Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][NH+:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([OH:7])=O.[NH2:13][CH:14]1[C:32](=[O:33])[N:16]2[C:17]([C:29]([OH:31])=[O:30])=[C:18]([CH2:21][S:22][C:23]3[S:24][C:25]([CH3:28])=[N:26][N:27]=3)[CH2:19][S:20][C@H:15]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([NH:13][CH:14]1[C:32](=[O:33])[N:16]2[C:17]([C:29]([OH:31])=[O:30])=[C:18]([CH2:21][S:22][C:23]3[S:24][C:25]([CH3:28])=[N:26][N:27]=3)[CH2:19][S:20][C@H:15]12)=[O:7]
Reactant: CO[NH+]=C(C(=O)O)c1csnn1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)c1csnn1
Yield: 61.6 %

Procedure:
2-Methoxyiminio-2-(1,2,3-thiadiazol-4-yl)acetic acid (anti isomer) (1.0 g.) and 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (2.16 g.) were reacted according to similar manners to those of Examples 1(b) and 8 to give pale yellow powder of 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (anti isomer) (1.68 g.), mp 104° to 115° C. (dec.).
Reaction SMILES: C[O:2][C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[C:4]=1[CH3:16].B(Br)(Br)Br>ClCCl.O>[OH:2][C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[C:4]=1[CH3:16]
Reactant: COc1c(C)c(=O)c2ccccc2[nH]c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1c(O)c(=O)[nH]c2ccccc2c1=O
Yield: 70.5 %

Procedure:
To a solution of 3-methoxy-4-methyl-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.47 g) in dichloromethane was added boron tribromide (6.5 mL). The precipitate which formed was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated. The solid was recrystallized from hot toluene to give the title compound (0.31 g); mp 252.3° C.; NMR: 2.07 (s,3); MS(EI): m/z=203(M). Analysis for C11H9NO3 ·0.2 H2O: Calculated: C, 63.89; H, 4.58; N, 6.77; Found: C, 63.79; H, 4.49; N, 6.73.
Reaction SMILES: N[C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[C:5]([Br:13])=[CH:4][C:3]=1[Cl:14].C1(C)C=CC=CC=1.S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(O)C>[Br:13][C:5]1[C:6]2[CH2:7][C:8]([CH3:11])([CH3:12])[O:9][C:10]=2[CH:2]=[C:3]([Cl:14])[CH:4]=1
Reactant: CC1(C)Cc2c(Br)cc(Cl)c(N)c2O1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)Cc2c(Br)cc(Cl)cc2O1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
A stirred solution of 5.1 grams (0.018 mole) of 7-amino-4-bromo-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran and 25 mL of toluene in 100 mL of ethanol is cooled in an ice bath, and 2 mL (0.036 mole) of concentrated sulfuric acid is added slowly. Upon completion of addition, 2.0 grams (0.029 mole) of sodium nitrite is then added. The ice bath is then removed, and the reaction mixture is warmed to 75° C., where it is stirred for 30 minutes. After this time the reaction mixture is warmed to 95 ° C., where it stirred for one hour. The reaction mixture is then cooled and poured into 200 mL of water. The mixture is extracted with two 150 mL portions of diethyl ether. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel. Elution is accomplished using petroleum ether. The product-containing fractions are combined and concentrated under reduced pressure, yielding 3.6 grams of 4-bromo-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [C:1]([C@@H:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH3:4])#[N:2].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=1)[O:18][C:19]1[CH:27]=[CH:26][C:22](C(O)=O)=[CH:21][CH:20]=1>>[C:1]([C@@H:3]([NH:5][C:6](=[O:12])[C:22]1[CH:21]=[CH:20][C:19]([O:18][C:17]2[CH:28]=[CH:29][CH:30]=[C:15]([O:14][CH3:13])[CH:16]=2)=[CH:27][CH:26]=1)[CH3:4])#[N:2]
Reactant: COc1cccc(Oc2ccc(C(=O)O)cc2)c1
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Product: COc1cccc(Oc2ccc(C(=O)N[C@@H](C)C#N)cc2)c1
Yield: 46.8 %

