Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([CH2:9][C:10]([NH2:12])=[O:11])#[N:8].[CH3:13][CH:14]([CH2:20][CH3:21])/[CH:15]=[CH:16]/[C:17](=O)[CH3:18].O=O.Cl>CS(C)=O.O>[CH:14]([C:15]1[CH:16]=[C:17]([CH3:18])[NH:12][C:10](=[O:11])[C:9]=1[C:7]#[N:8])([CH2:20][CH3:21])[CH3:13]
Reactant: CCC(C)/C=C/C(C)=O
Reactant: N#CCC(N)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=O
Solvent: CS(C)=O
Solvent: O
Product: CCC(C)c1cc(C)[nH]c(=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a stirred solution of t-BuOK (8 g, 71.42 mmol) and cyanoacetamide (6.6 g, 78.57 mmol) in DMSO (80 mL) was added (E)-5-methylhept-3-en-2-one, 2 (9 g, 71.42 mmol) under argon atmosphere at room temperature. The reaction mixture was stirred at room temperature for 1 h and then added additional t-BuOK (24 g, 214.28 mmol) was added. Then argon was displaced by oxygen and stirred at RT for 48 h. The reaction mixture was cooled to 0° C., diluted with water (36 mL) followed by 4N HCl (up to pH˜4) and the resulting reaction mixture was stirred for 15 min. The separated solid was collected by filtration, washed with water (10 mL), pet ether (100 mL) and dried to afford the title compound as yellow solid (7 g, 53%). 1H NMR (DMSO-d6, 400 MHz): δ 0.816-0.779 (t, 3H, J=7.6 Hz), 1.178-1.161 (d, 3H, J=6.8 Hz), 1637-1.505 (m, 2H), 2.24 (s, 3H), 2.814-2.760 (m, 1H), 6.239 (s, 1H), 12.324 (bs, 1H); LCMS (ES−) m/z=189.20 (M−H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH:12]([CH3:14])[CH3:13].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:41])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:41])=[CH:6][C:5]=1[O:11][CH:12]([CH3:13])[CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1OC(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1OC(C)C
Temperature: 70 °C
Yield: 50.8 %

Procedure:
The mixture of 2-isopropoxy-4-methyl-benzoic acid methyl ester (1.0 g, 4.8 mmol), dibenzoyl peroxide (100 mg), and NBS (0.85 g, 4.8 mmol) in CCl4 (20 mL) is heated at 70° C. overnight. The solid is filtered off and the filtrate is concentrated to a residue. The residue is purified by flash chromatography to afford the title compound as white solid (0.7 g, 51%). LC-ES/MS m/e 287.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][C:3]=1[O:18][CH3:19].[C:20](OC(=O)C)(=O)C>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:17])[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH2:20])[CH:5]=[CH:4][C:3]=1[O:18][CH3:19]
Reactant: COc1ccc(C(=O)Cc2ccccc2)c(Cl)c1Cl
Reactant: CC(=O)OC(C)=O
Product: C=C(C(=O)c1ccc(OC)c(Cl)c1Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Acetic anhydride (150 ml.) is added dropwise to a suspension of 2,3-dichloro-4-phenylacetylanisole (8.95 g., 30.3 mmol) in 15.3 ml. of N,N,N',N'-tetramethylenediaminomethane under an atmosphere of argon with ice-bath cooling. The reaction mixture stirred at 25° for 2 hrs. and poured into ice-water affords 11.9 g. of beige solid. An ethereal solution of the solid is washed with hydrochloric acid, water and then dried over magnesium sulfate. Removal of the solvent under reduced pressure provides 8.77 g. (94% yield) of 2,3-dichloro-4-(2-phenylacryloyl)anisole, m.p. 83.5°-86°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:14]O)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.C1(C)C=CC(S([Cl:32])(=O)=O)=CC=1.CCOC(C)=O>C(Cl)Cl>[Cl:32][CH2:14][C:6]1[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cc(CO)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(CCl)cc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 52.8 %

