Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([CH2:36][CH3:37])[CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([CH2:36][CH3:37])[CH:18]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(COc2nn(Cc3ccccc3)cc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CCc1cc(COc2nn(Cc3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
A mixture of {1-benzyl-3-[(3-ethyl-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazol-4-yl}methanol (0.23 g), activated manganese dioxide (0.70 g) and tetrahydrofuran (10 mL) was stirred at room temperature for 3 hrs. Manganese dioxide was removed by filtration and the filtrate was concentrated. The obtained crystals were collected by filtration to give 1-benzyl-3-[(3-ethyl-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carbaldehyde as colorless crystals (0.20 g, yield 87%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 128-129° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C)C=O>[CH2:11]([N:3]1[CH:4]=[C:5]([CH:7]=[O:8])[N:6]=[C:2]1[CH3:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc(C=O)c[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C=O)cn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a solution of 2-methyl-1H-imidazole-4-carbaldehyde (5.50 g) in N,N-dimethylformamide (100 mL) was slowly added sodium hydride (60%, oily, 2.4 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Benzylbromide (7.1 mL) was slowly added to the reaction mixture, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give 1-benzyl-2-methyl-1H-imidazole-4-carbaldehyde (3.8 g, yield 38%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). melting point 61° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[C:4]2[NH:13][CH:14]=[C:15]([C:16](=[O:36])[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[N:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:28]=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[O:18])[C:3]=12.[H-].[Na+].Cl.Cl[CH2:41][CH2:42][N:43]([CH3:45])[CH3:44]>CN(C=O)C>[CH3:44][N:43]([CH3:45])[CH2:42][CH2:41][N:10]1[CH:11]=[CH:12][C:8]([C:5]2[N:6]=[CH:7][C:2]([F:1])=[C:3]3[C:15]([C:16](=[O:36])[C:17]([N:19]4[CH2:24][CH2:23][N:22]([C:25]5[N:29]([C:30]6[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=6)[N:28]=[N:27][N:26]=5)[CH2:21][CH2:20]4)=[O:18])=[CH:14][NH:13][C:4]=23)=[N:9]1
Reactant: CN(C)CCCl
Reactant: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(-c3cc[nH]n3)ncc(F)c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCn1ccc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.6 %

Procedure:
1-(4-fluoro-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (40 mg, 0.08 mmol) in DMF (1 mL) was treated with sodium hydride (60% in oil, 33.0 mg, 0.8 mmol) and stirred at room temperature for 5 min. 2-chloro-N,N-dimethylethanamine hydrochloride (115.2 mg, 0.8 mmol) was added and the mixture was stirred at rt for 1 h. Reaction was quenched with H2O and concentrated under reduced pressure. The residue was dissolved in DMF and purified using reverse phase prep HPLC to afford the title compound as a white solid (15 mg, 34%). 1H NMR (500 MHz, MeOD) δ ppm 2.96 (s, 6 H) 3.37 (s, 2 H) 3.63 (s, 2 H) 3.82 (s, 2 H) 3.89 (s, 2 H) 4.76 (s, 2 H) 7.11 (s, 1 H) 7.59 (s, 1 H) 7.64 (s, 2 H) 7.68 (s, 2 H) 7.92 (s, 1 H) 8.25 (s, 1 H) 8.36 (s, 1 H). LCMS: m/e 558 (M+H)+, ret time 1.37 min (method 3).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:29][C:30]1[N:35]=[C:34]([CH2:36]Cl)[CH:33]=[CH:32][N:31]=1>CN(C=O)C>[Cl:29][C:30]1[N:35]=[C:34]([CH2:36][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:7]3[O:11][N:10]=[C:9]([C:12]4[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=4)[N:8]=3)=[N:5]2)[CH:33]=[CH:32][N:31]=1
Reactant: ClCc1ccnc(Cl)n1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1ccnc(Cl)n1
Reaction time: 0.08 h
Yield: 68.6 %

