Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([OH:28])[C:17]3=[C:18]([F:27])[CH:19]=[N:20][C:21]4[CH:22]=[C:23]([F:26])[C:24](=[O:25])[N:15]([C:16]=43)[CH2:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[NH:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>C(O)C>[F:27][C:18]1[CH:19]=[N:20][C:21]2[CH:22]=[C:23]([F:26])[C:24](=[O:25])[N:15]3[CH2:14][C:13]([CH2:12][N:35]4[CH2:36][CH2:37][CH:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:39][CH2:40]4)([OH:28])[C:17]=1[C:16]=23
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCC2(O)Cn3c(=O)c(F)cc4ncc(F)c2c43)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(CC2(O)Cn3c(=O)c(F)cc4ncc(F)c2c43)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of crude [3,8-difluoro-4-hydroxy-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl]methyl 4-methylbenzenesulfonate (1.2 g, 2.79 mmol) in ethanol (40 mL) was treated with sodium carbonate (889 mg, 8.38 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (615 mg, 3.07 mmol). The reaction mixture was stirred at room temperature for 18 hours under argon, evaporated and treated with water (200 mL). The aqueous layer was extracted with a 10% solution of methanol in dichloromethane (3×200 mL) and the combined organic extracts dried over magnesium sulphate and evaporated. The residue was chromatographed eluting with a 0-10% gradient of methanol in dichloromethane affording a yellow solid (1.1 g, 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-])=O)[CH:10]=1)=[O:8])([O-])=O.[O-2].[Ca+2].[H][H]>[Pd].ClCCCl>[NH2:1][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:16])[CH:10]=1)=[O:8]
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: [Ca+2]
Agent: [O-2]
Solvent: ClCCCl
Product: Nc1cccc(C(=O)c2cccc(N)c2)c1
Temperature: 70 °C

Procedure:
To an autoclave there are added 50 g (0.15 moles) of 3,3'-dinitro-4,4'-dichloro benzophenone, 21 g (0.38 moles) of calcium oxide, 1 g of 5% palladium/alumina catalyst (available from Nihon-Engelhardt Co., Ltd.) and 350 ml of 1,2-dichloro ethane. The reaction is carried out for ten hours by introducing hydrogen into the autoclave, with the mixture being stirred at 30°-35° C., to keep the pressure at 10 Kg/cm2.G. After the completion of the reaction, the reaction mixture is heated up to 70° C. and subjected to a hot filtering so as to remove the catalyst and the inorganic salt. On cooling the mixture there are obtained yellow needle-like crystals of 3,3'-diamino benzophenone. The crystals are filtered, washed with 10 ml of 1,2-dichloro ethane and dried. Yield 21.2 g (67%). M.P. 149°-150.5° C. Recrystallization from ethanol gives pure crystals. M.P. 150°-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21]O)[C:9]2=[O:23])[CH:7]=1.P(Cl)(Cl)[Cl:28]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:19])([F:20])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21][Cl:28])[C:9]2=[O:23])[CH:7]=1
Reactant: ClP(Cl)Cl
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(CO)c2cc(C(F)(F)F)ccc21
Solvent: ClCCl
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(CCl)c2cc(C(F)(F)F)ccc21
Reaction time: 0.5 h

