Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CN(C=O)C>[OH:13][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](O)c1ccccc1
Yield: 86.7 %

Procedure:
Ethyl phenylglyoxylate (1.6 mmol) was asymmetrically reduced in the same manner as in Example 6, except that DMF was used as the reaction medium, giving 0.25 g of ethyl (R)-(-)-2-hydroxy-2-phenylacetate, having specific rotation [α]D20 of 38.8° (cl. 00, CHCl3). The synthesis yield was 80% and the optical yield was 75% e.e.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:10])([CH3:3])[CH3:2].[N+:21]([C:24]1[CH:25]=[C:26]([S:30]([CH2:33][CH2:34]O)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[N+:21]([C:24]1[CH:25]=[C:26]([S:30]([CH2:33][CH2:34][O:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][NH:11][C:9](=[O:10])[CH2:8][O:7][C:6]2[CH:18]=[CH:19][CH:20]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: CC(C)c1cccc(OCC(=O)NCCCC(=O)O)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)CCO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)c1cccc(OCC(=O)NCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Yield: 97.5 %

Procedure:
A mixture of 4-(3-isopropylphenoxyactamido)butyric acid (Intermediate 24, 3.1 g, 11.1 mmol, 1.1 eq), 2-(3-nitrobenzenesulfonyl)ethanol (2.3 g, 10.0 mmol), and TsOH.H2O (0.5 g) in 100 mL of benzene was heated overnight to reflux temperature with a Dean-Stark trap. Thereafter the mixture was concentrated by evaporation and the resulting residual oil was purified by column chromatography (CH2Cl2 to 1% MeOH in CH2Cl2) to give Intermediate 25 (4.8 g, 97%) as a light yellow oil which solidified on standing.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][C:29]1[CH:33]=[C:32]([CH2:34][C:35](O)=[O:36])[O:31][N:30]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][C:32]5[O:31][N:30]=[C:29]([CH3:28])[CH:33]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: Cc1cc(CC(=O)O)on1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: Cc1cc(CC(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4CCO5)CC3)CC2)on1

Procedure:
The title compound, white solid (68 mg, 75%), MS (ISP) m/z=454.4 [(M+H)+], mp 172.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and 2-(3-methylisoxazol-5-yl)-acetic acid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3]1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH2:16]([N:23]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCCC(=O)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1CCCC(=NCc2ccccc2)C1
Reaction time: 8 h

Procedure:
A reaction mixture of tert-butyl 3-oxocyclohexylcarbamate (4 mmol, 852 mg) and benzylamine (4 mmol, 436 μL) in refluxing toluene (25 mL) in a Dean-Stark apparatus was stirred for overnight. The product, tert-butyl 3-(benzylimino)cyclohexylcarbamate, was obtained after evaporation of solvent.
Reaction SMILES: O=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6]CC)=O.S(O)(O)(=O)=O.[CH2:17]([NH:19][C:20]([NH2:22])=[NH:21])[CH3:18].[Na].C(O)(=O)C>C(O)C>[CH2:17]([NH:19][C:20]1[N:22]=[C:4]([OH:6])[CH:3]=[C:2]([CH2:9][CH2:10][CH3:11])[N:21]=1)[CH3:18]
Reactant: CCNC(=N)N
Reactant: CCCC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCc1cc(O)nc(NCC)n1
Reaction time: 0.17 h
Yield: 85 %

Procedure:
Ethyl 3-oxo-hexanoate (4.74 g; 30 mM) and N-ethylguanidine sulphate (4.08 g; 30 mM) were dissolved in a solution prepared by dissolving sodium (1.4 g; 0.65 g atom) in ethanol (100 ml) and the mixture was heated under reflux on the steam bath for 18 hours. Acetic acid (5 ml) was added to the cooled mixture which was stirred for 10 minutes. Insoluble material was removed by filtration and the filtrate was evaporated. The residue was partitioned between water (50 ml) and methylene chloride (50 ml). The aqueous layer was extracted twice with methylene chloride (50 ml). The combined extracts were dried and the solvent evaporated. The residue was crystallised from cyclohexane to give 2-ethylamino-4-hydroxy-6-propylpyrimidine as a solid (4.6 g; 85% yield), m.p. 108°-110° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]([O:20][CH3:21])=[O:19])=[N:6][C:7]=1[CH:8]1[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1.C(O)(=O)C(O)=O.C([O-])(O)=O.[Na+].C(OCC)(=O)C>CC(C)=O.O.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]([O:20][CH3:21])=[O:19])=[N:6][C:7]=1[CH:8]1[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]1
Reactant: COC(=O)c1ccc(F)c(C2CCC3(CC2)OCCO3)n1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(F)c(C2CCC(=O)CC2)n1
Reaction time: 72 h
Yield: 98 %

