Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH:3]=1.[CH2:20]([CH2:22][NH2:23])[OH:21]>>[ClH:1].[Cl:19][C:14]1[CH:13]=[C:12]([C:4]2[CH:3]=[C:2]([NH:23][CH2:22][CH2:20][OH:21])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: Clc1ccc(-c2cc(Cl)c3ccccc3n2)cc1Cl
Reactant: NCCO
Product: Cl
Product: OCCNc1cc(-c2ccc(Cl)c(Cl)c2)nc2ccccc12

Procedure:
The title compound, m.p. 256-25° C., and MS: m/e=333.1 (M+H+), was prepared from 4-chloro-2-(3,4-dichloro-phenyl)-quinoline and ethanolamine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1.Br[CH2:24][CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.Br>C(#N)C>[Br-:10].[C:18]([CH2:17][O:16][C:15]1[CH:21]=[CH:22][C:12]([CH2:11][N:3]2[C:2]([Cl:1])=[C:6]([Cl:7])[N+:5]([CH2:24][CH2:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][CH:27]=3)=[CH:4]2)=[CH:13][CH:14]=1)([OH:20])=[O:19]
Reactant: BrCCc1cccc2ccccc12
Reactant: Clc1nc[nH]c1Cl
Reactant: O=C(O)COc1ccc(CBr)cc1
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)COc1ccc(Cn2c[n+](CCc3cccc4ccccc34)c(Cl)c2Cl)cc1
Product: [Br-]

Procedure:
4,5-dichloroimidazole (1.00 g, 7.36 mmol) was dissolved in acetonitrile. Potassium hydroxide (0.828 g, 14.72 mmol) was added to the solution and allowed to reflux for 30 min. 1 equivalent of 2-(4-(bromomethyl)phenoxy)acetic acid (1.80 g, 7.36 mmol) was added to the solution and refluxed for 5 h. Solution was filtered to remove the KBr precipitate and placed back onto reflux. An equivalent of 1-(2-bromoethyl)naphthalene (1.73 g, 7.36 mmol) was added to solution and refluxed for 2.5 h. The solution was neutralized with 6M HBr, volatiles removed in vacuo, and the resulting product will be collected and analyzed.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([N:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To a mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (100 mg, 0.19 mmol), HOBt (3 mg, 0.1 eq.), EDAC.HCl (44 mg, 1.2 eq.) and morpholine (18 mg, 1.1 eq.) in DMF (2 mL) at rt was added TEA (0.067 mL, 2.5 eq.). After stirring at rt for 7 days, the reaction was concentrated, diluted with DCM (10 mL) and methanol (0.5 mL) and then mixed with solid sodium bicarbonate. After stirring at rt for 15 mins, the suspension was loaded onto a silica gel column to give the titled compound as a reddish-orange solid.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19]([O:22][C:23]1[N:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)([CH3:21])[CH3:20]>>[CH:19]([O:22][C:23]1[N:28]=[CH:27][C:26]([NH:29][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[CH:25][CH:24]=1)([CH3:21])[CH3:20]
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: CC(C)Oc1ccc(N)cn1
Product: CC(C)Oc1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)cn1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 6-isopropoxypyridine-3-amine as the starting materials.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:21])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:20])([C:14]([NH:16][CH2:17][CH2:18][OH:19])=[O:15])[CH2:6][CH2:5]2.C(C#N)(C)=[O:23].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].CCOC(C)=O>O>[OH:23][C:7]([CH3:20])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:21])[C:14]([NH:16][CH2:17][CH2:18][OH:19])=[O:15]
Reactant: CC(=O)C#N
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCO)O2
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCO)=C(C)C1=O
Temperature: 0 °C

Procedure:
6-Hydroxy-N-(2-hydroxyethyl)-2,5,7,8-tetramethylchroman-2-carboxamide (2.38 g, 8.11 mmol) was dissolved into 150 mL AcCN, cooled to 0° C. and treated with 9.75 g CAN (17.84 mmol) in 30 mL H2O over 20 minutes. EtOAc (150 mL) and H2O (20 mL) were then added, layers separated and the organic phase washed 21×20 mL H2O. The aqueous phase was back extracted 4×50 mL EtOAc and the combined organics washed with saturated NaCl, dried over Na2SO4 and concentrated to a yellow powder. Flash chromatography yielded 1.68 g of 2-hydroxy-N-(2-hydroxyethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow solid.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([Br:26])[CH:24]=2)[NH:19][CH:18]=1)=O)C1C=CC=CC=1.B(F)(F)F.C(S)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH3:11].[Br:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH2:16][C@H:12]1[CH2:13][CH2:14][CH2:15][NH:11]1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCS
Solvent: ClCCl
Product: Brc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Product: N
Yield: 124.3 %

