Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[CH:28](I)([CH3:30])[CH3:29]>C1COCC1>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@:22]([CH:28]([CH3:30])[CH3:29])([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: CC(C)I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@@]1(C(C)C)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a 1.00 M solution of lithium hexamethyldisilazide in THF (202 mL) at −78° C. was added a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (22.10 g, 91.59 mmol) in THF (36.2 mL) over 10 min. The solution was stirred at −78° C. for 30 min before isopropyl iodide (10.0 mL, 100 mmol) was added in one portion. The mixture was then moved to a freezer reading at −24° C. and kept overnight. The reaction was quenched with aqueous ammonium chloride and the resulting solution was extracted with ether three times. The ether layers were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica eluting with 10% ethyl acetate/hexane to give the title compound (20.2 g). MS calculated for C15H25NO4:(M+H)+284; found 184.2 (M-Boc+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN(C=O)C.[Cl-].[Na+].O>[N+:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:11])=[O:10]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1CN1CCCC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 1-(bromomethyl)-2-nitrobenzene (2.10 g) in DMF (20 mL) was added pyrrolidine (0.95 mL) and N,N-diisopropylethylamine (2.54 mL), and the mixture was stirred at 60° C. for 24 hours. The resulting mixture was poured into ethyl acetate and brine. The organic phase was separated and washed with brine, dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography to give 1-(2-nitrobenzyl)pyrrolidine (1.92 g) as a pale yellow oil.
Reaction SMILES: ClC1C=C(C2(C(F)(F)F)ON=C(C3C4C(=CC=CC=4)C(C(NCCSC)=O)=CC=3)C2)C=C(Cl)C=1.[Cl:35][C:36]1[CH:37]=[C:38]([C:43]2([C:73]([F:76])([F:75])[F:74])[O:47][N:46]=[C:45]([C:48]3[C:57]4[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=4)[C:51]([C:58]([NH:60][CH2:61][CH2:62][S:63]([CH3:72])(=NC(=O)C(F)(F)F)=[O:64])=[O:59])=[CH:50][CH:49]=3)[CH2:44]2)[CH:39]=[C:40]([Cl:42])[CH:41]=1.C1C=C(Cl)C=C(C(OO)=O)C=1>ClCCl>[Cl:42][C:40]1[CH:39]=[C:38]([C:43]2([C:73]([F:74])([F:76])[F:75])[O:47][N:46]=[C:45]([C:48]3[C:57]4[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=4)[C:51]([C:58]([NH:60][CH2:61][CH2:62][S:63]([CH3:72])=[O:64])=[O:59])=[CH:50][CH:49]=3)[CH2:44]2)[CH:37]=[C:36]([Cl:35])[CH:41]=1
Reactant: CS(=O)(CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12)=NC(=O)C(F)(F)F
Agent: CSCCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: -74 °C
Reaction time: 2.5 h
Yield: 99 %

Procedure:
To a stirred solution of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-(methylthio)ethyl]-1-naphthalenecarboxamide (i.e. the title product of Step A) (100 mg) in dichloromethane (10 mL) was added MCPBA (47 mg, 70%) at −78° C. The reaction mixture was stirred at −78 to −70° C. for 2.5 h, then quenched with saturated sodium bicarbonate, extracted with dichloromethane, washed with brine, dried with sodium sulfate, and concentrated to afford the title compound as a white solid (102 mg, 99% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(O)C>[F:22][C:21]([F:24])([F:23])[C:18]1[CH:17]=[N:16][C:15]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1-c1ccc(C(F)(F)F)cn1
Temperature: 100 °C
Yield: 99.5 %