Procedure:
To a solution of methyl 5-fluoro-6-(1,4-dioxaspiro[4.5]decan-8-yl)picolinat (1.0 equiv.) in acetone and water (1:1, 0.04 M) was added oxalic acid dehydrate (2.0 equiv.) and the reaction mixture was stirred for 3 days. The solution was then neutralized by the addition of solid NaHCO3, the mixture was added to ethyl acetate and brine, the organic phase was dried over magnesium sulfate, filtered, and concentrated. Methyl 5-fluoro-6-(4-oxocyclohexyl)picolinate was obtained in 98% yield. LC/MS=252.1 (M+H), Rt=0.68 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24](O)=[O:25])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN(C=O)C.C(Cl)(=O)C([Cl:41])=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24]([Cl:41])=[O:25])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CS(=O)(=O)c1ccc(Cn2c(C(=O)O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Cn2c(C(=O)Cl)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (1.0 g) in THF (10 ml) was added DMF (0.1 ml), and oxalyl chloride (0.4 ml) was added dropwise under ice-cooling. The reaction mixture was allowed to warm to room temperature, stirred for 30 min., and concentrated under reduced pressure. The obtained crystals were washed with diisopropyl ether to give the title compound (1.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:9]([CH3:20])[CH2:8]1.[C:22]([O:26][C:27]([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:22]([O:26][C:27]([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH:9]([CH3:20])[CH2:8]1)=[O:44])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC1CN(c2c(N)cnn2C)CCN1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnn2C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 21.6 %

Procedure:
To a solution of tert-butyl (±)-4-(4-amino-1-methyl-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate (400 mg, 2.05 mmol), 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (630 mg, 2.46 mmol), HATU (0.83 g, 8.19 mmol) in DMF (15 mL) was added TEA (1.5 mL). The reaction mixture was stirred at 25° C. for 20 hours and poured into water (100 mL). The mixture was extracted with EtOAc (50 mL×2). The combined organic layers was washed with water (50 mL×2) and brine (30 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using DCM/MeOH (1:1) as eluting solvents to afford tert-butyl (±)-4-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate (280 mg, 52%) as white solid. 1H NMR (500 MHz, CDCl3) δ (ppm): 10.32 (s, 1H), 8.70 (s, 1H), 7.80 (s, 1H), 7.38-7.35 (m, 1H), 7.06-7.03 (m, 2H), 4.34 (s, 1H), 3.94-3.97 (m, 1H), 3.81 (s, 3H), 3.67-3.40 (m, 1H), 3.20-3.25 (m, 2H), 3.04-3.06 (m, 1H), 2.88-2.90 (m, 1H), 1.55 (s, 9H), 1.47 (s, 9H), 1.34-1.36 (d, J=6.4 Hz, 3H); MS (ESI) m/z=434 (M+H+).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C(O)(=O)[C:13]1[CH:21]=[CH:20][C:18](O)=[C:15]([O:16]C)[CH:14]=1.C(O)CCCCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:2]([O:16][CH2:15][CH2:14][CH2:13][CH2:21][CH2:20][CH3:18])(=[O:1])[C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: COc1cc(C=O)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCO
Product: CCCCCCOC(=O)c1ccc(O)c(OC)c1
Yield: 86 %