Procedure:
To a solution of (S)-3-(5-chloro-2-methoxyphenyl)-1-(hydroxymethyl)-3-fluoro-6-(trifluoromethyl)indolin-2-one ((S)-VI) (64.5 g, 0.166 mol) in CH2Cl2 (700 mL) was added PCl3 (2.0 M in CH2Cl2, 255.0 mL, 0.510 mol) dropwise at 0° C. under N2 over a period of 50 min. The resultant mixture was warmed to rt. and the stirring continued overnight (16 h). The mixture was quenched with ice at 0° C. and the resultant mixture was stirred vigorously for 30 min. The organic layer was separated and the aqueous layer was washed with CH2Cl2. The combined organic layer was washed with brine and dried over Na2SO4. Chromatography (silica gel, EtOAc/Hexanes) provided the title compound as a white dry foam (42.0 g, 62% yield). LC/MS m/e: (no molecular ion), 97% purity. 1H NMR (CDCl3): δ 3.55 (s, 3H), 5.39 (d, J=10.5 Hz, 1H), 5.95 (d, J=11.0 Hz, 1H), 6.76 (dd, J=1.5, 9.0 Hz, 1H), 7.28 (m, 2H), 7.35 (dd, J=1.5, 9.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.78 (dd, J=1.0, 2.5 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([Br:12])[N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]=1[CH2:19]Br)=[O:5])[CH3:2].[CH2:21]([O:23][C:24](=[O:34])[CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:22]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([Br:12])[N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]=1[CH2:19][N:26]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:34])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1c(Br)c(Br)n(-c2ccccc2)c1CBr
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c(Br)c(Br)n1-c1ccccc1)C(=O)OC(C)(C)C

Procedure:
Prepared in analogy to that of Example 1(c) from 4,5-dibromo-2-bromomethyl-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester and tert-butoxycarbonylamino-acetic acid ethyl ester. The title compound, ESI MS (m/z): 609 (M+Na+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][N:31]3[CH2:32][CH2:33][N:28]([C:23]4[N:22]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:29][CH2:30]3)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NOC(CCC=O)C2)cc1OC
Reactant: c1cnc(N2CCNCC2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C2=NOC(CCCN3CCN(c4ncccn4)CC3)C2)cc1OC
Yield: 68.3 %

Procedure:
3-[3-(3,4-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]propanal (24.9 mg, 0.092 mmol), 1-(2-pyrimidyl)piperazine dihydrochloride (20.0 mg, 0.084 mmol), molecular sieve (5 beads), NaBH(OAc)3 (53.6 mg, 0.252 mmol) and diisopropylethylamine (53.9 L, 0.168 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 23.6 mg (68.2%) of the target compound was obtained.
Reaction SMILES: C(/N=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([Cl:14])[C:8]=1[CH2:15][CH3:16])CCC.C(OCC)(=[O:19])C.CCCCCCC>>[Cl:14][C:9]1[C:8]([CH2:15][CH3:16])=[C:7]([C:12]([F:13])=[CH:11][CH:10]=1)[CH:6]=[O:19]
Reactant: CCCC/N=C/c1c(F)ccc(Cl)c1CC
Reactant: CCOC(C)=O
Solvent: CCCCCCC
Product: CCc1c(Cl)ccc(F)c1C=O

Procedure:
3-Chloro-2-ethyl-6-fluoro-benzaldehyde was prepared from butyl-[1-(3-chloro-2-ethyl-6-fluoro-phenyl)-meth-(E)-ylidene]-amine by flash chromatography (silica gel, ethyl acetate/heptane gradient): yellow oil; 1H-NMR (CDCl3): 1.21 (3H, t, CH3), 3.16 (2H, q, CH2), 6.99 (1H, dd, ArH), 7.55 (1H, dd, ArH), 10.45 (1H, s, CH═O).
Reaction SMILES: C1(C)C=CC(S([NH:10][N:11]=[CH:12][C:13](Cl)=[O:14])(=O)=O)=CC=1.[F:17][C:18]1[CH:19]=[C:20]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:21]=[CH:22][C:23]=1/[CH:24]=[CH:25]/[CH2:26][OH:27].CN(C)C1C=CC=CC=1.C(N(CC)CC)C>ClCCl>[N+:11](=[CH:12][C:13]([O:27][CH2:26]/[CH:25]=[CH:24]/[C:23]1[CH:22]=[CH:21][C:20]([NH:28][C:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:38])=[CH:19][C:18]=1[F:17])=[O:14])=[N-:10]
Reactant: Cc1ccc(S(=O)(=O)NN=CC(=O)Cl)cc1
Reactant: O=C(Nc1ccc(/C=C/CO)c(F)c1)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: [N-]=[N+]=CC(=O)OC/C=C/c1ccc(NC(=O)OCc2ccccc2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Glyoxylic acid chloride p-toluenesulfonylhydrazone (2.2 g, 8.5 mmol, prepared as described by C. J. Blankley, F. J. Sauter and H. O. House, Organic Syntheses, Coll. Vol. V, p. 258; John Wiley, New York (1973)) was added to a suspension of benzyl 3-fluoro-4-[(1E)-3-hydroxyprop-1-enyl]phenylcarbamate (2.14 g, 7.1 mmol) in dichloromethane (55 mL). The mixture was cooled to 0° C. and treated with N,N-dimethylaniline (1.0 mL, 7.81 mmol). After 30 minutes, triethylamine (4.9 mL, 35.5 mmol) was added and the mixture stirred 30 minutes at 0° C. and 15 minutes at room temperature. The reaction mixture was then concentrated to about 15 mL and 50 mL of water added. The mixture was extracted with two portions of diethyl ether and the combined organic solutions washed with saturated NaHCO3, brine and dried (MgSO4), filtered and concentrated. Purification by column chromatography (0-25% ethyl acetate-hexane) provided the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:26][CH:27]([CH3:29])[CH3:28]>>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:20][CH2:21]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCNCC3)c2n1
Reactant: CC(C)CI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCN(CC(C)C)CC3)c2n1

