Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)[C:3]([CH:5]1[CH:10]2[CH2:11][CH2:12][N:7]([CH:8]([CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]2=O)[CH2:6]1)=[O:4].[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:31]=1[CH2:32][NH2:33].O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:31]=1[CH2:32][NH:33][CH:9]1[CH:8]([CH:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:7]2[CH2:12][CH2:11][CH:10]1[CH:5]([C:3]([NH2:2])=[O:4])[CH2:6]2
Reactant: COc1ccc(OC)c(CN)c1
Reactant: CN(C)C(=O)C1CN2CCC1C(=O)C2C(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(OC)c(CNC2C3CCN(CC3C(N)=O)C2C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.7 %

Procedure:
A mixture of 48 (1.2 g, 3 mmol), 2,5-dimethoxybenzyl amine (0.6 g, 3.3 mmol) camphor sulfonic acid (45 mg) in toluene (15 ml) was heated at reflux with removal of water for 3 hours and then the solvent was removed. The residue was dissolved in small amount of THF (3 ml) and this solution was added to a solution of sodium triacetoxyborohydride (1.7 g, 8 mmol) in acetic acid (40 ml) at room temperature. The mixture was stirred at room temperature for 3 hours and the solvent was removed. Water was added and the mixture was neutralized with NaHCO3 and extracted with EtOAc three times. The combined extracts were dried over Na2SO4 and concentrated. Recrystallization from MeOH/acetone to give by-product. The mother liquor was concentrated and the residue was purified by recrystallization from MeOH/EtOAc to give 50 (0.27 g, 0.56 mmol, 19%)
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]4[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][C:21]([CH2:22]O)=[CH:20][C:19]=4[C:30]([F:33])([F:32])[F:31])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:34]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[CH:1]1([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]4[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][C:21]([CH2:22][Br:34])=[CH:20][C:19]=4[C:30]([F:33])([F:32])[F:31])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1cc(C(F)(F)F)c(Oc2ccc3[nH]cc(CC4CCCCC4)c3c2)c(C(F)(F)F)c1
Solvent: CC#N
Product: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1Oc1ccc2[nH]cc(CC3CCCCC3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Preparation is carried out in analogy to the procedure of Example VII from 2.0 g (4.18 mmol) of benzyl alcohol derivative from Example XXI and 2.82 g (6.69 mmol) of dibromotriphenylphosphorane in 40 ml of acetonitrile. After stirring for 3 hours at room temperature, 0.3 equivalent of dibromotriphenylphosphorane is again added. The mixture is additionally stirred for 5 hours at 70° C. and afterwards overnight at room temperature. The purification of the product is carried out on silica gel using toluene as eluent.
Reaction SMILES: [CH3:1][C@H:2]([CH2:8]Cl)[CH2:3][S:4]([NH2:7])(=[O:6])=[O:5].[SH-:10].[K+].C(O)C.C[O-].[Na+].CO.Cl[C:21]1[CH:22]=[CH:23][C:24]2[N:25]([CH:27]=[CH:28][N:29]=2)[N:26]=1>CO>[CH3:1][C@H:2]([CH2:3][S:4](=[O:6])(=[O:5])[NH2:7])[CH2:8][S:10][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([CH:27]=[CH:28][N:29]=2)[N:26]=1
Reactant: [SH-]
Reactant: C[C@H](CCl)CS(N)(=O)=O
Reactant: Clc1ccc2nccn2n1
Agent: C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: C[C@@H](CSc1ccc2nccn2n1)CS(N)(=O)=O
Temperature: 70 °C