Procedure:
Hexyl vanillate was synthesized according to the method of Pearl, I.A., and McCoy, J. F. "Reaction of Vanillin and its Derived Compounds. Some Esters of Vanillic Acid." J. AM. CHEM. SOC. 69: 3071 (1947). Vanillic acid (20.2 g, 0.12 mol) was refluxed with n-hexanol (29.9 ml, 0.24 mol) in the presence of p-toluenesulfonic acid (0.2 g) for 26 hours. After the unreacted alcohol was removed by distillation in a vacuum, the hexyl vanillate was distilled and obtained in 86% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[CH:41]=[CH:40][N:39]2[N:42]=[CH:43][C:44](B3OC(C)(C)C(C)(C)O3)=[C:38]2[CH:37]=1.C(=O)([O-])[O-].[K+].[K+].C(N[C@H](C(O)=O)CS)(=O)C>O.CC(N(C)C)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:44]2[CH:43]=[N:42][N:39]3[CH:40]=[CH:41][C:36]([CH3:35])=[CH:37][C:38]=23)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccn2ncc(B3OC(C)(C)C(C)(C)O3)c2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccn2ncc(-c3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)c2c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 46.1 %

Procedure:
To a 25 mL reaction flask equipped with magnetic stir bar and thermometer was added tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (200 mg, 0.401 mmol) and 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (124 mg, 0.481 mmol), followed by potassium carbonate (325 mesh powder) (111 mg, 0.802 mmol), DMA (6 mL), and water (0.400 mL). The mixture was stirred at room temperature for 3 min before degassing with vacuum and N2 back-fill (5×). To the resulting deep purple mixture was added Pd-118 (10.93 mg, 0.016 mmol). The reaction mixture was degassed again with vacuum and N2 back-fill (5×). The flask was wrapped tightly with plastic film, placed in an oil bath, and the reaction mixture was stirred at 80° C. for 18 hours. Solid N-acetyl cysteine (65.4 mg, 0.401 mmol) was added and the mixture was stirred at 70° C. for 2 h. The mixture was subsequently diluted with water and extracted with EtOAc (200 mL). The organic layer was dried and concentrated to give a residue, which was purified by preparative HPLC, eluting with a gradient of 55-80% ACN (0.035% TFA) and water (0.05% TFA). The fractions were collected to give, upon basic work-up, the title compound as a light yellow solid (110 mg, 46%).
Reaction SMILES: O[C:2]1([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21]>C(OCC)(=O)C.CCCCCC>[CH3:21][C:3]1([CH3:22])[CH:2]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4]1
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)CCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2CCc1ccccc1
Yield: 92 %

Procedure:
Using N-(3-hydroxy-2,2,6,7-tetramethyl-3-(2-phenylethyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 240, the title compound was synthesized in the same manner as in Example 271. Yield: 92%. Melting point: 158-159° C. (ethyl acetate-hexane).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:13])[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][N:17]=1>ClC1C=CC=CC=1>[CH3:14][O:15][C:16]1[N:17]=[CH:18][C:19]([NH:22][CH:4]=[C:5]([C:11](=[O:13])[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:20][CH:21]=1
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Reactant: COc1ccc(N)cn1
Solvent: Clc1ccccc1
Product: CCOC(=O)C(=CNc1ccc(OC)nc1)C(C)=O
Temperature: 135 °C
Yield: 84.1 %

Procedure:
A mixture of ethyl 2-(ethoxymethylene)-3-oxobutanoate (100 g, 0.54 mol) and 2-methoxy-5-aminopyridine (67 g, 0.54 mol) in chlorobenzene (500 mL) was heated at 135° C. for 4 h in a round bottomed flask that was equipped with a distillation apparatus to collect the ethanol generated during the reaction. The reaction mixture was cooled and concentrated and the residue was triturated in diethylether and filtered to obtain the desired product (120 g, 84%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 12.74 (d, 12.3 Hz, 1H), 8.35 (d, J=13.0 Hz, 1H), 8.07 (d, J=2.8 Hz, 1H), 7.55 (d, J=8.8, 2.9 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 4.30 (q, J=7.1 Hz, 2H), 2.55 (s, 3H), 1.33 (t, J=7.1 Hz, 1H); ESI MS m/z 265 [M+H]+.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-])=O.[Cl:10][C:11]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=1C=O>N1C=CC=CC=1>[Cl:10][C:11]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=1[CH:3]=[CH:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)CC(=O)[O-]
Solvent: c1ccncc1
Product: CCOC(=O)C=Cc1cc([N+](=O)[O-])ccc1Cl
Yield: 31 %

