Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[N:9]3[CH:11]=[CH:12][CH:13]=[C:8]3[C:7]3([CH2:18][CH2:17][N:16](C(OCC4C=CC=CC=4)=O)[CH2:15][CH2:14]3)[O:6][C:5]=2[N:4]=[CH:3][CH:2]=1.CC(O)=O>CO.[Pd]>[CH:1]1[C:10]2[N:9]3[CH:11]=[CH:12][CH:13]=[C:8]3[C:7]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:6][C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)Oc1ncccc1-n1cccc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: c1cnc2c(c1)-n1cccc1C1(CCNCC1)O2

Procedure:
A solution of benzyl spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate (220 mg, 0.586 mmol), AcOH (33 μL, 0.59 mmol) and Pd/C (22 mg, 0.21 mmol) in MeOH (2 mL) was stirred under a balloon on H2 for 6 hours. The mixture was filtered through celite and the fitrate was evaporated to give spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine] (ESI-MS m/z calc. 241.1. found 242.5 (M+1)+; Retention time: 0.46 minutes (3 min run)). The residue was then taken up in THF (3 mL) before Na2CO3 (1.2 mL of 2.0 M, 2.4 mmol) was added. Boc2O (156 mg, 0.70 mmol) was added and the mixture was stirred at room temperature for 12 hours. N,N-dimethylethylenediamine (0.5 mL) was added and the mixture was stirred at room temperature for 30 min. The mixture was poured into water and was extracted with EtOAc (3×). The organics were combined, washed with 0.1N HCl (3×), brine, dried (Na2SO4) and filtered through a plug of silica to give tert-butyl spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate (134 mg, 67%). 1H NMR (400 MHz, DMSO) δ 8.18-8.13 (m, 1H), 8.12-8.00 (m, 1H), 7.69-7.56 (m, 1H), 7.32-7.12 (m, 1H), 6.39 (dd, J=5.8, 3.0 Hz, 1H), 6.33-6.20 (m, 1H), 3.94 (d, J=11.9 Hz, 2H), 3.26 (s, 2H), 2.02 (s br, 4H), 1.48 (d, J=2.3 Hz, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])=[O:17])[CH3:15])=[CH:10][CH:9]=1.S(=O)(=O)(O)[OH:23].O.[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])(=[O:23])=[O:17])[CH3:15])=[CH:10][CH:9]=1
Reactant: O=S(=O)(O)O
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(c1ccc(-c2ccccc2F)cc1)S(=O)(=O)CC(=O)O

Procedure:
170 gm (0.556 mol) of a diastereoisomeric mixture of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid were dissolved in 1.7 liters of acetone, and a solution of 19.9 gm (0.195 mol) of concentrated sulfuric acid inf 70 ml of water was added. While stirring, 67.2 gm (0.425 mol) of potassium permanganate were added in small portions, and the temperature was maintained at 20°-25° C. The mixture was stirred for 1 hour, the manganese dioxide was suction-filtered off, the filter cake was washed with acetone, and the filtrate was evaporated in vacuo. The residue was diluted with 4 liters of glacial acetic acid, and the precipitated crystalline reaction product was suction-filtered off, washed, dried and recrystallized from toluene. Yield: 158.2 gm (88.5% of theory); m.p. 144°-146° C.
Reaction SMILES: [Br:1]Br.[CH:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:16])=[O:4].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Br:1])[CH:13]=2)[NH:8][C:7]1=[O:16])=[O:4]
Reactant: BrBr
Reactant: O=CNC1Cc2ccccc2NC1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=CNC1Cc2cc(Br)ccc2NC1=O
Reaction time: 1 h
Yield: 66.1 %

