Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:12]4[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[C:29]([C:33]1[O:37][N:36]=[C:35]([NH:38][C:39](=O)[O:40]C2C=CC=CC=2)[CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[C:29]([C:33]1[O:37][N:36]=[C:35]([NH:38][C:39]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([O:10][C:11]4[C:12]5[CH2:19][NH:18][CH2:17][C:13]=5[N:14]=[CH:15][N:16]=4)=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[O:40])[CH:34]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: CC(C)(C)OC(=O)N1Cc2ncnc(Oc3ccc4[nH]ccc4c3)c2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)n2ccc3cc(Oc4ncnc5c4CNC5)ccc32)no1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Tert-butyl 4-(1H-indol-5-yloxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (127 mg, 0.360 mmol) is dissolved in THF (8 mL), flushed with nitrogen and cooled to 0° C. Sodium hydride (23 mg, 0.575 mmol, 60% in mineral oil) is added and the mixture is stirred for 10 minutes. Phenyl 5-tert-butylisoxazol-3-ylcarbamate (140 mg, 0.538 mmol) is added neat and the reaction is allowed to stir at room temperature overnight. The reaction is cooled in an ice bath and quenched with a saturated solution of ammonium chloride (100 mL). The mixture is then diluted with ethyl acetate and the product is extracted (2×100 mL EtOAc). The organic layers are combined, dried and concentrated to a brown oil that is dissolved in 10 mL of DCM and cooled in an ice bath and 10 mL of TFA is added. Following completion of the reaction the DCM and TFA are removed and ethyl acetate is added to the residue along with ammonium hydroxide to quench the remaining TFA. The mixture is diluted with water and extracted with ethyl acetate (2×50 mL). The organic layers are removed, dried, and concentrated. The residue is absorbed onto silica and separated via FCC (0-6% Methanol/DCM) to obtain N-(5-tert-butylisoxazol-3-yl)-5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-1H-indole-1-carboxamide. MS (ESI) m/z 419.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.56 (s, 1 H) 8.29 (d, J=8.84 Hz, 1 H) 8.17 (d, J=3.79 Hz, 1 H) 7.47 (d, J=2.27 Hz, 1 H) 7.15 (dd, J=8.97, 2.40 Hz, 1 H) 6.76 (d, J=3.28 Hz, 1 H) 6.68 (s, 1 H) 4.07-4.14 (m, 4 H) 1.34 (s, 9 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].C(O)(=O)C.[CH3:22][C:23]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:24]=1[NH2:25]>C(O)C>[CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[N:25][C:24]2[C:26]([CH3:31])=[CH:27][C:28]([CH3:30])=[CH:29][C:23]=2[CH3:22])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: CC1=C(C)C(c2ccccc2C=O)C(C)=C1C
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: CC(=O)O
Solvent: CCO
Product: CC1=C(C)C(c2ccccc2C=Nc2c(C)cc(C)cc2C)C(C)=C1C
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of 2-(2,3,4,5-tetramethylcyclopentadienyl)benzaldehyde (10.0 mmol) in ethanol (30.0 mL) were added dropwise acetic acid (1.0 mmol) and 2,4,6-trimethylaniline (10.5 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature. After disappearance of the aldehyde was confirmed by gas chromatography, the solvent was distilled off under reduced pressure to give N-[2-(2,3,4,5-tetramethylcyclopentadienyl)phenylmethylene]-N-(2,4,6-trimethylphenyl)amine (3.43 g, yield 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].[C:12](Cl)(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>N1C=CC=CC=1.ClCCl>[C:12]([NH:1][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7])(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC(=O)Cl
Reactant: N#Cc1ccc(N)cc1C#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ccc(C#N)c(C#N)c1
Reaction time: 2 h
Yield: 70.9 %

