Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([CH3:17])=[C:13]([CH2:15]I)[N:14]=2)=[CH:6][CH:5]=1.[OH:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([O:25][CH2:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:28]=2[C:29]([O:31][CH3:32])=[O:30])[CH2:20]1.C(OC)(C)(C)C>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([CH3:17])=[C:13]([CH2:15][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH:21]([O:25][CH2:26][C:27]4[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:28]=4[C:29]([O:31][CH3:32])=[O:30])[CH2:20]3)[N:14]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CI
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cccc1COC1CCCC(OCc2nc(-c3ccc(Br)cc3)oc2C)C1
Reaction time: 1 h

Procedure:
At room temperature, 50 mg of a 60% sodium hydride suspension and then 408 mg of 2-(4-bromophenyl)4-iodomethyl-5-methyloxazole were added to a solution of 200 mg of methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate in 5 ml of dimethylformamide. After one hour, methyl tert-butyl ether was added, and the mixture was extracted with water. The organic phase was dried over magnesium sulfate, the solvents were removed under reduced pressure and the residue was purified by RP-HPLC. This gave 49 as a light-yellow oil. C27H30BrNO5 (528.45), MS(ESI): 528.2, 530.2 (M+H+).
Reaction SMILES: C[O:2][C:3](=O)[N:4]([C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=[CH:8][C:7]=1[N+:23]([O-])=O)[CH3:5]>CO.O1CCCC1.[Ni]>[CH2:16]([O:15][CH2:14][CH2:13][O:12][C:10]1[CH:9]=[CH:8][C:7]2[NH:23][C:3](=[O:2])[N:4]([CH3:5])[C:6]=2[CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)N(C)c1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(=O)[nH]c2ccc(OCCOCc3ccccc3)cc21
Yield: 97.4 %

Procedure:
To a solution of [5-(2-benzyloxy-ethoxy)-2-nitro-phenyl]-methyl-carbamic acid methyl ester (0.93 g, 2.58 mmol) in methanol (50 ml) and tetrahydofuran (50 ml) was added Raney Ni and the mixture was stirred under a hydrogen atmosphere (1 atm) until all starting material was consumed as indicated by TLC. The catalyst was filtered, washed generously with tetrahydofuran, and the filtrate evaporated. The residue was washed with anhydrous tetrahydofuran and evaporated (2×15 ml). The oil was dissolved in anhydrous tetrahydofuran (30 ml) and NaH was added (0.31 g, 60%, 7.75 mmol), and the reaction mixture was heated to reflux under nitrogen for 3.5 h. The reaction was quenched with NH4Cl (sat) (20 ml), water (20 ml) and ethyl acetate (20 ml). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×25 ml). The combined organics were washed with brine (25 ml), dried over MgSO4, filtered, and evaporated to give 6-(2-benzyloxy-ethoxy)-1-methyl-1,3-dihydro-benzoimidazol-2-one (0.75 g, 97%) as a solid. Analysis calculated for C17H18N2O3 : C, 68.44; H, 6.08; N, 9.39. Found: C, 68.64; H, 6.13; N, 8.96.
Reaction SMILES: [C:1]([C@:5]1([CH3:34])[C@@H:18]2[C@@:9]3([CH2:20][CH2:19][C@:16]4([CH2:17]2)[C@@:11]25[C:27]6[C:22](=[CH:23][CH:24]=[C:25]([OH:29])[C:26]=6[O:28][C@@H:10]32)[CH2:21][C@H:15]4[N:14]([CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH2:13][CH2:12]5)[O:8][CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:35](S(CCC)=O)[CH2:36]C>>[C:1]([C@:5]1([CH3:34])[C@@H:18]2[C@@:9]3([CH2:20][CH2:19][C@:16]4([CH2:17]2)[C@@:11]25[C:27]6[C:22](=[CH:23][CH:24]=[C:25]([OH:29])[C:26]=6[O:28][C@@H:10]32)[CH2:21][C@H:15]4[N:14]([CH2:30][CH:31]2[CH2:32][CH2:33]2)[CH2:13][CH2:12]5)[O:8][CH:7]([CH2:35][CH3:36])[O:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@@]1(C)OCO[C@]23CC[C@@]4(C[C@@H]21)[C@H]1Cc2ccc(O)c5c2[C@@]4(CCN1CC1CC1)[C@H]3O5
Reactant: CCCS(=O)CCC
Product: CCC1O[C@]23CC[C@@]4(C[C@@H]2[C@@](C)(C(C)(C)C)O1)[C@H]1Cc2ccc(O)c5c2[C@@]4(CCN1CC1CC1)[C@H]3O5