Procedure:
5-(5-Methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (200 mg, 0.643 mmol) was placed in DMF (5 ml) and Cs2CO3 (251 mg, 0.771 mmol) was added. The reaction was stirred for 5 min and 2-chloro-4-(chloromethyl)pyrimidine (126 mg, 0.771 mmol) was added. The reaction was stirred at 45° C. overnight and then partitioned between H2O (50 mL) and EtOAc (50 mL). The organic layer was separated, washed with H2O (2×50 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product which was purified by silica gel chromatography (EtOAc/Hexane 10%-100% EtOAc) to afford the desired compound as an orange solid (193 mg, 68%). MS (ES+) C17H11ClF3N7O2 requires: 437, 439. found 438, 440 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 8.81 (d, J=5.1 Hz, 1H), 8.21 (d, J=8.7 Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 7.52 (d, J=5.1 Hz, 1H), 5.81 (s, 2H), 2.59 (s, 3H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:3]=1.C1COCC1.Cl>[Zn].CO>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[C:9]([NH2:11])[C:10]=3[CH:2]=[N:3]2)[CH:16]=1
Reactant: O=[N+]([O-])c1cccc2c1c(I)nn2Cc1cccnc1
Agent: Cl
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc2c1cnn2Cc1cccnc1
Reaction time: 1 h
Yield: 48 %

Procedure:
To a vial containing 3-iodo-4-nitro-1-(pyridin-3-ylmethyl)-1H-indazole (0.145 g, 0.381 mmol) was added THF (2.4 mL) and MeOH (1.2 mL). To this solution was added Zn dust (0.249 g, 3.81 mmol) followed by HCl (2.54 mL, 7.63 mmol, 3.0 M aqueous). The mixture was stirred for 1.0 hours. The mixture was filtered through GF/F paper and the collected solids were washed with CHCl3 (30 mL). A saturated aqueous KOAc solution was added to the filtrate until the pH was neutral and then a saturated aqueous Rochelle's Salt solution was added. The mixture was stirred vigorously, the layers were separated and the aqueous phase was extracted with CHCl3. The combined organic extracts were washed with brine and dried over Na2SO4, filtered and concentrated. The product was purified by column chromatography (1 to 10% MeOH/CH2Cl2) to afford the product as a thick oil (0.041 g, 47%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6](O)[CH2:7][N:8]1[C:12]2[C:13]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])(=[O:3])[CH3:2].CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.CN(C)C=O.C(OCC)(=O)C>[C:1]([O:4][CH2:5][CH:6]1[CH2:7][N:8]2[C:9](=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])[C:12]=32)[N:22]1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])(=[O:3])[CH3:2]
Reactant: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CC(O)COC(C)=O)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCN(CC)c1cccc2nc3n(c12)CC(COC(C)=O)N3c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 3-[2-[(2,4-dichlorophenyl)amino]-7-(diethylamino)-1H-benzimidazol-1-yl]-2-hydroxypropyl acetate (Reference Example 89; 32.5 mg, 0.0698 mmol) in pyridine (0.7 mL) was added methanesulfonyl chloride (0.0270 mL, 0.349 mmol) at 0° C. After the resultant mixture was stirred at room temperature for 1.5 hr, the mixture was quenched with aqueous sodium hydrogen carbonate, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was diluted with N,N-dimethylformamide, and potassium carbonate (19.3 mg, 0.140 mmol) was added. After being stirred for 0.5 hr at 80° C., the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-60% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (30.5 mg, 0.0684 mmol, 98%).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:34][NH:35][C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:38]4[CH2:39][CH2:40][C@H:36]([NH:35][CH3:34])[CH2:37]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CN[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CN[C@H]1CCN(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and (S)-3-methylaminopyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 3.66 (m, 2H), 3.49 (m, 2H), 3.32 (m, 2H), 2.36 (s, 3H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.30 (m, 2H). m/z: 437 [M+H]
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>CO>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: BrCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(OCCCCCBr)cc1
Temperature: 70 °C
Yield: 19.9 %

