Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([C:12]1[C:13]([CH3:35])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3([C:32](O)=[O:33])[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:48][S:49]([NH2:52])(=[O:51])=[O:50].N12CCCN=C1CCCCC2>C1COCC1.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][CH2:9][C@H:10]([C:12]1[C:13]([CH3:35])=[N:14][O:15][C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3([C:32]([NH:52][S:49]([CH3:48])(=[O:51])=[O:50])=[O:33])[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)=[CH:21][CH:22]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1[C@H](O)COCc1ccccc1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1[C@H](O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
1-{4′-[4-((S)-2-benzyloxy-1-hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (0.232 g, 0.49 mmol) was dissolved in THF (4.6 mL) along with 4-dimethylaminopyridine (0.0065 g, 0.05 mmol) and carbonyldiimidazole (0.200 g, 1.24 mmol). After stirring at room temperature for 3.5 hours, carbonyldiimidazole (0.040 g, 0.25 mmol) was added. The reaction stirred for 1 hour then methanesulfonamide (0.117 g, 1.23 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.242 mL, 1.62 mmol) were added and the reaction was heated to 100° C. After 40 minutes the reaction was cooled and submitted to standard aqueous workup. The residue was purified on silica gel (0-100% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [Li+].[OH-].[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C@@H:22]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:23][NH:24][C:25]([CH3:38])([CH3:37])[CH2:26][C:27]2[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=2)[C:30]([O:32]C)=[O:31])=[C:15]2[C:20]=1[NH:19][C:18](=[O:21])[CH:17]=[CH:16]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C1COCC1.CO.O>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C@@H:22]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:23][NH:24][C:25]([CH3:38])([CH3:37])[CH2:26][C:27]2[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=2)[C:30]([OH:32])=[O:31])=[C:15]2[C:20]=1[NH:19][C:18](=[O:21])[CH:17]=[CH:16]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Yield: 89.1 %

Procedure:
Solid LiOH (370 mg, 15.4 mmol) was added to a stirring solution of Intermediate 100 (950 mg, 1.55 mmol) in THF/MeOH/H2O (15 mL, 3/1/1) at rt. The reaction mixture was stirred over night then pH was adjusted to 1 with 1 N HCl. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give crude acid (1.09 g) as yellow solid. Recrystallization (CH2Cl2/Et2O) afforded the title compound (830 mg, 89%) as off white solid. ES/MS calcd. for C35H45N2O5Si+ 601.3. Found m/z=601.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[C:32]([O:36][C:37]([N:39]1[CH:43]=[CH:42][CH:41]=[C:40]1B(O)O)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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.C(OCC)(=O)C>[C:32]([O:36][C:37]([N:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:27]1[CH:28]=[CH:29][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:31])([CH3:7])[CH3:6])=[CH:10][CH:11]=3)[N:19]=2)=[CH:25][CH:26]=1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
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: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccn4C(=O)OC(C)(C)C)cc3)oc2C)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl-propionic acid ethyl ester (907 mmol) (see Ex. 2, part B) and 1-(t-butoxycarbonyl)pyrrole-2-boronic acid (0.998 mmol) in toluene:ethanol (18.2 mL of a 1:1 solution) was treated with Na2CO3 (aq) (0.906 mL of a 2M solution). A nitrogen atmosphere was applied, Pd(PPh3)4 (52.5 mg) was added, and the orange mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate (20 mL) and H2O (30 mL). The layers were separated, and the aqueous phase was back-extracted with ethyl acetate (2×10 mL). Combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (20 g SiO2, 3:7 ethyl acetate:hexanes) to yield the product in 92% yield as an oil; Rf=0.50 in 1:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ7.92 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 7.34 (t, J=2.4 Hz, 1H), 6.79 (d, J=9.4 Hz, 2H), 6.74 (d, J=9.4 Hz, 2H), 6.21 (d, J=2.4 Hz, 2H), 4.20 (q, J=6.8 Hz, 2H), 4.16 (t, J=6.8 Hz, 2H), 2.93 (d, J=6.8 Hz, 2H), 2.34 (s, 3H), 1.49 (s, 6H), 1.33 (s, 9H), MS (EI) 598.2 (M+Na)+, 575.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:22][CH2:21][CH2:20][C:19]4=[O:23])=[C:14]([F:24])[CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.Cl[C:26]1[CH:27]=[CH:28][N:29]=[C:30]2[C:35]=1[N:34]=[CH:33][C:32]([O:36][CH3:37])=[CH:31]2.CC(O)CC>>[F:24][C:14]1[CH:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([CH2:2][NH:1][C:26]4[C:35]5[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][N:34]=5)[N:29]=[CH:28][CH:27]=4)=[N:4][N:5]=3)[N:8]=2)[CH:17]=[CH:16][C:15]=1[N:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23]
Reactant: NCc1nnc2ccc(-c3ccc(N4CCCC4=O)c(F)c3)nn12
Reactant: COc1cnc2c(Cl)ccnc2c1
Solvent: CCC(C)O
Product: COc1cnc2c(NCc3nnc4ccc(-c5ccc(N6CCCC6=O)c(F)c5)nn34)ccnc2c1
Reaction time: 4 h

