Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:26][C:27]1[CH:28]=[CH:29][C:30]([CH:33](OS(C(F)(F)F)(=O)=O)[C:34]([F:37])([F:36])[F:35])=[N:31][CH:32]=1>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][CH:33]([C:30]3[CH:29]=[CH:28][C:27]([Br:26])=[CH:32][N:31]=3)[C:34]([F:37])([F:36])[F:35])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Reactant: O=S(=O)(OC(c1ccc(Br)cn1)C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NC(c3ccc(Br)cn3)C(F)(F)F)cc2)COC1(C)C
Reaction time: 0.25 h
Yield: 37.9 %

Procedure:
To a stirred solution of (S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (150 mg, example 6b) in dry THF (0.2 ml) under an argon atmosphere was added sodium hydride (34 mg, 60% dispersion in mineral oil) and stirring was continued for 15 minutes. Trifluoro-methanesulfonic acid 1-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl ester (182 mg) was then added and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed sequentially with water and with saturated brine. The organic phase was separated, dried over sodium sulphate, and concentrated in vacuo. The reside was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-(2-{4-[1-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethylamino]-phenyl}-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (99 mg, 38%) as a yellow oil. MS (ISP): 560.1 ([{81Br}M+H]+), 558.1 ([{79Br}M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: Oc1ccccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Cl)ccc1-c1ccccc1OCc1ccccc1
Temperature: 70 °C

Procedure:
To a solution of 2-(benzyloxy)phenol (4.2736 g, 21.34 mmol) and 2,5-dichloronitrobenzene (4.302 g, 22.41 mmol) in 40 mL of DMSO was added cesium carbonate (13.8 g, 42.7 mmol). The reaction was heated to 70° C. under argon for one hour, then cooled to room temperature. The solution was poured into EtOAc, washed with water, sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The titled product was obtained as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]#[N:11])=[C:4](Cl)[N:3]=1>C1CCCCC1.CCOC(C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]#[N:11])=[CH:4][N:3]=1
Reactant: N#Cc1cc(C#N)c(Cl)nc1N
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: N#Cc1cnc(N)c(C#N)c1
Yield: 73 %

Procedure:
2-Amino-3,5-dicyanopyridine (5) was prepared from 3 using the procedure described below for the preparation of 5 except that 5 was recrystallised from MeCN [methyl cyanide; acetonitrile) (instead of EtOH). The yield was 73% (7.00 g from 12.0 g (67.2 mmol) of 3] of product homogeneous on TLC (cyclohexane-EtOAc, 1:1); mp 220° C. dec; 1H NMR (Me2SO-d6) δ7.90 (s, NH2), 8.40 and 8.58 (two d, 4-H and 6H, J=2 Hz).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][OH:29]>CCCCCC.C(OCC)(=O)C>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][O:29][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1
Reactant: OCc1cccc(F)c1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Fc1cccc(COc2ncc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)n2)c1

Procedure:
2-Methylthio-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (from Reference Example 3) was reacted with 3-fluorobenzyl alcohol according to the procedures described in Example 1 to afford 2-(3-fluorobenzyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine as the higher Rf product.(95/5 hexane/ethyl acetate TLC. HPLC/MS: 460 (M+); Rt=4.66 min; 1H-NMR 500 MHz (CDCl3): δ 5.53 (s, 2H), 7.04 (d over m, J=9 Hz, 3H), 7.2-7.3 (m, 6H), 7.36-7.4 (m, 2H), 8.61 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][C:2]1[N:3]([S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])[CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1cc[nH]c1C
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1ccn(S(=O)(=O)c2ccccc2)c1C

