Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22](OC4C=CC=CC=4)=[O:23])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:31])=[N:9]2)=[CH:4][CH:3]=1.[CH:32]([NH2:36])([CH2:34][CH3:35])[CH3:33]>C(OC(C)C)(C)C>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([NH:36][CH:32]([CH2:34][CH3:35])[CH3:33])=[O:23])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:31])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reactant: CCC(C)N
Solvent: CC(C)OC(C)C
Product: CCC(C)NC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 65 °C

Procedure:
A mixture of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (8.6 g.) and sec-butylamine (40 cc.) is heated at 65° C. until dissolution. The reaction mixture is then diluted with diisopropyl ether (240 cc.). The precipitate formed is filtered off and recrystallised from acetonitrile (60 cc.). 2-(7-Chloro-1,8-naphthyridin-2-yl)-3-sec-butylaminocarbonyloxy-isoindolin-1-one (3 g.), melting at 220°-222° C., is thus obtained.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.N(OCCC(C)C)=O>CN(C=O)C.C1COCC1>[CH2:10]([O:9][C:7]([C:4]1[S:3][CH:2]=[N:6][CH:5]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1cnc(N)s1
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cncs1
Temperature: 25 °C

Procedure:
A solution of 2-amino-5-(ethoxycarbonyl)thiazole (50 g, 0.29 mmol) in a mixture of DMF (83 mL) and THF (317 mL) was added dropwise over 87 minutes to a stirred 41° C. solution of isoamyl nitrite (59 mL, 0.44 mol) in DMF (130 mL). A maximum temperature of 60° C. was observed during the exothermic addition. After another 40 minutes the THF was removed under vacuum at 45° C. The concentrated DMF solution was cooled to 25° C. and diluted with toluene (420 mL) and water (440 mL). The toluene layer was extracted with 3×120 mL water, then dried with Na2SO4 (50 g) for 1 hour. After filtration the toluene layer was stripped on a rotary evaporater at 50° C. bath temperature, then on a vacuum pump at 21° C. The crude residue containing the title compound weighed 65.6 g. This material was used directly in the next step. A sample of similarly prepared material was purified by column chromatography to give a yellow oil. 1H NMR (CDCl3) δ 8.95 (s, 1H), 8.51 (s, 1H), 4.39 (q, 2H), 1.40 (t, 3H). 13C NMR (CDCl3) δ 161.0, 157.9, 148.6, 129.8, 61.6, 14.1.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10](OCC)=[O:11])[C:3]1=[O:15].[NH2:16][C:17]1[S:18][CH:19]=[N:20][N:21]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[S:18][CH:19]=[N:20][N:21]=2)=[O:11])[C:3]1=[O:15]
Reactant: Nc1nncs1
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Solvent: Brc1ccccc1
Product: Cc1cc(O)c(C(=O)Nc2nncs2)c(=O)n1C
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 74.7 %

Procedure:
213 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 94 mg of 2-amino-1,3,4-thiadiazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 6.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature, then, the resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 185 mg of 1,6-dimethyl-4-hydroxy-2-oxo-N-(1,3,4-thiadiazol-2-yl)-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 16) represented by the formula:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)=[N:5]2.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH:25][C:24]1[CH:26]=[CH:27][CH:28]=[C:22]([C:21]([F:20])([F:29])[F:30])[CH:23]=1)=[O:16])=[N:5]2
Reactant: O=C(O)c1cccc(Oc2ccc3nccn3n2)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(Oc2ccc3nccn3n2)c1
Yield: 58 %

