Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C.CCOC(C)=O>[Si:15]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Reaction time: 16 h
Yield: 61.9 %

Procedure:
(3) 4-Hydroxybenzaldehyde (20 g, 0.164 mol) was dissolved in DMF (60 ml) and stirred at RT as imidazole (22.3 g, 0.328 mol) and tert-butyldimethylsilyl chloride (32.1 g, 0.213 mol) were added. The reaction mixture was stirred for 16 h. The solution was diluted with EtOAc, washed with water, brine, then dried (MgSO4) and concentrated in-vacuo to afford 24 g of crude 4-(tert-butyldimethylsilanyloxy)benzaldehyde.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:42]3[CH2:43][CH2:44][CH:39]([OH:38])[CH2:40][CH2:41]3)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OC1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(O)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-hydroxy-piperidine (Aldrich) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C33H40N5O3Cl2 [(M+H)+] 624.2503, observed 624.2505.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:29][CH2:30][CH:31]1[CH:36]([C:37]([NH:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:38])[CH2:35][CH:34]=[CH:33][CH2:32]1>C(Cl)Cl>[CH2:8]([NH:26][C:27](=[O:28])[O:29][CH2:30][CH:31]1[CH:36]([C:37]([NH:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:38])[CH2:35][CH:34]=[CH:33][CH2:32]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: O=C(NCCN1CCCCC1)C1CC=CCC1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC1CC=CCC1C(=O)NCCN1CCCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Triethylamine (0.96 ml) and octadecyl isocyanate (2.2 ml) were added to a solution of 6-(hydroxymethyl)-N-(2-piperidinoethyl)-3-cyclohexene-1-carboxamide (1.65 g) in methylene chloride (22 ml). After being stirred for 15 hours at room temperature, triethylamine (0.96 ml) and octadecyl isocyanate (2.2 ml) were further added to the reaction mixture and stirred for 5 hours at room temperature. The insoluble matters were filtrated out under a vacuum and washed with chloroform. The filtrate and washings were combined together and the mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 100 g, chloroform:methanol=30:1-10:1), thereby yielding the entitled compound (2.59 g) as white solid.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[C:13]2[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=2[N:11](C(OC(C)(C)C)=O)[C:10]1=[O:26])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[I:18][C:15]1[CH:16]=[CH:17][C:12]2[NH:11][C:10](=[O:26])[N:9]([CH2:8][C:6]([OH:7])=[O:5])[C:13]=2[CH:14]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(C(=O)OC(C)(C)C)c2ccc(I)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1c(=O)[nH]c2ccc(I)cc21
Temperature: 25 °C

Procedure:
2.10 g (4.43 mmol) of tert-butyl 3-tert-butoxycarbonylmethyl-5-iodo-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (VIIj) were dissolved in dichloromethane (50 ml) and, while stirring at room temperature, trifluoroacetic acid (25 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. Yield: 1.39 g (99%) of white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])[S:9][CH:10]=1)[CH3:2].[Cl:30]N1C(=O)CCC1=O>C(#N)C.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])[S:9][C:10]=1[Cl:30])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)Cc1nc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)sc1Cl
Reaction time: 1.5 h
Yield: 148.2 %

Procedure:
To a solution of {2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester (0.05 g, 0.12 mmol) in 2 ml of acetonitrile was added N-chlorosuccinimide (0.018 g, 0.13 mmol). The reaction mixture was stirred under nitrogen in a pressure bottle excluded from light for 1.5 hour at 80° C. The mixture was diluted with 15 ml of DCM, washed (1N HCl, saturated NaHCO3, water), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford the title compound (0.08 g, 15%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[N:28]1[C:37]2[C:32](=[CH:33][C:34]([C:38](O)=[O:39])=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38]([C:34]5[CH:33]=[C:32]6[C:37](=[CH:36][CH:35]=5)[N:28]=[CH:29][CH:30]=[CH:31]6)=[O:39])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc2ncccc2c1

