Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N+:4]([O-:15])[C:5]2[C:10]([C:11]=1[N+:12]([O-:14])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:16]([NH2:18])[CH3:17]>O1CCCC1>[CH2:16]([NH:18][C:2]1[CH:3]=[N+:4]([O-:15])[C:5]2[C:10]([C:11]=1[N+:12]([O-:14])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:17]
Reactant: O=[N+]([O-])c1c(Br)c[n+]([O-])c2ccccc12
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1c[n+]([O-])c2ccccc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Bromo-4-nitroquinoline-N-oxide (10 g, 0.037 mol) was dissolved in tetrahydrofuran (100 ml). To the solution, ethylamine (5.96 g, 70% in H2O) was added and the mixture was stirred at room temperature for 1 hour. Tetrahydrofuran was distilled off under vacuum from the whole reaction mixture and the residue was dissolved in chloroform. The chloroform layer was washed with water and dried with anhydrous sodium sulfate. Upon isolation and purification by chromatography on a silica gel column using chloroform as a developing solvent, 3-ethylamino-4-nitroquinoline-N-oxide was obtained in an amount of 5.4 g (yield, 62%).
Reaction SMILES: C([CH:3](O)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])=[CH:8][CH:7]=1)C.N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:43][C:44]1[CH:49]=[CH:48][C:47]([S:50]([NH:53][C@@H:54]([C@H:61]([NH2:68])[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)(=[O:52])=[O:51])=[CH:46][CH:45]=1.CCN(CC)CC>C(Cl)Cl>[CH2:13]([O:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][CH2:3][NH:68][C@H:61]([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[C@H:54]([NH:53][S:50]([C:47]2[CH:46]=[CH:45][C:44]([CH3:43])=[CH:49][CH:48]=2)(=[O:52])=[O:51])[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)=[CH:11][CH:10]=1)[CH2:14][CH2:15][CH2:16][C:17]#[CH:18]
Reactant: C#CCCCCOc1ccc(CCC(O)CC)cc1
Reactant: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C#CCCCCOc1ccc(CCCN[C@H](c2ccccc2)[C@H](NS(=O)(=O)c2ccc(C)cc2)c2ccccc2)cc1
Yield: 81.8 %

Procedure:
This compound was prepared according to general procedure 5 using 3 ethyl-3-(4-(hex-5-ynyloxy)phenyl)propan-1-ol (400 mg, 1.72 mmol), 2,6-lutidine (353 mg, 3.30 mmol), trifluoromethanesulfonic anhydride (787 mg, 2.80 mmol), (R,R)-TsDPEN (403 mg, 1.10 mmol), Et3N (263 mg, 2.60 mmol) and DCM (8 cm3). The product was purified by column chromatography as in the general procedure. TLC: silica gel, 30% EtOAc in petroleum ether, product Rf=0.36 with visualisation by UV and KMnO4, 2,6-lutidine Rf=0.29 with visualisation by UV, 2,6-lutidine elutes with the product). The fractions containing the product were collected, combined and dried under reduced pressure to give a white solid. The solid was then washed with pentane to remove residual 2,6-lutidine. The mixture was filtered and the solid dried to give the product as a white solid (524 mg, 0.900 mmol, 82% based on 403 mg, 1.1 mmol N-(2-aminoethyl)-4-methylbenzenesulfonamide)). Mp 123-124° C.; [α]D27−25.2 (c 0.25 in CHCl3) (R,R); (found (ESI): M++H, 581.2833 C36H41N2O3S requires M, 581.2832); υmax 3286, 3248, 2915, 1510, 1454, 1434, 1316, 1242, 1160, 1031, 808, 700 cm−1; δH (400 MHz, CDCl3) 7.37 (2H, d, J 8.5 Hz, CHArSO2), 7.13-7.11 (3H, m, CHAr), 7.05-6.88 (12H, m, CHAr and NHSO2 overlapping), 6.78 (2H, d, J 8.5 Hz, CHArSO2), 6.28 (1H, br