Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.[CH:25]([N:28]1[CH2:33][CH2:32][N:31]([C:34](=[S:36])[NH2:35])[CH2:30][CH2:29]1)([CH3:27])[CH3:26]>CCO>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:35]=[C:34]([N:31]2[CH2:32][CH2:33][N:28]([CH:25]([CH3:27])[CH3:26])[CH2:29][CH2:30]2)[S:36][C:2]=1[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1
Reactant: CC(C)c1nnc2ccc(C(Br)C(=O)c3ccc(F)cc3F)nn12
Reactant: CC(C)N1CCN(C(N)=S)CC1
Solvent: CCO
Product: CC(C)c1nnc2ccc(-c3sc(N4CCN(C(C)C)CC4)nc3-c3ccc(F)cc3F)nn12
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 62.8 %

Procedure:
To a solution of 2-bromo-1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.49 g, 1.24 mmol, Preparation #A.2) in EtOH (10 μL) was added 4-isopropylpiperazine-1-carbothioamide (0.21 g, 1.12 mmol, Preparation #AO.1.1). The reaction mixture was stirred at about 40° C. for about 2.5 h. The reaction mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. DCM (35 mL) and water (20 mL) were added. The layers were partitioned and the organic layer was washed with additional water (200 mL). The organic layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The crude residue was purified by silica gel column chromatography DCM/MeOH (gradient from 100:0 to 90:10) to afford the title compound (0.34 g, 56%) as a yellow solid: LC/MS (Table 1, Method a) Rt=2.06 min; MS m/z: 484.2 (M+H)+.
Reaction SMILES: [C:1]([N:9]1[C:14](=[O:15])[C:13](I)=[CH:12][N:11]([CH2:17][CH2:18][CH2:19][CH2:20][Cl:21])[C:10]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[CH:26][N:25]=1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>COCCOC.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>[C:1]([N:9]1[C:14](=[O:15])[C:13]([C:28]2[CH:27]=[CH:26][N:25]=[C:24]([CH3:23])[CH:29]=2)=[CH:12][N:11]([CH2:17][CH2:18][CH2:19][CH2:20][Cl:21])[C:10]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: O=C(c1ccccc1)n1c(=O)c(I)cn(CCCCCl)c1=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: COCCOC
Solvent: O
Product: Cc1cc(-c2cn(CCCCCl)c(=O)n(C(=O)c3ccccc3)c2=O)ccn1
Yield: 25.1 %

Procedure:
3-Benzoyl-1-(4-chloro-butyl)-5-iodo-1H-pyrimidine-2,4-dione (Prep 44, 433 mg, 1 mmol) was dissolved in degassed DME-water solution (5-1, 30 mL). 2-methyl-pyridine 4-boronic acid (205 mg, 1.5 mmol), Na2CO3 (212 mg, 2 mmol), 2-(dicyclohexylphosphino)biphenyl (70 mg, 0.2 mmol) and Pd(PPh3)4 (231 mg, 0.2 mmol) were added and the mixture was refluxed for 6 hours. The solvents were evaporated under vacuum and the crude was partitioned between ethyl acetate and water. The organic phase was dried (Na2SO4) and evaporated; the crude was purified by flash chromatography with DCM-MeOH—NH4OH (98-2-0.2) and SCX cartridge washing with MeOH and eluting with MeOH/NH3 95:5 to give the title compound (100 mg, 25% yield).
Reaction SMILES: Br[C:2]1[CH:16]=[C:15]([F:17])[C:5]([O:6][C:7]([CH3:14])([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([F:18])[CH:3]=1.[C:19](=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CB1OB(C)OB(C)O1>[F:17][C:15]1[CH:16]=[C:2]([CH3:19])[CH:3]=[C:4]([F:18])[C:5]=1[O:6][C:7]([CH3:14])([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)(C)Oc1c(F)cc(Br)cc1F
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1c(F)cc(C)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
Ethyl 2-(4-bromo-2,6-difluorophenoxy)-2-methylpropanoate (200 mg), tetrakis-triphenylphosphine palladium (36 mg) and sodium carbonate (200 mg) were dissolved in a mixed solvent of dioxane (4.0 ml) and water (1.0 ml), trimethylboroxine (0.26 ml) was added thereto, followed by stirring under an argon atmosphere at 100° C. overnight. After cooling to room temperature, an insoluble substance was removed by celite filtration and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to obtain, as a colorless oily product, ethyl 2-(2,6-difluoro-4-methylphenoxy)-2-methylpropanoate (115 mg).
Reaction SMILES: C(O[C:9](=O)[N:10]([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH3:22])=[CH:17][CH:16]=1)=[O:14])C)C1C=CC=CC=1>O1CCCC1.CO.[C].[Pd]>[C:27]([O:26][C:24](=[O:25])[NH:23][C@H:21]([C:18]1[CH:17]=[CH:16][C:15]([C:13](=[O:14])[CH2:12][NH:10][CH3:9])=[CH:20][CH:19]=1)[CH3:22])([CH3:29])([CH3:28])[CH3:30]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)CN(C)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CNCC(=O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Reaction time: 2 h

