Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:11][N:12]2[CH:17]([C:18](=[O:22])[CH:19]=[N+]=[N-])[CH2:16][N:15]([CH3:23])[C:14](=[O:24])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:30]>CCOCC.C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:11][N:12]2[CH:17]([C:18](=[O:22])[CH2:19][Cl:30])[CH2:16][N:15]([CH3:23])[C:14](=[O:24])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)C=[N+]=[N-]
Reactant: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)CCl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 3-benzyloxy-7-diazoacetyl-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (90 mg, 0.226 mmol) in Et2O (5 mL) and anhydrous CH2Cl2 (5 mL) was added 1.0M HCl in Et2O (272 μL, 0.272 mmol). The reaction was stirred at room temperature for 15 minutes, and the solvent was removed in vacuo to afford the title product as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 7.49-7.48 (m, 2H), 7.39-7.30 (m, 3H), 7.12 (br s, 1H), 6.03 (s, 1H), 5.57 (s, 1H), 5.22 (dd, J=11.4, 26.0 Hz, 2H), 4.28-4.24 (m, 2H), 4.09 (dd, J=4.6, 13.4 Hz, 1H), 3.88 (dd, J=4.6, 13.4 Hz, 1H), 2.98 (s, 3H), 1.26 (t, J=7.2, 3H); ES MS (M+Na)=428.
Reaction SMILES: Cl.C[O:3][C:4](=[O:33])[C@H:5]([CH2:29][CH2:30][S:31][CH3:32])[NH:6][C:7](=[O:28])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.[OH-].[Li+]>C1COCC1.O>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([NH:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][C@H:5]([C:4]([OH:33])=[O:3])[CH2:29][CH2:30][S:31][CH3:32])=[O:28])=[C:9]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:10]=2)[CH:17]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CNc2cccnc2)cc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSCC[C@H](NC(=O)c1ccc(CNc2cccnc2)cc1-c1ccccc1)C(=O)O
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of [4-(pyrid-3-ylaminomethyl)-2-phenylbenzoyl]methionine methyl ester hydrochloride (72 mg, 0.16 mmol) in THF (3 mL) was added a solution of lithium hydroxide hydrate (13 mg, 0.32 mmol) in water (1 mL) and the reaction mixture was stirred for 30 minutes. The THF was evaporated in vacuo and the residue was taken up in aqueous 3N HCl. The solution was concentrated and the residue was purified by preparative HPLC (70% acetonitrile-0.1% aqueous trifluoroacetic acid) to give [4-(pyrid-3-ylaminomethyl)-2-phenylbenzoyl]methionine (39 mg, 50%). 1H NMR (300 MHz., DMSO-d6) δ 8.48 (d, 1H), 8.17 (m, 1H), 7.97 (m, 1H), 7.56 (m, 2H), 7.29-7.44 (m, 7H), 4.51 (bd, 2H), 4.48 (ddd, 1H), 2.24 (m, 2H), 1.99 (s, 3H), 1.85 (m, 2H). MS (CI NH3) m/e 436 (M+H)+, 418, 319, 287, 194, 165. Anal calcd for C24H25N3O3S (+1.26 TFA): C, 55.00; H, 4.57; N, 7.25. Found: C, 54.97; H, 4.58; N, 7.33.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Cl[CH:6]([C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C(O)C.O>[NH2:1][C:2]1[S:3][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:4]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=O)C(Cl)C(=O)OCC
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1nc(N)sc1C(=O)OCC
Temperature: 25 °C

Procedure:
A solution of thiourea (1.7 g, 22 mmol) and diethyl 2-chloro-3-oxosuccinate (5.0 g, 22 mmol) in absolute ethanol (50 mL) was heated at reflux for one hour. After cooling to room temperature the solvent was removed leaving a white solid. The solid was dissolved in water (100 mL) and the resulting precipitate was filtered and dried (4.6 g, 87%). MS (ES): 245;
Reaction SMILES: [CH:1]1([CH:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[CH:29][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:23][S:24][CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:43]OS([O-])=O.[K+]>CO.O>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[CH:31][CH:32]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:23][S:24]([CH3:25])=[O:43])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(-c3ccc(C(F)(F)F)cc3)oc2CSC)C2CCCCC2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(-c3ccc(C(F)(F)F)cc3)oc2CS(C)=O)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
Ethyl 3-[({4-[(cyclohexyl{2-[(methylsulfanyl)methyl]-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methyl)amino]phenyl}carbonyl)amino]propanoate (482 mg) was dissolved in methanol (9 mL) and water (1 mL), OXONE (295 mg) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 100% ethyl acetate/hexane) to give the title compound (232 mg, 47%) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH3:26])[N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[S:27]1(=[O:34])(=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1>>[O:33]=[S:27]1(=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH3:26])[N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: O=S1(=O)CCCCN1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)cc3C#N)CC2)nc1C
Yield: 82.4 %

