Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrBr.[OH-:3].[Na+].[C:5]([C:8]1[CH:9]=[CH:10][C:11]2[O:20][C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[C:13]([CH3:22])([CH3:21])[C:12]=2[CH:23]=1)(=[O:7])C>O.O1CCOCC1>[CH3:21][C:13]1([CH3:22])[C:14]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[O:20][C:11]2[CH:10]=[CH:9][C:8]([C:5]([OH:7])=[O:3])=[CH:23][C:12]1=2
Reactant: [OH-]
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)c1cccnc1O2
Agent: BrBr
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)c2cc(C(=O)O)ccc2Oc2ncccc21
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
4.8 g of bromine is added dropwise to a solution of 3.3 g of sodium hydroxide in 28 ml of water at below 0°C, and the mixture is allowed to stand at 0°C for 15 minutes. To the mixture is added dropwise and slowly a solution of 2.4 g of 7-acetyl-5,5-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine in 10 ml of dioxane. The whole mixture is allowed to stand at room temperature for 2 hours, and then the solvent is removed by distillation under reduced pressure. To the residue are added water and benzene, and the mixture is warmed to 30°-40°C. The aqueous layer is neutralized with hydrochloric acid. The crystalline precipitate is recrystallized from aqueous acetic acid to give 1.9 g of 5,5-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine-7-carboxylic acid melting at 241°-242°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[CH:10]/[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1.[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]\[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1cccc(C(=C/C=C\C(=O)O)c2cccc(OC)c2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cccc(C(=C/C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccc(OC)c2)c1
Reaction time: 1 h
Yield: 85.5 %

Procedure:
A solution of (Z)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid (1.85 g) and 4-nitrophenol (0.912 g) in dichloromethane (25 mL) was treated with 1,3-dicyclohexylcarbodiimide (1.23 g). The mixture was stirred at 0°-5° C. for 1 hour, then at room temperature for 1 hour. The usual work up furnished 2.2 g of crude (Z)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester contaminated with the corresponding (E)-isomer, purification of the product by HPLC (dichloromethane-hexane; 3:1) yielded 1.2 g of the (Z)-isomer (Z)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester as an oil.
Reaction SMILES: [NH2:1][C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].C(=O)=O.OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.C(=O)(O)O.[Cl:32][CH2:33][CH2:34][N:35]([N:48]=[O:49])[C:36](=O)[O:37]C1C=CC=CC=1[N+]([O-])=O>C(O)C.O1CCCC1.C1C=CC=CC=1>[C@@H:2]1([NH:1][C:36](=[O:37])[N:35]([CH2:34][CH2:33][Cl:32])[N:48]=[O:49])[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: O=NN(CCCl)C(=O)Oc1ccccc1[N+](=O)[O-]
Reactant: N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C(O)O
Agent: O=C=O
Agent: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CCO
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: O=NN(CCCl)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 86.7 %

Procedure:
1.79 g (10 mmol) of 1-amino-1-deoxy-β-D-glucopyranose is dissolved (partially suspended) in 40 ml of anhydrous ethanol, and the solution is cooled to 0°-5° C. To this solution is added 2.2 g (50 mmol) of dry-ice little by little so as to convert the glucopyranose into its carbonic acid-addition salt. This acid-addition salt solution is then added dropwise to a solution prepared by dissolving 3.28 g (12 mmol) of o-nitrophenyl N-(2-chloroethyl)-N-nitrosocarbamate in a mixture of 40 ml anhydrous tetrahydrofuran and 10 ml benzene, while stirring, at 0°-5° C. over an hour. The resultant mixture is stirred further at 20°-25° C. for 2 hours, and the thus reacted solution is concentrated at 50° C. and below, under reduced pressure. The crystalline residue obtained is washed with anhydrous ethyl ether and then with acetone, dried under reduced pressure, and recrystallized from anhydrous isopropanol to give 2.72 g of 3-(β-D-glucopyranosyl)-1-(2 -chloroethyl)-1-nitrosourea. Yield 86.8%. mp 77°-78° C. (decomp.). [α]D25 -10.3° (C 1.0, water). Analysis for C9H16N3O7Cl (MW 313.69):
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:33])=[C:26]([S:28]([NH:31][CH3:32])(=[O:30])=[O:29])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.C(OCC)(=O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:33][CH2:2][C:3]([N:5]2[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:7][C@H:6]2[CH3:20])=[O:4])=[C:26]([S:28]([NH:31][CH3:32])(=[O:29])=[O:30])[CH:27]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Reactant: CNS(=O)(=O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Yield: 52.5 %