Procedure:
Dissolve [3-nitro-5-(trifluoromethyl)phenyl]methanol (1.1 g, 5.18 mmol) and triethylamine (1.62 mL) in DCM (20 mL), cool to 0° C., add slowly p-toluenesulfonyl chloride (1.1 g, 6.02 mmol). After the addition, stir the reaction at room temperature for 15 hrs. TLC (EtOAc:PE=1:15) shows the reaction is complete. Concentrate under reduced pressure to get the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:15) affords the title compound (655 mg, 55%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 4-hydroxybenzaldehyde (10 g, 81.9 mmol) in DMF (200 mL) was added K2CO3 (14.7 g, 106 mmol), tetrabutylammonium iodide (3.06 g, 8.2 mmol) and 4-methoxybenzyl chloride (14.1 g, 90 mmol). The reaction mixture was stirred for 14 h at rt and then poured into ice water. The product 4-(4-methoxy-benzyloxy)-benzaldehyde was isolated by filtration.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1.CN1CCOCC1.[C:25]1([CH2:31][S:32](Cl)(=[O:34])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:31]([S:32]([NH:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1)(=[O:34])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a solution of 3-amino6methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (960 mg, 4.0 mmol), as prepared in the preceding step, and N-methylmorpholine (840 μL, 8.0 mmol) in methylene chloride (40 mL) was added α-toluenesulfonyl chloride (765 mg, 4.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. Additional methylene chloride (50 mL) was added. The resulting methylene chloride solution was washed with saturated NaHCO3 (2×50 mL), 10% citric acid (3×50 mL) and brine (50 mL), and dried over Na2SO4. The solvent was concentrated to give a solid which was washed with ethyl acetate hexane (1:2, 60 mL) to give the title compound as a white solid (1.4 g, 89%). 1H-NMR (300 MHz, CDCl3) δ 7.35 (d, J=7.5 Hz, 1H), 7.31 (m, 5H), 7.20 (s, 1H), 6.02 (d, J=7.4 Hz, 1H), 4.75 (s, 2H), 4.31 (s, 2H), 2.27 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:15](=O)[CH:14]2[NH:17][CH:11]([CH2:12][CH2:13]2)[C:10]1=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:2]([N:9]1[CH2:15][CH:14]2[NH:17][CH:11]([CH2:12][CH2:13]2)[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1C2CCC(N2)C(=O)N1Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CN2CC3CCC(C2)N3)cc1
Reaction time: 0.5 h
Yield: 101.3 %

Procedure:
3-Benzyl-3,8-diazabicyclo[3.2.1]octan-2,4-dione (28 g, 0.10 mol; from step (d) above) was added in portions to a suspension of LiAlH4 (19 g, 0.50 mol) in THF (500 mL). After addition of the solid, the reaction was slowly warmed to reflux, and then refluxed overnight. The reaction was cooled in an ice bath. To the cold reaction mixture there was added sequentially H2O (19 mL), 15% NaOH solution (19 mL) and H2O (57 mL). The resulting mixture was stirred for 30 min then filtered through a pad of Celite®. The filtrate was concentrated in vacuo to afford 20.5 g (86%) of the sub-title compound as a golden oil. A hydrochloride salt may be obtained from CH3CN and a solution of hydrogen chloride in EtOAc.
Reaction SMILES: [NH2:1][C:2]1[S:20][C:5]2[CH2:6][N:7](C(OCC3C=CC=CC=3)=O)[CH2:8][CH2:9][C:4]=2[C:3]=1[C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Br.CCCCCC.[OH-].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[S:20][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:21](=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCN(C(=O)OCc1ccccc1)C2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: O
Product: Nc1sc2c(c1C(=O)c1ccccc1)CCNC2
Yield: 92 %

