Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6](F)[CH:5]=2)[CH2:3][CH2:2]1.Cl.Cl.[O:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]2)[CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([NH:28][CH:25]3[CH2:24][CH2:23][N:22]([CH:19]4[CH2:20][CH2:21][O:16][CH2:17][CH2:18]4)[CH2:27][CH2:26]3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(C2CC2)cc1F
Reactant: NC1CCN(C2CCOCC2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C2CC2)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 90 °C
Yield: 58.5 %

Procedure:
A stirred mixture of 4-cyclopropyl-2-fluoro-1-nitrobenzene (D37, 180 mg, 0.99 mmol), 1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine dihydrochloride (diHCl salt of D9, 280 mg, 1.1 mmol) and N,N-diisopropylethylamine (0.56 ml, 3.3 mmol), in dimethylformamide (5 ml) was stirred at room temperature for 3 hrs, then heated at 90° C. for 18 hrs. The cooled mixture was concentrated under vacuum and the residue treated with dilute K2CO3 solution (20 ml) and extracted with ethyl acetate (3×30 ml). The combined extract was washed with water, dried (MgSO4) and concentrated under vacuum. The residue was purified by chromatography on silica gel (40 g) eluting with 1-10% methanol/dichloromethane to afford the title compound as an orange solid (200 mg, 59%). M++H=346.0.
Reaction SMILES: [CH2:1](Cl)[C:2]#[CH:3].[NH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>CO>[CH2:1]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:2]#[CH:3]
Reactant: C#CCCl
Reactant: C1CCNCC1
Solvent: CO
Product: C#CCN1CCCCC1

Procedure:
With stirring, a solution of 2-propynyl chloride (40.31 g) in dry methanol (50 ml) was added dropwise to a solution of piperidine (92.14 g) in dry methanol (100 ml). The mixture was stirred at 25° C. for 3 hours and then filtered. The filtrate was concentrated under reduced pressure and the residue was distilled (boiling point: 163–165° C./atmospheric pressure).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)[C:13](O)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:29][NH2:30]>C1COCC1.C1(C)C=CC=CC=1.CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:16]=[CH:17][C:18]([N:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[CH:19][CH:20]=4)[C:13]([NH:30][CH3:29])=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1C=C(O)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1
Reactant: CN
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CNC1=CC(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc(N2CCOCC2)cc1

Procedure:
The compound was synthesized starting from 1-(1H-benzo[d]imidazol-5-yl)-4-hydroxy-5-(4-morpholinophenyl)-1H-pyrrol-2(5H)-one (0.50 g, 1.32 mmol) and saturated methylamine solution in THF (1 ml) in toluene/DMF (2:1; 5 ml) according to method 8b described above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[C:9](\[O-])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([N+:16]([O-])=O)=[CH:4][N:3]=1.[K+]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]2[CH:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:16][C:5]2=[CH:4][N:3]=1
Reactant: CCOC(=O)/C([O-])=C/c1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 60 °C
Yield: 18.9 %

