Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH:21]([CH3:24])[CH2:22][CH3:23]>CC(C)=O>[CH3:20][CH:21]([CH2:22][CH3:23])[CH2:24][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: CCC(C)CI
Reactant: COC(=O)c1cc([N+](=O)[O-])c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(C)Cn1cc([N+](=O)[O-])cc1C(=O)OC
Temperature: 25 °C
Yield: 70 %

Procedure:
Methyl 3-nitropyrrole-2-carboxylate (22) (2.7 g, 15.9 mmol), potassium carbonate (6.5 g), and iodo-2-methylbutane (5.2 ml) were dissolved in 100 ml of acetone and refluxed for 10 hours. The reaction mixture was then cooled to room temperature, concentrated in vacua, partitioned between 200 ml of dichloromethane and 200 ml of water and extracted with dichloromethane (2×200 ml). The combined organic layers were dried (sodium sulfate) and concentrated in vacuo. The resulting yellow oil was purified by flash chromatography to provide the substituted nitro pyrrole 23 (2.5 g, 70% yield). 1H NMR (DMSO-d6) δ8.30 (d, 1 H, J=2.0 Hz), 7.33 (d, 1 H, J=1.9 Hz), 4.15 (d, 2 H, J=7.4 Hz), 3.77 (s. 3H), 2.03 (m, 1 H, J=3.1 Hz), 0.80 (d. 6 H, J=6.7 Hz); 13C NMR (DMSO-d6) δ160.30, 134.79, 129.80, 122.40, 112.76, 105.00, 56.63, 52.41, 29.72, 19.73; FABMS, 226.096 calcd, 226.095 found.
Reaction SMILES: [CH3:1][N:2]1[CH:7]([CH3:8])[CH2:6][CH:5](O)[CH2:4][CH:3]1[CH3:10].S(Cl)([Cl:13])=O>C1C=CC=CC=1.O>[CH3:1][N:2]1[CH:7]([CH3:8])[CH2:6][CH:5]([Cl:13])[CH2:4][CH:3]1[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CC1CC(O)CC(C)N1C
Solvent: c1ccccc1
Solvent: O
Product: CC1CC(Cl)CC(C)N1C
Temperature: 70 °C

Procedure:
The starting material, 1,2,6-trimethyl-4-piperidinol, may be prepared by the method disclosed in Archi Kem, Volume 27, pages 189-192 (1955). To a cooled (ice-bath) solution of 1,2,6-trimethyl-4-piperidinol (12.2 g, 85.3 mmol) in 120 mL of dry benzene is slowly add thionylchloride (17 mL, 233 mmole). The dark reaction mixture is warmed to 70° C. for 20 min. The reaction is cooled and then suspended in water followed by filtration. The filtrate is extracted once with diethylether. The aqueous layer is separated and the basified with 30% NaOH solution. The product is then extracted twice with CH2Cl2, washed once with brine, dried (Na2SO4), filtered and the solvent removed to produce a crude brown liquid which is distilled (2-4 mmHg, 62°-64° C.) to give the title compound (8.0 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:38])[CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH:26]=2)[C:21]([OH:23])=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C:64]1[S:65][C:66]([CH3:69])=[CH:67][N:68]=1>CN(C=O)C>[CH2:16]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:38])[CH2:29][O:30][Si:31]([C:34]([CH3:36])([CH3:37])[CH3:35])([CH3:32])[CH3:33])[CH:26]=1)[C:21]([NH:63][C:64]1[S:65][C:66]([CH3:69])=[CH:67][N:68]=1)=[O:23])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: Cc1cnc(N)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
DIPEA (7.5 mL) was added to a suspension of 3-{(phenylmethyl)oxy}-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (4.5 g, 0.011 mol), HATU (8.6 g, 0.023 mol) and 2-amino-5-methylthiazole (2.46 g, 0.022 mol) in DMF (70 mL). The resulting mixture was stirred at ambient temperature for 72 hours. The DMF was removed in vacuo. Water (100 mL) was added and the mixture extracted with ethyl acetate (3×50 mL). The extracts were combined and washed with brine (100 mL). The solution was dried (MgSO4), filtered, and evaporated in vacuo to give the crude product which was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound. (1.7 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([C:10]([F:13])([F:12])[F:11])[N:4]=1.[CH2:14]([S:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=O)[CH3:15].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[CH2:14]([S:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]1[N:2]([CH3:1])[C:3]2=[N:4][C:5]([C:10]([F:11])([F:12])[F:13])=[CH:6][CH:7]=[C:8]2[N:9]=1)[CH3:15]
Reactant: CCSc1ccccc1C(=O)O
Reactant: CNc1nc(C(F)(F)F)ccc1N
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: CCSc1ccccc1-c1nc2ccc(C(F)(F)F)nc2n1C
Temperature: 25 °C
Yield: 57.8 %

