Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[S:8](N)([NH2:11])(=[O:10])=[O:9]>O1CCOCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: CN1CCN(S(N)(=O)=O)CC1

Procedure:
To a solution of 1-Methylpiperazine (1.58 g) in dioxane was added sulfamide (4.0 g) and the reaction mixture was then heated at reflux in dioxane for 18 h. The reaction mixture was then reduced in vacuo and the residue partitioned between EtOAc (100 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×100 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a white solid. Yield: 640 mg
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]#[N:21])=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.CCO>>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH2:21])=[CH:17][CH:18]=2)=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(OCCc2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NCCc1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 N NaOH solution (45.2 ml, 90.3 mmol) is added to a solution of {4-[2-(4-Fluoro-phenyl)-ethoxy]-phenyl}-acetonitrile (3.29 g, 12.9 mmol) in EtOH (45.2 mol) followed by Al—Ni Alloy (2.5 g) and the resulting reaction mixture is stirred for 1 hour at room temperature. The reaction mixture is filtered and the EtOH removed in vacuo. The product is extracted into DCM (2×80 ml), dried (MgSO4) and the solvent removed in vacuo to yield the title compound as a yellow oil.
Reaction SMILES: [CH3:1][S:2][CH2:3][O:4][N:5]=[C:6]([C:29]1[N:34]=[C:33]([NH:35]C=O)[CH:32]=[CH:31][N:30]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([O-:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8].Cl.C(=O)(O)[O-].[Na+]>CO>[CH3:1][S:2][CH2:3][O:4][N:5]=[C:6]([C:29]1[N:34]=[C:33]([NH2:35])[CH:32]=[CH:31][N:30]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([O-:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CSCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nccc(NC=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CSCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.7 %

Procedure:
A mixture of 7-[2-methylthiomethoxyimino-2-(4-formamidopyrimidin-2-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (1.9 g) and concentrated hydrochloric acid (0.7 ml) in methanol (19 ml) was stirred for 1.5 hours at room temperature. The mixture was adjusted to pH 4 with aqueous sodium bicarbonate and evaporated under reduced pressure. The residue was dissolved in water (200 ml) and subjected to column chromatography on a non ionic adsorption resin "HP-20" (300 ml). After the column was washed with water, the elution was carried out with 25% aqueous methanol. The eluate was evaporated to remove methanol under reduced pressure and lyophilized to give 7-[2-methylthiomethoxyimino-2-(4-aminopyrimidin-2-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (1.13 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:16][C:17]4[CH:24]=[CH:23][C:20]([CH3:21])=[CH:19][CH:18]=4)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: Sc1nnc(-c2ccc3c(c2)CCO3)o1
Reactant: Cc1ccc(CBr)cc1
Product: Cc1ccc(CSc2nnc(-c3ccc4c(c3)CCO4)o2)cc1
Yield: 75 %

Procedure:
In the same manner as in Example 1 and using 5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 4-methylbenzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 75%) was obtained as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:19]([CH2:20][CH2:21]O)[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.O>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:11]3=[N:12][C:13]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[N:19]3[CH2:20][CH2:21]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Nc2nc3cccnc3n2CCO)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCn3c2nc2cccnc23)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To a solution of 2-{2-[(4-nitrophenyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}ethanol (2.2 g) and triethylamine (10 mL) in THF (100 mL) was added methanesulfonyl chlorode (1.1 mL) at 0° C., and the mixture was stirred at 0° C. for 2 h. The mixture was poured into water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. A mixture of the residue and potassium carbonate (3.1 g) in NMP (30 mL) was stirred at 100° C. overnight. After cooling to room temperature, the mixture was diluted with water. The formed crystals were collected by filtration to give the title compound (1.7 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([OH:33])=O)=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([NH:34][C@@H:35]4[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:37][CH2:36]4)=[O:33])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:29])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)c2nccc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: Cc1c(C(=O)N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c2nccc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c3) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: FC1C([O:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([N:19]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=3)[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:34])[NH:28][C:29]4[N:30]=[N:31][NH:32][N:33]=4)=[CH:23][CH:22]=3)=[O:18])[CH:11]=2)=C(F)C(F)=C(F)C=1F.[CH3:50][NH2:51]>C1COCC1>[CH3:50][NH:51][C:9](=[O:8])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([N:19]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:42])[CH3:43])=[CH:37][CH:36]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:34])[NH:28][C:29]3[N:30]=[N:31][NH:32][N:33]=3)=[CH:23][CH:22]=2)=[O:18])[CH:11]=1
Reactant: CC(C)(C)c1ccc(N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)C(=O)Nc2cccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c2)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(NC(=O)N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)c2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the above resin bound 3-{3-(4-tert-butylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl) benzyl]-ureido}benzoic acid pentafluorophenyl ester was added a solution of methylamine in THF (2M, 5 mL). The mixture was shaken at 25° C. overnight, filtered and washed with THF (2×10 mL), affording the resin bound title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C.C(O)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:12][CH2:13][CH:14]([O:17][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:15][CH2:16]2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1csc(N2CCC(O)CC2)n1
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(N2CCC(OS(C)(=O)=O)CC2)n1
Reaction time: 0.17 h
Yield: 48.4 %