s, NH), 4.25 (1H, d, J 7.8 Hz, CHNSO2), 3.95 (2H, t, J 5.0 Hz, CH2OAr), 3.59 (1H, d, J 7.8 Hz, CHN), 2.51-2.38 (3H, m, ArCH2 and CH2N overlapping), 2.31 (3H, s, CH3), 2.29-2.24 (3H, m, HCCCH2 and CH2N overlapping), 1.96 (1H, t, J 2.6 Hz, HCCCH2), 1.92-1.85 (2H, m, CH2CH2CH2OAr), 1.75-1.61 (4H, m, CH2CH2N and HCCCH2CH2); δC (100 MHz, CDCl3) 157.20 (CAr), 142.70 (CAr), 139.33 (CAr), 138.39 (CAr), 137.09 (CAr), 133.79 (CAr), 129.21 (2 CHAr), 129.10 (2 CHAr), 128.31 (2 CHAr), 127.93 (2 CHAr), 127.58 (2 CHAr), 127.46 (CHAr), 127.41 (2 CHAr), 127.29 (CHAr), 127.13 (2 CHAr), 114.39 (2 CHAr) 84.18 (C), 68.64 (CH), 67.77 (CH), 67.29 (CH2), 63.09 (CH), 46.45 (CH2), 32.37 (CH2), 31.71 (CH2), 28.37 (CH2), 25.11 (CH2), 21.46 (CH3), 18.19 (CH2); m/z (ESI) 581.3 (M++1).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]2=[O:14])([O-])=O.[CH:15]1([SH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[CH:15]1([S:21][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[NH:8][C:7]3=[O:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: SC1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1NC(=O)c2cc(SC3CCCCC3)ccc21
Yield: 114.7 %

Procedure:
A mixture of 5-nitro-isoindole-1,3-dione (10.0 g), cyclohexanethiol (9.1 g) and potassium carbonate (18.7 g) in acetone (260 ml) was heated to reflux overnight. After cooling, the mixture was diluted with water (250 ml) and then acidified by 6N HCl to pH=4. Precipitate was collected and dried in vacuo to give the intermediate 5-cyclohexylsulfanyl-isoindole-1,3-dione (15.6 g). This intermediate was dissolved in acetone (170 ml) and to the mixture was added bromo ethylacetate (10.6 g) and potassium carbonate (23.8 g). The mixture was refluxed overnight. After cooling, reaction mixture was filtered and rinsed with ethyl acetate. Filtrate was concentrated and purified by silica gel chromatography (10%-50% ethyl acetate in methylene chloride) to give the title compound (13.1 g). 1H NMR (200 MHz, CDCl3) δ 7.73 (m, 2H), 7.56 (dd, J=7.8, 1.6 Hz, 1H), 4.40 (s, 2H), 4.21 (q, J=7.0 Hz, 2H), 3.37 (m, 1H), 2.07-1.28 (m, 13H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:14]([NH:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=1)=[O:19])[CH3:15].C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][CH2:9][C:10]([N:16]([CH2:14][CH3:15])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=1)=[O:19])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNCC(=O)c1ccc(F)c(C)c1
Reactant: O=C(Cl)COCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC(=O)c1ccc(F)c(C)c1)C(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
2.9 g benzyloxy-acetyl chloride was added to 3.7 g 2-ethylamino-1-(4-fluoro-3-methyl-phenyl)-ethanone hydrochloride and 5 mL triethylamine in 40 mL dichlormethane. The reaction was stirred 3 h at RT. The reaction was diluted with dichlormethane, washed with water, 1 mol/L aqueous hydrochloride acid and with 5% aqueous potassium carbonate solution. The organic layer was dried and evaporated to yield 5.2 g of the desired product. Rt: 0.91 min (method J), (M+H)+: 344
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26]([O:28]C)=[O:27])[N:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:30]=1.[OH-].[Na+].C1COCC1>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=[O:27])[N:21]=4)[CH2:18][CH2:19]3)[CH2:9][CH2:8][C:7]=2[CH:30]=1
