Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:10]=1[CH2:11][O:12][C:13]1[C:14]2[N:15]([C:20]([C:24]([NH:26][CH2:27][C@H:28]3[CH2:33][CH2:32][CH2:31][CH2:30][N:29]3C(OC(C)(C)C)=O)=[O:25])=[C:21]([CH3:23])[N:22]=2)[CH:16]=[C:17]([CH3:19])[CH:18]=1>Cl.C(OCC)C>[F:45][C:41]1[CH:42]=[CH:43][CH:44]=[C:9]([F:8])[C:10]=1[CH2:11][O:12][C:13]1[C:14]2[N:15]([C:20]([C:24]([NH:26][CH2:27][C@H:28]3[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]3)=[O:25])=[C:21]([CH3:23])[N:22]=2)[CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NC[C@H]3CCCCN3C(=O)OC(C)(C)C)n2c1
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NC[C@H]3CCCCN3)n2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
56 mg of tert-butyl (2R)-2-{[({8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]methyl}piperidin-1-carboxylate trifluoroacetate Example 183A (0.09 mmol) were initially charged in 2 M hydrochloric acid in diethyl ether, and the mixture was stirred at RT for 5 h. The resulting precipitate was filtered off and washed with diethyl ether, dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulphate, filtered, concentrated and lyophilized. This gave 30 mg (78% of theory; purity 95%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:15])=[CH:10][C:11](=O)[NH:12][N:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([Cl:18])=[CH:10][C:9]=2[CH3:15])=[CH:4][CH:3]=1
Reactant: Cc1cc(=O)[nH]nc1-c1ccc(Br)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc(Cl)nnc1-c1ccc(Br)cc1

Procedure:
A 10.0 g. portion of 6-(p-bromophenyl)-5-methyl-3(2H)-pyridazinone [Journal of Medicinal Chemistry 17, 281 (1974)] and 100 ml. of phosphorus oxychloride is heated at steam bath temperature for 3 hours. The mixture is added dropwise to cold water while stirring. The resulting solid is filtered and washed with water to afford 3-(p-bromophenyl)-6-chloro-4-methylpyridazine as a grey solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[N+:11]([O-])[C:10]([CH3:14])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:17])=O.CCN(CC)CC>C(Cl)Cl>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:14][Cl:17])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(-c2ccccc2)c[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClCc1ccc(-c2ccccc2)cn1
Reaction time: 0.5 h

Procedure:
To a solution of 75 g 5-phenyl-2-picoline N-oxide from Step 1 in 375 mL of CH2Cl2 were added simultaneously a solution of 41.5 mL phosphoryl chloride in 150 mL of CH2Cl2 and a solution of 62 mL Et3N in 150 mL of CH2Cl2. The rate of addition was adjusted so that the reaction reached reflux temperature. The addition completed, the reaction was poured into a solution of NH4OAc (25%), stirred 30 minutes, and extracted with EtOAc. The organic layer was dried over MgSO4, filtered on a silica gel bed, and evaporated to dryness. The resulting solid was recrystallised from petroleum ether (30°-60° C.) to afford pure title product, m.p.: 73° C. The filtrate was chromatographed on silica gel (hexane/EtOAc 9:1) to give the title product along with 4-chloro-5-phenyl-2-picoline and 6-chloro-5-phenyl-2-picoline.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:19]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[C:24]([CH:33]=O)[CH:23]=1)[CH2:20][CH3:21]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][NH:18][CH2:33][C:24]3[CH:23]=[C:22]([CH2:19][CH2:20][CH3:21])[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:25]=3)[CH2:14][CH2:15]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CCCc1cc(C=O)nn1-c1ccccc1
Product: CCCc1cc(CNCCN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)nn1-c1ccccc1
Yield: 78.6 %