Procedure:
To a solution of 1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-4-hydroxypiperidine (128 mg, 0.50 mmol) (obtained as described in Reference Example 13(2)) in methylene chloride (6.5 ml) was added methanesulfonyl chloride (0.043 ml, 0.56 mmol) and triethylamine (0.084 ml, 0.60 mmol) in an ice bath. The reaction mixture was brought to room temperature in 10 minutes and then stirred for 30 minutes. After checking the completion of the reaction, ethanol (1 ml) was added thereto in an ice bath and then the reaction mixture was stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was recrystallized from a solution of ethyl acetate:n-hexane (5:1) to afford 1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)4-methanesulfonyloxypiperidine (81.0 mg, yield 49%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[C:20]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:19]=[CH:18][N:17]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccnc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
4-amino-phenol (8.9 g, 81.6 mmol) and potassium tert-butoxide (10.7 g, 95.2 mmol) were suspended in DMF (100 mL) and stirred at RT for 30 min. 2,4-Dichloro-pyridine (10 g, 68 mmol) was added and the resulting mixture was heated to 90° C. for 3 h. The solvent was removed under vacuum and the residue was extracted with DCM (2×100 mL). The combined organics were dried (MgSO4), concentrated in vacuo and purified by silica gel chromatography to afford 4-(2-chloro-pyridin-4-yloxy)-phenylamine (9.0 g, 60% yield). 1H NMR (DMSO-d6): δ 8.21 (d, J=5.6 Hz, 1 H), 6.85-6.82 (m, 4 H), 6.61 (d, J=6.6 Hz, 2 H), 5.17 (s, 2 H); MS (ESI) m/z: 221 (M+H+).
Reaction SMILES: O.[OH-].[Na+].[CH3:4][C:5]([C:7]1([Cl:10])[CH2:9][CH2:8]1)=[O:6].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>C(O)C>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH:4][C:5]([C:7]2([Cl:10])[CH2:9][CH2:8]2)=[O:6])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C1(Cl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccc(Cl)cc1)C1(Cl)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
50 ml of water and 10 pellets of solid sodium hydroxide are added at room temperature to a mixture of 0 g (0.5 mol) of 1-chlorocyclopropyl methyl ketone, 70 g (0.5 mol) of 4-chlorobenzaldehyde and 250 ml of ethanol. The mixture is stirred at room temperature for 16 hours. The precipitated solid is then filtered off with suction. In this manner, 108.5 g (89% of theory) of 1-chlorocyclopropyl 4-chlorophenylethenyl ketone are obtained in the form of a solid substance of melting point 92° C.
Reaction SMILES: [CH3:1][N:2]1[C:15]([C:16](OC)=[O:17])=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:22])=[O:21].[NH2:23][C:24]1[O:25][CH:26]=[C:27]([CH3:29])[N:28]=1>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[C:15]([C:16]([NH:23][C:24]2[O:25][CH:26]=[C:27]([CH3:29])[N:28]=2)=[O:17])=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:22])=[O:21]
Reactant: Cc1coc(N)n1
Reactant: COC(=O)C1=C(O)c2c(c3ccccc3n2C)S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: Cc1coc(NC(=O)C2=C(O)c3c(c4ccccc4n3C)S(=O)(=O)N2C)n1
Yield: 19.8 %

