Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]([CH3:16])([CH2:12][N+:13]([O-:15])=[O:14])[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[BH4-].[Na+].[CH3:19]O>>[CH3:16][CH:2]([CH2:12][N+:13]([O-:15])=[O:14])[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)([OH:5])[CH3:19]
Reactant: CC(C)(CC(=O)c1cccnc1)C[N+](=O)[O-]
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CC(C[N+](=O)[O-])CC(C)(O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 3,3-dimethyl-4-nitro-1-pyridin-3-yl-butan-1-one (1 g, 4.5 mmol) in methanol (6 mL) under nitrogen add sodium borohydride (684 mg, 18 mmol). Stir at room temperature for 2 h, evaporate the methanol, dissolve in ethyl acetate and wash with water. Dry the organic layer over anhydrous sodium sulfate and concentrate to obtain 860 mg (85%) of the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:19]=[C:18]([O:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:17]=[CH:16][N:15]=1)[CH2:9][CH2:8]2)(=[O:4])=[O:3].C(N(CC)CC)C.Cl[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>C(Cl)Cl>[CH:38]([O:37][C:35]([N:24]1[CH2:25][CH2:26][CH:21]([O:20][C:18]2[CH:19]=[C:14]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH2:8][CH2:9]3)[N:15]=[CH:16][N:17]=2)[CH2:22][CH2:23]1)=[O:36])([CH3:40])[CH3:39]
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 4b (0.12 mmol) and triethylamine (0.2 mL, 12 eq) in 1 mL of DCM, was added the isopropyl chloroformate (1.3 eq). The mixture was stirred at room temperature for 22 h and the solvent volume was reduced to 0.7 mL under a stream of nitrogen. The residue was purified by preparative HPLC to afford 4-1, LCMS 461.2 (MH+).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[S:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[F:15][C:16]1[CH:26]=[C:25]([NH2:27])[CH:24]=[C:23]([F:28])[C:17]=1[C:18]([O:20][CH2:21]C)=[O:19]>>[F:15][C:16]1[CH:26]=[C:25]([NH:27][C:12]([C:6]2[S:7][C:8]([CH:9]([CH3:10])[CH3:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:14])[CH:24]=[C:23]([F:28])[C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CC(C)c1cc(C(=O)O)sc1C(C)C
Reactant: CCOC(=O)c1c(F)cc(N)cc1F
Product: COC(=O)c1c(F)cc(NC(=O)c2cc(C(C)C)c(C(C)C)s2)cc1F
Yield: 61.2 %

Procedure:
In the same manner as that of Example 24, 4,5-diisopropylthiophene-2-carboxylic acid (80 mg, 0.377 mmol) and ethyl 2,6-difluoro-4-aminobenzoate (137 mg, 0.681 mmol) were condensed, the reaction mixture was treated in a conventional manner, and then the residue was purified by silica gel chromatography [n-hexane-ethyl acetate (40:1)] to obtain methyl 2,6-difluoro-4-[(4,5-diisopropylthiophene-2-carbonyl)amino]benzoate (88 mg, 59%).
Reaction SMILES: [ClH:1].[OH:2][C:3]1([CH3:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[NH:9]C(=O)OC(C)(C)C>O1CCOCC1>[ClH:1].[NH2:9][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:3]1([CH3:17])[OH:2]
Reactant: CC(C)(C)OC(=O)NC1CCCCC1(C)O
Agent: Cl
Solvent: C1COCCO1
Product: CC1(O)CCCCC1N
Reaction time: 4 h