Procedure:
Prepared similarly to Example 24 from 2-(butyloxy)-8-(methyloxy)-9-(4-piperidinylmethyl)-9H-purin-6-amine and 1-iodo-2-methylpropane.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([C:10]([O-:12])=O)=[CH:7][CH:6]=1)=[O:4].[K+].CN(C)C=O.S(Cl)([Cl:21])=O>ClCCCl>[Cl:21][C:10]([C:8]1[S:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)=[O:12]
Reactant: COC(=O)c1ccc(C(=O)[O-])s1
Reactant: O=S(Cl)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1ccc(C(=O)Cl)s1
Temperature: 90 °C
Yield: 371.2 %

Procedure:
150 g (749 mmol) of dimethyl thiophene-2,5-dicarboxylate in 1350 mL of toluene was azeotropically distilled at 130° C. to evaporate 150 mL of it. The reaction solution was cooled to an inner temperature of 70° C., then stirred with 300 mL of 2.5 M potassium hydroxide/methanol for 40 minutes and cooled to room temperature, and the precipitated solid was washed with ethyl acetate by filtration and dried under reduced pressure to obtain 160 g of potassium 5-(methoxycarbonyl)-thiophene-2-carboxylate. 100 g (446 mmol) of potassium 5-(methoxycarbonyl)-thiophene-2-carboxylate in 700 mL of 1,2-dichloroethane was mixed with 1.73 mL of N,N-dimethylformamide and heated to 90° C., and 68.9 g (119 mmol) of thionyl chloride was added dropwise. The reaction solution was refluxed for 1 hour and then cooled to room temperature, and the resulting crystals were filtered off with 300 mL of 1,2-dichloroethane. The filtrate was concentrated to dryness to obtain 90.4 g (yield 99%) of methyl 5-(chlorocarbonyl)thiophene-2-carboxylate (TEC).
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:26])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[OH-].[Na+]>CCO>[Br:26][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([OH:7])=[O:5])[N:9]=1
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccccc3)ccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nc(Br)c2cc(Oc3ccccc3)ccc2c1O
Reaction time: 2 h
Yield: 100.2 %

Procedure:
A mixture of 1-Bromo-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (3.52 g, 8.45 mmol; Example A-65 e) aqueous 2N NaOH (50 ml, 100 mmol) and EtOH (50 ml) was refluxed with stirring for 2 h. Then the solution was concentrated in vacuo to ½ of its volume, diluted with water (180 ml), and was acidified by addition of aqueous 6N HCl (20 ml). After stirring at ambient temperature for 30 min the resulting suspension was submitted to vacuum filtration. The filter cake was washed thoroughly with water and dried in vacuo at 70° C. to give the title compound as a white solid (3.05 g); 1H NMR (DMSO-d6): δ=8.33 (d, 1H), 7.20 to 7.61 (m, 7H).
Reaction SMILES: [CH2:1]([C:4]1([CH3:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]1=[O:14])[CH:2]=[CH2:3].[CH3:16]OC(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:16][O:14][C:5]1[C:4]([CH2:1][CH:2]=[CH2:3])([CH3:15])[C:13]2[C:8]([CH2:7][CH:6]=1)=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: C=CCC1(C)C(=O)CCc2ccccc21
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: C=CCC1(C)C(OC)=CCc2ccccc21
Temperature: 25 °C
Yield: 73 %

