Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[NH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:28]([NH:36][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:34])=[C:18]([F:23])[CH:17]=1
Reactant: NN1CCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NN4CCCC4)c(F)c3)c2cc1OC
Yield: 69.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (50 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-aminopyrrolidine (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to the reaction solution to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (47 mg, yield 69%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][S:10](O)(=[O:12])=[O:11].C(Cl)(=O)C([Cl:19])=O>C1COCC1.CN(C=O)C>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][S:10]([Cl:19])(=[O:12])=[O:11]
Reactant: O=S(=O)(O)Cc1ccccc1C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=S(=O)(Cl)Cc1ccccc1C(F)(F)F
Yield: 87.5 %

Procedure:
To a suspension of (2-trifluoromethylphenyl)methanesulfonic acid (20.3 g, 84 mmol) in THF (1.9 L) and DMF (5.0 mL) at −20° C. was added oxalyl chloride (44.7 mL, 0.5 mol) slowly dropwise over 1 hr. The bath temperature was maintained below 0° C. for 4 h, at which point the reaction was evaporated to a volume of ˜250 mL and diluted with 500 mL of ethyl acetate. This solution was washed with brine in a separatory funnel and dried over magnesium sulfate. The solution was then evaporated to a brown oil. This oil was taken up in 500 mL of pet ether (30-50°) and heated with a heat gun until the oil went into solution. The solution was then placed into a dry-ice acetone bath to cool resulting in formation of a white crystalline material. This material was collected via filtration and dried to afford 19 g (85%) of (2-trifluoromethylphenyl)methanesulfonyl chloride as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[C:22](=[O:23])[N:4]2[C:5]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12.[Br:24]Br.[CH2:26]=[C:27]1[O:31][C:29](=[O:30])[CH2:28]1.O>C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C(OCC)(=O)C.C(Cl)Cl>[Br:24][CH2:31][C:27]([CH2:28][C:29]([NH:1][CH:2]1[C:22](=[O:23])[N:4]2[C:5]([C:9]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12)=[O:30])=[O:26]
Reactant: BrBr
Reactant: C=C1CC(=O)O1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CBr)CC(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 82.8 %

Procedure:
4-Nitrobenzyl 7-amino-3-cephem-4-carboxylate (5 g.) was dissolved in a solution of trimethylsilylacetamide (13.8 g.) and bis(trimethylsilyl)acetamide (10 ml.) in dry ethyl acetate (50 ml.) and stirred at 45° C. for 1.5 hours. A solution of bromine (2.88 g.) in methylene chloride (7 ml.) was added dropwise to a solution of diketene (1.5 g.) in methylene chloride (7 ml.) at -40° C. over 20 minutes and stirred at -30° C. for 1 hour. The solution obtained thus was added to dropwise to the above solution of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate under cooling at -15° C. and then stirred at the same temperature for 30 minutes. Water (50 ml.) was added to the resultant solution and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give oily 4-nitrobenzyl 7-[2-(2-bromoacetyl)acetamido]-3-cephem-4-carboxylate (6.15 g.).
Reaction SMILES: [OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[CH:3]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([CH2:32][C:33]([NH:36][C:37](=[O:39])[CH3:38])([CH3:35])[CH3:34])=[CH:28][NH:29]2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([CH2:32][C:33]([NH:36][C:37](=[O:39])[CH3:38])([CH3:35])[CH3:34])=[C:28]([CH:14]([C:3]3[C:4](=[O:13])[CH2:5][CH:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:2]=3[OH:1])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:29]2)=[CH:25][CH:24]=1
Reactant: O=C1C=C(O)C(c2ccccc2)C1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)NC(C)(C)Cc1c[nH]c2cc(Cl)ccc12
Product: CC(=O)NC(C)(C)Cc1c(C(C2=C(O)C(c3ccccc3)CC2=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) was reacted with benzaldehyde and N-[2-(6-chloro-1H-indol-3-yl)-1,1-dimethyl-ethyl]-acetamide to give N-(2-{6-chloro-2-[(2-hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl)-phenyl-methyl]-1H-indol-3-yl}-1,1-dimethyl-ethyl)-acetamide as a pale yellow solid. MS: 527.3 ([M+H]+).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:11]1([O:17][P:18]([CH2:27][NH:28][C@@H:29]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:41][CH:40]=2)[C:30]([NH:32][CH2:33][CH2:34][C:35](O)=[O:36])=[O:31])([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.CN(CCCN=C=NCC)C.C(OCC)(=O)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[C:11]1([O:17][P:18]([CH2:27][NH:28][C@@H:29]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[CH:43][CH:44]=2)[C:30]([NH:32][CH2:33][CH2:34][C:35]([O:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][CH2:2][CH2:3]3)=[O:36])=[O:31])([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Oc1ccc2c(c1)CCC2
Reactant: O=C(O)CCNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CCNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(Oc1ccccc1)Oc1ccccc1)Oc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Indanol (52.9 mg, 0.394 mmol) is added in one portion to a solution of (S)-N-[2-(diphenylphosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionic acid (200 mg, 0.394 mmol) in methylene chloride (25 ml). 4-(N,N-Dimethylamino)pyridine (48.1 mg, 0.394 mmol) is added followed by N-dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride (151 mg, 0.788 mmol). The solution is stirred at room temperature for 3 hours. Ethyl acetate (60 mL) and water (15 mL) are added. The organic layer is subsequently washed with a saturated solution of sodium bicarbonate (2×15 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel, eluting with ethyl acetate-hexane (1:1). Evaporation of the pure fraction yields 5-indanyl (S)-N-[2-(diphenylphosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionate, as a thick colorless oil that can be crystallized from ether, m.p. 89°-91°.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[NH:30]1[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:27]=[CH:28][N:29]=[C:2]([N:30]4[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]4)[CH:3]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Reactant: OC1CCNCC1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(N2CCC(O)CC2)c1

