Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@H:4]([CH:5]=O)[C@H:3]1[C:7]([O:9][CH3:10])=[O:8].[Br-].[O:13]=[C:14]([CH3:35])[CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClC(Cl)C>[CH3:1][C:2]1([CH3:11])[C@H:4](/[CH:5]=[CH:15]/[C:14](=[O:13])[CH3:35])[C@H:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1[C@@H](C=O)C1(C)C
Agent: [Br-]
Solvent: CC(Cl)Cl
Product: COC(=O)[C@@H]1[C@@H](/C=C/C(C)=O)C1(C)C
Yield: 80.3 %

Procedure:
A mixture of 5 g of methyl (1R,trans) 2,2-dimethyl-3-formyl-cyclopropane-1-carboxylate, 11.3 g of 2-oxopropyl-triphenylphosphonium bromide and 50 ml of dichloroethane was refluxed for 2 hours and the temperature was allowed to return to room temperature. The mixture was evaporated to dryness under reduced pressure and the 19 g of oil residue were empasted with ether and filtered. The filtrate was evaporated to dryness and the 5 g of oil residue were chromatographed over silica gel. Elution with a 7-3 cyclohexane-ethyl acetate mixture yielded 4.46 g of methyl (1R,trans) 2,2-dimethyl-3-[(E)-3-oxo-1-butenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+108°±2.5° (c=0.6% in benzene).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)[C:6](=[S:14])[NH:5][C:4](=[O:15])[CH:3]=1.[N:16]([O-])=[O:17].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)[C:6](=[S:14])[NH:5][C:4](=[O:15])[C:3]=1[N:16]=[O:17]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)[nH]c(=S)n1CC1CCCO1
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1c(N=O)c(=O)[nH]c(=S)n1CC1CCCO1
Temperature: 75 °C
Yield: 90.6 %

Procedure:
6-Amino-1-(2-tetrahydrofuryl-methyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.3 g, 5.6 mmol) was suspended in 10% aqueous acetic acid (25 mL). Sodium nitrite (0.43 g, 6.2 mmol) was added and this mixture was heated at 75° C. for 1 h. The purple solid was collected by filtration, washed and dried, giving the title product (1.3 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:13])[CH2:9][N:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:14][CH3:15].O[C:17]1[C:18]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH2:29])=[O:28])[C:19]=2[N:20]=[N:21][N:22]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH2:29])=[O:28])[C:19]=3[N:20]=[N:21][N:22]=2)[CH2:9][N:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: COc1cc([C@H](N)CN(C)C)ccc1Cl
Reactant: NC(=O)c1cccc2c(O)nnnc12
Product: COc1cc([C@@H](CN(C)C)Nc2nnnc3c(C(N)=O)cccc23)ccc1Cl

Procedure:
Compound 11 was prepared following general synthetic scheme 7 wherein (S)-1-(4-chloro-3-methoxyphenyl)-N2,N2-dimethylethane-1,2-diamine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [401 (M+1)], 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 9.27 (s, 1H), 9.09 (d, 1H), 8.58 (dd, 2H), 8.08 (t, 2H), 7.44 (d, 2H), 7.18 (dd, 1H), 6.26 (t, 1H), 3.89 (s, 3H), 3.83-3.76 (m, 1H), 3.62-3.57 (m, 1H), 2.92 (d, 6H).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:10]=[C:11]([C:23](O)=[O:24])[N:12]([CH2:14][CH2:15][NH:16][C@H:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[O:1]([CH2:8][C:9]1[CH:10]=[C:11]2[C:23](=[O:24])[N:16]([C@H:17]([CH3:22])[C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:15][CH2:14][N:12]2[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](NCCn1nc(COc2ccccc2)cc1C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](N1CCn2nc(COc3ccccc3)cc2C1=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 16.9 %

