Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:27]=[CH:28][CH:29]=1
Reactant: COc1cccc(N)c1
Reactant: COc1cc2c(=O)[nH]c3nccc(Cl)c3c2cc1OC
Product: COc1cccc(Nc2ccnc3[nH]c(=O)c4cc(OC)c(OC)cc4c23)c1
Yield: 6.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 212 using Compound 211 (50 mg, 0.17 mmol) and 3-methoxyaniline (27 mg, 0.22 mmol) to provide 214 (4 mg, 6% yield) as a white solid. LC-MS (M+H=378, obsd.=378).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:16]=[CH:17][C:10]=2[N:9]([CH3:33])[C:8]1=[O:34])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:34])[N:9]([CH3:33])[C:10]=3[CH:17]=[N:16][C:15]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:31][CH:30]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ncc21
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ncc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-6-(4-chlorophenyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate (16 mg, 0.032 mmol) in THF (0.5 mL) and H2O (0.5 mL) was added LiOH.H2O (2.7 mg, 0.064 mmol). The reaction was stirred at RT for 0.5 h then diluted with EA (5 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-6-(4-chlorophenyl)-3-(3-hydroxypropyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (6 mg, 80%) as a white solid. 1H NMR (CDCl3) δ: 8.79 (s, 1H), 7.42-7.33 (m, 2H), 7.28 (d, J=1.9 Hz, 1H), 7.26 (s, 1H), 7.17 (d, J=8.4 Hz, 2H), 6.80 (d, J=8.4 Hz, 2H), 4.64 (s, 2H), 4.17 (t, J=6.2 Hz, 2H), 3.74 (s, 3H), 3.46 (dd, J=11.5, 5.9 Hz, 2H), 2.70 (t, J=6.7 Hz, 1H), 1.96-1.71 (m, 2H). LCMS: MH+ 470 and TR=2.924 min.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C(N(CC)C(C)C)(C)C.[N:19]([CH2:22][C:23]([O:25]CC)=[O:24])=[C:20]=[O:21]>ClCCl.CN(C=O)C>[OH:6][C:5]1[NH:4][C:2](=[O:3])[NH:1][C:8](=[O:9])[C:7]=1[C:20]([NH:19][CH2:22][C:23]([OH:25])=[O:24])=[O:21]
Reactant: CCOC(=O)CN=C=O
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1c(O)[nH]c(=O)[nH]c1=O
Reaction time: 8 h
Yield: 22 %

Procedure:
Barbituric acid (512 mg, 4 mmol) was dissolved in a mixture of dichloromethane (3 mL) and DMF (5 mL). N,N-Diisopropylethylamine (2 mL) was added followed by ethyl isocyanatoacetate (645 mg, 5 mmol) and the solution was stirred overnight. After evaporation of all volatiles, the residue was re-dissolved in a mixture of ethanol (5 mL) and 1M aqueous NaOH (5 mL). After stirring at room temperature for one hour, this solution was neutralized by addition of 1M aqueous HCl. The resulting solid was collected, washed with water, and dried under vacuum overnight to give the title compound (202 mg, 22%). LC/MS m/z 230 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[C:15]3[S:19][C:18](SC)=[N:17][C:16]3=[O:22])[CH:12]=2)[N:7]=[CH:6][CH:5]=1)[CH3:2].[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH2:34])[CH3:24].CCN(C(C)C)C(C)C>>[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH:34][C:18]1[S:19]/[C:15](=[CH:14]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][CH:5]=[C:4]3[O:3][CH2:1][CH3:2])/[C:16](=[O:22])[N:17]=1)[CH3:24]
Reactant: CCOc1ccnc2ccc(C=C3SC(SC)=NC3=O)cc12
Reactant: CCOc1ccccc1CCN
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccccc1CCNC1=NC(=O)/C(=C/c2ccc3nccc(OCC)c3c2)S1

