Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[N+:16]([O-])([OH:18])=[O:17].Cl>CC(OC(C)=O)=O.CC(O)=O>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[C:12]([N+:16]([O-:18])=[O:17])[CH:13]=2)[CH2:6][CH2:7]1)=[O:4]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)C1(c2ccc(OC)cc2)CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C1(c2ccc(OC)c([N+](=O)[O-])c2)CC1
Yield: 98.1 %

Procedure:
To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (30.0 g, 146 mmol) in Ac2O (300 mL) was added a solution of HNO3 (14.1 g, 146 mmol, 65%) in AcOH (75 mL) at 0° C. The reaction mixture was stirred at 0˜5° C. for 3 h before aq. HCl (20%) was added dropwise at 0° C. The resulting mixture was extracted with EtOAc (200 mL×3). The organic layer was washed with sat. aq. NaHCO3 then brine, dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(4-methoxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methyl ester (36.0 g, 98%), which was directly used in the next step. 1H NMR (CDCl3, 300 MHz) δ 7.84 (d, J=2.1 Hz, 1H), 7.54 (dd, J=2.1, 8.7 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 3.97 (s, 3H), 3.65 (s, 3H), 1.68-1.64 (m, 2H), 1.22-1.18 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH:11]([OH:15])[CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16].O.[NH3:18]>O1CCOCC1>[NH2:18][C:2]1[N:10]=[C:9]([CH:11]([OH:15])[CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16]
Reactant: CCCC(O)c1nc(Cl)c2ncn(C)c2n1
Reactant: N
Solvent: C1COCCO1
Solvent: O
Product: CCCC(O)c1nc(N)c2ncn(C)c2n1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To the solution of 1-(6-chloro-9-methyl-9H-purin-2-yl)butan-1-ol (1.8 g, 7.47 mmol) in dioxane (10 ml) was added 30% w/w water solution of ammonia (20 ml). The reaction mixture was stirred overnight in an autoclave at 70° C. The solution was evaporated at atmospheric pressure at 50° C. and then under reduced pressure. The residue was purified by flash chromatography (DCM/MeOH: 95/5).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[O:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH:7]1[CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][C:19]([CH2:24]O)([CH3:23])[CH2:18]1>>[Cl:3][CH2:24][C:19]1([CH3:23])[CH2:20][CH2:21][CH2:22][N:17]([CH2:16][CH:7]2[O:6][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8]2)[CH2:18]1
Reactant: CC1(CO)CCCN(CC2COc3ccccc3O2)C1
Reactant: O=P(Cl)(Cl)Cl
Product: CC1(CCl)CCCN(CC2COc3ccccc3O2)C1

Procedure:
A mixture of phosphorus oxychloride (1.93 ml, 0.02 mmol) and [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol (0.2 g, 0.72 mmol) was refluxed for 3 h. Excess of phosphorus oxychloride was evaporated. Water was slowly added and the reaction mixture was made alkaline with aq NaOH and extracted with DCM (3×5 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (DCM/MeOH, 90:10).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][S:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])(=[O:5])[C:2]([CH3:4])=[CH2:3].COC1C=CC(O)=CC=1.C(Cl)(Cl)Cl.CO.CC(O)=O>FC(F)(F)C(O)=O>[C:1]([O:6][CH2:7][CH2:8][S:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCSCC(=O)OC(C)(C)C
Agent: COc1ccc(O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: C=C(C)C(=O)OCCSCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
3 (2 g, 7.7 mmol, 1 eqv.) was slowly dissolved in trifluoroacetic acid (TFA) (10 mL) on ice under nitrogen. A trace amount of hydroquinone monomethyl ether (MEHQ) was added to the reaction mixture to prevent polymerisation. The reaction mixture was allowed to warm to room temperature and the reaction mixture was stirred for 2 hours at 55 C. Completion of the reaction was monitored by TLC(CHCl3/MeOH/HOAc, 9:1:0.1 (v/v), Rf: 0.17). Excess of TFA was removed by evaporation and coevaporation with CH2Cl2 and the residue was purified on a silica gel column (Hex/EtOAc, 4:1 (v/v)). Pure 4 was dried with MgSO4 and filtered through Ø 185 mm whatman filter papers. The filtrate was concentrated in vacuo. 1 g (63% yield) 4 was obtained as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=1[F:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([CH:7]=1)[O:8][CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=1[F:37]
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reactant: N#Cc1ccc(CBr)c(F)c1
Product: N#Cc1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and 4-bromomethyl-3-fluoro-benzonitrile (CAS Reg. No. 105942-09-4). Light brown powder (78%). MS (Turbo Spray): m/z=510.2 (M+H).
Reaction SMILES: CN([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][C:7]=1[N+:17]([O-])=O)C>C(O)C.[Ni]>[F:16][C:13]([F:14])([F:15])[O:12][C:9]1[CH:8]=[C:7]2[C:6]([CH:5]=[CH:4][NH:17]2)=[CH:11][CH:10]=1
Reactant: CN(C)C=Cc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: FC(F)(F)Oc1ccc2cc[nH]c2c1
Reaction time: 18 h

