Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][CH3:5].BrBr.C([O-])(=O)C.[Na+].[C:14]1([CH2:20][CH2:21][NH:22][C:23]([NH2:25])=[S:24])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>CO>[C:14]1([CH2:20][CH2:21][NH:22][C:23]2[S:24][CH:1]=[C:2]([CH2:3][CH2:4][CH3:5])[N:25]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=S)NCCc1ccccc1
Reactant: CCCC(C)=O
Agent: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CO
Product: CCCc1csc(NCCc2ccccc2)n1
Temperature: 25 °C
Yield: 23 %

Procedure:
To a solution of 2-pentanone (1.72 g) in methanol (10 mL) was added bromine (3.20 g) at −30° C. The mixture was allowed to warm to room temperature and stirred until the red color of bromine disappeared. To the obtained colorless solution were added sodium acetate (3.20 g) and N-(2-phenylethyl)thiourea (2.70 g) and the mixture was stirred with heating under reflux for 4 hr. A saturated aqueous sodium hydrogencarbonate solution (10 mL) was added to the reaction mixture and the mixture was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9-2:1 in volume ratio) to give the title compound (850 mg, yield 23%) as pale-yellow crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31])#[N:24].C(=O)([O-])[O-].[K+].[K+].[F-].[K+]>CN(C)C=O.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])[CH:3]=1)#[N:24]
Reactant: N#Cc1ccccc1O
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Cl)ncn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Temperature: 80 °C
Reaction time: 23 h

Procedure:
(E)-methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate in N,N-dimethylformamide (256.8 g, 33.69% strength) was vacuum distilled to remove the solvent. A solution of the potassium salt of 2-cyanophenol was then prepared by mixing 2-cyanophenol (37.0 g) and potassium carbonate (56.7 g) in water (209 g). This solution was added to the (E)-methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate melt, which had previously been cooled to 80° C. Potassium fluoride (11.1 g) and tetrabutylammonium bromide (16.1 g) was then added to the reaction solution. The resulting mixture was stirred at 100° C. for 23 hours. Any distillates were allowed to come off under atmospheric conditions. Toluene and a further quantity of water was added to the solution. The organic layer was then separated. Toluene was removed from the organic phase by vacuum distillation (100° C., 20 mmHg). The melt was cooled to 90° C. after which methanol (108 ml) was added to help cooling to 65-75° C. The resulting mixture was cooled to 40° C. and kept at this temperature for 2 hours. It was then further cooled to 0-5° C. and held for another 1 hour period. The mixture was filtered to leave (E)-methyl 2-[2-(6-(2-cyanophenoxy)pyrimidin-4-yloxy)phenyl]-3-methoxypropenoate as the residue (67.0% isolated yield).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3([CH2:20][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:23][C:24]1[CH:40]=[CH:39][C:27]([C:28]([NH:30][CH2:31][C:32]([CH3:38])([CH3:37])[CH2:33][N:34]([CH3:36])[CH3:35])=[O:29])=[CH:26][C:25]=1[O:41][CH3:42].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.CO.O>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:20][CH2:19]3)[C:7](=[O:21])[N:6]([CH3:22])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:40]=[CH:39][C:27]([C:28]([NH:30][CH2:31][C:32]([CH3:37])([CH3:38])[CH2:33][N:34]([CH3:35])[CH3:36])=[O:29])=[CH:26][C:25]=4[O:41][CH3:42])=[N:12][C:11]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(C(=O)NCC(C)(C)CN(C)C)ccc1N
Reactant: CN1C(=O)C2(CC2)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)NCC(C)(C)CN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC1(CC1)C(=O)N2C
Temperature: 160 °C
Yield: 54.5 %