Procedure:
4M Hydrochloric acid in dioxan (40 ml, 160 mmol) was added to a solution of the more polar disatereoisomer of tert-butyl 2-hydroxy-2-methylcyclohexylcarbamate (1.52 g, 6.63 mmol) in dioxan (5 ml). The mixture was stirred for 4 h then the solvent was removed under reduced pressure and the residue dried in vacuo to afford a single diastereoisomer of 2-amino-1-methylcyclohexanol hydrochloride (1.05 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]2[CH:45]=1>O>[N:38]1[C:37]([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:9](=[O:23])[C:10]([CH3:21])([CH3:22])[O:11][C:12]=3[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:6][CH:7]=2)=[CH:45][N:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=12
Reactant: ClCc1cn2ccccc2n1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2=C(c3ccc(OCc4cn5ccccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 80 °C
Yield: 78.9 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2.5 g, 8.06 mmol) was added to a mixture of cesium carbonate (10.5 g, 32.2 mmol) and DMF (20 mL) at RT under nitrogen. The reaction mixture was stirred at RT for 30 min, upon which 2-(chloromethyl)imidazo[1,2-a]pyridine (2.4 g, 12.0 mmol) was added. The mixture was heated at 80° C. for 4 h (reaction was monitored by TLC). The reaction mixture was allowed to cool to RT, diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh), to afford 4-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2.8 g, 77.7%,) as Off-white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.55 (d, 1H), 8.0 (s, 1H), 7.55 (Ar, 3H), 7.3-6.85 (Ar, 8H), 5.15 (s, 2H) 3.85 (s, 3H), 1.25 (s, 6H). MS: [M+H]+: m/z=441.2. HPLC: (97.3%, Condition-A).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[C:6]([N+:13]([O-:15])=[O:14])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])#[N:4].O1CCCC1>C(O)C>[OH:9][CH2:8][C:7]1[C:6]([N+:13]([O-:15])=[O:14])=[C:5]([CH:12]=[CH:11][CH:10]=1)[C:3]#[N:4]
Reactant: N#Cc1cccc(C=O)c1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1cccc(CO)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of NaBH4 (0.2 g) in ethanol (10 ml) at ice bath temperature was added a solution of 3-cyano-2-nitrobenzaldehyde from Example 2c (0.93 g) in ethanol:tetrahydrofuran (15 ml:15 ml). After the addition was completed, the solution was warmed to ambient temperature and stirred for 30 minutes. The volatiles were removed under aspirator vacuum and the residue suspended in water. Dilute (1% aqueous) hydrochloric acid was added slowly until gas evolution had ceased. Ethyl acetate was then added followed by saturation of the aqueous layer with K2CO3. The layers were separated and the ethyl acetate layer was washed with brine, dried (Na2SO4) and concentrated to leave the title product (0.85 g, 90%) as a yellow solid; tlc, Rf =0.25, silica gel, ethyl acetate:hexane (1:1).
Reaction SMILES: C[C:2]1(C)[CH2:12][C:11](=O)[C:5]2[C:6]([CH2:9][OH:10])=[CH:7][O:8][C:4]=2[CH2:3]1.[Li]CCCC.CCOC(C)=O>C1COCC1>[O:8]1[C:4]2[CH:3]=[CH:2][CH:12]=[CH:11][C:5]=2[C@H:6]([CH2:9][OH:10])[CH2:7]1
Reactant: CC1(C)CC(=O)c2c(CO)coc2C1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC[C@@H]1COc2ccccc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
The crude oxirane 19 from above (2.4 g, 7.84 mmol) is dissolved in 50 ml of THF and cooled to −78° C. in a dry-ice bath. At this temperature, n-BuLi (1.6M in hexane, 4.9 ml, 7.84 mmol) is added drop wise. The mixture is then stirred for one hour and allowed to warm up to 0° C. After careful hydrolysis and extraction with EtOAc the crude is purified by Flash-chromatography (ethyl acetate/hexanes (from 5:95 to 25:75), silicagel).
Reaction SMILES: CN(C=O)C.[OH:6][C:7]1[CH:12]=[CH:11][C:10](C(=O)C)=[CH:9][CH:8]=1.Br[CH2:17][C:18]([NH:20]C1C=CC(Br)=CC=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[O:6]([CH2:17][C:18]([NH2:20])=[O:19])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=C(CBr)Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)COc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 223.1 %

