Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([OH:9])[C:3]=1[N:10]1[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]([CH3:21])[C:11]1=[O:22].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]#[CH:31].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH2:31][C:30]#[CH:29])[C:3]=1[N:10]1[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[N:12]([CH3:21])[C:11]1=[O:22]
Reactant: C#CCBr
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(O)cc(F)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(F)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Temperature: 65 °C
Reaction time: 5 h
Yield: 92.5 %

Procedure:
4.8 g (15 mmol) of 3-(2,4-difluoro-6-hydroxyphenyl)-1-methyl-6-trifluoromethyluracil and 3.2 g (23 mmol) of potassium carbonate were suspended in 50 ml of N,N-dimethylformamide, and 2.5 g (21 mmol) of propargyl bromide was dropwise added thereto at room temperature. After stirring at from 60 to 70° C. for 5 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained crude crystals were washed with isopropyl ether to obtain 5.0 g (yield: 92.63%) of the desired product as yellowish brown powder. Melting point: 159-162° C.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:10]=[C:11]([CH2:14][CH2:15][C:16]#[N:17])[C:12]#[N:13]>>[C:1]1([S:7][CH2:10][CH:11]([CH2:14][CH2:15][C:16]#[N:17])[C:12]#[N:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(C#N)CCC#N
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: N#CCCC(C#N)CSc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of thiophenol (3.63 g.), 2N aqueous sodium hydroxide (25 ml.) and 2-methyleneglutaronitrile (3.2 g.) was stirred at room temperature for 18 hours. The mixture was extracted with diethyl ether, and the ether extract washed with water and then dried and evaporated to dryness to give 2-(phenylthiomethyl)glutaronitrile which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[C:28]([CH:29]=O)=[CH:27][CH:26]=[CH:25][N:24]=1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:29]([C:28]3[C:23]([O:22][CH3:21])=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1ncccc1C=O
Product: COc1ncccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Br)cnc2[nH]1
Yield: 63.8 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and 2-Methoxy-pyridine-3-carbaldehyde (22.3 mg, 0.163 mmol) were reacted to produce 43 mg (64%) of the title compound. mp: 201° C., 1H NMR (300 MHz, DMSO-d6): 12.64 (s, 1H), 8.45 (d, J=8 Hz, 1H), 8.32 (s, 1H), 8.07 (s, 1H), 7.75 (s, 1H), 7.22 (m, 2H), 7.17 (d, J=8 Hz, 1H), 6.39 (s, 1H), 6.36 (s, 1H), 5.23 (t, J=8 Hz, 1H), 4.05 (s, 3H), 2.89 (s, 1H), 2.78 (s, 1H), 2.62 (d, J=8 Hz, 1H), 2.25 (d, J=8 Hz, 1H), 1.39 (d, J=8 Hz, 1H). MS: 455, 457 (M+H), HPLC: 2.39 min (G method).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:17])[C:10](=[CH2:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:18][NH2:19]>CO>[Si:1]([O:8][C@H:9]([CH3:17])[C@H:10]([CH2:16][NH:19][CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CN
Reactant: C=C(C(=O)OCC)[C@@H](C)O[Si](C)(C)C(C)(C)C
Solvent: CO
Product: CCOC(=O)[C@@H](CNC)[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of ethyl (3R)-3-t-butyldimethylsilyloxy-2-methylidenebutanoate (130 g) in methanol (1.3 l) was added a solution of 30% methylamine in methanol (63 ml). The resulting mixture was allowed to stir at ambient temperature for 2 days. Evaporation of the solvent gave ethyl (2S,3R)-3-t-butyldimethylsilyloxy-2-(methylaminomethyl)butanoate (150.0 g).
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Li][CH2:16]CCC.CI>C1COCC1>[C:10]([O:9][C:8](=[O:14])[NH:7][S:4]([C:1]1([CH3:16])[CH2:2][CH2:3]1)(=[O:6])=[O:5])([CH3:11])([CH3:13])[CH3:12]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)C1CC1
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NS(=O)(=O)C1(C)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
A solution of tert-butyl cyclopropylsulfonylcarbamate (4.3 g, 20 mmol) was dissolved in dry THF (100 ml) and cooled to −78° C. To this solution was added n-BuLi (17.6 ml, 44 mmol, 2.5 M in hexane) slowly. The reaction mixture was allowed to warm to room temperature over a period of 1.5 h. This mixture was then cooled to −78° C., and a solution of n-BuLi (20 mmol, 8 ml, 2.5M in hexane) was added, stirred for 1 h and a neat solution of methyl iodide (5.68 g, 40 mmol) was added. The reaction mixture was allowed to warm to room temperature with stirring overnight; then was quenched with aqueous saturated NH4Cl (100 ml) at room temperature. The mixture was extracted with EtOAc (100 ml). The organic layer was washed with brine; dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil which was crystallized from hexane to afford the product as a slightly yellow solid (3.1 g, 81%). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.97 (s, 1H), 1.44 (s, 12H), 1.35-1.33 (m, 2H), 0.93-0.91 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([B:24]3[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33](OC(N1CCCC1C(O)=O)=O)(C)(C)[CH3:34]>>[C:1]([O:5][C:6]([N:8]1[CH:9]([C:13]2[NH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([B:24]4[O:25][C:26]([CH3:32])([CH3:31])[C:27]([CH3:30])([CH3:29])[O:28]4)=[CH:20][CH:19]=3)=[CH:16][N:17]=2)[CH:10]2[CH2:11][CH:12]1[CH2:33][CH2:34]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1