Procedure:
Bromine (16.0 g, 0.1 mol) was added to a stirred solution of 3-(formylamino)-3,4-dihydro-2(1H)quinolinone (19.0 g, 0.1 mol) and anhydrous sodium acetate (12.7 g, 0.2 mol) in acetic acid (500 mL). After 1 hour, water (1.5 L) was added and the precipitate was filtered off and air dried to give 17.8 g of 3-(formylamino)-6-bromo-3,4-dihydro-2(1H)quinolinone, mp 275°-282° C. (dec). This was dissolved in trifluoracetic acid (300 mL) and sodium nitrate (9.0 g) was added to the stirred solution. After 1 hour, water was added and the precipitate was filtered off and air dried to give 18.2 g of 3-(formylamino)-6-bromo-3,4-dihydro-8-nitro-2(1H)quinolinone, mp 232°-235° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:25])[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]3[CH2:22][CH2:23][CH2:24][C@H:18]3[CH2:17]2)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:26](OC(N1CCCCC1C(O)=O)=O)(C)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:25])[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]3[CH2:26][CH2:22][CH2:23][CH2:24][CH:18]3[CH2:17]2)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(=O)CCC(=O)N2CCN3CCC[C@H]3C2)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Product: COc1ccc(C(=O)CCC(=O)N2CCN3CCCCC3C2)cc1OC

Procedure:
360 mg of the title compound were prepared as described for 1-(3,4-dimethoxyphenyl)-4-((S)-hexahydropyrrolo[1,2-a]pyrazin-2-yl)butane-1,4-dione, using 1-(tert-butoxycarbonyl)piperidine 2 carboxylic acid instead of BOC-protected proline.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1[N:49]([CH:50]2[CH2:52][CH2:51]2)[N:48]=[N:47][N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[N:49]([CH:50]4[CH2:52][CH2:51]4)[N:48]=[N:47][N:46]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: ClCc1nnnn1C1CC1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3nnnn3C3CC3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-cyclopropyl-1H-tetrazole and isolated as red gum. MS (m/e): 405.3 (MH+).
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[CH3:6][O:7][CH:8]([O:11][CH3:12])[CH2:9][NH2:10].[BH3-]C#N.[Na+].CC(O)=O>CO>[CH:1]1([CH2:4][NH:10][CH2:9][CH:8]([O:11][CH3:12])[O:7][CH3:6])[CH2:3][CH2:2]1
Reactant: O=CC1CC1
Reactant: COC(CN)OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(CNCC1CC1)OC
Reaction time: 24 h
Yield: 61 %

Procedure:
A solution of cyclopropanecarboxaldehyde in MeOH (0.2 M) was treated with 2,2-dimethoxyethylamine (1.2 eq). The solution was cooled with an ice/water bath and treated portionwise with NaCNBH3 (1.0 eq). The pH of the resulting solution was adjusted to 6 with AcOH, and the reaction left at RT for 24 h. The mixture was concentrated, diluted with EtOAc, washed with sat. aq. NaHCO3, brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the product (61%). 1H NMR (300 MHz, DMSO-d6, 300 K) δ 0.05-0.07 (m, 2H), 0.15-0.17 (m, 2H), 0.87-0.93 (m, 1H), 2.39-2.41 (m, 2H), 2.64-2.66 (m, 2H), 3.3 (s, 6H), 4.46 (t, J 3.0, 1H), 5.38 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[C:18]([NH:26][C:27]1[CH:36]=[C:35](Br)[CH:34]=[CH:33][C:28]=1[C:29]([O:31]C)=[O:30])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C(=O)C>[C:18]([NH:26][C:27]1[CH:36]=[C:35]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:34]=[CH:33][C:28]=1[C:29]([OH:31])=[O:30])(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cc(-c2ccc(F)cc2F)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 28.4 %

Procedure:
56 mg of 2,4-difluorophenylboronic acid, 63 mg of sodium carbonate and 34 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) were added to 2.5 mL of N,N-dimethylacetamide solution containing 80 mg of methyl 2-(benzamido)-4-bromobenzoate, and starred at 90° C. for 20 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and ethyl acetate and 1.2 mol/L hydrochloric acid were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. 1.0 mL of 1.0 mol/L aqueous sodium hydroxide and 4.0 mL of ethanol were added to the obtained residue and stirred at room temperature for 1 hour. 0.6 mol/L hydrochloric acid, was added to the reaction mixture and a solid substance was separated by filtration to obtain 24 mg of 2-(benzamido)-4-(2,4-difluorophenyl)benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].[CH2:11](O)[CH2:12][CH2:13][OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:14][CH2:13][CH2:12][CH2:11][O:7]2)=[CH:4][C:3]=1[F:10]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1cc(C2OCCCO2)ccc1Br

