Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].C(=O)(O)[O-].[Na+].COCCOCCOC>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:22])[CH2:10][N:9]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CN=C(c2ccccc2F)c2cc(I)ccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: Fc1ccccc1C1=NCC(=S)Nc2ccc(I)cc21
Yield: 82 %

Procedure:
A mixture of 31 g (0.08 mol) of 1,3-dihydro-5-(2-fluoro phenyl)-7-iodo-1,4-benzodiazepin-2(2H)-one [ref. G. F. Field and L. H. Sternbaoh, Swiss patents Nos. 561,706; May 1975; and 562,222; April 1975], 20 g (0.09 mol) of phosphorus pentasulfide, 20 g of sodium bicarbonate and 300 ml of diglyme was stirred and heated to 80°-85° C. for 3 hours. The reaction mixture was then poured onto ice and diluted with water. After stirring for 30 minutes, the solid yellow product was filtered off, washed with water, 2-propanol and little ether. It was sucked dry in the funnel and further dried in vacuum to leave 26 g (80%) of 1,3-dihydro-5-(2-fluorophenyl)-7-iodo-1,4-benzodiazepine-2(2H)-thione which was further transformed as described below. Pure material was obtained by recrystallization from tetrahydrofuran/ethanol and had m.p. 242°-244° C.
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10](Br)[CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15].CON(C)[C:22]([C@@H:24]1[CH2:28][S:27][C:26]([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[N:34](S(C2C=CC=CC=2)(=O)=O)[CH:33]=[CH:32]3)=[N:25]1)=[O:23]>C1COCC1.[OH-].[Na+].C(O)C>[NH:34]1[C:35]2[C:31](=[CH:30][C:29]([C:26]3[S:27][CH:28]=[C:24]([C:22]([C:10]4[CH:9]=[C:8]([O:7][CH3:6])[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=4)=[O:23])[N:25]=3)=[CH:37][CH:36]=2)[CH:32]=[CH:33]1
Reactant: CON(C)C(=O)[C@@H]1CSC(c2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2)=N1
Reactant: COc1cc(Br)cc(OC)c1OC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(C(=O)c2csc(-c3ccc4[nH]ccc4c3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of n-BuLi (1.6 M, 1.7 mL) in 8 mL THF was added a solution of 3,4,5-trimethoxybromobenzene (2.47 mmol) in 3 mL THF under −78° C. The mixture was allowed to stir for 2 h and a solution of Weinreb amide 65a (1.24 mmol) in 3 mL THF was charged. The temperature was allowed to increase at RT and stirred overnight. The reaction mixture was quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was refluxed in 1 N NaOH in 5 mL ethanol solution to obtain the deprotected compound 31 and purified by column chromatography to obtain pure compound as a light yellow solid (36.3%). 1H NMR (300 MHz, CDCl3) δ 8.36 (br, s, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 7.92, 7.89 (dd, 1H, J=1.8, 2.7 Hz), 7.46 (d, 1H,) 7.62 (s, 2H, J=8.7 Hz), 7.29 (t, 1H, J=2.7 Hz), 6.64 (br, 1H), 3.97 (s, 6H), 3.97 (s, 3H); MS (ESI) m/z 417.1 (M+Na)+, 392.9 (M−H)−.
Reaction SMILES: [C:1]([C:4]1[C:5](I)=[N:6][N:7]2[C@H:12]3[CH2:13][O:14][CH2:15][C@H:11]3[N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:8]=12)(=[O:3])[NH2:2].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[F:31].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[C:1]([C:4]1[C:5]([C:27]2[CH:28]=[CH:29][C:30]([F:31])=[C:25]([Cl:24])[CH:26]=2)=[N:6][N:7]2[C@H:12]3[CH2:13][O:14][CH2:15][C@H:11]3[N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:8]=12)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(I)nn2[C@H]2COC[C@H]21
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(-c3ccc(F)c(Cl)c3)nn2[C@H]2COC[C@H]21
Temperature: 80 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
To a stirred solution of Intermediate 352F (0.370 g, 0.852 mmol) and (3-chloro-4-fluorophenyl)boronic acid (0.297 g, 1.704 mmol) in dioxane (2 mL) was added a solution of K3PO4 (0.543 g, 2.56 mmol) in water (0.5 mL) and the reaction mixture was purged with nitrogen for 10 min. PdCl2(dppf)CH2Cl2 (0.052 g, 0.064 mmol) was then added and the reaction mixture was heated to 80° C. and stirred for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated. The crude compound was purified by silica gel chromatography (12 g REDISEP® column, eluting with 4% MeOH in CHCl3). Fractions containing the product were combined and evaporated to afford Intermediate 352G (0.270 g, 54%) as an off-white solid. MS(ES): m/z=437 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH2:18][CH2:17][C:16](=O)[CH:15]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22]>CCO.N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH2:18][CH2:17][C:16](=[N:21][OH:22])[CH:15]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1C=C(c2ccc(Sc3ccc(F)cc3)o2)CC1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1C=C(c2ccc(Sc3ccc(F)cc3)o2)CC1
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a stirred solution of 3-[5-(4-fluorophenylthio)-2-furyl]-2-cyclopentenone (5.9 g; 21.5 mM) in EtOH-pyridine (50 ml-12 ml) was added hydroxylamine hydrochloride (2.24 g; 32.3 mM) at room temperature. After stirring overnight, solvent was removed. To the residue was added 0.5N aqueous HCl (80 ml), and the whole was extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with water (70 ml), brine (70 ml), dried over MgSO4, and concentrated in vacuo to give 6 g (yield 97%) of crude subtitle compound as a brown oil, which was used without further purification.
Reaction SMILES: [I:1][C:2]1[C:3]2[C:4](=[CH:8][NH:9][N:10]=2)[N:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])[C:3]=12
Reactant: Ic1ccnc2c[nH]nc12
Reactant: CC(C)(O)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(O)CCn1ncc2nccc(I)c21
Temperature: 120 °C

