Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[S:5][C:4](=[S:21])[NH:3]1.[NH2:22][CH2:23][C@H:24]([OH:34])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[OH:34][C@H:24]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[CH2:23][NH:22][CH:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH:7]=[C:6]3[S:5][C:4](=[S:21])[NH:3][C:2]3=[O:1])=[CH:9][CH:10]=2)[CH2:15][CH2:16]1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Reactant: O=C1CCN(c2ccc(C=C3SC(=S)NC3=O)cc2)CC1
Product: O=C1NC(=S)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1

Procedure:
The title compound was prepared from 1-[4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidine-4-one (which was obtained in Example 34) and 4-[(2S)-3-amino-2-hydroxy-propoxy]-phenol (which was obtained in Example 5) according to the procedure of Example 73 as a pale yellowish solid; MS (ES) m/z: 485.9 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[O:37]1[CH2:41][CH:40](O)[CH:39]([OH:43])[CH2:38]1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([CH:21]2[CH2:22][CH2:23][C:24]3([O:43][C@H:39]4[CH2:38][O:37][CH2:41][C@H:40]4[O:27]3)[CH2:25][CH2:26]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: OC1COCC1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)O[C@H]2COC[C@H]2O3)c2ncnn12
Temperature: 110 °C
Reaction time: 3 h
Yield: 110.4 %

Procedure:
A mixture of 3′-fluoro-4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1 g), tetrahydrofuran-3,4-diol (0.26 g), p-toluenesulfonic acid monohydrate (0.005 g) and toluene (50 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 3 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.3 g, 100%).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]([C:8]1[C:9]([S:22][CH3:23])=[C:10]([CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19])[C:11]([O:13]C)=[O:12])=[O:7]>CO.O>[CH3:4][O:5][C:6]([C:8]1[C:9]([S:22][CH3:23])=[C:10]([CH:15]=[CH:16][C:17]=1[C:18]([F:19])([F:20])[F:21])[C:11]([OH:13])=[O:12])=[O:7]
Reactant: COC(=O)c1ccc(C(F)(F)F)c(C(=O)OC)c1SC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1c(C(F)(F)F)ccc(C(=O)O)c1SC
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
Lithium hydroxide monohydrate (1.87 g) was added to a solution of methyl 3-methoxycarbonyl-2-(methylsulphenyl)-4-trifluoromethylbenzoate (13.71 g) in methanol and water. The mixture was stirred at room temperature overnight and the methanol was removed by evaporation. The residual aqueous solution was acidified to pH 1 and extracted with ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 3-methoxycarbonyl-2-(methylsulphenyl)-4-trifluoromethylbenzoic acid (10.85 g) as an off-white solid, NMR (CDCl3) 2.45(s, 3H), 3.95(s,3H), 5.45-6.1(bs, 1H), 7.2(d, 1H), 7.95(d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.FC(F)(F)C(O)=[O:12].OO>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:12]
Reactant: Clc1cccc(Cl)n1
Reactant: O=C(O)C(F)(F)F
Agent: OO
Solvent: O
Product: [O-][n+]1c(Cl)cccc1Cl

Procedure:
24 g of 2,6-dichloropyridine, 200 ml of trifluoroacetic acid and 28 ml of 33% hydrogen peroxide are heated to 100° C. for 4 hours. The mixture is cooled, 600 ml of water are then added and the resulting mixture is concentrated under vacuum to a volume of 50-100 ml. It is alkalinized with sodium hydrogen carbonate and then extracted with DCM, and the organic phase is separated after settling has taken place and dried over sodium sulphate. It is filtered and concentrated under vacuum, and the residue is recrystallized from AcOEt to obtain 18.8 g of 2,6-dichloropyridine N-oxide; m.p.=138°-140° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=2)[CH:16]=1)[CH2:12][CH3:13])(C)(C)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH2:39])=[CH:33][C:32]=1[CH3:40]>>[CH2:12]([N:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:39][CH2:38][CH2:37][C:34]3[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[C:32]([CH3:40])[CH:33]=3)[N:22]=2)[CH:16]=1)[CH2:10][CH2:9][CH2:8][NH2:7])[CH3:13]
Reactant: COc1ccc(CCN)cc1C
Reactant: CCN(CCCNC(=O)OC(C)(C)C)Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CCN(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(OC)c(C)c3)n2)c1