Procedure:
The title compound 4 was prepared similar to the procedure described in Example 1 for compound 3 using dipropyl sulfoxide instead of DMSO. After column chromatography, 117 mg (53.7% yield, >99.9 purity) of compound 4 was isolated as an off-white solid as a mixture of two epimers in a 96.1:3.9 ratio.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[O:9]1[CH2:13][CH2:12][C@H:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10]1>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([C@@H:11]2[CH2:12][CH2:13][O:9][CH2:10]2)[C:4](=[O:8])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCOC2)cc1
Reactant: O=c1cc(Br)cc[nH]1
Product: O=c1cc(Br)ccn1[C@@H]1CCOC1
Yield: 18 %

Procedure:
The title compound was prepared from 4-bromo-1H-pyridin-2-one and (S)-toluene-4-sulfonic acid tetrahydrofuran-3-yl ester following a procedure analogous to that described for Intermediate 8. Yield: 18% of theory; LC (method 3): tR=2.18 min; Mass spectrum (ESI+): m/z=244/246 (Br) [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:18](O)=[O:19])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[O:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH:46]1[O:51][NH2:52]>C(Cl)Cl.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]([CH3:25])([S:21]([CH3:24])(=[O:22])=[O:23])[C:18]([NH:52][O:51][CH:46]2[CH2:47][CH2:48][CH2:49][CH2:50][O:45]2)=[O:19])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOC1CCCCO1
Reactant: CC(CCn1ccc(OCc2ccccc2)cc1=O)(C(=O)O)S(C)(=O)=O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(CCn1ccc(OCc2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (670 mg, 1.77 mmol) in methylene chloride (18 mL) at ambient temperature was added 1,(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (474 mg, 2.47 mmol), 1-hydroxy benzotriazole monohydrate (487 mg, 3.18 mmol), triethylamine (443 uL, 3.18 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (310 mg, 2.65 mmol). The resulting mixture was stirred at ambient temperature overnight. The mixture was diluted with methylene chloride and water. The phases were separated and the aqueous layer was extracted with methylene chloride two times. The organic extracts were combined and dried over magnesium sulfate, filtered and concentrated to a crude residue. The crude residue was purified via silica gel chromatography eluting with methylene chloride and methanol. The fractions containing desired product were combined and concentrated to afford 4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide as an oil. 536.3 mg
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.C(N(CC)CC)C.[Br:15][CH2:16][C:17](Br)=[O:18]>C(Cl)(Cl)Cl>[Br:15][CH2:16][C:17]([NH:7][C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)=[O:18]
Reactant: Cc1cc(N)no1
Reactant: O=C(Br)CBr
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)CBr)no1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-methyl-isoxazol-3-ylamine (4.0 g, 40.8 mmol) and triethylamine (6.8 ml, 50 mmol) in chloroform (20 ml) cooled to −40° C., is added bromoacetyl bromide (3.9 ml, 44.9 mmol) in chloroform (20 ml). The reaction mixture is stirred at −40° C. for 30 minutes and then allowed to warm to room temperature. The resultant suspension is filtered, washed with DCM and dried in vacuo to yield the titled compound.
Reaction SMILES: N#N.[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[C:6]([F:12])[C:5]=1[F:13].CCN(CC)CC.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:24][S:21]([O:9][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([Br:3])=[C:5]([F:13])[C:6]=1[F:12])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(Br)c(F)c1F
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(Br)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-bromo-2,3-difluorobenzyl alcohol (175 mg, 0.70 mmol) in dry CH2Cl2 (2 mL) was treated at 0° C. with Et3N (0.14 mL, 1.01 mmol) followed by DMAP (10 mg, 0.08 mmol) and Ms-Cl (0.06 mL, 0.82 mmol). After stirring at 0° C. for 0.5 h and at rt for 1 h, the reaction was quenched with water (2 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-bromo-2,3-difluorophenyl)methyl methanesulfonate as a yellow oil. This material was dissolved in dry DMF (3 mL) and treated with NaN3 (46 mg, 0.71 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 1-(azidomethyl)-4-bromo-2,3-difluorobenzene as a colorless oil. LC-MS-conditions 07: tR=0.89 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[Li+].CC([N-]C(C)C)C.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33](=[O:38])N(OC)C)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.C1COCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33](=[O:38])[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:8]([F:9])([F:10])[F:11])[C:2]=2[F:1])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Fc1ccccc1C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccc(C(F)(F)F)c2F)CC1
Temperature: -78 °C
Reaction time: 2.75 h
Yield: 52.4 %