Procedure:
The title compound, off-white solid (120 mg, 99%), MS (ISP) m/z=486.4 [(M+H)+], mp 227° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and quinoline-6-carboxylic acid.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][OH:18])=[O:6])[CH:2]=[CH2:3].[C:19]([O-:22])(=[S:21])[CH3:20].[K+].C(OCC)(=O)C>CN(C)C=O>[C:19]([S:21][C@@H:10]1[CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C@H:8]([CH2:17][OH:18])[CH2:9]1)(=[O:22])[CH3:20]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CO
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CO
Temperature: 65 °C
Reaction time: 5 h
Yield: 85.5 %

Procedure:
A solution of (2S,4R)-1-allyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (19.32 g: 69.17 mmole) and 90% potassium thioacetate (10.73 g: 89.9 mmole) in dimethylformamide (217 ml) is heated with stirring at 65° C. for 5 hours. To the reaction mixture ethyl acetate (200 ml) and ice water (200 ml) are added. The organic layer is taken, successively washed with aqueous 0.05N-sodium hydroxide, 0.1N-hydrochloric acid, water and saturated brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel chromatography to give (2S,4S)-4-acetylthio-1-allyloxycarbonylpyrrolidine-2-methanol (15.34 g). Yield: 90%. NMR δ(CDCl3) ppm: 1.5 to 1.7(m, 1H), 2.34(s, 3H), 2.4 to 2.6(m, 1H), 3.19(dd, J=8.0 Hz, J=11.5 Hz, 1H), 3.6 to 3.8(m, 2H), 3.8 to 4.0(m, 1H), 4.0 to 4.2(m, 2H), 4.6(m, 2H), 5.2 to 5.4(m, 2H), 5.8 to 6.1(m, 1H).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16].[F-].[K+].O>CN(C=O)C>[CH:15]([C:14]1[CH:13]=[C:12]([CH:19]=[CH:18][CH:17]=1)[O:11][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])=[O:16]
Reactant: Cc1ccc(C#N)c(Cl)n1
Reactant: O=Cc1cccc(O)c1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C#N)c(Oc2cccc(C=O)c2)n1
Yield: 97.9 %

Procedure:
2-Chloro-6-methylnicotinonitrile (0.50 g, 3.3 mmol), 3-hydroxybenzaldehyde (0.40 g, 3.3 mmol) and potassium fluoride (0.57 g, 9.8 mmol) were heated with stirring in dry DMF (5 mL) at 120° C. for 7 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (4×), water (4×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 2-(3-formyl-phenoxy)-6-methyl-nicotinonitrile (0.77 g, 97%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](OC)=[N:4][NH:5][C:6]([O:8]C)=O.[CH3:12][NH2:13]>CO>[CH3:1][O:2][C:3]1[N:13]([CH3:12])[C:6](=[O:8])[NH:5][N:4]=1
Reactant: CN
Reactant: COC(=O)NN=C(OC)OC
Solvent: CO
Product: COc1n[nH]c(=O)n1C
Temperature: 70 °C

Procedure:
8.11 g (0.05 mol) of methyl N′-dimethoxymethylenehydrazinecarboxylate were dissolved in 25.4 g of methanol and admixed with 3.26 g (0.105 mol) of methylamine, dissolved in methanol, and the mixture was heated in an autoclave at 70° C. for 14 hours. The reaction mixture was concentrated under reduced pressure and taken up in water (10 ml). The mixture was acidified by addition of conc. HCl. The crystals which precipitated at 4° C. were filtered off and dried. This gave 1.89 g (29.3%) of 5-methoxy-4-methyl-2,4-dihydro-1,2,4-triazol-3-one in the form of a colourless solid. Melting point 146-148° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:24])([CH3:23])[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:22])[CH2:15][C@H:16]1[CH2:20][C:19](=[O:21])[CH:18]=[CH:17]1.O1CCC[CH2:26]1.C[Li]>CCOCC>[CH3:24][Si:2]([CH3:23])([CH3:1])[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:22])[CH2:15][C@H:16]1[CH2:20][C@@:19]([CH3:26])([OH:21])[CH:18]=[CH:17]1
Reactant: C1CCOC1
Reactant: C[C@H](C[C@@H]1C=CC(=O)C1)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Agent: [Li]C
Solvent: CCOCC
Product: C[C@H](C[C@@H]1C=C[C@](C)(O)C1)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Temperature: -78 °C
Yield: 84 %

