Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([C:29]([OH:31])=[O:30])=[CH:21]2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([C:29]([O-:31])=[O:30])=[CH:21]2)[CH2:17][CH2:16]1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC2(C=C(C(=O)O)c3ccccc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C([O-])C1=CC2(CCNCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2 mL) was added to a stirred solution of 1′-(tert-butyoxycarbonyl)spiro[indene-1,4′-piperidine]-3-carboxylic acid (C4) (0.25 g, 0.76 mmol) in dichloromethane (5 mL) and the solution was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and dried under high vacuum for 18 h to provide spiro[indene-1,4′piperidine]-3-carboxylate (D1) as an oil (0.26 g, quantitative, TFA salt). LC/MS (10-90% over 3 min with 0.9% FA) m/z 230.3 (M+1), Rt 1.3 minutes. 1HNMR (500 MHz, DMSO-d6): 12.91 (brs, 1H), 7.95 (s, 1H), 7.88 (d, 1H), 7.35 (m, 3H), 3.31-3.43 (m, 4H), 2.27 (m, 2H), 1.42 (m,2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14]>C(Cl)Cl>[Cl:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:14]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: Nc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a stirred solution of aniline (0.4 mL, 4.30 mmol) in anhydrous CH2Cl2 (10 mL) was added 3-chloromethylbenzoyl chloride (360 mg, 1.90 mmol). The reaction mixture was allowed to stir at room temperature overnight. The solvent was removed under reduced pressure. Purification of the residue on strong acid ion exchange resin column (elution with methanol) afforded the title compound (400 mg, 86%) as a white solid.
Reaction SMILES: C(OC([NH:11][C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[CH:15]=[CH:14][CH:13]=1)=O)C1C=CC=CC=1.[OH-].[Na+]>C(O)C>[NH2:11][C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Nc1cccc2c1C(=O)c1ccccc1C2=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Yield: 96.1 %

Procedure:
0.50 g of 1-benzyloxycarbonylaminoanthraquinone, 25 ml of ethanol and 25 ml of 50% strength aqueous sodium hydroxide solution were heated under reflux for 6 hours and the solution was then concentrated in vacuo. The residue was taken up in chloroform/water, the phases were separated and the organic phase was washed twice with water. The organic phase was concentrated in vacuo and 0.30 g of 1-aminoanthraquinone (99% pure; 95% of theory) was obtained.
Reaction SMILES: C1(C)C=CC(S(CC[O:12][C:13](=[O:54])[CH2:14][O:15][C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([S:23]([N:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=[C:27]3[S:35]([CH2:37][C:38]3[C:43]([CH3:44])=[C:42]([O:45][CH2:46][C:47]([F:50])([F:49])[F:48])[CH:41]=[CH:40][N:39]=3)=[O:36])(=[O:25])=[O:24])=[C:18]([CH:51]([CH3:53])[CH3:52])[CH:17]=2)(=O)=O)=CC=1.C([O-])(O)=O.[Na+:60]>CC#N.O>[Na+:60].[CH3:44][C:43]1[C:38]([CH2:37][S:35]([C:27]2[N:26]([S:23]([C:19]3[C:20]([CH3:22])=[CH:21][C:16]([O:15][CH2:14][C:13]([O-:54])=[O:12])=[CH:17][C:18]=3[CH:51]([CH3:53])[CH3:52])(=[O:24])=[O:25])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[N:28]=2)=[O:36])=[N:39][CH:40]=[CH:41][C:42]=1[O:45][CH2:46][C:47]([F:49])([F:48])[F:50]
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)COc2cc(C)c(S(=O)(=O)n3c(S(=O)Cc4nccc(OCC(F)(F)F)c4C)nc4ccccc43)c(C(C)C)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(OCC(=O)[O-])cc(C(C)C)c1S(=O)(=O)n1c(S(=O)Cc2nccc(OCC(F)(F)F)c2C)nc2ccccc21
Temperature: 65 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a solution of 4-[2-{3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-methanesulfinyl}-benzimidazole-1-sulfonyl]-3-isopropyl-5-methylphenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 68, 1.6 g, 1.95 mmol) in 15 mL of CH3CN was added the solution of NaHCO3 (200 mg, 2.34 mmol, 1.2 eq) in 8 mL of H2O. The mixture was heated to 65° C. for 1.5 h. Thereafter all volatile materials were removed under vacuum, the mixture was washed with ether (2×), and then the aqueous layer was lyophilized overnight. The solid was dissolved in 110 mL of ether-EtOAc (10:1), and then the mixture was filtered to remove insoluble material. The filtrate was concentrated and the residual oil was dissolved in 10 mL of ether-EtOAc (10:1). Hexane was added to the mixture to precipitate a white solid. The precipitate was filtered, washed with hexane, and dried under vacuum to yield 1.0 g (77%) of 4-[2-{3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-methanesulfinyl}-benzimidazole-1-sulfonyl]-3-isopropyl-5-methylphenoxyacetic acid sodium salt (Compound 39) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][NH:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:35]([CH3:34])[CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CNCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N(C)CCc4ccccc4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and N-methyl-2-phenylethylamine. ES-MS m/e (%): 504 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13](Cl)=[O:14].[NH2:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([F:30])([F:28])[F:29])=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Reactant: Nc1ccnc2cc(C(F)(F)F)ccc12
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1onc(-c2ccccc2)c1C(=O)Nc1ccnc2cc(C(F)(F)F)ccc12
Temperature: 70 °C
Yield: 55.8 %