Reactant: COC(=O)c1ncnc(N2CCC(N3CCc4cc(OC)ccc4NC3=O)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCN(C1CCN(c3ncnc(C(=O)O)n3)CC1)C(=O)N2

Procedure:
0.27 g (0.64 mmol) methyl 4-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-[1,3,5]triazine-2-carboxylate and 0.5 mL (2 mmol) of a 4M NaOH solution were stirred in 0.5 mL water and 4.0 mL THF for 3 days at RT. The organic solvent was eliminated by rotary evaporation and the reaction mixture was combined with 0.5 mL of a 4M HCl solution. The precipitated solid was suction filtered and dried.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: COc1ccc(Br)cn1
Product: COc1ccc(-c2ccc(Br)cc2)cn1

Procedure:
The 5-bromo-2-methoxypyridine was reacted with 4-bromobenzeneboronic acid using the procedure described in Example 25 for the preparation of the compound of formula 2. The product was purified by flash column chromatography on silica gel using a gradient of n-pentane to 3% ethyl acetate in n-pentane to give 5-(4-bromophenyl)-2-methoxypyridine as an oil (0.56 g), NMR: 3.9(3H,s), 6.9(1H,d), 7.61(4H,s), 8.0(1H,dd) and 8.5(1H,d).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:12])=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+]>O1CCCC1.CO>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[CH:23][N:22]=[C:21]([N:18]2[CH2:17][CH2:16][CH:15]([CH2:14][NH:13][C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=3)=[O:12])[CH2:20][CH2:19]2)[N:26]=1
Reactant: COC(=O)c1ccc(C(=O)NCC2CCN(c3nccc(C(F)(F)F)n3)CC2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCC1CCN(c2nccc(C(F)(F)F)n2)CC1)c1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.4 %

Procedure:
To a suspension of methyl-5-{[({1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methyl)amino]carbonyl}pyridine-2-carboxylate (272 mg, 0.643 mmol) in tetrahydrofuran, methanol, and water (5 ml, in a ratio of 3:2:1, respectively) was added lithium hydroxide (108 mg, 2.57 mmol). The reaction was stirred at ambient temperature for 18 h and then concentrated in vacuo to afford the title compound as a white solid (230 mg). Mass spectrum (ESI) 410 (M+1). 1H NMR (500 MHz, CD3OD) δ 8.96 (s, 1H), 8.54 (d, 1H, J=4.8 Hz), 8.24 (d, 1H, J=8.3 Hz), 8.05 (d, 1H, J=8 Hz), 6.81 (d, 1H, J=4.8 Hz), 4.70-5.0 (m, 2H), 2.94-3.01 (m, 2H), 1.97-2.03 (m, 1H), 1.88 (d, 2H, J=12.8 Hz), 1.21-1.34 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14]>>[ClH:1].[CH:13]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:18][CH2:17]1)([CH3:15])[CH3:14]
Reactant: CC(C)N1CCNCC1
Reactant: COc1ccc2nc(Cl)sc2c1
Product: COc1ccc2nc(N3CCN(C(C)C)CC3)sc2c1
Product: Cl
Temperature: 120 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
A mixture of 2-chloro-6-methoxybenzothiazole (0.20 g, 1.0 mmol) and 1-isopropylpiperazine (0.26 g, 2.0 mmol) was stirred at 120° C. for 2 h. The reaction mixture was allowed to cool and worked up by extraction with ethyl acetate. The organic extract was washed with a NaHCO3 solution and water (3×). The organic phase was extracted with 0.25 M hydrochloric acid (10 mL). The acidic aqueous extract was concentrated and re-evaporated with ethanol. The residue was crystallized from a mixture of ethanol and ethyl acetate to give 260 mg (80%) of 2-(4-isopropylpiperazin-1-yl)-6-methoxybenzothiazole, hydrochloride.