Procedure:
By a similar operation as in Reference Example 41 and using ethyl 2-methyl-1H-pyrrole-3-carboxylate (8.81 g), sodium hydride (60% in oil, 2.58 g) and benzenesulfonyl chloride (7.8 mL), the title compound was obtained as white crystals (yield 14.3 g, 85%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=O)[CH2:6][C:4](=[O:5])[CH2:3]1.[C:11](#[N:17])[CH:12]([CH2:14][C:15]#[N:16])[OH:13].N1CCCCC1>CCO>[CH3:10][C:2]1([CH3:1])[CH2:3][C:4](=[O:5])[CH2:6][C:7](=[C:14]([C:15]#[N:16])[CH:12]([OH:13])[C:11]#[N:17])[CH2:9]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: N#CCC(O)C#N
Solvent: C1CCNCC1
Solvent: CCO
Product: CC1(C)CC(=O)CC(=C(C#N)C(O)C#N)C1
Yield: 70.7 %

Procedure:
To a stirred solution of dimedone (98.0 g, 700.0 mmol) and malonitrile (46.2 g, 700.0 mmol) in EtOH (400 mL) at r.t. was added piperidine (8.5 g, 9.9 mL, 100.0 mmol) dropwise over 15 minutes. The reaction mixture was then heated to reflux for 3 days before cooling. The solvent was removed in vacuo and the residue was re-dissolved in EtOAc (500 mL) and dried (MgSO4). Filtration and concentration in vacuo gave a black oil that was purified by column chromatography (SiO2, 1:6 MeOH/DCM) to give the title compound as a yellow solid (108.0 g, 82%). δH (DMSO-d6) 8.31 (2H, br. s), 2.51 (2H, t, J 1.8 Hz), 2.30 (2H, s), 1.04 (6H, s). LCMS (ES−) 187.3 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].C1(C#C)C=CC=CC=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)C#N>C(#N)C1C=CC=CC=1>[NH2:15][C:16]1[CH:17]=[CH:18][CH:21]=[C:22]([C:4]#[C:3][C:2]([CH3:6])([CH3:5])[CH3:1])[CH:23]=1
Reactant: N#Cc1cccc(N)c1
Reactant: C#CC(C)(C)C
Solvent: N#Cc1ccccc1
Solvent: C#Cc1ccccc1
Product: CC(C)(C)C#Cc1cccc(N)c1
Reaction time: 45 h
Yield: 48 %

Procedure:
The procedure was identical to Example 2, with the exception that 3,3-dimethyl-1-butyne (0.488 ml; 0.329 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 3-aminobenzonitrile (0.236 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 45 h at 65° C. showed the presence of 0.96 mmol (48% yield) of 1-amino-3-(3,3-dimethyl-1-butynyl)benzene and 1.00 mmol of 3-aminobenzonitrile remaining in the reaction mixture.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][N:7]=[C:6]1SC.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1>>[Br:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][N:7]=[C:6]1[N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]1
Reactant: CSc1nnc(C)c(=O)n1Cc1cc(F)ccc1Br
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Product: Cc1nnc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2cc(F)ccc2Br)c1=O
Temperature: 135 °C
Reaction time: 0.08 h

Procedure:
The mixture of 4-(2-bromo-5-fluorobenzyl)-6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (17, 180 mg, 0.523 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (208 mg, 1.04 mmol) was ground for 5 min and then heated in a tube under nitrogen atmosphere at 135° C. for 13 h. The mixture was separated by silica gel column, and eluted with 10-50% ethyl acetate in petroleum ether to give (R)-tert-butyl 1-(4-(2-bromo-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate (18). MS: m/z, 496 (100%, M+1), 498 (100%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:36]1[NH:41][CH2:40][CH2:39][N:38]2[CH2:42][CH2:43][CH2:44][CH:37]12.C(=O)([O-])[O-].[K+].[K+].CN=C=O>CS(C)=O.ClCCl>[F:34][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:41]3[CH2:40][CH2:39][N:38]4[CH2:42][CH2:43][CH2:44][C@H:37]4[CH2:36]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Reactant: C1CC2CNCCN2C1
Agent: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2CCN3CCC[C@H]3C2)cc1-c1ccccc1Cl
Temperature: 150 °C
Reaction time: 12 h

