Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].[Cl:14][C:15]1[C:16]([O:25][C:26]2[C:31]([Cl:32])=[CH:30][C:29]([N:33]=[C:34]=[O:35])=[CH:28][C:27]=2[Cl:36])=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1>>[Cl:14][C:15]1[C:16]([O:25][C:26]2[C:31]([Cl:32])=[CH:30][C:29]([NH:33][C:34]([N:8]=[C:4]([O:5][CH2:6][CH3:7])[C:3]3[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=3[F:13])=[O:35])=[CH:28][C:27]=2[Cl:36])=[N:17][CH:18]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:20]=1
Reactant: CCOC(=N)c1c(F)cccc1F
Reactant: O=C=Nc1cc(Cl)c(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Product: CCOC(=NC(=O)Nc1cc(Cl)c(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1)c1c(F)cccc1F

Procedure:
In a similar manner to that described in step (e) of Example I ethyl 2,6-difluorobenzimidate is reacted with 3-chloro-5-trifluoromethyl-2-(2,6-dichloro-4-isocyanatophenoxy)pyridine to give ethyl N-[4-(3-chloro-5-trifluoromethylpyrid-2-yloxy)-3,5-dichlorophenylcarbamoyl]-2,6-difluorobenzimidate (Compound IV). The intermediate isocyanate is obtained by the procedure of step (c) of Example 1 from 2-(4-amino-2,6-dichlorophenoxy)-3-chloro-5-trifluoromethylpyridine. This compound is described in Japanese published patent application No. 79-125699 (Chemical Abstracts, vol. 92, 146618d).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1.Cl[C:22]1[C:23]2[N:30]=[CH:29][S:28][C:24]=2[N:25]=[CH:26][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[N:30]1[C:23]2[C:22]([NH:18][CH2:17][CH2:16][C:13]3[CH:12]=[CH:11][C:10]([O:9][C:4]4[CH:5]=[N:6][CH:7]=[CH:8][C:3]=4[C:2]([F:19])([F:1])[F:20])=[CH:15][CH:14]=3)=[N:27][CH:26]=[N:25][C:24]=2[S:28][CH:29]=1
Reactant: Clc1ncnc2scnc12
Reactant: NCCc1ccc(Oc2cnccc2C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: FC(F)(F)c1ccncc1Oc1ccc(CCNc2ncnc3scnc23)cc1
Yield: 73.5 %

Procedure:
2-[4-(4-Trifluoromethylpyridin-3-yloxy)-phenyl]-ethylamine (0.25 g, 0.88 mmol), 7-chlorothiazolo[5,4-d]pyrimidine (0.15 g, 0.88 mmol) and K2CO3 (3 g) were dissolved with magnetic stirring in DMSO (7 mL) in a 25 mL round bottom flask equipped with a dry nitrogen line at 25° C. After placing the flask in a sonication bath for 3 min, the reaction mixture was heated on a steam bath for 2 min. The mixture was filtered, and the filter cake was washed with acetone. The combined filtrates were diluted with 0.15 N HCl (100 mL) and washed successively with Et2O (2×50 mL) and EtOAc (2×50 mL). The pooled organic fractions were filtered and concentrated in vacuo to provide 0.27 g of a yellow gum. The gum was dissolved in a small volume of EtOAc and passed through a short SiO2 column with 1% MeOH/EtOAc as eluent. The appropriate fractions were pooled and concentrated in vacuo to provide a clear colorless oil (0.17 g). Trituration in Et2O followed by decanting of the solvent afforded thiazolo[5,4-d]pyrimidin-7-yl-{2-[4-(4-trifluoromethylpyridin-3-yloxy)-phenyl]-ethyl}-amine (Compound 43; 170 mg) as a yellow solid: mp 83-87° C.; 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.34 (s, 1H), 7.54 (s, 1H), 7.30 (d, J=8.6 Hz, 2H), 7.06-6.99 (m, 2H), 6.22 (s, 1H), 3.94 (dd, J=12.9, 6.5 Hz, 2H), 3.04 (t, J=7.1 Hz, 2H); ESIMS m/z 418.2 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:19]=[C:20]([N:25]=[C:26]=[O:27])[CH:21]=[CH:22][C:23]=1[F:24]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:20]2[CH:21]=[CH:22][C:23]([F:24])=[C:18]([F:17])[CH:19]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccc(F)c(F)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)c(F)c2)cc1-c1c(Br)cnn1C
Yield: 39.2 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.035 g, 0.12 mmol) was treated with 3,4-difluorophenyl isocyanate (0.021 g, 16.0 μL, 0.13 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 10 (0.021 g, 0.047 mmol, 38%) as a white solid. LCMS m/z (%)=437 (M+H79Br, 100), 439 (M+H81Br, 99). 1H NMR (400 MHz, acetone-d6) δ: 8.29 (s, 1H), 8.16 (s, 1H), 7.74 (dddd, J=2.5, 7.4, 13.4 Hz, 1H), 7.68 (dd, J=2.7, 9.0 Hz, 1H), 7.49 (s, 1H), 7.42 (d, J=2.7 Hz, 1H), 7.11-7.26 (m, 2H), 7.13 (d, J=9.0 Hz, 1H), 3.82 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [C:1](=[O:19])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([OH:18])[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O>[C:1](=[O:19])([O:2][C:3]([CH3:6])([CH3:5])[CH3:4])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([O:18][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)Oc1ccc(C(C)(C)C)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Oc1ccc(C(C)(C)C)c(OCc2ccccc2)c1
Temperature: 65 °C
Yield: 96.2 %