Reaction SMILES: CN(C)[C:3]1(OC)[CH2:7][CH2:6][CH2:5][N:4]1[CH3:8].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][C:18]#[N:19])=[CH:15][CH:14]=1.C(O)(C)C>C1C=CC=CC=1>[C:18]([C:17](=[C:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH3:8])[C:16]1[CH:20]=[CH:21][C:13]([Cl:12])=[CH:14][CH:15]=1)#[N:19]
Reactant: COC1(N(C)C)CCCN1C
Reactant: N#CCc1ccc(Cl)cc1
Solvent: CC(C)O
Solvent: c1ccccc1
Product: CN1CCCC1=C(C#N)c1ccc(Cl)cc1
Yield: 23.1 %

Procedure:
Stir 7.9 g of the title compound of Example 85 and 7.05 g of 4-chlorobenzylcyanide in 30 ml of benzene for 3 hours at 45°. Free the resulting reaction mixture from solvent by distillation to produce a dark-brown crystalline residue. Take up this residue with 10 ml of isopropanol and filter it to obtain 2.5 g of the title compound as yellowish crystals of m.p. 68° to 71°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1N=[C:11]([C:15]([OH:17])=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[N:20]1.[CH2:28]1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:28]=[C:11]([C:15]([O:17][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[N:20]2)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: On1nnc2ccccc21
Reactant: Cn1cc(NC(=O)OC(C)(C)C)nc1C(=O)O
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)On1nnc2ccccc21
Yield: 89 %

Procedure:
The Boc-imidazole-acid 12 (2 g, 8.3 mmol) was in dissolved in 10 ml of DMF and 1-hydroxybenzotriazole was added (1.2 g, 9 mmol) followed by DCC (2.4 g, 9 mmol). After 6 hours the precipitate was removed by filtration and washed with 4 ml of DMF. The DMF solution was added dropwise to 250 ml of well stirred ice water and the resulting precipitate was collected by vacuum filtration. The filter cake was ground and dried in vacuo over P2O5 to give (2.7 g, 89%) of 13 as a pale yellow power contaminated with a small amount of DCU (2.7 g, 89%). 1H NMR (DMSO-d6) δ9.62 (s, 1H), 7.96 (s, 1H), 7.68 (d, 1H), 7.52 (d, 1H). 7.38 (d, 1H), 7.23 (s, 1H), 3.85 (s, 3H), 1.33 (s, 9H).
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]([C:11]([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[NH:9][CH3:10])(C)(C)C>Cl>[C:11]([N:8]([CH2:7][C:6]([OH:28])=[O:5])[NH:9][CH3:10])([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12]
Reactant: CNN(CC(=O)OC(C)(C)C)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Product: CNN(CC(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21
Yield: 70.7 %

Procedure:
1 L, two-neck, round-bottomed-flask was fitted with a glass stopper and reflux condenser connected to a calcium tube. (N-Fmoc-N′-methyl-hydrazino)-acetic acid t-butyl ester (20 g, 52 mmol) was added. A solution of HCl (150 mL, 4 M solution in dioxane) was added slowly with vigorous stirring in an ice water bath. The reaction mixture was stirred at RT over 1 day. The solution was concentrated completely under reduced pressure at 40° C. A saturated aq. NaHCO3 solution (100 mL) was added and the aqueous layer was washed with diethyl ether (100 mL). Conc. HCl was added dropwise slowly at 0° C. (pH 2-3). The mixture was extracted and the organic layer was retained (500 mL, MC). The solution was dried with sodium sulfate and evaporated in vacuo. The residue was purified by recrystallization with n-hexane and ethyl acetate to give (N-Fmoc-N′-methyl-hydrazino)-acetic acid (12 g, 72%). 