Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@:9]23[CH2:24][C@H:16]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.CN(C1C=CC=CN=1)C.Cl.C(N=C=NCCCN(C)C)C.[CH2:46]([O:48][CH2:49][C:50](O)=[O:51])[CH3:47].[OH-].[Na+]>C(Cl)Cl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]2[C@H:16]3[CH2:24][C@:9]([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:50](=[O:51])[CH2:49][O:48][CH2:46][CH3:47])[CH2:3][CH2:4]4)([C:10]4[C:15]3=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:22]=2[CH:21]=1
Reactant: CCOCC(=O)O
Reactant: NC1CCN(C[C@@]23C[C@@H](c4ccccc42)c2ccc(Cl)cc23)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CCOCC(=O)NC1CCN(C[C@@]23C[C@@H](c4ccccc42)c2ccc(Cl)cc23)CC1
Reaction time: 18 h
Yield: 85.5 %

Procedure:
To a stirred solution of 4-amino-1-[(9S,10S)-2-chloro-9,10-dihydro-9,10-methanoanthracene-9-ylmethyl]piperidine (752 mg, 2.22 mmol), dimethylaminopyridine (542 mg, 4.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (848 mg, 4.44 mmol), in methylene chloride (15 mL) was added ethoxyacetic acid (0.25 mL, 2.44 mmol). After stirring for 18 h, the mixture was treated with 1N sodium hydroxide (75 mL), and extracted with methylene chloride (3×75 mL). The combined extracts were washed with 1N sodium hydroxide (2×75 mL) and brine (50 mL), dried (sodium sulfate), filtered and concentrated to give a milky white syrup. Chromatography of this material over silica gel (eluant: ethyl acetate) provided the title compound as a colorless glass (807 mg, 86%), mp 68.0°-70.0° C.; MS(CI): 425 (M+H); [α]D23 =+41° (c=0.01, CHCl3); NMR (300 MHz,DMSO-d6): 1.13(t, 3H, J=7.0 Hz), 1.49(m, 2H), 1.61(m, 2H), 2.26(m, 2H, J=11.9 Hz), 2.46(br s, 2H), 2.94(m, 2H), 3.33(m, part. submerged, 2H), 3.43(q, 2H, J=7.0 Hz), 3.62(m, 1H), 3.78(s, 2H), 4.33(s, 1H), 6.94(m, 3H), 7.23(br m, 4H), 7.48(d, 1H, J=8.3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]([C:18]1[O:22][N:21]=[C:20]([NH2:23])[CH:19]=1)([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:23][C:20]2[CH:19]=[C:18]([C:15]([CH3:17])([CH3:16])[C:14]([F:24])([F:13])[F:25])[O:22][N:21]=2)=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: CC(C)(c1cc(N)no1)C(F)(F)F
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(c1cc(NC(=O)Cc2ccc(Br)cc2F)no1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.4 %

Procedure:
To a mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (100 mg, 0.429 mmol) in DCM (50 mL) was added 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine (92 mg, 0.472 mmol), HATU (245 mg, 0.644 mmol) and Et3N (0.179 mL, 1.287 mmol). Then the mixture was stirred at 25° C. for 12 h. The mixture was concentrated and the crude material was purified by preparative TLC (PE/EA=2:1, Rf=0.4) to yield a yellow oil of 2-(4-bromo-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (50 mg, 0.109 mmol, 25.4% yield): 1H NMR (400 MHz, CDCl3) δ: 8.12 (s., 1H) 7.35-7.27 (m, 2H) 7.23-7.18 (m, 1H) 6.95 (s, 1H) 3.72 (s, 2H) 1.55 (s, 6H); ES-LCMS m/z 411 (M+2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1.[CH:22](OC)(OC)OC>CN(C=O)C.Cl.C(Cl)Cl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:22][N:9]([CH:10]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[C:3]=2[CH:4]=1
Reactant: COC(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)ccc2N)C1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cnc3ccc(Br)cc32)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of tert-butyl 3-((2-amino-5-bromophenyl)amino)pyrrolidine-1-carboxylate (320 mg, 0.938 mmol), HC(OCH3)3 (5 mL) in DMF (10 mL) was added concentrated HCl (two drops). The mixture was then stirred at room temperature for 16 h before concentration. The residue was then diluted with DCM (50 mL) and washed with saturated NaHCO3 solution (25 mL), water (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the crude desired product (250 mg, Yield 80%) which was used on the next step without further purification. LCMS (m/z): 366.1 (M+1).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][N:6]=1.O>C(#N)C>[Cl:4][C:5]1[N:6]=[CH:7][C:8]([CH2:11][NH:3][CH2:1][CH3:2])=[CH:9][CH:10]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CCN
Solvent: CC#N
Solvent: O
Product: CCNCc1ccc(Cl)nc1
Reaction time: 0.25 h
Yield: 82 %