Procedure:
General procedure D was used to deprotect 0.62 mmols of 4 and immediately coupled to 0.62 mmols of 28 using general procedure F. After flash chromatography, 0.29 mmols (0.087 g) of the title product was recovered. 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J=8.9, 2H), 7.27 (dd, J=6.7, 9.6, 1H), 7.00 (d, J=8.9, 2H), 6.83 (d, J=8.0, 1H), 6.73 (dd, J=2.4, 8.3, 1H), 6.64-6.55 (m, 2H), 5.13 (dq, J=7.2, 14.5, 1H), 3.78 (s, 3H), 1.65 (d, J=7.2, 3H). 13C NMR (126 MHz, CDCl3) δ 166.03, 161.07, 156.72, 130.44, 129.26, 128.99, 126.89, 119.48, 117.83, 111.97, 110.17, 105.93, 77.29, 77.04, 76.78, 55.41, 36.33, 19.46, 18.59.
Reaction SMILES: [SH-:1].[Na+].O.O.O.O.O.O.[Cl-].[Mg+2].[Cl-].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([CH3:21])[CH:14]=1>CN(C)C=O>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[S:1])=[C:15]([CH3:21])[CH:14]=1
Reactant: [SH-]
Reactant: Cc1cc(Br)ccc1C#N
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1C(N)=S
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 7.1 %

Procedure:
To a slurry solution of sodium hydrosulphide (2.80 g, 50 mmol) and magnesium chloride hexahydrate (5.05 g, 25 mmol) in dimethylformamide (50 ml) is added 4-bromo-2-methyl benzonitrile (4.90 g, 50 mmol) in one portion and the resulting green slurry is stirred at room temp for 90 minutes. The reaction mixture is poured onto water (200 ml) and the resultant precipitate filtered and washed with water. This yellow solid is then suspended in 2N HCl (200 ml) and stirred for 1 hour, then filtered, washed with water and hexane and dried in vacuo to give 4-bromo-2-methyl-thiobenzamide (820 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[F:10][C:11]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13](O)=O.[OH-].[Na+]>CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:13]([C:12]3[CH:16]=[CH:17][C:18]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:19][C:11]=3[F:10])=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2nc3cc(Br)ccc3[nH]2)c(F)c1
Temperature: 195 °C
Yield: 43.3 %

Procedure:
4-bromobenzene-1,2-diamine (1.75 g, 9.39 mmol) and 2-fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.39 mmol) were dissolved in polyphosphoric acid (70 g). This mixture was heated at 195° C. for three and half hours. Reaction mixture cooled to rt and diluted with ice water (100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 9. Work up (EtOAc/H2O) followed by removal of EtOAc afforded the crude. Crude was purified on combiflash with a gradient mixture of EtOAc and Petether (33:67) to obtain the titled compound (1.5 g) as an off-white solid.
Reaction SMILES: N[CH:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3].[H+].[CH3:12][C@H:13]([NH2:22])[C@H:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-]>C(O)(=O)C>[C:5]1([CH2:4][CH2:2][CH2:3][NH2:22])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:12][C@@H:13]([NH2:22])[C@@H:14]([OH:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(N)Cc1ccccc1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Agent: [Cl-]
Agent: [H+]
Solvent: CC(=O)O
Product: C[C@@H](N)[C@@H](O)c1ccccc1
Product: NCCCc1ccccc1

