Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[C:23]([C:25]([NH:27][C:28]4[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=4[F:35])=[O:26])[CH:22]=[CH:21][C:20]=3[F:36])[CH:15]=[CH:14][N:13]=2)[NH:9][CH:8]=1)=[O:6].C(N(CC)C(C)C)(C)C.Br[CH2:47][C:48]([O:50][CH3:51])=[O:49].O>CN(C=O)C>[F:36][C:20]1[CH:21]=[CH:22][C:23]([C:25]([NH:27][C:28]2[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=2[F:35])=[O:26])=[CH:24][C:19]=1[O:18][C:16]1[CH:15]=[CH:14][N:13]=[C:12]([C:10]2[NH:9][CH:8]=[C:7]([C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:47][C:48]([O:50][CH3:51])=[O:49])=[O:6])[CH:11]=2)[CH:17]=1
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCN)c[nH]4)c3)c2)c1
Reactant: COC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CNCCNC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-(2-aminoethyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide (80 mg, 0.16 mmol) in 10 ml of anhydrous DMF, were added N,N-diisopropylethylamine (60 mg, 0.47 mmol) and methyl bromoacetate (30 mg, 0.20 mmol). The mixture was stirred at room temperature for 1 hour and poured into 100 ml of water. The precipitates were filtered, washed with water, and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with a gradient of 3˜5% of methanol in chloroform to give methyl ({2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]ethyl}amino)acetate as white solid. Yield: 38 mg, 41%.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])C.CC([O-])(C)C.[K+].O.OS(O)(=O)=O>C1COCC1>[CH2:16]([CH:13]([CH2:14][CH3:15])[CH2:12][C:6]1([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)[CH3:17]
Reactant: CCOC(=O)C1(CC(CC)CC)CCCCC1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)CC1(C(=O)O)CCCCC1
Temperature: 54 °C
Reaction time: 20 h
Yield: 98.9 %

Procedure:
1-(2-Ethyl-butyl)-cyclohexanecarboxylic acid ethyl ester (2.0 g, 8.32 mmol) was added dropwise under stirring to a solution of KOtBu (3.735 g, 33.3 mmol) in THF (15 mL) containing a small amount of water (225 mg, 12.5 mmol). The mixture was stirred 20 h at 54° C., cooled to room temperature, slowly poured onto a mixture of ice and 4N H2SO4 and extracted with DCM (2×150 mL) after adjusting to pH 1. The organic phases were washed with diluted aq. NaCl (100 mL), combined, dried over sodium sulfate and concentrated to afford 1.748 g (99%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid, purity 95.2% (GC with internal standard).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:25][C:26]3[NH:27][CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[NH:31]1[CH:35]=[CH:34][C:33]([CH:36]=O)=[N:32]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH2:25][C:26]3[NH:30][CH:29]=[CH:28][N:27]=3)[CH2:36][C:33]3[NH:32][N:31]=[CH:35][CH:34]=3)=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCN(CCC)Cc1ccc(NCc2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: O=Cc1cc[nH]n1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(NCc2ccc(CN(Cc3ccn[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (72.0 mg) obtained in Example 43-1 was dissolved in methanol (3.5 ml) and then added with pyrazole-3-carboxaldehyde (24.5 mg) and sodium cyanoborohydride (35.9 mg). The reaction solution was adjusted to pH 5 with the addition of acetic acid, followed by stirring at room temperature for 14 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then extracted with chloroform. Then, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining hydrochloride (52.3 mg) of the subject compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[S:16][C:15]3[C:14]([NH:17][CH2:18][CH2:19][C:20]4[S:24][C:23]([NH:25][C:26]([NH:28][C:29]5C=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=5)=[O:27])=[N:22][CH:21]=4)=[N:13][CH:12]=[N:11][C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=NN=N1.C(N(CC)[P:47]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])C.C([O:64]O)(C)(C)C.OS([O-])=O.[Na+]>C1COCC1.CC#N>[F:36][C:35]([F:38])([F:37])[C:31]([CH:32]=[CH2:33])=[CH:30][CH2:29][NH:28][C:26](=[O:27])[NH:25][C:23]1[S:24][C:20]([CH2:19][CH2:18][NH:17][C:14]2[C:15]3[S:16][C:8]([C:4]4[CH:3]=[C:2]([O:1][P:47](=[O:64])([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])[O:53][C:54]([CH3:55])([CH3:56])[CH3:57])[CH:7]=[CH:6][CH:5]=4)=[CH:9][C:10]=3[N:11]=[CH:12][N:13]=2)=[CH:21][N:22]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ncc(CCNc2ncnc3cc(-c4cccc(O)c4)sc23)s1