Procedure:
Using 3-(imidazo[1,2-b]pyridazin-6-yloxy)benzoic acid (128 mg, 0.50 mmol), 3-(trifluoromethyl)aniline (97 mg, 0.60 mmol), 1-hydroxybenzotriazole hydrate (92 mg, 0.60 mmol), N,N-dimethylformamide (5 mL), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (192 mg, 1.00 mmol) and triethylamine (0.209 mL, 1.50 mmol), and in the same manner as in Example 448, the title compound (114 mg, 0.29 mmol, yield 57%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:14]1[CH:18]=[C:17]([C:19]([OH:21])=O)[O:16][N:15]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:34]([O:40][CH2:41][CH3:42])(=[O:39])[CH2:35]C([O-])=O>>[CH2:41]([O:40][C:34](=[O:39])[CH2:35][C:19]([C:17]1[O:16][N:15]=[C:14]([CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH:18]=1)=[O:21])[CH3:42]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)c1cc(C(=O)O)on1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCOC(=O)CC(=O)c1cc(C(CC(C)C)NC(=O)OC(C)(C)C)no1

Procedure:
The title compound was prepared from 3-(1-tert-butoxycarbonylamino-3-methyl-butyl)-isoxazole-5-carboxylic acid by treatment with carbonyldiimidazole followed by the magnesium salt of mono-ethyl malonate as described in Angew. Chem. Int Ed. Eng., 18 (1979), p. 72.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:10](Br)([F:12])[F:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[OH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:26]=[C:25]([N:27]2[C:31]([C:32]([F:35])([F:34])[F:33])=[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:29]=[N:28]2)[CH:24]=[CH:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:12])([F:11])[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[N:26]=[C:25]([N:27]3[C:31]([C:32]([F:35])([F:34])[F:33])=[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:29]=[N:28]3)[CH:24]=[CH:23][CH:22]=2)=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3O)n2)c1C(F)(F)F
Reactant: O=Cc1cc(Br)ccc1C(F)(F)Br
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OC(F)(F)c3ccc(Br)cc3C=O)n2)c1C(F)(F)F

Procedure:
By analogy to Example 300 Step A, reaction of the title compound from Example 302 Step C with the title compound from Example 1 Step B provided the title compound: LCMS m/z 592.5 [M−F]+.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22][NH2:23])[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22][N:23]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])[CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCCCc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2ccccc2CN1CCCc1cccc(Cl)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.115 g, 0.5 mmol), 3-(3-chloro-phenyl)-propylamine (0.102 g, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (3 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[3-(3-chloro-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.105 g, 71%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.96 (m, 2H), 2.69 (t, 2H), 3.66 (t, 2H), 4.36 (s, 2H), 7.12-7.58 (m, 7H), 7.84 (d, 1H). GC-MS: m/z 285 (M)+.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[CH3:20])[C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:21]([NH:23][CH3:24])=[O:22].[F:25][C:26]1[C:31](OC(=O)C(F)(F)F)=[C:30]([F:39])[C:29]([F:40])=[C:28]([F:41])[C:27]=1[F:42].N1C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[F:25][C:26]1[C:31]([O:7][C:6](=[O:8])[C:5]2[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=3[CH3:20])=[C:10]([F:11])[C:2]([F:1])=[C:3]([C:21]([NH:23][CH3:24])=[O:22])[CH:4]=2)=[C:30]([F:39])[C:29]([F:40])=[C:28]([F:41])[C:27]=1[F:42]
Reactant: CNC(=O)c1cc(C(=O)O)c(Nc2ccc(I)cc2C)c(F)c1F
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CNC(=O)c1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(Nc2ccc(I)cc2C)c(F)c1F
Reaction time: 17 h
Yield: 45.1 %

