Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C@@H:6]([CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:5][C:4](=[O:25])[C:3]=1[O:26]/C=C/C>CO>[OH:26][C:3]1[C:4](=[O:25])[O:5][C@H:6]([CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:2]=1[OH:1]
Reactant: C/C=C/OC1=C(O)[C@@H](CC/C=C\CCCCCCCCCCCCCC)OC1=O
Solvent: CO
Product: CCCCCCCCCCCCCC/C=C\CC[C@H]1OC(=O)C(O)=C1O

Procedure:
(R)-3,4-Dihydroxy-5-[(Z)-3-octadecenyl]-2(5H)-furanone was prepared as for the S-isomer from (R)-4-hydroxy-5-[(Z)-3-octadecenyl]-3-[(E)-propenyloxy]-2(5H)-furanone in similar yield: mp 65°-67° C.; [α]D25 9.5° (c=0.5 CH3OH); IR (neat, cm-1) 3421 (br), 2917, 2850, 1754, 1666, 734, 719; 1H NMR (CD3COCD3) δ 5.49-5.28 (m, 2H), 4.67 (dd, J=3.4, 7.8 Hz, 1H), 2.32-1.88 (m, 4H), 1.69-1.51 (m, 2H), 1.44-1.25 (m, 24H), 0.87 (t, J=6.7 Hz, 3H); HRMS calculated for C22H38O4 (M+), 366.2770 found 366.2780; analysis calculated for C22H38O4 +0.33 H2O: C, 70.93; H, 10.46: Found: C, 70.53; H, 10.25.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1.C(N(CC)CC)C.N1C2C(=CC=CC=2)C=NC=1>O1CCOCC1>[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Clc1ncnc2ccc(I)cc12
Agent: c1ccc2ncncc2c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Ic1ccc2ncnc(N3CCc4ccccc4C3)c2c1
Yield: 87 %

Procedure:
0.75 g of 4-chloro-6-iodoquinazoline, 0.45 g of 1,2,3,4-tetrahydroisoquinoline and 0.63 ml of triethylamine in 6.0 ml of dioxane are heated at 80° C. in a flask until the quinazoline has reacted completely (HPLC check, about 3 hours). The cooled reaction solution is evaporated to dryness in a rotary evaporator. The residue is purified by means of column chromatography (gradient heptane: EA 10-100% in 20 min.), giving 0.87 g of 4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-iodoquinazoline as yellowish solid (yield 90%, content 92%); MS-FAB (M+H+)=388.0; Rf (polar method): 1.84 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[N:26]=3)[CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22]
Reactant: COc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Reactant: FC(F)(F)c1cccc(CBr)n1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C(F)(F)F)n3)c3ccccc3c2=O)cc1C
Yield: 25.3 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 100 mg (0.341 mmol) of 3-(4-Methoxy-3-methyl-benzoyl)-1H-quinolin-4-one, 98.2 mg (0.409 mmol) of 2-bromomethyl-6-trifluoromethyl-pyridine, 16.4 mg (0.409 mmol, 60% dispersion in oil), and 3.5 mL of N,N-dimethylformamide. The crude product was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane to yield 39 mg of 3-(4-Methoxy-3-methyl-benzoyl)-1-(6-trifluoromethyl-pyridin-2-ylmethyl)-1H-quinolin-4-one. LC-MSD, m/z for C25H19F3N2O3 [M+H]: 453.13 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.5 min.
Reaction SMILES: FC(F)(F)CN.[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25](NCC1C=CC(F)=CC=1)[N:24]=[C:23]2[NH:39][CH2:40][C:41]([F:44])([F:43])[F:42]>>[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:13][CH:14]=1)[N:24]=[C:23]2[NH:39][CH2:40][C:41]([F:42])([F:44])[F:43]
Reactant: Fc1ccc(CNc2nc(NCC(F)(F)F)c3cc(Br)ccc3n2)cc1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Agent: NCC(F)(F)F
Product: NS(=O)(=O)c1ccc(CNc2nc(NCC(F)(F)F)c3cc(Br)ccc3n2)cc1

