Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].C(N(C(C)C)CC)(C)C.[C:32]1([CH2:38][NH2:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[CH2:38]([NH:39][C:20](=[O:21])[CH2:19][N:3]1[CH2:4][CH2:5][C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:2]1=[O:1])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NCc1ccccc1
Reaction time: 8 h

Procedure:
To 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.031 g, 0.105 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.044 g, 0.115 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.027 mL, 0.157 mmol) followed by phenylmethanamine (0.014 mL, 0.126 mmol). After stirring overnight, the reaction was loaded onto a silica gel column (Analogix® SF15-12, Burlington, Wis.), and the product was eluted with a gradient of 0.4% to 5.25% methanol/dichloromethane over 20 minutes with a flow rate of 30 mL/minute. The product residue was dissolved in dichloromethane/diethyl ether followed by the addition of hexanes which upon concentration gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.11-7.34 (m, 15H), 6.23 (t, J=5.8 Hz, 1H), 4.32 (d, J=5.8 Hz, 2H), 4.06 (s, 2H), 3.50 (t, J=6.5 Hz, 2H), 2.80 (t, J=6.5 Hz, 2H); MS (ESI−) m/z 383 (M−H)−.
Reaction SMILES: [O-2].[Mg+2].[CH:3]1([CH3:16])[CH2:8][CH2:7][CH:6]([CH:9]([CH3:11])[CH3:10])[CH:5]([O:12][C:13](Cl)=[O:14])[CH2:4]1.[CH3:17][N:18]1[C:24]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:23]=2[CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:21][CH2:20][C:19]1=[O:36]>CC(C)=O>[CH3:17][N:18]1[C:24]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:23]=2[CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:21]([C:13]([O:12][CH:5]2[CH:6]([CH:9]([CH3:11])[CH3:10])[CH2:7][CH2:8][CH:3]([CH3:16])[CH2:4]2)=[O:14])[CH2:20][C:19]1=[O:36]
Reactant: CC1CCC(C(C)C)C(OC(=O)Cl)C1
Reactant: CN1C(=O)CNC(c2ccccc2)c2cc(Cl)ccc21
Agent: [Mg+2]
Agent: [O-2]
Solvent: CC(C)=O
Product: CC1CCC(C(C)C)C(OC(=O)N2CC(=O)N(C)c3ccc(Cl)cc3C2c2ccccc2)C1

Procedure:
0.2 g. of magnesium oxide and 1.21 g. (0.0055 moles) of menthyloxycarbonyl chloride are added to a solution of 1.34 g. (0.005 moles) of 1-methyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 20 ml. of acetone, and the mixture is stirred overnight. Next day carbon is added to the mixture, the suspension is filtered, and the filtrate is evaporated to dryness. The oily residue is dissolved in 20 ml. of ethyl acetate, the solution is shaken with 3×5 ml. of 0.1 N hydrochloric acid, the organic phase is washed with water until neutral, then dried over sodium sulfate. The drying agent is filtered off, and the filtrate is evaporated. The residue is admixed with hexane, and the solids are filtered off. 0.82 g. of 1methyl-4-menthyloxycarbonyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one, melting at 144°- 144.5° C., are obtained. The obtained substance is recrystallized from a mixture of ethanol and water. Rf2 = 0.8.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=[C:5]([O:20][CH3:21])[CH:4]=1.[C-:22]#[N:23].[K+]>C(O)C.O>[C:22]([CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=[C:5]([O:20][CH3:21])[CH:4]=1)#[N:23]
Reactant: [C-]#N
Reactant: COc1ccc(-c2nc3c(CBr)cc(OC)cc3s2)cc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nc3c(CC#N)cc(OC)cc3s2)cc1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
To a solution of 4-bromomethyl-6-methoxy-2-(4-methoxy-phenyl)-benzothiazole (0.47 g, 1.29 mmol) in ethanol (6 mL) was added a solution of potassium cyanide (0.1 g, 1.54 mmol) in water (0.5 mL). The mixture was refluxed for 1.5 h, then cooled to room temperature. Ethanol was evaporated and the mixture was extracted with ethylacetate. After chromatographic purification gave 4-cyanomethyl-6-methoxy-2-(4-methoxy-phenyl)-benzothiazole as a yellow solid (0.29 g, 73% yield). Mass spec: MH+=311.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:6]2)=O.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@:25]([OH:40])([C@H:32]([S:34][CH:35]([CH2:38][OH:39])[CH2:36][OH:37])[CH3:33])[CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@@:25]([OH:40])([CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)[C@H:32]([S:34][C@@H:35]1[CH2:36][O:37][C@@H:1]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:6]3)[O:39][CH2:38]1)[CH3:33]
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: COC(=O)c1ccc2cc(C=O)ccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc([C@H]3OC[C@H](S[C@H](C)[C@](O)(Cn4cncn4)c4ccc(F)cc4F)CO3)ccc2c1
Temperature: 0 °C