Procedure:
2′-chloro-9′-cyclohexyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 270; 86 mg, 0.27 mmol) and 4-amino-N-(3-dimethylamino-2,2-dimethyl-propyl)-3-methoxy-benzamide (Intermediate 22; 75 mg, 0.27 mmol) were taken up in 4-methyl-2-pentanol (3 mL) and p-toluenesulphonic acid monohydrate (102 mg, 0.54 mmol) added. The reaction mixture was heated at 160° C. for 1 hour by microwave irradiation. After cooling, the reaction mixture was diluted with methanol (5 mL) and water (5 mL) and the resultant solution loaded onto an SCX-3 (5 g) cartridge. The cartridge was washed with methanol (40 mL) and then eluted with 2M ammonia in methanol (25 mL). Evaporation of the ammoniacal solution gave an opaque cream coloured film which was purified by base modified reverse phase preparative HPLC to yield the title compound as a white foam (83 mg, 55%)
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:29])[C:9]=1[N:10]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])=[O:4]>CCOCC>[CH2:22]([N:10]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:9]1[C:8]([CH3:29])=[CH:7][S:6][C:5]=1[C:3]([OH:4])=[O:2])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1scc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C)csc2C(=O)O)cc1
Yield: 106 %

Procedure:
In the same manner as described in Example 11, 1.366 g (2.622 mmol) of the product of Example 8 provide 1.16 g (87%) of the desired carboxylic acid as a white solid after trituration with ether. Electrospray Mass Spec: 416 (M-H)--.
Reaction SMILES: O[N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].ClC1C=CC(B(O)O)=CC=1.N1C=CC=CC=1>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2].O>[C:6]1(=[O:7])[NH:2][C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]12
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OB(O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: O=C1NC(=O)c2ccccc21
Reaction time: 18 h
Yield: 136.9 %

Procedure:
A mixture of N-hydroxyphthalimide (664 mg, 4.07 mmol), 4-chlorophenylboronic Acid (635 mg, 4.06 mmol) and powdered 4 Å molecular sieves (1.02 g) in dichloromethane (20 mL) was stirred open to the air. Pyridine (0.37 mL, 4.6 mmol) and Cu(OAc)2.H2O (812 mg, 4.07 mmol) were added, and stirring was continued for 18 h. Silica gel (10 g) was added, and the mixture was concentrated to dryness. The residue was added to the top of a silica gel chromatography column, and eluted with hexanes-EtOAc (4:1) to provide 2-4-chlorophenoxy)phthalimide as a white solid (820 mg). This was dissolved in chloroform (37 mL) and methanol (4 mL) and hydrazine hydrate (0.56 mL, 12 mmol) was added. The solution was stirred at room temperature for 24 h. Silica gel (10 g) was added, and the slurry was concentrated to dryness. The solid was added to the top of a silica gel chromatography column, and eluted with hexanes-EtOAc (4:1) to provide O-(4-chlorophenyl)hydroxylamine as a yellow oil (416 mg). This was dissolved in ethanol (5 mL) and treated with HCl/dioxane (4N, 1 mL), followed by gradual addition of EtOAc (50 mL) to precipitate the product. The mixture was filtered and dried under vacuum to provide the titled salt as an off-white crystalline solid (442 mg, 60%). 1H NMR (300 MHz, CD3OD) δ ppm 7.15-7.22 (m, 2H), 7.42-7.49 (m, 2H).
Reaction SMILES: [F-].[Cs+].Br[C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[CH:15][N:14]=3)[C:7]([NH2:10])=[N:8][CH:9]=1.B([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)(O)O>CO.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:10][C:7]1[N:8]=[CH:9][C:4]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)=[CH:5][C:6]=1[C:11]1[O:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[CH:15][N:14]=2
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Nc1ncc(Br)cc1-c1nc2cccnc2o1
Agent: Cl[Pd]Cl
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CO
Product: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1-c1nc2cccnc2o1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 95.5 %