Procedure:
4-methoxycarbonylphenyl boronic acid (541 mg) and 2-chloro-5-trifluoromethylpyridine (718 mg) were added to a suspension of bisbenzonitriledichloropalladium (119 mg) and 1,4-bisdiphenylphosphinobutane (131 mg) in toluene (10 ml) at ambient temperature and then ethanol (5 ml) and saturated aqueous sodium hydrogencarbonate solution (5 ml) were added to the mixture. This mixture was heated at reflux for 5 hours at 100° C. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue diisopropyl ether was added to afford the desired compound (841 mg) as a white powder which include some impurity.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:15][C:16]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]3[C:17]=2[CH:18]=[CH:19][NH:20]3)[C:7]1=[O:26].C([OH:32])(C)(C)C>[Zn]>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:15][C:16]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]3[C:17]=2[CH2:18][C:19](=[O:32])[NH:20]3)[C:7]1=[O:26]
Reactant: CC(C)(C)O
Reactant: COC(=O)CCn1c(=O)n(Cc2cc(Cl)cc3[nH]ccc23)c2ccccc21
Agent: [Zn]
Product: COC(=O)CCn1c(=O)n(Cc2cc(Cl)cc3c2CC(=O)N3)c2ccccc21
Yield: 36 %

Procedure:
3-[3-(6-Chloro-1H-indol-4-ylmethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-propionic acid methyl ester (248 mg, 0.64 mmol) is dissolved it tert-butanol (20 mL) at 40° C. The reaction is stirred and pyridiniumtrbromide is added portion wise over 5 minutes. The reaction is stirred for 10 minutes and concentrated in vacuo. The crude material is dissolved in acetic acid (10 mL) and zinc powder (211 mg, 3.2 mmol)is added to the reaction. The reaction is stirred at room temperature for one hour, then the solvent evaporated in vacuo. The residue is taken up in dimethyl sulfoxide and filtered. The crude material is purified by preparative reverse phase LC to give the title compound (34 mg 0.09 mmol, 36%).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[C:3](=[O:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[Br:13]Br>>[Br:13][CH:4]([N:5]1[CH:9]=[N:8][CH:7]=[N:6]1)[C:3](=[O:10])[C:2]([CH3:12])([CH3:11])[CH3:1]
Reactant: BrBr
Reactant: CC(C)(C)C(=O)Cn1cncn1
Product: CC(C)(C)C(=O)C(Br)n1cncn1

Procedure:
Thus, for example, 3,3-dimethyl-1-(4-methoximino-methyl-phenoxy)-1-(1,2,4-triazol-1-yl)-butan-2-one formula ##STR11## can be prepared by reacting 3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one initially with bromine to form 1-bromo(1,2,4-triazol-1-yl)-3,3-dimethyl-butan-2-one and subsequently reacting this with 4-hydroxybenzaldehyde O-methyloxime ether in the presence of a base. This synthesis can be illustrated by the formulae as follows:
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]([CH3:19])[N:11]=2)=[C:5]([CH3:20])[CH:4]=1.Br>C(O)(=O)C>[CH3:9][C:8]1[CH:7]=[C:6]([C:10]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]([CH3:19])[N:11]=2)[C:5]([CH3:20])=[CH:4][C:3]=1[OH:2]
Reactant: COc1cc(C)c(-c2cc(C(F)(F)F)n(C)n2)cc1C
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc(-c2cc(C(F)(F)F)n(C)n2)c(C)cc1O
Yield: 101.7 %

Procedure:
A mixture of 3-(4-methoxy-2,5-dimethyl-phenyl)-1-methyl-5-trifluoromethyl-1H-pyrazole (described in Reference Preparation example 85) 3 g, 47% hydrobromic acid 29 ml and acetic acid 29 ml was stirred with heating under reflux for twenty one hours. The solvent was distilled off and to the resulting residues was added ice water 90 ml. The precipitates were filtered and were washed with ice water 90 ml and hexane 100 ml, and then were concentrated under reduced pressure to give 2,5-dimethyl-4-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-phenol 2.9 g.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([CH:13]([OH:22])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[CH:10]=[CH:9][C:8]2=[O:23])=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13](=[O:22])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[CH:10]=[CH:9][C:8]2=[O:23])=[CH:24][CH:25]=1
Reactant: COc1cccc(C(O)c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cccc(C(=O)c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)c1
Yield: 100 %