Procedure:
65-70% ethylamine solution (70 g, 1 mol), acetonitrile 50 mL were added into a three necked round bottom flask mounted with pressure-equalizing dropping funnel and thermometer. The solution was stirred in ice bath for 15 min to control the temperature near 0° C. Then, 2-chloro-5-(chloromethyl)pyridine (16.10 g, 0.10 mol) in 25 ml acetonitrile was added by pressure-equalizing dropping funnel in 3.5 hrs with a speed of 3 drop/min. After completion, water was added and the reaction mixture was extracted with DCM. The organic phase was collected, thereby obtaining 14 g N-((6-chloropyridin-3-yl)methyl)ethanamine as oil with 70% yield. GC-MS: m/z (%)=170 ([M]+, 20), 155 (80), 126 (100), 114 (10), 90 (12).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=3[O:22][CH3:23])=[CH:7][N:8]=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1.[CH2:72]([SH:79])[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:72]([S:79][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=3[O:22][CH3:23])=[CH:7][N:8]=[N:9]2)=[CH:4][CH:3]=1)[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1
Reactant: SCc1ccccc1
Reactant: COc1cc(C(F)(F)F)ccc1-c1cnnc2cc(Cl)ccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(C(F)(F)F)ccc1-c1cnnc2cc(SCc3ccccc3)ccc12
Yield: 78.5 %

Procedure:
To a 2-5 ml microwave vial charged with 7-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)cinnoline (0.140 g, 0.413 mmol) was added Xantphos (0.048 g, 0.083 mmol), Pd2(dba)3 (0.038 g, 0.041 mmol), dioxane (1.653 ml) DIEA (0.144 ml, 0.827 mmol) and benzyl mercaptan (0.051 ml, 0.434 mmol). The mixture was purged with argon and microwave irradiated at 140° C. for 10 hrs. The mixture was filtered through diatomaceous earth, dried under reduced pressure and the crude residue purified with a 40 g HP silicycle column (SiliCycle, Inc. Quebec City, Canada) ramping EtOAc in heptane (0 to 50%, 5% DCM throughout) providing 7-(benzylthio)-4-(2-methoxy-4-(trifluoromethyl)phenyl)cinnoline (0.138 g, 0.324 mmol, 78% yield) as an off-white solid. m/z (ESI) 427.3 (M+H)+.
Reaction SMILES: [C@@H:1]1([OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[OH:7].[C:9](=O)(OC)[O:10]C.C[O-].[Na+]>>[O:7]1[CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]2[O:8][C:9]1=[O:10]
Reactant: O[C@@H]1CCCC[C@H]1O
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: O=C1OC2CCCCC2O1
Yield: 93 %

Procedure:
Into 10 g (86 mmol) of trans-1,2-cyclohexanediol (CAS No. 1460-57-7) and 87.7 g (86 mmol) of dimethyl carbonate was added 0.5 g (9 mmol) of sodium methoxide. The resulting mixture was refluxed for 1 hour. After methanol was removed from the mixture, rectification was carried out. A purified hexahydro-1,3-benzodioxol-2-one (trans isomer) was recovered with a yield of 93%.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)#[N:20].CS(C)=O.[OH-].[Na+]>O>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Oc1ccccc1
Reactant: N#Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc([N+](=O)[O-])c(Oc3ccccc3)c2Cl)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 14.2 gm of 2,3-dichloro-6-nitro-1-phenoxy-benzene, 6.5 gm of 4-cyano-phenol, 40 ml of dimethylsulfoxide and 50 ml of 10 N sodium hydroxide was stirred for 3 hours at 100° C. Thereafter, the reaction mixture was diluted with water, the aqueous mixture was extracted with chloroform, the organic extract solution was dried, and the chloroform was distilled off. The residue was purified by passing it through a silicagel column and recrystallizing it from ethanol, yielding 11 gm (60.2% of theory) of the colorless crystalline title compound, m.p. 140°-142° C.
Reaction SMILES: [OH-].[K+].[CH:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:16]3[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=3[NH:14][C:12](=[O:13])[CH:11](C([O-])=O)[N:10]=2)=[CH:7][CH:8]=1.O[K].[K+].S(OC)(O[CH3:32])(=O)=O.C(OC(C)C)(C)C.C(=O)=O>CCOCC.C(O)(=O)C.O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]2[N:14]([CH3:32])[C:12](=[O:13])[CH2:11][N:10]=[C:9]([C:6]3[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=3)[C:16]=2[CH:17]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C([O-])C1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
Agent: O=C=O
Agent: O[K]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reaction time: 2 h
Yield: 80 %