Procedure:
A solution of methyl 6-formyl-2-naphthalenecarboxylate (227 mg, 1.06 mmol) obtained in example 3 (2), (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (381 mg, 1.06 mmol) and p-toluenesulfonic acid monohydrate (363 mg, 1.91 mmol) in anhydrous tetrahydrofuran (50 ml) was concentrated at room temperature using a rotary evaporator under reduced pressure and then using a vacuum pump. A solution of the residue in anhydrous tetrahydrofuran (40 ml) was concentrated according to the procedure described above. The same procedure was repeated twice. A solution of the resulting residue in tetrahydrofuran (50 ml) was poured into a saturated aqueous sodium hydrogencarbonate solution cooled to 0° C. with stirring. The mixture was extracted with ethyl acetate and the organic layer was washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The oily residue was chromatographed on a silica gel column using ethyl acetate-hexane (1:2) as the eluant to afford methyl 6-[trans-5-[((1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-2-naphthalenecarboxylate (trans isomer, 331 mg, yield 56%) as a white solid, and then using ethyl acetate-hexane (3:1) as the eluant to afford methyl 6-[cis-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-2-naphthalenecarboxylate (cis isomer, 77 mg, yield 14%) as a colorless oil. The trans isomer was recrystallized from ethyl acetate-hexane to give white fluffy crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([O:13][C@H:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][CH2:16][C@H:15]2[C:21]([CH3:29])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])[O:10][C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31](=[O:40])[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[CH:12]([C:11]([O:13][C@H:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][CH2:16][C@H:15]2[C:21]([CH3:29])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:22])=[O:10])[CH:31]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:40][C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCc1ccccc1
Reactant: C[C@@H]1CC[C@@H](C(C)(C)c2ccccc2)[C@@H](Oc2cn(Cc3ccccc3)c(=O)o2)C1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H]1CC[C@@H](C(C)(C)c2ccccc2)[C@@H](OC(=O)C2C(CCc3ccccc3)OC(=O)N2Cc2ccccc2)C1
Temperature: -78 °C
Yield: 98 %

Procedure:
Under argon atmosphere, in 3 ml of methylene chloride was dissolved 202.8 mg (0.5 mmol) of 3-benzyl-5-((1S,2S,5R)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyloxy)-2(3H)-oxazolone, and after the solution was cooled to −78° C., 67.1 mg (0.5 mmol) of hydrocinnamaldehyde and 63 μl (0.1 mmol) of boron trifluoride diethyl etherate were added to the solution and the mixture was reacted for 1.0 hour. After the temperature of the mixture was raised up to the room temperature, 15 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the resulting reaction mixture and the mixture was extracted with 15 ml of methylene chloride. The organic layer was washed twice with 15 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 264.9 mg (0.49 mmol) of 3-benzyl-4-((1S,2S,5R)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyloxy)carbonyl-5-(2-phenylethyl)-2-oxazolidinone as pale yellowish viscous liquid. A formation ratio of cis/trans isomers was cis isomer/trans isomer=29/71 according to 1H-NMR, and they were each single diastereomer. Yield based on 3-benzyl-5-((1S,2S,5R)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyloxy)2(3H)oxazolone was 98.2%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CC(C)([O-])C.[K+].CN(C=O)C>O>[N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[O:20][C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=1
Reactant: OC1(CNc2c(Br)cnc3ccccc23)CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C1=Nc2c(cnc3ccccc23)OC12CCCCC2
Temperature: 130 °C
Reaction time: 1 h