Procedure:
A mixture of (R)-5-phenoxymethyl-2-[2-(1,2,2-trimethyl-propylamino)-ethyl]-2H-pyrazole-3-carboxylic acid (130 mg, 0.38 mmol) and HATU (143 mg, 0.38 mmol) in DMF (3 mL) was stirred for 5 minutes at room temperature, then DIPEA (0.16 mL, 0.945 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours and then washed with a saturated solution of NH4Cl and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo. The desired product was triturated with diethyl ether to yield (R)-2-phenoxymethyl-5-(1,2,2-trimethyl-propyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (21 mg, 17% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 0.98 (s, 9H), 1.21 (d, J=7.2 Hz, 3H), 3.66-3.79 (m, 2H), 4.27-4.40 (m, 2H), 4.73 (q, J=7.2 Hz, 1H), 5.09 (s, 2H), 6.93 (s, 1H), 6.96 (t, J=7.4 Hz, 1H), 7.00 (d, J=7.8 Hz, 2H), 7.27-7.32 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[N:10]1([CH2:16][CH2:17][OH:18])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(CC)CC)C>ClCCl>[Cl:8][C:6]1[N:5]=[C:4]([CH3:9])[N:3]=[C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH2:16][CH2:17][OH:18])[CH2:11][CH2:12]2)[CH:7]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: OCCN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)cc(N2CCN(CCO)CC2)n1
Reaction time: 4 h

Procedure:
To a solution of 4,6-dichloro-2-methylpyrimidine (3.00 g) in dichloromethane (35 mL) was added 2-(piperazin-1-yl)ethanol (4.51 mL) at room temperature, and the mixture was stirred for 4 hr. To the reaction mixture was added triethylamine (0.513 mL) at room temperature, and the reaction mixture was stirred overnight. The resulting solid was collected by filtration, washed with dichloromethane, and dried under reduced pressure to give the title compound (4.08 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:29]2[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]2=[O:39])[CH:5]=[CH:6][C:7]=1[C:8]1C(OC)=N[C:11]([O:14][C@@H:15]2[CH2:20][O:19][C:18]3=[N:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][N:17]3[CH2:16]2)=[N:12][CH:13]=1.[CH3:40][O:41][C:42](=[O:63])[C:43]1C=C(Br)C=N[C:44]=1O[C@@H]1COC2=NC([N+]([O-])=O)=CN2C1>>[CH3:40][O:41][C:42](=[O:63])[C:43]1[CH:44]=[C:8]([C:7]2[CH:6]=[CH:5][C:4]([N:29]3[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]3=[O:39])=[CH:3][C:2]=2[F:1])[CH:13]=[N:12][C:11]=1[O:14][C@@H:15]1[CH2:20][O:19][C:18]2=[N:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][N:17]2[CH2:16]1
Reactant: COc1nc(O[C@@H]2COc3nc([N+](=O)[O-])cn3C2)ncc1-c1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Reactant: COC(=O)c1cc(Br)cnc1O[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Product: COC(=O)c1cc(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)cnc1O[C@@H]1COc2nc([N+](=O)[O-])cn2C1

Procedure:
(S,S)—N-(3-{3-Fluoro-4-[4-methoxy-2-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxy)-pyrimidin-5-yl]-phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide. The title compound was prepared by following the same procedure as described in the preparation of Example 7, except 5-bromo-2-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6(S)-yloxy)-nicotinic acid methyl ester was used in place of 6(S)-(5-bromo-pyridin-2-yloxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine. ESI MS m/z 571.5 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: BrCc1cncnc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2cncnc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.5 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (483 mg, 3.4 mmol) was dissolved in absolute ethanol (70 mL), and triethylamine (1.4 mL, 10.2 mmol) and 5-(bromomethyl)pyrimidine (882 mg, 5.1 mmol) were added. The mixture was stirred overnight at room temperature. The solid was filtered. The filtrate was evaporated. The residue was triturated in water, filtered, and washed with water followed with diethyl ether. The solid was dissolved in DCM and purified on silica gel using 10% DCM/MeOH to afford 6-methyl-2-[(pyrimidin-5-ylmethyl)sulfanyl]pyrimidin-4-ol (12 mg, 2% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H), 4.34 (s, 2H), 6.02 (bs, 1H), 8.88 (s, 2H), 9.05 (s, 1H); LRMS (ES) m/z 235 (100%, M+1).
Reaction SMILES: O=[CH:2][CH2:3][NH:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6].[CH2:17]([NH:20][CH:21]1[CH2:29][CH2:28][C:24]2[N:25]=[CH:26][S:27][C:23]=2[CH2:22]1)[CH2:18]C>>[CH2:17]([N:20]([CH:21]1[CH2:29][CH2:28][C:24]2[N:25]=[CH:26][S:27][C:23]=2[CH2:22]1)[CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6])[CH3:18]
Reactant: CCCNC1CCc2ncsc2C1
Reactant: O=CCNC(=O)c1ccc2ccccc2c1
Product: CCN(CCNC(=O)c1ccc2ccccc2c1)C1CCc2ncsc2C1
Yield: 34 %