Procedure:
To a solution of 0.78 g of 2-(S)-methyl-3-chloro-1-propanesulfonamide in 20 ml of methanol was added 20 ml of 2N potassium hydrosulfide-ethanol solution, followed by refluxing at 70° C. for an hour in a stream of nitrogen. Further, to the mixture were added 1.0 g of 28% sodium methoxide-methanol solution and 0.73 g of 6-chloroimidazo[1,2-b]pyridazine, followed by refluxing for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue to which 10 ml of water were added was adjusted to pH 6.0 with 1N-hydrochloric acid and then extracted with tetrahydrofuran-ethyl acetate (1:1). The extract was dried over anhydrous magnesium sulfate and distilled to remove the solvent under reduced pressure. The residue was subjected to a silica gel column chromatography, eluting with chloroform-methanol (10:1). The corresponding fractions were concentrated under reduced pressure to obtain 0.29 g of the title compound. This product was dissolved in 2 ml of hydrochloric acid-methanol, and the resultant was concentrated under reduced pressure. The residue was recrystallized from a mixture of methanol-ethyl ether to obtain 0.2 g of hydrochloride of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[CH3:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH:14]=O.[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1>>[N:18]1([CH:14]([NH:7][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[CH2:13][C:12]([CH3:17])([CH3:16])[CH3:11])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(C)(C)CC=O
Reactant: NC(=O)c1cccc(Cl)c1
Product: CC(C)(C)CC(NC(=O)c1cccc(Cl)c1)n1nnc2ccccc21

Procedure:
A suspension of 3-chlorobenzamide, 3,3-dimethyl-butyraldehyde, and benzotriazole were processed as described in Example 1C to provide the desired product
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[OH:63][CH2:64][C@H:65]1[CH2:69][CH2:68][CH2:67][NH:66]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:66]1[CH2:67][CH2:68][CH2:69][C@@H:65]1[CH2:64][OH:63])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: OC[C@H]1CCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCC[C@@H]3CO)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (2R)-2-hydroxymethyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13]Br.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CC=CC=1>C(O)C>[N+:10]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:15])[N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13]2)([O-:12])=[O:11]
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: Nc1ccccc1
Solvent: CCO
Solvent: c1ccncc1
Product: O=C1c2c(cccc2[N+](=O)[O-])CN1c1ccccc1
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 2-bromomethyl-6-nitro-benzoic acid methyl ester (0.40 g, 1.46 mmol) and aniline (0.23 g, 2.44 mmol) in ethanol (20 ml) was added with pyridine (0.15 g, 1.95 mmol), and the mixture was refluxed by heating for 30 hours. The reaction solution was cooled to room temperature, and then poured into ice water, and the deposited crystals were collected by filtration, washed with ethanol and water, and dried. The resulting crystals were recrystallized (acetone) to obtain 7-nitro-2-phenyl-2,3-dihydro-isoindol-1-one as pale yellow crystals (0.23 g, yield: 62.9%).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:29]([Cu])#[N:30].O.Cl>CN(C=O)C.C(Cl)Cl>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:29]#[N:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: N#C[Cu]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3c(C)cccc3C)cc2c1O
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3c(C)cccc3C)cc2c1O
Yield: 82 %

Procedure:
A mixture of 1-bromo-6-(2,6-dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (2 g, 4.5 mmol) (prepared according to U.S. Pat. No. 7,928,120) and CuCN (0.81 g, 9.0 mmol) in DMF (30 mL) was refluxed for 1.5 h. The resulting mixture was poured into a mixture of water (200 mL) and CH2Cl2 (200 mL). 4 M HCl was added with vigorous stirring until no solid was observed. The aqueous layer was extracted with additional CH2Cl2, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (10-80% CH2Cl2/hexanes) to give 1.44 g of the title compound as a pale pink solid. MS: (+) m/z 391.34 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][C:11]1=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:18](=[S:20])=[S:19].Cl/[CH:22]=[CH:23]\Cl>CS(C)=O>[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[C:12](=[C:18]2[S:20][CH:23]=[CH:22][S:19]2)[C:11]1=[O:17])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: S=C=S
Reactant: Cl/C=C\Cl
Reactant: O=C1CCN(Cc2ccccc2)C(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1CCN(Cc2ccccc2)C(=O)C1=C1SC=CS1
Reaction time: 2 h

