Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[C-]#N.[Na+].CN(C)[CH2:19][CH2:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C.O>[C:1]([CH:20]([C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CN(C)CCC(=O)c1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C(=O)c1ccccc1)C(=O)c1ccccc1

Procedure:
A solution of 21.2 g (0.2 mol) of benzaldehyde and 100 ml of absolute dimethylformamide is added dropwise in the course of 1/2 hour to a mixture of 9.8 g (0.2 mol) of NaCN and 100 ml of absolute dimethylformamide in a manner analogous to Example 3. Stirring is continued for 21/2 hours at 35° C. A solution of 26.6 g (0.15 mol) of dimethyl-β-benzoyl-ethylamine and 100 ml of absolute dimethylformamide is then slowly added dropwise in the course of 2 hours. Stirring is continued for 2 hours at the same temperature and water is then added to the reaction mixture in three times its quantity. The reaction product precipitates immediately. After cooling in an ice bath, the precipitated product is suction filtered and thoroughly washed with water. 34.3 g of crude product are isolated. 21.6 g (60.5% of the theory) of dibenzoyl ethane are isolated by recrystallisation from ethanol; m.p. 143° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[C:5]([NH:7][S:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:6].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].C(N(CC)CC)C>C(#N)C.O>[CH2:24]([N:26]([CH2:27][CH3:28])[C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:11]([S:8]([NH:7][C:5](=[O:6])[C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=2[O:2][CH3:1])(=[O:10])=[O:9])=[CH:12][CH:13]=1)[CH3:25]
Reactant: CCNCC
Reactant: COc1ccccc1C(=O)NS(=O)(=O)c1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc(S(=O)(=O)NC(=O)c2ccccc2OC)cc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-[[(2-methoxybenzoyl)amino]sulfonyl)benzoyl chloride (1 mol) and diethylamine (1 mol) in acetonitrile (1000 ml), was added triethylamine (1 mol) at 10° C. The mixture was stirred for 2 hours at 20° C. and diluted with water (500 ml). The white precipitate was filtered off, washed and dried to give the title compound. The yield of product obtained was 98% of theory, and the purity 98%.
Reaction SMILES: FC1C=C(F)C=CC=1S[C:10]1[CH:11]=[C:12]([C:19](=[O:22])[CH2:20]C)[CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O.[CH3:23][N:24](CC(C1C=CC=CC=1)=O)[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].[CH3:42][S:43](Cl)(=[O:45])=[O:44]>N1C=CC=CC=1>[C:19]([C:12]1[CH:13]=[CH:14][C:15]([NH:16][S:43]([CH3:42])(=[O:45])=[O:44])=[C:10]([N:24]([CH3:23])[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH:11]=1)(=[O:22])[CH3:20]
Reactant: CN(CC(=O)c1ccccc1)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Reactant: CCC(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Solvent: c1ccncc1
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(N(C)c2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of 4'-amino-3'-[N-methyl-N-(2,4-difluorophenyl)aminoacetophenone (1.2 g) and methanesulfonyl chloride (0.6 g) in pyridine was stirred at room temperature for 7 hours. The mixture was evaporated and the residue was stirred with 5% sodium hydroxide (30 ml) overnight. The mixture was washed with toluene, and the aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was concentrated and the residue was recrystallized from ethanol to give pale brown prisms of 4'-acetyl2'-[N-methyl-N-(2,4-difluorophenyl)amino]methanesulfonanilide (0.49 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH2:12][C:9]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([CH2:10][CH2:11]1)[CH2:8][CH:7]2[OH:22])=[O:5])[CH3:2].C1(C)C=CC=CC=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH2:12][C:9]([NH:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([CH2:10][CH2:11]1)[CH2:8][CH:7]2[O:22][S:38]([CH3:37])(=[O:40])=[O:39])=[O:5])[CH3:2]
Reactant: CCOC(=O)C12CCC(NCc3ccccc3)(CC1)CC2O
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C12CCC(NCc3ccccc3)(CC1)CC2OS(C)(=O)=O

