Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]([NH2:10])=[O:9])[CH2:2][CH2:3][CH3:4].[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15]N.N>>[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][NH:10][C:8](=[O:9])[CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CN(C)CCCN
Reactant: CCCCOCCC(N)=O
Agent: N
Product: CCCCOCCC(=O)NCCCN(C)C

Procedure:
145.2 g (1.0 mole) of 3-n-butoxypropionamide are heated with 107.3 g (1.05 mole) of 3-dimethylaminopropylamine for 8 hours in a temperature range of 150°-170° C. until the evolution of ammonia is complete. In the subsequent distillation in a high vacuum, 204 g (0.89 mole =89% of the theoretical yield) of colorless liquid are obtained having a Bp0.1 of 122° to 124° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].Br[Mg][CH2:13][CH:14]([CH3:16])[CH3:15].Cl.C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>C(OCC)C.C(Cl)Cl.C(OCC)(=O)C>[CH3:13][CH:14]([CH3:16])[CH2:15][C:6]([C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:7]
Reactant: COc1cccc(C=O)c1
Reactant: CC(C)C[Mg]Br
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)CC(C)C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
To a stirred solution of 3-(methyloxy)benzaldehyde (4.77 g, 35 mmol) in diethyl ether (100 mL) at 0° C. was added bromo(2-methylpropyl)magnesium (21 mL, 42 mmol). The solution was stirred for 10 min at 0° C. and then worked-up with 0.6M HCl (150 mL) and ethyl acetate (200 mL), to afford a crude material. In another round bottom flask of oxalyl chloride (4.60 mL, 52.5 mmol) in DCM (150 mL) at −78° C. was added DMSO (4.97 mL, 70.0 mmol), dissolved in dry DCM (20 mL), followed by a solution of the above crude material dissolved in dry DCM (25 mL). The resulting mixture was stirred for 1 h at −78° C., then triethylamine (24.39 mL, 175 mmol) was added and the solution stirred at −78° C. for 1 h. The reaction was quenched at −78° C. and the product was extracted by DCM and washed with water/brine. The crude material was purified by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in hexane, to afford the title compound (4.12 g). LCMS (B) m/z: 193 [M+1]+, Rt 3.11 min.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[F:15])[CH3:2].O[CH:19]=[C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][C:21]1=[O:29]>>[CH2:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:19]=[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]2=[O:29])=[CH:10][C:9]=1[F:15])[CH3:17]
Reactant: CCN(CC)CCCOc1ccc(N)cc1F
Reactant: O=C1Nc2ccccc2C1=CO
Product: CCN(CC)CCCOc1ccc(NC=C2C(=O)Nc3ccccc32)cc1F
Yield: 23.5 %

Procedure:
In a manner similar to that described in Example 231, 4-(3-Diethylamino-propoxy)-3-fluoro-phenylamine (400 mg, 1.1 equiv.) and 3-hydroxymethylene-1,3-dihydro-indol-2-one (242 mg, 1.5 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (135 mg, 24%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:19]3=[C:20]([C:22](=[O:32])[C:23]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:24][N:18]3[C:17]3[CH:16]=[CH:15][C:14]([O:33][CH3:34])=[CH:13][C:12]2=3)[CH:21]=1)C1C=CC=CC=1.C([O-])(=O)C.[Na+].[H][H]>C(O)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:19]3=[C:20]([C:22](=[O:32])[C:23]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:24][N:18]3[C:17]3[CH:16]=[CH:15][C:14]([O:33][CH3:34])=[CH:13][C:12]2=3)[CH:21]=1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)c1cc(OCc3ccccc3)cc3c(=O)c(Cc4cccnc4)cn2c31
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)c1cc(O)cc3c(=O)c(Cc4cccnc4)cn2c31
Yield: 68.5 %

