Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1N[N:8]=[C:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH3:10].[CH2:20](O)[CH3:21].OS(O)(=O)=O>O>[CH3:10][C:9]1[NH:8][C:11]2[C:12]([C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)=[CH:13][C:20]([CH3:21])=[CH:10][CH:9]=2
Reactant: CC(Cc1ccc(F)cc1)=NNc1ccccc1C
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc2[nH]c(C)c(-c3ccc(F)cc3)c2c1

Procedure:
The crude hydrazone (100 g), ethanol (700 ml) and conc. aqueous H2SO4 (40 ml) were refluxed for 18 h. After cooling to room temperature water (0.5 l) was added. The thus obtained mixture was extracted with (2×700 ml) ethyl acetate and the combined organic phases were washed with brine, dried and the solvents were evaporated in vacuo. This afforded the title compound, which was purified by column chromatography on silica gel (eluted with ethyl acetate/heptane 1:4) and crystallized from heptane. Yield: 75.5 g, mp:124°-128° C. In a corresponding manner the following indole derivative was prepared: 5-Chloro-3-phenyl-2-methyl-1H-indole 24b, (oil).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[F:33])=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:25][C:24]=1[F:33]
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccc(C(F)(F)F)cc3F)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1ccc(C(F)(F)F)cc1F

Procedure:
The 2-trifluoroacetamido-3-(2-fluoro-4-trifluoromethylphenyl)-6-benzoyl-imidazo[1,2-a]pyridine (8.03 g, 16.2 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 6.00 g. (92.8%). EA, MS(FD).
Reaction SMILES: ClCC1C=CC(C#N)=CC=1.Br[CH2:12][C:13]1[O:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1.[CH2:22]([NH:29][C:30]([C:32]1[S:36][C:35]([N:37]2[CH2:41][CH2:40][NH:39][C:38]2=[O:42])=[N:34][C:33]=1[CH3:43])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][C:30]([C:32]1[S:36][C:35]([N:37]2[CH2:41][CH2:40][N:39]([CH2:12][C:13]3[O:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[C:38]2=[O:42])=[N:34][C:33]=1[CH3:43])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Agent: N#Cc1ccc(CCl)cc1
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)o3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 27 %

Procedure:
Following the procedure as described in Example 23, making variations as required to replace 4-(chloromethyl)benzonitrile with 2-(bromomethyl)-5-(trifluoromethyl)furan to react with N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 27% yield: mp 143-145° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.35-7.28 (m, 5H), 6.76-6.75 (m, 1H), 6.39 (d, J=3.0 Hz, 1H), 5.90 (t, J=6.0 Hz, 1H), 4.57 (d, J=6.0 Hz, 2H), 4.51 (s, 2H), 4.11 (t, J=9.0 Hz, 2H), 3.64 (t, J=9.0 Hz, 2H), 2.62 (s, 3H); MS (ES+) m/z 465.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14](=[O:15])[N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:12]([C:25](O)=[O:26])=[C:11]([Cl:28])[CH:10]=2)[CH:3]=1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O.O1CCCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14](=[O:15])[N:13]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[C:12]([C:25]([NH:36][CH2:35][C:34]3[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)=[O:26])=[C:11]([Cl:28])[CH:10]=2)[CH:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: COc1ccc(Cn2c(C(=O)O)c(Cl)cc(Nc3cc(N)ncn3)c2=O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)c2c(Cl)cc(Nc3cc(N)ncn3)c(=O)n2Cc2ccc(OC)cc2)cc1
Reaction time: 40 h