Procedure:
5-Methyl-3-phenylisoxazole-4-carbonyl chloride (100 mg) and 4-amino-7-trifluoromethylquinoline (250 mg) were dissolved in dichlorormethane (5 mL) and pyridine (0.3 mL). The reaction solution was heated at 70° C. overnight and then diluted with ethyl acetate (60 mL). The organic solution was washed with water (60 mL), dried, evaporated and purified by flash column chromatography (EtOAc/hexanes=1/6) to give 5-methyl-3-phenyl-N-(7-trifluoromethyl-4-quinolinyl)-4-isoxazolecarboxamide (100 mg) as a white solid. 1H NMR (CDCl3): δ 2.91 (s, 3H), 7.33-7.69 (m, 9H), 8.39 (s, 1H, NH), 8.99 (d, J=5.1 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ-63.26; LCMS: ret. time: 34.04 min.; purity: 98.90%; MS (m/e): 398.77 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([F:20])=[CH:15][N:14]=1.CO>O>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[NH:8][C:4]=3[CH:3]=2)[C:16]([F:20])=[CH:15][N:14]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Solvent: O
Solvent: CO
Product: O=c1[nH]c2ccc(Nc3nc(Cl)ncc3F)cc2[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70 %

Procedure:
To a vial with 5-amino-1H-benzo[d]imidazol-2(3H)-one (298.3 mg, 2.0 mmol) and 2,4-dichloro-5-fluoropyrimidine (434.1 mg, 2.6 mmol), MeOH (8 mL) and H2O (2 mL) were added. The turbid solution was stirred at rt for 3 days. Precipitate from reaction mixture was collected by filtration, and washing with EtOAc (3 mL×2), and was further dried in vacuo. 5-(2-Chloro-5-fluoropyrimidin-4-ylamino)-1H-benzo[d]imidazol-2(3H)-one was obtained as an off-white solid: 390.3 mg (70% yield); 1H NMR (300 MHz, DMSO) δ 10.69 (s, 1H), 10.63 (s, 1H), 9.87 (s, 1H), 8.27 (d, J=3.6, 1H), 7.35 (d, J=1.9, 1H), 7.18 (dd, J=1.9, 8.3, 1H), 6.93 (d, J=8.3, 1H); LCMS (M+) m/z 279.80.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: Nc1ccccn1
Reactant: COC(=O)CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CCCCNc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a solution of methyl 5-oxopentanoate (3.0 g, 23 mmol) in methylene chloride (75 mL) was added 2-aminopyridine (2.38 g, 25.3 mmol). The mixture was stirred at room temperature for 30 minutes. Then, the sodium triacetoxy borohydride (7.31 g, 34.5 mmol) was added and the mixture was stirred at room temperature for 4.5 hours. A saturated solution of sodium bicarbonate (40 mL) was added and the reaction mixture was extracted with ether (4×30 mL). The organic layer was washed with 0.1N NaOH, water (2×40 mL), dried (MgSO4) and concentrated. The residue was purified by flash chromatography 1:1 (Acetone: methylene chloride) to obtain 2.31 g (48%) of the product. 1H NMR (CDCl3) 8.09–8.06 (m, 1H), 7.42–7.38 (m, 1H), 6.59–6.52 (m, 1H), 6.37 (d, J=9 Hz, 1H), 4.52 (br s, 1H), 3.68 (s, 3H), 3.29 (q, J=6 Hz, 2H), 2.40–2.31 (m, 2H), 1.8–1.61 (m, 4H).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([CH:45]=2)[C:41]([NH:43][CH3:44])=[O:42])=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([CH:45]=2)[C:41]([NH:43][CH3:44])=[O:42])=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CNC(=O)c1cncc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=O)c1cncc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)c1
Yield: 42.3 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 5-{4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl}-N-methylnicotinamide (1.44 g) and pyridine hydrochloride (466 mg), the title compound (360 mg) was obtained as a colorless amorphous powder.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=4)[N:22]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.FC(F)(F)C1[N:36]2[N:37]=[C:38](N3CCC(C4C=CC(O)=CC=4)CC3)[CH:39]=[CH:40]C2=NN=1>>[N:37]1([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[CH:19][C:20]5[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=5)[N:22]=4)[CH2:13][CH2:12]3)=[CH:7][CH:6]=2)[CH:38]=[CH:39][CH:40]=[N:36]1
