Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:93]=[C:94]([F:96])[CH:95]=1)[CH2:50][N:51]1[C:55]([CH3:56])=[C:54]([C:57]2[C:65]3[C:60](=[N:61][CH:62]=[C:63]([C:66]4[CH:67]=[C:68]([O:80][CH3:81])[C:69]([NH:72][C:73](=[O:79])[O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[N:70][CH:71]=4)[CH:64]=3)[N:59](S(C3C=CC(C)=CC=3)(=O)=O)[CH:58]=2)[C:53]([CH3:92])=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:93]=[C:94]([F:96])[CH:95]=1)[CH2:50][N:51]1[C:55]([CH3:56])=[C:54]([C:57]2[C:65]3[C:60](=[N:61][CH:62]=[C:63]([C:66]4[CH:67]=[C:68]([O:80][CH3:81])[C:69]([NH:72][C:73](=[O:79])[O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[N:70][CH:71]=4)[CH:64]=3)[NH:59][CH:58]=2)[C:53]([CH3:92])=[N:52]1
Reactant: COc1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cc(F)cc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)cnc1NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(-c2cnc3[nH]cc(-c4c(C)nn(Cc5cc(F)cc(F)c5)c4C)c3c2)cnc1NC(=O)OC(C)(C)C
Yield: 63.9 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl (5-(3-(1-(3,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-methoxypyridin-2-yl)carbamate (200 mg, 0.279 mmol) was hydrolyzed by lithium hydroxide (118 mg, 2.798 mmol) in THF/methanol/water (5/5/2 ml) to yield 100 mg (63.6% yield) of the titled compound. MS: m/z=560.9 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH3:2]>CO.CCOC(C)=O.[Pt]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:14][CH2:15][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH2:21][CH2:20]3)[CH2:17][CH2:18]2)[CH:7]=[CH:8][C:9]=1[NH2:10])[CH3:2]
Reactant: CCOc1cc(N2CCN(C3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOc1cc(N2CCN(C3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1N
Reaction time: 20 h
Yield: 95.4 %

Procedure:
A mixture of 1-[3-(ethyloxy)-4-nitrophenyl]-4-{1-[2-(methylsulfonyl)ethyl]-4-piperidinyl}-piperazine (290 mg, 0.65 mmol) and platinum (sulfided, 5 wt. % on carbon, 50 mg, 0.013 mmol) in 20% MeOH/EtOAc (20 mL) was added to a high-pressure hydrogenation reaction flask. The reaction was purged with N2 and vacuum (3×). The reaction was purged with H2 and vacuum (3×). The reaction was then treated with H2 at 50 psi and stirred for approximately 20 h. The reaction was degassed, then poured through a Teflon filter, washing the solid with MeOH and DCM. The filtrate was concentrated under vacuum to give the title compound of step B (256 mg, 0.62 mmol, 97%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 6.50 (d, 1H, J=8.43 Hz), 6.44 (d, 1H, J=2.38 Hz), 6.26 (cd, 1H, J=2.38 and 8.43 Hz), 4.17 (br s, 2H), 3.95 (q, 2H, J=6.96 Hz), 3.25 (t, 2H, J=6.69 Hz), 3.01 (s, 3H), 2.91 (M, 6H), 2.65 (t, 2H, J=6.78 Hz), 2.57 (m, 4H), 2.10-2.20 (m, 1H), 1.89-1.97 (m, 2H), 1.76 (m, 2H), 1.28-1.32 (m, 5H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][CH:4]=1.[H][H]>CC(O)C.[C].[Pd]>[OH:1][CH2:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COC(=O)/C=C/c1cccc(CO)n1
Agent: [Pd]
Solvent: CC(C)O
Product: COC(=O)CCc1cccc(CO)n1
Yield: 98.9 %