1H-NMR (DMSO-d6) δ 12.38 (s, 1H), 8.56 (b, 1H), 7.89˜7.86 (d, J=9 Hz, 2H), 7.70˜7.67 (d, J=9 Hz, 2H), 7.43˜7.29 (m, 4H), 4.29˜4.27 (d, J=6 Hz, 2H), 4.25˜4.20 (t, J=6 Hz, 1H), 3.47 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([C:20]2([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:19]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2.[CH3:28][I:29]>C(#N)C>[I-:29].[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([C:20]2([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:19]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N+:13]([CH3:28])=[CH:12][CH:11]=[CH:10]2
Reactant: COC1(c2cc(F)cc(OCc3ccc4ncccc4c3)c2)CCOCC1
Reactant: CI
Solvent: CC#N
Product: COC1(c2cc(F)cc(OCc3ccc4c(ccc[n+]4C)c3)c2)CCOCC1
Product: [I-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
A mixture of 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran -4-yl]phenoxy)methyl]quinoline (0.367 g), methyl iodide (0.2 ml) and acetonitrile (7 ml) was stirred at ambient temperature for 16 hours. The precipitate was filtered off to give 6-[(3-fluoro-5-[4-methoxy -3,4,5,6-tetrahydro-2H-pyran-4-yl]phenoxy)methyl]-1-methylquinolinium iodide (0.29 g) in 57% yield, m.p. 190° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=O)[CH:9]([CH2:11][CH2:12][CH3:13])[O:10][C:6]=2[CH:5]=[C:4]([O:15][CH3:16])[C:3]=1[Cl:17].N12[CH2:26][CH2:25][CH2:24][C:23]1=NCCC2.C(C(C)=[O:30])=C>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8]3=[CH:9][C:11](=[O:30])[CH2:12][CH2:13][C:26]3([CH2:25][CH2:24][CH3:23])[O:10][C:6]=2[CH:5]=[C:4]([O:15][CH3:16])[C:3]=1[Cl:17]
Reactant: CCCC1Oc2cc(OC)c(Cl)c(Cl)c2C1=O
Reactant: C=CC(C)=O
Reactant: C1CN=C2CCCN2C1
Solvent: C1CCOC1
Product: CCCC12CCC(=O)C=C1c1c(cc(OC)c(Cl)c1Cl)O2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4,5-dichloro-6-methoxy-3-oxo-2-propylbenzofuran (0.785 g, 0.0029 mole) in tetrahydrofuran (THF) (8 ml) was warmed to 40° C. and treated with 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) (10 μl) and then with methyl vinyl ketone (2 ml) over a 10 minute period. The reaction mixture was heated at 55° C. for 1/2 hour during which time DBN (2 x 10 μl) was added. The THF was evaporated in vacuo, the residual oil dissolved in ether and ethyl acetate, washed with water, dried over MgSO4 and evaporated in vacuo. The residual oil consisting of 4,5-dichloro-6-methoxy-3-oxo-2-(3-oxobutyl)-2-propylbenzofuran (0.81 g) was dissolved in ethanol (10 ml) and water (5 ml), treated with 5% NaOH (1 ml) and stirred at 25° C. for 72 hours. Treatment of the reaction mixture with water (5 ml) caused precipitation of 1,2-dichloro-3-methoxy-8-oxo-5a-propyl-5a,6,7,8,-tetrahydrodibenzofuran (0.6 g) which melted at 172°-173° C.