Procedure:
Bis(triphenylphosphine) palladium (II) chloride (0.121 g) and caesium fluoride (1.56 g) were added to a degassed solution of 5-bromo-3-oxazolo[5,4-b]pyridin-2-yl-pyridin-2-amine (1 g) and 4-boronobenzoic acid (0.570 g) in methanol (15 ml) under nitrogen atmosphere. The suspension was stirred at 120° C. for 20 min in a 300 W microwave reactor. The reaction mixture was then stirred at 130° C. for 20 minutes in a 300 W microwave reactor. The mixture was diluted with water (25 ml) and stirred for 30 min. The yellow suspension was filtered, washed with water (4×15 ml), washed with diethyl ether (4×15 ml) and dried overnight to give 4-(6-amino-5-oxazolo[5,4-b]pyridin-2-yl-3-pyridyl)benzoic acid (1.090 g, 95%). NMR Spectrum: (DMSOd6) 7.54 (dd, 1H), 7.89 (d, 2H), 7.95 (bs, 2H), 8.03 (d, 2H), 8.30 (dd, 1H), 8.41 (dd, 1H), 8.60 (d, 1H), 8.71 (d, 1H); Mass spectrum: M+H+ 333
Reaction SMILES: [Na].C(C(CC)(C([O-])=O)C([O-])=O)C.[H-].[Na+].[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[N+:26]([C:29]1[CH:46]=[CH:45][C:32]([CH2:33][N:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[N:36]=[C:35]2[CH2:43]Cl)=[CH:31][CH:30]=1)([O-:28])=[O:27]>CN(C=O)C.C(OCC)(=O)C>[N+:26]([C:29]1[CH:46]=[CH:45][C:32]([CH2:33][N:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[N:36]=[C:35]2[CH2:43][CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]([O:23][CH2:24][CH3:25])=[O:22])=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Cn2c(CCl)nc3ccccc32)cc1
Agent: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1nc2ccccc2n1Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The sodium salt of diethylmalonate was generated from 0.35 g of NaH (50% oil dispersion) and 1.1 mL of diethyl malonate in 15 mL of dried DMF with ice cooling. To the above mixture was added 2 g of 1-(4-nitrobenzyl)-2-chloromethylbenzimidazole and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried and concentrated in vacuo. The crude produce was purified by flash column chromatography (hexane/ethyl acetate, 1:1) to give a yellowish thick oil which was crystallized from absolute ethanol to give a white solid; m.p. 135°.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:11]=1[C:12]([O:14][CH3:15])=[O:13].[C:24](=[O:26])=[O:25]>O1CCCC1>[F:9][C:10]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:18][C:19]=1[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1c(F)cccc1C(F)(F)F
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1c(C(F)(F)F)ccc(C(=O)O)c1F
Temperature: -78 °C
Reaction time: 3 h

Procedure:
A solution of lithium diisopropyl amide in dry tetrahydrofuran (prepared from diisopropylarnine (17.0 ml) and n-butylithium (48.4 ml) in dry tetrahydrofuran)was added to a solution of methyl 2-fluoro-6-trifluoromethylbenzoate (22.39 g) in dry tetrahydrofuran while maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 3 hours. The solution was poured onto solid carbon dioxide pellets and stirred until it had warmed to room temperature. The mixture was evaporated and treated with hydrochloric acid (2 M). It was extracted with ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-fluoro-3-methoxycarbonyl-4-trifluoromethylbenzoic acid (24.43 g) as an off-white solid, NMR (CDCl3) 3.95(s,3H), 7.55(d,1H), 8.15(t,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20]O)[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>C(Cl)Cl>[Br:23][CH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][CH2:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Clc1ccc2ccc(COc3cccc(CBr)c3)nc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To the benzylic alcohol of Step 2 (47.0 g, 157 mmol) and CBr4 (60.08 g, 181 mmol) in CH2Cl2 (750 mL) at 0° C., a solution of 1,2-bis(diphenylphosphino) ethane (DIPHOS, 36.29 g, 91.1 mmol) in CH2Cl2 (350 mL) was added and the resulting mixture was stirred at 0° C. for 45 min. and at r.t. for 30 min. Ether was then added and the mixture was filtered through a pad of silica and the silica was washed with EtOAc:toluene 20:80 to yield 40.35 g (70%) of the pure title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[CH:8]=[C:9]3[CH2:17][O:16][CH2:15][CH2:14][C:10]3=[N+:11]([O-:13])[CH:12]=2)=[N:2]1.C(Cl)(Cl)Cl.[N+:22]([O-])([OH:24])=[O:23]>>[O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:8]([N+:22]([O-:24])=[O:23])=[C:9]3[CH2:17][O:16][CH2:15][CH2:14][C:10]3=[N+:11]([O-:13])[CH:12]=2)=[N:2]1
Reactant: [O-][n+]1cc(Nc2ccon2)cc2c1CCOC2
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1c(Nc2ccon2)c[n+]([O-])c2c1COCC2
Temperature: 55 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of 653 mg of Compound 5 obtained in the above step (1) as crystals in 3.2 ml of fuming nitric acid is stirred at 55° C. for 3 hours. The reaction mixture is chilled, poured onto ice water and shaken with chloroform. The extract is washed with water, aqueous disodium hydrogen phosphate and saturated saline in this order, dried over anhydrous magnesium sulfate and concentrated to remove the solvent. The resultant residue is washed with methanol to give 551 mg of the titled compound 6 as light yellow crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([C:22]([O:24]CC)=[O:23])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)/[CH:9]=[CH:10]/[C:11]1[S:12][CH:13]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=1.[OH-].[K+]>C(O)C.CO.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[C:22]([C:2]([CH3:27])([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)/[CH:9]=[CH:10]/[C:11]1[S:12][CH:13]=[C:14]([CH:16]([CH3:17])[CH3:18])[N:15]=1)([OH:24])=[O:23]
Reactant: CCOC(=O)C(C)(C)CCOc1cccc(/C=C/c2nc(C(C)C)cs2)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CC(C)c1csc(/C=C/c2cccc(OCCC(C)(C)C(=O)O)c2)n1
Yield: 66.3 %