Procedure:
To an acetone (100 mL) solution of tert-butyl 4-tert-butyl-3-hydroxyphenyl carbonate (J. Org. Chem. 2001, 66, 3435) (5.5 g, 20.7 mmol) were added potassium carbonate (8.6 g, 63 mmol) and benzyl bromide (3.0 ml, 25.0 mmol). The stirred mixture was refluxed at 65° C. for 4 hours. The precipitate was filtered off and washed with acetone. The filtrate was concentrated under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane= 1/30 to furnish 7.1 g (96% yield) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5][CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[CH3:2].[N+:18]([C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[N+:29]([O-:31])=[O:30])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C(OCC)C>[CH2:11]([O:10][C:8]([CH2:7][C@@H:6]1[CH2:5][C@@:4]([C:1](=[O:3])[CH3:2])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C@@H:27]([C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:26][CH:25]=2)[C@@H:28]1[N+:29]([O-:31])=[O:30])=[O:9])[CH3:12]
Reactant: O=[N+]([O-])/C=C/c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C=CCC(C(C)=O)C(=O)OCC
Solvent: CCOCC
Product: CCOC(=O)C[C@@H]1C[C@@](C(C)=O)(C(=O)OCC)[C@@H](c2ccc([N+](=O)[O-])cc2)[C@@H]1[N+](=O)[O-]
Reaction time: 24 h
Yield: 81 %