Reactant: CC(C)(C)OO
Reactant: CCN(CC)P(OC(C)(C)C)OC(C)(C)C
Agent: O=S([O-])O
Agent: [Na+]
Agent: c1nnn[nH]1
Solvent: CC#N
Solvent: C1CCOC1
Product: C=CC(=CCNC(=O)Nc1ncc(CCNc2ncnc3cc(-c4cccc(OP(=O)(OC(C)(C)C)OC(C)(C)C)c4)sc23)s1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of compound 57.1 (0.20 mmol) in THF (20 mL) was added 1-H-tetrazole (6.0 mL of a 3% w/w in CH3CN). The reaction was purged with nitrogen and di-tert-butyl diethylphosphoramidite (1.06 mmol) was added. After stirring at room temperature for 3.5 hours, tert-butyl hydroperoxide (5 mL of 70% aqueous solution) was added. After stirring for 1 hour, the reaction was cooled to 0° C. followed by the addition of NaHSO3 (15 mL of a 5% aqueous solution). After an additional 1 hour, the reaction mixture was extracted with dichloromethane, washed with brine, dried and concentrated to give phosphoric acid di-tert-butyl ester 3-[4-(2-{2-[3-(3-trifluoromethyl-penta-2,4-dienyl)-ureido]-thiazol-5-yl}-ethylamino)-thieno[3,2-d]pyrimidin-6-yl]-phenyl ester (compound 57.2)
Reaction SMILES: F[B-](F)(F)F.C([O+:8]([CH2:11][CH3:12])[CH2:9][CH3:10])C.[Cl:13][C:14]1[CH:22]=C2[C:17]([CH2:18][NH:19]C2=O)=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:11]([O:8][C:9]1[C:10]2[C:17](=[CH:16][CH:15]=[C:14]([Cl:13])[CH:22]=2)[CH2:18][N:19]=1)[CH3:12]
Reactant: CC[O+](CC)CC
Reactant: O=C1NCc2ccc(Cl)cc21
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC1=NCc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A solution of 151 g of triethyloxonium tetrafluoroborate in 3,200 ml of methylene chloride was stirred under argon at room temperature for 3.5 hours after the addition of 106.6 g of 6-chloro-2, 3-dihydro-1H-isoindol-1-one. The mixture was then treated within 40 minutes with 1.28 l of saturated sodium hydrogen carbonate solution, the organic phase was separated and washed with 1.28 l of water. After drying over sodium sulphate the organic phase was filtered and evaporated. The residue was taken up in 1.3 l of diethyl ether, whereupon it was stirred at room temperature for about 30 minutes. After removing insoluble material by filtration the filtrate was evaporated. There was obtained 110.5 g of 1-ethoxy-6-chloro-3H-isoindole with a m.p. of 64°-66°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13]([C:15]#[N:16])=[CH:12][CH:11]=1)([O-:3])=[O:2].[OH-:17].[K+].[ClH:19].[NH2:20]O>C(O)(C)C>[ClH:19].[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13]([C:15](=[N:20][OH:17])[NH2:16])=[CH:12][CH:11]=1)([O-:3])=[O:2]
Reactant: [OH-]
Reactant: NO
Reactant: N#Cc1ccc(-c2ccccc2[N+](=O)[O-])o1
Agent: Cl
Agent: [K+]
Solvent: CC(C)O
Product: NC(=NO)c1ccc(-c2ccccc2[N+](=O)[O-])o1

Procedure:
A mixture of 5-(2-nitrophenyl)-2-furonitrile (34 g, 0.16 mole), KOH (9.5 g, 0.17 mole), hydroxylamine hydrochloride (11.5 g, 0.165 mole) and absolute alcohol (400 ml) was heated under reflux for 2 hours. The reaction mixture was cooled in ice, and the insoluble material was collected by filtration. The solvent was removed on a rotary evaporator, and the residual oil (44 g) was triturated with water several times. It was dissolved in anhydrous ether (ca. 2l. ) and the insoluble material was removed by filtration. Gaseous HCl was introduced into the filtrate yielding a solid that was collected by filtration and washed with anhydrous ether to give 33 g (73%). An analytical sample, m.p. 205°-206°, was obtained by recrystallization from isopropanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH3:13])[CH:6]=1.[Li][CH2:16]CCC.C(NC(C)C)(C)C.CI>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]([CH3:16])[C:3]([O:2][CH3:1])=[O:14])=[CH:6][C:7]=1[O:12][CH3:13]
Reactant: [Li]CCCC
Reactant: COC(=O)Cc1ccc(Cl)c(OC)c1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CI