Procedure:
2-benzyloxy-10-methoxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (470 mg) obtained in Example 252 was dissolved in acetic acid. To the solution were added sodium acetate (259 mg) and palladium carbon (116 mg), and the mixture was heated under reflux in a hydrogen atmosphere for 3 hours. The reaction mixture was filtered, and the filtrate was distilled to remove the solvent under reduced pressure. To the residue was added an aqueous solution of sodium hydrogencarbonate until the termination of foaming. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:methylene chloride/methanol=20:1) to obtain the title compound (257 mg, 62%).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[CH:21][S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([CH:47]=O)=[CH:43][CH:42]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[CH:21][S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:47]([C:44]3[CH:43]=[CH:42][C:41]([CH2:40][N:37]4[CH2:36][CH2:35][N:34]([C:32]([O:31][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:33])[CH2:39][CH2:38]4)=[CH:46][CH:45]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C=O)cc2)CC1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cscn3)CC2)c1[N+](=O)[O-]
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3nc4c(N5CCN(Cc6cscn6)CC5)c(Br)cnc4[nH]3)cc2)CC1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-(thiazol-4-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.054 g, 0.13 mmol), EtOH (2.3 mL) and DMF (0.31 mL), tert-butyl-4-(4-formylbenzyl)piperazine-1-carboxylate (0.045 g, 0.15 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.40 mL, 0.40 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8). The title compound was obtained as a solid after trituration with diethyl ether (0.031 g, 35%); 1H-NMR (500 Mz, DMSO-d6): δ 1.39 (s, 9H, C(CH3)3), 2.34 (t, J=4.8 Hz, 4H), 2.65-2.72 (m, 4H), 3.30-3.36 (m, 4H), 3.55 (s, 2H, NCH2), 3.68 (m, 4H), 3.77 (s, 2H, NCH2), 7.47 (d, J=8.0 Hz, 2H, ArH, C6H4), 7.58 (d, J=2.0 Hz, 1H, thiazole 5-H), 8.14 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 9.07 (d, J=2.0 Hz, 1H, thiazole 2-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (method B)-MS (ESI, m/z) 2.50 min—653/655 [(M+H)+], Br isotopic pattern]. ESI-HRMS: Found: 653.2023, calculated for C30H38BrN8O2S (M+H)+: 653.2022.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[C:16]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])[N:15]=1)[C:10](=[O:13])[C:11]#[CH:12]>CN(CCN(C)C)C>[F:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[C:16]1[N:15]2[C:14]([CH:19]=[CH:18][C:17]=1[CH2:20][OH:21])=[C:9]([C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:10](=[O:13])[CH:11]=[CH:12]2
Reactant: C#CC(=O)C(c1ccc(CO)c(-c2ccc(F)cc2F)n1)c1c(F)cccc1F
Agent: CN(C)CCN(C)C
Product: O=c1ccn2c(-c3ccc(F)cc3F)c(CO)ccc2c1-c1c(F)cccc1F
Yield: 46 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)-1-[6-(2,4-difluorophenyl)-5-(hydroxymethyl)pyridin-2-yl]but-3-yn-2-one (from Step E above, 1.0 g) in TMEDA was heated to 110° C. until reaction completed. The mixture was concentrated and purified by silica gel (100% acetone) to give title compound as a yellow solid (0.46 g).
Reaction SMILES: [F:1][C:2]1(F)[C:11]2[C:6](=[CH:7][C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1(F)[F:21].FC1(F)C2C(=CC([C@H]3CC[C@H](CCC)CC3)=CC=2)C(F)=CC1F.[NH4+].[OH-].N>C1COCC1.[Zn]>[F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]3[CH2:13][CH2:14][C@H:15]([CH2:18][CH2:19][CH3:20])[CH2:16][CH2:17]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[F:21]
Reactant: CCC[C@H]1CC[C@H](c2ccc3c(c2)C=CC(F)(F)C3(F)F)CC1
Agent: CCC[C@H]1CC[C@H](c2ccc3c(c2)C(F)=CC(F)C3(F)F)CC1
Agent: N
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](c2ccc3c(F)c(F)ccc3c2)CC1
Reaction time: 27 h