Procedure:
An aqueous solution prepared by dissolving 7 g. of potassium hydroxide in 15 ml. of water is added to an aqueous solution of 3 g. of compound 4306 CB, then 1.8 g. of dimethyl sulphate is gradually added (about 5 minutes) with stirring, care being taken that the temperature does not rise above 25°C. After the addition is ended, the mixture is left for 2 hours at room temperature, then acidified with acetic acid. A pasty product separates which is covered with diisopropyl ether, and the suspension thus formed is heated to boiling for a few minutes; evolution of carbon dioxide takes place. The product is cooled, diluted with ether and the aqueous phase is separated. Upon evaporation of the solvent, there is obtained a residue which is crystallized from diisopropyl ether. Yield: 80%; m.p. 132°C. The product is identical with the product obtained according to Example 16.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][NH2:16])=[CH:5][CH:4]=1.Cl[CH2:18][C:19]([NH2:21])=[O:20].C(=O)(O)[O-].[Na+].CCOCC.CCCCC>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][NH:16][CH2:18][C:19]([NH2:21])=[O:20])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccccc2CN)cc1
Reactant: NC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: CCCCC
Product: COc1ccc(-c2ccccc2CNCC(N)=O)cc1

Procedure:
A reaction vessel was charged with 800 mg (3.8 mmole) of [(4-methoxyphenyl)phenyl]methylamine dissolved in 30 ml of absolute ethanol together with 340 mg (3.7 mmole) of chloracetamide and 330 mg (4 mmole) of sodium bicarbonate. The suspension was brought to reflux and held at reflux for 3 days. Solvent was evaporated and the residue was dissolved in dichloromethane and water. The organic phase was dried over potasium carbonate and the solvent evaporated under reduced pressure. The oil obtained was solidified by stirring in an ether pentane mixture. The solid was crystallized in cyclohexane with a few drops of ethyl acetate.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C:15](=O)[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:11]=[CH:12][C:13]=1[Cl:14]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[C:10]([C:15](=[CH2:1])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)CCC(=O)c1ccc(Cl)c(Cl)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: c1ccccc1
Product: C=C(CCC(=O)OC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.9 %

Procedure:
330 mg (0.92 mmole) of methyltriphenylphosphonium bromide and 105 mg (0.94 mmole) of potassium t-butoxide were suspended in 4 ml of dried benzene, and the mixture was stirred under a stream of nitrogen at room temperature for 4 hours. A solution prepared by dissolving 200 mg of methyl 4-(3,4-dichlorophenyl)-4-oxobutanoate [prepared as described in step (a) above] in 1 ml of benzene was added to the reaction mixture, and the mixture was then stirred for 18 hours. At the end of this time, the reaction mixture was filtered through a Celite (trade mark) filter aid and washed with diethyl ether. The filtrate was then concentrated by evaporation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a 23:2 by volume mixture of hexane and diethyl ether as the eluent, to give 95 mg (yield 64%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]1.C(N(CC)CC)C>ClCCl>[C:9]([N:12]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]1)([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(O)C1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
A solution of 35.6 ml of benzylchloroformate in 200 ml of dichloromethane was added dropwise to a mixture of 10 g of (racemic)-3-pyrrolidinol, 48.3 ml of triethylamine and 725 ml of dichloromethane which was cooled to 0° C. The mixture was stirred for 48 hours at room temperature. The dichloromethane solution was extracted with 5% hydrochloric acid and 5% aqueous sodium bicarbonate. The acid and bicarbonate washes were combined, salted with sodium chloride and extracted with 2×750 ml of ethyl acetate. The combined organic extracts were dried and concentrated, giving 22.7 g of (racemic)-N-carbobenzyloxy-3-pyrrolidinol. A mixture of 2.5 g of (racemic)-N-carbobenzyloxy-3-pyrrolidinol, 2.0 ml of methyl iodide and 5.1 g of silver oxide in 50 ml of dimethylformamide was stirred at room temperature for 2 days. The mixture was diluted with ether and then filtered. The filtrate was concentrated to a small volume. The ether solution was washed with water, dried and concentrated to dryness in vacuo. The residue was purified by chromatography (silica gel) to give 2.4 g of (racemic)-N-carbobenzyloxy-3-methoxypyrrolidine as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[OH-].[Na+].P(=O)(O)(O)O.S(=O)(=O)(O)O>C(O)C.Cl.O.C(OCC)(=O)C>[C:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: O=C1CCCCC1
Reactant: Nc1ccccc1
Agent: Cl
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(C2=CCCCC2)cc1
Yield: 49 %

