Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH2:8][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:23][O:24][CH2:25][CH2:26]Br.[OH-].[Na+].Cl>CO.O.C(OCC)(=O)C.CN(C)C=O>[CH3:23][O:24][CH2:25][CH2:26][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH2:8][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1=Cc2ccc(O)cc2CC1
Reactant: COCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCCOc1ccc2c(c1)CCC(C(=O)O)=C2
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A mixture of 7-hydroxy-1,2-dihydro-3-naphthoic acid (1 g), potassium carbonate (5 g), potassium iodide (2.5 g), N,N-dimethylformamide (30 ml) and methoxy ethyl bromide (2 ml) is stirred for 12 hours at 100° C. After cooling, water (300 ml) and ethyl acetate (200 ml) are added to the reaction mixture, and the mixture is shaken thoroughly. The organic layer is separated, washed with water, dried and evaporated under reduced pressure. the residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1) to give a colorless oily product, which is dissolved in methanol (50 ml). To the solution is added an aqueous solution (10 ml) of sodium hydroxide (2 g). The mixture is left standing for one hour, and then acidified with hydrochloric acid, followed by addition of water (300 ml). The resulting precipitates are collected by filtration and recrystallized from a mixture of methanol and water to give 7-methoxyethoxy-1,2-dihydro-3-naphthoic acid (0.65 g) as colorless needles, m.p. 122°-127° C.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[F:17][C:18]1[CH:19]=[C:20](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])[CH:21]=[CH:22][C:23]=1[F:24].FC(F)(F)C(O)=O>C1COCC1>[CH2:10]([N:4]1[CH2:3][CH:25]([C:20]2[CH:21]=[CH:22][C:23]([F:24])=[C:18]([F:17])[CH:19]=2)[CH:26]([C:27]([OH:29])=[O:28])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C(O)/C=C/c1ccc(F)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(O)C1CN(Cc2ccccc2)CC1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (48.3 g, 204 mmol) and (E)-3-(3,4-difluoro-phenyl)-acrylic acid (15 g, 81.5 mmol) in THF (200 mL) was added trifluoroacetic acid (0.312 mL, 0.0041 mol) at 0° C. The mixture was gradually warmed to room temperature and stirred overnight. It was then concentrated in vaccuo and the residue was diluted with n-heptane (500 mL) followed by vigorous stirring for 1 hour. The resulted white precipitation was collected and washed with heptane affording 26 g (100%) of the title compound as a white solid. MS m/e: 318.1 (M+H+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH2:11][C@@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][OH:10].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[CH3:18][S:19]([O:10][CH2:9][C@H:8]([O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:11][C@@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15][CH3:16])(=[O:21])=[O:20]
Reactant: CCCC[C@H](C)C[C@H](CO)OC1CCCCO1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCC[C@H](C)C[C@H](COS(C)(=O)=O)OC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A mixture of 1.51 g of (2R,4S)-2-tetrahydropyranyloxy-4-methyloctanol obtained in Step 9 and 15 ml of pyridine was kept at -5° C., and 1.06 g of methanesulfonyl chloride was added thereto, followed by stirring at that temperature for 1 hour. The reaction mixture was poured into ice-water and extracted with diethyl ether. The extract was adjusted to pH 5 with 1% hydrochloric acid, washed with water, dried, and distilled to remove the solvent to obtain 1.74 g (77.81%) of the titled compound.