Procedure:
A mixture of 1,1,2,2-tetrafluoro-6-(trans-4-propylcyclohexyl)-1,2-dihydronaphthalene and 1,1,2,4-tetrafluoro-6-(trans-4-propylcyclohexyl)-1,2-dihydronaphthalene, 10.0 g (30.6 mmol) in THF was stirred with zinc dust (10 g, 153 mmol) and aqueous 30% NH4OH at ambient temperature. After 27 h, GC analysis showed that the mixture contained <1% of the starting material. The mixture was filtered, and the zinc was washed with hexanes. The filtrate was transferred to a separatory funnel, the phases were separated, and the solvent was evaporated from the organic phase. The weight of product recovered was 8.6 g. GC analysis of the product showed that it contained 0.9% 1,1,2,2-tetrafluoro-6-(trans-4-propylcyclohexyl)-1,2-dihydronaphthalene, 13.4% 1,2,4-trifluoro-6-(trans-4-propylcyclohexyl)naphthalene, and 82% 1,2-difluoro-6-(trans-4-propylcyclohexyl)naphthalene. This example shows that when ammonia is not buffered to reduce the pH, more by-products are formed compared to the reaction in which buffered ammonia is used (Example 8).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][C@@H:6]([NH:8][C:9]2[C:14]([I:15])=[C:13]([O:16][CH3:17])[N:12]=[C:11]([S:18][CH3:19])[N:10]=2)[C@H:5]([OH:20])[C@@H:4]1[OH:21].CO[C:24](OC)([CH3:26])[CH3:25].CCN(CC)CC>CC(C)=O.CS(O)(=O)=O>[I:15][C:14]1[C:9]([NH:8][C@H:6]2[C@@H:5]3[O:20][C:24]([CH3:26])([CH3:25])[O:21][C@@H:4]3[C@@H:3]([CH2:2][OH:1])[CH2:7]2)=[N:10][C:11]([S:18][CH3:19])=[N:12][C:13]=1[O:16][CH3:17]
Reactant: COc1nc(SC)nc(N[C@@H]2C[C@H](CO)[C@@H](O)[C@H]2O)c1I
Reactant: COC(C)(C)OC
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1nc(SC)nc(N[C@@H]2C[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c1I
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Compound 5 (4.00 g, 9.36 mmol) was dissolved in acetone (10 mL) and 2,2-dimethoxypropane (5.75 mL, 46.8 mmol) was added. The solution was cooled to 0° C. and methanesulfonic acid (2 drops) was added. The solution was stirred for 15 min and Et3N (1 mL) was added. The acetone was evaporated and the residue was dissolved in EtOAc, washed with water and brine, dried (MgSO4), filtered and concentrated. The residue was purified via column chromatography on silica gel (EtOAc/hexanes) to give the title compound as a white solid. 1H NMR (CDCl3) δ 6.21 (d, J=8 Hz, 1H), 4.65-4.59 (m, 2H), 4.45-4.44 (m, 1H), 3.94 (s, 3H), 3.89-3.85 (m, 1H), 3.76-3.73 (m, 1H), 2.61-2.55 (m, 1H), 2.52 (s, 3H), 2.40-2.34 (m, 1H), 1.85 (br s, 1H), 1.65-1.57 (m, 2H), 1.49 (s, 3H), 1.28 (s, 3H); LCMS 2.54 min, 468 (M+H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[C:38]1([NH:37][S:34]([C:30]2[CH:29]=[C:28]([NH:27][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([C:2]([F:25])([F:1])[F:26])=[CH:4][C:5]([C:15]5[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=5)=[N:6][C:7]=34)=[O:13])[CH:33]=[CH:32][CH:31]=2)(=[O:35])=[O:36])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Nc1cccc(S(=O)(=O)Nc2ccccc2)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)Nc2ccccc2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-phenyl-benzenesulfonamide [commercially available] according to general procedure II. Yellow solid. MS (ISP) 604.0 [(M−H)−]; mp 258° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([O:18]CC)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([OH:18])=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2sc(NC(C)=O)nc2C)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)O)n2)s1
Reaction time: 1 h