Procedure:
7-Iodo-2H-pyrazolo[4,3-b]pyridine (357 mg, 1.457 mmol), 4-bromo-2-methylbutan-2-ol (243 mg, 1.457 mmol) and Cs2CO3 (475 mg, 1.457 mmol) were combined in DMF (5 mL) and heated in a microwave at 120° C. for 40 minutes. The reaction was then cooled, filtered, and concentrated to give a residue which was purified by silica chromatography eluted with a step gradient of EtOAc in hexanes to give 4-(7-iodo-1H-pyrazolo[4,3-b]pyridin-1-yl)-2-methylbutan-2-ol which was dried and used immediately.
Reaction SMILES: O1CCCC1.[CH3:6][N:7]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]1.[C:14](=S)=[S:15]>>[N:13]([CH:10]1[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]1)=[C:14]=[S:15]
Reactant: S=C=S
Reactant: CN1CCC(N)CC1
Solvent: C1CCOC1
Product: CN1CCC(N=C=S)CC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred mixture of 412 parts of N,N'-methanetetraylbis[cyclohexanamine] and 2225 parts of tetrahydrofuran there were added dropwise 1092 parts of carbon disulfide and, after cooling to -10° C., portionwise 228 parts of 1-methyl-4-piperidinamine. The whole was stirred for 1 hour at room temperature and was then evaporated. The residue was recrystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 416.6 parts (100%) of 4-isothiocyanato-1-methylpiperidine (interm. 16).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=[O:11])#[CH:2].Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:27][CH:26]=2)[N:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=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.[Cu]I>[NH2:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:18]1[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:14][N:15]=[C:16]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:29][CH:30]=2)[N:17]=1
Reactant: C#Cc1ccccc1CC(N)=O
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3CC(N)=O)n2)cc1
Temperature: 120 °C
Yield: 74 %