Procedure:
4-Aminophthalonitrile (3.60 g, 25.2 2.mmole) was dissolved in 8.6 mL of pyridine. Hexanoyl chloride (8.6 10, 61.5 mmole) was added and the mixture was stirred under N2 for 2 hours. The pyridine was distilled under vacuum until a yellow-orange residue was obtained. This residue was dissolved in dichloromethane and washed with 0.1 M HCl (5×15 mL) and then neutralized with aqueous sodium bicarbonate (3×50 mL). The organic solution was separated and dried over magnesium sulfate. Purification by column chromatography (silica, dichloromethane: methanol 5%) afforded 4.3 g (71% yield) of 4-hexanamidophthalonitrile as a light yellow compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:3]=1.[N+:12]([O-])([OH:14])=[O:13]>>[OH:8][C:6]1[C:7]([N+:12]([O-:14])=[O:13])=[C:2]([OH:1])[N:3]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:5]=1
Reactant: CC(C)c1nc(O)cc(O)n1
Reactant: O=[N+]([O-])O
Product: CC(C)c1nc(O)c([N+](=O)[O-])c(O)n1
Reaction time: 1 h

Procedure:
220 g of 4,6-dihydroxy-2-isopropyl-pyrimidine are added at 0°C to 500 ml of 100 % nitric acid and the mixture is stirred for 1 hour. Subsequently the nitration mixture is poured on ice water, filtered, washed with water, and dried in vacuo over P2O5, to yield 110 g of 4,6-dihydroxy-2-isopropyl-5-nitro-pyrimidine; mp. 300°C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([C:15]2[N:20]=[CH:19][C:18]([CH:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH2:22][NH2:23])=[CH:17][CH:16]=2)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:23][CH2:22][CH:21]([C:18]1[CH:19]=[N:20][C:15]([CH:12]2[CH2:14][CH2:13]2)=[CH:16][CH:17]=1)[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1ccc(C2CC2)nc1)N1CCOCC1
Product: O=C(NCC(c1ccc(C2CC2)nc1)N1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(6-cyclopropyl-pyridin-3-yl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[N:15]=[C:16]([CH3:19])[N:17]([CH3:18])[C:13]=2[CH:12]=[C:11]([NH:20][C:21](=[O:23])[CH3:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]I.[H-].[Na+].O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:14]2[N:15]=[C:16]([CH3:19])[N:17]([CH3:18])[C:13]=2[CH:12]=[C:11]([N:20]([CH3:24])[C:21](=[O:23])[CH3:22])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cc(OCc2ccccc2)c2nc(C)n(C)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(C)c1cc(OCc2ccccc2)c2nc(C)n(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a suspension of 5.8 g (18.8 mmol) N-(7-benzyloxy-2,3-dimethy-3H-benzimidazol-5-yl)-acetamide in tetrahydrofuran (200 ml) were added 1.3 ml (20.5 mmol) methyl iodide and 0.74 g (20.5 mmol) sodium hydride (60%) in portions. The reaction was stirred at room temperature for 1 h and then poured into water (100 ml) and extracted with ethyl acetate (4×50 ml). The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue afforded 6.0 g (99%) of the title compound as ochre solid. m.p. 144°-149° C.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH2:24][Cl:25].O>CN(C=O)C>[Cl:25][CH2:24][CH2:23][CH2:22][N:11]1[CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:14])[NH:9][C:10]1=[O:13]
Reactant: ClCCCBr
Reactant: O=c1[nH]cc(-c2ccccc2)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n(CCCCl)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 5-phenyl-2,4(1H,3H)-pyrimidinedione (527 mg, commercially available from Akos) and K2CO3 (386 mg) in dry DMF (10 mL) was stirred for 1 hour at room temperature. 1-Bromo-3-chloropropane (0.28 mL) was added and the mixture was stirred at room temperature for 20 hours. One more portion of 1-bromo-3-chloropropane (0.14 mL) was added and the mixture was stirred at room temperature for 20 hours. Water was added and the resulting mixture was extracted with ethyl acetate. The organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by a silica flash chromatography (eluting with A: dichloromethane, B: dichloromethane/methanol=9/1 at ratio A:B=6:4) to give the title compound as a colourless oil (150 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](C(C)(C)C)[C:8]2[O:12][C:11](=[O:13])[CH:10](O)[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.Cl>ClC1C=CC=CC=1Cl.CN(C)C1C=CN=CC=1>[C:1]([C:5]1[CH:15]=[C:9]([C:9]([CH3:15])([CH3:10])[CH3:8])[C:8]2[O:12][C:11](=[O:13])[C:10](=[C:10]3[C:7]4[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:15]=[C:9]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:8]=4[O:12][C:11]3=[O:13])[C:7]=2[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2=C1C(=O)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 109.5 %

