Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O.C(O)(=O)C.Cl.[OH-].[Na+]>O>[N:12]1([CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(CCN2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(CCN2CCCCC2)cc1
Temperature: 65 °C
Yield: 58.4 %

Procedure:
1-[2-(4-Nitro-phenyl)-ethyl]-piperidine (0.1178 gms.) is suspended in 4.5 mL of a 1:1 (v:v) solution of acetic acid and water. The suspension is then immersed in a 65° C. oil bath and treated in dropwise fashion with 9 mL of an ˜10 wt. % solution of TiCl3 in 20–30 wt. % HCl. Over the course of the addition a color change from colorless to purple to black ensues. The reaction mixture is maintained in the 65° C. oil bath overnight following the addition of TiCl3. The reaction mixture is then cooled to 0° C., and made basic with the addition of a 10% aqueous solution of NaOH. The basic reaction mixture is then extracted with chloroform. The emmulsion that forms is filtered through glass wool, re-extracted with chloroform, and then dried over anhydrous sodium sulfate. Following evaporation of the solvent the residue is chromatographed by flash silica gel chromatography (10% methanol in chloroform) to yield 60 mg of 4-(2-piperidin-1-yl-ethyl)-phenylamine.
Reaction SMILES: Br[CH2:2][CH2:3][Cl:4].[CH3:5][C:6]1[C:15]([C:16]2[S:17][C:18]([C:27]3[N:31]=[CH:30][N:29]([CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][O:33]4)[N:28]=3)=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:20]=2)=[C:9]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][N:8]2[N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:4][CH2:3][CH2:2][O:14][C:11]1[CH:12]=[CH:13][N:8]2[N:7]=[C:6]([CH3:5])[C:15]([C:16]3[S:17][C:18]([C:27]4[N:31]=[CH:30][N:29]([CH:32]5[CH2:37][CH2:36][CH2:35][CH2:34][O:33]5)[N:28]=4)=[C:19]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:20]=3)=[C:9]2[CH:10]=1
Reactant: Cc1nn2ccc(O)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1nn2ccc(OCCCl)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Yield: 93.6 %

Procedure:
The title compound has been prepared according to the similar manner described in 85-B (ii) from 1-bromo-2-chloroethane (163 μL, 1.96 mmol), 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyrazolo[1,5-a]pyridin-5-ol (300 mg, 0.654 mmol) obtained in Example 31-B-(i) and cesium carbonate (639 mg, 1.96 mmol). The crude product has been roughly purified by simple filtration through silica gel pad (5 g) and then washed with diethyl ether (20 mL) to give title compound (319 mg, 93%) as a colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][CH:42]([O:45][C:46](=[O:60])[NH:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([NH:36][CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([O:45][C:46](=[O:60])[NH:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH2:41][CH2:40]2)=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: NCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: O=Cc1ccc(C(=O)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: ClCCl
Product: O=Cc1ccc(C(=O)NCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A mixture of 4-carboxybenzaldehyde (0.95 g, 6.35 mmol) and HATU (3.02 g, 7.94 mmol) in 55 mL of DCM was stirred at room temperature for 1 hour and then biphenyl-2-ylcarbamic acid 1-(2-aminoethyl)piperidin-4-yl ester (3 g, 5.29 mmol; prepared as described in Preparation 7) and DIPEA (4.6 mL, 26.45 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours and then diluted with 100 mL of DCM and washed with saturated sodium bicarbonate (150 mL) and brine (150 mL). The organic layer was dried over MgSO4, filtered and concentrated to provide 2.3 g of the title intermediate (92% yield), which was suitable for use without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>O>[OH:9][C:5]1[C:4]([CH3:10])=[CH:3][C:2]([NH:1][C:11](=[O:13])[CH3:12])=[C:7]([CH3:8])[CH:6]=1
Reactant: Cc1cc(O)c(C)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1cc(C)c(O)cc1C
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 90.4 %