Procedure:
To a stirred solution of 2-fluorobenzotrifluoride (19.4 g, 118 mmol) and anhydrous THF (300 mL) at −78° C. under nitrogen was added was added LDA (65.0 mL of a 2.0 M solution in heptane/tetrahydrofuran/ethylbenzene, 130 mmol) dropwise over 25 min. After 165 min, a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (40.1 g, 147 mmol) in anhydrous THF (100 mL) was added dropwise over 50 min and the reaction stirred at −78° C. for 20 min and at room temperature for 85 min. The reaction was quenched with saturated ammonium chloride (40 mL) and the mixture concentrated. The residue was taken up in ethyl acetate (400 mL) and washed successively with 1 N HCl (200 mL), 5% aqueous potassium carbonate, water (200 mL), and brine (200 mL). The organic phase was dried over magnesium sulfate, filtered, and the solvent removed to give an amber oil. The product was chromatographed on silica gel (300 g), using a step gradient elution of 20% ethyl acetate/heptane to 60% ethyl acetate/heptane, to afford 23.2 g (52%) of the desired product as an off-white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][N:4]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][O:1][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH:8]=1
Reactant: COc1ccnc(CO)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccnc(COS(=O)(=O)c2ccc(C)cc2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 103.7 %

Procedure:
The 2-hydroxymethyl-4-methoxypyridine, (3.48 g, 0.024 mol) was dissolved in 50 ml CH2Cl2 and cooled to 0° C. The p-toluenesulfonyl chloride (5.7 g, 0.03 mol) was added followed by triethylamine (5 g), in 10 ml of CH2Cl2. After 15 minutes, the reaction was stirred at room temperature for one hour. The reaction was diluted with CH2Cl2 (200 ml) and washed with water. The organic layer was separated and dried with MgSO4, filtered and concentrated to afford 7.3 g of crude subtitle compound suitable for further use.
Reaction SMILES: CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C(N(CC)C1C=CC=CC=1)C.B.[Br:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[C:40]([F:48])[CH:39]=1)=[O:37]>CC(OC)(C)C>[Br:34][CH2:35][C@@H:36]([C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[C:40]([F:48])[CH:39]=1)[OH:37]
Reactant: O=C(CBr)c1ccc(C(F)(F)F)c(F)c1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: CCN(CC)c1ccccc1
Solvent: COC(C)(C)C
Product: O[C@@H](CBr)c1ccc(C(F)(F)F)c(F)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
A solution of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (0.83 mL, 1.4 mmol) and borane diethylaniline (2.5 mL, 14 mmol) in MTBE (25 mL) prepared at RT and heated to 40° C. A solution of 2-bromo-1-(3-fluoro-4-(trifluoromethyl)phenyl)ethanone (143a, 4.0 g, 14 mmol, CASRN 54429-22-3) and MTBE (30 mL) was added dropwise to the above solution and the reaction was stirred at 40° C. for 30 min. The reaction was quenched by adding MeOH followed by 1M HCl and the reaction mixture was then poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with EtOAc/hexane (9:1) to afford 3.2 g (79%) of (R)-2-bromo-1-(3-fluoro-4-(trifluoromethyl)phenyl)ethanol (258).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[CH:21]1[CH:22]=C[C:24]2[N:29](O)N=[N:27][C:25]=2[CH:26]=1.NC1C=NC=CC=1>CN(C=O)C>[N:29]1[CH:22]=[CH:21][CH:26]=[C:25]([NH:27][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: On1nnc2ccccc21
Agent: Nc1cccnc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)Nc1cccnc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
To a solution of (2S)-2-tert-butoxycarbonylamino-3,3-dimethylbutanoic acid (3 g, 12.99 mmol) in DMF (25 mL) is added EDC (2.73 g, 14.29 mmol) and HOBT (1.93 g, 14.29 mmol). The resulting solution is stirred at 25° C. for 0.5 h and 3-aminopyridine (1.83 g, 19.48 mmol) is; added and the reaction is heated to 50° C. for 18 h. The mixture is concentrated, diluted with EtOAc (50 mL), and washed with saturated aqueous sodium bicarbonate. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to provide (2S)-2-tert-butoxycarbonylamino-3,3-dimethylbutanoic acid 3-pyridylamide as a foam (1.6 g, 40% yield).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:12][C:13]([C:15]2[C:16](Br)=[C:17]([C:24]([N:26]3[CH2:30][CH2:29][CH2:28][C@@H:27]3[CH3:31])=[O:25])[N:18]3[CH2:23][CH2:22][O:21][CH2:20][C:19]=23)=[O:14])[CH2:10][CH3:11])=[CH:5][CH:4]=1.[CH3:35][Sn](C)(C)C>CN(C)C=O.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]([F:34])([F:33])[C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:12][C:13]([C:15]2[C:16]([CH3:35])=[C:17]([C:24]([N:26]3[CH2:30][CH2:29][CH2:28][C@@H:27]3[CH3:31])=[O:25])[N:18]3[CH2:23][CH2:22][O:21][CH2:20][C:19]=23)=[O:14])[CH2:10][CH3:11])=[CH:5][CH:4]=1
Reactant: C[Sn](C)(C)C
Reactant: CC[C@@H](NC(=O)c1c(Br)c(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C(F)(F)F)nc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)c1c(C)c(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C(F)(F)F)nc1
Yield: 92 %