Reaction SMILES: [N:1]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][C@H:2]1C(OC)=O.C([Mg]Br)C.[CH2:29]1[CH2:33][O:32]C[CH2:30]1>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[OH:32][C:33]1([C@@H:2]2[CH2:3][N:4]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:5][CH2:6][N:1]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:30][CH2:29]1
Reactant: C1CCOC1
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CC[Mg]Br
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@H](C2(O)CC2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-1,4-di-tert-butyl 2-methyl piperazine-1,2,4-tricarboxylate (3 g; 8.7 mmol) and titanium tetraisopropoxide (0.77 ml; 2.6 mmol), cooled to 0° C. under N2, a 3M solution of ethyl magnesium bromide in THF (8.7 ml; 26 mmol) was added dropwise over 45 minutes. The reaction mixture was left to warm up to room temperature and stirred for 18 hours. The reaction mixture was quenched with a 1M hydrochloric acid aqueous solution. The reaction mixture was diluted with water. Extractions were carried out with ethyl acetate. The combined organics were backwashed with a saturated sodium bicarbonate aqueous solution and brine. The organic was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel (40 g), eluting with petrol/ethyl acetate (0 to 40%). The product was obtained as colourless oil (1.4 g; 50%). 1H NMR (CDCl3) 1.37-1.41 (18H, m), 1.52 (4H, s), 2.80-2.90 (1H, m), 3.10-3.40 (2H, m), 3.50-3.70 (2H, m), 3.80-4.20 (2H, m).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]([O:13]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:3][CH2:2]1.[NH:23]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:24]1.O>ClCCl>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]2[CH2:26][CH2:27][N:23]([C:11]([N:4]3[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[O:1][CH2:2][CH2:3]3)=[O:13])[CH2:24]2)[CH:29]=1
Reactant: c1cncc(C2CCNC2)c1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCOc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(N1CCC(c2cccnc2)C1)N1CCOc2ccccc21
Temperature: 100 °C
Yield: 92.2 %

Procedure:
0.2 g of 4-nitrophenyl 2,3-dihydro-4H-1,4-benzoxazine-4-carboxylate, 0.1 g of 3-(pyrrolidin-3-yl)pyridine and 1.5 ml of water are introduced into a 10 ml glass tube. The tube is sealed and then heated at 100° C. under microwave irradiation for 35 minutes. Dichloromethane is added. The organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a dichloromethane/methanol gradient from 1/0 to 95/5. 0.19 g of 4-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazine is obtained.
Reaction SMILES: [CH2:1]([N:6](C)[C:7](=[O:11])[O:8][CH2:9]Cl)[CH2:2][CH2:3][CH2:4][CH3:5].[OH:13][C@@H:14]([C@H:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([O-:35])=[O:34])=[C:20]([S:23]/[CH:24]=[CH:25]\[C:26]3[S:30][CH:29]=[N:28][C:27]=3[CH2:31][OH:32])[C@H:21]([CH3:22])[C@H:17]12)[CH3:15].[Na+]>>[OH:13][C@@H:14]([C@H:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([O:35][CH2:9][O:8][C:7]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:11])=[O:34])=[C:20]([S:23]/[CH:24]=[CH:25]\[C:26]3[S:30][CH:29]=[N:28][C:27]=3[CH2:31][OH:32])[C@H:21]([CH3:22])[C@H:17]12)[CH3:15]
Reactant: CCCCCN(C)C(=O)OCCl
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CCCCCNC(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 32.1 %

Procedure:
In the same manner as in step b) in Example 125, 125 mg of the title compound was prepared from 160 mg of chloromethyl N-pentan-1-yl-N-methylcarbamate and 300 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethyl-thiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: C([O-])(=O)C.[Na+].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:21])[CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[N:17][CH:16]=2)=[CH:9][CH:8]=1.[Br:22]Br.O>C(O)(=O)C>[Br:22][CH:14]([C:15]1[CH:20]=[CH:19][N:18]=[N:17][CH:16]=1)[C:13]([C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=1)=[O:21]
Reactant: BrBr
Reactant: O=C(Cc1ccnnc1)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1ccc(F)cc1)C(Br)c1ccnnc1
Reaction time: 0.5 h

Procedure:
0.70 g (5.2 mmol) of sodium acetate is added to a solution of 1.02 g (4.70 mmol) of 1-(4-fluorophenyl)-2-pyridazin-4-ylethanone in 20 ml of acetic acid and then 0.26 ml (5.2 mmol) of bromine in solution in a few ml of acetic acid is added dropwise (slight exotherm). After 30 minutes at ambient temperature, the reaction medium is cooled and 60 ml of water are added. The product is extracted with diethyl ether. The cooled organic phase is washed with an aqueous solution of sodium hydrogen carbonate, dried over sodium sulfate and filtered.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH2:10]1[CH2:14]OC[CH2:11]1>C(OCC)C.[Ti]>[C:2]1([C@H:1]([OH:8])[CH2:14][CH:10]=[CH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=Cc1ccccc1
Agent: [Ti]
Solvent: O
Solvent: CCOCC
Product: C=CC[C@@H](O)c1ccccc1
Temperature: -74 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A solution of 2.25 mmol of the titanium compound of Example 1b in 120 ml of diethyl ether is cooled to -74° C. and 0.2 ml (2.0 mmol) of freshly distilled benzaldehyde is added. The beige suspension is stirred for a further 2 hours at -74° C. and 5 ml of a 5N H2O/THF solution are added. The beige suspension is warmed to RT, stirred for a further hour at this temperature, filtered with suction and concentrated on a rotary evaporator. The crude product (1.53 g of yellow-brown oil) is flash-chromatographed twice (80 g of silica gel, 25 cm long, cross-section 2 cm, 10 ml/fraction, 0.5 bar, 20:1 toluene/ethanol); (50 g of silica gel, 25 cm long, cross-section 2 cm, 15 ml/fraction, 0.5 bar, 15:1 toluene/ethanol). 0.2 g of product are obtained. Yield: 66%, ee: 82%.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([O:37][CH3:38])[CH:32]=1.C(N(CC)CC)C>C(O)CO>[CH3:38][O:37][C:33]1[CH:32]=[C:31]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)[CH:36]=[CH:35][N:34]=1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: COc1cc(Cl)ccn1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: COc1cc(N2CCN(C(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)ccn1

Procedure:
In the manner given in Example 5, a mixture of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine, 4-chloro-2-methoxypyridine and triethylamine is heated in ethylene glycol at 80° C. to give 1-(2-methoxypyridin-4-yl)-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][C:17]3[CH:18]=[N:19][C:20]([C:23]4([C:30]#[N:31])[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]4)=[CH:21][CH:22]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:32]1(=[O:38])[O:37][C:35](=[O:36])[CH2:34][CH2:33]1.ClC1C=CC=CC=1Cl>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4([C:30]#[N:31])[CH2:24][CH2:25][CH:26]([O:29][C:32](=[O:38])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:27][CH2:28]4)=[N:19][CH:18]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: Cc1c(C(=O)Nc2ccc(C3(C#N)CCC(O)CC3)nc2)cnn1-c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: Cc1c(C(=O)Nc2ccc(C3(C#N)CCC(OC(=O)CCC(=O)O)CC3)nc2)cnn1-c1ccc(Cl)cc1
Temperature: 150 °C
Reaction time: 7 h
Yield: 40.7 %

Procedure:
1-(4-Chlorophenyl)-N-[6-(1-cyano-4-hydroxycyclohexyl)pyridin-3-yl]-5-methyl-1H-pyrazole-4-carboxamide (0.42 g), succinic anhydride (0.11 g) and p-toluenesulfonic acid hydrate (5 mg) were added to 1,2-dichlorobenzene (4 ml) and stirred at 150° C. for seven hours. The reaction solution was treated with water and the precipitated solid was recrystallized from aqueous isopropanol to give the titled compound (0.21 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[S:9]([NH2:12])(=[O:11])=[O:10].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:54]1[CH:59]=[C:58]([O:60][CH3:61])[N:57]=[C:56]([S:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([F:70])[C:65]=2[F:71])[N:55]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:71][C:65]1[C:66]([F:70])=[CH:67][CH:68]=[CH:69][C:64]=1[CH2:63][S:62][C:56]1[N:55]=[C:54]([NH:12][S:9]([N:3]2[CH2:4][C@@H:5]([CH3:8])[NH:6][CH2:7][C@@H:2]2[CH3:1])(=[O:10])=[O:11])[CH:59]=[C:58]([O:60][CH3:61])[N:57]=1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: C[C@@H]1CN(S(N)(=O)=O)[C@@H](C)CN1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(NS(=O)(=O)N2C[C@@H](C)NC[C@@H]2C)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
