Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19]#[N:20])[CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=[O:34].[K+].[K+].OO>CS(C)=O.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19]([NH2:20])=[O:34])[CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(OCc2ccccc2)cc2c(NCc3ccc(C(F)(F)F)cc3)ncnc12
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cc(OCc2ccccc2)cc2c(NCc3ccc(C(F)(F)F)cc3)ncnc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
To a solution of the 6-Benzyloxy-4-(4-trifluoromethyl-benzylamino)-quinazoline-8-carbonitrile (380 mg, 1 eq) in DMSO (20 mL) was added 10 wt % aqueous K2CO3 (6.68 mL, 5 eq) followed by 33% H2O2 (790 □L, 8 eq) at room temperature. The resulting light suspension was stirred for 12 h at room temperature and then diluted with water (˜20-40 mL). A white precipitate formed that was collected by filtration (crop A). The filtrate was then extracted with ethyl acetate (3×25 mL) and the combined organic layers were dried over sodium sulfate, concentrated to an oil and columned (50 to 90% ethyl acetate/heptane) to afford an off-white solid (crop B). The two crops of carboxamide product (A+B, each ˜90% pure by HPLC) were then combined in a 20 mL vial and triturated with minimal dichloromethane followed by ether. Trituration afforded a white solid (342.6 mg, 86%) LCMS (ESI) 453 (M+H)
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[C:6]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][C@@H:16]([CH3:20])[CH2:15]1)=[CH:10][C:9]2=[O:21])[CH3:3].[F:27][C:28]1[CH:29]=[C:30]([CH:32]=[C:33]([F:35])[CH:34]=1)[NH2:31]>CC(N(C)C)=O.C(OCC)(=O)C>[F:27][C:28]1[CH:29]=[C:30]([NH:31][CH:2]([C:4]2[CH:5]=[C:6]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][C@@H:16]([CH3:20])[CH2:15]2)=[CH:10][C:9]3=[O:21])[CH3:3])[CH:32]=[C:33]([F:35])[CH:34]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@@H](C)C3)oc12
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@@H](C)C3)oc12
Yield: 59.7 %

Procedure:
A solution of 8-(1-bromoethyl)-N,N-dimethyl-2-((S)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (670 mg, 1.42 mmol) and 3,5-difluoroaniline (736 mg, 5.70 mmol) in DMA (4 mL) were stirred at 50° C. for 4 hrs then at rt over the weekend. The reaction mixture was diluted with ethyl acetate, washed with a sat. aq. sol. of sodium hydrogenocarbonate, water brine, dried over magnesium sulfate and concentrated to afford the crude product, which was purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness and the obtained foam was triturated with diethyl ether to give a white solid which was collected by filtration and dried under vacuum to give 8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-((S)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (400 mg, 60%). Mass Spectrum: M+H+ 472. NMR Spectrum (CDCl3): 1.25 (d, 3H), 1.61 (d partially hidden by H2O, 3H), 2.83 (ddd, 1H), 2.90 (bs, 3H), 3.08 (bs, 3H), 3.18 (dddd, 1H), 3.63-3.82 (m, 4H), 4.02 (ddd, 1H), 4.37 (bs, 1H), 4.88-4.97 (m, 1H), 5.55 (s, 1H), 5.97 (d, 2H), 6.13 (t, 1H), 7.72 (d, 1H), 8.12 (d, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[N-:16]=[N+:17]=[N-:18].[Na+]>CS(C)=O>[CH3:15][O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:16]=[N+:17]=[N-:18]
Reactant: COC(=O)CCCCCCCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)CCCCCCCCCCN=[N+]=[N-]
Temperature: 66 °C
Yield: 97.4 %

Procedure:
A mixture of 13.3 g of methyl 11-bromoundecanoate and 3.12 g of sodium azide in 50 mL of DMSO was heated at 66° C. under nitrogen for 2 days. The reaction mixture was cooled down and mixed with 200 mL of ice water. The aqueous layer was extracted with ether (1×100 mL, subsequently 3×50 mL). The organic layers were combined, washed twice with 25 mL of brine and dried over Na2SO4. Removal of the solvents in vacuo gave 11.2 g of a yellow oil. Purification by column chromatography (silica gel; petroleum ether (40-60° C.)/ether=9:1 (v/v)) gave 10.94 g of the pure product as a colorless oil, which was stored at 4° C. to prevent degradation. 1H NMR (300 MHz, CDCl3): δ 3.65 (s, 3H); 3.24 (t, 2H, J=7.0 Hz); 2.29 (t, 2H, J=7.5 Hz); 1.65-1.53 (m, 2H); 1.42-1.21 (m, 14H) ppm. 13C NMR (75 MHz, CDCl3): δ 174.24; 51.44; 51.37; 34.04; 29.35; 29.27; 29.15; 29.07; 28.80; 26.66; 24.89 ppm. IR (neat, cm−1): 2929 (m); 2856 (m); 2096 (s); 1741 (s).
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][C:3]=2[O:2]1.[C:12]([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[C:12]([NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:6][C:5]2[CH:8]=[CH:9][C:10]3[O:11][CH2:1][O:2][C:3]=3[CH:4]=2)[CH2:23][CH2:22]1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C(NC1CCN(Cc2ccc3c(c2)OCO3)CC1)c1ccccc1
Reaction time: 3 h

