Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C(C)=CC(C)=CC=1C.[C:10]([O:14][C:15](=[O:26])[CH2:16][N:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]([NH2:24])[C:18]1=[O:25])([CH3:13])([CH3:12])[CH3:11].[CH2:27]([S:34](Cl)(=[O:36])=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C>[C:10]([O:14][C:15](=[O:26])[CH2:16][N:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]([NH:24][S:34]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:36])=[O:35])[C:18]1=[O:25])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CC#N
Solvent: Cc1cc(C)nc(C)c1
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 46.1 %

Procedure:
Collidine (0.59 mL, 4.5 mmole) was added in one portion to a stirred solution of the compound of Example 94 (0.89 g, 3.7 mmole) and benzylsulfonyl chloride (0.86 g, 4.5 mmole) in acetonitrile (20 ml) cooled in an ice bath. The solution was stirred for 5 minutes at 0° C., followed by 45 min at room temperature. The reaction mixture was quenched with water, then diluted with ethyl acetate (100 mL), washed with 3% HCl (until aqueous layer is pH 1), and brine, dried over magnesium sulfate, and the solvent was removed. The residue was dissolved in methanol, concentrated to a volume of approximately 3 mL, and the product was precipitated with the addition of diethyl ether. The precipitate was filtered to give 0.67 g of the title compound. The filtrate was concentrated and chromatographed on flash silica gel using 20-67% ethyl acetate hexanes as eluent. An additional 0.20 g of the title compound was recovered. A total of 0.87 g of the title compound (59% yield) was recovered. Rf=0.29 (silica gel, 33% ethyl acetate/hexanes).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:25][C:26]1([CH2:36][CH:37]=O)[CH2:35][CH2:34][C:29]2([O:33][CH2:32][CH2:31][O:30]2)[CH2:28][CH2:27]1.[OH-].[Na+]>O1CCCC1.O.C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:37][CH2:36][C:26]2([OH:25])[CH2:35][CH2:34][C:29]3([O:30][CH2:31][CH2:32][O:33]3)[CH2:28][CH2:27]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: O=CCC1(O)CCC2(CC1)OCCO2
Reactant: C[C@H](N)c1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NCCC1(O)CCC2(CC1)OCCO2)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-1-(4-Bromo-phenyl)-ethylamine (2.68 g), sodium triacetoxyborohydride (2.84 g), and acetic acid (0.77 mL) are added in the given order to a solution of (8-hydroxy-1,4-dioxa-spiro[4.5]dec-8-yl)-acetaldehyde (7.86 g) in tetrahydrofuran (150 mL) at room temperature. The resulting mixture is stirred at room temperature overnight. Water (100 mL) and 1 M aqueous NaOH solution (100 mL) are then added and the mixture is stirred for another 20 min. The mixture is extracted with ethyl acetate, and the combined extracts are washed with water and brine. After drying (MgSO4), the solvent is evaporated to give the crude title compound that is used without further purification. Yield: 2.91 g (crude); LC (method 3): tR=2.00 min; Mass spectrum (ESI+): m/z=384/386 (Br) [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[C:4](I)[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]#[CH:20]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[C:4]([C:20]#[C:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[Cl:12])[CH:3]=1
Reactant: C#Cc1ccccc1Cl
Reactant: COc1cc(Cl)cc(I)c1N
Product: COc1cc(Cl)cc(C#Cc2ccccc2Cl)c1N

Procedure:
The title compound was prepared in analogy to example 10 step A from 4-chloro-2-iodo-6-methoxy-phenylamine (300 mg, 1.06 mmol) and 1-chloro-2-ethynyl-benzene (174 mg, 1.27 mmol). Brown solid (220 mg, 71%). LC-MS (ESI): 292 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][C:15]=1[Cl:24]>CN(C)C=O.C(OCC)(=O)C>[BrH:12].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:16][C:15]=2[Cl:24])[CH:9]=1