Procedure:
Similar procedure as described in example 40c was used, starting from 5-(4-ethoxy-quinolin-6-ylmethylene)-2-methylsulfanyl-thiazol-4-one (example 40b), 2-(2-ethoxy-phenyl)-ethylamine and DIEA to give 2-[2-(2-ethoxy-phenyl)-ethylamino]-5-[1-(4-ethoxy-quinolin-6-yl)-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 448 (MH+).
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([CH3:32])=[C:12]([C:19](=[O:31])[C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([O:29][CH3:30])[CH:21]=2)[N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2)(=O)C.O.C(OCC)(=O)C>O1CCOCC1>[OH:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([CH3:32])=[C:12]([C:19]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([O:29][CH3:30])[CH:21]=2)=[O:31])[N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2
Reactant: COc1cc(C(=O)c2c(C)c(OCCOC(C)=O)c3ccccn23)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(C(=O)c2c(C)c(OCCO)c3ccccn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
1.52 ml of 1 N sodium hydroxide are added to 420 mg (1.02 mmol) of 2-{[3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-1-yl]oxy}ethyl acetate, a compound of Example 79, dissolved in 6 ml of dioxane, and the medium is stirred at room temperature for 6 hours. The reaction medium is poured over water and ethyl acetate. The organic phase is separated after settling out, washed with water, dried over sodium sulphate and concentrated under reduced pressure. 340 mg of an orange-coloured powder are obtained, which powder is used without further purification in the subsequent nitro reduction step.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][N:9]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:8]([C:28]([O:30][CH3:31])=[O:29])[CH2:7]1)=O.B.CO>O1CCCC1>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([N:9]2[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:6]([CH2:4][CH2:3][O:2][CH3:1])[CH2:7][CH:8]2[C:28]([O:30][CH3:31])=[O:29])(=[O:18])=[O:19])=[CH:21][CH:22]=1
Reactant: COCC(=O)N1CC(C(=O)OC)N(S(=O)(=O)c2ccc(OC)cc2)Cc2ccccc21
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: COCCN1CC(C(=O)OC)N(S(=O)(=O)c2ccc(OC)cc2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A mixture of 1.6 g (3.57 mmol) of methyl 1-(methoxyacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate and 32 ml of borane in tetrahydrofuran (1.0 M) was refluxed under nitrogen overnight. Methanol was added and the solvent removed. To the residue was added 25 ml of CH2Cl2 and 25 ml of 2 N HCl and the mixture stirred at room temperature for 1 hour. The organic layer was separated and washed with H2O and concentrated to dryness. The residue was triturated with ethyl acetate-hexane, cooled and filtered to give 1.2 g of white crystals, m.p. 86°-90° C.; Mass spectrum (ES) 435.4 (M+H). Anal. for C21H26N2O6S: Calc'd: C, 58.1; H, 6.0; N, 6.5; Found: C, 58.5; H, 6.0; N, 6.5.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]2[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:3].[NH2:23][C:24]1[C:29]([C:30]#[N:31])=[C:28](Cl)[N:27]=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:23][C:24]1[N:25]=[CH:26][N:27]=[C:28]([NH:1][C@H:2]([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]3[C:16]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:3])[C:29]=1[C:30]#[N:31]
Reactant: COC(=O)c1cccc2nc([C@H](C)N)c(-c3ccccc3)n12
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3C#N)c(-c3ccccc3)n12
Temperature: 110 °C
Reaction time: 5.5 h

Procedure:
To the crude (S)-methyl 2-(1-aminoethyl)-3-phenylimidazo[1,2-a]pyridine-5-carboxylate (500 mg, 1.69 mmol) and 4-amino-6-chloro-pyrimidine-5-carbonitrile (268 mg, 1.69 mmol) in n-butanol (5 mL) was added DIEA (0.5 mL, 2.54 mmol) at 25° C. The reaction mixture was stirred at 110° C. for 5-6 h. The mixture was extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography using silica gel (100-200 mesh) and 0-40% acetone in hexane to provide (S)-methyl 2-[1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl]-3-phenylimidazo-[1,2-a]pyridine-5-carboxylate: 1H NMR (400 MHz, DMSO-d6) δ 1.471 (d, J=6.8 Hz, 3H), 3.111 (s, 3H), 5.352-5.420 (m, 1H), 6.935-6.954 (m, 1H), 7.259-7.518 (m, 9H), 7.882-7.941 (m, 2H); LC-MS (ESI) m/z 414.1 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:22][C:23]1[C:24]2[C:29]([CH:30]=[C:31]3[C:36]=1[CH:35]=[CH:34][CH:33]=[CH:32]3)=[CH:28][CH:27]=[CH:26][CH:25]=2>>[CH:25]1[C:24]2[C:29](=[CH:30][C:31]3[C:36]([C:23]=2[CH2:22][N:8]2[C:9]([S:10][C:11]4[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=4)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1c2ccccc2cc2ccccc12
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2c3ccccc3cc3ccccc23)c1
Yield: 44.7 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 9-chloromethyl anthracene were reacted by the same way with the example 1 to obtain the titled compound (215 mg, yield: 44.7%).
Reaction SMILES: O(Cl)Cl.[Zr:4].Cl.[P:6](=[O:10])([OH:9])([OH:8])[OH:7]>O>[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[Zr+4:4].[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[Zr+4:4].[Zr+4:4]
Reactant: [Zr]
Reactant: O=P(O)(O)O
Agent: Cl
Agent: ClOCl
Solvent: O
Product: O=P([O-])([O-])[O-]
Product: [Zr+4]
Reaction time: 0.33 h