Procedure:
10 g of 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one (prepared as described in Example 1 of U.S. Pat. No. 5,614,572) are introduced in 25 ml of 1,2-dichlorobenzene as initial charge and admixed with 0.5 g of 4-dimethylaminopyridine and 3 ml of thionyl chloride. The solution is then gradually heated to 100° C. so that the evolution of HCl and SO2 remains lively, but still controllable. Thereafter the reaction mixture is stirred at 100° C. for a further ½ h. The temperature is subsequently raised to the reflux point. After 75 min, the 1,2-dichlorobenzene is distilled off, at the end with reduced pressure. The isoxindigo is crystallized out by the addition of 30 ml of acetonitrile to the residue, filtered off, washed with acetonitrile and dried to leave 6.8 g (73% of theory) of 5,7,5′,7′-tetra-tert-butyl[3,3′]bibenzofuranylidene-2,2′-dione of the formula (XV).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15].C(#N)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH:9]=[CH:13][N:14]([CH3:16])[CH3:15]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccccc1Cl
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CN(C)C=CC(=O)c1ccccc1Cl
Temperature: 83 °C
Yield: 101.7 %

Procedure:
To a 5 liter, 3-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser capped with a nitrogen inlet, and a heating mantle were added o-chloroacetophenone (305.8 g), N,N-dimethylformamide dimethyl acetal (707.0 g), and acetonitrile (dried over molecular sieves, 3.0 L) giving an orange solution. The mixture was heated gradually to reflux (83° C.) over 1.5 hours, then maintained at reflux for 18 hours. After the dark red solution was cooled to room temperature, the acetonitrile was evaporated, leaving a heavy red oil. The oil was redissolved in toluene (1L). The toluene was evaporated to afford the crude enamine which was further dried under high vacuum overnight to afford 2'-chloro-3-dimethylaminopropenophenone (422 g) which was used without further purification.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]([CH2:19][CH:20](OC)OC)[CH3:18])=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O>[CH3:18][N:17]1[CH:19]=[CH:20][N:14]([C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][CH:12]=2)[C:15]1=[O:16]
Reactant: COC(CN(C)C(=O)Nc1ccc(Oc2ccccc2)cc1)OC
Agent: Cl
Solvent: O
Product: Cn1ccn(-c2ccc(Oc3ccccc3)cc2)c1=O

Procedure:
N-(4-Phenoxyphenyl)-N'-(2,2-dimethoxyethyl)-N'-methylurea (5.0 grams, 0.015 mole), water (30 ml) and concentrated hydrochloric acid (3 ml) were charged into a glass reaction vessel fitted with a mechanical stirrer thermometer and condenser. The reaction mixture was refluxed for a period of about 15 minutes, cooled and extracted with ethyl acetate. The ethyl acetate solution was washed with dilute aqueous sodium bicarbonate and with portions of water and dried. The ethyl acetate was removed by mild warming under reduced pressure to yield a residue. This was recrystallized from ethyl acetate to yield the desired product 1-methyl-3-(4-phenoxyphenyl)-4-imidazolin-2-one as a solid having a melting point of 112° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C@H:12]4[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][CH2:14][C@H:13]4[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([C:37]([F:40])([F:39])[F:38])[CH:29]=1>>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[C:4]3[C:9]4=[C:10]([C@H:12]5[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:16][CH2:15][CH2:14][C@H:13]5[N:8]4[CH2:7][CH2:6][CH2:5]3)[CH:11]=2)=[C:30]([C:37]([F:38])([F:39])[F:40])[CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CCC3
Reactant: COc1ccc(B(O)O)c(C(F)(F)F)c1
Product: COc1ccc(-c2cc3c4c(c2)[C@H]2CN(C(=O)OC(C)(C)C)CCC[C@H]2N4CCC3)c(C(F)(F)F)c1
Yield: 92.9 %

