Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1.Cl.Cl[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23]>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 35.4 %

Procedure:
Potassium carbonate (3.2 g, 12.3 mmol) was added to a solution of 4-chloro-2-nitro-phenol (6.0 g, 34.6 mmol) in DMF (60 mL). The mixture was cooled to 0° C. 2-Chloro-N,N-dimethyl ethyl amine hydrochloride (9.96 g, 69.1 mmol) was added in portions. The reaction mixture was allowed to warm to rt, stirred for 4 h, heated to 95° C., stirred for 16 h, allowed to cool to rt, quenched by addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography (CHCl3/MeOH, 98:2) to provide 3.0 g of the title compound. tR: 0.12 min (LC-MS 2); ESI-MS: 245 [M+H]+ (LC-MS 2); Rf=0.29 (CHCl3/MeOH, 9:1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[NH:12]2)=[CH:8][CH:7]=1.Cl[Sn](Cl)(Cl)Cl.C(Cl)Cl.[CH3:27][C:28]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31].[O-]S([O-])(=O)=O.[Mg+2]>ClCCl.[N+](C)([O-])=O.CCOC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:36]([N+:37]([O-:39])=[O:38])[C:28]=3[CH3:27])=[C:11]([C:15]([O:17][CH3:18])=[O:16])[NH:12]2)=[CH:8][CH:7]=1
Reactant: COCCOc1ccc2cc(C(=O)OC)[nH]c2c1
Reactant: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: COCCOc1ccc2c(C(=O)c3cccc([N+](=O)[O-])c3C)c(C(=O)OC)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 104 %

Procedure:
To a homogeneous, colorless solution of methyl 6-(2-methoxyethoxy)-1H-indole-2-carboxylate (0.934 g, 3.75 mmol) in dichloromethane (18.74 mL) at 0° C. under nitrogen was added 1M perchlorostannane/CH2Cl2 (4.87 mL, 4.87 mmol) over 10 min. After 5 min, the cold bath was removed, and the yellow, heterogeneous solution was stirred to room temperature for 30 min. A solution of 2-methyl-3-nitrobenzoyl chloride (0.897 g, 4.50 mmol) in nitromethane (18.74 mL, previously dried over MgSO4 overnight) was added over 20 min. After 3.25 hr, additional acid chloride (0.350 g) in nitromethane (3 mL) was added to the reaction. Thirty minutes later, the reaction was poured into ice water (50 mL) and stirred for 15 min. It was diluted with EtOAc (150 mL) and washed with water (50 mL), sat. aq. NaHCO3 (50 mL) and brine (25 mL). The organic solution was dried over MgSO4 and concentrated in vacuo to give the desired product (1.6103 g, 3.90 mmol, 104% yield) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]2[C:8]([CH3:10])(C)[CH:5](C2)[CH2:4][CH:3]=1.N1C=CC=CC=1.C[N+]1([O-])[CH2:23][CH2:22][O:21]CC1.CC(C)=[O:27]>>[C@@:22]12([OH:21])[CH2:23][C@@H:3]([C:2]1([CH3:7])[CH3:1])[CH2:4][CH2:5][C:8]2([OH:27])[CH3:10]
Reactant: CC1=CCC2CC1C2(C)C
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Solvent: c1ccncc1
Product: CC1(O)CC[C@H]2C[C@]1(O)C2(C)C

