Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([OH:11])=[C:6]([OH:12])[CH:5]=1.[CH3:14]OS(OC)(=O)=O.[OH-].[Na+].OS(O)(=O)=O>O>[OH:12][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH3:14])[C:7]=1[OH:11])[C:3]([O:2][CH3:1])=[O:13]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cc(O)c(O)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 47 %

Procedure:
To a solution of 3,4,5-trihydroxy-benzoic acid methyl ester (50 g, 0.27 mol) and Na2B4O7 (50 g) in water (1000 mL) was added Me2SO4 (120 mL) and aqueous NaOH solution (25%, 200 mL) successively at room temperature. The mixture was stirred at room temperature for 6 h before it was cooled to 0° C. The mixture was acidified to pH ˜2 by adding conc. H2SO4 and then filtered. The filtrate was extracted with EtOAc (500 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g 47%), which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11].C(OCC)C>OS(O)(=O)=O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([N+:10]([O-:12])=[O:11])=[C:4]([CH3:9])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(=O)[nH]c(N)n1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: Cc1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a mixture of 2-amino-6-methylpyrimidin-4(3H)-one (50 g, 0.4 mol) in 250 mL of H2SO4 at 0° C. was added 40 mL of HNO3 with an additional funnel. After being stirred at room temperature for 3 h, the reaction mixture was slowly poured into 3.6 L of diethyl ether and stirred for 15 min. Decant the ether solution and added 1.0 L of ethyl acetate to the solid and stirred for 10 h. The solid (54.8 g, 81% yield) was filtered and used for next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH3:10])[C:3]=1[F:11].[Br:12]Br>>[Br:12][C:7]1[CH:6]=[CH:5][C:4]([O:8][CH2:9][CH3:10])=[C:3]([F:11])[C:2]=1[Cl:1]
Reactant: BrBr
Reactant: CCOc1cccc(Cl)c1F
Product: CCOc1ccc(Br)c(Cl)c1F
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
504 g of the compound (b44) was added to a reactor in a nitrogen atmosphere, to which 434 g of bromine was added dropwise over 1 hour in a temperature range of 20 to 40° C., followed by stirring for 30 minutes. The resulting reaction mixture was washed with a saturated sodium thiosulfate aqueous solution, a 10% sodium hydroxide aqueous solution, and water. The residue was subjected to fractional distillation under reduced pressure to obtain 605 g of 1-bromo-2-chloro-4-ethoxy-3-fluorobenzene (C12). The resulting compound (C12) was white solid and had a melting point of 48.0 to 48.5° C. and a boiling point of 88 to 90° C./1 mmHg.
Reaction SMILES: [CH2:1]([C@@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[K+].[K+].I[CH2:38][CH3:39]>CC(C)=O>[CH2:38]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([F:23])=[CH:8][CH:7]=2)[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@@H:3]([CH2:1][CH3:2])[C:4]1=[O:24])[CH3:39]
Reactant: CCI
Reactant: CC[C@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC(C)=O
Product: CC[C@H]1C(=O)N(CC)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Temperature: 51 °C
Reaction time: 4 h
Yield: 70.1 %

Procedure:
To a stirred solution of (3S)-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (0.25 g, 0.76 mmol) in acetone (6 mL) under nitrogen was added cesium carbonate (0.133 g, 0.41 mmol), potassium carbonate (0.057 g, 0.41 mmol) and iodoethane (0.20 mL, 0.39 g, 2.5 mmol). The reaction was stirred at 51° C. for 4 h. The solvent was evaporated, and the residue was partitioned between methylene chloride and water. The organic layer was separated and washed with water. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The product was purified via Biotage Horizon® (SiO2, gradient from 4% EtOAc/hexane to 38% EtOAc/hexane) to yield 0.19 g (75%) of (3S)-1,3-diethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one. MS (ESI) m/z 357 ([M+H]+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[C:7]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:6]1.Cl[C:27]1[N:32]=[C:31]([NH2:33])[C:30]([N+:34]([O-:36])=[O:35])=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:33][C:31]1[N:32]=[C:27]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=3)[C:7]([NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])=[CH:6]2)[CH:28]=[CH:29][C:30]=1[N+:34]([O-:36])=[O:35]
Reactant: CCc1ccc(-c2cn(CCCN)cc2NC(=O)OC(C)(C)C)cc1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(-c2cn(CCCNc3ccc([N+](=O)[O-])c(N)n3)cc2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 75 %