Procedure:
Tert-butyl (±)-cis-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline-11-carboxylate (56 mg, 91%) was prepared by the general method of Example 319, step A from tert-butyl (±)-cis-2-bromo-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline-11-carboxylate (50 mg, 0.12 mmol) and 4-methoxy-2-(trifluoromethyl)phenylboronic acid (54 mg, 0.25 mmol) as a white foam. MS (ESI): 503.6 (base, M+H).
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15](/[C:16](=[N:28]/[O:29][CH3:30])/[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C([C@@H]1C2[C@](C)(CCC(=[O:51])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[CH3:30][O:29]/[N:28]=[C:16]1/[C@@H:15]2[C@@H:25]([C@:23]3([CH3:24])[CH:18]([CH2:17]/1)[CH2:19][C:20](=[O:51])[CH2:21][CH2:22]3)[CH2:26][CH2:27][C@@:4]1([CH3:5])[C@H:6]2[CH2:7][CH2:8][C:3]1=[O:12]
Reactant: CO/N=C1\CC2CCCC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@H]12
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: CO/N=C1\CC2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Yield: 55 %

Procedure:
The title compound II-br was prepared in 55% yield from 3,3:17,17-bis(ethylendioxy)-7(E)-methoxyiminoandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The crude product was purified by flash chromatography (SiO2, n-hexane/EtOAc 6/4). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS: δ 3.72 (s, 3H), 2.89 (m, 1H), 2.63-0.93 (m, 19H), 1.12 (s, 3H), 0.82 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[C:8](=[O:9])[N:7]2[CH:10]=[CH:11][C:12]([CH2:14][CH2:15][C:16]3[S:17][CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[N:20]=3)=[CH:13][C:6]2=[N:5][C:4]=1[N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([C:30]([O-])=[O:31])[CH2:25]1)=O.FC(F)(F)COP([CH2:45][C:46]([O:48][CH3:49])=[O:47])(=O)OCC(F)(F)F.C1CCN2C(=NCCC2)CC1.[Cl-].[Li+]>O1CCCC1>[CH:30]([CH:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:4]2[N:5]=[C:6]3[CH:13]=[C:12]([CH2:14][CH2:15][C:16]4[S:17][CH:18]=[C:19]([CH:21]([CH3:22])[CH3:23])[N:20]=4)[CH:11]=[CH:10][N:7]3[C:8](=[O:9])[C:3]=2/[CH:1]=[CH:45]/[C:46]([O:48][CH3:49])=[O:47])[CH2:25]1)=[O:31]
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(C=O)c(N4CCCC(C(=O)[O-])C4)nc3c2)n1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C=C/c1c(N2CCCC(C=O)C2)nc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-{3-Formyl-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}-3-piperidylformate (94.0 mg, 0.207 mmol) and bis(2,2,2-trifluoroethyl)-(methoxycarbonylmethyl)phosphonoate (0.131 ml, 0.620 mmol) were dissolved in tetrahydrofuran (2 ml), added with DBU (0.085 ml, 0.620 mmol) and lithium chloride (26.3 mg, 0.620 mmol), and then the mixture was stirred at room temperature for 1 hour.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH:6]([NH:9][C:10]([N:12]1[C:16]([CH3:17])=[CH:15][C:14]([O:18][C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=2[Cl:30])=[N:13]1)=[O:11])([CH3:8])[CH3:7]>C(O)(=O)C>[CH:6]([NH:9][C:10]([N:12]1[C:16]([CH3:17])=[C:15]([Cl:4])[C:14]([O:18][C:19]2[C:20]([Cl:30])=[CH:21][C:22]([C:26]([F:29])([F:27])[F:28])=[CH:23][C:24]=2[Cl:25])=[N:13]1)=[O:11])([CH3:8])[CH3:7]
Reactant: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C(=O)NC(C)C
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: Cc1c(Cl)c(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.1 %

Procedure:
Sulfuryl chloride (0.16 g, 1.2 mmol) was added to a solution of N-isopropyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.40 g, 1.0 mmol) in acetic acid (5 ml), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/20), to give a white solid of N-isopropyl-4-chloro-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.19 g, yield: 44.1%) [mp: 109-111° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.20 (d, J=7.5 Hz, 6H), 2.61 (s, 3H), 3.85-4.10 (m, 1H), 6.25-6.50 (m, 1H), 7.67 (s, 2H).] and a white solid of N-isopropyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-trichloromethylpyrazole-1-carboxamide (0.04 g, yield: 8.0%) [mp: 105-106° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.22 (d, J=6.5 Hz, 6H), 3.85-4.15 (m, 1H), 6.25-6.55 (m, 1H), 7.69 (s, 2H), 8.24 (s, 1H)].
Reaction SMILES: [Cl:1][C@H:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:6]([CH3:11])[CH2:7][S:8](=[O:10])(=[O:9])[C@H:3]12.Cl.[CH3:31]NC.C=O.C(O)(C)(C)C>C(Cl)Cl>[Cl:1][C@H:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:13])=[C:6]([CH3:11])[C:7](=[CH2:31])[S:8](=[O:9])(=[O:10])[C@H:3]12
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](Cl)[C@H]2S(=O)(=O)C1
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: C=C1C(C)=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](Cl)[C@H]2S1(=O)=O
Temperature: 95 °C
Yield: 37.7 %

