Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH2:32][CH2:33]O)[CH:29]=2)[CH:24]=[CH:23][CH:22]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:33][CH2:32][O:31][C:28]2[CH:29]=[C:30]3[C:25]([CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:26][CH:27]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCOc1ccc2cccnc2c1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc3cccnc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 44.1 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.267 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.305 g), stirred for 15 minutes and treated with the mesylate prepared from 1.135 g of 2-(7quinolyloxy)ethanol. The mixture was heated under argon at 60° C. for 5 hours. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with dichloromethane and dilute cold sodium bicarbonate solution. The dichloromethane extracts were washed with water, dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (ethyl acetate) and crystallized from dichloromethane-hexane to provide 0.93 g of alpha-oxo-4-[[2-(7-quinolyloxy)ethyl]oxy]benzeneacetic acid methyl ester as a colorless solid, mp 92°-94° C.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[C:19]([O:21][CH2:22][CH3:23])=[CH:18][CH:17]=[C:16]([C:24]([O:26]C3C=CC([N+]([O-])=O)=CC=3)=O)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([Cl:36])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:37][C:38]1[CH:39]=[N:40][CH:41]=[C:42]([Cl:45])[C:43]=1[NH2:44].[H-].[Na+].Cl>CN(C=O)C>[Cl:37][C:38]1[CH:39]=[N:40][CH:41]=[C:42]([Cl:45])[C:43]=1[NH:44][C:24]([C:16]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:36])[CH:13]=3)[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:20]=2[C:19]([O:21][CH2:22][CH3:23])=[CH:18][CH:17]=1)=[O:26]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: CCOc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2c3cc(Cl)ccc3n(Cc3ccccc3)c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cc(Cl)ccc3n(Cc3ccccc3)c12
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a solution of 4-nitrophenyl 9-benzyl-6-chloro-1-ethoxy-9H-4-carbazolecarboxylate (31 mg, 0.062 mmoles) and 3,5 dichloro-4-aminopyridine (10.1 mg, 0.062 mmoles) in dry DMF (3 ml), under N2 atmosphere, 60% sodium hydride (5.40 mg, 0.124 mmoles) was added at 25° C. and the reaction mixture was stirred overnight. The reaction mixture was poured into ice-cold water and neutralized with 1N HCl. The compound was extracted with chloroform (3×10 ml), combined the organic layers and washed with water (3×10 ml) and with brine (10 ml). The organic layer was dried over anhydrous sodium sulphate and concentrated to give 22.5 mg of the title compound as an off-white crystalline solid. m. p: 221-223° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OCCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
In analogy to example 15.1, 5-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-yn-1-ol and methane sulfonyl chloride were converted to yield Methanesulfonic acid 5-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester as a light yellow oil, MS: 405 (M, 1Cl).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([OH:14])[C:3]=1[C:15](=[O:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].Cl.[C:25](Cl)(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.O>CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]2[C:3]=1[C:15](=[O:17])[CH:16]=[C:25]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[O:14]2
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(=O)c1c(O)cc(N2CCOCC2)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=c1cc(-c2cccnc2)oc2cc(N3CCOCC3)cc(O)c12
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 12 %

Procedure:
To a suspension of 1-(2,6-dihydroxy-4-morpholin-4-yl-phenyl)-ethanone (86 mg, 0.362 mmol) and K2CO3 (250 mg, 1.81 mmol) in acetone (3 mL) was added nicotinoyl chloride hydrochloride (0.71 mL, 0.399). The reaction vessel was sealed and heated to 85° C. for 24 h. After cooling to room temperature, water (about 2 mL) was added, and the mixture was allowed to stir for about 10 min. The contents were transferred to a separatory funnel containing water (5 mL) and extracted with EtOAc (3×15 mL). The organic layer was dried (MgSO4) and concentrated. The concentrate was purified via Biotage chromatography with gradient elution from 100% hexanes to 100% EtOAc to yield 14 mg (12%) of 5-hydroxy-7-morpholin-4-yl-2-pyridin-3-yl-chromen-4-one. Rf=0.22 (100% EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:8]=1)[NH2:7].[C:10](OCC)(=[O:13])[CH:11]=[CH2:12].CC(N=NC(C#N)(C)C)(C#N)C>CS(C)=O.O>[Cl:1][C:2]1[CH:8]=[C:6]2[C:5]([CH2:12][CH2:11][C:10](=[O:13])[NH:7]2)=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCC
Reactant: Nc1cc(Cl)ccc1I