Procedure:
A solution of ethyl 2′-(acetylamino)-4′-methyl-4,5′-bi-1,3-thiazole-2-carboxylate, Compound (1), (200 mg; 0.64 mmol; 1 eq.) in THF (6 ml) is cooled down to 0° C. Sodium hydroxide (1.60 ml; 5 M; 8.03 mmol; 12.50 eq.) is added dropwise. After 1 h, no starting material can be detected. The mixture is neutralized at 0° C. with HCl 5M solution (1.607 ml; 5 M; 8.03 mmol; 12.50 eq.). The resulting precipitate is filtrated, washed with water and Et2O, affording Compound (4) as white-off powder (137.5 mg; 76%). 1H NMR (DMSO-d6, 300 MHz) δ 2.12 (s, 3H), 2.44 (s, 3H), 7.48 (s, 1H), 12.01 (s, 1H). M− (ESI): 282; M+ (ESI): 284. HPLC (method A), Rt: 1.90 min (purity: 99.50%). Analysis calculated for C10H9N3O3S2 2.0H2O: C, 37.61; H, 4.10; N, 13.16; Exp.: C, 37.73; H, 3.79; N, 13.14. Potassium salt of 2′-(acetylamino)-4′-methyl-4,5′-bi-1,3-thiazole-2-carboxylic acid, Compound (4), is prepared by suspending the parent molecule (90.6 mg; 0.32 mmol; 1 eq.) in THF (3 ml) and water (3 ml). Potassium hydroxide (640 μl; 0.50 M; 0.32 mmol; 1 eq.) is added. The solution is diluted with water, filtered through cotton and lyophylized. The potassium salt of Compound (4) is isolated as white-off solid (104.1 mg; quantitative). 1H NMR (DMSO-d6, 300 MHz) δ 2.12 (s, 3H), 2.44 (s, 3H), 7.48 (s, 1H), 12.01 (br s, 1H). M− (ESI): 282; M+ (ESI): 284. HPLC (method A), Rt: 1.87 min (purity: 99.4%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH2:11][CH2:12][OH:13].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.O>C1COCC1>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:13][CH2:12][CH2:11][C:5]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=1[CH3:3]
Reactant: Cc1cccc(C)c1CCO
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C)c1CCOCCCCCCBr
Yield: 52.7 %

Procedure:
NaH (46% dispersion in oil; 4.2 g) was added portionwise to a solution of 2,6-dimethylbenzenethanol (6.0 g) and 1,6-dibromohexane (19.52 g) in THF (50 ml) under nitrogen. The mixture was refluxed for 18 h and treated cautiously with H2O (20 ml). The resulting emulsion was extracted with ER (3×100 ml) and the dried extract was evaporated to leave a yellow oil. Excess 1,6-dibromohexane was removed under reduced pressure and the residue was purified on a column of silica (300 ml) [B] to give the title compound as a colourless oil (6.6 g) b.p. 110°-115°/0.4 mmHg.
Reaction SMILES: CO.N1CCCC1.[CH3:8][CH2:9][CH2:10][CH2:11][C:12](=O)[CH2:13][CH2:14][CH2:15][CH3:16].[CH:18]1[CH2:22][CH:21]=[CH:20][CH:19]=1>O.C(OCC)C>[CH2:11]([C:12]([CH2:13][CH2:14][CH2:15][CH3:16])=[C:19]1[CH:18]=[CH:22][CH:21]=[CH:20]1)[CH2:10][CH2:9][CH3:8]
Reactant: C1=CCC=C1
Reactant: CCCCC(=O)CCCC
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: CCCCC(CCCC)=C1C=CC=C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 82.2 %

Procedure:
Under a nitrogen atmosphere, a 200-mL three-necked flask was charged with 15 mL of methanol and 11.8 mL (146 mmol) of pyrrolidine. The mixture was cooled in an ice bath. Subsequently, 20.21 g (144 mmol) of 5-nonanone and 11.0 mL (146 mmol) of cyclopentadiene were added, and the mixture was stirred at room temperature for 22 hours. 100 mL of diethyl ether and 100 mL of water were added to extract the soluble fraction. This organic layer was washed two times with water and once with saturated brine, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography to obtain a target product as a yellow oil (yield 22.53 g (82%)). The target product was identified by 1H-NMR.
Reaction SMILES: [K].S(=O)(=O)(O)O.C(=O)([O-])[O-:8].[Na+].[Na+].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[Cl:24]>O>[Cl:24][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:14]=1[N:13]=[O:8])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(N=O)c(Cl)c1
Temperature: 0 °C

Procedure:
8.00 g (29.6 mmol) potassium peroxodisulphate are added to 6.0 ml of conc. sulphuric acid with stirring, stirred for 30 minutes at ambient temperature under a nitrogen atmosphere, the mixture is stirred into 50 g ice and neutralised with 14 g sodium carbonate. The solution obtained is combined with a suspension of 2.78 g (15.0 mmol) methyl 4-amino-3-chloro-benzoate in 300 ml of water and stirred for 16 hours at ambient temperature. The reaction mixture is suction filtered, the filter cake is washed with water, dried in the air and purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 9:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH3:26].Cl>C(#N)C>[CH2:25]([N:15]1[CH2:16][CH2:17][CH:12]([C:4]2[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:14]1)[CH3:26]
Reactant: CS(=O)(=O)c1cc(F)cc(C2CCNCC2)c1
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(c2cc(F)cc(S(C)(=O)=O)c2)CC1

