Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[C:3]=1[OH:17].C(N(C(C)C)CC)(C)C.[CH3:27][O:28][CH2:29]Cl>C1COCC1.O>[Br:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[C:3]=1[O:17][CH2:27][O:28][CH3:29]
Reactant: CCCc1cc2cc(OC)ccc2c(O)c1Br
Reactant: COCCl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2cc(OC)ccc2c(OCOC)c1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.7 %

Procedure:
To a solution of 2-Bromo-6-methoxy-3-propyl-naphthalen-1-ol (94) (1.41 g, 4.78 mmol) in dry THF (23 mL) at 0° C. was added diisopropylethylamine (3.3 mL, 19.1 mmol) followed by chloromethyl methyl ether (1.1 mL, 14.3 mmol) slowly. Reaction mixture was stirred at ambient temperature for 24 h. Reaction mixture was diluted with water and the aqueous layer was extracted with DCM, washed organic layer with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified using 1:9 EtOAc:hexanes to provide 1.26 g (78%) of the title compound (95) as a solid. 1H NMR (400 MHz, d-CDCl3): δ 1.01 (t, J=7.4 Hz, 3H), 1.70-1.75 (m, 2H), 2.85 (t, J=7.7 Hz, 2H), 3.72 (s, 3H), 3.91 (s, 3H), 5.23 (s, 2H), 7.04 (s, 1H), 7.12 (dd, J1=2.6 Hz, J2=9.1 Hz, 1H), 7.39 (s, 1H), 8.03 (d, J=9.1 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][NH:6][C:7](=[O:36])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=3)=[CH:22][CH:21]=2)[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:9]=1.[OH-].[Na+].Cl>C1COCC1>[F:35][C:32]([F:33])([F:34])[C:29]1[CH:30]=[CH:31][C:26]([C:23]2[CH:24]=[CH:25][C:20]([CH:15]([O:14][C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[O:36])=[CH:13][CH:12]=3)[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:21][CH:22]=2)=[N:27][CH:28]=1
Reactant: CCCCC(Oc1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(C(=O)NCCC(=O)O)cc1)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1

Procedure:
3-(4-{1-[4-(5-trifluoromethyl-pyridin-2-yl)-phenyl]-pentyloxy}-benzoylamino)-propionic acid methyl ester (50 mg) is taken into THF (1.0 mL) and treated with NaOH (1.0 mL, 5.0 N), then refluxed under nitrogen. The reaction mixture is neutralized with HCl (1.0 mL, 5.0 N), extracted with ethyl ether, dried over sodium sulfate. Concentration gives the title compound. MS (ES): 499.2 [M+H]−, the structure is also confirmed by proton NMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20]4[N:21]([N:32]=[CH:33][C:34]=4[C:35](O)=[O:36])[C:22]=3[NH:23][C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[CH3:31])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:38]1([S:41]([NH2:44])(=[O:43])=[O:42])[CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20]4[N:21]([N:32]=[CH:33][C:34]=4[C:35]([NH:44][S:41]([CH:38]4[CH2:40][CH2:39]4)(=[O:43])=[O:42])=[O:36])[C:22]=3[NH:23][C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[CH3:31])=[O:16])[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(c4ccc(F)c(F)c4)CC3)cnc3c(C(=O)O)cnn23)c1
Product: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(c4ccc(F)c(F)c4)CC3)cnc3c(C(=O)NS(=O)(=O)C4CC4)cnn23)c1
Yield: 64.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-[4-(3,4-difluorophenyl)piperidine-1-carbonyl]-7-(2,5-dimethylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (100 mg, 0.20 mmol) obtained in Example 88, step 4 and cyclopropanesulfonamide (121 mg, 1.0 mmol), the title compound (79 mg, 65%) was obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[Br:14][C:15]1[C:16](Cl)=[N:17][CH:18]=[C:19]([CH:34]=1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)=[O:21]>CN(C=O)C>[Br:14][C:15]1[C:16]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:17][CH:18]=[C:19]([CH:34]=1)[C:20]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]([F:32])([F:31])[F:33])=[CH:27][CH:28]=1)=[O:21]
Reactant: OC1CCOCC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(OC2CCOCC2)c(Br)c1
Temperature: 120 °C
Reaction time: 3.5 h