Procedure:
reacting α-pinene with catalytic potassium osmate in a solution of pyridine, N-methylmorpholine-N-oxide and aqueous acetone to form cis-pinanediol;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][N:21]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[NH:23][C:22]4=[O:30])[CH2:14][CH2:13]3)[C:11](=[O:31])[N:10]([CH2:32][C:33]3[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=3)[C:36]([O:38]C)=[O:37])[CH2:9]2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][N:21]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[NH:23][C:22]4=[O:30])[CH2:14][CH2:13]3)[C:11](=[O:31])[N:10]([CH2:32][C:33]3[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=3)[C:36]([OH:38])=[O:37])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-((1-(4-fluorophenyl)-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.25 g, 0.44 mmol) in methanol (3 mL) was added lithium hydroxide monohydrate (0.037 g, 0.88 mmol) in water (1 mL). After stirring at room temperature for 18 h, the reaction mixture was concentrated in vacuo and isolated by reverse phase HPLC to obtain the title compound as an acetate salt (0.05 g, 13%); 1H NMR (DMSO-d6): δ 1.62 (d, 2H, J=13.2 Hz), 1.81 (t, 2H, J=6.4 Hz), 2.27-2.37 (m, 4H), 2.50-2.69 (m, 4H), 3.83 (t, 2H, J=6.8 Hz), 4.56 (d, 4H, J=15.2 Hz), 6.88-6.91 (m, 2H), 6.95-6.98 (m, 3H), 7.08 (d, 2H, J=5.2 Hz), 7.13-7.16 (m, 1H), 7.47-7.52 (m, 2H), 7.85-7.87 (m, 2H), 10.81 (s, 1H), 13.10 (br, 1H); MS for C31H32FN5O4 m/z 558.02 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[NH2:16].[CH3:17][C:18]1([CH3:27])[CH2:23][CH2:22][C:21](B(O)O)=[CH:20][CH2:19]1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:18]1([CH3:27])[CH2:23][CH2:22][C:21]([C:2]2[CH:7]=[C:6]([C:8]3[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=3)[CH:5]=[CH:4][C:3]=2[NH2:16])=[CH:20][CH2:19]1
Reactant: CC1(C)CC=C(B(O)O)CC1
Reactant: COc1ccc(-c2ccc(N)c(Br)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(-c2ccc(N)c(C3=CCC(C)(C)CC3)c2)cn1

Procedure:
The title compound was prepared from 2-bromo-4-(6-methoxy-pyridin-3-yl)-phenylamine (as prepared in the previous step, 20 mg, 0.07 mmol), 4,4-dimethylcyclohexen-1-yl boronic acid (14 mg, 0.086 mmol), Pd(PPh3)4 (8.0 mg, 0.007 mmol) and 2M Na2CO3 (0.28 mL, 0.56 mmol) according to the procedure in Example 44, step (b) (16 mg, 76%). Mass spectrum (ESI, m/z): Calcd. for C20H24N2O, 309.1 (M+H), found 309.2.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:19](Cl)([CH3:22])(=[O:21])=[O:20].C(N(CC)CC)C.O>ClCCl>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2c(ccn2C(=O)c2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc2c(ccn2C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
1-benzoyl-5-amino-1H-indole (25 mg, 0.106 mmol) was dissolved in dichloromethane (1.0 ml) at room temperature and mesyl chloride (0.01 ml. 0.116 mmol) and triethylamine (0.016 ml, 0.115 mmol) were added. The solution was stirred at room temperature for 30 minutes to complete the reducing reaction. After pouring water (2 ml), dichloromethane layer was separated, washed with brine, dried over anhydrous magnesium sulfate and then, purified through flash column chromatography (an eluent:ethyl acetate/n-hexane=1/2, v/v). As a result, the present compound (20 mg, productive yield 60%) was obtained.
Reaction SMILES: [CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.[NH2:22][C@@H:23]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:24][C@H:25]([OH:44])[C@@H:26]([NH:34][C:35]([O:37][CH2:38][C:39]1[S:43][CH:42]=[N:41][CH:40]=1)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C1COCC1>[CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:19]([NH:22][C@@H:23]([CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[CH2:24][C@H:25]([OH:44])[C@@H:26]([NH:34][C:35]([O:37][CH2:38][C:39]1[S:43][CH:42]=[N:41][CH:40]=1)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:21])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:10])[CH3:11])[S:7][CH:8]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Yield: 74.6 %

Procedure:
A solution of 70 mg (0.223 mmol) of N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine, 79 mg (0.186 mmol) of (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane, 30 mg (0.223 mmol) of 1-hydroxybenzotriazole hydrate, and 51 mg (0.266 mmol) of N-ethyl-N′-dimethylaminopropyl carbodiimide in 2 ml of THF was stirred at ambient temperature for 16 h. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel chromatography using 97:3 CH2Cl2:CH3OH to provide 100 mg (74%) of the desired compound (Rf 0.4, 95:5 CH2Cl2:CH3OH) as a solid.
Reaction SMILES: S(F)(=O)(=O)[OH:2].[Sb](F)(F)(F)(F)F.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.[OH:22]O>S(F)(Cl)(=O)=O>[CH:20]1[C:21]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:19]=1[OH:22].[C:20]1([OH:2])[C:21]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: OO
Reactant: c1ccc2ccccc2c1
Reactant: O=S(=O)(O)F
Agent: F[Sb](F)(F)(F)F
Agent: O=S(=O)(F)Cl
Product: Oc1ccc2ccccc2c1
Product: Oc1cccc2ccccc12
Yield: 4.4 %
Yield: 54.2 %