Procedure:
Potassium (1Z)-1-(2-chloro-5-nitropyridin-4-yl)-3-ethoxy-3-oxoprop-1-en-2-olate (2.86 g, 9.20 mmol) was dissolved in acetic acid (140 mL) and iron powder (2.11 g, 37.7 mmol) was added. The mixture was heated at 60° C. for 6 h. The mixture was filtered through a pad of diatomaceous earth and washed with water followed by ethanol. The filtrate was concentrated to dryness. The residue was dissolved in 1:1 methylene chloride/methanol, filtered through a bed of silica gel and washed with 1:1 ethyl acetate/methylene chloride until the filtrate was no longer UV-active. Concentration of the filtrate provided ethyl 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (0.39 g, 19%) as a brown solid: mp 170-175° C. dec.; 1H NMR (300 MHz, CD3OD) δ1.42 (3H, t, J=7.1 Hz), 4.44 (2H, q, J=7.1 Hz), 7.17 (1H, s), 7.72 (1H, s), 8.60 (1H, s); ESI MS m/z 225 [C10H9ClN2O2+H]+; HPLC (Method A) 94.9% (AUC), tR=18.1 min.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:34][CH2:35][CH3:36])=[C:8]([N:10]=[C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14](=[O:23])[C:13](=[C:24]3[N:28]([CH3:29])[C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[S:25]3)[S:12]2)[CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.C1COCC1>[CH2:16]([N:15]1[C:14](=[O:23])[C:13](=[C:24]2[N:28]([CH3:29])[C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[S:25]2)[S:12][C:11]1=[N:10][C:8]1[CH:9]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[NH:34][CH2:35][CH3:36])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCNc1ccc(C(C)O)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
The product of Example 38 was reduced with sodium borohydride in 1:1 MeOH/THF and chromatographed (TEA-washed silica gel, 0–10% MeOH/DCM) to afford the title compound. 1H-NMR (CDCl3): δ 7.47–7.54 (3H, m), 7.28–7.37 (4H, m), 7.17 (1H, m), 6.99–7.06 (3H, m), 6.57 (1H, d), 5.19 (2H, s), 4.80 (1H, q), 3.76 (3H, s), 3.01 (2H, q), 1.48 (3H, d), 1.04 (3H, s); MS(ESI): 517 (MH+).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrCl.P.C[OH:24].C(Cl)CCl>>[C:14]1([P:7](=[O:24])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CO
Agent: ClBr
Agent: P
Solvent: ClCCCl
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of triphenylphosphine (2.62 g, 10 mmol) in a methanol-EDC mixture (100 mL, 50:50, Vol.) was placed in a 250-mL round bottom flask and cooled in an ice bath. Stabilized BrCl (15 wt. % solution, 7.5 mL, 12 mmol) was added dropwise to the homogeneous phosphine solution. The reddish-brown color of the BrCl solution disappeared instantaneously as it was added. An orange color persisted during the addition of the last 0.5 mL, indicating total conversion. The reaction mixture was allowed to stand for 30 minutes at room temperature and then was quenched with a few drops of sodium sulfite solution which totally decolorized it. Dilution with EDC (100 mL) and washing with water (100 mL) was followed by phase separation. The organic layer was dried (Na2SO4) and concentrated to afford 2.64 g (95% yield) of triphenylphospine oxide as a white solid in 97% purity (3% starting material).
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:5])[C:3]#[CH:4]>[Cu]Cl.C(OCCCC)(=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[O:15][C:3](=[CH2:4])[C:2]([CH3:1])([CH3:5])[N:6]=2)=[CH:9][CH:10]=1
Reactant: C#CC(C)(C)NC(=O)c1ccc(Cl)cc1
Agent: Cl[Cu]
Solvent: CCCCOC(C)=O
Product: C=C1OC(c2ccc(Cl)cc2)=NC1(C)C
Temperature: 95 °C
Yield: 100.2 %

Procedure:
A round bottom flask was charged with N-(3-methylbutyn-3-yl)-4-chlorobenzamide (4.5 g, 19.09 mmol), copper(I) chloride (9.5 mg, 0.5 mol %), and n-butyl acetate (20 mL). The resulting mixture was heated to 95° C. for 4 h, then cooled to room temperature. The reaction was washed with 1 M hydrochloric acid solution and with water. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was dried in a vacuum oven to afford 2-(4-chlorophenyl)-4,4-dimethyl-5-methyleneoxazoline (4.24 g, 94% yield) as a pale yellow oil (bp 95° C., 0.6 mm Hg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[CH:11]1[N:15]=[CH:14][N:13]2[CH2:16][CH2:17][C:18](=[O:19])[C:12]=12>>[F:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][C:7]([C:18]3([OH:19])[C:12]4[N:13]([CH:14]=[N:15][CH:11]=4)[CH2:16][CH2:17]3)=[CH:8][C:4]=2[CH:3]=1
Reactant: O=C1CCn2cncc21
Reactant: Fc1ccc2sccc2c1
Product: OC1(c2cc3cc(F)ccc3s2)CCn2cncc21
Yield: 34.6 %