Procedure:
159 mg of the compound [2-2] was dissolved in a mixed solvent of 4 mL of tetrahydrofuran and 2 mL of methanol, then 48 mg of 10% palladium carbon catalyst was added thereto, and the mixture was further stirred for 2 hours under hydrogen atmosphere. Thereto, 95 mg of 10% palladium carbon catalyst was further added and stirred for 3.5 hours under hydrogen atmosphere. The insolubles were filtered through celite and the filtrate was concentrated under reduced pressure, to obtain tert-butyl{(1S)-1-[4-(N-methylglycyl)phenyl]ethyl}carbamate [2-3] (hereinafter, referred to as the compound [2-3]) as crude and purified products. The compound [2-3] was used in the subsequent reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[S:18](Cl)(=[O:20])=[O:19]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:18]([C:12]2[C:13]([CH3:17])=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])(=[O:19])=[O:20])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Reactant: Nc1cc(Br)cnc1Cl
Product: Cc1cccc(Cl)c1S(=O)(=O)Nc1cc(Br)cnc1Cl

Procedure:
Prepared according to the methods described in reagent preparation 26 using 5-bromo-2-chloropyridin-3-amine and 2-chloro-6-methylbenzene-1-sulfonyl chloride in step 1. MS (EI) for C12H9BrCl2N2O2S: 393, 395, 397 (Br+Cl isotopes, MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1(B(O)O)[CH2:15][CH2:14][CH2:13][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>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(O)C>[C:11]1([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: OB(O)C1=CCCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
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: COCCOC
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C2=CCCC2)cc1
Temperature: 105 °C
Yield: 83.2 %

Procedure:
To 1-bromo-4-nitro-benzene (700 mg, 3.46 mmol), 1-cyclopentenylboronic acid (392 mg, 3.50 mmol), Pd(PPh3)4 (200 mg, 0.17 mmol), and Cs2CO3 (2258 g, 6.93 mmol) was added DME (8.4 mL) and ethanol (1.4 mL) and the reaction mixture was heated at 105° C. for 3 h. The reaction was concentrated in vacuo and purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to provide 1-(1-cyclopentenyl)-4-nitro-benzene (545 mg, 83% yield). 1H NMR (400.0 MHz, CDCl3) δ 8.19-8.15 (m, 2H), 7.58-7.52 (m, 2H), 6.44-6.42 (m, 1H), 2.77-2.71 (m, 2H), 2.62-2.56 (m, 2H), 2.11-2.03 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24]CC4C=CC=CC=4)=[C:20]([CH3:32])[CH:19]=3)([CH2:16][CH3:17])[CH2:14][CH3:15])=[N:10][C:9]=2[CH:33]=1)=[O:4]>[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([CH2:16][CH3:17])([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:32])[CH:19]=3)[CH2:14][CH3:15])=[N:10][C:9]=2[CH:33]=1)=[O:4]
Reactant: CCC(CC)(c1ccc(OCc2ccccc2)c(C)c1)c1nc2cc(C(=O)OC)ccc2o1
Agent: [Pd]
Product: CCC(CC)(c1ccc(O)c(C)c1)c1nc2cc(C(=O)OC)ccc2o1
Yield: 80.4 %

Procedure:
2-[1-(4-Benzyloxy-3-methyl-phenyl)-1-ethyl-propyl]-benzooxazole-5-carboxylic acid methyl ester (3.28 g, 7.39 mmol) and Pd—C (300 mg, 10%) is hydrogenated analogous to Example 1, step F to give the title product (2.10 g, 80%). MS (ES) m/e: 354.2 (M+1), 352.2 (M−1).
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cccc(O)c1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(O)c1O

