Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([O:13][C:14](=[O:20])[CH:15](Br)[CH2:16][CH2:17][CH3:18])[CH3:12].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[CH2:11]([O:13][C:14](=[O:20])[CH:15]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])[CH2:16][CH2:17][CH3:18])[CH3:12]
Reactant: CCCC(Br)C(=O)OCC
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC(Oc1ccc(Cl)cc1C=O)C(=O)OCC
Temperature: 140 °C
Yield: 84.3 %

Procedure:
A mixture of 5-chloro-2-hydroxy-benzaldehyde (15 g, 0.1 mol), 2-bromo-pentanoic acid ethyl ester (27 g, 0.13 mol) and K2CO3 (27 g, 0.2 mol) in DMF (100 mL) was heated at 140° C. for 1 h. After cooled to room temperature, the mixture was poured into water and the aqueous phase was extrated with EtOAc thrice. The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a colorless oil (24 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C@H:11]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=3[F:22])[C@@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:31]([O-])=O.[BH4-].[Na+].C(Cl)Cl>CO.O1CCCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:31][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][C@H:11]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=3[F:22])[C@@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:9]2)=[N:7][C:2]=1[NH2:1]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(c2ccc([N+](=O)[O-])c(N)n2)CC[C@@H]1c1cc(F)c(F)cc1F
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CN(c2ccc(N)c(N)n2)CC[C@@H]1c1cc(F)c(F)cc1F
Reaction time: 0.17 h

Procedure:
To 85 mg (0.18 mmol) of the product of Step A in 4 mL of 3:1 methanol/tetrahydrofuran at 0° C. was added 2.5 mg (0.01 mmol) of nickel (II) chloride hexahydrate followed by 40 mg (1.0 mmol) of sodium borohydride in four 10 mg portions every 5 min. The reaction mixture was stirred for an additional 10 min and poured into 20 mL of a 1:1 mixture of methylene chloride/saturated aqueous ammonium chloride solution. The layers were separated and the aqueous phase extracted with three 10-mL portions of methylene chloride. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to yield a purple solid which was purified by preparative thin layer chromatography using an Analtech® 1500 micron plate (1:2 hexane/ethyl acetate solvent) to give the title compound as a purple crystalline solid. LC/MS 438.1 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH2:13][CH3:14])[C:7]=2[C:6](=[O:15])[NH:5][C:4]1=[O:16])[CH3:2].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][P:23]([O:28][CH2:29][CH3:30])(=[O:27])[O:24][CH2:25][CH3:26]>>[CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH2:13][CH3:14])[C:7]=2[C:6](=[O:15])[N:5]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][P:23](=[O:27])([O:28][CH2:29][CH3:30])[O:24][CH2:25][CH3:26])[C:4]1=[O:16])[CH3:2]
Reactant: CCOP(=O)(CCCCCBr)OCC
Reactant: CCCn1cnc2c1c(=O)[nH]c(=O)n2CC
Product: CCCn1cnc2c1c(=O)n(CCCCCP(=O)(OCC)OCC)c(=O)n2CC

Procedure:
The title substance was prepared from 0.0225 mol of 3-ethyl-7-propyl-xanthine and 0.027 mol of diethyl 5-bromopentanephosphonate analogously to Example 46.
Reaction SMILES: [CH2:1]([N:8]([CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@@H:9]1[CH2:16][N:15]2[C:17]3[CH:18]=[C:19]([C:30]([O:32]C)=[O:31])[CH:20]=[CH:21][C:22]=3[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:14]2[C:13]2[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:12]=2[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>O1CCOCC1>[CH2:1]([N:8]([CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@@H:9]1[CH2:16][N:15]2[C:17]3[CH:18]=[C:19]([C:30]([OH:32])=[O:31])[CH:20]=[CH:21][C:22]=3[C:23]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[C:14]2[C:13]2[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:12]=2[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(CCNC(=O)OC(C)(C)C)Cc1ccccc1)COc1cc(F)ccc1-3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCN(Cc1ccccc1)[C@H]1COc2cc(F)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Temperature: 60 °C

Procedure:
To a solution of methyl (7R)-7-(benzyl{2-[(tert-butoxycarbonyl)amino]ethyl}amino)-14-cyclohexyl-3-fluoro-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate in dioxane (0.1 M) was added 2M KOH aqueous solution (3 eq). The mixture was warmed to 60° C. After 2 h the mixture was neutralized by addition of 1N aqueous HCl and all volatiles were evaporated in vacuo. The residual material was taken up with EtOAc and water. The organic phase was separated and the aqueous layer was extracted with EtOAc. After drying the organic phases over Na2SO4 all volatiles were evaporated in vacuo (97%). (ES+) m/z 652 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([O:28][CH:29]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])=[C:15](OS(C(F)(F)F)(=O)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:44]([Sn](CCCC)(CCCC)CCCC)=[CH2:45].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN1CCCC1=O.[Cl-].[Zn+2].[Cl-]>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([O:28][CH:29]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:27])=[C:15]([CH:44]=[CH2:45])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(=O)(=O)C(F)(F)F)CS[C@H]12
Agent: [Cl-]
Agent: [Zn+2]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN1CCCC1=O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.4645 g (0.00073 mole) of diphenylmethyl 7-phenylacetamido-3-trifluoromethylsulfonyloxy-3-cephem4-carboxylate, 0.279 g (0.00088 mole) of ethenyl tri-n-butylstannane, 0.200 g (0.00146 mole) of zinc chloride and 0.0068 g (0.000029 mole) of tri-(2-furyl)phosphine in 6 mL of dry 1-methyl-2-pyrrolidinone, under an Argon atmosphere, was degassed for 30 seconds. Then 0.0084 g (0 000014 mole) of palladium(0) bis(dibenzylidene acetone) was added all at once. The reaction mixture was stirred at room temperature for 1 hr. The reaction mix was then diluted with ethyl acetate and the organic solution washed with dilute ammonium chloride. The ethyl acetate was removed at reduced pressure and replaced with acetonitrile. The organic phase was washed with n-pentane and the acetonitrile removed at reduced pressure. The residue was crystallized from ethanol/methylene chloride yielding 0.320 g (85%) of diphenylmethyl 7-phenylacetamido-3-ethenyl-3-cephem-4-carboxylate. The nuclear magnetic resonance spectrum was consistent for the desired structure.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[CH3:15][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO.C(OCC)C>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH3:15])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.0 g (29.4 mmol) of [4-(trifluoromethyl)phenyl]acetic acid were dissolved in 67.1 ml of toluene and 46.2 ml of methanol, and 26.5 ml (52.9 mmol) of a 2 M solution of trimethylsilyldiazomethane in diethyl ether were added dropwise with cooling. After the addition had ended, cooling was removed and the mixture was stirred at RT for another 1 h, after which excess trimethylsilyldiazomethane was destroyed by addition of 2.0 ml of acetic acid. The reaction mixture was concentrated under reduced pressure and the crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 80:1). This gave 4.33 g of the target compound (67.6% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21](I)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:25].C[Si](C)(C)[O:31][CH2:32][C:33]#[CH:34].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:34]#[C:33][CH2:32][OH:31])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:25]
Reactant: C#CCO[Si](C)(C)C
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4ccc(I)cc34)cc2Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OCC#Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-iodoquinazolin-4-amine (1.52 g), trimethyl(prop-2-ynyloxy)silane (0.7 mL), triethyl amine (0.5 mL) in DMF (10 mL) was added Pd(PPh3)2Cl2 (106 mg), CuI (114 mg) and the mixture was heated at 40° C. overnight. The solvent was removed, then methanol (10 mL) and 4N HCl (2 mL) were added. The reaction mixture was stirred at room temperature for one hour and the solvent was removed. Another 10 mL methanol and triethyl amine (2 mL) were added and the reaction mixture was stirred at room temperature for one hour. The solvent was removed and the residue was purified by flash chromatography, eluting with EtOAc to give the desired product. LCMS ESI(+) m/z: 434 (M+1). Yield: 86%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[S:28][C:29]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:30][N:31]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[S:28][C:29]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:30][N:31]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(O)c1cnc(Br)s1
Product: O=S(=O)(O)c1cnc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 2-bromo-thiazole-5-sulfonic acid (220 mg, 0.9 mmol, prepared according to: Helv. Chim. Acta, 1945, 28, 985) according to general procedure II. Obtained as an orange solid (75 mg, 14%). MS (ISN) 516.8 [(M−H)−]; mp >295° C.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][S:11][C:10]=1[NH:14][C:15](=[O:20])[C:16](Br)([CH3:18])[CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:21]=[N+]=[N-].[Na+].[N-]=[N+]=[N-].[Cl-].[NH4+]>C(O)C.[Zn]>[NH2:21][C:16]([CH3:18])([CH3:17])[C:15]([NH:14][C:10]1[S:11][CH:12]=[CH:13][C:9]=1[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(Br)C(=O)Nc1sccc1C(=O)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(N)C(=O)Nc1sccc1C(=O)c1ccccc1
Yield: 65 %

Procedure:
3.4 g of the compound of Example 1 was boiled with sodium azide in ethanol under reflux. The crude azide was directly reduced with zinc and ammonium chloride in boiling ethanol to give 65% of the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[C:40]([F:48])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:47])[F:46])=[C:40]([F:48])[CH:39]=2)[C:35]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
A solution of triphenylphosphine (312 mg, 1.19 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (212 mg, 1.19 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionic acid (300 mg, 0.99 mmol). The resulting reaction mixture was stirred at 0° C. for 15 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminothiazole (218 mg, 2.18 mmol). The resulting reaction mixture was stirred at 25° C. for 3 d. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide (243 mg, 64%) as a white solid: mp 194-195° C.; EI-HRMS m/e calcd for C18H18F4N2OS (M+) 386.1076, found 386.1076.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@H:7]2[NH:8][CH2:9][C@H:4]([O:5][C:6]2=[O:10])[CH2:3]1.CN(C)C=O.C(N(CC)CC)C.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>Cl>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([N:8]2[CH2:9][C@H:4]3[CH2:3][C:2]([CH3:11])([CH3:1])[C@@H:7]2[C:6](=[O:10])[O:5]3)(=[O:40])=[O:39])=[CH:34][CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1(C)C[C@@H]2CN[C@H]1C(=O)O2
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)C[C@@H]2CN(S(=O)(=O)c3ccc(OCc4ccccc4)cc3)[C@H]1C(=O)O2
Reaction time: 1 h

Procedure:
A solution of (1R,4R)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (compound of formula XXXVI, 10 mmol) and dimethylformamide (20 ml) at about 0° C. was treated with triethylamine (10–20 mmol) and 4-benzyloxybenzenesulfonyl chloride (15 mmol). After stirring for about 1 hours, the mixture is warmed to a temperature of about 20° C. to about 25° C. and stirred for about an additional 12 hours. The mixture is diluted with 1M hydrochloric acid, extracted twice with ethyl acetate, and the combined organic layers are dried over sodium sulfate, filtered and concentrated in vacuo to give (1R,4R)-5-(4-benzyloxy-benzenesulfonyl)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one as a colorless syrup.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:44]2[CH:45]=[C:46]([N:50]3[CH2:55][CH2:54][S:53](=[O:57])(=[O:56])[CH2:52][CH2:51]3)[CH:47]=[CH:48][CH:49]=2)O1.[OH-].[Na+]>COCCOC.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13]([C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([N:50]5[CH2:55][CH2:54][S:53](=[O:56])(=[O:57])[CH2:52][CH2:51]5)[CH:45]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cccc(N3CCS(=O)(=O)CC3)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(N6CCS(=O)(=O)CC6)c5)nc43)cc2)CCC1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A mixture of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (50.0 mg, 0.101 mmol), 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]thiomorpholine 1,1-dioxide (51.5 mg, 0.153 mmol), Pd(dppf)2Cl2.DCM (8.32 mg, 0.0102 mmol), and 2M NaOH aq. (0.150 mL, 0.310) in DME (2 mL) was heated at 80° C. for 10 hours under nitrogen. After cooling to room temperature, the mixture was diluted with DCM and filtered through a Celite pad. The combined filtrate and washings were concentrated. The residue was purified by silica gel column chromatography (CHCl3/EtOAc=2:1→1:1→1:2) to afford desired product (38.4 mg, 56.6%) as pale yellow foam.
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=O.[Br:19][C:20]1[CH:21]=[N:22][C:23]([NH2:26])=[N:24][CH:25]=1.O>CN(C=O)C>[Br:19][C:20]1[CH:21]=[N:22][C:23]2[N:24]([C:2]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:3]([C:5]3[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=3)[N:26]=2)[CH:25]=1
Reactant: O=Cc1ccc(C(=O)C(Br)c2ccccc2)cc1
Reactant: Nc1ncc(Br)cn1
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2nc3ncc(Br)cn3c2-c2ccccc2)cc1
Temperature: 90 °C

Procedure:
0.15 g (0.5 mM) of 4-[bromo(phenyl)acetyl]benzaldehyde and 2.0 equivalents of 5-bromopyrimidin-2-amine are dissolved in 6 ml DMF. The reaction mixture is heated at 90° C. overnight. The reaction mixture is cooled and water is added. It is then extracted with ethyl acetate. The organic layer is dried and concentrated. The crude product is purified by column chromatography to obtain the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])=[CH:4][CH:3]=1.C(OC(Cl)=O)C(C)C.[BH4-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[CH:20][C:21]([CH2:22][OH:23])=[CH:25][CH:26]=4)[C:11]=3[N:10]=[C:9]2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4Cl)nc32)cc1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1c2cnn(-c3ccc(CO)cc3)c2nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Reaction time: 1.5 h

Procedure:
4-[5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzoic acid (115 mg, 0.225 mmol) is dissolved in 6 mL of THF. To the solution TEA (68.0 mg, 0.674 mmol) and isobutylchloroformate (46.0 mg, 0.337 mmol) are added and the mixture is stirred for 1.5 h. The resulting mixture is added to a solution of sodium borohydride (33.3 mg, 0.898 mmol) in 3 mL of water and then stirred for 3 h, concentrated, and extracted with water/ethyl acetate and purified by column chromatography. 1H NMR (dioxane, 400 MHz) δ 8.33 (s, 1H), 8.00 (d, 2H), 7.45 (s, 1H), 7.39 (d, 2H), 7.16 (d, 1H), 7.29-7.19 (m, 5H), 7.03 (m, 1H), 4.53 (d, 2H), 3.71 (t, 1H). HPLC-MS calculated for C24H15Cl3N4O2 (M+H+) 497.0, Found 497.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][C:8]1[CH:29]=[CH:28][C:11]2[N:12]([CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16][C:17]([O:19]CC)=[O:18])[CH:13]=[N:14][C:10]=2[CH:9]=1)=[O:6]>Cl>[NH2:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][C:8]1[CH:29]=[CH:28][C:11]2[N:12]([CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[N:14][C:10]=2[CH:9]=1)=[O:6]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3cccc(N)c3)ccc21
Agent: Cl
Product: Nc1cccc(C(=O)Nc2ccc3c(c2)ncn3C(CC(=O)O)c2ccccc2)c1

Procedure:
A solution of ethyl 3-{5-[(3-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (50 mg, 117 μmol) in hydrochloric acid (20 mL of a 5N solution) was stirred at room temperature for 110 hours. The solution was then evaporated in vacuo, and the residue was purified by RP-HPLC to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=3.25 min, MH+ 401].
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH2:10][C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=1)(=[O:24])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH:10]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C:4](=[N:3][O:2][CH3:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:33][CH:32]=1)(=[O:24])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCC(=O)CC(=NOC)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(=O)C(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=NOC)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.7 %

Procedure:
A mixture of 50 mg (0.218 mmol) of ethyl 2-methoxyimino-4-oxooctanoate (from Step A), 83 mg (0.218 mmol) of [2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl bromide (from Step E), 36 mg (0.262 mmol) of freshly pulverized anhydrous potassium carbonate, and 0.6 mL of dry DMF was stirred vigorously for 24 hours at room temperature at which time the starting material was all consumed [TLC (5:1 hexane/EtOAc)]. The mixture was partitioned between 10 mL of EtOAc and 10 mL of 0.2N HCl. The EtOAc layer was then washed with 3×10 mL H2O, 1×5 mL brine, and dried briefly over anhydrous sodium sulfate. The filtrate, obtained from filtration over sintered glass, was concentrated to dryness and the resulting residue was flash chromatographed over 20 mL silica gel (column packed using hexane, sample introduced as a solution in CH2Cl2) eluting with 20/1 hexane/ethyl acetate, to give 83 mg (71%) of the desired product as an oil, homogeneous by TLC. Rf =0.35 in 5:1 hexane/EtOAc. 1H NMR (200 MHz, CDCl3, ppm)=δ0.88 (t, J=7.2 Hz, 3H), 1.00 (s, 9H), 1.31 (m, 5H), 1.52 (m, 2H), 2.32 (t, J=7.0 Hz, 2H), 3.03 (m, 1H), 3.40 (m, 1H), 3.61 (s, 1H), 4.04 (s, 3H), 4.25 (m, 3H), 7.16-7.52 (m, 7H), 8.15 (m, 1H), Mass spectrum: FAB (m/e) 531 (M+1)+.
Reaction SMILES: [CH3:1][S:2]([CH:5]=[CH2:6])(=[O:4])=[O:3].[CH3:7][NH2:8].[ClH:9]>C(O)C>[ClH:9].[CH3:7][NH:8][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CN
Reactant: C=CS(C)(=O)=O
Agent: Cl
Solvent: CCO
Product: CNCCS(C)(=O)=O
Reaction time: 8 h

Procedure:
Methylvinyl sulphone (2.1 g, 19.78 mmol) and methylamine (33% solution in IMS, 40 ml , excess) were mixed and heated at reflux under a nitrogen atmosphere for 6 hours. After standing overnight at room temperature, the mixture was concentrated in vacuo to give a yellow oil, which was treated with ethereal HCl to give a sticky solid. Trituration with absolute ethanol gave the title compound as a white solid which was collected by filtration and dried at 60° C. in vacuo (1.01 g, 5.82 mmol, 29%); δH [2H6]DMSO 9.27 (2H, br s), 3.59 (2H, dd), 3.31 (2H, dd), 3.12 (3H, s), 2.57 (3H, s).