Procedure:
The reaction and purification in the same manner as in Example 1 using 5-fluorobenzo[b]thiophene (0.30 g) and 5,6-dihydro-7H-pyrrolo[1,2-c]imidazol-7-one (0.18 g) afforded the title compound (0.14 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:39][C:40]([NH2:42])=[NH:41])[CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1.C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:41]=[C:40]([NH:39][C:29]3[CH:30]=[CH:31][C:32]([N:33]4[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]4)=[C:27]([O:26][CH3:25])[CH:28]=3)[N:42]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Solvent: O=[N+]([O-])O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc(-c3ccc(Cl)cc3)cc(C(F)(F)F)n2)ccc1-n1cnc(C)c1
Temperature: 78 °C
Yield: 10.9 %

Procedure:
A mixture of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (50 mg, 0.2 mmol), N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (74 mg, 0.2 mmol), and triethylamine (0.14 mL, 1.0 mmol) in ethanol (0.5 mL) was heated to 78° C. for 18 h. The mixture was cooled, diluted with ethyl acetate (30 mL), and then washed with sat. sodium carbonate solution (5 mL) and with brine (5 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residual material was purified by column chromatography on silica gel (5 g) using ethyl acetate/0-10% ethanol as eluent to give the title compound (10 mg, 11%) as light-yellow solid. Mp 202-204° C.
Reaction SMILES: CO[C:3](=O)[NH:4][C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=3)[N:11]([CH2:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:8]2=[N:9][CH:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:12]2[N:11]([CH2:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:8]3=[N:9][CH:10]=[C:5]([NH:4][CH3:3])[CH:6]=[C:7]3[CH:13]=2)=[CH:16][CH:17]=1)[CH3:23]
Reactant: CCOc1ccc(Cc2cc3cc(NC(=O)OC)cnc3n2CC2CCOCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc3cc(NC)cnc3n2CC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.2 %

Procedure:
To a solution of [2-[(4-ethoxyphenyl)methyl]-1-[(tetrahydro-2H-pyran-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-carbamic acid methyl ester (153 mg, 0.36 mmol) in THF (25 ml) at 0° C. was added lithium aluminum hydride (35 mg, 0.90 mmol). The mixture was stirred for 48 hours at room temperature. The reaction was then cooled to 0° C. and quenched by dropwise addition of water (35 □L), followed by 4M NaOH aqueous solution (35 μL) and water (105 μL). After stirring at room temperature for 30 minutes, the suspension was filtered over Diatomaceous earth and concentrated in vacuo to give 100 mgs of colorless oil. 1H NMR (400 MHz, CHLOROFORM-D) δ 1.40 (m, 5 H), 1.59 (m, 2 H), 2.05 (m, 1 H), 2.87 (s, 3 H), 3.36 (m, 2 H), 3.66 (m, 2 H), 4.01 (m, 6 H), 5.99 (s, 1 H), 6.83 (d, J=8.79 Hz, 2 H), 6.98 (s, 1 H), 7.05 (d, J=2.54 Hz, 1 H), 7.10 (d, J=8.79 Hz, 2 H), 7.79 (d, J=2.54 Hz, 1 H). MS (ESI) (M+H)+: 380.
Reaction SMILES: [F:1][C:2]1[C:3](=[N:17][NH2:18])[N:4]=[C:5]([S:15][CH3:16])[NH:6][C:7]=1[NH:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1.[CH:19]1([CH2:24][C@H:25]([CH2:29][N:30]([CH:38]=[O:39])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH:19]1([CH2:24][C@@H:25]([C:26]([NH:18][NH:17][C:3]2[C:2]([F:1])=[C:7]([NH:8][CH2:9][C:10]3[S:11][CH:12]=[CH:13][N:14]=3)[N:6]=[C:5]([S:15][CH3:16])[N:4]=2)=[O:27])[CH2:29][N:30]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH:38]=[O:39])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CSc1nc(=NN)c(F)c(NCc2nccs2)[nH]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CSc1nc(NCc2nccs2)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)n1
Reaction time: 8 h
Yield: 56.5 %