Procedure:
A mixture of N2-methyl-6-trifluoromethylpyridin-2,3-diamine (0.96 g), 2-ethylsulfanylbenzoic acid (1.01 g), WSC (1.06 g), and pyridine (5 ml) was stirred under reflux for hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. To the resulting residue, a mixture of tripotassium phosphate (2.65 g) and 1-propanol (10 ml) was added, and stirred under reflux for hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.98 g of 2-(2-ethylsulfanylphenyl)-3-methyl-5-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 151).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C1N2CN3CN(C2)C[N:12]1C3.Cl>C(Cl)(Cl)Cl>[NH2:12][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: NCC(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 106.9 %

Procedure:
2-Bromoacetophenone (18 g, 90 mmol) was dissolved in 900 ml of chloroform. Hexamethylenetetraamine (13.87 g, 99 mmol) was added thereto and the reaction mixture was stirred at 60° C. for 4 hours. After stirring, the reaction mixture was cooled down to room temperature, filtered, and the collected precipitate was suspended in 180 ml of ethanol. To the suspension thus obtained was added dropwise 90 ml of conc. HCl, and the reaction mixture was stirred at room temperature for 18 hours. Then, the reaction mixture was filtered to remove a white precipitate, the filtrate was concentrated under reduced pressure to obtain a yellow solid. This solid was recrystallized from a mixture of methanol and ethyl acetate (1:50, v/v) to obtain 13 g of 2-aminoacetophenone as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].[CH3:9][S:10][C:11](SC)=[C:12]([C:16](=O)[CH3:17])[C:13](=[O:15])[CH3:14].C(OCC)(=O)C>[Cl-].[Na+].O>[CH3:17][C:16]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:8]=[C:11]([S:10][CH3:9])[C:12]=1[C:13](=[O:15])[CH3:14]
Reactant: CSC(SC)=C(C(C)=O)C(C)=O
Reactant: NNc1ccccn1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1nn(-c2ccccn2)c(C)c1C(C)=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of pyridin-2-yl-hydrazine (1.0 equivalent) and 3-(bis-methylsulfanyl-methylene)-pentane-2,4-dione (1.0 equivalent) was stirred at 60° C. overnight. To the reaction mixture was added ethyl acetate and brine, the organic phase was washed by brine twice, dried over magensium sulfate, and filtered. The organic solvent was removed under reduced pressure to provide the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:16].[CH2:17]([O:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH3:19].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:5]([CH2:4][CH2:3][CH2:2][N:24]1[CH2:25][CH2:26][CH:21]([O:20][CH2:17][CH2:18][CH3:19])[CH2:22][CH2:23]1)[C:6](=[O:16])[CH2:7][CH2:8]2
Reactant: O=C1CCc2cc(F)ccc2N1CCCCl
Reactant: CCCOC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOC1CCN(CCCN2C(=O)CCc3cc(F)ccc32)CC1
Reaction time: 20 h
Yield: 47.4 %

