Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([C:31]2[C:32](=[O:44])[N:33]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[N:34]=[CH:35][CH:36]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:16]=[C:17](I)[C:10]=12.[N:45]1([C:51]([C:53]2[CH:58]=[CH:57][C:56](B(O)O)=[CH:55][CH:54]=2)=[O:52])[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([C:31]2[C:32](=[O:44])[N:33]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[N:34]=[CH:35][CH:36]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:16]=[C:17]([C:56]3[CH:55]=[CH:54][C:53]([C:51]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[O:52])=[CH:58][CH:57]=3)[C:10]=12
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(Cn2nc(-c3ccc(C(=O)N4CCOCC4)cc3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 70 °C

Procedure:
To a small round bottom flask was added N-(3-fluoro-4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (30 mg, 0.0425 mmol), 4-(morpholine-4-carbonyl)phenylboronic acid (20.0 mg, 0.0849 mmol), and Pd(PPh3)4 (2.45 mg, 0.00212 mmol) and the mixture was dissolved in 3:1 DME:aqueous 2N Na2CO3 (2 mL). The mixture was stirred at 70° C. until the reaction was determined to be complete by LC/MS (1-18 hours). The reaction mixture was then partitioned between ethyl acetate (15 mL) and water (30 mL). The organic layer washed with brine, dried over Na2SO4 and evaporated to afford crude product. Purified by silica gel column chromatography (Biotage 12M) eluting with 1-5% MeOH/CHCl3 to give the desired product. Yield: 40.2 mg, 81%. LRMS (APCI pos) m/e 770.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:33])[CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:10][O:11][C:12](=[O:33])[CH:13]=[CH:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Cl)nc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccc(Cl)nc1
Yield: 90.7 %

Procedure:
To 6-chloro-pyridine-3-carboxaldehyde (300 mg, 2.12 mmol) in toluene was added methyl(triphenylphosphoranylidene)acetate (708 mg, 2.12 mmol) and the solution was refluxed for 6 hrs. The reaction mixture was diluted with EtOAc and then washed three times with H2O, brine, dried. Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was column-chromatographed to yield 3-(6-chloro-pyridin-3-yl)-acrylic acid methyl ester (380 mg, 90%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[O:10][CH3:11].[Cl:12][CH2:13][CH2:14][CH2:15][OH:16].[H-].[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:12][CH2:13][CH2:14][CH2:15][O:16][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[O:10][CH3:11]
Reactant: OCCCCl
Reactant: COc1cc(F)ccc1CCl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1COCCCCl
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
To an ice-cold solution of 0.36 g (2.06 mmol) of 1-chloromethyl-4-fluoro-2-methoxy-benzene and 0.195 g (4.12 mmol) of 1-chloro-3-propanol in 3 ml of dry N,N-dimethyl-formamide were added 92.5 mg (3.09 mmol) of sodium hydride (80% dispersion in refined oil) in 3 portions at one hour intervals. After complete addition the stirring was continued for 2 hours at room temperature, then 2 ml of an saturated aqueous sodium hydrogencarbonate solution were added and the reaction mixture evaporated under reduced pressure. Subsequently, the residue was treated with a mixture of dichloromethane and water, the organic phase was separated and dried over sodium sulfate. Finally, the solvent was evaporated under reduced pressure and the crude product was purified by chromatography on silica gel with a 1:1 mixture of hexane and dichloromethane as the eluent. There were obtained 0.29 g (60% of theory) of 1-(3-chloro-propoxymethyl)-4-fluoro-2-methoxy-benzene as a colorless liquid; MS: 232 (M)+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Br:11])[CH:3]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[Br:11][C:4]1[CH:3]=[C:2]([I:1])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:17][CH3:18])=[O:7]
Reactant: O=C(O)c1ccc(I)cc1Br
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(I)cc1Br
Temperature: 80 °C
Yield: 92 %

Procedure:
To a stirred solution of 4-iodo-2-bromobenzoic acid (5 g, 15.29 mmol) in ethyl alcohol (EtOH; 100 mL) was added sulfuric acid (H2SO4; 5 mL), and the reaction mixture was heated at 80° C. for 18 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was diluted with EtOAc (2×100 mL) and washed with H2O (100 mL). The combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the compound as a pale yellow solid (5 g, 92%): 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J=1.2 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1)[CH:14]([CH3:16])[CH3:15]>CN(C)C=O>[CH2:13]([C:17]1[CH:18]=[CH:19][C:20]([C:23]([O:25][Si:2]([CH3:5])([CH3:4])[CH3:3])=[CH2:24])=[CH:21][CH:22]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(=O)c1ccc(CC(C)C)cc1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(O[Si](C)(C)C)c1ccc(CC(C)C)cc1
Yield: 29 %