Procedure:
This compound was prepared similarly as described in J. v. Braun et al., J. Liebigs Ann. Chem., 472 (1929), 1-89, from refluxing aniline (2 equivalents), cyclohexanone (1 equivalent) in ethanol and 37% hydrochloric acid for 4-5 days, followed by addition of ethyl acetate, water, and sodium hydroxide, neutralisation with 85% phosphoric acid, phase separation, and distillation of the organic phase. The residue was added a catalytic amount of sulphuric acid and distilled (180° C., 5-7 mbar). The distillate was redistilled (120° C., 3 mbar) to afford (in the residue) a 49% yield of the desired 4-cyclohex-1-enylaniline.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[S:11][C:10]([C:15]([O:17]CC)=[O:16])=[CH:9][C:8]2=[O:20])[CH:2]=[CH2:3].C(=O)(O)[O-].[Na+].CO>O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[S:11][C:10]([C:15]([OH:17])=[O:16])=[CH:9][C:8]2=[O:20])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc2sc(C(=O)OCC)cc(=O)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CCOc1ccc2sc(C(=O)O)cc(=O)c2c1

Procedure:
A mixture of 3 parts of ethyl 6-allyloxy-1-thiachromone-2-carboxylate, 0.87 parts of sodium bicarbonate and 4 parts of methanol in 25 parts of water was heated under reflux for several minutes then the methanol was distilled. The aqueous solution was diluted with 25 parts of water, filtered and acidified with concentrated hydrochloric acid to give a precipitate which was filtered off, washed with water and dried to give 2.6 parts of 6-allyloxy-1-thiachromone-2-carboxylic acid, melting point, 200°-200.5°C.
Reaction SMILES: [CH2:1]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Cl)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[F:14][C:15]1[C:20]([F:21])=[C:19]([C:22]#[N:23])[CH:18]=[CH:17][C:16]=1[OH:24].[O-]CC.[Na+]>C(O)C>[CH2:1]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][O:24][C:16]2[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[C:20]([F:21])[C:15]=2[F:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: N#Cc1ccc(O)c(F)c1F
Reactant: CCCCCc1ccc(CCl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCc1ccc(COc2ccc(C#N)c(F)c2F)cc1

Procedure:
A mixture of 0.12 mole of p-pentylbenzyl chloride and 20 ml of ethanol is added to a mixture of 0.1 mole of 2,3-difluoro-4-cyanophenol (prepared as in Example 1) and 0.1 mole of sodium ethoxide in 60 ml of ethanol, and the mixture is heated at the boil for 5 hours. After the ethanol has been distilled off, the reaction mixture is allowed to cool and is poured onto 15 ml of 5% aqueous sodium hydroxide solution. Working up in the customary manner gives 4-(4-pentylbenzyloxy)-2,3-difluorobenzonitrile.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:15][OH:16]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[N:15][OH:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Reactant: NO
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc2c(c1)C(=NO)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 7-nitro-3,4-dihydro-2H-naphthalen-1-one (500 mg, 2.62 mmol) in pyridine (2 mL) was added hydroxylamine solution (1 mL, ˜50% solution in water). The reaction was stirred at room temperature for 1 h, then concentrated and purified by column chromatography (10-50% ethyl acetate-hexanes) to yield 7-nitro-3,4-dihydro-2H-naphthalen-1-one oxime (471 mg, 88%). HPLC ret. time 2.67 min, 10-99% CH3CN, 5 min run; ESI-MS 207.1 m/z (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH2:17][CH3:18])[C:10]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:3]=1[Cl:24].Cl[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[C:28](F)[C:27]=1OCC.NC1C(F)=C(Cl)N=C(C(OC)=O)C=1Cl.[F-].[Cs+].P(C1C=C(S([O-])(=O)=O)C=CC=1)(C1C=C(S([O-])(=O)=O)C=CC=1)C1C=C(S([O-])(=O)=O)C=CC=1.[Na+].[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(#N)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH2:17][CH3:18])[C:10]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH2:23][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:21])[C:3]=1[Cl:24].[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH2:17][CH3:18])[C:10]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:3]=1[Cl:24]
Reactant: CCOc1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCOc1c(Cl)ccc(-c2nc(C(=O)OC)c(Cl)c(N)c2F)c1F
Solvent: O
Solvent: CC#N
Product: CCOc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)c(Cl)c(N)c2F)c1F
Temperature: 150 °C