Procedure:
Using 5-bromo-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (413 mg) described in Preparation Example 172 and [1,2]thiazinane 1,1-dioxide (176 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (385 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH:23]=O)[N:22]=2)[CH2:14][C@H:13]1[O:30][CH3:31])=[O:10].C([O-])(=O)C.[Na+].Cl.[NH2:38][OH:39]>C(O)C>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21](/[CH:23]=[N:38]/[OH:39])[N:22]=2)[CH2:14][C@H:13]1[O:30][CH3:31])=[O:10]
Reactant: NO
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1/C=N/O

Procedure:
A solution of Cis(±)-ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-formyl-1,3-thiazole -5-carboxylate (0.10 g, 0.2 mmol, Example 252), sodium acetate (0.041 g, 0.5 mmol) and hydroxylamine hydrochloride (0.028 g, 0.4 mmol) were heated to reflux in absolute ethanol for 3 hours. After cooling to room temperature the ethanol was removed under reduced pressure followed by EtOAc/H2O partitioning, drying with MgSO4 and concentrating to a yellow solid (0.081 g) MS (ES): 504 NMR: 1.25 (t, 3H) 1.75 (s, 2 H) 2.18 (s, 3 H) 3.31 (s, 3 H) 3.36 (s, 3 H) 3.55 (s, 1 H) 3.95 (s, 1 H) 4.18-4.26 (m, 2 H) 4.26 (d, 2 H) 7.16 (d, 1 H) 8.61 (s, 1 H) 11.72 (s, 1 H) 12.16 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][C:8]3(OCC[O:15]3)[CH2:7][CH2:6][C:5]2=1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][C:8](=[O:15])[CH2:7][CH2:6][C:5]2=1
Reactant: Clc1ccc2[nH]c3c(c2c1)CCC1(C3)OCCO1
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCc2c([nH]c3ccc(Cl)cc23)C1
Yield: 26 %

Procedure:
A suspension of 6-chloro-2,2-ethylenedioxy-1,2,3,4-tetrahydrocarbazole in 200 ml. of 1:1 acetic acid/water was heated at reflux under nitrogen for 1.5 hours. The mixture was filtered hot and the filtrate was cooled in an ice bath and again filtered. Crystallization of the solid from methylene chloride/30°-60° petroleum ether gave 5.74 g. (26% yield) of 6-chloro-1,2,3,4-tetrahydrocarbazole-2-one as a flocculent solid, mp 194°-196°.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH:7]([CH2:12][C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([OH:27])=[O:26].O>C(O)(=O)C>[C:1]([CH:5]1[CH2:10][CH2:9][C:8]2[N:21]([C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=[O:26])[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:7]=2[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CC(C)(C)C1CCC(=O)C(CC(=O)c2ccccc2)C1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)C1CCc2c(cc(-c3ccccc3)n2-c2cccc(C(=O)O)c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
A solution of 4-tert-butyl-2-(2-oxo-2-phenylethyl)-cyclohexanone (0.219 gm) in glacial acetic acid (3.0 mL) in a 25-mL round-bottomed flask, under nitrogen, was fitted with a heating mantle and reflux condenser. To this solution was added 3-aminobenzoic acid (0.138 gm), which was then heated at 110 C for 3 hr. The solution was cooled to ambient temperature, 8 mL water was added, and the suspension was stirred 18 hr under nitrogen. The solid was filtered, washed with water, and recrystallized in acetonitrile to provide 0.123 gm of the pure product.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8](OC)=[O:9])(=[O:4])(=[O:3])[NH2:2].[NH2:15][NH2:16]>CO>[NH:15]([C:8]([C:7]1[CH:6]=[C:5]([S:1]([NH2:2])(=[O:4])=[O:3])[CH:14]=[CH:13][CH:12]=1)=[O:9])[NH2:16]
Reactant: NN
Reactant: COC(=O)c1cccc(S(N)(=O)=O)c1
Solvent: CO
Product: NNC(=O)c1cccc(S(N)(=O)=O)c1
Yield: 50.9 %