Procedure:
A 0.5-2 mL microwave vial was charged with 1-(4-(3-(aminomethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-fluorophenyl)pyrrolidin-2-one (0.0792 g, 0.243 mmol), 8-chloro-3-methoxy-1,5-naphthyridine (0.0590 g, 0.303 mmol), and butan-2-ol (1.00 ml, 0.243 mmol), sealed, then placed in a Personal Chemistry Microwave for 4 hours at 120° C. The mixture was concentrated, then triturated with MeOH to give 1-(2-fluoro-4-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)pyrrolidin-2-one as the hydrochloric salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:31]=[CH:30][C:22]2[O:23][C:24]([CH3:29])([CH3:28])[O:25][C:26](=[O:27])[C:21]=2[CH:20]=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:17]=[CH:16][C:13](/[CH:14]=[N:18]/[C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24]([CH3:28])([CH3:29])[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)c2cc(N)ccc2O1
Reactant: O=Cc1ccc(C#Cc2ccc(Cl)cc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)c2cc(/N=C/c3ccc(C#Cc4ccc(Cl)cc4)cc3)ccc2O1
Yield: 92.4 %

Procedure:
A solution of 4-[(4-chlorophenyl)ethynyl]benzaldehyde (2.60 g, 10.9 mmol, intermediate which may be prepared according to methods disclosed in EP03103780.7) and 6-amino-2,2-dimethyl-4H-1,3-benzodioxin-4-one (2.00 g, 10.36 mmol) in toluene (40 mL) was heated at reflux for 2 hrs with azeotropic removal of water. Then the temperature was cooled down slowly. A yellow solid precipitated out and MeOH (40 mL) was added. The precipitate was filtered, washed with MeOH (2×) and dried under reduced pressure to give 3.98 g (92%) of the title compound as a yellow powder. 1H NMR (CDCl3) δ: 8.53 (s, 1H), 7.90 (d, J=8.2 Hz, 2H), 7.85 (d, J=2.5 Hz, 1H), 7.64 (d, J=8.2 Hz, 2H), 7.53 (dd, J=8.6, 2.5 Hz, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 7.03 (d, J=8.6 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([Br:10])[C:3]=1[NH2:4].Cl[C:12]([CH:14]([CH3:20])[CH2:15][P:16](Cl)(C)=[O:17])=[O:13].[OH2:21]>>[Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([Br:10])[C:3]=1[NH:4][C:12]([CH:14]([CH3:20])[CH2:15][PH:16](=[O:21])[OH:17])=[O:13]
Reactant: CC(CP(C)(=O)Cl)C(=O)Cl
Reactant: O
Reactant: Nc1c(Br)cc(Br)cc1Br
Product: CC(C[PH](=O)O)C(=O)Nc1c(Br)cc(Br)cc1Br