Procedure:
Compound 32 is prepared from 32B and 1C as described for 1. The salt of oxalic acid is crystallized from ethanol/diethylether.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:17]3[CH:34]=[CH:33][C:20]([O:21][CH2:22][C:23]4[CH:32]=N[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=4)=[CH:19][CH:18]=3)=[N:9][N:10]([CH2:12]C(F)(F)F)[CH:11]=2)=[CH:3][CH:2]=1.CN1C=C(C2C=CN=CC=2)C(C2C=CC(O)=CC=2)=N1.[Cl:54][C:55]1C2C(=CC=CC=2)N=C(CO)C=1>>[Cl:54][C:55]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23]([CH2:22][O:21][C:20]2[CH:19]=[CH:18][C:17]([C:8]3[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[CH:11][N:10]([CH3:12])[N:9]=3)=[CH:34][CH:33]=2)[CH:32]=1
Reactant: FC(F)(F)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3cnc4ccccc4n3)cc2)n1
Reactant: OCc1cc(Cl)c2ccccc2n1
Agent: Cn1cc(-c2ccncc2)c(-c2ccc(O)cc2)n1
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3cc(Cl)c4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-{4-[4-Pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoxaline but substituting 4-(1-Methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenol and (4-Chloro-quinolin-2-yl)-methanol provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=4.6 Hz, 2 H), 8.18 (d, J=8.7 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.73 (m, 2H), 7.60 (t, J=7.1 Hz, 1 H), 7.52 (s, 1 H), 7.37 (d, J=9.1, Hz, 2 H), 7.12 (d, J=6.2 Hz, 2H), 6.98 (d, J=8.7 Hz, 2 H), 5.30 (s, 2H), 3.90 (s, 3 H); MS: (M+H m/z=427.1).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:11](=[O:16])[NH:12][CH:13]2[CH2:15][CH2:14]2)=[N:8][O:9][CH:10]=1)=[O:5])C.[Li+].[OH-].C(OCC)C>C1COCC1.C(O)C>[CH:13]1([NH:12][C:11]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][N:8]=2)=[O:16])[CH2:14][CH2:15]1
Reactant: CCOC(=O)c1conc1C(=O)NC1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1conc1C(=O)NC1CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 3-(cyclopropylcarbamoyl)-isoxazole-4-carboxylic acid ethyl ester (600 mg, 2.68 mmol) in THF (7 ml) and ethanol (3 ml) was added LiOH (1M; 5.35 ml, 5.35 mmol) at 0-5° C. The mixture was stirred at 20° C. for 1 h, poured into 50 ml diethyl ether and extracted. The organic phase was washed with water. The combined aqueous phases were acidified with 1M HCl (6 ml) and extracted with dichloromethane. The organic layers were dried and evaporated to yield the product as yellow oil (464 mg, 80%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]#[CH:18])[CH:8]=[CH:9][C:2]1=2.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][C:17]#[CH:18])[CH:8]=[CH:9][C:2]1=2
Reactant: C#CCNCCOCCc1ccc2sccc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCN(CCOCCc1ccc2sccc2c1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
In 3 ml of N,N-dimethylformamide is dissolved 0.60 g of N-[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl]-N-(2-propynyl)amine, to which are added 0.40 g of benzyl bromide and 0.35 g of potassium carbonate. The mixture is stirred at ambient temperature for one hour. Water and ethyl acetate are added to the reaction mixture, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by column chromatography (eluent: chloroform:methanol=10:1 to 7:1) to obtain 0.67 g of N-[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl]-N-benzyl-N-(2-propynyl)amine as an oily product.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].[Cl:21][C:22]([Cl:26])([Cl:25])[C:23]#[N:24].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:21][C:22]([Cl:26])([Cl:25])[C:23](=[NH:24])[O:7][C@H:6]1[O:8][C@@H:9]([CH3:20])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:5]1[O:4][C:1](=[O:3])[CH3:2]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)OC(O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](OC(=N)C(Cl)(Cl)Cl)O[C@@H](C)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
A mixture of 2,3,4-tri-O-acetyl-L-fucopyranose (anomer mixture) (0.85 g, 2.93 mmol), trichloroacetonitrile (3 ml, 30 mmol) and potassium carbonate (2.73 g, 19.7 mmol) in dry dichloromethane (12 ml) is stirred under nitrogen at room temperature for about 4 h. After filtration through kieselguhr, the solvent is removed. After chromatographic purification (petroleum ether/diethyl ether 2:5), a mixture of O-(2,3,4-tri-O-acetyl-α-L-fucopyranosyl) trichloroacetimidate (3) and O-(2,3,4-tri-O-acetyl-β-L-fucopyranosyl) trichloroacetimidate (2) is obtained in a yield of 76% (α:β=1:1.3). α-Anomer: [α]D =-116.0 (c=1, chloroform), Rf =0.54 (petroleum ether/ethyl acetate 2:1), m.p. 107°-109° C. β-Anomer: [α]D =-24.5 (c=1, chloroform), Rf =0.34 (petroleum ether/ethyl acetate 2:1), m.p. 60°-63° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:20][CH:21]([CH3:23])[CH3:22])=[O:9])[CH2:4][CH2:3]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1O>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][C:30]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([C:10]2[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:20][CH:21]([CH3:23])[CH3:22])=[O:9])[CH2:6][CH2:7]1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)CC1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2cc(C(F)(F)F)ccc2F)CC1
Yield: 35 %

