Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=3)=[O:11])[CH:5]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(C(=O)CC(c2cccc(Br)c2)c2ccccc2C)ccn1
Product: Cc1cc(C(=O)CC(c2cccc(-c3ccc(S(C)(=O)=O)cc3)c2)c2ccccc2C)ccn1

Procedure:
In analogy to example 22, from 3-(3-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 98, step 5) and 4-(methylsulfonyl)phenylboronic acid was prepared the title compound as light yellow foam, MS (ESI+): m/z=470.2 ([M+H]+).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[F:16][C:17]1[C:22](C=O)=[C:21]([F:25])[C:20]([F:26])=[C:19]([F:27])[C:18]=1[F:28]>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][CH:8]([C:22]2[C:21]([F:25])=[C:20]([F:26])[C:19]([F:27])=[C:18]([F:28])[C:17]=2[F:16])[O:7][C:1](=[O:6])[CH:2]=1
Reactant: O=Cc1c(F)c(F)c(F)c(F)c1F
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2c(F)c(F)c(F)c(F)c2F)O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared as described in General Method 1 using 2.5 mL of methyl acetoacetate, 1.0 g of NaH 60% dispersion in oil, 12.5 mL of 2.0M n-butyl lithium in hexane, 3.4 mL of pentafluorobenzaldehyde and 75 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 10 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 176°-178° C.). 1H NMR (CDCl3) δ 2.89 (dd, 1 H), 3.15 (dd, 1 H), 3.70 (dd, 2 H), 6.02 (dd, 1 H).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH2:12])[N:3]=1.Cl.[OH:14][CH:15]([CH2:18][CH2:19][CH3:20])[CH2:16][NH2:17].C(N(CC)CC)C.N>C(Cl)(Cl)Cl.CN(C=O)C>[NH2:12][C:4]1[N:3]=[C:2]([NH:17][CH2:16][CH:15]([OH:14])[CH2:18][CH2:19][CH3:20])[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=1
Reactant: CCCC(O)CN
Reactant: Nc1nc(Cl)c2c(n1)CCCC2
Agent: Cl
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCC(O)CNc1nc(N)nc2c1CCCC2
Temperature: 90 °C
Yield: 51.1 %

Procedure:
A mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (184 mg, 1 mmol), 2-hydroxypentylamine hydrochloride (140 mg, 1 mmol), triethylamine (202 mg, 2 mmol) and DMF (1 ml) was warmed for 5 hours in a bath (bath temperature, 90° C.). The solvent in the filtrate was removed in vacuo and the residue was purified by silica gel column chromatography (CHCl3:MeOH:NH4OHaq=100:10:0.4) to give the crude product (210 mg). To the crude product was aqueous ammonia solution (5 ml) and chloroform (30 ml) and it was extracted. The organic layer was washed with saturated brine (20 ml), dried over sodium sulfate, filtered and the solvent in the filtrate was removed in vacuo to give the object compound (128 mg, 51%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1>C(O)C.[Pt](=O)=O>[NH2:11][C:6]1[CH:5]=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: COCc1ccc(O)c([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: CCO
Product: COCc1ccc(O)c(N)c1
Reaction time: 16 h
Yield: 85 %

Procedure:
A mixture of 4-[(methyloxy)methyl]-2-nitrophenol D55 (0.72 g, 3.93 mmol) and platinum (IV) oxide (0.089 g, 0.393 mmol) in ethanol (15 mL) was stirred under an atmosphere of hydrogen for 16 hr. The catalyst was removed by filtration through celite and the filtrate concentrated to dryness in vacuo to afford the title compound as a green/brown solid 0.51 g, 85%.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][OH:18])[CH:15]=2)[O:10][C:9]([C:19]2[N:24]=[CH:23][N:22]3[CH:25]=[CH:26][CH:27]=[C:21]3[CH:20]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=2)[O:10][C:9]([C:19]2[N:24]=[CH:23][N:22]3[CH:25]=[CH:26][CH:27]=[C:21]3[CH:20]=2)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(CO)cc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
To a solution of 6-Hydroxymethyl-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 144C) (575 mg, 1.58 mmol) in dichloromethane (60 ml), was added a Dess Martin solution (15 wt. % in DCM) (6.7 ml; 2.37 mmol). After 1 hour stirring at room temperature, an additional amount of Dess Martin solution (6 ml) was added to complete the reaction. The reaction mixture was quenched with water and added to a 1:1 solution of saturated sodium hydrogenocarbonate and 5% aq solution of Na2S2O3. After extraction with ethyl acetate, the organic layers were washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography over silica gel (gradient cyclohexane/ethyl acetate: 0-40%) to afford the title compound (355 mg, 62%) as a yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([S:13]([C:16]2([C:21]#[N:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>O1CCCC1>[C:7]1([S:13]([C:16]2([CH2:21][NH2:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:14])=[O:15])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#CC1(S(=O)(=O)c2ccccc2)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCC1(S(=O)(=O)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 41.8 %