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCc2ccc(Cl)cc2N1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a solution of 5-chloro-2-iodoaniline (14.0 g, 0.0552 mol) in dimethyl sulphoxide, ethyl acrylate (30.38 mL, 0.276 mol) and n-tributyltinhydride (22.3 mL, 0.0828 mol), AIBN (3.6 g, 0.022 mol) was added at room temperature. The reaction mixture was heated to 120° C. and stirred for 16 h. The reaction mixture was cooled to room temperature; the reaction mixture was diluted with water. The aqueous phase was extracted with ethyl acetate (3×500 mL), the combined organic layer was washed with cold water, saturated aqueous sodium chloride solution and dried over sodium sulphate, the solvent was evaporated under vacuum and the residue was purified with silica gel (60-120 mesh) silica gel column chromatography by 0-20% ethyl acetate in hexane to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 7.17-7.15 (d, J=7.6 Hz, 1H), 6.93-6.91 (d, J=8.0 Hz, 1H), 6.85 (s, 1H), 2.85-2.81 (t, J=7.2 Hz, 2H), 2.44-2.41 (t, J=8 Hz, 2H); MS (M+1): 181.9.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.S(Cl)(Cl)=O.[F:23][C:24]([F:35])([F:34])[C:25]1[C:33]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=2[NH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:35][C:24]([F:23])([F:34])[C:25]1[C:33]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=2[N:27]([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]3)[N:26]=1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(CO)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Cn3nc(C(F)(F)F)c4c3CCCC4)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.1 %

Procedure:
(S)—N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (23 mg, 0.086 mmol) was dissolved in DCM (5 mL) and thionyl chloride (51 mg, 0.43 mmol) was added. The reaction mixture was stirred at room temperature for 1 h before being concentrated to dryness. The whole was dissolved in DMF (2 mL) to this was added 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (25 mg, 0.086 mmol) followed by potassium carbonate (24 mg, 0.172 mmol). The reaction mixture was heated to 65° C. for 3 h before being quenched with water (2 mL) and the organics extracted with EtOAc (3×5 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Purification by preparative basic HPLC gave the title compound (1.2 mg, 2.7 μmol, 2.9%). MS (ESI): m/z [M+H]+ 442.2
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8](Cl)=[O:9])[CH2:3]1.Cl.[CH3:12][NH:13][O:14][CH3:15].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:15][O:14][N:13]([CH3:12])[C:8]([CH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]1)=[O:9]
Reactant: CNOC
Reactant: CC1CCCC(C(=O)Cl)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CON(C)C(=O)C1CCCC(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of 3-methylcyclohexanecarbonyl chloride (1.13 g, 7.03 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.755 g, 7.74 mmol) in CHCl3 (70 mL) at 0° C. was added pyridine (1.252 mL, 15.48 mmol) dropwise. The ice bath was removed and the mixture was warmed to RT. After 1 h, the reaction was evaporated to dryness, diluted with 1:1 mixture of ether and CH2Cl2 (40 ml) and then washed with brine. The aqueous layer was washed once more with 1:1 mixture of ether and CH2Cl2. The organic layers were combined, dried with MgSO4, filtered, and concentrated to afford the crude N-methoxy-N,3-dimethylcyclohexanecarboxamide (1.1 g, 84% yield) as clear yellowish oil which was used without further purification. MS (ESI) m/z: 186.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 3.74-3.65 (m, 3H), 3.20-3.14 (m, 3H), 2.71 (m., 1H), 1.85-1.12 (m, 10H), 0.94-0.88 (m, 3H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10])=[C:4]([F:17])[CH:3]=1.N1C=CC=CC=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>CC(C)=O>[F:17][C:4]1[CH:3]=[C:2]([NH:1][C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])[CH:7]=[CH:6][C:5]=1[CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC(=O)C(C(=O)OC)c1ccc(N)cc1F
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: COC(=O)C(C(=O)OC)c1ccc(NC(=O)Oc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a stirred solution of dimethyl 2-(4-amino-2-fluorophenyl)malonate (3.0 g, 12.448 mmol, 1.0 eq) in acetone (30 mL) was added pyridine (3.0 mL, 37.344 mmol, 3.0 eq) and phenyl chloroformate (1.89 mL, 14.937 mmol, 1.2 eq) at 0° C. and the mixture was stirred at RT for 1 h. The solvent was evaporated, the residue diluted with EtOAc (50 mL), washed with water (100 mL), brine (20 mL) and the solvent evaporated. The resulting residue was purified by CC using EtOAc/PE (1:4) as eluent to get dimethyl 2-(2-fluoro-4-(phenoxycarbonylamino)phenyl)malonate (3.5 g, 78%, white solid; TLC system: EtOAc/PE (3:7), Rf: 0.5).