Procedure:
Compound is formed by reacting 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide and piperidin-4-ol under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.39 (s,1H), 8.29 (d, 1H), 8.21 (m, 1H), 7.85 (m, 1H), 7.59 (m, 2H), 7.41 (m, 2H), 7.15 (d, 1H), 7.05 (d, 1H), 4.31 (t, 2H), 4.10 (m, 2H), 3.75 (m, 1H), 3.60 (t, 4H), 3.20 (m, 2H), 2.89 (m, 2H), 2.59 (m, 4H), 1.81 (m, 2H), 1.40 (m, 2H). MS: 477.3 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:39])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:18][N:17](S(C4C=CC(C)=CC=4)(=O)=O)[C:14]3=[N:15][CH:16]=2)[N:8]=[N:7][C:6]=1[NH2:38])=[O:4].CN(C)C=O.[OH-].[K+]>CO>[CH3:39][N:2]([CH3:1])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[N:8]=[N:7][C:6]=1[NH2:38])=[O:4]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(C(=O)N(C)C)c(N)nn3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc(C(=O)N(C)C)c(N)nn3)cc12
Reaction time: 5 h
Yield: 14.1 %

Procedure:
Crude 3-amino-6-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridazine-4-carboxylic acid dimethylamide (56.6 mg, 0.104 mmol) was dissolved in methanol (0.5 mL) and dimethylformamide (0.5 mL) and 50% w/v aqueous potassium hydroxide (0.2 mL) was added. After 5 hours, the reaction was quenched by addition of acetic acid (0.5 mL). The mixture was carefully poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered and dried to a residue which was purified by preparative HPLC to afford 3-amino-6-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridazine-4-carboxylic acid dimethylamide (5.7 mg, 14.1%, 3 steps). 1H-NMR (500 MHz, dimethylsulfoxide-d6) δ 2.90 (s, 3H), 3.0 (s, 3H), 3.82 (s, 3H), 6.44 (s, 2H), 7.07 (dt, J=7.5 Hz, J=1.0 Hz, 1H), 7.13 (br d, J=7.5 Hz, 1H), 7.30 (dt, J=7.5 Hz, J=1.5 Hz, 1H), 7.61 (dd, J=7.5 Hz, J=2.0 Hz, 1H), 7.83 (d, J=2.5 Hz, 1H), 7.92 (s, 1H), 8.55 (d, J=2.0 Hz, 1H), 8.87 (d, J=2.5 Hz, 1H), 11.89 (s, 1H). MS: m/z 389 (M+H+).
Reaction SMILES: [OH-].[K+].F[C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25]>CS(C)=O>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:16]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:17]=1
Reactant: Oc1ccccc1F
Reactant: O=C(c1ccccc1)c1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(c1ccccc1)c1ccc(Oc2ccccc2F)cc1
Yield: 87 %