Procedure:
A 4 mL vial was charged with 1-(3-chloropropyl)-6-fluoro-3,4-dihydro-1H-quinolin-2-one (92LH79) (0.242 g, 1.00 mmol), 4-propoxypiperidine (0.143 g, 1.00 mmol), KI (0.250 g, 1.50 mmol), and K2CO3 (0.207 g, 1.50 mmol) in MeCN (2 mL) and shaken at 40° for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; EtOAc, MeOH/EtOAc 1:4) to give the title compound (107LH70) (0.165 g, 47%). 1H NMR (CD3OD) δ 7.19-7.15 (m, 1H), 7.01-6.97 (m, 2H), 3.96 (t, J=7.4 Hz, CH2), 3.40 (t, J=6.6 Hz, CH2), 3.35-3.30 (m, 3H), 2.88 (t, J=6.8 Hz, 2H), 2.76 (m, 2H), 2.60-2.57 (m, 2H), 2.43-2.39 (m, 2H), 2.22-2.17 (m, 2H), 1.90-1.78 (m, 4H), 1.61-1.50 (m, 4H), 0.91 (t, J=7.4 Hz, CH3); 13C NMR (CD3OD) δ 172.2, 160.0 (d, J=242.2 Hz), 136.7 (d, J=2.3 Hz), 130.6 (d, J=7.7 Hz), 117.8 (d, J=8.5 Hz), 115.9 (d, J=23.1 Hz), 114.64 (d, J=22.3 Hz), 75.6, 70.7, 56.5, 52.0, 41.6, 32.4, 31.8, 26.1, 25.5, 24.2, 11.0; HPLC-MS (ammonium acetate) [M+H+]=349.30.
Reaction SMILES: [O-]CC.[K+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[N:17]=1>C(OCC)C.C(O)C>[CH2:13]([O:12][C:5](=[O:11])[C:6](=[O:8])[CH2:25][C:18]1[N:17]=[C:16]([Cl:15])[CH:21]=[CH:20][C:19]=1[N+:22]([O-:24])=[O:23])[CH3:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(=O)Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of potassium ethoxide (134 mg, 1.59 mmol) in diethyl ether (5 mL) and ethanol (1 mL) was added diethyl oxalate (218 μL, 1.59 mmol) in one portion and the resulting solution was stirred for 30 min at rt. 2-Chloro-6-methyl-5-nitropyridine (Preparation 2, 250 mg, 1.45 mmol) was added as a suspension in diethyl ether (2 mL) and stirring was continued for 17 h at rt. The mixture was filtered on a sinter, washing with cold diethyl ether. The collected precipitate was dissolved in glacial acetic acid then evaporated to dryness in vacuo to give the title compound. δH (CDCl3): 1.40 (3H, t), 4.38 (2H, q), 7.33 (1H, d), 7.37 (1H, s), 8.40 (1H, d).
Reaction SMILES: Br[CH2:2][C:3](OCC)=[O:4].[CH3:8][O:9][C:10]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=[S:13].[OH-].[Na+]>>[CH3:8][O:9][C:10]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:11]=1[C:12]1[S:13][CH2:2][C:3](=[O:4])[NH:15][N:14]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C(=S)NN)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C2=NNC(=O)CS2)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl bromoacetate (5.0 g.) was added to a stirred suspension of 2,4-dimethoxythiobenzohydrazide (6.5 g.) in aqueous 3N-sodium hydroxide solution (25 ml.) and the mixture was stirred at 25° C. for 18 hours and then filtered. The solid product was purified by flash chromatography on a silica gel column (Merck 9385) using a 30:1 v/v mixture of chloroform and methanol as eluant. The aqueous filtrate was acidified with aqueous 2N hydrochloric acid and the mixture was filtered. The solid products, both from the chromatographic purification and from the acidification, were combined and crystallised from aqueous methanol. There was thus obtained (2-(2,4-dimethoxyphenyl)-4H,6H-1,3,4-thiadiazin-5-one, m.p. 162°-164° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O.C(N(CC)C(C)C)(C)C.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH2:56]([O:63][C:64](=[O:72])[CH2:65][C@@H:66]([NH2:71])[CH2:67][N:68]([CH3:70])[CH3:69])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>CN(C)C=O>[CH2:56]([O:63][C:64](=[O:72])[CH2:65][C@@H:66]([NH:71][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]1[CH:17]=[CH:18][C:19]([F:20])=[C:2]([F:1])[CH:3]=1)[CH2:67][N:68]([CH3:69])[CH3:70])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: O=C(O)CCCCCCCOCc1ccc(F)c(F)c1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCOCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.9 %