Procedure:
According to Scheme 7 Method C: 1-(4-Chlorobenzyl)-5-(hydroxy(3-methoxyphenyl)-methyl)pyridin-2(1H)-one (1 eq, 0.28 mmol, 0.10 g, Example 41) and manganese dioxide (30 eq, 8.43 mmol, 0.73 g) were stirred overnight at room temperature in CH2Cl2 (10 mL). Upon completion, the crude mixture was filtered through a pad of celite and the filtrate was concentrated. The crude residue was partitioned between water and CH2Cl2. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4 and concentrated under vacuum to afford the title compound as a white solid (0.28 mmol, 0.10 g, 100%).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]>N1C=CC=CC=1>[S:8]([N:1]([CH2:5][CH2:6][O:7][S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:2][CH2:3][O:4][S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9])([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCNCCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCN(CCOS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Yield: 85 %

Procedure:
A solution of 32.5 g (0.31 mole) of diethanolamine in 60 cm3 of pyridine are added slowly to a solution of 185 g (0.97 mole) of tosyl chloride in 220 cm3 of pyridine at 0° C. so that the temperature does not exceed 5° C. After the addition is complete, the mixture is maintained at this temperature for 1 h, then it is poured into 220 cm3 of ice-cold water with vigorous stirring. After filtration, washing and drying 148.4 g of precipitate are obtained (yield 85%; Rf=0.6 silica/CH2Cl2 /acetone/98/2).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][C:7](=[O:11])[N:6]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([N:21]=[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:14]=1)=[O:4].[Cl:35][C:36]1[S:40][C:39]([O:41][CH2:42][C:43](O)=[O:44])=[CH:38][CH:37]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([C:43](=[O:44])[CH2:42][O:41][C:39]2[S:40][C:36]([Cl:35])=[CH:37][CH:38]=2)[CH2:8][C:7](=[O:11])[N:6]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([N:21]=[C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=1)=[O:4]
Reactant: O=C(O)COc1ccc(Cl)s1
Reactant: COC(=O)C1CNCC(=O)N1Cc1ccc(C#N)c(N=C(c2ccccc2)c2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)C1CN(C(=O)COc2ccc(Cl)s2)CC(=O)N1Cc1ccc(C#N)c(N=C(c2ccccc2)c2ccccc2)c1
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a solution containing (±)-1-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-6-oxo-piperazine-2-carboxylic acid methyl ester (1.17 g, 2.6 mmol), EXAMPLE 784, Part B, 5-chlorothiophen-2-yloxyacetic acid (0.5 g, 2.6 mmol), EXAMPLE 24, and N-methylmorpholine (0.58 g, 5.72 mmol) in anhydrous DMF (10 mL) is added HATU (1.09 g, 2.86 mmol) at ambient temperature. After 1.5 h, the reaction mixture is diluted with CH2Cl2 (100 mL) and aqueous NaHCO3 (100 mL) and the layers are separated. The aqueous phase is washed four times with CH2Cl2 (100 mL) and the combined organic phase is washed once with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude amide is purified by flash silica gel chromatography (hexane/EtOAc, 4:1 to 1:2) to afford 1.5 g of the title compound which is used directly in the next reaction. 1H NMR (300 MHz, CDCl3, ˜2:1 mixture of rotomers) major rotomer: δ3.55 (d, J=15.2 Hz, 1H), 3.60 (m, 1H), 3.69 (m, 5H), 4.37 (d, J=17.7 Hz, 1H), 4.62 (m, 2H), 4.79 (d, J=13.3 Hz, 1H), 5.35 (d, J=15.2 Hz, 1H), 6.05 (d, J=3.9 Hz, 1H), 6.52 (m. 2H), 6.84 (d, J=8.1 Hz, 1H), 7.18-7.49 (m, 11H), 7.76 (m, 1H) ppm; MS (ISP loop): m/z 627 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.ClC1C=C(C(OO)=[O:20])C=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N+:7]([O-:20])[CH:6]=[CH:5]2
Reactant: Brc1ccc2cnccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
To a solution of 51.0 g (245.1 mmol) of 6-bromo-isoquinoline (3) in 800 ml of dichloromethane were added under mechanical stirring 90.6 g (367.6 mmol) of 3-chloro-benzenecarboperoxoic acid (70%). After stirring for 4 h at room temperature and standing overnight, saturated sodium hydrogen carbonate-solution was added until two clear layers were obtained. The dichloromethane solution was separated and washed with saturated NaCl-solution. The aqueous layers were extracted with a chloroform/isopropanol (3:1) mixture and the organic layers were combined, washed again with saturated NaCl-solution, dried over magnesium sulfate and evaporated. The obtained crude product (53.0 g) was used without further purification. Rt=0.89 min (Method C). Detected mass: 226.2 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[OH-].[Na+].[ClH:14].[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[CH:17]([CH2:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29](Br)[CH:28]=1)=[O:25])[CH2:16]2>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:14].[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[CH:17]([CH2:23][C:24]([NH:26][C:27]1[CH:28]=[C:29]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:2][OH:1])[CH:30]=[CH:31][CH:32]=1)=[O:25])[CH2:16]2
Reactant: O=C(CC1CN2CCC1CC2)Nc1cccc(Br)c1
Reactant: OCc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(CC1CN2CCC1CC2)Nc1cccc(-c2ccccc2CO)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
48.1 mg (0.32 mmol) of 2-(hydroxymethyl)phenylboronic acid, 0.95 ml (0.95 mmol) of 1M sodium hydroxide solution and 51.7 mg (0.06 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride are added to a solution of 150 mg (0.32 mmol) of 2-(1-azabicyclo[2.2.2]oct-3-yl)-N-(3-bromophenyl)acetamide hydrochloride in 2 ml of DMF. The reaction mixture is stirred at 80° C. for 18 h. The same amounts of 2-(hydroxymethyl)phenylboronic acid, 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and sodium hydroxide solution are again added, and the mixture is heated at 80° C. for a further 24 h. The reaction mixture is cooled, filtered through kieselguhr and then purified by preparative HPLC. The product fractions are concentrated, taken up in methanol, mixed with 4M HCl in dioxane and again concentrated. Drying under high vacuum results in 86.5 mg (64.1% of theory) of the title compound.
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:8][C:9]3[C:14]([N:15]=2)=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=3)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:29]I>O1CCCC1>[CH:1]1([N:5]([CH3:29])[C:6]2[C:7]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[N:8][C:9]3[C:14]([N:15]=2)=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=3)[CH2:2][CH2:3][CH2:4]1
Reactant: CI
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC3CCC3)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C3CCC3)nc2c1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-(cyclobutylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (67 mg, 0.19 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (30 mg, 60%) and CH3I (135 mg, 0.95 mmol). The resulting solution was stirred overnight at 10° C. The reaction was then quenched by the addition of NH4Cl solution (50 mL), extracted with ethyl acetate (4×20 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (2%-10% ethyl acetate in petroleum ether) to afford methyl 3-[cyclobutyl(methyl)amino]-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (70 mg, crude).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][C:10](=O)[CH3:11])=[CH:4][C:3]=1[CH3:14].Cl.[NH2:16]O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:13][N:16]=[C:10]([CH3:11])[CH:9]=2)=[CH:4][C:3]=1[CH3:14]
Reactant: CC(=O)CC(=O)c1ccc(Br)c(C)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(-c2ccc(Br)c(C)c2)on1

