Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10][N:11]=2)[N:8]=1)#[CH:2].[N-:21]=[N+:22]=[N-:23].[Na+].CN(C=O)C>O>[N:21]1[CH:2]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]3[N:7]([C:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[N:10][N:11]=3)[N:8]=2)[NH:23][N:22]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C#Cc1ccc2nnc(CNC(=O)OC(C)(C)C)n2n1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1nnc2ccc(-c3cnn[nH]3)nn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (6-ethynyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.109 g, 0.399 mmol) and sodium azide (0.0285 g, 0.439 mmol) were dissolved DMF (2 mL) at RT. The reaction mixture was stirred overnight at RT then at 70° C. for 3 h. Water was added at RT and the aqueous layer was extracted with EtOAc and 1-butanol. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][C:8]2=[O:17])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:27][C:28]([F:43])([F:42])[S:29]([NH:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36])(=[O:31])=[O:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:17]=[C:8]1[CH2:9][CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]1[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=2[NH:32][S:29]([C:28]([F:43])([F:27])[F:42])(=[O:31])=[O:30])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1NS(=O)(=O)C(F)(F)F
Reactant: Nc1ccc(CN2C(=O)CCc3ccccc32)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(CN2C(=O)CCc3ccccc32)cc1)c1ccccc1NS(=O)(=O)C(F)(F)F
Reaction time: 16 h

Procedure:
A mixture of 2.52 g of 1-p-aminobenzyl-1,2,3,4-tetrahydro-2-oxoquinoline, 3 ml of triethylamine, 0.5 g of 4-dimethylaminopyridine and 120 ml of methylene chloride is cooled to 5° and a solutoin of 2.88 g of o-trifluoromethanesulfonamidobenzoyl chloride in 20 ml of methylene chloride is added dropwise. The mixture is stirred for a further 16 hours at 20°, evaporated and worked up in conventional manner to give 1,2,3,4-tetrahydro-2-oxo-1-[4-(2-trifluoromethanesulfonamidobenzamido)benzyl]quinoline.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:25])[CH2:6][C:7]1[C:8]([CH3:24])=[N:9][N:10]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[CH3:24][C:8]1[C:7]([CH2:6][C:5]([OH:25])=[O:4])=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:9]=1
Reactant: COC(=O)Cc1c(C)nn(-c2cnccn2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nn(-c2cnccn2)c(-c2ccccc2)c1CC(=O)O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
0.073 g (1.819 mmol) of 2-molar aqueous sodium hydroxide solution was added to 0.165 g (0.455 mmol) of methyl[3-methyl-5-phenyl-1-(pyrazin-2-yl)-1H-pyrazol-4-yl]acetate (see A3) dissolved in 5 ml of methanol, and the mixture was stirred at 20° C. for 1 h. The methanol was removed under reduced pressure and the residue was poured into a mixture of 10 ml of water and 15 ml of dichloromethane. The aqueous phase was extracted with 15 ml of dichloromethane, acidified with concentrated hydrochloric acid (pH=3) and extracted three times with in each case 15 ml of dichloromethane. Drying of the combined organic phases and removal of the solvent under reduced pressure gave 0.080 g (59.7% of theory) of a colorless foamy solid, melting point 125° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.O[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:23][C:22]([F:25])([F:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccccc1C(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (25 g, 124 mmol), 2-hydroxy-benzotrifluoride (22 g, 136 mmol) and triphenylphosphine (39 g, 149 mmol) in THF was added diethyl azodicarboxylate (23.5 mL, 149 mmol) dropwise at 0° C. The mixture was then warmed to room temperature and stirred for 14 h. The mixture was concentrated and diluted with Et2O, washed with 1 N NaOH and water and then dried over Na2SO4. The mixture was concentrated and diluted with Et2O/hexanes (35:65). The precipitated phosphine oxide was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluting with 35% Et2O/hexanes) to give tert-butyl 4-[2-(trifluoromethyl)phenoxy]-piperidine-1-carboxylate as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](B(O)O)=[CH:17][N:16]=1>>[C:9]1([C:6]2[N:7]=[CH:8][C:3]([CH2:2][C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]=[N:16][CH:17]=3)=[CH:4][CH:5]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1cncc2ccccc12
Reactant: BrCc1ccc(-c2ccccc2)nc1
Product: c1ccc(-c2ccc(Cc3cncc4ccccc34)cn2)cc1
Reaction time: 0.5 h