Procedure:
To a nitrogen de-gassed solution of 2-(2-ethynylphenyl)acetamide (I39) (0.054 g, 0.788 mmol) and tert-butyl 2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I37) in dry DMF (4 mL) were added triethylamine (0.159 mL, 1.138 mmol), triphenylphosphine (0.011 g, 0.043 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (0.020 g, 0.028 mmol) and CuI (0.008 g, 0.04 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes. The reaction was concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-5% methanol in EtOAc) to give the title compound (I40) (0.122 g, 74% yield) as a yellow glassy solid; 1H NMR (400 MHz, d6-DMSO) δ 10.48 (s, 1H), 8.82 (s, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.65-7.55 (m, 1H), 7.55-7.47 (m, 1H), 7.47-7.33 (m, 3H), 7.16 (d, J=8.5 Hz, 2H), 7.01 (s, 1H), 5.29-5.22 (m, 1H), 3.92 (d, J=13.1 Hz, 1H), 3.70 (s, 2H), 2.71 (t, J=13.3 Hz, 1H), 2.34-2.24 (m, 1H), 1.82-1.68 (m, 1H), 1.54 (d, J=11.3 Hz, 2H), 1.45-1.22 (m, 11H). LCMS Method C: rt 6.52 min; m/z 578.3 [M−H]−.
Reaction SMILES: [CH3:1][N:2]1[CH:9]=[CH:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].[CH3:10][C:11]1[S:12][C:13]2[CH:20]=[CH:19][C:18]3[CH:21]=[C:22]([CH2:25][CH2:26][CH3:27])[CH:23]=[CH:24][C:17]=3[CH:16](O)[C:14]=2[N:15]=1>C(O)(=O)C>[CH3:1][N:2]1[CH:9]=[C:8]([CH:16]2[C:14]3[N:15]=[C:11]([CH3:10])[S:12][C:13]=3[CH:20]=[CH:19][C:18]3[CH:21]=[C:22]([CH2:25][CH2:26][CH3:27])[CH:23]=[CH:24][C:17]2=3)[C:6](=[O:7])[NH:5][C:3]1=[O:4]
Reactant: CCCc1ccc2c(c1)C=Cc1sc(C)nc1C2O
Reactant: Cn1ccc(=O)[nH]c1=O
Solvent: CC(=O)O
Product: CCCc1ccc2c(c1)C=Cc1sc(C)nc1C2c1cn(C)c(=O)[nH]c1=O

Procedure:
A mixture of the 1-methyluracil (0.5 g) and the product from step (xi) in acetic acid (50 ml) was heated at reflux 2 h. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate/water. The organic layer collected and dried over MgSO4. The solvent evaporated and the crude product purified by flash chromatography eluting with ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11]>>[Br:1][C:2]1[C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(Br)cccc1Br
Product: Cc1c(Br)ccc([N+](=O)[O-])c1Br
Temperature: 0 °C

Procedure:
To 38 g of 2,6-dibromotoluene (0.152 mol) was added dropwise with stirring, over a period of thirty minutes, 76 ml of 70% nitric acid. An exothermic reaction was observed. The resulting mixture was stirred for an additional sixty minutes, after which time the mixture was poured into 1500 ml of ice water. The solids which separated were collected by filtration and dried to yield 44.62 g of 2,6-dibromo-3-nitrotoluene. Recrystallization of the reaction product from ethyl alcohol-water yielded material melting at 47°-48° C.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]2[CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16][C:4]=12)=O.Cl.[NH2:25]O>C(O)=O>[CH2:16]1[C:4]2=[C:3]([C:1]#[N:25])[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]2[CH2:12][CH2:13][NH:14][CH2:15]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCc2c(C=O)c3ccccc3n2CC1
Agent: Cl
Solvent: O=CO
Product: N#Cc1c2n(c3ccccc13)CCNCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of tert-butyl 11-formyl-1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,7-a]indole-3-carboxylate in formic acid (1 mL) is treated with hydroxylamine hydrochloride (90 mg, 1.3 mmol) and heated to reflux. After 18 hrs, the reaction mixture is cooled to rt, quenched with 1M sodium hydroxide (15 mL), and extracted twice with ethyl acetate (20 mL). The combined organics are washed once with brine (20 mL), dried over MgSO4, filtered, and concentrated to give 224 mg of a crude solid. This material is purified by LC (230-400) silica gel eluting with 5% methanol/dichloromethane to afford 123 mg of 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole-11-carbonitrile as a red solid, mp 161-164° C. IR (drift) 3313, 2935, 2906, 2203, 1539, 1463, 1421, 1351, 1328, 1272, 1208, 1185, 822, 769, 752 cm−1.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[C@H:15]([CH2:19][S:20](Cl)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:26]1[C:31]2[S:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:30]=2[CH2:29][CH2:28][NH:27]1.C(N(CC)CC)C>ClCCl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[C@H:15]([CH2:19][S:20]([N:27]1[CH2:28][CH2:29][C:30]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[S:32][C:31]=2[CH2:26]1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: c1ccc2c3c(sc2c1)CNCC3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@@H](CS(=O)(=O)N1CCc2c(sc3ccccc23)C1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.5 %