Procedure:
A mixture of 5.5 g of 3-bromo-N-(1-hydroxycyclohexylmethyl)-4-quinolinamine, 2.2 g of potassium tert-butoxide and 50 ml of DMF was heated at 130° C. for 1 hour and then poured into 250 ml of water. The product was extracted with dichloromethane and ethyl acetate, dried and concentrated, and the residue was purified by HPLC using dichloromethane:MeOH=95:5 as the eluent. The fractions containing the product were combined and concentrated. The residue was taken up in water and stirred for 1 hour, and the solid was filtered and recrystallized from toluene. The yield was 2.6 g, mp 164°-165° C.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([CH3:29])[C@H:26]([C:30]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[O:31])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][C@@H:24]1[CH2:28][N:27]([CH3:29])[C@H:26]([C:30]([N:32]2[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]2)=[O:31])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C)CC3)N(C)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 ml of trifluoroacetic acid, followed by 510 liters of trifluoromethanesulfonic acid were added, whilst ice-cooling, to a solution of 1050 mg of (2S,4S)-4-(4-methoxybenzylthio)-2-(4-methyl-1-piperazinylcarbonyl)-1-methylpyrrolidine [prepared as described in step (i) above] in 3 ml of anisole, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was triturated with diethyl ether to cause solidification. The solid was washed with diethyl ether five times and dried, to give 1350 mg of the title compound as a powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[C:15]([NH:17][C:18](=[O:26])OC3C=CC=CC=3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1.[CH3:27][C:28]1[CH:29]=[C:30]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:31]=[C:32]([CH3:34])[CH:33]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[C:15]([NH:17][C:18]([N:38]3[CH2:39][CH2:40][N:35]([C:30]4[CH:31]=[C:32]([CH3:34])[CH:33]=[C:28]([CH3:27])[CH:29]=4)[CH2:36][CH2:37]3)=[O:26])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: O=C(Nc1cc(-c2cccnc2)nc2ccccc12)Oc1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(C)cc(N2CCN(C(=O)Nc3cc(-c4cccnc4)nc4ccccc34)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
Phenyl N-[2-(pyridin-3-yl)quinolin-4-yl]carbamate(171 mg, 0.5 mmol) and 1-(3,5-dimethylphenyl)piperazine(95 mg, 0.5 mmol) were dissolved in anhydrous tetrahydrofuran and DBU(117 mg, 0.75 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove tetrahydrofuran, and purified by column chromatography(ethylacetate:hexane=1:1) to obtain the titled compound.
Reaction SMILES: [C:1]([CH2:4][C:5]1([NH:9][C:10]([C:12]2[CH:17]=[C:16](Cl)[C:15]([CH:19]3[CH2:21][CH2:20]3)=[CH:14][N:13]=2)=[O:11])[CH2:8][O:7][CH2:6]1)(=[O:3])[NH2:2].[F:22][C:23]([F:28])([F:27])[C@H:24]([OH:26])[CH3:25].[H-].[Na+]>CN(C=O)C>[C:1]([CH2:4][C:5]1([NH:9][C:10]([C:12]2[CH:17]=[C:16]([O:26][C@H:24]([CH3:25])[C:23]([F:28])([F:27])[F:22])[C:15]([CH:19]3[CH2:21][CH2:20]3)=[CH:14][N:13]=2)=[O:11])[CH2:8][O:7][CH2:6]1)(=[O:3])[NH2:2]
Reactant: C[C@@H](O)C(F)(F)F
Reactant: NC(=O)CC1(NC(=O)c2cc(Cl)c(C3CC3)cn2)COC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](Oc1cc(C(=O)NC2(CC(N)=O)COC2)ncc1C1CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7 %