Procedure:
A solution of 8-(3,4-difluoro-benzyloxy)-octanoic acid (153 mg, 0.53 mmol), N,N-diisopropylethylamine (414 mg, 3.21 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophophate (244 mg, 0.64 mmol) in N,N-dimethylformamide was stirred for 1 h at room temperature, then a solution of (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride (198 mg, 0.64 mmol) in N,N-dimethylformamide (1 mL) was added. The reaction mixture was stirred for 16 h at room temperature, then evaporated. Chromatography (SiO2, dichloromethane-[dichloromethane/methanol/25% aq. ammonia solution 110:10:1] gradient) produced (R)-3-[8-(3,4-difluoro-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester (136 mg, 50%). Light yellow oil, m/e=505.4 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[OH:11][C:12]1[C:7]2[C:2](=[C:3]([OH:8])[CH:4]=[CH:5][CH:6]=2)[N:1]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccccc1O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc2c(O)cccc2c1O
Temperature: 25 °C
Yield: 5.6 %

Procedure:
A mixture of 2-aminophenol (5.457 g) and diethyl ethoxymethylenemalonate (10.81 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature. Diphenyl ether (50 mL) is added and the mixture is heated to 240° C. for 90 min with removal of ethanol by a Dean-Stark trap. The solution is cooled to room temperature and the resulting solid is collected and washed with hexanes. The crude solid is recrystallized from acetone to yield 0.650 g of ethyl 4,8-dihydroxyquinoline-3-carboxylate. A mixture of this ester (0.500 g) and 4-chlorobenzylamine (1.518 g) are heated to 180° C. for 1 h. The solution is cooled to room temperature and diluted with CH2Cl2. The resulting solid is collected and chromatographed on silica, eluting with 3% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo. The residue is sonicated with CH2Cl2 /hexanes. The resulting solid is collected and dried to afford 0.349 g of the desired product as an off-white solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.[OH-].[NH4+:12]>C(O)CCC>[I:8][C:6]1[CH:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH2:12])[CH:7]=1
Reactant: COc1cc(I)cc(F)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCCCO
Product: COc1cc(I)cc(N)n1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a solution of 2-fluoro-4-iodo-6-methoxypyridine (7.1 g, 28 mmol) in n-butanol (64 ml) was added 28% solution of ammonium hydroxide (20 ml, 140 mmol). The reaction mixture was heated to 120° C. After 16 hours LRMS indicated incomplete conversion to product. Additional 28% solution of ammonium hydroxide (20 ml, 140 mmol) was added and the reaction mixture was reheated to 120° C. After 16 h LRMS indicated incomplete conversion to product. Additional 28% solution of ammonium hydroxide (8.0 ml, 56 mmol) was added and the reaction mixture was reheated to 120° C. After 24 h the reaction mixture was cooled, partially concentrated, diluted with ethyl ether, washed with water, then dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (ethyl ether/isohexane gradient) to give 4-iodo-6-methoxypyridin-2-amine LRMS (ESI) calculated for C6H8IN2O [M+H]+, 251.0 found 250.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:4]=1[C:5](=[O:15])[C:6](=[O:14])[NH:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29]>CN(C)C=O.O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:4]=1[C:5](=[O:15])[C:6](=[O:14])[N:7]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29]
Reactant: COc1ccc(OC)c2c1NC(=O)C2=O
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOCCN1C(=O)C(=O)c2c(OC)ccc(OC)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of 4,7-dimethoxy-1H-indole-2,3-dione (1.8 g, 8.7 mmol) in anhydroud N,N-dimethylformamide (20 mL) and anhydrous tetrahydrofuran (120 mL) at ambient temperature was added cesium carbonate (11.4 g, 35.0 mmol), The mixture was stirred at ambient temperature for 30 min and 1-bromo-2-(2-methoxyethoxy)ethane (2.35 mL, 17.4 mmol) was added in one portion. The mixture was stirred at ambient temperature for 16 h, concentrated in vacuo to a small volume and poured into ice water (300 mL). The mixture was extracted with ethyl acetate and the combined organic extracts were filtered through a pad of diatomaceous earth. The filtrate was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Trituration of the residue in hexanes afforded 4,7-dimethoxy-1-[2-(2-methoxyethoxy)ethyl]-1H-indole-2,3-dione (2.2 g, 82%).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH2:12][C@@H:13]([O:38][C:39]([N:41]2[CH2:46][CH2:45][CH:44]([N:47]3[CH2:53][CH2:52][C:51]4[CH:54]=[CH:55][CH:56]=[CH:57][C:50]=4[NH:49][C:48]3=[O:58])[CH2:43][CH2:42]2)=[O:40])[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:27][CH2:26][N:25](C(OCC4C=CC=CC=4)=O)[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])[CH:3]=1.[H][H]>CO.[Pd]>[O:58]=[C:48]1[N:47]([CH:44]2[CH2:45][CH2:46][N:41]([C:39]([O:38][C@H:13]([CH2:12][C:4]3[CH:3]=[C:2]([CH3:1])[C:7]4[O:8][CH2:9][CH2:10][O:11][C:6]=4[CH:5]=3)[C:14](=[O:15])[N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)[CH2:18][CH2:17]3)=[O:40])[CH2:42][CH2:43]2)[CH2:53][CH2:52][C:51]2[CH:54]=[CH:55][CH:56]=[CH:57][C:50]=2[NH:49]1
Reactant: [H][H]
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C(=O)OCc4ccccc4)CC3)CC2)cc2c1OCCO2
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCNCC3)CC2)cc2c1OCCO2