Procedure:
3.0 gm (9.1 millimols) of methyl 2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino-[5,6-b]indole-3-carboxylate-1,1-dioxide and 0.98 gm (10 millimols) of 2-amino-4-methyloxazole were refluxed for 4 hours in 250 ml of xylene. Upon cooling, the raw product crystallized out. Recrystallization from ethanol yielded 0.7 gm (20% of theory) of 2,5-dihydro-2,5-dimethyl-4-hydroxy-N-(4-methyl-2-oxazolyl)-1,2-thiazino[5,6-b]-indole-3-carboxamide-1,1-dioxide; M.p.: 128° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].F[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][C:8]=1[N+:19]([O-:21])=[O:20]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][C:8]=1[N+:19]([O-:21])=[O:20]
Reactant: COCCN
Reactant: O=[N+]([O-])c1cc(-c2ccccc2)ccc1F
Solvent: CCO
Product: COCCNc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-methoxyethaneamine (1.5 mL) is added to a solution of 4-fluoro-3-nitrobiphenyl (200 mg, 0.92 mmol) in ethanol. The reaction may be stirred at room temperature overnight and concentrated. The residue may be purified by any appropriate method, such as Biotage column chromatography to give N-(2-methoxyethyl)-3-nitrobiphenyl-4-amine (228 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][CH3:24])=[O:22])=[CH:16][CH:15]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)O1>>[NH2:37][C:36]1[CH:38]=[CH:39][C:33]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][CH3:24])=[O:22])=[CH:16][CH:15]=3)[N:3]=2)=[CH:34][CH:35]=1
Reactant: CNC(=O)Nc1ccc(-c2nc(Cl)nc(N3CCOCC3)n2)cc1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3CCOCC3)n2)cc1
Yield: 45 %

Procedure:
The title compound was prepared by following the procedure of Example 462 step 4 using 1-(4-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. Yield 2 g, 45% yield.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[CH:10]=2)[C:5]2[N:26]=[CH:27][CH:28]=[CH:29][C:4]=2[N:3]=1.[Br:30]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:30][CH2:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[CH:10]=2)[C:5]2[N:26]=[CH:27][CH:28]=[CH:29][C:4]=2[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2cccnc2n(-c2cccc(NC(=O)c3cc(Cl)cc(Cl)c3)c2)c1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cccc(-n2c(=O)c(CBr)nc3cccnc32)c1)c1cc(Cl)cc(Cl)c1
Yield: 26.8 %

Procedure:
The mixture of 2-methyl-4-[3-(3,5-dichlorobenzoylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (4.4 g), N-bromosuccinimide (2.39 g) and benzoylperoxide in chloroform (40 ml) was refluxed for 3 hours. The mixture was washed with water and extracted by chloroform (80 ml), and evaporated. The crude product was purified by chromatography to obtain 2-bromomethyl-4-[3-(3,5-dichlorobenzoylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (1.4 g).
Reaction SMILES: [O:1]([CH2:19][C:20]1([CH2:28][N:29]2[CH:33]=[C:32]([CH2:34][OH:35])[N:31]=[C:30]2[N+:36]([O-:38])=[O:37])[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[CH3:48][O:49][CH2:50]Cl.C(=O)(O)[O-].[Na+]>ClCCl>[O:1]([CH2:19][C:20]1([CH2:28][N:29]2[CH:33]=[C:32]([CH2:34][O:35][CH2:48][O:49][CH3:50])[N:31]=[C:30]2[N+:36]([O-:38])=[O:37])[CH2:25][O:24][C:23]([CH3:26])([CH3:27])[O:22][CH2:21]1)[Si:2]([C:15]([CH3:16])([CH3:18])[CH3:17])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC1(C)OCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(Cn2cc(CO)nc2[N+](=O)[O-])CO1
Reactant: COCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOCc1cn(CC2(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)COC(C)(C)OC2)c([N+](=O)[O-])n1
Temperature: 0 °C
Reaction time: 26 h
Yield: 78.9 %

Procedure:
101 mg (0.19 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-[(4-hydroxymethyl-2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane was dissolved in 2.0 mL of dichloromethane and cooled to about 0° C. in an ice bath. 125 μL (0.72 mmol equivalents) of N,N-diisopropylethylamine and 41 μL (0.51 mmol equivalents) of methoxymethyl chloride were added thereto, and the mixture was stirred for 26 hours while increasing the temperature to room temperature (25° C.). After completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added dropwise, and the mixture was extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, then dried with anhydrous magnesium sulfate, and subsequently concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=2/1) to give 86 mg (0.15 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-[(4-methoxymethoxymethyl-2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane.
Reaction SMILES: O[C:2]1([CH:8]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[C:9]2[N:10]=[N:11][NH:12][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O>ClCCl>[C:2]1(=[C:8]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[C:9]2[N:10]=[N:11][NH:12][CH:13]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: N#Cc1ccc(C(c2c[nH]nn2)C2(O)CCCCC2)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(C(=C2CCCCC2)c2c[nH]nn2)cc1
Reaction time: 2 h
Yield: 36.5 %