Procedure:
To a solution of 5-((6-aminopyrimidin-4-yl)amino)-3-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid (5, 0.40 g, 0.99 mmol) and 4-methoxybenzylamine (0.16 g, 1.19 mmol) in dimethylformamide (20 mL) was added N,N-diisopropylethylamine (0.39 g, 2.99 mmol) and HATU (0.57 g, 1.99 mmol) at room temperature. The reaction mixture was stirred for 40 h. Progress of the reaction was monitored by LCMS. To the reaction mixture was added tetrahydrofuran (20 mL) and the reaction was refluxed for 7 h. After completion, the reaction was diluted with water (20 mL) and extracted with 10% methanol in dichloromethane (2×30 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain the crude. The crude was purified by flash column chromatography eluting at 1% methanol in dichloromethane. The best fractions were concentrated to afford 5-((6-aminopyrimidin-4-yl)amino)-3-chloro-N,1-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxamide (6) as yellow solid. Yield: 0.44 g, 84%; MS (ESI) m/z 521.16 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.35 (m, 1H), 8.74 (s, 1H), 8.53 (s, 1H), 8.17 (s, 1H), 7.19-7.16 (m, 4H), 6.87-6.80 (m, 4H), 6.53 (s, 2H), 6.17 (s, 1H), 5.07 (s, 2H), 4.34 (s, 2H), 3.73 (s, 6H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.I[C:24]1C2C(=CC(/C=C3/C(=O)N(C)C4C/3=CC=CC=4)=CC=2)NN=1>>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH3:24])[C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: CN1C(=O)/C(=C/c2ccc3c(I)n[nH]c3c2)c2ccccc21
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(I)n[nH]c2c1
Product: CN1C(=O)[C@@]2(C[C@H]2c2ccc3c(I)n[nH]c3c2)c2ccccc21

Procedure:
The title compound was synthesized according to the method of (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one, except substituting (E)-3-((3-iodo-1H-indazol-6-yl)methylene)-1-methylindolin-2-one (545 mg, 1.36 mmol) to give the title compound as a 9:1 mixture of diastereomers (405 mg, 72%); MS ESI 416.0 [M+H]+, calcd for [C18H14IN3O+H]+ 416.03.
Reaction SMILES: C[O:2][C:3](=O)/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[C:23]([Cl:25])[Cl:24])=[CH:18][C:17]=1[CH3:26])=[N:5]/[O:6][CH3:7].COC(=O)/[C:31](/C1C=CC=CC=1COC1C=CC(C=C(Cl)Cl)=CC=1Cl)=[N:32]/OC>>[Cl:24][C:23]([Cl:25])=[CH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2/[C:4](=[N:5]\[O:6][CH3:7])/[C:3]([NH:32][CH3:31])=[O:2])=[C:17]([CH3:26])[CH:18]=1
Reactant: CO/N=C(/C(=O)OC)c1ccccc1COc1ccc(C=C(Cl)Cl)cc1C
Reactant: CO/N=C(/C(=O)OC)c1ccccc1COc1ccc(C=C(Cl)Cl)cc1Cl
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1ccc(C=C(Cl)Cl)cc1C
Yield: 86 %

Procedure:
The procedure of Example 40 was repeated except for using methyl-(E)-2-(2-((4-(2,2-dichlorovinyl)-2-methylphenoxy)methyl)phenyl)-2-methoxyiminoacetate (0.408 g, 1 mmol) obtained in Example 41 instead methyl-(E)-2-(2-((2-chloro-4-(2,2-dichlorovinyl)phenoxy)methyl)phenyl)-2-methoxyiminoacetate to obtain the title compound (0.350 g, 86%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][C:25]=1[C:34](O)=[O:35]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:34]([C:25]3[CH:26]=[N:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:24]=3)=[O:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(O)c1cnc2ccccc2n1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1cnc2ccccc2n1
Yield: 12 %