Procedure:
194 mg (5.1 mmol) of lithium aluminum hydride is added to a solution of 1 g (4.2 mmol) of 1-benzenesulfonyl-cyclopentanecarbonitrile in 20 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature (RT) for 20 h. It is then hydrolyzed with 194 μl of water, 194 μl of a 15% soda solution and then 582 μl of water, stirred for 5 minutes, then filtered. The filtrate is evaporated and the residue is chromatographed on silica gel (dichloromethane then dichloromethane/methanol, 90/10, v/v). 420 mg of C-(1-benzenesulfonyl-cyclopentyl)-methylamine is obtained in the form of a colorless oil. (Yield=42%).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:12])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13](Cl)(=O)[CH3:14]>>[CH3:13][C:14]1[O:1][N:2]=[C:3](/[CH:4]=[CH:5]/[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:12]=1
Reactant: CC(=O)Cl
Reactant: N=C(/C=C/c1ccccc1)NO
Product: Cc1nc(/C=C/c2ccccc2)no1
Yield: 27 %

Procedure:
(2E)-N-Hydroxy-3-phenyl-2-propenimidamide (1.6 g, 10 mmol) was mixed with excess acetyl chloride (30 mL), and heated to reflux. After 1 h the solution was cooled and the excess acetyl chloride was removed in vacuo. The resultant solids were triturated in hot ethyl acetate-hexane-acetone solution, and the supernatant was removed. The remaining solids were dried under high vacuum to afford 5-methyl-3-[(E)-2-phenylethenyl]-1,2,4-oxadiazole (0.50 g, 27% yield from cinnamonitrile) as a pale yellow powder. M.p. 166–168° C. 1H NMR (DMSO-d6, 300 MHz) δ 7.59 (m, 3H), 7.42 (m, 3H), 6.58 (d, J=16 Hz, 1H), 2.17 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C@H:6]1[O:11][C@H:10](OC(C)=O)[C@H:9]([O:16][C:17]([CH3:19])=[O:18])[C@@H:8]([O:20][C:21]([CH3:23])=[O:22])[C@@H:7]1[O:24][C@@H:25]1[O:30][C@H:29]([CH2:31][O:32][C:33]([CH3:35])=[O:34])[C@@H:28]([O:36][C:37]([CH3:39])=[O:38])[C@H:27]([O:40][C:41]([CH3:43])=[O:42])[C@H:26]1[O:44][C:45]([CH3:47])=[O:46])=[O:3].[BrH:48]>C(O)(=O)C>[CH3:35][C:33]([O:32][CH2:31][C@H:29]1[O:30][C@@H:25]([O:24][C@H:7]2[C@H:8]([O:20][C:21]([CH3:23])=[O:22])[C@@H:9]([O:16][C:17]([CH3:19])=[O:18])[C@@H:10]([Br:48])[O:11][C@@H:6]2[CH2:5][O:4][C:2]([CH3:1])=[O:3])[C@H:26]([O:44][C:45]([CH3:47])=[O:46])[C@@H:27]([O:40][C:41]([CH3:43])=[O:42])[C@@H:28]1[O:36][C:37]([CH3:39])=[O:38])=[O:34]
Reactant: CC(=O)OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Br
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
α-D-Cellobiosyl bromide heptaacetate was prepared form α-D-cellobiose octaacetate and hydrogen bromide in glacial acetic acid using a modified procedure of Freudenberg and Nagari1.
Reaction SMILES: [Si]([O:8][C@H:9]([C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([NH:55][CH:56]=[O:57])[CH:49]=1)[CH2:10][NH:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([NH:20][C:21]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([O:31][C:32](=[O:46])[NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:27][CH2:26]2)=[O:22])=[C:15]([CH3:47])[CH:14]=1)(C(C)(C)C)(C)C.ClCCl.F.F.F.C(N(CC)CC)C>C(OCC)(=O)C>[CH:56]([NH:55][C:50]1[CH:49]=[C:48]([C@@H:9]([OH:8])[CH2:10][NH:11][CH2:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([NH:20][C:21]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32](=[O:46])[NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:27][CH2:26]3)=[O:22])=[C:15]([CH3:47])[CH:14]=2)[CH:53]=[CH:52][C:51]=1[OH:54])=[O:57]
Reactant: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1CNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(NC=O)c1
Agent: F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1CNC[C@H](O)c1ccc(O)c(NC=O)c1
Temperature: 25 °C