Procedure:
To a solution of (2R, 5S)-2-Chloro-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone (375 mg, 1.26 mmol) in butanone (12 ml) was added 5-Chloro-2-hydroxy-N-methyl-benzenesulfonamide (280 mg, 1.26 mmol), potassium carbonate (348 mg, 2.52 mmol) and potassium iodide (209 mg, 1.26 mmol). The resulting reaction mixture was refluxed for 4 hours. It was allowed to cool, diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the above titled compound (320 mg, 53% yield).
Reaction SMILES: CN(C)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][O:15][CH2:16][C@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[C:27]3[CH:28]=[CH:29][C:30]([O:32]CC4C=CC=CC=4)=[CH:31][C:26]=3[S:25][N:24]=2)[CH2:18]1>ClCCl>[CH3:14][O:15][CH2:16][C@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[C:27]3[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:26]=3[S:25][N:24]=2)[CH2:18]1
Reactant: COC[C@@H]1CN(c2nsc3cc(OCc4ccccc4)ccc23)C(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: COC[C@@H]1CN(c2nsc3cc(O)ccc23)C(=O)O1
Temperature: -8 °C
Yield: 88.1 %

Procedure:
8.7 ml (68 mmol) of dimethylaniline and 6.9 g (0.051 mol) of aluminium chloride are added in three portions over 4 hours to a solution of 2.10 g (5.67 mmol) of (S)-5-methoxymethyl-3-[6-(phenylmethoxy)-1,2-benzisothiazol-3-yl]oxazolidin-2-one in 76 ml of dichloromethane, which solution is cooled at -8° C. The mixture is poured into ice-water and the product is extracted with dichloromethane. The organic phase is dried over sodium sulphate and concentrated under reduced pressure. After purification by chromatography on a silica column with dichloromethane and methanol, in proportions of 99:1, and trituration in diisopropyl ether, 1.4 g of product are obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].FC1C=C(F)C=CC=1C1C=CC(OCC2C=CC=C([N+]([O-])=O)C=2)=CC=1>CC(C)=O>[F:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[CH:25][CH:26]=1
Reactant: Oc1ccc(-c2cc(F)c(F)cc2F)cc1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1cccc(COc2ccc(-c3ccc(F)cc3F)cc2)c1
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Yield: 47 %

Procedure:
1-Bromomethyl-3-nitro-benzene (0.9 g, 4.2 mmol), 2′,4′,5′-trifluoro-biphenyl-4-ol (1.15 g, 4.2 mmol), and dried, finely ground potassium carbonate (725 mg, 5.25 mmol) in 40 mL acetone were refluxed under argon for 19 hrs similar to 2,4-difluoro-4′-(3-nitro-benzyloxy)-biphenyl above. The crude product was purified by flash chromatography with 0-6% ethyl acetate in hexanes to yield 0.71 g (47%) of 2,4,5-trifluoro-4′-(3-nitro-benzyloxy)-biphenyl. LC-MS (ES) calculated for C19H12F3NO3, 359.31; found m/z 358 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]3)[N:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]([NH2:30])([CH3:29])[C:27]#[CH:28]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:30][C:26]([CH3:29])([CH3:25])[C:27]#[C:28][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: C#CC(C)(C)N
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(Br)cc3)n2)CC(C)(C)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(N)C#Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
To a solution of [4-(4-bromo-phenyl)-pyrimidin-2-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (62 mg, 0.16 mmol) (Example 180) in 10 ml triethylamine were added bis(triphenylphosphine)palladium dichloride (22 mg, 0.03 mmol), 1,1-dimethyl-prop-2-ynylamine (166 μl, 1.43 mmol) and CuI (9.5 mg, 0.05 mmol). The mixture was stirred at 95° C. for 16 hours. The reaction mixture was concentrated, the residue taken up in EtOAc and the organic phase was washed with water. The organic layer was dried and concentrated. Purification using preparative HPLC gave the title compound. Yield: 26 mg (42%).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C=C(C2NC3=NC=CC=C3C=2)C2C=CC(S(C)=[O:40])=CC=2)CCCC1.[Mn]([O-])(=O)(=O)=O.[K+]>CO.O>[CH:1]1([CH2:6][CH:7]([C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:16])(=[O:40])=[O:15])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Reactant: CS(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Reaction time: 1.5 h
Yield: 23 %

