Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[N:9]2[CH:22]=[CH:23][CH:24]=[C:8]2[C:7]=1[OH:25])=[O:5])C.[NH2:26][CH2:27][C:28]([O-:30])=[O:29].[Na+]>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH2:13][N:10]1[C:11](=[O:12])[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])=[C:7]([OH:25])[C:8]2=[CH:24][CH:23]=[CH:22][N:9]12
Reactant: NCC(=O)[O-]
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2ccc(F)cc2F)c1=O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2ccc(F)cc2F)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-(2,4-difluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 378 (M+H)+.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH3:27])=[CH:3]\[C:4](OCC)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1]/[C:2](/[CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH3:27])=[CH:3]\[CH2:4][OH:5]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC/C(C)=C/C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC/C(C)=C/CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
Ethyl (2E,7Z,10Z,13Z,16Z,19Z)-3-methyl-docosa-2,7,10,13,16,19-hexaenoate (2E:2Z=9:1), (0.40 g, 1.08 mmol) was dissolved in dry THF (5 mL) and added dropwise to a cold suspension of LAH (0.045 g, 1.19 mmol) in dry THF (10 mL). The mixture was stirred at 0° C. under inert atmosphere for 30 minutes, followed by 18 hours at ambient temperature. The reaction was quenched by addition of 10% NH4Cl (20 mL) and the mixture was extracted twice with heptane (30 mL). The combined organic extracts were washed with brine (20 mL) and dried (Na2SO4). Purification by flash chromatography (heptane:EtOAc 4:1) afforded 0.16 g (45%) of 3-methyl-(2E,7Z,10Z,13Z,16Z,19Z)-docosa-2,7,10,13,16,19-hexaen-1-ol as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH:4]([CH3:7])[CH:5]=[CH2:6].[CH3:9][C:10]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:30]=[CH:29][C:25]([CH:26]=[N:27][OH:28])=[CH:24][CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1>>[CH3:1][O:2][C:3](=[O:8])[CH:4]([CH:5]1[O:28][N:27]=[C:26]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=[C:10]([CH3:9])[CH:19]=3)=[CH:30][CH:29]=2)[CH2:6]1)[CH3:7]
Reactant: Cc1cc(COc2ccc(C=NO)cc2)c2ccccc2n1
Reactant: C=CC(C)C(=O)OC
Product: COC(=O)C(C)C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Yield: 55 %

Procedure:
Following a procedure analogous to that used in Example step 1c, but using 2-methyl-but-3-enoic acid methyl ester and 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde oxime from step 1b, the crude product was prepared. The crude product was purified by FCC (flash column chromatography) on silica gel to give 2-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid methyl ester (0.13 g, 55%) as a solid residue. MS found: (M+H)+=405.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[NH2:19][C:20]1[C:21]([CH3:29])=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH2:25])=[O:24].C(O)(=O)C.[OH-].[Na+]>CN(C=O)C.O>[NH2:25][C:23]([C:22]1[C:21]([CH3:29])=[C:20]([CH:28]=[CH:27][CH:26]=1)[NH:19][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17])=[O:24]
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Reactant: Cc1c(N)cccc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncc(C(N)=O)c(Nc3cccc(C(N)=O)c3C)c2cc1OC
Temperature: 100 °C
Yield: 63.4 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g, 0.17 mmol), 3-amino 2-metylbenzamide (0.036 g, 0.24 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100° C. for 18 h. After cooling the reaction mixture was diluted with water (20 ml) and made alkaline with 1 M NaOH. The precipitate was filtered of, rinsed with water and dried to give the title compound (41 mg, 61%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13]C)[C:9]([CH3:16])([CH3:15])[CH2:8][CH2:7][C:6]2([CH3:18])[CH3:17].B(Br)(Br)Br>C(Cl)Cl>[CH3:17][C:6]1([CH3:18])[CH2:7][CH2:8][C:9]([CH3:15])([CH3:16])[C:10]2[CH:11]=[C:12]([OH:13])[C:3]([OH:2])=[CH:4][C:5]1=2
Reactant: COc1cc2c(cc1OC)C(C)(C)CCC2(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(O)c(O)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,2,3,4-tetrahydro-6,7-dimethoxy-1,1,4,4-tetramethylnaphthalene (Example 1, 0.7 g, 2.82 mmol) was dissolved in anhydrous CH2Cl2. At −78° C., BBr3 (2.96 mL, 2.96 mmol, 1.0M in CH2Cl2) was slowly added. The reaction mixture was allowed to warm up to room temperature and stir for 30 minutes before being quenched with ice water. The layers were separated, and the aqueous layer extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide the title compound. 1H NMR (CDCl3): 1.22 (s, 12H), 1.64 (s, 4H), 4.98 (s, 2H, —OH), 6.78 (s, 2H). This compound was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([NH:6][C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])=[S:8])=[C:4]([F:18])[CH:3]=1.[C-]#N.[K+].Cl.[CH2:23]([OH:25])C>O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([N:6]2[C:23](=[O:25])[C:10]3([OH:15])[CH:9]([CH2:14][CH2:13][CH2:12][CH2:11]3)[C:7]2=[S:8])=[C:4]([F:18])[CH:3]=1
Reactant: O=C1CCCCC1C(=S)Nc1ccc(Br)cc1F
Reactant: CCO
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: O=C1N(c2ccc(Br)cc2F)C(=S)C2CCCCC12O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
In 350 ml of ethanol was dissolved 33.0 g of 4'-bromo-2'-fluoro-2-oxocyclohexane-1-thiocarboxanilide, and a solution of 7.0 g of potassium cyanide in 35 ml of water was added to the solution with stirring at room temperature over a 10-minute period, followed by adding 9.2 ml of concentrated hydrochloric acid at 10° to 20° C. over a 1 hour period, while cooling. After stirring was continued at room temperature for 1 hour, 30 ml of concentrated hydrochloric acid and 30 ml of water were added to the reaction mixture, and the mixture was warmed and stirred at 50° to 60° C. for 10 minutes. Upon cooling, there resulted crystals, which were collected by filtration, washed with dilute ethanol and dried, thereby producing 24.5 g (yield of 68%) of the subject compound. Recrystallization from ethanol yielded slightly yellow crystals, m.p. 163°-164° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].Br[CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].[OH-].[Na+]>CN(C)C=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16]
Reactant: Sc1ccc2ccccc2c1
Reactant: O=C(CCBr)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CCSc1ccc2ccccc2c1)c1ccccc1
Yield: 22.1 %

