Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.C(OP([CH2:24][C:25]1[CH:30]=[C:29]([O:31][CH2:32][CH3:33])[C:28]([CH2:34]P(OCC)(OCC)=O)=[CH:27][C:26]=1[O:43][CH2:44][CH3:45])(OCC)=O)C.[C:46](O[K])([CH3:49])([CH3:48])[CH3:47].S(=O)(=O)(O)O>O1CCCC1.O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:34][C:28]2[CH:27]=[C:26]([O:43][CH2:44][CH3:45])[C:25]([CH:24]=[C:47]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:46]3[CH:49]=[CH:15][C:2]([Br:1])=[CH:3][CH:48]=3)=[CH:30][C:29]=2[O:31][CH2:32][CH3:33])=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: CCOc1cc(CP(=O)(OCC)OCC)c(OCC)cc1CP(=O)(OCC)OCC
Reactant: CC(C)(C)O[K]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C=C(c2ccccc2)c2ccc(Br)cc2)c(OCC)cc1C=C(c1ccccc1)c1ccc(Br)cc1
Reaction time: 3.5 h

Procedure:
Under an inert atmosphere, 4-bromobenzophenone (2.611 g, 10 mmol), and 1,4-bis(diethylphosphonomethyl)-2,5-diethoxybenzene (1.912 g, 4.10 mmol) are dissolved in tetrahydrofuran (30 g). At room temperature, tetrahydrofuran (10.92 g) solution of tert-butoxy potassium (1.380 g, 12.30 mmol) is added dropwise for 5 minutes, and successively stirred for 3.5 hours. The reaction mixture is charged into water (200 ml) and neutralized with 5% sulfuric acid. After neutralization, a hydrophobic solvent is added and the organic layer is partitioned. The organic layer is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the resultant raw product is purified by silica gel chromatography or recrystallization to give a desired product.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[I:13]I>C(Cl)Cl>[I:13][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[CH2:1][CH2:2][CH3:3])[C:8]([OH:10])=[O:9]
Reactant: II
Reactant: CCCc1ccc(C(=O)O)cc1
Solvent: ClCCl
Product: CCCc1ccc(C(=O)O)cc1I
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.3 %

Procedure:
A mixture of 4-propylbenzoic acid (0.3 g; 1.83 mmol), CF3SO3Ag (0.47 g; 1.83 mmol) and I2 (0.46 g; 1.83 mmol) in CH2Cl2 was stirred for 48 h at room temperature, then filtered through Celite pad, washed with fresh CH2Cl2 (2×15 ml). The combined filtrates were washed with 5% NaHSO3, H2O, brine, dried over anhydrous MgSO4, filtered and filtrate evaporated under reduced pressure to give the title compound (0.49 g; 92%) as creamy solid. 1H-NMR (CDCl3) 1.0 (tr, 3H, J=9 Hz); 1.57-1.7 (m, 2H); 1.72-1.77 (m, 2H); 7.28 (d, 1H, 9 Hz); 7.98 (dd, 1H, J=3, 6 Hz); 8.53 (d, 1H, J=3 Hz).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[CH3:28]>>[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH:15][C:14]([C:12]2[S:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[O:16])=[CH:22][C:21]=1[CH3:28]
Reactant: Cc1cc(C=O)ccc1O
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: Cc1cc(C=CC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)ccc1O