Procedure:
3-(1-Benzyloxycarbonylpyrrolidin-2(R)-ylmethyl)-5-bromo-1H-indole (see Preparation 35B) (5.00 g, 12.10 mmol) was dissolved in dichioromethane and the resulting solution was added dropwise to a stirred mixture of boron-trifluoride.etherate (17.15 g, 14.9 ml, 12.1 mmol) and ethane thiol (21.4 g, 25.5 ml, 344 mmol) at room temperature under nitrogen. After 68 hours the reaction mixture was added by pipette to a 10% aqueous sodium carbonate solution (500 ml) and extracted with ethyl acetate (3×400 ml). The combined organic extract was dried (Na2SO4) and the solvent evaporated under reduced pressure. Purification by column chromatography on silica gel, eluting with dichioromethane: methanol:0.880 aqueous ammonia (90:10:1), yielded the title compound as a foam (2.1 g). Found: C,55.04; H,5.29; N,9.83. C13H15BrN2.3/50CH2Cl2 requires: C,55.10; H,5.35; N,9.83%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:22])([CH3:21])[CH2:9][NH:10][C:11]2[N:16]=[N:15][C:14]([C:17]([O:19][CH3:20])=O)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[OH2:23].[NH2:24][NH2:25].C(O)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:22])([CH3:21])[CH2:9][NH:10][C:11]2[N:16]=[N:15][C:14]([C:17]3[O:19][C:20](=[O:23])[NH:25][N:24]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O
Reactant: NN
Reactant: COC(=O)c1ccc(NCC(C)(C)c2ccc(F)cc2)nn1
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(CNc1ccc(-c2n[nH]c(=O)o2)nn1)c1ccc(F)cc1
Temperature: 90 °C
Yield: 67 %

Procedure:
To a 25 mL round bottom flask was added methyl 6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-3-carboxylate (100 mg, 0.3 mmol, 1.0 equiv), hydrazine hydrate (1 mL), and ethanol (5 mL)). The reaction was refluxed for 2 h and concentrated. N,N′-Carbonyldiimidazole (100 mg, 0.6 mmol, 2.0 equiv) and DMF (1 mL) were then added to the crude product and the reaction was heated to 90° C. for 1.5 h. The reaction mixture was directly purified by reverse phase column chromatography to afford 72 mg (67%) of 5-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)-1,3,4-oxadiazol-2(3H)-one as a white solid, m/z=330.0 [M+H].
Reaction SMILES: ClC1C=CC(C2N=C(N3C=CN=C3C)OC=2CCCCO[C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)=CC=1.O1CCCC1.[OH-].[Na+]>C(O)C>[C:22]([OH:24])(=[O:23])[C:21]1[CH:26]=[CH:27][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(OCCCCc2oc(-n3ccnc3C)nc2-c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1
Temperature: 62.5 °C
Reaction time: 3 h

Procedure:
To a mixture of methyl 4-[4-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]butoxy]benzoate (1.86 g), tetrahydrofuran (20 ml) and ethanol (10 ml) was added 15 ml of a 1 N aqueous solution of sodium hydroxide, and the resulting mixture was stirred at 60-65° C. for 3 hours. The reaction mixture was concentrated and then diluted with a 10% aqueous solution of citric acid, and the resulting precipitate was filtered, washed with water and air-dried to give crystals of 4-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]butoxy]benzoic acid. Recrystallization from tetrahydrofuran-isopropyl ether gave colorless prisms (1.15 g, 51%). Melting point 214-216° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]#[N:29].C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([O:19][CH2:27][C:28]#[N:29])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(OCC#N)c2ccccc12
Yield: 98.3 %