Procedure:
To a solution of 4-Chloro-5-cyclopropyl-pyridine-2-carboxylic acid (3-carbamoylmethyl-oxetan-3-yl)-amide (Example 63b, 40 mg, 129 μmol) in dry DMF (1.5 mL) in a microwave-vial were added (R)-1,1,1-trifluoropropan-2-ol (CAN 17628-73-8, 42.1 mg, 258 μmol) and sodium hydride 60% (15.5 mg, 387 μmol) and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was heated to 100° C. for 30 minutes under microwave radiation. The reaction was directly purified by preparative HPLC without any work-up to yield the title compound (3.5 mg, 7.0%) as a grey solid. MS (ESI, m/z): 388.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:19]Br>O1CCCC1.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH:12]([Br:19])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Temperature: 2.5 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
A solution of 4-Oxo-piperidin-1-carboxylic acid tert-butyl ester (10 grams, 50 mmol) and aluminium chloride (0.67 grams, 5 mmol) in tetrahydrofuran (30 mL) and diethyl ether (30 mL) was cooled to 0° C., and then treated with bromine (2.6 mL, 50 mmol) over a period of 30 minutes. Stirred the reaction mass for 24 hours at 0-5° C. After completion of reaction, the obtain solids were filtered and the mother liquor was concentrated under vacuum. The obtain crude was triturated with diethyl ether and solids were filtered and dried under vacuum to obtain the title compound (10 grams).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][N:4]([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8]2)[C:3]1=[S:17].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[CH2:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15][CH2:16][CH:7]1[N:4]1[C:3](=[S:17])[N:2]([NH:1][C:18](=[O:20])[CH3:19])[CH:6]=[N:5]1
Reactant: CC(=O)OC(C)=O
Reactant: Nn1cnn(C2CCc3ccccc3C2)c1=S
Product: CC(=O)Nn1cnn(C2CCc3ccccc3C2)c1=S

Procedure:
substituting 4-amino-2-(1,2,3,4-tetrahydronaphthalen-2-yl)-2,4-dihydro[1,2,4]triazole-3-thione and acetic anhydride gave N-[1-(1,2,3,4-tetrahydronaphthalen-2-yl)-5-thioxo-4,5-dihydro-1H-[1,2,4]triazol-4-yl]acetamide, m.p. 199°-201° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1.C([O-])([O-])=O.[Cs+].[Cs+]>C(COC)OC.C(O)C.Cl[Pd]Cl>[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[N:11]=[C:10]([NH:12][CH2:13][C@@H:14]4[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]4)[C:9]4[C:4](=[N:5][CH:6]=[CH:7][N:8]=4)[CH:3]=3)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CNc2nc(Cl)cc3nccnc23)C1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CNc2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Temperature: 160 °C
Reaction time: 0.75 h
Yield: 73 %

Procedure:
A mixture of (S)-tert-butyl 3-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)piperidine-1-carboxylate (0.15 mmol), 4-morpholinophenylboronic acid (0.23 mmol), PdCl2 (dppf) (0.015 mmol) and Cs2CO3 (0.30 mmol) in dimethoxyethane/ethanol was sealed in a microwave reaction and stirred at 160° C. for 45 minutes in a microwave reactor. The mixture was cooled to room temperature, concentrated, and purified by chromatography to afford the title compound (73% yield). MS (m/z): 505 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[Li]CCCC.[S:17](Cl)([Cl:20])(=[O:19])=[O:18].C(Cl)Cl>C1COCC1>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:2]2[S:1][C:5]([S:17]([Cl:20])(=[O:19])=[O:18])=[CH:4][CH:3]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: c1cncc(-c2cccs2)c1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=S(=O)(Cl)c1ccc(-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.1 %