Procedure:
DMF (20 ml) was added to 1-(4-hydroxyphenyl)ethanone (1.81 g, 13.3 mmol), 2-bromo-N-(4-bromophenyl)acetamide (3.00 g, 10.2 mmol), and potassium carbonate (4.25 g, 30.7 mmol), and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by alumina column chromatography (developing solvent; ethyl acetate), and powderized with ethyl acetate-diisopropyl ether (1:5) to give a phenoxyacetamide derivative (3.44 g). The title compound was obtained by similar operations as in Reference Example 20, Reference Example 21, Example 10 and Example 6 and using this compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[O:13])[CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: Cc1cc(CO)cnc1C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C=O)cnc1C(F)(F)F
Temperature: 40 °C
Yield: 79.8 %

Procedure:
To a solution of [5-methyl-6-(trifluoromethyl)-3-pyridinyl]methanol (152 mg, 0.795 mmol) in DCM (10 mL) was added CrO2 (Magtrieve) (1336 mg, 15.90 mmol). The suspension was heated at 40° C. in a pressure tube overnight. The suspension was filtered over nylon membrane 0.45 μm and it was rinsed with DCM. The filtrate was evaporated to afford 120 mg (80%) of title compound pure enough to be used in the next step.
Reaction SMILES: CO[C:3](=[O:15])[NH:4][C:5]1[NH:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[N:6]=1.[CH3:16][O:17][CH2:18][CH2:19][NH2:20].O>CN1CCCC1=O>[OH:14][C:11]1[CH:12]=[CH:13][C:7]2[N:6]=[C:5]([NH:4][C:3]([NH:20][CH2:19][CH2:18][O:17][CH3:16])=[O:15])[NH:9][C:8]=2[CH:10]=1
Reactant: COCCN
Reactant: COC(=O)Nc1nc2ccc(O)cc2[nH]1
Solvent: O
Solvent: CN1CCCC1=O
Product: COCCNC(=O)Nc1nc2ccc(O)cc2[nH]1

Procedure:
A solution of (6-hydroxy-1H-benzoimidazol-2-yl)-carbamic acid methyl ester (300 mg, example 61) and 2-methoxy-ethylamine (630 IA) in N-methylpyrrolidinone (8 ml) was heated at 90° C. in a sealed tube for 20 hours. The reaction mixture was poured into water (160 ml) and extracted three times with ethyl acetate (40 ml). The combined extracts were dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (95 C:5 C, v/v) to 1-(6-hydroxy-1H-benzoimidazol-2-yl)-3-(2-methoxy-ethyl)-urea as a yellow solid (180 mg). Mass spectrum: 251 [M+H]+; retention time=0.55 minutes.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.[N:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:35][C:32]1[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1ccncc1
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cnc2c(c1)CCCC2N(Cc1ccncc1)Cc1nc2ccccc2[nH]1
Reaction time: 18 h
Yield: 70.2 %