Procedure:
To a solution of hydroquinone (2.0 g, 18.2 mmol) in MeOH (10 mL), KOH (1.02 g, 18.2 mmol) was added. Then, 1,5-dibromopentane (3.09 mL, 22.7 mmol) was added dropwise over 10 min. After the addition was complete, the mixture was refluxed for 12 hours at 70° C. The reaction mixture was concentrated and quenched with water (100 mL), and then the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was washed with water, then brine, and dried over Na2SO4. The solvent was evaporated to give a colorless oil, which was purified by column chromatography to isolate intermediate 14a (0.94 g, 3.62 mmol, 20% yield). 1H NMR (CDCl3, 400 MHz) δ 6.76-6.84 (m, 4H), 4.50 (s, 1H), 3.93 (t, J=6.4 Hz, 2H), 3.46 (t, J=6.4 Hz, 2H), 1.92-1.96 (m, 2H), 1.77-1.84 (m, 2H), 1.60-1.67 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].S(OC)(O[CH3:25])(=O)=O.S(=O)(=O)(O)O>>[CH3:25][S:6][C:3]([CH3:5])([CH3:4])[C@H:2]([C:7]([OH:9])=[O:8])[NH2:1]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: CSC(C)(C)[C@@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.6 %

Procedure:
A suspension of D-Penicillamine (10.0 g, 67.01 mmol) in 0.4N solution of barium hydroxide octahydrate (330 mL, 67.01 mmol) is chilled on an ice water bath. Dimethyl sulfate (6.6 mL, 70.36 mmol, 1.05 equiv) is added dropwise over a period of 30 minutes. The suspension stirred for 18 hours at room temperature. A solution of 1 N sulfuric acid is added to the solution (pH˜2) to precipitate out the barium sulfate. The supernatent is decanted and the precipitate is washed several times with water. The pH of the supernatent is adjusted to 6 with concentrated ammonium hydroxide and the water is evaporated off to give a pure white solid (10.9 g, 100% yield).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]([NH:14][C@H:15]([C:20]([NH:22][C@H:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:21])[CH2:16][CH2:17][CH2:18][NH2:19])=[O:13].CN(C=O)C.[N+](C1C=CC(N[C:50](=[O:59])[O:51][CH2:52][CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]2)=CC=1)([O-])=O.C(N(CC)CC)C>O>[CH:53]1([CH2:52][O:51][C:50]([NH:19][CH2:18][CH2:17][CH2:16][C@@H:15]([C:20]([NH:22][C@H:23]2[CH2:27][CH2:26][CH2:25][C@H:24]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:21])[NH:14][C:12]([C:4]2[N:3]([CH3:2])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:13])=[O:59])[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)OCC1CCCCC1
Reactant: Cn1c(C(=O)N[C@@H](CCCN)C(=O)N[C@H]2CCC[C@H]2C(=O)OC(C)(C)C)cc2ccccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1c(C(=O)N[C@@H](CCCNC(=O)OCC2CCCCC2)C(=O)N[C@H]2CCC[C@H]2C(=O)OC(C)(C)C)cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a mixture of tert-butyl (1R,2S)-2-({N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate hydrochloride (0.41 g) and DMF (4.0 ml) were added cyclohexylmethyl 4-nitrophenylcarbamate (0.28 g) and triethylamine (94 mg) under ice-cooling, followed by stirring at room temperature for 1 hour. To the reaction mixture was added water (10 ml) under ice-cooling, followed by stirring at room temperature for 1 hour. The solid precipitated was collected by filtration, washed with water, and purified by silica gel column chromatography (chloroform/THF=10:1) to obtain tert-butyl (1R,2S)-2-({N5-[(cyclohexylmethoxy)carbonyl]-N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (0.41 g).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][S:6][C:5]([SH:8])=[N:4]1.[CH2:9](N(CC)CC)C.ClCCN=C=S>ClCCl>[OH:1][CH2:2][C@@H:3]1[CH2:7][S:6][C:5]([S:8][CH3:9])=[N:4]1
Reactant: OC[C@@H]1CSC(S)=N1
Reactant: CCN(CC)CC
Agent: S=C=NCCCl
Solvent: ClCCl
Product: CSC1=N[C@H](CO)CS1
Reaction time: 2 h
Yield: 95 %