Product: COC(=O)C(C)c1ccc(Cl)c(OC)c1
Reaction time: 1 h

Procedure:
The product of step (i) (0.5 g) was added to a solution of nBuLi (1.75 ml, 1.6 M in THF) and diisopropylamine (0.4 ml) in THF (10 ml) at −78° C. and stirred for 1 h, then methyl iodide (0.18 ml) was added, stirred for 1 h at −78° C. then at room temperature for 1 h and quenched with water. The product was extracted with ether, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography (eluent 1:1 isohexane/ether) to give the subtitle compound (0.21 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@H:10]([CH2:26][C:27](O)=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11](=[O:25])[C@H:10]([CH2:26][C:27]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)C[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NC(=O)C[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
To a solution of 2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetic acid (Example 41) (83 mg, 0.192 mmol), methanesulfonamide (22.59 mg, 0.230 mmol) and 4-dimethylaminopyridine (1.057 mg, 0.00865 mmol) in DCM (2 mL) was added diisopropylethylamine (80 μL, 0.461 mmol). The reaction mixture was stirred at room temperature for one minute before adding bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (125 mg, 0.269 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with 1N HCl and the aqueuos layer was extracted with DCM (10 mL). The combined organic layers were washed with 1N HCl, 1N NaOH, sat. aq. NaCl solution and concentrated under reduced pressure. The residue was purified by reversed phase preparatory HPLC (column: Gemini-NX C18 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN +0.1% TFA in water +0.1% TFA, over 20 minutes) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13](O)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>CN(C=O)C>[F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([Cl:21])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)c1ccc(Oc2ccc(F)cc2)cc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 6 h

Procedure:
The sulphonic acid intermediate (2b) was then dissolved in an excess of thionyl chloride, a catalytic amount of DMF (few drops) was added, and the resulting mixture was stirred for 6 h at reflux. The solvent was evaporated and the residue dissolved in Et2O (40 mL). The ether solution was washed with 5% aqueous NaOH (3×40 mL) and water (6×40 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo. After drying in high vacuum overnight, the pure product was obtained as a white solid. Yield: 1.04 g, 3.63 mmol, 72% (white solid). 1H-NMR (CDCl3): δ 7.99 (d, 3J=9.1 Hz, 2H, ArH), 7.19-7.02 (m, 6H, ArH).
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[N:15]([CH3:16])[C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:8]=1.[CH2:21](Br)[CH:22]=[CH2:23]>CN(C=O)C>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[N:15]([CH3:16])[C:14]([CH2:17][C:18]([O:20][CH2:23][CH:22]=[CH2:21])=[O:19])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: C=CCBr
Reactant: Cc1ccc(C(=O)c2ccc(CC(=O)O)n2C)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: C=CCOC(=O)Cc1ccc(C(=O)c2ccc(C)cc2)n1C
Temperature: 25 °C
Yield: 84.6 %

Procedure:
The sodium salt of tolmetin (15.0 g, 47.6 mmol) and allyl bromide (4.3 ml, 49.9 mmol) were dissolved in DMF (50 ml) and the mixture was stirred at room temperature until the esterification was complete (~30 h). The solvent was removed in vacuo and the residue was partitioned between ether and water. The organic layer was separated, washed with water, 1 M sodium hydroxide, and brine, and dried over sodium sulfate. Evaporation gave allyl 5-(4-methylbenzoyl)-1-methylpyrrole-2-acetate (11.97 g, 85%) as a solid. ##STR26##