Reactant: NC(=O)c1cc(Cl)cnc1N
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Br
Product: CS(=O)(=O)c1ccc(Cn2cc(Cl)cc(C(N)=O)c2=N)c(Cl)c1
Temperature: 100 °C
Reaction time: 14 h
Yield: 22.6 %

Procedure:
To a solution of 2-amino-5-chloronicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 1-(bromomethyl)-2-chloro-4-(methylsulfonyl)benzene (0.37 g), and the mixture was stirred at 100° C. for 14 hr. The reaction mixture was diluted with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate. The obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (90 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1.[CH:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[CH2:22].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:26]1[CH:27]=[CH:28][C:23]([CH:21]=[CH:22][C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]3[CH2:13][CH2:12][N:11]3[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(C=Cc2ccncc2)c1
Yield: 68.9 %

Procedure:
To a solution of 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 54b (1.03 g, 3.0 mmol) in acetonitrile (20 mL) and triethylamine (12.5 mL) was added 4-vinylpyridine (0.65 mL, 6 mmol), palladium acetate (125 mg, 0.56 mmol) and tri-o-tolylphosphine (625 mg). The mixture was heated at reflux for 16 hours. The solvent was removed, and the residue was washed with saturated sodium bicarbonate was added to free the amine, and the mixture was extracted with EtOAc, dried (MgSO4), and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane:ether 1:2 to 0:1 to afford the title compound (760 mg, 69%). MS (CI/NH3) m/z 368 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.43 (s, 9H), 2.35 (m, 2H), 3.90 (m, 2H), 4.20 (m, 1H), 4.40 (m, 1H), 4.55 (m, 1H), 7.10 (m, 1H), 7.2 (m, 1H), 7.38 (m, 2H), 7.45 (br s, 1H), 8.29 (m, 1H), 8.37 (s, 1H), 8.61 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH:3]=1.[O-:25][C:26]#[N:27].[Na+]>C(O)(=O)C.O>[CH3:17][S:14]([NH:13][C:11]1[C:10]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:9][C:6]2[C:7](=[O:8])[C:2]([NH:1][C:26]([NH2:27])=[O:25])=[CH:3][O:4][C:5]=2[CH:12]=1)(=[O:15])=[O:16]
Reactant: N#C[O-]
Reactant: CS(=O)(=O)Nc1cc2occ(N)c(=O)c2cc1Oc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc2occ(NC(N)=O)c(=O)c2cc1Oc1ccccc1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
500 mg of 3-amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was dissolved in 20 ml of acetic acid and 10 ml of water. The solution was heated to 35° C. Thereto was dropwise added a solution of 190 mg of sodium cyanate dissolved in 5 ml of water, in 5 minutes. The mixture was stirred for 30 minutes at the same temperature. 20 ml of water was added thereto. The resulting crystal was collected by filtration and recrystallized from acetic acid to obtain 350 mg (yield: 62.3%) of 7-methylsulfonylamino-6-phenoxy-3-ureido-4H-1-benzopyran-4-one having a melting point of >250° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([OH:10])[CH2:8][OH:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[O:9]1[C:4]2([CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[O:10][CH2:7][CH2:8]1
Reactant: C1CCOCC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: C1CC2(CCO1)OCCO2
Yield: 90.1 %

Procedure:
Tetrahydro-4H-pyran (6.00 g, 60.0 mmol) was dissolved in benzene (120 mL), to which ethylene glycol (11.2 g, 180 mmol) and p-toluenesulfonic acid monohydrate (1.14 g, 6.00 mmol) were added. Using a Dean-Stark tube, the resulting mixture was refluxed for two hours while removing water generated. To the resulting reaction liquid, a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with ethyl acetate. The resulting organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (hexane:ethyl acetate, 100:0-0:100, V/V) to give the desired title compound (7.79 g, yield 90%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:11](=[C:12]=[O:13])[C:10]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=[C:4]1[C:5]([OH:7])=O.