Procedure:
Synthesized using compound 61a (109 mg, 0.44 mmol) and isoquinolin-4-ylboronic acid (114 mg, 0.66 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:1) as eluent. After flash chromatography the product was solved in ethyl acetate and a few drops of conc. HCl and water were added. After stirring for 30 minutes the phases were separated and water phase was neutralized with aqueous Na2CO3-solution (2M). After extraction with ethyl acetate and drying over MgSO4 the solvent was removed under vacuum. Beige solid. Yield: 20 mg, 19%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=4.43 (s, 2H), 7.37-7.54 (m, 4H), 7.59-7.65 (m, 2H), 7.65-7.75 (m, 1H), 7.89-8.07 (m, 4H), 8.48 (s, 1H), 8.65-8.70 (m, 1H), 9.23 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=33.2, 120.3, 123.1, 126.7, 127.2, 128.4, 128.6, 128.6, 128.7, 128.9, 130.7, 133.6, 134.6, 136.7, 139.0, 143.7, 149.7, 152.3, 155.7; (ESI): m/z=296.95 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7](Br)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[CH3:24][OH:25]>[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([O:25][CH3:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CO
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
1-Bromo-6-methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (60 mg, 0.18 mmol) obtained in Step 1 was dissolved in methanol (10 mL), silver nitrate (37.20 mg, 0.22 mmol) was added thereto, stirred for 3 hrs at RT, and filtered. The organic layer was separated, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 14 mg of the titled compound (yield: 24%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N+:11]([O-])=O)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H][H]>[Ni].O1CCOCC1>[Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]([NH2:11])=[CH:6][C:7]=1[NH2:8]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(-c2ccccc2)c(Cl)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: C1COCCO1
Product: Nc1cc(N)c(Cl)c(-c2ccccc2)c1

Procedure:
A solution of 10.00 g. (0.0359 mole) of 2-chloro-3,5-dinitrobiphenyl in 200 ml. of dioxane is hydrogenated at 3 atmospheres of hydrogen using Raney nickel Catalyst. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure. 110 ml. of benzene is added to the residue and this is removed by distillation. The resulting oil is used directly in the following reaction.
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([C:14]1[N:18]=[C:17]([NH2:19])[NH:16][N:15]=1)(=[O:13])=[O:12].[C:22](OCC)(=[O:27])[CH2:23][C:24]([CH3:26])=O>CO>[F:21][C:3]([F:2])([F:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([C:14]1[N:18]=[C:17]2[N:19]=[C:24]([CH3:26])[CH:23]=[C:22]([OH:27])[N:16]2[N:15]=1)(=[O:12])=[O:13]
Reactant: Nc1nc(S(=O)(=O)Nc2ccccc2C(F)(F)F)n[nH]1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Solvent: CO
Product: Cc1cc(O)n2nc(S(=O)(=O)Nc3ccccc3C(F)(F)F)nc2n1
Reaction time: 120 h

