Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:46])[CH2:32][N:31](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:30]2)=[C:25]([F:47])[CH:24]=1)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>C1C=CC=CC=1>[C:2]([N:31]1[CH2:32][C:29]([C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[CH:24][C:25]=2[F:47])([OH:46])[CH2:30]1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=C(Nc1ccc(C2(O)CN(C(c3ccccc3)c3ccccc3)C2)c(F)c1)OCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccccc1
Product: O=C(Nc1ccc(C2(O)CN(C(=O)OCc3ccccc3)C2)c(F)c1)OCc1ccccc1

Procedure:
Benzyl chloroformate (3.8 mL, 26.6 mmol) was added to a solution of 3-(N-carbobenzyloxy-3-fluoroanilin-4-yl)-3-hydroxy-1-(1, 1-diphenylmethyl)azetidine (Example 81, Step 2, 1.60 g, 3.32 mmol) in benzene (30 mL) and then heated under reflux under nitrogen for 2 hr. The benzene was evaporated and the residue chromatographed over silica gel (150 g, 40-60 μm) eluting with 20-60% ethyl acetate-hexane. The title compound was obtained as a white foam. 1H NMR δ (CDCl3): 3.32, 4.19, 4.42, 5.08, 5.17, 6.98, 7.11, 7.19, 7.24-7.43.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[F:8][C:9]([F:20])([F:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[C:17]=[S:18].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([F:8])([F:19])[F:20])[C:17]1=[S:18])[CH3:2]
Reactant: CCNCC(=O)O
Reactant: FC(F)(F)c1ccccc1N=C=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2ccccc2C(F)(F)F)C1=S
Yield: 18.7 %

Procedure:
The tide compound was prepared by the procedure described in Example 4 using 9.2 g of N-ethyl glycine, 10.2 g of 2-(trifluoromethyl)-phenyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. The residue was further purified by flash chromatography on silica gel (methylene chloride). Crystallization from ethanol afforded the title compound (2.7 g), m.p. 82°-85° C. Anal. Calcd. for. C12H11F3N2O S: C, 50.00; H, 3.85; N,9.72. Found: C, 50.00; H, 3.61; N, 9.61. Mass spectrum (EI, M.+) m/z 288.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH3:22][C:23]([CH3:26])([O-])[CH3:24].[K+]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][C:23]([CH3:26])([CH3:24])[CH3:22])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: CC(C)(C)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cccc(Cl)n1
Reaction time: 3 h
Yield: 45.9 %

Procedure:
6-Chloropyridine-2-carboxylic acid (5.00 g, 31.7 mmol) was dissolved in DCM (150 mL) and oxalyl chloride (5.45 mL, 63.5 mmol) and DMF (1 mL) were added. The reaction mixture was stirred for 3 h, concentrated in vacuo and azeotroped with DCM. The residue was dissolved in THF (150 mL) and potassium tert-butoxide (3.39 mg, 47.6 mmol) was added. The reaction mixture was stirred for 18 h, quenched with water (250 mL) and extracted with DCM (3×150 mL). The combined organic fractions were washed with sat aq NaHCO3 (150 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (3.11 g, 46%) as a white solid. LCMS (ES+): 236.1 [MNa]+.
Reaction SMILES: Cl[C:2]1(Cl)[CH2:5][C:4](=[O:6])[CH2:3]1.CC(O)=O.O.[CH:13]([OH:16])([CH3:15])[CH3:14].O>[Zn]>[C:4]1(=[O:6])[CH2:3][CH2:2][CH2:5][CH2:15][C:13](=[O:16])[CH2:14]1
Reactant: O=C1CC(Cl)(Cl)C1
Reactant: CC(C)O
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCCC(=O)C1
Reaction time: 1 h

