Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]([C:11]1[S:12][C:13](SC)=[C:14]2[C:19](=[O:20])[CH2:18][C:17]([CH3:22])([CH3:21])[CH2:16][C:15]=12)#[N:10]>>[C:9]([C:11]1[S:12][C:13]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:14]2[C:19](=[O:20])[CH2:18][C:17]([CH3:22])([CH3:21])[CH2:16][C:15]=12)#[N:10]
Reactant: Cl[Mg]C1CCCCC1
Reactant: CSc1sc(C#N)c2c1C(=O)CC(C)(C)C2
Product: CC1(C)CC(=O)c2c(C3CCCCC3)sc(C#N)c2C1
Yield: 28 %

Procedure:
In the same way as described in Example 6, Step 1, using cyclohexylmagnesium chloride and 1-cyano-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound (0.63 g, 28%) was isolated as a cream solid. mp 129-132° C. 1HNMR (360 MHz, CDCl3) δ 1.07 (6H, s), 1.20-1.55 (5H, m), 1.75-1.85 (3H, m), 2.01-2.06 (2H, m), 2.42 (2H, s), 2.84 (2H, s), 3.85-3.94 (1H, M).
Reaction SMILES: ClC(Cl)(Cl)CC(=N)O[CH:6]([C:8]1[CH:9]=[N:10][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([N:26]([CH3:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:20]=3)[N:15]=2)=[CH:12][CH:13]=1)[CH3:7].[F:37][C:38]([F:42])([F:41])[CH2:39][OH:40].C(Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:33][N:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[N:22]=[C:23]([NH2:25])[N:24]=[C:19]([C:16]2[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([CH:6]([O:40][CH2:39][C:38]([F:42])([F:41])[F:37])[CH3:7])=[CH:9][N:10]=3)[O:18][N:17]=2)[N:20]=1
Reactant: CC(OC(=N)CC(Cl)(Cl)Cl)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)nc1
Reactant: OCC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(OCC(F)(F)F)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)nc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 5 %

Procedure:
1-[6-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridin-3-yl]ethyl 2,2,2-trichloroethanecarboximidate (Intermediate 139, 0.497 g, 0.93 mmol) was suspended in DCE (8 mL). 2,2,2-Trifluoroethanol (0.669 mL, 9.29 mmol) and tetrafluoroboric acid diethyl ether complex (0.025 mL, 0.19 mmol) were added and the mixture was stirred at room temperature for 7 h. LCMS showed incomplete conversion, so further tetrafluoroboric acid diethyl ether complex (0.125 mL, 0.93 mmol) was added and the mixture stirred at room temperature for 21 h. DCM (100 mL) and saturated aq. sodium bicarbonate (50 mL) were added. The organic layer was separated, washed with brine (30 mL), dried over sodium sulfate and concentrated under vacuum to yield a brown solid, which was purified by FCC using a gradient of 0-5% MeOH in DCM. The crude product was then purified by preparative HPLC, Method D, to afford an off-white solid. This was further purified by FCC using a gradient of 0-3% MeOH in DCM to afford the title compound as an off-white solid (0.022 g, 5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[CH3:19][S:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])=[O:21]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:26]1[CH2:27][CH2:28][N:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH2:24][CH2:25]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CC#N
Product: C[C@@H](N1CCN(S(C)(=O)=O)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 36.4 %

Procedure:
The epoxide IV (300 mg, 1.19 mmol) and LiClO4 (235 mg, 1.43 mmol) were dissolved in 12 mL dry acetonitrile and 1-methanesulfonylpiperazine (190 mg, 1.79 mmol) was added. The mixture was heated to reflux for 4 days, cooled and the solvent evaporated. The residue was dissolved in dichloromethane and then washed with water and brine. The solution was dried over Na2SO4 and the solvent evaporated. The crude reaction products were eluted through a silica gel column using 3% MeOH/97% EtOAc as eluent to give the title compound (180 mg, 36%) as a colorless solid.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]O)=[CH:24][C:23]=1[F:30].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:19][C:16]2[CH:17]=[CH:18][N:13]([C:10]3[CH:11]=[CH:12][C:5]4[N:4]=[C:3]([CH2:1][CH3:2])[N:7]([CH3:8])[C:6]=4[CH:9]=3)[C:14](=[O:20])[CH:15]=2)=[CH:24][C:23]=1[F:30]
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Reactant: OCc1ccc(Cl)c(F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2ccc(-n3ccc(OCc4ccc(Cl)c(F)c4)cc3=O)cc2n1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
To a solution of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (500 mg), (4-chloro-3-fluorophenyl)methanol (596 mg) and tributylphosphine (1.13 g) in THF (20 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.41 g), and the reaction mixture was stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by NH silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-water to give the title compound (265 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: Oc1ccccc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1Br
Yield: 99.2 %

