Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[NH:4].[CH:8](=[C:10]([C:16](OCC)=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:9]>C(O)C>[CH3:9][C:8]1[N:4]=[C:3]([C:2]([F:7])([F:6])[F:1])[NH:5][C:16](=[O:17])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CC=C(C(=O)OCC)C(=O)OCC
Reactant: N=C(N)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)c1c(C)nc(C(F)(F)F)[nH]c1=O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Trifluoroacetamidine (2.47 g) and diethyl ethylidenemalonate (3.64 ml) were dissolved in ethanol (50 ml) and the mixture was stirred at 90° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water. The mixture was adjusted to pH 4 with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and the obtained oil (570 mg) was dissolved in carbon tetrachloride (45 ml). N-Bromosuccinimide (381 mg), 2,2′-azobis(2-methylpropionitrile) (16 mg) and potassium carbonate (2.90 g) were added and the mixture was heated under reflux for 30 min. The reaction mixture was cooled to room temperature, and water was added. The aqueous layer was separated, adjusted to pH 3 with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object compound (313 mg) as a powder.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:4][CH:5]=[N:6][C:7]=1[CH2:8][S+:9]([O-])[C:10]1[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[N:18]=1>C(O)C>[CH3:1][C:2]1[C:7]([CH2:8][S:9][C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[N:18]=2)=[N:6][CH:5]=[CH:4][C:3]=1[O:20][CH2:21][C:22]([F:23])([F:25])[F:24]
Reactant: Cc1c(OCC(F)(F)F)ccnc1C[S+]([O-])c1nc2ccccc2[nH]1
Solvent: CCO
Product: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1

Procedure:
The present invention relates to a process for preparing the Crystalline Form A of Lansoprazole, which comprises dissolving Lansoprazole obtained by oxidation of 2-([3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl)thio-1H-benzimidazole in ethanol, adding water thereto, stirring the mixture at the temperature range of from 15 to 40° C. for 0.5 to 4 hours, and filtering and drying the resulting product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=O)[CH2:11][F:12])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl.[CH3:21][O:22][NH2:23]>CO.Cl>[CH3:21][O:22][N:23]=[C:10]([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:11][F:12]
Reactant: CON
Reactant: O=C(CF)CCc1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C(CF)CCc1ccc(Cl)cc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To a stirred suspension of 4-(4-chloro-phenyl)-1-fluoro-butan-2-one (0.13 g; 0.62 mmol) in methanol (1.3 ml) was added pyridine (80 μl; 0.99 mmol) followed by a portion wise addition of methoxyamine hydrochloride (78 mg; 0.93 mmol). The reaction mixture was stirred for 16 h at 23° C. The mixture was poured in 1 N hydrochloric acid (5 ml), extracted with dichloromethane (3×3 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford 0.13 g (94% of theory) of 4-(4-chloro-phenyl)-1-fluoro-butan-2-one O-methyl-oxime (mixture of E/Z-isomers) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=O)[NH2:12])[CH2:7][CH2:6]1)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>O1CCCC1>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=[S:23])[NH2:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)[C@H]1CC[C@H](C(N)=O)CC1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(N)=S)CC1

Procedure:
A solution of trans-4-carbamoyl-cyclohexanecarboxylic acid methyl ester (2.00 g, 10.8 mmol) and Lawesson's reagent (2.2 g, 5.4 mmol) in tetrahydrofuran (55 ml) was heated at reflux for 3.5 h. The heating bath was removed and the solvent was evaporated. The residue was purified by flash-chromatography with n-heptane/ethyl acetate as eluent to give a pink solid, which was triturated in toluene (10 ml). The precipitate was collected by filtration and dried in vacuo to give the title compound (1.04 g, 48%) as off-white solid. MS m/e: 202 ([M+H]+)
Reaction SMILES: [F:1][C:2]([F:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C@@H:3]([NH:11][C@H:12]([C:18]12OCC(C)(C[O:23]1)C[O:19]2)[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.Cl.[OH-].[Na+]>C1COCC1.O>[F:33][C:2]([F:1])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C@@H:3]([NH:11][C@@H:12]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:18]([OH:23])=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1
Reactant: CC(C)(C)C[C@H](N[C@@H](c1ccc(F)cc1)C(F)(F)c1ccccn1)C12OCC(C)(CO1)CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@H](N[C@@H](c1ccc(F)cc1)C(F)(F)c1ccccn1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a solution of [2,2-difluoro-1(S)-(4-fluorophenyl)-2-pyridin-2-ylethyl]-[3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)butyl]amine (265 mg, 0.571 mmol) in a mixture of THF (5 ml) and water (5 ml) was added 1N HCl (2 ml, 2 mmol) and the reaction mixture was stirred at room temperature for 2 h. 1N NaOH (3.6 ml, 3.6 mmol) was added and stirring was continued at room temperature for 4 h. The solvent was evaporated using rotavap and 6N HCl was added dropwise to adjust the pH to 6. The precipitates were filtered and dried to obtain 2(S)-[2,2-difluoro-1(S)-(4-fluorophenyl)-2-pyridin-2-ylethylamino]-4,4-dimethylpentanoic acid (100 mg) as a white solid which was converted to the title compound as described in Example 1, Step 12 above. LC/MS: 443.2 (M−1)−1, 445.4 (M+1)+1, 466.9 (M+Na). 1HNMR (DMSO-d6): δ 8.7 (d, 1H), 8.6 (s, 1H), 7.95 (t, 1H), 7.6 (d, 1H), 7.55 (t, 1H), 7.4 (d, 2H), 7.2 (d, 2H), 4.6 (m, 1H), 2.6 (t, 1H), 1.3 (m, 4H), 0.6 (S, 10H), 0.25 (t, 1H).