Procedure:
330 g (1 mol) of 2,4,6-tribromoaniline was reacted as described in Example 1 with 207 g (1.02 mol) of [2-(chloroformyl-)2-(methyl)ethyl-]methyl phosphinic acid chloride (prepared as described by V. K. Khairullin et al., C.A. 69, 106816 k (1968)). After hydrolysis with 6 liters of water, the resulting [2-(2,4,6-tribromophenylcarbamoyl-) 2-(methyl)ethyl-]methyl phosphinic acid was filtered off and dried at 80° C under vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10](OC)(=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[SH:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10](=[O:18])[N:6]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(Br)c2)sc2ccccc12
Yield: 20.6 %

Procedure:
A mixture of 3-bromobenzonitrile (2.00 g, 11 mmol), methyl thiosalicylate (2.87 g, 17 mmol), triethylamine (1.95 g, 19 mmol) and toluene (10 ml) was heated and refluxed under a nitrogen flow for 40 hours. The precipitated crystals were taken by filtration and recrystallized from tetrahydrofuran-ethyl acetate to give the title compound (0.72 g, 21%) as crystals.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.Cl.[CH2:17]([O:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:21]=1)[CH3:18]>ClCCl.CN(C=O)C.C(OCC)(=O)C>[CH2:17]([O:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]2[CH2:28][CH2:29][N:30]([C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH2:31][CH2:32]2)[CH:21]=1)[CH3:18]
Reactant: CCOc1cc(C)nc(N2CCNCC2)c1
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1cc(C)nc(N2CCN(C(=O)/C=C/C(F)(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.7 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (17 mg, 0.12 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (11 μl, 0.12 mmol) was added and the resulting solution was stirred at room temperature for 10 minutes. This solution was added to a solution of 1-(4-ethoxy-6-methyl-2-pyridyl)piperazine hydrochloride (22 mg, 0.086 mmol) and TEA (42 μl, 0.3 mmol) in anhydrous DMF (0.5 ml) and the resulting mixture was stirred at room temperature for one hour. The mixture was diluted with ethyl acetate, washed with sat. sodium bicarbonate solution, brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters X-Bridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 12 mg of a solid (0.035 mmol, yield 41%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([OH:14])=[C:6]([CH:9]=[C:10]([CH:12]=O)[CH:11]=1)[C:7]#[N:8])[CH3:2].[C:15]1([C:21](=O)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH2:30][C:31]([NH2:33])=[O:32].Cl>CCO.CO.CCOC(C)=O>[CH2:1]([O:3][C:4]1[C:5]([OH:14])=[C:6]([CH:9]=[C:10]([CH:12]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:33][C:31](=[O:32])[NH:30]2)[CH:11]=1)[C:7]#[N:8])[CH3:2]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc(C#N)c1O
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc(C#N)c1O
Yield: 45.4 %

Procedure:
A mixture of 3-ethoxy-5-formyl-2-hydroxybenzonitrile (285 mg, 1.5 mmol), 1,2-diphenylethanone (320 mg, 1.6 mmol), and urea (270 mg, 4.5 mmol) in anhydrous EtOH (5 mL) was added concentrated HCl solution (0.5 mL). The reaction mixture was refluxed overnight. TLC (EtOAc:MeOH=10:1) showed 40% of the starting materials were consumed. The reaction mixture was concentrated, and purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC to afford Compound 69 as a yellow solid (280 mg, yield: 45.7%). 1H NMR (DMSO-d6 400 MHz TMS): δ 10.30 (s, 1H), 8.70 (d, J=1.2 Hz, 1H), 7.47 (s, 1H), 7.20-7.27 (m, 5H), 7.16 (d, J=1.6 Hz, 1H), 6.98-7.06 (m, 4H), 6.80-6.82 (m, 2H), 5.14 (d, J=2.4 Hz, 1H), 4.00-4.10 (m, 2H), 1.33 (t, J=7.2 Hz, 3H); MS (ESI): m/z 412.1 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2[N:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=1)([O-])=O.C(OCC)(=O)C>CO.[Pd]>[NH2:1][C:4]1[CH:18]=[CH:17][C:7]2[N:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=1
Reactant: COC(=O)Cn1c(=O)oc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Cn1c(=O)oc2cc(N)ccc21
Yield: 99 %