Procedure:
To a 1 L round-bottom flask was added biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(tert-butyldimethylsilanyloxy)-2-(3-formylamino-4-hydroxyphenyl)ethylamino]methyl}-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (21.5 g, 27.1 mmol) and dichloromethane (200 mL). The resulting mixture was stirred at room temperature until the ingredients dissolved and then triethylamine trihydrofluoride (8.85 mL, 54.2 mmol) was added and the resulting mixture was stirred at 25° C. for about 48 hours. The solvent was removed on a rotary evaporator to provide a thick paste. Dichloromethane (100 mL) and ethyl acetate (200 mL) were added to the paste and the resulting mixture was stirred for 30 minutes. The resulting slurry was slowly filtered under dry nitrogen and the filter cake was washed with a 1:2 mixture of dichloromethane and ethyl acetate (100 mL total), dried under nitrogen for 2 hours and then dried under vacuum overnight to provide biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester as a hydrofluoride salt (25 g, 96.9% purity) which was a hard clay-like solid. MS [M+H+] found 680.8.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[OH-].[Na+]>CO>[C:22]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:20][C:19]([CH:12]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][N:6]=2)=[O:31])=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(-c3ccccc3)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(-c3ccccc3)cc2)nc1
Temperature: 25 °C
Yield: 28.3 %

Procedure:
A solution of 6-(2-biphenyl-4-yl-3-cyclopentyl-propionylamino)-nicotinic acid methyl ester (prepared in Example 22, 100 mg, 0.23 mmol) in methanol (2 mL) was treated with a 1N aqueous sodium hydroxide solution (350 mL, 0.35 mmol). The reaction mixture was heated under reflux for 30 min and then allowed to cool to 25° C. The reaction mixture was then concentrated in vacuo. The resulting residue was partitioned between water and ethyl acetate, and the layers were separated. The aqueous layer was further extracted with ethyl acetate (1×25 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate then 100% methanol) afforded 6-(2-biphenyl-4-yl-3-cyclopentyl-propionylamino)-nicotinic acid (27 mg, 28%) as a white solid: mp 271-272° C. (dec); FAB-HRMS m/e calcd for C26H26N2O3 (M+H)+ 415.2021, found 415.2010.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]([C:26]2[CH:27]=[C:28]([CH:40]=[CH:41][CH:42]=2)[CH2:29][S:30][CH2:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[O:25])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[F:46][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]([C:26]2[CH:27]=[C:28]([CH:40]=[CH:41][CH:42]=2)[CH2:29][S:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:25])[CH:11]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(Cl)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(Cl)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 15 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-chlorophenyl)carbamoyl)benzylthio)propanoate (350 mg, 0.51 mmol, 1.00 equiv) in dichloromethane (5.0 mL), and trifluoroacetic acid (581.4 mg, 5.10 mmol, 10.00 equiv). The resulting solution was stirred overnight at 15° C. The resulting mixture was concentrated under vacuum. The crude product (340 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained 250 mg (78%) of a white solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.988 (s, 1H), 12.228 (s, 1H), 9.595-9.560 (m, 1H), 9.020-9.003 (d, J=5.1 Hz, 1H), 8.631-8.601 (d, J=9.0 Hz, 1H), 8.448 (s, 1H), 8.118-8.126 (d, J=2.4 Hz, 1H), 7.917-7.899 (d, J=5.4 Hz, 2H), 7.837-7.812 (d, J=7.5 Hz, 1H), 7.727-7.510 (m, 6H), 4.662-4.643 (d, J=5.7 Hz, 2H), 3.904 (s, 2H), 2.637-2.594 (m, 2H), 2.538 (m, 2H). MS (ES, m/z): 628 [M+H]+
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[K].[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.CN(C=O)C>O>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:10]2[O:9][C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[N:26]3[C:25](=[O:27])[C:24]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]4[C:22]3=[O:32])=[N:12][C:11]=2[CH:13]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1c1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 120 °C
Reaction time: 6 h
Yield: 61.6 %