Reaction SMILES: [C:1]1([CH3:22])[C:2]([NH:7][CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2Br)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][CH:4]=[CH:5][CH:6]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[C:1]1([CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8]1
Reactant: CCOC(=O)C(=CNc1ccccc1C)c1ccccc1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccccc2C)c2ccccc12
Temperature: 77.5 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
A mixture of ethyl 3-(o-toluidino)-2-(2-bromophenyl)acrylate (1.326 g, 3.68 mmol), cuprous iodide (38 mg, 0.38 mmol), potassium phosphate (1.652 g, 7.8 mmol) and N,N-dimethylformamide (16 mL) was stirred at 75-80° C. under nitrogen gas atmosphere for 16 hours. The reaction mixture was allowed to cool to room temperature. Solvent was removed under reduced pressure. Water (16 mL) was added to the residue and the mixture was extracted with ethyl acetate (8 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=20:1) to give pure ethyl 1-(o-tolyl)-1H-indole-3-carboxylate as a pale yellow solid (0.789 g, 77%). LRMS (M+H+) m/z: calcd 279.13. found 279. 1H NMR (300 MHz, CDCl3): δ 8.26 (dd, J=7.9, 0.7 Hz, 1H), 7.89 (d, J=0.7 Hz, 1H), 7.53-7.11 (m, 6H), 7.02 (dd, J=8.1, 0.8 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 2.07 (s, 3H), 1.45 (t, J=7.2 Hz, 3H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][CH:33]([CH3:37])[C:34]([OH:36])=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl:38][C:39]1[CH:44]=[C:43]([NH2:45])[N:42]=[C:41]([NH2:46])[CH:40]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:25]([O:29][C:30](=[O:31])[NH:32][CH:33]([C:34](=[O:36])[NH:46][C:41]1[CH:40]=[C:39]([Cl:38])[CH:44]=[C:43]([NH2:45])[N:42]=1)[CH3:37])([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cc(Cl)cc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(Cl)cc(N)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
HATU (2.7 g, 7.1 mmol) is added to a mixture of 2-{[(tert-butoxy)carbonyl]amino}-propanoic acid (850 mg, 4.5 mmol), 4-chloropyridine-2,6-diamine (1 g, 7.0 mmol), DIPEA (4.6 ml, 26.5 mmol) and NMP (7 ml) and the mixture is stirred at RT for 18 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 770 mg (55%). HPLC-MS: M+H=315 (Method—2).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)[NH:7][CH:6]=1)=[O:4]>C(O)C.C(O)(=O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)[NH:7][CH:6]=1)(=[O:4])[CH:2]=[O:1]
Reactant: O=C(CO)c1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: O=CC(=O)c1c[nH]c2ccc(OCc3ccccc3)cc12

Procedure:
A solution of 20 in ethanol was treated with copper(II) acetate monohydrate in 50% aqueous acetic acid as described above for 15. Work-up gave nearly pure 3-glyoxalyl-5-(benzyloxy)indole 21.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][CH:8]([C:13](=[O:36])[NH:14][C@H:15]1[CH2:33][C:32]2=[CH:34][N:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=32)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]1=[O:35])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl>>[CH3:11][CH:10]([CH3:12])[CH2:9][CH:8]([C:13](=[O:36])[NH:14][C@H:15]1[CH2:33][C:32]2=[CH:34][N:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=32)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]1=[O:35])[CH2:7][C:6]([OH:37])=[O:5]
Reactant: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCCNC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC(CC(=O)O)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCCNC1=O
Reaction time: 2.5 h

Procedure:
The less polar stereoisomer of (11S)-5-methyl-3-(10-oxo-1,9-diazatricyclo[11.6.1.014,19 ]eicosa-13(20),14(19),15,17-tetraen-11-yl-carbamoyl)hexanoic acid t-butyl ester (300 mg) was covered with 5 mL of a 10% trifluoroacetic acid/methylene chloride solution and left to stir. After 2.5 hours, TLC indicated that the reaction was complete. All volatiles were removed under reduced pressure. The residue was taken up in CH2Cl2 (40 mL) and transferred to separatory funnel and washed consecutively with 0.5% HCl (40 mL) and brine (40 mL). The organic phase was dried (MgSO4), filtered and concentrated to provide the less polar stereoisomer of (11S)-5-methyl-3-(10-oxo-1,9-diazatricyclo[11.6.1.014,19 ]eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanoic acid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:17])[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=1)#[N:2].[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].C([NH+](CC)CC)C>CN1CCCC1=O.O>[O:17]=[C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]2[NH:20][N:19]=[N:18][N:2]=2)=[CH:8][N:7]=1)[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CCC(=O)Nc1ccc(C#N)cn1
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)CCC(=O)Nc1ccc(-c2nnn[nH]2)cn1
Yield: 25 %

Procedure:
A mixture of methyl 4-[(5-cyano-2-pyridyl)amino]-4-oxo-butanoate A1 (0.200 g, 0.857 mmol), sodium azide (0.169 g, 0.09 ml, 2.57 mmol) and triethylammonium chloride (0.187 g, 0.17 ml, 1.33 mmol) was stirred 4 h at 150° C. in 1-methyl-2-pyrrolidinone (10 mL). The mixture was cooled down and diluted with water. After acidification with aqueous hydrochloric acid (1N), the filtrate was extracted twice with ethyl acetate. The organic phases were combined, dried over sodium sulfate and concentrated. The residue was suspended in ethyl acetate and filtered to give methyl 4-oxo-4-[[5-(1H-tetrazol-5-yl)-2-pyridyl]amino]butanoate A65 (0.06 g, 25% yield). M.p.: 246-248° C., LC-MS (Method F) RT 0.53, 277 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:5]([O:6][CH2:7][C:8]([N:10]([CH3:17])[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:9])=[C:4]([CH3:22])[C:3]=1[CH3:23].[CH2:24](Br)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[NH2:1][C:2]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:5]([O:6][CH2:7][C:8]([N:10]([CH3:17])[CH:11]2[CH2:16][CH2:15][N:14]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:13][CH2:12]2)=[O:9])=[C:4]([CH3:22])[C:3]=1[CH3:23]
Reactant: BrCCc1ccccc1
Reactant: Cc1c(C)c(OCC(=O)N(C)C2CCNCC2)c(C)c(C)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C)c(OCC(=O)N(C)C2CCN(CCc3ccccc3)CC2)c(C)c(C)c1N
Temperature: 60 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
To a mixture solution of 99 mg of the compound (1) obtained in the Example 1 and 42.3 μl of phenethyl bromide in 2 ml of acetonitrile was added 65 μl of triethylamine, and the mixture was stirred for 5 hours at 60° C. After the reaction, saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saline, dried and concentrated under reduced pressure to give the residue. The obtained residue was purified by amine-coated silica gel (Fuji Silysia Chemical Ltd.) column chromatography (dichloromethane : ether =1:1) to give 86 mg (65%) of the above-mentioned compound (6).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14](Br)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CN(C)[CH:31]=[O:32].[Cl-].[NH4+]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([CH:31]=[O:32])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: Cc1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1nc2c(cc1C=O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.2 %

Procedure:
A solution of 0.41 g (1.07 mmol) (4R,9aR)-7-bromo-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 6, intermediate) in 28 mL diethyl ether was cooled to −100° C. and treated with 0.80 mL (1.18 mmol) tert-butyl lithium (1.5M solution in n-pentane). After 15 min. 0.12 mL N,N-dimethylformamide was added and the temperature was raised to −78° C. After 45 min. the solution was poured into 10% aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and filtered. The solvent was removed at a rotary evaporator and the residue was purified by column chromatography on silica gel (0.040–0.063 mm) with ethyl acetate:n-hexane (1:2) as eluant to give the compound as a yellow foam (80.2%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:19]([O-])=O)[CH:5]=[C:6]([CH3:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[CH:10]=1>[Pt].C(O)C>[CH3:18][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([CH3:1])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:16])[CH3:17])[CH:10]=1)[NH2:19]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1cccc(C(C)C)c1
Agent: [Pt]
Solvent: CCO
Product: Cc1cc(N)cc(C)c1Oc1cccc(C(C)C)c1

Procedure:
3,5-Dimethyl-4-(3'-isopropylphenoxy)-nitrobenzene (5.21 g) and 521 mg of 10% platinum on carbon in 150 ml ethanol are reduced under hydrogen on a Parr shaker. The solution is filtered through Celite to remove catalyst and the filtrate is stripped to give 3,5-dimethyl-4-(3'-isopropylphenoxy)-aniline which is then fused with 50 g of dimethyl oxalate at 120° for four hours. The resulting mixture is concentrated under high vacuum and the residue chromatographed on silica gel with 9:1 toluene:ethyl acetate as eluent to yield methyl N-[3,5-dimethyl-4-(3'-isopropylphenoxy)-phenyl]oxarnate; NMR (CDCl3): δ 5 1.2 (6H, d), 2.1 (6H,s), 2.8 (1H,m), 4.0 (3H,s), 6.5 (1H, d of d), 6.7 (1H,t), 6.9 (1H, d of d), 7.2 (1H, t), 7.4 (2H,s), 8.8 (1 h, br s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[F:14][C:15]([F:31])([F:30])[O:16][C:17]1[CH:22]=[CH:21][C:20](C2C=CC(O)=CC=2)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].N#N>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:14][C:15]([F:30])([F:31])[O:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)/C=C/c1ccc(Br)cc1
Reactant: Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Yield: 85 %

Procedure:
A solution of methyl (E)-3-(4-bromophenyl)-2-propenoate (99) (0.500 g, 2.07 mmol) and 4-(trifluoromethoxy)phenylboronic acid (44) (0.612 g, 2.97 mmol) in dioxane (40 mL) and aqueous K2CO3 (2M, 10 mL, 20 mmol) was purged with N2. Pd(dppf)Cl2 (0.050 g, 0.06 mmol) was added and the solution was refluxed under N2 for 1 h. The dioxane was removed and the residue was extracted with EtOAc, the organic fraction was dried and the solvent was removed. Column chromatography of the residue on silica gel using gradient elution (hexanes to CH2Cl2) gave methyl (2E)-3-[4′-(trifluoromethoxy)[1,1′-biphenyl]-4-yl]-2-propenoate (100) (0.567 g, 85%) as a white solid: mp 98-100° C.; 1H NMR (CDCl3) δ 7.73 (d, J=16.0 Hz, 1H), 7.56-7.63 (m, 6H), 7.30 (dd, J=8.8, 0.9 Hz, 2H), 6.48 (d, J=16.0 Hz, 1H), 3.82 (s, 3H). APCI MS m/z 323 [M+H]+.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[K].[O-]CCCC.[CH:28]1[C:41]2[C:42]3=[C:43]4[C:38](=[CH:39][CH:40]=2)[CH:37]=[CH:36][CH:35]=[C:34]4[CH:33]=[CH:32][C:31]3=[C:30]([S:44][C:45]2[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=2[CH:47]=O)[CH:29]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH:28]1[C:41]2[C:42]3=[C:43]4[C:38](=[CH:39][CH:40]=2)[CH:37]=[CH:36][CH:35]=[C:34]4[CH:33]=[CH:32][C:31]3=[C:30]([S:44][C:45]2[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=2[CH:47]=[CH2:2])[CH:29]=1
Reactant: O=Cc1ccccc1Sc1ccc2ccc3cccc4ccc1c2c34
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[O-]
Agent: O=C([O-])O
Agent: [I-]
Solvent: C1CCOC1
Product: C=Cc1ccccc1Sc1ccc2ccc3cccc4ccc1c2c34
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