Procedure:
A solution of the mixture of 2-[2-cyclopentyl-1-(4-methanesulfinyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine and 2-[2-cyclopentyl-1-(4-methanesulfinyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (1.7 g) in methanol (50 mL) at 0° C. was treated dropwise with a solution of potassium permanganate (800 mg, 5.09 mmol) in water (15 mL). The resulting mixture was stirred to 1.5 h. The mixture was then partitioned between water (100 mL) and chloroform (100 mL). The aqueous layer was then extracted with ethyl acetate (2×100 mL). The combined organic layers were then dried over magnesium sulfate, filtered and the filterate concentrated in vacuo. Purification using a Biotage flash chromatography system (40 M column, 50% ethyl acetate/hexanes) afforded 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (420 mg, 23%) as a yellow foam which still contained some impurities. After standing overnight, a white solid had formed and this was then collected by filtration and the solids lightly washed with 10% ethyl acetate/hexanes to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (300 mg) as a white solid: 1H NMR (300 MHz, CDCl3) δ ppm 9.81 (br s, 1H), 8.18 (dd, J=4.8, 1.5 Hz, 1H), 7.86 (d, J=8.2 Hz, 2H), 7.81-7.90 (m, 1H), 7.48 (d, J=8.2 Hz, 2H), 7.05 (dd, J=7.7, 4.8 Hz, 1H), 6.37 (d, J=1.5 Hz, 1H), 4.25 (t, J=7.9 Hz, 1H), 3.02 (s, 3H), 2.19-2.31 (m, 1H), 2.05-2.17 (m, 1H), 1.61-1.88 (m, 5H), 1.41-1.54 (m, 2H), 1.08-1.24 (m, 2H).
Reaction SMILES: [N:1]1[C:14]2[N:8]3[C:9](=[O:13])[NH:10][CH:11]=[CH:12][C:7]3=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:17](Cl)[O:18][CH3:19]>CN(C=O)C>[CH3:17][O:18][CH2:19][N:10]1[CH:11]=[CH:12][C:7]2=[CH:6][C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:14]=3[N:8]2[C:9]1=[O:13]
Reactant: O=c1[nH]ccc2cc3cccnc3n12
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCn1ccc2cc3cccnc3n2c1=O
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
To a cooled (0° C.) solution of 11a (250 mg, 1.4 mmol) in DMF (10 ml), NaH (65 mg, 1.6 mmol) was added. The mixture was stirred for 10 min. and MOMCl (103 μl, 1.4 mmol) was dropwise added. The mixture was stirred at 0° C. for 1 h and quenched with water (1 ml). The solvent was evaporated and the residue dissolved in CH2Cl2. The organic solution was washed with aq. Na2CO3, evaporated and purified by flash column chromatography. Elution with CH2Cl2/MeOH (95/5) gave 12 (267 mg, 87%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]([N:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.CN(C)[CH:36]=[O:37].O>O1CCCC1>[CH2:7]([N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:5]1[CH:21]=[CH:22][C:2]([CH:36]=[O:37])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: O=Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 52.7 %