Procedure:
N-[1-(3-aminopropyl)-4-(4-ethylphenyl)pyrrol-3-yl](tert-butoxy)carboxamide (1 eq) and 6-chloro-3-nitro-2-pyridylamine (1.2 eq) were dissolved in DMA with stirring under argon at rt. Hünig's Base (1.5 eq) was added to the clear dark brown solution which was heated to 60° C. for 12 hours until completion was determined by LC/MS and TLC, eluting with EtOAc/Hexane (3:2, v/v) (Rf=0.3). EtOAc was added to the reaction mixture which was then washed with water, brine, dried (Na2SO4), filtered, and concentrated to dryness to give the crude brown product. The brown residue was purified by silica column chromatography eluting with EtOAc/Hexane (24:26, v/v). After collecting the purified fractions and concentrating, the product was isolated as a light yellow solid (75% yield).
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[O:15]=[C:16]1[NH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=2)[NH:18][CH:17]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCOCC1>[O:15]=[C:16]1[NH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=2)[N:18]=[C:17]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C(c1ccccc1)N2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(=O)[nH]c2c1

Procedure:
DDQ (21.25 g, 93.6 mmol, 2.62 equiv) was added to a stirred solution of methyl 3-oxo-2-phenyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (10.07 g, 35.7 mmol, 1.00 equiv) in dioxane (750 mL) and allowed to react, with stifling, overnight at room temperature. The solids were collected by filtration. The filter cake was washed with 2×500 mL of aqueous K2CO3 (saturated). This resulted in 7.29 g (crude) of methyl 3-oxo-2-phenyl-3,4-dihydroquinoxaline-6-carboxylate as an off-white solid. LC-MS (ES, m/z): 281 [M+H]+.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[N:13]=[C:12]([Cl:18])[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[C:10]2[Cl:26].[CH3:27][N:28]1[C:32]([C:33]([C:35]2[CH:36]=[N:37][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:40]=2)=[O:34])=[CH:31][N:30]=[CH:29]1>C1COCC1>[Cl:18][C:12]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[C:10]([Cl:26])[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]([C:33]([C:32]3[N:28]([CH3:27])[CH:29]=[N:30][CH:31]=3)([C:35]3[CH:36]=[N:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=3)[OH:34])[CH:8]=2)[N:13]=1
Reactant: Cc1cc(Br)cc2c(Cl)c(-c3cccc(F)c3)c(Cl)nc12
Reactant: Cn1cncc1C(=O)c1ccc(C(F)(F)F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(O)(c2ccc(C(F)(F)F)nc2)c2cncn2C)cc2c(Cl)c(-c3cccc(F)c3)c(Cl)nc12
Temperature: -78 °C
Reaction time: 0.02 h