Procedure:
33 g (250 millimoles) of monoethyl malonate and 27 g (150 millimoles) of 2-chloro-5-nitrobenzaldehyde in 100 ml of pyridine were reacted similarly to Example 1, and the mixture was worked up in a conventional manner. Yield: 31%, mp. 138°-140° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[Cl:19][S:20](O)(=[O:22])=[O:21]>>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:20]([Cl:19])(=[O:22])=[O:21])[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:9])[F:10]
Reactant: O=S(=O)(O)Cl
Reactant: Cn1nc(-c2ccc(Cl)cc2)c(Cl)c1OC(F)F
Product: Cn1nc(-c2ccc(Cl)c(S(=O)(=O)Cl)c2)c(Cl)c1OC(F)F
Temperature: 130 °C
Reaction time: 4 h

Procedure:
47.9 g (0.16 mol) of 4-chloro-3-(4-chlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole were added a little at a time at 0° C. to 91 ml of chlorosulfonic acid. The mixture was stirred at 130° C. for 4 hours and then cooled, and the solution was poured carefully into ice-water. Product dissolved in the aqueous phase was extracted twice with dichloromethane. The combined organic phases were subsequently washed with saturated sodium hydrogen carbonate solution and with sodium chloride solution, then dried over magnesium sulfate and finally concentrated. Yield: 47.9 g.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[O:17])=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:28])[C:3]([OH:29])=[O:2])=[CH:10][CH:9]=1)=[O:17]
Reactant: COC(=O)C(=O)c1ccc(OCCCNC(=O)c2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCCCNC(=O)c2ccc3ccccc3c2)cc1
Yield: 58.7 %

Procedure:
A mixture of 4-[[3-(2-naphthoylamino)propyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.76 g) in hot methanol (10 mL) and sufficient tetrahydrofuran to dissolve the solids was treated with 1N sodium hydroxide (4.0 mL) and diluted with water. The organic solvent was removed under vacuum and the residue was mixed with water, acidified with excess 2N hydrochloric acid, and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from acetone-hexane provided 0.43 g of 4-[[3-(2-naphthoylamino) propyl]oxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 169°-170° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][CH2:17]3)=[CH:12][N:11]=2)=[CH:5][C:4]([C:26]2[N:33]=[CH:32][CH:31]=[C:30]([N:34]3[CH2:46][CH2:45][N:37]4[C:38]5[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=5[CH:44]=[C:36]4[C:35]3=[O:47])[C:27]=2[CH:28]=[O:29])=[CH:3]1.[BH4-].[Na+]>CO>[OH:29][CH2:28][C:27]1[C:26]([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:17][CH2:18][N:19]([CH:22]5[CH2:23][O:24][CH2:25]5)[CH2:20][CH2:21]4)=[CH:12][N:11]=3)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[N:33][CH:32]=[CH:31][C:30]=1[N:34]1[CH2:46][CH2:45][N:37]2[C:38]3[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=3[CH:44]=[C:36]2[C:35]1=[O:47]
Reactant: Cn1cc(-c2nccc(N3CCn4c(cc5c4CCCC5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2nccc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reaction time: 0.5 h
Yield: 16.5 %

Procedure:
To the solution of 104c (360 mg, 0.6 mmol) in methanol (50 mL) was added sodium borohydride (70 mg, 1.8 mmol) at 0° C. and stirred for another 30 minutes. Then the reaction mixture was quenched with water (2 mL) and concentrated. The residue was purified with reverse-phase prep-HPLC to afford 104 (63 mg, 16%) as an off-white solid. LCMS: [M+H]+ 637. 1H NMR (500 MHz, DMSO) δ 8.70 (d, J=3.0, 1H), 8.65 (d, J=5.5, 1H), 8.34 (s, 1H), 7.85 (d, J=3.0, 1H), 7.60 (d, J=2.5, 1H), 7.36-7.37 (m, 2H), 7.22-7.23 (m, 1H), 6.56 (s, 1H), 5.12 (t, J=5.5, 1H), 4.55-4.56 (m, 2H), 4.43-4.45 (m, 4H), 4.14-4.16 (m, 3H), 3.93-3.95 (m, 1H), 3.60 (s, 3H), 3.43-3.44 (m, 1H), 3.05-3.08 (m, 4H), 2.61-2.63 (m, 2H), 2.46-2.47 (m, 2H), 2.36-2.39 (m, 4H), 1.68-1.78 (m, 4H).
Reaction SMILES: C([C@](O)(C(C)=C)C(O)=O)C.[CH2:11]([N:13]([CH2:29][CH3:30])[C:14]([C:16]1([CH2:27][CH3:28])[C:24]2[CH:23]=CNC(=O)[C:19]=2C(=O)[O:17]1)=[O:15])[CH3:12].C(N(C(C)C)C(C)C)C.S(Cl)(Cl)=O.C(NCC)C>ClCCl>[CH2:29]([N:13]([CH2:11][CH3:12])[C:14](=[O:15])[C@@:16]([CH2:27][CH3:28])([OH:17])[C:24]([CH3:23])=[CH2:19])[CH3:30]
Reactant: CCN(CC)C(=O)C1(CC)OC(=O)c2c1cc[nH]c2=O
Agent: C=C(C)[C@@](O)(CC)C(=O)O
Solvent: ClCCl
Solvent: CCNCC
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@](O)(CC)C(=O)N(CC)CC
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 65 %

