Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.Br[C:35]([CH3:41])([CH3:40])[C:36]([NH:38][CH3:39])=[O:37]>C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>[CH:29]([N:25]1[C:24]([C:18]2[S:19][C:20]3[CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([CH:10]5[CH2:11][N:8]([C:35]([CH3:41])([CH3:40])[C:36]([NH:38][CH3:39])=[O:37])[CH2:9]5)[CH:33]=[CH:32][C:15]=4[C:16]=3[N:17]=2)=[N:28][CH:27]=[N:26]1)([CH3:31])[CH3:30]
Reactant: CNC(=O)C(C)(C)Br
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)C(C)(C)N1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1

Procedure:
Following the procedure of Example 319, a suspension of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (200 mg, 0.42 mmol) and 2-bromo-2,N-dimethyl-propionamide in cesium carbonate and DMF were reacted at 80° C. to give 464 isolated as a white solid (33 mg, 17%). LCMS: RT=7.62 min, [M+H]+=467. 1H NMR δ (ppm) (DMSO-d6): 8.27 (1H, d, J=8.17 Hz), 8.06 (1H, s), 7.63 (1H, s), 7.16 (1H, dd, J=8.20, 1.82 Hz), 6.96 (1H, s), 5.83-5.73 (1H, m), 4.32 (2H, t, J=5.01 Hz), 3.53 (2H, s), 3.39 (2H, t, J=5.02 Hz), 2.58 (3H, d, J=4.63 Hz), 1.50 (6H, d, J=6.59 Hz), 1.06 (6H, s). 3 Protons obscured by water peak
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[C:9](=O)[CH3:10].O.[NH2:13][NH2:14]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:9]([CH3:10])=[N:13][NH:14]2
Reactant: NN
Reactant: CC(=O)c1c(F)cccc1F
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1n[nH]c2cccc(F)c12
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 85 %

Procedure:
2′,6′-Difluoroacetophenone (0.468 g, 3 mmol) was dissolved in anhydrous hydrazine (2 ml), followed by irradiating microwaves thereon with stirring at 150° C. for 5 min. The addition of water (0.5 ml) at 0° C. terminated the reaction. Afterwards, the reaction solution was diluted with ethyl acetate (10 ml) and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated using vacuum evaporation. The residue was re-crystallized in dichloromethane to give the title compound (Yield 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].C(N(C(C)C)C(C)C)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([NH:1][S:43]([CH3:42])(=[O:45])=[O:44])[CH:3]=[CH:4][C:5]=2[NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccc(N)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(NCC2CCNCC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reaction time: 8 h
Yield: 55.2 %

Procedure:
A suspension of 5-amino-N-(5-chloropyridin-2-yl)-2-[(1-Boc-piperidin-4-yl)methylamino]benzamide (0.55 g, 1.2 mmol) in 12 mL of dichloromethane at 0° C. was treated with ethyldiisopropylamine (231 μL, 1.3 mmol) followed by methanesulfonyl chloride (93 μL, 1.2 mmol). The reaction mixture was allowed to reach room temperature overnight, then it was concentrated in vacuo to a crude residue. The residue was directly applied to an SCX column, which was washed with methanol and allowed to stand overnight. Elution with 1:1 dichloromethane-1 N ammonia in methanol provided yellow fractions, which were combined and concentrated in vacuo to a crude residue. Purification by silica gel chromatography, eluting with 9:1 dichloromethane-2 N ammonia in methanol, afforded solid material which was taken up in ac tonitrile and sonicated for several minutes. The resulting suspension was filtered, giving rise to the title compound (0.29 g, 56%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C@@H:24]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:25]([OH:40])[CH2:26][C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]1[C:33]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:23][C@@H:24]([CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C@H:25]([OH:40])[CH2:26][C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]1[C:33]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCC[C@H]1C[C@@H](O)[C@@H](N)Cc1ccccc1
Product: CC(C)(C)NC(=O)[C@@H]1CCCC[C@H]1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 44.1 %