Procedure:
A solution of 7-bromo-6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propyl]-amide (Comp. No. 16ru) (55 mg, 0.101 mmol), tetramethylstannane (101 mg, 0.57 mmol) and tetrakis(triphenylphosphino)palladium(0) (6 mg, 5 pmol) in dimethylformamide (2 ml) was heated at 110° C. under microwave irradiation for 1 h. The crude product was purified by reverse phase HPLC to give 45 mg (92%) of 7-methyl-6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propyl]-amide. LC/MS (method 3): Rt=1.85 min; m/z=479.32 (M+H+).
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4].C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23].CCCCCC>C(Cl)Cl>[C:21]([O:13][C:10]1[CH:11]=[CH:12][C:7]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:4])=[O:5])=[CH:8][CH:9]=1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: C=C(C)C(=O)Cl
Reactant: CN(c1ccc(O)cc1)S(C)(=O)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1ccc(N(C)S(C)(=O)=O)cc1
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To a solution of 20.13 g (0.10 mol) of N-methyl-N-(4-hydroxyphenyl)methanesulfonamide, 10.12 g (0.10 mol) of triethylamine and 300 ml of methylene chloride cooled to 0° C., was added a solution of 10.45 g (0.10 mol) of methacryloyl chloride in 50 ml of methylene chloride for a 15-minute period. The solution was stirred for another 2 hours at reduced temperature, washed three times with water, dried over magnesium sulfate and concentrated to a white solid. Recrystallization from 500 ml of 1:1 benzene:hexane gave 16.4 g (60.9 percent yield) of N-(4-methacryloyloxyphenyl)-N-methylmethanesulfonamide, m.p.=126° to 127° C.
Reaction SMILES: C([NH:8][N:9]1[C:15](=[O:16])[CH2:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)(OC(C)(C)C)=O.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:31][CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CN(C=O)C>[ClH:31].[NH2:8][N:9]1[C:15](=[O:16])[CH:14]([CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:13]2[CH:12]=[CH:20][CH:19]=[CH:18][C:17]=2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:11][C:10]1=2
Reactant: CC(C)(C)C(=O)CCl
Reactant: CC(C)(C)OC(=O)NN1C(=O)Cc2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)CC1C(=O)N(N)c2ccccc2-c2ccccc21
Product: Cl
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (0.2 g, 0.617 mmol) (Example 7-E) in DMF was treated with Cs2CO3 (0.3 g, 0.925 mmol) and warmed to 60° C. To the reaction mixture was added 1-chloro-3,3-dimethyl-2-butanone (0.096 ml, 0.74 mmol) (Aldrich) and stirring continued for 17 h. After cooling to 23° C., the mixture was diluted with CH25Cl2, washed with several portions of brine and dried over Na2SO4. The title compound was isolated as a colorless solid. C25H30N2O4 (MW=422.522); mass spectroscopy (MH+) 423
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][CH2:12][C:13]#[CH:14])=[O:10].[C:15]([C:17]1[CH:34]=[CH:33][C:20]([O:21][CH2:22][CH:23]([NH:25][C:26](=[O:32])[C@H:27]([CH:29]([CH3:31])[CH3:30])[NH2:28])[CH3:24])=[CH:19][CH:18]=1)#[N:16].O>C(Cl)Cl>[C:15]([C:17]1[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH:23]([NH:25][C:26](=[O:32])[C@H:27]([CH:29]([CH3:30])[CH3:31])[NH:28][C:9]([O:11][CH2:12][C:13]#[CH:14])=[O:10])[CH3:24])=[CH:33][CH:34]=1)#[N:16]
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](N)C(C)C
Reactant: C#CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: C#CCOC(=O)N[C@H](C(=O)NC(C)COc1ccc(C#N)cc1)C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.9 %