Procedure:
Methyl 3-sulfamoylbenzoate (110 mg, 0.511 mmol) was added to the hydrazine (32.8 mg, 1.022 mmol) in methanol and refluxed for 8 h at 65° G. Following cooling, reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by flash chromatography (5% methanol/DCM) to yield the 3-(hydrazinecarbonyl)benzenesulfonamide (57 mg, 0.260 mmol, 50.8% yield) as a white solid. 1H NMR (CD3OD, 400 MHz): δ 8.32 (m, 1H), 8.04 (d, 1H, J=7.6 Hz), 7.97 (d, 1H, J=7.6 Hz), 7.63 (t, 1H, J=8.0 Hz). Mass [M+H]+: 216.0
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]2=[O:12].CN1CCOCC1.[C:27]12([CH2:37][C:38](Cl)=[O:39])[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2>O1CCOCC1>[C:27]12([CH2:37][C:38]([NH:1][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][N:6]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]4=[O:12])=[O:39])[CH2:34][CH:33]3[CH2:32][CH:31]([CH2:30][CH:29]([CH2:35]3)[CH2:28]1)[CH2:36]2
Reactant: Nc1cccc2c(=O)n(Cc3ccccc3)ccc12
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1cccc2c(=O)n(Cc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 5-amino-2-benzylisoquinolin-1(2H)-one (50 mg, 0.2 mmol) and NMM (0.022 mL, 0.2 mmol) in 1,4-dioxane (3 mL) was added dropwise at room temperature a solution of 1-adamantaneacetic acid chloride (43 mg, 0.2 mmol) in 1,4-dioxane (5 mL). The reaction mixture was stirred at room temperature for 1 h. The volatiles were removed on a rotary evaporator. The crude product was purified by prep. HPLC affording 2-Adamantan-1-yl-N-(2-benzyl-1-oxo-1,2-dihydro-isoquinolin-5-yl)-acetamide (45.5 mg, 0.11 mmol, 53% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([NH:19][NH:20][C:21](=S)[NH2:22])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1>O1CCOCC1>[NH2:22][C:21]1[O:18][C:17]([C@@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][N:11]2[S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[N:19][N:20]=1
Reactant: NC(=S)NNC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Solvent: C1COCCO1
Product: Nc1nnc([C@@H]2CCCCN2S(=O)(=O)c2ccc(F)cc2)o1
Reaction time: 4 h
Yield: 41.6 %

Procedure:
Mercuric oxide (204 mg) was added to a solution of 2-((2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidylcarbonyl)-1-hydrazinecarbothioamide (170 mg) [see Preparation 45] in 1,4-dioxane (5 ml). The reaction mixture was heated under reflux and stirred for 4 hours. The resulting suspension was filtered through a plug of ARBOCEL (trade mark) filter aid, washing with dichloromethane:methanol (90:10, by volume). The filtrate was evaporated under reduced pressure and purified by column chromatography on silica gel eluting with, 100:0 changing to 90:10 (in 5% increments), by volume, dichloromethane:methanol. The product was further purified by column chromatography on silica gel eluting with 0:100 changing to 60:40, by volume, ethyl acetate:hexane, to afford 2-amino-5-[(2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidyl]-1,3,4-oxadiazole (64 mg) as a white solid.
Reaction SMILES: [H-].[Na+].C#CCN1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[N:18]3)[CH2:8][CH2:7]1.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27]>C1COCC1>[CH3:24][N:25]([CH3:29])[C:26](=[O:27])[O:23][C:20]1[CH:21]=[CH:22][C:13]([CH2:12][N:9]2[CH2:8][CH2:7][CH:15]([CH2:14][C:13]#[CH:12])[CH2:11][CH2:10]2)=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2
Reactant: CN(C)C(=O)Cl
Reactant: C#CCN1CCN(Cc2ccc(O)c3ncccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCC1CCN(Cc2ccc(OC(=O)N(C)C)c3ncccc23)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
To a suspension of NaH (24 mg, 0.6 mmol 1.2 equiv) in anhydrous THF, HLA20 (140 mg, 0.5 mmol, 1.0 equiv) was added under Ar at 0° C. The resulting mixture was stirred for 20 min at 0° C. A solution of dimethyl carbamoyl chloride (1.1 equiv) in anhydrous THF was added, and the stirring was continued for 24 h at room temperature. After evaporation of the solvent, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried with NaSO4. Evaporation of the solvent gave a crude product that was purified by RP HPLC.
Reaction SMILES: C1([O:7][C:8](=[O:18])[C:9]2[CH:17]=[CH:16][C:12]([C:13]([O-])=[O:14])=[CH:11][CH:10]=2)C=CC=CC=1.[NH3:19]>>[C:13]([NH2:19])(=[O:14])[C:12]1[CH:16]=[CH:17][C:9]([C:8]([OH:7])=[O:18])=[CH:10][CH:11]=1
Reactant: N
Reactant: O=C([O-])c1ccc(C(=O)Oc2ccccc2)cc1
Product: NC(=O)c1ccc(C(=O)O)cc1
Yield: 99 %