Procedure:
A 1.5 ml solution of acetonitrile anhydride containing 219 mg of 3-hydroxyazetidine hydrochloride (5) was cooled to 0° C. in the stream of nitrogen, and, to this solution, there were added 0.31 ml of triethylamine and subsequently a 0.3 ml solution of acetonitrile anhydride containing 250 mg of chloroethylisothiocyanate dissolved therein, and the resultant solution was stirred for 30 minutes at the same temperature, and, after left still until it had a room temperature, the solution was further stirred for two hours. Next, dichloromethane was added to the reaction liquid, and the resultant solution was washed with a saturated aqueous solution of potassium carbonate, and, thereafter, the dichloromethane layer was dried with magnesium sulfate, and then was condensed under reduced pressure, and, thus, there was obtained 300 mg (yield: 95%) of 3-hydroxy-1-(1,3-thiazolin-2-yl)azetidine (6) in the form of colorless needle crystal.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17](N1C=CN=C1)=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]([F:29])([F:28])[CH2:26][NH2:27]>C1COCC1>[Cl:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:16][C:17](=[O:18])[N:27]([CH2:26][C:25]([F:29])([F:28])[F:24])[C:1]2([OH:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(F)(F)F
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)n1ccnc1
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C(O)(c2ccccc2)N1CC(F)(F)F
Temperature: 50 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
To a suspension of N-(2-benzoyl-4-chlorophenyl)-1H-imidazole-1-carboxamide (39.3 g, 120.5 mmol) in THF (200 mL) was added 2,2,2-trifluoroethylamine (14.0 g, 141.0 mmol). The reaction was heated to 50° C. for 16 h. A second portion of 2,2,2-trifluoroethylamine (3.6 gm, 36.4 mmol) was added and warming continued at 50° C. for 3 h. The reaction was cooled to ambient temperature and concentrated in vacuo. The light yellow oil was partitioned between n-butyl chloride (500 mL) and aqueous 10% citric acid (300 mL) with vigorous stirring. The resulting precipitate was collected by vacuum filtration and placed under vacuum alongside P2O5 for 16 h to give 35.4 g (82.4%) of 6-chloro-4-hydroxy-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one as an off-white solid. 1H NMR (CDCl3, 400 MHz) 8.41 (brs, 1H); 7.47 (d, J=8.06 Hz, 2H); 7.36 (m, 3H); 7.27 (m, 1H); 7.21 (dd, J=2.26 Hz and 8.52 Hz, 1H); 6.76 (d, J=8.52 Hz, 1H); 4.37 (m, 1H); 3.55 (m, 1H); 3.25 (s, 1H). MS (Electrospray): m/z 357.0 (M+H).
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45](O)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1.[CH3:50][C:51]1[N:52]=[CH:53][C:54]([CH2:57][NH2:58])=[N:55][CH:56]=1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45]([NH:58][CH2:57][C:54]4[CH:53]=[N:52][C:51]([CH3:50])=[CH:56][N:55]=4)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:48][CH:49]=1
Reactant: Cc1cnc(CN)cn1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Product: Cc1cnc(CNC(=O)c2sc(-n3cnn(Cc4ccc(F)cc4)c3=O)nc2C)cn1
Yield: 64 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with (5-methylpyrazin-2-yl)methanamine, the title compound was obtained as a white solid in 64% yield: mp 188-189° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.53 (s, 1H), 8.40 (s, 1H), 8.26 (s, 1H), 7.43-7.33 (m, 2H), 7.10-6.99 (m, 2H), 6.97 (t, J=4.8 Hz, 1H), 4.98 (s, 2H), 4.72 (d, J=4.8 Hz, 2H), 2.66 (s, 3H), 2.58 (s, 3H); MS (ES+) m/z 440.2 (M+1).
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([CH2:20]O)[C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([CH2:20][Br:24])[C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCn1c(=O)c(CO)c(OC)c2cc(C)ccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCn1c(=O)c(CBr)c(OC)c2cc(C)ccc21
Reaction time: 0.08 h