Procedure:
To a suspension of 4,5-difluoro-6-(-4-iodo-2-methyl-phenylamino)-N-methyl-isophthalamic acid (0.13 g, 0.29 mmol) in N,N-dimethylformamide (5 mL) is added trifluoroacetic acid pentafluorophenyl ester (0.055 mL, 0.32 mmol) and pyridine (0.03 mL, 0.32 mmol). After stirring for 17 hours the reaction mixture is diluted with ethyl acetate and transferred to a separatory funnel, washed twice with 1.0 M HCl, twice with 5% aqueous NaHCO3 solution, 2 times with water and once with saturated brine solution. The organic layers were collected and dried over Na2SO4, filtered and concentrated in vacuo affording 4,5-difluoro-6-(4-iodo-2-methyl-phenylamino)-N-methyl-isophthalamic acid pentafluorophenyl ester (0.08g, 45.2%). To a suspension of 4,5-difluoro-6-(-4-iodo-2-methyl-phenylamino)-N-methyl-isophthalamic acid pentafluorophenyl ester (0.08 g, 0.13 mmol) in freshly distilled THF (3 mL) is added cyclopropylmethylamine hydrochloride (0.016 g, 0.13 mmol), and N,N-diisopropylethylamine (0.07 mL, 0.39 mmol). After stirring at room temperature for 17 hours the reaction mixture was partitioned between ethyl acetate and 1.0 M HCl solution. The organic layer was washed twice with water, twice with saturated brine solution, dried over MgSO4, filtered and concentrated in vacuo. Purification was performed by silica column chromatography in 2:1 ethyl acetate:hexanes affording N1-cyclopropylmethoxy-4,5-difluoro-6-(4-iodo-2-methyl-phenylamino)-N3-methyl-isophthalamide (0.033, 42.8%); mp 198–202° C.; 1H NMR (400 MHz; DMSO-d6) 8.59 (s, 1H), 8.01 (s, 1H), 7.44 (d, 1H, J=5.2), 7.32 (s, 1H), 7.18 (d, 1H, J=7.6), 6.36 (m,1H), 3.34 (d, 2H, J=6.8), 2.56 (d, 3H, J=4.0), 1.99 (s, 3H), 0.82 (m, 1H), 0.27 (d, 2H, J=8.4), 0.00 (m, 2H); MS(APCI)m+1=516;
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=2)[N:7]([CH2:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:6]=1.[C:24](O)(C(F)(F)F)=O.C=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.Cl.O1CCOCC1>C(#N)C>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=3)[N:7]([CH2:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[C:6]=2[CH2:24]1
Reactant: CNCCc1cn(CCc2ccc(C)nc2)c2ccc(C)cc12
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CN(C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The title compound was prepared by General Method 4. 150 mg of N-methyl-2-(5-methyl-1-(2-(6-methylpyridin-3-yl)ethyl)-1H-indol-3-yl)ethanamine was dissolved in acetonitrile (4 mL) containing 5% TFA and the reaction mixture was heated to reflux. 37% aqueous formaldehyde (0.04 mL) was added and the reflux was continued for additional 1.5 h. The reaction mixture was cooled to 25° C., concentrated under reduced pressure and partitioned between ethyl acetate and satd. Aqueous NaHCO3. The organic layer was dried over sodium sulfate, evaporated under reduced pressure and the residue was purified by silica gel chromatography (eluent Methanol:aqueous NH3, 95:5) to obtain the product. The free base was converted into its dihydrochloride salt by treatment of dioxane-HCl. 1H NMR (DMSO) δ 11.7 (bs, 1H), 8.6 (s, 1H), 8.3 (d, 1H), 7.7 (d, 1H), 7.3 (d, 1H), 7.25 (s, 1H), 6.9 (d, 1H), 4.8 (m, 1H), 4.4 (m, 1H), 4.35 (t, 2H), 3.7 (bs, 1H), 3.55 (s, 3H), 3.5 (m, 1H), 3.4 (bs, 1H), 3.1 (t, 2H), 3.05 (bs, 1H), 2.65 (3, 3H), 2.35 (s, 3H). MS m/z observed 320. HPLC RT 3.63 min.
Reaction SMILES: [N:1]([CH2:4][CH2:5][S:6][CH2:7][C:8]1[O:12][C:11]([CH2:13][N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=1)=[C:2]=[S:3].[NH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH2:28][N:29]([CH3:31])[CH3:30])[CH:25]=[CH:26][CH:27]=1>C(#N)C>[CH3:15][N:14]([CH2:13][C:11]1[O:12][C:8]([CH2:7][S:6][CH2:5][CH2:4][NH:1][C:2]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([CH3:30])[CH3:31])[CH:23]=2)=[S:3])=[CH:9][CH:10]=1)[CH3:16]
Reactant: CN(C)Cc1ccc(CSCCN=C=S)o1
Reactant: CN(C)Cc1cccc(OCCCN)c1
Solvent: CC#N
Product: CN(C)Cc1cccc(OCCCNC(=S)NCCSCc2ccc(CN(C)C)o2)c1
Yield: 89.6 %

