Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:21][CH:22]=O)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:24]=[C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][N:26]1[CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(=O)(O)[O-].[Na+]>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:21][CH2:22][N:37]2[CH2:38][CH2:39][CH:34]([N:26]3[CH2:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:25]3=[O:24])[CH2:35][CH2:36]2)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reactant: O=C1c2ccccc2CN1C1CCNCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C[C@@H](CCN1CCC(N2Cc3ccccc3C2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Product: Cl
Reaction time: 0.25 h
Yield: 172.4 %

Procedure:
(S)-N-[2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methylbenzamide (270 mg) in methanol (2 mL) was added to a solution of 4-(1-oxoiso-indolin-2-yl)piperidine (200 mg) and acetic acid (0.053 mL) in methanol (3 mL). After 15 minutes, sodium cyanoborohydride (58 mg) in methanol (1 mL) was added in a single portion. After 6 hours, the reaction mixture was diluted with aqueous sodium bicarbonate, stirred for 30 minutes, and extracted with dichloromethane. The organic extracts were dried, evaporated, and chromatographed, with dichloromethane:methanol (gradient 98:2, 95:5) as the eluent. The resulting material was dissolved in dichloromethane, precipitated out as the hydrochloride salt with ethereal hydrogen chloride, evaporated, and placed under high vacuum overnight to give the title compound (390 mg) as a white solid; MS: m/z=550(M+1). Analysis for C31H33Cl2N3O2 ·1.65 HCl·0.40 (CH3CH2O): Calculated: C, 61.14; H, 6.08; N, 6.56; Found: C, 61.09; H, 6.10; N, 6.48.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Si]([O:21][C@H:22]([CH2:35][CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)[C@H:23]([CH3:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(C(C)(C)C)(C)C.[CH3:43][N:44]([C:46]1[CH:51]=[CH:50][CH:49]=[C:48](Br)[N:47]=1)[CH3:45]>C1C=CC([P]([Pd]([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)=CC=1.C(O)C>[CH3:43][N:44]([CH3:45])[C:46]1[N:47]=[C:48]([C:28]2[CH:27]=[CH:26][C:25]([O:24][C@@H:23]([CH3:34])[C@H:22]([OH:21])[CH2:35][CH2:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[CH:30][CH:29]=2)[CH:49]=[CH:50][CH:51]=1
Reactant: CN(C)c1cccc(Br)n1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2cccc(N(C)C)n2)cc1)[C@H](O)CCc1cccnc1
Temperature: 120 °C
Yield: 50.1 %

Procedure:
Prepared according to the method described in Example 15g) from toluene (4 ml), 2M aqueous sodium carbonate (0.5 ml), (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-yl-butoxy]benzeneboronic acid (0.200 g, Example 15f)), ethanol (1 ml), 6-bromo-2-N,N-dimethylaminopyridine (0.201 g, Example 18a)) and tetrakis(triphenylphosphine)palladium(0) (0.020 g) with heating at 120° C. for 4 hours. The product was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as an oil (0.091 g).