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([C:31]2[CH:32]=[C:33](/[C:43](=[CH:47]\[C@H:48]3[CH2:68][CH2:67][C:50]4([O:54][C@H:53]([C:55]5[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=5)[C@@H:52]([C:61]5[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=5)[O:51]4)[CH2:49]3)/[C:44](O)=[O:45])[CH:34]=[CH:35][C:36]=2[S:37]([CH:40]2[CH2:42][CH2:41]2)(=[O:39])=[O:38])[CH2:30][CH2:29]1.[NH2:69][C:70]1[CH:79]=[CH:78][C:73]([C:74]([O:76]C)=[O:75])=[CH:72][N:71]=1>ClCCl.N1C=CC=CC=1.O>[CH:28]1([C:31]2[CH:32]=[C:33](/[C:43](=[CH:47]\[C@H:48]3[CH2:68][CH2:67][C:50]4([O:54][C@H:53]([C:55]5[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=5)[C@@H:52]([C:61]5[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=5)[O:51]4)[CH2:49]3)/[C:44]([NH:69][C:70]3[CH:79]=[CH:78][C:73]([C:74]([OH:76])=[O:75])=[CH:72][N:71]=3)=[O:45])[CH:34]=[CH:35][C:36]=2[S:37]([CH:40]2[CH2:41][CH2:42]2)(=[O:39])=[O:38])[CH2:29][CH2:30]1
Reactant: O=C(O)/C(=C/[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Reactant: COC(=O)c1ccc(N)nc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(C(=O)O)cn1)/C(=C/[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Reaction time: 0.25 h
Yield: 26.7 %

Procedure:
To a solution of triphenylphosphine (607 mg) in dichloromethane (10 mL) was added N-bromosuccinimide (412 mg) under ice-cooling, followed by stirring for 15 minutes under ice-cooling. A solution of (2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]acrylic acid (600 mg) in dichloromethane (10 mL) was added thereto under ice-cooling, followed by stirring at room temperature for 0.5 hour. A solution of methyl 6-aminonicotinate (160 mg) in dichloromethane (10 mL) and pyridine (0.17 mL) were added thereto at room temperature, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was sequentially washed with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-1:1). To the solution of the obtained pale yellow amorphous dioxane (4 mL) was added a 1 M aqueous sodium hydroxide solution (1.2 mL), followed by stirring at 50° C. for 1 hour. 1 M Hydrochloric acid was added thereto to adjust the pH to 2, and then saturated brine was added thereto. The mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography (hexane:ethyl acetate=1:1-3:1) to obtain 6-({(2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]prop-2-enoyl}amino)nicotinic acid (194 mg) as a white amorphous substance.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[NH:70][N:69]=[N:68][N:67]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.Cl.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:14])=[S:16])=[C:18]([CH2:64][S:65][C:66]4[NH:70][N:69]=[N:68][N:67]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=S)OC(c4ccccc4)c4ccccc4)=C(CSc4nnn[nH]4)CS[C@H]23)cs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Solvent: O
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(O)=S)=C(CSc4nnn[nH]4)CS[C@H]23)cs1
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetyl]amino-3-(5-tetrazolyl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (942 mg: containing ca. 10% of byproduct) in a mixture of anisole (3 ml) and nitromethane (12 ml) cooling at -30° to -40° C. is added a solution of aluminum chloride (980 mg: 7.37 mMol.) in anisole (3 ml), and the mixture is stirred at -30° to -40° C. for 1 hour. The reaction mixture is diluted with 1N-hydrochloric acid (7.5 ml) and water, washed with ethyl acetate, concentrated under reduced pressure to remove the organic solvents, and subjected to styrene-divinylbenzene copolymer chromatography (methanol: water=2:3). The resulting powder is washed with ethyl acetate to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetyl]amino-3-(tetrazol-5-yl)thiomethylthio-3-cephem-4-carboxylic acid as pale yellow powder (289 mg). Yield: 28% (from 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetyl]amino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH:28]([NH2:30])[CH3:29]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][CH:28]([CH3:29])[CH2:27][O:26][CH3:25])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: COCC(C)N
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: COCC(C)NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-methoxypropan-2-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (d, J=6.82 Hz, 3H) 2.44 (s, 3H) 3.29 (s, 3H) 3.30-3.33 (m, 1H) 3.44 (dd, J=9.47, 6.44 Hz, 1H) 4.15-4.32 (m, 1H) 7.67 (d, J=8.08 Hz, 1H) 7.74 (s, 1H) 7.78 (br. s., 1H) 8.19 (br. s., 1H) 8.43 (d, J=6.82 Hz, 1H) 8.50 (d, J=7.83 Hz, 2H) 8.87-8.96 (m, 1H) 13.19 (br. s., 1H). MS m/z [M+H]+ 392.2