Procedure:
To a solution of diethyl 5-acetylhex-2-enedioate (4a, 0.3 mmol, 1.0 eq) and 1-nitro-4-((E)-2-nitrovinyl)benzene (0.6 mmol, 2.0 eq) in diethyl ether (0.4 mL) was added catalyst VI (Q-NH2) (0.06 mmol, 0.2 eq) at room temperature (22° C.). The resulting mixture was stirred vigorously for 24 hours, then the reaction was continued for about 6 hours after removal of the solvent. After the reaction was completed (monitored by TLC and crude NMR), the title product was afforded by flash chromatography over silica gel (Et2O:Hexane=1:10 to 1:3) in 81% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]([NH2:27])=[O:26])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][CH2:15][NH:16]C(=O)OC(C)(C)C)[C:6]=2[N:24]=1.[ClH:28]>CO>[ClH:28].[NH2:1][C:2]1[C:3]([C:25]([NH2:27])=[O:26])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][CH2:15][NH2:16])[C:6]=2[N:24]=1
Reactant: CC(C)(C)OC(=O)NCCn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Agent: Cl
Solvent: CO
Product: NCCn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl {2-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]ethyl}carbamate (xvi-a, 35.0 mg, 0.095 mmol) in MeOH (2 mL) was added conc. HCl (1 mL). The reaction was stirred at RT. After 2 h, the reaction was concentrated and lyophilized to yield 2-amino-9-(2-aminoethyl)-9H-pyrido[2,3-b]indole-3-carboxamide hydrochloride as a white solid (16, 27 mg, 93%). NH4OAc standard conditions. DAD Retention time=4.48 min. M+H=270. 1H NMR (300 MHz, D2O): 8.16 (s, 1), 7.74 (d, J=7.6 Hz, 1H), 7.73-7.42 (m, 1H), 7.36-7.28 (m, 2H), 4.32 (t, J=5.7 Hz, 2H), 3.37 (t, J=5.7 Hz, 2H).
Reaction SMILES: N1C=CC=CC=1.O=[Cr](=O)=O.C1C=CC=CN=1.C1C=CC=CN=1.[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[C:36]=1[O:45][CH2:46][O:47][CH3:48])[OH:34].[O-][Si]([O-])=O.[Mg+2]>ClCCl.[O-2].[O-2].[O-2].[Cr+6]>[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](=[O:34])[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[C:36]=1[O:45][CH2:46][O:47][CH3:48]
Reactant: COCOc1ccccc1C(O)c1ccc(OC)c(OC)c1OCOC
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: O=[Si]([O-])[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCOc1ccccc1C(=O)c1ccc(OC)c(OC)c1OCOC
Temperature: 25 °C

Procedure:
A mixture 12.3 g (126 mmol) of chromium trioxide in 153 ml of dichloromethane was cooled to 0° C. and 20.3 ml (252 mmol) of pyridine were added with stirring to obtain, after 45 min, a yellow-brown solution (Collin's reagent). (2-Methoxymethoxyphenyl)(3,4-dimethoxy-2-methoxymethoxyphenyl)methanol (7.67 g, 21 mmol) was added with stirring and the mixture allowed to warm to room temperature with stirring overnight. Twenty grams of florisil were added and the mixture was concentrated by evaporation under reduced pressure and filtered through celite and then further eluted with ether. The resulting mixture was concentrated under reduced pressure and purified by liquid chromatography using a Waters Prep 500 Chromatograph with a silica gel column and eluting with a 70:30 mixture of hexane and ethyl acetate to obtain 6.0 g (79 percent of theory) of the title compound as an oil. The proton and carbon NMR and infrared spectra were consistent with the assigned structure.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[N+:12]([O-])=O)[C:2]#[CH:3].O.O.[Sn](Cl)Cl.[BH4-].[Na+].[N+](NC1C=CC=CC=1)([O-])=O.[OH-].[Na+]>C(O)C.O>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH2:12])[C:2]#[CH:3]
Reactant: C#CCNc1ccc(F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=[N+]([O-])Nc1ccccc1
Agent: [BH4-]
Solvent: O
Solvent: CCO
Product: C#CCNc1ccc(F)cc1N
Temperature: 60 °C
Yield: 117.1 %

Procedure:
Under a nitrogen atmosphere, 5.0 grams (0.026 mole) of N-(2-propyn-1-yl)-4-fluoro-2-nitroaniline in 250 mL of ethanol was added to 25.8 grams (0.114 mole) of stirred tin(II) chloride dihydrate. The reaction mixture was then warmed to 60° C. over a one hour period, after which 98% sodium borohydride pellets were added portionwise until thin layer chromatographic analysis of the reaction mixture indicated that the intermediate nitroaniline had been consumed. Consumption of the nitroaniline required about 2.0 grams (0.052 mole) of sodium borohydride. The reaction mixture was then cooled to about 10° C., and 50 mL of cold water, followed by 15 mL of cold aqueous 10% sodium hydroxide, was added dropwise. After this time, the reaction mixture was concentrated under reduced pressure to remove the majority of the ethanol solvent. The concentrate was extracted with four 75 mL portions of diethyl ether. The combined extracts were washed with aqueous 5% sodium hydroxide and then with an aqueous solution saturated with sodium chloride. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil, which was subjected to column chromatography on silica gel, with 1:3 ethyl acetate:hexane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 5.0 grams of 2-(2-propyn-1-ylamino)-5-fluoroaniline. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:14][CH3:15])[CH:13]=1)[NH:10][C:9](=[O:16])[CH2:8][CH2:7]2)(=[O:3])[CH3:2].[Br:17]Br>C(Cl)(Cl)Cl>[Br:17][CH2:2][C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:14][CH3:15])[CH:13]=1)[NH:10][C:9](=[O:16])[CH2:8][CH2:7]2)=[O:3]
Reactant: COc1cc(C(C)=O)cc2c1NC(=O)CC2
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)CBr)cc2c1NC(=O)CC2
Temperature: 25 °C
Yield: 75.9 %