Procedure:
A 1.76 g amount of the compound (1-10), (4S)-4-{(2R)-2-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-propyl}-2-cyclopenten-1-one was placed into a 300 ml eggplant-shaped flask. A 150 ml amount of tetrahydrofuran was added and the solution stirred and cooled to -78° C., and then, 6.5 ml of an ether solution of methyllithium (1.16 mol/liter) was added, followed by stirring for 15 minutes. A 50 ml amount of saturated saline was added, the excess methyllithium was broken down, then 100 ml of ether was added for separation. The organic layer was washed with saturated saline, then was dried over anhydrous magnesium sulfate. The desiccant was filtered out, the solvent was distilled off under reduced pressure, and the crude product was purified by a silica gel column (Merck gel: 300 g, hexane/ethyl acetate=15/1 to 9/1) to obtain the desired product (1-11), (1R,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-propyl}-1-methyl-2-cyclopenten-1-ol in an amount of 1.55 g (yield 84%) and the desired product (1-12), (1S,4S)-4-{(2R)-2-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-propyl}-1-methyl-2-cyclopenten-1-ol, in an amount of 0.27 g (yield 14%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[C:22][C:23]2[C:28](=[O:29])[N:27](CC3C=CC(OC)=CC=3)[CH:26]=[C:25]([Cl:39])[N:24]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>ClCCl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[O:29][C:28]3=[N:27][CH:26]=[C:25]([Cl:39])[N:24]=[C:23]3[CH:22]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1ccc(Cn2cc(Cl)nc(C#CC3CCN(C(=O)OC(C)(C)C)CC3)c2=O)cc1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2cc3nc(Cl)cnc3o2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Silver triflate (6 mg) and trifluoroacetic acid (0.36 mL) are added to a solution of 4-[6-chloro-4-(4-methoxy-benzyl)-3-oxo-3,4-dihydro-pyrazin-2-ylethynyl]-piperidine-1-carboxylic acid tert-butyl ester (430 mg) in dichloromethane (6 mL). The reaction mixture is stirred at room temperature for 20 min, diluted with dichloromethane and washed with aqueous NaHCO3 solution and brine. The organic phase is dried (MgSO4) and the solvent is evaporated. The residue is chromatographed on silica gel (ethyl acetate/cyclohexane 25:70) to give the title compound as a colorless solid.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:7]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:6]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:5][CH:3]1O.CN(C=O)C.C(Br)(=O)C([Br:42])=O>ClCCl>[F:1][C@@H:2]1[C@@H:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:7]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:6]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:5][CH:3]1[Br:42]
Reactant: O=C(Br)C(=O)Br
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: F[C@H]1C(Br)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2-Deoxy-2-fluoro-3,4,6-tri-O-benzyl glucopyranose (450 mg) was dissolved in dichloromethane (5.0 mL) and dry DMF (180 μL) was added. The reaction solution was cooled to 0° C. and oxalyl bromide (102 μL) was added. The resulting solution was stirred for 3-5 hours at 0° to 5° C. The solution was then diluted with dichloromethane (50 mL) and washed with water (2×50 mL), dried over sodium sulfate, filtered and evaporated to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21](O)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:48][CH:49]([NH2:51])[CH3:50].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:48][CH:49]([NH:51][C:21]([C@H:9]1[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:22])[CH3:50]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Reactant: CC(C)N
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: CC(C)NC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 130.1 %

