Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:8])[CH:6]=[CH2:7])[CH:2]=[CH2:3].[CH3:9][SiH:10]([Cl:12])[Cl:11]>C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:5]([O:4][CH2:1][CH2:2][CH2:3][Si:10]([CH3:9])([Cl:12])[Cl:11])(=[O:8])[CH:6]=[CH2:7]
Reactant: C=CCOC(=O)C=C
Reactant: C[SiH](Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=CC(=O)OCCC[Si](C)(Cl)Cl
Temperature: 65 °C
Yield: 68.3 %

Procedure:
To a three-necked flask equipped as in Example 1 there was added 260 grams allylacrylate (2.32 moles), 0.5 grams catalyst prepared in accordance with U.S. Pat. No. 3,814,730 (2.6 weight percent Pt) and 1.04 grams phenothiazine. The mixture was heated with stirring to 65° C. and, using the vent of the condenser, purged with nitrogen. The heat source was then turned off and 237 grams (2.32 moles) CH3SiHCl2 was added dropwise, the temperature of the reaction mass being maintained at about 70° C. Upon completion of the addition of methyldichlorosilane the crude product was cooled to room temperature. One gram phenothiazine and 0.05 gram triphenyl phosphine were added to the product prior to distillation. Acryloxypropylmethyldichlorosilane (360 grams, 68% yield) was distilled at 109°-112° C./10 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:55][N:56]([CH3:58])[NH2:57]>CN(C=O)C>[CH3:55][N:56]([CH3:58])[NH:57][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)nc1
Reactant: CN(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NN(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a solution of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) in DMF (5 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.36 mmol), N,N-diisopropyl ethyl amine (0.27 mL, 8.1 mmol) and N,N-dimethylhydrazine (21 mg, 0.35 mmol). The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated and then diluted with water and extracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated in vacuo. Concentration and purification by chromatography (silica, 0 to 5% methanol in dichloromethane) afforded the title compound (31 mg, 27%) as a white solid. MS: m/e=353.3 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([NH2:17])=[O:16])[CH3:2].[CH3:18][C:19](=O)[CH2:20][CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[C:4]2[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[S:6][C:5]=2[C:15](=[O:16])[NH:17][C:19]1([CH2:20][CH3:21])[CH3:18])[CH3:2]
Reactant: CCNc1cc(-c2ccncc2)sc1C(N)=O
Reactant: CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCN1c2cc(-c3ccncc3)sc2C(=O)NC1(C)CC
Temperature: 120 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A mixture of 3-(ethylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.100 g, 0.400 mmol), 2-butanone (2.5 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 1 h at 120° C. in a sealed tube. Then, this mixture was stirred for 3 h at 150° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate (100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. The oil was purified by column chromatography (Combiflash, 40 g silica gel, dichloromethane to ethyl acetate) to afford the title compound (0.0547 g, 45%) as a yellow solid:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:41](=[O:43])[CH3:42])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:35][CH2:36][CH:37]([NH:40][C:41](=[O:43])[CH3:42])[CH2:38][CH2:39]3)(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC(=O)NC1CCN(S(=O)(=O)c2ccccc2Br)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CC(=O)NC1CCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)CC1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and N-(1-((2-bromophenyl)sulfonyl)piperidin-4-yl)acetamide. MS (ESI): mass calcd. for C23H24FN5O3S, 469.16; m/z found, 470.