Procedure:
Tetrahydro-2h-pyran-4-ol (0.361 mL, 3.79 mmol) and K2CO3 (314 mg, 2.275 mmol) were added to a suspension of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 44.2, 300 mg, 0.758 mmol) in DMF (2 mL) and the RM was stirred at 120° C. for 3.5 h. The solvent was evaporated off under reduced pressure. The residue was purified by flash chromatography (RediSep® Silica gel column, 40 g, EtOAc/n-hexane, isocratic 2:8) to afford 5-bromo-6-(tetrahydro-2h-pyran-4-yloxy)-N-(4-(trifluoromethoxy)phenyl)nicotinamide, of which (25 mg, 0.054 mmol) together with pyrimidin-5-ylboronic acid (30 mg, 0.160 mmol), Pd(Ph3P)4 (10 mg, 8.13 μmol) K3PO4 (35 mg, 0.163 mmol) and toluene (0.4 mL) was stirred at 110° C. for 10 h under an argon atmosphere. The cooled RM was diluted with MeOH, filtered through a cartridge of PL-Thiol MP-Resin, and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by preparative SFC (Column 4-EP; gradient 7% to 12% in 6 min.) and lyophilized to afford an off-white powder. UPLC-MS (Condition 2) tR=1.06 min, m/z=461.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.61-1.75 (m, 2H) 2.04 (m, J=10.00 Hz, 2H) 3.54 (m, J=8.80, 8.80 Hz, 2H) 3.70-3.80 (m, 2H) 5.37-5.47 (m, 1H) 7.39 (d, J=8.47 Hz, 2H) 7.87 (d, J=9.03 Hz, 2H) 8.50 (s, 1H) 8.82 (s, 1H) 9.15 (s, 2H) 9.22 (s, 1H) 10.45 (s, 1H).
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[C:5]2[C:21]([O:23][C:24](=O)[C:3](=[C:4]23)[CH:2]=1)=[O:22].[C:26]([C:30]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:33][C:31]=1[NH2:32])([CH3:29])([CH3:28])[CH3:27].N1C=CN=C1>O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[C:26]([C:30]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:33][C:31]=1[N:32]1[C:21](=[O:22])[C:5]2[C:4]3[C:19]4[C:8](=[CH:7][CH:6]=2)[C:9]2[C:20]5[C:13]([CH:12]=[CH:11][CH:10]=2)=[CH:14][CH:15]=[CH:16][C:17]=5[C:18]=4[CH:1]=[CH:2][C:3]=3[C:24]1=[O:23])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(C(C)(C)C)cc1N
Reactant: O=C1OC(=O)c2ccc3c4cccc5cccc(c6ccc1c2c63)c54
Agent: CC(=O)[O-]
Agent: [Zn+2]
Agent: c1c[nH]cn1
Solvent: O
Product: CC(C)(C)c1cc([N+](=O)[O-])c(C(C)(C)C)cc1N1C(=O)c2ccc3c4cccc5cccc(c6ccc(c2c36)C1=O)c54
Temperature: 170 °C