Procedure:
A 20-mL vial was charged with ((2R)-1,4-bis(tert-butoxycarbonyl)-2-piperazinecarboxylic acid (1.57 g, 4.76 mmol, ASW MedChem Inc., New Brunswick, N.J.), HATU (2.17 g, 5.72 mmol, ChemImpex International Inc., Wood Dale, Ill.), propan-2-amine (0.450 mL, 5.28 mmol, Sigma-Aldrich, St. Louis, Mo.), DIPEA (1.70 mL, 9.76 mmol) and DMF (8 mL). The mixture was stirred at room temperature for 2.5 h. The reaction mixture was partitioned between water (80 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (50 mL). and the combined organic phases were washed with saturated aqueous NaHCO3 (100 mL), water (100 mL), then brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford di-tert-butyl (2R)-2-((1-methylethyl)carbamoyl)-1,4-piperazinedicarboxylate (2.30 g) as a light-brown foam.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:31])[CH:3]=1.[C:32]([Cu])#[N:33]>N1C=CC=CC=1>[C:32]([C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:18][CH:19]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:31])[CH:3]=1)#[N:33]
Reactant: N#C[Cu]
Reactant: CCc1nc2c(C)cc(Br)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: c1ccncc1
Product: CCc1nc2c(C)cc(C#N)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 160 °C
Reaction time: 4 h
Yield: 71.5 %

Procedure:
A mixture of 5-bromo-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (41 mg), CuCN (80 mg), and pyridine (0.2 mL) was heated with stirring to 160° C. for 4 hours. The pyridine distilled off during the course of the heating. The cooled dark mass was dissolved in 2 mL of 20% aqueous KCN by heating to 50° C. for 15 minutes. Acetic acid (2 mL) (Caution! HCN is evolved.) was added and the mixture was extracted (2×EtOAc). The organic layers were dried (Na2SO4), concentrated, and purified (SiO2, 80/20/1 CH2Cl2 --MeOH--NH4OH) to give 26 mg of the title compound as a solid. 1H NMR (250 MHz, CD3OD) δ7.66-7.45 (m, containing a singlet at 7.57, 5H), 7.15-7.04 (m, 4H), 5.53 (s, 2H), 2.91 (q, 2H, J=7.5 Hz), 2.66 (s, 3H), 1.27 (t, 3H, J=7.5 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]([NH2:14])=[NH:13])[S:9][CH:10]=1)=O)C.O.[NH2:16][NH2:17]>C(O)C>[NH:11]([C:8]1[S:9][CH:10]=[C:6]([C:4]([NH:16][NH2:17])=[O:3])[N:7]=1)[C:12]([NH2:14])=[NH:13]
Reactant: NN
Reactant: CCOC(=O)c1csc(NC(=N)N)n1
Solvent: CCO
Solvent: O
Product: N=C(N)Nc1nc(C(=O)NN)cs1
Yield: 82.1 %

Procedure:
16.7 g (0.0779 mol) of 2-guanidino-4-thiazole carboxylic acid ethyl ester was combined with 25 ml (0.514 mol) of hydrazine hydrate in 200 ml absolute ethanol. The slurry was heated to reflux. After 1.5 hour reflux a solid began to form from the clear solution. After 2 hours reflux the reaction slurry was cooled and the resulting solid was collected by filtration and was washed with isopropyl alcohol and ether to give 12.8 g (82%) 2-guanidino-4-thiazole carboxylic acid hydrazide, mp 247° (dec.).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:18]=1)[C:10](=[O:17])[C:11]1[CH2:16][CH2:15][CH2:14][C:12]=1[N:13]=2)=[O:4].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.C[O-].[Na+]>CO>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[C:14]1[C:12]2[N:13]=[C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:18][N:9]3[C:10](=[O:17])[C:11]=2[CH2:16][CH2:15]1
Reactant: COc1cccc(C=O)c1
Reactant: COC(=O)c1ccc2nc3c(c(=O)n2c1)CCC3
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(C=C2CCc3c2nc2ccc(C(=O)O)cn2c3=O)c1