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCC(c4ccc(OCCBr)cc4)CC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCC(c4ccc(OCCn5cccn5)cc4)CC3)nn12

Procedure:
The starting 6-[4-[4-(2-bromoethoxy)phenyl]piperidin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was obtained in 29% yield by an analogous method to Example 847, preparation of starting materials, starting from 4-[4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-1-yl]phenol (obtained as described in Example 513, preparation of starting materials).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC.[C:47]([OH:51])(=[O:50])[CH:48]=[CH2:49]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:49]=[CH:48][C:47]([OH:51])=[O:50])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Nc1ccc(I)cc1)c1ccccc1
Reactant: C=CC(=O)O
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)C=Cc1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 100 °C
Yield: 98.4 %

Procedure:
To a solution of 28 (500 mg, 1.39 mmol), in DMF (10 mL) at room temperature were added tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3; 38 mg, 1.67 mmol), tri-o-tolylphosphine (P(o-tol)3, 25 mg, 0.83 mmol), Et3N (483 μL, 3.48 mmol) and finally acrylic acid (84 μL, 1.67 mmol). The resulting solution was degassed and purged several times with N2 then heated overnight at 100° C. The solution was filtrated through a Celite pad with a fritted glass funnel then the filtrate was evaporated. The residue was purified by flash chromatography using CH2Cl2/MeOH (95:5) as solvent mixture yielding the title compound 35 (415 mg, 99%) as yellowish solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH3:54][O:55][C:56](=[O:66])[CH2:57][CH2:58][CH2:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1.Br[C:68]1[CH:73]=[CH:72][C:71]([C:74]([F:77])([F:76])[F:75])=[CH:70][CH:69]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:54][O:55][C:56](=[O:66])[CH2:57][CH2:58][CH2:59][CH:60]1[CH2:65][CH2:64][N:63]([C:68]2[CH:73]=[CH:72][C:71]([C:74]([F:77])([F:76])[F:75])=[CH:70][CH:69]=2)[CH2:62][CH2:61]1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: COC(=O)CCCC1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CCCC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
A mixture of palladium (II) acetate (42 mg; 0.185 mmol), (±)-2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (170 mg; 0.275 mmol), cesium carbonate (867 g; 2.66 mmol) in dioxane (5 mL) is placed in an ultrasonic bath for 30 minutes. 4-Piperidin-4-yl-butyric acid methyl ester hydrochloride (290 mg; 1.33 mmol, prepared in accordance with Example 131) and 1-bromo-4-trifluoromethyl-benzene (299 mg; 1.33 mmol) are then added and the reaction mixture is stirred for 2 hours under reflux. After dilution with ethyl acetate, the mixture is filtered and the filtrate concentrated under high vacuum. The obtained residue is purified by column chromatography on silica gel (hexanes/dichloromethane 50:50 v/v to 100) to afford the desired compound (284 mg; 0.86 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][C:8]#[N:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].Cl.[NH2:17][OH:18].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5](/[CH:6]=[CH:7]/[C:8](=[N:17][OH:18])[NH2:9])=[CH:4][C:3]=1[C:12]([F:13])([F:14])[F:15]
Reactant: N#CC=Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(/C=C/c1ccc(Cl)c(C(F)(F)F)c1)=NO
Yield: 40.1 %