Procedure:
A solution of 1 ml of 12N hydrochloric acid in 250 ml of methanol was added to a mixture of 20.0 g (65.1 mmol) of N-(2-trifluoromethylphenyl)-5-amino-1,2,4-triazole-3-sulfonamide and 9.2 ml (72.2 mmol) of ethyl acetoacetate and the mixture heated to reflux with stirring. After about 5 days, most but not all of the starting material was found to have reacted by thin layer chromatrography. The sollution was chilled and the precipitate that formed was collected by filtration, washed with cold methanol and dried to obtain 16.5 g (67.9 percent of theory) of the title compound as a white solid hemihydrate melting at 245°-7° C.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][NH:17][C:16](=[O:20])[CH:15]=2)=[CH:10][CH:9]=1)=[O:5]>C(O)C.CO.[Pd]>[CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]2)=[CH:12][CH:13]=1)=[O:5]
Reactant: Cc1cccc(C)c1C(=O)NCc1ccc(-c2cc[nH]c(=O)c2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Cc1cccc(C)c1C(=O)NCc1ccc(C2CCNC(=O)C2)cc1

Procedure:
To a solution of 2,6-dimethyl-N-(4-(2-oxo-1,2-dihydropyridin-4-yl)benzyl)benzamide (see compound 5 of example 3B) in ethanol/methanol (5:1), 10% Pd/C was added and the mixture was hydrogenated (1 atm) at 23° C. for 12 hours. The catalyst was filtered through celite pad and washed with methanol. Filtrate and washings were combined and the solvent was then concentrated and chromatographed (SiO2, 3-15% EtOAc/MeOH) to provide the title compound. MS found for C21H24N2O2 as (M+H)+ 337.1 1H NMR (400 MHz, dmso-d6): δ: 8.76 (t, J=5.6 Hz, 1H); 7.52 (brs, 1H), 7.27-7.14 (m, 4H); 7.13-6.99 (m, 3H); 4.40 (d, J=6.4 Hz, 2H); 3.23-3.16 (m, 2H); 3003-2.98 (m, 1H); 2.35-2.21 (m 2H); 2.17 (s, 6H); 1.88-1.78 (m, 2H).
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].Cl.NO>C(O)C>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[O:6][N:2]=[CH:3][C:4]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:8][CH:9]=1
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccncc1
Agent: Cl
Agent: NO
Solvent: CCO
Product: Fc1ccc(-c2oncc2-c2ccncc2)cc1
Yield: 97.9 %

Procedure:
A mixture of 3-dimethylamino-1-(4-fluorophenyl)-2-(pyridin-4-yl)-2-propen-1-one (6.15 g) and hydroxylamine hydrochloride (4.75 g) in dry ethanol (40 ml) was refluxed for 20 minutes. The mixture was cooled and concentrated in vacuo. The residue was dissolved in dilute hydrochloric acid and then treated with an aqueous saturated sodium bicarbonate solution. The precipitates were collected by filtration, washed with water, and dried to give 5-(4-fluorophenyl)-4-(pyridin-4-yl)isoxazole (5.35 g)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:35][C:34]4[CH:33]=[N:32][N:31]([CH3:36])[C:30]=4[NH:29][C:28]4[CH:37]=[CH:38][CH:39]=[CH:40][C:27]3=4)=[O:25])=[CH:20][C:19]=2[F:41])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:42]>CO.O1CCOCC1>[ClH:42].[ClH:42].[F:41][C:19]1[CH:20]=[C:21]([C:24]([N:26]2[CH2:35][C:34]3[CH:33]=[N:32][N:31]([CH3:36])[C:30]=3[NH:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])[CH:22]=[CH:23][C:18]=1[O:17][CH2:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(OCCCN3CCN(C(=O)OC(C)(C)C)CC3)c(F)c1)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(OCCCN3CCNCC3)c(F)c1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 4-{3-[2-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-propyl}-piperazine-1-carboxylic acid tert-butyl ester from Example E49.1 (615 mg, 1.09 mmol) in methanol (2 ml) at 0° C. was treated with 4N HCl in dioxan (5 ml). The solution was allowed to warm to room temperature and stirred for 1 h. Solvents were removed in vacuo to give a white foam identified as the title compound (585 mg, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:2]=1.[CH2:16](OC1C=CC(C=O)=CC=1)C1C=CC=CC=1>>[N:1]1[CH:2]=[CH:16][C:4]([CH2:3][O:7][C:8]#[C:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: C(#Cc1ccccc1)Oc1cccnc1
Product: C(#Cc1ccccc1)OCc1ccncc1