Procedure:
In a manner analogous to that described in Example 6, 78 mg (0.26 mmol) of N-benzyloxycarbonyl-L-phenylalanine were coupled with 90 mg (0.26 mmol) of 2(S)-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide to give 72 mg of 2(S)-[3(S)-[[N-(benzyloxycarbonyl)-L-phenylalanyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide as a while solid; MS m/e 628 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=2)[NH:8][CH:7]=1)[C:3](Cl)=[O:4].[OH-].[NH4+:23].Cl>>[O:1]=[C:2]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=2)[NH:8][CH:7]=1)[C:3]([NH2:23])=[O:4]
Reactant: [NH4+]
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccc(Oc3ccccc3)cc12
Agent: Cl
Agent: [OH-]
Product: NC(=O)C(=O)c1c[nH]c2ccc(Oc3ccccc3)cc12
Yield: 96.4 %

Procedure:
Combine 2-oxo-(5-phenoxy-1H-indol-3-yl)acetyl chloride (2.15 g, 7.18 mmol), and ammonium hydroxide (28-30%, 32 ml, 680 mmol) and stir for 2 hours. Pour the reaction mixture into 10% (aq.) HCl, extract with dichloromethane, combine the organic layers and dry over Na2SO4, evaporate solvent in vacuo to give 1.94 g (96%) of title compound: 1H NMR (300 MHz, CDCl3) 4.87 (s, 2H), 7.51-7.91 (m, 7H), 8.13-8.24 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].Cl.[CH3:14][O:15][C:16](=[O:25])[C@H:17]([NH2:24])[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:14][O:15][C:16](=[O:25])[C@@H:17]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[NH:24][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COC(=O)[C@H](N)C1CCCCC1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](NC(=O)c1ccccc1[N+](=O)[O-])C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
To a mixture of 2-nitrobenzoyl chloride (0.5 mL, 3.69 mmol) and (R)-amino-cyclohexyl-acetic acid methyl ester hydrochloride (1.0 g, 4.82 mmol), (prepared according to example A), in dichloromethane (10 mL) is added diisopropyl ethylamine (DIPEA) (1.5 mL, 8.61 mmol). The mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated and the resulting residue is purified by flash chromatography with 40% EtOAc in Hexane as the eluent to afford (R)-cyclohexyl-(2-nitro-benzoylamino)-acetic acid methyl ester (1.16 g, 98%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([O:27]CC)=[O:26])[CH:4]=[N:3]1.O.[OH-].[Li+]>CO.O>[CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=[O:26])[CH:4]=[N:3]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 75.1 %

Procedure:
A mixture of ethyl 1-methyl-5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylate (1.22 g, 3.05 mmol) and lithium hydroxide monohydrate (641 mg, 15.3 mmol) in methanol (30 ml) and water (5 ml) is stirred for 6 hours at 50° C. The solvent is evaporated, the residue diluted with water, acidified to pH=0 with 2N aqueous hydrochloric acid. The precipitated solid is collected by filtration, washed with ethyl acetate and dried affording 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (851 mg, 75%) as a light yellow solid. MS: m/z=369.9 (M−H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]3[CH:13]=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=4)=[CH:16][C:9]=23)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>CN(C=O)C.C1COCC1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]3[CH:13]=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:31]([C:27]5[S:26][CH:30]=[CH:29][CH:28]=5)=[O:32])[N:18]=4)=[CH:16][C:9]=23)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cccs1
Reactant: Nc1nccc(-c2ccc3noc(-c4cccc(Br)c4)c3c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1nccc(-c2ccc3noc(-c4cccc(Br)c4)c3c2)n1)c1cccs1
Temperature: 25 °C
Yield: 24.6 %

Procedure:
4-[3-(3-bromophenyl)-benzo[c]isoxazol-5-yl]-pyrimidin-2-ylamine (100 mg; 0.272 mmol) was dissolved in 3 mL of a mixture (2:1) of dry DMF/THF and stirred under a nitrogen atmosphere at ambient temperature. Sodium hydride (15 mg, 0.375 mmol, 60% oil dispersion) was added To the reaction and stirred for 30 minutes. Thiophenecarbonylchloride (32 μL; 43.7 mg; 0.299 mmol) in 500 μL of dry DMF was added dropwise over 2 minutes and the reaction was stirred for 18 hours at ambient temperature. Workup was affected by removing the solvents under reduced pressure and the resulting residue was triturated with methyltertbutyl ether. The crude solid was purified via silica column chromatography with 5% ethanol in methylenechloride to yield 32 mg of a tan powder; 24% yield. 1H NMR (500 MHz, DMSO-d6) δ 11.2 (s, 1H), 8.92 (s, 1H), 8.88 (d, 1H), 8.39 (d, 1H), 8.35 (s, 1H), 8.3 (d, 1H), 8.23 (d, 1H), 8.15 (d, 1H), 7.95 (d, 1H), 7.9 (d, 1H), 7.87 (d, 1H), 7.65 (t, 1H), 7.24 (t, 1H) in ppm. LC-MS (ES+) m/e=477/479 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([F:17])[CH:12]=3)[N:10]=[C:4]2[CH:3]=1.[C:18](=[O:25])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH2:19]>>[C:21]([O:20][C:18](=[O:25])[NH:19][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([F:17])[CH:12]=3)[N:10]=[C:4]2[CH:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: Fc1cc(-c2nc3cc(Br)ccn3n2)ccn1
Reactant: CC(C)(C)OC(N)=O
Product: CC(C)(C)OC(=O)Nc1ccn2nc(-c3ccnc(F)c3)nc2c1
Yield: 0.1 %