Procedure:
Prepared in analogy to Example 4 from (4-hydroxy-piperidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 3(a)) and 2-fluoro-5-(trifluoromethyl)phenol. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 35%). MS (m/e): 504.4 (M+H+, 100%).
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:9]1[N:10]=[C:11]([NH:14][CH:15]=[O:16])[S:12][CH:13]=1)[C:6]([OH:8])=O)[CH3:2].C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[NH2:28][CH:29]1[C:46](=[O:47])[N:31]2[C:32]([C:43]([OH:45])=[O:44])=[C:33]([CH2:36][S:37][C:38]3[S:39][CH:40]=[N:41][N:42]=3)[CH2:34][S:35][C@H:30]12.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(OCC)(=O)C.O.CN(C)C=O>[CH2:1]([O:3][N:4]=[C:5]([C:9]1[N:10]=[C:11]([NH:14][CH:15]=[O:16])[S:12][CH:13]=1)[C:6]([NH:28][CH:29]1[C:46](=[O:47])[N:31]2[C:32]([C:43]([OH:45])=[O:44])=[C:33]([CH2:36][S:37][C:38]3[S:39][CH:40]=[N:41][N:42]=3)[CH2:34][S:35][C@H:30]12)=[O:8])[CH3:2]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Reactant: CCON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 0.5 h
Yield: 37 %