Procedure:
To a solution of 2,3-dihydroxybenzoic acid (33.0 g, 214 mmol) in methanol (200 mL) was added sulfuric acid (5.0 mL) and the mixture was refluxed for 14 hours. The solvent was then distilled off under reduced pressure. To that residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 35.0 g of methyl 2,3-dihydroxybenzoate. A mixture of this compound (35.0 g, 208 mmol), ethyl bromoacetate (70.0 g, 420 mmol), and potassium carbonate (58.0 g, 420 mmol) in acetone (400 mL) was stirred for 14 hours, and filtered. The filtrate was concentrated under reduced pressure to provide 58.0 g of the title compound. Yield 80%. Oil.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C@@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]3[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=3)=[O:17])[CH2:12]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:32][C:33]([O:36][C:37]([NH:39][CH2:40][C@@H:41]1[CH2:46][CH2:45][C@H:44]([C:47](O)=[O:48])[CH2:43][CH2:42]1)=[O:38])([CH3:35])[CH3:34]>>[CH3:35][C:33]([O:36][C:37]([NH:39][CH2:40][C@@H:41]1[CH2:46][CH2:45][C@H:44]([C:47]([N:14]2[CH2:15][C@@H:11]([N:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]3)[CH2:12][C@H:13]2[C:16]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[CH:21][CH:20]=2)=[O:17])=[O:48])[CH2:43][CH2:42]1)=[O:38])([CH3:32])[CH3:34]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(S(C)(=O)=O)CC3)CN2)cc1
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](C(=O)N2C[C@@H](N3CCN(S(C)(=O)=O)CC3)C[C@H]2C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)CC1

Procedure:
Following the procedure described in Example 8, the compound prepared in Example 6 was treated with cis-4-[({[(2-methyl-2-propanyl)oxy]carbonyl}amino)methyl]cyclohexanecarboxylic acid to give the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>O>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([O:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Oc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Oc2cccnc2)cc1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
Equimolar portions (0.106 moles) of 3-hydroxypyridine, sodium hydroxide and p-toluenesulfonyl chloride were combined in 100 ml of water and stirred at 50° C. for 2.5 hours. The aqueous solution was extracted with chloroform, dried over sodium sulfate and distilled to yield an oil which crystallized on standing. Recrystallization from cyclohexane yielded a white solid, mp 76°-78° C., lit. mp 79° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: Fc1ccc(Br)cc1
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Product: COc1ncc(-c2cccc(-n3cnc(C(=O)c4ccc(F)cc4)c3)c2)c(OC)n1

Procedure:
This compound is prepared by method C using compound 12m and 1-bromo-4-fluorobenzene
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[NH2:15][C@@H:16]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:37][C:32]1[CH:31]=[C:30]([CH2:29][C@H:16]([NH:15][C:12]([C:9]2[S:10][CH:11]=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[CH:8]=2)=[O:14])[CH2:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])[CH:35]=[CH:34][C:33]=1[Cl:36]
Reactant: N[C@@H](Cc1ccc(Cl)c(Cl)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1csc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1nccc1-c1csc(C(=O)N[C@@H](Cc2ccc(Cl)c(Cl)c2)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (160 mg, 0.62 mmol) [prepared according to the procedure of Example 146], 2-[(2S)-2-amino-3-(3,4-dichlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (0.26 g, 0.67 mmol) [prepared according to the procedure of Preparation 6 except substituting 3,4-dichloro-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-phenylalanine (2.03 g, 6.07 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (376 mg, 0.80 mmol) in chloroform (4 mL). DIEA (0.55 mL, 3.15 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (25-75% EtOAc/Hex) affording the title compound (149 mg, 30%): LC-MS (ES) m/z=539 (M+H)+
Reaction SMILES: CCO[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:20](=[CH:22][CH:23]=1)[N:21]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]2[OH:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(Cl)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(Cl)cc2c1O

Procedure:
Using the procedure of Example 2, ethyl ethoxymethylene malonate and 4-chloro-aniline were reacted and treated with phenyl oxide to obtain ethyl 6-chloro-4-hydroxy-3-quinoline-carboxylate melting at >260° C.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[C:14]([C:15](=[O:16])[C:4]=2[CH:3]=1)=[CH:13][C:12]1[NH:17][C:18]2[CH:25]=[CH:24][C:23](C)=[CH:22][C:19]=2[C:20](=[O:21])[C:11]=1[CH:10]=3>O>[CH:23]1[CH:22]=[C:19]2[C:20]([C:11]3[C:12]([NH:17][C:18]2=[CH:25][CH:24]=1)=[CH:13][C:14]1[C:15]([C:4]2[C:5]([NH:8][C:9]=1[CH:10]=3)=[CH:6][CH:7]=[CH:2][CH:3]=2)=[O:16])=[O:21]
Reactant: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Reaction time: 7 h