Reaction SMILES: [Cl:1]C1C=CC(N)=CC=1[N+]([O-])=O.C(Cl)(Cl)Cl.ClC1C=CC(N[S:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])(=[O:26])=[O:25])=CC=1[N+]([O-])=O>N1C=CC=CC=1>[CH2:27]([S:24]([Cl:1])(=[O:26])=[O:25])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCS(=O)(=O)Cl

Procedure:
Hexadecanesulfonylchloride, which was prepared by the method as described in J. M. Sprague, et al., J. Amer. Chem. Soc., Vol. 59, page 1837 (1937), was reacted with 2-chloro-5-aminonitrobenzene in a chloroform solution in the presence of pyridine to prepare 2-chloro-5-hexadecanesulfonamidonitrobenzene.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]#[N:13])(=O)OCC)C.[CH2:14]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)=[O:18])[CH3:15]>O1CCCC1>[CH2:14]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=[CH:11][C:12]#[N:13])[CH2:21][CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(=CC#N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 12.85 g (321.28 mmol) of sodium hydride (60% suspension in mineral oil) in 500 ml of anhydrous tetrahydrofuran at 0° C., was added 56.91 g (321.28 mmol) of diethyl-(cyanomethyl)-phosphonate over a 10-min period. The reaction mixture was stirred for 2 h at room temperature and then 44.05 g (292.07 mmol) of 4-oxo-piperidine-1-carboxylic acid ethyl ester in 230 ml of anhydrous tetrahydrofuran was added dropwise over 30 min. The resulting mixture was stirred at room temperature for 16 h.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[S:9]1[C:13](B(O)O)=[CH:12][C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]1=2.[CH2:21]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([N:26]1[CH2:27][CH2:28][CH:29]([NH:32][C:2]2[N:7]=[C:6]([C:13]3[S:9][C:10]4[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=4[CH:12]=3)[CH:5]=[CH:4][N:3]=2)[CH2:30][CH2:31]1)=[O:25])[CH3:22]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Clc1ccnc(Cl)n1
Product: CCOC(=O)N1CCC(Nc2nccc(-c3cc4ccccc4s3)n2)CC1

Procedure:
The title compound was prepared analogous to Method A, starting from 2,4-dichloro-pyrimidine, benzo[b]thiophen-2-boronic acid and ethyl-4-amino-1-piperidinecarboxylate.
Reaction SMILES: [O:1]=[C:2]([CH3:6])[CH2:3][CH2:4][OH:5].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>O1CCCC1>[O:1]=[C:2]([CH3:6])[CH2:3][CH2:4][O:5][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)CCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To 400 ml of tetrahydrofuran in a reactor, 15.0 g (0.17 mol) of 3-oxo-1-butanol and 26.3 g (0.19 mol) of benzoyl chloride were dissolved, followed by drop-wise adding 20.6 g (0.20 mol) of triethylamine under ice-cooling. After the end of drop-wise addition, the reaction liquid was stirred at room temperature for 3 hours. Hydrochloric acid salt of triethylamine was filtered, followed by adding water to the filtrate and extracting with ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium carbonate, water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:5 to 1:3) to obtain 31.5 g (yield: 96%) of 3-oxobutylbenzoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=O)OCC(C)C)[CH:5]=[CH:6][C:7]=1[I:8].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:27]([O:32][CH2:33][C@@H:34]1[O:36]C1)(=[O:31])CCC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][C@H:33]([CH2:34][OH:36])[O:32][C:27]2=[O:31])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: CC(C)COC(=O)Nc1ccc(I)c(F)c1
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of isobutyl 3-fluoro-4-iodophenylcarbamate (Org. Process Res. Dev. 2001, 5(1), 80–83, 5.00 g, 14.83 mmol) in dry tetrahydrofuran (59 mL) at −78° C. under nitrogen is treated with lithium hexamethyldisilazide (1.0M in tetrahydrofuran, 15.6 mL, 15.57 mmol) dropwise and stirred at −78° C. for 45 minutes. Then, (R)-glycidyl butyrate (2.21 mL, 15.57 mmol) is added dropwise, and the resulting mixture is stirred at −78° C. for 1 h and at ambient temperature for 2.75 days. The reaction mixture is then quenched with saturated aqueous ammonium chloride (20 mL), diluted with water (20 mL) and the layers are separated. The aqueous phase is extracted with ethyl acetate (25 mL), and the combined organic phase is washed with water (25 mL) and saline (25 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product mixture is then chromatographed on a Flash 40M silica gel (90 g, 32–63 μm) cartridge, eluting with a gradient of methanol/methylene chloride (1/99–2/98), and those fractions with an Rf=0.25 by TLC (methanol/chloroform, 5/95) are pooled and concentrated to give the title compound, mp 116–117° C.; MS (ESI+) for C10H9FINO3 m/z 338 (M+H)+; [α]25D=−41 (c 0.98, DMSO).