Procedure:
Using the general method of Example 181 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 4.78 mmol) was reacted with 2-quinoxalinecarboxylic acid (1.0 g, 5.74 mmol) to provide 270 mg of N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl} quinoxaline-2-carboxamide as a yellow crystalline solid, m.p. 85-87° C. Analysis: Calculated for C26H27N7O2: % C, 66.51; % H, 5.80; % N, 20.88; Found: % C, 66.12; % H, 5.70; % N, 20.62.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][NH2:39]>>[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][C:29]([C:32]([NH:39][CH2:38][CH2:37][N:36]([CH3:40])[CH3:35])=[O:33])=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc2c(c1)c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1ccc2c(c1)c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 269 using 268 (30 mg, 0.07 mmol) and N*1*,N*1*-dimethyl-ethane-1,2-diamine to provide 270. LC-MS (M+H=521, obsd.=521).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.I[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1>CS(C)=O>[N:11]1[CH:12]=[CH:13][C:8]([O:7][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:9][CH:10]=1
Reactant: N#Cc1ccc(I)cc1
Reactant: Oc1ccncc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccncc2)cc1
Temperature: 160 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
Potassium tert-butoxide (1.0 M in THF, 10.5 mL) was slowly added to a solution of 4-hydroxypyridine (997 mg, 10.5 mmol) in anhydrous DMSO (10.0 mL). After the mixture was stirred for 3 hours, a solution of 4-iodobenzonitrile (1.2 g, 5.2 mmol) in DMSO (10.0 mL) was added and the reaction mixture was heated at 160° C. for 44 hours. The mixture was cooled to room temperature and partitioned between methylene chloride (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with methylene chloride (2×100 mL). The organic layers were combined and concentrated in vacuo. The crude solid was purified by silica gel column chromatography (Hex/EtOAc 1:1) then (CH2Cl2/MeOH 98:2 to 96:4) to give the product as a light yellow solid (480 mg, 47%). 1H NMR (500 MHz, CDCL3) δ(ppm): 6.52 (2H, d, J=8.0 Hz), 7.53 (2H, d, J=8.8 Hz), 7.64 (2H, d, J=8.0 Hz), 7.87 (2H, d, J=8.8 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 112.4, 117.6, 119.8 (CH), 123.2 (CH), 134.5 (CH), 138.2 (CH), 146.2, 179.0. MS (FAB+): 197 (MH+). HRMS for O12H8N2O (MH+): calculated: 197.0715; found 197.0716.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.[CH3:14][Si](C=[N+]=[N-])(C)C>C(OCC)(=O)C.C(O)C>[CH3:14][O:12][C:11]([C:10]1[C:2]([NH2:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[CH2:6][CH2:5][CH2:4]2)=[O:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1c(C(=O)O)ccc2c1CCC2
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc2c(c1N)CCC2
Reaction time: 1 h
Yield: 75.6 %

Procedure:
Add 30% aqueous hydrogen peroxide solution (5 mL) in water (44 mL) to a solution of 1,6,7,8-Tetrahydro-1-aza-as-indacene-2,3-dione (3.80 mg, 20.3 mmol) and NaOH (5.03 g, 126 mmol) in water (97 mL) over a period of 30 minutes, stir the mixture at room temperature for 1 h. Acidulate with 1N hydrochloric acid, filter the solid, wash with water and dry to afford 4-amino-indan-5-carboxylic acid (3.13 g, 87%). Dissolve 4-amino-indan-5-carboxylic acid (3.07 g, 17.3 mmol) in ethyl acetate (87 mL) and ethanol (87 mL) and add (trimethylsilyl) diazomethane (17.3 mL, 34.6 mmol, 2 M in hexanes) at room temperature and stir the solution for 1 h. Remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (2.50 g, 76%). 1H NMR (MeOD, 300 MHz) δ 2.12 (quintuplet, J=7.6 Hz, 2H), 2.75 (t, J=7.5 Hz, 2H), 2.89 (t, J=7.5 Hz, 2H), 3.83 (s, 3H), 6.53 (d, J=8.1 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H). MS (ES+): 192 (M+H).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C[NH+]=CC=1.[Br:26][Br-]Br>C1COCC1.C(Cl)(Cl)Cl>[Br:26][C:8]1[NH:9][C:10]2[C:15]([C:7]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
Adapting the procedure of L. Chu (Tet. Lett. 1997, 38, 3871) methyl 3-cyclohexyl-6-indole carboxylate (4.65 g, 18.07 mmol) was dissolved in a mixture of THF (80 mL) and CHCl3 (80 mL). The solution was cooled in an ice bath and pyridinium bromide perbromide (pyridine tribromide, 7.22 g, 22.6 mmol, 1.25 equivalent) was added. After stirring for 1.5 h at 0° C., the reaction was judged complete by TLC. It was diluted with CHCl3 (200 mL), washed with 1M NaHSO3 (2×50 mL), saturated aqueous NaHCO3 (2×50 mL) and brine (50 mL). After drying over Na2SO4, the solvent was removed under reduced pressure and the residue crystallized from TBME-hexane. The desired 2-bromoindole derivative was collected by filtration, washed with hexane and dried (3.45 g). Evaporation of mother liquors gave a red solid that was purified by flash chromatography using 15% EtOAc in hexane yielding an additional 3.62 g of pure material. Total yield was 5.17 g (85% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[N:12]=2)[CH:4]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17]([C:25]4[CH:26]=[CH:27][C:22]([NH2:21])=[CH:23][CH:24]=4)[CH:18]=[C:13]3[N:12]=2)[CH:4]=1
Reactant: COc1ccnc(CCc2nc3cc(Br)cnc3[nH]2)c1
Reactant: Nc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(N)cc4)cnc3[nH]2)c1
Yield: 52.3 %