Reaction SMILES: [C:1]([NH2:6])(=O)[CH:2]([CH3:4])[CH3:3].[CH3:7]N(C(OC)OC)C.CC(N(C)C)=O.[CH3:21][O:22][C:23](=[O:39])[C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=2)[CH:27]=[C:26]([NH:37][NH2:38])[CH:25]=1>C(O)(=O)C>[CH3:21][O:22][C:23](=[O:39])[C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=2)[CH:27]=[C:26]([N:37]2[C:1]([CH:2]([CH3:4])[CH3:3])=[N:6][CH:7]=[N:38]2)[CH:25]=1
Reactant: COC(=O)c1cc(NN)cc(-c2ccc(C)cn2)c1
Reactant: COC(OC)N(C)C
Reactant: CC(C)C(N)=O
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(-n2ncnc2C(C)C)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Isobutyramide (6.02 g, 69 mmol) and DMFDMA (9.22 mL) were added to 10 mL of DMA in a first flask, and the mixture was heated to 80° C. with stirring for one hour. In a second flask, a suspension of 3-hydrazino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (6.42 g, 23 mmol) was suspended in acetic acid and heated t 80° C. The contents of the first flask were slowly added to the second flask, and the combined mixture was stirred at 80° C. for two hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was diluted with EtOAc, washed with saturated aqueous NaHCO3 and water, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (hexanes/EtOAc 4: - - - 2:1) to give 2.06 g of 3-(5-isopropyl-[1,2,4]triazol-1-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester as a clear oil, MS (M+H)=337.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][C@@H:12]([NH:14][C:15]2[CH:20]=[C:19]([NH:21][C@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[O:31][CH3:32])[N:18]=[CH:17][N:16]=2)[CH2:11][C@@H:10]1[CH2:33][OH:34])(C(C)(C)C)(C)C.N1C=CC=CC=1.Cl[S:42]([NH2:45])(=[O:44])=[O:43]>C(#N)C>[S:42](=[O:44])(=[O:43])([O:34][CH2:33][C@H:10]1[CH2:11][C@H:12]([NH:14][C:15]2[CH:20]=[C:19]([NH:21][C@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[O:31][CH3:32])[N:18]=[CH:17][N:16]=2)[CH2:13][C@H:9]1[OH:8])[NH2:45]
Reactant: NS(=O)(=O)Cl
Reactant: CO[C@@H]1Cc2ccccc2[C@@H]1Nc1cc(N[C@H]2C[C@H](CO)[C@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Solvent: CC#N
Solvent: c1ccncc1
Product: CO[C@@H]1Cc2ccccc2[C@@H]1Nc1cc(N[C@H]2C[C@H](COS(N)(=O)=O)[C@H](O)C2)ncn1
Reaction time: 3 h
Yield: 57 %

Procedure:
A solution of {(1R,2R,4S)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)amino]cyclopentyl}methanol (0.112 g, 0.231 mmol) (azetroped with toluene) and pyridine (0.0374 mL, 0.462 mmol) in anhydrous acetonitrile (2.3 mL) was cooled to 0° C. A 2 N solution of chlorosulfonamide in acetonitrile (0.116 mL) was added dropwise and the reaction was stirred for 3 h. Additional 2 N solution of chlorosulfonamide in acetonitrile (0.026 mL) and pyridine (0.0041 g, 0.052 mol) were added and the reaction was stirred for 1 h then quenched with methanol. The solution was concentrated in vacuo and purified by flash chromatography (0 to 10% MeOH/DCM) to afford the title compound as a white solid (0.059 g, 57%). 1H NMR (CD3OD, 400 MHz, δ): 8.26 (s, 1H); 8.01 (s, 1H); 7.26-7.16 (m, 3H); 5.70 (s, 1H); 5.47-5.33 (bs, 1H); 4.35 (t, J=4.5 Hz, 1H); 4.31 (d, J=7.5 Hz, 1H); 4.28 (d, J=7.5 Hz, 1H); 4.25-4.21 (m, 1H); 4.15-4.11 (dd, J=7.3 Hz; J=2.5 Hz, 1H); 3.36 (s, 3H); 3.16-3.00 (m, 2H); 2.54-2.45 (m, 1H); 2.26-2.19 (m, 1H); 2.10-1.98 (m, 1H); 1.87-1.78 (m, 1H); 1.77-1.69 (m, 1H). LC/MS: Rt=1.11 min, ES+ 450 (FA standard).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=[O:8].[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[O:17][CH3:18])[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:21]=[C:2](/[CH:25]=[CH:24]/[C:23]([O:27][CH3:28])=[O:26])[CH:3]=[CH:4][C:5]=1[F:22]
Reactant: COc1ccc(CNC(=O)c2cc(Br)ccc2F)cc1OC
Reactant: C=CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(F)c(C(=O)NCc2ccc(OC)c(OC)c2)c1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 5-bromo-N-(3,4-dimethoxybenzyl)-2-fluorobenzamide (200 mg) in dimethylformamide (2 mL) were added methyl acrylate (0.068 mL), triethylamine (0.09 mL) and dichlorobis(triphenylphosphine)pailadium(II) (13.4 mg), and the mixture was stirred for 6 hours at 120° C. in a sealed tube. The resulting mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate (9:1) to give N-(3,4-dimethoxybenzyl)-2-fluoro-5-[trans-2-(methoxycarbonyl)ethenyl]benzamide (117 mg) as a solid substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:7][CH2:8][C:9]([OH:11])=[O:10]>C(OCC)(=O)C>[Cl-:7].[C:9]([CH2:8][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:11])=[O:10]
Reactant: c1ccncc1
Reactant: O=C(O)CCl
Solvent: CCOC(C)=O
Product: O=C(O)C[n+]1ccccc1
Product: [Cl-]
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of pyridine (4.0 g) in ethyl acetate (10 mL) was added chloroacetic acid (4.7 g) at room temperature, and the mixture was heated under reflux overnight. After the reaction mixture was cooled to room temperature, the precipitated solid was collected by filtration, and dried under reduced pressure to give 1-carboxymethyl pyridinium chloride (5.7 g). To a solution of the obtained compound (5.7 g) in toluene (300 mL) were added acrylonitrile (8.7 g), manganese dioxide (16.4 g) and triethylamine (4.0 g), and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (2.8 g).