Procedure:
To a solution of Example 123A (10.1 g, 50.5 mmol), trimethylorthoformate (20 mL), p-toluenesulfonic acid monohydrate (60 mg, 0.315 mmol) in methanol (100 mL) was heated at 60 C for 2 hours. After cooling to room temperature, the solution was concentrated in vacuo, and the resultant residue was purified by column chromatography employing 70-230 mesh silica gel eluting with hexane to provide the title compound as a colorless oil (7.8 g, 73%). 1H NMR (300 MHz, DMSO-d6): δ 1.38 (s, 3H), 2.44 (dd, J=13.8, 7.4 Hz, 1H), 2.65 (dd, J=13.6, 7.0 Hz, 1H), 3.41 (d, J=3.7 Hz, 2H), 3.54 (s, 3H), 4.75 (m, 2H), 4.90 (t, J=3.7 Hz, 1H), 5.24 (m, 1H), 7.10 (m, 2H), 7.19 (m, 1H), 7.40 (d, J=7.8 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18](Br)=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27](C([Sn])=C(CCCC)CCCC)[CH2:28]CC.C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18]([CH:27]=[CH2:28])=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2cccc3cncc(Br)c23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: C=Cc1cncc2cccc(O[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c12

Procedure:
A solution of Intermediate 121 (500 mg), tri(n-butyl)vinyltin (518 μl, Tokyo Kasei Kogyo), tetrakis(triphenylphosphine)palladium(0) (28.1 mg) and 2,6-di-tert-butyl-p-cresol (3.2 mg, Tokyo Kasei Kogyo) in toluene (10 ml) was stirred at 110° C. for 3 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (409.5 mg).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].Cl[CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1/[CH:20]=[CH:21]/[C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH2:1]([N:4]([CH2:5][CH2:6][CH3:7])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1/[CH:20]=[CH:21]/[C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1)[CH2:2][CH3:3]
Reactant: ClCCCCOc1ccccc1/C=C/c1nc2ccccc2s1
Reactant: CCCNCCC
Product: CCCN(CCC)CCCCOc1ccccc1/C=C/c1nc2ccccc2s1
Yield: 35 %