Procedure:
6.0 grams (0.025 mols) of monophenylterephthalate were brought together with 26.2 grams of liquid ammonia for reaction under the same conditions specified in Example 10. After working up the product as in all of the preceding examples, there were obtained 4.1 grams (99% of theory) of terephthalic acid monoamide.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([F:11])[CH:3]=1.C([Li])CCC.CN(C)[CH:19]=[O:20].[Cl-].[NH4+]>O1CCCC1.CCCCC>[F:11][C:4]1[CH:3]=[C:2]([CH:19]=[O:20])[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=1
Reactant: Fc1cc(Br)c2occc2c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: O=Cc1cc(F)cc2ccoc12
Temperature: -97.5 °C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
7-Bromo-5-fluoro-benzofuran (7 g, 32 mmol, Step B) was dissolved in a mixture of tetrahydrofuran (350 mL) and pentane (100 mL), cooled to −95 to −100° C., and treated with n-butyl lithium (14 mL, 35 mmol, 2.5M in hexane, Aldrich). After stirring for 5 minutes, a solution of dimethylformamide (5 mL) in tetrahydrofuran (15 mL) was added dropwise and the reaction temperature raised to −20° C. This was treated with aqueous ammonium chloride (50 mL) and stirred for 0.5 hour at ambient temperature. The reaction mixture was concentrated in vacuo and diluted with hexane. The organic fraction was washed with water and dried (Na2SO4). Removal of solvent afforded crude 5-fluoro-benzofuran-7-carbaldehyde (˜30%) as an oil. Purification was by silica gel chromatography (5-10% ethyl ether/hexane). HRMS, observed: 163.0201; Calcd for (M+H)+: 163.0195
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].C(=O)([O-])O.[Na+].[CH2:26](O)[CH3:27]>>[CH2:26]([O:10][C:9]([C:8]1[CH:12]=[C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:15][C:7]=1[OH:6])=[O:11])[CH3:27]
Reactant: COCCOc1ccc(O)c(C(=O)O)c1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cc(OCCOC)ccc1O

Procedure:
Concentrated sulphuric acid (0.5 ml) was added to a stirred solution of 2-hydroxy-5-(2-methoxyethoxy)benzoic acid (2 g) in ethanol (50 ml). The mixture was heated at reflux for 12 hours. The reaction mixture was added to sodium hydrogen carbonate solution (5% by weight in water, 200 ml) and the aqueous mixture was extracted with ethyl acetate (4×50 ml). The organic extracts were combined, washed with water (50 ml), brine, (50 ml), dried (MgSO4) and evaporated to give 2-ethoxycarbonyl-4-(2-methoxyethoxy)phenol (1.85 g) as an oil; NMR: 1.35(3H,t), 3.31(3H,s), 3.6(2H,m), 4.0(2H,m), 4.3(2H,q), 6.9(1H,d), 7.18(1H d of d), 7.2(1H,d); m/z 241(MH). This was converted into the trifluoromethane sulphonate ester using an analogous procedure to that described in Example 1 for the preparation of ethyl 3-(3-allyl-4-trifluoromethylsulphonyloxy)propionate. There was thus obtained after chromatography on silica gel (Varian bond elut S1 silica gel) using a gradient of 5 to 25% ethyl acetate in hexane as eluent as an oil; NMR(6): 1.3(3H,t), 3.3(3H,s), 3.62(2H,m), 4.2(2H,m), 4.34(2H,q), 7.35(1H, d of d), 7.49(2H,m); m/z 373(M+H).
Reaction SMILES: [Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[C:20]([F:27])=[C:21]([OH:26])[C:22]([F:25])=[CH:23][CH:24]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:28]([O:33][CH3:34])(=[O:32])[C@H:29]([CH3:31])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[C:20]([F:27])=[C:21]([C:22]([F:25])=[CH:23][CH:24]=2)[O:26][C@H:29]([CH3:31])[C:28]([O:33][CH3:34])=[O:32])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: Oc1c(F)ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)c1F
Reactant: COC(=O)[C@H](C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: COC(=O)[C@@H](C)Oc1c(F)ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)c1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 86 %