Procedure:
To a cooled and stirred suspension of protected 2-amino-3-benzoyl-6-benzyloxycarbonyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (0.01 mol) in acetic acid (2 mL), as prepared in Example 7, was added a solution of HBr (33%) in acetic acid (10 mL). After stirring at room temperature for 4 h (TLC control), n-hexane was added and the resulting suspension was evaporated under vacuum to give a solid which was dissolved in water (10 mL) and neutralized with NaOH (5% solution). The precipitated solid was chromatographed on a silica gel column eluting with ethyl acetate and petroleum ether mixture to give 2-amino-3-benzoyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine. (m.p.160-162° C., 92% yield). 1H-NMR (CDCl3): 1.86 (m, 1 H); 1.95 (m, 2H); 2.79 (t, 2H); 3.79 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:10]([OH:12])=O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].P(Cl)(Cl)(Cl)=O>C(#N)C>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:10](=[O:12])[CH:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:13][S:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(CSc2cccc(OC)c2)C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C2CSc3cc(OC)ccc3C2=O)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To acetonitrile solution (120 ml) of 2-(4-methoxyphenyl)-3-(3-methoxyphenylthio)propionic acid (4) (12.8 g, 40.3 mmol) obtained above was added potassium carbonate (1.59 g, 11.5 mmol) and phosphorus oxychloride (18.7 ml, 200 mmol) at 0° C. and then stirred for 18 hours at 60° C. The reaction solution was quenched with ice-water and extracted with ether. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent. The obtained crude product was washed with ether to obtain 6.8 g of the first crop of 7-methoxy-3-(4-methoxyphenyl)thiochroman-4-one (5). Further, the filtrate was concentrated and the residue was then purified with silica gel column chromatography (ethyl acetate:hexane=1:3) to obtain 1.0 g of the second crop of 7-methoxy-3-(4-methoxyphenyl)thiochroman-4-one (5) (total yield: 7.8 g, 65%). NMR data of the compound (5) was identical to that described in Example 25.
Reaction SMILES: [O:1]([CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH2:2][CH3:3].C([Li])CCC.[CH2:15]([N:18]([CH2:32][CH2:33][CH3:34])[C:19]([C:21]1[CH:22]=[C:23]([CH:28]=[C:29](I)[CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])=[O:20])[CH2:16][CH3:17]>O1CCCC1.C(OCC)C.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH2:32]([N:18]([CH2:15][CH2:16][CH3:17])[C:19]([C:21]1[CH:22]=[C:23]([CH:28]=[C:29]([C:6]2[N:5]([CH2:4][O:1][CH2:2][CH3:3])[CH:9]=[CH:8][N:7]=2)[CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])=[O:20])[CH2:33][CH3:34]
Reactant: CCCN(CCC)C(=O)c1cc(I)cc(C(=O)OC)c1
Reactant: CCOCn1ccnc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2nccn2COCC)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C. stirred solution of 1-ethoxylmethylimidazole (J. Am. Chem. Soc. 1978, 100, 3918) (420 mg, 3.3 mmol) in tetrahydrofuran (10 mL) is added n-butyllithium (1.6 M in hexanes, 2.3 mL, 3.6 mmol). After 30 min, zinc chloride (9.9 mL of a 1 M solution in diethyl ether, 9.9 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is then added methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate (1.17 g, 3 mmol) followed by palladium(0) tetrakis(triphenylphosphine) (173 mg, 0.15 mmol). The reaction mixture is heated at reflux for 2 h. The reaction mixture is diluted with ethyl acetate (50 mL), washed with water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 1–5% methanol/methylene chloride) provides the title compound in pure form. 1H NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 8.10 (s, 1H), 8.03 (s, 1H), 8.19 (s, 2H), 5.28 (s, 2H), 3.95 (s, 3H), 3.59 (q, J=7 Hz, 2H), 3.49 (m, 2H), 3.21 (m, 2H), 1.70 (m, 2H), 1.54 (m, 2H), 1.25 (t, J=7 Hz, 3H), 0.99 (m, 3H), 0.75 (m, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)(=O)C.O.CN(C)C(=O)C>[CH2:21]([O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[N:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Yield: 207.7 %

Procedure:
L-Phenylalanine (50 g), pulverized potassium carbonate (167 34 g), and sodium iodide (22.68 g) were added to N,N-dimethylacetamide (500 ml) while stirring, and water (25 ml) was added thereto. After elevating the temperature to 60° C., benzyl chloride (118.78 g) was dropwise added. After the dropwise addition, the mixture was vigorously stirred at 60°-65° C. for 6 hours. After the reaction, the reaction mixture was cooled to 20°-30° C., and water (750 ml) and ethyl acetate (500 ml) were added thereto for extraction. The ethyl acetate layer was separated, washed with water (500 ml), an aqueous solution of 10% sodium hydrogensulfite (500 ml×2), and water (500 ml), and concentrated to dryness under reduced pressure to give N,N-dibenzyl-L-phenylalanine benzyl ester (136.88 g) as a yellow, oily substance.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19]C(=O)C)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)(=O)C.Cl>CO>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]=[N:11][C:8]2[CH:9]=[CH:10][C:5]([NH2:4])=[CH:6][CH:7]=2)=[CH:18][CH:17]=1
Reactant: CC(=O)Nc1ccc(N=Nc2ccc(NC(C)=O)cc2)cc1
Agent: Cl
Solvent: CO
Product: Nc1ccc(N=Nc2ccc(N)cc2)cc1
Yield: 76.8 %