Procedure:
3-(4-Hydroxy-3-methylphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)ethanone and 4-hydroxy-3-methylbenzaldehyde according to general procedure B. The evaporation residue is washed with dichloromethane.
Reaction SMILES: [CH:1]1([CH:13]=[CH:14][C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Mg].CCCCCC.C(OCC)C>CO>[CH:1]1([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C=CC1CCCCCCCCCCC1
Agent: [Mg]
Solvent: CO
Solvent: CCOCC
Solvent: CCCCCC
Product: COC(=O)CCC1CCCCCCCCCCC1
Temperature: 160 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
To a solution of 12.6 g (50 mmol) of methyl 3-cyclododecylprop-2-enoate in 100 ml of methanol is added 3.6 g (150 mmol), 3 equiv) of magnesium metal (activated by prior heating to 160° C.) and the mixture is stirred at room temperature for 2 hours (ice bath cooling is applied when necessary to control exothermic excursions). The reaction mixture is digested with ice cold 2N hydrochloric acid and is extracted with ethyl ether (3 times). The combined ethereal extracts are washed with 2N hydrochloric acid and are dried over magnesium sulfate. Filtration and evaporation gives an oily solid. Flash chromatography on silica gel using hexane/ethyl ether (10:1) as eluting solvent affords 7.80 g of the title compound: IR 1748cm-1 ; NMR (CDCl3) δ 1.33 (m, 23H), 1.54 (t, 2H, J=8 Hz), 2.31 (t, 2H, J=8 Hz), 3.66(s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12](O)[N:11]3[N:15]=[CH:16][CH:17]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O.CN(C)C1C=CC=CC=1>>[Cl:20][C:12]1[N:11]2[N:15]=[CH:16][CH:17]=[C:10]2[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(-c2ccc(Cl)cc2)nc2ccnn12
Solvent: CN(C)c1ccccc1
Product: Clc1ccc(-c2cc(Cl)n3nccc3n2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A mixture of 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidin-7-ol (4.8 g, 19.5 mmol), phosphorous oxychloride (7.2 mL, 78 mmol), and N,N-dimethylaniline (0.87 mL, 7.0 mmol) was stirred at 100° C. for 2 h. The mixture was evaporated in vacuo and the residue was partitioned between water and dichloromethane. The organic phase was washed with water, dried (Na2SO4), and evaporated in vacuo. The remaining solid was crystallized from EtOAc to give 7-chloro-5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine (3.50 g, 66%) as a yellow solid; mp 151-153° C.
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[OH:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[CH2:13][CH2:12][CH:11]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[C:10]1=[O:27].C(=O)([O-])[O-].[K+].[K+].C(NCC)C>CN(C=O)C>[CH2:8]([N:9]([CH2:10][CH3:11])[CH2:2][C:3]([OH:5])=[O:4])[CH3:7].[OH:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[CH2:13][CH2:12][CH:11]([N:16]2[C:17](=[O:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]2=[O:25])[C:10]1=[O:27]
Reactant: O=C(O)CBr
Agent: O=C([O-])[O-]
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)CC(=O)O

Procedure:
2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione bromoacetate (409 mg) was dissolved in DMF (10 mL). Potassium carbonate powder (800 mg) was added. Diethylamine solution (0.4 mL) was added dropwise while stirring. The reaction mixture was stirred for 24 hrs at room temperature. The solvent and the residual diethylamine were removed by rotary evaporation in vacuo. The resultant solid mixture was subjected to silica gel column chromatography (eluted with acetic ether:petroleum ether=2:1) and then a white solid (128 mg) was obtained. 1H NMR (CDCl3, ppm) δ 7.87-7.90 (m, 2H), 7.76-7.79 (m, 2H), 4.97-5.04 (m, 1H), 4.28-4.33 (m, 2H), 4.08-4.16 (m, 2H), 3.30 (s, 2H), 2.97-3.02 (m, 1H), 2.76-2.85 (m, 2H), 2.61-2.68 (m, 4H), 2.10-2.14 (m, 1H), 1.02-1.06 (m, 6H). MS (m/e): 416 (M+H+).
Reaction SMILES: [CH:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:25])C=1.S([O-])([O-])(=[O:30])=S.[Na+].[Na+]>ClCCl>[O:25]1[C@H:4]2[C@@H:3]1[CH2:2][C@H:1]([C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])[CH2:6][CH2:5]2.[O:30]1[C@@H:4]2[C@H:3]1[CH2:2][C@H:1]([C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])[CH2:6][CH2:5]2
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OCc1ccccc1)C1CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H]1CC[C@@H]2O[C@@H]2C1
Product: O=C(OCc1ccccc1)[C@@H]1CC[C@H]2O[C@H]2C1
Reaction time: 2 h

Procedure:
Benzyl (±)-3-cyclohexene-1-carboxylate (40 g) was dissolved in dichloromethane (500 ml), and m-chloroperbenzoic acid (86 g) was added under ice cooling to stir the mixture for 2 hours. After a 10% aqueous solution of sodium thiosulfate was added to conduct stirring for 20 minutes, an organic layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:9) to obtain the title compound (23.4 g) and benzyl (1R,3R*,4S*)-3,4-epoxycyclohexane-1-carboxylate (12.1 g) as colorless oils.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4].[CH2:13]([OH:17])[CH2:14]CC.CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(O)CO>[Br:1][CH2:2][C:3]1([C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)[O:17][CH2:13][CH2:14][O:4]1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: CCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: OCCO
Product: N#Cc1ccc(C2(CBr)OCCO2)cc1
Reaction time: 4 h