Procedure:
0.20 g (0.93 mmol) of perylene-3,4-dicarboxylic anhydride is mixed with 0.47 g (1.9 mmol) of 2,5-di-t-butyl-4-nitroaniline, 0.20 g of zinc acetate dihydrate and 4 g of imidazole, and the mixture is heated under argon at 170° C. for 22 h. The product is removed from the flask by washing with ethanol, treated with 2N hydrochloric acid and then boiled until all the ethanol has evaporated. The solid product is filtered off with suction, washed twice with water and then boiled in 10% potassium carbonate solution. The reaction product is again filtered off with suction while hot and washed several times with hot water until the filtrate run-off is no longer yellow. The residue is dried in a drying cabinet at 120° C. and then chromatographed on silica gel using toluene. The solution thus obtained is filtered through a D5 sintered crucible in order to remove any adhering silica gel. Yield 0.09 g (26%) of a red powder showing a red solid fluorescence, m.p. >360° C., Rf (CHCl3 /silica gel)=0.31, UV (CHCl3): λmax (ε)=514 (24450), 489 (25850), 356 (3100), 265 (33790). Fluorescence (CHCl3): λmax (Ired)=543 (1), 576 (0.45).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:8][CH:7]([C:9]([O:11]CC)=[O:10])[CH:6]1N1CCCCC1)[CH:2]([CH3:4])[CH3:3].C1(C)C=CC(S(OC)(=O)=O)=CC=1>O>[CH2:1]([CH:5]1[CH2:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)C1CC(CC(C)C)C1N1CCCCC1
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: O
Product: CC(C)CC1C=C(C(=O)O)C1
Temperature: 110 °C
Reaction time: 2 h
Yield: 41.9 %

Procedure:
Ethyl 3-isobutyl-2-piperidin-1-ylcyclobutanecarboxylate (994 g) and methyl p-toluenesulfonate (337 mL) were mixed. The mixture was stirred at 110° C. for 2 hr and water (1100 mL) was added to the mixture. The resulting mixture was washed with tert-butyl methyl ether/hexane=1/1 (600 mL) and hexane (600 mL). To the aqueous layer was added potassium hydroxide (503 g) at ice temperature. The resulting mixture was stirred at 95° C. for 4 hr. The reaction mixture was washed with diethyl ether (500 mL) and diethyl ether/hexane=1/1 (500 mL). To the aqueous layer was added concentrated hydrochloric acid (672 mL) at ice temperature. The mixture was extracted with ethyl acetate (1 L×2). The combined organic layer was washed with water (500 mL×2) and brine (500 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (240 g) as a crude product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=[CH2:15])[C:10]([O:12]CC)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)C>[CH2:15]=[C:9]([CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]([OH:12])=[O:11]
Reactant: C=C(CCc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=C(CCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
4-phenyl-2-methylenebutyric acid, ethyl ester (10 g, 49 mmole) was dissolved in 100 mL of absolute ethanol, Potassium hydroxide (3.32 g, 85%, 50 mmole) was added to the solution and the solution stirred overnight at room temperature. After 18 hours, all of the ester was hydolyzed. The solvent was removed under reduced pressure and the syrup dissolved in water. Enough concentrated HCl was added to acidify the solution (pH>3) and the product was extracted with ether (3×50 mL). The solution was dried over MgSO4, filtered and the solvent removed under reduced pressure. Recovered 8.6 g of product (97% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][NH:10]C(=O)OC(C)(C)C)[CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][NH2:10])[CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCCc1cccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
(See FIG. 10.) To a solution of 29 (249 mg, 1.05 mmol) in CH2Cl2 (3 mL) at 0° C. was added TFA (2 mL, excess), the ice bath was removed and the resultant solution was stirred at ambient temperature for 1 h. The solvent and excess TFA were removed with a stream of nitrogen and the residue was partitioned between HCl(aq) (1.0 M, 2 mL) and EtOAc (10 mL). The aqueous fraction was collected and subsequently washed with EtOAc (2×10 mL). To the remaining aqueous fraction was added CH2Cl2 (20 mL) and water (20 mL) and the pH was adjusted to 10 with NaOH(aq) (10 N) while stirring. The organic fraction was collected and the remaining aqueous fraction was extracted with CH2Cl2 (2×15 mL). The combined organic fractions were dried (Na2SO4), filtered and the solvent was removed in vacuo to afford the title compound 30 (97 mg, 68% yield) as a yellow oil: 1H NMR (CDCl3) δ 8.35 (m, 2H), 7.42 (m, 1H), 7.12 (m, 1H), 2.67-2.54 (m, 4H), 1.73-1.63 (m, 4H); LRMS (ESI) m/z calcd for C8H13N2 [M+H]+ 137. found 137.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(Br)cn1
Product: Nc1ccc(-c2ccc(C(F)(F)F)cc2)cn1
Yield: 70.5 %