Reaction SMILES: [CH:1]1([C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:16][CH:15]=2)([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)O)[CH2:3][CH2:2]1.[BrH:27].O>C(O)(=O)C>[Br:27][CH2:3][CH2:2][CH:1]=[C:4]([C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:16][CH:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1
Reactant: CCN(CC)C(=O)c1ccc(C(O)(c2cccc(OC)c2)C2CC2)cc1
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1ccc(C(=CCCBr)c2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
1-Cyclopropyl-1-(4-diethylcarbamoylphenyl)-1-(3-methoxyphenyl)Methanol (90.9 mg) was dissolved in acetic acid (1.8 ml), added with 48% hydrobromic acid (1.8 ml) with ice cooling and stirred at room temperature for 1.5 hours. The reaction mixture was added with water (5 ml) and extracted twice with dichloromethane (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 102 mg of the title compound. Yield: 95%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: BrCc1ccccc1Oc1ccccc1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccccc1Oc1ccccc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-2-phenoxybenzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.93 min.; [M+H]+: 418.01 g/mol.
Reaction SMILES: [Cl:1][C@H:2]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:3](O)=[O:4].S(Cl)([Cl:14])=O>>[Cl:1][C@H:2]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:3]([Cl:14])=[O:4]
Reactant: COC(=O)CC[C@@H](Cl)C(=O)O
Reactant: O=S(Cl)Cl
Product: COC(=O)CC[C@@H](Cl)C(=O)Cl
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A mixture of (R)-2-chloro-4-methoxycarbonylbutyric acid (3.85 g) and thionyl chloride (2.4 ml) was stirred at 75° C. for 1 hour and the excess thionyl chloride was removed by distillation to give (R)-2-chloro-4-methoxycarbonylbutyryl chloride as an oil. A solution of this oil in ethyl acetate (10 ml) was then added dropwise to a stirred and ice-cooled mixture of 3-amino-5,6,7,8-tetrahydro-2-naphthol hydrobromide (5.20 g), sodium bicarbonate (4.48 g), water (20 ml) and ethyl acetate (30 ml). The whole was stirred at 0° C. for 1.5 hour and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate. The combined organic layer was washed with water and dried over magnesium sulfate. Evaporation of the solvent gave methyl (R)-4-chloro-4-[N-(3-hydroxy-5,6,7,8-tetrahydro-2naphthyl)carbamoyl]butyrate as an oil (6.20 g). A mixture of this oil, powdered potassium carbonate (2.95 g) and dimethylformamide (20 ml) was then stirred at room temperature for 1.5 hour. Dilution with water gave methyl (S)-3-(3,4,6,7,8,9-hexahydro-3-oxo-2H-naphtho[2,3-b][1,4]oxazin-2-yl)propionate was crystals (2.52 g, 40.9%). Purification by column chromatography on silica gel with ethyl acetate-hexane (3:2, v/v), followed by recrystallization from ethyl acetate-ethyl ether gave colorless crystals (2.22 g, 36.0%), m.p. 138°-139° C. [α]D26 -7.8° (c=0.3, CHCl3).