Procedure:
5-Fluoro-2-(methylthio)-6-[(1,3-thiazol-2-ylmethyl)amino]-4(1H)-pyrimidinone hydrazone (0.1958 g, 0.685 mmol) and (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (0.355 g, 0.823 mmol) were dissolved in DMF (5 mL). NMM (0.30 mL, 2.7286 mmol) was added, followed by HOAt (0.112 g, 0.824 mmol) and EDC (0.157 g, 0.819 mmol). After stirring overnight, the reaction mixture was purified by RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-(methylthio)-6-[(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide as an orange solid (0.2197 g, 57%). LCMS: (M+H)+=568.2.
Reaction SMILES: [C:1]1([N:7]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][CH2:9][C:8]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:21].S(Cl)(Cl)(=O)=O>C(Cl)(Cl)Cl>[Cl:21][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][CH2:9][C:8]2=[O:19])=[CH:2][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1CCCC(c2ccccc2)N1c1ccccc1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C1CCCC(c2ccccc2)N1c1ccc(Cl)cc1
Yield: 73.9 %

Procedure:
To 0.25 g of 1,6-diphenyl-2-piperidone were added 0.30 g of phosphorus pentachloride, 0.5 ml of sulfuryl chloride and 5 ml of chloroform, and the mixture was refluxed for 1.5 hours. The reaction mixture was concentrated under reduced pressure, made alkaline with an aqueous sodium hydrogen carbonate solution, and extracted with 30 ml of ethyl acetate. The ethyl acetate extract was washed with water, dried, and concentrated to give 0.21 g of 1-(4-chlorophenyl)-6-phenyl-2-piperidone.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:19](Cl)(=[O:24])[CH2:20][CH2:21][CH:22]=[CH2:23]>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:19](=[O:24])[CH2:20][CH2:21][CH:22]=[CH2:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC(=O)Cl
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
To a cooled (−78° C.) solution of (R)-4-benzyloxazolidin-2-one (2.242 g, 12.652 mmol) in 30 mL of THF, was added n-BuLi (5.6 mL, 13.917 mmol, 2.5 M in hexane). The resulting mixture was stirred at −78° C. under N2 for 15 min and then pent-4-enoyl chloride (1.500 g, 12.652 mmol) was added. After stirring at −78° C. for 1 h the reaction was warmed to room temperature under N2 and stirred overnight. The reaction mixture was quenched with 60 mL of aqueous NH4Cl solution and extracted with dichloromethane (50 mL×3). The combined organic extracts were dried, filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel) eluting with 0-30% ethyl acetate/hexanes to give the title compound as colorless oil (2.146 g, 65% yield). GC-MS: tR=4.2 min; m/z 259 (M+).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[C@@H:18]3[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:12][CH2:11][CH2:10]2)=[O:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C[NH:26][CH2:27][CH2:28][NH:29][CH3:30].N1C=CN=C1>COCCOC.C(Cl)Cl.[Cu]I>[N:26]1([C:2]2[S:6][CH:5]=[C:4]([C:7]([N:9]3[CH:18]4[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]4)[CH2:12][CH2:11][CH2:10]3)=[O:8])[CH:3]=2)[CH:27]=[CH:28][N:29]=[CH:30]1
Reactant: CNCCNC
Reactant: O=C(c1csc(Br)c1)N1CCC[C@@H]2CCCC[C@@H]21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: O=C(c1csc(-n2ccnc2)c1)N1CCCC2CCCCC21
Temperature: 120 °C
Yield: 274.8 %

