Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18]>C(Cl)Cl>[OH:18][CH2:17][CH2:1][NH:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5]
Reactant: CNC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCCO
Yield: 67 %

Procedure:
The hydrochloride salt of L-tryptophan 2-hydroxyethylamide was prepared and coupled with 3 as described for the hydrochloride salt of L-tryptophan methylamide in Example 1 except that 3 was activated with 1,1'-carbonyldiimidazole for 20 minutes in methylene chloride at room temperature. The crude product was a mixture of 0.7 g (67% yield) of the diastereoisomers 12A,B: Rf (C) 12A 0.38, Rf (C) 12B 0.19.
Reaction SMILES: [CH3:1][C:2]([N:10]([CH2:20][CH2:21][C:22](=O)[CH3:23])[C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[K+]>C(O)C>[CH3:1][C:2]([N:10]1[CH2:20][CH2:21][C:22]([CH3:23])=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]1=[O:19])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)CCN(C(=O)Cc1ccccc1)C(C)(C)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2ccccc2)CC1
Yield: 67 %

Procedure:
7.1 g (0.022 mol) of N-(α,α-dimethylbenzyl)-N-(3-oxobutyl)phenylacetamide prepared by the method of Reference Example 10, was dissolved in 50 ml of ethanol, and 0.33 g (0.005 mol) of potassium hydroxide powder was added thereto. The mixture was reflux under heating for 1.5 hours. Then, the reaction mixture was returned to room temperature, and ethanol was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. Then ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. The solent was distilled off under reduced pressure. the residue thereby obtained was recrystallized from ethanol to obtain 4.5 g (yield: 67.2%) of the desired compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]([OH:34])=O)[CH2:27][CH2:26]1.Cl.[NH2:36][C@@H:37]([C@H:42]([OH:44])[CH3:43])[C:38]([O:40][CH3:41])=[O:39].CN1CCOCC1>ClCCl>[OH:44][C@H:42]([CH3:43])[C@H:37]([NH:36][C:32](=[O:34])[CH2:31][N:28]1[CH2:27][CH2:26][O:25][CH2:30][CH2:29]1)[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: O=C(O)CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](NC(=O)CN1CCOCC1)[C@@H](C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
HATU (7.66 g, 20.1 mmol) was added to a solution of 2-morpholinoacetic acid (2.44 g, 16.8 mmol) and (2S,3R)-methyl 2-amino-3-hydroxybutanoate hydrochloride (2.84 g, 16.8 mmol) in dichloromethane (20 mL) at 0° C. N-Methylmorpholine (5.1 g, 50.4 mmol) was added and the reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=100:1 to 60:1) to afford (2S,3R)-methyl 3-hydroxy-2-(2-morpholinoacetamido)butanoate (2.1 g, 48% yield).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([CH2:8][NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[O:11])#[N:7].C(N(C(C)C)CC)(C)C>ClCCl>[C:6]([CH2:8][NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:24][CH:23]=1)(=[O:20])=[O:21])=[O:11])#[N:7]
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1ccc(S(=O)(=O)C[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (0.140 mL, 1.81 mmol) was added dropwise to a stirred solution of trans-N-cyanomethyl-2-(4-hydroxymethylbenzenesulfonylmethyl)-cyclohexanecarboxamide (0.576 g, 1.645 mmol) and diisopropylethylamine (0.344 mL, 1.97 mmol) in dichloromethane (5 mL) chilled to 5° C. The ice bath was removed and the reaction was allowed to proceed with stirring overnight. The reaction was not complete, so additional diisopropylethylamine (0.172 ml, 1.0 mmol) was added, followed by additional methanesulfonyl chloride (0.070 mL, 0.90 mmol). The reaction was allowed to stir an additional hour at ambient temperature. Dichloromethane (100 mL) was added and the solution was washed with water, 1N HCl, and then saturated aqueous sodium bicarbonate. The organic layer was dried with magnesium sulfate, filtered, and concentrated by rotary evaporation to yield trans-methanesulfonic acid 4-[2-(cyanomethyl-carbamoyl)-cyclohexylmethanesulfonyl]-benzyl ester as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:5]([CH3:7])[CH3:6].[OH-].[Na+].CO>O>[C:8]1([CH:4]([CH:5]([CH3:7])[CH3:6])[C:3]([OH:14])=[O:2])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C(c1ccccc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C(C(=O)O)c1ccccc1
Yield: 94.4 %