Procedure:
To a stirred solution of 112 parts of 4-(2-bromoacetyl)-benzonitrile in 320 parts of butanol are added 5 parts of 4-methylbenzenesulfonic acid and 360 parts of benzene. Then there are added dropwise 46.5 parts of 1,2-ethanediol. Upon completion, stirring is continued for 4 hours at reflux. The reaction mixture is evaporated. The oily residue is crystallized from 2,2'-oxybispropane. The product is filtered off and recrystallized from methanol, yielding 95.12 parts of 4-[2-(bromomethyl)-1,3-dioxolan-2-yl]benzonitrile; mp. 92.4° C.
Reaction SMILES: CO.C(N[C:12]1[CH:20]=[C:19](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH:18]=[CH:17][C:13]=1C(O)=O)(=O)C1C=CC=CC=1.[C:30]([O:33]CC)(=[O:32])C>[C].[Pd]>[OH:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]1[C:13]([CH2:12][CH3:20])=[C:17]([CH:18]=[CH:19][CH:21]=1)[C:30]([OH:33])=[O:32]
Reactant: CCOC(C)=O
Reactant: O=C(Nc1cc(/C=C/c2ccccc2O)ccc1C(=O)O)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCc1c(C(=O)O)cccc1-c1ccccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
12 mg of 5% palladium-carbon was added to a mixed solution of 1.5 mL of methanol and 1.5 mL of ethyl acetate containing 60 mg of 2-(benzamido)-4-((E)-2-(2-hydroxyphenyl)vinyl)benzoic acid and stirred under hydrogen atmosphere at room temperature for 3 hours and minutes. 6.0 mg of 5% palladium-carbon was added to the reaction mixture and stirred under hydrogen atmosphere at room temperature for 3 hours and 20 minutes. 6.0 mg of 5% palladium-carbon was added to the reaction mixture and stirred under hydrogen atmosphere at room temperature for 2 hours and 40 minutes. Insoluble were removed by filtration and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 47 mg of 2-(benzamido)-4-(2-(2-hydroxyphenyl(ethyl)benzoic acid as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:18][CH:19]([NH:22][OH:23])[CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:24](OC=O)(=[O:26])C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:18][CH:19]([N:22]([OH:23])[CH:24]=[O:26])[CH2:20][CH3:21])(=[O:16])=[O:17])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CC(=O)OC=O
Reactant: CCC(CS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1)NO
Solvent: C1CCOC1
Product: CCC(CS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1)N(O)C=O
Reaction time: 2 h
Yield: 40.5 %