Procedure:
Intermediate 3 was coupled with 2-(4-Methoxy-3-methyl-phenyl)-ethylamine following procedure F. The resulting product was deprotected by procedure G. LC-MS showed the product had the expected M+H+ of 434. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.4 (m, 2H) 8.0 (s, 1H) 7.6-7.8 (m, 2H) 7.47 (d, 1H) 6.82 (d, 1H) 6.67 (m, 2H) 4.5 (s, 2H) 3.81 (s, 3H) 3.4 (m, 4H) 3.28 (m, 4H) 3.03 (t, 2H) 2.68 (t, 2H) 2.16 (m, 2H) 1.4 (t, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=O)[CH3:6].P(Cl)(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1.Cl.[NH2:22][C:23]1[CH:24]=[C:25]([C:29]2[O:30][CH:31]=[CH:32][C:33]=2[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:26]=[CH:27][CH:28]=1>C(OCC)(=O)C>[CH3:6][C:5]1[N:22]([C:23]2[CH:24]=[C:25]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:26]=[CH:27][CH:28]=2)[CH2:2][CH2:3][N:4]=1
Reactant: CCOC(=O)c1ccoc1-c1cccc(N)c1
Reactant: CC(=O)NCCCl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccoc1-c1cccc(N2CCN=C2C)c1
Temperature: 2.5 °C
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
N-(2-chloroethyl)acetamide (1.21 g) in ethyl acetate (10 mL) was added over 10 min to a stirred suspension of phosphorus pentachloride (2.08 g) in ethyl acetate (2 ml) at 0° C. under nitrogen to give a clear pale straw solution. After 45 min. at 0° C. toluene (12 ml) was added, and ethyl 2-(3-aminophenyl)-3-furoate hydrochloride (1.78 g) was added in one portion into the above solution at 0-5° C. The mixture was stirred at 0-5° C. for 10 min. and then allowed to warm up to 20° C. After 2 h formation of the amidine was essentially complete (HPLC ethyl 2-(3-aminophenyl)-3-furoate hydrochloride <2% (220 nm, a/a). The mixture was cooled to 0-5° C., crushed ice (18 g) was added over 20 min. to destroy phosphorus oxychloride. Ammonium hydroxide (28%, 6.49 mL) was added at a rate that the internal temperature was kept below 25° C. (ca. 15 min). After 1 h at 20° C. additional ethyl acetate (12 ml) added to the above mixture, the organic layer was separated, washed with deionized water (2×12 ml), and concentrated under reduced pressure. The residue was dissolved in acetone (5 ml) and ethyl acetate (5 ml), and treated with oxalic acid (0.72 g) at 40° C. for 30 min. After aging at <20° C. for at least 12 h, the precipitate was collected by filtration, washed with acetone (2×0.5 vol), and dried in vacuo at 45-50° C. to yield 1.9 g (73%) of white solid.
Reaction SMILES: CS([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1)=O.[CH3:28][O-:29].[Na+].Cl>O1CCCC1>[CH3:28][O:29][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1
Reactant: CS(=O)c1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
2-(Methylsulfinyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (60 mg) was suspended in tetrahydrofuran (2 ml), sodium methoxide (28% methanol solution, 200 mg) was added thereto under ice-cooling, and the mixture was stirred for 10 min. To the reaction mixture was added 1M hydrochloric acid (3 ml), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained white residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (39 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CO>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([N:34]1[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CN1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCN(C(=O)C(C)(C)NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-benzyloxycarbonylamino-2-methyl-propionic acid (2.37 g) in tetrahydrofuran (20 mL) was added 1,1′-carbonylbis-1H-imidazole (1.78 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1-methylpiperazine (2.0 mL), and the mixture was stirred at 40° C. for 3.5 days. To the reaction mixture was added methanol, and the resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give 1-(2-benzyloxycarbonylamino-2-methyl-propionyl)-4-methylpiperazine (1.99 g). This material was dissolved in methanol (10 mL). To the solution was added 10% palladium-carbon powder (0.4 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (1.14 g).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH3:19])[C:10]([O:14][CH2:15][CH:16]=[CH2:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH:19]=[CH:27][C:26]3[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=3)[C:10]([O:14][CH2:15][CH:16]=[CH2:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C=CCOc1ccc2c(C)cc(=O)oc2c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-allyloxy-8-acetylcoumarin (1.93 g, 0.0075 mol) and 4-chlorobenzaldehyde (1.05 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 1.1 g of product m.p. 153-155° C., 1H-NMR (CDCl3) δ: 2.42 (d, J=1.2 Hz, 3H), 4.65 (m, 2H), 5.2 (m, 2H), 6.15 (m, 1H), 6.91-7.61 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([OH:8])=[N:6][CH:7]=1.O[CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[C:5]([O:8][CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[N:6][CH:7]=1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: Oc1ncc(Br)cc1C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CN(CCOc1ncc(Br)cc1C(F)(F)F)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 76.4 %