Procedure:
N-tertbutyloxycarbonyl-4-amino-1-naphthol (1.0 g, 3.86 mmol), potassium carbonate (1.06 g, 7.7 mmol) and bromoacetonitrile (0.4 ml, 5.8 mmol) in anhydrous dimethylformamide (10 ml) are stirred at room temperature for 5 hours. The mixture is poured into ethyl acetate (100 ml) and washed with water (2×100 ml). The organic layer is then dried over anhydrous sodium sulfate and evaporated to dryness to give (4-cyanomethoxynaphthalen-1-yl)-carbamic acid tert-butyl ester as a red brown solid (1.132 g). 1H NMR 300 MHz (CDCl3) 8.2 (d, 1H, J=11.5 Hz), 7.85 (d, 1H, J=111.5 Hz), 7.55-7.75 (m, 3H), 6.9 (d, 1H, J=14 Hz), 6.62 (s, 1H), 4.95 (s, 2H), 1.5 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](O)([C:12]([F:15])([F:14])[F:13])[C:7](=O)[NH:8]2)=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1.CN(C=O)C>[F:15][C:12]([F:13])([F:14])[C:6]1[C:5]2[C:9](=[CH:10][C:2]([NH2:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1
Reactant: Nc1ccc2c(c1)NC(=O)C2(O)C(F)(F)F
Agent: B
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccc2c(C(F)(F)F)c[nH]c2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To a solution of 6-amino-3-hydroxy-3-(trifluoromethyl)indolin-2-one (58 mg, 0.25 mmol) in THF (0.5 mL) at 0° C. was added BH3THF complex (1 M in THF, 1 mL, 0.95 mmol) dropwise. The reaction mixture was stirred for 5 min at 0° C. then for 3 h at room temperature. The reaction mixture was quenched by adding very carefully 6M HCl (3.5 mL) until no more gas release was observed. The reaction mixture was then stirred at 80° C. for 2 h. The solvent was removed under reduce pressure and the solid residue obtained was dissolved in DMF (3 mL), filtered and purified by reverse phase HPLC (10-99% CH3CN/H2O) to provide 3-(trifluoromethyl)-1H-indol-6-amine (30 mg, 54%, TFA salt).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1.[CH3:31][NH:32][CH3:33]>CN1C(=O)CCC1.CO>[CH3:31][N:32]([CH3:33])[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1
Reactant: CNC
Reactant: Cc1ccc(NC(=O)Nc2ccccc2)cc1-c1cc2cnc(Cl)cc2n(C)c1=O
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cc1ccc(NC(=O)Nc2ccccc2)cc1-c1cc2cnc(N(C)C)cc2n(C)c1=O
Temperature: 100 °C

Procedure:
1-(3-(7-chloro-1,2-dihydro-1-methyl-2-oxo-1,6-naphthyridin-3-yl)-4-methylphenyl)-3-phenylurea A6 (50 mg, 0.12 mmol) is dissolved in NMP (1 mL) and treated with dimethyl amine (0.60 mL of a 2.0 M solution in methanol). The reaction mixture is heated to 100° C. for 12 h. Upon cooling to rt the reaction is purified by preparative LCMS.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[C:15]([CH:16]=O)=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18]/[C:19](/[CH3:25])=[CH:20]\[C:21]([O:23][CH3:24])=[O:22].Cl.[CH3:27][OH:28]>>[CH3:25][C:19]1[NH:18][C:19]2[CH2:27][O:28][C:21](=[O:22])[C:20]=2[CH:16]([C:15]2[C:9]3[S:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=3[CH:12]=[CH:13][CH:14]=2)[C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: O=Cc1cccc2nc(-c3ccccc3)sc12
Reactant: CO
Reactant: COC(=O)/C=C(/C)N
Agent: Cl
Product: COC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1cccc2nc(-c3ccccc3)sc12
Reaction time: 0.5 h
Yield: 30 %

Procedure:
10 mmol of 2-phenyl-benzothiazole-7-carboxaldehyde, 10 mmol of 4-acetoxyacetoacetic ester and 10 mmol of methyl 3-aminocrotonate are boiled in 20 ml of methanol overnight, then 6 ml of dilute hydrochloric acid are added and the mixture is boiled for 30 minutes. It is concentrated and purified on a silica gel column (cyclohexane/ethyl acetate=1:1). Yield: 30% M.p.: 275° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][O:11][CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=O)([O-])[O-].[K+].[K+].IC>CS(C)=O.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][O:11][CH2:12][CH3:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CS(C)=O
Product: CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 12 h