Procedure:
6-Bromo-2-methanesulfonyl-quinazolin-4-yl)-(2,2,2-trifluoro-ethyl)-amine was reacted with 4-Aminomethyl-benzenesulfonamide in a manner analogous to 6-Bromo-N2-(4-fluoro-benzyl)-N4-(2,2,2-trifluoro-ethyl)-quinazoline-2,4-diamine as described in Example 49. The product was characterized as follows: MS (m/z) 490 [M+H]+; HPLC Rt=1.90 minutes (Method B).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([S:18](=[O:26])(=[O:25])[NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:13]3[N:12]=[CH:11][C:10]=2[C:27](OCC)=[O:28])=[C:4]([CH3:32])[CH:3]=1.Cl.[F:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[CH:37][CH:36]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([S:18]([NH:19][CH2:20][C:21]([F:22])([F:23])[F:24])(=[O:25])=[O:26])=[C:13]3[N:12]=[CH:11][C:10]=2[C:27]([N:44]2[CH2:45][CH2:46][CH:41]([C:38]3[CH:37]=[CH:36][C:35]([F:34])=[CH:40][CH:39]=3)[CH2:42][CH2:43]2)=[O:28])=[C:4]([CH3:32])[CH:3]=1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NCC(F)(F)F)cnn2c1Nc1ccc(F)cc1C
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: Cl
Product: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(c3ccc(F)cc3)CC2)cnc2c(S(=O)(=O)NCC(F)(F)F)cnn12
Yield: 15.4 %

Procedure:
Using ethyl 7-(4-fluoro-2-methylphenylamino)-3-[N-(2,2,2-trifluoroethyl)sulfamoyl]pyrazolo[1,5-a]pyrimidine-6-carboxylate (0.142 g, 0.298 mmol) obtained in step 1 and 4-(4-fluorophenyl)piperidine hydrochloride (0.072 g, 0.335 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (0.028 g, 21%) was obtained.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([CH2:13][OH:14])[O:4]1.[H-].[Na+].[CH3:17]I.O>O1CCCC1>[CH3:1][O:2][C@H:3]1[C@H:7]2[C@H:6]([O:10][C:9]([CH3:12])([CH3:11])[O:8]2)[C@@H:5]([CH2:13][O:14][CH3:17])[O:4]1
Reactant: CO[C@@H]1O[C@H](CO)[C@H]2OC(C)(C)O[C@@H]12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
A stirred solution of [(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol (J. Heterocycl. Chem., 13 1966, 485) (43.1 g, 0.21 mol) in dry tetrahydrofuran (400 ml), at 0° C. and under an atmosphere of nitrogen, was carefully treated with sodium hydride, (7.7 g of an 80% dispersion in mineral oil, 0.26 mol). The resultant mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was cooled to 0° C. and a solution of methyl iodide (15.8 m, 0.25 mol) in dry tetrahydrofuran (30 ml) added slowly. The resultant mixture was stirred for a further 30 min at 0° C. and then at room temperature for 24 hr. Water (1000 ml) was added carefully and the mixture extracted with diethyl ether (3×500 ml). The combined organic extracts were washed with brine, dried with anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a solvent system of diethyl ether:pentane (1:4), to afford the title compound as an oil (36.5 g).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]([NH:13][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=O)=O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([O:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]2[S:27][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=3)=[CH:14][N:13]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCCCOc1ccc(C(=O)NCC(=O)c2ccc(Br)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCOc1ccc(-c2ncc(-c3ccc(Br)cc3)s2)cc1
Reaction time: 1.5 h
Yield: 105.5 %