Procedure:
35 mg (0.04 mmol) benzyl 4-(1-{(R)-3-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-piperidin-4-yl)-piperazin-1-carboxylate (Example 6.12) were dissolved in 10 mL MeOH and combined with 50 mg 10% Pd/C. The mixture was hydrogenated at 50° C. and 3 bar hydrogen pressure until the theoretical hydrogen uptake had occurred (for 3 h). Then the catalyst was filtered off, the filtrate was evaporated to dryness i.vac., the residue was taken up in 2 mL DMF and purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([N:13]([CH2:28][CH3:29])[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH:26]=O)=[CH:20]2)[CH3:12].N1CCCCC1>C(O)C>[CH2:28]([N:13]([CH2:11][CH3:12])[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH:26]=[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])=[CH:20]2)[CH3:29]
Reactant: CCN(CC)CCOc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCOc1ccc2[nH]c(C=C3C(=O)Nc4ccccc43)cc2c1
Temperature: 100 °C
Yield: 66.6 %

Procedure:
A mixture of oxindole (26 mg, 0.2 mmol), 5-(2-diethylamino-ethoxy)-1H-indole-2-carbaldehyde (50 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 50 mg (67%) of the title compound.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[S:14][C:15]([C:19]([O:21]CC)=O)=[C:16]([CH3:18])[N:17]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]>C(O)C>[CH3:18][C:16]1[N:17]=[C:13]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH3:3])[CH:6]=2)[S:14][C:15]=1[C:19]([NH:2][CH3:1])=[O:21]
Reactant: CN
Reactant: CCOC(=O)c1sc(-c2ccc(OC)c(OC)c2)nc1C
Solvent: CCO
Product: CNC(=O)c1sc(-c2ccc(OC)c(OC)c2)nc1C
Yield: 66 %

Procedure:
Into a mixed solvent of 80 ml of 40% methylamine and 600 ml of ethanol, 15.4 g of ethyl 2-(3,4-dimethoxyphenyl)-4-methylthiazole-5-carboxylate was dissolved, and then, in a similar manner as in Example 1, the object is obtained as colourless aciculate melting at 181.5° to 183° C. in an amount of 9.6 g corresponding to the yield of 66%.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:47]1([NH2:53])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>CN(C=O)C>[CH:47]1([NH:53][C:9]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:4][CH:5]=2)=[O:11])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Reactant: NC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
To 6-(trifluoromethyl)-3-pyridinecarboxylic acid (2.0 g, 10.5 mmol) in DMF (10 mL) was added HATU (4.18 g, 11.0 mmol) followed by Hunig's base (1.83 mL, 10.5 mmol). After 15 minutes, cyclohexylamine (2.40 mL, 20.9 mmol) was added, and the reaction mixture was stirred for 45 minutes at room temperature. The reaction was poured onto water (˜300 mL). After 5 minutes, the resulting aqueous mixture was filtered, and the white solid was air dried for ˜15 minutes to afford the title compound (2.57 g). LC-MS (ES) m/z=273 [M+H]+.