Procedure:
Sodium hydride (60% despersion in oil) (432 mg) is suspended in dimethylsulfoxide (10 ml), and to the suspension is added dropwise a solution of 1-benzyl-2,4-dioxopiperidine (1.0 g) and carbon disulfide (0.33 ml) in dimethylsulfoxide (20 ml). The mixture is stirred for 2 hours, and thereto is added dropwise a solution of cis-1,2-dichloroethylene (0.42 ml) in dimethylsulfoxide (5 ml). The mixture is stirred at room temperature for 1.5 hour and further at 50° C. for 1 hour. The reaction mixture is poured onto water and extracted with benzene. The extract is washed with water, dried and then distilled to remove the solvent. The residue is recrystallized from isopropyl alcohol to give 1-benzyl-3-(1,3-dithiol-2-ylidene)-2,4- dioxopiperidine (486 mg) as pale yellow needles. m.p. 122°-124° C.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([O-:6])=[C:3]1[OH:4].[NH2:13][C:14]1[C:19]2[C:20]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=4)=[O:31])=[CH:25][CH:24]=3)=[CH:21][S:22][C:18]=2[C:17]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][OH:47])[CH:44]=2)=[CH:16][N:15]=1.O1CCCC1>O>[NH2:13][C:14]1[C:19]2[C:20]([C:23]3[CH:24]=[CH:25][C:26]([NH:29][C:30]([NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=4)=[O:31])=[CH:27][CH:28]=3)=[CH:21][S:22][C:18]=2[C:17]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][OH:47])[CH:44]=2)=[CH:16][N:15]=1.[O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: Nc1ncc(-c2cnn(CCO)c2)c2scc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)c12
Solvent: O
Solvent: C1CCOC1
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
There is further provided a process for preparing N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl)-N′-(3-fluorophenyl)urea ascorbate in a solid crystalline form, wherein the crystalline form is Form VII, comprising: a) providing a mixture comprising (i) N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl)-N′-(3-fluorophenyl)urea free base solid, tetrahydrofuran, water, and ascorbic acid; b) causing N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl)-N′-(3-fluorophenyl)urea ascorbate crystalline Form VII to exist in the mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[N:15]2)[N:4]=1>CCOC(C)=O.CCO.O=[Pt]=O>[NH2:19][C:17]1[CH:16]=[N:15][N:14]([CH2:13][CH2:12][NH:11][C:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=2)[CH:18]=1
Reactant: COc1cc(OC)nc(NCCn2cc([N+](=O)[O-])cn2)n1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(OC)nc(NCCn2cc(N)cn2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 4,6-dimethoxy-N-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidin-2-amine (3.39 g, 11.54 mmol) in EtOAc (8.0 mL, degassed) and EtOH (32 mL, degassed), PtO2 (1.23 g, 1.15 mmol) was added and the reaction mixture was stirred at rt under a H2-atmosphere for 3 h. The mixture was diluted with EtOH, filtered over celite and the filter cake was rinsed with EtOH. The filtrate was concentrated to obtain the title compound of a pale pink solid. LC-MS conditions A: tR=0.42 min, [M+H]+=265.13.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F-].[K+].[CH3:13][C@H:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1>CS(C)=O>[CH3:13][C@H:14]1[N:19]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:15]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1c([N+](=O)[O-])cnn1C
Temperature: 100 °C
Yield: 87.6 %