Procedure:
To a suspension of 4-amino-2,5-dimethyl-phenol (6.85 g, 50 mmol) in 30 mL of water was added acetic anhydride (5.67 mL, 60 mmol). The mixture was vigorously stirred at 70° C. for 20 min and then cooled down to room temperature. The solid was collected by filtration and washed with water to give N-(4-hydroxy-2,5-dimethyl-phenyl)-acetamide as gray solid (8.1 g, 90%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[CH2:22]([O:30][C:31](Cl)=[O:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C1C=CC=CC=1>[C:31](=[O:32])([O:30][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: CCCCCCCCOC(=O)Cl
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 10 ml. of absolute pyridine and reacted with 0.423 g. of chloroformic acid n-octyl ester as in Example 1. The 0.721 g. of brownish oil obtained according to the procedure described in Example 1 is dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.620 g. of colorless crystals which are recrystallized from ether-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-octyl carbonate obtained melts at 51.64° and has a clearing point of 67.7°. UV (EtOH): ε 270 = 26000.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[C:42]3[C:38]([CH:39]=[N:40][NH:41]3)=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:35]2[CH:43]=[C:42]3[C:38]([CH:39]=[N:40][NH:41]3)=[CH:37][CH:36]=2)[CH:3]=1)=[O:15]
Reactant: CC1(C)OB(c2ccc3cn[nH]c3c2)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4cn[nH]c4c3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 74 from 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (59.4 mg, 0.243 mmol), DMSO(1.5 mL), sodium carbonate (0.281 mL, 0.562 mmol), and bis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol). The final product was collected as 55 mg (65%). LCMS E-S (M+H)=456.0 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49-1.65 (m, J=6.4 Hz, 6 H), 2.14 (s, 3 H), 2.23 (s, 3 H), 4.43 (d, J=4.6 Hz, 2 H), 5.36 (quin, J=6.7 Hz, 1 H), 5.87-5.97 (m, 1 H), 7.52-7.72 (m, 2 H) 7.92 (d, J=8.6 Hz, 1 H), 8.08 (d, J=8.6 Hz, 1 H), 8.16 (s, 1 H), 8.26 (s, 1 H), 8.37-8.49 (m, 2 H), 8.96-9.14 (m, 1 H), 11.59 (br. s., 1 H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:47][O:48][CH3:49])[C:21]([NH:23][CH:24]2[C:45](=[O:46])[N:26]3[CH:27]([C:31]([O:33][CH:34]([CH2:40][O:41][CH:42]([CH3:44])[CH3:43])[CH2:35][O:36][CH:37]([CH3:39])[CH3:38])=[O:32])[CH:28]=[CH:29][S:30][C@H:25]23)=[O:22])[N:19]=1)=[O:13].CSC>C(Cl)Cl>[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:47][O:48][CH3:49])[C:21]([NH:23][CH:24]2[C:45](=[O:46])[N:26]3[C:27]([C:31]([O:33][CH:34]([CH2:35][O:36][CH:37]([CH3:38])[CH3:39])[CH2:40][O:41][CH:42]([CH3:43])[CH3:44])=[O:32])=[CH:28][CH2:29][S:30](=[O:9])[C@H:25]23)=[O:22])[N:19]=1)=[O:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(COC(C)C)COC(C)C)C=CS[C@H]12)c1csc(NC=O)n1
Solvent: ClCCl
Solvent: CSC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(COC(C)C)COC(C)C)=CCS(=O)[C@H]12)c1csc(NC=O)n1
Reaction time: 0.33 h

Procedure:
A solution of m-chloroperbenzoic acid (70% purity: 3.2 g) in methylene chloride (50 ml) was dropwise added to a stirred solution of 2-isopropoxy-1-isopropoxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-cephem-4-carboxylate (syn isomer, 7.5 g) in methylene chloride (75 ml) at 2° to 5° C. over 25 minutes, and stirred at 0° to 5° C. for 20 minutes. Dimethylsulfide (1 ml) was added to the resultant mixture. The resultant mixture was washed with an aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride in turn. After drying the solution over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was triturated with diethylether (100 ml), and then the precipitates were collected by filtration to give 2-isopropoxy-1-isopropoxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate-1-oxide (syn isomer, 6.77 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]1[CH2:9][CH:8]1[C:10]([OH:13])([CH3:12])[CH3:11].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]2[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)[N:16]=1>>[CH3:28][C:26]1([CH3:29])[CH2:27][CH:22]([NH:21][C:17]2[N:16]=[C:15]([C:5]3[S:1][C:2]([CH2:6][CH:7]4[CH2:9][CH:8]4[C:10]([OH:13])([CH3:11])[CH3:12])=[CH:3][CH:4]=3)[CH:20]=[CH:19][N:18]=2)[CH2:23][C:24]([CH3:31])([CH3:30])[NH:25]1
Reactant: CC(C)(O)C1CC1Cc1cccs1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Product: CC1(C)CC(Nc2nccc(-c3ccc(CC4CC4C(C)(C)O)s3)n2)CC(C)(C)N1
Yield: 20 %