Procedure:
To a mixture of N-(tert-butoxycarbonyl)-O-ethylserine (5.3 g, 22 mmol) and potassium carbonate (6.3 g, 45 mmol) in DMSO (80 mL) was added iodomethane (6.5 g, 45 mmol) at room temperature. After 12 hours, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via chromatography on silica gel to afford methyl N-(tert-butoxycarbonyl)-O-ethylserinate. MS ESI calc'd. for C11H22NO5 [M+H]+ 248. found 248. 1H NMR (400 MHz, CDCl3) δ 5.36 (d, J=8.0 Hz, 1H), 4.42-4.39 (m, 1H), 3.84-3.81 (m, 1H), 2.75 (s, 3H), 3.64-3.60 (m, 1H), 3.49-3.45 (m, 2H), 1.45 (s, 9H), 1.15 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH-:1].[Na+].[N+]([C:6]1C=CC=C[C:7]=1[C:8]([O-:10])=O)([O-])=O.[CH2:15]([O:22][C:23]([NH:25][C@@H:26]([CH2:34][SH:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(O)(C)C>[CH2:15]([O:22][C:23]([NH:25][C@@H:26]([CH2:34][S:35][CH2:6][C@H:7]([OH:1])[CH2:8][OH:10])[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)[C@H](CS)NC(=O)OCc1ccccc1
Reactant: O=C([O-])c1ccccc1[N+](=O)[O-]
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)[C@H](CSC[C@H](O)CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of (25)-(+)-glycidyl-4-nitrobenzoate (1.1 eq) and 1M NaOH (1.1 eq) in tBuOH (0.1 M) was stirred at room temperature until complete hydrolysis of the nitrobenzoate was observed (30 minutes). To the resulting mixture, a solution of (R)-tert-butyl 2-(benzyloxycarbonylamino)-3-mercaptopropanoate (12, 1 eq) in tBuOH (1 M) was introduced and the reaction stirred at room temperature for 15 hours. The reaction mixture was concentrated en vaccuo to remove tBuOH then dissolved in EtOAc. The EtOAc solution was washed three times with water, once with brine, then dried over Na2SO4 and concentrated. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-90% EtOAc/Hex to give the title product as a colorless viscous oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([B:7]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]2)=[CH:5][CH:4]=[N:3]1.[Cl:16]N1C(=O)CCC1=O.O1CCCC1>>[Cl:16][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[B:7]1[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1B1OC(C)(C)C(C)(C)O1
Yield: 92.6 %

Procedure:
A solution of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00 g, 4.81 mmol) and N-chlorosuccinimide (0.671 g, 5.05 mmol) in tetrahydrofuran (10 mL, 100 mmol) was stirred at 70° C. for 2 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by combi-flash chromatography and eluted with EtOAc/hexane (10-80%). The purification afforded 1.08 g (78% yield) of the desired product as white solid.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:13][C:14]3[C:19]([N:20]=2)=[CH:18][C:17]([C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=3)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].CO.ClCCl.[OH-].[Na+]>O>[C:1]([NH:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[C:12]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:13][C:14]3[C:19]([N:20]=2)=[CH:18][C:17]([C:21]([OH:23])=[O:22])=[CH:16][CH:15]=3)[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(NC(C)=O)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC1CCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 100-mL round-bottom flask was placed methyl 3-(4-acetamidopiperidin-1-yl)-2-phenylquinoxaline-6-carboxylate (100 mg, 0.25 mmol, 1.00 equiv), methanol (15 mL), dichloromethane (7 mL). To this was added a solution of sodium hydroxide (1.5 g, 37.50 mmol, 151.50 equiv) in water (7 mL). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum and diluted with 10 ml of H2O. The pH of the aqueous solution was adjusted to 3 with hydrochloric acid. The resulting solids were collected by filtration. This resulted in 95 mg (94%) of 3-(4-acetamidopiperidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][C:28]1[O:29][C:30]2[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][C:31]=2[N:32]=1.BrC1C=CC2N=C(C)OC=2C=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:35]5[CH:34]=[CH:33][C:31]6[N:32]=[C:28]([CH3:27])[O:29][C:30]=6[CH:36]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1nc2ccc(B(O)O)cc2o1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Agent: Cc1nc2ccc(Br)cc2o1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc6nc(C)oc6c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-methyl-benzoxazol-6-boronic acid (prepared from 6-bromo-2-methyl-benzoxazole in analogy to the procedure described for Intermediate 46) following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=0.65 min; Mass spectrum (ESI+): m/z=490 [m+H]+.
Reaction SMILES: O[CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5].B(F)(F)F.CC[O:23][CH2:24][CH3:25].[OH2:26].[Pb](=O)=O>O1CCOCC1.C(OCC)C>[CH2:2]([C:2]1[C:24](=[O:23])[CH:25]=[CH:5][C:4](=[O:26])[CH:3]=1)[CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5]
Reactant: O
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Reactant: CCOCC
Agent: FB(F)F
Agent: O=[Pb]=O
Solvent: C1COCCO1
Product: CC(C)=CCCC(C)=CCCC(C)=CCC1=CC(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 2.3 %

