Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:24][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Solvent: CS(C)=O
Product: CCn1ncc2c(NCc3ccccc3)c3ccccc3nc21
Temperature: 80 °C
Yield: 91.6 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (15.0 g, 0.065 mol), benzylamine (15.6 mL, 0.14 mol) and DMSO (100 mL) was heated at 80° C. overnight. The reaction mixture was poured into ice/water and the gummy solid which formed was collected by filtration. The solid was dissolved in ethyl acetate, dried over MgSO4, filtered and concentrated. The residual oil was crystallized from ethyl acetate to afford 18 g (92%) of 1-ethyl-N-(phenyl methyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 130°-132° C.
Reaction SMILES: [CH:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[CH2:24]([N:13]1[CH2:14][CH2:15][CH:10]([C:8](=[O:9])[C:7]2[CH:16]=[CH:17][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)[CH2:11][CH2:12]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)c1ccc(C(=O)C2CCNCC2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(C(=O)C2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66 %

Procedure:
To a solution of 4-(4-isopropylbenzoyl)piperidine in N,N-dimethylformamide (100 mL), potassium carbonate (9.60 g, 69.5 mmol) and benzyl bromide (8.50 g, 71.5 mmol) were added, and the resulting mixture was stirred for 20 hours at room temperature. The mixture was poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from hexane to obtain the title compound (13.53 g, yield 66%).
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Si]([O:21][C@H:22]([CH2:35][CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)[C@H:23]([CH3:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(C(C)(C)C)(C)C.Br[C:44]1[C:45]([O:52][CH3:53])=[N:46][C:47]([O:50][CH3:51])=[N:48][CH:49]=1>C(O)C.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>[CH3:51][O:50][C:47]1[N:46]=[C:45]([O:52][CH3:53])[C:44]([C:28]2[CH:27]=[CH:26][C:25]([O:24][C@H:23]([C@H:22]([OH:21])[CH2:35][CH2:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)[CH3:34])=[CH:30][CH:29]=2)=[CH:49][N:48]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: COc1ncc(Br)c(OC)n1
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: CCO
Solvent: Cc1ccccc1
Product: COc1ncc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)c(OC)n1
Temperature: 120 °C

Procedure:
Toluene (4 ml), 2M aqueous sodium carbonate (0.5 ml), (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.200 g, example 15f)), and tetrakis(triphenylphosphine)palladium(0) (0.020 g) were added to a solution of 5-bromo-2,4-dimethoxypyrimidine (0.209 g) in ethanol (1 ml). The mixture was heated at 120° C. for 4 hours.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]([CH2:24][CH2:25][CH3:26])[C:21](=[O:23])[CH3:22].[CH2:27](O)[CH2:28][OH:29].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]([CH2:24][CH2:25][CH3:26])[C:21]1([O:29][CH2:28][CH2:27][O:23]1)[CH3:22]
Reactant: CCCC(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br)C(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCC(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br)C1(C)OCCO1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A mixture of 1.5 g. of N-[4-bromo-3(1-propyl-2-oxopropoxy)phenyl]-3,4,5,6-tetrahydrophthalimide, 0.7 g. of ethyleneglycol, 0.1 g. of p-toluenesulfonic acid and 30 ml. of benzene was refluxed with stirring under removing water for 5.5 hours and the reaction mixture was cooled to room temperature and 0.4 ml. of triethylamine was added. The solvent was distilled off under a reduced pressure. The residue was purified by a chromatography on a column of silica gel (developing solvent: ethyl acetate:n-hexane:triethylamine of 30:80:1) to obtain 1.2 g. of Compound No. 49 shown in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH:5]([OH:27])[CH2:6][NH:7][CH:8]([CH3:26])[CH2:9][C:10]1[CH:25]=[CH:24][C:13]([O:14][CH2:15][C:16]2[O:17][CH:18]=[C:19]([OH:23])[C:20](=[O:22])[CH:21]=2)=[CH:12][CH:11]=1.[CH3:31][NH:32][CH3:33].[CH2:34]=O>C(O)C.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH:5]([OH:27])[CH2:6][NH:7][CH:8]([CH3:26])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]2[O:17][C:18]([CH2:31][N:32]([CH3:34])[CH3:33])=[C:19]([OH:23])[C:20](=[O:22])[CH:21]=2)=[CH:24][CH:25]=1
Reactant: CC(Cc1ccc(OCc2cc(=O)c(O)co2)cc1)NCC(O)c1cccc(Cl)c1
Reactant: C=O
Reactant: CNC
Solvent: CCO
Solvent: O
Product: CC(Cc1ccc(OCc2cc(=O)c(O)c(CN(C)C)o2)cc1)NCC(O)c1cccc(Cl)c1
Reaction time: 1 h

