Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:42]([CH3:44])[CH3:43])[CH2:28][CH2:29][CH2:30][N:31]4C(=O)C5C(=CC=CC=5)C4=O)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.CO>CN>[CH3:1][O:2][C:3]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:24])([CH3:25])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:42]([CH3:44])[CH3:43])[CH2:28][CH2:29][CH2:30][NH2:31])[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(CCCN3C(=O)c4ccccc4C3=O)C(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CN
Solvent: CO
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(CCCN)C(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)-propyl)isoindoline-1,3-dione (1.37 g, 2.00 mmol) was dissolved in 2M methylamine in methanol (30 mL, 60 mmol). The solution was stirred at room temperature for 5 minutes then heated at 55-60° C. After 1 h, the SM was consumed by HPLC. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resultant tan oil was taken up in 20 mL MeOH and concentrated. The procedure was repeated to an oil. The material was placed on high vacuum to yield a solid which contained the title compound along with N-methylphthalimide and was used as is in the next step: MS (ESI+) for C29H42N6O5 m/z 555.4 (M+H)+; HPLC ret. time 2.57 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1>CN(C)C=O>[Cl:12][C:13]1[N:14]=[CH:15][N:16]=[C:17]([O:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)[CH:18]=1
Reactant: OCCN1CCOCC1
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cc(OCCN2CCOCC2)ncn1
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 58.1 %

Procedure:
To a solution of N-(2-hydroxyethyl)morpholine (1.09 g, 8.27 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (364 mg, 9.10 mmol, 60% dispersion in oil) in portions. The mixture was stirred at room temperature for 1 h and at 45° C. for 1.5 h. The greenish solution was added dropwise over 5 min to a solution of 4,6-dichloropyrimidine (3.0 g, 20.1 mmol) in N,N-dimethylformamide (5 mL). The solvent was removed in vacuo, and the residue was partitioned between water and ethyl acetate. The organic layer was dried (Na2SO4) and the solvent was removed in vacuo. The crude product was purified on a silica gel column using ethyl acetate as the eluent affording 1.17 g (58% yield) of the title compound as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 8.57 (s, 1H), 6.80 (s, 1 H), 4.53 (t, J=6 Hz, 2 H), 3.72 (t, J=5 Hz, 4 H), 2.77 (t, J=6 Hz, 2 H), 2.55 (t, J=4 Hz, 4 H); 13C NMR (CDCl3, 100 MHz) δ 170.0, 160.7, 158.1, 108.0, 66.9, 64.6, 57.1, 53.9; MS (ESP) m/z 244 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:23](O)(=[O:25])[CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[S:19]([C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:8]2[N:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([NH:1][C:23](=[O:25])[CH3:24])=[CH:3][CH:4]=3)[N:9]=2)=[CH:18][CH:17]=1)(=[O:21])(=[O:20])[NH2:22]
Reactant: CC(=O)O
Reactant: Nc1ccc2cnc(Nc3ccc(S(N)(=O)=O)cc3)nc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc2cnc(Nc3ccc(S(N)(=O)=O)cc3)nc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-(7-aminoquinazolin-2-ylamino]-benzenesulfonamide (1 eq) (For synthesis see example 43) in THF was added acetic acid (5 eq), HBTU (4 eq) and DIEA (10 eq). The reaction mixture was stirred at room temperature for 48 h. The reaction does not go to completion. Diluted with ethyl acetate and washed with water, brine and dried over sodium sulfate. Filtered, concentrated and purified by semi-prep HPLC to provide N-(2-(4-sulfamoylphenylamino) quinazolin-7-yl)acetamide ES/MS m/z 358.0 (MH+).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:19][CH:18]3[CH:14]([NH:15][CH2:16][CH2:17]3)[CH2:13]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[NH:15]1[CH2:16][CH2:17][CH:18]2[CH2:19][N:12]([C:10]3[C:9]4[C:4](=[N:5][CH:6]=[CH:7][N:8]=4)[CH:3]=[C:2]([C:29]4[CH:28]=[CH:27][C:26]([N:23]5[CH2:22][CH2:21][O:20][CH2:25][CH2:24]5)=[CH:31][CH:30]=4)[N:11]=3)[CH2:13][CH:14]12
Reactant: Clc1cc2nccnc2c(N2CC3CCNC3C2)n1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: c1cnc2c(N3CC4CCNC4C3)nc(-c3ccc(N4CCOCC4)cc3)cc2n1
Temperature: 180 °C
Reaction time: 1 h