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.41-8.38 (m, 1H), 8.08 (d, J=1.4, 1H), 8.01-7.97 (m, 1H), 7.90 (m, 1H), 7.80 (d, J=7.6, 1H), 7.77-7.72 (m, 1H), 7.68-7.63 (m, 1H), 7.46-7.42 (m, 1H), 7.33-7.24 (m, 2H), 3.61-3.50 (m, 1H), 3.26-3.18 (m, 2H), 2.59-2.52 (m, 2H), 1.76 (s, 3H), 1.67-1.59 (m, 2H), 1.27-1.15 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[S:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[CH:11]=[C:10]([C:20]([F:23])([F:22])[F:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[Cl:19][C:16]1[S:15][C:14]([C:12]2[CH:11]=[C:10]([C:20]([F:23])([F:22])[F:21])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:28]4[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)s2)nc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cccc(-c3nc(-c4ccc(Cl)s4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidine (example B.3) (0.25 g, 0.6 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.157 g, 0.71 mmol) according to the general procedure III. Obtained as a yellow solid (0.083 g, 32%). MS (ISP) 433.2 [(M+H)+]; mp 99° C.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1.[CH2:25]([NH2:27])[CH3:26]>CN(C)C=O.CCOCC>[CH2:25]([NH:27][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1)[CH3:26]
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)cc2C1=O
Reactant: CCN
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCNCc1nc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
0.66 g (1.9 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one was dissolved in 20 ml of N,N-dimethylformamide. A weak stream of ethylamine gas was introduced at room temperature, the reaction temperature rising to 36°. After stirring at room temperature for 16 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with methylene chloride/methanol 19:1 as the eluent. After concentration there was obtained a beige foam which was taken up in ether. There was obtained 0.40 g (59%) of 3-(5-ethylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as beige crystals; m.p. 166°-168°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][CH:14]1[CH2:16][CH:15]1[CH3:17].C(O)(=O)C>[Fe].O>[CH3:11][C:5]1[CH:4]=[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH:15]2[CH3:17])[C:2]([CH3:1])=[CH:7][C:6]=1[NH2:8]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1OCC1CC1C
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(OCC2CC2C)c(C)cc1N
Temperature: 80 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
A mixture of 0.70 g of 2,5-dimethyl-1-[(2-methylcyclopropyl)methoxy]-4-nitrobenzen e, 0.83 g of iron powder, 15 mL of acetic acid and 15 mL of water was stirred at 80° C. for 1 hour. The reaction mixture was cooled to around room temperature, and then concentrated under reduced pressure. The resulting residue was converted into basic with an aqueous 1 N sodium hydroxide solution, then ethyl acetate was added, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water, and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 0.46 g of 2,5-dimethyl-4-[(2-methylcyclopropyl)methoxy]phenylamine.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@@H:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12].Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1(C)C=CC=CC=1>[NH2:13][C:11]([C@@H:10]([NH:9][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH3:15])=[O:12]
Reactant: CC[C@H](N)C(N)=O
Reactant: CCOC(=O)CCCBr
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCN[C@@H](CC)C(N)=O
Temperature: 80 °C