Procedure:
To a solution of 2-(4-pentyloxybenzamido)-4′-bromoacetophenone (3.39 g) in tetrahydrofuran (34 ml) was added phosphorus pentasulfide (2.43 g), and refluxed for 30 minutes. The reaction mixture was cooled, and poured into saturated sodium hydrogen carbonate aqueous solution (400 ml), and stirred for 1.5 hours. The resulting precipitate was collected by filtration to give 2-(4-pentyloxyphenyl)-5-(4-bromophenyl)thiazole (2.32 g).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:11](=[O:22])[CH2:12][CH2:13][C:14]1([CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=O>C(O)C>[CH3:21][C:14]12[CH2:13][CH2:12][C:11](=[O:22])[N:7]3[C:15]1=[C:16]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=13)[CH2:17][CH2:18][CH2:19]2
Reactant: COC(=O)CCC1(C)CCCCC1=O
Reactant: NNc1ccccc1
Solvent: CCO
Product: CC12CCCc3c1n(c1ccccc31)C(=O)CC2

Procedure:
A mixture of phenylhydrazine (1.08 g), 1-methyl-2-oxocyclohexanepropionic acid methyl ester (1.98 g), described in Example 6, and ethanol is heated at reflux for 3 hr. The mixture is evaporated to dryness keeping the temperature of the mixture at about 40° C. The residue is heated with 200 ml of 10% aqueous sulfuric acid at reflux temperature for 1 hr. The mixture is cooled and extracted with ether. The extract is washed with 10% sodium hydroxide and brine, and then evaporated. The residue is subjected to chromatography on silica gel. Elution with benzene gives 1,2,3,3a,4,5-hexahydro-3a-methyl-6H-pyrido[3,2,1-jk]carbazol-6-one (6, R1 = CH3, R2 and R3 = H, m = 3 and n = 2) mp 93°-95° C. Further elution with 5% ethyl acetate in hexane as the eluant gives the title compound, nmr (CDCl3) δ 1.27 (s, 3H), 3.6 (s, 3H), 7.0-7.6 (m, 4H), 7.9 (b, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:13]2([C:19](O)=[O:20])[CH2:18][CH2:17][S:16][CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.Cl.[NH2:41][OH:42].C(N(CC)CC)C>C(Cl)Cl.O1CCCC1.O>[OH:42][NH:41][C:19]([C:13]1([N:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17][S:16][CH2:15][CH2:14]1)=[O:20]
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C2(C(=O)O)CCSCC2)cc1
Reactant: NO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C2(C(=O)NO)CCSCC2)cc1
Temperature: 20 °C
Reaction time: 36 h

Procedure:
To a solution of 4-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-carboxy-tetrahydrothiopyran (413.0 mg, 1.0 mmol) in methylene chloride (10 mL) containing dimethylformamide (80.0 mg, 1.1 mmol) is added a 2N solution of oxalyl chloride in methylene chloride (1.0 ml, 2.0 mmol) at -10° C. The mixture is allowed to warm to 20° C. for 30 minutes. This mixture is added to a pre-stirred mixture of hydroxylamine hydrochloride (280.0 mg, 4.0 mmol) in tetrahydrofuran (10 ml)/water (1 ml) containing triethylamine (650.0 mg, 6.0 mmol) at 0° C. dropwise. The reaction mixture is allowed to slowly warm to room temperature and stirring is continued for 1.5 days. The reaction is worked up by partitioning between 1 N hydrochloric acid and ethyl acetate. The aqueous layer is removed and repeatedly extracted with ethyl acetate. The combined organic layers are dried (Na2SO4) and the solvent is evaporated. The crude product is purified by silica gel chromatography (2% methanol/methylene chloride) to give 4-[N-hydroxy-carbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-tetrahydrothiopyran, m.p. 179°-181° C.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH2:12][C:13]([O:15][CH3:16])=[O:14])([CH2:5]3)[CH2:3]1)[CH2:9]2.[Cl-].[Cl-].[Cl-].[Al+3]>C1C=CC=CC=1>[C:2]1([C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][C:4]([CH2:12][C:13]([O:15][CH3:16])=[O:14])([CH2:5]4)[CH2:3]2)[CH2:9]3)[CH:11]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC12CC3CC(CC(Br)(C3)C1)C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: COC(=O)CC12CC3CC(C1)CC(c1ccccc1)(C3)C2
Yield: 202 %