Procedure:
A mixture of 2-naphthalenethiol (12.94 g), 3-bromopropiophenone (17.35 g), cuprous oxide (5.83 g), sodium hydroxide (3.24 g) and dimethylformamide (130 ml) was heated to reflux for 18 hours. The mixture was concentrated and the residue was partitioned between diethyl ether and water. The organic phase was dried (MgSO4) and evaporated. The residue was dissolved in a mixture of ethyl acetate and hexane and treated with charcoal. The solution was filtered and evaporated. The residue was recrystallised from a mixture of methanol and water to give 3-(naphth-2-ylthio)propiophenone (5.23 g, 22%), m.p. 90°-91° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:29]=[C:28]([O:30][CH3:31])[C:11]2[N:12]([CH2:24][CH2:25][O:26][CH3:27])[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)=[N:14][C:10]=2[C:9]=1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([Sn](CCCC)(CCCC)C=C)[CH2:34]CC>C1COCC1.[Pd](Cl)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>[CH2:1]([C:8]1[CH:29]=[C:28]([O:30][CH3:31])[C:11]2[N:12]([CH2:24][CH2:25][O:26][CH3:27])[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)=[N:14][C:10]=2[C:9]=1[CH:33]=[CH2:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(I)c(Cc3ccccc3)cc(OC)c21
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=Cc1c(Cc2ccccc2)cc(OC)c2c1nc(-c1ccc(C(C)C)cc1)n2CCOC

Procedure:
A mixture of 300 mg (0.556 mmol) 5-benzyl-4-iodo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole, 40 mg bis(triphenylphosphine) palladium (II) dichloride and 0.2 ml tributyl(vinyl)stannane in 3 ml THF is stirred at reflux temperature for 24 h. The reaction mixture is concentrated in vacuo and the residue is purified by flash-chromatography on silica gel (hexane:EtOAc=6:1) to afford 278 mg of the title compound as a yellow crystalline solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]N3CCN(C)CC3)=[CH:8][C:7]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)=[N:6]2)[CH2:3][CH2:2]1.C1(CN2C(=O)C(COS(C)(=O)=O)=CC(C3C=CC4OCCC=4C=3)=N2)CC1.[C:55]([O:59][C:60]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)=[O:61])([CH3:58])([CH3:57])[CH3:56]>>[C:55]([O:59][C:60]([N:62]1[CH2:67][CH2:66][N:65]([CH2:12][C:9]2[C:10](=[O:11])[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:6]=[C:7]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)[CH:8]=2)[CH2:64][CH2:63]1)=[O:61])([CH3:58])([CH3:56])[CH3:57]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN1CCN(Cc2cc(-c3ccc4c(c3)CCO4)nn(CC3CC3)c2=O)CC1
Agent: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(CC2CC2)c1=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(-c3ccc4c(c3)CCO4)nn(CC3CC3)c2=O)CC1
Yield: 97.6 %