Procedure:
A solution of 1-(4-bromo-3-methylphenyl)butane-1,3-dione (D77) (615 mg; 0.0024 ml) in ethanol (15 ml) was treated with hydroxylamine hydrochloride (170 mg; 0.0024 mol) and potassium carbonate (336 mg; 0.0024 mol), and the mixture heated at reflux for 2.5 hours, then overnight at room temperature. The solvent was evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4) and concentrated in vacuo to leave the crude isoxazole, which was purified by chromatography on silica gel, eluting with pentane, 60-80 petroleum-ether and ethyl acetate, to afford the title compound as a yellow crystalline material (477 mg, 78%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23](I)[CH2:24][CH2:25][CH3:26]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([CH2:23][CH2:24][CH2:25][CH3:26])=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccccc2)on1
Reactant: CCCCI
Product: CCCCc1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Yield: 66 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.3 g) and butyl iodide (0.17 ml) were subjected to reaction and post-treatment in a similar manner to that described in Example 14(a) to obtain the title compound (0.23 g, 66%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[S-:13][C:14]#[N:15].[K+].BrBr>C(O)(=O)C>[NH2:15][C:14]1[S:13][C:11]2[C:2](=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:1]=1
Reactant: COC(=O)c1cc(C)ccc1N
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(C)cc2sc(N)nc12
Temperature: 0 °C