[NH2:25][C:26]1[C:34]2[N:33]=[C:32]([CH3:35])[N:31]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:30]=2[CH:29]=[CH:28][CH:27]=1.OS1C2C=CC=CC=2N=C1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][CH:3]1[C:11](=[C:12]=[O:13])[C:10]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=[C:4]1[C:5]([NH:25][C:26]1[C:34]2[N:33]=[C:32]([CH3:35])[N:31]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:30]=2[CH:29]=[CH:28][CH:27]=1)=[O:7]
Reactant: Cc1nc2c(N)cccc2n1C(=O)OC(C)(C)C
Reactant: COC1C(=C=O)C(N2CCCCc3ccccc32)=CC=C1C(=O)O
Agent: O[SH]1C=Nc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC1C(=C=O)C(N2CCCCc3ccccc32)=CC=C1C(=O)Nc1cccc2c1nc(C)n2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
A mixture of 2-methoxy-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-carbonylbenzoic acid (200 mg), 4-amino-1-tert-butoxycarbonyl-2-methyl-1H-benzimidazole (152 mg), WSCD·HCl [water soluble carbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 141 mg] and 1-hydroxybenzotiazole (100 mg) in N,N-dimethylformamide (5 ml) was stirred at room temperature overnight, and the mixture was diluted with ethyl acetate. The solution was washed successively with saturated aqueous sodium hydrogencarbonate solution, water, and brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography using chloroform as an eluent to give 2-methoxy-N-[2-methyl-1-(tert-butoxycarbonyl)-1H-benzimidazol-4-yl]-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-carbonylbenzamide (185 mg).
Reaction SMILES: FC1C=CC(S(N(S(C2C=CC(N3CC[C@@H](O)C3=O)=CC=2)(=O)=O)C2SC=CN=2)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[Cl:57][C:58]1[CH:59]=[C:60]([CH:65]2[O:70][CH2:69][CH2:68][NH:67][CH2:66]2)[CH:61]=[C:62]([Cl:64])[CH:63]=1>C(Cl)Cl>[Cl:64][C:62]1[CH:61]=[C:60]([C@H:65]2[O:70][CH2:69][CH2:68][NH:67][CH2:66]2)[CH:59]=[C:58]([Cl:57])[CH:63]=1
Reactant: Clc1cc(Cl)cc(C2CNCCO2)c1
Agent: O=C1[C@H](O)CCN1c1ccc(S(=O)(=O)N(c2nccs2)S(=O)(=O)c2ccc(F)cc2)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Clc1cc(Cl)cc([C@@H]2CNCCO2)c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Synthesized according to General procedure 31, Method A. A stirring suspension of ((R)-4-fluoro-N-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)phenylsulfonyl)-N-(thiazol-2-yl)benzenesulfonamide (500 mg, 1.00 mmol), N,N-diisopropylethylamine (465 μL, 3.00 mmol), and CH2Cl2 (5.0 mL), under N2, was cooled to −20° C. Triflic anhydride (220 μL, 1.3 mmol) was added dropwise over 10 minutes. The suspension was stirred at −20° C. for 1 hour. A solution of (R)-2-(3,5-dichlorophenyl)morpholine (248 mg, 1.00 mmol) [this enantiomer of 2-(3,5-dichlorophenyl)morpholine was obtained by preparative SFC separation of its racemic mixture: Chiralpak AD-H column (2×25 cm), 50% ethanol (0.1% DEA)/CO2, 50 mL/min)] and CH2Cl2 (1.0 mL) was added dropwise over 5 minutes. The mixture was stirred at −20° C. for 1.5 hours. Morpholine (174 μL, 2.0 mmol) was added dropwise over 5 minutes. The mixture was stirred at −20° C. for 2 hours. The solution was allowed to warm to room temperature and concentrated to dryness under reduced pressure. The residue was purified via silica gel chromatography using 2% MeOH in CH2Cl2 to obtain the desired lactam as a white solid (420 mg, 0.76 mmol, 76% yield). 1H-NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 7.84-7.77 (m, 4H), 7.54-7.50 (m, 1H), 7.44 (d, J=1.8 Hz, 2H), 7.24 (d, J=4.6 Hz, 1H), 6.82 (d, J=4.6 Hz, 1H), 4.57 (dd, J=1.7, 9.8 Hz, 1H), 3.97-3.91 (m, 1H), 3.79-3.62 (m, 4H), 3.21-3.17 (m, 1H), 2.95-2.86 (m, 2H), 2.69-2.66 (m, 1H), 2.22-2.12 (m, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=553.3; tR=1.45 min. SFC (Chiralpak AS-H, (0.46×25 cm), 55% methanol (1% DEA)/CO2, 3 mL/min): tR=5.6 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][CH:17]([C:18]([NH2:20])=[O:19])[C:16]([CH3:24])(C)[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:29](OCC)=[CH2:30].