Procedure:
1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid methyl ester, m.p. 153°-154° C. (3.3 g) was reacted with 3-methoxybenzaldehyde (5.52 g) in methanol (145 g) in the presence of sodium methoxide (2.97 g) under stirring at reflux temperature for 144 hours. After cooling the precipitate was filtered and treated with formic acid and then with water: the crude compound was recovered by filtration, washed with water until neutral and crystallized from CH2Cl2 /methanol to give 2.73 g of 3-(3-methoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid, m.p. 310°-312° C., NMR (CF3COOD) δ ppm: 3.42 (br) (4H, cyclopentane protons), 4.11 (s) (3H, OCH3), 7.2-7.6 (m) (4H, phenyl protons), 7.61 (br) (1H, =CH--), 8.41 (d) (1H, C-5 proton), 9.11 (d.d) (1H, C-6 proton), 10.20 (d) (1H, C-8 proton).
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C>>[NH2:14][C:13]1[C:8]2[N:9]([C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)=[N:6][C:7]=2[C:15]2[CH2:16][CH2:17][N:18]([C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:28])[CH2:19][CH:20]=2)[CH:10]=[CH:11][N:12]=1
Reactant: Nc1nccn2c(C3CCC3)nc(C3=CCNCC3)c12
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccn2c(C3CCC3)nc(C3=CCN(C(=O)c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-cyclobutyl-1-(1,2,3,6-tetrahydropyridin-4-yl)-imidazo[1,5-a]pyrazin-8-ylamine (20.0 mg, 0.0742 mmol), benzoic acid (9.97 mg, 0.0817 mmol), TBTU (47.7 mg, 0.148 mmol), DIEA (0.0647 mL, 0.371 mmol) and DMF (1 mL, 0.01 mol) was stirred at rt for 10 min. The reaction mixture was directly given for Gilson HPLC purification. The fractions containing the pure product were collected and concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=1.96-2.06 (m, 1H) 2.09-2.23 (m, 1H) 2.40-2.63 (m, 4H) 2.72-2.93 (m, 2H) 3.57-3.88 (m, 3H) 3.98-4.34 (m, 1H) 4.47 (br. s., 1H) 5.13-5.45 (m, 2H) 5.72-6.14 (m, 1H) 7.04-7.08 (m, 2H) 7.42-7.51 (m, 5H). MS (ES+): m/z 374.07 (100) [MH+]. HPLC: tR=2.13 min (polar—5 min).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([CH3:15])([CH3:14])[C:8](=O)[CH2:7]2)([OH:3])=[O:2].Cl.[NH2:18][OH:19]>C(O)C.N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([CH3:15])([CH3:14])[CH2:8][C:7]2=[N:18][OH:19])([OH:3])=[O:2]
Reactant: NO
Reactant: CC1(C)Oc2ccc(C(=O)O)cc2CC1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC1(C)CC(=NO)c2cc(C(=O)O)ccc2O1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
14.9 g of 6-carboxy-2,2-dimethyl-3-chromanone are dissolved in 100 ml of ethanol and 100 ml of pyridine, and after addition of 5.16 g of hydroxylamine hydrochloride the mixture is heated at 80° C. with stirring for 6 hours. The solvent is distilled off on a rotary evaporator. The residue is treated with water and adjusted to pH<1 using conc. hydrochloric acid, and the colorless crystals are filtered off.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[C:26]([O:30][C:31]([NH:33][NH2:34])=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>>[NH2:20][C:18]([O:17][CH2:16][CH:15]1[C:6]2[C:4]([OH:5])=[C:3]([N:34]=[N:33][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[C:2]([CH3:1])=[C:8]([OH:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22])=[O:19]
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC12C(COC(N)=O)c3c(O)c(N=NC(=O)OC(C)(C)C)c(C)c(O)c3N1CC1NC12
Yield: 42.9 %

Procedure:
In a similar manner to that described in Example 17, mitomycin A (250 mg), tert-butoxycarbonylhydrazine (284 mg) and potassium carbonate (150 mg) are treated to obtain the desired product (138 mg) with a yield of 42.7%.