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH:10]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)([CH3:12])[CH3:11]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:17][C:16]2[CH:18]=[CH:19][C:13]([CH:10]([CH3:12])[CH3:11])=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(NCc2ccc(Br)cc2)cc1
Yield: 57.6 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-bromobenzaldehyde (1.9 g) and 4-isopropylaniline (1.4 g) as starting materials, [(4-bromophenyl)methyl](4-isopropylphenyl)amine (1.8 g) was obtained. melting point: 30° C.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][C:7]2=[N:6][CH:5]=1)(=[O:3])[NH2:2].[S:14]([O:19]C)([O:17][CH3:18])(=[O:16])=[O:15]>C(O)CCC>[CH3:18][O:17][S:14]([O-:19])(=[O:16])=[O:15].[C:1]([C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][C:7]2=[N+:6]([CH3:18])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1cnc2n(c1=O)CCC2
Reactant: COS(=O)(=O)OC
Solvent: CCCCO
Product: COS(=O)(=O)[O-]
Product: C[n+]1cc(C(N)=O)c(=O)n2c1CCC2
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 5.37 g. of 3-carbamoyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine in 540 ml. of n-butanol 3.78 g. of dimethyl sulphate are added and the reaction mixture is stirred for 3 hours at 100° C. whereafter the solvent is distilled off. The residue is triturated with acetone and the obtained crystals are filtered. 3.7 g. (51%) highly hygroscopic 3-carbamoyl-1-methyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidinium methyl sulphate are obtained melting at 190° C. under decomposition.
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[NH:3][CH:2]=1.[N:16]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[N:1]1[CH:5]=[C:4]([CH2:6][N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[CH2:22][C:19]2[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=2)[NH:3][CH:2]=1
Reactant: O=Cc1ccncc1
Reactant: COc1cccc(NCc2cnc[nH]2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1cccc(N(Cc2ccncc2)Cc2cnc[nH]2)c1
Temperature: 40 °C
Reaction time: 72 h
Yield: 10 %

Procedure:
To a solution of (3H-imidazol-4-ylmethyl)-(3-methoxy-phenyl)-amine (0.05 g, 0.25 mmol, Example 186 step a) in 1,2-dichloroethane (2 ml) were added pyridine-4-carbaldehyde (0.06 ml, 0.64 mmol) and sodium triacetoxyborohydride (0.21 g, 0.98 mmol). The reaction mixture was stirred at 40° C. for 72 h. The reaction mixture was then concentrated in vacuo and the residue was purified using flash chromatography (column: Isolute® Flash-NH2 (Separtis); eluent: methanol/dichloromethane gradient) to yield a yellow oil (7 mg, 10%); MS (ISP): 295.3 ((M+H)+.).
Reaction SMILES: [I-].[CH3:2][N+:3]1([CH3:23])[C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][C:6]2[C:14]([I:22])=[CH:15][C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:17][C:5]=2[CH2:4]1.[C:24]([O-:27])(=[O:26])[CH3:25]>C(O)(=O)C>[OH2:7].[CH3:23][N+:3]1([CH3:2])[C:8]2([CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:25][C:24]([O-:27])=[O:26])[O:7][C:6]2[C:14]([I:22])=[CH:15][C:16]([C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:17][C:5]=2[CH2:4]1.[CH3:23][N+:3]1([CH3:2])[C:8]2([CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:25][C:24]([O-:27])=[O:26])[O:7][C:6]2[C:14]([I:22])=[CH:15][C:16]([C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:17][C:5]=2[CH2:4]1
Reactant: CC(C)(C)c1cc(I)c2c(c1)C[N+](C)(C)C1(CCCCC1)O2
Reactant: CC(=O)[O-]
Agent: [I-]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(I)c2c(c1)C[N+](C)(C)C1(CCCCC1CC(=O)[O-])O2
Product: O

Procedure:
The corresponding spirobenzoxazinium iodide (Example 1) (1.36 g., 0.0025 mole) is dissolved in 50% aqueous acetic acid (200 ml) and passed down a column of Dowex-1 × 2 acetate resin. The first 350 ml. that is collected is evaporated to dryness. The residue is crystallized from ethanolether (1:100) to obtain 3,3-dimethyl-3,4-dihydro-6-(1,1-dimethylethyl)-8-iodospiro[2H-1,3-benzoxazinium-2,1'-cyclohexane]acetate hemihydrate (0.8 g.), m.p. 159°-160° (dec).