Procedure:
A solution of Example 75C (0.24 g, 0.72 mmol) in THF (30 mL) cooled to 0° C. was treated with formic acetic anhydride (64 mg, 0.72 mmol), stirred for 2 hours, partitioned between water and dichloromethane, dried (Mg2SO4), filtered, and concentrated to afford 0.25 g of crude product which was recrystallized in ethyl acetate to provide 106 mg (41%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([OH:22])=[CH:19][CH:20]=3)[C:15](=[O:23])[N:14]2[CH3:24])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:25]=[C:26]1[NH:31][CH2:30][CH2:29][CH2:28][N:27]1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([OH:22])=[CH:19][CH:20]=3)[C:15](=[O:23])[N:14]2[CH3:24])[CH2:10][CH2:11][N:35]2[CH2:36][CH2:37][CH:32]([N:27]3[CH2:28][CH2:29][CH2:30][NH:31][C:26]3=[O:25])[CH2:33][CH2:34]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: CN1C(=O)c2cc(O)ccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Product: CN1C(=O)c2cc(O)ccc2C1C(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 122.7 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(5-hydroxy-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.23 g) was coupled to 4-(2-oxoperhydropyrimidine-1-yl)piperidine (0.136 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.220 g); mp 200°-210° C; MS: m/z=531(M+1); NMR: 1.0 (s,3), 1.99 (s,1), 2.36 (m,2), 2.7 (m,2), 3.26 (s,3),4.65 (s,1), 5.94 (d,1, J=7.7), 7.18-7.41 (m,9), 7.54 (d,1, J=8.31), 7.77 (d, J=7.5). Analysis for C32H35Cl2N3O2.1.0 HCl.1.5 H2O: Calculated: C, 54.51; H, 6.09, N, 9.41; Found: C, 54.82; H, 5.78; N, 9.41.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[C:9]=2[F:11])[N:4]([CH3:16])[CH:3]=1.[OH-].[Na+]>O1CCCC1.CO.ClCCl>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[C:9]=2[F:11])[N:4]([CH3:16])[CH:3]=1
Reactant: COC(=O)c1ccc2c(c(Cl)cn2C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1cc(Cl)c2c(F)c(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The ester thus obtained was dissolved in a mixture of tetrahydrofuran (10 mL), methanol (10 mL) and dichloromethane (3 mL). 2 M sodium hydroxide (4.31 mL) was added and the mixture stirred at room temperature for 3 h. Further 2 M sodium hydroxide (4.31 mL) was added and the reaction stirred at room temperature for 16 h. The mixture was concentrated in vacuo, diluted with water and ethyl acetate added. The resultant emulsion was acidified with 1 M hydrochloric acid (pH=2-3) and extracted with ethyl acetate. The combined ethyl acetate phases were dried and concentrated to give the title compound (0.274 g) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)=[N:17][C:9]2[C@H:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:55]1[CH:59]=[C:58]([CH2:60][NH2:61])[O:57][CH:56]=1>C(Cl)Cl.CCOCC>[O:57]1[CH:56]=[CH:55][CH:59]=[C:58]1[CH2:60][NH:61][C:29]([C:28]1[CH:32]=[CH:33][C:25]([C:7]2[C:8]3[C:15](=[O:16])[N:14]4[C@H:10]([C:9]=3[N:17]=[C:18]([CH2:19][C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)[C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:12][CH2:13]4)=[CH:26][CH:27]=1)=[O:30]
Reactant: NCc1ccco1
Reactant: CCOC(=O)c1c(Cc2ccsc2)nc2c(c1-c1ccc(C(=O)O)cc1)C(=O)N1CCC[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1c(Cc2ccsc2)nc2c(c1-c1ccc(C(=O)NCc3ccco3)cc1)C(=O)N1CCC[C@@H]21
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
A stirred solution of 28 mg (0.060 mmol) of 4-[(9aS)-3-(ethoxycarbonyl)-5-oxo-2-(3-thienylmethyl)-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl]benzoic acid, 14 mg (1.2 equiv, 0.072 mmol) of EDCI and 10 mg (1.2 equiv., 0.072 mmol) of HOBT in 1 mL of DCM was treated with 13 mg (2.2 equiv., 0.133 mmol) of 2-furfurylamine. The resulting solution was stirred at room temperature for 3 h. The reaction mixture was then poured into Et2O (10 mL) and extracted with H2O (1×10 mL) and NaHCO3 (1×10 mL). The organic layer was separated, dried (MgSO4), filtered to remove solids, and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography on an Elution Solutions medium pressure chromatography system using a gradient elution of hexanes/EtOAc 1:1 to 1:4 to afford a clear golden oil. The oil was then triturated with Et2O to afford 22 mg (68%) the title compound as a light yellow solid: 1H NMR (CDCl3, 400 MHz) δ 7.78 (d, 2H, J=7.9), 7.40 (d, 2H, J=7.9), 7.35 (s, 1H), 7.19 (m, 1H), 7.02 (s, 1H), 6.97 (d, 1H, J=4.8), 6.47 (m, 1H), 6.29 (d, 2H, J=15.4), 4.70 (dd, 1H, J=6.3, 10.2), 4.61 (d, 2H, J=5.4), 4.33 (AB quartet, 2H, J=14.5, 41.7), 3.86 (q, 2H, J=6.9), 3.65 (m, 1H), 2.47 (m, 1H), 2.30 (m, 2H), 1.41 (m, 1H), 1.22 (m, 2H), 1.18 (t, 3H, J=6.9); low resolution MS (ES+) m/e 543, (MH+1), 542 (MH+); TLC (hexanes/EtOAc (1:5)): Rf=0.25; HPLC (Dynamax RP-18, 4.6 mm×25 cm; 50–100% CH3CN/H2O with 0.1% TFA; 25 minutes; 1 mL/min): tR=7.73 min, 97% purity; Anal. (C30H27N3O5S) Calc. C, 66.53; H, 5.02; N, 7.76. Found C, 66.26; H, 4.87; N, 7.96.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[C:4]([CH3:23])[CH:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([C@H:34]2[CH2:39][CH2:38][C@H:37]([C:40]([OH:42])=O)[CH2:36][CH2:35]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1.O.[CH3:44]N(C)C=O>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH:34]2[CH2:39][CH2:38][CH:37]([C:40]([N:1]([CH3:44])[C:2]3[CH:7]=[CH:6][C:5]([CH2:8][N:9]4[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C@@H:11]([CH3:22])[CH2:10]4)=[C:4]([CH3:23])[CH:3]=3)=[O:42])[CH2:36][CH2:35]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: O=C(O)[C@H]1CC[C@H](S(=O)(=O)c2ccc(Cl)cc2)CC1
Reactant: CN(C)C=O
Reactant: Cc1cc(N)ccc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Solvent: O
Product: Cc1cc(N(C)C(=O)C2CCC(S(=O)(=O)c3ccc(Cl)cc3)CC2)ccc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Reaction time: 20 h
Yield: 45 %