Procedure:
The product was prepared in the same manner as described in example 1c using 7-bromo-2-(2-fluoropyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (1.2 g, 4.09 mmol) and tert-butyl carbamate (576 mg, 4.91 mmol) as starting materials. The reaction affords [2-(2-fluoro-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-carbamic acid tert-butyl ester (1.126 mg, 83.5%) as light brown powder. MS: m/z=330.0 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][O:9][C:10]2=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][NH:15][CH3:16]>C(O)C>[OH:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]=1[C:10]([N:15]([CH3:16])[CH3:14])=[O:11]
Reactant: O=C1OCc2ccc([N+](=O)[O-])cc21
Reactant: CNC
Solvent: CCO
Product: CN(C)C(=O)c1cc([N+](=O)[O-])ccc1CO
Reaction time: 5 h

Procedure:
To a stirred solution of 6-nitrophthalide (2 g.) in ethanol (120 ml.) at room temperature was added dimethylamine (in ethanol 33.3% solution: 50 ml.). After stirring for 5 hours the solvent was evaporated off. The resulting gum was dissolved in ethyl acetate. On addition of petrol 60°-80° a white solid crystallised out.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8].[BH4-].[Na+]>C(O)C.O>[OH:11][CH:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(=O)c1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)C(O)c1cccs1
Reaction time: 0.17 h
Yield: 88.4 %

Procedure:
To a stirred solution of methyl 2-thiopheneglyoxylate (1.01 g) in ethanol (20 ml) in an ice bath was added sodium borohydride (0.113 g) in 1 ml of water, and the mixture was stirred for 10 minutes. The reaction was quenched with aqueous acetic acid and the mixture was partitioned between methylene chloride and water. The organic extract was washed with brine, dried (sodium sulfate) and evaporated to give methyl α-hydroxy-2-thienylacetate as an oil (0.903 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12]C=CC=2)[N:5]=[C:4]([O:14][CH2:15][CH2:16][CH:17]([CH3:19])C)[CH:3]=1.ClC1C=C(Cl)N=[C:23]([C:28]2C=CC=[CH:30][CH:29]=2)N=1.ClC1C=C(Cl)N=C(CCC)N=1.C(C(CCCC)CO)C>CC(C)CCO>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:13][CH3:12])[N:5]=[C:4]([O:14][CH2:15][CH:16]([CH2:17][CH3:19])[CH2:23][CH2:28][CH2:29][CH3:30])[CH:3]=1
Reactant: CC(C)CCOc1cc(Cl)nc(-c2ccccc2)n1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Agent: CCCc1nc(Cl)cc(Cl)n1
Solvent: CC(C)CCO
Solvent: CCCCC(CC)CO
Product: CCCCC(CC)COc1cc(Cl)nc(CCC)n1

Procedure:
The compound of Example 21 is prepared analogously to the compound of Example 3, with 4,6-dichloro-2-phenylpyrimidine being replaced by 4,6-dichloro-2-propylpyrimidine and 3-methylbutanol by 2-ethylhexanol.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)[CH:2]=1.[CH2:32]([O:34][C:35](=[O:47])[C:36]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42](O)[CH:41]=1)([CH3:38])[CH3:37])[CH3:33].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:32]([O:34][C:35](=[O:47])[C:36]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:14][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([C:3]3[CH:2]=[C:1]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:6]=[CH:5][CH:4]=3)[O:8][C:9]=2[CH3:25])[CH:41]=1)([CH3:38])[CH3:37])[CH3:33]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1cccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)c1