Procedure:
4-(R)-Benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)oxazolidin-2-one (370 mg) was added to a solution of 1,2,3,4-tetrahydro-benzo[4,5]thieno[2,3-c]pyridine hydrochloride (230 mg) and triethylamine (0.30 ml) in dichloromethane (20 ml) and the reaction stirred at room temperature for 18 h. The mixture was washed with water (30 ml) and brine (20 ml), dried (MgSO4), filtered and evaporated under reduced pressure to give the title compound (180 mg) in crude form.
Reaction SMILES: [CH3:1][C@H:2]([CH2:7][C:8](OC)=O)[C:3](OC)=O.[NH2:12][C@H:13]([CH3:16])[CH2:14][OH:15]>>[CH3:1][C@@H:2]1[CH2:7][CH2:8][N:12]([C@H:13]([CH3:16])[CH2:14][OH:15])[CH2:3]1
Reactant: C[C@@H](N)CO
Reactant: COC(=O)C[C@@H](C)C(=O)OC
Product: C[C@@H]1CCN([C@H](C)CO)C1

Procedure:
The title compound was synthesized as described in Intermediate 11 using (R)-dimethyl 2-methylsuccinate and (R)-2-aminopropan-1-ol as starting materials. 1H NMR (CDCl3): δ 3.57 (dd, 1H), 3.32 (dd, 1H), 3.02 (br s, 1H), 2.81 (dd, 1H), 2.69 (m, 2H), 2.60 (m, 1H), 2.20 (m, 1H), 2.12 (dd, 1H), 1.98 (m, 1H), 1.32 (m, 1H), 1.04 (m, 6H); MS: 144.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@@H:9]1[CH2:22][OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCCCCC.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:9]1[CH:22]=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of 77E (800 mg, 2.3 mmol) in DCM (15 mL) was added 4-methylmorpholine N-oxide (541 mg, 4.6 mmol, 2 equiv) followed by the addition of TPAP (177 mg, 0.5 mmol, 0.22 equiv). The mixture was stirred at rt for 3 h. The mixture was diluted with hexane (10 mL), loaded on a layer of silica gel and eluted with 25% EtOAc/hexane. The filtrate was concentrated to gave the desired product 77F (711 mg, 90%): Rf (30% EtOAc/hexane) 0.87; HPLC (Phenomenex Luna 5 u C18 4.6×50 mm, linear gradient over 4 min) retention time 4.1 min (100%); MS (ES) m/z 344.1 [M+1]+; HRMS calcd for C17H34NO4Si 344.2257, Found 344.2259.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8](=[O:15])[N:9]2[CH2:12][CH2:13][CH3:14])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[OH:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.[OH-].[K+].Cl>O.CS(C)=O>[N+:17]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:24]1[CH:25]=[CH:26][C:21](=[O:20])[CH:22]=[CH:23]1)[N:9]([CH2:12][CH2:13][CH3:14])[C:8](=[O:15])[C:7](=[O:16])[NH:6]2)([O-:19])=[O:18]
Reactant: Oc1ccncc1
Reactant: CCCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccc(=O)cc3)cc21
Temperature: 130 °C
Reaction time: 3.5 h
Yield: 67.8 %

Procedure:
First, 1.244 g of 7-fluoro-6-nitro-1-(n-propyl)-1,4-dihydroquinoxaline-2,3-dione, 952 mg of 4-hydroxypyridine, and 711 mg of powdered potassium hydroxide were added to 10 ml of dry dimethylsulfoxide. The mixture was stirred at 130° C. for 3.5 hours in a nitrogen atmosphere. Then, 50 ml of water was added to the reaction mixture and the mixture was made acidic (pH 2 to 3) with 4N hydrochloric acid to give a yellow precipitate. The precipitate was filtered and recrystallized with dimethylformaldehyde to give 1.08 g of 6-nitro-7-(4-oxo-4H-pyridin-1-yl)-1-(n-propyl)-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: Br[C:2]([CH3:8])([CH3:7])[C:3]([NH:5][CH3:6])=[O:4].[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C1(C)C=CC=CC=1.[Ag]=O>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][N:19]([C:2]([CH3:8])([C:3](=[O:4])[NH:5][CH3:6])[CH3:7])[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CNC(=O)C(C)(C)Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=[Ag]
Solvent: Cc1ccccc1
Product: CNC(=O)C(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 93.2 %