Procedure:
Dichlorocyclobutanone 3 (128 g, 0.48 mol) was dissolved in 520 mL of 1:1 isopropanol-water in a 2 L, 3-neck flask with an overhead stirrer. Zinc granules (126 g, 1.9 mol, −30+100 mesh) were added in one portion. After 60 min at room temperature, 130 mL of AcOH plus 260 mL of water were added dropwise via addition funnel (ca. 4 mL are added initially, followed by a 10 min hold to check for exotherms; 20 ml were then added, followed by another 10 min hold; once any exotherm has abated, the remaining acid solution was added dropwise; the entire addition takes 1.5-2 h). After 16 h, the mixture was transferred to a separatory funnel, decanting away from most of the zinc (several small isopropanol rinses were used). The isopropanol-AcOH-water mixture was then extracted with 5 portions of toluene (250 mL each), which are combined and concentrated to provide 51.7 g of product as a dark, orange-brown oil (85% crude mass balance, ca. 85% pure by 1H nmr). This material is suitable for subsequent reactions, or can be purified by distillation, which provided 29.4 g (0.23 mol, 49% yield) of product as a clear, colorless oil (b.p. 65-75° C. at 1.2 mm). It's spectral properties (1H nmr, GC/MS) were identical to samples prepared by the oxymercurafion route of Chandrasekaran (Synthetic Communications 1984, 14, 339-345).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]34[CH2:20][CH2:19][C:16]([C:21]5O[C:23]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=6[C:32]([F:35])([F:34])[F:33])=[N:24][N:25]=5)([CH2:17][CH2:18]3)[CH2:15][CH2:14]4)[O:10][N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH3:43][NH2:44]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]34[CH2:14][CH2:15][C:16]([C:21]5[N:44]([CH3:43])[C:23]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=6[C:32]([F:34])([F:35])[F:33])=[N:24][N:25]=5)([CH2:19][CH2:20]3)[CH2:17][CH2:18]4)[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2noc(C34CCC(c5nnc(-c6ccccc6C(F)(F)F)o5)(CC3)CC4)n2)cc1
Reactant: CN
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(c3nc(-c4ccc(F)cc4)no3)(CC1)CC2

Procedure:
A mixture of above 1,2,4-oxadiazole (7-E) (115.2 mg, 0.238 mmol) and the trifluoroacetic acid salt of methylamine (1.73 g, 11.9 mmol) in a 2M solution of methylamine in methanol (4 mL) was heated at 150° C. in a sealed tube for 48 h. The mixture was then concentrated, and the residue was taken up in dichloromethane, washed with saturated sodium bicarbonate aqueous solution. The organics were concentrated and the residue was purified using reverse-phase HPLC with TFA-buffered acetonitrile/water (40-80%) as eluent. The fractions containing the product were combined, neutralized with saturated sodium bicarbonate aqueous solution and lyophilized from acetonitrile/water to provide 3-(4-fluorophenyl)-5-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole (7-F). 1HNMR (CDCl3) δ 2.25-2.35 (m, 12H), 3.53 (s, 3H), 7.21 (t, J=8.7 Hz, 2H), 7.54 (m, 1H), 7.73 (m, 2H), 7.88 (m, 1H), 8.13 (m, 2H). ESI-MS m/z (M+H) 498.2.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][CH:8]=[CH:7][C:6]1=O)[CH2:2][CH2:3][CH3:4].CC[O:14]CC>>[CH2:1]([C@@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:14])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOCC
Reactant: CCCCC1CCC=CC1=O
Product: CCCC[C@@H]1CCCC(=O)C1
Yield: 75 %

Procedure:
Prepared according to the general procedure from 3-butylcyclohexen-2-one (168 mg, 1.09 mmol) in 0.2 M Et2O for 43 h at room temperature to provide the title compound as a colorless oil (128.3 mg, 75% yield, 88% ee) after purification by flash chromatography on silica gel (5% Et2O/pentane). The physical data were identical in all respects to those previously reported (Jones et al. (1998). Tetrahedron 54:1471; and Moritani et al. (2000), J. Am. Chem. Soc. 122:6797 (reported a rotation of −17° for the (S)-enantiomer that is 87% ee)). The enantiomeric ratio was determined by GLC using a Hydrodex-B-TBDAc (50 m×0.25 mm) column (150° C. isotherm, 1 mL/min.); (S) isomer tr=37.0 min. and (R) isomer tr=36.0 min. [α]D22=+15.5° (c=1.00, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]2[C:10](Cl)=[CH:9][C:8]([CH2:12][CH3:13])=[N:7][C:6]=12.[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH:29][CH3:30])=[CH:24][CH:23]=1)#[N:15]>C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([N:29]([CH2:28][C:25]3[CH:26]=[CH:27][C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:14]#[N:15])=[CH:23][CH:24]=3)[CH3:30])=[CH:9][C:8]([CH2:12][CH3:13])=[N:7][C:6]=12
Reactant: CNCc1ccc(-c2ccccc2C#N)cc1
Reactant: CCc1cc(Cl)n2ncc(Cl)c2n1
Solvent: CCO
Product: CCc1cc(N(C)Cc2ccc(-c3ccccc3C#N)cc2)n2ncc(Cl)c2n1