Procedure:
50 g (0.303 mol) of methyl 2-amino-5-methylbenzoate are dissolved in 300 ml of glacial acetic acid, and 120.6 g (1.24 mol) of potassium thiocyanate--dissolved in 200 ml of glacial acetic acid--are added. At 10° C., 17.42 ml (0.335 mol) of bromine are added dropwise, and the mixture is then stirred without cooling for 2 hours. The suspension is tipped into 3 l of ice-water, while stirring, and the precipitated product is filtered off with suction and washed with dilute sodium carbonate solution and water. The filter cake is suspended in H2O and the suspension is stirred at 100° C. overnight. After cooling, the product is filtered off with suction, washed with H2O and dried at 40° C. in vacuo.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]([O:23][C:24]([CH2:26][CH2:27][C:28]1[O:29][C:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:31]([C:33](O)=[O:34])[N:32]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:25])[CH2:26][CH2:27][C:28]1[O:29][C:30]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[C:31]([C:33](=[O:34])[NH:18][C:15]2[CH:16]=[CH:17][N:13]([CH2:12][C:10]3[O:11][C:7]([C:2](=[O:6])[CH3:1])=[CH:8][CH:9]=3)[N:14]=2)[N:32]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)CCc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(CCC(=O)OC(C)(C)C)oc3-c3ccccc3)n2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-(2-tert-butoxycarbonyl-ethyl)-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.09 min; [M+H]+=505.42.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:28]=[CH:27][CH:26]=[CH:25][C:6]=1[CH2:7][S:8]([NH:11][C:12]([NH:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[N:16]=1)=[S:13])(=[O:10])=[O:9])=[O:4].BrBr>N1C=CC=CC=1>[CH3:24][O:23][C:17]1[CH:18]=[C:19]([O:21][CH3:22])[N:20]2[S:13][C:12](=[N:11][S:8]([CH2:7][C:6]3[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=3[C:3]([O:2][CH3:1])=[O:4])(=[O:10])=[O:9])[N:14]=[C:15]2[N:16]=1
Reactant: COC(=O)c1ccccc1CS(=O)(=O)NC(=S)Nc1nc(OC)cc(OC)n1
Agent: BrBr
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1CS(=O)(=O)N=c1nc2nc(OC)cc(OC)n2s1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
N-(2-Methoxycarbonylbenzyl)sulfonyl-N'-(4,6-dimethoxy-2-pyrimidinyl) thiourea (1.0 g) is dissolved in 15 ml of pyridine and cooled to -10°~-5° C., to which 0.4 g of bromine is dropwise added. After stirring for 1.5 hours at the same temperature, the reaction mixture is poured into 100 ml of ice water and the white crystals are collected by filtration. The product is washed with water, dried and washed with hot acetonitrile to give 0.78 g of the title compound as white powdery crystals. mp 153°~154° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.O>[CH3:20][S:21]([NH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Ethyl 4-amino-benzoate (5 g, 30 mmol, 1.0 equiv) was mixed in 50 mL of CH2Cl2 with Et3N (6.1 g, 60 mmol, 2.0 equiv). The solution was cooled to 0° C. and methanesulfonyl chloride (3.8 g, 33 mmol. 1.1 equiv) was added as a solution in 15 mL of CH2Cl2 dropwise over a 15 min period. The reaction was stirred for 4 h at which time it was diluted with 50 mL of water. Layers were separated and the organic layer was washed with 50 mL of saturated sodium bicarbonate solution and concentrated. The resulting ester was dissolved in 50 mL of MeOH and treated with 50 mL of 5 N NaOH for 4 h. The reaction solution was extracted with Et2O and the aqueous layer was acidified to give a white precipitate that was collected by filtration. The solid was dried and used without further purification.