Procedure:
To a solution of 1.000 g of compound (20) as obtained from example 14 (6.95 mmol) in 30 mL dichloromethane were added dropwise at −15° C. 2.5 mL N-ethyldiisopropyl amine (14.60 mmol, 2.1 eq) and after additional 8 min. 1.53 mL thionyl chloride (20.85 mmol, 3.0 eq). After 50 min., a solution of 7.22 mL diethylamine (69.5 mmol, 10.0 eq) in 20 mL dichloromethane was added dropwise using a syringe pump (addition time: 60 min.). The reaction mixture was allowed to slowly warm up to room temperature overnight. The reaction mixture was diluted with 50 mL dichloromethane and was then washed with 50 mL aqueous hydrochloric acid (1.0 M). The organic phase was dried over 5 g sodium sulfate and was filtered. The solid was washed with 10 mL dichloromethane. After evaporation of solvent in a rotary evaporator (40° C./10 mbar), the crude product (1.36 g, 98% by weight) was obtained as a yellow oil, which was purified by column chromatography with heptane/ethyl acetate (9:1) yielding the title compound (0.900 g, 4.515 mmol, 65% by weight, er=93.4:6.6) as yellow oil.
Reaction SMILES: I[C:2]1[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)CCC.[Cl-].[Li+].O>CN(C)C=O>[CH3:23][C:21]1[C:20]([CH3:24])=[CH:19][C:3]([O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[C:2]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:22]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COc1cc2nccc(Oc3cc(C)c(C)cc3I)c2cc1OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3cc(C)c(C)cc3-c3ccccn3)c2cc1OC
Temperature: 100 °C
Reaction time: 1 h
Yield: 4 %

Procedure:
4-(2-Iodo-4,5-dimethyl-phenoxy)-6,7-dimethoxyquinoline (compound 164) (95 mg), tri-n-butyl(2-pyridyl)tin (0.25 ml), and tetrakistriphenylphosphine palladium (64 mg) were dissolved in N,N-dimethylformamide (7 ml), lithium chloride (102 mg) was added to the reaction system, and the mixture was stirred at 100° C. for one hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (3 mg, yield 4%).
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:6]=[CH:7][C:8]2[S:12][CH:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=1>CN1CCCC1=O>[C:2]([C:5]1[CH:6]=[CH:7][C:8]2[S:12][CH:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=1)#[N:3]
Reactant: Cc1csc2ccc(Br)cc12
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: Cc1csc2ccc(C#N)cc12
Reaction time: 17 h
Yield: 90.1 %

Procedure:
To copper (I) cyanide (0.569 g, 6.35 mmol) was added 5-bromo-3-methyl benzo thiophene (1.179 g, 5.19 mmol) in N-methylpyrrolidinone (10 ml) and the mixture was stirred at 180°-190° C. for 17 h. This was then partitioned between ether (75 ml) and ammonia solution (75 ml). The ether layer was separated, washed with more ammonia solution (2×50 ml), dried (Na2SO4) and evaporated in vacuo to leave 0.81 g of an off-white solid. Chromatography on flash silica, eluting with 10% ethyl acetate/petroleum ether yielded 0.76 g (85%) of the title compound as a white solid. δ (CDCl3) 2.47 (3H, s), 7.23 (1H, s), 7.55 (1H, dd, J=8.3 and 1.5 Hz), 7.93 (1H, d, J=8.4 Hz), 8.03 (1H, d, J=1.4 Hz).