Procedure:
To 4-(benzylamino)-2-hydroxybicyclo[2.2.2]octane-1-carboxylic acid ethyl ester (6.0 g, 19.8 mmol), there were added toluene (42.0 g), tetrahydrofuran (10.8 g) and triethylamine (4.0 g, 39.6 mmol) and then the resulting mixture was stirred. Methanesulfonyl chloride (2.9 g, 24.9 mmol) was added dropwise to the mixture, followed by the stirring thereof for one hour and 30 minutes. After quenching the reaction mixture with water, the resulting mixture was subjected to extraction procedures and the organic phase was quantitatively analyzed (according to the LC technique). As a result, the yield of the desired product was found to be 100% (the internal standard substance used was m-xylene).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7](=[O:21])[CH:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:7](=[O:21])[CH:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: O=C1NC(CCc2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)C(CCc3ccccc3Cl)NC(=O)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
7-Chloro-3-(2-chlorophenethyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (1.0 g, 1 eq), 1-(chloromethyl)-4-methoxybenzene (448 mg, 1 eq), and potassium carbonate (1.19 g, 3 eq) were suspended in DMF (11.5 mL), and the mixture was stirred at room temperature overnight. Water was then added and the mixture was stirred for 30 minutes. The solid was collected by filtration, and the solid was returned to a flask and concentrated from toluene to remove water. The crude material was purified by chromatography (gradient: 9:1 hexanes:EtOAc to 1:1 hexanes:EtOAc) yielding a white solid (970 mg, 72% yield). 1H-NMR (300 MHz, DMSO-d6) δ 8.90 (d, 1H), 7.60-7.50 (m, 3H), 7.38-7.17 (m, 4H), 6.97 (d, 2H), 6.78 (d, 2H), 5.32 (d, 1H), 4.81 (d, 1H), 3.80 (m, 1H), 3.65 (s, 3H), 2.74 (t, 2H), 2.10 (m, 1H), 1.90 (m, 1H). MS (ES+) m/z 490.9 (M+Na).
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([C:5](=[O:10])[CH2:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[CH3:19][Si:20](Cl)([CH3:22])[CH3:21]>C1COCC1>[CH2:1]1[CH:9]2[CH:4]([C:5]([O:10][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCCC2CCCC12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OC1=CCCC2CCCC12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
Add dropwise hexahydro-1H-inden-4(2H)-one (1.6 g, 11.6 mmol) in dry THF (5 mL) to a solution of LDA (23.2 mL, 23.2 mmol) in THF (30 mL). Stir the reaction mixture for 30 min and then add dropwise TMSCl (3.5 g, 32.0 mmol) to the reaction mixture. Stir the resultant solution for additional 1 hour. Pour the mixture into ice water (50 mL) and extract the aqueous mixture with EtOAc (50 mL×3). The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford crude (2,3,3a,6,7,7a-hexahydro-1H-inden-4-yloxy)trimethylsilane (2.45 g, 100%) as yellowish oil, MS (m/z): 209 (M−1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][C:7]=1[O:19][CH3:20])[CH2:2][CH2:3]C.[CH2:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][C:25]=1[O:37][CH3:38])[CH3:22]>>[CH:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][C:7]=1[O:19][CH3:20])([CH2:2][CH3:3])[CH3:21].[CH3:1][CH:2]([CH3:3])[CH2:22][CH2:21][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][C:25]=1[O:37][CH3:38]
Reactant: CCOc1ccc(-c2ccc(=O)[nH]n2)cc1OC
Reactant: CCCCOc1ccc(-c2ccc(=O)[nH]n2)cc1OC
Product: CCC(C)Oc1ccc(-c2ccc(=O)[nH]n2)cc1OC
Product: COc1cc(-c2ccc(=O)[nH]n2)ccc1OCCC(C)C

Procedure:
In an analogous manner, 6-(4-n-butoxy-3-methoxyphenyl)-3[2H]pyridazinone, m.p. 193°; 6-(4-ethoxy-3-methoxyphenyl)- 3[2H]pyridazinone, m.p. 186°; 6-(4-sec.-butoxy-3-methoxyphenyl)-3[2H]pyridazinone, m.p. 168°, 6-[4-(3-methylbutoxy)-3-methoxyphenyl]-3[2H]pyridazinone, m.p. 170°, are obtained from the correspondingly substituted 3-benzoylacrylic acids.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[N:10][C:3]=12.ClC1C=CC=C(C(OO)=[O:19])C=1>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:19])=[C:4]2[NH:8][CH:9]=[N:10][C:3]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccnc2[nH]cnc12
Solvent: CC(=O)O
Product: [O-][n+]1ccc(Cl)c2nc[nH]c21