Procedure:
The above compound was also prepared as follows: To a solution of 50.02 g of methyl 3-(6-hydroxymethylpyridin-2-yl)-trans-acrylate in IPA 502 mL, was added 2.51 g of 5% palladium-carbon (containing 50% water) under argon atmosphere, the reaction mixture was stirred under 1-4 atom hydrogen atmosphere at 50° C. for 2.5 hours. After cooling, the catalyst was filtrated off and the solvent was removed off under reduced pressure from the reaction mixture, which gave 50 g of methyl 3-(6-hydroxymethylpyridin-2-yl)propionate as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.[CH3:11][Mg]Br.O>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:11])=[C:4]([CH3:10])[CH:3]=1
Reactant: C[Mg]Br
Reactant: Cc1cc(Br)ccc1C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Br)ccc1C(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of 4-bromo-2-methylbenzaldehyde (1 g, 5 mmol) in tetrahydrofuran (30 mL) was added methylmagnesium bromide (3N in tetrahydrofuran, 2 mL) at −40° C. Then the mixture was stirred at 25° C. for 3 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give 1-(4-bromo-2-methylphenyl)ethanol (600 mg, 56%).
Reaction SMILES: [F:1][C:2]([F:55])([F:54])[C:3]1[CH:4]=[C:5]([CH:51]=[CH:52][CH:53]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]([CH2:27][CH2:28][O:29][CH3:30])[CH2:23][CH2:24][O:25][CH3:26])[CH:19]=[CH:18][C:17]=2[NH:31][C:32]([C:34]2[CH:35]=[C:36]([CH:48]=[CH:49][CH:50]=2)[CH2:37][S:38][CH2:39][CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])=[O:33])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[F:55][C:2]([F:1])([F:54])[C:3]1[CH:4]=[C:5]([CH:51]=[CH:52][CH:53]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]([CH2:27][CH2:28][O:29][CH3:30])[CH2:23][CH2:24][O:25][CH3:26])[CH:19]=[CH:18][C:17]=2[NH:31][C:32]([C:34]2[CH:35]=[C:36]([CH:48]=[CH:49][CH:50]=2)[CH2:37][S:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:33])[CH:11]=1)=[O:9]
Reactant: COCCN(CCOC)c1ccc(NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCN(CCOC)c1ccc(NC(=O)c2cccc(CSCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(bis(2-methoxyethyl)amino)phenyl)-carbamoyl)benzylthio)propanoate (160 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (8 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred for 4 h at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product (125 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 81.1 mg (41%) of as a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.86 (s, 1H), 9.49 (t, J=5.7 Hz, 1H), 8.94 (d, J=5.1 Hz, 1H), 8.25 (s, 1H), 8.12 (d, J=6.5 Hz, 1H), 7.82 (s, 2H), 7.71 (m, 2H), 7.62 (m, 5H), 7.15 (d, J=2.4 Hz, 1H), 6.90 (m, 1H), 4.61 (d, J=6.0 Hz, 2H), 3.87 (s, 2H), 3.56 (m, 8H), 3.27 (s, 6H), 2.63 (m, 2H), 2.51 (m, 2H). MS (ES, m/z): 725 [M+H]+.
Reaction SMILES: COC(=O)[CH2:4][CH:5]1[CH:9]2[CH2:10][CH2:11][CH:6]1[CH2:7][CH2:8]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:21]CC)C>>[CH:9]12[CH:5]([CH2:4][OH:21])[CH:6]([CH2:11][CH2:10]1)[CH2:7][CH2:8]2
Reactant: COC(=O)CC1C2CCC1CC2
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCC1C2CCC1CC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
In a flask was placed bicyclo[2.2.1]hept-7-yl-acetic acid (554 mg, 3.95 mmol), diethyl ether (20 mL) and methanol (5 mL) and cooled to 0° C. in an ice bath. The mixture was then treated with a 2M solution of (trimethylsilyl)diazomethane in diethyl ether (3.95 mL, 7.9 mmol) dropwise. After the addition was complete, the mixture was warmed to 25° C. and stirred for 1 h. The mixture was concentrated in vacuo to afford bicyclo[2.2.1]hept-7-yl-acetic acid methyl ester (theoretical yield 3.95 mmol) which was used on crude. Bicyclo[2.2.1]hept-7-yl-acetic acid methyl ester (3.95 mmol) in diethyl ether (10 mL) was added dropwise to a stirred suspension of lithium aluminum hydride (224 mg, 5.9 mmol) in diethyl ether (20 mL) cooled to 0° C. The mixture was stirred for an additional 3 h at 0° C. and quenched with a saturated sodium sulfate solution (15 mL), extracted with diethyl ether (3×20 mL). The combined organics were dried over sodium sulfate, concentrated in vacuo and purified by AnaLogix IntelliFlash flash chromatography (12 g column, 20% ethyl acetate/hexanes to 40% ethyl acetate/hexanes) to afford bicyclo[2.2.1]hept-7-yl-methanol (180 mg, 36%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[C:10]([CH3:14])([CH3:13])[CH2:11][OH:12].Cl.N1C=CC=CC=1.Cl>CCOCC>[Br:9][C:6]1[CH:7]=[CH:8][C:3]2[O:2][CH:11]([OH:12])[C:10]([CH3:14])([CH3:13])[C:4]=2[CH:5]=1
Reactant: COc1ccc(Br)cc1C(C)(C)CO
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC1(C)c2cc(Br)ccc2OC1O
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
2-(2-(Methoxy-5-bromophenyl)-2-methyl-1-propanol (30 g, 0.115 mole) was added to molten pyridine hydrochloride (60 g) and the mixture heated with stirring at 190°-200° C. for 50 minutes. Addition to ice-water containing a little hydrochloric acid and isolated through ether gave, after recrystallisation from petroleum ether (b.p. 80°-100° C.) 11.7 g (42%) title product m.p. 114°-5° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:13]C[O:11][CH2:10]1)C1C=CC=CC=1.N[CH2:48]C1(N(CC2C=CC=CC=2)CC2C=CC=CC=2)COC1>>[NH2:8][C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][C:36]([CH3:48])=[CH:37][C:31]=4[S:30](=[O:38])(=[O:39])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:10][O:11][CH2:13]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Reactant: NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1
Product: Cc1ccc2c(c1)S(=O)(=O)CCN(c1cc(NCC3(N)COC3)c3cc(C)ccc3n1)C2