Procedure:
3-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester was prepared following the procedure for 2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester, substituting 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester for Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester. LCMS-ESI+: calc'd for C26H36BN3O4: 465.28 (M+); Found: 466.21 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.Cl.[NH2:15]O.O>C(O)=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[C:5]#[N:15]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: O=CO
Product: N#Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A solution containing 0.92 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.49 g of hydroxylamine hydrochloride in 5.0 ml of formic acid was refluxed for 1 h. 50 ml of water was added and the product was filtered and washed with water. Yield 0.3 g (33%), m.p. 175°-178° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].[CH3:18]I.O>CN(C)C=O>[CH3:18][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([F:13])([F:14])[F:15])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C(F)(F)F)c(O)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C(F)(F)F)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-hydroxy-4-(trifluoromethyl)benzoate (see WO 2007/129745) (2.00 g) in N,N-dimethylformamide (9.00 mL), sodium hydride (60% dispersion in mineral oil, 545 mg) was added in small portions under cooling with ice. After stirring the mixture at room temperature for 30 minutes, methyl iodide (0.849 mL) was added. After stirring the reaction mixture at room temperature for 2.5 hours, iced water was added and two extractions were conducted with ethyl acetate. The combined organic layers were washed with water three times and thereafter dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-85:15) to give methyl 3-methoxy-4-(trifluoromethyl)benzoate as a colorless solid (2.11 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37].O>C1COCC1>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([N:38]([CH2:39][CH3:40])[CH2:36][CH3:37])[N:3]=3)[N:25]=2)=[CH:34][CH:33]=1
Reactant: CCNCC
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
At RT, 60 mg (0.11 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.023 ml (0.22 mmol) of diethylamine were stirred in 1.5 ml of THF for 30 min. About 15 ml of water were added to the reaction mixture, and the aqueous phase was extracted 3× with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, concentrated by evaporation and dried under high vacuum. This gave 67 mg (99% of theory, purity 95%) of the desired target compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>[OH-].[Na+].C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)=[CH:8][CH:9]=1)(=[O:3])[CH:2]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccccc1)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 50.3 %

Procedure:
A solution of 1-(4-acetylphenyl)-4-(4-pyridyl)piperazine (1.0 g), benzaldehyde (177 mg) and concentrated sodium hydroxide (3 drops) in ethanol (25 ml) was stirred at ambient temperature overnight to give a solid which was filtered, washed with ethanol and dried to give 1-(4-cinnamoylphenyl)-4-(4-pyridyl)piperazine (310 mg), m.p. 208-210° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][N:10]=[C:11]3[C:16]([CH3:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=23)=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:17][C:16]1[C:11]2[C:12](=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[O:9][N:10]=2)[CH:13]=[C:14]([Cl:18])[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)cc2c(-c3ccc(Br)cc3)onc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(CBr)c2noc(-c3ccc(Br)cc3)c2c1
Yield: 84.3 %

Procedure:
A mixture of 2.1 g (0.0065 mole) of 3-(4-bromophenyl)-5-chloro-7-methyl-2,1-benzisoxazole, 1.2 g (0.0067 mole) of N-bromosuccinimide and a few crystals of dibenzoyl peroxide in 100 ml of carbon tetrachloride was heated at reflux for 2.5 hr under flood light illumination and an argon atmosphere and then filtered while still hot. The filtrate was concentrated under reduced pressure to a solid residue. The solid was recrystallized twice from 2-propanol to give 2.2 g (85%) of light-yellow needles, m.p. 147°-150° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH2:14](I)[CH2:15][CH2:16][CH3:17].Cl>C(O)C.O>[Cl:3][C:4]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(O)cc1Cl
Reactant: CCCCI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCOc1ccc(C(=O)O)c(Cl)c1
Reaction time: 5 h
Yield: 71.7 %