Procedure:
Farnesol (33.4 g; 150 mmole) was dropwise added to a solution of 1,4-hydroquinone (33.0 g; 300 mmole) and boron trifluoride ethyl etherate (17.0 g; 120 mmole) in 300 ml of dioxane at 50° C. over two hours. After stirring the resultant solution at that temperature for two hours, the reaction solution was poured into 500 ml of water and was extracted twice with diethyl ether (500 ml). The extract was washed once with 500 ml of 5% (w/v) aqueous sodium hydroxide solution, twice with water (500 ml) and then once with saturated aqueous solution of sodium chloride (500 ml) and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off and the resultant residue was chromatographed with a silica gel column. The fractious eluted with hexane-ethyl acetate (3:1) was evaporated to dryness to thereby obtain 6.63 g of waxy substance. This was dissolved in 40 ml of diethylether, then 24.5 g (103 mmole) of lead dioxide was added thereto and the solution was stirred at room temperature for two days. After removing lead dioxide by filtration, the filtrate was concentrated and the concentrate was chomatographed through a column packed with silica gel to obtain 1.1 g (3.5 mmole) of 2-farnesyl-1, 4-benzoquinone from the fractions eluted through the column with hexane-ethyl acetate (10:1) in an yield of 2.3%. Then, this compound (1.08 g; 3.46 mmole) was dissolved in 5 ml of pyridine and was heated under reflux for 2.5 hours. The reaction solution was poured into 50 ml of ice-water and was extracted twice with diethyl ether (50 ml). The extract was washed twice with water (50 ml) and then once with saturated aqueous sodium chloride solution (50 ml) followed by drying it over anhydrous magnesium sulfate, distilling off the solvent and subjecting the resultant residue to silica gel column chromatography. Thus, 470 mg (1.5 mmole) of 2-methyl-2-(4,8-dimethyl-3,7-nonadienyl)-6-chromenol was recovered from the fractions eluted with hexane-ethyl acetate (5:1) in an yield of 44% which corresponded to the overall yield, from farnesol, of 1.0%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][C:10]=1[CH3:27])#[N:2].[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([NH:38][C:39]3[NH:43][N:42]=[C:41]([CH3:44])[N:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>Cl>[O:28]1[C:32]2([CH2:33][CH2:34][CH:35]([N:38]3[C:17](=[O:18])[C:16]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[C:10]([CH3:27])[CH:11]=4)=[C:22]([CH2:23][CH2:24][CH3:25])[N:43]4[N:42]=[C:41]([CH3:44])[N:40]=[C:39]34)[CH2:36][CH2:37]2)[O:31][CH2:30][CH2:29]1
Reactant: Cc1n[nH]c(NC2CCC3(CC2)OCCO3)n1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c(C)c1)C(=O)OCC
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(C)c2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Temperature: 180 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-2-methylbiphenyl-4-yl)methyl]-3-oxohexanoate (3.00 g), N-(1,4-dioxaspiro[4.5]dec-8-yl)-3-methyl-1H-1,2,4-triazol-5-amine (1.00 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.3 mL) and N,N-diethylaniline (10 mL) was stirred at 180° C. overnight, allowed to cool and poured into 1 M hydrochloric acid (50 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a brown oil (1.20 g, 53%).