Procedure:
A solution of 2-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl]phenoxymethyl]-5-hydroxy-4H-pyran-4-one 0.8 g) in ethanol, was added to a mixture of dimethylamine (0.28 ml of a 33% solution, in ethanol) and formaldehyde (0.175 ml of a 37% aq. solution) in ethanol:water (95:5), (50 ml), at room temperature and allowed to stand for 1h. The solvent was evaporated in vacuo, the residue was partitioned between ethyl acetate and water separated and the organic extracts dried (magnesium sulphate), filtered and evaporated to an oil which was chromatographed on silica. Elution with chloroform: methanol (95:5) gave 2-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl]phenoxymethyl]-5-hydroxy-6-dimethylaminomethyl-4H-pyran-4-one (0.4 g) as a 49:51 mixture of diastereoisomers.
Reaction SMILES: [OH-].[Na+].O.[CH2:4]([O:11][C@H:12]([C@@H:14]([N:17]1[C:21](=[O:22])[N:20]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:35]4[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=4)[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[CH:19]=[N:18]1)[CH2:15][CH3:16])[CH3:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CC1C=CC(S(O[CH2:53][C@H:54]2[CH2:58][C@:57]([CH2:67][N:68]3[CH:72]=[N:71][CH:70]=[N:69]3)([C:59]3[CH:64]=[CH:63][C:62]([F:65])=[CH:61][C:60]=3[F:66])[O:56][CH2:55]2)(=O)=O)=CC=1>CS(C)=O>[N:68]1([CH2:67][C@@:57]2([C:59]3[CH:64]=[CH:63][C:62]([F:65])=[CH:61][C:60]=3[F:66])[O:56][CH2:55][C@@H:54]([CH2:53][O:41][C:38]3[CH:39]=[CH:40][C:35]([N:32]4[CH2:31][CH2:30][N:29]([C:26]5[CH:27]=[CH:28][C:23]([N:20]6[C:21](=[O:22])[N:17]([C@H:14]([CH2:15][CH3:16])[C@@H:12]([O:11][CH2:4][C:5]7[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=7)[CH3:13])[N:18]=[CH:19]6)=[CH:24][CH:25]=5)[CH2:34][CH2:33]4)=[CH:36][CH:37]=3)[CH2:58]2)[CH:72]=[N:71][CH:70]=[N:69]1
Reactant: CC[C@@H]([C@H](C)OCc1ccccc1)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO[C@@](Cn3cncn3)(c3ccc(F)cc3F)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC[C@H]([C@H](C)OCc1ccccc1)n1ncn(-c2ccc(N3CCN(c4ccc(OC[C@@H]5CO[C@@](Cn6cncn6)(c6ccc(F)cc6F)C5)cc4)CC3)cc2)c1=O
Temperature: 52.5 °C
Reaction time: 0.75 h

Procedure:
A solution of sodium hydroxide (9.2 g) and water (10 ml) was cooled to 25-35° C. and added dimethyl sulfoxide (350 ml), followed by 1-((2S,3S)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one (50 gms) compound of formula-20 at 25-35° C. The reaction mixture was stirred for 45 minutes at the same temperature. ((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluoro phenyl)tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (50 μms) compound of formula-10 was added to the above reaction mixture and heated to 45-60° C. The reaction mixture was stirred for 6 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with water and neutralized with hydrochloric acid. The reaction mixture was stirred for 1 hour at 25-35° C. Filtered the solid and washed with water. Dried the solid to get the title compound. Yield: 79 g
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].[C:27]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[N:24]([CH3:27])[C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1nc2cccc(-c3cc4c(n3C)CCNC4=O)c2nc1NC(C)(C)C
Temperature: 50 °C
Reaction time: 24 h
Yield: 34.4 %