Reaction SMILES: S(C1C(F)=C(F)C(F)=C(F)C=1C(O)=O)(O)(=O)=O.FS(C1C(F)=C(F)C(F)=C(F)C=1C(F)=O)(=O)=O.[S:35]1[CH2:41][C:39](=[O:40])[NH:38][C:36]1=[S:37].[F:42][C:43]1[C:48]([CH:49]=O)=[C:47]([F:51])[C:46]([F:52])=[C:45]([F:53])[C:44]=1[F:54]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[F:42][C:43]1[C:44]([F:54])=[C:45]([F:53])[C:46]([F:52])=[C:47]([F:51])[C:48]=1[CH:49]=[C:41]1[S:35][C:36](=[S:37])[NH:38][C:39]1=[O:40]
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1c(F)c(F)c(F)c(F)c1F
Agent: O=C(F)c1c(F)c(F)c(F)c(F)c1S(=O)(=O)F
Agent: O=C(O)c1c(F)c(F)c(F)c(F)c1S(=O)(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1NC(=S)SC1=Cc1c(F)c(F)c(F)c(F)c1F
Reaction time: 1 h
Yield: 73.8 %

Procedure:
Production of 2-sulpho tetrafluorobenzoic acid ##STR61## and 2-fluorosulphonyl tetrafluorobenzoyl fluoride ##STR62## 38 g of triethylamine were added dropwise to a well stirred suspension of 50 g of rhodanine and 70 g of pentafluorobenzaldehyde in 100 ml of chloroform, the temperature being held below 40° C. by external cooling. After one hour, the solution was washed with dilute HCl, then water. The solvent was removed and the resultant yellow residue recrystallised from IMS/water to give 82 g of 2,3,4,5,6-pentafluorobenzylidene rhodanine having a melting point of 132°-135° C.
Reaction SMILES: F[B-](F)(F)F.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH:14]1[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[N:21]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].Cl[CH2:33]Cl>>[C:6]([O:10][C:11]([N:13]1[CH:14]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[N:21]=2)[C:15]([O:19][CH3:33])=[N:16][CH2:17][CH2:18]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1c1nc(-c2cccc(Cl)c2)no1
Reactant: ClCCl
Agent: F[B-](F)(F)F
Product: COC1=NCCN(C(=O)OC(C)(C)C)C1c1nc(-c2cccc(Cl)c2)no1
Reaction time: 8 h
Yield: 61 %

Procedure:
Trimethyloxoniuim tetrafluoroborate (169.4 mg, 1.15 mmol) was added to 2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (450 mg, 1.15 mmol) in dichloromethane (3 mL) under argon at room temperature and then stirred overnight. The reaction mixture was directly purified by flash chromatography on basic alumina using 30% ethyl acetate in hexanes to afford the titled compound (284.6 mg, 61%). 1H NMR (CDCl3) δ (ppm): 8.09 (m, 1H), 7.97 (m, 1H), 7.46 (m, 2H), 4.88 (m, 1H), 4.01 (m, 1H), 3.72 (s, 3H), 3.51 (m, 3H), 3.35 (m, 1H), 2.90 (m, 1H), 1.34 (m, 9H).