Procedure:
20 g of C.I. pigment red 122 (in which the content of metal ions having a valence of at least 2 was 385 ppm), 80 g of the above aqueous dispersion of the pigment derivative (g) and 60 g of deionized water were mixed, and the mixture was dispersed with a paint shaker in the presence of zirconia beads as media for approximately 7 hours, to obtain a water-based pigment dispersion.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=O)=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=1>>[CH3:15][O:16][C:17]1[C:22]([NH:23][CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: COc1ncccc1N
Product: COc1ncccc1NCCc1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 33, step 1, (4-trifluoromethyl-phenyl)-acetic acid (commercially available) was coupled with 2-methoxy-pyridin-3-ylamine (commercially available) to give the title compound.
Reaction SMILES: [CH2:1]([C:3](=[CH:9][CH2:10][O:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])[CH2:13]1)[C:4]([O:6]CC)=[O:5])[CH3:2].[OH-].[Na+].Cl>CO.C(OCC)(=O)C>[CH2:1]([C:3](=[CH:9][CH2:10][O:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])[CH2:13]1)[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(=CCO[C@@H]1CCC[C@H](OCc2nc(-c3ccc(F)cc3)oc2C)C1)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(=CCO[C@@H]1CCC[C@H](OCc2nc(-c3ccc(F)cc3)oc2C)C1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
0.5 g of ethyl 2-ethyl-4-{(1R,3S)-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}but-2-enoate is dissolved in 5 ml of methanol, and 2.5 ml of a 1N aqueous sodium hydroxide solution are added. After 12 h of stirring at room temperature, the mixture is acidified with 3 ml of 1 N hydrochloric acid and the resulting precipitate is taken up in ethyl acetate. The solvent is removed under reduced pressure and the residue of the ester hydrolysis, 2-ethyl4-{(1R,3S)-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}but-2-enoic acid, is obtained as 0.45 g of a white solid. C23H28FNO5 (417.48) MS(ESI): 418 (M+H+)
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].Cl[C:24]([O:26][CH2:27][Cl:28])=[O:25]>ClCCl>[C:24](=[O:25])([O:22][CH2:21][CH2:20][CH:17]1[CH2:18][CH2:19][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH2:15][CH2:16]1)[O:26][CH2:27][Cl:28]
Reactant: O=C(Cl)OCCl
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCOC(=O)OCCl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine (3.22 ml) was added to an ice-cold solution of 2-(1-(tert-butoxycarbonyl)-4-piperidyl)-ethanol (7.6 g) in dichloromethane (33 ml) followed by chloromethyl chloroformate (3.23 ml) at such a rate that the temperature was kept below 10° C. After stirring overnight at room temperature the reaction mixture was washed twice with 0.5 M HCl followed by water and aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered and evaporated in vacuo to yield the title compound as a colourless oil.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12]3[CH:20]=[C:19]([NH:21][CH2:22][C:23]4[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=4[F:30])[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:7][CH:6]=2)[CH2:2]1.C[C:32](N(C)C)=[O:33].C(O)(C(F)(F)F)=O>CN(C=O)C>[F:30][C:24]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=1[CH2:22][NH:21][C:19]1[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([CH:3]3[CH2:4][N:1]([CH:32]=[O:33])[CH2:2]3)=[CH:6][CH:7]=2)[CH:20]=1
Reactant: CC(=O)N(C)C
Reactant: NC(=O)c1cnc(Nc2ccc(C3CNC3)cc2)cc1NCc1cc(F)ccc1F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cnc(Nc2ccc(C3CN(C=O)C3)cc2)cc1NCc1cc(F)ccc1F

Procedure:
Compound 6-(4-(azetidin-3-yl)phenylamino)-4-(2,5-difluorobenzylamino)nicotinamide (Example 213) (35 mg, 0.08 mmol) was stirred in 4 mL DMF with DMA (300 μL) at 120° C. in a sealed tube for three days. The mixture was acidified with 0.5 mL TFA and subjected to reverse phase preparative HPLC to isolate the title compound (15 mg). MS found for C23H21F2N5O2 as (M+H)+ 438.4. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.17 (1H, s), 8.02 (1H, s), 7.44 (2H, dt, J=8.0; 1.6 Hz), 7.21 (1H, m), 7.15-7.04 (3H, m), 5.85 (1H, s), 4.67 (1H, m), 4.51 (2H, s), 4.46 (1H, m), 4.27 (1H, m), 4.04 (2H, m) ppm.