Procedure:
To a solution of 6-acetyl-8-methoxy-3,4-dihydrocarbostyril (3.1 g) in chloroform (30 ml) was added dropwise a solution of bromine (2.26 g) in chloroform (20 ml) with stirring at room temperature. After completion of addition, the mixture was stirred for 30 minutes at room temperature, thereafter, the reaction mixture was concentrated and the residue was recrystallized from methanol to give 3.2 g of 6-(α-bromoacetyl)-8-methoxy-3,4-dihydrocarbostyril.
Reaction SMILES: [O:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)=[N:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[O:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:13]=[CH:12][C:9](/[CH:10]=[CH:22]/[CH:23]=[O:24])=[CH:8][CH:7]=2)=[N:2]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-c2ncon2)cc1
Product: O=C/C=C/c1ccc(-c2ncon2)cc1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 30 by substituting 4-(1,2,4-oxadiazol-3-yl)benzaldehyde (prepared as described in Reference Example 75) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 201 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.Br[CH2:20][C:21]([NH2:23])=[O:22]>>[C:17]([C:9]1[C:10]([C:13]([F:14])([F:15])[F:16])=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH2:20][C:21]([NH2:23])=[O:22])[C:4]([CH:1]1[CH2:2][CH2:3]1)=[CH:12]2)#[N:18]
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Reactant: NC(=O)CBr
Product: N#Cc1ccc2c(cc(C3CC3)n2CC(N)=O)c1C(F)(F)F

Procedure:
Synthesized as described in Example 4 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 2-bromoacetamide: 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J=8.4 Hz, 1H), 7.71 (bs, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.35 (bs, 1H), 6.37 (s, 1H), 5.02 (s, 2H), 1.94 (m, 1H), 0.99 (m, 2H), 0.77 (m, 2H); MS (ES) m/z 308 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH2:13][C:14]2[C:22]([F:23])=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([F:24])[CH:15]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl.CN(C)CCCN=C=NCC.[N:37]1([S:41]([NH2:44])(=[O:43])=[O:42])[CH2:40][CH2:39][CH2:38]1>ClCCl.CN(C)C1C=CN=CC=1.CS(C)=O>[N:37]1([S:41]([NH:44][C:18](=[O:20])[C:17]2[CH:21]=[C:22]([F:23])[C:14]([CH2:13][O:12][C:4]3[CH:5]=[N:6][C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[C:2]([Cl:1])[CH:3]=3)=[CH:15][C:16]=2[F:24])(=[O:43])=[O:42])[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)Oc1ncc(OCc2cc(F)c(C(=O)O)cc2F)cc1Cl
Reactant: NS(=O)(=O)N1CCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)Oc1ncc(OCc2cc(F)c(C(=O)NS(=O)(=O)N3CCC3)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.3 %