Reaction SMILES: [F:1][CH:2]([F:13])[N:3]1[CH:7]=[C:6]([S:8](Cl)(=[O:10])=[O:9])[C:5]([CH3:12])=[N:4]1.[F:14][C:15]([F:33])([F:32])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([C@H:29]([NH2:31])[CH3:30])=[CH:25][CH:24]=1>>[F:14][C:15]([F:32])([F:33])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([C@H:29]([NH:31][S:8]([C:6]2[C:5]([CH3:12])=[N:4][N:3]([CH:2]([F:13])[F:1])[CH:7]=2)(=[O:10])=[O:9])[CH3:30])=[CH:25][CH:24]=1
Reactant: Cc1nn(C(F)F)cc1S(=O)(=O)Cl
Reactant: C[C@@H](N)c1ccc(-c2ccccc2OC(F)(F)F)cc1
Product: Cc1nn(C(F)F)cc1S(=O)(=O)N[C@H](C)c1ccc(-c2ccccc2OC(F)(F)F)cc1

Procedure:
Palladium acetate (34 mg, 0.150 mmol) was added to a mixture of 2-(trifluoromethoxy)phenylboronic acid (773 mg, 3.75 mmol) and (R)-(+)-1-(4-bromophenyl)ethylamine (300 mg, 1.50 mmol) in water (12 ml). This mixture was heated in a microwave oven at 150° C. for 10 min, then diluted with methanol (200 ml) and purified on a SCX column (eluted with 2M ammonia in methanol) to give (R)-1-(2′-trifluoromethoxy-biphenyl-4-yl)-ethylamine (345 mg, 1.23 mmol, 81.9%) as a gum. The title compound was then prepared in a similar manner to (R)-2,5-dimethyl-furan-3-sulfonic acid [1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 10) using 1-difluoromethyl-3-methylpyrazole-4-sulfonyl chloride and (R)-1-(2′-trifluoromethoxy-biphenyl-4-yl)-ethylamine. Title compound: 1H NMR (400 MHz, CDCl3): δ 7.95 (s, 1H), 7.42-7.16 (m, 8H), 6.97 (s, 1H), 4.88 (d, 1H), 4.52 (m, 1H), 2.30 (s, 3H), 1.56 (d, 3H) ppm; MS (ESI) m/z: 476 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@@H:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C@@:6]([CH3:41])([C:33]([NH:35][O:36]C(C)(C)C)=[O:34])[CH2:5]1)(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([N:4]1[CH2:9][CH2:8][C@@H:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C@@:6]([CH3:41])([C:33]([NH:35][OH:36])=[O:34])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC[C@@H](NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@@](C)(C(=O)NOC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CC[C@@H](NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@@](C)(C(=O)NO)C1
Temperature: 40 °C
Yield: 23.8 %

Procedure:
(3S,4R)-1-Acetyl-N-tert-butoxy-3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide (326 mg, 0.559 mmol) was dissolved in trifluoroacetic acid (5 mL) and heated at 40° C. overnight. The solvent was concentrated and the residual oil was treated with saturated aqueous NaHCO3 and extracted with ethyl acetate (3×). The combined organic extracts were dried over Na2SO4, then purified via column chromatography on silica gel eluting with 5% MeOH/CH2Cl2 to give (3S,4R)-1-acetyl-N-hydroxy-3-methyl-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]piperidine-3-carboxamide (70 mg, 0.133 mmol, 24%) as a colorless solid. LCMS (M−H): 1.58 min, 525.4; 1H NMR (400 MHz, MeOD) δ ppm 0.97 (s, 2H) 1.09-1.20 (m, 4H) 1.44 (d, J=13.14 Hz, 1H) 1.65-1.75 (m, 1H) 1.90-1.97 (m, 5H) 2.55 (d, J=14.40 Hz, 2H) 2.60-2.64 (m, 4H) 2.93-3.03 (m, 1H) 3.05-3.16 (m, 2H) 3.67 (s, 1H) 5.58 (s, 3H) 7.16 (d, J=9.09 Hz, 3H) 7.46-7.54 (m, 3H) 7.62-7.69 (m, 2H) 7.78 (dd, J=8.97, 2.15 Hz, 3H) 7.90 (d, J=8.59 Hz, 2H) 7.99 (d, J=8.08 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]1[NH:12][CH:13]=[CH:14][N:15]=1.C1COCC1.[OH-].[K+].[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26]>O.C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH:10]([C:11]1[NH:15][CH:14]=[CH:13][N:12]=1)[CH2:26][CH2:25][C:24]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: O=C(Cc1ncc[nH]1)c1ccc(Cl)cc1Cl
