Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9](Cl)(Cl)=[S:10].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]=[C:9]=[S:10]
Reactant: Nc1ccccc1F
Reactant: S=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Fc1ccccc1N=C=S
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
Into a solution of 2-fluoroaniline (1.0 g, 9.0 mmol) in 30 mL of toluene at room temperature, thiophosgene (1.06 mL, 13.5 mmol) and triethylamine (1.55 mL, 13.5 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The combined organic layer was then concentrated to give the desired product (1.05 g, 76%). 1H NMR (CDCl3) δ 7.1-7.3 (m, 4H).
Reaction SMILES: [C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3([CH2:27][OH:28])[CH2:26][CH2:25]3)[O:15][N:14]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3([CH2:27][O:28][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:26][CH2:25]3)[O:15][N:14]=2)=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2noc(C3(CO)CC3)c2-c2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2noc(C3(COS(C)(=O)=O)CC3)c2-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture consisting of (1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropyl)-methanol (Example 1, Compound E, 2.0 g) in dichloromethane (30 mL) is added sequentially pyridine (0.60 mL), methanesulfonyl chloride (0.55 mL), and 4-dimethylaminopyridine (0.06 g) at 0° C. under a nitrogen atmosphere. The mixture is stirred at 0° C. for 30 minutes and is warmed to room temperature. The mixture is stirred at room temperature for four hours and is then diluted with dichloromethane (30 mL.) The mixture is washed 0.5 N hydrochloric acid solution and with brine solution. The organic layer is separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate is purified by flash silica gel column chromatography to afford the synthetic intermediate methanesulfonic acid 1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropylmethyl ester (2.35 g.)
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:21][C:22]1[CH:28]=[C:27]([I:29])[CH:26]=[CH:25][C:23]=1[NH2:24]>O1CCCC1>[Cl:21][C:22]1[CH:28]=[C:27]([I:29])[CH:26]=[CH:25][C:23]=1[NH:24][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccncc1F
Reactant: Nc1ccc(I)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccncc1Nc1ccc(I)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To suspension of 3-fluoroisonicotinic acid (2.00 g, 14.17 mmol, in tetrahydrofuran (50 ml) at −78° C. was added lithium bis(trimethylsilyl)amide (14.3 ml, 17.01 mmol). The dark colored suspension was stirred for 15 min. In another flask, to a solution of 2-chloro-4-iodoaniline (4.7 g, 18.43 mmol) in THF (50 ml) was added lithium bis(trimethylsilyl)amide (24.9 ml, 29.77 mmol) at −78° C. under N2. The resulting green colored solution was stirred for 15 min. To this green colored solution the lithiated acid solution was added. The cold bath was removed, allowed to warm to room temperature, and stirred overnight. The mixture was filtered, and the crude was diluted with EtOAc (400 ml). It was then washed with dilute HCl (25 ml), H2O (25 ml), and dried. During concentration of the solvent, 3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid was separated out as an yellow solid. (1.3 g, 24%)
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][C@H:24]([NH:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH2:23]3)O1>C1COCC1>[F:9][C:8]([F:11])([F:10])[C:5]1[O:4][C:3]([CH2:2][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][C@H:24]([NH:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:31])=[O:32])[CH2:23]3)=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Cc3ccc(C(F)(F)F)o3)cc2C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
2-(bromomethyl)-5-(trifluoromethyl)furan (0.123 mmol, 28.2 mg), (S)—N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (0.123 mmol, 45 mg) and Bromo(N-succinimidyl)bis-(triphenylphosphine)palladium(II) (6.16 μmol, 4.98 mg) were suspended in THF (1 mL) and 2M NaCO3 (0.5 mL) added. The mixture was heated to 100° C. for 10 min. After this time the reaction mixture was irradiated for a further 20 min at 100° C. before standing overnight. The mixture was concentrated to remove THF before partitioning between DCM/H2O. The organic layer was collected and dried using a hydrophobic filter tube. Concentration and purification on basic HPLC gave the title compound (7.5 mg, 0.019 mmol, 15.7%). MS (ESI): m/z [M−H]− 386.3.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=3)[CH2:21][CH2:22]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: c1ccc(CN2CCNCC2)nc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(Cc3ccccn3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (9 ml) was added 1-[(2-pyridyl)-methyl]-piperazine (0.097 g, 0.55 mmol) followed by diisopropylethylamine (0.10 ml, 0.57 mmol). The reaction mixture was heated at 45° C. for 20 h, then allowed to cool to room temperature. The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.163 g, 83%); 1H-NMR (500 MHz, DMSO-d6) 2.57 (br s, 4H, piperazine N(CH2)2), 3.08 (br s, 4H, piperazine N(CH2)2), 3.65 (s, 2H, NCH2), 6.97 (s, 2H, NH2), 7.26 (ddd, J=7.45, 4.80, 1.00 Hz, 1H), 7.46 (d, J=7.80 Hz, 1H), 7.77 (td, J=7.66, 1.80 Hz, 1H) and 8.48 (dm, J=4.09 Hz, 1H) (pyrid-2-yl protons), 8.16 (s, 1H, 6-H);
Reaction SMILES: [Br:1][C:2]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[B-](F)(F)(F)[F:33].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O>C(#N)C>[Br:1][C:2]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[C:17]=3[F:33])[N:9]=[C:4]2[CH:3]=1
Reactant: COc1cc(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Product: COc1cc(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)c(F)c(OC)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (25.0 mg, 0.0498 mmol) and 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (17.6 mg, 0.0498 mmol) in acetonitrile (0.3 mL)/water (0.06 mL) was stirred at 50° C. overnight. The solvent was removed and the residue was used in the next step w/o purification. LCMS calculated for C22H20BrFN3O4S (M+H)+: m/z=520.0. Found 520.0.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4].[C:19]([O:22][CH2:23][CH2:24][CH2:25]Br)(=[O:21])[CH3:20]>>[CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[CH:16]=[CH:15][C:14]([O:17][CH2:25][CH2:24][CH2:23][O:22][C:19](=[O:21])[CH3:20])=[CH:13][C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)OCCCBr
Reactant: CCCCOc1c(O)c2cc(O)ccc2oc1=O
Product: CCCCOc1c(O)c2cc(OCCCOC(C)=O)ccc2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-butoxy-4,6-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 3-bromopropyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-butoxy-4-hydroxy-6-(3-acetoxypropoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([OH:19])[CH2:13][CH2:14][C:15]([O:17]C)=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].CC1C=CC(S(O)(=O)=O)=CC=1.O>C(Cl)Cl>[O:17]=[C:15]1[O:19][C@H:12]([C:9]2[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=2)[CH2:13][CH2:14]1
Reactant: COC(=O)CC[C@H](O)c1ccc(NS(C)(=O)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)Nc1ccc([C@@H]2CCC(=O)O2)cc1
Temperature: 0 °C
Yield: 76.1 %