Procedure:
To a solution of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(2-chlorophenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577; 0.11 mmol) in dry DMSO (1 ml) S -octahydropyrrolo[1,2-a]pyrazine, (0.22 mmol) and potassium carbonate (0.22 mmol) were added and the resulting mixture was shaken for 12 hours at 150° C. After cooling the dichloromethane was added (2 ml) and then isocyanate polymer bound was added (2.0 mmol), and the resulting mixture was shaken at room temperature overnight. Then the resin was filtered and the filtrate was concentrated under reduced pressure. Purifications were carried out using mass directed HPLC:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1.[C:15]1([CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](O)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH:10][C:22](=[O:23])[CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:7][CH:6]=1
Reactant: Nc1ncc(Cc2ccccc2Cl)s1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ncc(Cc2ccccc2Cl)s1)C(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
5-(2-Chloro-benzyl)-thiazol-2-ylamine (45 mg, 0.20 mmol) and diphenyl-acetic acid (42 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (10.3 mg, 0.0246 mmol, 12%). ESI-MS m/z calc. 418.1. found 419.2 (M+1)+ Retention time 3.85 minutes. 1H NMR (400 MHz, DMSO-d6) δ 4.19 (s, 2H), 5.30 (s, 1H), 7.23-7.47 (m, 15H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:8][C:9]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(C(F)(F)F)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of methyl 2-t-butoxycarbonylamino-5-trifluoromethylbenzoate (3.80 g; prepared in Reference Example 27.) in methylene chloride (30 ml), trifluoroacetic acid (6 ml) was added. The mixture was stirred for 8 hours at room temperature. The solvent was distilled off azeotropically with toluene three times. To the reaction mixture, an aqueous sodium hydrogencarbonate solution was added to neutralize. The mixture was extracted with ethyl acetate, washed, dried, filtered and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt 5:1) to give the title compound (2.35 g) having the following physical data.
Reaction SMILES: C([O:4][CH:5]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]#[CH:20])=[C:13]([O:21][CH3:22])[CH:12]=1)=[S:7])(=O)C.[OH-].[Na+].CO>O>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH:5]([OH:4])[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]#[CH:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[S:7])=[CH:28][CH:27]=1
Reactant: C#CCOc1ccc(CCNC(=S)C(OC(C)=O)c2ccc(Cl)cc2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#CCOc1ccc(CCNC(=S)C(O)c2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-acetoxy-2-(4-chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-thioacetamide (compound A1.03; 0.603 g), sodium hydroxide (1.4 ml 1 n solution in water) and methanol (5 ml) is stirred for 6 hours at room temperature. Water (30 ml) is added. The reaction mixture is extracted with ethyl acetate (2×100 ml). The organic layers are washed with brine (20 ml), dried and the solvent is evaporated. 2-(4-Chloro-phenyl)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-thioacetamide is obtained which is purified by flash-column-chromatography on silica gel using ethyl acetate/hexane, yielding a resin, 1H-NMR (300 MHz, CDCl3, δ(ppm)): 2.5(t, 1H), 2.9(t, 2H), 3.8(s, 3H), 3.85–4.05(m, 2H), 4.25 (s, 1H), 4.75(d, 2H), 5.1(s, 1H), 6.5(dd, 1H), 6.65(d, 1H), 6.9(d, 1H), 7.2(d, 2H), 7.3(d, 2H), 7.7–7.8(m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:12][S:13][C:14](=[N:17][C:18]#[N:19])SC>>[C:18]([NH:17][C:14](=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[S:13][CH3:12])#[N:19]
Reactant: NCCSCc1ccccn1
Reactant: CSC(=NC#N)SC
Product: CSC(=NCCSCc1ccccn1)NC#N

Procedure:
The reaction of 2-((2-aminoethyl)thiomethyl)pyridine with dimethylcyanodithioimidocarbonate by a method similar to that described in Example (3d) afforded N-cyano-N'-[2-(2-pyridylmethylthio)ethyl]-S-methylisothiourea, m.p. 85°-88°. (from isopropyl alcohol-ether) (Found: C, 49.6; H, 5.4; N, 21.0; S, 24.0% C11H14N4S2 requires: C, 49.6; H, 5.3; N, 21.0; S, 24.1%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl:42][C:43]1[CH:44]=[C:45]([CH2:49][C:50](O)=[O:51])[CH:46]=[CH:47][CH:48]=1.CO>C1COCC1>[Cl:42][C:43]1[CH:44]=[C:45]([CH2:49][C:50]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[N:18]=4)=[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][N:10]4[N:9]=3)[CH:3]=2)=[O:51])[CH:46]=[CH:47][CH:48]=1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Cc1cccc(Cl)c1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.9 %

