Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[CH2:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15].C(N(C(C)C)C(C)C)C>CO>[OH:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH2:2][N:3]([CH2:15][CH2:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4][CH2:5]2
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Oc1ccc2c(c1)CCNC2
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)CCN1CCc2cc(O)ccc2C1
Yield: 79.8 %

Procedure:
A solution of 1,2,3,4-tetrahydroisoquinolin-6-ol hydrobromide (345 mg, 1.5 mmol), tert-butyl acrylate (0.44 ml, 3.0 mmol) and N-ethyl-N-isopropylpropan-2-amine (2.6 ml, 15.0 mmol) in MeOH was irradiated in the microwave at 90° C. for 1800 s. Removal of the solvents gave the residue which was purified on ISCO column (2% to 5% MeOH/CH2Cl2) to provide the title compounds (332 mg, 80%). 1H NMR (400 MHz, CD3OD) δ 6.85 (d, 1H), 6.55 (dd, 1H), 6.54 (s, 1H), 3.55 (s, 2H), 2.83 (m, 4H), 2.76 (m, 2H), 2.54 (dd, 2H), 1.45 (s, 9H). MS (ESI) m/z: Calculated: 277.17; Observed: 277.90 (M++1).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=O)[CH2:17][CH2:16][C@H:15]1[C:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH:13]=1)[CH2:4][CH2:3]2.NN.[OH-].[K+].Cl>C(O)COCCO.O>[CH3:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C:14](=[CH:13][CH2:12][C:11]4[CH:10]=[C:9]([OH:20])[CH:8]=[CH:7][C:6]=43)[C@@H:15]1[CH2:16][CH2:17][CH2:18]2
Reactant: C[C@]12CC[C@H]3C(=CCc4cc(O)ccc43)[C@@H]1CCC2=O
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: OCCOCCO
Solvent: O
Product: C[C@@]12CCC[C@H]1C1=CCc3cc(O)ccc3[C@H]1CC2
Yield: 13.9 %

Procedure:
To a suspension of equilin (100.2 mg, 0.3733 mmol) in 2 mL of diethylene glycol were added hydrazine (59 μL, 1.9 mmol) and potassium hydroxide (0.04 g, 0.7 mmol). See FIG. 14. The mixture was stirred in an oil bath at 200°-214° C. for 2h, after which the cooled reaction was diluted with 10 mL of water, neutralized with 1N HCl, and extracted three times with 25 mL of ether. The combined organic extracts were washed with 10 mL of brine, dried over magnesium sulfate, filtered, concentrated, and purified by preparative TLC (silica gel, 15% ethyl acetate/hexane eluent) to give a yellow resin. Product was further purified by decolorizing with charcoal and recrystallization from aqueous ethanol to give tan crystals (13.2 mg, 51.9 μM, 14%), m.p. 130°-134° C. (NA-1993B-25C)
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[CH3:12][O:13][N:14]=[CH:15][CH2:16][CH2:17][CH2:18][N:19]1[C:31]2[C:30]3[N:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:21]=[C:20]1[CH2:32][CH2:33][CH3:34].[OH-].[NH4+:36].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH3:12][O:13][N:14]=[CH:15][CH2:16][CH2:17][CH2:18][N:19]1[C:31]2[C:30]3[N:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:36])[C:22]=2[N:21]=[C:20]1[CH2:32][CH2:33][CH3:34]
Reactant: CCCc1nc2cnc3cccnc3c2n1CCCC=NOC
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cccnc3c2n1CCCC=NOC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Chloroperoxybenzoic acid (3.43 g of 70%, 19.9 mmol, 2.0 eq) was added to a solution of 4-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyraldehyde O-methyloxime (3.1 g, 9.96 mmol, 1.0 eq) in chloroform (45 mL). The reaction was stirred at ambient temperature for one hour. Analysis by thin layer chromatography indicated that the reaction was incomplete so additional 3-chloroperoxybenzoic acid (0.70 g) was added. After one additional hour of string, ammonium hydroxide (12 mL of 15M) and p-toluenesulfonyl chloride (2.1 g, 11 mmol, 1.1 eq) were added dropwise. The reaction mixture was stirred for an additional hour, filtered to remove the resulting white solid, and diluted with dichloromethane (60 mL) and saturated aqueous sodium bicarbonate (75 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×20 mL). The combined organics were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide a dark orange oil. The material was triturated with acetonitrile to afford 0.94 g of 4-(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyraldehyde O-methyloxime as a tan solid material. The filtrate from the trituration was purified by BIOTAGE HORIZON High-Performance Flash Chromatography (HPFC) instrument (eluting with chloroform/methanol/ammonium hydroxide (CMA) (80/18/2):chloroform ranging in ratios from 0:100 to 25:75) to provide an additional 0.84 g of product.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([CH:40]=[CH:41][C:42]([OH:44])=[O:43])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2]>O1CCCC1.CO.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([F:39])([F:37])[F:38])[CH:27]=3)[C:22]([CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C=CC(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CCC(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(2-carboxyvinyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (500 mg) is dissolved in a mixed solution of tetrahydrofuran (15 ml) and methanol (5 ml), then thereto is added 10% palladium/carbon (160 mg), and the mixture is stirred at room temperature under hydrogen for 3 hours and 30 minutes. The reaction solution is filtered, and concentrated under reduced pressure to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-carboxyethyl)-pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (498 mg). MS (m/z): 656 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]O)=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:34])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][Cl:34])=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Cn1c(CO)c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2c1=O
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(CCl)c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 86.3 %