Procedure:
0.166 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-bromo-3H-imidazo[4,5-b]pyridine (example 6) and 0.13 g of 4-aminophenylboronic acid are dissolved in 8 ml of degassed dioxane. Then a solution of 0.21 g of potassium carbonate and 0.042 g of lithium chloride in 6.5 ml of degassed water and 0.058 g of tetrakis(triphenylphosphine)palladium(0) are added. The mixture is heated to reflux under N2 for 24 hours and, after cooling and addition of water, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 30–15:1). Concentration of the chromatographically pure fractions gives 0.09 g of the title compound as a yellow solid of m.p. 117–119° C. The mass spectrum shows the molecular peak MH+ at 346.3 Da.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][CH3:14])[C:5]([NH2:12])=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1.[CH:15](=O)[CH3:16].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][CH3:14])[C:5]2[NH:12][CH:15]([CH3:16])[NH:11][S:8](=[O:10])(=[O:9])[C:6]=2[CH:7]=1
Reactant: CCc1cc(Cl)cc(S(N)(=O)=O)c1N
Reactant: CC=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC#N
Product: CCc1cc(Cl)cc2c1NC(C)NS2(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 25 mL RB flask was added 5-chloro-3-ethyl-2-aminobenzenesulfonamide D (0.4074 g, 1.74 mmol), 8.5 mL acetonitrile, and 3Å molecular sieves. The stirring solution was cooled to 0° C. and acetaldehyde (0.15 mL, 2.68 mmol) and (±) 10-camphor sulphonic acid (catalytic) were added. After 1 h at 0° C., the reaction was filtered through Celite and solvent was removed to give crude D1. The light brown solid was dissolved in EtOAc, passed through silica, and concentrated to give pure D1 (0.4426 g, 98%), m.p. 181-183° C. 1H NMR (300 MHz, DMSO): δ7.70 (1H, d, J=11.8 Hz), 7.35 (1H, d, J=2.2 Hz), 7.21 (1H, d, J=2.2 Hz), 6.24 (1H, s), 4.80 (1H, m), 2.52 (2H, m), 1.48 (3H, d, 7.1 Hz), 1.13 (3H, t, J=7.4 Hz). 13C NMR (500 MHz, DMS0): δ140.2, 132.4, 131.1, 122.2, 120.5, 120.0, 62.2, 23.2, 20.1, 12.7. FT-IR (KBr): 3405.9, 3232.5, 3001.5, 2942.7, 2884.0, 1490.5, 1438.5, 1309.6, 1282.4, 1160.2, 1140.1, 864,5, 743.8, 718.0, 567.5 cm-1. HRMS: M+ calculated=260.0386, found=260.0386.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([N:7]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[CH2:30]([C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:1]([O:3][C:4](=[O:29])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:42][C:41]2[CH:43]=[CH:44][C:38]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:39][CH:40]=2)=[O:25])=[CH:27][CH:28]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)=[O:6])[CH3:2]
Reactant: CCCCCCCCc1ccc(N)cc1
Reactant: CCOC(=O)C(=O)N(Cc1ccc(C(=O)O)cc1)Cc1ccc(C(F)(F)F)cc1
Product: CCCCCCCCc1ccc(NC(=O)c2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)C(=O)OCC)cc2)cc1
Yield: 22 %