Procedure:
Combine N,N-dimethyl-2-(2-nitro-4-trifluoromethoxyphenyl)vinylamine (4.64 g, 16.8 mmol) and Raney® nickel (900 mg) in ethanol (100 ml). Hydrogenate at 60 psi (410 kPa). and ambient temperature. After 18 hours, filter through celite, concentrate the filtrate to residue, and chromatograph on silica gel eluting with hexanes/ethyl acetate (30/70) to give, after evaporation, the title compound as an off-white powder: mp 59° C. MS (ACPI): m/e 200.0 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:20][C:21]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=O)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=O)[CH:5]=[CH:6][C:7]=1[F:8].C[N:34](C)C=O>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:20]=[C:21]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)[N:34]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(CC(CC(=O)c1ccccc1O)c1ccc(F)c(F)c1)c1ccc2ccccc2c1
Reactant: CN(C)C=O
Product: Oc1ccccc1-c1cc(-c2ccc(F)c(F)c2)cc(-c2ccc3ccccc3c2)n1
Temperature: 100 °C

Procedure:
A mixture of 3-(3,4-difluorophenyl)-1-(2-hydroxyphenyl)-5-(naphthalen-2-yl)-1,5-pentanedione on Wang resin (2.0 g, 1.76 mmol), NH4OAc (1.0 g), and ACOH (1.5 mL) in dimethylformamide (40 mL) was heated at 100° C. for 18 h. The resin was filtered, and washed with dimethylformamide (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight. The dried resin was treated with 50% TFA/CH2Cl2 (15 mL) for 1 h. After filtration of the reaction mixture, the filtrate was concentrated to dryness. The residue was repeatedly dissolved in CH2Cl2 (10 mL) and concentrated to remove traces of TFA. Purification by flash chromatography gave 2-[4-(3,4-difluoro-phenyl)-6-naphthalen-2-yl-pyridin-2-yl]-phenol; mp 165-167° C.; 1H NMR (DMSO-d6) d 6.99 (m, 2 H), 7.38 (m, 1 H), 7.65 (m, 4 H), 8.06 (m, 4 H), 8.24 (d, J=6.8 Hz, 1 H), 8.42 (m, 2 H), 8.49 (d, J=1.2 Hz, 1 H), 8.74 (s, 1 H), 14.35 (s, 1 H); IR (KBr) 1602 cm−1; MS [M+H]+m/z =410. Anal. calcd for C27H17F2NO: C, 79.21; H, 4.19; N, 3.42; Found: C, 79.33; H, 4.19; N, 3.22.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([NH2:27])([CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH3:20]>>[CH3:26][S:23]([CH2:22][CH2:21][C:19]([NH:27][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:20])[CH3:18])(=[O:25])=[O:24]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)(N)CCS(C)(=O)=O
Product: CC(C)(CCS(C)(=O)=O)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 2-methyl-4-(methylsulfonyl)-2-butanamine (CAN 1250515-16-2) as starting materials; LC-MS (UV peak area/ESI) 95%, 381.1843 (M+H)+.
Reaction SMILES: C([Mg]Cl)(C)C.[C:6]([Si:10]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:11][CH2:12][C@H:13]([CH3:18])[C:14](OC)=[O:15])([CH3:9])([CH3:8])[CH3:7].Cl.[CH3:32][O:33][NH:34][CH3:35]>O1CCCC1>[CH3:8][C:6]([Si:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[O:11][CH2:12][C@H:13]([CH3:18])[C:14]([N:34]([O:33][CH3:32])[CH3:35])=[O:15])([CH3:7])[CH3:9]
Reactant: CNOC
Reactant: COC(=O)[C@@H](C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)[C@@H](C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 99.9 %