Procedure:
To a solution of 5-[[[2-(isothiocyanato)ethyl]thio]methyl]-N,N-dimethyl-2-furanmethanamine (0.77 g) in dry acetonitrile (3 ml) was added a solution of 3-(3-aminopropoxy)-N,N-dimethylbenzenemethanamine (0.63 g) in dry acetonitrile (3 ml). After 1 hour the solution was evaporated to dryness to give an oil which was chromatographed (silica/methanol-0.88 ammonia 79:1). The appropriate eluate was evaporated to dryness to give the title compound (1.25 g) as an oil.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:4]=[CH:5][C:6]([NH:9][C@H:10]2[CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][CH:8]=1.[Br:25]N1C(=O)CCC1=O>C(Cl)Cl.C(#N)C>[Br:25][C:5]1[C:6]([NH:9][C@H:10]2[CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[N:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1Br
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]carbamate (11.61 g, 33.5 mmol) in DCM (70 ml) and acetonitrile (35 ml) at 0° C. under was added 1-bromopyrrolidine-2,5-dione (12.53 g, 70.4 mmol). The reaction was allowed to warm to room temperature and stirred for 20 hours. The mixture was concentrated in vacuo and then purified by column chromatography (silica, 0-50% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl[C:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:24])[C:14]=1[NH:25][C:26](=[O:29])[CH2:27][CH3:28].[CH3:30][O:31][CH2:32][CH2:33][OH:34]>>[C:26]([NH:25][C:14]1[C:15](=[O:24])[C:16]2[C:21]([C:22](=[O:23])[C:13]=1[O:34][CH2:33][CH2:32][O:31][CH3:30])=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:29])[CH2:27][CH3:28]
Reactant: COCCO
Reactant: CCC(=O)NC1=C(Cl)C(=O)c2ccccc2C1=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(=O)NC1=C(OCCOC)C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
15.2 g (0.1 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 50 ml of ethylene glycol monomethyl ether are added to a suspension of 26.35 g (0.1 mol) of 3-chloro-2-propionylamino-1,4-naphthoquinone in 100 ml of ethylene glycol monomethyl ether, and the mixture is stored at room temperature overnight. After cooling to 0° C., the mixture is filtered and the precipitate is thoroughly washed with cold methanol. Yield: 19.3 g (64% of theory), melting point 116°-17° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:37][CH3:38])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:14]4[C:15](=[O:31])[N:16]([CH:28]([CH3:30])[CH3:29])[CH2:17][CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][C:13]=4[C:12]([C:32]4[S:33][CH:34]=[CH:35][CH:36]=4)=[C:9]3[C:10]=2[CH:11]=1.C1(OC)C=CC=CC=1.CO.Cl>O1CCOCC1>[CH:28]([N:16]1[C:15](=[O:31])[C:14]2[N:8]3[CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([O:37][CH3:38])[C:2]([Br:1])=[CH:11][C:10]=4[C:9]3=[C:12]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:13]=2[CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:30])[CH3:29]
Reactant: COc1cc2c(cc1Br)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: COc1ccccc1
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc2c(cc1Br)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCNC3
Reaction time: 5 h
Yield: 87.7 %