Procedure:
All the components (301 g of 46 percent aqueous KOH, 501 g of fluorobenzophenone, 800 mL of DMSO, and 269 g of fluorophenol), plus 5 mole percent BHT (25 g) were mixed together under a nitrogen atmosphere and distillation of water was carried out at a maximum temperature of 80° C. Reaction continued at 70° C. for a total of 12 hr. Purification by lights distillation gave an 87 percent yield of 4-(2-fluoro-phenoxy)benzophenone.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[N-:14]=[C:15]=[O:16].[CH3:17][O:18][C:19](=[O:26])[C@H:20]([C@H:22]([CH2:24][CH3:25])[CH3:23])N>C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:10][CH2:11][CH2:12][CH3:13])[C:15]([NH:14][C@H:20]([C:19]([O:18][CH3:17])=[O:26])[CH:22]([CH3:23])[CH2:24][CH3:25])=[O:16])=[CH:4][CH:3]=1
Reactant: CCCCNCc1ccc(Br)nc1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Reactant: [N-]=C=O
Solvent: CCOC(C)=O
Product: CCCCN(Cc1ccc(Br)nc1)C(=O)N[C@H](C(=O)OC)C(C)CC
Reaction time: 0.5 h

Procedure:
A solution of 0.73 g (3 mmol) of the compound from Example VI in 5 ml of ethyl acetate is added at 0° C. to a solution of 0.93 g (2.16 mmol) of (S)-isoleucine methyl ester isocyanate (prepared by reacting (S)-isoleucine methyl ester hydrochloride with trichloromethyl chloroformate in toluene at 120° C.) in 10 ml of ethyl acetate, and the mixture is stirred at this temperature for 30 min. Subsequently, the reaction mixture is washed successively with dilute hydrochloric acid, water and saturated solutions of sodium hydrogen carbonate and sodium chloride, and the organic phase is then concentrated and the residue purified on silica gel using petroleum ether/ethyl acetate (2:1).
Reaction SMILES: Br[C:2]1[N:11]2[C:5]([CH2:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10]2)=[N:4][N:3]=1.[O-:16][CH2:17][CH3:18].[Na+]>>[CH2:17]([O:16][C:2]1[N:11]2[C:5]([CH2:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10]2)=[N:4][N:3]=1)[CH3:18]
Reactant: Brc1nnc2n1C=Cc1ccccc1C2
Reactant: CC[O-]
Agent: [Na+]
Product: CCOc1nnc2n1C=Cc1ccccc1C2

Procedure:
The reaction of 3-bromo-11H-s-triazolo[3,4-b][3]benzazepine with sodium ethoxide yielded 3-ethoxy-11H-s-triazolo[3,4-b][3]benzazepine. Colorless needles (as recrystallized from acetone), melting point: 143°-144° C. Infrared absorption spectrum of this compound was identical with that of the products obtained in Examples 35 and 36.
Reaction SMILES: [CH2:1]([Si:7]([CH3:10])([CH3:9])O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CN(C)C=O.C(Cl)([Cl:18])=O>ClCCCl>[CH2:1]([Si:7]([CH3:10])([CH3:9])[Cl:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(Cl)Cl
Reactant: CCCCCC[Si](C)(C)O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCCC[Si](C)(C)Cl
Yield: 91.1 %