Procedure:
Without further purification, 4,4′-bis(acetamido)azobenzene (II) (16.0 g, 0.054 mol) is placed in a 500-mL round-bottomed flask equipped with a condenser and a magnetic stirrer, along with methanol (150 mL) and 6N hydrochloric acid (150 mL). The mixture is heated under reflux for 1.5 hours. The reaction mixture is cooled, and the violet solid is collected on a Büchner funnel. The mixture is heated under reflux for 1.5 hours. The reaction mixture is cooled, and the violet solid collected on a Büchner funnel. The damp product is suspended in 500 mL of water in a 1 L beaker equipped with a stirrer, and the mixture is slowly neutralized by the addition of 2.5N sodium hydroxide, during which the salt dissolves and the free base separates. The crude product is collected on a Büchner funnel, washed with water, and dried under reduced pressure. The yellow powder is then recrystallized from N-methylpyrrolidinone to afford yellow crystals of DAAB (III) (8.8 g, 42%), m.p. 244.5-247.9° C. (dec.). FT-IR (KBr, cm−1): 3417, 3333, 3212 (NH2), 3040, 1627, 1592, 1502, 1294, 1150, 839. 1H-NMR (DMSO-d6, δ in ppm): 5.72 (s, 4H, NH2), 6.61-6.63 (d, 4H, Ar—H), 7.51-7.53 (d, 4H, Ar—H). 13C-NMR (DMSO-d6, δ in ppm): 113.4, 123.7, 143.1, 150.9. Purification of (III) by column chromatography met with limited success due to its poor solubility in most organic solvents.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.CCOC(C)=O>[CH3:11][N:8]1[CH:7]=[C:6]2[C:10]([C:2]([C:14]3[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[CH3:12])=[CH:3][CH:4]=[CH:5]2)=[N:9]1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Reactant: Cn1cc2cccc(Br)c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(-c2cccc3cn(C)nc23)c(C)c1
Temperature: 25 °C
Yield: 50.5 %

Procedure:
7-Bromo-2-methyl-2H-indazole (4; 0.35 g, 1.66 mMol) and Pd(PPh3)4(0) (58 mg, 0.05 mMol) were stirred in 6 mL DME under argon for 30 min. 2,4,6-Trimethylbenzeneboronic acid (0.54 g, 3.3 mMol) was added, immediately followed by a solution of sodium carbonate (0.62 g, 5.8 mMol) in 5 mL water. The mixture was heated at a gentle reflux for 20 hr, then cooled to rt and diluted with EtOAc (75 mL). The mixture was then washed with brine and dried over MgSO4. Evaporation of the solvent afforded a light yellow solid which was flash chromatography on silica and eluted with hexane:EtOAc (9:1) which afforded 4b as a off-white solid 0.21 g (53%).
Reaction SMILES: F[C:2]1[C:3]([CH3:11])=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[Cl:12][C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][C:2]2[C:3]([CH3:11])=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)[CH:16]=[CH:15][N:14]=1
Reactant: Cc1cc([N+](=O)[O-])ncc1F
Reactant: Oc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ncc1Oc1ccnc(Cl)c1
Temperature: 88 °C
Reaction time: 48 h
Yield: 79.9 %

Procedure:
A mixture of 5-fluoro-4-methyl-2-nitropyridine (2 g, 12.81 mmol) and 2-chloro-4-hydroxypyridine (1.66 g, 12.81 mmol) in DMF (26 mL) was sparged with Ar, treated with K2CO3 (2.66 g, 19.22 mmol), heated at 88° C. for 24 h, then at 50° C. for 2 days. The mixture was treated with water and the resulting solid collected via filtration and dried to afford 5-((2-chloropyridin-4-yl)oxy)-4-methyl-2-nitropyridine (2.72 g, 80%). 1H NMR (400 MHz, DMSO-d6): δ 8.49 (s, 1H), 8.47 (s, 1H), 8.35 (d, J=5.7 Hz, 1H), 7.24 (d, J=2.3 Hz, 1H), 7.12 (dd, J=5.7, 2.3 Hz, 1H), 2.32 (s, 3H); MS (ESI) m/z: 266.0 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)[C:7]#[N:8])([O-:3])=[O:2]>[Fe]>[NH2:12][C:10]1[CH:9]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=1)[C:7]#[N:8]
Reactant: N#Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Fe]
Product: N#Cc1cc(N)cc([N+](=O)[O-])c1

Procedure:
3-amino-5-nitrobenzonitrile is prepared by iron reduction of 3,5-dinitrobenzonitrile as in example 9, m.p. 168°-170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]2[C:24]([O:26]CC)=[O:25])=[CH:5][CH:4]=1.[OH-].[Na+].O>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:10]2[C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1C(c2ccccc2)c2ccccc2C1c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C2c3ccccc3C(c3ccccc3)C2C(=O)O)cc1
Yield: 83.4 %