To a solution of (2R,5S)-2,5-dimethylpiperazine (2 g) in dioxane (100 ml) was added sulfamide (2.5 g) and the reaction mixture was then heated at reflux in dioxane (100 ml) for 72 h. The reaction mixture was partitioned between EtOAc (150 ml) and H2O (150 ml) and the aqueous re-extracted with EtOAc (2×150 ml). Organics were collected, dried and reduced in vacuo to give (2S,5R)-2,5-dimethylpiperazine-1-sulfonamide as a white solid (1.2 g). A mixture of (2S,5R)-2,5-dimethylpiperazine-1-sulfonamide (0.38 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.43 g) and, 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product from example 35 step i), 0.4 g) in dioxane (20 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 4 h. The reaction mixture was then reduced in vacuo and the residue partitioned between DCM (150 ml) and H2O (150 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give a yellow solid. This residue was then purified by prep HPLC to give the title compound as a white solid. Yield: 9 mg
Reaction SMILES: C([Li])(CC)C.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH:16]2[CH2:18][CH2:19][CH2:20][CH:15]2[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CN(C)CCN(C)C.[CH2:29]([O:31][C:32](Cl)=[O:33])[CH3:30].Cl.O1CCCC1>C1CCCCC1.C(OCC)C.C(OCC)(=O)C>[CH:14]1([C:32]([O:31][CH2:29][CH3:30])=[O:33])[CH:15]2[CH2:20][CH2:19][CH2:18][CH:16]2[CH2:17][N:13]1[C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:12]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC2CCCC2C1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCOC(=O)C1C2CCCC2CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
Sec-butyl lithium (26.8 mL of a 1.4M solution in cyclohexane; 1.2 eq) was added dropwise to a solution of N-tert-butyloxycarbonyl-octahydrocyclopenta[c]pyrrole (6.6 gm) and tetramethylethylenediamine (TMEDA) (4.69 mL, 1 eq) in diethyl ether (63 mL) at −78° C., and allowed to stir for 1.5 hours. Ethylchloroformate (6 mL, 2 eq) in diethylether (10 mL) was added dropwise to the reaction mixture (maintaining the temperature at −78° C.), and the reaction mixture was allowed to rise to room temperature over a period of 2.5 hours. The temperature was then reduced to −78° C., and quenched by careful addition of hydrochloric acid in tetrahydrofuran (2.2 eq). The reaction was then diluted with ethyl acetate, and washed successively with 1N hydrochloric acid, water, brine, and then dried over anhydrous sodium sulfate. Evaporation of the organic layer under reduced pressure gave crude product, which was purified by column chromatography on silica gel, eluting with 9% ethyl acetate/hexane, to give 2-tert-butyl 1-ethyl hexahydrocyclopenta[c]pyrrole-1,2(1H)-dicarboxylate (2.5 gm).
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29]3[O:30][C:31]4[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:32]=4[N:33]=3)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=[O:15])=[O:7].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O.O>[CH3:38][C:35]1[CH:36]=[CH:37][C:31]2[O:30][C:29]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([C:19]4[CH:20]=[CH:21][C:16]([C:14]([C@@H:9]5[CH2:10][CH2:11][CH2:12][CH2:13][C@H:8]5[C:6]([OH:7])=[O:5])=[O:15])=[CH:17][CH:18]=4)=[CH:23][CH:24]=3)=[N:33][C:32]=2[CH:34]=1
Reactant: Cc1ccc2oc(Nc3ccc(-c4ccc(C(=O)[C@@H]5CCCC[C@H]5C(=O)OCC[Si](C)(C)C)cc4)cc3)nc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2oc(Nc3ccc(-c4ccc(C(=O)[C@@H]5CCCC[C@H]5C(=O)O)cc4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
To a solution of trans-2-(trimethylsilyl)ethyl-2-({4′-[(5-methyl-1,3-benzoxazol-2-yl)-amino]biphenyl-4-yl}carbonyl)cyclohexanecarboxylate (64 mg, 0.12 mmol) in THF (2 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 0.70 mL), and then the reaction mixture was stirred at rt for 16 h. Saturated aqueous NH4Cl was added, and the reaction mixture was diluted with EtOAc and water. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with water and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was treated with MeOH, and the precipitate was collected by filtration and dried in a vacuum oven to give trans-2-({4′-[(5-methyl-1,3-benzoxazol-2-yl)amino]biphenyl-4-yl}carbonyl)cyclohexanecarboxylic acid (44.3 mg, 84%). LC-MS m/z 455.3 (MH+), ret. time 3.57 min. 1H NMR (400 MHz, DMSO-d6) δ 1.21 (m, 1H), 1.37 (m, 2H), 1.63 (m, 1H), 1.85 (m, 3H), 2.05 (m, 1H), 2.38 (s, 3H), 2.69 (m, 1H), 3.95 (m, 1H), 7.03 (d, 1H), 7.33 (d, 2H), 7.76 (m, 4H), 7.85 (d, 2H), 7.93 (d, 2H), 10.73 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:46])([O:4][C:5]([NH:7][CH:8]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH:9]([OH:38])[CH2:10][N:11](CC1C=CC=CC=1)[CH2:12][CH:13]([OH:30])[CH:14]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6])[CH3:3]>CO>[NH:11]([CH2:10][CH:9]([OH:38])[CH:8]([NH:7][C:5](=[O:6])[O:4][C:2]([CH3:46])([CH3:3])[CH3:1])[CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[CH2:12][CH:13]([OH:30])[CH:14]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)CN(Cc1ccccc1)CC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CC1CCCCC1)C(O)CNCC(O)C(CC1CCCCC1)NC(=O)OC(C)(C)C