Procedure:
cis-(5-Bromo-thiophen-3-yl)-(octahydro-quinolin-1-yl)-methanone (0.15 mmol) was added to a solution of potassium carbonate (0.15 mmol), N,N′-dimethylethylene-diamine (0.03 mmol), imidazole (0.3 mmol) and copper (I) iodide (0.03 mmol) in DME (1 mL). The reaction mixture was heated under nitrogen to 120° C. for 90 hours and then diluted with DCM (5 mL) and washed with water. The organic solution was dried and filtered and the solvent evaporated. The residue was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum to give the title compound as a pale brown solid (26 mg). LCMS m/z 316.06 [M+H]+ RT=6.44 min. (Analytical Method 2).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:20][CH3:21])=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][CH:9]=[C:10]1[C:15](=[O:16])OC(C)(C)OC1=O.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[Br:1][C:2]1[C:3]([O:20][CH3:21])=[N:4][CH:5]=[C:6]2[C:7]=1[NH:8][CH:9]=[CH:10][C:15]2=[O:16]
Reactant: COc1nccc(NC=C2C(=O)OC(C)(C)OC2=O)c1Br
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: COc1ncc2c(=O)cc[nH]c2c1Br
Temperature: 250 °C

Procedure:
A two neck RBF equipped with an air condenser was charged with 5-[(3-Bromo-2-methoxy-pyridin-4-ylamino)-methylene]-2,2-dimethyl-[1.3]dioxane-4,6-dione (23 g, 64 mmol) and diphenyl ether (230 mL). The reaction mixture was heated at 250° C. for 30 min under nitrogen atmosphere after which it was cooled to RT, diluted with hexane and filtered to obtain a dark solid. The crude product was refluxed in hexane for 30 min and filtered to obtained 8-Bromo-7-methoxy-1H-[1.6]naphthyridin-4-one as a brown solid.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[C:10]([NH:11][CH3:12])=[CH:9][C:8]([Cl:13])=[N:7][CH:6]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].CO.C(OCC)(=O)C>C1COCC1>[Cl:13][C:8]1[N:7]=[CH:6][C:5]([CH2:4][OH:3])=[C:10]([NH:11][CH3:12])[CH:9]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1NC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1cc(Cl)ncc1CO
Temperature: -78 °C
Reaction time: 1 h

Procedure:
6-Chloro-4-methylaminonicotinic acid ethyl ester (33 g, 156 mmol) was dissolved in anhydrous THF (500 mL) and cooled to −78° C. To the solution was slowly added a solution of LAH (12.5 g, 330 mmol) in THF (500 mL). After the addition was complete, the reaction was kept at −78° C. for 1 h. The mixture was warmed to rt and a small amount of MeOH/ethyl acetate (1/1) was slowly added to destroy the excess LAH. The crude reaction mixture was filtered through a celite plug, washing twice with ethyl acetate. The filtrate was concentrated, and the crude residue was purified by silica gel chromatography (1:1 hexanes/ethyl acetate eluant). The title compound was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.36 (s, 1H), 6.48 (s, 1H), 5.55 (bs, 1H), 4.63 (s, 2H), 2.89 (d, J=5.1 Hz, 3H).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH:9]=[C:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.O.[OH-].[Na+]>C(Cl)(Cl)Cl>[C:1]1(/[CH:7]=[CH:8]/[CH:9]=[C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=C/C=C/c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Product: C(/C=C/c1ccccc1)=C1CCNCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of Compound 255a (752 mg, 2.51 mmol) in CHCl3 (15 mL) was added trifluoroacetic acid (0.967 mL, 12.6 mmol) and the reaction mixture was stirred at 25° C. for 24 h, until the complete conversion of the reagent was observed by LC-MS. Water was added followed by aq. NaOH (2 N) to give alkaline pH. Separation of the organic layer and extraction of the aqueous layer with CH2Cl2, washing with brine and drying over Na2SO4 the combined organic layers, afforded the title compound. The crude was purified by flash chromatography (CHCl3-1.6 M methanolic ammonia 100:5) affording the title product (359 mg).
Reaction SMILES: CO.[CH2:3]([O:10][C:11]1[C:16]([N+:17]([O-])=[O:18])=[CH:15][C:14]([OH:20])=[C:13]([CH3:21])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[K+].S(OC)(O[CH3:28])(=O)=O>O>[CH2:3]([O:10][C:11]1[C:16]([N:17]=[O:18])=[CH:15][C:14]([O:20][CH3:28])=[C:13]([CH3:21])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(OCc2ccccc2)c([N+](=O)[O-])cc1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(N=O)c(OCc2ccccc2)cc1C
Yield: 50 %