Procedure:
The title compound was prepared analogous to Method C, starting from 2-(2-thiophen-2-ylmethyl-cyclopropyl)-propan-2-ol and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine. Yield: 20%.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:14][CH2:13][CH2:12][CH2:11][O:10]2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[O:10][CH2:11][CH2:12][CH2:13][O:14]2)=[CH:7][CH:8]=1)=[O:23]
Reactant: CSc1ccc(C2OCCCO2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccc(C2OCCCO2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-methylsulfanyl-phenyl)-[1,3]dioxane (2 g, 9.5 mmol) in DCM (50 mL) at 0° C. is added m-CPBA (2.46 g, 10.5 mmol). The mixture is stirred at 0° C. for 1 h after which Ca(OH)2 (770 mg, 10.5 mmol.) is added. The reaction is stirred an additional 30 min, then the reaction mixture is diluted with DCM and filtered through celite. The filtrate is collected and concentrated to give 2-(4-methanesulfinyl-phenyl)-[1,3]dioxane as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](C)(O)[C:17]([O:19][CH3:20])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]1[CH:31]=[CH:30][C:27](CBr)=[CH:26][CH:25]=1>[Ag]=O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH:17]([O:19][CH2:20][C:27]2[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=2)[C:6]([O:5][CH3:1])=[O:7])=[CH:14][CH:15]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)C(C)(O)c1ccc(OCC(=O)OC(C)(C)C)cc1
Agent: O=[Ag]
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1ccc(OCC(=O)OC(C)(C)C)cc1)OCc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 4-(t-butoxycarbonylmethoxy)phenyllactate (3.0 g), 4-fluorobenzylbromide (2.4 ml), silver oxide (9.0 g) and toluene (60 ml) was stirred at 80° C. under a nitrogen atmosphere for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column using hexane:ethyl acetate=5:1 as the eluant to afford the title compound (2.9 g, Rf=0.39: thin layer chromatography on a silica gel plate using hexane:ethyl acetate=3:1 as the eluant).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([OH:10])[CH2:4][C:5](OCC)=[O:6].[NH4+:13]>CO>[F:1][C:2]([F:12])([F:11])[CH:3]([OH:10])[CH2:4][C:5]([NH2:13])=[O:6]
Reactant: [NH4+]
Reactant: CCOC(=O)CC(O)C(F)(F)F
Solvent: CO
Product: NC(=O)CC(O)C(F)(F)F
Yield: 87.6 %

Procedure:
A solution of ethyl 4,4,4-trifluoro-3-hydroxybutanoate (3.0 g, 16.1 mmol) in MeOH (8 mL) was stirred with aqueous ammonium (16 mL) at room temperature overnight. The mixture was concentrated to afford 4,4,4-trifluoro-3-hydroxybutanamide (2.19 g, yield: 87.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8].C([Li])CCC.[Br:15]Br>O1CCCC1>[Br:15][C:5]1[S:4][C:3]([C:7]([OH:9])=[O:8])=[C:2]([CH3:1])[CH:6]=1
Reactant: BrBr
Reactant: Cc1ccsc1C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(Br)sc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.9 %