Procedure:
The general procedure of Example 1 (6) was repeated by use of 2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl-1-piperazine carboxylate, to thereby yield the title compound as a yellow oil (yield: 97.6%).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1Br.[C:21]([O-:24])(=O)[CH3:22]>CN(C)P(=O)(N(C)C)N(C)C>[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:8]1[CH2:9][CH2:22][C:21](=[O:24])[CH2:6][CH2:7]1
Reactant: CC(=O)[O-]
Reactant: CC1CCc2c(Br)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CCc2c(N3CCC(=O)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 160 °C
Yield: 55.1 %

Procedure:
A mixture of 3 g of 9-fluoro-8-bromo-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 5 g of 4-piperidineethylene acetate and 30 ml of hexamethylphosphoric triamide was heated at 160° C. on an oil bath for 6 hours. After completion of reaction, hexamethylphosphoric triamide was distilled off under reduced pressure, and to the residue was added ethyl acetate to precipitate crystals which then were recrystallized from dimethylformamide containing a small amount of dilute hydrochloric acid to give 0.87 g of 9-fluoro-8-(4-oxo-1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. not lower than 300° C., white rhombic crystals.
Reaction SMILES: C(N(CC)/[CH:4]=[CH:5]/[C:6]([C:8]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:9]=1[O:10][CH2:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])=O)C.CO.C([O-])(=O)C.[Na+].C(O)(=O)C(O)=O.[CH2:43]([NH:47][NH2:48])[CH2:44][CH2:45][CH3:46]>CC(OC)(C)C.O>[CH2:43]([N:47]1[C:6]([C:8]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:9]=2[O:10][CH2:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[CH:5][CH:4]=[N:48]1)[CH2:44][CH2:45][CH3:46]
Reactant: CCN(/C=C/C(=O)c1ccc(OC)cc1OCc1ccccc1C(=O)OC)CC
Reactant: CCCCNN
Agent: CC(=O)[O-]
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCn1nccc1-c1ccc(OC)cc1OCc1ccccc1C(=O)OC
Yield: 104.8 %

Procedure:
To a 5 L round bottomed flask was added (E)-methyl 2-[[2-[3-(diethylamino)-1-oxo-2-propenyl]-5-methoxyphenoxy]methyl]benzoate (150 g, 0.37 mol), 2.9 L of methanol and 0.45 L of water. After complete dissolution, a premixed quantity of sodium acetate (294 g, 3.58 mol) and n-butylhydrazine oxalate salt (133 g, 0.746 mol) was added via a powder funnel in rapid portions over a period of 20 minutes. The reaction mixture was blanketed with nitrogen during the reaction period. After 20 hours the reaction mixture was partitioned between 3 L of ethyl acetate and 3 L of water. The aqueous was removed and poured into 2 L of ethyl acetate and the aqueous was separated once again. This operation was repeated once more with 1.2 L of ethyl acetate (a total of 6 L of ethyl acetate used in total). The combined organic extracts were dried (magnesium sulfate) and concentrated under reduced pressure to 187 g of a thick oil. Flash chromatography (50% TBME/Hex) afforded the title compound (153 g, 73% yield) as a colourless oil which slowly solidified on standing: 1H NMR (300 MHz, CDCl3) δ 8.02 (1H, d), 7.6 (1H, d), 7.52-7.22 (3H, m), 7.12 (1H, d), 6.64 (1H, d), 6.54 (1H, dd), 6.20 (1H, s), 5.48 (2H, s), 4.01 (2H, t), 3.89 (s 3H), 3.76 (3H, s), 1.7-1.5 (2H, m), 1.2-1.05 (2H, m), 0.7 (3H, t).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[C:14]4[CH:22]=[CH:21][CH:20]=[CH:19][C:15]4=[CH:16][CH:17]=3)[NH:12][C:11](=[O:23])[N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].C([Sn]([N:37]=[N+:38]=[N-:39])(CCCC)CCCC)CCC.[OH-].[Na+]>CN(C=O)C>[NH:37]1[C:1]([C:3]2[CH:4]=[C:5]([C:9]3[C:18]4[C:13](=[C:14]5[CH:22]=[CH:21][CH:20]=[CH:19][C:15]5=[CH:16][CH:17]=4)[NH:12][C:11](=[O:23])[N:10]=3)[CH:6]=[CH:7][CH:8]=2)=[N:2][N:39]=[N:38]1
Reactant: N#Cc1cccc(-c2nc(=O)[nH]c3c2ccc2ccccc23)c1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1nc(-c2cccc(-c3nnn[nH]3)c2)c2ccc3ccccc3c2[nH]1
Temperature: 110 °C
Reaction time: 18 h
Yield: 54.6 %