Procedure:
A mixture of the toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (66.9 mmol) and 2-(3-hydroxyphenoxy)-2-methylpropanoic acid ethyl ester (Columbia University WO 9731530) (12.5 g, 55.71 mmol) and Cs2CO3 (22.7 g, 69.6 mmol) was heated at 55° C. in DMF (45 mL) for 18 h. The reaction was partitioned between ethyl acetate (160 mL) and H2O (180 mL), and the aqueous phase extracted with ethyl acetate (150 mL). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure to an oil which was purified by column chromatography (1500 mL SiO2, 10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) to provide 2-{3-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid ethyl ester. Rf=0.50 in 20% ethyl acetate/hexanes; 1H NMR (400 MHz, CDCl3) δ8.18 (s, 1H), 7.95 (d, 1H), 7.65-7.59 (m, 3H), 7.44-7.39 (m, 3H), 7.36 (t, 1H), 7.08 (t, 1H), 6.55 (d, 1H), 6.41 (s, 1H), 6.37 (d, 1H), 4.20-4.14 (m, 4H), 2.97 (t, 2H), 2.38 (s, 3H), 1.57 (s, 6H), 1.20 (t, 3H); MS (EI) 508.2 (M+Na)+, 486.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])[CH:5]=[C:4]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][CH:34]=2)[C:3]=1[CH3:41].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:50]1(B(O)O)[CH2:52][CH2:51]1.C1(C)C=CC=CC=1>O>[CH:50]1([C:2]2[CH:7]=[C:6]([C:8]3([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]3[O:11][C:12](=[O:14])[CH3:13])[OH:9])[CH:5]=[C:4]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([CH2:39][CH3:40])=[CH:37][CH:38]=3)[C:3]=2[CH3:41])[CH2:52][CH2:51]1
Reactant: OB(O)C1CC1
Reactant: CCc1ccc(Cc2cc(C3(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(Br)c2C)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccc(Cc2cc(C3(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(C3CC3)c2C)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A flask charged with 1-bromo-3-(4-ethylbenzyl)-2-methyl-5-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzene (0.30 g), potassium phosphate (0.38 g), cyclopropylboronic acid (50 mg), toluene (2 mL) and water (1 mL) is flushed with Ar for 5 min. Then, palladium acetate (11 mg) and tricyclohexylphosphonium tetrafluoroborate (36 mg) are added. The flask is tightly sealed and the mixture is stirred at 100° C. overnight. After cooling to room temperature, the mixture is diluted with water and ethyl acetate and treated with charcoal. After filtration, the organic layer is separated, washed with brine and dried (magnesium sulphate). The solvent is removed under reduced pressure and the resulting crude product is submitted to deacetylation without further purification.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:14][CH:13]=[C:12]([CH:15]=[O:16])[CH:11]=1.C1OCCOCCOCCOCCOC1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:33]=1>>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:14]([S:38]([C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)(=[O:40])=[O:39])[CH:13]=[C:12]([CH:15]=[O:16])[CH:11]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2Br)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: O=Cc1cc(-c2ccccc2Br)n(S(=O)(=O)c2cccnc2)c1

Procedure:
By a similar operation as in Reference Example 154 and using sodium hydride (60% in oil, 91.0 mg), 5-(2-bromophenyl)-1H-pyrrole-3-carbaldehyde (396 mg), 15-crown-5 (418 mg) and pyridin-3-ylsulfonyl chloride (309 mg), the title compound was obtained as a pale-yellow solid (yield 560 mg, 91%).
Reaction SMILES: [NH2:1][C:2]1[N:7](C)[C:6](=[O:9])[NH:5][C:4](=[O:10])[CH:3]=1.Cl[CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([O:18][CH3:19])[CH3:17].CS(C)=O.[H-].[Na+]>O>[NH2:1][C:2]1[NH:7][C:6](=[O:9])[N:5]([CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([O:18][CH3:19])[CH3:17])[C:4](=[O:10])[CH:3]=1
Reactant: CO[C@H](C)CCCCCl
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CO[C@H](C)CCCCn1c(=O)cc(N)[nH]c1=O
Temperature: 90 °C
Yield: 63 %