Procedure:
A solution of 2-bromophenol (5 mL, 47 mmol), imidazole (8 g, 118 mmol) and tert-butyldimethylsilyl chloride (8.6 g, 57 mmol) in DMF (50 mL) was stirred at rt overnight. The reaction was treated with water (150 mL) and extracted with Et2O (4×25 mL). The organic phase was washed with 50% aq lithium chloride solution twice, dried over MgSO4 and filtered. The solvent was evaporated and the crude product was purified by filtration through silica gel, washing with 1:1 EtOAc/hexanes to afford bromo-2-[(tert-butyl)dimethylsiloxy]benzene (13.4 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:31]=[CH:32][C:33]([N:36]3[CH2:41][CH2:40][CH:39]([NH:42]C(=O)OC(C)(C)C)[CH2:38][CH2:37]3)=[N:34][CH:35]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:42][CH:39]1[CH2:38][CH2:37][N:36]([C:33]2[N:34]=[CH:35][C:30]([C:16]3[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:19]([CH3:20])=[C:14]([CH:15]=3)[C:12]([NH:11][CH2:10][C:3]3[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])=[O:13])=[CH:31][CH:32]=2)[CH2:41][CH2:40]1
Reactant: CCN(c1cc(-c2ccc(N3CCC(NC(=O)OC(C)(C)C)CC3)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(c1cc(-c2ccc(N3CCC(N)CC3)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 903.1 %

Procedure:
To a stirred solution of tert-butyl (1-(5-(3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperidin-4-yl)carbamate (0.39 g, 0.058 mmol) in DCM (4 mL) at 0° C., TFA (2 mL) was added and reaction was stirred for 1 h at room temperature. After completion, reaction was concentrated to dryness. The residue was then basified with aqueous sat. bicarbonate solution (30 mL) till pH 8 and aqueous layer extracted with 20% methanol in DCM (50 mL×4). Combined organic phase was dried over Na2SO4 and solvent removed under reduced pressure to afford the title compound (0.3 g, 90.63%) which was used as such for next reaction.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH2:4][CH2:5][CH2:6][N:7]=1.[Br:8][C:9]1[CH:42]=[CH:41][C:12]2[N:13]=[C:14]([NH:16][C@H:17]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:18][NH:19][C:20](=[O:33])[C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29](OC)=[O:30])=[CH:23][CH:22]=3)[S:15][C:11]=2[CH:10]=1>C1COCC1>[Br:8][C:9]1[CH:42]=[CH:41][C:12]2[N:13]=[C:14]([NH:16][C@H:17]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:18][NH:19][C:20](=[O:33])[C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][C:29](=[O:30])[NH:1][C:2]4[NH:7][CH2:6][CH2:5][CH2:4][N:3]=4)=[CH:25][CH:26]=3)[S:15][C:11]=2[CH:10]=1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](Nc2nc3ccc(Br)cc3s2)C(=O)OC(C)(C)C)cc1
Reactant: NC1=NCCCN1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)Nc1nc2ccc(Br)cc2s1
Reaction time: 3 h
Yield: 34.5 %

Procedure:
66 mg of 2-amino-1,4,5,6-tetrahydropyrimidine is added to a solution of 70 mg of 11-2 in 2 ml of THF, and agitation is carried out at ambient temperature for 3 hours. The reaction medium is then chromatographed eluting with a CH2Cl2/AcOEt mixture 80/20 then with MeOH/CH2Cl2 10/90. 27 mg of expected product 11-3 is obtained.
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.F[C:10]1[CH:18]=[C:17]([NH2:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>CN(C=O)C>[F:1][CH:2]1[CH2:7][CH2:6][N:5]([C:10]2[CH:18]=[C:17]([NH2:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])[CH2:4][CH2:3]1
Reactant: FC1CCNCC1
Reactant: Nc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Product: Nc1cc(N2CCC(F)CC2)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 4.5 h