Procedure:
Methyl (γS)-4-[(methylsulfonyl) amino]-γ-hydroxybenzenebutanoate (17.9 g, 62.3 mmol) from Preparation 2 was placed in a flask with 350 ml of CH2Cl2 and the resulting slurry was cooled to 0° C. To this mixture was added 0.12 g of p-TsOH•H2O (1.5 mol %). The reaction was monitored for completion by HPLC until NMT 2% hydroxy ester remained (expect 4-6 h). The reaction mixture was washed with H2O (2×250 ml) and brine (250 ml) while maintaining the temperature at 0° C. The pH of the final wash must be maintained at GT 5). The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The resulting solids were recrystallized from EtOAc (25 ml) to provide 12.1 g (76% yield) of the title compound as white solids (95 area %, 97% ee). Melting point 101-102° C. 1H NMR (400 MHz, CDCl3) δ 7.24 (dt, J=8.0, 8.6 Hz, 4H), 5.43 (m, 1H), 2.97 (s, 3H), 2.63 (m, 3H), 2.14 (m, 1H); 13C NMR (100 MHz, CDCl3) δ C 177.0, 137.2, 136.0; CH 126.8, 120.7, 80.9; CH2 30.7, 29.0; CH3 39.4; MS m/z calcd for C11H13NO4S, 255.056 (M+); found 254.95 (M+).
Reaction SMILES: C([O:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:10]=1[NH2:11])C1C=CC=CC=1>[Pd].CO>[NH2:11][C:10]1[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:9]=1[OH:8]
Reactant: Nc1c(F)cccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1c(O)cccc1F
Yield: 99.2 %

Procedure:
2-(Benzyloxy)-6-fluoroaniline (Step 2, 5.00 g, 0.0230 mol) and 10% palladium on carbon (0.5 g) in methanol (100 ml) are stirred under a hydrogen atmosphere (balloon) for 2 h. The catalyst is removed by filtration through a pad of celite and the filtrate concentrated to give pure product as a tan solid (2.9 g, 99%); mp 125-6° C.
Reaction SMILES: C(OC([O:11][C:12]1([CH2:47][CH3:48])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:46])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:41])([CH3:40])[CH2:33][CH2:34][CH2:35][O:36][C:37](=[O:39])[CH3:38])=[C:23]2[CH:42]=[CH:43][CH:44]=[CH:45][C:22]2=[N:21][C:20]3=1)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:47]([C:12]1([OH:11])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:46])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:40])([CH3:41])[CH2:33][CH2:34][CH2:35][O:36][C:37](=[O:39])[CH3:38])=[C:23]2[CH:42]=[CH:43][CH:44]=[CH:45][C:22]2=[N:21][C:20]3=1)[CH3:48]
Reactant: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(C)=O

