Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:40][CH2:39][CH2:38][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([NH:10][C@H:11]([C:28]([O:30]CC1C=CC=CC=1)=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[Cl:23])=[O:18])=[O:9])[CH3:7])=[O:4].[OH-].[Na+].C(Cl)(Cl)Cl.CO>CO>[N:1]1([C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[CH2:40][CH2:39][CH2:38][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([NH:10][C@H:11]([C:28]([OH:30])=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[Cl:23])=[O:18])=[O:9])[CH3:7])=[O:4]
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
At 0° C. to the solution of 135 mg (0.2 mmol) of Boc-Pro-Ala-Lys(ClZ)-OBzl in 5 ml of methanol 5 ml of the solution of NaOH in methanol (2 mol/L) were added. The reaction mixture was stirred at 0° C. for 2 h and TLC (chloroform/methanol, 15:1) indicated complete disappearance of Boc-Pro-Ala-Lys(ClZ)-OBzl. The reaction mixture was neutralized to pH 7 and evaporated at room temperature to remove methanol. The residue was acidified to pH 1–2 with hydrochloric acid (2 mol/L) to provide 100 mg (86%) of the title compound as a colorless powder.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:16]([O:30][CH2:31][CH3:32])[C:17]3[C:22]([O:23][C:24]=2[CH:25]=1)=[CH:21][C:20]([O:26][C:27](=[O:29])[CH3:28])=[CH:19][CH:18]=3)(=[O:10])[CH3:9].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl>[C:27]([O:26][C:20]1[CH:19]=[CH:18][C:17]2[C:16]([CH2:4][CH2:3][C:2]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)=[O:1])([O:30][CH2:31][CH3:32])[C:15]3[C:24]([O:23][C:22]=2[CH:21]=1)=[CH:25][C:12]([O:11][C:8](=[O:10])[CH3:9])=[CH:13][CH:14]=3)(=[O:29])[CH3:28]
Reactant: CCOC1c2ccc(OC(C)=O)cc2Oc2cc(OC(C)=O)ccc21
Reactant: OC1CCNCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC1(CCC(=O)N2CCC(O)CC2)c2ccc(OC(C)=O)cc2Oc2cc(OC(C)=O)ccc21
Yield: 104 %

Procedure:
A solution of 4-hydroxypiperidine (506 mg, 5.00 mmol, 2.5 eq, Aldrich) and 9-(2-(N-succinimidyloxy-carbonyl))ethyl)-3,6-diacetoxy-9-ethoxy-9H-xanthene, 7a (1.023 g, 2.00 mmol, prepared according to Prober, et al., EP-A 252,683) in dry dichloromethane (20 ml) was stirred for 30 min. The reaction was added to 1M aqueous potassium phosphate buffer (30 mL; pH =7) and extracted with dichloromethane (3×30 mL). The organic extracts were dried over calcium sulfate, concentrated, and dried under vacuum overnight to afford crude amide 8a (1.039 g, 104%) as an off-white foam. This material was >90% pure according to NMR and TLC and was used without further purification in the next step.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2C(=O)[N:16]([N:19]=[CH:20][CH:21](C)[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.[CH3:29][OH:30].[BH4-].[Li+].Cl>O1CCCC1.O>[CH:20]1([NH:19][N:16]2[C:29](=[O:30])[C:12]([C:4]3[NH:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[S:2](=[O:1])(=[O:28])[N:3]=3)=[C:13]([OH:27])[C:14]3[S:26][CH:25]=[CH:24][C:15]2=3)[CH2:21][CH2:22][CH2:8][CH2:7][CH2:6][CH2:11]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1NC1CCCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.06 g, 0.13 mmol) in tetrahydrofuran (4 mL) and methanol (0.011 mL, 0.26 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.10 mL, 0.2 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid a pH of approximately 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 98:2 dichloromethane/methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.35 (m, 4 H) 1.50 (m, 4 H) 1.64 (m, 3 H) 1.86 (m, 1 H) 2.56 (m, 1 H) 5.62 (d, J=2.94 Hz, 1 H) 7.12 (d, J=5.52 Hz, 1 H) 7.19 (d, J=8.09 Hz, 1 H) 7.26 (t, J=7.54 Hz, 1 H) 7.53 (m, 1 H) 7.64 (d, J=7.72 Hz, 1 H) 7.72 (d, J=5.15 Hz, 1 H) 15.92 (s, 1 H). MS (ESI−) m/z 457 (M−H)−.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@H:19]([C:28]([N:30]([CH2:40][C:41]1[C:42]2[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=2[S:44][CH:45]=1)[C@@H:31]([CH3:39])[CH:32]([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[S:44]1[CH:45]=[C:41]([CH2:40][N:30]([C@@H:31]([CH3:39])[CH:32]([O:33][CH2:34][CH3:35])[O:36][CH2:37][CH3:38])[C:28](=[O:29])[C@@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:12]([CH3:13])[NH:11][C:9](=[O:10])[NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[C:42]2[CH:49]=[CH:48][CH:47]=[CH:46][C:43]1=2
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 77 mg (0.32 mmol) was coupled with (S)-tert-butyl 3-amino-4-((benzo[b]thiophen-3-ylmethyl)((S)-1,1-diethoxypropan-2-yl)amino)-4-oxobutanoate (Compound IV-18) 100 mg (0.22 mmol) to obtain the title compound.
Reaction SMILES: [H-].[Na+].C1C=CC=CC=1.[F:9][C:10]([F:30])([F:29])[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[CH:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[C:25]([F:28])([F:27])[F:26])[OH:18].[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>CN(C)C=O>[F:28][C:25]([F:27])([F:26])[C:24]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[CH:17]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:11]=1[C:10]([F:9])([F:29])[F:30])[O:18][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: OC(c1cnccc1C(F)(F)F)c1cnccc1C(F)(F)F
Reactant: CC(C)(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OC(c1cnccc1C(F)(F)F)c1cnccc1C(F)(F)F
Temperature: 50 °C
Yield: 63.4 %