Procedure:
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro-6-methylquinolin-2-yl)-8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloro-6-methylquinoline) and 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J=7.83 Hz, 1 H), 7.68 (d, J=3.03 Hz, 2 H), 7.41 (d, J=6.57 Hz, 1 H), 7.33 (d, J=8.59 Hz, 1 H), 7.25 (dd, J=8.59, 1.52 Hz, 1 H), 6.42 (t, J=5.56 Hz, 1 H), 6.19 (s, 1 H), 5.05 (brs, 2 H), 4.45 (d, J=5.81 Hz, 3 H), 4.39 (d, J=6.06 Hz, 3 H), 3.60 (t, J=4.55 Hz, 2 H), 3.55 (d, J=5.31 Hz, 2 H), 2.37 (s, 3 H), 2.31 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[C:31]([Cl:32])=[CH:30][C:29]([C:33]([O:35]C)=[O:34])=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([O:5][C:6](=[O:37])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[C:31]([Cl:32])=[CH:30][C:29]([C:33]([OH:35])=[O:34])=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:8])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(C(=O)OC)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(C(=O)O)cc1Cl
Reaction time: 12 h
Yield: 102.5 %

Procedure:
2-[(4-{2-[[3-Chloro-5-(methoxycarbonyl)pyridin-2-yl](heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (2.50 g) obtained in Example 281-1 was dissolved in ethanol (25 mL), 1N aqueous sodium hydroxide solution (5 mL) was added, and the mixture was left standing for 12 hr. The reaction mixture was concentrated, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=50:1) to give 2-[(4-{2-[(5-carboxy-3-chloropyridin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (2.5 g) as a colorless oil. Without purification, the present compound was dissolved in dichloromethane (20 mL), WSCD (0.72 g) and ammonia/methanol solution (7M, 1 mL) was added, and the mixture was stirred at room temperature for 12 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:2) to give the title compound (0.86 g) as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[N:14]1([C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C.O>CN(C=O)C>[N:21]1[CH:22]=[CH:23][CH:24]=[N:25][C:20]=1[N:14]1[CH2:19][CH2:18][N:17]([CH2:2][C:3]2[NH:4][C:5]3[C:10]([C:11](=[O:13])[N:12]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:16][CH2:15]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=c1[nH]c(CCl)nc2ccccc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=c1nc(CN2CCN(c3ncccn3)CC2)[nH]c2ccccc12
Temperature: 25 °C
Yield: 74.5 %