Procedure:
A mixture of 4-fluoropiperidine×HCl (691 mg, 4.9 mmol), TEA (2.2 ml, 16 mmol), 2-fluoro-4-amino-5-nitro-benzoic acid (900 mg, 4.5 mmol) and DMF (15 mL) is stirred for 4.5 h at 50° C. Then the mixture is concentrated, diluted with water and the precipitate is filtered and dried.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:36])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[C:16]([Cl:36])=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2-c2ccc(OC)cc2)c1OC(C)=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2-c2ccc(OC)cc2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 124(b) from 4-acetoxy-7-cyano-1-(4-methoxy-phenyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and NCS in MeCN. The title compound, ESI MS (m/z): 414 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]#[C:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][C:11]([C:19]4[CH:20]=[N:21][CH:22]=[N:23][CH:24]=4)=[CH:12][CH:13]=3)[C@@:8]3([CH2:28][O:27][C:26]([NH2:29])=[N:25]3)[C:7]=2[CH:6]=1.[OH2:32]>C(O)(C(F)(F)F)=O>[NH2:29][C:26]1[O:27][CH2:28][C@@:8]2([N:25]=1)[C:7]1[CH:6]=[C:5]([C:4](=[O:32])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[CH:18]=[CH:17][C:16]=1[O:15][C:14]1[C:9]2=[CH:10][C:11]([C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)C#Cc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Reactant: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC(=O)c1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 40 °C

Procedure:
(4R)-2′-(3,3-Dimethylbut-1-ynyl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (70 mg, 171 μmol) was dissolved in TFA (1.31 ml) at RT and water (31 μl, 1705 μmol) was added. The mixture then was heated at 40° C. for 1 hr. TFA was removed in a stream of nitrogen and yellow residue was treated with 1.5 ml of 2N ammonia in methanol for 15 min at RT. The solution was concentrated in vacuo, residue was diluted with ethyl acetate (5 ml), the solution was washed with saturated NaHCO3 solution, brine, dried with magnesium sulfate and concentrated to give 1-((4S)-2-amino-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2′-yl)-3,3-dimethyl-1-butanone.
Reaction SMILES: [OH:1][NH:2][C:3]([C@H:5]1[C@@H:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[OH:1][NH:2][C:3]([C@H:5]1[C@@H:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:8][NH:7][CH2:6]1)=[O:4]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C(=O)NO)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CNC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the stirred solution of 74 mg of tert-butyl cis-3-[(hydroxyamino)carbonyl]-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-1-carboxylate in 4 mL of dichloromethane was slowly added 2 mL of trifluoroacetic acid. The solution was stirred at room temperature for 3 hr. After removal of the volatile material in vacuo cis-N-hydroxy-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxamide was obtained in quantitative yield. MS: 457.0 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[C:22](=O)[CH2:23][N:24]([CH3:28])[S:25](=[O:27])(=[O:26])[C:20]=4[CH:19]=[CH:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[C:22](=[N:31][OH:32])[CH2:23][N:24]([CH3:28])[S:25](=[O:27])(=[O:26])[C:20]=4[CH:19]=[CH:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN1CC(=O)c2c(ccn2CCCN2CCN(c3ccc(F)cc3)CC2)S1(=O)=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC(=NO)c2c(ccn2CCCN2CCN(c3ccc(F)cc3)CC2)S1(=O)=O
Temperature: 60 °C
Reaction time: 21 h
Yield: 82.7 %

Procedure:
A suspension of 168 mg (0.4 mmol) of Compound 25 and 111 mg (1.6 mmol) of hydroxylamine hydrochloride in 10 ml of pyridine was stirred for 21 hours over an oil bath of 60° C. Post-treatment was conducted in a similar manner as in Example 18. The residue was purified by chromatography on a silica gel column (eluent:methanol/chloroform=1/99), whereby 144 mg of the title compound were obtained (yield: 83%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[OH-].[NH4+:12]>>[NH2:12][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CC(=O)c1ccc(Cl)nc1
Agent: [OH-]
Product: CC(=O)c1ccc(N)nc1
Temperature: 130 °C