Procedure:
Using a 1:1 molar mixture of fluorosulfuric acid and antimony pentafluoride diluted with sulfuryl chloride fluoride, a solvent of low nucleophilicity, the reaction of naphthalene with hydrogen peroxide (90% solution) at temperatures between -78% and -70° C., gave 54.2% of β-naphthol with 4.4% of α-naphthol. About 6% of dihydroxynaphthalenes were also formed with only traces of polymeric material and 22% naphthalene was recovered. The yield of β-naphthol is 69% with an isomeric purity of 92.5%. Similar results showing high regioselectivity in the formation of β-naphthol were also obtained in other superacidic systems, such as in hydrogen fluoride-antimony pentafluoride, hydrogen fluoride-tantalum pentafluoride, trifluoromethanesulfonic acid-antimony pentafluoride, and the like.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4]Br.[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([OH:26])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:29])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:29])[CH:10]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC(OC)OC
Temperature: 110 °C
Yield: 34.8 %

Procedure:
Bromoacetaldehyde dimethyl acetal (0.74 ml, 3.1 mmol) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (10 g, 3.13 mmol), (prepared as described for the starting material in Example 2), and anhydrous potassium carbonate (2.16 g, 15.6 mmol) in DMF (30 ml). The mixture was stirred and heated at 110° C. for 4 hours, then allowed t6 cool and the volatiles were removed by evaporation. Water was added to the residue and the aqueous mixture was extracted with methylene chloride (×4). The extracts were combined, washed with brine and dried by filtration through phase separating paper. The volatiles were removed by evaporation, the residue was triturated with ether, collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-7-(2,2-dimethoxyethoxy)-6-methoxyquinazoline (440 mg, 35%).
Reaction SMILES: N[C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(Cl)(=O)OCC.[NH2:20][C@H:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][C@H:22]1[O:32][CH3:33].C([N:36](CC)CC)C>ClC(Cl)Cl>[NH2:36][N:20]([C:6](=[O:8])[C:5]1[CH:9]=[C:10]([Cl:11])[CH:2]=[CH:3][C:4]=1[O:12][CH3:13])[C@H:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][C@H:22]1[O:32][CH3:33]
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CCOC(=O)N1CC[C@H](N)[C@H](OC)C1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CC[C@H](N(N)C(=O)c2cc(Cl)ccc2OC)[C@H](OC)C1
Reaction time: 0.75 h
Yield: 80 %

Procedure:
To a stirred solution of 22.5 parts of 4-amino-5-chloro-2-methoxybenzoic acid in 405 parts of trichloromethane were added dropwise successively 11.8 parts of N,N-diethylethanamine and 13 parts of ethyl carbonochloridate at a temperature below 10° C. Stirring was continued for 45 minutes at a temperature below 10° C. Then there was added dropwise a solution of 19.15 parts of cis-ethyl 4-amino-3-methoxy-1-piperidinecarboxylate in 360 parts of trichloromethane at the same temperature. Upon completion, stirring was continued for 18 hours at room temperature. The reaction mixture was washed successively three times with water, once, with a 5% sodium hydroxide solution and again twice with water. The organic phase was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 29.3 parts (80%) of cis-ethyl 4-(amino-5-chloro-2-methoxybenzoylamino)-3-methoxy-1 -piperidinecarboxylate as a residue (compound 168).
Reaction SMILES: C1CO[C:3]([CH3:10])([CH2:4][CH2:5][CH2:6][C:7]([CH3:9])=[CH2:8])[O:2]1.C(=O)(O)[O-].[Na+]>CC(C)=O.Cl>[CH3:9][C:7]([CH2:6][CH2:5][CH2:4][C:3](=[O:2])[CH3:10])=[CH2:8]
Reactant: C=C(C)CCCC1(C)OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C(C)CCCC(C)=O
Yield: 70.8 %