Procedure:
Starting from N-Boc-L-cyclohexylalanine in place of N-Boc-L-phenylalanine, the title Compound 14 (white solid) was prepared using procedures analogous to those described for Compounds 1b(i), 4b, and 7. [α]D =-33.7° (c 0.18, MeOH). 13C NMR (CDCl3): δ26.1, 26.4, 26.5, 28.4, 32.3, 34.2, 34.3, 38.1, 51.0, 51.6, 72.7, 79.5, 156.4. Mass Spec. (M+H )+ @556. High Resolution FAB; exact mass calcd. for C30H58O6N3 (M+H)+, 556,4325; Found 556.4304.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][C:9]1[O:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11][C:10]=1[CH2:20][O:21][C:22]1[CH:42]=[CH:41][C:25]([CH2:26][N:27]2[C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([OH:40])[C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:24][C:23]=1[O:43][CH3:44].Br[C@H:46]([CH2:52][CH3:53])[C:47]([O:49][CH2:50][CH3:51])=[O:48]>O>[CH3:44][O:43][C:23]1[CH:24]=[C:25]([CH:41]=[CH:42][C:22]=1[O:21][CH2:20][C:10]1[N:11]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:13][C:9]=1[CH3:8])[CH2:26][N:27]1[C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([O:40][C@@H:46]([CH2:52][CH3:53])[C:47]([O:49][CH2:50][CH3:51])=[O:48])[C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2
Reactant: COc1cc(Cn2c3ccccc3c3c(O)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOC(=O)[C@H](Br)CC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CC)Oc1cccc2c1c1ccccc1n2Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
41 mg of sodium hydride (60%) was added to N,N-dimethylformamide (2.5 mL) solution of 500 mg of 9-{4-[(5-methyl-2-phenyloxazole-4-yl)methoxy]-3-methoxybenzyl}-9H-carbazole-4-ol while being cooled in an ice bath, and stirred at room temperature for 1 hour. Thereafter, 239 mg of ethyl (R)-2-bromobutyrate was added thereto dropwise at −5° C., and was stirred for 30 minutes. Water was added to the reaction mixture, and extracted twice with ethyl acetate. The combined extract was washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo, the residue was purified by NH silica gel chromatography (ethyl acetate:n-hexane=1:4), and 650 mg of the subject compound was prepared. Optical purity 95% ee (HPLC).
Reaction SMILES: C1(C)C=CC(S(CC[O:12][C:13](=[O:50])[C:14]2[CH:19]=[C:18]([S:20]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[C:24]3[S:32]([CH2:34][C:35]3[C:40]([CH3:41])=[C:39]([O:42][CH2:43][C:44]([F:47])([F:46])[F:45])[CH:38]=[CH:37][N:36]=3)=[O:33])(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=2[O:48][CH3:49])(=O)=O)=CC=1.C([O-])(O)=O.[Na+:56].O.CC(O)C>CC#N>[Na+:56].[CH3:49][O:48][C:15]1[CH:16]=[CH:17][C:18]([S:20]([N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]=[C:24]2[S:32]([CH2:34][C:35]2[C:40]([CH3:41])=[C:39]([O:42][CH2:43][C:44]([F:46])([F:47])[F:45])[CH:38]=[CH:37][N:36]=2)=[O:33])(=[O:22])=[O:21])=[CH:19][C:14]=1[C:13]([O-:50])=[O:12]
Reactant: COc1ccc(S(=O)(=O)n2c(S(=O)Cc3nccc(OCC(F)(F)F)c3C)nc3ccccc32)cc1C(=O)OCCS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)n2c(S(=O)Cc3nccc(OCC(F)(F)F)c3C)nc3ccccc32)cc1C(=O)[O-]
Temperature: 70 °C
Yield: 63.5 %

Procedure:
A mixture of 2-methoxy-5-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}benzoic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 8, 400 mg, 0.52 mmol) and NaHCO3 (52 mg, 0.62 mmol, 1.2 eq) in CH3CN (3 mL)-H2O (2 mL)-i-PrOH (1 mL) was heated to 70° C. for 1.5 h. Then volatile materials were removed by evaporation and the residual oil was dissolved in CH2Cl2-MeOH, the mixture was filtered to remove insoluble solids. The filtrate was concentrated by evaporation. The residual syrup was dissolved in H2O, and the mixture was extracted with CH2Cl2 (2 times) to remove the starting material, lansoprazole and tolyl vinyl sulfone. The water solution was freeze-dried to yield 200 mg (65%) Compound 3 sodium salt as a light yellow solid.