Procedure:
To a solution of chlorotrimethylsilane (16.3 g) and triethylamine (30.3 g) in N,N-dimethylformamide (50 ml) was added 4'-isobutylacetophenone (22.0 g). The yellow solid was immediately filtered off, and the filtrate was refluxed for 20 hours. The mixture was cooled, diluted with hexane, and washed with cooled aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated. The residue was distilled under reduced pressure to give 4-isobutyl-α-trimethylsilyloxystyrene (9.0 g) as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]3[N:35]=[C:34]([C:36]([OH:38])=[O:37])[C:33]([C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][O:46][C:47]5[CH:52]=[CH:51][CH:50]=[C:49]([NH:53]C(OC(C)(C)C)=O)[CH:48]=5)[CH:40]=4)=[CH:32][CH:31]=3)[CH:28]=2)[CH2:23][CH2:22][CH2:21]1)=[O:19]>C(Cl)Cl>[NH2:53][C:49]1[CH:48]=[C:47]([CH:52]=[CH:51][CH:50]=1)[O:46][CH2:45][C:41]1[CH:40]=[C:39]([C:33]2[C:34]([C:36]([OH:38])=[O:37])=[N:35][C:30]([C:27]3[CH:28]=[C:29]4[C:24]([CH2:23][CH2:22][CH2:21][N:20]4[C:18](=[O:19])[NH:17][C:9]4[S:8][C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=5[N:10]=4)=[CH:25][CH:26]=3)=[CH:31][CH:32]=2)[CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(OCc2cccc(-c3ccc(-c4ccc5c(c4)N(C(=O)Nc4nc6ccccc6s4)CCC5)nc3C(=O)O)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(OCc2cccc(-c3ccc(-c4ccc5c(c4)N(C(=O)Nc4nc6ccccc6s4)CCC5)nc3C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The title compound 3-(3-((3-aminophenoxy)methyl)phenyl)-6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)picolinic acid (34) was prepared by the following procedure: Trifluoroacetic acid (0.5 mL) was added to a solution of 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-(3-((3-(tert-butoxycarbonylamino)phenoxy)methyl)phenyl)picolinic acid (34E) (0.016 g, 0.022 mmol) in anhydrous DCM (0.75 mL). The reaction mixture was stirred at rt for 1.5 hours, concentrated under reduced pressure, and the crude material triturated in diethyl ether to provide the desired product 3-(3-((3-aminophenoxy)methyl)phenyl)-6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)picolinic acid (34): 1H NMR (300 MHz, DMSO) δ 8.43 (1H, s, br), 8.08 (1H, d), 7.99 (1H, d), 7.85-7.77 (2H, m), 7.67 (1H, s), 7.55-7.41 (4H, m), 7.37 (1H, t), 7.31 (1H, d), 7.22 (1H, t), 7.12 (1H, t), 6.59-7.50 (2H, m), 6.47 (1H, d), 5.11 (2H, s), 3.97 (2H, t), 2.84 (2H, t), 1.96 (2H, m). MS (ESI(+)) m/z 628.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][C:10](=[O:19])[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:20][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10](=[O:19])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CC(=O)CC(=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(=O)cc(-c2ccc(Cl)cc2)o1
Temperature: 0 °C

Procedure:
A solution of ethyl 6-(4-chlorophenyl)-2,4,6-trioxohexanoate (0.26 g) in cold concentrated sulphuric acid (3 ml) was stirred for 3 hours at 0-5° C. then poured on to ice (10 g). The solid product was recrystallised from ethanol-water to give the title product identical (mp, IR and NMR, and thin-layer chromatography) with the product described in Example 12.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:11](=O)[CH2:12]Cl)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[NH2:15][C:16]([NH2:18])=[S:17].C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O.CO>[NH2:18][C:16]1[S:17][CH:12]=[C:11]([C:5](=[N:4][O:3][CH2:1][CH3:2])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:15]=1
Reactant: NC(N)=S
Reactant: CCON=C(C(=O)CCl)C(=O)OCC
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCON=C(C(=O)OCC)c1csc(N)n1
Temperature: 48 °C
Reaction time: 0.67 h
Yield: 34.8 %