Procedure:
To the same reactor as used in Example 1 were added 40.1 g (0.25 mole) of hexyldimethylsilanol, 160 g of 1,2-dichloroethane and 1.83 g (0.025 mole) of N,N-dimethylformamide, and 27.2 g (0.275 mole) of phosgene was introduced into the resulting mixture at a temperature of from 40° to 45° C. over 2 hours with stirring. After completion of the introduction, the same procedure as in Example 7 was carried out to obtain 40.7 g of hexyldimethylchlorosilane.
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[N:23]([CH3:24])[C@H:12]1[CH2:11]3.[Cl:27][C:28](=[CH2:31])[CH2:29][NH2:30]>CO>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([NH:30][CH2:29][C:28]([Cl:27])=[CH2:31])=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[N:23]([CH3:24])[CH:13]3[C:14]12[O:21][CH3:22]
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@@H]3[C@H](CN21)N3C
Reactant: C=C(Cl)CN
Solvent: CO
Product: C=C(Cl)CNC1=C(C)C(=O)C2=C(C1=O)C(CO)C1(OC)C3C(CN21)N3C
Product: NC(=O)O
Reaction time: 3 h
Yield: 34 %

Procedure:
A solution of 50 mg (0.138 mmol) of N-methylmitomycin A in 6 ml of anhydrous methanol was stirred with 0.2 ml of 2-chloroallylamine. The progress of the reaction was checked periodically by TLC and appeared to be complete in 3 hours. The solvent was then evaporated under reduced pressure and the residue was chromatographed using silica-gel as adsorbent. The fraction obtained by eluting the column with a mixture of chloroform and ethyl acetate (1:1 by volume) was evaporated under reduced pressure. Recrystallization from a mixture of chloroform and hexane gave 20 mg (34% yield) of the desired product as purple-colored crystals having a melting point of 71°-72° C. (decomposing) and providing the following analysis:
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[H-].[Na+].I[CH3:20]>CN(C)C=O>[CH3:20][N:8]1[C:2](=[O:1])[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]1=2
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2ccccc2Nc2ccccc21
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a solution of 11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine (10 g, 0.048 mol, Synthesis, (1985), 550) in dry dimethylformamide (100 ml) kept under an atmosphere of nitrogen, sodium hydride (2.1 g, 0.052 mol, 60% dispersion in oil) was added, and the reaction mixture was stirred for 1.5 h. iodomethane (3.27 ml, 0.052 mol) was slowly added keeping the temperature below 30° C. and the mixture was stirred overnight. The reaction mixture was quenched with saturated ammonium chloride (20 ml) and poured onto ice water (300 ml). The solid was filtered off and washed with plenty of water and dried. This yielded 10.4 g of crude 10-methyl-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine which was recrystallised from methanol (200 ml), to give 6.7 g (63%) of 10-methyl-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine. M.p. 210°-211° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[CH:19]=[CH:18][C:17]([OH:20])=[N:16]1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(N(CC)CC)C.N1C=CC=CC=1.C(OCC)(=[O:49])C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:10][C:11]([F:14])([F:12])[F:13])=[O:49])=[CH:4][C:3]=1[N:15]1[CH:19]=[CH:18][C:17]([O:20][C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:28][CH:27]=2)=[N:16]1
Reactant: CCOC(C)=O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(F)c(-n2ccc(O)n2)cc1SCC(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(F)c(-n2ccc(Oc3ccc(C(F)(F)F)cc3)n2)cc1S(=O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.5 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole was dissolved in 20 mL of dichloromethane, and 0.44 g of 4-trifluoromethylbenzeneboronic acid, 0.47 g of triethylamine, 0.37 g of pyridine, 0.43 g of copper(II) acetate and 0.5 g of powdery molecular sieves 4 A were added, followed by stirring at room temperature for 12 hours. To this solution, ethyl acetate was added, followed by washing with a saturated aqueous solution of citric acid, and then the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in 10 mL of chloroform, and under cooling with ice, 80 mg of m-chloroperbenzoic acid (purity: 75%) was added. After stirring for one hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.15 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-{4-(trifluoromethyl)phenoxy}pyrazole.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:10]2[N:11]=[C:12]([C:30]([CH3:33])([CH3:32])[CH3:31])[NH:13][C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[N:16]=2)=N[C:7]=1[O:8][CH3:9].BrC1N=C(C(C)(C)C)N([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])C=1C1C=CN=C(NC2C=CN=C(OC)C=2)N=1.[CH3:67]OC1C(N)=NC=C(B2OC(C)(C)C(C)(C)O2)N=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:10]2[N:11]=[C:12]([C:30]([CH3:32])([CH3:31])[CH3:33])[N:13]([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])[C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[N:16]=2)=[CH:67][C:7]=1[O:8][CH3:9]
Reactant: COc1cc(Nc2nccc(-c3[nH]c(C(C)(C)C)nc3-c3cnc(N)c(OC)n3)n2)ccn1
Reactant: COc1nc(B2OC(C)(C)C(C)(C)O2)cnc1N
Reactant: COc1cc(Nc2nccc(-c3c(Br)nc(C(C)(C)C)n3COCC[Si](C)(C)C)n2)ccn1
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: [Na+]
Solvent: COCCOC
Product: COc1cc(Nc2nccc(-c3c(-c4cnc(N)c(OC)c4)nc(C(C)(C)C)n3COCC[Si](C)(C)C)n2)ccn1
Temperature: 100 °C
Yield: 69 %