Procedure:
3,4-Methylenedioxybenzyl chloride (5.76 g.), 4-benzamido-piperidine (6.89 g.) and anhydrous potassium carbonate (7.00 g.) were stirred at room temperature for 5 hours in isopropanol (50 ml.). Additional isopropanol (100 ml.) was added and stirring continued for 3 hours. The mixture was then heated to the boiling point and filtered whilst hot. Filtration provided the title compound as the hemi-hydrate (7.94 g.), m.p. 179.5°-180.5° C. A second crop (1.23 g.) was obtained on concentration of the mother liquors. (Found: C, 69.2; H, 6.55; N, 8.2. C20H22N2O3. 1/2H2O requires C, 69.15; H, 6.7;N, 8.1%).
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3].[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1Cl)=[O:12]>C(O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11](=[O:12])[CH2:10][CH:4]([C:2]#[N:3])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1ccc(F)cc1Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C#N)CC(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 86.7 g of sodium in 4,500 ml of anhydrous ethanol is added at 15° C. to a solution of 528 g of ethyl cyanoacetate in 500 ml of anhydrous ethanol. After one hour, the mixture is cooled to 0° C. and a solution of 620 g of 2-chloro-4-fluoroacetophenone in one liter of ethanol is added to the solution obtained. The reaction mixture is left for 12 hours at room temperature, then hydrolyzed with 200 ml of water and concentrated. The residue is taken up in one liter of water and this aqueous phase is neutralized to pH 7 and extracted with dichloromethane, followed by concentration.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.O.[CH:12]([CH:14]=O)=[O:13]>C(O)(=O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[N:10]=[CH:14]/[CH:12]=[O:13])=[CH:5][CH:4]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=CC=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C/C=N/Nc1ccc(F)cc1
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A mixture of 1-(4-fluorophenyl)hydrazine hydrochloride (5.0 g, 30.75 mmol), water (20 mL), and acetic acid (20 mL) was added with stirring to a 40% aqueous solution of glyoxal (17.6 mL, 153.8 mmol) over 20 minutes. Stirring was continued for 2 hours and the mixture was then filtered. The precipitate washed with water and dried to afford 5.0 g (98%) of the desired product. 1H NMR (400 MHz, CDCl3) δ 9.56 (d, 1H), 8.63 (br s, 1H), 7.24 (m, 1H), 7.16 (m, 2H), 7.06 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −120.3. LRMS (ESI pos) m/e 151.1 (M−16).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1.[F:29][CH:30]([F:42])[O:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:41])=[C:36]([CH:40]=1)[C:37](O)=[O:38]>>[F:29][CH:30]([F:42])[O:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:41])=[C:36]([C:37]([N:23]2[CH2:24][CH2:25][CH:20]([N:18]3[C:17](=[O:26])[C:16]([CH3:28])([CH3:27])[C:15]([C:7]4[C:8]5[CH2:9][C:10]([CH3:14])([CH3:13])[O:11][C:12]=5[C:4]([O:3][CH3:2])=[CH:5][CH:6]=4)=[N:19]3)[CH2:21][CH2:22]2)=[O:38])[CH:40]=1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Reactant: Cc1ccc(OC(F)F)cc1C(=O)O
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OC(F)F)ccc4C)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B5) and 5-(difluoromethoxy)-2-methylbenzoic acid (compound F4) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:34]>>[NH2:34][C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1ncccc1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 150 °C
Yield: 98 %