Procedure:
4-Bromo-3-fluorobenzaldehyde (100.00 g, 492.6 mmol) was added to toluene (1 L). Propane-1,3-diol (42.72 mL, 591.1 mmol), and p-toluenesulfonic acid monohydrate (4.685 g, 24.63 mmol) were added to above and the reaction mixture was brought to reflux. The solvent (500 mL) was azeotroped off using a dean stark trap. The reaction mixture was cooled and extracted with sat. aqueous sodium bicarbonate (500 mL). The organics were dried over magnesium sulfate and concentrated in vacuo to give 2-(4-bromo-3-fluorophenyl)-1,3-dioxane as a white solid. MS (ESI) m/z: Calculated: 260.0/262.0; Observed: 260.9 (M++1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.Br[CH2:27][C:28]([OH:30])=[O:29]>C(Cl)(Cl)Cl>[OH:12][P:11]([CH2:27][C:28]([OH:30])=[O:29])([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:13]
Reactant: O=C(O)CBr
Reactant: OP(O)CCCCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(O)CP(=O)(O)CCCCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid (0.5 g, 0.002525 mole) in chloroform (10 ml) was added triethylamine (1.16 ml, 0.00833 mole) and the solution was cooled in an ice bath to 0° C. Trimethyl silyl chloride (1.06 ml, 0.00833 mole) was added to the above solution dropwise, followed by bromoacetic acid (0.36 g, 0.00277 mole). The ice bath was removed and the mixture stirred at room temperature for 3 hours and poured into 10% aqueous HCl (30 ml) and crushed ice (20 g). After shaking the mixture in a separatory funnel, the chloroform layer was separated and the aqueous layer extracted with dichloromethane (2×50 ml). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvents removed on a rotavap. The resulting crude thick oil (0.6 g) was dissolved in 30 ml ether; hexane was added dropwise to get a turbid solution and left at room temperature overnight to complete the crystallization. The resulting product was cooled in the freezer for 12 hours, filtered and the solid was washed very thoroughly with hexane (50 ml), ether (50 ml) and again very thoroughly with hexane (50 ml), ether (50 ml) in that order. The solid was vacuum dried to get 0.5 g (83%) of title compound.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][C:3]=2[O:2]1.[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:29]=[C:28]([NH2:30])[CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>>[CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:19]=[CH:20][C:21]([C:24]5[N:29]=[C:28]([NH2:30])[CH:27]=[CH:26][CH:25]=5)=[CH:22][CH:23]=4)[CH2:14][CH2:13]3)=[CH:4][C:3]=2[O:2]1
Reactant: BrCc1ccc2c(c1)OCO2
Reactant: Nc1cccc(-c2ccc(C3CCNCC3)cc2)n1
Product: Nc1cccc(-c2ccc(C3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)n1

Procedure:
Prepared from Example 13, using 3,4-methylenedioxybenzyl bromide to alkylate 6-[4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine, in 82%, mp 150-165° C. as the hydrochloride salt.
Reaction SMILES: [Br-].[O:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:44][O:45][C:46]1[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=1[CH:48]=O>C1COCC1>[CH3:44][O:45][C:46]1[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=1[CH:48]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(OCCCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccccc1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccccc1C=CCCCCCOc1ccccc1

Procedure:
1-(2-Methoxyphenyl)-7-phenoxy-1-heptene (7.3) was synthesized as described in 7.1 using 6.1 (2.0 g, 3.85 mmol), dry THF (30 mL), potassium bis(trimethylsilyl)amide (0.77 g, 3.85 mmol), and 2-methoxybenzaldehyde (0.20 g, 1.47 mmol). The title compound (7.3) was isolated as a colorless liquid after purification by flash column chromatography (0.396 g, 91% yield, predominantly cis, cis:trans=93:7).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[C:36]([CH:41]3[CH2:43][CH2:42]3)=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[C:36]([CH:41]3[CH2:42][CH2:43]3)=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2C2CC2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2C2CC2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(2-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K29) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow oil (223 mg, 58%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[F:1][C:2]1[C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(F)ccc1F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(F)cc([N+](=O)[O-])c1F
Temperature: 28 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a stirred solution of 2,5-difluorotoluene (0.544 g, 4.25 mmol, Aldrich, used as received) in conc. H2SO4 (5.0 mL) at 0° C., KNO3 (0.430 g, 4.25 mmol) was added in one portion. The resulting pale yellow solution was warmed to 28° C. and stirred at that temperature overnight. It was then poured into ice (25 g) and extracted with ethyl acetate (40 mL). The extract was dried over Na2SO4 and evaporated to afford 0.555 g (91%) of the title compound as a light red oil; 1H NMR (CDCl3): 2.369 (d, 3H, J=1.8 Hz), 7.127 (dd, 1H, J1 =8.1 Hz, J2 =6.0 Hz), 7.734 (dd, 1H, J1 =8.4 Hz, J2 =6.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=O)[CH2:11][C:10](=[O:15])[CH2:9]1.C([O-])(=O)C.[NH4+:20]>C(O)C>[NH2:20][C:12]1[CH2:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:9][C:10](=[O:15])[CH:11]=1
Reactant: [NH4+]
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC1=CC(=O)CC(c2ccccc2Cl)C1
Yield: 88.4 %