Procedure:
A solution of 1 -hexyl-3-hydroxymethyl-4-methoxy-6-methyl-2(1H)-quinolinone (Example 12, 0.6 g) in methylene chloride (12 ml) containing carbon tetrabromide (1 g) was treated with triphenylphosphine (0.87 g) and stirred at ice bath temperature for 5mins and then at room temperature for hr. The reaction mixture was then evaporated under reduced pressure and the crude product was chromatographed on silica-gel (25 g). Elution with ether-hexane gave 1-hexyl-3-bromomethyl-4-methoxy-6-methyl-2(1H)-quinolinone as a white crystralline solid. That the expected product was obtained was confirmed by the spectral data: MS: m/e 365,367 (M+); NMR (CDCl3): δ4.12 (s, 3H, OCH3) 4.68 (s, 2H, CH2Br).
Reaction SMILES: FC1C=C(F)C=CC=1COC1C=CC(CO)=CC=1.C[O:20][C:21](=[O:49])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=3[F:47])=[CH:34][CH:33]=2)=[CH:26][C:25]=1[CH3:48]>>[F:47][C:41]1[CH:42]=[C:43]([F:46])[CH:44]=[CH:45][C:40]=1[CH2:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][S:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:22][C:21]([OH:49])=[O:20])=[C:25]([CH3:48])[CH:26]=2)=[CH:33][CH:34]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(F)cc3F)cc2)cc1C
Agent: OCc1ccc(OCc2ccc(F)cc2F)cc1
Product: Cc1cc(SCc2ccc(OCc3ccc(F)cc3F)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 3B using 31A. MS m/z 233 (M-Cl). Step 3. Preparation of {4-[4-(2,4-Difluoro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid methyl ester (Compound 31C)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[CH:4][C:3]=1[C:11]([OH:13])=[O:12].[C:14](=O)(O)[O-].[Na+]>CO.S(=O)(=O)(O)O>[CH3:14][O:12][C:11]([C:3]1[CH:4]=[C:5]2[CH:10]=[CH:9][S:8][C:6]2=[N:7][C:2]=1[NH2:1])=[O:13]
Reactant: Nc1nc2sccc2cc1C(=O)O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2ccsc2nc1N
Reaction time: 24 h
Yield: 72 %

Procedure:
6-Amino-thieno[2,3-b]pyridine-5-carboxylic acid (44 mg, 0.23 mmol) was dissolved in a mixture solution of methanol (1 mL) and sulfuric acid (0.5 mL), and the solution was stirred for 24 hours under reflux. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=2:1), and the title compound (34 mg, 0.16 mmol, 72%) was obtained as a white solid.
Reaction SMILES: [OH:1][CH:2]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=1)[CH2:3][N:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([CH2:7][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)[CH2:5]1>CCO.[Pd]>[NH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH:2]([OH:1])[CH2:3][N:4]2[CH2:11][CH:10]3[CH2:12][CH:6]([CH2:7][N:8]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9]3)[CH2:5]2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC(CN(CC(O)COc3ccc([N+](=O)[O-])cc3)C2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CC(O)COc3ccc(N)cc3)C2)C1

Procedure:
The title compound was prepared quantitatively from tert-butyl 7-[2-hydroxy-3-(4-nitrophenoxy)propyl]-3,7-diazabicyclo[3.3.1 ]nonane-3-carboxylate (see Example 12 above) using catalytic hydrogenation on 5% Pd/C in EtOH at 1 atm.