Procedure:
Preparation according to Example 1: 4-[3-fluoro-5-(methylsulfonyl)phenyl]piperidine (0.4 g, 1.55 mmol), acetonitrile (5 ml), potassium carbonate (0.42 g, 3.0 mmol), 1-iodoethane (0.147 ml, 1.55 mmol). Yield: 0.28 g (63%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 176-178° C. MS m/z (relative intensity, 70 eV) 285 (M+, 15), 284 (16), 271 (16), 270 (bp), 84 (15).
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[C:11]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][C:9]([C:16]2[C:17](=[O:27])[N:18]([CH3:26])[C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[C:8]([F:28])[CH:7]=1.Cl.CN.[CH2:32]([N:34](CC)CC)C>O>[Cl:5][C:6]1[C:11]([S:12](=[O:14])(=[O:13])[NH:34][CH3:32])=[CH:10][C:9]([C:16]2[C:17](=[O:27])[N:18]([CH3:26])[C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[C:8]([F:28])[CH:7]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc(S(=O)(=O)Cl)c(Cl)cc2F)c1=O
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CNS(=O)(=O)c1cc(-c2ccc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 25 ml of chloroform, 0.6 g (1.5 mmol) of 3-(4-chloro-5-chlorosulfonyl-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone and 1.8 g (26.7 mmol) of methylamine hydrochloride were added, and 6.0 g (59.4 mmol) of triethylamine was dropwise added thereto under cooling with ice, followed by stirring at room temperature for 2 hours. This reaction solution was poured into water and extracted with chloroform. After washing with water and a 10% citric acid aqueous solution, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.4 g (yield:67) of the desired product. Melting point: 150-151° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[NH:6]2.[Mg].CO>O>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH2:4][CH:5]([C:12]([O:14][CH3:15])=[O:13])[NH:6]2
Reactant: COC(=O)c1cc2c(C)ccc(C)c2[nH]1
Agent: [Mg]
Solvent: O
Solvent: CO
Product: COC(=O)C1Cc2c(C)ccc(C)c2N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
A flask dried with heating was charged with 1.6 g (7.9 mmol) of methyl 4,7-dimethylindole-2-carboxylate and 3.8 g (158 mmol) of chipped magnesium. After addition of 400 ml of anhydrous methanol, the reaction mixture was stirred vigorously for 30 minutes. The flask was placed in an ice bath to cool the reaction mixture to 0° C., and the reaction mixture was stirred overnight. The reaction mixture was diluted with 300 ml of water, filtered and extracted with 100 ml of methylene chloride three times. The methylene chloride layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solids thus obtained were purified by silica gel column chromatography to provide 1.28 g of light red crystals. Yield: 79%
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].[CH2:20](Cl)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(O)C>[C:1]([NH:4][C:5]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCCCCCCCC=CCCCCCCCCCl
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCC=CCCCCCCCCC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 4 %

Procedure:
Diethyl 2-acetamidomalonate (15 g) was dissolved in 200 ml of dry ethanol and 5.6 g of sodium ethoxide was added thereto. To the reaction mixture, 22 g of 9-octadecenyl chloride was added while stirring at room temperature. The inside of the reaction vessel was displaced with nitrogen and the mixture was refluxed for about 15 hours. The mixture was neutralized with ethanol-concentrated hydrochloric acid (11:1) and concentrated. The concentrate was purified by silica gel column chromatography to give 1.3 g of diethyl 2-acetamido-2-(9-octadecenyl)malonate as a colorless, oily and viscous substance.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][S:30][CH2:31][CH2:32]O.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:29][S:30][CH2:31][CH2:32][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: CSCCO
Reactant: O=Cc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSCCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 15.5 h

Procedure:
To a mixture of 1.00 g of 3-hydroxybenzaldehyde, 25 ml of tetrahydrofuran, 2.40 g of triphenylphosphine and 0.78 ml of 2-methylthioethanol was added dropwise 3.50 ml of diethyl azodicarboxylate (40% toluene solution), and the mixture was stirred at room temperature for 15.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 0.71 g of oily 3-(2-methylthioethoxy)benzaldehyde [Compound No. (f)].