Procedure:
A solution of 165.8 g (0.87 mol) of 2-phenyl-3-methylbutyric acid methyl ester, 52.0 q (1.30 mol) of sodium hydroxide, 1200 ml of methanol and 600 ml of water was heated to reflux for one hour. After evaporation of the methanol under reduced pressure, dilution with water and acidification with conc. hydrochloric acid, the aqueous solution was extracted with ether. The ethereal extracts were washed with water, dried over sodium sulfate and evaporated under reduced pressure, to obtain 146.3 g (95%) of 2-phenyl-3-methylbutyric acid in the form of a yellow oil which was used directly in the next step.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:42])=[C:9]([CH2:11][O:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26](N(OC)C)=[O:27])=[CH:22][N:21]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:20]=3)=[CH:15][C:14]=2[O:40][CH3:41])[N:10]=1.[CH3:43][Mg]Br.Cl>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:42])=[C:9]([CH2:11][O:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26](=[O:27])[CH3:43])=[CH:22][N:21]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:20]=3)=[CH:15][C:14]=2[O:40][CH3:41])[N:10]=1
Reactant: C[Mg]Br
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)N(C)OC)ccc1OCc1nc(-c2ccco2)oc1C
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(C)=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-N-methoxy-N-methyl-2-propenamide (0.40 g) and tetrahydrofuran (30 mL) was added dropwise methylmagnesium bromide (1M tetrahydrofuran solution, 2.8 mL) at 0° C. and the mixture was stirred at room temperature for 2 hrs. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give (3E)-4-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-3-buten-2-one as colorless crystals (0.25 g, yield 68%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 177-178° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]>O1CCCC1>[N:1]1([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)C(=O)Cl
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)n1ccnc1
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a suspension of imidazole (12.2 g, 175 mmol) in tetrahydrofuran (250 ml) was added ethyl chlorooxoacetate (10 mL, 90 mmol) in tetrahydrofuran (250 ml) at 0° C., and the mixture was stirred for 1 hour and then filtered off and washed with cold tetrahydarofuran (100 mL). The solvent was evaporated off under the reduced pressure to obtain 14.4 g of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:12]#[N:13])=[C:8]([C:10]#[N:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[CH2:1]([C:5]1[N:9]([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)[C:8]([C:10]#[N:11])=[C:7]([C:12]#[N:13])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCCCc1nc(C#N)c(C#N)[nH]1
Product: CCCCc1nc(C#N)c(C#N)n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
2-n-Butyl-4,5-dicyano-1-(4-nitrobenzyl)imidazole was prepared from 2-n-butyl-4,5-dicyanoimidazole by the procedure in Example 1, Part A using 4-nitrobenzyl bromide as the alkylating agent. The product was obtained as an oil. NMR (200 MHz, CDCl3) δ 8.29 (d, 2H, J=10 Hz); 7.29 (d, 2H, J=10 Hz); 5.36 (s, 2H); 2.67 (t, 2H, J=7 Hz); 1.70 (t of t, 2H, J=7,7 Hz); 1.36 (t of q, 2H, J=7,7 Hz); 0.86 (t, 3H, J=7 Hz); Mass Calcd. for C16H15N5O2 : 309.1225. Found: 309.1211.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:3]=1.[CH2:18]([O:20][C:21](=[O:28])[CH2:22][C:23](=O)[CH:24]([CH3:26])[CH3:25])[CH3:19]>CCO.C(OCC)(=O)C>[CH2:18]([O:20][C:21]([C:22]1[C:23]([CH:24]([CH3:26])[CH3:25])=[N:8][C:5]2[C:4]([C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:28])[CH3:19]
Reactant: Nc1ccc(Cl)cc1C#Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)C(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Yield: 22.9 %

Procedure:
To a solution of 4-chloro-2-(2-chloro-phenylethynyl)-phenylamine (prepared as described in example 10 step A, 100 mg, 0.38 mmol) and 4-methyl-3-oxo-pentanoic acid ethyl ester (0.092 ml, 0.57 mmol) in anhydrous EtOH (10 ml), was added p-TsOH—H2O (72.56 mg, 0.38 mmol) and the mixture was refluxed for 72 h. After cooling, the reaction mixture was diluted with ethyl acetate and the organic layer was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate, concentrated in vacuo. The crude residue was purified by flash column chromatography (elution with 3% EtOAc in hexane) to give 6-chloro-4-(2-chloro-benzyl)-2-isopropyl-quinoline-3-carboxylic acid ethyl ester (35 mg, 23% yield) as a yellow sticky solid. LC-MS: 402 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12](N)=[CH:11][CH:10]=[CH:9]2)=[N+:2]=[N-:3].S(=O)(=O)(O)[OH:16].N([O-])=O.[Na+]>O>[N:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[OH:16])[CH:7]=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: O=S(=O)(O)O
Reactant: [N-]=[N+]=Nc1cccc2cccc(N)c12
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1cccc2cccc(O)c12