Procedure:
9 g of caustic soda are dissolved in 200 ml of ethanol. To the thus-prepared solution there are added 17.25 g of 2-chloro-4-hydroxybenzoic acid and 18.4 g of butyl iodide. The resulting solution is heated at reflux under stirring for 5 hours, cooled, poured into 200 ml of water and acidified, to pH=1, with hydrochloric acid. The precipitate is filtered-off, washed with water and dried to give 16.4 g of ortho-chloro-para-n-butyoxybenzoic acid which is recrystallized from hexane. The yield of the recrystallized product is 13.8 g (60.5%), M.p. 92°-93° C.
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[OH-].[K+].[CH2:15]([CH:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18]Br)[CH3:16]>C1(C)C(C)=CC=CC=1>[CH2:15]([CH:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH3:16]
Reactant: CCCCC(CC)CBr
Reactant: OCCCCCCCCCCO
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CCCCC(CC)COCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.1 %

Procedure:
A 1-liter flask equipped with a stirrer and distiller was charged with 25 g (0.14 mol) of 1,10-decanediol, 8.09 g (0.14 mol) of KOH and 300 ml of xylene, and the resultant mixture was heated at 120° C. for 1 hour, thereby distilling off water formed. To this reaction mixture, were added 23.1 g (0.12 mol) of 2-ethylhexyl bromide, and the resulting mixture was heated and stirred for 15 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and washed with water. After the solvent was distilled off under reduced pressure, the resulting residue was purified by column chromatography on silica gel, thereby obtaining 24.8 g (yield: 72%) of 10-(2-ethylhexyloxy)decanol.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(O)(=O)C>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:22](=[O:24])[CH3:23])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reaction time: 16 h
Yield: 100.8 %

Procedure:
(R)—N2-indan-1-yl-quinoline-2,6-diamine (551 mg, 2 mmol) was dissolved in acetic acid (5 mL) then acetic anhydride (378 ul, 4 mmol) was added and the mixture was stirred at for 16 h. The reaction mixture was extracted with ethyl acetate and sat. NaHCO3-sol., the organic layers were combined, dried over MgSO4, filtered and the solvents evaporated to give the title compound as a light brown foam (640 mg, 100%); MS: m/e=318.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:18]([O:20][CH3:21])=[O:19])=[C:13]([F:17])[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[C:22]([O:26][C:27]([NH:29][C:30]1([C:33](O)=[O:34])[CH2:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:22]([O:26][C:27]([NH:29][C:30]1([C:33]([NH:1][C:2]([C:5]2[CH:10]=[CH:9][C:8]([C:11]3[C:12]([C:18]([O:20][CH3:21])=[O:19])=[C:13]([F:17])[CH:14]=[CH:15][CH:16]=3)=[CH:7][CH:6]=2)([CH3:4])[CH3:3])=[O:34])[CH2:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: COC(=O)c1c(F)cccc1-c1ccc(C(C)(C)N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1c(F)cccc1-c1ccc(C(C)(C)NC(=O)C2(NC(=O)OC(C)(C)C)CC2)cc1
Reaction time: 8 h
Yield: 62.2 %

Procedure:
The above-mentioned amine (80 mg, 0.28 mmol), was dissolved in anhydrous DCM (4 mL). To this stirred solution was added 1-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylic acid (67 mg, 0.33 mmol), HOBt.H2O (8 mg, 0.08 mmol) and lastly EDCI (69 g, 0.36 mmol). This mixture was allowed to stir overnight. Solvent was then removed under reduced pressure and the residue was subjected to silica gel chromatography eluting with a 1-3% MeOH in DCM gradient to provide methyl 4′-{1-[({1-[(tert-butoxycarbonyl)amino]cyclopropyl}carbonyl)amino]-1-methylethyl}-3-fluoro-1,1′-biphenyl-2-carboxylate (82 mg), giving LC/MS and proton NMR spectra consistent with theory.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([S:21][CH2:22][CH2:23][OH:24])=[CH:15][C:14]=3[F:25])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([S:21]([CH2:22][CH2:23][OH:24])=[O:36])=[CH:15][C:14]=3[F:25])=[O:9])=[CH:26][CH:27]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(SCCO)cc2c1O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(S(=O)CCO)cc2c1O