Procedure:
To a stirred solution of 3-methyl-2-thiophenecarboxylic acid (6.00 g, 42.20 mmol) in tetrahydrofuran (90 mL) under nitrogen atmosphere at −78° C. was added dropwise n-butyllithium (2.5 M solution in hexanes, 40.5 mL, 101.2 mmol). The resulting reaction mixture was stirred at the same temperature for 1 h, and then bromine (3.00 mL, 58.38 mmol) was added dropwise. After 1 h at −78° C. the cooling bath was removed, and the mixture was allowed to warm to ambient temperature during 1 h, and then quenched with water (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL), and the combined aqueous layer was acidified at 0° C. with 37% aqueous hydrochloric acid to pH˜1-2. The aqueous layer was extracted with ethyl acetate (2×100 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with ethyl acetate in hexanes to afford 5-bromo-3-methylthiophene-2-carboxylic acid as a beige solid (3.44 g, 37%): 1H NMR (300 MHz, CDCl3) δ 6.94 (s, 1H), 2.52 (s, 3H); MS (ES−) m/z 219.1 (M−1), 221.1 (M−1).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[C:17]([F:32])=[C:18]([C:23]2[C:24]([C:30]#[N:31])=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[C:19]([F:22])=[CH:20][CH:21]=1>>[F:1][C:2]1[C:3]2[N:4]([C:12]([C:20]3[C:19]([F:22])=[C:18]([C:23]4[C:24]([C:30]#[N:31])=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[C:17]([F:32])=[CH:16][CH:21]=3)=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9]
Reactant: N#Cc1cc(F)ccc1-c1c(F)ccc(Br)c1F
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(F)cc4C#N)c3F)cnc2c1F
Yield: 36.4 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol (194 mg, 1.0 mmol) and 3′-bromo-4,2′,6′-trifluorobiphenyl-2-carbonitrile (343 mg, 1.1 mmol) were coupled following the procedure in Example 6 to afford 3′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]-4,2′,6′-trifluorobiphenyl-2-carbonitrile (155 mg, 36%) as a white solid: δH (360 MHz, CDCl3) 1.74 (6H, s), 2.07 (1H, s), 7.19-7.26 (2H, m), 7.41-7.49 (1H, m), 7.54-7.65 (3H, m), 7.73 (1H, s), 7.93 (1H, dd, J 7 and 7); m/z (ES+) 426 (100%, [MH]+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:23][C:24]([CH3:35])([O:26][C:27]([NH:29][C@@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=[O:28])[CH3:25].C(N(CC)CC)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:32]4[CH2:33][CH2:34][C@@H:30]([NH:29][C:27]([O:26][C:24]([CH3:35])([CH3:25])[CH3:23])=[O:28])[CH2:31]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)c(F)cc2c1=O

Procedure:
When the above reaction was run using 15.6 g (50 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester, 10.2 g (55 mmol) of (R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]pyrrolidine, 10.1 g (0.1 mol) triethylamine and 100 ml of acetonitrile, the yield of the title compound was 23.8 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16](Cl)=[N:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2.[OH-:21].[Na+]>C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16]([O:21][CH2:4][CH2:3][CH2:12][CH3:11])=[N:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2
Reactant: [OH-]
Reactant: COc1cc2c(cc1OC)-c1cc(Cl)nc(=O)n1CC2
Agent: [Na+]
Solvent: CCCCO
Product: CCCCOc1cc2n(c(=O)n1)CCc1cc(OC)c(OC)cc1-2
Yield: 85 %

Procedure:
1.46 g of 9,10-dimethoxy-6,7-dihydro-2-chloro-4H-pyrimido(6,1-a)-isoquinolin-4-one are added to a mixture of 1.0 g of sodium hydroxide and 50.0 ml of n-butanol. The reduction mixture is refluxed for 6 hours. The solent is removed under reduced pressure. The residue is treated with water and extracted with chloroform. The extract is dried over anhydrous Na2SO4 and evaporated to give a white solid. After crystallization from a chloroform-ether mixture, 0.7 g of the title compound is obtained, m.p. 158°-159° C.
Reaction SMILES: Br[CH:2]([NH:8][C:9](=[O:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:12][OH:13]>>[C:9]([NH:8][CH:2]([NH:12][OH:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:11])[CH3:10]
Reactant: NO
Reactant: CCOC(=O)C(Br)NC(C)=O
Product: CCOC(=O)C(NO)NC(C)=O

Procedure:
Using ethyl 2-bromo-2-acetamidoacetate (2.10 g, 9.37 mmol) and anhydrous NH2OH (0.93 g, 28.00 mmol) gave an oily residue. The residue was purified by flash column chromatography on SiO2 gel (5% MeOH/CHCl3) to give the desired product. The product was recrystallized from EtOH to give a white flaky solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:19]N1C(C)(C)C(=O)N(Cl)C1=O.S(=O)(O)[O-].[Na+]>ClCCl>[NH2:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([S:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:10]=2)[C:5]([Cl:19])=[CH:6][CH:7]=1
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: Nc1cccn2nc(SCc3ccccc3)nc12
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ccc(Cl)n2nc(SCc3ccccc3)nc12
Reaction time: 2 h