Procedure:
To a solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (355 mg, 2.2 mmol) and potassium fluoride (511 mg, 8.8 mmol) in dry DMSO (20 mL) was added (R)-tert-butyl 3-methylpiperazine-1-carboxylate (507 mg, 2.53 mmol) and the mixture was heated in the microwave at 100° C. for 10 hr. The mixture was partitioned between water (40 mL) and EtOAc (100 mL) and the organic layer passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (R)-tert-butyl 3-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperazine-1-carboxylate as an orange gum (627 mg). To a solution of this gum (179 mg, 0.55 mmol) and ammonium formate (256 mg, 4.4 mmol) in MeOH (10 mL) under nitrogen was added 10% palladium on carbon (59 mg, 0.55 mmol). The mixture was heated at 70° C. for 4 hr before being cooled, filtered and concentrated under reduced pressure. The residue was partitioned between water (20 mL) and DCM (60 mL) and the organic layer separated, passed through a phase separation cartridge and concentrated under reduced pressure to give (R)-tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-methylpiperazine-1-carboxylate as a brown gum (150 mg, 80% over two steps). LCMS (ES+) m/z 296 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[N+:12]([O-])([OH:14])=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Product: O=C(O)c1cc(Cl)c(O)c([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
3-chloro-4-hydroxybenzoic acid (5.0 g) was added in small portions to stirred fuming HNO3 (90%, 15 mL) cooled on ice. After completion of addition, the orange mixture was allowed to warm to 20° C. and stirring was continued for 2 h. Ice water (50 mL) was added, and the precipitated product was collected by vacuum filtration to yield 5.4 g of 3-chloro-4-hydroxy-5-nitrobenzoic acid as a bright yellow solid.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[CH2:13]([O:15][C:16](=[O:29])[CH:17]([N:21]=CC1C=CC=CC=1)[CH2:18][CH2:19][CH3:20])[CH3:14].ICCC>O1CCCC1.CCCCCC>[CH2:13]([O:15][C:16](=[O:29])[C:17]([NH2:21])([CH2:18][CH2:19][CH3:20])[CH2:2][CH2:1][CH3:3])[CH3:14]
Reactant: CCCC(N=Cc1ccccc1)C(=O)OCC
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCCI
Product: CCCC(N)(CCC)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A solution of 10.4 ml of diisopropylamine in 200 ml of tetrahydrofuran was combined dropwise at 0° C. with stirring under a stream of dry nitrogen with 49 ml of a 1.6 molar solution of n-butyllithium in n-hexane. After cooling to -78° C., a solution of 18.31 g of the product from stage 2 in 80 ml of tetrahydrofuran was added dropwise. The entire reaction batch was stirred for 30 minutes and a solution of 8.8 ml of 1-iodopropane in 40 ml of tetrahydrofuran was then added dropwise. The reaction batch was stirred for 16 hours, wherein the temperature slowly rose to 20° C. The solvent was removed by distillation. The resultant orange-coloured residue was redissolved in 500 ml of 1 N hydrochloric acid. After 1 hour's stirring at 20° C., extraction was performed three times with 100 ml portions of diethyl ether. The phase acidified with hydrochloric acid was adjusted to a pH of between 10 and 12 with potassium hydroxide and then extracted three times with 100 ml portions of diethyl ether. The extracts were combined, washed twice with a saturated sodium chloride solution and dried over sodium sulphate. The crude product obtained after removing the solvent by distillation was purified by passage through a silica gel column with ethyl acetate. 9.84 g of 2-amino-2-propylpentanoic acid ethyl ester (67% of th.) were obtained in the form of a slightly coloured oil.
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:12]=[O:13])[CH3:2].O1CCCC1.[CH2:19]([Mg]Br)[CH:20]([CH3:22])[CH3:21].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:12]([OH:13])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:2]
Reactant: CC(C)C[Mg]Br
Reactant: CCc1c(C=O)oc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1c(C(O)CC(C)C)oc2ccccc12
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution (50 mL) of 3-ethyl-1-benzofuran-2-carbaldehyde (2.27 g) synthesized above in tetrahydrofuran was added dropwise 1.0M isobutylmagnesium bromide tetrahydrofuran solution (19.5 mL) at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:17, volume ratio) to give the title object compound (1.55 g, 51%) as a yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[Cl:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>>[Cl:26][C:27]([F:32])([F:31])[C:28]([O:30][C:4]1([N:7]=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:29]
Reactant: O=C(O)C(F)(F)Cl
Reactant: ON=C1CCOCC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: O=NC1(OC(=O)C(F)(F)Cl)CCOCC1