Procedure:
Following General Procedure B: To a solution of (1-tert-butoxycarbonyl-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine (120 mg, 0.32 mmol) and 4-pyridinecarboxaldehyde (30 μL, 0.32 mmol) in CH2Cl2 (5 mL) was added sodium triacetoxyborohydride (136 mg, 0.64 mmol) and the reaction stirred for 18 h. The resulting crude material was taken up in neat TFA (1 mL) and stirred 3 h. Saturated aqueous sodium bicarbonate (5 mL) was added, and the resulting mixture was extracted with CH2Cl2 (3×10 mL) then the combined organic extracts were dried (MgSO4), and concentrated in vacuo. Purification of the crude material by radial chromatography (1 mm plate, 50:1:1 CH2Cl2-MeOH—NH4OH) afforded the title compound (83 mg, 70%) as a white solid. 1H NMR (CDCl3) δ 1.68-1.72 (m, 1H), 1.97-2.06 (m, 2H), 2.26-2.30 (m, 1H), 2.74-2.77 (m, 1H), 2.80-2.86 (m, 1H), 3.77 (s, 2H), 3.92 (d, 1H, J=16 Hz), 4.09 (dd, 1H, J=9.7 Hz), 4.17 (d, 1H, J=16 Hz), 7.18-7.22 (m, 3H), 7.36 (d, 2H, J=6 Hz), 7.44 (dd, 1H, J=7.1 Hz), 7.52 (br d, 1H, J=7 Hz), 7.66 (br d, 1H, J=7 Hz), 8.46 (dd, 2H, J=5.2 Hz), 8.70 (dd, 1H, J=5.1 Hz); 13C NMR (CDCl3) δ 21.2, 23.8, 29.0, 49.1, 53.0, 60.5, 110.9, 118.8, 121.4, 121.9, 122.5, 123.3, 133.7, 134.7, 137.4, 144.2, 146.9, 148.7, 149.8, 155.4, 156.9. ES-MS m/z 370 (M+H). Anal. Calcd. for C23H23N5.0.2H2O.0.2CH2Cl2: C, 71.44; H, 6.15; N, 17.95. Found: C, 71.63; H, 6.30; N, 17.77.
Reaction SMILES: [CH3:1][C@@H:2](CCCC1C=CC=CC=1)[C:3](=[O:11])[CH2:4][P:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][C@@H:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3](=[O:11])[CH2:4][P:5](=[O:10])([O:6][CH3:7])[O:8][CH3:9]
Reactant: COP(=O)(CC(=O)[C@@H](C)CCCc1ccccc1)OC
Reactant: BrCc1ccccc1
Product: COP(=O)(CC(=O)[C@@H](C)Cc1ccccc1)OC

Procedure:
(S)-(+)-Dimethyl (3-methyl-2-oxo-4-phenylbutyl)phosphonate was prepared in the same manner as the second alternative preparation of (S)-(+)-dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i)) using the same sequence of reactions except that benzyl bromide was used instead of (3-bromopropyl)benzene. The crude product was purified by silica gel chromatography. Elution with ethyl acetate-heptane (80:20 v/v) afforded the title compound (680 mg) as a colorless oil; TLC Rf 0.35 (solvent system: 80:20 v/v ethyl acetate:heptanes; MS (ESI+) m/z 271.1 (M+H)+; 1H-NMR (CDCl3) δ 7.29-7.14 (m, 5H), 3.71 (dd, 6H, J=10.99, 19.04 Hz), 3.12-2.89 (m, 4H), 2.58 (dd, 1H, J=7.69, 13.55 Hz), 1.11 (d, 3H, J=6.96 Hz); [α]Tλ=α/cl, [α]21.9D=0.249/(0.01501 g/1.5 mL)(0.5)=+49.8° (c=1, CHCl3).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[OH:27][CH2:28][CH2:29][C:30](O)=O>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:30]([CH2:29][CH2:28][OH:27])[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: O=C(O)CCO
Product: CON=C1C[C@@H](c2noc(CCO)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and 3-hydroxypropanoic acid, the title compound was obtained in 61% purity by HPLC. MS(ESI+): m/z=407.2.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]>C(OCC)(=O)C>[Cl:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[C:15]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1Cl
Reactant: O=S(=O)(O)Cl
Solvent: CCOC(C)=O
Product: O=C(c1cccc(S(=O)(=O)Cl)c1)c1cc(Cl)ccc1Cl
Temperature: 0 °C