Procedure:
In an argon atmosphere, the obtained 4-bromo-N,N-dibenzylaniline (425 mg, 1.21 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to −78° C. A 1.6 M n-butyl lithium hexane solution (1.1 mL, 1.8 mmol) was added thereto, and, 5 minutes thereafter, dimethylformamide (0.186 mL, 2.4 mmol) was further added thereto, followed by stirring for 5 minutes. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (9:1 hexane/ethyl acetate) to obtain 4-(dibenzylamino)benzaldehyde (192 mg, 53%).
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])=[CH:12][C:11]=2[N+:22]([O-])=O)[CH2:4][CH2:3]1>CCOC(C)=O.CO.[Pd]>[NH2:22][C:11]1[CH:12]=[C:13]([NH:16][S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])[CH:14]=[CH:15][C:10]=1[NH:9][CH2:8][CH:5]1[CH2:4][CH2:3][C:2]([F:1])([F:25])[CH2:7][CH2:6]1
Reactant: CCS(=O)(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCS(=O)(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c(N)c1
Yield: 103.1 %

Procedure:
N-(4-{[(4,4-Difluorocyclohexyl)methyl]amino}-3-nitrophenyl)ethanesulfonamide (23.4 g) and Pd/C 10% in EtOAc (800 mL) were shaken together overnight under H2 atmosphere (50 PSI) in a Parr hydrogenation apparatus. The reaction mixture was diluted with MeOH (400 mL) and filtered over celite bed. The solvent was removed to provide the desired title product (22.2 g) as beige solid.
Reaction SMILES: [CH:1]1([C:4]([O:6][CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=O)=O)[CH2:3][CH2:2]1.C([NH2:20])(=O)C.B(F)(F)F.CCOCC>O>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[N:20]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[O:6][CH:7]=2)=[CH:11][CH:12]=1
Reactant: O=C(COC(=O)C1CC1)c1ccc(Br)cc1
Reactant: CC(N)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Product: Brc1ccc(-c2coc(C3CC3)n2)cc1
Yield: 64.5 %

Procedure:
To a mixture of 2-(4-bromophenyl)-2-oxoethyl cyclopropane carboxylate (6.00 g, 21.19 mmol) and acetamide (6.60 g, 111.73 mmol) was added BF3/Et2O (4 ml). The mixture was heated to 140C for 2.5 h. Upon cooling, water was added, and the mixture was extracted with Et2O (4×125 ml). The combined organic phases were dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (CH2Cl2/hexanes, 7:3) to provide the title compound as a yellow solid (3.61 g, 64%).
Reaction SMILES: [OH:1][C:2]1([C:12]2[CH:21]=[CH:20][C:15]([C:16]([NH:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.C([O-])(O)=O.[Na+].C(OCC)(=O)C.CCCCCC>C1COCC1.Cl>[OH:1][C:2]1([C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)[CH2:11][CH2:10][C:5](=[O:6])[CH2:4][CH2:3]1
Reactant: CNC(=O)c1ccc(C2(O)CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CNC(=O)c1ccc(C2(O)CCC(=O)CC2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 118.4 %