Procedure:
300 mg of 2-(chloromethyl)quinazolin-4(3H)-one and 300 mg 2-(piperazin-1-yl)pyrimidine were dissolved in 5 ml of DMF at room temperature. After a few seconds, 0.5 ml of triethylamine was added, and the reaction mixture was stirred at ambient temperature, while being monitored by TLC. Once the reaction was completed (overnight), additional 0.2 ml of triethylamine was added, followed by 3 ml of water, and the mixture was cooled to 0° C. The solid precipitate was thereafter collected by vacuum filtration, washed with cold water and dried for 2 hours at 50° C., to give 370 mg (75% yield) of the product.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:19][NH:18][C:17](=O)[CH2:16][CH:15]([CH3:21])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>C1COCC1>[CH3:21][CH:15]1[N:14]2[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[C:13]2[CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: CC1CC(=O)NCc2nc3c(N)nc4ccccc4c3n21
Solvent: C1CCOC1
Product: CC1CCNCc2nc3c(N)nc4ccccc4c3n21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Borane THF complex (2.76 mL of a 1 M solution in THF) was added to a solution of 6-amino-12-methyl-8,9,11,12-tetrahydro-10H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-10-one (0.389 g, 1.38 mmol) in THF (5 mL), and the mixture was stirred at room temperature overnight and then heated at reflux for six hours. An analysis by LC/MS indicated the reaction was incomplete, and additional borane tetrahydrofuran complex (2.76 mL) was added. The reaction mixture was heated at reflux overnight, allowed to cool, and concentrated under reduced pressure. The residue was treated with chloroform, and a solid was present that was isolated by filtration to provide 12-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine as a yellow solid.
Reaction SMILES: CO[C:3]1[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=1.[CH2:9]([Mg]Cl)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)(=O)C>[CH2:9]([C:3]1[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cl[Mg]CCc1ccccc1
Reactant: COC1=CC(=O)CC1
Solvent: CCOC(C)=O
Product: O=C1C=C(CCc2ccccc2)CC1
Yield: 93.8 %

Procedure:
The general procedure for the preparation of substrates using 3-methoxycyclopentenone (1.29 g, 11.5 mmol) and phenethylmagnesium chloride (23 mmol, 1M in THF) gave, afler flash chromatography (4:1 hexanes:ethyl acetate), the title compound as a colorless liquid (2.01 g, 94%). Spectroscopic data were consistent with previously reported data for this compound.4
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:32])[C:5]([NH:9][C:10](=[C:17]([C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26])[C:18](OCCCC)=[O:19])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][C:7]=1[F:8].OC1C(NC=C(C(OCC)=O)C(OCC)=O)=NC=CC=1>>[C:11]1([C:10]2[N:9]=[C:5]3[C:4]([OH:32])=[CH:3][C:2]([CH3:1])=[C:7]([F:8])[N:6]3[C:18](=[O:19])[C:17]=2[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCCOC(=O)C(C(=O)OCCCC)=C(Nc1nc(F)c(C)cc1O)c1ccccc1
Agent: CCOC(=O)C(=CNc1ncccc1O)C(=O)OCC
Product: CCCCOC(=O)c1c(-c2ccccc2)nc2c(O)cc(C)c(F)n2c1=O

Procedure:
By substituting [(5-methyl-6-fluoro-3-hydroxy-2-pyridyl)amino] benzylidenemalonic acid, di-n-butyl ester for the [(3-hydroxy-2-pyridyl)amino]methylenemalonic acid, diethyl ester, there is obtained the named compound.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2].P(Cl)(Cl)(Cl)=O.O.[OH-].[Na+].CN([CH:23]=[O:24])C>>[CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH:23]=[O:24])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1cc2ccccc2[nH]1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCc1[nH]c2ccccc2c1C=O
Temperature: 40 °C

Procedure:
2-Ethylindole (0.5 g, 3.4 mmol) dissolved in DMF (2 mL) was added to a cold (0° C.) premixed (30 minutes) mixture of DMF (1.15 mL) and phosphorous oxychloride (0.64 g, 4.16 mmol). After addition of 2-ethylindole, the mixture was heated to 40° C. for 1 h, water (5 mL) was added and the pH adjusted to 5 by means of 1 N sodium hydroxide. The mixture was subsequently extracted with diethyl ether, the organic phase isolated, dried with MgSO4 and evaporated to dryness affording 2-ethylindole-3-carbaldehyde (300 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:28])[C:5]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[C:6]([C:16](OC)=[O:17])[NH:7]2.[OH-].[Na+]>ClCCl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:28])[C:5]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)=[C:6]([CH2:16][OH:17])[NH:7]2
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)c(C(=O)OC)[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)c(CO)[nH]c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.3 %