Procedure:
To 100 ml of methanol, there were added 24.6 g (95.0 mmol) of 4-benzyloxy-2-methyl-5-nitrophenol and 6.38 g (114 mmol) of potassium hydroxide and heated under reflux. To the obtained solution, there was added 14.4 g (114 mmol) of dimethyl sulfate and heated under reflux for additional one hour. After cooling and adding 200 ml of water, the crystals thus precipitated were filtered and recrystallized from hexane-acetone (2:1 (v:v)). Thus 13.0 g (47.5 mmol) of 4-benzyloxy-2-methyl-5-nitrosoanisole was obtained as yellow crystals. The yield was 50%.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:8][C:9]=1[N:10]([S:19]([C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([Cl:29])=[CH:24][C:23]=1[CH3:30])(=[O:21])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([I:18])[CH:13]=1)=[O:4].O[Li].O>C1COCC1.CO.O>[Cl:29][C:25]1[C:26]([CH3:28])=[CH:27][C:22]([S:19]([N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([I:18])[CH:13]=2)[C:9]2[CH:8]=[C:7]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])(=[O:20])=[O:21])=[C:23]([CH3:30])[CH:24]=1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(Cc1cccc(I)c1)S(=O)(=O)c1cc(C)c(Cl)cc1C
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)N(Cc2cccc(I)c2)c2cc(-c3ccccc3)sc2C(=O)O)c(C)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.8 %

Procedure:
3-[(4-Chloro-2,5-dimethyl-benzenesulfonyl)-(3-iodo-benzyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (25 mg, 0.038 mmol) was taken in a mixture of THF:MeOH:H2O (3:2:1, 3 mL) and then added 1N aqueous solution of LiOH.H2O (0.24 mL, 0.228 mmol). The reaction mixture was stirred at room temperature for 12 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10% KHSO4 solution. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using dichloromethane and methanol (9:1) to obtain 3-[(4-Chloro-2,5-dimethyl-benzene-sulfonyl)-(3-iodo-benzyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (22 mg, 88%) as a white solid. 1H NMR (CDCl3, 400 MHz): 7.69 (m, 3H), 7.57 (m, 3H), 7.42 (m, 3H), 7.33 (d, 1H), 7.16 (s, 1H), 6.04 (dd, 1H), 4.90 (bs, 2H), 2.36 (s, 6H).
Reaction SMILES: [Se](=O)=O.[O:4]1CCOCC1.O.[C:11]([CH:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:23]=[CH:24][C:25]3[S:29][C:28]([CH3:30])=[N:27][C:26]=3[CH:31]=2)[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([CH:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:23]=[CH:24][C:25]3[S:29][C:28]([CH:30]=[O:4])=[N:27][C:26]=3[CH:31]=2)[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C1COCCO1
Reactant: Cc1nc2cc(OC3CCC(C(C)(C)C)CC3)ccc2s1
Agent: O=[Se]=O
Solvent: O
Product: CC(C)(C)C1CCC(Oc2ccc3sc(C=O)nc3c2)CC1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
Selenium dioxide (180 mg, 1.6 mmol) was combined with 1,4-Dioxane (5 mL, 60 mmol) and Water (0.5 mL, 30 mmol) at room, temperature open to the atmosphere. The mixture was then treated with 5-(4-tert-Butyl-cyclohexyloxy)-2-methyl-benzothiazole (250 mg, 0.82 mmol) and resulting mixture was heated to 65° C. for 2 hours. The heat was increased to 90° C. and 4 additional eq. of SeO2 were added. Reaction was stirred for additional 5 hours. LCMS shows nearly complete conversion. Reaction become dark and solids formed in reaction mixture. Reaction was cooled to RT and allowed to stand over night. Solids were removed via filtration. Concentrated to dryness then purified directly via column chromatography using a gradient of 0-40% Ethylacetate/hexane to give the title compound as a dark solid.