Procedure:
The commercially available precursor to dextroamphetamine is 1R,2S-(−)-norephedrine. Attempts were made to O-acetylate the norephedrine free base, but produced mostly N-acetylamphetamine according to an analysis of the carbonyl region of the infrared spectra. In one experiment, norephedrine free base in acetic acid was treated with 0.5 equivalents of sulfuric acid and then treated with 1.1 equivalents of acetic anhydride with heating to 63° C. to obtain a clear solution. Catalytic reduction followed by basification gave an oil that was composed of 13.96% amphetamine and 68% norephedrine, an indication that the acetylation procedure on a sulfate salt was only partially successful. In another experiment, a 10 mol portion of norephedrine hydrochloride was acetylated with a 20% excess of acetic anhydride in 2 mL acetic acid/g of salt and progress of the reaction followed fours (Table 2). The reaction mixture was diluted with 130 mL water and subjected to catalytic hydrogenation for 22 hours to obtain 10.4 g of oil. The long reaction time is attributed to the presence of acetic acid in the reduction mixture. Yield of amphetamine from norephedrine hydrochloride based on the weight of product and HPLC analysis is 66% (Experiments A and B). For these experiments, it can be seen that the best results were obtained with the salts of phenylpropylamine or norephedrine, particularly the hydrochloride salt.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:9][CH:10]=1.[NH2:23][O:24][K].C(O)(=O)C>CO.CO.C(Cl)(Cl)Cl>[OH:24][NH:23][C:3](=[O:2])[CH2:4][CH2:5][C:6]1[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:9][CH:10]=1
Reactant: COC(=O)CCC1=CCN(CCCc2ccc(C)cc2)C1=O
Reactant: NO[K]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(CCCN2CC=C(CCC(=O)NO)C2=O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
100 mg of 3-[2-oxo-1-(3-p-tolyl-propyl)-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl ester (40ag) prepared by the above Step 7 was dissolved in methanol solution (0.33 mM) and then 1.7 M methanolic suspension solution containing NH2OK (0.82 ml, 5.0 mM) was added thereto at 0° C. and the resulting mixture was stirred for 8 hrs at room temperature. The resulting mixture was neutralized with 0.02 ml of acetic acid, diluted with 10% methanol/chloroform solution, filtered and concentrated in vacuo. The resulting compound was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:9) as an eluant to give 50 mg of N-hydroxy-3-[2-oxo-1-(3-p-tolyl-propyl)-2,5-dihydro-1H-pyrrol-3-yl]-propionamide (40ah) (yield: 50%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[NH:23][N:22]=2)=[CH:4][C:5]([NH:10][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH3:12])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:29](O)(=O)C.C(N)=N.C(=O)(O)[O-].[Na+].CCOC(C)=O>CCO>[CH:26]1([C:24]2[NH:23][N:22]=[C:21]([N:20]3[C:3]4[CH:4]=[C:5]([NH:10][C@H:11]([C:13]5[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=5)[CH3:12])[C:6]([C:7]#[N:8])=[CH:9][C:2]=4[N:1]=[CH:29]3)[CH:25]=2)[CH2:28][CH2:27]1
Reactant: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c(N)cc1C#N)c1ccc(F)cc1
Reactant: CC(=O)O
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cc2c(cc1C#N)ncn2-c1cc(C2CC2)[nH]n1)c1ccc(F)cc1
Yield: 81.9 %

Procedure:
A mixture of (s)-5-amino-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-[1-(4-fluorophenyl)ethylamino]benzonitrile (Method 69; 3.85 g, 10.2 mmol) and formamidine acetate (2.13 g, 20.5 mmol) in EtOH (50 ml) was heated at reflux for 2 hrs. After cooling, the reaction mixture was treated with saturated sodium bicarbonate solution (10 ml) and EtOAc (30 ml). The organic layer was separated, washed with brine (10 ml), and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc:MeOH=30:1) to give the title compound as an off-white solid (3.23 g, 82%). NMR (400 MHz) 12.79 (s, 1H), 8.44 (s, 1H), 7.95 (s, 1H), 7.53 (m, 2H), 7.14 (m, 2H), 7.01 (s, 1H), 6.10 (s, 1H), 6.09 (d, J=7.6 Hz, 1H), 4.63 (m, 1H), 1.97 (m, 1H), 1.55 (d, J=6.8 Hz, 3H), 1.03 (m, 2H), 0.76 (m, 2H). MS: Calcd.: 386; Found: [M+H]+ 387.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[C:20]([NH:22][CH3:23])[N:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[Cl:24][C:25]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[C:27]([Cl:35])[C:26]=1[N:36]=[C:37]=[O:38].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:28]=[C:27]([Cl:35])[C:26]=1[NH:36][C:37](=[O:38])[N:22]([C:20]1[CH:21]=[C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([N:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:8][CH2:7]3)=[CH:14][CH:13]=2)[N:17]=[CH:18][N:19]=1)[CH3:23]
Reactant: O=C=Nc1c(Cl)ccc(C(F)(F)F)c1Cl
Reactant: CCN1CCN(c2ccc(Nc3cc(NC)ncn3)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4c(Cl)ccc(C(F)(F)F)c4Cl)ncn3)cc2)CC1
Reaction time: 1.5 h