Procedure:
7-Chloro-3H-imidazo[4,5-b]pyridine (15 g, 97.7 mMol) was dissolved in 150 mL of glacial acetic acid and m-chloroperbenzoic acid (23 g, 131 mMol) was added in portions to the stirred solution. After 12 hours the solid was isolated and washed with ether. The solid was suspended in 400 mL of hot ethanol, stirred, and isolated. The product, 7-chloro-3H-imidazo[4,5-b]pyridine-4-oxide, was dried in vacuo. Yield 14.98 g (8.83 mMol, 90.4%); m.p. 200° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[CH:25]=[CH:24][N:23]([CH3:26])[C:18]4=[N:19][C:20]=3[O:21][CH3:22])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:29](Cl)(=[O:33])[C:30](Cl)=[O:31].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.O>C(Cl)Cl>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:25]([C:29](=[O:33])[C:30]([N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)=[O:31])=[CH:24][N:23]([CH3:26])[C:18]4=[N:19][C:20]=3[O:21][CH3:22])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C1CCNC1
Reactant: COc1nc2c(ccn2C)cc1C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: O
Solvent: ClCCl
Product: COc1nc2c(cc1C(=O)N1CCC(Cc3ccc(F)cc3)CC1)c(C(=O)C(=O)N1CCCC1)cn2C
Reaction time: 4 h
Yield: 53.1 %

Procedure:
To a solution of [4-(4-Fluoro-benzyl)-piperidin-1-yl]-(6-methoxy-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-methanone (100 mg, 0.26 mmol) in anhydrous CH2Cl2 (15 mL) was added oxalyl chloride (0.52 mL, 1.05 mmol, 2 M in CH2Cl2) at RT. The reaction mixture was stirred for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was dried under vacuum for I h and dissolved in CH2Cl2 (15 mL). An excess amount of pyrrolidine (74 mg, 1.04 mmol) was added to the reaction mixture. After stirring for 1 h, the reaction mixture was treated with water. The organic layer was separated and washed with brine, dried and concentrated. The residue was purified by chromatography on silica gel eluting with CH2Cl2:MeOH (95:5) to give the desired product (70 mg) in 53% yield as a white solid. M+H+(507).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].[H-].[Na+].[CH3:23][O:24][C:25](=[O:28])[CH2:26]Br>CN(C=O)C>[CH3:23][O:24][C:25](=[O:28])[CH2:26][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=1)(=[O:11])=[O:12])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1
Reactant: COC(=O)CBr
Reactant: CCOc1ccc(S(=O)(=O)Nc2ccc(C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(S(=O)(=O)N(CC(=O)OC)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.1 %

Procedure:
The crude N-aryl-benzenesulfonamide building block XIII, e.g. 4-ethoxy-N-(4-methylphenyl)benzenesulfonamide (3.087 g, 10.6 mmol), was dissolved in DMF (10 mL) and was added to a suspention of NaH (13.6 mmol, 0.593 mg of NaH 55-65% in oil) in DMF (30 mL). The mixture was stirred 45 min at room temperature. 2-Bromoacetic acid methyl ester (1.45 mL, 15.9 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. The solvents were evaporated, affording the desired product, e.g. methyl{[(4-ethoxyphenyl)sulfonyl]-4-methylanilino}acetate (3.816 g, quantitative crude yield) as a light yellow solid, in 96.1% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]2)[CH:3]=1.[NH2:30][CH2:31][CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39]>>[O:39]=[C:35]1[CH2:36][CH2:37][CH2:38][N:34]1[CH2:33][CH2:32][CH2:31][NH:30][C:19]([C:16]1[S:15][C:11]2[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:22][C@H:23]3[CH2:24][CH2:25][C@H:26]([OH:29])[CH2:27][CH2:28]3)[C:10]=2[C:17]=1[CH3:18])=[O:21]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](O)CC3)c12
Reactant: NCCCN1CCCC1=O
Product: Cc1c(C(=O)NCCCN2CCCC2=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](O)CC3)c12