Procedure:
A solution of 5-(2-chlorophenyl)cyclohexane-1,3-dione (2.5 g) and ammonium acetate (2.6 g) in ethanol (50 ml) was refluxed for 12 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crystals, which were recrystallized from ethyl acetate-hexane to give pale yellow crystals of 1-amino-5-(2-chlorophenyl)cyclohexen-3-one (2.2 g).
Reaction SMILES: [I:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25]S(C)(=O)=O)=[CH:21][CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[OH-].[Na+].Cl>O1CCCC1.O>[I:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: CS(=O)(=O)Oc1ccc(-c2c3ccccc3c(I)c3sc4ccccc4c23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(-c2c3ccccc3c(I)c3sc4ccccc4c23)cc1
Reaction time: 18 h
Yield: 101.7 %

Procedure:
To a solution of methanesulfonic acid 4-(6-iodo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenyl ester (1.00 g, 1.89 mmol) in tetrahydrofuran (5 mL) was added a 2.5 N aqueous solution of sodium hydroxide (6.0 mL) and the biphasic reaction mixture was heated at reflux for 5 hours and then heated in a sealed pressure tube at 110 C. for about 18 hours. The reaction mixture was diluted with water (100 mL), acidified with 10% hydrochloric acid and the organics were extracted with ether (2×100 mL). The extracts were combined, washed with water (100 mL), concentrated and chased with petroleum ether to give the title compound (0.869 g, over theoretical); NMR (DMSO-d6); δ 9.85 (s, 1H, OH), 8.15 (d, J=8 Hz, 1H), 8.02 (d, J=8 Hz, 1H), 7.73 (ddd, J=8, 7, 1 Hz, 1H), 7.69-7.44 (m, 3H), 7.21-7.16 (m, 3H), 7.09-7.06 (m, 2H), 6.68 (d, J=8Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][N:3]=1.S(Br)([Br:12])=O>ClCCl>[Br:12][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=S(Br)Br
Reactant: OCc1ccnc(Cl)c1
Solvent: ClCCl
Product: Clc1cc(CBr)ccn1
Reaction time: 0.25 h

Procedure:
To a solution of 2-chloropyridine-4-methanol (1.02 g, 7.10 mmol) in 15 mL of dichloromethane was added thionyl bromide (1.77 g, 8.53 mmol) dropwise. After 15 min, the reaction was quenched with saturated aqueous ammonium chloride. The organic solution was washed 2× with water, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 4-(bromomethyl)-2-chloropyridine that gave a mass ion (ES+) of 208.0 for [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: Sc1cccs1
Reactant: O=C(O)CCCCCBr
Product: O=C(O)CCCCCSc1cccs1