Procedure:
To a mixture of 0.029 g of sodium hydride in 20 ml of a 1:1 solution of benzene and dimethylformamide were added 0.25 grams of 1,1-bis-(4-trifluoromethylpyrid-3-yl)methanol. After the gas evolution had subsided, 0.14 grams of pivaloyl chloride were added. After stirring for an hour at 50° C., the reaction mixture was partitioned between 25 ml of water and 50 ml of ethyl ether. The ethyl ether layer was washed with water, washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 0.24 g of the crude product as a light brown semisolid. This crude material was then purified via chromatography on a silica gel column using ethyl acetate-hexane (1:3) as the eluant to afford 0.2 g of 1,1-bis-(4-trifluoromethylpyrid-3-yl)-1-trimethylacetoxymethane as a light brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15]N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[C:20](=O)[CH2:19][CH2:18]2.S(=O)(=O)(O)O>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:10]2[NH:15][C:20]3[CH:21]4[CH2:24][CH2:25][N:17]([CH2:18][C:19]=3[C:11]=2[CH:12]=[CH:13][CH:14]=1)[CH2:23][CH2:22]4)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN2CCC1CC2
Reactant: NNc1ccccc1OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: c1ccc(COc2cccc3c4c([nH]c23)C2CCN(CC2)C4)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Under nitrogen, (2-(benzyloxy)phenyl)hydrazine (214 mg, 1.0 mmol, International Publication No. WO2009001129) was mixed with the product of Example 1A (139 mg, 1.0 mmol) and sulfuric acid (0.2 mL, 3.76 mmol; J. T. Baker) in dry dioxane (10 mL). Then the mixture was heated to 80° C. and stirred for 16 hours in a sealed tube. The mixture was concentrated and basified with 1.0 M NaOH and then extracted with ethyl acetate (3×20 mL). The organic phase was concentrated and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.01-2.13 (m, 4 H), 3.01-3.13 (m, 3 H), 3.17-3.28 (m, 2 H), 4.22 (s, 2 H), 5.21 (s, 2 H), 6.66 (dd, J=7, 2 Hz, 1 H), 6.83-6.93 (m, 2 H), 7.28-7.41 (m, 3 H), 7.48-7.55 (m, 2 H); MS (DCI/NH3) m/z 319 (M+H)+.
Reaction SMILES: N1C=C[CH:3]=N1.[N:6]1([CH:11](C)[CH2:12][NH:13][C:14]([C:16]2[C:20]([Br:21])=[C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[NH:18][N:17]=2)=[O:15])[CH2:10][CH2:9]C[CH2:7]1>>[CH2:10]([N:6]([CH3:7])[CH2:11][C@H:12]([NH:13][C:14]([C:16]1[C:20]([Br:21])=[C:19]([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[NH:18][N:17]=1)=[O:15])[CH3:3])[CH3:9]
Reactant: c1cn[nH]c1
Reactant: CC(CNC(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br)N1CCCC1
Product: CCN(C)C[C@@H](C)NC(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br