Procedure:
To a solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-phenyl-2-pyrimidine (30 mg, 0.08 mmol) (see Example 3, Step H) in THF (3 mL) was added CDI (14 mg, 0.09 mmol). The resultant mixture was stirred at rt for 1 hour. To the mixture was added (3-chlorophenyl)acetic acid (15 mg, 0.09 mmol) and then stirred at rt for 15 h. Methanol (2 mL) was added and the mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (hexanes/EtOAc) to give the title compound (25 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6): δ 3.68 (s, 2H), 6.53 (d, 1H, J=5.3 Hz), 6.92 (m, 1H), 6.92 (m, 1H), 7.12 (m, 1H), 7.21-7.50 (m, 9H), 7.68-7.76 (m, 3H), 7.89 (m, 1H), 8.26 (d, 1H, J=5.3 Hz), 8.47 (m, 1H), 8.83 (d, 1H, J=6.8 Hz), 9.56 (s, 1H), 10.35 (s, 1H). ES-LC/MS m/z=531 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[CH3:9].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[Cl:1][C:2]1[CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(I)cc1Cl
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a suspension of tetrakis(triphenylphosphine)palladium (213 mg) in toluene (7 ml) was added 2-chloro-4-iodotoluene (2.33 g) at room temperature. The mixture was stirred at room temperature for 30 min, and a solution of phenylboronic acid (1.35 g) in ethanol (2 ml) and 2 M aqueous sodium carbonate solution (9.25 ml) were added to this mixture, which was followed by reflux under heating. After 3 hr, the reaction mixture was cooled and the organic layer was separated. The aqueous layer was extracted with hexane (4 ml). The organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate solution (4 ml) and saturated brine (4 ml), and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. To the residue (2.11 g) were added hexane (10 ml) and silica gel (4 g) and the mixture was stirred at room temperature for 1 hr. Silica gel was filtered off and the filtrate was concentrated to give 2-chloro-4-phenyltoluene as a pale-brown oil (1.86 g, 99.4%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+].O>C(O)C>[OH:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[N:17][OH:18]
Reactant: NO
Reactant: O=Cc1ccc(-c2ccccc2)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(-c2ccccc2)cc1O
Temperature: 80 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
2-Hydroxy-4-phenylbenzaldehyde (3.7 g), hydroxylamine hydrochloride (1.4 g), sodium acetate (3.1 g) and water (10 mL) were suspended in ethanol (50 mL), and the mixture was stirred at 80° C. for 3 hours. To the reaction mixture was added water (50 mL), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give the title compound (3.0 g).
Reaction SMILES: Br[C:2]([CH3:16])([CH3:15])[C:3]([NH:5][C:6]1[O:10][N:9]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1)=[O:4].[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[N:23][CH:24]=1>C(#N)C.O.[Ag-]=O>[C:11]([C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:16])([O:25][C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:26])([F:17])[F:27])=[CH:24][N:23]=2)[CH3:15])[O:10][N:9]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)no1
Reactant: Oc1ccc(C(F)(F)F)cn1
Agent: O=[Ag-]
Solvent: CC#N
Solvent: O
Product: CC(C)(Oc1ccc(C(F)(F)F)cn1)C(=O)Nc1cc(C(C)(C)C)no1
Temperature: 60 °C
Yield: 5 %