Procedure:
n-BuLi (1.6 M in hexane, 1.91 mL, 3.05 mmol) was added over approximately 1 minute to a solution of 6-bromo-2,4-dichloro-3-(3-fluorophenyl)-8-methylquinoline (1.23 g, 3.20 mmol, Intermediate 50, step c) in THF (10 mL) under argon at −78° C. After 1 minute, a solution of (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (817 mg, 3.20 mmol, Intermediate 15, step c) in 10 mL THF under argon was added via cannula. The resulting mixture was stirred at −78° C. for 10 minutes, then transferred to an ice water bath and stirred 1 hour. The reaction was quenched by addition of saturated aqueous NH4Cl, diluted with water and extracted with EtOAc (3×). The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 45-60% CH3CN in [2% conc. aqueous NH4OH in DCM, aqueous phase removed]) to afford the title compound as a cream colored solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.83 (s, 1H), 8.14 (dd, J=1.83, 7.46 Hz, 1H), 7.92 (d, J=8.31 Hz, 1H), 7.65 (d, J=8.31 Hz, 1H), 7.57-7.62 (m, 1H), 7.44-7.53 (m, 1H), 7.20 (td, J=2.20, 8.31 Hz, 1H), 7.09 (t, J=6.60 Hz, 1H), 7.01-7.07 (m, 1H), 6.29 (d, J=0.98 Hz, 1H), 6.02 (br. s., 1H), 3.37 (s, 3H), 2.74 (s, 3H). MS m/e 561.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](I)[C:5]([OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]#[CH:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[O:9][C:5]3[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Oc1ccc(Cl)nc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc3nc(Cl)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-chloro-2-iodo-pyridin-3-ol (1.00 g) in N,N-dimethylformamide (10 mL) copper (I) iodide (120 mg), Pd(PPh3)2Cl2 (140 mg), and triethylamine (550 μL) are added. The mixture is stirred at room temperature for 1 h. A solution of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (860 mg) in N,N-dimethylformamide (3 mL) is added and the resulting mixture is stirred at 70° C. over night. After cooling to room temperature the mixture is concentrated and chromatographed on silica gel (ethyl acetate/cyclohexane 25:75) to give the title compound. Yield: 241 mg (18% of theory); LC (method 2): tR=1.41 min; Mass spectrum (ESI+): m/z=337 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:32])[C:23]3[CH:28]=[C:27]([F:29])[C:26]([OH:30])=[C:25]([F:31])[CH:24]=3)[C@@H:14]([CH3:33])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:41][CH2:42][C:43]([CH3:49])([CH3:48])[C:44]([O:46][CH3:47])=[O:45]>CN(C=O)C>[C:9]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C@H:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]([C:23]2[CH:28]=[C:27]([F:29])[C:26]([O:30][CH2:41][CH2:42][C:43]([CH3:49])([CH3:48])[C:44]([O:46][CH3:47])=[O:45])=[C:25]([F:31])[CH:24]=2)=[O:32])[C@@H:14]([CH3:33])[CH2:13]1)(=[O:11])[CH3:10]
Reactant: COC(=O)C(C)(C)CCBr
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2cc(F)c(O)c(F)c2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CCOc1c(F)cc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
N-(4-chlorophenyl)-N-[(2S,4R)-1-(3,5-difluoro-4-hydroxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (150 mg, 0.32 mmol) was dissolved in DMF at room temperature and Cs2CO3 (259 mg, 0.80 mmol) was added. Methyl 4-bromo-2,2-dimethylbutanoate (157 mg, 0.48 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (hexanes-ethyl acetate system) to afford the product (118 mg, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:18])=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[NH:9][C:8]1([CH2:16][CH2:15][CH2:14]1)[CH2:7][C:6]2=[O:17].[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:18])=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[NH:9][C:8]1([CH2:14][CH2:15][CH2:16]1)[CH2:7][CH:6]2[OH:17]
Reactant: COc1c(C)cc2c(c1C)C(=O)CC1(CCC1)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1c(C)cc2c(c1C)C(O)CC1(CCC1)N2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6′-methoxy-5′,7′-dimethyl-1′H-spiro[cyclobutane-1,2′-quinolin]-4′(3′H)-one (1 g) in a mixture of 35 mL methanol and 15 mL CH2Cl2, was added NaBH4 (2 g) slowly at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes and then at room temperature for three days. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried with Na2SO4 and evaporated, to yield 6′-methoxy-5′,7′-dimethyl-3′,4′-dihydro-1′H-spiro[cyclobutane-1,2′-quinolin]-4′-ol was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:27])([C:16]#[C:17][CH2:18][CH2:19][O:20]C3CCCCO3)[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:27])([C:16]#[C:17][CH2:18][CH2:19][OH:20])[CH3:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(O)(C#CCCOC1CCCCO1)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(O)(C#CCCO)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 12 h