Procedure:
To a solution of 4-(3-cyanophenyl)-1H-benzo[h]quinazolin-2-one (112 mg, 0.377 mmol) in DMF (2 mL) was added tri-n-butyltin azide (312 μL, 1.13 mmol), and stirred at 110° C. for 18 hours. After cooled to room temperature, the reaction mixture was poured into 1M sodium hydroxide, and washed with ethyl acetate. After aqueous layer was neutralized with 1M hydrochloric acid, the precipitated solid was collected by filtration, washed with methanol, and with water. The obtained crystal was dried to give the titled compound as a yellow crystal (70 mg, yield 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[OH-].[K+].[I:15]I>CO>[I:15][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]=1[OH:9]
Reactant: II
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(I)c(O)c([N+](=O)[O-])c1
Yield: 57.3 %

Procedure:
A solution of 4-Methoxy-2-nitrophenol (5 g, 29.6 mmol) in MeOH (100 mL) was cooled to 0° C. and treated with KOH (1.8 g, 32.6 mmol) followed by portionwise addition of I2 (8.2 g, 32.6 mmol). The reaction was worked-up by quenching the excess I2 by adding a 10% Na2SO3 aq solution. The MeOH was stripped off and 2 N HCl aq. was added and the aqueous extracted with EtOAc. The EtOAc was washed with saturated NaHCO3, brine and dried over MgSO4. The solution was concentrated and triturated twice with MeOH to yield 5 g of material that consisted of a 2:1 mixture of product to starting material that was used as is for the next step.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:18][CH:19]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:18][CH:19]=2)=[N:13]1
Reactant: COC(=O)c1ccccc1S
Reactant: CCOC(=O)CCCCCOc1ccc(C#N)cn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCOc1ccc(-c2nc(=O)c3ccccc3s2)cn1
Yield: 14.5 %

Procedure:
A mixture of methyl thiosalicylate (0.71 g, 4.2 mmol), ethyl 6-(5-cyanopyridin-2-yl)oxyhexanoate (1.00 g, 3.8 mmol), triethylamine (0.63 ml, 4.5 mmol) and toluene (12 ml) was refluxed under nitrogen atmosphere for 30 hrs. The reaction mixture was concentrated. The residue was subjected to a silica gel column chromatography, eluted with ethyl acetate-hexane (2:1, v/v) and recrystallized from ethyl acetate-isopropylether to give the titled compound (0.22 g, 14%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[C:22](=O)([O-])O.[Na+]>CO>[CH3:22][O:2][C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: O=C(O)c1cccc(-c2ccc(O)cc2)c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(-c2ccc(O)cc2)c1

Procedure:
Solid 3'-carboxybiphenyl-4-ol (1.5 g) was suspended in methanol (10 ml) and concentrated sulfuric acid (1 ml). The mixture was heated at reflux for 16 hours. After cooling, the mixture was basified by the addition of solid sodium hydrogen carbonate. The white solid which formed was filtered and washed with copious amounts of water to give the sub-title compound as a white solid (1.5 g).
Reaction SMILES: Cl[C:2]([C:4]1[N:8]([CH3:9])[C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)=[O:3].[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCOCC.C1(C)C=CC([Mg]Br)=CC=1>C1CCCCC1>[CH3:9][N:8]1[C:4]([C:2]([C:19]2[CH:20]=[CH:21][C:16]([CH3:22])=[CH:17][CH:18]=2)=[O:3])=[CH:5][CH:6]=[C:7]1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)Cc1ccc(C(=O)Cl)n1C
Agent: Cc1ccc([Mg]Br)cc1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CCOC(=O)Cc1ccc(C(=O)c2ccc(C)cc2)n1C
Temperature: -60 °C
Yield: 10 %