Procedure:
A mixture of 7-chloro-5-(hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)pyrido[4,3-b]pyrazine (47 mg, 0.17 mmol), 4-morpholinophenylboronic acid (105 mg, 0.51 mmol), and PdCl2(dppf) (10 mg), Cs2CO3 (130 mg, 0.51 mmol) in dioxane (5 mL) was sealed in a microwave reaction cube, stirred at 180° C. for 60 minutes in a microwave reactor, cooled to ambient temperature, concentrated under reduced pressure, and the residue was purified by chromatography to give the title compound. MS (m/z): 403 (M+H)+.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:27](=[N:28][C:29]2[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=2[CH3:37])[CH:26]=[C:13]2[C:14]3[C:19]([CH2:20][CH2:21][N:12]2[C:11]1=[O:38])=[CH:18][C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3>O.Cl>[C:2]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:27](=[N:28][C:29]2[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=2[CH3:37])[CH:26]=[C:13]2[C:14]3[C:19]([CH2:20][CH2:21][N:12]2[C:11]1=[O:38])=[CH:18][C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)(=[O:1])[NH2:3]
Reactant: COc1cc2c(cc1OC)-c1cc(=Nc3c(C)cc(C)cc3C)n(CCCCN)c(=O)n1CC2
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc2c(cc1OC)-c1cc(=Nc3c(C)cc(C)cc3C)n(CCCCNC(N)=O)c(=O)n1CC2
Temperature: 80 °C
Yield: 64.1 %

Procedure:
Sodium cyanate (0.28 g, 4.32 mmol) in water (6 ml) was added dropwise to a stirred solution of 2 (1.0 g, 2.16 mmol) in water (30 ml) and 1N HCl (4.3 ml) at 80° C. After 2 h at 80° C. the mixture was cooled and extracted with dichloromethane (3×20 ml) and the extract dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography on silica gel [dichloromethane/methanol (97:3)] to obtain the title compound (0.70 g, 64%) as a yellow solid.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH3:10])[N:3]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C.O.COCCOC>[CH3:9][O:8][C:7]1[C:2]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([C:12]([F:23])([F:22])[F:11])[CH:18]=2)=[N:3][C:4]([CH3:10])=[CH:5][CH:6]=1
Reactant: COc1ccc(C)nc1Br
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: COc1ccc(C)nc1-c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
To the 2-bromo-3-methoxy-6-methyl-pyridine synthesized above (1.2 g, 5.94 mmol), 3-trifluoromethylphenylboronic acid (1.69 g, 8.91 mmol), PPh3 (0.31 g, 1.19 mmol), K2CO3 (2.46 g, 17.82 mmol) and Pd(OAc)2 (0.13 g, 0.59 mmol) was added DME (15 mL), and EtOH—H2O (1:1, 6 mL). Ar gas was bubbled through the stirred reaction for 5 min. The reaction was stirred at 80° C. under Ar for 20 h. The reaction was cooled to room temperature, concentrated, and H2O and dichloromethane (40 mL each) were added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic extracts were dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using 1:1 dichloromethane-hexanes then dichloromethane to afford 1.36 g (86%) of 3-methoxy-6-methyl-2-(3-trifluoromethyl-phenyl)-pyridine (I-4, Y═R1═CH3, R2═CF3) as a light yellow solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:43])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH:33]=[CH2:34])[N:23]=4)[N:20]=3)[N:15]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]>CO.[Pd]>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:43])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH2:33][CH3:34])[N:23]=4)[N:20]=3)[N:15]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:41])([CH3:40])[CH3:42])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C=CCn1nc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: [Pd]
Solvent: CO
Product: CCCn1nc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
To a solution of 2-(1-allyl-6-chloro-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (50 mg, 0.08 mmol) in MeOH (6 ml) was added 10% Pd on carbon (wet, 17 mg). The reaction mixture was stirred under an atmosphere of hydrogen (balloon) for 1.5 h then filtered over Celite, rinsing with EtOAc. The filtrate was concentrated and the residue was purified by silica gel chromatography with 50% to 100% EtOAc/heptane to afford 38 mg (76%) of 2-(6-chloro-1-propyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a viscous colorless oil.
Reaction SMILES: [N:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([CH2:18][CH2:19][CH2:20][CH3:21])[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)[C:14]=2[CH:42]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH2:18]([C:16]1[N:15]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[C:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:27][CH:28]=2)[C:14]2[CH:42]=[C:10]([NH:9][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[CH:11]=[CH:12][C:13]=2[N:17]=1)[CH2:19][CH2:20][CH3:21]
Reactant: O=C(Cl)N1CCCC1
Reactant: CCCCc1nc2ccc(N)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCc1nc2ccc(NC(=O)N3CCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 24 h

Procedure:
2.0 g (15 mMol) of pyrrolidinocarbonyl chloride are placed in 50 ml of dry chloroform and 2.3 g (6 mMol) of tert.-butyl 4'-[(6-amino-2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate dissolved in 50 ml of dry pyridine are added dropwise for one hour. The reaction solution is stirred for a further 24 hours and then concentrated by rotary evaporation. The oily residue is distributed in ethyl acetate and 10% sodium hydrogen carbonate solution, the organic phase is separated off and, after drying with magnesium sulphate, concentrated by rotary evaporation. Purification is carried out using a silica gel column (particle size: 0.063-0.2 mm), eluting with petroleum ether/ethyl acetate=3:7. The corresponding column fractions are concentrated by rotary evaporation and dried in vacuo at 50° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[C:23]=1Cl>C(Cl)Cl.C1CCCCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2c1cc(Cl)c(N)c2Cl
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc(N)ccc21

Procedure:
From 20 g (0.061 mol) of 7-amino-5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one there is obtained, in analogy to the details in Example 45, 7-amino-6,8-dichloro-5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one of melting point 105° (methylene chloride/cyclohexane).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].CO.[OH-].[Na+].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Cl>O>[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][O:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(CO)Nc1ccccc1
Reactant: ClCc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(COCc1ccccc1Cl)Nc1ccccc1
Reaction time: 2 h

Procedure:
2-Hydroxyacetanilide (15.1 parts) is added to methanol (60 parts). Into this mixture is further added a solution of sodium hydroxide (4.8 parts) in water (14 parts). The resulting mixture is kept at 0° to 5° C. and add dropwise 2-chlorobenzyl chloride (18.3 parts) within 30 minutes, and the reaction is continued for 2 hours at 0° to 5° C., for additional 6 hours at 30° to 40° C. and further for additional 2 hours at 65° C. After completion of the reaction, the reaction mixture is poured into cold water (250 parts) and is then filtered. The filter cake obtained is washed with water and the resulting white cake is dried at 80° C. to yield the intended product (22.3 parts) having melting point 130° to 132° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH3:5][C:6]1[S:7][CH:8]=[C:9]([CH3:12])[C:10]=1O.[OH-].[Na+]>[Cl-].[Zn+2].[Cl-]>[CH3:5][C:6]1[S:7][CH:8]=[C:9]([CH3:12])[C:10]=1[NH:4][CH2:1][CH2:2][CH3:3]
Reactant: Cc1csc(C)c1O
Reactant: CCCN
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: CCCNc1c(C)csc1C
Temperature: 1700 °C

Procedure:
In an atmosphere of inert gas, 34.6 g (0.59 mol) of propylamine were admixed with 10.6 g (78 mmol) of anhydrous zinc chloride powder in the course of which the temperature of the mixture rose strongly. The solution was then admixed with 50 g (0.39 mol) of 2,4-dimethyl-3-hydroxythiophene, introduced into an autoclave and heated at 1700° C. under pressure (approximately 5 bar) for 16 hours. After cooling, the mixture was made alkaline using 50 ml of 33% strength aqueous sodium hydroxide solution and extracted twice with hexane, the combined organic phases were washed three times with water, dried over magnesium sulfate, filtered and concentrated under water pump vacuum, and the residue was distilled. Yield 31.2 g (47%), b.p. 88° C. (2 mbar). 1H NMR (270 MHz in CDCl3):δ=0.96 (t, 3H), 1.56 (sext., 2H), 2.12 (s, 3H), 2.31 (s, 3H), 2.96 (t, 2H), 3.18 (s, 1H), 6.61 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[N:7][C:6]=2[N:5]([CH2:12][CH3:13])[CH:4]=[C:3]1[C:14]([O:16]CC)=[O:15].C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[O:1]=[C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[N:7][C:6]=2[N:5]([CH2:12][CH3:13])[CH:4]=[C:3]1[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1cn(CC)c2ncncc2c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cncnc21

Procedure:
0.6 g. of this ester and 10 cm3 of a 10% solution of Na2CO3 are heated under reflux for 20 minutes. After cooling, the solution is acidified by means of acetic acid. The precipitate (0.5 g.) is filtered off and recrystallised from water. 0.2 g. of 5-oxo-8-ethyl-5,8-dihydro-pyrido-(2,3-d)pyrimidine-6-carboxylic acid is obtained, melting point 225°C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([NH:44][CH:45]1[CH2:47][CH2:46]1)=O>>[CH:45]1([NH:44][CH2:42][CH2:41][O:39][C:38]2[CH:37]=[CH:36][C:4]([CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]3[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=3[CH:16]3[CH2:25][CH2:24][C:23]4[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=4[CH2:17]3)=[CH:3][C:2]=2[F:1])[CH2:47][CH2:46]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: O=C(CCl)NC1CC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCNC3CC3)c(F)c2)C(C)C)c1
Yield: 39.6 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (26 mg) and 2-chloro-N-cyclopropylacetamide (13 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (10 mg) was obtained.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][CH:14]([C:24]([O:26]CC)=[O:25])[C:15]([CH2:22][CH3:23])([OH:21])[C:16]([O:18]CC)=[O:17])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Li+].Cl>O1CCOCC1.C(OCC)(=O)C>[Si:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][CH:14]([C:24]([OH:26])=[O:25])[C:15]([CH2:22][CH3:23])([OH:21])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)C(O)(CC)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCC(O)(C(=O)O)C(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)C(=O)O
Temperature: 60 °C
Reaction time: 22 h
Yield: 92.6 %

Procedure:
To a solution of diethyl 3-(4-t-butyldimethylsilyloxybenzyl)-2-ethyl-2-hydroxysuccinate 425 mg (0.968 mmol) in 1,4-dioxane (3.9 mL) was added 1 M lithium hydroxide aqueous solution (3.9 mL, 3.9 mmol) at room temperature, and the mixture was stirred at 60° C. for 22 h. The reaction mixture was adjusted to pH 1 with 1 M hydrochloric acid with stirring under ice cooling. The solvent was evaporated under reduced pressure, and the residue thus obtained was dissolved in ethyl acetate, and washed with water and brine. The organic layer was concentrated under reduced pressure and dried in vacuum to give 343 mg (crude) of 3-(4-t-butyldimethylsilyloxybenzyl)-2-ethyl-2-hydroxysuccinic acid as a solid.
Reaction SMILES: Br[C:2]1[C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:38])[C@@H:18]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH2:19][N:20]([CH:28]([CH3:30])[CH3:29])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][CH2:12]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:45][N:46]1[CH:50]=[C:49](B2OC(C)(C)C(C)(C)O2)[CH:48]=[N:47]1>O1CCOCC1.O.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>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C@H:18]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:3]3[C:2]([C:49]4[CH:48]=[N:47][N:46]([CH3:45])[CH:50]=4)=[CH:7][N:6]=[C:5]4[NH:8][CH:9]=[CH:10][C:4]=34)[CH2:16][CH2:15]2)=[O:38])[CH2:19][N:20]([CH:28]([CH3:29])[CH3:30])[C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[CH:32][CH:33]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
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: O
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(-c3cnn(C)c3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 150 °C
Yield: 9.9 %

Procedure:
(S)-tert-Butyl 3-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate (0.05 g, 0.083 mmol, see Example 4) was placed in dioxane (1 mL) and Na2CO3 (aq., 0.087 g, 0.82 mmol) in H2O (0.3 mL). 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.034 g, 0.16 mmol) and PS-Pd(PPh3)4 (0.075 g, 0.1 g/mmol) were then added. The reaction was heated to 150° C. in a microwave for 1 hour. The reaction was then diluted with water and extracted with DCM. The organic fractions were dried, filtered, and concentrated. Purification of the crude residue (500:10 to 500:20 DCM:MeOH) gave (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (0.005 g, 9.9% yield).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:20][P:21]([CH:24]([NH:28][C:29](=[O:38])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:25]([CH3:27])[CH3:26])([OH:23])=[O:22])[C:17]([OH:19])=[O:18])=O)C1C=CC=CC=1>O1CCOCC1.O.[OH-].[Pd+2].[OH-]>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:20][P:21]([CH:24]([NH:28][C:29](=[O:38])[CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH:25]([CH3:26])[CH3:27])([OH:23])=[O:22])[C:17]([OH:19])=[O:18]
Reactant: CC(C)C(NC(=O)CCc1ccccc1)P(=O)(O)CC(CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C(NC(=O)CCc1ccccc1)P(=O)(O)CC(CCCCN)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The crude 6-benzyloxycarbonylamino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoic acid (181 mg) obtained in the above step (g) was dissolved in a mixed solvent of dioxane and water (1:1) (4 ml). The solution was added with palladium hydroxide (37 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was filtered with celite and the filtrate was concentrated. The residue was purified with HP-20 (Diaion, 20 cc, methanol:water=1:9 to acetone:water=1:1) to obtain the title compound: 6-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoic acid (74 mg, 54%) (a diastereoisomeric mixture of 3:1).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[F:14][C:15]([F:20])([F:19])C([O-])=O.[K+].[I-].C([O-])(O)=O.[Na+]>CN(C=O)C.[Cu]>[F:14][C:15]([F:20])([F:19])[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C([O-])C(F)(F)F
Reactant: COC(=O)c1ccc(OC)c(I)c1
Agent: [Cu]
Agent: O=C([O-])O
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(C(F)(F)F)c1
Yield: 77.1 %

Procedure:
9.7 g of methyl 3-iodo-4-methoxybenzoate, 9.4 g of potassium trifluoroacetate and 12.9 g of copper(l) iodide were heated at 160° C. for 5 h in 250 ml of DMF. The mixture was poured onto 500 ml of NaHCO3 solution, the precipitate which was deposited was filtered off and both the precipitate and the aqueous phase were extracted with ethyl acetate. The combined organic phases were concentrated, and the residue was purified by flash chromatography using hexane/ethyl acetate 3:1. 6 g of methyl 3-trifluoromethyl-4-methoxybenzoate were obtained;