2,4,6-cycloheptatrien-1-one (14.5 g), potassium carbonate (12.5 g), dimethyl sulfate (12.5 g) and 2-butanone (145 ml) is heated at reflux for 1 hour. The mixture is filtered and the precipitate is washed with water and suspended in ethyl actate. Hydrochloric acid (10%) is added until the solution is acidic. The organic phase is collected and dried over sodium sulfate. Evaporation of the solvent and crystallization of the residue from ethyl acetate-hexane gives 2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]amino]-2,4,6-cycloheptatrien-1-one, mp 163°-164° C. The above filtrate is evaporated and the residue is subjected to chromatography on silica gel using ethyl acetate-hexane (3:1). Evaporation of the eluates are crystallization of the residue from ethyl acetate gives 2-methoxy-3-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-one, mp 101°-102° C and 2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-one, mp 94.5° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17].[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)c1ccccc1S
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
Triethylamine (2.65 g, 26.2 mmol) was slowly added to a mixture of 2-mercapto-benzoic acid methyl ester (4.0 g, 23.8 mmol) and trityl chloride (6.63 g, 23.8 mmol) in CH2Cl2 at rt. The reaction mixture was stirred at rt for 3 h and washed with water (100 mL). The two phases were separated and the aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to provide 2-tritylsulfanyl-benzoic acid methyl ester (9.6 g), which was used directly to the next reaction without further purification. MS ESI(+) m/e: 411.15 (M+1).
Reaction SMILES: CS(C)=O.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][CH:7]=1.[OH-].[K+].Br[C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[Br:37]>C1(C)C=CC=CC=1>[Br:37][C:36]([F:39])([F:38])[C:35]([F:41])([F:40])[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2([C:25]3[CH:26]=[CH:27][C:28]([O:31][C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[Br:37])=[CH:29][CH:30]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]3[C:24]2=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][CH:11]=1
Reactant: Oc1ccc(C2(c3ccc(O)cc3)c3ccccc3-c3ccccc32)cc1
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: FC(F)(Br)C(F)(F)Oc1ccc(C2(c3ccc(OC(F)(F)C(F)(F)Br)cc3)c3ccccc3-c3ccccc32)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
Into a 2 liter 5-necked round bottom flask fitted with a mechanical stirrer, Dean-Stark trap topped with a nitrogen padded reflux condenser and a thermocouple attached to a temperature controller, are placed DMSO (650 ml) and toluene (200 ml). While the stirred solution is purged with nitrogen, 9,9-bis(4'-hydroxyphenyl)fluorene (200.0 g, 0.57 mole) is added to the flask. While purging with nitrogen continues, potassium hydroxide (85% pellets, 77.5 g, 1.17 mole) is added all at once, and the mixture is heated to 100° C. with constant stirring. After two hours, the temperature is increased until the solution begins to reflux (130° C.). Water is removed by azeotropic distillation for 24 hours. The Dean-Stark trap is replaced by a Soxhlet extractor containing anhydrous sodium sulfate, and the toluene is refluxed through the Soxhlet for 5 hours. A small amount of toluene (60 ml) is then removed by simple distillation. Then the reactor is cooled to 35° C. Addition of 1,2-dibromotetrafluoroethane (315 g, 1.21 mole) via dropping addition funnel is then maintained at a rate that keeps the reaction temperature at 35°-38° C. When the addition is complete, the mixture is heated at 50° C. for 8 hours, then cooled to room temperature with constant stirring. The mixture is filtered, and the precipitate is washed twice with acetone. The filtrates are combined and evaporated thoroughly. The residue from the evaporation is washed with water to remove residual potassium bromide (KBr). After the residue is air dried for 24 hours, it is purified by column chromatography (on neutral alumina, using hexane eluent) to provide as product, 9,9-bis(4'-[2"-bromotetrafluoroethoxy]phenyl)fluorene (331.4 g, 0.468 mole, 82% yield), melting point 157°-158° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH2:9][O:10][CH3:11])[N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[CH2:20][CH2:21][NH2:22].C(=O)(O)[O-].[Na+].O>CCO>[Cl:8][C:6]1[N:5]=[C:4]([CH2:9][O:10][CH3:11])[N:3]=[C:2]([NH:22][CH2:21][CH2:20][C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[Cl:12])[CH:7]=1
Reactant: COCc1nc(Cl)cc(Cl)n1
Reactant: NCCc1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COCc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Yield: 44.4 %

Procedure:
A solution of 4,6-dichloro-2-methoxymethyl-pyrimidine (250 mg, 1.3 mmol), 2-(2,4-dichloro-phenyl)-ethylamine (196 μL, 1.3 mmol), and sodium bicarbonate (218 mg, 2.6 mmol) in EtOH (5 mL) is heated at 80° C. for three hours and poured into water (20 mL) and extracted thrice with EtOAc (30 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and evaporated. The residue is subjected to chromatography on silica gel eluting with 30% ethyl acetate:heptane to afford (6-chloro-2-methoxymethyl-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (200 mg, 44%) as a solid.