Procedure:
A mixture of 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (193) (0.10 g, 0.28 mmol), K2CO3 (0.13 g, 0.92 mmol), and MeI (0.027 mL, 0.43 mmol) in DMF (4 mL) was stirred at 50° C. in 24 h. The reaction mixture was cooled, added H2O, the solid was filtered, dried and purified by ISCO (0-30% EtOAc/DCM) to give the title compound (35 mg, 34% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.71-7.78 (1H, m), 7.40-7.50 (1H, m), 7.35 (1H, t, J=7.6 Hz), 6.86 (1H, br. s.), 6.22 (1H, s), 5.87 (1H, s), 3.39-3.50 (3H, m), 3.11-3.21 (2H, m), 2.77 (2H, t, J=6.8 Hz), 2.51 (3H, s), 1.28 (9H, s). m/z (ESI, +ve) 364.0 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[OH-].[Na+].O.Cl[C:10]1[N:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[N:11]=1>CC(C)=O>[Cl:17][C:12]1[CH:13]=[C:14]([Cl:16])[N:15]=[C:10]([NH:4][C:3]([NH2:5])=[NH:2])[N:11]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: N=C(N)Nc1nc(Cl)cc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.7 %

Procedure:
A solution of 141.8 g (1.48 mole) of guanidine hydrochloride, 59.3 g (1.48 m) of sodium hydroxide and 709 ml of water was added to a solution of 183.4 g (0.74 m) of 2,4,6-trichloropyrimidine in 2127 ml of acetone causing a mild exothermic reaction. After stirring for 1 hour at room temperature, a mixture of solid and oil had formed. Refrigeration caused complete crystallization. The crystals were filtered, then suspended in 1200 ml of water and stirred for 1 hour, filtered, washed with water, then acetone and air dried to give 53.0 g (35%) of 4,6-dichloro-2-guanidinopyrimidine, mp>360°.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[CH2:15][O:14]2)=[C:8]([Cl:21])[CH:7]=1>C1(C)C=CC=CC=1.O1CCCC1>[Cl:21][C:8]1[CH:7]=[C:6]([N:5]=[C:1]=[O:2])[CH:11]=[CH:10][C:9]=1[CH2:12][N:13]1[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[CH2:15][O:14]1
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)CON(Cc2ccc(N=C=O)cc2Cl)C1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a stirred solution of 7.9 grams (0.08 mole) of phosgene in toluene was added dropwise a solution of 5.0 grams (0.02 mole) of 2-(4-amino-2-chlorophenyl)methyl-4,4-dimethyl-3-isoxazolidinone in tetrahydrofuran. Upon completion of addition the reaction mixture was warmed to 80° C. where it stirred for 3 hours. The reaction mixture was concentrated under reduced pressure to give 5.6 grams of 2-(2-chloro-4-isocyanatophenyl)methyl-4,4-dimethyl-3-isoxazolidinone as a residual solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]1[CH2:13][O:12][CH2:11][CH2:10]1.[Se:14]1C=CC=[C:15]1[C:19]1[Se:20][C:21]([C:24]2[Se:25][CH:26]=[CH:27][CH:28]=2)=[CH:22][CH:23]=1.CN([CH:32]=[O:33])C>C(OCC)(=O)C>[CH:32]([C:26]1[Se:25][C:24]([C:21]2[Se:20][C:19]([C:15]3[Se:14][C:10]([CH:11]=[O:12])=[CH:9][CH:13]=3)=[CH:23][CH:22]=2)=[CH:28][CH:27]=1)=[O:33]
Reactant: C1CCOC1
Reactant: CN(C)C=O
Reactant: c1c[se]c(-c2ccc(-c3ccc[se]3)[se]2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2ccc(-c3ccc(C=O)[se]3)[se]2)[se]1
Temperature: -78 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
LDA (1.0 M solution in THE, 1.0 mL) was added to an anhydrous THF solution (4 mL) containing 2,2′:5′,2″-terselenophene (100 mg) under N2 at −78° C. The solution was stirred at −78° C. for 3 h, anhydrous DMF (2 mL) was added, stirred at −78° C. for 1 h, and slowly warmed to room temperature. The reaction solution was diluted with ethyl acetate (100 mL) and washed with H2O (4×100 mL). The organic layer was separated, dried over MgSO4, filtered, and the solvent was removed under vacuum. The residue was chromatographed over silica gel using (5:1) CH2Cl2/ethyl acetate to afford 2,5″-diformyl-5,2′:5′,2″-terselenophene in 75% yield.
Reaction SMILES: CN(C)CCCOC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][C:38]=3[C:44]([F:47])([F:46])[F:45])=[N:33][CH:32]=2)=[CH:27]1.Cl.Cl[CH2:50][CH2:51][N:52]([CH2:55][CH3:56])[CH2:53][CH3:54]>C(Cl)Cl.CO>[CH2:51]([N:52]([CH2:55][CH3:56])[CH2:53][CH2:54][O:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]2[S:35][C:31]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)=[CH:32][N:33]=2)=[C:38]([C:44]([F:47])([F:46])[F:45])[CH:39]=1)[CH3:50]
Reactant: CCN(CC)CCCl
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1
Agent: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCOc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-ylamino)-3-trifluoromethyl-phenol (Example 28) and using (2-chloroethyl)-diethylamine hydrochloride. The title compound: ES-MS: 441.9 [M+H]+; single peak at tR=3.41 min (System 2); Rf=0.25 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][N:14]1[C:19]2=[CH:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[C:18]2[C:17](=[O:31])[N:16]([CH3:32])[C:15]1=[O:33].C([O:37][B:38](OC(C)C)[O:39]C(C)C)(C)C>C1COCC1>[CH3:13][N:14]1[C:19]2=[CH:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:22]([B:38]([OH:39])[OH:37])=[C:18]2[C:17](=[O:31])[N:16]([CH3:32])[C:15]1=[O:33]
Reactant: Cn1c(=O)c2cn(COCC[Si](C)(C)C)cc2n(C)c1=O
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(B(O)O)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Butyl lithium (1.26M, 28.4 mL, 35.8 mmol) was added dropwise to a solution of diisopropylamine (3.63 g, 35.8 mmol) in THF (20 mL) at −78° C., keeping the internal temperature below −40° C. Once the addition was complete, the contents of the flask were allowed to warm to −5° C., then were re-cooled to −78° C. The resulting mixture was cannulated over a period of about 30 minutes into a suspension of 1,3-dimethyl-6-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (step 1) (6.93 g, 22.4 mmol) in THF (75 mL) at −78° C. The mixture was stirred at −78° C. for 30 minutes, then triisopropylborate (8.3 mL, 35.8 mmol) was added dropwise. The solution was stirred at −78° C. for 1.5 hours, then was quenched by carefully adding sat ammonium chloride (200 mL). The mixture was allowed to reach room temperature and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried with magnesium sulfate and the solvent was removed under vacuum. The crude material was triturated with ether/hexane and dried under vacuum at 50° C. The solid was recombined with the mother liquor which was reduced under vacuum. The resultant semi-solid material was triturated with iso-hexane and dried under vacuum at 50° C. to afford the title compound;
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]([CH:28]1[CH2:30][NH:29]1)#[N:27].C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([N:29]3[CH2:30][CH:28]3[C:26]#[N:27])=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: N#CC1CN1
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: COC12C(CO)C3=C(C(=O)C(C)=C(N4CC4C#N)C3=O)N1CC1NC12
Product: NC(=O)O
Yield: 30 %