Reactant: C=CC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCC(C(=O)c1ccc(Cl)cc1Cl)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 108 %

Procedure:
1-(2,4-dichlorophenyl)-2-imidazolylethan-1-one (0.80 M) was dissolved with heating as necessary in a stirred mixture of THF (250 ml) and abs. ethanol (250 ml). After cooling to room temperature, potassium hydroxide (0.20 M) was added followed by a dropwise addition of ethyl acrylate (45.8 ml) via addition funnel over 10 min. A room temperature water bath was used to cool the exothermic reaction for the first 30 min. After stirring for 14-16 hours, the reaction was neutralized with gla. acetic acid (10 ml) and concentrated under reduced pressure. The residual dark reddish black slurry was dissolved in abs. ethanol (100 ml) and concentrated again under reduced pressure giving ethyl 5-(2,4-dichlorophenyl)-4-imidazolyl-5-oxopentanoate (2) in 108% yield. The crude material is contaminated with potassium salts and is used without further purification.
Reaction SMILES: CS[C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:31][C:32]2[CH:36]=[CH:35][S:34][CH:33]=2)[CH:10]2[CH2:15][CH2:14][N:13]([C@H:16]([CH3:30])[CH2:17][CH2:18][NH:19][C:20]([C:22]3[C:23]([CH3:29])=[N:24][CH:25]=[N:26][C:27]=3[CH3:28])=[O:21])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.O[O:38][S:39]([O-:41])=O.[K+].[CH3:43]O>O>[CH3:43][S:39]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:31][C:32]2[CH:36]=[CH:35][S:34][CH:33]=2)[CH:10]2[CH2:15][CH2:14][N:13]([C@H:16]([CH3:30])[CH2:17][CH2:18][NH:19][C:20]([C:22]3[C:27]([CH3:28])=[N:26][CH:25]=[N:24][C:23]=3[CH3:29])=[O:21])[CH2:12][CH2:11]2)=[CH:7][CH:8]=1)(=[O:41])=[O:38]
Reactant: CSc1ccc(N(Cc2ccsc2)C2CCN([C@H](C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Solvent: O
Product: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2ccsc2)c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
To a solution of COMPOUND 307 (273 mg, 0.522 mmol) in MeOH (5 mL) cooled to −15° C. was added a solution of OXONE® (1.41 g, 2.30 mmol) in H2O (5 mL) and the mixture was stirred at −15° C. for 15 minutes. Standard work-up and purification afforded COMPOUND 308 as a white solid (69 mg, 23%). 1H NMR (CDCl3) δ 0.96-1.25 (m, 2H), 1.03 (d, 3H, J=6.6 Hz), 1.54-1.61 (m, 1H), 1.71-1.84 (m, 3H), 2.21 (t, 1H, J=10.2 Hz), 2.53 (s, 6H), 2.60 (t, 1H, J=11.1 Hz), 2.77-2.92 (m, 3H), 2.99 (s, 3H), 3.31-3.38 (m, 1H), 3.66-3.74 (m, 1H), 3.82-3.89 (m, 1H), 3.98 (s, 2H), 6.67 (d, 2H, J=9.0 Hz), 6.98-7.01 (m, 2H), 7.32 (dd, 1H, J=5.1, 3.0 Hz), 7.66 (d, 2H, J=9.0 Hz), 8.49-8.50 (m, 1H), 8.92 (s, 1H). 13C NMR (CDCl3) δ 13.85, 22.35, 29.53, 30.67, 31.23, 40.34, 43.92, 45.40, 45.54, 52.25, 55.99, 60.54, 112.25, 121.23, 126.45, 126.93, 129.57, 130.66, 131.26, 139.96, 152.59, 157.99, 163.51, 166.72. ES-MS m/z 556 (M+H). Anal. Calcd. for C28H37N5O3S2.0.6H2O: C, 59.36; H, 6.80; N, 12.36; S, 11.32. Found: C, 59.38; H, 6.74; N, 12.07; S, 11.22.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@H:5](O)[CH2:4][C@H:3]1[CH2:8][O:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.CCN(S(F)(F)[F:22])CC>C(Cl)Cl>[F:22][C@@H:5]1[CH2:6][N:2]([CH3:1])[C@H:3]([CH2:8][O:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:4]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CN1C[C@H](O)C[C@H]1COc1cccnc1