Procedure:
A mixture of 1.41 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 1.85 g of phthalimide potassium and 8 ml of DMF was stirred while heating at 120° C. After six hours, 0.92 g of phthalimide potassium was added and stirred while heating at 140° C. for further one hour. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, which followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, sequentially, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.26 g of N-{4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-yl}phthalimide.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22]OS(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>C(#N)C>[CH2:1]([NH:4][CH2:22][CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[F:14])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccc2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCNCCc1ccccc1F
Temperature: 80 °C
Reaction time: 6 h
Yield: 66.2 %

Procedure:
0.89 ml of allylamine (11.9 mmol) and 0.311 ml of diisopropyl ethylamine (1.78 mM) were added to the reaction solution (1.2 mmol) containing 350 mg of toluen-4-sulfonate-2-(2-fluoro-phenyl)-ethyl ester (u) prepared by above Step 1 dissolved in acetonitrile solution with stirring for 6 hrs at 80° C. After the reaction mixture was neutralized with 10% NaOH solution, the mixture was extracted with chloroform, washed with saturated NaCl solution, dried over MgSO4, filtered, and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:9) as an eluant to give 141 mg of allyl-[2-(2-fluoro-phenyl)-ethyl]-amine (v) (yield: 66%).
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][C:27]=1[CH3:34]>C1(C)C=CC=CC=1>[Br:25][C:26]1[CH:33]=[CH:32][C:29](/[CH:30]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[CH:28][C:27]=1[CH3:34]
Reactant: Cc1cc(C=O)ccc1Br
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(Br)c(C)c1
Temperature: 90 °C
Yield: 52.9 %

Procedure:
2.1 g (6.45 mmol, 1.5 eq) of methyl triphenylphosphoranylideneacetate are added to a solution of 900 mg of 4-bromo-3-methylbenzaldehyde in 5 ml of toluene. The reaction mixture is heated at 90° C. for 1 hour. The solvent is evaporated off and the residual oil is chromatographed on silica gel (8/2 heptane/ethyl acetate). 610 mg of methyl (E)-3-(4-bromo-3-methylphenyl)acrylate are obtained in oil form. Yield=55% over steps a, b and c.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]([C:8]1[CH:9]=[C:10]([C:19]2[O:20][CH:21]=[C:22]([CH2:24][CH2:25]I)[N:23]=2)[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])([CH3:7])([CH3:6])[CH3:5].C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCCCCC>[C:4]([C:8]1[CH:9]=[C:10]([C:19]2[O:20][CH:21]=[C:22]([CH2:24][CH2:25][C:1]#[N:2])[N:23]=2)[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)c1cc(-c2nc(CCI)co2)cc(C(C)(C)C)c1O
Reactant: [C-]#N
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(-c2nc(CCC#N)co2)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
To a solution of sodium cyanide (84.5 mmole, 5.50 g) in dimethylsulfoxide (120 ml) at 92° C. was added 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-(2-iodoethyl)oxazole (70.4 mmole, 30.08 g) via a powder addition funnel over an eightyfive minute period. Approximately 1.5 hours later, the reaction was cooled to room temperature and treated with 1:1 ethyl acetate:hexane (250 ml) and 10% aqueous potassium carbonate (250 ml). Three distinct phases result. The lowest phase was separated and discarded. The remaining phases were separated. The aqueous phase was extracted with 1:1 ethyl acetate:hexane (2×200 ml). Combined organic phases were dried over sodium chloride, filtered, reduced in volume and subjected to preparatory chromotography. The material was eluted with 10 to 30% ethyl acetate:hexane. Fractions containing the desired product were combined, dried over MgSO4, filtered and concentrated in vacuo to afford 18.25 g (79%).
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:2]([C:10]([NH:12][C@@H:13]([C:15]([NH:17][CH2:18][C:19]([O:21]CC1C=CC=CC=1)=[O:20])=[O:16])[CH3:14])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.[Pd]>[NH:1]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[C@H:2]([C:10]([NH:12][C@@H:13]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[CH3:14])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Yield: 99.9 %