Procedure:
A mixture of ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (syn isomer 38.7 g.), thiourea (13.2 g.), sodium acetate (14.3 g.), methanol (95 ml.) and water (95 ml.) was stirred at 48° C. for 40 minutes. After the resultant solution was adjusted to pH 6.5 with an aqueous solution of sodium bicarbonate, the appeared precipitates were collected by filtration and washed with diisopropyl ether to give ethyl 2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetate (syn isomer, 14.7 g.), mp 130° to 131° C.
Reaction SMILES: [CH:1]1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:17]1>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][C@H:16]([NH:15][C:12]([C:7]3([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH2:8][CH2:9][CH2:10][CH2:11]3)=[O:14])[CH2:17]2)=[CH:24][CH:25]=1
Reactant: O=C(O)C1(C2CCCCC2)CCCC1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C1(C2CCCCC2)CCCC1

Procedure:
1-Cyclohexyl-1-cyclopentanecarboxylic acid and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-cyclohexyl-1-cyclopentanecarboxamide.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1([CH3:16])[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.C1(P(=[CH:36][C:37]([O:39][CH3:40])=[O:38])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:40][O:39][C:37](=[O:38])[CH:36]=[C:12]1[CH2:13][CH2:14][C:9]([CH3:16])([CH3:8])[CH2:10][CH2:11]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)CCC(=O)CC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)C=C1CCC(C)(C)CC1
Temperature: 65 °C
Yield: 13.7 %

Procedure:
To a toluene (5 mL) solution containing 4,4-dimethyl-cyclohexanone (500 mg, 4.0 mmol) was added methyl (triphenylphosphoranylidene)acetate (2.0 g, 6.0 mmol) and the reaction was heated to 60-70° C. for 48 h. The reaction was monitored by TLC. The reaction was cooled to room temperature, diluted with dichloromethane, washed with water, concentrated under vacuum, and the crude product was purified on a silica gel column to afford (4,4-dimethyl-cyclohexylidene)-acetic acid methyl ester (100 mg, 14% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[NH2:15].[CH3:16][O:17][C:18]([N:20]=[C:21]=[S:22])=[O:19]>CC(C)=O>[CH3:16][O:17][C:18]([NH:20][C:21](=[S:22])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[NH:15][C:21]([NH:20][C:18]([O:17][CH3:16])=[O:19])=[S:22])=[O:19]
Reactant: Nc1ccc(Sc2ccccc2)cc1N
Reactant: COC(=O)N=C=S
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(Sc2ccccc2)cc1NC(=S)NC(=O)OC

Procedure:
1.6 G. 1,2-diamino-4-phenylthiobenzene is dissolved in 30 ml. acetone and treated with 4 g. methoxycarbonyl isothiocyanate at room temperature overnight. The mixture is concentrated under vacuum and the residue triturated with ether. Recrystallization from methanol-chloroform yields pure 1,2-bis-(3-methoxycarbonyl-2-thioureido)-4-phenylthiobenzene.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH3:19].[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23]>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH3:19])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:20](=[O:24])[CH2:21][CH2:22][CH3:23])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCC(=O)Cl
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCN
Product: CCCC(=O)NCCCn1c(C)nc2c(N)nc3ccccc3c21
Yield: 42 %

Procedure:
Using the general method of Example 205, 1-(3-aminopropyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 7.83 mmol) was reacted with butyryl chloride (835 mg, 7.83 mmol). The product was recrystallized from methanol to provide 1.07 g of N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]butanamide as a white powder, m.p. 221.8-223.3° C. Analysis: Calculated for C18H23N5O.0.25 CH4O: % C, 65.74; % H, 7.26; % N, 21.00. Found: % C, 65.79; % H, 7.14; % N, 21.25.
Reaction SMILES: C[Mg]Br.CCO[CH2:7][CH3:8].[N:9]1[C:16]([Cl:17])=[N:15]C(Cl)=[N:12][C:10]=1[Cl:11]>ClCCl.O>[Cl:11][C:10]1[N:9]=[C:16]([Cl:17])[N:15]=[C:7]([CH3:8])[N:12]=1
Reactant: CCOCC
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: C[Mg]Br
Solvent: O
Solvent: ClCCl
Product: Cc1nc(Cl)nc(Cl)n1
Temperature: -5 °C
Reaction time: 4 h