Procedure:
Prepared analogously to 1.4 from 0.042 g 4-[4-fluoro-2-(trans-4-hydroxycyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and 0.015 g 1-(3-aminopropyl)-2-pyrrolidinone. The residue was purified by chromatography.
Reaction SMILES: CC[O:3]C(C[NH3+])=O.[Cl-].C([O-])(=O)C.[Na+].[OH:14][C:15]1[N:20]=[CH:19][NH:18][C:17]2=[C:21]([C@@H:24]3[NH:31][C@H:28]([CH2:29]O)[C@@H:26]([OH:27])[CH2:25]3)[CH:22]=[N:23][C:16]=12>CO>[OH:14][C:15]1[N:20]=[CH:19][NH:18][C:17]2=[C:21]([C@@H:24]3[NH:31][C@H:28]([CH3:29])[C@@H:26]([OH:27])[C@H:25]3[OH:3])[CH:22]=[N:23][C:16]=12
Reactant: CCOC(=O)C[NH3+]
Reactant: OC[C@H]1N[C@@H](c2cnc3c(O)nc[nH]c2-3)C[C@@H]1O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1N[C@@H](c2cnc3c(O)nc[nH]c2-3)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Glycine hydrochloride ethyl ester (0.76 g) and sodium acetate (0.9 g) were added to a stirred solution of the product from Example 1.3 (0.51 g) in methanol (10 ml). The mixture was stirred at room temperature for 16 h and then concentrated to dryness. Chromatography of the residue gave the (1S)-N-tert-butoxycarbonyl-5-O-tert-butyldimethylsilyl-1-C-[1-cyano-2-N-(ethoxycarbonylmethylamino)ethenyl]-1,4-dideoxy-1,4-imino-2,3-O-isopropylidene-D-ribitol (4) (0.48) g as a diastereomeric mixture.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl>C(#N)C>[OH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([O:1][CH2:17][CH:19]2[O:21][CH2:20]2)=[CH:3][CH:4]=1
Reactant: OCCc1ccc(O)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCc1ccc(OCC2CO2)cc1
Yield: 100 %

Procedure:
30.0 g p-hydroxyphenethyl alcohol, 60 g of anhydrous potassium carbonate and 50.28 g of epichlorohydrin were refluxed in 250 mL of acetonitrile for 5 hrs. After cooling, filtering and removing acetonitrile at reduced pressure, 300 mL of toluene were added and the toluene removed under reduced pressure. The residual oil solidifies on standing and is used directly in the next step. Yield=43.2 g, c. 100% yield. This solid after recrystallization in water has a melting point of 56°-58.5° C.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH3:7][N:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([OH:21])(=O)=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1>ClCCl.CN(C=O)C>[CH3:7][N:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([Cl:4])(=[O:21])=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CN1CCCc2cc(S(=O)(=O)O)ccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCCc2cc(S(=O)(=O)Cl)ccc21
Reaction time: 2 h
Yield: 20.3 %

Procedure:
Oxalyl chloride (20 g, 157.60 mmol) was added dropwise at room temperature to a solution of 1-methyl-1,2,3,4-tetrahydroquinoline-6-sulfonic acid (5 g, 22.00 mmol) in dichloromethane (100 mL) and DMF (10 mL). The resulting solution was stirred for 2 hours, then quenched by adding 200 mL of iced water. The resulting solution was extracted using dichloromethane (2×100 mL), and the combined organics were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using a 1:4 ethyl acetate/petroleum ether solvent system to afford 1.1 g (20.1%) of 1-methyl-1,2,3,4-tetrahydroquinoline-6-sulfonyl chloride as a yellow solid. 1H NMR (CDCl3) δ 7.69 (d, 1H), 7.51 (s, 1H), 6.54 (d, 1H), 3.57 (t, 2H), 3.02 (s, 3H), 2.78 (d, 2H), 1.98 (m, 2H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:50])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:42][CH:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:50])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:42][CH:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(Cc2ccc(C(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(C(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
A mixture of hydroxylammonium chloride (1.79 g), sodium hydrogen carbonate (2.87 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(4-tert-butylbenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.86 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.33 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.55 g, 57%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:14])[CH:12]=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].CC1C=CC=C(C)[N+]=1[O-:23].C(OO)(=O)C>C(OCCCC)(=O)C.C(OCC)(=O)C>[OH:13][C:12]([CH:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=1)[CH3:14])=[O:23]
Reactant: Cc1cccc(C)[n+]1[O-]
Reactant: CC(C)Cc1ccc(C(C)C=O)cc1
Agent: CC(=O)OO
Solvent: CCCCOC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Yield: 94.9 %