Procedure:
This oil is re-dissolved in 2 ml of toluene and added portion-wise to a boiling solution of N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine (156 mg, 0.50 mmol; Example 145A) in 6 ml of toluene during 10 min. After 1.5 h, another 2 eq of 2,6-dichloro-3-trifluoromethyl-phenylisocyanate are added and stirring is continued for totally 2 h. Then the reaction mixture is diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted twice with DCM. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; CH2Cl2/MeOH/NH3aq, 95:5:0.5) gives the title compound: ESI-MS: 568/570 [MH]+; tR=4.1 min (gradient J); TLC: Rf=0.3 (DCM/MeOH+1% NH3aq, 95:5).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:19]1[CH:27]=[CH:26][C:25]([C:28]([NH2:30])=[O:29])=[C:24]2[C:20]=1[C:21]1[CH2:34][NH:33][CH2:32][CH2:31][C:22]=1[NH:23]2>C(OCCCC)(=O)C.CO.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:19]1[CH:27]=[CH:26][C:25]([C:28]([NH2:30])=[O:29])=[C:24]2[C:20]=1[C:21]1[CH:34]=[N:33][CH:32]=[CH:31][C:22]=1[NH:23]2
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4c(c23)CNCC4)cccc1-n1cnc2ccccc2c1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: CCCCOC(C)=O
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4ccncc4c23)cccc1-n1cnc2ccccc2c1=O
Temperature: 110 °C
Reaction time: 60 h
Yield: 35.7 %

Procedure:
A mixture of 9-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide (10 mg, 0.022 mmol) and activated manganese dioxide (19.34 mg, 0.222 mmol) in butyl acetate (0.5 mL) was heated on an oil bath at 110° C. for 5.25 h, then at 90-100° C. for 2.5 days, then at 125° C. for 20 h. The mixture was cooled to room temperature, diluted with methanol, filtered and concentrated under vacuum. The residue was purified by preparative HPLC. The effluent containing the desired product was concentrated under vacuum to provide a fine aqueous suspension. This was extracted three times with EtOAc, and the combined organic phases were dried and concentrated to provide the desired product as an off-white solid (3.5 mg, 33% yield). LCMS (M+H)+ m/z 446.2. 1H NMR (400 MHz, methanol-d4) δ 8.31-8.47 (3.6 H, m), 8.06-8.16 (1.4 H, m), 7.87-7.96 (1 H, m), 7.76-7.87 (1 H, m), 7.55-7.70 (5 H, m), 7.24-7.36 (1 H, m), 1.90 (3 H, 2s).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:10]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.S(Cl)([Cl:32])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:32][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:10]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1nn(-c2ccccc2)c2ccccc12)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: ClC(c1nn(-c2ccccc2)c2ccccc12)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of cyclohexyl(1-phenyl-1H-indazol-3-yl)methanol (716 mg) synthesized above, pyridine (284 μL) and toluene (20 mL) was added thionyl chloride (256 μL), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (767 mg, quantitative) as a pale-yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>ClCCl>[Br:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)nc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1ccc(N2CCNCC2)cn1
Reaction time: 16 h
Yield: 141.3 %