Procedure:
To a solution of 130 mg of 10l, 30 mg of anisole and 100 ul of methanol in 1 ml of dioxane was added 400 μl of 4N HCl in dioxane. The reaction mixture was stirred for 5 h and then quenched by addition of 10 ml of 5% aq. NaHCO3 and extracted with ethyl acetate. The organic layer was washed once with water, dried and concentrated. The residue was treated with diisopropyl ether, to afford 95 mg of 10u as white crystalline material; Mp 201-203° C.; Rf 0.20 (heptane-acetone 1/1). MS-ESI: [M+1] 499.94 and 501.95. NMR (CDCl3) 1.30 (d, 6, isoC3H7), 3.88 (s, 3, OCH3), 4.72 (m, 1, isoC3H7), 6.70, 7.18 (2×s, 2, Ar—H), 6.93, 7.13, 7.41 (3×m, 3, thiophene-H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]O.Cl.[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]N)=[CH:13][CH:12]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:15]2[C:14](=[CH:13][CH:12]=[C:11]([F:10])[CH:16]=2)[NH:17][CH:7]=1
Reactant: OCCCCCCCl
Reactant: NNc1ccc(F)cc1
Agent: Cl
Product: Fc1ccc2[nH]cc(CCCCCl)c2c1

Procedure:
from 6-chlorohexan-1-ol and 4-fluorophenylhydrazine hydrochloride
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12](=[O:30])[N:13]([CH2:15][CH2:16][O:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=4)[N:21]=[CH:20][CH:19]=3)[CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[C:38](Cl)(=[O:44])[O:39][CH2:40][CH:41]([CH3:43])[CH3:42]>C(Cl)Cl>[CH3:29][O:28][C:24]1[CH:23]=[C:22]2[C:27]([C:18]([O:17][CH2:16][CH2:15][N:13]3[C:12](=[O:30])[CH:11]=[CH:10][C:9]([C:4]4[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH:1][C:38](=[O:44])[O:39][CH2:40][CH:41]([CH3:43])[CH3:42])[CH:3]=4)=[CH:14]3)=[CH:19][CH:20]=[N:21]2)=[CH:26][CH:25]=1
Reactant: COc1ccc2c(OCCn3cc(-c4ccc(C)c(N)c4)ccc3=O)ccnc2c1
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(OCCn3cc(-c4ccc(C)c(NC(=O)OCC(C)C)c4)ccc3=O)ccnc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.1 %

Procedure:
To a solution of 5-(3-amino-4-methylphenyl)-1-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridin-2(1H)-one (0.10 g, 0.25 mmol) in 10 mL of CH2Cl2 at rt was added triethylamine (0.083 ml, 0.60 mmol) followed by isobutyl chlorocarbonate (0.048 ml, 0.37 mmol). The reaction was stirred at rt for 4 hours and was then concentrated in vacuo. The residue was dissolved in 50 mL of EtOAc and the resulted organic phase was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine. The organic solution was dried over Na2SO4 and concentrated in vacuo. The residue was washed with 50% hex/EtOAc to give white solid as desired product (0.0879 g, 70% yield). MS (ESI pos. ion) m/z (MH+): 502.1. Calc'd Exact Mass for C29H31N3O5: 501.23.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=O)C1C=CC=CC=1.O.[H][H]>C(O)C.[C].[Pd]>[CH3:20][N:19]([CH3:21])[C:17]([C@@H:12]1[CH2:13][C@@H:14]([OH:16])[CH2:15][NH:11]1)=[O:18]
Reactant: [H][H]
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-dimethylaminocarbonyl-4-hydroxypyrrolidine (5.97 g) in ethanol (60 ml), 10% palladium-carbon (containing water 50 (1.20 g) was added, and the mixture was hydrogenated at room temperature for 3 hours under an atmospheric pressure of hydrogen. After removal of the catalyst by filtration, the filtrate was evaporated to remove the solvent to give (2S,4R)-2-dimethylaminocarbonyl-4-hydroxypyrrolidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[CH3:16][S:17]([NH2:20])(=[O:19])=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2/[CH:14]=[N:20]/[S:17]([CH3:16])(=[O:19])=[O:18])=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: CS(N)(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1/C=N/S(C)(=O)=O