Procedure:
Compound 51 was prepared using the same method as that of Example 1 except that 4-(4-nitrophenyl)piperazin-1-ylethylamine and 5-propyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:19][C:20]1[CH:33]=[CH:32][C:23]2[S:24][C:25]([S:28](Cl)(=[O:30])=[O:29])=[C:26]([CH3:27])[C:22]=2[CH:21]=1>>[Cl:19][C:20]1[CH:33]=[CH:32][C:23]2[S:24][C:25]([S:28]([NH:1][C:2]3[CH:3]=[C:4]([CH:8]4[CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11]4)[CH:5]=[CH:6][CH:7]=3)(=[O:29])=[O:30])=[C:26]([CH3:27])[C:22]=2[CH:21]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: CC(C)(C)OC(=O)N1CC(c2cccc(N)c2)C1
Product: Cc1c(S(=O)(=O)Nc2cccc(C3CN(C(=O)OC(C)(C)C)C3)c2)sc2ccc(Cl)cc12
Yield: 71 %

Procedure:
Following the same procedure as described in Example 1.7, tert-butyl 3-(3-aminophenyl)azetidine-1-carboxylate (100 mg, 0.40 mmol) was coupled with 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (118 mg, 0.42 mmol) to give tert-butyl 3-(3-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonamido)phenyl)azetidine-1-carboxylate (140 mg, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(O)C.[CH3:27][C:28]1[CH:29]=[C:30]([C:34]([N:36]=[C:37]=[S:38])=[O:35])[CH:31]=[CH:32][CH:33]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:36][C:34](=[O:35])[C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([CH3:27])[CH:29]=2)=[S:38])=[CH:18][C:17]=1[F:23]
Reactant: Cc1cccc(C(=O)N=C=S)c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (64 mg, yield 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:31][O:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][O:38][CH3:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:35]([CH2:36][CH2:37][O:38][CH3:39])[CH2:34][CH2:33][O:32][CH3:31])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCCNCCOC
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Product: COCCN(CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cc1OC)CCOC

Procedure:
In the mamner of Example 103, 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide and bis-(2-methoxy-ethyl)-amine was converted to 52.3 mg of the title compound as the bis-trifluoroacetate salt mass spectrum (electrospray, m/e): M+H 542.0.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[S:10]([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)([O:13][CH2:14][C@@H:15]1[O:17][CH2:16]1)(=[O:12])=[O:11].C(=O)([O-])O.[Na+]>C(#N)C>[Cl:1][C:2]1[N:3]([CH2:16][C@@H:15]([OH:17])[CH2:14][O:13][S:10]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:12])=[O:11])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OC[C@H](O)Cn2cc([N+](=O)[O-])nc2Cl)cc1
Yield: 66.3 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (10 g, 67.79 mmol) and (R)-(−)-glycidyl tosylate (17.02 g, 74.58 mmol) were dissolved in acetonitrile (50 ml), sodium hydrogencarbonate (6.26 g, 74.15 mmol) was added to the solution, and the resulting mixture was stirred under reflux for 3.5 hours. The reaction mixture was allowed to return to room temperature. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/2) to afford (R)-2-chloro-1-[2-hydroxy-3-(4-methylbenzenesulfonyloxy)propyl]-4-nitroimidazole (16.9 g, yield 66%) as a light yellow oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:14][C@H:15]1[C@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:19]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@:18]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([CH2:46][C:47]3[CH:48]=[CH:49][C:50]4[O:54][CH2:53][CH2:52][C:51]=4[CH:55]=3)[CH:40]=2)([O:37][CH3:38])[O:17][C@@H:16]1[CH2:56][OH:57])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:7]([O:14][C@H:15]1[C@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:19]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@:18]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([CH2:46][C:47]3[CH:48]=[CH:49][C:50]4[O:54][CH2:53][CH2:52][C:51]=4[CH:55]=3)[CH:40]=2)([O:37][CH3:38])[O:17][C@@H:16]1[CH:56]=[O:57])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc4c(c3)CCO4)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc4c(c3)CCO4)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Oxalyl chloride (0.76 mL, 8.91 mmol) was dissolved in 10 mL methylene chloride and cooled to −78° C., followed by dropwise addition of 10 mL of mixed solution (methylene chloride and dimethyl sulfoxide, v:v=10:0.85). The reaction mixture was stirred for 15 minutes. Then 25 mL solution of [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 5h (4.2 g, 5.94 mmol) in methylene chloride was dropwise added before the mixture was stirred for 40 minutes. The reaction mixture was warmed to room temperature and stirred for 2 hours after triethylamine (4.29 mL, 29.69 mmol) was dropwise added. Thereafter, the reaction mixture was partitioned after 35 mL 1 M hydrochloric acid were added, the organic extract was washed with saturated sodium chloride solution (35 mL×2), combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmeth-yl)phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 51 (4.19 g, pale yellow grease), which was used directly in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([CH3:14])=[CH2:13].[Br:20]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([CH2:14][Br:20])=[CH2:13]
Reactant: C=C(C)c1ccccc1OCc1ccc(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: C=C(CBr)c1ccccc1OCc1ccc(Cl)cc1Cl
Reaction time: 12 h
Yield: 41 %