Procedure:
Methyl 3-bromoadamantaneacetate (80 g) (Aldrich Chemical Co. Milwaukee Wis.) was dissolved in benzene (1.6 L) under nitrogen. Aluminum trichloride (37.12 g) was added portionwise over 75 min. at ambient temperature. The reaction mixture was then quenched by the addition of 0.5M phosphoric acid (1.6 L). The layers were separated and the organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo to give methyl 3-phenyl-1-adamantaneacetate (80 g).
Reaction SMILES: C[NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[C:19](C3C=CC(C(N4CCN(C)CC4)=O)=CC=3)[CH:20]=2)[CH:4]=1.[O:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH:46]=[C:45](B3OC(C)(C)C(C)(C)O3)[CH:44]=[N:43]2)[CH2:38][CH2:37]1.BrC1C=C(C2C=C(N)N=C(C3C=CC=CN=3)C=2)C=NC=1>>[O:36]1[CH2:37][CH2:38][CH:39]([N:42]2[CH:46]=[C:45]([C:19]3[CH:20]=[C:15]([C:5]4[CH:4]=[C:3]([NH2:2])[N:8]=[C:7]([C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=5)[CH:6]=4)[CH:16]=[N:17][CH:18]=3)[CH:44]=[N:43]2)[CH2:40][CH2:41]1
Reactant: CNc1cc(-c2cncc(-c3ccc(C(=O)N4CCN(C)CC4)cc3)c2)cc(-c2ccccn2)n1
Reactant: CC1(C)OB(c2cnn(C3CCOCC3)c2)OC1(C)C
Agent: Nc1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Product: Nc1cc(-c2cncc(-c3cnn(C4CCOCC4)c3)c2)cc(-c2ccccn2)n1

Procedure:
This compound is prepared analogously to [4-(6′-Methylamino-[2,2′;4′,3″]terpyridin-5″-yl)-phenyl]-(4-methyl-piperazin-1-yl)-methanone (Example 2.1) by replacing (4-methyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone with 1-(tetrahydro-pyran-4-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Intermediate B18) and by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine with 5″-Bromo-[2,2′;4′,3″]terpyridin-6′-ylamine (Example 1.31).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[CH2:15](I)[CH2:16][CH3:17].C(I)C>>[CH2:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([N:3]2[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]2[CH3:7])[N:9]=1)[CH2:15][CH2:16][CH3:17]
Reactant: Cc1cccc(-n2c(C)ccc2C)n1
Reactant: CCCI
Solvent: CCI
Product: CCCCc1cccc(-n2c(C)ccc2C)n1
Yield: 64.4 %

Procedure:
The product from Example 2a 1.0 g, 5.37 mmol) was reacted with propyl iodide 0.55 mL, 5.64 mmol) in place of ethyl iodide following the procedure from Example 2b to give the title compound (790 mg, 64%).
Reaction SMILES: C[S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].ClC1C=CC(S(=O)(=O)[NH:30][CH3:31])=CC=1C(O)=O.N1CCCC1>>[CH3:31][NH:30][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCNC1
Product: CNS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Yield: 45 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-methylsulfamoyl-benzoic acid and pyrrolidine and obtained in 45% yield. MS (m/e): 283.1 (MH−, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:7]=[C:6]([N:16]2[CH2:21][CH2:20][S:19][CH2:18][CH2:17]2)[C:5]=1[N+:22]([O-:24])=[O:23])[CH3:2].I([O-])(=O)(=O)=[O:26].[Na+]>CO.O>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[N:7]=[C:6]([N:16]2[CH2:17][CH2:18][S:19](=[O:26])[CH2:20][CH2:21]2)[C:5]=1[N+:22]([O-:24])=[O:23])[CH3:2]
Reactant: CCOc1nc(N2CCNCC2)nc(N2CCSCC2)c1[N+](=O)[O-]
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]