Solvent: ClCCl
Product: CN1C[C@@H](F)C[C@H]1COc1cccnc1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
A 100 mg (0.5 mmol) sample of 3-((trans-1-methyl-4-hydroxy-2(S)-pyrrolidinyl)methoxy)pyridine, from Example 23 above, above was dissolved in 10 mL of methylene chloride and cooled to -78° C. To this was added 0.165 mL (1.25 mmol) of DAST, and the mixture was stirred for 4 hours while allowing the reaction mixture to warm to room temperature. The reaction was quenched by addition of satd NaHCO3 solution, and the mixture was extracted with chloroform. The solvent was removed, and the residue was purified by chromatography on silica gel, eluting with 20:1 CHCl3 :methanol, to give 30 mg of title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)[C:7](=[O:19])[CH:6]3[CH2:20][O:21][CH2:22][CH2:23][N:5]3[C:4]=2[N:3]=1.IC.[CH3:26]C([O-])(C)C.[Na+]>CS(C)=O.O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)[C:7](=[O:19])[C:6]3([CH3:26])[CH2:20][O:21][CH2:22][CH2:23][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Cn1ccc(CN2C(=O)C3COCCN3c3nc(Cl)ncc32)n1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CI
Product: Cn1ccc(CN2C(=O)C3(C)COCCN3c3nc(Cl)ncc32)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (100 mg, 0.299 mmol) and iodomethane (0.037 mL, 0.597 mmol) were mixed in DMSO (2 mL) in a sealed scintillation vial. The mixture was frozen then sodium 2-methylpropan-2-olate (57.4 mg, 0.597 mmol) was added and covered with a layer of DMSO. The mixture was refrozen then allowed to warm to room temperature and stirred overnight. An additional 1 eq of iodomethane was added. After 1 hour the reaction was diluted with water and extracted into EtOAc. The organic layer was dried over magnesium sulfate, filtered, and evaporated in vacuo to give 2-chloro-6a-methyl-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one as a yellow oil, which was used without further purification. MS [M+H] Found 349
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:10][CH2:11][CH2:12][OH:13].C>C(OC(C)C)(C)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:10][CH2:11][CH2:12][O:13][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: OCCOc1ccc(Cl)c(Cl)c1
Reactant: NS(=O)(=O)Cl
Solvent: CC(C)OC(C)C
Product: NS(=O)(=O)OCCOc1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared by the procedures of Example 4228 from sulfamoyl chloride and to 2-(3,4-dichlorophenoxy)ethanol. The tan colored solid obtained was dissolved in isopropyl ether and the solution treated with charcoal and filtered through Celite®. The filtrate was evaporated under reduced pressure and the solid residue was recrystallized from isopropyl ether to give the title compound, mp 84°-85° C., in 19% yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].NC1C=CC(C[CH2:21][OH:22])=CC=1>>[OH:22][CH2:21][CH2:5][C:4]1[CH:3]=[CH:2][C:9]([NH:10][OH:12])=[CH:8][CH:7]=1.[N+:10]([C:9]1[CH:2]=[CH:3][C:4]([C:5]#[N:6])=[CH:7][CH:8]=1)([O-:12])=[O:11]
Reactant: N#Cc1ccc([N+](=O)[O-])c(Cl)c1
Reactant: Nc1ccc(CCO)cc1
Product: N#Cc1ccc([N+](=O)[O-])cc1
Product: OCCc1ccc(NO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 3-chloro-4-nitrobenzonitrile (Tsuji, K. Chem. Pharm. Bull. 1992, 40, 2399) and 4-aminophenylethyl alcohol.