Procedure:
To a solution of tert-butyl (2S)-4-[(4-amino-2-methylphenyl)methyl]-2-methylpiperazine-1-carboxylate (90.6 mg, 0.30 mmol), which is a known compound, and trans-4-[(4-chlorophenyl)sulfonyl]cyclohexanecarboxylic acid (100 mg, 0.30 mmol) synthesized in (10C) in N,N-dimethylformamide (8 mL), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholium chloride hydrate (106 mg, 0.36 mmol) was added at room temperature, and then, the resulting mixture was stirred at the same temperature for 20 hours. Then, to the reaction solution, water was added, and extraction was performed once with ethyl acetate. The obtained organic layer was washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20 to 50:50 (v/v)), whereby the title compound was obtained as an oil (80.2 mg, yield: 45%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35].O>CN(C=O)C>[CH2:17]([NH:16][C:11]1=[N:12][C:13](=[O:15])[S:14]/[C:10]/1=[CH:9]\[CH:6]1[CH2:7][CH2:8][N:3]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:35])([F:36])[F:37])[CH2:4][CH2:5]1)[C:18]#[CH:19]
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added potassium carbonate (345 mg) and 1-(bromomethyl)-2-(trifluoromethyl)benzene (0.09 mL). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (120 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C@@H:21]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=2)=[O:26])[CH2:20][C@@H:19]1[C:36](O)=[O:37])=[O:17])([CH3:14])([CH3:13])[CH3:12].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=1[NH:10][C:36]([C@H:19]1[CH2:20][C@H:21]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=2)=[O:26])[CH2:22][CH2:23][N:18]1[C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])=[O:37]
Reactant: Cc1cc(N)c(N)cc1C
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc(C#N)cc2)C[C@@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N)c(NC(=O)[C@H]2C[C@H](NC(=O)Nc3ccc(C#N)cc3)CCN2C(=O)OC(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
4,5-dimethylbenzene-1,2-diamine (39 mg, 0.286 mmol) was added to a mixture of (2R,4R)-1-(tert-butoxycarbonyl)-4-(3-(4-cyanophenyl)ureido)piperidine-2-carboxylic acid (100 mg, 0.258 mmol), BOP (120 mg, 0.27 mmol) and DIEA (0.09 mL, 0.52 mmol) in DMF (1 mL), and the resulting solution was stirred at room temperature for 8 hours. Water (10 mL) was added to the reaction mixture and then extracted with ethyl acetate (2×20 mL). The organic layers were dried over MgSO4 and concentrated to give a red solid. Purification was done by Companion (ReadySep, 12 g, silica gel packed) with ethyl acetate/heptane from 50-80% to give the title compound as a white solid 104 mg (80%). LC-MS: 507.3, 505.4 (t=2.4 min).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([NH:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[N:13][C:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][C:27]3[C:32]([F:33])=[CH:31][C:30]([O:34][CH2:35][CH3:36])=[CH:29][C:28]=3[F:37])[N:18]=2)=[N:15][CH:16]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+].ClCCl.C(O)(C)C>ClCCl>[NH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([NH:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[N:13][C:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][C:27]3[C:28]([F:37])=[CH:29][C:30]([O:34][CH2:35][CH3:36])=[CH:31][C:32]=3[F:33])[N:18]=2)=[N:15][CH:16]=1
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCNC(=O)OC(C)(C)C)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCN)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Temperature: 25 °C

Procedure:
28.6 mg of tert-butyl[2-({2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-yl}oxy)ethyl]carbamate (4-23, 0.046 mmol, 1.0 eq.) were dissolved in 2 ml of dry dichloromethane. 0.071 ml of trifluoroacetic acid (0.926 mmol, 20.0 eq.) were added at 0° C. The reaction mixture was stirred over night at room temperature. Then a mixture 2 N sodium carbonate and dichloromethane/isopropanol 4:1 was added and the mixture was stirred for 30 min. The phases were separated and the aqueous layer (slightly brown) was extracted twice with dichloromethane/isopropanol 4:1. The combined organic layers were dried over a magnesium sulfate and concentrated in vacuo. The residue was purified by crystallization from ethylacetate to yield 6.8 mg (0.01 mmol, 27.0%) of the analytically pure target compound.