Procedure:
2-[2-(2,4-Dichlorobenzyloxy)phenyl]-1-propene (1.0 g, 3.41 mmole), N-bromosuccinimide (0.61 g, 3.41 mmole) and azobisisobutyronitrile (2.8 mg, 0.017 mmole) were suspended in carbon tetrachloride (4 ml) and the suspension was refluxed with stirring for 12 hours. Then, the mixture was poured into water (30 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water (50 ml) and dried over anhydrous soidum sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to chromatography on a silica gel column and eluted with n-hexane to obtain the title compound (0.52 g, 41.0%). 1H-NMR (CDCl3, δ): 4.50 (s, 2H, CH2Br), 5.20 (s, 2H, ##STR49## 5.33 (d, 1H, =CH), 5.57 (d, 1H, =CH), 6.80-7.57 (m, 7H, aromatic).
Reaction SMILES: [C@H:1]1([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>CN(C=O)C>[C:36]([NH:28][S:25]([C:22]1[CH:23]=[CH:24][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][C@H:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][O:2]3)[CH2:14][CH2:15]2)=[CH:20][CH:21]=1)(=[O:27])=[O:26])(=[O:38])[CH3:37]
Reactant: NS(=O)(=O)c1ccc(N2CCN(CC[C@@H]3OCCc4ccccc43)CC2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NS(=O)(=O)c1ccc(N2CCN(CC[C@@H]3OCCc4ccccc43)CC2)cc1
Reaction time: 1 h

Procedure:
(S)-(-)-4-[4-[2-(Isochroman-1-yl)ethyl]piperazin-1-yl]benzenesulfonamide (EXAMPLE 49, 0.203 g) is stirred in DMF (2 ml) and triethylamine (0.211 ml) and acetyl chloride (0.108 ml) is added. The mixture is stirred at 20°-25° for one hr and then at 50° for 4 days. After cooling, the mixture is partitioned between dichloromethane and aqueous sodium bicarbonate. The organic phases are dried over sodium sulfate, concentrated, and the residue is chromatographed (silica gel; ethyl acetate/dichloromethane (20/80)) to give the title compound after crystallization from methanol/dichloromethane/hexane, mp 160°-161°; MS (m/z) 443; IR (mineral oil) 1593, 1157, 1094, 1136 and 1109 cm-1.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[CH:11]=[C:10]([C:13]([OH:15])=O)[S:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:16][C:17]1[C:18]([O:32][CH3:33])=[C:19]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:23]([C:21]1[CH:20]=[C:19]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:18]([O:32][CH3:33])=[C:17]([NH:16][C:13]([C:10]2[S:9][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=3[CH:11]=2)=[O:15])[CH:22]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(O)c1cc2c([N+](=O)[O-])cccc2s1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1c(NC(=O)c2cc3c([N+](=O)[O-])cccc3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.4 %