Procedure:
143.6 ml (1.035 mole) of triethylamine are added to a suspension of 47.75 g (0.345 mole) of (S)-2-amino-butanamide hydrochloride ([alpha]D25 : +26.1°; c=1, methanol) in 400 ml of toluene. The mixture is heated to 80° C. and 67.2 g (0.345 mole) of ethyl 4-bromobutyrate are introduced dropwise.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][C@@H:8]([CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O)[C@@H:9]([CH3:13])[CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[N-:27]=[N+:28]=[N-:29].[Na+].O>CS(C)=O>[C:1]([O:5][C:6](=[O:26])[CH2:7][C@@H:8]([CH2:14][N:27]=[N+:28]=[N-:29])[C@@H:9]([CH3:13])[CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CC(=O)OC(C)(C)C)[C@@H](C)C(C)C)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)[C@H](C)[C@H](CN=[N+]=[N-])CC(=O)OC(C)(C)C
Yield: 79.3 %

Procedure:
A solution of the tosylate 21 (1.19 g, 3.1 mmol) and sodium azide (402 mg, 6.2 mmol) in DMSO (15 mL) was warmed to 60° C. for 2.5 hours. Water (100 mL) was added and the solution extracted with ether. The combined organic phases were dried (MgSO4) and concentrated. Flash chromatography (9:1 hexane/ethyl acetate) gave the azide 22 (628 mg, 80%) as a colorless oil. 1H NMR (CDCl3) δ 3.4 (dd, 1H, J=12.21 and 6.11 Hz), 3.3 (dd, 1H, J=21.11 and 6.59 Hz), 2.30 (dd, 1H, J=15.14 and 3.66 Hz), 2.25 (m, 1H), 2.05 (dd, 1H, J=15.14 and 9.04 Hz), 1.55 (m, 1H), 1.45. (s, 9H), 1.35 (m, 1H), 0.95 (d, 1H, J=6.59 Hz ), 0.90 (d, 1H, J=6.83 Hz), 0.80 (d, 1H, J=7.08 Hz). MS (m/z): (relative intensity): 228 [M−N2, 35%], 172 [M−N2−tBu, 100%].
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C@@H:13]([OH:16])[CH2:14][OH:15].C([Sn](=O)CCCC)CCC.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.CCN(CC)CC>C(Cl)Cl>[CH3:37][C:27]1[CH:32]=[CH:31][C:30]([S:33]([O:15][CH2:14][C@@H:13]([C:3]2[C:4]([CH3:12])=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[Cl:1])[OH:16])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc2ccccc2c(Cl)c1[C@@H](O)CO
Agent: CCCC[Sn](=O)CCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H](O)c2c(C)cc3ccccc3c2Cl)cc1
Reaction time: 15 h

Procedure:
To a stirred solution of (R)-1-(1-chloro-3-methylnaphthalen-2-yl)ethane-1,2-diol (2.30 g, 9.74 mmol) in CH2Cl2 (97 mL), dibutyltinoxide (48.5 mg, 0.19 mmol), p-toluenesulfonyl chloride (2.08 g, 10.90 mmol), and Et3N (1.60 mL, 11.58 mmol) were added at room temperature). After stirring for 15 h, the reaction mixture was quenched with saturated aqueous NH4Cl, and then diluted with CH2Cl2. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give (R)-2-(1-chloro-3-methylnaphthalen-2-yl)-2-hydroxyethyl 4-methylbenzenesulfonate. 1H-NMR: 400 MHz, (CDCl3) δ 8.18 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.57-7.54 (m, 5H), 5.82 (t, J=5.6 Hz, 1H), 4.44 (dd, J=10.0, 6.8 Hz, 1H), 4.35 (dd, J=10.4, 5.6 Hz, 1H), 2.59 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.Cl.[NH:19]1[CH2:22][CH:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:20]1>CN(C)C=O.O>[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[N:19]1[CH2:22][CH:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:20]1
Reactant: Clc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(c2ccc3ccccc3n2)C1
Temperature: 120 °C
Yield: 80 %

Procedure:
Cesium carbonate (4.68 g, 14.4 mmol), 2-chloroquinoline (0.782 g, 4.8 mmol) and tert-butyl azetidin-3-yl-carbamate hydrochloride (1.0 g, 4.8 mmol) were dissolved in dry dimethylformamide (15 mL) and the resulting mixture was heated at 120° C. overnight. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (30 mL) and brine (30 mL), then dried over sodium sulfate. The organic was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 40% ethyl acetate in petroleum ether) to give tert-butyl (1-(quinolin-2-yl)azetidin-3-yl)-carbamate (1.14 g, 3.84 mmol, 80% yield) as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10](Cl)(Cl)=[S:11].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([N:8]=[C:10]=[S:11])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1ccnc(Cl)c1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccnc(Cl)c1N=C=S
Yield: 17.4 %