Procedure:
Boc-Phe-D-Ala-Gly-OBzl (2.4 g, 4.96 mmole) was dissolved in MeOH (50 ml), and H2 gas was passed through the solution in the presence of Pd-C for 4 hours. Pd-C was removed by filtration, and MeOH was distilled off. To the thus-obtained residue MeOH/Et2O and N-hexane were added. The thus-precipiated powder was separated by filtration and reprecipitated with AcOEt/n-hexane to obtain the desired product (1.95 g, 100%). (4) Synthesis of Z-Cys(4-CH3Bzl)-Phe-D-Ala-Gly-OH
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:27]=[N:28][CH:29]=2)[C:5]([N:20]2[CH2:24][CH2:23][C@@H:22]([O:25]C)[CH2:21]2)=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([CH:27]=[N:28][CH:29]=2)[C:5]([N:20]2[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]2)=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1
Reactant: CO[C@@H]1CCN(c2c(C(C)Nc3ncnc4[nH]cnc34)cc(Cl)c3cncn23)C1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cncn2c1N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.7 %

Procedure:
To a cooled solution of N-(1-{8-chloro-5-[(3R)-3-methoxypyrrolidin-1-yl]imidazo[1,5-a]pyridin-6-yl}ethyl)-9H-purin-6-amine (27.0 mg, 0.0654 mmol) in methylene chloride (1.0 mL) at −78° C. under an atmosphere of nitrogen was added slowly 1.0 M boron tribromide in methylene chloride (0.47 mL, 0.47 mmol). The mixture was allowed to warm up to room temperature and stirred for 30 minutes. The resultant mixture was quenched with Na2CO3 (aq). The cloudy suspension was filtered and washed with water. The filtrate was extracted with ethyl acetate and the organic layer was washed with brine and evaporated. Purification by preparative LCMS (pH 10) gave the desired compound (2.8 mg, 11%). LCMS calculated for C18H20ClN8O (M+H)+: m/z=399.1. found: 398.9.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](Cl)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:14][C@H:12]([C:10]2[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]3[CH:21]=[C:4]([F:3])[CH:5]=[CH:6][C:7]=3[N:11]=2)[CH3:13])[N:26]=[CH:25][N:24]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Yield: 64.3 %

Procedure:
(S)-1-(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (328 mg, 1.00 mmol) was placed in a sealed tube with 4-amino-6-chloropyrimidine-5-carbonitrile (154.5 mg, 1.00 mol), DIPEA (0.7 mL, 4.00 mol) and IPA (1 mL). The tube was flushed with argon, sealed and the contents heated at 90° C. for 16 h. The cooled mixture was evaporated then diluted with EtOAc and water. The organic layer was washed with brine, dried (MgSO4) and evaporated. The crude residue was purified by chromatography on silica (Si—PCC, 1-80% EtOAc in DCM). The product containing fractions were pooled and evaporated almost to dryness. The residue was triturated in ether to afford 246 as a cream solid (240 mg, 65%). 1H NMR (CDCl3, 400 MHz): δ 8.01 (1H, s), 7.69 (1H, dd, J=8.8, 4.7 Hz), 7.59-7.49 (3H, m), 7.43-7.36 (2H, m), 7.02 (1H, td, J=9.2, 1.1 Hz), 6.77 (1H, dd, J=8.6, 2.4 Hz), 6.18 (1H, d, J=7.5 Hz), 5.52 (1H, quin, J=7.2 Hz), 5.30 (2H, br s), 1.54 (3H, d, J=6.9 Hz). LCMS (Method K): RT 3.80 min [M+H]+ 374