Procedure:
12.1 g (0.05 mol) of 4-chloro-3-trifluoromethylcinnamonitrile are added to a solution consisting of 7.2 g (0.10 mol) of hydroxylamine hydrochloride and 7.3 g (0.10 mol) of sodium carbonate in 100 ml of water and 100 ml of ethanol. The mixture is heated at reflux temperature until the reaction is complete (24 hours) and the whole batch is subsequently stirred into 250 ml of water. The solid material which separates off during this process is filtered off with suction, washed with a little water and dried. 5.3 g (39.3% of theory) of (E)-4-chloro-3-trifluoromethylcinnamamide oxime are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH2:16][CH2:17]O)[C:13]2[C:19]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][C:21]([F:23])=[CH:22][C:12]=2[N:11]=1.CS(Cl)(=O)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2=[N:11][C:12]3[C:13](=[C:19]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH:20]=[C:21]([F:23])[CH:22]=3)[N:14]2[CH2:15][CH2:16][CH2:17]1
Reactant: CCN(CC)c1cc(F)cc2nc(Nc3ccc(Cl)cc3Cl)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCN(CC)c1cc(F)cc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reaction time: 2.5 h
Yield: 92.3 %

Procedure:
To a stirred solution of 3-{2-[(2,4-dichlorophenyl)amino]-7-(diethylamino)-5-fluoro-1H-benzimidazol-1-yl}propan-1-ol (Reference example 176, 170 mg, 0.400 mmol) in pyridine (2 mL) was added methanesulfonyl chloride (61.9 μL, 0.800 mol) at 0° C. After being stirred for 2.5 h, the reaction mixture was quenched with aqueous sodium hydrogen carbonate, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound as a colorless solid (150 mg, 0.369 mmol, 92%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][C:2]1[C:11]([NH:12][C:13]([N:35]2[CH2:34][CH2:33][N:32]([C:26]3[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=3)[CH2:37][CH2:36]2)=[O:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc4ccccc4nc3C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Phenyl N-(2-methylquinolin-3-yl)carbamate(140 mg, 0.5 mmol) and 1-(3,5-dimethoxyphenyl)piperazine(112 mg, 0.5 mmol) were dissolved in tetrahydrofuran and DBU(117 mg, 0.75 mmol) was added and then the mixture was stirred at room temperature for 2 hrs. The above solution was concentrated under the reduced pressure to remove tetrahydrofuran and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][S:4]([CH2:7][CH:8]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[C:9]([OH:11])=O)(=[O:6])=[O:5].[NH2:22][CH:23]([CH2:37][CH3:38])[C@@H:24]([C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:27]=1)[OH:25]>>[CH3:21][CH:2]([CH3:1])[CH2:3][S:4]([CH2:7][C@H:8]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[C:9]([NH:22][C@H:23]([C:24]([C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:27]=1)=[O:25])[CH2:37][CH3:38])=[O:11])(=[O:5])=[O:6]
Reactant: CCC(N)[C@H](O)c1nc(-c2ccccc2)no1
Reactant: CC(C)CS(=O)(=O)CC(CC(=O)N1CCOCC1)C(=O)O
Product: CC[C@H](NC(=O)[C@@H](CC(=O)N1CCOCC1)CS(=O)(=O)CC(C)C)C(=O)c1nc(-c2ccccc2)no1