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.O>COCCOC.FC(F)(F)C(O[Pd]OC(=O)C(F)(F)F)=O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:25]([F:26])([F:27])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:20][CH:29]=[CH2:30])=[O:19])=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC1(C)C=C(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)C=CC1C(N)=O
Reactant: C=COCC
Agent: O=C(O[Pd]OC(=O)C(F)(F)F)C(F)(F)F
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Solvent: COCCOC
Product: C=CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 25 °C
Reaction time: 19 h
Yield: 88 %

Procedure:
In a solution of 0.50 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-2-methyl benzoic acid amide synthesized in Synthetic Example 29, 0.865 g of ethyl vinyl ether and 0.022 g of 1,10-phenanthroline in 10 ml of 1,2-dimethoxyethane, 0.04 g of bis(trifluoroacetoxy) palladium (II) was added and stirred at room temperature for 19 hours. After the completion of the reaction, 30 ml of water was added in the reaction mixture, and extracted with ethyl acetate (40 ml×1), the organic phase was dehydrated and dried with saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, then filtered through silica gel, and the solvent was distilled under reduced pressure to obtain 0.45 g of the aimed product as pale yellow resinous substance.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH:26]=[O:27])=[C:10]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N+:28]([CH:30](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:31])#[C-:29].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:26]3[O:27][CH:29]=[N:28][C:30]=3[CH3:31])=[C:10]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)CCc1c(C=O)nc2c(cnn2CC)c1-c1cncc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCn1ncc2c(-c3cncc(C)c3)c(CCC(=O)O)c(-c3ocnc3C)nc21
Yield: 31.2 %

Procedure:
A mixture of ethyl 3-[1-ethyl-6-formyl-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (30 mg), 1-[(1-isocyanoethyl)sulfonyl]-4-methylbenzene (17.6 mg), potassium carbonate (17 mg) in MeOH (1 ml) was refluxed for 1.5 hours. After cooling, the mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified to pH3-4 by adding 1N HCl and extracted with CHCl3. The organic layer was washed with water, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography eluting with a mixture of MeOH and CHCl3 (1:10). Crystallization from EtOAc-n-hexane gave 3-[1-ethyl-6-(4-methyl-1,3-oxazol-5-yl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoic acid (10 mg) as a colorless crystal.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].O>CN(C)C=O.C(OCC)C>[CH:13]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)([CH3:15])[CH3:14]
Reactant: c1c[nH]c(-c2nccs2)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1cccc1-c1nccs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
2-(1H-Pyrrol-2-yl)-1,3-thiazole (1.42 g, 9.45 mmol) known in the literature {Eur. J. Org. Chem. (European Journal of Organic Chemistry) vol. 2000, no. 13, 2449-2458 (2000)} was dissolved in N,N-dimethylformamide (100 mL), and cooled to 0° C. Sodium hydride (60% oil, 570 mg, 14.3 mmol) and triisopropylsilyl chloride (4.0 mL, 18.7 mmol) were added, and stirring was carried out at room temperature for 30 minutes under nitrogen atmosphere. Water (100 mL) and diethyl ether (100 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: hexane) to afford the desired compound (2.33 g, yield 80%) as a pale yellow oil.