Procedure:
Into a 3 L three-neck flask equipped with a stirrer, and a cooling tube, chlorosulfonic acid (233.0 g, 2 mol) was added, and then 2,5-dichlorobenzophenone (100.4 g, 400 mmol) was added. The mixture was reacted for 8 hours using an oil bath at 100° C. After a predetermined period of time, the reaction liquid was slowly poured into broken ice (1000 g), and extraction using ethyl acetate was carried out. An organic layer was washed with a saline solution, and was dried with magnesium sulfate. Then, the ethyl acetate was distilled away, thereby obtaining a crude crystal of pale yellow (3-(2,5-dichlorobenzoyl)benzene sulfonic acid chloride). The crude crystal was employed at the subsequent step without purification.
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([C:41]2[N:45]([CH3:46])[CH:44]=[N:43][CH:42]=2)=[O:40])=[CH:35][CH:34]=1>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:39]([C:36]3[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=3)([C:41]3[N:45]([CH3:46])[CH:44]=[N:43][CH:42]=3)[OH:40])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(Cl)cc3)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 2.67 mL, 6.66 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (3.00 g, 7.00 mmol, Intermediate 16) in dry THF (80 mL) at −78° C. After 3 minutes, a solution of (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (1.65 g, 7.48 mmol, Intermediate 1: step b) in dry THF (80 mL) was added dropwise over the course of 3 minutes. The reaction mixture was stirred for 10 minutes at −78° C., then the reaction flask was removed from the cooling bath. After 10 minutes, the reaction flask was placed into an ice-water bath. After 30 minutes, saturated aqueous ammonium chloride solution (10 mL) was added. The biphasic mixture was warmed to room temperature then partitioned between half-saturated aqueous ammonium chloride solution (300 mL) and ethyl acetate (300 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (150 mL). The organic layers were combined. The combined solution was dried with sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 20% acetone-dichloromethane initially, grading to 100% acetone) to provide the title compound as an off-white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.11 (d, J=2.1 Hz, 1H), 7.85 (d, J=2.5 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.58-7.54 (m, 2H), 7.54-7.51 (m, 1H), 7.40-7.34 (m, 3H), 7.33-7.27 (m, 4H), 6.43 (t, J=2.1 Hz, 1H), 6.41-6.38 (m, 1H), 4.31 (s, 2H), 4.08 (s, 3H), 3.72 (s, 1H), 3.38 (s, 3H). MS (ESI): mass calcd. C31H25Cl2N5O2, 569.1; m/z found, 570.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Cl[C:25]1[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:27][N:26]=1.CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][C:25]1[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:35])([F:33])[F:34])=[CH:27][N:26]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cnc(Oc2c(Cl)cc(OCc3ccccc3)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
Then, 0.85 g of 2,6-dichloro-4-benzyloxyphenol, 0.48 g of potassium carbonate, 0.75 g of 2,3-dichloro-5-trifluoromethylpyridine and 10 ml of N,N-dimethylformamide were charged into a reaction vessel, and stirred at 85° to 90° C. for 3 hours. Then, the reaction solution was cooled to room temperature, poured into water and extracted twice with 50 ml of diethyl ether. The ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 1.39 g of 3,5-dichloro-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-1-benzyloxybenzene, (yield, 98%).
Reaction SMILES: [C:1]([CH2:3][C:4](=S)[NH2:5])#[N:2].BrCC.[O-]CC.[Na+].[NH2:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O>>[Cl:24][C:22]1[CH:23]=[C:15]2[C:16]([C:17](=[O:19])[N:5]=[C:4]([CH2:3][C:1]#[N:2])[NH:14]2)=[CH:20][CH:21]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: N#CCC(N)=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCBr
Product: N#CCc1nc(=O)c2ccc(Cl)cc2[nH]1
Reaction time: 6 h
Yield: 18.5 %

Procedure:
2-cyanoethanethioamide (300 mg, 3.00 mmol) and bromoethane (299 μL, 4.00 mmol) were added to an ethanolic solution of sodium ethoxide (4.00 mmol, 3 mL). The resulting mixture was stirred for 6 hours, 2-amino-4-chlorobenzoic acid (500 mg, 2.91 mmol) was added, and the reaction was refluxed overnight with stirring. A solid precipitate formed upon cooling of the reaction mixture, which was recovered by vacuum filtration and washed sequentially with ethanol, water, ethanol, and diethyl ether. The solid was then dried to yield 2-(7-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)acetonitrile (118 mg, 18%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.19 (s, 2H), 7.57 (dd, J1=8.5 Hz, J2=2.1 Hz, 1H), 7.74 (d, J=2.0 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[S:6](F)(=[O:15])([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)=[O:7].C(N(CC)CC)C>C(O)CCC>[CH3:1][O:2][CH2:3][CH2:4][NH:5][S:6]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)(=[O:15])=[O:7]
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Reactant: COCCN
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COCCNS(=O)(=O)c1ccc(N)cc1
Yield: 65.4 %