Procedure:
To a suspension of 5-bromo-3-(trifluoromethyl)pyridin-2-ol (500 mg) in 1,4-dioxane (10 ml), tert-butyl 2-hydroxyethyl(methyl)carbamate (475 mg) and triphenylphosphine (684 mg) were added. Then diisopropyl azodicarboxylate (556 mg) was dropwised and stirred at 20° C. for 1.5 h. The mixture was evaporated off the solvent and purified by Biotage SNAP cartridge KP-Sil column (50 g, heptane:ethyl acetate=1:0, 5:1, 4:1, 3:1 to 2:1) to give 630 mg yellow oil as tert-butyl 2-(5-bromo-3-(trifluoromethyl)pyridin-2-yloxy)ethyl(methyl)carbamate (76%).
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18](=O)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:17]=1)=[O:12])[CH3:9]>FC(F)(F)C(O)=O>[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH:17]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc(C(=O)Cc2ccc(F)cc2)c[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(CCc2ccc(F)cc2)c[nH]1
Yield: 57 %

Procedure:
Triethylsilane (3.84 mL, 24.1 mmol) was added to a stirring, room temperature solution of 71 (2.1400 g, 7.77 mmol) in trifluoroacetic acid (TFA) (18.5 mL, 0.42 M) under N2. When the reaction was judged complete by HPLC, the TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na2SO4, filtered, concentrated, and purified by preparative reverse phase HPLC with the following conditions: 0 to 12 min, 35:65 H2O:CH3CN; 14-15 min, 35:65 to 0:100 H2O:CH3CN; 20 mL/min.; λ=254 nM; 3.67 g/mL, 0.2 mL/injection. 1.1571 g (57.0%) of 72 was obtained as a fluffy white solid. (Note: An undesired impurity has a retention time of 11.414 min by HPLC.) 1H (CDCl3, 400 MHz): δ 9.33 (1H, broad s), 7.13 (2H, dd, J=8.5, 5.6 Hz), 6.96 (2H, t, J=8.8 Hz), 6.79 (1H, s), 6.66 (1H, s), 4.33 (2H, t, J=7.1 Hz), 2.86 (2H, t, J=7.1 Hz), 2.77 (2H, t, J=7.1 Hz), 1.36 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): 6161.31, 161.22 (d, J=242 Hz), 137.46 (d, J=3.2 Hz), 129.71 (d, J=7.7 Hz), 125.22, 122.52, 120.84, 114.89 (d, J=21.9 Hz), 114.79, 60.19, 36.44, 28.73, 14.37 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.37; CH2 carbons: 60.19, 36.44, 28.73; CH carbons: 129.71 (d, J=7.7 Hz), 120.84, 114.89 (d, J=21.9 Hz), 114.79 ppm. HPLC: 10.797 min.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].O1CCCCC1[O:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([NH:26][NH2:27])[CH:23]=[CH:22][N:21]=1>CO.Cl>[NH2:6][C:5]1[N:26]([C:24]2[CH:23]=[CH:22][N:21]=[C:20]([O:19][CH2:18][CH2:17][OH:16])[CH:25]=2)[N:27]=[C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])[CH:4]=1
Reactant: NNc1ccnc(OCCOC2CCCCO2)c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(N)n(-c2ccnc(OCCO)c2)n1

Procedure:
4,4-Dimethyl-3-oxopentanenitrile (293 mg, 2.34 mmol) and Intermediate 67b (593 mg, 2.34 mmol) were suspended in MeOH (10 mL) and a few drops of concentrated HCl added and the reaction heated to reflux for 72 h. The reaction was cooled, concentrated in vacuo and partitioned between H2O and EtOAc. The organic layer was separated, and the aqueous extracted again with EtOAc. The combined organics were dried over MgSO4 and subjected to FCC, eluting with 10-50% EtOAc/cyclohexane to afford the title compound after crystallisation (139 mg, 21%). LCMS (Method 3) Rt 2.77 min, m/z 277.3 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>C(OCC)(=O)C>[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:14]2[N:15]=[CH:16][C:11]3[CH:10]=[C:9]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[C:22](=[O:23])[N:21]([CH3:24])[C:12]=3[N:13]=2)=[CH:28][CH:27]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: CCOC(C)=O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc(Cl)cc3)nc21
Temperature: 238 °C
Reaction time: 0.08 h