Procedure:
3.1 g (14.4 mmol) of the chloro compound (Example 3, Step A) and 3.2 g (14.4 mmol) of the amine (Example 1, Step C) were heated in 75 ml ethanol according to Example 4, Step C. The title compound was obtained as an oil after chromatography (silica gel; dichloromethane with ascending polarity by addition of up to 3% ethanol).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([NH:12][NH2:13])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)[C:18](=O)[CH3:19].C(Cl)(=O)C>O>[CH3:18][C:19]1[O:11][C:10]([CH2:9][O:8][C:7]2[CH:14]=[CH:15][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:12][N:13]=1
Reactant: CC(=O)N(C)C
Reactant: NNC(=O)COc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)Cl
Solvent: O
Product: Cc1nnc(COc2ccc([N+](=O)[O-])cc2)o1
Reaction time: 2 h
Yield: 56 %

Procedure:
To a mixture of 2-(4-nitrophenoxy)acetohydrazide (1.57 g) and N,N-dimethylacetamide (50 mL) was added dropwise acetyl chloride (0.70 g) at room temperature. The reaction mixture was stirred for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. A mixture of the obtained residue, diphosphorus pentaoxide (1.76 g), hexamethyldisiloxane (4.03 g) and 1,2-dichlorobenzene (10 mL) was stirred at 140° C. for 3 hrs. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-methyl-5-[(4-nitrophenoxy)methyl]-1,3,4-oxadiazole as colorless crystals (0.41 g, yield 56%) from a fraction eluted with hexane-ethyl acetate (3:2-1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 105-106° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@H:4]([CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)[NH2:5].[OH:20][N:21]=[C:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23](O)=[O:24].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[CH3:1][O:2][C:3](=[O:19])[C@H:4]([CH2:6][C:7]1[CH:8]=[C:9]([O:17][CH3:18])[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=1)[NH:5][C:23](=[O:24])[C:22](=[N:21][OH:20])[CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)CC(=NO)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1cc(OC)c(OC)c(OC)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1cc(OC)c(OC)c(OC)c1)NC(=O)C(CC(C)C)=NO
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
To a solution of 34.47 g of 3,4,5-trimethoxyphenylalanine methyl ester, 18.87 g of α-hydroxyiminoisocaproic acid, 14.96 g of N-hydroxysuccinimide in 1 liter of dioxane, was added 26.82 g of N,N'-dicyclohexylcarbodiimide, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was filtrated, and the filtrate was subjected to distillation to remove the solvent. The resulting residue was purified by means of a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:2) to obtain 42.70 g of N-(2-hydroxyimino-4-methylpentanoyl)-(3,4,5-trimethoxy)phenylalanine methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2/[CH:26]=[CH:14]/[C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Product: COc1cc(C(=O)/C=C/c2c[nH]c3ccc(Cl)cc23)cc(OC)c1OC
Yield: 79.2 %

Procedure:
Substantially the same procedure as in Example 12 was repeated using 3',4',5'-trimethoxyacetophenone (2.1 g) and 5-chloroindole-3-carboxaldehyde (1.8 g) to give Compound 30 (2.94 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][CH2:19][O:20][CH2:21][CH:22]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C3=CCOCC3)cc2C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2ccc(C3CCOCC3)cc2C1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a stirred solution 7.27 mmol 5-(3,6-dihydro-2H-pyran-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester in 60 ml methanol were added 1.60 g 10% palladium on charcoal and 72.7 mmol ammonium formate and the mixture was heated at reflux for 30 min. The reaction mixture was then cooled to room temperature, filtered, and the filtrate concentrated in vacuo. The residue was taken up in THF and washed with brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid (92% yield). MS (m/e): 248.3 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C@H:8]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@H:18]([CH3:23])[O:17][C@@H:9]2[S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([O:21][C@@H:20]2[C@H:19]([O:22][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][CH:29]=3)[C@H:18]([CH3:23])[O:17][C@H:9]([S:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:8]2[O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:25][CH:24]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: Cc1ccc(CO[C@H]2[C@H](O)[C@H](O)[C@H](C)O[C@@H]2Sc2ccccc2)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: Cc1ccc(CO[C@H]2[C@H](OC(=O)c3ccc(Cl)cc3)[C@H](OC(=O)c3ccc(Cl)cc3)[C@H](C)O[C@@H]2Sc2ccccc2)cc1

Procedure:
Starting from compound of example 17 (30 g) and using 4-chlorobenzoyl chloride (26.7 ml) the title compound is obtained according to the methodology described in example 18: 50.3 g of yellow syrup.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:30])([F:29])[C:13]2[N:18]=[CH:17][C:16]([CH2:19][O:20][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=3)=[CH:15][CH:14]=2)[CH2:11][O:10]1.[NH:31]1[CH:35]=[N:34][N:33]=[N:32]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:11][N:31]1[CH:35]=[N:34][N:33]=[N:32]1)[C:12]([C:13]1[N:18]=[CH:17][C:16]([CH2:19][O:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=2)=[CH:15][CH:14]=1)([F:29])[F:30]
Reactant: N#Cc1ccc(OCc2ccc(C(F)(F)C3(c4ccc(F)cc4F)CO3)nc2)nc1
Reactant: c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)nc1
Temperature: 55 °C
Reaction time: 36 h