Procedure:
A sample of 8-azido-1-naphthylamine (0.368 g., 0.02 mole) was dissolved in warm, dilute sulfuric acid (3 ml. of conc. H2SO4 diluted with 30 ml. of water). The solution was cooled to O°C. and diazotized with a solution of NaNO2 (160 mg., 0.023 mole) in 2 ml. of water. The excess of nitrous acid was destroyed by the addition of urea. The yellow solution of the diazonium salt was diluted with 100 ml. of water and heated at 60°for 1.5 hr. The precipitated material was washed with water, dried and filtered through activated charcoal. Removal of ether left a residue which weighed 35 mg. Recrystallization from petroleum ether gave 1-azido-8-hydroxynaphthalene in the form of pale yellow needles (20 mg., 5.4 percent), m.p. 65°C.-67°C.
Reaction SMILES: Br[CH:2]([C:4]1[C:5]([F:27])=[CH:6][C:7]2[O:16][CH2:15][CH2:14][N:13]3[C:9](=[N:10][C:11]([C:17]4[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=4)=[CH:12]3)[C:8]=2[CH:26]=1)[CH3:3].[CH2:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:29].CCN(C(C)C)C(C)C>O1CCOCC1>[CH2:28]([N:30]1[CH2:35][CH2:34][N:33]([CH:2]([C:4]2[C:5]([F:27])=[CH:6][C:7]3[O:16][CH2:15][CH2:14][N:13]4[CH:12]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[N:10]=[C:9]4[C:8]=3[CH:26]=2)[CH3:3])[CH2:32][CH2:31]1)[CH3:29]
Reactant: CCN1CCNCC1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(C(C)Br)c(F)cc2OCC3)n(C(C)C)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(C(C)c2cc3c(cc2F)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Yield: 65 %

Procedure:
A solution of 9-(1-bromoethyl)-8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (85 mg, 0.20 mmol), N-ethylpiperazine (27 μL, 0.22 mmol) and DIPEA (54 μL, 0.30 mmol) in dioxane (2 mL) was stirred at RT for 24 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (Si-PPC, gradient 0-10% 2 M NH3/MeOH in DCM) to give 374 (61 mg, 0.13 mmol, 65% over 2 steps) as a white solid. LCMS (Method K): RT 2.74 min [M+H]+ 468.2. 1H NMR (CD3OD, 400 MHz): δ 8.55 (1H, d, J=8.2 Hz), 7.68 (1H, s), 6.76 (1H, d, J=11.1 Hz), 5.83 (1H, sept., J=6.7 Hz), 4.48 (4H, br s), 3.84 (1H, q, J=6.8 Hz), 2.50 (8H, br s), 2.38 (2H, q, J=7.4 Hz), 2.33 (3H, s), 1.53 (3H, d, J=6.7 Hz), 1.52 (3H, d, J=6.7 Hz), 1.40 (3H, d, J=6.8 Hz), 1.03 (3H, t, J=7.4 Hz)
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]([CH3:30])=[C:20]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[CH3:29])[N:21]=2)=[CH:13][CH:12]=1>>[C:11]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]([CH3:30])=[C:20]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[CH3:29])[N:21]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from phenyl boronic acid (174 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 16 mg (16%). MS (m/e) 347.3 (M+1)
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]2[O:15][C:16]3[C:22]([Cl:23])=[CH:21][C:20]([Br:24])=[CH:19][C:17]=3[CH:18]=2)(=O)=O)=CC=1.[CH3:25][O:26][CH:27]([O:30][CH3:31])[CH2:28][NH2:29].O>O1CCOCC1>[Br:24][C:20]1[CH:21]=[C:22]([Cl:23])[C:16]2[O:15][C:14]([CH2:13][CH2:12][NH:29][CH2:28][CH:27]([O:30][CH3:31])[O:26][CH3:25])=[CH:18][C:17]=2[CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cc3cc(Br)cc(Cl)c3o2)cc1
Reactant: COC(CN)OC
Solvent: C1COCCO1
Solvent: O
Product: COC(CNCCc1cc2cc(Br)cc(Cl)c2o1)OC
Temperature: 90 °C
Yield: 75.3 %

Procedure:
To a solution of the product of Example 84, step C (2.0 g, 4.65 mmol) in dioxane (10 mL) was added 2,2-dimethoxyethanamine (1.47 g, 13.95 mmol). The reaction mixture was heated to 90° C. for 3 h, cooled to ambient temperature, treated with water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and the filtrate concentrated in vacuo. Purification by flash column chromatography (SiO2, hexanes/ethyl acetate) gave N-(2-(5-bromo-7-chlorobenzofuran-2-yl)ethyl)-2,2-dimethoxyethanamine (1.27 g, 75%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.49 (d, J=1.8 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 6.44 (s, 1H), 4.48 (t, J=5.5 Hz, 2H), 3.38 (s, 6H), 3.09-2.94 (m, 4H), 2.78 (d, J=5.4 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=O)[O:19]C4C=CC=CC=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[OH:35][CH2:36][C@H:37]1[NH:41][C:40](=[O:42])[CH2:39][CH2:38]1>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:19])[O:35][CH2:36][C@@H:37]4[CH2:38][CH2:39][C:40](=[O:42])[NH:41]4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)Oc1ccccc1
Reactant: O=C1CC[C@@H](CO)N1
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OC[C@@H]1CCC(=O)N1
Temperature: 100 °C