Procedure:
3.6 gm (0.01 mol) of 6-ethoxy-5-nitro-2-piperazino-4-thiomorpholino-pyrimidine were dissolved in 100 ml of methanol, a solution of 2.2 gm (0.01 mol) of sodium metaperiodate in 50 ml of water was added, and the mixture was refluxed for 4 hours. The reaction mixture was then poured into water, and the aqueous mixture was extracted with chloroform. The chloroform phase was dried, the chloroform was distilled off in vacuo, and the residue was recrystallized from ethanol. Yield: 2.9 gm (77% of theory); m.p. 223°-224°C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.C(N(CC)CC)C.[Cl:17][C:18]1[CH:26]=[C:25]([O:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].S(Cl)(Cl)=O.CC(C)(O)C#N>C(Cl)Cl.C(#N)C>[Cl:17][C:18]1[CH:26]=[C:25]([O:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:24]=[CH:23][C:19]=1[C:20]([CH:5]1[C:6](=[O:8])[CH2:7][CH:2]([CH3:1])[CH2:3][C:4]1=[O:9])=[O:21]
Reactant: CC1CC(=O)CC(=O)C1
Reactant: CS(=O)(=O)Oc1ccc(C(=O)Cl)c(Cl)c1
Agent: CC(C)(O)C#N
Solvent: O=S(Cl)Cl
Solvent: CC#N
Solvent: ClCCl
Product: CC1CC(=O)C(C(=O)c2ccc(OS(C)(=O)=O)cc2Cl)C(=O)C1
Reaction time: 0.5 h

Procedure:
To a solution of 5-methylcyclohexane-1,3-dione (1.79 g, 14.0 mmol) in 20 ml of methylene chloride containing triethylamine (2.90 ml, 20.8 mmol) is added, dropwise at 0°, a solution of 2-chloro-4-methylsulfonyloxybenzoyl chloride, prepared from the corresponding acid (3.50 g, 14.0 mmol) and thionyl chloride, in methylene chloride (10 ml). After the addition is complete, the mixture is stirred for another 30 min. at 0°, after which it is diluted with methylene chloride, washed, dried and evaporated to dryness. The crude enol ester is treated with triethylamine (3.97 ml, 2 eq.) and acetone cyanohydrin (0.4 ml) in 25 ml of acetonitrile. After stirring overnight at RT, the reaction mixture is concentrated and poured into water. The combined organic extracts are washed with dilute HCl and with brine, dried and evaporated to dryness. The crude product is crystallized from ether to give 2-(2-chloro-4-methylsulfonyloxybenzoyl)-5-methyl-cyclohexane-1,3-dione.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH:12]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:8][CH2:7]1)=[O:5])C>CO.[OH-].[Na+]>[CH:12]1([N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(C2CCCCCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C3CCCCCCC3)CC2)cc1

Procedure:
1-Cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (8 g, 18.3 mmol) dissolved in methanol (200 ml) and 10 N NaOH (25 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.36 g (32%); white powder; mp 180° C.; MS: 410 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[N-:18]=[C:19]=[O:20].[K+].FC(F)(F)C(O)=O>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:19](=[O:20])[NH2:18])=[CH:9][CH:8]=1
Reactant: OCc1ccc(OCc2cccc(F)c2)cc1
Reactant: [N-]=C=O
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: NC(=O)OCc1ccc(OCc2cccc(F)c2)cc1

Procedure:
In analogy to the procedure described in Example 24 b), the reaction of [4-(3-fluoro-benzyloxy)-phenyl]-methanol with potassium isocyanate and trifluoroacetic acid in benzene yielded the carbamic acid 4-(3-fluoro-benzyloxy)-benzyl ester as a white solid; MS: m/e=293 (M+NH4)+.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]([CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)C1C=CC=CC=1.Cl>C(O)C.C(OCC)(=O)C.O.[Pd]>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([N:11]([CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:30][CH:31]=2)[CH2:10][CH2:9][OH:8])=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(OCCCN(CCOCc2ccccc2)c2ccc(Cl)cc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)c1ccc(OCCCN(CCO)c2ccc(Cl)cc2)cc1
Reaction time: 27 h
Yield: 43.1 %