Procedure:
Three hundred and twenty-two (322) g of zirconium oxychloride (ZrOCl2.8H2O) is dissolved in 4 liter of water, and to this solution is added 200 g of concentrated hydrochloric acid. To the resulting acidic solution is added further aqueous solution consisting of 250 g of 98% phosphoric acid and 5 liter of water, and, after stirred for about 20 minutes, the solution is left overnight. Precipitates of zirconium phosphate formed in the solution are centrifuged, washed with water sufficiently and dried at about 80° C. The solid matter obtained is put again in a water to be broken, and the resulting precipitates in the water are centrifuged, dried and sieved to prepare the desired compound particles of 24-32 meshes.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:18]([NH2:20])[CH3:19])[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:18]([NH:20][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH3:19])[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C[C@H](N)c1cc2ccc(F)cc2nc1-c1cccnc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2ccc(F)cc2nc1-c1cccnc1

Procedure:
Prepared according to Procedure H using (1S)-1-(7-fluoro-2-(pyridin-3-yl)-quinolin-3-yl)ethanamine (0.067 g, 0.236 mmol), 6-chloropurine (0.044 g, 0.283 mmol, 1.2 eq) and DIEA (0.48 mmol, 2.0 eq) in n-butanol (3 mL). N—((S)-1-(7-fluoro-2-(pyridin-3-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=23 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.99 (s, 1 H), 8.57-8.65 (m, 2 H), 8.33 (d, J=7.83 Hz, 1 H), 8.16 (s, 1 H), 8.08 (s, 1 H), 7.85-7.96 (m, 2 H), 1.62 (d, 3 H), Mass Spectrum (ESI) m/e=402 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH2:22])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:30]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([NH:22][C:34]([CH:30]2[CH2:33][CH2:32][CH2:31]2)=[O:35])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:14][CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H](CC1CCCCC1)CN1CCN(c2ncccn2)CC1
Reactant: O=C(Cl)C1CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H](CC1CCCCC1)CN1CCN(c2ncccn2)CC1)C1CCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 0.2 g (0.66 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(pyrimidin-2-yl)-piperazin-1-yl]-ethyl}-amine and 0.18 mL (1.32 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.082 g (0.69 mmol) of cyclobutanecarboxylic acid chloride in dichloromethane (2 mL). The reaction mixture was allowed to stir under nitrogen for two hours at 0° C. and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H2O and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride salt of the title compound with ethereal HCl to yield 0.18 g (62%) as a white solid; mp=112-114° C.; MS (+) ESI m/z=386 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][OH:7])(=[O:3])[CH3:2].[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].N1C=CN=C1.O>CN(C=O)C>[C:11]([Si:8]([CH3:10])([CH3:9])[O:7][CH2:6][CH2:5][CH2:4][C:1](=[O:3])[CH3:2])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(=O)CCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 66 h
Yield: 58.6 %

Procedure:
A solution of 3-acetyl-1-propanol (3.000 g, 29.37 mmol), tert-butyldimethylsilyl chloride (4.522 g, 30.00 mmol), and imidazole (5.004 g, 73.5 mmol) in DMF (40 mL) was heated at 40° C. for 5 h and was stirred at room temperature for 66 h. Water (60 mL) was added and the product was extracted into EtOAc (4×50 mL). The combined organic extracts were washed with water (2×50 mL), dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (hexanes:EtOAc 9:1) provided the title compound (3.722 g). 1H NMR (400 MHz, CDCl3) δ 3.59 (t, 2H), 2.49 (t, 2H), 2.13 (s, 3H), 1.76 (m, 2H), 0.86 (s, 9H), 0.02 (s, 6H); MS 217 (M+1).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=[CH2:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[N+](=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N-]>>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]2[CH2:20][CH:25]2[C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)C1CC1c1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 135 °C
Yield: 50 %