Procedure:
To a solution of ethyl (1RS,2SR,3SR)-1-(4-methoxyphenyl)-3-phenylindane-2-carboxylate, (5.5 g, 14.8 mmol) in EtOH (70 ml) was added 5M NaOH (9 ml, 45 mmol). The resulting mixture was stirred under an argon atmosphere for 1 d, at which time H2O (70 ml) was added. The mixture was concentrated under reduced pressure. The aqueous residue was extracted with Et2O, and the Et2O extracts were discarded. The aqueous phase was acidified with 6M HCl and extracted several times with EtOAc. The combined EtOAc extracts were washed successively with H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo to provide an oily residue which crystallized upon standing. The solid material was recrystallized from EtOAc/hexanes to afford the title compound (4.25 g, 83%); m.p. 164°-166° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[C:12](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:12]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccccc1C(F)(F)F
Yield: 111.8 %

Procedure:
A mixture of 10 g 2-trifluoromethyl phenol, 17 g potassium carbonate, 150 ml acetone and 7.7 ml iodomethane was heated under reflux for 2 hr. After cooling, the insoluble matters were removed by filtration, and the filtrate was evaporated. The resulting residue was dissolved in ethyl acetate, and washed with water and brine. It was dried over anhydrous magnesium sulfate, filtered, and evaporated to give 12.15 g of 2-trifluoromethyl anisole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:16]([N+:17]([O-])=O)[CH2:15][CH2:14][CH:13]([O:20][C:21](=[O:23])[CH3:22])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O)(=O)C>C(O)C.[Zn]>[NH2:17][CH:16]1[CH2:15][CH2:14][CH:13]([O:20][C:21](=[O:23])[CH3:22])[CH2:12][CH:11]1[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C2CC(OC(C)=O)CCC2[N+](=O)[O-])cc1OC
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(C2CC(OC(C)=O)CCC2N)cc1OC

Procedure:
2.1 g of (±)-acetic acid (1SR,3RS,4RS)-3-(3,4-dimethoxyphenyl)-4-nitrocyclohexyl ester (compound C5) are dissolved in 50 ml of ethanol and treated with 2 g of zinc powder. 5 ml of acetic acid are added dropwise at boiling heat. After 1 h the reaction mixture is filtered and the filtrate is concentrated. The residue is used without further purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](SC)=[CH:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[CH3:17][NH2:18]>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([NH:18][CH3:17])=[CH:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CN
Reactant: CSC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1
Solvent: CC#N
Product: CNC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1
Yield: 92.6 %

Procedure:
A mixture of 2.0 g of 1-(6-chloro-3-pyridylmethylamino)-1-methylthio-2-nitroethylene, 1.8 g of 40% aqueous methylamine solution and 20 ml of acetonitrile was refluxed for 3 hours and, then concentrated. The residue was washed with dichloromethane to give 1.73 g of 1-(6-chloro-3-pyridylmethylamino)-1-methylamino-2-nitroethylene. Mp 181°-183° C.
Reaction SMILES: [CH2:1]([C:5]1([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:13][C:12]2[C:7](=[C:8]([Cl:16])[C:9]([Cl:15])=[C:10]([OH:14])[CH:11]=2)[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[F:29][C:30]([F:36])([F:35])[S:31](Cl)(=[O:33])=[O:32].O>CN(C)C=O>[CH2:1]([C:5]1([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:13][C:12]2[C:7](=[C:8]([Cl:16])[C:9]([Cl:15])=[C:10]([O:14][S:31]([C:30]([F:36])([F:35])[F:29])(=[O:33])=[O:32])[CH:11]=2)[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CCCCC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC1(C2CCCC2)Cc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Racemic 2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-1H-inden-1-one (34.1 g, 0.1M) was stirred in dimethylformamide (100 ml) with K2CO3 (41.5 g, 0.3M) at 25° for 20 minutes. The mixture was cooled to 15°, and trifluoromethanesulfonyl chloride (19.4 g, 0.115M) was added at 15°-20° over 20 minutes. The mixture was then stirred at 25° for 30 minutes and poured into a liter of ice and water. The oil was extracted with diethyl ether (4×125 ml) and the combined organic extracts were thoroughly washed with water, dried over (MgSO4) and concentrated under vacuum to obtain the product as a viscous amber oil weighing 47.3 g. This product was used in the next step without further purification.