Procedure:
Prepared as described in example C.32 (step 4) from commercially available 2-amino-5-bromo-pyridine (3.46 g, 20.0 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (4.18 g, 22.0 mmol). Obtained as an off-white solid (3.36 g, 71%). Mp 130° C.
Reaction SMILES: C[O:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C(Cl)Cl.O>C(Cl)Cl>[C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:20]=[CH:21][C:3]([OH:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 28.1 %

Procedure:
4-(4-Methoxy-phenoxy)-biphenyl (1.0 g, 3.6 mmol) in anhydrous CH2Cl2 (10 mL) was cooled to −78° C. and 1M boron tribromide (10.8 mL, 10.8 mmol) in CH2Cl2 was added dropwise over period of 20 min under nitrogen. The resulting mixture was stirred at −78° C. for 2 h and at rt for 1 h. Then it was cooled to 0° C. and poured slowly over 1:1 mixture of CH2Cl2/water. CH2Cl2 layer was separated, washed with water, brine, dried over anhydrous MgSO4 and concentrated. The crude product was purified using silica gel flash chromatography (20% EtOAc/Hexane) to obtain the product as yellow solid (265 mg, 28%): MS; m/z 260.9 (M−H); 1H NMR (400 MHz, DMSO-d6); δ 6.79-6.82 (m, 1H), 6.91-6.98 (m, 2H), 7.30-7.49 (m, 4H), 7.60-7.68 (m, 6H), 8.36 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([NH:13]C(OC(C)(C)C)=O)[C@H:10]([CH3:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[NH2:13][C@H:11]1[CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:22])[C@H:10]1[CH3:21]
Reactant: C[C@@H]1C(=O)N(Cc2ccccc2)C[C@@H]1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C(=O)N(Cc2ccccc2)C[C@@H]1N
Reaction time: 1 h

Procedure:
In 15 ml of trifluoroacetic acid was dissolved 1.76 g of Compound (44). After 1 hour, the solution was concentrated under reduced pressure. To the residue was added 100 ml of water, and the mixture was washed with benzene. The aqueous layer was adjusted to a pH of 12 with sodium hydroxide and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain the titled compound (45) as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([C:6]1[C:7]([Cl:14])=[N:8][C:9](Cl)=[CH:10][C:11]=1[CH3:12])#[N:5]>O1CCOCC1.C(OCC)(=O)C>[Cl:14][C:7]1[C:6]([C:4]#[N:5])=[C:11]([CH3:12])[CH:10]=[C:9]([N:2]([CH3:3])[CH3:1])[N:8]=1
Reactant: CNC
Reactant: Cc1cc(Cl)nc(Cl)c1C#N
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(N(C)C)nc(Cl)c1C#N
Reaction time: 2 h