Procedure:
A mixture of 2-vinylphenyl 4-(trifluoromethyl)benzenesulfonate (1.8 g, 5.5 mmol) and ethyl diazoacetate (0.70 mL, 6.7 mmol) under argon is heated at 135° C. for 90 min. The product is purified on silica gel in methylene chloride and ethyl acetate-methylene chloride mixtures. The product, ethyl 2-[2-({[4-(trifluoromethyl)phenyl]sulfonyl}oxy)phenyl]cyclopropanecarboxylate, is obtained as a mixture of isomers. A yield of 50% is obtained.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[C@@H:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:25][CH2:24][N:23]2[C:33](=[O:42])[C:34]2[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])=[CH:18][CH:17]=1.[C:43]1(=O)[CH2:47][CH2:46][CH2:45][CH2:44]1>ClC(Cl)C>[CH:43]1([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C@H:22]3[C@@H:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:25][CH2:24][N:23]3[C:33](=[O:42])[C:34]3[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=3[F:41])=[CH:18][CH:17]=2)[CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)c2c(C)cccc2F)[C@H]1c1ccc(N)cc1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCOC(=O)[C@H]1CCCN(C(=O)c2c(C)cccc2F)[C@H]1c1ccc(NC2CCCC2)cc1
Temperature: 45 °C
Yield: 90.2 %