Procedure:
2 g (11.57 mmol) of 1-(6-chloropyrid-3-yl)ethanone and 70 mL of ammonium hydroxide are placed in a Parr reactor. The solution is heated at 130° C. overnight. The mixture obtained is evaporated to dryness, and the residue is taken up in ethyl acetate and washed with water and with saturated NaCl solution. The organic phase is dried over sodium sulfate and evaporated to dryness to give 1.14 g of 1-(6-aminopyrid-3-yl)ethanone, the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]3[CH:52]=[CH:51][C:16]([CH2:17][N:18]([CH2:43][C:44]([O:46]C(C)(C)C)=[O:45])[C:19](=[O:42])[C:20]4[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:41])[CH2:28][C:29]5[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=5[C:37]([F:40])([F:39])[F:38])=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.[C:53](O)([C:55](F)(F)F)=O>C(Cl)Cl>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([C:19]([N:18]([CH2:43][C:44]([OH:46])=[O:45])[CH2:17][C:16]3[CH:15]=[CH:14][C:13]([C:11]4[N:12]=[C:8]([C:5]5[CH:6]=[CH:7][C:2]([C:2]6[CH:7]=[CH:6][C:53]([CH3:55])=[CH:4][CH:3]=6)=[CH:3][CH:4]=5)[O:9][CH:10]=4)=[CH:52][CH:51]=3)=[O:42])=[CH:21][CH:22]=2)=[O:41])=[C:30]([C:37]([F:38])([F:40])[F:39])[CH:31]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(-c4coc(-c5ccc(Br)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4coc(-c5ccc(-c6ccc(C)cc6)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a stirring solution of tert-butyl 2-(N-(4-(2-(4-bromophenyl)oxazol-4-yl)benzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-45 (118 mg, 0.152 mmol) in THF (1 mL) and acetonitrile (1 mL) were added sodium carbonate (0.30 mL, 0.30 mmol, 1 M aqueous solution) and p-tolylboronic acid (25.0 mg, 0.18 mmol). The reaction mixture was de-gassed and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (5.50 mg, 7.60 μmol) was added. The reaction mixture was heated in a microwave at 130° C. for 30 min. The reaction mixture was diluted with DCM (4 mL) and NaHCO3 (10 mL), stirred for 15 min and split through a hydrophobic frit. The organics were evaporated and purified by column chromatography (EA/isohexanes) to yield tert-butyl 2-(N-(4-(2-(4-bromophenyl)oxazol-4-yl)benzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate. To tert-butyl 2-(N-(4-(2-(4-bromophenyl)oxazol-4-yl)benzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate in DCM (2 mL) was added TFA (2 mL) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was evaporated and re-slurried from acetonitrile (4 mL) to afford 59 mg (53%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(2-(4′-methyl-[1,1′-biphenyl]-4-yl)oxazol-4-yl)benzyl)benzamido)acetic acid 364 as a white solid. LCMS-ESI (m/z) calculated for C42H34F3N3O6: 733; found 734 [M+H]+, tR=9.36 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.76 (s, 1H), 10.34 (s, 1H), 8.75 (s, 1H), 8.13 (d, J=6.7 Hz, 2H), 7.90-7.85 (m, 4H), 7.70-7.59 (m, 4H), 7.50-7.42 (m, 2H), 7.41-7.31 (m, 5H), 7.25-7.16 (m, 2H), 4.70 (s, 1H), 4.62 (s, 1H), 4.02 (s, 1H), 3.92 (s, 1H), 3.86 (s, 2H), 3.83 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([F:13])=[C:7]2[C:12]=1[CH2:11][NH:10][CH2:9][CH2:8]2.[C:14]1([C@@H:20]2[CH2:22][C@H:21]2[C:23](O)=[O:24])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CN(C)C1C=CN=CC=1.CCOC(C)=O>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([F:13])=[C:7]2[C:12]=1[CH2:11][N:10]([C:23]([C@@H:21]1[CH2:22][C@H:20]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:24])[CH2:9][CH2:8]2
Reactant: Fc1ccc(Br)c2c1CCNC2
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCc2c(F)ccc(Br)c2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 8-bromo-5-fluoro-1,2,3,4-tetrahydro-isoquinoline hydrochloride (200 mg, 0.75 mmol, 1.0 eq.) and the acid (1R,2R)-2-phenyl-cyclopropanecarboxylic acid (122 mg, 0.75 mmol, 1.0 eq.) in DMF (9 mL) was treated with 4-(dimethylamino)pyridine (367 mg, 3.00 mmol, 4.0 eq.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (216 mg, 1.13 mmol, 1.5 eq.) and the resulting solution was stirred at r.t. for 18 hours. The reaction mixture was diluted with AcOEt (70 mL). The diluted solution was washed with 1N aq. HCl (3×30 mL), sat. aq. NaCl soln. (1×30 mL), dried over MgSO4, filtered, and concentrated in vacuo to give the desired compound as a pale yellow oil. The product was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[NH:10][C:9]=2[CH:18]=O)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[NH:30][C:31](=[O:35])[CH2:32][O:33][CH3:34])[NH:26][C:25](=[O:36])[CH2:24]2>>[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[NH:30][C:31](=[O:35])[CH2:32][O:33][CH3:34])[NH:26][C:25](=[O:36])[C:24]2=[CH:18][C:9]1[NH:10][C:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:12]=2[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Reactant: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: COCC(=O)Nc1cc2c(cc1F)C(=Cc1[nH]c3c(c1-c1ccc(F)cc1)C(=O)NCC3)C(=O)N2
Yield: 54.4 %