Procedure:
To a stirred solution of 10.0 g (52.6 mmol) of 2-(4-isobutylphenyl)propionaldehyde (ibuprofen aldehyde)in n-butyl acetate (53 mL) cooled in a wet-ice bath (ca. 2° C.) was added 6.5 g (52.6 mmol) of 2,6-dimethylpyridine N-oxide (2,6-lutidine N-oxide). To this solution was then added slowly dropwise 29 mL (78.8 mmol) of a 20.0 weight percent solution of peracetic acid in ethyl acetate, at a rate slow enough such that the reaction temperature did not exceed 10° C. (ca. 25 minutes). After the initial exotherm, the temperature returned to 2° C., and the reaction was maintained at this temperature for an additional 4 hours. The cold reaction solution was then transferred into a separatory funnel, was diluted with n-butyl acetate (100 mL), and was washed with a 1% aqueous solution of sodium thiosulfate (Na2S2 O3, 100 mL). The butyl acetate layer was further washed with two portions of water (100 mL each), and the combined water washes were back-extracted with n-butyl acetate (100 mL). The combined butyl acetate layers were extracted with two portions of a 5% aqueous solution of sodium hydroxide (NaOH, 100 mL each). The combined NaOH solutions were acidified to pH=1 with a 10% aqueous solution of hydrochloric acid. The resulting solution was extracted with two portions of dichloromethane (100 mL each), and the extract was dried over anhydrous Na2SO4. The extract was filtered and concentrated in vacuo to give 10.3 g (94.6%) of ibuprofen as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][C:12]([NH:14][CH2:15][C:16]3[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][N:17]=3)=O)[CH:10]=1)[N:7]([CH2:26][CH:27]([CH3:29])[CH3:28])[N:6]=[CH:5]2.P(Cl)(Cl)(Cl)=O.O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][C:12]3[N:17]4[CH:18]=[CH:19][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:21][C:16]4=[CH:15][N:14]=3)[CH:10]=1)[N:7]([CH2:26][CH:27]([CH3:29])[CH3:28])[N:6]=[CH:5]2
Reactant: COC(=O)c1ccnc(CNC(=O)Cc2cc(Cl)cc3cnn(CC(C)C)c23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccn2c(Cc3cc(Cl)cc4cnn(CC(C)C)c34)ncc2c1
Temperature: 90 °C
Reaction time: 22.5 h
Yield: 52.7 %

Procedure:
A solution/suspension of compound 59 (0.184 g, 0.44 mmol) in toluene was treated with phosphorus oxychloride (1 ml) and stirred at 90° C. under a nitrogen atmosphere for 22.5 h. The mixture was cooled and treated with water (20 ml) then neutralised by addition of solid sodium hydrogen carbonate. The mixture was then extracted with ethyl acetate (2×25 ml) and the organics separated and dried over sodium sulphate, filtered and evaporated to dryness. The residue was chromatographed on silica gel eluting with an ethyl acetate/isohexane gradient to give the title compound as a yellow oil (0.092 g, 52%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH2:25][CH2:26][CH2:27][O:28][CH:29]2[CH2:34]CCC[O:30]2)[S:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:18])(=[O:13])=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:35]([OH:38])(=[O:37])[CH3:36]>C1COCC1.O.C(O)(=O)/C=C/C(O)=O>[OH:28][CH2:27][CH2:26][CH2:25][N:10]([CH:7]1[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]1)[S:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]1[S:20][C:21]([Cl:24])=[CH:22][CH:23]=1)=[O:18])(=[O:12])=[O:13].[C:29]([O-:30])(=[O:28])/[CH:34]=[CH:36]/[C:35]([O-:38])=[O:37]
Reactant: CC(C)N1CCC(N(CCCOC2CCCCO2)S(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1
Reactant: CC(=O)O
Agent: O=C(O)/C=C/C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N1CCC(N(CCCO)S(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1
Product: O=C([O-])/C=C/C(=O)[O-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
220 mg (0.38 mmol) 5-Chloro-thiophene-2-carboxylic acid (2-{(1-isopropyl-piperidin-4-yl)-[3-(tetrahydro-pyran-2-yloxy)-propyl]-sulfamoyl}-ethyl)-amide were dissolved in a mixture of 4 ml THF, 8 ml conc. acetic acid and 2 ml water. The resulting mixture was stirred for 8 h at 60° C., concentrated under reduced pressure and purified by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA). The product was taken up in dichloromethane and treated with a saturated NaHCO3-solution. After phase separation the organic phase was concentrated and the resulting residue was dissolved in water containing 1 equiv. of fumaric acid. Lyophilisation gave the title compound as its fumarate in form of a colorless amorphous material.