Procedure:
Method in which thiophene-2-thiol is reacted with 6-bromo hexanoic acid to obtain 6-(2-thienylsulfanyl) hexanoic acid represented by Chemical Formula [5].
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:13]([NH2:15])=[O:14].[CH:16](O)=[O:17]>O>[CH2:10]([N:7]1[CH2:8][CH2:9][C:4]2[C:3]([C:13]([NH2:15])=[O:14])=[C:2]([NH:1][CH:16]=[O:17])[S:12][C:5]=2[CH2:6]1)[CH3:11]
Reactant: CCN1CCc2c(sc(N)c2C(N)=O)C1
Reactant: O=CO
Solvent: O
Product: CCN1CCc2c(sc(NC=O)c2C(N)=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of compound F4 (225 mg, 1.00 mmol) in formic acid (5 mL) and water (1 mL) was stirred overnight at room temperature. After that time, the reaction mixture was concentrated under reduced pressure. The residue was mixed with saturated aqueous sodium bicarbonate (50 mL) and extracted with methylene chloride (3×150 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with methanol/methylene chloride (15:85) to afford compound N1 as an off-white solid (208 mg, 82%): 1H NMR (300 MHz, DMSO-d6) δ 11.44 (s, 1H), 8.40 (s, 1H), 7.52 (bs, 1H), 7.03 (bs, 1H), 3.48 (s, 2H), 2.76 (d, J=4.8 Hz, 2H), 2.65 (d, J=4.8 Hz, 2H), 2.54-2.47 (m, 2H), 1.07 (t, J=7.0 Hz, 3H). MS (M+H) 254.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1>O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:18][CH2:17][CH:14]1[CH2:16][CH2:15]1
Reactant: CCS(=O)(=O)c1ccc(F)c(Br)c1
Reactant: NCC1CC1
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(NCC2CC2)c(Br)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of Example 84b (0.534 g, 2.00 mmol) and cyclopropylmethanamine (0.427 g, 6.00 mmol) in dioxane (5 mL) was heated at 100° C. for overnight. The reaction mixture was cooled to ambient temperature and filtered to remove the solid. The filtrate was concentrated. The residue was purified by flash chromatography (silica gel, 40% ethyl acetate in hexanes) to afford the title compound (0.63 g, 99%).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].Cl.[Cl:7][C:8]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][C:9]=1[NH2:10]>Cl.O>[Cl:7][C:8]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:9]=1[N:10]=[C:3]([CH3:4])[CH:2]=[CH:1]2
Reactant: C/C=C/C=O
Reactant: COc1ccc(Cl)c(N)c1
Agent: Cl
Solvent: O
Product: Cc1ccc2c(O)ccc(Cl)c2n1
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Crotonaldehyde (17.5 mL, 0.21 mol) was added dropwise to a refluxing solution of 2-chloro-5-methoxyaniline hydrochloride (10.36 g, 53.4 mmol) in 5 N hydrochloric acid (450 mL) and reflux continued for a further 0.5 h. The reaction mixture was cooled and diluted with water (500 mL), then extracted with ether (400 mL). The aqueous layer was separated and basified using 50% aqueous NaOH (pH 14), and then extracted into dichloromethane (3×300 mL). The combined organic phases were dried (Na2SO4) and evaporated in vacuo to give a dark oil which was purified by chromatography on silica gel (˜200 g) eluting with 20% ethyl acetate in hexane to give a brown oil (5.17 g) which was heated at reflux in a mixture of acetic acid (30 mL) and 48% hydrobromic acid (30 mL) for 66 h. Reaction mixture was evaporated in vacuo and the residue suspended in sat. NaHCO3 (aq), then extracted into dichloromethane (3×50 mL). The combined organic phases were dried (Na2SO4) and evaporated in vacuo to give a brown solid (2.90 g, 28%).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1c(Oc2ccccc2)cccc1[N+](=O)[O-]
Yield: 76.9 %

Procedure:
A solution of 2,6-dinitrobenzonitrile (2.0 g, 10.5 mmol), phenol (1.42 g, 15.1 mmol) and K2CO3 (1.45 g, 10.5 mmol) in DMF (20 mL) was stirred at rt under N2 for 4.5 hours. Upon completion, the reaction was diluted with EtOAc (100 mL), washed with H2O, dried over MgSO4, filtered and concentrated. The residue was recrystallized from Hexane/EtOAc to provide 2-nitro-6-phenoxybenzonitrile (1.94 g, 77%). 1H NMR (400 MHz, MeOD) δ 7.20 (m, 2H), 7.28 (dd, J=8.6, 1.1 Hz, 1H), 7.34 (m, 1H), 7.51 (m, 2H), 7.78 (t, J=8.7 Hz, 1H), 8.05 (dd, J=8.2, 0.8 Hz, 1H).