Procedure:
A solution of iso-propylmagnesium chloride (2M in tetrahydrofuran, 28 mL) was added dropwise to a stirred mixture of (2S)-3-(tert-butyl-diphenyl-silanyloxy)-2-methyl-propionic acid, methyl ester (Eur. J. Org. Chem. 2006, 3645, 7.5 g), O,N-dimethylhydroxylamine hydrochloride (2.55 g) and tetrahydrofuran (65 mL) at 0° C. After completion the mixture was quenched with sat. aqueous NH4Cl and extracted into ethyl acetate. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give the crude product as a solid (8.1 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([OH:12])([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH3:5].[CH3:13]OS(OC)(=O)=O>O1CCCC1>[CH3:3][C:4]([O:12][CH3:13])([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH3:5]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)=CCCC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(C)CCC=C(C)C
Reaction time: 16 h

Procedure:
To sodium hydride (93.5 g, 3.9 mol) suspended in tetrahydrofuran (300 mL) was added 2,6-dimethylhept-5-en-2-ol (500 g, 3.5 mol) in tetrahydrofuran (1000 mL). The mixture was heated at reflux until gas evolution was complete. Dimethylsulfate (274 mL, 2.9 mol) in tetrahydrofuran (226 mL) was added to the cold (0° C.) mixture. After standing for 16 h, the mixture was heated at reflux for 7 hours. Aqueous workup yielded 2,6-dimethyl-2-methoxyhept-5-ene, bp40 65°-68° C. (461.5 g); NMR(CDCl3)δ1.2(s,6H), 1.4-1.6(m,2H), 1.6(s,3H), 1.7(s,3H), 1.9-2.1(m,2H), 3.2(s,3H), 5.1-5.2(m,1H); IR(neat) 2970, 2932, 1462, 1442, 1373, 1357, 1195, 1072 cm-1 ; MS(m/e) 41, 67, 73, 109, 124, 142.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:6](O)=O)[CH3:2].C=O.N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1)[CH3:2]
Reactant: CCOC(=O)C(CCCCCCC1CCCC1)C(=O)O
Agent: C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C=C(CCCCCCC1CCCC1)C(=O)OCC

Procedure:
11.5 g of 8-cyclopentyl-2-methyleneoctanoic acid ethyl ester, in the form of a nearly colourless oil, which is purified by chromatography on silica gel (migrating agent: 95:5 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1b) from 22.1 g of (6-cyclopentylhexyl)-malonic acid ethyl ester, 2.8 g of paraformaldehyde, 22 ml of pyridine and 1 ml of piperidine.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([S:29][CH3:30])[N:24]=1.O>CN(C=O)C>[Br:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)=[CH:10][CH:11]=2)[N:6]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([S:29][CH3:30])[N:24]=2)[CH:5]=1
Reactant: CSc1nccc(Cl)n1
Reactant: O=[N+]([O-])c1cccc(-c2ccc3c(Br)c[nH]c3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nccc(-n2cc(Br)c3ccc(-c4cccc([N+](=O)[O-])c4)cc32)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
Sodium hydride (60% in mineral oil, 38 mg, 0.946 mmol) was added to a mixture solution of 3-bromo-6-(3-nitrophenyl)-1H-indole (100 mg, 0.315 mmol) in anhydrous DMF (2 mL) at room temperature. 10 minutes later, 4-chloro-2-(methylthio)pyrimidine (44 μL, 0.378 mmol) was added. After stirring at room temperature for 2 hours, water was added. Thus produced solid was filtered and dried. The target compound (140 mg) was obtained as white solid.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[K+].[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([C@H]1[N:30]2[C@@H]([S:25][CH2:26][CH2:27][C@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:29]2=[O:31])CCC1)=O>[I-].C[P+](OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.C1COCC1.[NH4+].[Cl-]>[O:31]=[C:29]1[C@@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:27][CH2:26][S:25][C@H:17]2[CH2:11][CH2:16][CH2:15][C@@H:14]([CH:13]=[CH2:12])[N:30]12
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C=O)N2C1=O
Agent: C[P+](Oc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)OC(C)(C)C)C(=O)N12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.2 %