Procedure:
Dimethylamine (8 mL) was added to a solution of 3-cyano-2,6-dichloro-4-methylpyridine (11.6 g) in dioxan (100 mL). After stirring for 2 hours the reaction mixture was diluted with ethyl acetate (1 L), washed with water, dried, filtered, and evaporated to a volume of 20 mL. The crystalline material was filtered to give 5.4 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]3[N:25]4[CH:26]([CH3:31])[CH2:27][CH2:28][O:29][CH2:30][C:24]4=[N:23][C:18]=3[CH:19]=[N:20]2)=[CH:15][CH:14]=1.[OH-].[NH4+]>C(Cl)(Cl)Cl>[Br:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]3[N:25]4[CH:26]([CH3:31])[CH2:27][CH2:28][O:29][CH2:30][C:24]4=[N:23][C:18]=3[CH:19]=[N+:20]2[O-:9])=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1CCOCc2nc3cnc4cc(Br)ccc4c3n21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC1CCOCc2nc3c[n+]([O-])c4cc(Br)ccc4c3n21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
MCPBA (4.39 g of 77% purity, 25 mmol) was added to a solution of 3-bromo-12-methyl-11,12-dihydro-8H,10H-[1,4]oxazepino[4′,3′:1,2]imidazo[4,5-c]quinoline (2.6 g, 7.8 mmol) in chloroform (20 mL), and the reaction mixture was stirred overnight at room temperature. Aqueous ammonium hydroxide was added. The aqueous layer was separated and extracted twice with chloroform. The combined organic fractions were concentrated under reduced pressure and further dried under high vacuum to provide 3-bromo-12-methyl-5-oxido-11,12-dihydro-8H,10H-[1,4]oxazepino[4′,3′:1,2]imidazo[4,5-c]quinoline.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>>[CH2:30]([N:32]([CH2:33][CH3:34])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1)[CH3:31]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Reactant: CCNCC
Product: CCN(CC)c1nc(-n2cc(C(=O)O)cn2)nc2cc(F)c(-c3ccccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and diethylamine in step E. MS (ESI): predicted mass calcd. for C23H22FN5O2, 419.2
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:10]=[N:11][CH:12]=[N:13][CH:14]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[Li+:16].C1COCC1>C(O)(=O)C>[CH3:8][C:2]([C:9]1[CH:14]=[N:13][CH:12]=[N:11][CH:10]=1)([CH3:1])[C:3]([O-:5])=[O:4].[Li+:16]
Reactant: CCOC(=O)C(C)(C)c1cncnc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C(=O)[O-])c1cncnc1

Procedure:
A mixture of ethyl 2-methyl-2-(5-pyrimidinyl)propionate (4.64 g), 1.0N lithium hydroxide (26 mL) and THF (100 mL) was heated to reflux under argon for 26 h. The mixture was allowed to cool, adjusted to pH 7 with acetic acid, and concentrated to dryness to give 4.11 g of lithium 2-methyl-2-(5-pyrimidinyl)propionate as a pale solid.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5]>[OH-].[NH4+].O>[NH2:15][C:12]1[CH:13]=[CH:14][C:2]([OH:1])=[C:3]([CH:11]=1)[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5]
Reactant: O=C(O)CCC(=O)c1cc([N+](=O)[O-])ccc1O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(O)c(C(=O)CCC(=O)O)c1
Reaction time: 1 h
Yield: 45.7 %

Procedure:
A solution of 3-(2-hydroxy-5-nitrobenzoyl)propionic acid (5.5 g, 0.023 mole) in ammonium hydroxide solution (5N; 100 ml) was added to a stirred, boiling solution of ferrous sulphate heptahydrate (45 g, 0.161 mole) in water (200 ml). Stirring under reflux was continued for a futher 1 hour, ammonium hydroxide solution was added to pH 9, the mixture was filtered through Kieselguhr and evaporated to dryness. The solid residue was crystallised from ethanol to give pale yellow needles of 3-(5-amino-2-hydroxybenzoyl)propionic acid (2.2 g, 46%, m.p. 158°-160°).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>CO.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>[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10]
Reactant: N#CCc1ccccc1I
Reactant: OB(O)c1cccc(F)c1F
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: CO
Product: N#CCc1ccccc1-c1cccc(F)c1F

Procedure:
To a suspension of (2-iodo-phenyl)-acetonitrile (Aldrich, 2.4 g, 10 mmol) and 2,3-difluorophenylboronic acid (Aldrich, 2.4 g, 15 mmol) in anhydrous methanol (10 mL) and toluene (20 mL) was added Cs2CO3 (9.8 g, 30 mmol). The mixture was degassed with nitrogen, followed by the addition of tetrakis(triphenylphosphine)palladium (1.2 g, 1 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[CH:6]=[CH:7][CH:8]=O.[C:16]([CH2:18][C:19]([N-:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])#[N:17]>>[C:24]1([CH2:23][CH2:22][NH:21][C:19](/[C:18](=[CH:8]/[CH:7]=[CH:6]/[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:12]([OH:13])=[C:11]([O:14][CH3:15])[CH:10]=2)/[C:16]#[N:17])=[O:20])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N#CCC(=O)[N-]CCc1ccccc1
Reactant: COc1cc(C=CC=O)cc(OC)c1O
Product: COc1cc(/C=C/C=C(\C#N)C(=O)NCCc2ccccc2)cc(OC)c1O
Yield: 82.6 %