Procedure:
Step c) NaBH(OAc)3 (14.12 g, 66.60 mmol) was added to a solution of ethyl (2R,3S)-2-(4-aminophenyl)-1-(2-fluoro-6-methylbenzoyl)piperidine-3-carboxylate (16 g, 41.65 mmol), and cyclopentanone (10.51 g, 125 mmol) in dry dichloroethane (200 mL) at rt. The reaction mixture was heated to 45° C. for 3 h, cooled to rt, quenched with saturated aqueous NaHCO3 solution, extracted with dichloromethane, dried and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, ethyl acetate/hexanes 15-40%) to afford ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)piperidine-3-carboxylate as white solid (17 g, 90%). MS: (ES) m/z 453 (M+H+).
Reaction SMILES: [CH2:1]([CH:3]([CH2:28][CH3:29])[CH:4]([NH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:2].O1CCCC1.[OH-].[Na+]>C(O)C>[CH2:28]([CH:3]([CH2:1][CH3:2])[CH:4]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:29]
Reactant: CCC(CC)C(Nc1ccc(C(=O)OC)cc1)c1oc2ccc(OC)cc2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(CC)C(Nc1ccc(C(=O)O)cc1)c1oc2ccc(OC)cc2c1C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a mixture of methyl 4-{[2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butyl]amino}benzoate (718 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5.00 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (5.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (574 mg, 83%) as a white solid.
Reaction SMILES: C(O)(=O)C.C(OC([NH:12][C:13]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:20])=[O:16])=O)(C)(C)C.[CH:38]([C:41]1[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=1)([CH3:40])[CH3:39]>CO>[NH2:12][C:13]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:45][C:44]2[CH:47]=[CH:48][C:41]([CH:38]([CH3:40])[CH3:39])=[CH:42][CH:43]=2)[CH2:25][CH2:24]1)=[O:20])=[O:16]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1C(=O)NCC(=O)NCC1CCNCC1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)c1ccc(CN2CCC(CNC(=O)CNC(=O)c3cc(OC(F)(F)F)ccc3N)CC2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Acetic acid (10 mL) was added to a mixture of 4-[[N-(2-(tert-butoxycarbonylamino)-5-(trifluoromethoxy)benzoyl)glycyl]aminomethyl]piperidine (0.050 mmol) with 4-isopropylbenzaldehyde (0.060 mmol), NaH3CN (0.15 mmol) and methanol (1.3 mL), and the resulting mixture was stirred at 60° C. for 8 hours, cooled to room temperature, then loaded onto a Varian™ SCX column and washed with methanol (10 mL). The obtained crude product was eluted with a 2 M methanol solution of NH3 (5 mL) and concentrated. A 4 M dioxane solution of HCl (2 mL) was then added to the resulting residue, and the obtained solution was stirred at room temperature overnight, concentrated and then purified by preparative TLC to provide 4-[[N-(2-amino-5-trifluoromethoxybenzoyl)glycyl]aminomethyl]-1-(4-isopropylbenzyl)piperidine (Compd. No. 1903) (6.6 mg, 26%). The purity was determined by RPLC/MS (93%). ESI/MS m/e 507 (M++H, C26H33F3N4O3).
Reaction SMILES: [CH2:1]([C@H:8]([NH:48]C(=O)OC(C)(C)C)[CH2:9][C@H:10]([OH:47])[C@@H:11]([NH:25][C:26](=[O:46])[C@@H:27]([N:32]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[N:39]=2)[C:33]1=[O:45])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:48][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][C@H:10]([OH:47])[C@@H:11]([NH:25][C:26](=[O:46])[C@@H:27]([N:32]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[N:39]=2)[C:33]1=[O:45])[C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:17][CH:18]=1
Reactant: Cc1cccc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccc(-c4ccccn4)cc3)[C@@H](O)C[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccc(-c4ccccn4)cc3)[C@@H](O)C[C@@H](N)Cc3ccccc3)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing the product from Example 132A (0.017 g, 0.023 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred at 25° C. for 1 hour, and concentrated. The residue was partitioned between ethyl acetate and saturated NaHCO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the product, which was used without further purification.
Reaction SMILES: C([Mg]Cl)(C)(C)C.[Cl:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][C:17]([OH:19])=O.COC([C:24]1[CH:35]=[CH:34][C:27]2[N:28]([CH3:33])[C:29](=[O:32])[CH2:30][O:31][C:26]=2[CH:25]=1)=O.Cl>C(OCC)C.C1COCC1.O>[Cl:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][C:17]([C:24]1[CH:35]=[CH:34][C:27]2[N:28]([CH3:33])[C:29](=[O:32])[CH2:30][O:31][C:26]=2[CH:25]=1)=[O:19]
Reactant: COC(=O)c1ccc2c(c1)OCC(=O)N2C
Reactant: COc1ccc(CC(=O)O)c(Cl)c1
Agent: CC(C)(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COc1ccc(CC(=O)c2ccc3c(c2)OCC(=O)N3C)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 1M solution of tert-butylmagnesium chloride (CAS Reg. No. 677-22-5) in diethyl ether (2.1 ml) was added to 2-chloro-4-methoxyphenylacetic acid (CAS 91367-09-8) (200 mg) in THF (5 ml). The mixture was stirred at room temperature for 30 min. A solution of 4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid methyl ester (200 mg, CAS Reg. No. 201294-27-1) in THF (3 ml) was added and the resulting mixture was stirred overnight. Aqueous HCl (25%, 0.5 ml) and water (10 ml) were added and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, 10 to 50% EtOAc/heptane) to give the title compound (100 mg) as a light yellow solid. MS (m/e)=346.1 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[CH:20]([N:23]=[C:24]=[O:25])([CH3:22])[CH3:21]>CN(C=O)C.CCOC(C)=O>[CH2:8]([O:7][C:5](=[O:6])[C:4]1[CH:10]=[CH:11][N:12]=[C:2]([NH:1][C:24]([NH:23][CH:20]([CH3:22])[CH3:21])=[O:25])[CH:3]=1)[CH3:9]
Reactant: CCOC(=O)c1ccnc(N)c1
Reactant: CC(C)N=C=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccnc(NC(=O)NC(C)C)c1
Temperature: 140 °C

Procedure:
To a solution of ethyl 2-aminoisonicotinate (500 mg, 3.01 mmol) in DMF (10 ml) is added triethylamine (1.26 ml, 9.03 mmol) and then isopropyl isocyanate (512 mg, 6.02 mmol). The reaction mixture is heated in a microwave at 140° C. for 2 hours. The reaction mixture is diluted with EtOAc, washed with water (×5), brine, dried (MgSO4) and concentrated in vacuo. Chromatography (SiO2, MeOH/DCM) affords 2-(3-Isopropyl-ureido)-isonicotinic acid ethyl ester; [M+H]+ 252