Procedure:
A solution of methylmagnesium bromide in ether (3M, 30 ml, 90 mmole) was added dropwise to a stirred solution of cyanuric chloride (3.91 g, 21.20 mmole) in anhydrous dichloromethane at −10° C. After the addition was complete, the reaction mixture was stirred at −5° C. for 4 h, after which time water was added dropwise at a rate such that the temperature of the reaction stayed below 10° C. After warming to room temperature, the reaction mixture was diluted with additional water and methylene chloride and passed through a pad of cilite. The organic layer was dried and evaporated to give 2,4-dichloro-6-methyl-1,3,5-triazine of 4 as yellow solids (3.02 g, 87%). 1H NMR (CDCl3) δ 2.70 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[O:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2)[CH3:23]>>[CH3:23][O:22][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:27]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: COc1ccc2c(c1)CC(=O)N2
Product: COc1ccc2c(c1)C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCCCC1)CC3)C(=O)N2
Yield: 39.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-methoxyl-1,3-dihydro-indol-2-one (prepared according to U.S. Pat. No. 6,114,371) as starting materials to give 2-(5-methoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (17 mg, 39.9%) as an orange solid.
Reaction SMILES: C[O-].[Na+].[CH3:4][N:5]1[CH2:10][CH2:9][CH:8]([SH:11])[CH2:7][CH2:6]1.Cl[CH2:13][C:14](=[O:16])[CH3:15]>O1CCCC1>[CH3:4][N:5]1[CH2:10][CH2:9][CH:8]([S:11][CH2:13][C:14](=[O:16])[CH3:15])[CH2:7][CH2:6]1
Reactant: CC(=O)CCl
Reactant: CN1CCC(S)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CSC1CCN(C)CC1
Reaction time: 24 h

Procedure:
Sodium methylate (5.9 g) is added in portions to a solution of 1-methylpiperidine-4-thiol (14 g) in anhydrous tetrahydrofuran (100 ml) at room temperature. After 2 hours at this temperature, chloroacetone (8.8 ml) is added dropwise. After 24 hours, the precipitate is filtered off and the filtrate is concentrated and chromatographed on silica gel (eluent: ethyl acetate, then ethanol) to give 1-methyl-4-[(2-oxopropyl)thio]piperidine (11.5 g) in the form of an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]3[NH:15][C:14](=[O:16])[O:13][C:11](=[O:12])[C:10]3=[CH:17][CH:18]=2)=[CH:3][CH:2]=1.[CH2:19](Br)[CH3:20]>>[CH2:19]([N:15]1[C:14](=[O:16])[O:13][C:11](=[O:12])[C:10]2=[CH:17][CH:18]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH:8]=[C:9]12)[CH3:20]
Reactant: CCBr
Reactant: O=c1[nH]c2cc(-c3ccncc3)ccc2c(=O)o1
Product: CCn1c(=O)oc(=O)c2ccc(-c3ccncc3)cc21

Procedure:
It was found that the 2-nitro-4-(4-pyridinyl)benzoic acid prepared in the preceding examples could be converted to 1-ethyl-1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylic acid by (a) reducing it to 2-amino-4-(4-pyridinyl)benzoic acid, (b) reacting the 2-amino-4-(4-pyridinyl)benzoic acid with phosgene to form 4-(4-pyridinyl)isatoic anhydride, (c) alkylating the 4-(4-pyridinyl)isatoic anhydride with ethyl bromide to produce N-ethyl-4-(4-pyridinyl)isatoic anhydride, (d) reacting the N-ethyl-4-(4-pyridinyl)isatoic anhydride with the potassium salt of ethyl formyl acetate to form ethyl 1-ethyl-1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylate, and (e) hydrolyzing that ester.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].Cl[CH2:29][C:30]1[N:31]=[C:32]([CH3:35])[S:33][CH:34]=1>>[OH:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[N:9]([CH2:29][C:30]2[N:31]=[C:32]([CH3:35])[S:33][CH:34]=2)[C:8]1=[O:21]
Reactant: Cc1nc(CCl)cs1
Reactant: COc1ccc(COn2c(=O)[nH]c3c(oc4ccccc43)c2=O)c(OC)c1
Product: Cc1nc(Cn2c(=O)n(O)c(=O)c3oc4ccccc4c32)cs1