Procedure:
Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed with (5S)-5-(hydroxymethyl)tetrahydro-1H-2-pyrrolone (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase LC/MS to give [(2S)-5-oxotetrahydro-1H-2-pyrrolyl]methyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (10 mg, 0.02lmmol). 1H NMR (CDCl-d) δ 1.90(m, 1H), 2.06(m, 4H), 2.34(m, 1H), 2.41(m, 2H), 3.64(m, 2H), 3.94 (s, 3H), 4.04(m, 2H), 4.14(m, 2H), 4.98(m, 1H), 5.33(m, 3H), 6.10(s, 1H), 6.98(s, 1H), 7.04 (s, 1H), 7.09(m, 1H), 7.31(s, 1H), 8.11(bs, 1H), 8.32(s, 1H). LC/MS: MH+481.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[C:19]([O:22][C@@H:23]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@@H:24]1OC(=N)C(Cl)(Cl)Cl)(=[O:21])[CH3:20].C(=O)([O-])O.[Na+]>ClCCl>[C:19]([O:22][C@@H:23]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@H:24]1[O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][C:8]1[CH:17]=[CH:18][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:6][CH:7]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C=CCOc1ccc(Cc2ccccc2O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOc1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of 2-(4-allyloxybenzyl)phenol (0.20 g) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose(0.45 g) in dichloromethane(8.5 mL) was added boron trifluoride-diethyl ether complex (0.12 g), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1) to give 2-(4-allyloxybenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.44 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH3:18][O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH2:22]>>[CH3:18][O:19][C:20](=[O:27])[C@@H:21]([NH:22][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]2)=[CH:16][CH:15]=1)[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-oxo-piperidine-1-yl)-benzoic acid (which was obtained in Example 151) and L-leucine methyl ester hydrochloride according to the procedure of Example 154 as a gum; 1H NMR (300 MHz, CDCl3) δ 0.96 (t, J=6.2 Hz, 6H), 1.60-1.80 (m, 3H), 2.57 (t, J=6.1 Hz, 4H), 3.71 (t, J=6.1 Hz, 4H), 3.77 (s, 3H), 4.80-4.90 (m, 1H), 6.40 (d, J=8.2 Hz, 1H), 6.94 (d, J=7.0 Hz, 2H), 7.75 (d, J=7.0 Hz, 1H); MS (ES) m/z: 347.4 (MH+); HRMS Calcd. for C19H26N2O4 (M+): 346.1892. Found: 346.1881.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].Br[C:25]1[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:25]4[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccc(S(N)(=O)=O)s4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.11) (168 mg, 0.5 mmol) and commercially available 5-bromo-thiophene-2-sulfonamide (121 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (119 mg, 48%). MS (ISN) 495.2 [(M−H)−]; mp 216° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Reactant: OCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, benzyl alcohol and DBU in DME. EI-MS m/e (%): 303 (M+H+, 100).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC([O-])(C)C.[K+].CN(C=O)C>[Cu]I.C(OCC)(=O)C>[C:11]1([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc2ocnc2c1
Reactant: Clc1ccccc1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(-c2nc3ccccc3o2)cc1
Yield: 10 %

Procedure:
Copper(I) iodide (19.1 mg, 0.1 mmol), benzoxazole (119 mg, 10.0 mmol), chlorobenzene (450 mg, 4.0 mmol), t-BuOK (336 mg, 3.0 mmol), and DMF (1.0 mL). After column chromatography (hexanes, then 10% ethyl acetate in hexanes) and preparative HPLC (5% ethyl acetate in hexanes) 78 mg (40%) of 2-phenylbenzoxazole is obtained. Table I, entry 1.
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:22][CH:23]([C:27](O)=[O:28])[C:24](O)=[O:25])[CH:19]=[CH:20][CH:21]=1>>[OH:28][C:27]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:24](=[O:25])[C:23]=1[S:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=1
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: COc1cccc(SC(C(=O)O)C(=O)O)c1
Product: COc1cccc(Sc2c(O)cc(-c3ccccc3)oc2=O)c1

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(3-methoxyphenyl)thio]propanedioic acid (1.51 g, 5.07 mmol). m.p. 130°-131° C. 1H NMR (400 MHz, DMSO-d6) δ 3.69 (s, 3H), 6.69 (dd, 1H), 6.72 (dd, 1H), 6.89 (s, 1H), 7.2 (dt, 2H), 7.58 (m, 3H), 7.88 (m, 2H).