Procedure:
4-(8-Hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-N-methylbenzamide (410 mg, 1.4 mmol) was dissolved in the mixture solvent of 7 mL of THF and 7 mL of 1 N HCl aqueous solution at room temperature. The reaction mixture was then stirred at 60° C. for 1 h. The solution was cooled down to room temperature, adjusted to pH 7-8 with saturated NaHCO3 aqueous solution. The organic layer was separated, and the aqueous layer was extracted twice with EA (20 mL×2). The combined organic extracts were dried over MgSO4 and evaporated to give an oil residue. Chromatography on silica gel (flash chromatography grade) with 40% Ethyl acetate-hexane gave 410 mg (90%) of the desired product: 1H NMR (CDCl3) δ 7.78 (2 H, d, J=11.2 Hz), 7.51 (2 H, d, J=10.9 Hz), 4.10 (H, s), 3.37 (3 H, s), 2.79-2.74 (2 H, m), 2.63-2.49 (2 H, m), 1.95-1.89 (2 H, m), 1.67-1.59 (2 H, m); MS: 248 (M+1)+.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:33])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)C.[OH-].[K+]>C(O)C.O>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:34])=[O:3])[N:7]=2)=[O:33])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of {2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (prepared in Example 12B-a, 276 mg, 0.58 mmol) in ethanol (20 mL) at 25° C. was treated with a solution of potassium hydroxide (100 mg, 1.78 mmol) in water (6 mL). This light yellow solution was stirred at 25° C. for 2 h and then concentrated in vacuo to remove ethanol. The resulting aqueous solution was acidified to pH=2 with a 1N aqueous hydrochloric acid solution and then extracted with methylene chloride (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 10/90 hexanes/ethyl acetate plus 1% acetic acid) afforded {2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid (222 mg, 80%) as a white foam: FAB-HRMS m/e calcd for C25H26N2O4S (M+H)+ 451.1691, found 451.1686.
Reaction SMILES: [CH:1]1([Li:6])[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl[P:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10].C([Li])CCC.CCCCCC>CCOCC>[CH:9]([P:8]([C:1]1([Li:6])[CH:5]=[CH:4][CH:3]=[CH:2]1)[CH:12]([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)P(Cl)C(C)C
Reactant: [Li]C1C=CC=C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: [Li]C1(P(C(C)C)C(C)C)C=CC=C1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
50 ml of ether were placed in a round-bottomed flask containing 1.68 g (0.023 moles) of cyclopentadienyllithium. After cooling of the reaction flask to −20° C., 3.6 g (0.023 moles) of chlorodiisopropylphosphine were added dropwise. When the addition was complete, the cooling bath was heated to 0° C. and the reaction mixture was stirred for 1 h. Ether was then removed under vacuum, the product was dissolved in toluene and the solution was filtered. After the frit had been rinsed with 2×10 ml of toluene, the reaction mixture was cooled to −20° C. and 9.3 ml of a 2.5 molar solution of butyllithium in hexane (0.023 moles) were added to form an orange coloured solution. A small fraction was taken for NMR studies and, after separation of the toluene under vacuum and washing of the resulting oil with hexane, a pale yellow solid (18) was obtained. 1H NMR (400 MHz, THF): δ=5.89 (m, 2H); 5.83 (bs, 2H); 1.86 (m, 2H); 1.0-0.8 (m, 12H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]2[N:43]=[CH:44][N:45]([C:47]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:46]=2)=[CH:32][CH:31]=1>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]3[N:43]=[CH:44][N:45]([C:47]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[CH:46]=3)=[CH:34][CH:35]=2)[C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccc(-c2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)cc2)C1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 1, Step I) and 4-bromomethyl-2'-[1-(triphenylmethyl)imidazol-4-yl]-1,1'-biphenyl by the procedure described in Example 2, Step E.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:6]=1[CH3:12])(=[O:3])[CH3:2].[C:13](=O)([O-])[O-].[K+].[K+].CI.C1(C)C=CC=CC=1>C(#N)C.O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:13])[C:6]=1[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(O)c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC#N
Product: COc1cccc(OC(C)=O)c1C
Temperature: 90 °C
Reaction time: 1.6 h
Yield: 86.8 %

Procedure:
A solution of 5.01 g (30.0 mmol) of 2-acetoxy-6-hydroxytoluene in 50 mL of acetonitrile was added with 12.44 g (90.0 mmol) of potassium carbonate and 12.77 g (90.0 mmol) of methyl iodide and heated and stirred on a 90° C. oil bath for 96 minutes. The reaction mixture which had been allowed to stand at room temperature for about 3 hours was added to a mixture of 100 mL of toluene and 100 mL of water stirred on an ice-water bath, and after stirred for two minutes, transferred to a separatory funnel and then settled. The aqueous layer was separated and discarded and after the organic layer was washed with 20 mL of 1 N aqueous sodium hydroxide and 20 mL of water three times, and the solvent was evaporated to obtain 4.69 g of title compound.