Procedure:
To a solution of 4-{[(5-chloro-6-isopropoxypyridin-3-yl)oxy]methyl}-2,5-difluorobenzoic acid (Preparation 15, 100 mg, 0.28 mmol) in dichloromethane (3 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80 mg, 0.42 mmol) and 4-dimethylaminopyridine (51 mg, 0.42 mmol). The reaction was allowed to stir at room temperature for 20 minutes, before the addition of azetidine-1-sulfonamide (Preparation 19, 57 mg, 0.42 mmol). The reaction was stirred at room temperature for 18 hours. The solvent was removed in vacuo to leave a yellow solid. The crude material was dissolved in dimethylsulphoxide (2 mL) and purified twice by preparative HPLC to afford the title compound as a white powder (27 mg, 13%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:15]([O:17][C@H:18]4[C@H:22]5[O:23][CH2:24][C@@H:25]([OH:26])[C@H:21]5[O:20][CH2:19]4)=[N:16][C:11]3=[CH:10][C:9]=2[Cl:35])=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:43](=[O:46])[O:44][CH3:45])[CH2:38][CH2:37]1>>[Cl:35][C:9]1[CH:10]=[C:11]2[N:16]=[C:15]([O:17][C@@H:18]3[CH2:19][O:20][C@@H:21]4[C@H:25]([OH:26])[CH2:24][O:23][C@H:22]34)[N:14]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:12]2=[N:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([N:36]2[CH2:37][CH2:38][CH:39]([NH:42][C:43](=[O:46])[O:44][CH3:45])[CH2:40][CH2:41]2)=[CH:3][CH:4]=1
Reactant: COC(=O)NC1CCNCC1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(Br)cc3)nc21
Product: COC(=O)NC1CCN(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)CC1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(5-(4-bromophenyl)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and methyl piperidin-4-ylcarbamate following a procedure analogous to that described for Intermediate 23. LC (method 1): tR=0.97 min; Mass spectrum (ESI+): m/z=660 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:17]2([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][C:32]([S:35]([N:38]5[CH2:42][CH2:41][CH2:40][C@@H:39]5[CH2:43][OH:44])(=[O:37])=[O:36])=[CH:31][CH:30]=4)[N:24]=3)=[O:21])[CH2:19][CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:17]2([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][C:32]([S:35]([N:38]5[CH2:42][CH2:41][CH2:40][C@@H:39]5[CH2:43][OH:44])(=[O:37])=[O:36])=[CH:31][CH:30]=4)[N:24]=3)=[O:21])[CH2:18][CH2:19]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: [H][H]
Reactant: COc1ccc(C2(C(=O)Nc3cccc(-c4ccc(S(=O)(=O)N5CCC[C@@H]5CO)cc4)n3)CC2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C2(C(=O)Nc3cccc(-c4ccc(S(=O)(=O)N5CCC[C@@H]5CO)cc4)n3)CC2)cc1O
Yield: 33.2 %

Procedure:
(R)-1-(3-(Benzyloxy)-4-methoxyphenyl)-N-(6-(4-(2-(hydroxymethyl)pyrrolidin-1-ylsulfonyl)phenyl)pyridin-2-yl)cyclopropanecarboxamide (28 mg, 0.046 mmol) was dissolved in ethanol (3 mL). Palladium on charcoal (10%, 20 mg) was added and the reaction was stirred overnight under 1 atm of hydrogen. The catalyst was filtered off and the product was isolated by silica gel chromatography (50-80% EtOAc in hexane) to provide (R)-1-(3-hydroxy-4-methoxyphenyl)-N-(6-(4-(2-(hydroxymethyl)pyrrolidin-1-ylsulfonyl)phenyl)pyridin-2-yl)cyclopropanecarboxamide (8 mg, 34%). ESI-MS m/z calc. 523.4, found 524.3 (M+1)+. Retention time of 3.17 minutes.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:11]([CH:14]3[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[CH2:15]3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:29][O:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=[C:33]([NH2:46])[N:32]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[NH2:46][C:33]1[N:32]=[C:31]([O:30][CH3:29])[C:36]([C:2]2[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]3[CH:10]([C:22]4[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=4)[N:11]([CH:14]4[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[CH2:15]4)[C:12](=[O:13])[C:4]=3[CH:3]=2)=[CH:35][N:34]=1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(C1CCC(=O)N(C)C1)C2=O
Reactant: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1nc(N)ncc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(C1CCC(=O)N(C)C1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-6-(4-chloro-phenyl)-1-isopropyl-5-(1-methyl-6-oxo-piperidin-3-yl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate Q) and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (Intermediate U) were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a beige solid. tR: 2.35 min (HPLC 5); ESI-MS: tR=0.81 min, [M+H]+ 509/511 (LC-MS 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][NH:11][C:12]([NH:14][CH2:15][C:16]([O:18]CC)=[O:17])=[O:13])=O)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:12](=[O:13])[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CNC(=O)NNC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1c(-c2ccc(Cl)cc2)n[nH]c1=O
Temperature: 25 °C