Procedure:
This compound was prepared from N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(2-hydroxyethyl)sulfanyl]-3-quinolinecarboxamide (Example No. 171) and an equimolar amount of m-chloroperbenzoic acid according to a procedure similar to described in Example 175.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Cl[C:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: Clc1ncccn1
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: COc1ccc(CC2c3cc(Oc4ncccn4)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 2-chloro-pyrimidine
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17]CC)=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[Br:20][C:21]1[CH:22]=[C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc(Br)c1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(Br)c1

Procedure:
The product is prepared according to the procedure described in Example 9, using 300 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of Example 1 and 0.61 ml of 3-bromoaniline in place of the 2-fluoroaniline. 105 mg of N-(3-bromophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][CH2:2][C:3]1([O:10][CH3:11])[CH2:7][CH2:6][CH:5]([O:8][CH3:9])[O:4]1.C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:19]([NH:1][CH2:2][C:3]1([O:10][CH3:11])[CH2:7][CH2:6][CH:5]([O:8][CH3:9])[O:4]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC1CCC(CN)(OC)O1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC1CCC(CNC(=O)c2ccccc2)(OC)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
10 g (62 mmol) of 2-aminomethyl-2,5-dimethoxytetrahydrofuran and 17 ml (123 mmol) triethylamine were dissolved in 100 ml of anhydrous tetrahydrofuran. At 0° C., 7.2 ml (62 mmol) of benzoyl chloride were added dropwise, and the mixture was stirred at 0° C. for 1 h and then filtered, and the filtrate was concentrated under reduced pressure to yield 17 g of the crude product which was immediately reacted further.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:16])[C:5](=NO)[C:6](=[O:13])[NH:7]2.CN(C=[O:21])C>Cl.[Pd]>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[C:4]([OH:16])=[C:5]([OH:21])[C:6]([OH:13])=[N:7]2
Reactant: CN(C)C=O
Reactant: Cc1cc(C)c2c(c1)NC(=O)C(=NO)C2=O
Agent: [Pd]
Agent: Cl
Product: Cc1cc(C)c2c(O)c(O)c(O)nc2c1
Reaction time: 12 h
Yield: 50 %

Procedure:
The procedure of Baker and Almaula, J. Org. Chem. 27:4672-74 (1962), was adapted. A mixture of 5,7-dimethylquinoline-2,3,4-trione-3-oxime (45 mg, 0.21 mmol) and 30% Pd/C (10 mg) in DMF (2 mL) and 4N HCl (2 mL) was hydrogenated at 50 psi for 12 h. A crystalline colorless solid was observed in the reaction mixture. The mixture was filtered and the solid was stirred with acetone/methanol (1:1) and filtered to remove the black catalyst. The acetone/methanol solution was added into the 1N HCl solution (10 mL) to give white crystals. It was filtered and washed with water (1×1 mL), and dried to leave 21 mg of the title compound (50%), which is pure by NMR. mp 280°-2° C. IR (KBr, cm-1): 3452, 3178, 3108, 1663, 1621, 1585. 1H NMR (DMSO-d6): δ 2.248 (s, 3H); 2.638 (s, 3H); 6.704 (s, 1H); 6.876 (s, 1H); 8.595 (s, 1H); 9.542 (s, 1H); 11.424 (s, 1H). HRMS: calcd for C11H11NO3 m/z: 205.0738; found: 205.0729. Purity:>99% by HPLC (tautomers 71.5% and 28.4%).
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=3)[C:7](=O)[NH:6][N:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(C3CC3)n[nH]c(=O)c2c1
Product: COc1ccc2c(C3CC3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-cyclopropyl-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH2:7])=[N:2]1.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][N:19]([C:22]2[S:23][C:24]([C:28](O)=[O:29])=[C:25]([CH3:27])[N:26]=2)[C:18](=[O:31])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][C:28]([C:24]2[S:23][C:22]([N:19]3[CH:20]=[CH:21][C:16]([O:15][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:17][C:18]3=[O:31])=[N:26][C:25]=2[CH3:27])=[O:29])=[N:2]1
Reactant: NCc1cc[nH]n1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1cc[nH]n1
Yield: 43 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (1H-pyrazol-3-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 43% yield: 1H NMR (300 MHz, DMSO-d6) δ 12.63 (br s, 1H), 8.74-8.54 (m, 2H), 7.63-7.31 (m, 6H), 6.38 (dd, J=8.1, 2.5 Hz, 1H), 6.22 (d, J=2.5 Hz, 1H), 6.13 (d, J=1.0 Hz, 1H), 5.15 (s, 2H), 4.37 (d, J=5.6 Hz, 2H), 2.53 (s, 3H); MS (ES+) m/z 422.2 (M+1).