Reaction SMILES: [OH:1][C@@H:2]([CH3:7])[CH2:3][C:4]([O-:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][N:51]=[C:50]([NH:54][C:55]3[CH:60]=[CH:59][C:58]([N:61]4[CH2:66][CH2:65][O:64][CH2:63][CH2:62]4)=[CH:57][CH:56]=3)[N:49]=2)=[CH:44][CH:43]=1>CN(C=O)C>[OH:1][C@@H:2]([CH3:7])[CH2:3][C:4]([NH:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][N:51]=[C:50]([NH:54][C:55]3[CH:56]=[CH:57][C:58]([N:61]4[CH2:62][CH2:63][O:64][CH2:65][CH2:66]4)=[CH:59][CH:60]=3)[N:49]=2)=[CH:44][CH:43]=1)=[O:6]
Reactant: C[C@H](O)CC(=O)[O-]
Reactant: Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)CC(=O)Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
To a solution of (S)-3-hydroxybutyrate (0.180 g, 1.73 mmol), HATU (0.602 g, 1.58 mmol), DIEA (1.0 mL, 5.4 mmol) in DMF (3.0 mL) was added a solution of 4-(4-aminophenyl)-N-(4-morpholinophenyl)pyrimidin-2-amine (0.500 g, 1.44 mmol) in DMF (1.0 mL). The reaction mixture was stirred at rt for 2 hours, at which time it was quenched with saturated NaHCO3 (10 mL, aq.), extracted into DCM (3×), and washed with brine (1×). The organic layers were dried with sodium sulfate and concentrated. The product was purified by reverse phase HPLC to afford (S)-3-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)butanamide (0.136 g, 22% yield) as a light brown solid. (363) 1H-NMR (400 MHz, DMSO-d6): 10.14 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.77 (d, 2H), 7.68 (d, 2H), 7.27 (d, 1H), 6.94 (d, 2H), 4.79 (d, 1H), 4.11 (m, 1H), 3.74 (m, 4H), 3.05 (m, 4H), 2.47 (dd, 1H), 2.35 (dd, 1H)), 1.15 (d, 3H); MS (EI) m/z for C24H28N5O3: 434.3 (MH+).
Reaction SMILES: [CH2:1]([Li])CCC.[Si:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Si:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH2:1])=[CH:16][CH:15]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: [Li]CCCC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
p-OSi-St chain transfer agent was synthesized in two steps. In a 500 ml flask equipped with a magnetic stirring bar, 70.4 g of imidazole was mixed with 52.4 g (0.42 mol) of 4-hydroxybenzaldehyde and 77.4 g of t-butyldimethylsilyl chloride in THF solution. The mixture was stirred at ambient temperature for 4 hours before being poured into cold water. The organic layer was separated and extracted with ether, then dried with magnesium sulfate. After evaporating the solvent, 94 g of 4-(t-butyldimethylsilyloxy)benzaldehyde (90% yield), a deep yellow color liquid, was obtained. The second reaction step was performed under a nitrogen atmosphere. In a 500 ml flask equipped with a magnetic stirring bar, 123.6 g of methyltriphenylphosphonium bromide suspended in THF was treated with 149.6 ml of n-butyllithium (2.5M in hexane). After 1 hour, 80.0 g of 4-(t-butyldimethylsilyloxy)benzaldehyde was introduced dropwise into the red solution. The mixture was stirred overnight at room temperature and then poured into cold water. The organic layer was separated by ether extraction and dried with magnesium sulfate. Further purification was performed by distillation under vacuum (10 Torr) at elevated temperature (80° C.). 65 g of p-OSi-St was obtained with a yield of more than 90%. Its structure was confirmed by 1H NMR spectrum.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:28][C:29](=[O:42])[CH:30]([N:35]([CH3:41])[CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:31][CH:32]([CH3:34])[CH3:33])[C:17](=[O:27])[NH:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25]O[CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1(CCN)CCCC[CH2:44]1.[N-]=C=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([NH:28][C:29](=[O:42])[CH:30]([N:35]([CH3:41])[CH2:36][CH2:37][CH:38]([CH3:39])[CH3:40])[CH2:31][CH:32]([CH3:33])[CH3:34])[C:17](=[O:27])[NH:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:44][CH2:23][CH2:22]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCN(C)C(CC(C)C)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NCCN1CCOCC1