Procedure:
2-Ethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (3.0 g.) and dry ethyl acetate (40 ml.) were added at 0° to 5° C. with stirring to a suspension of Vilsmeier reagent prepared from dry dimethylformamide (1.0 g.) and phosphorus oxychloride (2.1 g.) in dry ethyl acetate (4.0 ml.) by conventional method, and the resulting mixture was stirred for 30 minutes at the same temperature. The solution was added at -10° C. with stirring to a solution of 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (3.7 g.), trimethylsilylacetamide (10.3 g.) and bis-(trimethylsilyl)acetamide (6.8 g.) in dry ethyl acetate (80 ml.), and the mixture was stirred for 1.5 hours at the same temperature. After addition of water (50 ml.) to the reaction mixture, an insoluble material was filtered off, the ethyl acetate layer in the filtrate was separated and extracted with an aqueous solution of sodium bicarbonate (50 ml.). The aqueuous extract was washed with ethyl acetate and acidified to pH 2.0 with conc. hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give powder of 7-[2-ethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.3 g.).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26]2[N:31]=[C:30]3[NH:32][N:33]=[C:34]([C:35]4[CH:40]=[CH:39][N:38]=[C:37]([S:41][CH3:42])[N:36]=4)[C:29]3=[CH:28][N:27]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>ClCCl.CO>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26]2[N:31]=[C:30]3[NH:32][N:33]=[C:34]([C:35]4[CH:40]=[CH:39][N:38]=[C:37]([S:41]([CH3:42])=[O:9])[N:36]=4)[C:29]3=[CH:28][N:27]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CSc1nccc(-c2n[nH]c3nc(NC4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
m-CPBA (428 mg, 2.4 mmol) was added slowly to a solution of 4-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (from Example 12 supra) (550 mg, 1.2 mmol) in a mixture of dichloromethane and methanol (100 mL, 1:1). The reaction mixture was stirred at room temperature for 20 minutes. The solvent was then removed under reduced pressure and the solid was purified by column chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1) to afford 4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-piperidine-1-carboxylic acid tert-butyl ester. (Yield 180 mg, 31.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl>[N:13]1[C:14]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[O:4][C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[NH:1][S:26]([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccccc1Oc1cccc2cccnc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccccc1Oc1cccc2cccnc12)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.54 g of 8-(2-aminophenoxy)quinoline are dissolved in 70 ml of dichloromethane, and a solution of 3.17 g of 4-chlorobenzenesulphonyl chloride in 30 ml of dichloromethane is added at 25° C. After 1 hour, 2.42 ml of pyridine are added, and the mixture is stirred for 15 hours at 25° C. After removal of the solvent by evaporation, the residue is stirred with water. The product is filtered off and recrystallized from ethanol.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:28][C:20]3[C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:36]([C:38]1[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=1[CH2:40]Br)#[N:37]>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:29])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:28]([CH2:40][C:39]3[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=3[C:36]#[N:37])[C:20]3[C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1CBr
Reactant: CCn1ccc2nc(C3CCCC(NC(=O)OCc4ccccc4)C3)[nH]c2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ccc2nc(C3CCCC(NC(=O)OCc4ccccc4)C3)n(Cc3ccccc3C#N)c2c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 54.9 %

Procedure:
To a solution of [3-(5-ethyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (0.1 g, 0.25 mmol) in DMF (3 mL) were added Cs2CO3 (0.17 g, 0.51 mmol) and 60 mg (0.30 mmol) of 2-cyanobenzyl bromide as a solution in 3 mL of DMF. After stirring at room temperature for 17 h, the reaction mixture was diluted with water (10 mL) then extracted with CH2Cl2. The combined extracts were dried with MgSO4, and concentrated in vacuo. The crude product was purified by flash chromatography, eluting with 1% MeOH in CH2CH2 to give {3-[3-(2-cyano-benzyl)-5-ethyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl]-cyclohexyl}-carbamic acid benzyl ester (70 mg, 54% yield). 1H-NMR (CDCl3): δ 7.73 (m, 1H), 7.49 (m, 1H), 7.34 (m, 6H), 7.13 (m, 1H), 6.89 (d, 1H, J=8.4 Hz), 6.69 (m, 1H), 6.19 (m, 1H), 5.94 (m, 1H), 5.06 (s, 2H), 4.73 (m, 1H), 4.07 (m, 2H), 3.58 (m, 1H), 2.79 (m, 1H), 2.02 (m, 2H), 1.87 (m, 1H), 1.68 (m, 2H), 1.51 (m, 2H), 1.38 (t, 3H, J=7.2 Hz), 1.16 (m, 1H). MS: calculated for C30H31N5O3+H 510.3; found: 510.5.
Reaction SMILES: C([O:3][C:4]([C:6]([F:17])([F:16])[CH:7]([O:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])[CH2:8][CH3:9])=[O:5])C.[OH-].[Na+]>O>[OH:5][C:4]([C:6]([F:16])([F:17])[CH:7]([O:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])[CH2:8][CH3:9])=[O:3]
Reactant: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 2 L reactor was charged with 80.0 g (purity 66%), 208 mmol) of methacrylic acid 1-ethoxycarbonyl-1,1-difluoro-2-butyl ester and 80.0 g of water, followed by cooling down to 0° C., adding dropwise 84.8 g (320 mmol/1.5 equivalents) of 15 wt % sodium hydroxide aqueous solution, and stirring at room temperature for 1 hour. The reaction liquid was washed with 800 g of diisopropyl ether. The obtained aqueous layer was washed with diluted hydrochloric acid, followed by extraction with diisopropyl ether two times, removing water by magnesium sulfate, conducting filtration, and distilling diisopropyl ether out, thereby obtaining 15.2 g of the target methacrylic acid 1-hydroxycarbonyl-1,1-difluoro-2-butyl ester.