Procedure:
4-Nitro-benzo[b]thiophene-2-carboxylic acid (369 mg, 1.65 mmol) and N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (500 mg, 1.84 mmol) were dissolved in 25 mL DMF and stirred at room temperature. After about 10 min, EDC (317 mg, 1.65 mmol) and HOBt (224 mg, 1.65 mmol) were added and the brown solution was stirred at room temperature 12 h. After stirring 12 h, the reaction was partitioned between EtOAc (150 mL) and water (50 mL). The layers were separated and the organic portion was washed with water (2×25 mL), brine (25 mL), dried (MgSO4), filtered and the solvent was removed in vacuo to afford a brown solid. Column chromatography on silica gel afforded 4-nitro-benzo[b]thiophene-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide as a pale yellow solid (200 mg, 25%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[S:11][C:10]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:9][N:5]2[C:6](=[O:8])[CH:7]=1.[IH:19]>>[I:19][C:2]1[N:3]=[C:4]2[S:11][C:10]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: CCCCCCSc1nn2c(=O)cc(Cl)nc2s1
Reactant: I
Product: CCCCCCSc1nn2c(=O)cc(I)nc2s1
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 8.4 g of the thus obtained 7-chloro-2-hexylthio-5H-1,3,4-thiadiazolo[3,2-a]-pyrimidin-5-one and 88.2 g of a 57% hydroiodic acid aqueous solution was heated to 95°~110° C. and stirred for 2 hours. After cooling, the solution was filtered. The residue was washed with water and dissolved in toluene. The toluene solution was washed with a sodium hydrogen carbonate aqueous solution, a sodium thiosulfate aqueous solution and water respectively and dried over anhydrous sodium sulfate. The solvent was distilled off and thus 9.8 g of 80% pure 7-iodo-2-hexylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 72%.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH2:16])=[CH:6][CH:5]=1.[BrH:17]>>[BrH:17].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH2:16])=[CH:6][CH:5]=1
Reactant: COc1ccc2cccc(CCN)c2c1
Agent: Br
Agent: Cl
Product: NCCc1cccc2ccc(O)cc12
Yield: 80 %

Procedure:
13.8 g (5.81×10-2 mol) of 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride and 46 cm3 of 47% hydrobromic acid solution are introduced into a 250-cm3 round- bottom flask with a ground neck. The mixture is brought to reflux for 6.5 hours. After cooling, the reaction medium is filtered. The precipitate is washed with water and then with hexane. Recrystallization of the crude product is carried out in an ethyl acetate/hexane mixture to obtain 2-(7-hydroxy-1-naphthyl)ethylamine hydrobromide (yield 80%; melting point: 174°-175° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-])=O)[C:12]=2[OH:21])(=[O:10])=[O:9])=[CH:3][CH:2]=1.[H][H]>[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([NH2:18])[C:12]=2[OH:21])(=[O:10])=[O:9])=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Nc2ccncc2)c1O
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)Nc2ccncc2)c1O
Yield: 91 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, N-(4-pyridinyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (22.0 mg, 0.066 mmol) was reduced with hydrogen and Pd/C (10.3 mg) to form the desired product (18.0 mg, 90%). EI-MS m/z 298(M-H)−.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)([OH:26])[CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[CH:11][C:6]=2[O:5][CH2:4]1.I[CH3:37]>C1COCC1>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)([O:26][CH3:37])[CH:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)(c2ccc3c(c2)OCO3)c2ccc3c(c2)OCO3)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1ccc2c(c1)OCO2)(c1ccc2c(c1)OCO2)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a slurry of NaH (88 mg, 2.2 mmol, 60% in mineral oil) in dry THF (5.0 mL) was added tert-butyl 4-(bis(benzo[d][1,3]dioxol-5-yl)(hydroxy)methyl)piperidine-1-carboxylate (100 mg, 0.22 mmol). After 30 min, iodomethane (468 mg, 143 mmol) was added and the reaction mixture was stirred for an additional 2 h. The reaction was quenched by the addition of a saturated solution of NH4Cl (30 mL) and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by SiO2 flash chromatography (20% EtOAc/hexanes) to give tert-butyl 4-(bis(benzo[d][1,3]dioxol-5-yl)(methoxy)-methyl)piperidine-1-carboxylate as a clear viscous oil (94 mg, 91%): 1H NMR 600 MHz (CDCl3) δ 6.79-6.74 (m, 6H), 5.96-5.95 (m, 4H), 4.08 (bs, 2H), 2.86 (s, 3H), 2.76-2.65 (m, 2H), 2.48-2.43 (m, 1H), 1.76 (d, J=13.2 Hz, 3H), 1.38 (s, 9H), 0.94-0.81 (m, 2H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])(=O)=O)=CC=1.[OH:22][C:23]1[CH:31]=[CH:30][C:26]2[CH2:27][CH2:28][O:29][C:25]=2[CH:24]=1>>[CH3:20][CH:13]([CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:12][CH2:11][O:22][C:23]1[CH:31]=[CH:30][C:26]2[CH2:27][CH2:28][O:29][C:25]=2[CH:24]=1
Reactant: Oc1ccc2c(c1)OCC2
Reactant: CC(C)=CCCC(C)CCOS(=O)(=O)c1ccc(C)cc1
Product: CC(C)=CCCC(C)CCOc1ccc2c(c1)OCC2