Procedure:
0.2 g of N-methylmorpholine, and subsequently 0.2 g of propargyl chloroformate were added to a suspension containing 0.5 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide suspended in 30 ml of methylene chloride at -15° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.5 g of the desired product in the form of white powder (yield: 78%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[C:12]1([CH3:25])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[S:20]([O:23][NH2:24])(=[O:22])=[O:21].C(OCC)C>ClCCl>[CH3:19][C:14]1[CH:15]=[C:16]([CH3:18])[CH:17]=[C:12]([CH3:25])[C:13]=1[S:20]([O-:23])(=[O:22])=[O:21].[NH2:24][N+:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]#[C:4][CH2:3][O:2][CH3:1]
Reactant: COCC#Cc1ccccn1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: CCOCC
Solvent: ClCCl
Product: COCC#Cc1cccc[n+]1N
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(3-methoxy-1-propynyl)pyridine (13.2 g) dissolved in dichloromethane (50 mL) was added a solution of O-mesitylenesulfonylhydroxylamine (Reference; Synthesis, 1997, 1) (21 g) in dichloromethane (80 mL) dropwise while cooling with ice, and the reaction mixture was stirred for 30 minutes. Diethyl ether (1 L) was added to the obtained reaction mixture to precipitate crystals, which were collected by filtration and dried under reduced pressure to afford a crude product of 1-amino-2-(3-methoxy-1-propynyl)pyridinium 2,4,6-trimethyl-1-benzenesulfonate as ecru crystals (27.1 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][C:16]([F:19])([F:18])[F:17])[C@H:10]([C:12]([OH:14])=O)[CH3:11])=[CH:5][C:4]=1[C:20]([F:23])([F:22])[F:21])#[N:2].[CH3:24][NH:25][CH3:26]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][C:16]([F:18])([F:19])[F:17])[C@H:10]([C:12]([N:25]([CH3:26])[CH3:24])=[O:14])[CH3:11])=[CH:5][C:4]=1[C:20]([F:22])([F:21])[F:23])#[N:2]
Reactant: C[C@@H](C(=O)O)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: CNC
Product: C[C@@H](C(=O)N(C)C)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 3 using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoroethyl)alanine and dimethylamine: 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=8.8 Hz, 1H), 7.10 (d, J=2.7 Hz, 1H), 7.01 (dd, J=9.0, 2.7 Hz, 1H), 4.80 (q, J=7.0 Hz, 1H), 4.30 (m, 2H), 3.07 (s, 3H), 2.96 (s, 3H), 1.48 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=4[O:17][CH3:18])[CH2:10][CH2:9][NH:8]3)=[CH:4][C:3]=2[O:2]1.Br[CH2:26][C:27](Br)=[O:28].[NH2:30][C:31]1[S:32][CH:33]=[N:34][N:35]=1>>[CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=4[O:17][CH3:18])[CH2:10][CH2:9][N:8]3[CH2:26][C:27]([NH:30][C:31]3[S:32][CH:33]=[N:34][N:35]=3)=[O:28])=[CH:4][C:3]=2[O:2]1
Reactant: Nc1nncs1
Reactant: O=C(Br)CBr
Reactant: COc1ccc(OC)c2c1CCNC2Cc1ccc2c(c1)OCO2
Product: COc1ccc(OC)c2c1CCN(CC(=O)Nc1nncs1)C2Cc1ccc2c(c1)OCO2

Procedure:
prepared by reaction of 1-(3,4-Methylenedioxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-amino-1,3,4-thiadiazole