Procedure:
A mixture of 2-bromo-2,N-dimethyl-propionamide (312 mg), 1-BOC-piperazine (323 mg) and silver oxide (800 mg) was stirred in toluene (5 mL) at reflux. After 24 h the reaction mixture was cooled, filtered through celite, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent was removed in vacuo to yield 4-(1-methyl-1-methylcarbamoyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (461 mg). Removal of the BOC group with HCl yielded the desired compound, which was isolated as the hydrochloride salt.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH2:28])[CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH:28][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([OH:1])[CH:3]=2)[CH:27]=1
Reactant: COc1ccc(-c2cc3ccccc3[nH]2)cc1N
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2cc3ccccc3[nH]2)cc1NCc1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
3-Hydroxy-4-nitrobenzaldehyde (0.334 g, 2.0 mmol) was added to a stirred mixture of 5-(1H-indol-2-yl)-2-methoxy-phenylamine (0.476 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture is stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution was stirred at room temperature for 3 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture is stirred for 2 hours. The mixture was shaken, the organic layer was separated and dried over Na2SO4. The solvent was evaporated to give a brown gum. Recrystallization from methanol gave the product (500 mg), mp 134-135° C.
Reaction SMILES: [C:1]([C:5]1[CH:29]=[CH:28][C:8]([O:9][CH2:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:17]([O:26]C)[CH:16]=2)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.B(Br)(Br)Br>C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:23])=[O:24])=[C:17]([OH:26])[CH:16]=2)=[O:12])=[CH:28][CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(CNC(=O)COc2ccc(C(C)(C)C)cc2)ccc1NS(C)(=O)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(O)c2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 68 %

Procedure:
To a solution of 2-(4-tert-butylphenoxy)-N-{3-methoxy-4-[(methylsulfonyl)amino]benzyl}acetamide (Example 11) (446 mg, 1.06 mmol) in methylene dichrolide (20 ml) was added 1.0 M methylene dichloride solution of boron(III)bromide (5.3 ml, 5.3 mmol) at 0° C. After being stirred for 1.5 hours at 0° C., the mixture was quenched with water and crude residue was extracted with methylene dichloride. The organic layer was separated, then washed with brine, dried over magnesium sulfate. Then, filtration to remove magnesium sulfate, evaporation under removed pressure gave the residue, which was applied to a silica gel chromatography column and eluted with a volume mixture of hexane : ethyl acetate (2/3) to furnish 293 mg (55% yield) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[N:12][CH:11]=[C:10]([O:23][CH3:24])[C:9]=3[C:8]2=[O:25])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1.C(O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[N+:12]([O-:36])[CH:11]=[C:10]([O:23][CH3:24])[C:9]=3[C:8]2=[O:25])=[CH:26][CH:27]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cnc(N(C)S(C)(=O)=O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Solvent: CCO
Solvent: ClCCl
Product: COc1c[n+]([O-])c(N(C)S(C)(=O)=O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of N-[6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl]-N-methylmethanesulfonamide (0.35 g, 0.89 mmol) in CH2Cl2 (10 mL) was added mCPBA (1.08 g, 6.23 mmol) in portions. After stirring for 3.5 hours at reflux, the product mixture was cooled to room temperature, 1 mL of ethanol was added, and the solution was concentrated. The residue was partitioned between CHCl3 and saturated Na2SO3. The organic layer was extracted repeatedly with saturated sodium bicarbonate. The organic extract was dried with Na2SO4, filtered, and concentrated under vacuum to provide the crude title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4](Cl)[C:3]=1C(OCC)=O.[BrH:25]>C(O)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([Br:25])[CH:3]=1
Reactant: Br
Reactant: CCOC(=O)c1c(Cl)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Solvent: CC(=O)O
Product: Nc1cc(Br)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
A mixture of 5-amino-4-carboethoxy-3-chloro-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole (3.3 g), hydrobromic acid (45%; 30 ml) and acetic acid (50 ml) was boiled under reflux for 18 h. The mixture was evaporated to low bulk and basified with sodium hydroxide solution (2 M), and the product was filtered off, dried (2.9 g) and recrystallized from a mixture of ethanol and water to give 5-amino-3-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole (2.5 g), m.p. 132.5°-134° C. in the form of a colorless solid.