Procedure:
4-Nitrosotetrahydro-2H-pyran-4-yl 2-chloro-2,2-difluoroacetate was prepared from tetrahydro-pyran-4-one oxime, lead tetraacetate and chlorodifluoroacetic acid using conditions of General Method 3. 1H NMR (360 MHz, chloroform-d) δ 4.06-4.23 (2H, m), 3.52-3.86 (2H, m), 2.27-2.70 (2H, m), 1.72-2.07 (2H, m).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=2)=[O:12])[C:4](=[O:28])[CH:3]=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH:45]2[CH2:47][CH2:46]2)=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH:45]2[CH2:47][CH2:46]2)=[C:32]([C:2]2[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=3)=[O:12])[C:4](=[O:28])[CH:3]=2)[CH:31]=1
Reactant: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1Br
Reactant: CC1(C)OB(c2cc(Cl)ccc2C2CC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C1CC1
Reaction time: 8 h

Procedure:
Under argon (in a flask dried by heating), 125 mg (0.27 mmol) of tert-butyl 4-{[2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate (racemate), 92 mg (0.33 mmol, 1.2 eq.) of 2-(5-chloro-2-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 114 mg (0.82 mmol, 3.0 eq.) of potassium carbonate and 22 mg (0.03 mmol, 0.1 eq.) of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were suspended in 5.0 ml of dioxane and stirred overnight in an oil bath already preheated to 110° C. The reaction mixture was filtered through Celite and the residue was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The residue was triturated with water, filtered off, washed with water, dried under reduced pressure and purified by flash chromatography (silica gel-50, cyclohexane/ethyl acetate gradient). Yield: 114 mg (79% of theory)
Reaction SMILES: [NH2:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[S:12][CH:13]=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.P(Cl)(Cl)(Cl)=O.[CH:34]([NH:36][C:37]1[S:38][C:39]([Br:49])=[C:40]([C:42](=[N:46][O:47][CH3:48])[C:43](O)=[O:44])[N:41]=1)=[O:35]>C(OCC)(=O)C.CN(C)C=O>[CH:34]([NH:36][C:37]1[S:38][C:39]([Br:49])=[C:40]([C:42](=[N:46][O:47][CH3:48])[C:43]([NH:1][CH:2]2[C:19](=[O:20])[N:4]3[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]4[S:12][CH:13]=[N:14][N:15]=4)[CH2:7][S:8][C@H:3]23)=[O:44])[N:41]=1)=[O:35]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Reactant: CON=C(C(=O)O)c1nc(NC=O)sc1Br
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1nc(NC=O)sc1Br
Yield: 59.6 %

Procedure:
A solution of 7-amino-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 1.1 g.) and trimethylsilylacetamide (3.4 g.) in dry ethyl acetate (30 ml.) and a mixture of dimethylformamide (0.3 ml.), phosphoryl chloride (0.35 ml.), 2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 1.0 g.) and dry ethyl acetate (30 ml.) were treated in a similar manner to that of Example 1-(1) to give 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 1.2 g.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[F:11][CH:12]([F:27])[CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[N:16]=[C:15]1S(C)(=O)=O.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[N:14]([CH2:13][CH:12]([F:11])[F:27])[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nc2cccnc2n1CC(F)F
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Cn1c(Oc2ccc(Br)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a stirred solution of 4-bromophenol (238 mg) in DMF (4 mL) was added NaH (60% in oil, 55.1 mg) at room temperature. The mixture was stirred at room temperature for 30 min and then 3-(2,2-difluoroethyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (360 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (387 mg).