Procedure:
A mixture of 8-(2-chloro-pyridine-3-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (example 188, 40 mg, 0.08 mmol) and ammonium hydroxide (2M solution in water, 8 mL) was heated in an autoclave at 150° C. for 16 h. The reaction mixture was concentrated in vacuo to give a crude residue which was purified by flash column chromatography (5% methanol in chloroform) to yield the desired product as a white solid (36 mg, 98%). MS (ESI): 471.2 (MH+).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.COC1C=C([Br:30])C=CC=1C=O>>[Br:30][C:3]1[CH:2]=[CH:7][C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([O:18][CH3:19])[CH:4]=1
Reactant: COc1cc(Br)ccc1C=O
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Product: COc1cc(Br)ccc1C(O)C#Cc1ccccc1
Yield: 96 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2-methoxy-4-bromobenzaldehyde was reacted to give the title compound as a pale yellow oil (1.43 g, 96%). LCMS (Method B): RT=4.53 min, [M+H]+=299/301.
Reaction SMILES: C([O:4][C:5](=O)[CH2:6][N:7]1[C:11]2[C:12]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=2[N:9]=[C:8]1[NH:22][C:23]1[C:28]([CH3:29])=[CH:27][C:26]([Cl:30])=[CH:25][C:24]=1[O:31][CH3:32])(C)C.[BH4-].[Li+]>O1CCCC1.O>[Cl:16][C:15]1[C:10]2[N:9]=[C:8]([NH:22][C:23]3[C:28]([CH3:29])=[CH:27][C:26]([Cl:30])=[CH:25][C:24]=3[O:31][CH3:32])[N:7]([CH2:6][CH2:5][OH:4])[C:11]=2[C:12]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:14]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3OC)n(CC(=O)OC(C)C)c12
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3OC)n(CCO)c12
Yield: 62.3 %

Procedure:
To a solution of isopropyl[4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]acetate (453 mg, 0.920 mmol) in tetrahydrofuran (5 mL) was added lithium tetrahydroborate (60 mg, 2.76 mmol), and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (X2). The combined organic layer was washed with brine (X1), dried over sodium sulfate and concentrated in vacuo. The residual solid was recrystallized with ethyl acetate-n-hexane to give 250 mg (0.573 mmol, 62.3%) of the title compound as a colorless crystal. The filtrate was concentrated in vacuo, and the residual solid was recrystallized with ethyl acetate-hexane to give 91 mg (0.209 mmol, 22.7%) of the title compound as a colorless crystal.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:14]([CH:20]=[C:21]([CH2:27][CH3:28])[C:22]([O:24]CC)=[O:23])[O:13][C:12]1([CH3:30])[CH3:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>C(O)C.O.[OH-].[K+]>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:14]([CH:20]=[C:21]([CH2:27][CH3:28])[C:22]([OH:24])=[O:23])[O:13][C:12]1([CH3:30])[CH3:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)CC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
517 mg of ethyl 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-ethyl-2-propenoate was dissolved in 3.10 ml of an ethanol/water (9/1) solution of 2N potassium hydroxide, and the solution was stirred at room temperature for 3 hours. Then, the reaction solution was adjusted to pH2 with 1N hydrochloric acid under cooling with ice and after an addition of 24 ml of water, extracted three times with 20 ml of ethyl acetate. The organic layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-ethyl-2-propenoic acid as colorless oily substance.
Reaction SMILES: [C:1]1([S:7]([CH:9](Cl)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.[Na].[CH3:21][SH:22]>C(Cl)Cl>[C:1]1([S:7]([CH:9]([S:22][CH3:21])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(c1ccccc1)C(Cl)c1ccccc1
Reactant: CS
Agent: [Na]
Solvent: ClCCl
Solvent: CC#N
Product: CSC(c1ccccc1)S(=O)c1ccccc1
Yield: 82.6 %

Procedure:
220 mg of (alpha-chlorobenzyl) phenyl sulfoxide was dissolved in 5 ml. of acetonitrile, and with addition of 3 ml. of a 20% aqueous solution of sodium salt of methyl mercaptan, the mixture was stirred for four days at room temperature. Methylene chloride (50 ml.) was added, and the product was dried with anhydrous sodium sulfate. The solvent was removed at reduced pressure. The product was separated by column-chromatography (silica gel, chloroform). There was obtained (alpha-methylthiobenzyl) phenyl sulfoxide as colorless crystals having a melting point of 104° - 105° C. in a yield of 82.6%.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH2:12]([O:14][C:15](=[O:29])[C:16]([C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:17]OCC)[CH3:13]>C1(C)C=CC=CC=1>[CH2:12]([O:14][C:15](=[O:29])[C:16]([C:21](=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[CH:17][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[C:2]([F:10])([F:11])[F:1])[CH3:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1ccccc1
Reactant: Nc1ccccc1C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccccc1C(F)(F)F)C(=O)c1ccccc1
Reaction time: 18 h
Yield: 82.2 %

Procedure:
A mixture of 2-(trifluoromethyl)aniline(4.6 g, 28.8 mmol) and 2-benzoyl-3-ethoxy-acrylic acid ethyl ester 7.2 g, 28.8 mmol) in toluene (125 ml) was heated to reflux. After 18 hr, the reaction was cooled, concentrated and purified by column chromatography (eluent 10% EtOAc/hexane) to give 2-benzoyl-3-(2-trifluoromethyl-phenylamino)-acrylic acid ethyl ester (8.6 g, Yield=82%); MS (ESI) m/z 364(M+H)+; Anal Calcd for C19H16F3NO3: C, 62.81; H, 4.44; N, 3.85. Found: C, 62.87; H, 4.21; N, 3.76.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH2:30])[CH2:24][N:25]2[CH2:28][CH:27]([OH:29])[CH2:26]2)=[CH:19][C:18]=1[C:31]([F:34])([F:33])[F:32]>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH:30][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:24][N:25]2[CH2:26][CH:27]([OH:29])[CH2:28]2)=[CH:19][C:18]=1[C:31]([F:34])([F:32])[F:33]
Reactant: N[C@H](CN1CC(O)C1)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: NC(=O)c1ccnc2c(N[C@H](CN3CC(O)C3)c3ccc(Cl)c(C(F)(F)F)c3)ncnc12