Procedure:
To a solution of 3-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-2,6 difluoro-phenol (0.570 g, 1.29 mmol), commercially available (S)-lactic acid, methyl ester. (0.246 mL, 2.58 mmol) and triphenylphosphine (0.677g, 2.58 mmol) in dry benzene (7 mL) was added diethylazodicarboxylate (0.406 mL, 2.58 mmol) dropwise at room temperature under a dry nitrogen atmosphere. The reaction mixture was sealed in a pressure bottle and immersed in a pre-heated oil bath at 105° C. After heating for 2.5 hours the mixture was stirred at ambient temperature for about 14 hours. The reaction mixture was then diluted with methylene chloride and combined with silica gel. The solvents were removed and the adsorbate was flash chromatographed (90/10 petroleum ether/ethyl acetate) to give (R)-2-[3-(6-bromo-benzo[b]naphtho[2,3-d ]thiophen-11-yl)-2,6-difluoro-phenoxy]-propionic acid, methyl ester as a white solid (0.59 g, 86%). To a solution of this methyl ester (0.46 g, 0.929 mmol) in tetrahydrofuran (18 mL) and methanol (6 mL) was added a 1 N aqueous solution of potassuim hydroxide (1.39 mL, 1.39 mmol) dropwise at room temperature. After stirring for 2 hours the solvents were removed and the residue was combined with water (50 mL) and acidified with 10% HCl. The solid was extracted into ether. The layers were shaken together well, separated, and the organic layer was washed with water and concentrated to give the title compound as a white solid (0.396 g, 88%): [a]D25=+13.22 (9.383 mg/mL methanol); NMR (400 MHz, DMSO-d6): δ13.11 (s, 1 H), 8.31 (d, J=8 Hz, 1H), 8.10-8.08 (m, 1H), 7.83-7.78 (m, 1H), 7.65-7.46 (m, 4 H), 7.32-7.19 (m, 2 H), 6.82-6.75 (m, 1 H), 4.98-4.93 (m, 1 H), 1.53-1.50 (m, 3 H); MS (-FAB): (M-H): one bromine pattern observed: 511/513 (2%); Anal. Calc. for C25H15BrF2O3S: C, 58.49, H, 2.95, N, 0.00. Found: C, 58.41, H, 3.44, N, 0.02.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:39][C:40](OC(C)=O)=[O:41]>C(Cl)Cl>[C:40]([N:16]1[CH2:15][C:14]([CH3:28])([CH3:27])[C:13]2[N:12]=[C:11]([CH:29]([CH3:31])[CH3:30])[C:10]([CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([OH:9])=[O:8])=[C:19]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:18]=2[CH2:17]1)(=[O:41])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1Cc2c(nc(C(C)C)c(C(OC(C)(C)C)C(=O)O)c2-c2ccc(F)cc2)C(C)(C)C1
Reaction time: 3 h
Yield: 83.5 %

Procedure:
To a stirred solution of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1)(0.012 g, 0.028 mmol) and Et3N (0.139 ml, 1 mmol) in CH2Cl2 (5 mL) was added Ac2O (0.026 ml, 0.280 mmol) at room temperature. After 3 h, the reaction mixture concentrated and purified by preparative-HPLC (MeCN/H2O/NH4OAc) to afford 2-(6-acetyl-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-tert-butoxyacetic acid (0.011 g, 76% yield) as white powder and mixture of rotomers. 1H NMR (500 MHz, CDCl3) δ ppm 7.41-7.54 (1H, m), 7.11-7.23 (3H, m), 4.91 (1H, br. s.), 4.49 (0.7H, d, J=17.4 Hz), 4.28 (0.3H, d, J=16.5Hz), 4.08 (0.7H, d, J=17.7 Hz), 3.93 (0.3H, d, J=16.8 Hz), 3.39-3.52 (2H, m), 3.15-3.27 (1H, m), 2.15 (2H, s), 1.95 (1H, s), 1.27-1.39 (9H, m), 1.15 (3H, d, J=5.5Hz), 0.90 (3H, s), 1.00 (6H, s). LCMS (M+H) calcd for C27H36FN2O4: 471.27. found: 471.3.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28](/[CH:33]=[CH:34]/C)[CH2:29][C:30]([OH:32])=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Li+].[OH-]>C1COCC1.CO>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@H:28]([CH:33]=[CH2:34])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: C/C=C/[C@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C[C@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of 1 (0.040 g, 0.082 mmol) in THF/MeOH (2/1) (1.5 mL) was added a 1 M solution of LiOH (0.50 mL, 0.50 mmol). The resulting mixture was stirred overnight at 23° C., quenched with excess 1 N HCl, and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The crude residue was purified by silica gel chromatography (0 to 40% EtOAc/hexanes) to afford 19 (0.022 g, 59% yield). MS ESI (neg.) m/e: 461.2 (M−H)+.