Procedure:
11.20 ml (150.77 mmol) of trifluoroacetic acid are slowly added to a suspension of 5.16 g (15.08 mmol) of 1,1-dimethylethyl 4-(6-bromo-3-pyridyl)-1-piperazine-carboxylate, obtained in step 7.2., in 70 ml of dichloromethane. Stirring is continued at room temperature for 16 hours. The reaction mixture is concentrated under reduced pressure, the residue is taken up in 40 ml of chloroform and 4 ml of aqueous sodium hydroxide solution (10M) are then slowly added. The aqueous phase is separated out and then extracted twice with chloroform. The organic phases are combined and are washed with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and the filtrate is concentrated under reduced pressure. 5.16 g of product are thus obtained in the form of an orange-colored oil that crystallizes at room temperature. This product is used without further purification in the following step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].Br[CH:19]([CH3:29])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].C(OC1C=CC(/C=C2/C(=O)N(CCCNC(=O)OC(C)(C)C)C(=O)S/2)=CC=1)C>>[CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[N:11]([CH:19]([CH3:29])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(Br)CNC(=O)OC(C)(C)C
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Agent: CCOc1ccc(/C=C2\SC(=O)N(CCCNC(=O)OC(C)(C)C)C2=O)cc1
Product: CCOc1ccc(/C=C2\SC(=O)N(C(C)CNC(=O)OC(C)(C)C)C2=O)cc1
Yield: 15.4 %

Procedure:
The title compound 21c was prepared from compound 2 (300 mg, 1.20 mmol) and tert-butyl (2-bromopropyl)carbamate (286 mg, 1.20 mg) in a manner similar to that described for 21a. Yield=15.4%, 75 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[N:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[C:26]([F:37])([F:36])[F:25])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[N:3]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Cc1ccn2c(-c3cccc(OS(=O)(=O)C(F)(F)F)c3)cnc2n1
Product: Cc1ccn2c(-c3cccc(-c4ccccc4C(F)(F)F)c3)cnc2n1
Yield: 35.4 %

Procedure:
Trifluoromethanesulfonic acid 3-(7-methylimidazo[1,2-a]pyrimidin-3-yl)phenyl ester (0.1 g, 0.28 mmol) was coupled to 2-trifluoromethylbenzeneboronic acid (52 μl, 0.59 mmol) as described in Example 21 to give 7-methyl-3-(2′-trifluoromethylbiphenyl-3-yl)-imidazo[1,2-a]pyrimidine as a white solid (35 mg): δH (400 MHz, CDCl3) 2.65 (3H, s), 6.77 (1H, d, J 7), 7.39 (1H, m), 7.48-7.62 (6H, m), 7.78 (1H, d, J 7.2), 7.82 (1H, s), 8.52 (1H, d, J 7); m/z (ES+) 354 (M++H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]N)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].C(O)(=[O:17])C.N([O-])=O.[Na+]>O.C(OCC)(=O)C>[CH2:1]([O:5][CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:17])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCOCc1ccc(CN)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCOCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a mixture of 4-butoxymethyl-benzylamine (250 mg) described in Manufacturing Example 43-2, acetic acid (2 mL), and water (2 mL) was added sodium nitrite (1.1 g) at 0° C., which was stirred for 40 minutes at room temperature. The reaction mixture was added to a mixture of ethyl acetate and water, and then extracted. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with saturated brine. The solvent was evaporated from the organic layer under a reduced pressure. Methanol (2 mL) and potassium carbonate (360 mg) were added to the residue, and the reaction mixture was stirred for 1.5 hours at room temperature. The solvent was evaporated from the reaction mixture under a reduced pressure. The residue was purified by neutral silica gel column chromatography (ethyl acetate:heptane=1:1) to obtain the titled compound (200 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[N:6][CH:7]=1.Cl[C:12]1[C:21]([N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23])=[N:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]=2)[N:13]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[Br:1][C:2]1[CH:3]=[C:4]([C:12]2[C:21]([N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23])=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]=3)[N:13]=2)[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cncc(Br)c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of 5-bromopyridin-3-ylboronic acid (288.0 mg, 1.43 mmol) in dioxane (5 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 140.0 mg, 0.48 mmol), K3PO4 (302.0 mg, 1.43 mmol), Pd(PPh3)4 (27.6 mg, 0.02 mmol) and three drops water. The reaction mixture was stirred for 1 h at 90° C. with an inert atmosphere of nitrogen and then concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2-(5-bromopyridin-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (150.0 mg, 72%) as a light yellow solid.