Procedure:
A mixture of Compound 59 (180 mg, 0.27 mmol), 10% palladium on carbon (36 mg, 20%) in 6 mL of ethanol was hydrogenated for 18 hours at a balloon pressure of hydrogen at 21° C. The catalyst was removed by filtration over celite and the filtrate was evaporated to give a crude product, which was chromatographed to give the desired product.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH:19][CH2:20][CH:21]([CH2:23]O)[OH:22].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CCOC(C)=O.CCCCCC>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:23][CH:21]([CH2:20][OH:19])[OH:22])=[O:17])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: OCC(O)CO
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(O)CO
Reaction time: 8 h

Procedure:
CBz-L-valine (4.35 g, 17.3 mmol) was added to a fivefold excess of glycerol (8 ml, 86.9 mmol) together with dicyclohexylcarbodiimide (4.29 g 20.8 mmol) and 4-dimethylaminopyridine (0.212 g) at room temperature. After stirring overnight the suspension was filtered and DMF removed in vacuo from the filtrate. The residue was redissolved in CH2Cl2, washed successively with saturated NaHCO3, brine, and water and then dried. The crude material was chromatographed on silica gel with 4/1 EtOAc-hexane as eluent to yield 2.465 g. Rf (4/1 EtOAc-hexane) 0.17, (20/1 CH2C2-methanol) 0.12.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1F)[C:29]#[N:30].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:8][C:6]1[CH:5]=[CH:4][C:3]([CH:9]([CH3:24])[C:10]([OH:15])([C:16]2[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=2)[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=1)[C:29]#[N:30]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: N#Cc1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(c1ccc(Oc2ccc(C#N)cc2Cl)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 197, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 196) was reacted with 3-chloro-4-fluorobenzonitrile and cesium carbonate to give the title compound as a colorless solid. MS (m/e)=497.3 [M+H+].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[CH:11][C:10]2[N:9]=[CH:8][C:7]3[N:13]=[N:14][N:15]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[C:6]=3[C:5]=2[N:4]=1.[C:22]([O:25][C@@H:26]([CH3:30])[C:27](Cl)=[O:28])(=[O:24])[CH3:23].CCN(CC)CC>C(Cl)Cl>[C:22]([O:25][C@@H:26]([CH3:30])[C:27]([N:19]1[CH2:20][CH2:21][CH:16]([N:15]2[C:6]3[C:5]4[N:4]=[C:3]([Cl:2])[CH:12]=[CH:11][C:10]=4[N:9]=[CH:8][C:7]=3[N:13]=[N:14]2)[CH2:17][CH2:18]1)=[O:28])(=[O:24])[CH3:23]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Clc1ccc2ncc3nnn(C4CCNCC4)c3c2n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H](C)C(=O)N1CCC(n2nnc3cnc4ccc(Cl)nc4c32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a solution of 8-chloro-1-(piperidin-4-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridine hydrochloride (1 g, 3.08 mmol) in 10 mL of CH2Cl2 was added (S)-1-chloro-1-oxopropan-2-yl acetate (1.4 g, 9.23 mmol) and Et3N (2.2 mL). After the mixture was stirred at room temperature for 2 h, it was quenched with water (10 mL). The resulting mixture was extracted with CH2Cl2 (2×20 mL). The combined organic layer was dried over anhydrous Na2SO4, and then was concentrated in vacuo to afford the (S)-1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-1-oxopropan-2-yl acetate (1.2 g). MS (m/z): 403 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:10][C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:12]=[CH:13][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CO
Reactant: COc1ccc(C=CC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccc(OC)cc1

Procedure:
A suspension of 300 g of 4-methoxycinnamic acid (J. Chem. Soc., Chem. Comm., 355, (1978)) and 25 ml of concentrated sulfuric acid in 1.7 liters of methanol is heated to reflux for 96 hours. The solution is concentrated, cooled, and filtered to give as a white solid, 4-methoxycinnamic acid methyl ester, mp 85°-86° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Br[C:24]1[C:25](=[O:33])[N:26]([CH2:30][CH2:31][CH3:32])[CH:27]=[CH:28][CH:29]=1>>[O:33]=[C:25]1[C:24]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)=[CH:29][CH:28]=[CH:27][N:26]1[CH2:30][CH2:31][CH3:32]
Reactant: CCCn1cccc(Br)c1=O
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: CCCn1cccc(N2CCC3(CC2)CCN(c2ccc(OC(F)(F)F)cc2)C3=O)c1=O

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 3-bromo-1-propyl-1H-pyridin-2-one. Off-white solid. MS (ESI): 450.2 (MH+)
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH2:12]([O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(N(CC)CC)C>[CH2:12]([O:19][C:20]1[CH:21]=[C:22]2[C:23](=[CH:25][CH:26]=1)[NH:24][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[C:2]2[CH3:11])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: CC(Br)C(=O)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)[nH]c2ccc(OCc3ccccc3)cc12