Procedure:
The title compound was prepared following the procedure described for Intermediate-2 using 2-chloro-4-methylpyridin-3-amine (4.0 g, 28 mmol), thiophosgene (3.2 g, 28 mmol), N-ethyl di-isopropyl amine (5 mL) in DCM (20 mL) to afford 0.900 g of the desired product.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][N:6]=1)=O.O.[NH2:14][NH2:15]>CO>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:3]([NH:14][NH2:15])=[O:2])[CH:10]=1
Reactant: NN
Reactant: COC(=O)c1cc(OC)ccn1
Solvent: O
Solvent: CO
Product: COc1ccnc(C(=O)NN)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
4-Methoxypyridine-2-carboxylic acid methyl ester (17.6 g, 0.105 mol) was dissolved in methanol (100 ml) and cooled to 0° C. before adding hydrazine hydrate (21 ml) dropwise over 10 min. The mixture was then refrigerated at 4° C. for 16 h. The resulting solid was filtered, washed with cold methanol and dried to afford 4-methoxypyridine-2-carboxylic acid hydrazide (14.3 g, 81%) as a white powder. 1H NMR (360 MHz, CDCl3) δH 3.89 (3H, s), 4.55 (2H, br s), 7.12 (1H, dd, J 3 and 6), 7.50 (1H, d, J 3), 8.42 (1H, d, J 6), 9.79 (1H, br s).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:16][C:17]([F:27])([F:26])[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](=[O:12])[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:17]([F:16])([F:26])[F:27])[CH:20]=1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Nc1cccc(OC(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1cccc(OC(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a mixture of Boc-L-proline (5 g, 23.23 mmol), 3-(trifluoromethoxy)aniline (3.73 mL, 27.88 mmol) and HBTU (13.2 g, 34.8 mmol) in DMF (60 mL) was added DIPEA (7.95 mL, 46.5 mmol) and the resulting yellow solution was stirred at RT under nitrogen. The solvent was concentrated under vacuum and the residue dissolved in EtOAc and washed with HCl 1N. The combined organic layers were neutralized by addition of an aqueous saturated solution of NaHCO3. The layers were separated and the aqueous one back-extracted twice with CH2Cl2. The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 3:1 to 2:1) to give the desired compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.57; MS (LC/MS): 397.1 [M+Na]+, 275.2 [MH−Boc]+, 373.3 [M−H]−; tR (HPLC conditions a) 3.81 min.
Reaction SMILES: [C:1]1([C@H:7]([NH:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH2:37][C:38](O)=[O:39])[CH:33]=[CH:34][C:35]=1[Cl:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([CH2:37][C:38]([N:21]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH2:10]2)=[O:39])[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: c1ccc([C@@H](CN2CC[C@H](OC3CCCCO3)C2)NOC2CCCCO2)cc1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N(OC1CCCCO1)[C@H](CN1CC[C@H](OC2CCCCO2)C1)c1ccccc1
Yield: 69.8 %

Procedure:
This was prepared from 1-(S)-Phenyl-N-tetrahydropyranyloxy-2-(3-(S)-tetrahydropyranyloxypyrroidin-1-yl)ethylamine and 3,4-dichlorophenylacetic acid in 69.8% yield as a clear brown Viscous oil according to a procedure similar to that described in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:10]([C:12]([O:14]C(OCC)C)=[O:13])[OH:11])=O)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].CS(Cl)(=O)=O.[CH2:37]1[CH2:41][O:40][CH2:39][CH2:38]1>CCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6]1[O:14][C:12](=[O:13])[CH:10]([O:11][CH:39]([O:40][CH2:41][CH3:37])[CH3:38])[CH:9]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:8]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(C)OC(=O)C(O)C(NC(=O)OC(C)(C)C)c1ccccc1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(C)OC1C(=O)OC(OC(C)(C)C)=NC1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 409 mg (1.16 mmol) of N-tertbutoxycarbonyl-O-(1-ethoxyethyl)-3-phenylisoserine (3) in 20 mL of THF was added 261 mg (2.33 mmol) of solid potassium tert-butoxide and the mixture was stirred at 25° C. for 30 min. A solution of 134 mg (1.16 mmol) of methanesulfonyl chloride in 3.2 mL of THF was added and the mixture was stirred at 25° C. for 1.5 h. The mixture was diluted with 80 mL of hexane and ethyl acetate and this solution was extracted with 20 mL of saturated aqueous sodium bicarbonate solution and 10 mL of brine. The organic phase was dried over sodium sulfate and concentrated to give 235 mg (70%) of 2-tertbutoxy-4-phenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin-6-one as a colorless oil.
Reaction SMILES: CC(C)([O-:4])C.[K+].[N+]([CH:10]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:14][C:13](=[O:22])[CH2:12][CH2:11]1)([O-])=O>ClCCl.CO>[O:4]=[C:10]1[CH2:11][CH2:12][C:13](=[O:22])[NH:14][CH:15]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCC([N+](=O)[O-])C(c2ccccc2)N1
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: O=C1CCC(=O)C(c2ccccc2)N1
Temperature: -78 °C