Procedure:
A solution of 6,6-ethylenedioxy-2-methyl-hept-1-ene (12.2 g) in acetone (300 ml) and 10% hydrochloric acid (12 ml) is stirred at room temperature for 1.5 hours. The reaction is neutralized to pH 7 with a sodium bicarbonate solution and the resulting solids are filtered. The acetone is removed in vacuo and the residue is partitioned between ether and brine. The ether extract is dried (Na2SO4) and evaporated in vacuo to give 2-methyl-6-oxo-hept-1-ene as a pale yellow liquid (6.4 g): nmr (CDCl3,δ) 1.7 (br s, CH3 --C=), 2.12 (s, CH3C=O), 2.4 (t, J=6 Hz, CH2C=O), 4.69 (br s, 2H, H2C=C).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.COCCOC.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:22]1([C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Br)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(-c3ccccc3)nc2)CC1

Procedure:
1-(6-Bromo-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine (0.89 g, 2.5 mmol), phenyl boronic acid (0.37 g, 3.0 mmol), tetrakis(triphenylphosphine)palladium(0) (0.15 g, 0.12 mmol), 1.2-dimethoxyethane (50 ml), potassium carbonate (1.0 g, 7.5 mmol) and water (7.5 ml) was stirred at reflux overnight. Water (50 ml) was added and the mixture was extracted twice with ethyl acetate (40 ml). Chromatography on silica gel with a mixture of petroleum: ethyl acetate (1:1) gave the title compound as an oil. Yield 0.83 g. 94%.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:20])=[CH:16][CH2:15][CH2:14][CH2:13]4)[CH3:2]>CC(C)=O.[Cr](O)(O)(=O)=O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:20])=[CH:16][CH2:15][CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@H]43)[C@@H]1CC[C@@H]2O
Agent: O=[Cr](=O)(O)O
Solvent: CC(C)=O
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@H]43)[C@@H]1CCC2=O
Yield: 83.4 %

Procedure:
Dissolve 13β-ethyl-gon-4-en-17β-ol (0.29 g.) in acetone (40 cc.) and 8N-chromic acid dropwise with stirring until the solution becomes permanently orange and then add isopropanol (3 cc.) and evaporate the solution to small bulk (ca. 5 cc.). Add water and extract the mixture with ether. Wash, dry and evaporate the ethereal solution to obtain 13β-ethyl-gon-4-en-17-one (0.24 g.), m.p. 101°-102° C. Purify by recrystallization from methanol to obtain the pure product, m.p. 102.5°-103.5° C.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([N:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][C:17]1=[O:30])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Al].C(OCC)(=O)C.CCCCCC>C(#N)C>[CH2:9]([N:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]([I:1])[C:17]1=[O:30])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1Cc1ccccc1
Reactant: O=C1CCC(=O)N1I
Agent: [Al]
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=c1c(I)c(OCc2ccccc2)ccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In accordance with a method similar to that described in Bossharth, E.; Desbordes, P; Monteiro, N.; Balme, G. Org. Lett., 5, 2441-2444, 2003, N-Iodosuccinimide (1.390 g, 6.18 mmol) was added to a solution of 1-benzyl-4-benzyloxy-2-pyridone 2 (1.00 g, 3.43 mmol) in acetonitrile (69 mL). The mixture was covered with aluminum foil and stirred at room temperature for 20 h. The reaction mixture was concentrated to afford a crude orange oil. This oil was purified via column chromatography on silica gel (gradient elution with 0-50% ethyl acetate/hexane) to afford an orange solid. Trituration with 50% ethyl acetate/hexane afforded 1-benzyl-4-benzyloxy-3-iodo-2-pyridone 3 as an off-white solid. MS (MH+) 418.0; Calculated 417 for C19H16INO2.
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9](O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:12]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]([NH:23][NH2:24])=O)=[CH:20][C:15]=2[NH:14][CH:13]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1.O=P(Cl)(Cl)Cl>>[C:1]1([S:7][CH2:8][C:9]2[S:34][C:21]([C:19]3[CH:18]=[CH:17][C:16]4[NH:12][CH:13]=[N:14][C:15]=4[CH:20]=3)=[N:23][N:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(O)CSc1ccccc1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(SCc2nnc(-c3ccc4[nH]cnc4c3)s2)cc1