Procedure:
Reaction of this product (5.0 g, 14.5 mmol) with dipropylamine produced 2.1 g (35% yield) of the named compound as the HCl salt, mp 155°-156° C. IR(KBr): 3400, 1600 cm-1. MS: 409(MH+). 1H NMR (CD3OD): δ 8.19-6.99 (m, 10H), 4.10 (t, J=5.2 Hz, 2H), 3.12(m, 6H), 1.85(m, 8H), 1.02 (m, 6H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][C:9]2[C:14]3=[C:15]([CH3:19])[C:16]([OH:18])=[CH:17][N:13]3[N:12]=[CH:11][N:10]=2)=[CH:6][N:5]=[C:4]2[NH:20][CH:21]=[CH:22][C:3]=12.[CH3:23][C:24]([OH:27])(C)[CH3:25]>C(N(CC)CC)C>[F:1][C:2]1[C:7]([O:8][C:9]2[C:14]3=[C:15]([CH3:19])[C:16]([O:18][CH2:23][C@H:24]([OH:27])[CH3:25])=[CH:17][N:13]3[N:12]=[CH:11][N:10]=2)=[CH:6][N:5]=[C:4]2[NH:20][CH:21]=[CH:22][C:3]=12
Reactant: Cc1c(O)cn2ncnc(Oc3cnc4[nH]ccc4c3F)c12
Reactant: CC(C)(C)O
Solvent: CCN(CC)CC
Product: Cc1c(OC[C@@H](C)O)cn2ncnc(Oc3cnc4[nH]ccc4c3F)c12
Temperature: 80 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
An oven dried sealed tube was charged with 4-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol (Example 5) (7.5 mg, 0.025 mmol), t-BuOH (0.25 mL), 0.5M of a solution of triethylamine in t-BuOH (5 μL, 0.0025 mmol) and R-(+)-propylene oxide (21 μL, 0.300 mmol). The tube was sealed and the mixture was stirred at 80° C. for 1 h. The reaction mixture was cooled and concentrated in vacuo. The crude material was purified by preparative HPLC to afford the title compound (5 mg, 56%) as a off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.17 (1H, s), 8.31 (1H, d, J=9.6 Hz), 7.95 (1H, s), 7.93 (1H, s), 7.61 (1H, t, J=3.0 Hz), 6.59 (1H, dd, J=1.9, 3.4 Hz), 4.91 (1H, d, J=4.8 Hz), 4.02-3.94 (1H, m), 3.92-3.83 (2H, m), 2.42 (3H, s), 1.16 (3H, d, J=6.3 Hz). LCMS: (M+H)+=358, (M−H)−=356.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([CH:38]=[C:39]([C:41]([N:43]4[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]4)=[O:42])[CH:40]=3)[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[C:21]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:22]([CH:30]=[CH:31][CH:32]=3)[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:9][C:4]=2[O:3][CH2:2]1.[C:49](OC(=O)C)(=[O:51])[CH3:50].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:49]([N:46]1[CH2:45][CH2:44][N:43]([C:41]([C:39]2[CH:38]=[C:12]([CH:11]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH:40]=2)[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[C:21]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:22]([CH:30]=[CH:31][CH:32]=2)[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:42])[CH2:48][CH2:47]1)(=[O:51])[CH3:50]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCNCC3)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)c2cc(OCCCCCCc3cccc(OCCCC(=O)O)c3CCC(=O)O)cc(-c3ccc4c(c3)OCO4)c2)CC1
Reaction time: 8 h

Procedure:
4-[3-{6-[3-Benzo[1,3]dioxol-5-yl-5-(piperazine-1-carbonyl)-phenoxy]-hexyl}-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (0.29 mmol), acetic anhydride (1.2 eq.), triethylamine (3 eq.) were combined in dichloromethane (2 mL) and stirred overnight. Then the reaction mixture was diluted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. The organic extract was concentrated under reduced pressure and purified by reverse-phase HPLC to yield the title compound.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[O:5]1[CH:7]([CH2:8][O:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH2:6]1>C(O)C>[CH:1]([NH:4][CH2:6][CH:7]([OH:5])[CH2:8][O:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)([CH3:3])[CH3:2]
Reactant: c1csc(OCC2CO2)n1
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)NCC(O)COc1nccs1