Procedure:
To a solution of 200 mg of 2-[trans-3-(3,3-dimethyl-3-ethoxycarbonylpropyloxy)styryl]-4-isopropylthiazole dissolved in 5 ml of ethanol were added 2 ml of 10% aqueous potassium hydroxide solution and three drops of 40% benzyltrimethylammonium hydroxide methanol solution, and the mixture was refluxed for 1 hour to effect hydrolysis of the ester. After completion of the reaction, ethanol was evaporated under reduced pressure and the residue was adjusted to pH 1-2 with addition of 10% hydrochloric acid and then extracted with ethyl ether. After drying of anhydrous magnesium sulfate, the solvent was evaporated and the solid formed was recrystallized from methanol to give 123 mg (yield 66%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:42]1[CH:43]=[C:44]2[C:61](=[N:62][CH:63]=1)[NH:60][C:59](=[O:64])[C:46]1([CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]1)[CH2:45]2>C(#N)CC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:6]([O:5][C:1](=[O:4])/[CH:2]=[CH:3]/[C:42]1[CH:43]=[C:44]2[C:61](=[N:62][CH:63]=1)[NH:60][C:59](=[O:64])[C:46]1([CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:53])[CH2:48][CH2:47]1)[CH2:45]2)([CH3:9])([CH3:8])[CH3:7]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Cc1cc(Br)cnc1NC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CC1(CCN(C(=O)OC(C)(C)C)CC1)C(=O)N2

Procedure:
Tert-Butyl acrylate (3.9 mL, 26.8 mmol), diisopropylethylamine (2.46 mL, 14.1 mmol) and P(o-tolyl)3 (409 mg, 1.34 mmol) were successively added to a suspension of tert-butyl 6-bromo-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-1′-carboxylate (2.66 g, 6.7 mmol) in propionitrile (107 mL) and dimethylformamide (40 mL) in a sealed tube. The resulting mixture was then purged with argon prior to the addition of palladium acetate (151 mg, 0.673 mmol). The mixture was purged with argon again and refluxed overnight. The reaction mixture was then filtered on Celite® and the cake was washed with DCM (50 mL). The filtrate was concentrated to dryness and the residue was triturated with dichloromethane. The title product was obtained as a light grey solid (1.83 g, 61%, py 79.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:17]=[CH:16][C:9]2[C@H:10]([CH2:13][CH2:14][NH2:15])[CH2:11][O:12][C:8]=2[CH:7]=1.[OH:23][CH:24]([CH:28]([CH3:30])[CH3:29])[C:25](O)=[O:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:17]=[CH:16][C:9]2[C@H:10]([CH2:13][CH2:14][NH:15][C:25](=[O:26])[CH:24]([OH:23])[CH:28]([CH3:30])[CH3:29])[CH2:11][O:12][C:8]=2[CH:7]=1
Reactant: NCC[C@@H]1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Reactant: CC(C)C(O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)C(O)C(=O)NCC[C@@H]1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
To a mixture of 2-((3S)-6-((2,4-dichlorobenzyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)ethanamine (33.8 mg) and DMF (dry) (5 mL) were added 2-hydroxy-3-methylbutanoic acid (17.72 mg), EDCI (31.0 mg) and HOBt (27.0 mg). The mixture was stirred at room temperature overnight. The mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (26.0 mg).
Reaction SMILES: O1CCCC1.CN(OC)[C:8](=[O:17])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH2:16].[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32](Br)=[CH:31][CH:30]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C([Li])CCC>C(OC(=O)C)C.O.CCCCCC>[NH2:16][C:10]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=1[C:8]([C:32]1[CH:31]=[CH:30][C:29]([CH2:28][NH:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])=[CH:34][CH:33]=1)=[O:17]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1cc(Cl)ccc1N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)c2cc(Cl)ccc2N)cc1
Yield: 25 %