Procedure:
Benzhydryl 7α-chloro-3-methyl-3-cephem-4-carboxylate 1,1-dioxide (9.3 g, 0.0215 mol) was dissolved in methylene chloride (35 ml), dimethylamine hydrochloride (4.9 g, 0.0645 mol), formaldehyde solution (2.25 g, 0.075 mol) and t-butyl alcohol (300 ml) were added and the mixture was heated to reflux at 95° C. for 4 hours. After removing the solvent under reduced pressure the residue was redissolved in methylene chloride, washed successively with water, dried over sodium sulfate and concentrated. The product was purified over a silica column using hexane-ethyl acetate mixture as the eluant to yield benzhydryl 7α-chloro-2-methylene-3-methyl-3-cephem-4-carboxylate 1,1-dioxide (3.6 g, 40%) as a white foam. IR (Nujol) ν max 1723, 1800 cm-1.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)=[O:4].[Br:15]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:12][C:8]1[N:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:14])([CH3:13])[CH3:1])[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(NC(=O)C(C)(C)C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)Nc1cccc(CBr)n1
Yield: 35.3 %

Procedure:
Carbon tetrachloride (CCl4, 300 mL) and the product from Example 1 (50.6 g, 0.26 mol) were placed in a 1-L flask equipped with a N2 inlet The solution was stirred until all solid dissolved. N-bromosuccinimide (NBS, 46.8 g, 0.26 mol) was then added to the reaction flask, followed by 2,2'-azobisisobutyronitrile (AIBN, 0.02 g). The reaction was heated to reflux for 7 h with a 500 watt reflector spot lamp. After cooling the reaction to room temperature, it was filtered and all solvent was removed under reduced pressure. Flash chromatography (15/85 ethyl acetate (EtOAc)/Hex) provided 24.89 g (37%) of title product.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.O1CCCC1>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]([F:29])([F:31])[F:30])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOCC(F)(F)F)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOCC(F)(F)F)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 77.9 %

Procedure:
A suspension of 7-[2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.5 g.), conc. hydrochloric acid (1.3 ml.), tetrahydrofuran (10 ml.) and methanol (30 ml.) was treated in a similar manner to that of Example 21-(3) to give 7-[2-(2-aminothiazol-4-yl)-2(2,2,2-trifluoroethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.1 g.).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[CH:22]([C:26](=[O:32])[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])C(O)=O)=[N:9]2)=[CH:4][CH:3]=1.[OH-:33].[Na+]>O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([NH:12][CH:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:20]([OH:21])=[O:33])[CH2:22][C:26](=[O:32])[CH2:27][CH2:28][CH:29]([CH3:30])[CH3:31])=[N:9]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CC(C)CCC(=O)C(C(=O)O)C1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Agent: [Na+]
Solvent: O
Product: CC(C)CCC(=O)CC(Nc1ccc2ccc(Cl)nc2n1)c1ccccc1C(=O)O
Temperature: 20 °C
Reaction time: 72 h

Procedure:
A suspension of 30 mg of (±)-2-[2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl]-6-methyl-3-oxoheptanoic acid in 4.7 cm3 of distilled water and 1.32 cm3 of a 0.1N aqueous sodium hydroxide solution is stirred at a temperature of approximately 20° C. for 72 hours. An insoluble product is removed by filtration and the filtrate is acidified to a pH=2 by addition of a 0.1N aqueous hydrochloric acid solution. The precipitate obtained is separated by filtration, washed with water and dried in air. 10 mg of (±)-2-{1-[(7-chloro-1,8-naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid are thus obtained whose characteristics are identical to those of the product of Example 1.