Procedure:
A mixture of methyl 2-(6-nitro-2-oxobenzo[d]oxazol-3(2H)-yl)acetate (0.570 g, 2.260 mmol) and 10% w/w Pd/C (a catalytic amount) in MeOH (30 ml) and ethyl acetate (30 ml) was hydrogenated in a Parr apparatus at 20 psi for 1 hour. The catalyst was filtered off and the solvent was removed affording methyl 2-(6-amino-2-oxobenzo[d]oxazol-3(2H)-yl)acetate (0.497 g, 2.237 mmol, 99% yield). MS/ESI+ 222.9 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[C:7]2[C:12]=1[N:11]([CH3:13])[C:10](=[O:14])[CH:9]=[CH:8]2.Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:28][O:27][C:25]([CH2:24][N:18]1[C:17](=[O:22])[CH:16]([CH2:15][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]3[C:7]=2[CH:8]=[CH:9][C:10](=[O:14])[N:11]3[CH3:13])[S:20][C:19]1=[O:21])=[O:26]
Reactant: COC(=O)CBr
Reactant: COc1ccc(CC2SC(=O)NC2=O)c2ccc(=O)n(C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)SC(Cc2ccc(OC)c3c2ccc(=O)n3C)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
350 mg of 5-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-ylmethyl)thiazolidine-2,4-dione was dissolved in 5 ml of DMF. 0.156 ml of methyl bromoacetate and 0.25 g of potassium carbonate were added to the solution, followed by stirring at room temperature overnight. Water was added, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated sodium chloride solution, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography and recrystallized from methanol-acetone, giving 245 mg (57% yield) of 3-methoxycarbonylmethyl-5-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-ylmethyl)thiazolidine-2,4-dione as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:29]([C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.O.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>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([CH:20]=[C:2]([C:34]3[CH:35]=[N:36][C:31]([CH:29]=[O:30])=[CH:32][CH:33]=3)[CH:3]=2)[C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH3:17])=[O:8])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=Cc1ccc(B(O)O)cn1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
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: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 66.1 %