Procedure:
To a suspension of 6-benzyloxy-3-hydroxymethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (2.89 g, 7 mmol) in toluene (30 mL) was added thionyl chloride (1.0 mL, 14 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-benzyloxy-3-chloromethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (2.61 g, 86.4%) as crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:16]([OH:18])=O)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.CC[N:21]([CH:25]([CH3:27])[CH3:26])C(C)C.C1(N)CC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CCOC(C)=O.CN(C=O)C>[CH:25]1([NH:21][C:16]([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]=[C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=2)=[O:18])[CH2:27][CH2:26]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COCCNc1cc(C(=O)O)c2ccccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCNc1cc(C(=O)NC2CC2)c2ccccc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a DMF (0.1 M) solution of 3-{[2-(methyloxy)ethyl]amino}-1-naphthalenecarboxylic acid (1 eq.) from the previous step, Hunig's base (3 eq.) and cyclopropylamine (1.5 eq.) was added portionwise O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.2 eq.). The resulting reaction solution was stirred at RT for 48 h. The now reddish solution was diluted with EtOAc and washed sequentially with 1 N aq. NaOH, water and brine. The organic extract was then dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford a brown oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 4:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH:39]=C)[CH2:10][N:11]([C:16]1[N:21]=[C:20]2[O:22][C:23]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[C:24]([C:25]([NH:27][CH3:28])=[O:26])[C:19]2=[CH:18][C:17]=1[C:36]([CH3:38])=C)[S:12]([CH3:15])(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[CH3:28][NH:27][C:25]([C:24]1[C:19]2[CH:18]=[C:17]3[C:36]([CH3:38])=[CH:39][C@H:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:10][N:11]([S:12]([CH3:15])(=[O:13])=[O:14])[C:16]3=[N:21][C:20]=2[O:22][C:23]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:26]
Reactant: C=C[C@@H](CN(c1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1C(=C)C)S(C)(=O)=O)OCc1ccccc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: Cc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc3c(cc12)C(C)=C[C@H](OCc1ccccc1)CN3S(C)(=O)=O
Temperature: 100 °C

Procedure:
To a solution of (S)-6-(N-(2-(benzyloxy)but-3-enyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methyl-5-(prop-1-en-2-yl)furo[2,3-b]pyridine-3-carboxamide (543 mg, 0.963 mmol) in toluene is added Hoveyda-Grubbs 2nd generation catalyst (6 mg, 0.0096 mmol), and the reaction mixture is heated to 100° C. for 18 h. After the reaction is judged complete by LCMS, the toluene is removed in vacuo, and the solid is triturated with methanol to afford (S)-7-Benzyloxy-2-(4-fluoro-phenyl)-9-methanesulfonyl-5-methyl-8,9-dihydro-7H-1-oxa-9,10-diaza-cyclohepta[f]indene-3-carboxylic acid methylamide that is taken directly to the next step.
Reaction SMILES: Cl.[CH:2]1([N:8]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:15][N:16]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH2:39]([S:43](Cl)(=[O:45])=[O:44])[CH2:40][CH2:41][CH3:42]>>[CH2:39]([S:43]([N:21]1[CH2:22][CH2:23][N:18]([CH2:17][C:14]2[S:13][C:12]([NH:11][C:9](=[O:10])[N:8]([CH:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)[CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:16][CH:15]=2)[CH2:19][CH2:20]1)(=[O:45])=[O:44])[CH2:40][CH2:41][CH3:42]
Reactant: O=C(Nc1ncc(CN2CCNCC2)s1)N(C1CCCCC1)C1CCCCC1
Reactant: CCCCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Yield: 60.2 %