Procedure:
7.6 g of crude 4-[1-hydroxycyclohex-1-yl-1-(1,2,3-triazolyl)methyl]benzonitrile is dissolved at 0° in 50 ml of dichloromethane and stirred at 0° for 1 hour with 22.7 ml of thionyl chloride. Then the mixture is concentrated to dryness under vacuum, dissolved in 50 ml of dichloromethane, stirred with 30 ml of triethylamine for 2 hours, diluted with water, extracted three times with ethyl acetate, washed with water, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, thus obtaining 2.6 g of 4-[1-cyclohexylidene-1-(1,2,3-triazolyl)methyl]benzonitrile as the free base. 132°-133° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].Cl.Cl[CH2:31][C:32]1[N:33]=[CH:34][S:35][CH:36]=1>O.CN(C)C(=O)C>[S:35]1[CH:36]=[C:32]([CH2:31][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[NH:10][CH:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]2)[N:33]=[CH:34]1
Reactant: ClCc1cscn1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2cscn2)C1
Reaction time: 3 h
Yield: 69.9 %

Procedure:
To a stirred mixture of 5.5 parts of ethyl 3-(1H-benzimidazol-2-ylamino)-1-pyrrolidinecarboxylate, 6.4 parts of sodium carbonate, 0.1 parts of potassium iodide and 81 parts of N,N-dimethylacetamide were added portionwise 4.3 parts of 4-(chloromethyl)thiazole hydrochloride at 130° C. Upon completion, stirring was continued for 3 hours at 130° C. After cooling, the reaction mixture was poured into 450 parts of water. The product was extracted twice with methylbenzene. The combined extracts were washed with water, dried, filtered and evaporated, yielding 5.2 parts (69.9%) of ethyl 3-[[1-(4-thiazolylmethyl)-1H-benzimidazol-2-yl]amino]-1-pyrrolidinecarboxylate as an oily residue (compound 32).
Reaction SMILES: C([O:4][C@H:5]1[C@@H:9]([O:10]C(=O)C)[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:32]#[N:33])=[N:18][C:19]=3[NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:7][C@@H:6]1[CH2:34][O:35]C(=O)C)(=O)C.N.[H][H]>C(O)C.[Pd]>[NH3:14].[NH2:33][CH2:32][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@H:8]2[C@H:9]([OH:10])[C@H:5]([OH:4])[C@@H:6]([CH2:34][OH:35])[O:7]2)=[C:19]([NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:18]=1
Reactant: [H][H]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Agent: N
Solvent: CCO
Product: NCc1nc(NCCc2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
A solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-[2-cyano-6-(phenethylamino)-9H-purin-9-yl]tetrahydro-3-furanyl acetate (1.0 g, 1.91 mmol) (Preparation 11) in ethanol (40 ml) saturated with ammonia gas was treated with 5% w/w palladium on charcoal (0.50 g), pressurised to 1034 kPa (150 psi) with hydrogen in a sealed vessel and stirred at room temperature for 18 hours. TLC analysis showed that some starting material still remained and therefore further 5% w/w palladium on charcoal (0.25 g) and ethanol (20 ml) saturated with ammonia were added and the mixture was again pressurised to 1034 kPa (150 psi) with hydrogen in a sealed vessel and stirred at room temperature for 18 hours. The mixture was filtered through a pad of Arbocel (trade mark) and the filtrate was evaporated under reduced pressure. The residue was azeotroped from dichloromethane, then purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (90:10:0.5 by volume) to afford the title compound as a white solid (340 mg).
Reaction SMILES: [N:1]1([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].[K+].[F:15][C:16]([F:21])([F:20])[C:17](F)=[O:18]>C1(C)C=CC=CC=1>[F:15][C:16]([F:21])([F:20])[C:17](=[O:18])[C:8](=[CH:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C=CN1CCCCC1
Reactant: O=C(F)C(F)(F)F
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C(=CN1CCCCC1)C(=O)C(F)(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
Methyl 3-piperidin-1-ylacrylate (97%, 25 g, 0.14 mol) and KF (12.5 g, 76.3 mmol) were initially charged in 250 ml of toluene and cooled to −30° C. At this temperature, trifluoroacetyl fluoride (99.5%, 18.3 g, 0.16 mol) was then introduced. The reaction mixture was stirred at −30° C. for 3 h and then, over a period of one hour, warmed to room temperature. The reaction mixture was washed with deionized water (100 ml). After phase separation, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined, washed with an aqueous sat. NaCl solution (100 ml) and then freed from the solvent under reduced pressure. Methyl 4,4,4-trifluoro-3-oxo-2-(piperidin-1-ylmethylidene)butyrate was obtained as an orange solid (amount: 38.0 g; purity according to GC: 98%; yield: 98%). 1H-NMR (CDCl3): δ=1.75 (m, 6H), 3.3 (m, 2H), 3.6 (m, 2H), 3.75 (s, 3H), 7.65 ppm (s, 1H).