Procedure:
A solution of 8-amino-2-benzylthio[1,2,4]triazolo[1,5-a]pyridine (14.0 g, 0.0546 mol) and 1,3-dichloro-5,5-dimethylhydantoin (5.4 g, 0.0273 mol) were combined in 500 mL of dichloromethane and the mixture was heated at reflux with stirring for two hours. Additional 1,3-dichloro-5,5-dimethylhydantoin (5.0 g, 0.025 mol) was added and the reaction was heated with stirring for an additional hour. The reaction mixture was cooled and dilute aqueous sodium bisulfite was added with stirring and allowed to react for an hour. The mixture was then washed with water and the volatiles were removed by evaporation under reduced pressure. The residue obtained was chromatographed on silica gel eluting with dichloromethane to obtain 6.0 g (38 percent of theory) of the title compound as a light tan powder melting at 113°-114° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>C(OCC)(=O)C>[CH2:19]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[F:1])[CH3:20]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-fluoro-5-nitro-benzoic acid (0.269 g, 1.45 mmol) in 3 mL ethanol, was added concentrated sulfuric acid (0.5 ml). The solution was refluxed under argon for 3 hours. The mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo to give pure 2-fluoro-5-nitro-benzoic acid ethyl ester.
Reaction SMILES: [OH-].[Na+].S(=O)(=O)(O)O.[NH2:8][CH2:9][C:10]#[N:11].[CH3:12][O:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>O.C(OCC)(=O)C>[CH3:12][O:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:11][CH2:10][C:9]#[N:8])=[O:20])=[CH:17][CH:16]=1
Reactant: COCc1ccc(C(=O)Cl)cc1
Reactant: N#CCN
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COCc1ccc(C(=O)NCC#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydroxide (18.868, 0.47M) was dissolved in water (150 ml) and added to a stirred mixture of aminoacetonitrile bisulphate (24.23 g, 0.157M) and 4-methoxymethyl benzoyl chloride (29.9 g, 0.157M) in ethyl acetate (150 ml). The reaction was stirred for 21/2 hours at room temperature, the ethyl acetate layer was separated off and the aqueous layer re-extracted with ethyl acetate. The ethyl acetate extracts were combined, dried over magnesium sulphate and evaporated to give a white solid. This was recrystallised from chloroform 80:100 petrol to give white plates, (24.5 gm), mpt 107°-108° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-n2cncn2)cc1F
Temperature: 70 °C
Reaction time: 20 h
Yield: 50.6 %

Procedure:
2,4-Difluoronitrobenzene (8.0 g) was dissolved in N,N-dimethylformamide (110 ml) and the solution was admixed with 1H-1,2,4-triazole (3.47 g) and potassium carbonate (6.95 g) and the mixture was stirred under a nitrogen atmosphere at 70° C. for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the ethyl acetate layers were combined and washed 5 times with water and then with saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1:1.3). A desired fraction was concentrated under reduced pressure and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to yield 1-(3-fluoro-4-nitrophenyl)-1H-1,2,4-triazole (5.29 g) as yellow powdery crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.F[C:18]1[CH:25]=[C:24]([C:26]([NH2:34])([C:28]2[N:29]([CH3:33])[CH:30]=[N:31][CH:32]=2)[CH3:27])[CH:23]=[CH:22][C:19]=1[C:20]#[N:21]>>[NH2:34][C:26]([C:24]1[CH:25]=[CH:18][C:19]([C:20]#[N:21])=[C:22]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)(=[O:10])=[O:9])[CH:3]=2)[CH:23]=1)([C:28]1[N:29]([CH3:33])[CH:30]=[N:31][CH:32]=1)[CH3:27]
Reactant: O=S(=O)(c1cccc(O)c1)N1CCOCC1
Reactant: Cn1cncc1C(C)(N)c1ccc(C#N)c(F)c1
Product: Cn1cncc1C(C)(N)c1ccc(C#N)c(Oc2cccc(S(=O)(=O)N3CCOCC3)c2)c1

Procedure:
Using the methods described in Example 24A, but substituting 3-hydroxybenzenesulfonylmorpholine (0.015 g, 0.061 mmol) and 2-fluoro-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile (as described in Example 24A, Step F), the title compound was prepared.