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (2 g, 7.5 mmol), methane sulfonamide (0.714 g, 7.5 mmol) and p-toluenesulfonic acid (0.010 g, 0.06 mmol) were combined in toluene. The reaction was heated to reflux for 24 hours with Dean-Stark apparatus in place. Upon cooling, the title compound precipitated from solution and was collected by filtration and used directly in the next step.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.S(Cl)(Cl)=O.[CH2:18]([C@@H:25]1[CH2:30][C@@H:29]([NH2:31])[CH2:28][CH2:27][N:26]1[C:32](=[O:41])[C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>>[CH2:18]([C@@H:25]1[CH2:30][C@@H:29]([NH:31][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:13])[CH2:28][CH2:27][N:26]1[C:32](=[O:41])[C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Reactant: O=C(O)c1ccc2ccccc2c1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1)c1ccc2ccccc2c1
Yield: 95.6 %

Procedure:
142 mg (0.825 mmol) of 2-naphthoic acid are reacted in analogy to Example 2a first with 2 ml (27 mmol) of thionyl chloride and subsequently with 200 mg (0.550 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine and 138 μl (0.991 mmol) of triethylamine to give the title compound (272 mg, 96%). ##STR83## TLC:methylene chloride/methanol/cone. ammonia (1000:50:1) Rf =0.73, FD-MS: (M+H)+ =516, 518, 520, IR:3420, 1625 cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.OO.S(=O)(=O)(O)[O-:13].[Na+].CC1C=C(C)C=C(O)C=1O>CC(C)CC(=O)C>[CH3:8][C:6]1[CH:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[C:7]=1[OH:13]
Reactant: Cc1cc(C)cc(O)c1
Reactant: O=S(=O)([O-])O
Agent: Cc1cc(C)c(O)c(O)c1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: Cc1cc(O)cc(C)c1O

Procedure:
In a vessel used in Example 52 were placed 100 g. (819 m. moles) of 3,5-dimethylphenol, 2.97 g. (29.7 m. moles) of 4-methyl-2-pentanone, 2.52 g. (44.5 m. moles) of 60 percent hydrogen peroxide and 0.01 g. of sodium bisulfate (NaHSO4.H2O), and the mixture was treated at 110° C. for 20 minutes in the same manner as in Example 52. As products, 2.19 g. (15.9 m. moles) of 3,5-dimethylcatechol and 1.25 g. (9.08 m. moles) of 2,6-dimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 56.1 percent.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:32])[CH2:11][S:12][CH2:13][C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]3[N:21]([CH2:30][CH3:31])[C:22]4[C:27]([C:28]=3[CH:29]=2)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:15])=[CH:5][CH:4]=1)#[N:2].C(#N)C.I([O-])(=O)(=O)=[O:37].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:32])[CH2:11][S:12]([CH2:13][C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]3[N:21]([CH2:30][CH3:31])[C:22]4[C:27]([C:28]=3[CH:29]=2)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:15])=[O:37])=[CH:5][CH:4]=1)#[N:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCn1c2ccccc2c2cc(NC(=O)CSCC(=O)Nc3ccc(C#N)cc3)ccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCn1c2ccccc2c2cc(NC(=O)CS(=O)CC(=O)Nc3ccc(C#N)cc3)ccc21
Temperature: 25 °C
Reaction time: 432 h
Yield: 23.3 %

Procedure:
To a solution of 2-({2-[(4-cyanophenyl)amino]-2-oxoethyl}sulfanyl)-N-(9-ethyl-9H-carbazol-3-yl)acetamide (55 mg, 0.12 mmol) in a mixed solvent of acetonitrile (4 mL) and water (2 mL) was added sodium periodate (29.2 mg, 0.14 mmol), and the mixture was stirred at room temperature for 18 days. Aqueous sodium thiosulfate solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium carbonate solution, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound (13 mg, 0.028 mmol, 23%) as a pale-yellow powder.