Procedure:
A mixture of 6-amino-1-methyluracil (141 mg, 1.0 mmol), (R)-1-chloro-5-methoxyhexane (150 mg, 1.0 mmol), dimethylsulfoxide (2 ml) and sodium hydride (30 mg, 1.2 mmol) was heated to 90° C. for 18 hours. After cooling to room temperature, the mixture was treated with water (7 ml) and extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate followed by 5% methanol-ethyl acetate to provide (R)-6-amino-3-(5-methoxyhexyl)uracil (152 mg, 60% yield) as an oil.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH:20]([OH:22])[CH3:21])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:57][C:58]1[S:59][CH:60]=[CH:61][N:62]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH:20]([OH:22])[CH3:21])=[CH:13][CH:12]=2)[C:8]([NH:57][C:58]2[S:59][CH:60]=[CH:61][N:62]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(O)CC#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(O)CC#Cc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Yield: 53.2 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(4-hydroxy-pent-1-ynyl)-phenyl]-propionic acid (100 mg, 0.30 mmol), benzotriazol-I -yloxytris(dimethylamino)phosphonium hexafluorophosphate (200 mg, 0.45 mmol), triethylamine (0.13 mL, 0.93 mmol) and 2-aminothiazole (52 mg, 0.45 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 2 h. At this time, the reaction was diluted with methylene chloride (10 mL). This solution was washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a half-saturated aqueous sodium chloride solution (1×10 mL). The aqueous layers were back extracted with methylene chloride (1×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(4-hydroxy-pent-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide (61 mg, 47.9%) as a white solid: mp 162-163° C.; EI-HRMS m/e calcd for C22H26N2O2S (M+) 382.1715, found 382.1718.
Reaction SMILES: [C:1]([C:3](=[C:9]([S:17][CH3:18])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([O:6]CC)=O)#[N:2].[CH3:19][N:20]=[C:21]=[O:22]>>[C:1]([C:3]1[C:4](=[O:6])[N:20]([CH3:19])[C:21](=[O:22])[N:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:9]=1[S:17][CH3:18])#[N:2]
Reactant: CN=C=O
Reactant: CCOC(=O)C(C#N)=C(Nc1ccccc1)SC
Product: CSc1c(C#N)c(=O)n(C)c(=O)n1-c1ccccc1
Yield: 27 %

Procedure:
This compound was synthesized from ethyl 2-cyano-3-methylthio-3-phenylaminoacrylate and methyl isocyanate according to the same process as described in Example 92b. Yield=27%.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[O:5][C:6]=1[CH:7]([OH:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:26][O:27][C:28](=[O:39])[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][C:32]=1[CH3:38].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:26][O:27][C:28](=[O:39])[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:15][CH:7]([C:6]2[O:5][C:4]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=3)=[N:3][C:2]=2[CH3:1])[CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:33][C:32]=1[CH3:38]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(O)Cc1ccccc1
Reactant: COC(=O)CCc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OC(Cc2ccccc2)c2oc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Yield: 45.1 %

Procedure:
To a solution of 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-2-phenyl-ethanone (1.2 g, 3.5 mmol) in 50 mL MeOH at 0° C. is added LiBH4 (0.086 g, 3.50 mmol) portionwise. After gas evolution had ceased a tic indicated that the reaction is complete and 50 mL of NH4Cl (aq.) is added and the resultant solution extraxted with ethyl acetate (3×50 mL). The combined organics are dried (Na2SO4), filtered and concentrated under vacuo. The resultant crude oil is purified by flash column chromatography (10%–20%) ethyl acetate/hexane to provide 1.1 g 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-2-phenyl-ethanol. To a solution of 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-2-phenyl-ethanol (0.50 g, 1.44 mmol), 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.28 g, 1.44 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (0.54 g, 2.16 mmol) in 15 mL toluene is added tributylphosphine (0.5 mL, 2.16 mmol). After 1 hr the volatiles are removed and the crude ester purified by flash column chromatography (10%–25%) ethyl acetate/hexane to provide 0.34 g (45%) of 3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-2-phenyl-ethoxy}-phenyl)-propionic acid methyl ester as the racemate. The ester is separated by HPLC utilizing a chiral column with ethanol as the eluent. This enatiomerically pure ester (0.097 g, 0.18 mmol) is hydrolyzed in the usual manner 3 eq. 1N LiOH in 0.5 mL 3:2:1 solution of THF:MeOH:H2O to provide 0.09 g (93%) of the title compound. MS (M++1) 510.