Procedure:
The same procedure as employed in the preparation of Example 10 (step a) but using 4-({[ethoxy(oxo)acetyl][4-(trifluoromethyl)benzyl]amino}methyl)benzoic acid and 4-octylaniline gave the title compound as a colorless oil (22%). 1H NMR (CDCl3, 300 MHz) δ 7.89-6.60 (m, 12H), 4.48 (s, 2H), 4.44-4.21 (m, 4H), 2.65-2.36 (m, 2H), 1.68-1.40 (m, 3H), 1.38-1.08 (m, 13H), 0.81 (t, J=6.9 Hz, 3H). M+(LC/MS(ESI)): 597.7. HPLC (Condition A), Rt: 6.75 min (HPLC purity: 98.9%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(F)c(F)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 3,4-difluorophenylacetic acid (5.00 g, 29.05 mmol) in methanol (73 mL) was slowly treated with concentrated sulfuric acid (4 mL). The resulting reaction mixture was heated under reflux for 65 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The resulting residue was slowly diluted with a saturated aqueous sodium bicarbonate solution (300 mL) and then extracted with ethyl acetate (1×300 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford (3,4-difluoro-phenyl)-acetic acid methyl ester (5.38 g, 99%) as a yellow oil which was used without further purification.
Reaction SMILES: F[B-](F)(F)F.C[O+:7]([CH3:9])[CH3:8].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[C:26]([O:32][CH2:33][C@@H:34]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C@@H:35]([C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=1)CO)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:26]([O:32][CH2:33][C@@H:34]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C@@H:35]([C:38]1[CH:39]=[CH:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=1)[CH2:8][O:7][CH3:9])(=[O:31])[C:27]([CH3:28])([CH3:30])[CH3:29]
Reactant: C[O+](C)C
Reactant: CC(C)(C)OC(=O)[C@H](COC(=O)C(C)(C)C)[C@H](CO)c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC[C@H](c1ccc(C(F)(F)F)cc1)[C@@H](COC(=O)C(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
Trimethyloxonium tetrafluoroborate (2.3 g, 16 mmol) was taken up in 10 mL of CH2Cl2. Proton sponge (3.3 g, 16 mmol) and (2S,3S)-2-(tert-butoxycarbonyl)-4-hydroxy-3-(4-(trifluoromethyl)phenyl)butyl pivalate (2.25 g, 5.2 mmol) were added to the mixture in 15 mL of CH2Cl2. The mixture was shielded from light and stirred for 3 hours. The mixture was carefully quenched with 70 mL of 10% aq HCl and extracted three times with 100 mL of CH2Cl2. The combined organic extracts were dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (5% to 25% EtOAc/hexanes) afforded (2S,3S)-2-(tert-butoxycarbonyl)-4-methoxy-3-(4-(trifluoromethyl)phenyl)butyl pivalate (1.4 g, 60% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.58 (d, J=8.02 Hz, 2H) 7.34 (d, J=8.02 Hz, 2H) 4.42-4.32 (m, 2H) 4.15-4.00 (m, 2H) 3.73-3.63 (m, 2H) 3.34 (s, 3H) 1.35 (s, 9H) 1.19 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[K+].Cl>O1CCOCC1.O>[NH2:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(N)c([N+](=O)[O-])cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc([N+](=O)[O-])c(N)cc1C(=O)O

Procedure:
To a suspension of 13.57 g of methyl 5-amino-2-methoxy-4-nitrobenzoate in 250 ml of dioxane was added a solution of 4.36 g of potassium hydroxide in 25 ml of water, and the mixture was refluxed for 4 hours. To the reaction solution was added 7 ml of concentrated hydrochloric acid. The solvent was evaporated under reduced pressure, and the residue, after addition of dioxane, was refluxed for an hour. The insoluble was removed by filtration, and the filtrate was allowed to stand to give the title compound, m.p. 252°-255° C., yield of 10.99 g.
Reaction SMILES: [F:1][C:2]1([F:23])[C:20]2[C:5](=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][C:13]=4F)=[N:9][C:8]=3[CH:19]=2)[C:4]([F:22])([F:21])[O:3]1.[C:24](=O)([O-])[O-:25].[K+].[K+].CO>O>[F:23][C:2]1([F:1])[C:20]2[C:5](=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][C:13]=4[O:25][CH3:24])=[N:9][C:8]=3[CH:19]=2)[C:4]([F:21])([F:22])[O:3]1
Reactant: Fc1cnccc1-c1nc2cc3c(cc2o1)C(F)(F)OC3(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cnccc1-c1nc2cc3c(cc2o1)C(F)(F)OC3(F)F
Temperature: 60 °C
Yield: 44.8 %

Procedure:
A mixture of 0.28 g of 5,5,7,7-tetrafluoro-2-(3-fluoropyridin-4-yl)-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole, 0.24 g of potassium carbonate and 3 ml of methanol was stirred while heating at 60° C. for 3.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.13 g of 5,5,7,7-tetrafluoro-2-(3-methoxypyridin-4-yl)-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole (hereinafter, referred to as “active compound 88”).