Procedure:
Methyl 4-amino-3-chloro-6-(4-chloro-3-ethoxy-2-fluorophenyl)-5-fluoropicolinate (Compound A). 2-(4-Chloro-3-ethoxy-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg, 1.7 mmol, 1.0 equiv) and methyl 4-amino-3,6-dichloro-5-fluoropicolinate (400 mg, 1.7 mmol, 1.0 equiv) were sequentially added to a 5 mL Biotage microwave vessel, followed by CsF (510 mg, 3.3 mmol, 2.0 equiv), palladium(II) acetate (19 mg, 0.084 mmol, 0.05 equiv), and sodium 3,3′,3″-phosphinetriyltribenzene-sulfonate (95 mg, 0.17 mmol, 0.10 equiv). A 3:1 mixture of water-acetonitrile (3.2 mL) was added, and the resulting brown mixture was heated in a benchtop microwave at 150° C. for 5 min. The cooled reaction mixture was diluted with water (150 mL) and extracted with CH2Cl2 (4×50 mL). The combined organic extracts were dried (MgSO4), gravity filtered, and concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (eluting with 33% EtOAc/hexane) to afford the desired product, methyl 4-amino-3-chloro-6-(4-chloro-3-ethoxy-2-fluorophenyl)-5-fluoropicolinate as a tan powder (450 mg, 63%): mp 170-172° C.; IR (thin film) 3485 (m), 3380 (s), 2951 (w), 1739 (s), 1610 (s) cm−1; 1H NMR (300 MHz, CDCl3) δ 7.20-7.30 (m, 2H), 4.95 (br s, 2H), 4.19 (q, J=7 Hz, 2H), 3.98 (s, 3H), 1.43 (t, J=7 Hz, 3H); ESIMS m/z 377 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].C([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29]CC1C=CC=CC=1)[CH2:24]Cl)C1C=CC=CC=1.[H-].[Na+]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:24][C:23]3[CH:26]=[CH:27][C:28]([OH:29])=[C:21]([OH:20])[CH:22]=3)[C:6]=2[C:5](=[O:11])[N:4]([CH2:24][C:23]2[CH:26]=[CH:27][C:28]([OH:29])=[C:21]([OH:20])[CH:22]=2)[C:3]1=[O:12]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: ClCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(Cc2ccc(O)c(O)c2)c(=O)c2c1ncn2Cc1ccc(O)c(O)c1
Temperature: 60 °C
Yield: 78 %

Procedure:
A solution of 3-methyl xanthine (200 mg, 1.2 mmol) in N,N-dimethylformamide (5 ml) was treated with 3,4-bis-benzyloxy-benzyl chloride (Lot #PRO-04-36B, 1.02 g, 3 mmol) and NaH (96 mg, 4 mmol) and 0.5 equivalent tetrabutyl ammonium iodide and was heated to 60° C. for 12 hrs. The reaction mixture was poured in water and extracted with ethyl acetate (3×30 ml). The combined organic extract was washed with water, brine solution (30 ml) each and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the product was purified by flash column chromatography over silica gel using 40% ethyl acetate/hexane to yield the desired product, 600 mg, 78% yield. This product was dissolved in ethyl acetate (25 ml) and methanol (10 ml) and acetic acid (1 ml) and hydrogenated in presence of 10% Pd—C at 55 PSI for 2 hr. Catalyst was filtered off and the solvent was removed under reduced pressure. The residue was purified on a silica gel column eluting with 50% ethyl acetate in hexane to 100% ethyl acetate. The desired product was isolated as an off white solid, Yield=400 mg PD 151.