Procedure:
Preparation of 4-(4-(5-amino-6-methoxypyrazin-2-yl)-2-tert-butyl-1H-imidazol-5-yl)-N-(2-methoxypyridin-4-yl)pyrimidin-2-amine: A mixture of 4-(4-bromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-N-(2-methoxypyridin-4-yl)pyrimidin-2-amine (100 mg, 0.19 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-amine (118 mg, 0.47 mmol, Example 18, Step 2), aqueous 2.0 M Na2CO3 solution (1 ml, 2.0 mmol), and Pd(PPh3)4 (22 mg, 0.019 mmol) in DME (2 mL) was sparged with N2 for 5 min. The reaction was sealed and heated to 100° C. for 2 h. The reaction was allowed to cool to rt, poured into EtOAc and partitioned with water. The layers were separated and the organic portion was washed with water, dried (MgSO4), and concentrated. The resulting residue was purified by flash chromatography (SiO2, 100:0-0:100, hexanes-25% MeOH in EtOAc) to afford 102 mg (69% purity) of 4-(4-(6-amino-5-methoxypyridin-3-yl)-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-N-(2-methoxypyridin-4-yl)pyrimidin-2-amine: LCMS (m/z): 578.5 (MH+), tR=0.74 min.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:21][CH2:22][CH:23]([F:25])[F:24])[N:3]=1.[N+:26]([O-])([OH:28])=[O:27]>OS(O)(=O)=O>[Cl:1][C:2]1[C:20]([N+:26]([O-:28])=[O:27])=[CH:19][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:21][CH2:22][CH:23]([F:24])[F:25])[N:3]=1
Reactant: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1ccc(Cl)nc1OCC(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(Cl)nc1OCC(F)F

Procedure:
The sub-title compound is prepared from 6-chloro-2-(2,2-difluoro-ethoxy)-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (7.2 g, 18.6 mmol) and fuming HNO3 (20 mL) in conc. H2SO4 (40 mL) in analogy with example 1c.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])=[CH:6][CH:7]=1.Cl.[CH3:24][NH:25][CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:21][C:17]1[CH:16]=[C:15]([C:14]#[C:13][C:11]2[N:10]=[C:9]([CH3:22])[N:8]([C:5]3[N:4]=[N:3][C:2]([N:25]([CH3:26])[CH3:24])=[CH:7][CH:6]=3)[CH:12]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CNC
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccc(Cl)nn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccc(N(C)C)nn1
Temperature: 140 °C

Procedure:
3-Chloro-6-[4-(3-chloro-phenylethynyl)-2-methyl-imidazol-1-yl]-pyridazine (100 mg, 0.30 mmol) was dissolved in 2 mL dimethylforamide and dimethyl-amine hydrochloride (124 mg, 1.5 mmol) and cesium carbonate (396 mg, 1.2 mmol) were added. The reaction mixture was heated in the microwave at 140° C. for 60 min. After cooling to room temperature the reaction mixture was treated with 50 mL water and extracted three times with ethyl acetate (50 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude material was purified by flash chromatography (methylene chloride/methanol 100:0->90:10 gradient) and the desired product was obtained as a white solid (57 mg, 55%), MS: m/e=338.1 (M+H+).