Procedure:
It is similarly prepared according to general procedure given for Example 2 above but using 2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyric acid and (S)-2-Amino-1-(3-phenyl-1,2,4-oxadiazol-5-yl)-butan-1-ol.
Reaction SMILES: [OH:1][C:2]1[CH:30]=[C:29]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][C@@H:10]([C:12]([NH:14][C@H:15]([C:26]([OH:28])=[O:27])[CH2:16]C2C3C(=CC=CC=3)NC=2)=[O:13])[NH2:11])=[CH:4][CH:3]=1.C(O)(=[O:33])C>Cl>[OH:1][C:2]1[CH:30]=[C:29]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][C@@H:10]([C:12]([NH:14][C@H:15]([C:26]([OH:28])=[O:27])[CH2:16][OH:33])=[O:13])[NH2:11])=[CH:4][CH:3]=1
Reactant: N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC(=O)O
Agent: Cl
Product: N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)N[C@@H](CO)C(=O)O

Procedure:
3.4 g (6.8 mmol) of the derivative obtained above according to (b) are dissolved in 25 ml of acetic acid saturated with hydrochloric acid, the solution is stirred for a few hours at ordinary temperature, the product is then precipitated in excess ethyl ether and filtered off and the precipitate is dried to give the title derivative in the pure state, which is identical to the product obtained according to Example 16.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[CH:9]=[C:8]([C:18]([OH:20])=O)[C:7]=2[C:6]([CH3:21])=[N:5]1)([CH3:3])[CH3:2].[NH2:22][CH2:23][C:24]1[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=1[CH3:30]>>[CH3:30][C:29]1[CH:28]=[C:27]([CH3:31])[NH:26][C:25](=[O:32])[C:24]=1[CH2:23][NH:22][C:18]([C:8]1[C:7]2[C:6]([CH3:21])=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:12]=2[CH:11]=[C:10]([C:13]2[CH:14]=[N:15][NH:16][CH:17]=2)[CH:9]=1)=[O:20]
Reactant: Cc1nn(C(C)C)c2cc(-c3cn[nH]c3)cc(C(=O)O)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cn[nH]c3)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The title compound was prepared from 1-isopropyl-3-methyl-6-(1H-pyrazol-4-yl)-1H-indazole-4-carboxylic acid and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (0.059 g, 0.387 mmol) in the same manner as described for example 80 (step c) wherein the contents were stirred at RT for 5 h. The product was collected as a pale yellow solid (30 mg, 20%). 1H NMR (DMSO-d6, 400 MHz): 1.563 (d, J=6.8 Hz, 6H), 2.207 (s, 3H), 2.455 (s, 3H), 2.556 (s, 3H), 4.616 (d, J=6 Hz, 2H), 4.781-4.798 (m, 1H), 5.899 (s, 1H), 7.236 (s, 1H), 7.488 (s, 1H) 7.522 (s, 1H), 7.797 (d, J=9.6 Hz, 2H). LCMS (ES+) m/z: 419.45.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18][OH:19])[CH2:16][S:17][C@H:12]23)=[O:9])=[CH:4][S:3]1.[CH2:25]=[C:26]1[O:30][C:28](=[O:29])[CH2:27]1>>[NH:1]=[C:2]1[NH:6][C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18][O:19][C:28](=[O:29])[CH2:27][C:26](=[O:30])[CH3:25])[CH2:16][S:17][C@H:12]23)=[O:9])=[CH:4][S:3]1
Reactant: N=c1[nH]c(CC(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CO)CS[C@H]23)cs1
Reactant: C=C1CC(=O)O1
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3csc(=N)[nH]3)[C@H]2SC1

Procedure:
A process as claimed in claim 17, wherein 7β-[2-(2-imino-4-thiazolin-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid or its salt is reacted with diketene to produce 7β-[2-(2-imino-4-thiazolin-4-yl)-acetamido]-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid or its salt.