Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[CH:8]=2)[N:3]=1.[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Br)[CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[CH2:30][N:6]1[C:2]([CH3:1])=[N:3][C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=3)[CH:8]=2)=[N:5]1
Reactant: Cc1nc(-c2cc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
To a solution of 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-isoxazole (257 mg, 0.83 mmol) and 1-bromo-3-(bromomethyl)benzene (206 mg, 0.83 mmol) in DMF (20 mL), was added K2CO3 (286 mg, 2.07 mmol). The mixture was stirred at RT for 16 h, then diluted with H2O (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure; the residue was purified by silica gel chromatography (Petroleum ether:EtOAc=1:1) to give the title compound as a white solid (230 mg, 58%). MS (ES+) C20H14BrF3N4O2 requires: 478. found: 479 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[F:11])#[N:2].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCO>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][C:4]=1[F:11])#[N:2]
Reactant: N#Cc1ccc(C=O)cc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(CO)cc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-cyano-3-fluorobenzaldehyde, as described in Example 11, Step B, (620 mg, 4.16 mmol) in EtOH (30 mL) at 0° C. was added NaBH4 (157 mg, 4.16 mmol) in one portion. The reaction mixture was stirred at 0° C. for 10 min, then 10% aqueous citric acid (10 mL) was added and the solvent was removed under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 (10 nmL) and CH2Cl2 (30 mL). The aqueous layer was extracted further with CH2Cl2 (30 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to provide the titled compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:31]>CN(C)C(=O)C>[N+:39]([C:36]1[CH:35]=[CH:34][C:33]([O:32][C:30](=[O:31])[NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]3=[CH:14][NH:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)=[CH:38][CH:37]=1)([O-:41])=[O:40]
Reactant: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(N)cc43)cc2)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)N(C)C
Product: CN1CCN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(NC(=O)Oc5ccc([N+](=O)[O-])cc5)cc43)cc2)CC1
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
An amount of 200 mg (0.53 mmol) of (4Z)-6-amino-4-({[4-(4-methylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione and 4-nitrophenyl chloroformate 320.0 mg (1.59 mmol) is stirred in N,N-dimethylacetamide at 100° C. for 1 hour. After cooling, the solvent is evaporated and stirred in 3 mL of water for 10 minutes. The solid precipitate is collected with ether to give 180 mg (70% yield) of (4-{[4(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dioxo-1,2,3,4-tetrahyro-isoquinolin-6-yl)-carbamic acid 4-nitro-phenyl ester.
Reaction SMILES: N1([C:6]([C:8]2[CH:9]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)[NH:10][C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13]=2[CH3:14])=[O:7])C=CN=C1.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][CH2:41][OH:42]>>[C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:9]2[C:8]([C:6]([O:42][CH2:41][CH2:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=3)=[O:7])=[C:13]([CH3:14])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=3)[C:11](=[O:25])[NH:10]2)=[CH:33][CH:32]=1)#[N:31]
Reactant: CC1=C(C(=O)n2ccnc2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: OCCc1ccccn1
Product: CC1=C(C(=O)OCCc2ccccn2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
45.1 mg (0.1 mmol) of the compound of Example 25 are added to 0.5 ml 2-(2-pyridinyl)ethanol. The reaction mixture is stirred at approx. 100° C. for 1 hour. After cooling the reaction mixture is purified by preparative HPLC (column: Agilent Zorbax Extend C18 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% conc. ammonia; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 500 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1
Reactant: Fc1ccccc1S
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(Sc3ccccc3F)n2)n[nH]1

Procedure:
Similar procedure as described in example 305 was used, starting from 2-fluoro-benzenethiol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(2-fluoro-phenylsulfanyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 351 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2].[CH:13](=O)[CH3:14].[BH3-]C#N.[Na+]>[Cl-].[Cl-].[Zn+2].CO>[CH2:13]([N:9]1[CH2:10][CH2:11][N:6]2[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:7]2[CH2:8]1)[CH3:14]
Reactant: O=[N+]([O-])c1cc2n(n1)CCNC2
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCN1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
A 150-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with methanol (60 mL), 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 205a (1.5 g, 8.9 mmol), ZnCl2 (2.43 g, 17.8 mmol), acetaldehyde (784 mg, 17.8 mmol), and NaBH3CN (1.12 g, 17.8 mmol). The mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was purified with silica-gel column chromatography eluting with 40:1 petroleum ether/ethyl acetate to afford 208a (1.4 g, 81%) as a yellow oil. MS-ESI: [M+H]+ 197
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][N+:8]([O-])=[C:7]([CH3:12])[C:6]=1[CH3:13])[CH2:2][CH3:3].[C:14]([O:17]C(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:17][CH2:12][C:7]1[C:6]([CH3:13])=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:10]=[CH:9][N:8]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCCOc1cc[n+]([O-])c(C)c1C
Product: CCCOc1ccnc(COC(C)=O)c1C
Yield: 111.2 %

Procedure:
To 20.3 g of 4-propoxy-2,3-dimethylpyridine-1-oxide, 44.0 g (4.0 eq.) of acetic anhydride was added, and the mixture was allowed to react for 4 hours at 90° C. Acetic anhydride was distilled off, and then the resulting concentrated residue was purified on a silica gel column, to obtain 27.8 g of 2-acetoxymethyl-3-methyl-4-propoxy-pyridine as an oily matter.
Reaction SMILES: C(N(CC)CC)C.[Cl-].[CH2:9]([NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1I)[CH:10]=[CH2:11]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:11][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:21])[NH:12][CH:9]=1
Reactant: C=CCNC(=O)c1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c[nH]c(=O)c2ccccc12
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Under an N2 atmosphere, 985 ml (7.07 mol) of triethylamine, 892 g (3.21 mol) of tetra-nbutylammonium chloride and 12.77 g (57 mmol) of Pd(OAc)2 are added to 815 g (2.8 mol) of 2-iodo-benzoic acid allylamide in 4.5 l of DMF, and heated to 100° C. After 4 h, cooling is effected to RT, and the mixture is partially concentrated by evaporation on a RE. The residue is partitioned between 5 l of water and 5 l of EtOAc, the water phase is separated and extracted twice with EtOAc. The organic phases are washed with water, 0.1 N HCl, water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2, EtOAc/toluene 1:1) and crystallisation from toluene yields 4-methyl-2H-isoquinolin-1-one; m.p. 175-176° C.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][C:15]([C:17]2[C:18]([S:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH:8]=1.CO.C1COCC1>O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][CH2:24][S:23][C:18]2[C:17]([C:15]([NH:14][CH2:13][C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:6]([OH:34])=[O:5])=[O:16])=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)c1cccc(CNC(=O)c2cccnc2SCCCc2ccc(F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(CNC(=O)c2cccnc2SCCCc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
A solution of 120 mg (2.92 mmol) of lithium hydroxide monohydrate in water (4 ml) was added to a solution of 320 mg (0.73 mmol) of 3-[[[2-[3-(4-fluorophenyl)-propylsulfanyl]-pyridine-3-carbonyl]amino]-methyl]-benzoic acid methyl ester (exemplary compound 129) in a MeOH/THF mixture (2:1 vv, 9 ml), and the mixture was stirred for 16 h at RT. Concentration in vacuo was then carried out. The residue was taken up in water and washed with EA. The aqueous phase was then adjusted to pH ˜2 with 2M hydrochloric acid at 0° C. The resulting precipitate was filtered off, taken up in toluene and concentrated in vacuo. The residue was washed with an ether/pentane mixture (1:4 vv), yielding 170 mg (0.4 mmol, 55%) of 3-[[[2-[3-(4-fluorophenyl)-propylsulfanyl]-pyridine-3-carbonyl]amino]-methyl]-benzoic acid. MS: m/z 425.1 [m+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[N:6][CH:7]=1.Cl.[NH2:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CN1CCOCC1>C1COCC1>[O:18]=[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][NH:15][C:11]([C:9]1[NH:8][C:5]2=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13]
Reactant: NCC(=O)c1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)cnc2[nH]1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(CNC(=O)c1cc2cc(Cl)cnc2[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Preparation 57, 50 mg, 0.25 mmol), 2-aminoacetophenone hydrochloride (48 mg, 0.28 mmol) and DMTMM (85 mg, 0.31 mmol) were dissolved in THF (5 mL) and 4-methylmorpholine (31 μL, 0.28 mmol). The reaction mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (20 mL) and EtOAc (3×20 mL). The combined organics were dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with methanol:dichloromethane (1:19) to give the title compound. m/z (ES+)=314 [M+H]+; RT=3.47 min.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+].[OH:17][CH:18]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19]/[CH:20]=[CH:21]/[I:22]>C(Cl)Cl.CCOCC>[O:17]=[C:18]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19]/[CH:20]=[CH:21]/[I:22]
Reactant: CCCCC(O)C/C=C/I
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCC(=O)C/C=C/I
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred suspension of 6.15 g of pyridinium chlorochromate (Tetrahedron Letters, 1975, 2647) in 20 ml of methylene chloride is added 450 mg of sodium acetate. After 5 minutes, a solution of 3.64 g of 4-hydroxy-1-iodo-trans-1-octene in 15 ml of methylene chloride is added in one portion. The dark mixture is stirred at room temperature for 75 minutes, diluted with 50 ml of ether, and decanted. The solid sludge is washed repeatedly with ether and decanted. The combined solutions are percolated through Florisil. The solution is concentrated to give and orange liquid, pmr spectrum (CDCl3): 3.20 (d, j=7 cps, =CHCH2CO).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH:13]([CH3:15])[C:12](=[O:16])[NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:17]>>[ClH:17].[CH3:15][CH:13]1[CH2:14][NH:8][CH2:9][CH2:10][NH:11][C:12]1=[O:16]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCNC1=O
Agent: Cl
Product: CC1CNCCNC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
6-Methyl-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (42 mg, 0.18 mmol) was suspended in hydrogen chloride solution (4 M in 1,4-dioxane, 0.5 ml) and stirred at room temperature for 4 h, then volatile material was removed by distillation, to afford the title compound (29 mg, 96%). Colorless gum, MS: 129.1 ([M−Cl]+).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[CH:12][N:11]=1>>[Cl:9][C:10]1[N:15]=[C:14]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: BrCc1ccccc1
Product: Clc1nccc(Cc2ccccc2)n1

Procedure:
The title compound (quantitiative yield) was prepared from benzyl bromide (1.71 g, 1.19 ml, 10 mmol) and 2,4-dichloropyrimidine (1.49 g, 10 mmol) in a similar manner to Intermediate 2, and was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([C@H:12]1[N:20]([C:21](=[O:48])[C@@H:22]([NH:26][C:27](=[O:47])[C@@H:28]([N:30]([CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])C(=O)OCC2C=CC=CC=2)[CH3:29])[CH:23]([CH3:25])[CH3:24])[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11]>[Pd].CO>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[NH:9][C:10]([C@H:12]1[N:20]([C:21](=[O:48])[C@@H:22]([NH:26][C:27](=[O:47])[C@@H:28]([NH:30][CH2:41][CH2:42][S:43]([CH3:46])(=[O:44])=[O:45])[CH3:29])[CH:23]([CH3:24])[CH3:25])[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(CCS(C)(=O)=O)C(=O)OCc1ccccc1)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@H](C)NCCS(C)(=O)=O)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
In a 100 mL round-bottomed flask, benzyl (S)-1-((S)-1-((S)-2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(2-(methylsulfonyl)ethyl)carbamate (33 mg, 48.1 μmol, Eq: 1.00) and 10% palladium on carbon (5.12 mg, 4.81 μmol, Eq: 0.1) were combined with MeOH (5 mL) to give a black suspension which was stirred under a hydrogen atmosphere (balloon) at rt for 1 h. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to give (S)-1-{(S)-2-[(S)-2-(2-methanesulfonyl-ethylamino)-propionylamino]-3-methyl-butyryl}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (2,6-difluoro-phenyl)-amide (18 mg), m/z=552 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH2:12][CH2:11][CH2:10][CH:9]=2)[CH:7]=1.C([Li])CCC.N1(C=O)CC[O:21][CH2:20]C1.O>CCOCC>[C:8]1([C:6]2[CH:7]=[C:2]([CH:20]=[O:21])[CH:3]=[N:4][CH:5]=2)[CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: Brc1cncc(C2=CCCC2)c1
Reactant: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: O=Cc1cncc(C2=CCCC2)c1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-5-cyclopenten-1-ylpyridine (9) (1 g, 4.5 mmol) in 25 ml of ether is added to a solution of n-butyllithium (1.6M in hexane, 4.2 ml, 6.7 mmol) in 25 ml of ether kept at −60° C. The reaction mixture is stirred for 2 h 30 min at −60° C. and then 1.4 ml of 4-morpholinecarboxaldehyde (13.4 mmol) are added. The reaction is stirred for 1 hour at −60° C. and then poured into water, the organic phase is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 80/20). The title product is obtained in the form of a beige solid (0.38 g).
Reaction SMILES: Br[C:2]1[C:3]([Cl:32])=[CH:4][C:5]([C:29](=[O:31])[NH2:30])=[C:6]([NH:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]3)[CH2:14][CH2:13]2)=[O:11])[CH:7]=1.[CH:33]1(B(O)O)[CH2:35][CH2:34]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:29]([C:5]1[CH:4]=[C:3]([Cl:32])[C:2]([CH:33]2[CH2:35][CH2:34]2)=[CH:7][C:6]=1[NH:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]2)[CH2:14][CH2:13]1)=[O:11])(=[O:31])[NH2:30]
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCN(C(=O)CNc3cc(Br)c(Cl)cc3C(N)=O)CC2)C1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(N2CCN(C(=O)CNc3cc(C4CC4)c(Cl)cc3C(N)=O)CC2)C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 46.2 %