Procedure:
Compound 70 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-1-(4-chloro-3-trifluoromethyl-phenyl)-2-(3-hydroxy-azetidin-1-yl)-ethylamine hydrochloride to give the title compound. LC/MS [467 (M+H)].
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[C:16]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cc(I)ccn1
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
Product: CC(C)(C)OC(=O)Nc1cc(-c2ccccc2)ccn1

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (340 mg, 0.29 mmol, 0.050 equiv) was added to a deoxygenated mixture of tert-butyl 4-iodopyridin-2-ylcarbamate (1-1, 1.87 g, 5.84 mmol, 1 equiv), phenyl boronic acid (1.07 g, 8.76 mmol, 1.50 equiv), and aqueous saturated sodium carbonate solution (2.0 M, 8.8 mL, 18 mmol, 3.0 equiv) in dioxane (50 mL), and the resulting mixture was heated at reflux for 18 h. The reaction mixture was cooled then concentrated. The residue was partitioned between half-saturated aqueous NaCl solution (100 mL) and EtOAc (100 mL). The organic layer was dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography (dichloromethane, initially, grading to 40% EtOAc in dichloromethane) to give tert-butyl 4-phenylpyridin-2-ylcarbamate (1-2) as an off-white solid. LRMS m/z (M+H) Calcd: 214.3 (minus t-Bu), 171.3 (minus Boc); found 215.0 and 171.0.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39](O)=[O:40])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:52])([CH2:50][OH:51])[CH2:48][OH:49].[Cl-].[NH4+]>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39](=[O:40])[NH:46][C:47]([CH2:50][OH:51])([CH3:52])[CH2:48][OH:49])=[CH:33][C:32]=3[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(N)(CO)CO
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1cc(/C=C/C(=O)NC(C)(CO)CO)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 26 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-2-carboxyvinyl]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1,3-propanediol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and ammonium chloride, respectively.
Reaction SMILES: COC1C=CC(C[CH:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20](=[O:36])[C@H:21]([CH:33]([CH3:35])[CH3:34])[NH:22][C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:15]([O:37][C:38](=[O:54])[C@H:39]([CH:51]([CH3:53])[CH3:52])[NH:40][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])[CH:14]=2)[C:9]([O-:11])=[O:10])=CC=1.C(O)(C(F)(F)F)=O>ClCCl>[C:41]([NH:40][C@H:39]([C:38]([O:37][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[O:19][C:20](=[O:36])[C@H:21]([CH:33]([CH3:35])[CH3:34])[NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH2:12][CH2:8][C:9]([OH:11])=[O:10])=[O:54])[CH:51]([CH3:52])[CH3:53])([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42]
Reactant: COc1ccc(CC(Cc2ccc(OC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)c(OC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)c2)C(=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc(CCC(=O)O)cc1OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Yield: 79.4 %

Procedure:
4-Methoxybenzyl-3,4-di-(N-CBZ-L-valyloxy)hydrocinnamate (10 g, 13 mmol) was dissolved in dichloromethane and 1,1,1 trifluoroacetic acid (30 ml) and left at ambient temperature for 3.5 h. Evaporation under reduced pressure and purification by chromatography (chloroform-methanol, 10:1) yielded 6.7 g (80%) pure title product. The compound can be activated and esterified to a drug or further modifiedas described below.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.Cl.Cl.[N:52]1([CH2:56][CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:55][CH2:54][CH2:53]1>CN(C)C=O>[N:52]1([CH2:56][CH:57]2[CH2:62][CH2:61][N:60]([C:13]([NH:12][C:8]3[CH:7]=[C:6]([O:5][C:4]4[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]5([C:40]([NH:41][C:42]6[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=6)=[O:49])[CH2:39][CH2:38]5)=[O:36])=[C:2]([F:1])[CH:3]=4)[CH:11]=[CH:10][N:9]=3)=[O:14])[CH2:59][CH2:58]2)[CH2:55][CH2:54][CH2:53]1
Reactant: C1CN(CC2CCNCC2)C1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CCC(CN2CCC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.1 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (2.0 ml) was added 4-(azetidin-1-ylmethyl)piperidine dihydrochloride (85.2 mg), followed by stirring at room temperature for 16 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (21.9 mg, 48.3%).