Procedure:
This example illustrates further methods according to the invention of preparing the compounds of formula I of the invention. In this example 0.6 g. of isopropyl amine is added to a solution of 0.3 g. of 1,2-epoxy-3-(thiazol-2-oxy)-propane in 20 ml. of anhydrous absolute ethanol at 20°C. The resulting mixture is monitored by thin-layer chromatographic analysis and allowed to stand until conversion of 1,2-epoxy-3-(thiazol-2-oxy)-propane is essentially complete. The mixture is then evaporated to dryness yielding a crude residue of 1-isopropylamino-3-(thiazol-2-oxy)-2-propanol which is then further purified by thin-layer chromatography.
Reaction SMILES: C([O:5][C:6]([C:8]1([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:43])[CH:20]([C:27]3[N:28]([C:36]4[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=4)[N:29]=[C:30]4[C:35]=3[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:14]([F:44])[CH:13]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C>C(O)=O>[Cl:42][C:39]1[CH:38]=[CH:37][C:36]([N:28]2[C:27]([CH:20]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:19]([NH:18][C:15]3[CH:16]=[CH:17][C:12]([O:11][C:8]4([C:6]([OH:7])=[O:5])[CH2:10][CH2:9]4)=[CH:13][C:14]=3[F:44])=[O:43])=[C:35]3[C:30]([CH2:31][CH2:32][CH2:33][CH2:34]3)=[N:29]2)=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)C1(Oc2ccc(NC(=O)C(c3c4c(nn3-c3ccc(Cl)cc3)CCCC4)C3CCCCC3)c(F)c2)CC1
Solvent: O=CO
Product: O=C(Nc1ccc(OC2(C(=O)O)CC2)cc1F)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 22, (−)-1-(4-{2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-acetylamino}-3-fluoro-phenoxy)-cyclopropanecarboxylic acid tert-butyl ester (example 21.5) was treated with formic acid to obtain the title compound as pink foam. MS: m/e=566.3 [M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([O:12][CH2:13][C:14]([F:19])([F:18])[CH:15]([F:17])[F:16])[CH:3]=1.[B:20]1(B2OC(C)(C)C(C)(C)O2)[O:24]C(C)(C)C(C)(C)[O:21]1.C([O-])(=O)C.[K+].I(O)(=O)(=O)=O>COC1CCCC1.[Pd](Cl)Cl.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].O>[F:18][C:14]([F:19])([CH:15]([F:17])[F:16])[CH2:13][O:12][C:4]1[CH:3]=[C:2]([B:20]([OH:24])[OH:21])[CH:7]=[CH:6][C:5]=1[C:8]([F:11])([F:10])[F:9]
Reactant: FC(F)C(F)(F)COc1cc(Br)ccc1C(F)(F)F
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: COC1CCCC1
Product: OB(O)c1ccc(C(F)(F)F)c(OCC(F)(F)C(F)F)c1
Temperature: 115 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
A solution of 4-bromo-2-(2,2,3,3-tetrafluoro-propoxy)-1-trifluoromethyl-benzene (482 mg, 1.36 mmol), pinacol diborane (379 mg, 1.49 mmol), palladium dichloride-diphenylphosphinoferrocene (111 mg, 0.136 mmol) and potassium acetate (400 mg, 4.08 mmol) in cyclopentyl methyl ether (2.41 mL) was heated with stirring at 115° C. for one hour in a nitrogen atmosphere. After cooling to room temperature, water (1 mL) was added to the reaction mixture, and the upper cyclopentyl methyl ether layer was extracted. Methanol (1 mL) was added to the organic layer. Periodic acid (1.24 g, 5.44 mmol) was added at 0° C., and the mixture was warmed to room temperature and stirred for one hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→1:1) and further treated with hexane to give 3-(2,2,3,3-tetrafluoro-propoxy)-4-trifluoromethylphenylboronic acid as a pale brown solid (260 mg, 60%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:22]([NH:23][CH:24]=[O:25])[C:21](=[O:26])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10].[I-:27].[Na+]>CC(C)=O>[CH:24]([NH:23][CH:22]1[C:21](=[O:26])[N:7]2[C:8]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:10])=[C:3]([CH2:2][I:27])[CH2:4][S:5][C@H:6]12)=[O:25]
Reactant: [I-]
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC=O)C(=O)N23)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(CI)CS[C@@H]3C(NC=O)C(=O)N23)cc1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
14.5 g (36.6 mM) of p-methoxybenzyl 3-chloromethyl-7-formamido-3-cephem-4-carboxylate was dissolved in 360 ml of acetone. Under cooling with ice, 13.7 g (91.4 mM) of sodium iodide was added to this solution, and the mixture was stirred for 30 minutes, and further at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the oily residue was dissolved by an addition of ethyl acetate. The organic layer was washed sequentially with water, a saturated sodium thiosulfate aqueous solution and a saturated sodium chloride aqueous solution. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The oily residue was subjected to silica gel column chromatography (Wakogel C-300, eluted with 20% ethyl acetate-chloroform), and the fraction containing the desired product was concentrated to obtain 15.7 g (yield: 87.9%) of p-methoxybenzyl 7-formamido-3-iodomethyl-3-cephem-4-carboxylate.