Procedure:
Potassium t-butoxide (1.68 g, 15 mmol) was added to a solution of 5-nitro-2-oxo-6-phenylpiperidine (3 g, 13.6 mmol; Example 2a) in a mixture of dichloromethane (50 ml) and methanol (50 ml) and the mixture was cooled to -78° C. under nitrogen. Ozone was bubbled through the solution for 3 h. A yellow-green solution resulted, and TLC indicated no starting material remained. The reaction mixture was purged with oxygen for 5 min to remove excess ozone, then dimethylsulfide (7 ml) was added and the reaction mixture was allowed to warm to 23° C. The solvent was removed in-vacuo and the residue was partitioned between dichloromethane and water. The layers were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were washed with brine, then dried (K2CO3) and concentrated to leave 3,6-diketo-2-phenylpiperidine as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[CH:13]3)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32]>>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[O:31][CH3:32])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: O=C(NCC1CCCC1)c1ccc2[nH]ccc2c1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(C(=O)NCC4CCCC4)cc23)c(OC)c1
Yield: 33 %

Procedure:
The starting indole (C) was prepared according to the procedure of Example 1, starting with 5-(N-cyclopentylmethylcarbamoyl)indole (A) and methyl 4-bromomethyl-3-methoxybenzoate (B) to yield methyl 4-[5-(N-cyclopentylmethylcarbamoyl)indol-3-ylmethyl]3-methoxybenzoate (C) (1.14 g, 33%) as a tan foam; partial NMR (80 MHz, CDCl3): 3.45(dd, 2H, CH2N), 3.93(s, 3H, OCH3), 3.95(s, 3H, OCH3), 4.17(s, 2H, ArCH2), 6.17(t, 1H, NHCO), 7.01(d, 1H, H2 -indole), 7.16(d, 1H), 8.04(br s, 1H, H4 -indole), 8.45(br s, 1H, NH).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([O:12][CH2:13][CH3:14])=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][S:4](=[O:16])(=[O:15])[N:3]=1.[CH:17]1([N:23]=[C:24]=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH:17]1([NH:23][C:24]([NH:1][C:2]2[C:7]3[C:8]([O:12][CH2:13][CH3:14])=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][S:4](=[O:16])(=[O:15])[N:3]=2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C=NC1CCCCC1
Reactant: CCOc1cccc2c1C(N)=NS(=O)(=O)O2
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1cccc2c1C(NC(=O)NC1CCCCC1)=NS(=O)(=O)O2
Reaction time: 18 h

Procedure:
0.15 g (0.61 mmol) of 4-amino-5-ethoxy-1,2,3-benzoxathiazine 2,2-dioxide is stirred with 0.1 g (0.79 mmol) of cyclohexyl isocyanate in 30 ml of dry tetrahydrofuran in the presence of 10 mg of DBU, first at room temperature for 1 hour and then at 40° C. for 18 hours. The mixture is concentrated under reduced pressure, and the residue is dissolved in dichloromethane and washed with water. The organic phase is dried over magnesium sulphate and concentrated under reduced pressure. This gives 0.15 g of crude product which, after dissolution in 14 ml of acetonitrile and 6 ml of water, is purified by means of reversed phase HPLC (Kromasil 100 C18, 250×40 mm, 5 μm, 0.01% HCOOH/H2O acetonitrile gradient 34/66, isocratic). This gives 55 mg (24.2% of theory) of compound I-24 as a white solid.