Procedure:
The compound was prepared as described in Example 3 by adding 3,5-dimethoxy-4-hydroxycinnamaldehyde (0.1 g, 0.48 mmol) to N-(cyanoacetyl)phenylethylamide (Example 20, 0.091 g, 0.48 mmol). The residue was purified by silica gel chromatography (CHCl3-hexane, 1:1) to give a yellow solid (0.15 g, 83% yield). The product gave the following analytical data:
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([CH:15]=[O:16])[CH:12]=[C:11]([O:17][CH3:18])[C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[BH4-].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[C:11]([O:17][CH3:18])[C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)COc1c(F)cc(C=O)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)COc1c(F)cc(CO)cc1OC
Yield: 60.9 %

Procedure:
The compound was prepared according to general procedure F with Ethyl 2-(2-fluoro-4-formyl-6-methoxyphenoxy)acetate (1.4 mmol) in THF (20 ml) and water (20 ml) and NaBH4 (1.4 mmol). 220 mg of compound were obtained. This compound was used without further purification. 1H NMR (250 MHz, CDCl3): δ 1.33 (t, J=7.1 Hz, 3H), 3.90 (s, 3H), 4.28 (q, J=7.1 Hz, 2H), 4.65 (s, 2H), 4.71 (s, 2H) 6.95 (s, 1H), 6.76 (m, 2H). MS (ESI): m/z 538.8 [2M+Na]+
Reaction SMILES: [CH2:1]([N:3]1[N:7]=[N:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:25])[N:11]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[C:10]2=[O:39])=[N:4]1)[CH3:2].[ClH:40]>O1CCOCC1>[ClH:40].[CH2:1]([N:3]1[N:7]=[N:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)[S:17][C:13]=3[C:12](=[O:25])[N:11]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:10]2=[O:39])=[N:4]1)[CH3:2]
Reactant: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccc(F)cc4)cc32)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)cc4)cc32)n1

Procedure:
Tert-butyl 4-{1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(4-fluorophenyl)-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (292 mg, compound B60) and a solution of hydrogen chloride in 1,4-dioxane (1.3 ml, 4.0 M) in 1,4 dioxane (8 ml) are reacted according to the procedure described in example B78 to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH2:8]Br.[C:21]([O-:24])(=[O:23])[CH3:22].[Na+]>CN(C=O)C.O>[C:21]([O:24][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:10](=[O:11])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)=[CH:3][C:2]=1[Br:1])(=[O:23])[CH3:22]
Reactant: CCOc1ccc(C(=O)c2ccc(CBr)c(Br)c2)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C(=O)c2ccc(COC(C)=O)c(Br)c2)cc1
Temperature: 68 °C
Reaction time: 2.5 h
Yield: 95 %

Procedure:
To a solution of (3-bromo-4-(bromomethyl)phenyl)(4-ethoxyphenyl)methanone (0.456 g, 1.15 mmol) in 15 mL of DMF was added sodium acetate (0.188 g, 2.29 mmol). After being stirred for 2.5 h at 68° C., the mixture was diluted with 15 mL of H2O and extracted 3× with ethyl acetate. The combined organic layers were washed once with saturated NH4Cl, once with saturated brine and dried over Na2SO4. Concentration under reduced pressure gave 0.412 g of the crude product, which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz): δ 7.95 (d, J=1.2 Hz, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.68 (dd, J=1.2, 8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 6.95 (d, J=8.8 Hz, 2H), 5.25 (s, 2H), 4.12 (q, J=7.0 Hz, 2H), 1.46 (t, J=7.0 Hz, 3H); MS ESI (m/z) 377 (M+1)+, calc. 376.