Procedure:
To a stirred and chilled (-60°C.) solution of 5.0 g. (0.022 mole) of ethyl 5-chlorocarbonyl-1-methylpyrrole-2-acetate in 300 ml. of dry toluene is added in one portion 0.70 g. (0.0044 mole) of anhydrous FeCl3, weighed under 5 ml. of toluene and dissolved in 2 ml. of ether. The freshly prepared Grignard solution of 0.023 mole of p-tolylmagnesium bromide in 15 ml. ether is added dropwise, under hydrogen, to the above reaction mixture at such a rate so as to maintain the reaction temperature at -60 ± 2°C. The mixture is stirred at that temperature for another hour, then hydrolyzed with ice water and made strongly acidic with 3N HCl-ice. The aqueous layer is washed 3 times with benzene and the combined organic layers are washed sequentially with 3-dimethylaminopropylamine-ice, 3N HCl-ice, and saturated NaHCO3 solution. The organic layer is dried over anhydrous MgSO4, filtered and the solvent evaporated off to give about 2.0 g. (20%) of a solid residue with thin layer chromatography (film, silica, 1:3 EtOAo/cyclohexane) showing two major spots (rf - 0.54, 0.90). Column chromatography on 50 g. of CC-4 silica and sequential elution with hexane, hexane-benzene, benzene and benzene-ether gives the desired product (eluted with 10% Et2O/benzene) as an oil (0.75 g., 12% yield). Crystallization from MeOH gives about 350 mg. of a white solid, ethyl 1-methyl-5-(p-toluoyl)pyrrole-2-acetate, m.p. 68°-70°C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[NH:15][CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O[CH2:27][CH2:28][CH2:29][NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:14][CH:13]2[N:15]([CH2:27][CH2:28][CH2:29][NH:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=3)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CC3CCC(C2)N3)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCCNc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(NCCCN2C3CCC2CN(Cc2ccccc2)C3)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
A mixture of 3-benzyl-3,8-diazabicyclo[3.2.1]octane (3.63 g, 17.9 mmol; from Preparation B, step (e) above), 3-(4-cyanoanilino)propyl 4-methylbenzenesulfonate (5.93 g, 17.9 mmol; from step (b) above) and potassium carbonate (2.47 g, 17.9 mmol) in dry DMF (85 mL) was stirred at 80° C. for 4 h. The reaction mixture was diluted with water (200 mL) and extracted with ether (4×200 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated ill vacuo to give the crude product. Flash chromatography on silica gel eluting with CH2Cl2:CMA (4:1) gave 6.26 g (97%) of the sub-title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33]C[CH2:31][CH2:30]1.O.C[N:37](C)C=O>>[C:12]([C:11]1[C:2]([N:37]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[CH2:30][CH2:31]2)=[N:3][C:4]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)#[N:13]
Reactant: N#Cc1c2cccccc-2nc1Cl
Reactant: COc1ccccc1N1CCCCC1
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccccc1N1CCN(c2nc3cccccc-3c2C#N)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.2 %

Procedure:
To a solution of 1.0 g (0.0053 mol) of 2-chloro-3-cyano-1-azaazulene in 20 ml of dimethylformamide were added 0.7 g (0.0053 mol) of anhydrous potassium carbonate and 1.2 g (0.0053 mol) of 2-methoxyphenylpiperadine hydrochloride. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into water with ice, and the precipitate was filtered and washed with water. After drying, the precipitate was recrystallized from mixture of ethyl acetate and petroleum ether to give 3.5 g of title compound (yield: 97.2%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CCN(CC)CC.ClC(OCC)=O.[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32]>C1COCC1>[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(O)c1cnccn1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cnccn1
Temperature: 5 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a solution of pyrazine-2-carboxylic acid (2.00 g, 16.1 mmol) and Et3N (2.50 ml, 17.7 mmol) in THF (40 mL) was added ethyl chloroformate (1.74 mL, 17.7 mmol) dropwise at 5° C. and the mixture was stirred at 5° C. for 1 hour. 4-Fluoro-3-nitroaniline (2.80 g, 17.7 mmol) was added to the mixture at 5° C. The mixture was warmed to room temperature, stirred at room temperature for 4 hours, and then evaporated. The residue was suspended in a mixture of H2O (100 ml) and i-Pr2O (100 ml) and stirred at room temperature for 30 minutes. The resulting crystal was collected by filtration and washed with H2O and i-Pr2O to give the desired product as pale brown crystals (2.91 g, 69%).