Procedure:
3,7-dimethyl-6-octenyl p-toluenesulfonate and 6-hydroxy-2,3-dihydrobenzofuran are reacted to produce 6-[(3,7-dimethyl-6-octenyl)-oxy]-2,3-dihydrobenzofuran of boiling point 126°-128° C./0.001 mmHg; nD20 = 1.5223; and 3,7-dimethyl-6-octenyl p-toluenesulfonate and 6-hydroxy-3-methyl-2,3-dihydrobenzofuran are reacted to produce 6-[(3,7-dimethyl-6-octenyl)-oxy]-3-methyl-2,3-dihydrobenzofuran of boiling point (bulb-tube) 130° C./0.14 mmHg; nD20 = 1.5150.
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+].[Na+].Br[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1>O.O1CCOCC1>[CH2:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([CH2:8][S:1]([OH:4])(=[O:3])=[O:2])[CH2:10]1)=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(OCc1ccccc1)N1CCCC(CBr)C1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCCC(CS(=O)(=O)O)C1

Procedure:
Sodium sulphite (12.6 g) in water (25 ml) was added to a stirred solution of benzyl 3-(bromomethyl)-1-piperidinecarboxylate (7.8 g) [Preparation 60] in dioxan (25 ml). The reaction mixture was stirred at reflux for 18 hrs, after which time the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The aqueous solution was separated and acidified with 2N aqueous hydrochloric acid. The product was then extracted with ethyl acetate, dried over magnesium sulphate and the solvent removed under reduced pressure to afford 1-[(benzyloxy)carbonyl]-3-piperidylmethanesulfonic acid as a hygroscopic solid (4.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8].[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=O)[O:17][C:15](=[O:16])[C:14]2=[CH:20][C:21]=1[Cl:22]>C(O)(=O)C>[Cl:10][C:11]1[CH:12]=[C:13]2[C:14](=[CH:20][C:21]=1[Cl:22])[C:15](=[O:16])[N:1]([C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8])[C:18]2=[O:17]
Reactant: NC(=O)c1sccc1N
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Solvent: CC(=O)O
Product: NC(=O)c1sccc1N1C(=O)c2cc(Cl)c(Cl)cc2C1=O

Procedure:
3-aminothiophene-2-carboxamide was added to an acetic acid solution of 4,5-dichlorophthalic anhydride and stirred all night heated to reflux to give 3-(5,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)thiophene-2-carboxamide. 1M NaOH aq was added to THF-MeOH solution of the obtained 3-(5,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)thiophene-2-carboxamide and stirred for 2.5 hours at 80° C. to give 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoic acid. Sulfuric acid was added to a MeOH-1,4-dioxane solution of the obtained 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoic acid and stirred for three days at 70° C. to give methyl 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoate.