Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)C)=O)=NC(O[CH:6](C)[CH3:7])=O.[O:15]=[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[N:17]1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>C1COCC1>[O:25]=[C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](=[O:15])[N:17]1[N:26]([CH2:6][CH3:7])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NN1C(=O)c2ccccc2C1=O
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: CCN(C(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Yield: 90 %

Procedure:
Diisopropyl azodicarboxylate (2.92 mL, 15.00 mmol) was added in one portion to a solution of tert-butyl 1,3-dioxoisoindolin-2-ylcarbamate (2.62 g, 10 mmol, prepared following the procedure described by Nicolas Brosse et al. in Eur. J. Org. Chem. 4757-4764, 2003), triphenylphosphine (3.93 g, 15.00 mmol) and ethanol (0.691 g, 15.00 mmol) in THF (20 mL) at 0° C. and the reaction solution was stirred at room temperature for 1 h (monitored by TLC until completion). Solvent was evaporated and the residue was purified by flash chromatography on silica gel using an automated ISCO system (80 g column, eluting with 5-35% ethyl acetate/hexanes) to provide tert-butyl 1,3-dioxoisoindolin-2-yl(ethyl)carbamate (2.6 g, 90% yield) as a white solid which was used as it in the next step
Reaction SMILES: [CH2:1]([N:8]1[CH:15](O)[C@H:14]2[N:10]([C@H:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:12][CH2:13]2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[O:26][C:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1.B(F)(F)F.CCOCC>ClCCl.CCOCC>[CH2:1]([N:8]1[C@@H:15]([CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][C:27]2=[O:26])[C@H:14]2[N:10]([C@H:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:12][CH2:13]2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1N(Cc2ccccc2)C(O)[C@@H]2CS[C@@H](c3ccccc3)N12
Reactant: C[Si](C)(C)OC1=CCCCC1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1CCCCC1[C@H]1[C@@H]2CS[C@@H](c3ccccc3)N2C(=O)N1Cc1ccccc1
Temperature: 20 °C

Procedure:
To a solution of compound 6-benzyl-7-hydroxy-3-phenyl-(3S, 7aR)-perhydroimidazo[1,5-C][1,3]thiazol-5-one of formula (6) (0.326 parts, 1 mmol) in dichloromethane (10 parts) was added 1-trimethylsilyloxy-1-cyclohexene (0.340 parts. 2 mmol). Then the solution was cooled to 20° C., and Lewis acid for example BF3.Et2O (0.142 parts, 1 mmol) was added drop wise. The reaction mixture was stirred at 20° C. for 10 mints. and the reaction mixture was quenched with saturated ammonium chloride (10 parts). Then the organic layer was separated, concentrated and column purification with ethylacetate:pet.ether (15:85) as eluent provided compound 6-benzyl-7-(2-oxocyclohexyl)-3-phenyl-(3S, 7S, 7aR)-perhydroimidazo[1,5-C][1,3]-thiazol-5-one of formula (7d) (viscous liquid, 0.398 parts, 0.98 mmol) in98% yield.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.O1CCOCC1>CO.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]>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: COc1cccc(B(O)O)c1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: COc1cccc(-c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)c1
Temperature: 110 °C
Yield: 0 %

Procedure:
A suspension of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 151 mmol), 3-methoxyphenylboronic acid (46 mg, 302 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 12 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (670 microliters of 1,4-dioxane and 330 microliters of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC, 45-70% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (5.2 mg, 9%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6 H) 3.85 (s, 3 H) 6.59 (d, J=2.27 Hz, 1 H) 7.22 (dd, J=8.08, 1.77 Hz, 1 H) 7.55 (t, J=7.83 Hz, 1 H) 7.59-7.70 (m, 4 H) 7.98-8.09 (m, 3 H) 8.20 (d, J=2.02 Hz, 1 H) 11.27 (s, 1 H). ESI-MS: m/z 403.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1.[CH3:16][O-:17].[Na+]>CO>[CH3:16][O:17][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(OC)nc1C(F)(F)F
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Methyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (1128 mg) was dissolved in MeOH (23 ml) before addition of sodium methoxide (380 mg), the reaction mixture was stirred for 2 hours in a sealed tube at 110° C. The solvent was evaporated, the product dissolved in ethyl acetate and washed with water, the organics were dried over Na2SO4, and concentrated in vacuo to afford title compound as a colourless oil. MS (ISP) 237.0 ([M+H]+)
Reaction SMILES: [NH:1]([C:18]([O:20]C(C)(C)C)=O)[C@@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.FC(F)(F)[C:27]([OH:29])=[O:28].ClCCl>>[NH:1]([C:27]([O:29][C:8]([CH3:13])([CH3:9])[CH3:7])=[O:28])[C@H:2]([C:18]([NH:1][C@@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:20])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Reaction time: 1 h

Procedure:
30 g (1.0 eq) Boc-D-Glu(OBzl)-NH2 was dissolved in 100 mL trifluoroacetic acid-dichloromethane (v/v=1:1), and the solution was stirred for 1 hour at r.t to remove Boc group. After the completion of the reaction, the TFA was removed under vacuum; the residue was repeatedly grinded and washed in anhydrous ether, and evaporated to dryness, and re-dissolved in tetrahydrofuran. The pH of the solution was adjusted to 7˜8 with N-methyl morpholine (NMM) in ice bath. The Boc-Ala-OSu solution was sparingly added to the solution in a few portions. The mixture was stirred for 5 hours in ice bath, and continued for 24 hours at r.t. After the completion of the reaction, the mixture was evaporated to dryness. The residue was dissolved in proper amount AcOEt and successively washed with diluted hydrochloric acid, saturated sodium bicarbonate aqueous solution and water. The AcOEt layer was separated, and dried with MgSO4 overnight. The mixture was filtered and the filtrate was evaporated to dryness. The residue was recrystallized from methanol and water, the crystal was washed with a big amount of ether to obtained 29.4 g target compound. Yield: 81%, m.p.=134˜135° C.
Reaction SMILES: [Br:1][C:2]1[C:3]2[O:11][CH:10]=[CH:9][C:4]=2[C:5](=O)[NH:6][CH:7]=1.P(Br)(Br)([Br:14])=O>>[Br:14][C:5]1[C:4]2[CH:9]=[CH:10][O:11][C:3]=2[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1[nH]cc(Br)c2occc12
Product: Brc1ncc(Br)c2occc12
Temperature: 70 °C
Yield: 75.7 %

Procedure:
A mixture of 7-bromo-5H-furo[3,2-c]pyridin-4-one (21.2 g, 99 mmol) and POBr3 (31.2 g, 109 mmol) was heated at 70° C. for 5 min, then heated to 120° C. for 2 h. After cooled to rt, the solid was crashed and quenched with aqueous Na2CO3 (200 mL), then diluted with EtOAc (300 mL). The insoluble material was filtered off through a pad of Celite. The organic phase was collected and dried over Na2SO4. The crude material was purified by silica gel chromatography eluting with Hexanes-EtOAc (90:10→85:15) to give the title compound as a white solid (20.75 g, 68%). 1H NMR (CDCl3, 400 MHz): δ=6.91 (d, J=2.3 Hz, 1H), 7.79 (d, J=2.3 Hz, 1H), 8.37 (s, 1H).
Reaction SMILES: O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:21][C@@H:22]1[CH:31]=[CH:30][CH2:29][C:24]2([CH2:28][CH2:27][CH2:26][CH2:25]2)[C@H:23]1[C:32](=[O:36])/[CH:33]=[CH:34]/[CH3:35]>C1C=CC=CC=1>[CH3:21][C@@H:22]1[CH:31]=[CH:30][CH2:29][C:24]2([CH2:28][CH2:27][CH2:26][CH2:25]2)[C@H:23]1[C:32](=[O:36])[CH2:33][CH2:34][CH3:35]
Reactant: C/C=C/C(=O)[C@H]1[C@H](C)C=CCC12CCCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCC(=O)[C@H]1[C@H](C)C=CCC12CCCC2
Reaction time: 0.08 h
Yield: 39.6 %

Procedure:
After argon bubbling, a mixture of benzene (70 ml) and water (0.15 ml) was treated with triphenylphosphine-cooper (I)-hydride hexamer (3.3 g, 1.68 mmol). The resulting mixture was stirred for five min., treated with a solution of (E)-1-(rel-(6S,7R)-7-methylspiro[4.5]dec-8-en-6-yl)but-2-en-1-one (2 g, 9.16 mmol) in benzene (10 ml) and stirred for 2 h at 20° C. The reaction mixture was then stirred for 30 min under air, filtered, and concentrated. FC (SiO2, hexane/MTBE 70:1) of the crude product (4.07 g) gave 1-(rel-(6S,7R)-7-methylspiro[4.5]dec-8-en-6-yl)butan-1-one (0.80 g, 40%). Boiling point: 100° C. (0.08 mbar).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])O[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20]>C(O)(=O)C>[Cl:1][C:2]1[C:3](=[O:14])[N:15]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:5](=[O:13])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)C(c2ccccc2)=C1Cl
Reactant: COCCCN
Solvent: CC(=O)O
Product: COCCCN1C(=O)C(Cl)=C(c2ccccc2)C1=O

Procedure:
A solution of 3-chloro-4-phenylfuran-2,5-dione (0.20 mmol, 42 mg) and 1-amino-3-methoxypropane (0.20 mmol, 18 mg) in glacial acetic acid (1 mL) was heated in a microwave reactor at 120° C. for two min. After cooling, the solvent was evaporated at reduced pressure. The crude product was used without purification.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:10]([OH:13])([OH:12])[OH:11]>C(O)C>[NH2:9][C:8]([P:10]([OH:13])([OH:12])=[O:11])([P:10]([OH:13])([OH:12])=[O:11])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OP(O)O
Reactant: N#CCc1ccccc1
Solvent: CCO
Product: NC(Cc1ccccc1)(P(=O)(O)O)P(=O)(O)O
Temperature: 150 °C
Yield: 40 %

Procedure:
Phenylacetonitrile (5.6 g, 0.05 mole) was mixed with phosphorous acid (8.2 g, 1.0 mole), ISOPAR-M (20 g), and wetting agents (0.25 g each). The mixture was heated at ambient pressure for 4 hours at 150° C. The product was worked up with ethanol to get colorless crystals of 1-amino-1,1-diphosphono-2-phenyl ethane (40%), m.p. 238° C (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][C@H:7]2[CH2:11][N:10](C(OC(C)(C)C)=O)[C@H:9]([C:19](=[O:35])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)[CH2:8]2)=[C:4]([CH3:38])[CH:3]=1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>C(Cl)Cl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][C@H:7]2[CH2:11][NH:10][C@H:9]([C:19]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)=[O:35])[CH2:8]2)=[C:4]([CH3:38])[CH:3]=1
Reactant: Cc1cc(F)ccc1C[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(F)ccc1C[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
The (2S,4R)-tert-butyl 4-(4-fluoro-2-methylbenzyl)-2-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidine-1-carboxylate (826 mg, 1.59 mmol) was dissolved in methylene chloride (5 mL) and then trifluoroacetic acid (5 mL) was added to the solution. The mixture was stirred at ambient temperature for 1 hour, concentrated in vacuo and dried under high vacuum to give (2S,4R)-4-(4-fluoro-2-methylbenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide trifluoroacetic acid (826 mg, 1.54 mmol, 100%) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: OCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Yield: 47.6 %

Procedure:
Using 5 g (25.6 mmol) of 4-cyano-4'-hydroxybiphenyl, 85 ml of acetonitrile, 4.63 g (25.6 mmol) of 6-bromohexanol and 7.09 g (51.2 mmol) of anhydrous potassium carbonate, synthetic treatment was carried out in the same manner as in Example 2. The obtained gray powder was recrystallized from methanol to obtain 3.6 g (yield: 48%) of 4-cyano-4'-(6-hydroxyhexyloxy)biphenyl (24) as a colorless powder.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:8]([CH3:15])[C:5]=1[CH:6]=[O:7]>C(O)C.Cl.O>[CH3:15][C:8]1[CH:9]=[C:10]([CH:12]([CH3:13])[CH3:14])[CH:11]=[C:4]([CH3:3])[C:5]=1[CH2:6][OH:7]
Reactant: Cc1cc(C(C)C)cc(C)c1C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(C)C)cc(C)c1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
A solution of sodium borohydride (0.04 g, 1.04 mmol) in 90% ethanol (5 mL) was added dropwise to a solution of 2,6-dimethyl-4-isopropylbenzaldehyde (Example 1) (0.55 g, 3.1 mmol) in absolute ethanol (5 mL). The reaction mixture was allowed to stir at room temperature for 1 hour, then heated at 60° C. for 30 min. The solution was cooled to 0° C. and the unreacted sodium borohydride was decomposed by the addition of a few drops of 3N HCl. The solvent was removed under reduced pressure to give a red oil which was suspended in water (10 mL) and extracted with ether (2×20 mL). The ether was removed under reduced pressure to afford a red oil which was purified by flash chromatography using silica gel (eluted with hexane-EtOAc, 93:3) to give 0.48 g (87%) of the title compound as a white solid; mp 75-77° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]#[N:16].C[O-].[Na+].C(O)(C)C>O>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[C:15]([C:11]2[O:10][CH:14]=[CH:13][CH:12]=2)[N:16]=1
Reactant: N#Cc1ccccc1N
Reactant: N#Cc1ccco1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Nc1nc(-c2ccco2)nc2ccccc12

Procedure:
5.4 g. (0.05 mol) of o-aminobenzonitrile, 4.7 g. (0.05 mol) of 2-furonitrile and 5.4 g. (0.1 mol) of sodium methoxide in 150 ml. of isopropanol are refluxed for 48 hours under a nitrogen atmosphere. The reaction mixture is then decomposed with water and the isopropanol is distilled off. 80 ml. of diethyl ether and 80 ml. of water are added and the precipitate is filtered off. The ethereal layer is separated and the ether is distilled off. The residue is identical to the solid already filtered off. The product is crystallized from a mixture of ethanol and petroleum ether (boiling range 40°-60°C.) to give 4-amino2-(2-furyl)quinazoline, m.p. 219°-221°C. The base is converted into the monohydrochloride, and the salt after crystallization from ethanol melts above 300°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([O:48][CH3:49])[C:34]=1[OH:50]>>[Cl:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:23][CH2:24]2)[CH:36]=[C:35]([O:48][CH3:49])[C:34]=1[OH:50]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(NCC4CCN(C(=O)OC(C)(C)C)CC4)c3c2)cc(Cl)c1O
Yield: 43.4 %

Procedure:
Following general procedure F, tert-butyl 4-{[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]methyl}piperidine-1-carboxylate (55 mg, 0.110 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (46 mg, 0.165 mmol) to afford the desired product (27 mg, 43%) as a yellow solid: ESI MS m/z 567 [C31H36ClN3O5+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:10]([O:11][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ncccc3O)c(Cl)cc2F)c1=O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1cccnc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
60 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxypyridine and 20 mg of methyl bromoacetate were dissolved in 2 ml of acetonitrile, to this was added 20 mg of potassium carbonate, and the mixture was stirred for 2 hours at 60° C. This reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 60 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-(methoxycarbonyl)methoxypyridine [present compound 2-7].
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:52]=[CH:51][N:50]=[C:49]([NH2:53])[CH:48]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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>[NH2:53][C:49]1[CH:48]=[C:47]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:52]=[CH:51][N:50]=1
Reactant: CC1(C)OB(c2ccnc(N)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
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+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccnc(N)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 39.2 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (250 mg, 0.42 mmol) was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (200 mg, 0.91 mmol), tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.08 mmol), and aqueous solution 2M of sodium carbonate (200 μl, 0.4 mmol) in N,N-dimethylformide (5 ml) according to the method described in Preparation 186 heating at 100° C. overnight. The crude was purified using SP1® Purification System (hexane-ethyl acetate) to obtain 100 mg (40% yield) of the title compound. Purity 98%.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br-:20].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CO>[Br:20][CH2:2][C:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(C(=O)Nc2ccc(F)cc2)cc1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: CO
Product: O=C(CBr)c1ccc(C(=O)Nc2ccc(F)cc2)cc1
Temperature: 40 °C

Procedure:
4-acetyl-N-(4-fluorophenyl)benzamide (1.5 g, 0.00583 mol) is dissolved in 100 ml of methanol. Pyridinium tribromide resin is added (4 g of resin to 2 mmol of Br3 per gram, 0.0081 mol) followed by heating for 4 hours at 40° C. The reaction medium is filtered on frit, rinsed with methanol and evaporated to dryness. A pale yellow-coloured powder is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=O)([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:70][O:71][NH3+:72].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](=[O:29])[NH:72][O:71][CH3:70])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1
Reactant: CO[NH3+]
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
To a mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (30 mg, 0.05 mmol), EDCI (20 mg, 0.1 mmol), HOBt (16 mg, 0.1 mmol) and DIPEA (40 mg, 0.3 mmol) in THF (1 mL) was added o-methylhydroxylamine hydrochloride (22 mg, 0.25 mmol). The mixture was stirred at room temperature overnight and purified by prep-HPLC to give the title compound as a white solid (11 mg).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=3[C:25]([O:27]CC)=[O:26])[CH:8]=2)[N:3]=1>[OH-].[Na+].C1COCC1>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=3[C:25]([OH:27])=[O:26])[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)c1ccccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C(=O)O)ccc2n1

Procedure:
A solution of 15.3 g of ethyl 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)-quinazolin-6-yl]benzoate in 70 ml of sodium hydroxide solution (2 N) and 100 ml of THF is stirred at 80° C. for 6 h. The mixture is extracted three times with 100 ml of diethyl ether each time, and the aqueous phase is adjusted to pH7, whereupon 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzoic acid precipitates out. The precipitate is filtered and dried at 50° C. in a drying cabinet.