Procedure:
The pyrazole acid, prepared as described in Procedure 8, was coupled with (R)—N-ethyl-N-methyl-1,2-propanediamine (prepared as shown in Procedure 2) using the method of Procedure 3.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:21])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:8]=1.[Br:22]N1C(=O)CCC1=O>C1COCC1>[Br:22][C:4]1[NH:3][C:2]([CH3:1])=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:8]=2)[C:5]=1[CH3:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c[nH]c(C)c1-c1ccnc(Nc2ccc(F)cc2)n1
Solvent: C1CCOC1
Product: Cc1[nH]c(Br)c(C)c1-c1ccnc(Nc2ccc(F)cc2)n1
Temperature: -50 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine (80 mg, 0.28 mmol) was dissolved in THF (4 mL) and cooled to −50° C. N-Bromosuccinimide (55 mg, 0.31 mmol) was dissolved in THF (2 mL) and added dropwise, keeping the internal temperature ≦−40° C. The mixture was stirred for 1 h with cooling then evaporated in vacuo. The residue was treated with H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extractss were washed (brine), dried (MgSO4), filtered, and evaporated in vacuo. The crude product was purified by SiO2 chromatography heptane/EtOAc gradient elution) to afford the title compound (19 mg) as an orange solid after recrystallisation from iPr2O. M.p. 181.4–183.3° C. MS: [M+H]+=362.9 (C16H14BrFN4 requires 361.2). 1H-NMR (CDCl3) δ: 2.10 (s, 3H, CH3), 2.36 (s, 3H, CH3) 6.56 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 6.97 (t, 2H, J=8.3 Hz, Ph-H), 7.00 (br. s, 1H, NH), 7.79–7.52 (m, 2H, Ph-H), 8.85 (br. s, 1H, NH), 8.26 (d, 1H, J=5.1 Hz, pyrimidinyl-H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([CH:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)[CH:5]=[C:4]([C:28]2[C:33]([OH:34])=[CH:32][CH:31]=[CH:30][C:29]=2[O:35][CH2:36][CH:37]2[CH2:39][CH2:38]2)[N:3]=1.C(N(CC)CC)C.Cl[C:48](Cl)([O:50]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[C:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][CH:15]([C:6]2[C:7]3[CH2:8][N:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:48](=[O:50])[NH:1][C:2]=3[N:3]=[C:4]([C:28]3[C:33]([OH:34])=[CH:32][CH:31]=[CH:30][C:29]=3[O:35][CH2:36][CH:37]3[CH2:38][CH2:39]3)[CH:5]=2)[CH2:16]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)NCc1c(C2CCCN(C(=O)OC(C)(C)C)C2)cc(-c2c(O)cccc2OCC2CC2)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1Cc2c(C3CCCN(C(=O)OC(C)(C)C)C3)cc(-c3c(O)cccc3OCC3CC3)nc2NC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 595.3 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-(2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-3-{[(ethoxycarbonyl)amino]methyl}-4-pyridinyl)-1-piperidine-carboxylate (0.145 g, 0.268 mmol), which was obtained in the step (1) of Example 23-2, and triethylamine (0.226 mL, 1.609 mmol) in tetrahydrofuran(30 mL) was added triphosgene (0.079 g, 0.268 mmol) in tetrahydrofuran (10 mL) under an argon atmosphere. The mixture was allowed to warm to room temperature, and the stirring was continued for 3 hrs. After quenched by water, the mixture was extracted with ethyl acetate. The separated organic phase was washed with water and brine successively, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (hexane/ethyl acetate=1/1) to give ethyl 5-[1-(tert-butoxycarbonyl)-3-piperidinyl]-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-carboxylate as a white solid (0.904 g, yield; 60%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[C:27]4[CH2:28][CH2:29][CH2:30][CH2:31][C:26]=4[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:33])[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:22]3[C:27]4[CH2:28][CH2:29][CH2:30][CH2:31][C:26]=4[S:25][C:23]=3[N:24]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c4c(sc3n2)CCCC4)cc1
Reactant: NCc1ccc(F)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(F)cc3)c3c4c(sc3n2)CCCC4)cc1