Procedure:
To a solution of 3-thiophen-2-yl-pyridine (0.35 g, 2.20 mmol) in 15 mL of THF at -78° C. is added n-BuLi (1.44 mL of a 1.6M solution in hexanes, 2.31 mmol). After stirring for 15 minutes, SO2 gas is bubbled through the solution for 30 minutes. The solution is then allowed to warm to room temperature and stirred overnight. The solution is concentrated to dryness and the resulting solid is suspended in 20 mL of hexane. Sulfuryl chloride (0.185 mL, 2.31 mmol) is added and the reaction mixture is stirred for 30 minutes and then a small amount of methylene chloride is added and the mixture is stirred for another 30 minutes. The mixture is then concentrated to dryness and diluted with ethyl acetate and washed with saturated NaHCO3 (aq), water and brine. The organic layer is dried over MgSO4, filtered and concentrated to give a brown solid as the title product (0.452 g, 1.74 mmol) which is used in the subsequent step without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([O:9][CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[N+:16]([O-:18])=[O:17])[CH2:7]O)(=[O:3])[CH3:2].C1(C)[C:20]([S:25](Cl)(=[O:27])=[O:26])=CC=CC=1>N1C=CC=CC=1>[C:1]([O:4][CH2:5][CH:6]([O:9][CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[N+:16]([O-:18])=[O:17])[CH2:7][S:25]([CH3:20])(=[O:27])=[O:26])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(CO)OCn1ccnc1[N+](=O)[O-]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)OCC(CS(C)(=O)=O)OCn1ccnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
117 mg of the thus-obtained 1-[1-acetoxymethyl-2-(hydroxy)ethoxy]methyl-2-nitroimidazole was placed in a flask together with dry pyridine, and 252 mg of toluenesulfonyl chloride was added. The mixture was stirred for 5 hours at room temperature. The reaction mixture was extracted with 30 ml of added ethyl acetate, and the obtained extract was subjected to partition and water washing, two times with 30 ml of water. The organic phase was dried over sodium sulfate, subsequently concentrated under reduced pressure, and purified by silica gel column chromatography, to obtain 1-[1-acetoxymethyl-2-mesylethoxy]methyl-2-nitroimidazole. 10 ml of dry DMF was added to dissolve the product, and the solution was added to a mixture which had been prepared by mixing 10 ml of acetonitrile and 1 ml of water in advance, adding 33.8 mg of potassium fluoride and 80 mg of 18-crown-6, and drying under reduced pressure. The resulting mixture was heated at 110° C. for 8 hours. To the obtained reaction mixture, 20 ml of ethyl acetate was added, and the mixture was washed with 20 ml of water. The aqueous phase was extracted two times with 20 ml of ethyl acetate, and the obtained extract was combined with the organic phase and dried to solid under reduced pressure. The dried product was purified by preparative high performance chromatography, to obtain 15.4 mg of 1-(1-hydroxymethyl-2-fluoro)ethoxymethyl-2-nitroimidazole. From the mass analysis results for this product, M+1(219) was recognized, and thus the structure was confirmed. Also, the elemental analysis values resulted in 38.55% of carbon, 4.11% of hydrogen, 19.28% of nitrogen, and 8.70% of fluorine, thus supporting the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:30]=[C:29]([C:31]([NH:33]O)=[NH:32])[CH:28]=[CH:27][N:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]4[O:22][N:33]=[C:31]([C:29]5[CH:28]=[CH:27][N:26]=[C:25]([NH2:24])[CH:30]=5)[N:32]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: N=C(NO)c1ccnc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: Nc1cc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(Cl)cc5)nc34)n2)ccn1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) (171 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyridine-4-carboxamidine (example B.6) (114 mg, 0.75 mmol) according to general procedure II. Obtained after trituration with water and further purification by crystallization (dichloromethane/hexane) as a yellow solid (112 mg, 49%). MS (EI) 457.1 [(M)+]; mp 252° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[CH2:9](B(CC)CC)[CH3:10].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:9]([C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1)[CH3:10]
Reactant: Fc1ccc(Br)cn1
Reactant: CCB(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(F)nc1

Procedure:
A mixture of 5-bromo-2-fluoropyridine (2-a, 5.03 g, 28.6 mmol, Lancaster Synthesis, Inc., Wyndham, N.H.), triethylborane (1M in tetrahydrofuran, 42.8 mL, 42.8 mmol), K2CO3 (15.8 g, 114.2 mmol) and Pd(PPh3)4 (1.65 g, 1.43 mmol) in N,N-dimethylformamide was heated at 85 C for 4 h. The reaction mixture was diluted with water and extracted with hexanes. The organic layer was then washed with water (×2), separated, dried (MgSO4), and concentrated in vacuo. Chromatography (50%, CH2Cl2 in hexanes) afforded the desired product (2-b); 1H NMR (500 MHz, CDCl3) δ 8.04 (d, 1 H, J=1.0 Hz), 7.60 (dt, 1 H, J=8.0, 2.5 Hz), 6.85 (dd, 1 H, J=8.3, 2.8 Hz), 2.65 (q, 2 H, J=7.8 Hz), 1.21 (t, 3 H, J=7.7 Hz)