Procedure:
To a stirred suspension of methyltriphenoxyphosphonium iodide (716 mg, 1.58 mmol) in dry THF (5 mL) under argon at 0° C. was added dropwise a solution of 0.5 M potassium hexamethyldisilazide in toluene (3.17 mL, 1.58 mmol). The reaction mixture was stirred for 10 min at 0° C. and then for 20 min at rt. Then, the reaction temperature was lowered to −78° C. and a solution of tert-butyl (4S,7S,10aS)-7-formyl-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (400 mg, 1.22 mmol) in dry THF (5.00 mL) was added. The reaction mixture was stirred for 3 hr at rt. The reaction mixture was diluted with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (2×40 mL). The combined EtOAc layers were washed with water, saturated aqueous NaCl, dried over Na2SO4, filtered & concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-30% EtOAc/Hex to give tert-butyl (4S,7S,10aS)-5-oxo-7-vinyloctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (360 mg, 1.10 mmol, 91% yield) as a white foam. 1H NMR (400 MHz, CDCl3) δ ppm 6.48-6.18 (m, 1H), 6.07-5.81 (m, 1H), 5.50-5.22 (m, 2H), 5.22-4.99 (m, 2H), 4.92-4.69 (m, 1H), 3.20-2.98 (m, 1H), 2.85-2.61 (m, 1H), 2.49-2.26 (m, 1H), 2.17-1.96 (m, 2H), 1.96-1.65 (m, 4H), 1.66-1.52 (m, 1H), 1.43 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1.C(=O)(O)[O-].[Na+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:13]2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc([N+](=O)[O-])c(Br)c2)C1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
A solution of 2-bromo-4-fluoro-1-nitrobenzene (1.5 g, 6.8 mmol), (S)-tert-butyl pyrrolidin-3-ylcarbamate (1.9 g, 10 mmol), and sodium bicarbonate (1.7 g, 20 mmol) in DMSO (40 mL) was heated at 80° C. for 1 h. The reaction mixture was cooled to room temperature, poured into excess water and the resulting precipitate was filtered. The solids were washed with aqueous ammonium chloride, brine and water to afford the desired product (2.5 g, 96%) as a yellow solid: 387 [C15H20BrN3O4+H]+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][S:11](/[CH:14]=[CH:15]/[C:16]2[S:26][C:25]3[N:27]4[C:18](=[CH:19][N:20]=[C:21]4[CH:22]=[CH:23][CH:24]=3)[CH:17]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1.Br[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(O)C>[C:32]1([CH2:31][CH2:30][CH2:29][N:3]2[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][S:11](/[CH:14]=[CH:15]/[C:16]3[S:26][C:25]4[N:27]5[C:18](=[CH:19][N:20]=[C:21]5[CH:22]=[CH:23][CH:24]=4)[CH:17]=3)(=[O:13])=[O:12])[CH2:5][CH2:4]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=S(=O)(/C=C/C1=Cc2cnc3cccc(n23)S1)NCC1CCNCC1
Reactant: BrCCCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=S(=O)(/C=C/C1=Cc2cnc3cccc(n23)S1)NCC1CCN(CCCc2ccccc2)CC1

Procedure:
A solution of 0.285 g (0.634 mM) of (E)-N-(piperidin-4-ylmethyl)-2-(5-thia-1,8b-diazaacenaphthylen-4-yl)vinylsulfonamide dihydrochloride, 0.15 g (0.76 mM) of 1-bromo-3-phenylpropane, and 0.31 ml (2.22 mM) of triethylamine in 20 ml of ethanol was refluxed for 1 day. This reaction mixture was then poured in aqueous solution of sodium hydrogen carbonate and extracted with 2 portions of ethyl acetate. The organic layers were combined and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate˜ethyl acetate/methanol : 9/1) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:7][CH2:6][C:5]([CH2:9][OH:10])([CH3:8])[CH2:4][O:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[CH2:29]([O:36][CH2:37][CH2:38]OS(C(F)(F)F)(=O)=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.ClCCl>[CH3:1][C:2]1([CH3:11])[O:3][CH2:4][C:5]([CH2:9][O:10][CH2:38][CH2:37][O:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([CH3:8])[CH2:6][O:7]1
Reactant: O=S(=O)(OCCOCc1ccccc1)C(F)(F)F
Reactant: CC1(CO)COC(C)(C)OC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1(COCCOCc2ccccc2)COC(C)(C)OC1
Temperature: -20 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 2,2-dimethyl-5-hydroxymethyl-5-methyl-1,3-dioxane (13.4 g, 0.084 mol) in 630 mL of anhydrous tetrahydrofuran was cooled to -20° C. under argon atmosphere. Then a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene (168 mL, 0.084 mol) was added and the mixture was stirred at -20° C. for 1 hr. The 2-benzyloxyethyltriflate (23.8 g, 0.084 mol) was added neat, keeping the temperature between -20° and -15° C. The resulting solution was stirred at this temperature for 1 hr, then gradually allowed to warm to 25° C. and stirred for 15 hrs. Dichloromethane (900 mL) was added and the solution was washed twice with 300 mL of water and once with 100 mL of saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and evaporation of the solvents under reduced pressure gave 2,2-dimethyl-5-benzyloxyethoxymethyl-5-methyl-1,3-dioxane (24.6 g, 0.084 mol, 100%) which was not purified.
Reaction SMILES: C([N:8]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH:15]=[CH:16][CH2:17][CH3:18])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH:15]([C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH3:14])[NH:8]1)=[CH:16][CH2:17][CH3:18]
Reactant: CCC=C[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC=C[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-(1-butenyl)-6-methylpiperidine (1.80 g, 7.65 mmol) in 15% trifloroacetic acid (38 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 90 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-(1-butenyl)-6-methylpiperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occurred. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid that was homogeneous by TLC analysis. mp 167-169.0° C.; 1H NMR (250 MHz) δ 9.4 (s, 2H), 5.71-5.58 (m, 2H), 4.17 (s, 1H), 3.54 (s, 1H), 2.2-1.4 (m, 11H), 0.98 (t, 3H); 13C NMR (62.7 MHz) δ 138.5 (s), 122.4 (s), 48.2 (s), 47.9 (s), 28.74 (s), 28.45 (s), 21.3 (s), 17.6 (s), 16.9 (s), 13.8 (s). FT-IR (neat): 3425, 3183, 3072, 2961, 2915, 1656, 1585, 1463, 1443, 1407, 1107, 1075, 960, 883, 803. Elemental Analysis for C10H20NCl: C, 63.29%; H, 10.65%; N, 7.38%. Found: C, 63.14%; H, 10.58%; N, 7.32%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].C(N1C=CN=C1)(N1[CH:17]=[CH:16]N=C1)=O.C(O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][CH2:16][CH3:17])=[O:6]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccnc(Cl)c1
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccnc(Cl)c1
Yield: 95.9 %