Reaction SMILES: Cl.[C:2]([C:5]1[NH:9][CH:8]=[C:7]([C:10]([OH:12])=[O:11])[C:6]=1[C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)(=[O:4])[NH2:3].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33].C(N(CC)CC)C>O1CCCC1.CCCCC>[C:2]([C:5]1[NH:9][CH:8]=[C:7]([C:10]([OH:12])=[O:11])[C:6]=1[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:32]([NH:31][C:22]2[CH:23]=[C:24]([C:27]([F:28])([F:30])[F:29])[CH:25]=[CH:26][C:21]=2[F:20])=[O:33])=[CH:15][CH:14]=1)(=[O:4])[NH2:3]
Reactant: NC(=O)c1[nH]cc(C(=O)O)c1-c1ccc(N)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CCN(CC)CC
Product: NC(=O)c1[nH]cc(C(=O)O)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 20 °C
Reaction time: 5 h
Yield: 46.9 %

Procedure:
To 0.14 g (0.497 mmol) of 5-carbamoyl-4-(4-aminophenyl)-1H-pyrrole-3-carboxylic acid hydrochloride dissolved in 18 cm3 of tetrahydrofuran are added, at a temperature in the region of 20° C. under an argon atmosphere, 0.072 cm3 (0.497 mmol) of 2-fluoro-5-trifluoromethylphenyl isocyanate and 0.07 cm3 (0.497 mmol) of triethylamine. After stirring for 5 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue, which is purified by flash chromatography [eluent: dichloromethane/methanol/acetonitrile (gradient of from 90/5/5 to 80/10/10 by volume)]. After concentrating the fractions under reduced pressure, a solid is obtained, which is then stirred in 5 cm3 of pentane for 3 hours. After filtering through a No. 3 sinter funnel, the solid is washed with twice 1 cm3 of pentane and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 30° C. for 15 hours to give 0.105 g of 5-carbamoyl-4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrole-3-carboxylic acid in the form of a yellow solid melting at 194° C.; 1H NMR (400 MHz, DMSO d6, δ in ppm): 5.37 (broad m, 1H); 7.23 (d, J=8.5 Hz, 2H); 7.23 (masked m, 1H); 7.39 (m, 1H); 7.42 (d, J=3.0 Hz, 1H); 7.49 (d, J=8.5 Hz, 2H); 7.50 (partially masked m, 1H); 8.64 (dd, J=2.5 and 7.5 Hz, 1H); 8.97 (d, J=2.0 Hz, 1H); 9.35 (s, 1H); 11.6 (broad m, 1H); 12.05 (broad s, 1H); ES+: m/z=451: [M+H]+; ES−: m/z=449: [M−H]−.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:29][CH:28]=3)=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)C=C.CCN([C:46]1[CH:47]=CC=C[CH:51]=1)CC>>[OH:4][C:5]1[C:14]([CH2:47][CH:46]=[CH2:51])=[C:13]2[C:8]([C:9]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:31][CH:32]=3)=[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=3)[C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1
Reactant: C=CCOc1ccc2c(Cc3ccc(OCCN4CCCC4)cc3)c(-c3ccc(C(F)(F)F)cc3)c(=O)oc2c1
Reactant: CCN(CC)c1ccccc1
Product: C=CCc1c(O)ccc2c(Cc3ccc(OCCN4CCCC4)cc3)c(-c3ccc(C(F)(F)F)cc3)c(=O)oc12
Temperature: 190 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
7-Prop-2-enyloxy-4-{(4-(2-pyrrolidinylethoxy)phenyl)methyl}-3-(4-(trifluoromethyl) Phenyl)-2H-chromen-2-one (0.150 g.) was dissolved in diethylaniline (4 mL) and allowed to stir at 190° C. for two hours. The resultant solution was extracted with methylene chloride (3×) and 1M hydrochloric acid. The organic layers were dried over sodium sulfate and filtered, and the solvent was removed under reduced pressure to afford a crude brown solid. The solid was purified via preparative-HPLC (40–100% acetonitrile/water, 20 mL/min.) to afford the title compound (0.027 g, 18% yield). 1H-NMR (CDCl3) δ 7.63 (d, 2H), 7.38 (d, 2H), 7.25 (d, 1H), 6.92 (d, 2H), 6.75 (d, 2H), 6.70 (d, 1H), 6.0 (m, 1H), 5.13 (dd, 2H), 4.12 (t, 2H), 3.94 (s, 2H), 3.66 (d, 2H), 3.05 (bs, 2H), 2.8 (bs, 4H), 1.25 (s, 2H). MS (m/z) 550 (M+1)+.