Procedure:
A tetrahydrofuran (30 ml) solution of N-methyl-N-methyloxy-2-amino-5-chlorobenzamide (3.21 g) and N-tert-butoxycarbonyl-4-bromobenzylamine (2.86 g) was cooled to −78° C. To the solution kas gradually added dropwise a hexane solution of n-butyl lithium (1.6 mol/L) (31 ml). To the mixture were then added water (100 ml) and acetic acid ethyl ester (100 ml). The organic layer was washed with water and dried over anhydrous MgSO4. The solvent was then distilled off, and the residue was purified by means of a silica gel column chromatography. followed by crystallization. The crystals were collected to give 2-amino-4′-tert-butoxycarbonylaminomethyl-5-chlorobenzophenone (0.9 g) as a pale yellow crystalline product.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([NH2:14])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O(CC)[C:16]([S-])=[S:17].[K+]>C(O)C>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]3[O:13][C:16]([SH:17])=[N:14][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1cc(-c2ccccc2)ccc1O
Agent: [K+]
Solvent: CCO
Product: Sc1nc2cc(-c3ccccc3)ccc2o1

Procedure:
4-Phenyl-2-aminophenol, 11.4 mmol (2.10 g) was dissolved in ethanol, 30 ml, and added potassium ethyl xanthate, 11.4 mmol (1.82 g). The reaction mixture was refluxed overnight, cooled, and excess of ethanol was distilled off, then the reaction mixture was poured into crushed ice. The pH was adjusted to 5 by the addition of acetic acid. The white precipitate formed was filtered and dried to give the crude 5-phenylbenzo[d]oxazole-2-thiol, 2.32 g (90%) that was directly used in the next step without any purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([O:17]CC2C=CC=CC=2)=[O:16])=[CH:13][N:12]=[C:11]([N:25]2[CH:29]=[CH:28][CH:27]=[N:26]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.O.[OH-].[K+]>CCO>[CH2:1]([O:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([N:25]2[CH:29]=[CH:28][CH:27]=[N:26]2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1cnc(-n2cccn2)nc1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(-n2cccn2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 13 %

Procedure:
To a solution of benzyl 4-(benzyloxy)-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylate, 2-d, (2 g crude) in EtOH(20 ml)/THF (20 ml)/water (20 ml) was added KOH (0.87 g, 15.5 mmol). The mixture was stirred at room temperature for 12 hours. The mixture was then concentrated under vacuum and the residue was diluted with water and basified to pH=2 with HCl followed by extraction with ethyl acetate. The organic layer was brine washed, dried over sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with the eluent of petroleum ether/ethyl acetate=7/1 to afford the compound 2-e (200 mg, 13%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].C(N(CC)C(C)C)(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)([CH2:13][CH2:14][O:15][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 2 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (200 mg, 0.44 mmol) and N,N-diisopropylethylamine (0.17 mL, 0.97 mmol) in dichloromethane (25 mL). Cool in a ice-bath. Add dropwise, methanesulfonyl chloride (0.066 g, 0.57 mmol). After 2 hours, extract with 1 M hydrochloric acid solution and 5% sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give the title compound: Rf=0.42 (silica gel, 6% methanol/dichloromethane); mp; 64.0-66.0° C.