Methyl triphenylphosphonium iodide (250 mg, 0.62 mmol) was dissolved in 20 mL of dry THF at 0° C. under dry nitrogen. To the mixture was added in one portion potassium tort-butoxide (75 mg, 0.66 mmol) and was stirred for 10 min at room temperature. 2-(pyrene-3-ylthio)-benzaldehyde (150 mg, 0.44 mmol) was added in one portion at 0° C. and the reaction mixture was stirred for additional 5 h at room temperature. The mixture was added to 50 mL of saturated sodium bicarbonate solution, and extracted with 3 portions of ether. The extracts were dried with magnesium sulfate and evaporated. The crude product was further purified by chromatography on silica gel using 20:1 petroleum ether (60-80):EtOAc as eluent to afford a yellow solid (100 mg, 70%). 1H-NMR (500 MHz, CDCl3): δ 5.36 (dd, J=1.3, 11.3 Hz, 1H), 5.77 (dd, J=1.3, 17.4 Hz, 1H), 6.92 (dd, J=1.3, 7.8 Hz, 1H), 7.02-7.05 (m, 1H), 7.20-7.23 (m, 1H), 7.37 (dd, J=10.8, 17.4 Hz, 1H), 7.61 (dd, J=1.3, 7.8 Hz, 1H), 7.94 (d, J=8.2 Hz, 1H), 8.01-8.22 (m, 8H), 8.61 (d, J=9.5 Hz, 1H). 13C-NMR (125 MHz, CDCl3): δ 116.4, 124.4, 124.5, 125.2, 125.3, 125.5, 126.1, 126.2, 126.9, 127.2, 127.8, 128.4, 128.5, 128.9, 130.9, 131.0, 131.1, 131.2, 131.4, 134.3, 137.9. EI-MS: m/z M+ Calculated 336.1, found 336.1.
Reaction SMILES: [C:1]([CH:4]([NH:13][NH:14][C:15]([N:17]1[C@H:21]([C:22]([O:24]CC)=[O:23])[CH2:20][S:19][CH:18]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33])=[O:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].Cl>[OH-].[Na+]>[C:1]([CH:4]([NH:13][NH:14][C:15]([N:17]1[C@H:21]([C:22]([OH:24])=[O:23])[CH2:20][S:19][CH:18]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33])=[O:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)[C@@H]1CSC(c2ccccc2O)N1C(=O)NNC(CCc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(CCc1ccccc1)NNC(=O)N1C(c2ccccc2O)SC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
The above diester (Example 50) can be dissolved in aqueous sodium hydroxide (2N; 5 ml) and stirred for 1 hr. The resulting solution can be acidified with dilute hydrochloric acid and the product (59) isolated by ion-exchange chromatography on DOWEX 50W-X4 resin.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][NH:23][CH2:24][CH2:25][OH:26]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:23]([CH3:22])[CH2:24][CH2:25][OH:26])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CNCCO
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CN(CCO)CCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 4, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and 2-(methylamino)ethanol were converted to yield 2-[[3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-methyl-amino]-ethanol, MS: 422 (MH+, 1Br).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[N+](C1C=CC([O:42][C:43](=O)[O:44][CH:45]2[CH:52]3[CH:48]([O:49][CH2:50][CH2:51]3)[O:47][CH2:46]2)=CC=1)([O-])=O.CCN(C(C)C)C(C)C>C(#N)C.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:21][CH2:22][CH:23]([NH:26][C:43]([O:44][CH:45]2[CH:52]3[CH:48]([O:49][CH2:50][CH2:51]3)[O:47][CH2:46]2)=[O:42])[CH2:24][CH2:25]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(N)CC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1COC2OCCC12
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(NC(=O)OC2COC3OCCC23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-[(4-amino-cyclohexyl)-(trans-4-methylcyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1ynyl)thiophene-2-carboxylic acid methyl ester (0.40 g, 0.873 mmol) in ACN (5.0 mL) was cooled to 0° C. and carbonic acid hexahydro-furo[2,3-b]furan-3-yl ester 4-nitro-phenyl ester (0.295 g, 1.0 mmol) was added, followed by DIEA (391 μL, 2.18 mmol) and DMAP (cat). The reaction mixture was warmed to rt, and stirred for 1 h. The solvent was removed under reduced pressure and the crude reaction mixture was partitioned between EtOAc and 2N K2CO3(aq). The layers were separated and the organics washed repeatedly with 2N K2CO3(aq). Both epimers of 5-(3,3-Dimethyl-but-ynyl)-3-[[4-(hexahydro-furo[2,3-b]furan-3-yloxycarbonylamino)-cyclohexyl]-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester were isolated by reverse phase HPLC and carried forward wet into the next reaction.