Procedure:
Prepared as for 4-(pyridine-3-yloxy)ethynylbenzene, using 4-benzyloxybenzaldehyde.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[CH3:29][O:30][CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:29][O:30][CH2:31][CH2:32][NH:33][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:14]
Reactant: COCCN
Reactant: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCCOC)ccc21
Yield: 37.4 %

Procedure:
1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (64.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (150.0 mg), 2-methoxy-ethylamine (38.0 mg), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 465; and 1H NMR (DMSO-d6, 400 MHz): δ 8.50 (1H, m), 8.25 (1H, br. s), 8.12 (1H, br. s), 7.82-7.78 (2H, m), 7.70-7.68 (1H, m), 7.57-7.54 (1H, m), 4.24 (2H, m), 3.51-3.43 (4H, m), 3.29 (3H, s), 1.35-1.31 (3H, t), —NH proton signal was not observed.
Reaction SMILES: I[CH2:2][CH3:3].[Br:4][C:5]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[C:9]([F:19])[C:8]([OH:20])=[C:7]([CH:21]=[O:22])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:4][C:5]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[C:9]([F:19])[C:8]([O:20][CH2:2][CH3:3])=[C:7]([CH:21]=[O:22])[CH:6]=1
Reactant: O=Cc1cc(Br)c(-c2ccc(F)cc2F)c(F)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1c(C=O)cc(Br)c(-c2ccc(F)cc2F)c1F
Reaction time: 2 h
Yield: 90.5 %

Procedure:
Iodoethane (0.77 g) was added at room temperature to a mixture of 6-bromo-2,2′,4′-trifluoro-3-hydroxybiphenyl-4-carbaldehyde (1.09 g), potassium carbonate (0.91 g), and DMF (20 mL), and the mixture was stirred at 60 C for 2 hours in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The organic layer was separated, washed with water and saturated saline in this order, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.07 g).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[N:5]2[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][N:21]3[CH:25]=[N:24][N:23]=[N:22]3)[C@H:4]2[S:3]1.CN(C)C=O>[Zn].C(O)(=O)C>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][N:21]3[CH:25]=[N:24][N:23]=[N:22]3)[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cn3cnnn3)[C@H]2S1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)Cn3cnnn3)[C@H]2S1
Reaction time: 1.5 h
Yield: 68.1 %

Procedure:
Zinc powder (2.4 g) was added under ice-cooling and stirring to a solution of 2,2,2-trichloroethyl 2-methyl-7-[2-(1H-tetrazol-1-yl)acetamido]-3-cephem-4-carboxylate (2.0 g) in a mixture of anhydrous dimethylformamide (10 ml) and acetic acid (3 ml), and the mixture was stirred for 1.5 hours at the same temperature. After the reaction, zinc powder was filtered off, and the filtrate was extracted by pouring into a mixture of ethyl acetate (50 ml), ice-water and 10% hydrochloric acid (5 ml). The aqueous layer was further extracted with ethyl acetate (10 ml) and the ethyl acetate extract was combined, washed twice with water and dried over magnesium sulfate. After the solvent was distilled off, the residue was crystallized by adding a small amount of ether to give colorless crystals of 2-methyl-7-[2-(1H-tetrazol-1-yl)acetamido]-3-cephem-4-carboxylic acid (0.97 g), mp 202° to 203° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14].O>CN(C=O)C>[C:13]([NH:17][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc2c(NC(C)(C)C)nc(Cl)nc12
Reaction time: 3 h
Yield: 91.3 %