Procedure:
4-[3-[N-(2-Benzyloxyethyl)-N-(4-chlorophenyl)amino]propoxy]benzoic acid (3.5 g) was dissolved in a mixed solvent of ethanol (60 ml) and ethyl acetate (15 ml), and thereto were added conc. hydrochloric acid (0.7 ml) and 10 % palladium/carbon (0.35 g), and the mixture was stirred under hydrogen and atmospheric pressure at room temperature for 27 hours. The reaction mixture was diluted with water, filtered, and neutralized with lN aqueous sodium hydroxide solution, and then, the mixture was concentrated under reduced pressure. The residue was washed with water, and crystallized from about 50 % aqueous methanol and collected by filtration. The resultant was further recrystallized from a mixed solvent of ethyl acetate/n-hexane [1:10 (v/v)] to give the desired product (1.20 g). mp. 120°-122° C.
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[CH2:19][CH2:18][C@H:17]([O:20][C:21](=[O:31])[C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>O1CCOCC1>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([C:21]([O:20][C@H:17]2[CH2:18][CH2:19][NH:15][CH2:16]2)=[O:31])=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O[C@H]1CCNC1)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
4 M hydrochloric acid/dioxane (3.0 ml) was added to a solution of (S)-1-t-butoxycarbonyl-3-(4-nitrobenzoyloxy)pyrrolidine [J. Org. Chem. 59, 2289 (1994)] (1.68 g, 5 mmol) in dioxane (10 ml), and they were stirred for 2 hours. The reaction liquid was poured into 1 M-aqueous NaOH solution cooled on ice/water. After the extraction with ethyl acetate, the organic layer was dried and the solvent was evaporated under reduced pressure to obtain (S)-3-(4-nitrobenzoyloxy)pyrrolidine in the form of a light yellow oil (799 mg, 68%).
Reaction SMILES: [I:1]I.[I-].[K+].[Cl:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[CH3:13])[NH2:9].C(=O)(O)[O-].[Na+]>O>[Cl:5][C:6]1[C:12]([CH3:13])=[CH:11][C:10]([I:1])=[C:8]([CH:7]=1)[NH2:9]
Reactant: Cc1ccc(N)cc1Cl
Reactant: II
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O
Product: Cc1cc(I)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.4 %

Procedure:
A solution of iodine (9.86 g; 38.84 mmol) and potassium iodide (6.45 g; 38.84 mmol) in water was added dropwise to a mixture of 3-chloro-4-methylaniline (5.00 g; 35.31 g), sodium bicarbonate (4.75 g; 56.50 mmol) in water. The resulting mixture was stirred 72 hours at room temperature filtrated and the solid dissolved in dichloromethane, washed with a saturated solution of sodium thiosulphate dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to yield 2.30 g (24%) of the title compound as a brown solid.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13](SC)[O:14][C:10]=3[CH:9]=2)=[N:6][NH:5][C:4](=[O:19])[CH2:3]1.[NH:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1>>[CH3:1][CH:2]1[C:7]([C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([N:20]4[CH2:25][CH2:24][S:23][CH2:22][CH2:21]4)[O:14][C:10]=3[CH:9]=2)=[N:6][NH:5][C:4](=[O:19])[CH2:3]1
Reactant: C1CSCCN1
Reactant: CSc1nc2ccc(C3=NNC(=O)CC3C)cc2o1
Product: CC1CC(=O)NN=C1c1ccc2nc(N3CCSCC3)oc2c1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
A mixture of 4.1 g (0.015 mol) 5-methyl-6-(2-methylsulphanyl-benzoxazol-6-yl)-4,5-dihydro-2H-pyridazin-3-one and 10.3 g (0.1 mol) thiomorpholine is stirred for 6 h at 130° C. Then the excess thiomorpholine is eliminated by rotary evaporation in vacuo, the residue is stirred with water and diisopropylether, the crystals obtained are suction filtered. The crude product is washed with water and isopropanol and then recrystallised from aqueous isopropanol.