Procedure:
The title compound was prepared under the same conditions as described in Example 46 with 3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide as starting materials to give N-{5-fluoro-3-[3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide (50 mg, 54.4%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([NH2:38])[CH:28]=[C:29]([N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)[CH:30]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:38][C:27]4[CH:28]=[C:29]([N:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)[CH:30]=[C:25]([Cl:24])[CH:26]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Reactant: CN1CCN(c2cc(N)cc(Cl)c2)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2cc(Cl)cc(Nc3ncnc4[nH]c(C5=CCN(C(=O)OC(C)(C)C)CC5)cc34)c2)CC1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (88.0 mg, 0.263 mmol), 3-chloro-5-(4-methylpiperazin-1-yl)-phenylamine (71.2 mg, 0.316 mmol), trifluoroacetic acid (203 μL, 2.63 mmol), and DMF (2 mL) was stirred in a sealed tube at 70° C. for 18 h. The mixture was concentrated in vacuo, sodium bicarbonate (221 mg, 2.63 mmol), di-tert-butyldicarbonate (86.1 mg, 0.394 mmol), and DMF (2 mL) were added to the residue, and the resulting mixture was stirred at rt under N2 for 16 h. After that time, the mixture was filtered, and the filtrate was concentrated in vacuo and submitted for MS-directed purification. One obtained the title compound as light-brown solid. 1H NMR (CD3OD, 400 MHz): δ=1.50 (s, 9H), 2.57 (brs, 2H), 2.86 (s, 3H), 3.29 (brs, 4H), 3.46 (brs, 4H), 3.67 (brs, 2H), 4.13 (brs, 2H), 6.29 (brs, 1H), 6.68 (s, 1H), 6.74 (s 1H), 7.44 (s, 1H), 7.47 (s, 1H), 8.28 (s, 1H). M (ES+): m/z 523.99/525.95(100/40) [MH+]. HPLC: tR (polar—5 mins)=2.28 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH2:1]([C:6]1[S:7][C:8]2[N:9]=[C:10]([NH2:21])[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:13]=2[N:14]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29](O)=[O:30])=[CH:25][CH:24]=1>>[NH2:21][C:10]1[N:11]=[C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:29](=[O:30])[CH2:28][O:27][C:26]3[CH:32]=[CH:33][C:23]([Cl:22])=[CH:24][CH:25]=3)[CH2:17][CH2:16]2)[C:13]2[N:14]=[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[S:7][C:8]=2[N:9]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: CCCCCc1nc2c(N3CCNCC3)nc(N)nc2s1
Product: CCCCCc1nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc2s1
Yield: 30 %

Procedure:
This compound was prepared from 2-pentyl-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-chlorophenoxyacetic acid in a yield of 30%, according to the procedure for the synthesis of example 50.