Procedure:
To a solution of tert-butyl 3-(4-(2-((5-bromo-2-carbamoyl-4-chlorophenyl)amino)acetyl)piperazin-1-yl)azetidine-1-carboxylate (350 mg, 0.66 mmol) and cyclopropylboronic acid (226 mg, 2.64 mmol) in toluene (10 mL) and water (2 mL), Pd(OAc)2 (15 mg, 0.07 mmol), PCy3 (37 mg, 0.132 mmol) and K3PO4 (487 mg, 2.31 mmol) were added. The mixture was stirred at 80° C. for 16 h. The mixture was allowed to cool to RT and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (1-5% methanol/dichloroethane) to afford the desired product (150 mg, 46% yield) as a solid.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.C([O:21][C:22](=O)[C:23]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:26]([O:39][CH2:40][CH2:41][OH:42])=[C:25]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[CH:44]=2)[CH:24]=1)C.Cl>C1COCC1>[CH2:1]([NH:13][C:22](=[O:21])[C:23]1[CH:24]=[C:25]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:51])([F:52])[F:50])[CH:44]=2)[C:26]([O:39][CH2:40][CH2:41][OH:42])=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: CCCCCCCCCCCCN
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 92.6 %

Procedure:
To a flame-dried flask containing dodecyl amine (0.278 g, 1.5 mmol) in THF (5 mL) cooled to −78° C. was added n-BuLi (titrated to 2.37 M in hexanes) (0.670 mL, 1.59 mmol) dropwise. The solution was stirred at −78° C. for 20 min. and then warmed to room temperature over 20 min. The reaction was then recooled to −40° C. and 3,5-bis-(m-trifluoromethylphenyl)4-(2-hydroxyethoxy)benzoic acid ethyl ester (0.215 g, 0.43 mmol) in THF (5 mL) was added. This mixture was allowed to warm to room, temperature over 20 min. The reaction mixture was then poured into 0.1 N HCl solution and extracted with EtOAc. The combined organic layers were washed with 2 N HCl solution (3×), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc:hexane) to afford N-dodecyl-3,5-bis(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)benzamide (0.254 g, 93%) as a white solid. 1H NMR (CDCl3) δ7.90 (m, 2H); 7.82-7.76 (m, 4H); 7.65-7.56 (m, 4H); 6.22 (bt, 1H); 3.45 (dd, 2H); 3.30 (m, 4H); 1.60 (m, 2H); 1.25 (m, 18H); 0.84 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][N:30](C(OC(C)(C)C)=O)[CH:31]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:29]1[CH:28]=[C:27]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=23)[CH:31]=[N:30]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A mixture of 4-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (1.63 g, 4.98 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.61 g, 5.48 mmol, Aldrich: Cat. #632732), tetrakis(triphenylphosphine)palladium(0) (288 mg, 0.249 mmol) and sodium carbonate (1.58 g, 14.9 mmol) in 1,4-dioxane (16.0 mL) and water (8.0 mL) was stirred at 110° C. for 2 hours. After cooling, the mixture was diluted with ethyl acetate, and washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was treated with ether, filtered and washed with ether to afford the desired product (1.08 g, 69%) which was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=315.1.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[C:12](=[C:14]([C:17]#[N:18])[C:15]#[N:16])[CH3:13])C.C(OC=C(C#N)C#N)C>C(O)C>[NH2:18][C:17]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:12]([CH3:13])[C:14]=1[C:15]#[N:16]
Reactant: CCOC(C)=C(C#N)C#N
Reactant: NNc1ccccc1
Agent: CCOC=C(C#N)C#N
Solvent: CCO
Product: Cc1nn(-c2ccccc2)c(N)c1C#N

Procedure:
Into a 250-mL 3-necked round-bottom flask, was placed a solution of 1-phenylhydrazine (31.5 g, 291.67 mmol, 1.14 equiv) in ethanol (105 mL) at room temperature. To the resulting mixture was then added 2-(1-ethoxyethylidene)malononitrile (35 g, 257.35 mmol, 1.00 equiv) in several batches at room temperature. After about half of the addition was completed, the solution was carefully heated to boiling. After all the ethoxymethylene malononitrile was added, the resulting solution was heated to reflux for 4 hr. The resulting mixture was then cooled with a water/ice bath, and the solids were collected by filtration to yield 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH2:11]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[CH2:27][C:28]([OH:30])=[O:29])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[CH2:27][C:28]([O:30][CH2:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:29])=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C(O)CC1CCCCN1C(=O)OCc1ccccc1
Product: O=C(CC1CCCCN1C(=O)OCc1ccccc1)OCC(=O)c1ccccc1

Procedure:
The title compound (4.0 g) was prepared from 2-bromoacetophenone (2.20 g) and 2-carboxymethyl-piperidine-1-carboxylic acid benzyl ester according to the method of description 36