Procedure:
To a magnetically stirred mixture of 6-((6-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-yl)methoxy)nicotinonitrile (BZ; 200 mg, 0.482 mmol) and 1H-tetrazole (67.5 mg, 0.963 mmol) in dry DMF (4.815 mL) was added K2CO3 (133 mg, 0.963 mmol) in a dry 25 mL vial under N2 atmosphere. The reaction mixture was stirred at 55° C. for 36 hours, then cooled to RT, and diluted with ice-water and ether. The layers were separated and the aq. layer was extracted again with ether (2×). The combined ether extracts were dried over sodium sulfate, filtered, and evaporated. The crude residue was purified on silica (40 gram column, gradient over 15 min to 40% EA/Hex, hold 10 min then 10 min at 80% EA/hex, monitor 240 and 254 nm). The respective product fractions were evaporated to afford the title compound contaminated with DMF. The material was diluted with water and extracted 3× with ether, the combined ether extracts were diluted with pet. ether and washed with sat'd NH4Cl (2×) and brine (1×), dried over MgSO4, filtered, and evaporated to afford 98. Yield=62 mg (25.2%) of a white foam. 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.63 (d, J=1.3 Hz, 1H), 8.48 (dd, J=2.3, 0.8 Hz, 1H), 7.91 (dd, J=8.2, 2.1 Hz, 1H), 7.85 (dd, J=8.7, 2.4 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.35 (td, J=9.0, 6.5 Hz, 1H), 6.92 (dd, J=8.5, 0.8 Hz, 1H), 6.76 (ddd, J=12.0, 8.5, 2.5 Hz, 1H), 6.71-6.61 (m, 1H), 5.56 (d, J=14.3 Hz, 1H), 5.50 (s, 2H), 5.13 (dd, J=14.2, 1.1 Hz, 1H). 1H-decoupled 19F NMR (376 MHz, CDCl3) δ −103.83 (ddd, J=42.2, 17.0, 10.2 Hz), −104.20 (d, J=16.3 Hz), −104.89 (d, J=16.3 Hz), −107.90-108.07 (m), −110.92 (dd, J=262.9, 42.2 Hz). MS (ESI): m/z 486.1 (M+H)+.
Reaction SMILES: C([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:19][CH3:20])[C:13]([S:15]([Cl:18])(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=O)C.Cl.[CH3:22][NH2:23]>>[ClH:18].[CH3:20][O:19][C:12]1[C:13]([S:15](=[O:17])(=[O:16])[NH:23][CH3:22])=[CH:14][C:7]2[CH2:6][CH2:5][NH:4][CH2:10][CH2:9][C:8]=2[CH:11]=1
Reactant: CN
Reactant: COc1cc2c(cc1S(=O)(=O)Cl)CCN(C(C)=O)CC2
Agent: Cl
Product: CNS(=O)(=O)c1cc2c(cc1OC)CCNCC2