Procedure:
A mixture of 0.113 g (0.29 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 in 0.50 g (3.90 mmol) of 4-chloroaniline was heated, with stirring, at the boiling point (238° C.) for 5 minutes. Ethyl acetate (3 mL) was added to the cooled dark blue reaction solution. Petroleum ether (3 mL) was added to completed precipitation of a dark solid. This was filtered and washed with 50% hexane-ethyl acetate; wt 0.078 g. The crude solid was purified to remove dark colors by silica gel chromatography, eluting with chloroform and then 50% hexane-ethyl acetate to obtain pure crystalline product; wt 0.056 g; mp 255°-256° C.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:23][C:24]1[CH:31]=[C:30]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:27]=[C:26]([C:25]2[CH:28]=[CH:29][C:30]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:31][C:24]=2[Cl:23])[N:2]([CH3:1])[N:3]=1
Reactant: CCCCCCCCCCCCc1ccc(C#N)c(Cl)c1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCc1ccc(-c2nc(-c3c(F)cccc3Cl)nn2C)c(Cl)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.50 g), 2-chloro-4-dodecylbenzonitrile (1.20 g), anhydrous aluminum chloride (0.60 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (100 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.80 g of desired compound (refractive index: 1.5490).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=[O:2].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([N:15]1[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1)=[O:8])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.9 %

Procedure:
To a solution of 3-formylbenzoic acid (600 mg, 3.99 mmol) in DCM (12 mL) were added tert-butyl piperazine-1-carboxylate (818.8 mg, 4.40 mmol), HATU (1.82 g, 4.80 mmol), NMM (1.1 mL, 9.99 mmol), and DMAP (49 mg, 0.39 mmol) at 0° C. Reaction was stirred at RT for 16 h. TLC analysis indicated complete consumption of starting material. The reaction mixture was diluted with DCM and washed with water. Organic layer was separated and dried over Na2SO4 and concentrated. Column chromatography of crude material afforded pure product tert-butyl 4-(3-formylbenzoyl)piperazine-1-carboxylate as off-white solid (990 mg, 78%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:34][C@@H:35]3[CH2:39][CH2:38][O:37][CH2:36]3)[C:14]([NH:16][C:17]3[S:18][C:19]([O:22][C:23]4[CH:24]=[CH:25][C:26]([CH3:33])=[C:27]([CH:32]=4)[C:28]([O:30]C)=[O:29])=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.CO>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:34][C@@H:35]3[CH2:39][CH2:38][O:37][CH2:36]3)[C:14]([NH:16][C:17]3[S:18][C:19]([O:22][C:23]4[CH:24]=[CH:25][C:26]([CH3:33])=[C:27]([CH:32]=4)[C:28]([OH:30])=[O:29])=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc(Oc2cnc(NC(=O)C(O[C@@H]3CCOC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)ccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(Oc2cnc(NC(=O)C(O[C@@H]3CCOC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.8 %

Procedure:
5-[2-[[2-(4-cyclopropylsulfonylphenyl)-2-[(3R)-tetrahydrofuran-3-yl]oxy-acetyl]amino]thiazol-5-yl]oxy-2-methyl-benzoic acid methyl ester (Example A3; 0.300 g, 0.524 mmol) was taken in THF(4 mL) and MeOH (0.1 mL), to it was added aqueous solution of LiOH (0.110 g, 2.62 mmol in 7 mL water) and stirred for 1-4 h at room temperature. After completion of the reaction, organic solvent was removed under reduced pressure. The aqueous layer was washed with diisopropyl ether then acidified with 1 N HCl to pH 2. The solid formed was filtered, washed with water, followed by washing with diisopropyl ether & dried under vacuum to get the title compound (0.260 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.N(CC[N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)N>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH2:24][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: NNCCN1CCOCC1
Reactant: CCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CCN1CCOCC1
Reaction time: 16 h

Procedure:
Compound 28 was synthesised following similar procedures outlined in Example 31 (Compound 18), using 4-(2-hydrazinylethyl)morpholine instead of ethyl hydrazine in Step 3. As a slightly modified procedure, Step 3 was performed at 60° C. for 16 h. The reaction mixture was concentrated in vacuo and the crude residue was purified by column chromatography (silica gel, gradient 50 to 100% ethyl acetate/isohexane), followed by preparative HPLC, yielding Compound 28 as a solid.
Reaction SMILES: [CH2:1]([NH:6][C:7](=[O:23])[C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1C(OCC1C=CC=CC=1)=O)[CH2:2][CH2:3][CH2:4][CH3:5].CCOCC>Br.C(O)(=O)C>[CH2:1]([NH:6][C:7](=[O:23])[C@@H:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCNC(=O)[C@@H]1CCCN1
Reaction time: 1 h
Yield: 117.5 %

Procedure:
5 g of N-benzyloxycarbonyl-L-proline n-pentylamide were dissolved in 20 ml of 4-N hydrogen bromide in acetic acid and the mixture was stirred for 1 hour. 150 ml of dry ether were then added. A clear oil precipitated out and was allowed to settle. The ether was decanted off and the oil washed with a further 100 ml of dry ether. Evaporation yielded 3.4 g (82%) of L-proline n-pentylamide in the form of an oil.