Procedure:
Prepared as described in general procedure (Q) using 1,1-dicyclohexyl-3-(5-piperazin-1-ylmethyl-thiazol-2-yl)-urea hydrochloride (30 mg, 0.06 mmol), DIEA (32 μL, 0.18 mmol) and butane-1-sulfonyl chloride (16 μL, 0.12 mmol) to afford 19 mg (61%) of the desired product after purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[I:13][C:14]1[C:19]([CH:20]=O)=[C:18]([O:22][CH3:23])[N:17]=[CH:16][CH:15]=1.O.C(=O)=O.II>CO.CN(C=O)C>[CH3:7][O:6][C:4]([C:3]1[C:2]2[NH:1][C:20]([C:19]3[C:18]([O:22][CH3:23])=[N:17][CH:16]=[CH:15][C:14]=3[I:13])=[N:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: COc1nccc(I)c1C=O
Reactant: COC(=O)c1cccc(N)c1N
Agent: II
Agent: O=C=O
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2nc(-c3c(I)ccnc3OC)[nH]c12
Temperature: 25 °C
Yield: 59 %

Procedure:
In a 250 mL round-bottomed flask, methyl 2,3-diaminobenzoate (1.5 g, 9.03 mmol) was combined with methanol (25 mL) to give a yellow solution that was stirred under nitrogen and cooled in a water/dry ice bath. To this was added drop wise 4-iodo-2-methoxynicotinaldehyde (2.37 g, 9.03 mmol) dissolved in methanol (15 mL) and DMF (10 mL). During the addition more methanol (25.0 mL) was added to the reaction. The reaction was kept in the water/dry ice bath for 2.5 hr, allowed to warm to room temperature over 3 hr, and then cooled in a water/dry ice bath. To this was added drop wise iodine (1.49 g, 5.87 mmol) dissolved in methanol (15 mL) and then the reaction was allowed to warm to room temperature overnight. The reaction was concentrated, diluted with ethyl acetate (200 mL) and saturated Na2S2O3 (200 mL) and mixed. Significant insoluble material was present and the mixture was filtered. The resulting solid was washed with ethyl acetate and water. The filtrate was separated and the resulting aqueous layer was extracted with ethyl acetate (100 mL) and DCM (3×150 mL). The organic layers were washed with saturated Na2S2O3 and brine, combined, dried over MgSO4, and concentrated as a red oil/solid. The insoluble solid from the original extract was washed with DCM (5×100 mL) and the filtrate was concentrated as a dark red/black solid. The liquid extracted crude and the solid extract crude were dissolved in minimal DCM, combined, and purified by flash chromatography (silica gel, 120 g, 0% to 60% ethyl acetate in hexanes) to give 2-(4-iodo-2-methoxy-pyridin-3-yl)-3-H-benzoimidazole-4-carboxylic acid methyl ester, as a purple solid, 0.73 g LC/MS calcd for C15H12IN3O3 (m/e) 409.0, obsd 410.0 (M+H); 1H NMR (DMSO-d6) δ: 12.68 (s, 1H), 8.05 (d, J=5.5 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.88-7.95 (m, 1H), 7.67 (d, J=5.3 Hz, 1H), 7.38 (t, J=7.9 Hz, 1H), 3.96 (s, 3H), 3.82 (s, 3H). The original insoluble solid remaining after being extracted with DCM was subsequently extracted with boiling methanol (5×20 ml). The methanol filtrate was concentrated and dried, yielding additional product (83% pure by LCMS), as the sodium salt (assumed) and as a dark purple solid, 0.57 g. The remaining original insoluble solid after the DCM and methanol extractions yielded additional product (90% pure by LCMS), as the sodium salt (assumed) and as a purple solid, 0.88 g. The combined yield was 59%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=3)=[O:22])=[C:7]([CH:18]([CH3:20])[CH3:19])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C([O:35][C:36](=O)[CH2:37][CH2:38][CH2:39]Br)C>CN1C(=O)CCC1.CCOC(C)=O>[CH2:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([N:1]3[CH2:39][CH2:38][CH2:37][C:36]3=[O:35])[CH:10]=2)[C:6]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[O:22])=[C:7]1[CH:18]([CH3:19])[CH3:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(N)cc2n1Cc1ccccc1
Reactant: CCOC(=O)CCCBr
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(N3CCCC3=O)cc2n1Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 125, 20 mg, 0.046 mmol) and ethyl4-bromobutanoate (13 μl, 0.092 mmol) in NMP (1 ml) was heated at 168° C. for 16 h, cooled to room temperature, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: C([O:3][C:4](=[O:55])[CH:5]([O:7][P:8]([CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:54])[NH:33][C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([NH:41][C:42]4[N:47]=[C:46]([C:48]5[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=5)[CH:45]=[CH:44][N:43]=4)[CH:35]=3)=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)([O:10]C1C=CC=CC=1)=[O:9])[CH3:6])C.[OH-].[Na+].Cl>C(#N)C.O>[OH:10][P:8]([CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32](=[O:54])[NH:33][C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([NH:41][C:42]4[N:47]=[C:46]([C:48]5[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=5)[CH:45]=[CH:44][N:43]=4)[CH:35]=3)=[CH:30][CH:31]=2)[CH2:21][CH2:20]1)([O:7][CH:5]([CH3:6])[C:4]([OH:55])=[O:3])=[O:9]
Reactant: CCOC(=O)C(C)OP(=O)(CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc2)CC1)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(CCP(=O)(O)OC(C)C(=O)O)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.9 %