Procedure:
3-Acetyl-7-chlorosulfonyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (2 g) was stirred with 10 ml of 40% aqueous methylamine, then was treated with hydrochloric acid and concentrated in vacuo to give 8-methoxy-7-(N-methylsulfamoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. This 8-methoxy-7-(N-methylsulfamoyl) compound was treated with boron tribromide in methylene chloride and then with methanol to give 8-hydroxy-7-(N-methylsulfamoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. 130°-135° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1C1CCCCC=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29](B(O)O)[CH:28]=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:29]1[CH:28]=[N:27][C:36]2[C:31]([CH:30]=1)=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: Cc1cc2ccccc2c(C2=CCCCC2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2ccccc2c(-c2cnc3ccccc3c2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(3-methyl-1-(quinolin-3-yl)naphthalen-2-yl)acetic acid (16) was prepared following the procedure to make (S)-2-tert-butoxy-2-(1-cyclohexenyl-3-methylnaphthalen-2-yl)acetic acid of Example 6, using quinolin-3-ylboronic acid instead of cyclohexenylboronic acid. The compound is an atropisomer mixture. 1H-NMR: 400 MHz, (CD3OD) δ: 9.20-8.50 (m, 2H), 8.18 (m, 1H), 8.08 (m, 1H), 7.95 (m, 1H), 7.80 (m, 3H), 7.40 (t. 1H), 7.25 (t, 1H), 7.06 (m, 1H), 5.19 (s, 1H), 2.62 (d, 3H), 0.95, 0.86 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C26H26NO3: 400.48. found: 400.2.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH2:12][CH2:13][F:14])[CH2:7][NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>C(#N)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH2:12][CH2:13][F:14])[CH2:7][N:8]([C:27]([NH:26][CH2:24][CH3:25])=[O:28])[S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1
Reactant: O=S1(=O)NCN(CCF)c2ccc(Cl)cc21
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCNC(=O)N1CN(CCF)c2ccc(Cl)cc2S1(=O)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 500 mg of the compound of Example 1 dissolved in 2.5 ml of acetonitrile there are added 0.5 ml of triethylamine and 2.5 ml of ethyl isocyanate. The reaction mixture is stirred at ambient temperature for 5 hours. The solvent is then removed under reduced pressure. The residue is taken up in 10 ml of acetone; charcoal is added to the resulting solution, which is then filtered; water is then added to the filtrate. The precipitate obtained is collected by filtration, washed with water and dried.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:25]=3[CH3:35])=[CH:18][CH:17]=2)[CH:10]=1)(=O)=O.[NH:43]1[CH2:53][CH2:52][CH2:51][CH2:50][CH:44]1[C:45]([O:47][CH2:48][CH3:49])=[O:46]>CN(C=O)C.C(OCC)(=O)C>[CH2:36]([N:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][CH2:6][N:43]2[CH2:53][CH2:52][CH2:51][CH2:50][CH:44]2[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:21][CH:20]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:25]=1[CH3:35])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCOC(=O)C1CCCCN1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCOS(C)(=O)=O)c2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCCN1CCOc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)c1
Temperature: 80 °C

Procedure:
The product from Example 92C (0.057 g, 0.0934 mmoles) in anhydrous DMF (1.0 mL) was treated with ethyl pipecolinate (0.072 mL, 0.467 mmoles) and heated at 80° C. overnight. The reaction was diluted with ethyl acetate, washed with H2O (2×), brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[C:12](Cl)=[N:13][C:14]([CH3:17])=[N:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]([O:23][CH3:24])(=[O:22])[CH2:20][OH:21]>O1CCCC1>[CH2:3]([O:10][C:11]1[C:12]([O:21][CH2:20][C:19]([O:23][CH3:24])=[O:22])=[N:13][C:14]([CH3:17])=[N:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CO
Reactant: Cc1ncc(OCc2ccccc2)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COc1nc(C)ncc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
68 mg of sodium hydride was added to a mixture of 0.4 g of 5-benzyloxy-4-chloro-2-methylpyrimidine, 0.17 g of methyl glycolate and 3.4 ml of tetrahydrofuran at 0° C. The mixture was stirred at room temperature for 1 hour, then, the reaction solution was stirred for 30 minutes at 90° C. 18 mg of methyl glycolate was additionally added to this, and the mixture was stirred for 30 minutes at 90° C. The reaction solution was cooled to room temperature, then, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.21 g of 5-benzyloxy-4-(methoxycarbonyl)methoxy-2-methylpyrimidine.
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[F:10][CH:11]([C:17]([CH3:19])=O)[C:12](OCC)=[O:13].S(=O)(=O)(O)O.O>O1CCOCC1>[F:10][C:11]1[C:12](=[O:13])[O:4][C:3]2[C:5]([C:17]=1[CH3:19])=[CH:6][CH:7]=[C:8]([OH:9])[C:2]=2[CH3:1]
Reactant: Cc1c(O)cccc1O
Reactant: CCOC(=O)C(F)C(C)=O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(F)c(=O)oc2c(C)c(O)ccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A solution of 2-methylresorcinol (3.23 g, 26.02 mmoles), ethyl 2-fluoro-acetoacetate [E. B. Banks, N. J. Lawrence, A. L. Popplewell, J. Chem. Soc., Chem. Commun, 343 (1994)] (3.85 g, 25.99 mmoles) in 0.5 mL of 1,4-dioxane was added dropwise, at 0° C. and under an inert atmosphere, to 25 mL of concentrated sulfuric acid. The reaction mixture was stirred for 1.5 hours, while the temperature was increased to 25° C. Cold water (100 mL) was added, the reaction mixture was stirred for 15 minutes and the resulting precipitate was collected by suction filtration, dried in vacuo, affording 4.56 g (84% yield) of 3-fluoro-4,8-dimethyl-7-hydroxycoumarin as a white solid. An analytical sample was obtained by recrystallisation from methanol:water: mp 260° C. (decomp.).