Procedure:
In 400 ml of tetrahydrofuran was dissolved 31.5 g of 2-chloroisonicotinic acid, and 32.5 g of 1,1′-carbonyldiimidazole was added thereto. The mixture was stirred under ice-cooling for an hour. To the solution was added 50 ml of ethanol, and the mixture was stirred at room temperature for 2 hours. The solution was concentrated, and extracted by adding ethyl acetate and water. The organic layer was dried over magnesium sulfate, and the residue was vacuum dried, to give 35.6 g of ethyl 2-chloroisonicotinate as shown in Table 132 below.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[S:10][C:11]([C:13]([C:15]3[CH:16]=[C:17]([CH:21]([CH2:26][CH2:27][CH2:28][CH3:29])[C:22]([O:24]C)=[O:23])[CH:18]=[CH:19][CH:20]=3)=[O:14])=[CH:12][C:7]=2[CH:6]=1)=[O:4].C>[OH-].[K+]>[C:3]([C:5]1[S:9][C:8]2[S:10][C:11]([C:13]([C:15]3[CH:16]=[C:17]([CH:21]([CH2:26][CH2:27][CH2:28][CH3:29])[C:22]([OH:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)=[O:14])=[CH:12][C:7]=2[CH:6]=1)([OH:4])=[O:2]
Reactant: CCCCC(C(=O)OC)c1cccc(C(=O)c2cc3cc(C(=O)OC)sc3s2)c1
Agent: [K+]
Agent: [OH-]
Product: CCCCC(C(=O)O)c1cccc(C(=O)c2cc3cc(C(=O)O)sc3s2)c1
Temperature: 20 °C
Reaction time: 17 h
Yield: 102.6 %

Procedure:
Methyl 2-{3-(5-methoxycarbonyl-thieno[2,3-b]thien-2-yl)carbonyl-phenyl}hexanoate (29.6 g), suspended in a mixture of potassium hydroxide pellets (15.5 g), distilled water (50 cc) and ethanol (100 cc), is stirred for 17 hours at a temperature of about 20° C. The solvents are distilled off under reduced pressure (30 mm Hg) at 40°-50° C. and the residue is dissolved in distilled water (150 cc). The solution obtained is stirred with decolourizing charcoal (0.5 g), filtered and acidified to pH 1 by the addition of a 5 N aqueous solution of hydrogen chloride. The resulting crystals are filtered off, washed three times with distilled water (total 150 cc) and dried under reduced pressure (20 mm Hg) at 70° C. in the presence of potassium hydroxide pellets. Crude 2-{3-(5-carboxy-thieno[2,3-b]thien-2-yl)carbonyl-phenyl}hexanoic acid (28.4 g), melting at 208° C., is thus obtained.