Procedure:
To a solution of 2-{[2-(4-{4-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenylcarbamoyl]-benzyl}-piperazin-1-yl)-ethyl]-phenoxy-phosphinoyloxy}-propionic acid ethyl ester (6 mg, 0.008 mmol) in 2:1 acetonitrile/water (0.3 mL) was added 1N NaOH (50 μL, 0.048 mmol). The solution was allowed to stir at room temperature for 1 hour when completion of the reaction was observed by LCMS. The reaction was acidified by 1N HCl (50 μL) solution and purified by RP HPLC using a C18 column with a gradient of H2O— Acetonitrile (5-100%) over 20 minutes to provide 2 mg (38%) of the product. 1H NMR (300 MHz, CD3OD) δ 1.51 (d, 3H, J=7 Hz), 2.04 (m, 2H), 2.33 (s, 3H), 2.96 (bs, 4H), 3.31 (m, 2H), 3.4 (bs, 4H), 3.89 (s, 2H), 4.88 (1H, possible overlap with solvent), 7.30 (m, 2H), 7.48-7.57 (m, 4H), 7.96-7.99 (m, 4H), 8.32 (s, 1H), 8.56 (d, 1H, J=5 Hz), 8.86 (d, 1H, J=2 Hz), 9.10 (dd, 1H, J=2, 5 Hz), 9.59 (s, 1H); 31P (121.4 MHz, CD3OD) δ 20.0; MS (m/z) 660 [M+H]+.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[CH:8]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:27][CH2:26]3)=[C:21]([CH2:28][C:29]3[CH:38]=[CH:37][C:32]4[O:33][CH2:34][CH2:35][O:36][C:31]=4[CH:30]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:39][O:40]C(=O)C)(=O)C.[OH-].[Li+]>CO.C1COCC1.O>[CH:25]1([C:22]2[CH:23]=[CH:24][C:19]([C@H:8]3[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:39][OH:40])[O:7]3)=[CH:20][C:21]=2[CH2:28][C:29]2[CH:38]=[CH:37][C:32]3[O:33][CH2:34][CH2:35][O:36][C:31]=3[CH:30]=2)[CH2:27][CH2:26]1
Reactant: CC(=O)OC[C@H]1OC(c2ccc(C3CC3)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: OC[C@H]1O[C@@H](c2ccc(C3CC3)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a stirred solution of acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (10.5 g, 17.61 mmol) in methanol:THF:water 3:2:1 (120 mL) was added lithium hydroxide (813 mg, 19.37 mmol). After stirring for 2 h at room temperature, the volatiles were evaporated under reduced pressure. The resulting residue was taken up in ethyl acetate (150 mL) and washed with brine (75 mL), brine containing 10 mL of 5% aqueous KHSO4 (75 mL), and brine (20 mL) again, then dried over sodium sulfate and concentrated to furnish (2S,3R,4R,5S,6R)-2-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (7.25 g)
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][CH:7]=[N:8][CH:9]=1)=[O:4].Br[CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1)=[O:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12]([CH2:11][N:6]2[C:5]([C:3]([OH:2])=[O:4])=[CH:9][N:8]=[CH:7]2)=[O:13])=[N:16][CH:17]=1
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: COC(=O)c1cnc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cn1cncc1C(=O)O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 200 mg 3H-Imidazole-4-carboxylic acid methyl ester, 396 mg), 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide and 220 mg K2CO3 in 2 ml DMF was stirred for 16 h at RT. The solvent was removed under reduced pressure and the precipitate dissolved in 5 ml THF/water 2:1. Then, 1.5 ml KOH 10% was added at RT and the reaction mixture was stirred for 16 h. Finally, 3 ml of halfconcentrated hydrochloric acid was added to precipitate the acid as a white solid. Yield: 260 mg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=[O:4].II.FC(F)(F)C(O[I:17](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.ClCCl>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([I:17])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cccs1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: II
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(I)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.4 %