Procedure:
To a stirred solution of 5-bromo-3-(cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.5 g, 1.12 mmol) and (6-formylpyridin-3-yl)boronic acid (0.39 g, 1.68 mmol) in dioxane/water mixture (15 mL+3 mL), Na2CO3 (0.42 g, 4.09 mmol) was added and the solution was purged with argon for 15 min. Then Pd(PPh3)4 (0.130 g, 0.112 mmol) was added the mixture was purged again for 10 min. Reaction mass was heated at 100° C. for 4 h. On completion, the mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.35 g, 66% yield).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:6]=1)[CH2:3][OH:4].[C:18]1([CH:24]2[CH2:26][CH:25]2[C:27](O)=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:2]([NH:1][C:27]([CH:25]2[CH2:26][CH:24]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:28])[CH2:3][OH:4])=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: N[C@@H](CO)c1ccc(F)c(N2CCOCC2)c1
Reactant: O=C(O)C1CC1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(CO)c1ccc(F)c(N2CCOCC2)c1)C1CC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
A mixture of (R)-2-amino-2-(4-fluoro-3-morpholin-4-yl-phenyl)-ethanol (0.1 mmol), 2-phenyl-cyclopropanecarboxylic acid (0.1 mmol), EDAC.HCl (0.2 mmol), DMAP (0.1 mmol), triethylamine (0.4 mmol) in dichloromethane (2 mL) was stirred at room temperature overnight. The reaction mixture was purified by flash chromatography with 3% methanol in ethyl acetate to give the desired product (27 mg) as a solid.
Reaction SMILES: CN(C=O)C.[OH:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[C:15]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:11]1=[O:28].C(=O)([O-])[O-].[K+].[K+].[C:35]1([C:41](Cl)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O>[OH:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[C:15]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[N:23]([C:41]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:22]3=[O:27])[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:11]1=[O:28]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1NC(=O)C(Cc2cccc3c2CCC(=O)N3CCCO)S1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2c(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cccc2N1CCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
A DMF solution (10 ml) of 1.0 g (2.99 mmol) of 5-[1-(3-hydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]thiazolidine-2,4-dione and 0.455 g (3.29 mmol) of potassium carbonate was cooled with ice, and 0.876 g (3.04 mmol) of triphenylmethylchloride was added thereto, followed by stirring at room temperature overnight. Water was added to the reaction liquid and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and once with saturated sodium chloride solution, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→ethyl acetate). The purified product was concentrated under reduced pressure and evaporated to dryness, giving 700 mg (40.6% yield) of 5-[1-(3-hydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]-3-tritylthiazolidine-2,4-dione as a colorless amorphous solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.Cl[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.N>O>[N:20]1[CH:21]=[CH:22][C:17]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=3)[CH2:6][CH2:5]2)=[CH:18][CH:19]=1
Reactant: Clc1ccncc1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: N
Solvent: O
Product: COc1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 31 %

Procedure:
4-(piperazin-1-yl)anisole (4.24 g) and 4-chloropyridine hydrochloride (3.35 g) were intimately mixed and heated at 160°-170° C. (bath temperature) for 7 minutes. The solid obtained on cooling was dissolved in water (75 ml) and the solution basified with aqueous ammonia. The solid precipitate was extracted into ethyl acetate and the organic extract washed with water, filtered through phase separating paper (Whatman 1PS) and evaporated. The residue was recrystallised from ethanol to give 4-[4-(4-pyridyl)-piperazin-1-yl]anisole (1.84 g) as a solid: m.p. 165°-167° C.; NMR (CDCl3) δ8.3(2H,d); 6.86(4H,m); 6.71(2H,d); 3.78(3H,s); 3.46(4H,m); 3.2(4H,m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)=[CH:16][C:15]([O:26]CC1C=CC=CC=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]>C(O)C.O1CCCC1.[C].[Pd]>[C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:37])[CH3:38])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1)=[CH:16][C:15]([OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c3ccc(OCc4ccccc4)cc23)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c3ccc(O)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
A suspension of tert-butyl[6-benzyloxy-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (4.21 g, 8 mmol) and 5% palladium carbon (2.0 g) in ethanol (20 ml) and tetrahydrofuran (20 ml) was stirred under a hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-hydroxy-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (3.28 g, 94.0%) as crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].[CH3:12][O:13][C:14]1[CH:23]=[CH:22][C:17]([C:18](=[O:21])[CH2:19][Br:20])=[CH:16][CH:15]=1>>[CH3:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:19][C:18]([C:17]3[CH:22]=[CH:23][C:14]([O:13][CH3:12])=[CH:15][CH:16]=3)=[O:21])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].[BrH:20]
Reactant: Cc1[nH]c2ncccc2c1C
Reactant: COc1ccc(C(=O)CBr)cc1
Product: Br
Product: COc1ccc(C(=O)Cn2cccc3c(C)c(C)nc2-3)cc1
Yield: 336.1 %

Procedure:
The title compound was prepared from 2,3-dimethylpyrrolo [2,3-b]pyridine (120 mg, 0.82 mmol) and p-methoxyphenacyl bromide (207 mg, 0.90 mmol) following the procedure in example 27 above furnishing 223 mg (73%) pure hydrobromide as a light yellow solid.