Reactant: NCCN1CCCCC1
Agent: [N-]=C=O
Solvent: ClCCl
Product: CC(C)CCN(C)C(CC(C)C)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NCCN1CCCCC1
Reaction time: 48 h

Procedure:
A suspension of N-(2-methylbutyl)-N-methyl-leucine-tyrosine(OBn) -Kaiser oxime resin (Example 57, IIc) in CH2Cl2 was treated with 1.5 equivalents of 2-piperdin-1-ylethylamine. The suspension was shaken for 48 hours. After the reaction was completed, additional CH2Cl2 and 1 equivalent of polymer supported isocyanate was added. After the suspension was shaken for 48 hours, the resin was filtered off, and the solvent was evaporated to yield the title product.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]1[CH2:14][CH2:13]OCC1>>[C:1]1([C:14]([C:13]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: C1COCCO1
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phenylmagnesium chloride (2W, 6.8 mmol, 1.5 eq.) was slowly added to a stirred solution of the aldehyde from Part A (3.00 g, 4.5 mmol, 1.0 eq.) in dioxane (25 mL) at 0° C. After 1 h, the reaction was quenched with methanol (5 mL), followed by water (25 mL). Trifluoroacetic acid (25 mL) was then added, and the mixture stirred at room temperature for 1 h. 10 N NaOH was added to adjust the pH to 10 and the organic solvents removed in vacuo leaving solid triphenylmethanol and an aqueous phase behind. The triphenylmethanol was filtered and the aqueous was acidified to pH=3 with conc. HCl producing a precipitate. The solids were filtered, dried, and recrystallized from hexane/ethyl acetate yielding 532 mg of a white solid: m.p. 137.0-145.0° C. NMR (DMSO-d6): δ 7.77"7.46 (m, 4); 7.46-7.30 (m, 5H); 6.94 (d, 2H, J=9Hz); 6.76 (d, 2H, J=9Hz); 6.37 (d, 1H, J=5Hz); 5.97 (d, 1H, J=5Hz); 5.09 (s, 2H); 2.25 (t, 2H, J=7Hz); 1.34 (t of t, 2H, J=7,7Hz); 1.17 (t of q, 2H, J=7,7H); 0.74 (t, 3H, J=7Hz). Anal. calcd. for C28H27ClN6O.(H2O)0.5 :C, 66.20; H, 5.56; Cl, 6.98. Found: 66.12; H, 5.51; Cl, 7.25.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:31]=[CH:30][N:29]([CH2:32][C:33]([CH3:36])([OH:35])[CH3:34])[N:28]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]([NH:26][C:27]2[CH:31]=[CH:30][N:29]([CH2:32][C:33]([OH:35])([CH3:34])[CH3:36])[N:28]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C(CC1CCOCC1)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCOCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
2-(3,4-Dichloro-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid (152 mg, 0.50 mmol) was dissolved in methylene chloride (5 mL) and N,N-dimethylfomamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 270 μL, 0.53 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes. After this time, the reaction was concentrated in vacuo and the residue was then taken up in methylene chloride (5 mL). This solution was then added dropwise to a flask containing a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in Example 80, 78 mg, 0.50 mmol), 2,6-lutidine (130 μL, 1.00 mmol), and methylene chloride (5 mL) which was 0° C. The reaction was allowed to warm to 25° C. and stirred for a period of 2 h. After this time, the reaction was quenched with a small amount of methanol and then concentrated in vacuo. It was then dissolved in ethyl acetate (25 mL) and washed with a 1N hydrochloric acid solution (1×10 mL) and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was then dried over sodium sulfate and concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 100% ethyl acetate) to afford 2-(3,4-dichloro-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (149 mg, 81%) a 1:1 enantiomeric reaction as a white foam.