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]furo[3,2-d]pyrimidine-2,4-dione was alkylated with 4-(chloromethyl)-2-methyl-1,3-thiazole and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 2.59 (s, 3H); 5.54 (s, 2H); 7.38 (dd, J=8 Hz, 1H); 7.44 (s, 1H); 7.62 (dd, J=8 Hz, 1H); 7.81 (d, J=8 Hz, 1H); 7.87 (d, J=8 Hz, 1H); Ret. time=2.01 min., m/z=330.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:17]#[N:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][CH3:10].[N+](C1C=CC([O:28][C:29]([N:31]2[CH:35]([C:36]3[CH:41]=[C:40]([F:42])[C:39]([F:43])=[C:38]([F:44])[CH:37]=3)[CH2:34][O:33][C:32]2=[O:45])=O)=CC=1)([O-])=O>C1COCC1>[C:17]([C:8]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH2:10][CH:5]([NH:4][CH2:3][CH2:2][NH:1][C:29]([N:31]2[CH:35]([C:36]3[CH:41]=[C:40]([F:42])[C:39]([F:43])=[C:38]([F:44])[CH:37]=3)[CH2:34][O:33][C:32]2=[O:45])=[O:28])[CH2:6][CH2:7]1)#[N:18]
Reactant: O=C1OCC(c2cc(F)c(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCC(C#N)(CCCNCCN)c1ccccc1
Solvent: C1CCOC1
Product: N#CC1(c2ccccc2)CCC(NCCNC(=O)N2C(=O)OCC2c2cc(F)c(F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[(2-amino-ethyl)-amino]-4-cyano-4-phenylhexane (25 mg, 0.103 mmol) in 10 mL of THF, 4-(3,4,5-trifluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester (30 mg, 0.079 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by MeOH:EtOAc=1:9 (Rf =0.60, MeOH:EtOAc=1:3) to obtain the title compound. The compound was dissolved in CH2Cl2 (3 mL) and was treated with 1N HCl in ether (1 mL). The solvent was removed in vacuo to give the corresponding hydrochloride salt as a pale yellow solid. M. P. 130-134° C.; [α]D =+43.5, (c=0.25, MeOH); Anal. Calcd. For C25H26N4O3F3Cl 1.10 C3H6O: C, 57.92; H, 5.60; N, 8.55. Found: C, 58.33; H, 5.90; N, 8.52.
Reaction SMILES: [Na+].[I-].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[H][H]>O>[OH:6][CH:5]([CH3:7])[CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: [H][H]
Reactant: CCOC(=O)CC(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(C)O
Temperature: 65 °C
Reaction time: 40 h
Yield: 62.6 %

Procedure:
Under a nitrogen gas atmosphere, 0.0096 g (7.3×10-6 mol) of [RuI(p-Cymene)((+)-SO3Na-BINAP)]I, 0.1164 g (7.8×10-4 mol) of NaI, 1 ml (7.5×10-3 mol) of ethyl acetoacetate, and 1.5 ml of water were charged in a 100 milli-liter autoclave. After displacing the inside atmosphere of the autoclave with a hydrogen gas, the autoclave was pressed at a hydrogen pressure of 50 kg/cm2 and the mixture was stirred for 40 hours at 65° C. After the reaction was over, the hydrogen gas was removed, and after added thereto 100 ml of water and 100 ml of ether, the ether extraction was carried out. The ether extract was recovered, dried with anhydrous sodium sulfate, and further ether was distilled off to provide 0.62 g (percent yield 63%) of ethyl 3-hydroxybutyrate. By the analysis of gas chromatography (PEG-HT), the conversion ratio was determined to be 99%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1.CCN(C(C)C)C(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1COCC1>[CH3:26][S:27]([O:1][CH2:2][C:3]1[CH:8]=[N:7][C:6]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])=[CH:5][CH:4]=1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CO)cn1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(COS(C)(=O)=O)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.1 %

Procedure:
To a mixture containing tert-butyl 5-(hydroxymethyl)pyridin-2-ylcarbamate (101; 4.5 g, 20.2 mmol) and DIPEA (16.0 g, 121 mmol) in THF (45 mL) was added MsCl (6.93 g, 60.5 mmol) over a period of 30 min at 0° C. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was then washed with water (2×5 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (10:1 petroleum ether/ethyl acetate) to afford (6-(tert-butoxycarbonylamino)pyridin-3-yl)methyl methanesulfonate 102 (3.0 g, 61%).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[O:4][CH2:5][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.Br[CH2:16][CH2:17][CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20]>>[CH2:19]([CH:18]([CH2:21][CH3:22])[CH2:17][CH2:16][C@@:2]1([CH3:1])[C:3](=[O:14])[O:4][CH2:5][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:7]1)[CH3:20]
Reactant: CCC(CC)CCBr
Reactant: CC1=N[C@@H](c2ccccc2)COC1=O
Product: CCC(CC)CC[C@]1(C)N[C@@H](c2ccccc2)COC1=O

Procedure:
The title compound was prepared from (5S)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (0.454 g, 2.39 mmol, see WO-A-02/051983) and 1-bromo-3-ethylpentane (see Bull. Soc. Chim. Fr., 1975, 201-205) according to the procedure outlined in Preparation 1. The total amount of compound synthesised was 0.07 g.