Procedure:
In 3 ml of DMF was dissolved 300 mg (1.4 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and after 150 mg (2.1 mmol) of t-butylamine was added to the resulting solution, the mixture was stirred for 3 hours. Water was added to the reaction mixture, and crystals thus precipitated were filtered to give 327 mg (yield: 93.4%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:21][C@H:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH3:23])=[O:9])[C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)cnc1COc1ccc(Cl)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2COc2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(4-chlorophenoxy)methyl]nicotinic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:16])([CH3:15])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=[O:7])[CH3:2].Cl[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[C:22]([CH3:30])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:16])([CH3:15])[C:6]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)=[CH:12][CH:13]=1)=[O:7])[CH3:2]
Reactant: Cc1cc(CCl)c2ccccc2n1
Reactant: CCOC(=O)C(C)(C)C(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C)C(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Reaction time: 24 h
Yield: 68.2 %

Procedure:
The 3-(4-hydroxy-phenyl)-2,2-dimethyl-3-oxo-propionic acid ethyl ester (0.72 g, 3.07 mmol) was combined with 4-chloromethyl-2-methyl-quinoline (0.69 g, 3.07 mmol) and cesium carbonate (12.0 mmol) in DMSO under nitrogen at room temperature. The reaction was stirred for 24 h, filtered to remove the solids, and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give 2,2-dimethyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-3-oxo-propionic acid ethyl ester (0.82 g, 70%) as a viscous oil. MS found: (M+H)+=392.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16]2([CH3:20])[CH2:19][O:18][CH2:17]2)=[C:4]([O:21][CH3:22])[CH:3]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[N:33]=1)[C:28](O)=[O:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][C:16]2([CH3:20])[CH2:19][O:18][CH2:17]2)[C:28](=[O:29])[C:27]2[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[N:33]=[C:25]([C:24]([F:39])([F:23])[F:38])[CH:26]=2)=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COc1cc(F)ccc1-c1ccncc1NCC1(C)COC1
Product: COc1cc(F)ccc1-c1ccncc1N(CC1(C)COC1)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-(3-methyl-oxetan-3-ylmethyl)-amine and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 16 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100) followed by a second chromatography using preparative HPLC (Gemini NX column) and a gradient of methanol:water (containing 0.1% formic acid) (20:80 to 98:2) as eluant. Colorless solid (12%). MS (ESI): m/z=544.15 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([F:14])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17]CC)=[O:16].[OH-].[Na+].Cl>O1CCCC1.O>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([F:14])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1cnc2c(F)cc(OC)cc2c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(F)c2ncc(C(=O)O)c(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A solution of ethyl 4-bromo-8-fluoro-6-(methoxy)-3-quinolinecarboxylate (12.2 g, 37.3 mmol) in tetrahydrofuran (450 mL) was diluted by addition of a solution of sodium hydroxide 2N (27 mL) in water (75 mL). The reaction mixture was stirred overnight at room temperature then acidified to pH 3 with a solution of hydrogen chloride 5N. The solvents were evaporated to half the volume in vacuo. The reaction mixture was acidified to pH 1 by further addition of hydrogen chloride 5N, cooled to 4° C. for 30 minutes then filtered. The precipitate was dried in vacuo to afford the product as a white solid (10.1 g, 90%); MS (+ve ion electrospray) m/z 301 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:17](=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:17])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(N)cc1
Yield: 50 %

Procedure:
To 4-aminophenylacetic acid (Aldrich, 5 g, 33 mmol) in 50 mL of anhydrous methanol was added 2.5 mL of concentrated sulfuric acid cautiously. The mixture was heated to reflux for 4 h. The reaction was cooled to room temperature and neutralized with sodium carbonate. The volatiles were evaporated on a rotoevaporator and the residue triturated with chloroform (80 mL) and saturated sodium bicarbonate (100 mL). The chloroform layer was separated and filtered through a small pack of silica gel. The solvent was evaporated and the residue purified through vacuum distillation at 130°-150° C. to give 2.7 g (50%) of methyl 4-aminophenylacetate as a light brown syrup.