Procedure:
To a solution of thiophene-2-carboxylic acid methyl ester (5.0 g, 28.7 mmol) in 35 mL of anhydrous carbon tetrachloride was added iodine (3.65 g, 14.37 mmol) and [Bis(trifluoroacetoxy)iodo] benzene (6.67 g, 15.52 mmol). This mixture was stirred overnight at room temperature. Dichloromethane was then added and the mixture was extracted with a solution of sodium thiosulfate 10%. The organic layer was evaporated and the residue was purified flash chromatography (hexane 40%:chloroform 60%) to give a solid which was triturated with pentane in order to remove remaining starting material affording compound P-1 as a white solid (4.8 g, 63% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[C:15](=[O:17])=[O:16]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=2[N:9]=[C:8]1[C:15]([OH:17])=[O:16]
Reactant: O=C=O
Reactant: c1cnc2ccoc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1nc2ccccc2o1
Reaction time: 0.5 h

Procedure:
Furopyridine (8, 0.71 g, 5.96 mmol) is treated with n-butyl lithium (2.5M in hexane, 2.86 ml, 7.15 mmol) in anhydrous THF (30 ml) at −78° C. After 30 minutes, dry carbon dioxide is passed through the reaction mixture and the temperature is allowed to rise gradually to room temperature in 3 hours. The mixture is concentrated to dryness. The residue is dissolved in water (˜10 ml) and extracted with ethyl acetate. The aqueous layer is acidified to pH˜3 with 1N HCl and kept in the refrigerator over night. The resulting precipitates are filtered and dried to give azabenzofuran carboxylic acid as a white powder (9)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:19]=[C:18](C(O)=O)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH3:23])[CH:16]=2)[N:11]=1)([OH:3])=[O:2].O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[CH3:23][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:1]([OH:3])=[O:2])[CH:19]=[CH:18]2
Reactant: Cc1ccc2nc(-c3ccccc3C(=O)O)cc(C(=O)O)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc2nc(-c3ccccc3C(=O)O)ccc2c1
Temperature: 180 °C
Yield: 35 %

Procedure:
In 1 ml of N,N-dimethylacetamide was dissolved 0.2 g of the 2-(2-carboxyphenyl)-6-methyl-4-quinolinecarboxylic acid obtained in Example 2 and heated at 180° C. for 1 hour. Then the reaction mixture was poured into water, made alkaline by adding sodium carbonate and washed with dichloromethane. The aqueous layer was neutralized with 3M hydrochloric acid until a precipitate was formed. After extracting with dichloromethane, 60 mg of 2-(6-methylquinolin-2-yl)benzoic acid was obtained. NMR (270 MHz, CD3OD): δ 7.58-8.32 (m,9H); 2.58 (s,3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1C(C2C=CC=CC=2C#N)C(C(OCC)=O)=C(C)[NH:15][C:16]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[CH2:1]([O:8][C:9](=[O:10])/[CH:11]=[C:16](\[NH2:15])/[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCc2ccccc2)C1c1ccccc1C#N
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccccc1
Yield: 65 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 2'-cyanobenzylideneacetoacetic acid ethyl ester and 75 mmols of β-aminocrotonic acid benzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-ethoxycarbonyl-4-(2'-cyanophenyl)-1,4-dihydropyridine-5-carboxylic acid benzyl ester of melting point 136° C (from ethanol).