Procedure:
To a solution of 2-bromo-N-(3-tert-butyl-isoxazol-5-yl)-2-methyl-propionamide (0.53 g, 1.78 mmol) and 5-trifluoromethyl-2-pyridinol (0.30 g, 1.84 mmol) in acetonitrile/water (95/5, 15 mL) is added silver (I) oxide (0.85 g, 3.68 mmol). The reaction is heated to 60° C. for 18 h. After cooling, the reaction mixture is filtered through a plug of Na2SO4/cotton wool. The filtrate is concentrated under reduced pressure to give a brown oil, which is triturated with heptanes/ethyl acetate to afford a grey powder. Further purification by column chromatography (silica, eluent heptanes, 2.5-20% ethyl acetate) afforded N-(3-tert-butyl-isoxazol-5-yl)-2-methyl-2-(5-trifluoromethyl-pyridin-2-yloxy)-propionamide as a white solid (33 mg, 5%). m/z 372 [M+H+]
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[C:28]1[CH:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH:12][C:34]([C:31]3[CH:32]=[CH:33][C:28]([C:22]4[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=4[Cl:20])=[CH:29][CH:30]=3)=[O:35])=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCC(CN(C)c2nc3cc(N)ccc3o2)C1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN1CCC(CN(C)c2nc3cc(NC(=O)c4ccc(-c5ccc(Cl)cc5Cl)cc4)ccc3o2)C1
Yield: 45.9 %

Procedure:
Combine rac-N2-methyl-N2-(1-methyl-pyrrolidin-3-ylmethyl)-benzooxazole-2,5-diamine (0.040 g, 0.154 mmol), 2′,4′-dichloro-biphenyl-4-carboxylic acid (0.062 g, 0.230 mmol), HATU (0.058 g, 0.154 mmol), polystyrene-bound diisopropylamine (0.385 g, loading: 2.0 to 3.5 mmol/g), and CH2Cl2 (10 mL). Shake the mixture overnight at room temperature. Filter the mixture and wash the polystyrene resin with 1:1 CH2Cl2/MeOH. Subject the mixture to flash column chromatography on an ISCO Companion (12 g column, eluting with 10% 2M NH3 in MeOH/CH2Cl2) to yield a colorless oil (0.036 g). Dissolve the oil in CH2Cl2, wash with 1.0M NaOH (3×25 mL), dry over Na2SO4, filter, concentrate in vacuo, and pump overnight on high vacuum to yield the desired product (0.031 g, 40%). mass spectrum (m/e): 509.0 (M+1), 507.0 (M−1). 1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.03 (d, J=8.8 Hz, 2H), 7.80-7.78 (m, 1H), 7.73-7.71 (m, 1H), 7.61-7.48 (m, 4H), 7.40-7.33 (m, 2H), 3.50 (d, J=8.0 Hz, 1H), 3.13 (s, 3H), 2.65-2.55 (m, 1H), 2.44-2.34 (m, 2H), 2.28-2.21 (m, 1H), 2.23 (s, 3H), 1.93-1.83 (m, 2H), 1.49-1.39 (m, 2H).
Reaction SMILES: [CH2:1]([NH:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[S:17])=[O:7])[CH2:2][CH2:3][CH3:4].BrBr.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:5]1[C:6](=[O:7])[N:8]2[C:9](=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=32)[S:17]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)n1c(=S)[nH]c2ccccc21
Agent: BrBr
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCn1sc2nc3ccccc3n2c1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 68.5 %

Procedure:
To a solution of 1-(butylcarbamoyl)-1,3-dihydrobenzimidazole-2-thione (39.89 g, 0.16 mole) in 250 mL of chloroform, was added 25.57 g (0.16 mole) of bromine, in 110 mL of chloroform, at 0° C. After the addition was complete, triethylamine (44.6 mL, 0.32 mole), in 80 mL of chloroform, was added dropwise to the reaction mixture. The mixture was stirred at 0° C. for an additional 4 h, and then stirred at room temperature for 14 h. The resulting mixture was washed with water and then with a 10% sodium sulfate solution. The organic layer was dried over magnesium sulfate and evaporated to give the crude product. Recrystallization from methanol gave 27.10 g (69%) of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one as colourless crystals: mp 153-154° C. (lit.: 156-157° C., Martin et al. Tetrahedron 1983, 39, 2311).