Procedure:
An amount of 3.6 g (0.015 mole) of 2-bromo-propiophenone and 6 g (0.03 mole) of 4-benzyloxy-aniline were refluxed for two hours in 15 ml of triethylamine. The mixture was evaporated to dryness, and the residue was heated for two hours to 180° C. After cooling, the residue was mixed with 10% hydrochloric acid and extracted with chloroform. The extracts were dried over sodium sulfate, filtered, and evaporated. The residue obtained was purified by column chromatography on silicagel with toluene as solvent.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([Br:12])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].I[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[C:1]([C:5]1[CH:6]=[C:7]([Br:12])[CH:8]=[CH:9][C:10]=1[O:11][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(Br)ccc1O
Reactant: CCCCCCI
Product: CCCCCCOc1ccc(Br)cc1C(C)(C)C
Yield: 95.8 %

Procedure:
Following the basic procedure of Example 46(a), by reacting 4.58 g (0.02 mol) of 3-tert-butyl-4-hydroxybromobenzene with 3.3 ml (0.022 mol) of 1-iodohexane, 6 g (97%) of 3-tert-butyl-4-hexyloxybromobenzene were obtained in the form of a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11].[OH-].[K+].Cl>CO>[O:1]=[C:2]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCCCCCCC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)O
Reaction time: 18 h

Procedure:
A suspension of 300 mg. of ethyl 9-oxoprostanoate in 20 ml. of aqueous methanol (1:1) containing 300 mg. of potassium hydroxide is stirred at 50° C. for 1 hour and then at room temperature for 18 hours. The resulting solution is acidified with 1N hydrochloric acid, concentrated and extracted several times with diethyl ether. The combined ether extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 256 mg. (94%) of product as an oil;λmax 5.75, 5.85 μ; nmr 1H broad singlet δ 9.89 (carboxyl proton, exchangeable).
Reaction SMILES: [NH3:1].[C:2]([O:5][C:6]1[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8][C:9]2[O:13][C:12]([CH2:15][N:16]=[C:17]=[S:18])([CH3:14])[CH2:11][C:10]=2[C:19]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:4])[CH3:3]>C(O)C>[C:2]([O:5][C:6]1[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8][C:9]2[O:13][C:12]([CH2:15][NH:16][C:17]([NH2:1])=[S:18])([CH3:14])[CH2:11][C:10]=2[C:19]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:4])[CH3:3]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CN=C=S)O2
Reactant: N
Solvent: CCO
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CNC(N)=S)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 4.16 g of a 28% aqueous ammonia solution in 10 ml of ethanol was added dropwise a solution of 5.15 g of (5-acetoxy-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl)methyl isothiocyanate in 20 ml of ethanol at room temperature. The mixture was stirred at room temperature for 2 hours, and then heated under reflux for further 1 hour. After cooling, ethanol was removed using an evaporator, and the mixture was combined with water and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography eluting with chloroform containing 10% methanol to give 5.3 g of 1-[(5-acetoxy-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl)methyl]thiourea (rotamer mixture) as a white solid (yield 99%).
Reaction SMILES: S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:5][C@H:6]1[O:8][CH2:7]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[C:24]12([CH2:34][NH:35][C:36](=[O:45])[C:37]3[C:42]([Br:43])=[CH:41][N:40]=[C:39]([OH:44])[CH:38]=3)[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>CN(C)C=O.O>[C:24]12([CH2:34][NH:35][C:36](=[O:45])[C:37]3[C:42]([Br:43])=[CH:41][N:40]=[C:39]([O:44][CH2:5][C@@H:6]4[CH2:7][O:8]4)[CH:38]=3)[CH2:31][CH:30]3[CH2:32][CH:26]([CH2:27][CH:28]([CH2:29]3)[CH2:33]1)[CH2:25]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(O)ncc1Br
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OC[C@@H]2CO2)ncc1Br
Temperature: 60 °C
Yield: 25.5 %

Procedure:
A suspension of (S)-glycidyl nosylate (0.29 g), caesium carbonate (1.82 g) and N-(1-adamantylmethyl)-5-bromo-2hydroxyisonicotinamide (0.41 g) (Example 35(ii)) in anhydrous N,N-dimethylformamide (6 ml) was heated at 60° C. under nitrogen for 2 hours. The reaction mixture was allowed to cool to room temperature, diluted with water (50 ml) and extracted into ethyl acetate (3×20 ml). The combined extracts were dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with dichloromethane:ethyl acetate (4:1 to 0:1) to afford the sub-titled compound (0.12 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH2:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:29]([N:36]=[C:37]=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH:28][C:37]([NH:36][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:38])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNC(=O)NCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(4-aminomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and benzyl isocyanate.