Procedure:
The compound was synthesized starting from (phenylthio)acetic acid (169 mg; 1 mmol), benzimidazol-5-carbohydrazide (176 mg; 1 mmol), Lawesson's reagent (606 mg; 1.5 mmol) and POCl3 (0.137 ml; 1.5 mmol) as described in method 3; yield: 0.019 g (5.9%); MS m/z: 325.7 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 4.77 (s, 2H); 7.21-7.25 (m, 1H); 7.31-7.35 (m, 2H); 7.43-7.45 (m, 2H); 7.79 (d, 1H, 3J=8.3 Hz); 7.89 (dd, 1H, 4J=1.7 Hz, 3J=8.3 Hz); 8.21 (br s, 1H); 8.83 (s, 1H); HPLC (METHOD [A]): rt 12.30 min (95.2%)
Reaction SMILES: C(OC([N:11]1[CH:16]2[CH2:17][NH:18][CH2:19][CH:12]1[CH2:13][O:14][CH2:15]2)=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].I[CH:27]([CH3:29])[CH3:28]>CN(C=O)C.CCOC(C)=O.CO.[Pd]>[CH:27]([N:18]1[CH2:17][CH:16]2[NH:11][CH:12]([CH2:13][O:14][CH2:15]2)[CH2:19]1)([CH3:29])[CH3:28]
Reactant: O=C(OCc1ccccc1)N1C2CNCC1COC2
Reactant: CC(C)I
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N1CC2COCC(C1)N2
Temperature: 80 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
To a solution of 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound X) (100 mg, 0.33 mmol) in DMF (5 mL) was added K2CO3 (91 mg, 0.66 mmol) and 2-iodopropane (111 mg, 0.66 mmol). The reaction mixture was heated to 80° C. and stirred for 16 hours. The mixture was diluted with EtOAc (60 mL), and then washed with sat. NH4Cl, sat. NaHCO3 and brine (20 mL) respectively. The organic layer was dried over Na2SO4, and then concentrated to give the crude product which was dissolved in MeOH (20 mL). To the solution was added 10% Pd on carbon (20 mg). The mixture was stirred under one atmosphere pressure of H2 at room temperature. After the reaction was completed, the mixture was filtered and concentrated to give the crude 7-isopropyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane (Compound AA) (32 mg, 57%) which was directly used for next step. MS: calc'd (MH+) 171, measured (MH+) 171.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=4)[N:19]=3)[N:14](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=1)[CH2:5]2.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:28])=[O:29])=[CH:25][CH:26]=4)[N:19]=3)[NH:14][CH:13]=1)[CH2:5]2
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N2Cc4cc(Br)ccc4C2=O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]cc(N4Cc5cc(Br)ccc5C4=O)c3n2)cc1
Reaction time: 8 h
Yield: 50.1 %

Procedure:
5-bromo-2-[2-(4-isopropylsulfonylphenyl)-5-trityl-pyrrolo[2,3-b]pyrazin-7-yl]isoindolin-1-one (50 mg, 0.06634 mmol) suspended in DCM (2 mL) under N2 and triethylsilane (53 μL, 0.3317 mmol) then TFA (300 μL, 3.894 mmol) added. RM stirred overnight then concentrated. Residue partitioned between DCM and saturated NaHCO3 solution. Organic phase washed with brine then dried and concentrated to a yellow solid. Dried at 60° C. in a vacuum oven to give title compound as a pale yellow solid (17 mg, 49%); 1H NMR (400 MHz, DMSO) δ1.22 (6H, d), 3.50 (1H, sep), 5.54 (2H, s), 7.77 (2H, s), 7.99 (2H, d), 8.08 (1H, s), 8.51-8.55 (3H, m), 9.11 (1H, s), 12.36 (1H, brs) ppm; MS (ES+) 512.0.
Reaction SMILES: N[C:2]1([C:12]([O:14][CH3:15])=[O:13])[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH2:3]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].Cl.[N:22]1C=CC=CC=1>>[CH3:16][S:17]([NH:22][C:10]1[CH:11]=[C:2]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:19])=[O:18]
Reactant: COC(=O)C1=CC=CC(N)(C(=O)OC)C1
Reactant: c1ccncc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: COC(=O)c1cc(NS(C)(=O)=O)cc(C(=O)OC)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of dimethyl 3-aminoisophthalate 25.3 g (121 mmol), methanesulfonyl chloride 10 mL (130 mmol) and pyridine (50 mL) was stirred at 50° C. for 4 hours. The reaction solution was poured into a 0.5 N hydrochloric acid (300 mL), and the precipitated solid was collected by filtering, washed with 0.5 N hydrochloric acid and dried under vacuum to give 34.8 g (121 mmol) of the title compound (yield: 100%).