Procedure:
To 38.5 g. of 2-(4'-chloro-4-biphenylyl)-6-(tetrahydropyran-2-yloxy)-3-hexyn-2-ol in 250 ml. of dioxane, is added dropwise with ice cooling, 100 ml. of 1 N HCl. The resulting mixture is stirred 12 hours more at 0°. After the usual work up, 2-(4'-chloro-4-biphenylyl)-3-hexyn-2,6-diol, m.p. 105°, is obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([O:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([O:20][CH2:21][C:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[S:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)COc1nc(-c2ccc(F)cc2)cs1
Reactant: C1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1nc(-c2ccc(F)cc2)cs1)N1CCCC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-yloxy]-acetic acid trifluoroacetic acid salt and 38.7 mg (0.54 mmol) of pyrrolidine. Yield: 6 mg.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:17])=[C:4]([S:9]([N:12]([O:15][CH3:16])[CH2:13][CH3:14])(=[O:11])=[O:10])[C:5](Cl)=[CH:6][CH:7]=1.[H][H]>CCO.[Pd]>[NH2:1][C:2]1[C:3]([OH:17])=[C:4]([S:9]([N:12]([CH2:13][CH3:14])[O:15][CH3:16])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(OC)S(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCN(OC)S(=O)(=O)c1cccc(N)c1O
Reaction time: 5 h

Procedure:
A dispersion of 10% Pd/C (200 mg) in a solution of 3-amino-6-chloro-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide (Int. FA step 2) (400 mg, 11.425 mmol) in EtOH (50 ml) was placed under a positive pressure of hydrogen at 0.5 bar above atmospheric pressure. After 5 hours, the catalyst was removed by filtration through Celite® (filter material), and the filtrate was reduced in vacuo. The resulting solid was used in the next step, without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[NH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.CC(C)([O-])C.[K+].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.O>CN(C)C=O>[CH3:1][S:2][C:3]1[C:4]2[C:5](=[CH:9][N:10]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[N:11]=2)[N:6]=[CH:7][N:8]=1
Reactant: CSc1ncnc2cn[nH]c12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncnc2cn(-c3ccc([N+](=O)[O-])cc3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
To a solution of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (500 mg) in N,N-dimethylformamide (10 mL) was added potassium tert-butoxide (405 mg) under ice-cooling, and the mixture was stirred at room temperature for 10 min. Subsequently, 1-fluoro-4-nitrobenzene (465 mg) was added, and the mixture was stirred at 70° C. for 30 min. After the completion of the reaction, water was added to the reaction mixture and the mixture was stirred at room temperature for 30 min. The resultant solid was collected by filtration, washed with diisopropyl ether and dried to give the title compound (860 mg) as brown crystals.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[C:3]=1[F:12].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([F:12])[C:4]=1[F:11]
Reactant: CO
Reactant: O=C(O)c1ccc(O)c(F)c1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c(F)c1F

Procedure:
4-hydroxy-2,3-difluoro-benzoic acid (2.0 g, 11.5 mmol) was dissolved in MeOH (20 mL) and catalytic quantity of sulfuric acid was added. The mixture was refluxed overnight, after that the solvent was evaporated under reduced pressure; the crude was dissolved in DCM and washed with saturated NaHCO3. The organic phase was dried and evaporated under reduced pressure, and the product was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]([Cl:24])[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7].Cl.C([O-])(O)=O.[Na+]>>[Cl:24][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:25])=[O:2])=[O:7])[N:9]=1
Reactant: COC(=O)CNC(=O)c1nc(Cl)c2ccccc2c1-c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(Cl)c2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 264 h
Yield: 73.4 %