Procedure:
The reaction procedure as above wherein 4-fluorobenzylamine is reacted with 4-(4-chloro-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(4-fluorobenzylamino)-5 ,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([C:12](O)=[O:13])=[CH:7][C:6]=2[CH:15]=1.S(Cl)([Cl:19])=O>CN(C)C=O>[OH:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([C:12]([Cl:19])=[O:13])=[CH:7][C:6]=2[CH:15]=1
Reactant: O=C(O)c1cc2cc(O)c(O)cc2oc1=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2cc(O)c(O)cc2oc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6,7-dihydroxy-2-oxo-2H-1-benzopyran-3-carboxylic acid (110 mg), thionyl chloride (5 mL), and dimethylformamide (one drop) was stirred for 2 hours at room temperature. The excess thionyl chloride was distilled off in vacuo. Benzene (20 mL) was added, followed by vacuum distillation and vacuum drying, to yield 6,7-dihydroxy-2-oxo-2H-1-benzopyran-3-carbonyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@@H:13]([OH:37])[C@H:14]([N:22](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@@H:13]([OH:37])[C@H:14]([NH2:22])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](O)[C@@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](O)[C@H](N)Cc1ccccc1
Reaction time: 0.03 h
Yield: 101.4 %

Procedure:
Dissolve 2-(S)-[(2-(R)-dibenzylamino-1-(S)-hydroxy-3-phenylpropyl)]-pyrrolidine-1-carboxylic acid tert-butyl ester (610 mg, 1.2 mmol) in methanol (13 mL). Add 20% palladium hydroxide on carbon (157 mg). Bubble hydrogen gas through the mixture and stir under 1 atmosphere of hydrogen gas overnight. Bubble nitrogen through the mixture for 2 min, filter through a filtering agent, wash with methanol and concentrate to give the title compound (390 mg, 99%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:11]([C:23]3[N:28]=[C:27]([CH3:29])[N:26]=[C:25](SC)[N:24]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[NH3:32]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:11]([C:23]3[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH2:32])[N:24]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: N
Reactant: COc1ccc(Nc2nc(-c3ccc(F)cc3)ncc2-c2nc(C)nc(SC)n2)cn1
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(-c3ccc(F)cc3)ncc2-c2nc(C)nc(N)n2)cn1
Temperature: 100 °C

Procedure:
A glass microwave reaction vessel was charged with 2-(4-fluorophenyl)-N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrimidin-4-amine (12 mg, 0.028 mmol), ammonia (0.5 mL, 30% in water) and dioxane (1 mL). The reaction mixture was stirred and heated in a oil bath at 100° C. for 17 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 80% EtOAc/hexanes to give 4-(2-(4-fluorophenyl)-4-(6-methoxypyridin-3-ylamino)pyrimidin-5-yl)-6-methyl-1,3,5-triazin-2-amine. 1H NMR (300 MHz, CDCl3) δ 9.60 (s, 1H); 8.35-8.54 (m, 3H); 8.12 (dd, J=8.84, 2.41 Hz, 1H); 7.15 (t, J=8.62 Hz, 2H); 6.86 (d, J=8.92 Hz, 1H); 5.44 (s, 2H); 3.99 (s, 3H); 2.56 (s, 3H). m/z (ESI, +ve ion) 405.0 (M+H)+.
Reaction SMILES: Cl[CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[C:11]([O-:14])(=[S:13])[CH3:12].[K+].[Cl-].[Na+]>CN(C)C=O.O>[C:11]([S:13][CH2:2][P:3]([O:7][CH2:8][CH3:9])([O:4][CH2:5][CH3:6])=[O:10])(=[O:14])[CH3:12]
Reactant: CCOP(=O)(CCl)OCC
Reactant: CC([O-])=S
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(CSC(C)=O)OCC
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 17.527 g (93.938 mM) of diethyl chloromethylphosphonate in 50 ml of N,N-dimethylformamide was added 12.9 g (113 mM) of potassium thioacetate and the mixture was stirred at 100° C. for 3 hours. This reaction mixture was poured in water, saturated with sodium chloride, and extracted with 4 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate:3/1 to 1/1) to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[C:19]1([CH2:18][O:17][C:5]2[CH:4]=[CH:3][C:2]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)=[CH:16][C:6]=2[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccccc1
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: O=C(Nc1cccnc1)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 100 °C