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1.[F:16][C:17]1[CH:18]=[C:19]([NH2:33])[CH:20]=[CH:21][C:22]=1[O:23][C:24]1[C:29]2=[CH:30][CH:31]=[CH:32][N:28]2[N:27]=[CH:26][N:25]=1>C(OCC)(=O)C.ClCCl>[F:16][C:17]1[CH:18]=[C:19]([NH:33][C:2]([NH:3][C:13](=[O:14])[CH2:12][C:9]2[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=2)=[S:1])[CH:20]=[CH:21][C:22]=1[O:23][C:24]1[C:29]2=[CH:30][CH:31]=[CH:32][N:28]2[N:27]=[CH:26][N:25]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ncnn3cccc23)c(F)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ncnn3cccc23)c(F)c1
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
To a homogeneous solution of sodium thiocyanate (21 mg, 0.26 mmol) in ethyl acetate (1 mL), at room temperature under a nitrogen atmosphere, was added 4-fluorophenyl-acetyl chloride (28 μL, 0.20 mmol). The mixture was stirred for 30 minutes before being added directly to a homogeneous solution of 3-fluoro-4-(pyrrolo[2,1-f][1,2,4]-triazin-4-yloxy)benzenamine (37 mg, 0.15 mmol, Compound C of Example 22) in anhydrous dichloromethane (3 mL), under a nitrogen atmosphere. The mixture was stirred at ambient temperature for 4 h before being concentrated in vacuo. Purification by silica gel (Merck KGaA, 230-400 mesh particle size) flash chromatography, eluting with chloroform, afforded the title compound (55 mg, 83%).
Reaction SMILES: CCN=C=NCCCN(C)C.OC(C(F)(F)F)=O.[NH2:19][CH2:20][C:21]([NH:23][CH:24]1[CH2:27][N:26]([CH:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25]1)=[O:22].[OH:40][C:41]1[CH:42]=[C:43]([C:50]([F:53])([F:52])[F:51])[CH:44]=[C:45]([CH:49]=1)[C:46](O)=[O:47]>>[OH:40][C:41]1[CH:49]=[C:45]([CH:44]=[C:43]([C:50]([F:51])([F:52])[F:53])[CH:42]=1)[C:46]([NH:19][CH2:20][C:21](=[O:22])[NH:23][CH:24]1[CH2:27][N:26]([CH:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25]1)=[O:47]
Reactant: NCC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1
Reactant: O=C(O)c1cc(O)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1cc(O)cc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from the EDCI coupling of 2-amino-N-[1-(4-phenyl-cyclohexyl)-azetidin-3-yl]-acetamide TFA salt (as prepared in Step D of Example 66) and 5-hydroxy-3-trifluoromethyl-benzoic acid (Alfa Aesar) using the procedure described in Step F of Example 1.