Procedure:
A mixture of [(1-chloro-4-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid methyl ester (50 mg, 0.14 mmol, Example D-74 b), and aqueous 6N HCl was stirred at ambient temperature for 11 days before the solution was neutralized by the addition of concentrated aqueous NaHCO3. The mixture was extracted with EtOAc (50 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid (35 mg); MS-(+)-ion: M+1=341.0.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)(=[O:19])=[O:18])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCOCC3)sc2Br)s1
Reaction time: 3 h
Yield: 77 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (136 mg; 0.33 mmol; 1 eq), is dissolved in DCM (10 ml). Morpholine (0.25 ml; 1.65 mmol; 5 eq) and DIEA (0.17 ml; 0.98 mmol; 3 eq) are added under a nitrogen atmosphere. After 3 hours, solvents are evaporated. The crude product is dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is purified by flash chromatography using cyclohexane/EtOAc (1/1) as eluent, affording the expected compound as an oil (118 mg; 77%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[Cl:13][C:14]1[N:15]=[C:16]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:17]2[S:22][C:21]([CH:23]=O)=[CH:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[C:17]2[S:22][C:21]([CH2:23][N:10]3[CH2:11][CH2:12][N:7]([CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH2:8][CH2:9]3)=[CH:20][C:18]=2[N:19]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: C1CN(C2CCOCC2)CCN1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN(C4CCOCC4)CC3)cc2n1

Procedure:
Prepared from 1-(tetrahydro-pyran-4-yl)-piperazine and 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde under reductive amination conditions described in Reference Example 39, to give, after silica chromatography purification, the title compound as a white solid (190 mg, 61%) [M+H]+ 439.4
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:10]=2[C:9]=1[O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:25]([O:27][C:28](=[O:31])[CH2:29]Br)[CH3:26].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:5][C:6]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][C:15]([O:17][CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:31])=[CH:16][C:10]=2[C:9]=1[O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)CBr
Reactant: CCCCOC(=O)c1sc2ccc(O)cc2c1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOC(=O)c1sc2ccc(OCC(=O)OCC)cc2c1OC(=O)C(C)(C)C

Procedure:
3.50 g (10 mmol) VII, 2.22 ml (20 mmol) bromoacetic acid ethyl ester and 2.48 g (25 mmol) K2CO3 were heated under reflux for 5 h in 250 ml acetone. The reaction mixture was filtered. The filtrate was freed from the solvent. After recrystallization from n-hexane, VIII was obtained in a yield of 4.00 g (9.2 mmol, 92%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:36])[CH2:34][OH:35])[NH:28][C:27](=[O:37])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:36])[CH2:34][OH:35])[NH:28][C:27](=[O:37])/[C:26]/2=[CH:20]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Reactant: O=C(CO)Nc1cc2c(cc1F)CC(=O)N2
Product: Cc1c(/C=C2\C(=O)Nc3cc(NC(=O)CO)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Yield: 76 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c obtained from step 3 of Example 28 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-acetamide 27b obtained from step 2 of Example 27 as starting materials to obtain (Z)—N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-acetamide 31 (50 mg, yield 76%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C:6]1[S:10][C:9]([NH2:11])=[N:8][CH:7]=1.[CH3:15][O:16][CH2:17][CH2:18]Br>>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C:6]1[S:10][C:9](=[NH:11])[N:8]([CH2:18][CH2:17][O:16][CH3:15])[CH:7]=1
Reactant: Nc1ncc(Cc2cccc(F)c2)s1
Reactant: COCCBr
Product: COCCn1cc(Cc2cccc(F)c2)sc1=N

Procedure:
A mixture of 5-(3-fluoro-benzyl)-thiazol-2-ylamine (330 mg, 1.59 mmol) and 2-bromoethyl methyl ether (0.50 mL, 5.34 mmol) was processed according to the method of Example 43A to afford the title compound: MS (LC/MS) m/z 267 (M+H)+.