Procedure:
To a microwave vial was added 5-bromo-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in example 2; 200 mg, 0.52 mmol), 1,4-dioxane (2 ml), 4-pyridinylboronic acid (64.1 mg, 0.52 mmol), 1M sodium carbonate (1.04 mL, 1.04 mmol) and tetrakis(triphenylphosphine)palladium(0) (36.2 mg, 0.03 mmol). The vial was sealed and heated to 100° C. for 30 min under microwave conditions. The mixture was evaporated under reduced pressure and the residue was purified using MDAP to yield the title compound. 41 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]([OH:14])=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:16][O:17][C:18](=[O:33])[C@H:19]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH2:20]>>[CH3:16][O:17][C:18](=[O:33])[C@H:19]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[NH:20][C:12](=[O:14])[CH:10]([CH3:11])[NH:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Agent: Cl
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above) and Nε-BOC-L-lysine methyl ester hydrochloride (Bachem), the title compound was prepared as a oil. The reaction was monitored by tlc (Rf=0.23 in 45% ethyl acetate/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:19]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([CH2:25][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:31][CH:30]=3)=[O:18])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Solvent: ClCCl
Solvent: CO
Product: O=C(/C=C/c1ccc(-c2ccc(Cl)cc2)cc1)Nc1ccc(CN2CCCCC2)cc1

Procedure:
Prepared analogously to Example 3.1.e. from [(E)-3-(4′-chlorobiphenyl-4-yl)acrylic acid and 4-piperidin-1-ylmethylphenylamine. Yield: 0.57 g (62.9% of theory); melting point: 265° C.-270° C.; C27H27ClN2O (M=430.98); calc.: molecular ion peak (M+H)+: 431/433; found: molecular ion peak (M+H)+: 431/433; Rf value: 0.31 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[O:7]=[CH:8][C:9]1[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[C:11]([OH:12])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CCO>[CH:2]1([O:12][C:11]2[CH:10]=[C:9]([CH:17]=[CH:16][C:13]=2[O:14][CH3:15])[CH:8]=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(C=O)cc1OC1CCCC1
Yield: 96.3 %

Procedure:
Bromocyclopentane (1.4 mL, 13 mmol) was added to a suspension of isovanillin (1.0 g, 6.6 mmol) and potassium carbonate (2.7 g, 10 mmol) in EtOH (15 mL) and treated according to Procedure 3. 3-Cyclopentyloxy-4-methoxybenzaldehyde (1.4 g, 97%) was obtained as a yellow oil; δH (400 MHz, CDCl3) 1.63 (m, 2H, CH2), 1.79-1.93 (m, 4H, CH2), 1.99 (m, 2H, CH2), 3.93 (s, 3H, OCH3), 4.85 (tt, J=6.4, 3.2 Hz, 1H, OCH), 6.96 (d, J5,6=8.0 Hz, 1H, H5), 7.39 (d, J2,6=2.0 Hz, 1H, H2), 7.42 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 9.84 (s, 1H, CHO); δC (100 MHz, CDCl3) 24.1, 32.7, 56.1, 80.5, 110.7, 112.1, 126.3, 130.0, 148.2, 155.4, 191.0; vmax 1001, 1132, 1261, 1431, 1508, 1584, 1683, 2956 cm−1.