Procedure:
A dichloromethane solution (30 ml) of methyl 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxylate (5.0 g, 13 mmol) was cooled to −78° C., and hydrogenated diisobutylaluminium (DIBAL-H, 1M toluene solution, 30 ml) was added thereto dropwise under a nitrogen atmosphere. After completion of the addition, the mixture was stirred at the same temperature for 3 hours. The reaction mixture was heated to room temperature, and 5N sodium hydroxide was added thereto, followed by extraction with dichloromethane. The thus-obtained organic layer was washed with water, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=10:1). The purified material was concentrated to dryness under reduced pressure, giving a yellow amorphous solid of 5-fluoro-2-hydroxymethyl-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (4.8 g, yield: 85%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:22][NH:23][O:24][CH3:25].C(N(CC)CC)C>ClCCl>[CH3:25][O:24][N:23]([CH3:22])[C:6]([CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[O:8]
Reactant: O=C(O)C1CCOC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of tetrahydrofuran-3-carboxylic acid (10 g, 86.1 mmol) in dichloromethane (200 mL). EDC.HCl (18.2 g, 94.9 mmol), N,O-dimethylhydroxylamine hydrochloride (10 g, 103 mmol) and triethylamine (24.0 mL, 172 mmol) were added and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with DCM (50 mL) and washed with aqueous HCl (1 M, 3×10 mL), sodium bicarbonate (sat., 2×30 mL) and brine (3×20 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the title compound as light yellow oil (6.71 g, 49%).
Reaction SMILES: FC1C=C([CH:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)=[CH:17][CH:16]=2)[CH2:10][C:11]([NH:13]C)=[O:12])C=CC=1F.[Cl:26][C:27]1[CH:28]=[C:29]([Mg]Br)[CH:30]=[CH:31][C:32]=1[Cl:33]>>[Cl:26][C:27]1[CH:28]=[C:29]([CH:9]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)=[CH:19][CH:20]=2)[CH2:10][C:11]([NH2:13])=[O:12])[CH:30]=[CH:31][C:32]=1[Cl:33]
Reactant: Clc1ccc([Mg]Br)cc1Cl
Reactant: CNC(=O)CC(c1ccc(-c2cn[nH]c2)cc1)c1ccc(F)c(F)c1
Product: NC(=O)CC(c1ccc(-c2cn[nH]c2)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
By following the procedure described in Example 9A and 9B but substituting 3,4-difluorophenylmagnesium bromide for 3,4-dichlorophenylmagnesium bromide, the title compound was obtained. LC/MS: (PS-A3) Rt 9.82 [M+H]+ 360.14, 362.12. 1H NMR (Me-d3-OD) δ 2.90-3.00 (2H, d), 4.50-4.60 (1H, t), 7.10-7.30 (3H, m), 7.40-7.45 (2H, d), 7.50-7.55 (2H, d), 7.85-8.05 (2H, br s).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([C:14]([NH2:16]=O)=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.[H][H].[ClH:31]>C(OCC)(=O)C.[Pd]>[ClH:31].[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:11]2([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:19][CH:20]=1
Reactant: [H][H]
Reactant: O=C([NH2+][O-])C1(c2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NC(=O)C1(c2ccc(F)cc2)CCNCC1
Temperature: 25 °C

Procedure:
1-Benzyl-4-(4-fluoro-phenyl)-piperidine-4-carboxylic acid amide N-oxide (5.3 g, 16.3 mmol) and 10% palladium-on-carbon (0.6 g) and acetic acid (100 mL) were combined in a pressure vessel. The reaction mixture was treated with hydrogen on a Parr apparatus at an initial pressure of 53 psi of hydrogen. When hydrogen consumption stopped the catalyst was removed by filtration. The filtrate was evaporated in vacuo to give a residue. The residue was dissolved in ethyl acetate (150 mL), acidified by the addition of 12M aqueous hydrochloric acid solution (5 mL), and heated to reflux for 10 minutes. The mixture was cooled to ambient temperature to give a solid which was collected by filtration, rinsed with ethyl acetate, recrystallized from methanol/ethyl acetate to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.C([O-])(=[O:22])C.[NH4+].C1(C)C=CC=CC=1>C(O)(=O)C>[OH:22][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1c(-c2ccc(Cl)nc2)c[nH]n1-c1ccccn1
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=c1c(-c2ccc(O)nc2)c[nH]n1-c1ccccn1

Procedure:
50.0 mg (0.18 mmol) of the compound from Example 7 and 600 mg (7.74 mmol) ammonium acetate are heated at 180° C. as a suspension in 3 ml glacial acetic acid in a single mode microwave (Explorer from CEM) for 2 h. After a complete conversion is detected by analytical HPLC, toluene is added and the volatile components are distilled off azeotropically. The residue is taken up in water and the solid which remains is filtered off. The slightly brownish powder is subsequently washed with water and then with MTBE. After drying, 39 mg (84% of th.) of the title compound are obtained.