Procedure:
A mixture of 2-methoxyethylamine (859 mg, 11.4 mmol), sulphanilyl fluoride (1.0 g, 5.71 mmol) and triethylamine (1.72 g, 22.9 mmol) in 1-butanol (15 ml) was heated at reflux for 18 hours. The mixture was allowed to cool and the volatiles were removed by evaporation. The residue was purified by chromatography eluting with ethyl acetate/hexane (50:50) increasing in polarity to (70:30) to give the title compound (860 mg, 65%). NMR: 2.78 (q, 2H), 3.15 (s, 3H), 3.25 (t, 2H), 5.87 (s, 2H), 6.58 (d, 2H), 7.10 (t, 1H), 7.40 (d, 2H); m/z 231.
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[C:3]1=O.[O:15]1[CH2:20]CC(=O)[CH2:17][CH2:16]1.N>CO>[N+:8]([C:6]1[CH:7]=[N:2][C:3]2[CH2:17][CH2:16][O:15][CH2:20][C:4]=2[CH:5]=1)([O-:10])=[O:9]
Reactant: O=C1CCOCC1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Agent: N
Solvent: CO
Product: O=[N+]([O-])c1cnc2c(c1)COCC2
Yield: 52.2 %

Procedure:
A mixture of 1-methyl-3,5-dinitro-2-pyridone (0.8 g, 4 mmol), tetrahydro-4H-pyran-4-one (0.4 g, 4 mmol) and ammonia solution in methanol (2.0 M, 40 mL) was refluxed for 4 h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The soluble portion was flash chromatographed over silica gel (eluent: 90:10 v/v ethyl acetate-hexane) to give a yellow solid (0.376 g, 52% yield).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([Cl:13])[C:6](Cl)=[N:7]2.[NH4+:14].[OH-]>CN(C=O)C.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([Cl:13])[C:6]([NH2:14])=[N:7]2
Reactant: [NH4+]
Reactant: Clc1nc2cccc(Br)c2nc1Cl
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc2cccc(Br)c2nc1Cl
Reaction time: 8 h
Yield: 27.4 %

Procedure:
To a solution of 5-bromo-2,3-dichloroquinoxaline (Leadgen Labs, Orange, Conn.; 2.00 g, 7.20 mmol) in 50 mL DMF at 0° C. was added NH4OH (30% NH3 in water; 18.68 ml, 144 mmol) dropwise via syringe. A thick solid formed. 2 mL DMF was added to promote stirring. The thick reaction was sealed and stirred for 2 h at RT. The reaction was diluted with 250 mL water and let stand overnight. In the morning, it was filtered and the solid was air dried, treated with silica gel and DCM, and concentrated in vacuo. The material was purified by silica gel chromatography using 0-50% EtOAc/hexane to separately provide 5-bromo-3-chloroquinoxalin-2-amine (0.510 g, 1.973 mmol, 27% yield) as a peach-colored solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.69-7.76 (1H, m), 7.43-7.61 (4H, m). m/z (ESI, +ve) 259.9 (M+H)+ and 8-bromo-3-chloroquinoxalin-2-amine (0.78 g, 3.02 mmol, 42% yield) as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.94 (1H, dd, J=7.6, 1.4 Hz), 7.73-7.79 (1H, m), 7.61 (2H, br. s.), 7.30 (1H, t, J=7.9 Hz). m/z (ESI, +ve) 259.9 (M+H)+.