Procedure:
Of the compound from Example 1A, 21.43 g (67.93 mmol) were admixed with 91 ml of a 3N aqueous sodium hydroxide solution and heated at reflux overnight. After cooling to RT, the mixture was adjusted to a pH of 1 by slow addition of approximately 20% strength hydrochloric acid. The precipitated solid was isolated by filtration, washed with water and dried at 60° C. under reduced pressure. Yield: 17.55 g (90% of theory, approximately 88% purity).
Reaction SMILES: ClC1C2C=CC(C(F)(F)F)=CC=2SC=1C([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=O.[Cl:29][C:30]1[C:31]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:32]=2[S:33][C:34]=1[C:35](Cl)=[O:36]>>[Cl:29][C:30]1[C:31]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:32]=2[S:33][C:34]=1[C:35]([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:36]
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1sc2cc(C(F)(F)F)ccc2c1Cl
Reactant: O=C(Cl)c1sc2cc(F)c(F)cc2c1Cl
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1sc2cc(F)c(F)cc2c1Cl

Procedure:
Following the 5a synthetic method, using 5-2 (66.77 mg, 0.25 mmol) instead of 5 gave 8a as a white powder; (91.63 mg, 92.6%). [α]D25: −15.9 (c=0.19, CHCl3); 1H-NMR (300 MHz, acetone-d6): δ 7.91 (s, 1H), 7.63-7.52 (m, 3H), 7.37-7.25 (m, 5H), 5.16-5.09 (m, 1H), 3.43-3.28 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 175.39, 160.02, 152.99, 151.92, 149.63, 148.61, 135.17, 133.75, 133.25, 129.45, 128.82, 127.53, 118.84, 110.98, 110.77, 110.50, 54.05, 37.28; HRMS (ESI): calcd for: C18H12ClF2NO3S [M−H]−=394.0122, obsd [M−H]−=394.0137.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]([C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1ncccc1-n1nc(C(C)(C)C)cc1N
Product: Cc1ncccc1-n1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Yield: 70.1 %

Procedure:
Following the procedure in Example 118A, 3-tert-butyl-1-(2-methylpyridin-3-yl)-1H-pyrazol-5-amine (679 mg, 2.94 mmol) was treated with phenyl chloroformate (1.50 mL, 12.0 mmol) to afford phenyl 3-tert-butyl-1-(2-methylpyridin-3-yl)-1H-pyrazol-5-ylcarbamate (722 mg, 2.06 mmol, 70%). 1H NMR (300 MHz, DMSO-d6) δ 10.24 (br s, 1H), 8.71 (s, 1H), 8.07 (d, 1H), 7.68 (br s, 1H), 7.41-7.36 (m, 2H), 7.23 (t, 1H), 7.04 (br s, 2H), 6.37 (s, 1H), 2.36 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 351 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[CH2:12]([N:11]([CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:18])=[O:2])=[CH:5][CH:6]=1)[CH2:15][CH2:16][CH3:17])[CH2:13][CH3:14]
Reactant: CCCN(CCC)Cc1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN(CCC)Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
The compound (883 mg) obtained in Example 29-2 was dissolved in methanol (18 ml) and added with a 1 mol/l sodium hydroxide aqueous solution (9.0 ml) and the whole was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in 1 mol/l hydrochloric acid, subjected to extraction with chloroform, and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off and the residue was dried under vacuum, thereby obtaining the subject compound (820 mg) as a white solid.