Procedure:
A solution of mitomycin A (100 mg. or 0.286 mmol) in 8 ml of anhydrous methanol was treated with 2-cyanoaziridine (38.9 mg. or 0.572 mmol) and 30 mg. of potassium carbonate, under nitrogen at room temperature. When thin-layer chromatography on silica gel (2:8 methanol-chloroform as solvent) showed that starting material was no longer present, the mixture was diluted with 50 ml of methylene chloride, filtered, and evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography on silica gel with a mixture of methanol and chloroform (2:8 by volume) as the solvent. This procedure gave 33 mg. (30% yield) of the desired product having a melting point of 87°-89° C. (decomposing) and providing the following analysis:
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][N:13]1[CH:17]=[N:16][NH:15][C:14]1=[S:18].[Cl:19][C:20]1[CH:47]=[CH:46][C:23]([C:24]([C:26]2[CH:27]=[C:28]3[C:33]4=[C:34]([O:36][CH2:37][N:32]4[C:31](=[O:38])[CH:30]=[C:29]3[C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=3)[CH:35]=2)=[O:25])=[CH:22][CH:21]=1>C1COCC1>[Cl:45][C:41]1[CH:40]=[C:39]([C:29]2[C:28]3[C:33]4=[C:34]([O:36][CH2:37][N:32]4[C:31](=[O:38])[CH:30]=2)[CH:35]=[C:26]([C:24]([C:23]2[CH:46]=[CH:47][C:20]([Cl:19])=[CH:21][CH:22]=2)([OH:25])[C:17]2[N:13]([CH3:12])[C:14]([SH:18])=[N:15][N:16]=2)[CH:27]=3)[CH:44]=[CH:43][CH:42]=1
Reactant: Cn1cn[nH]c1=S
Reactant: O=C(c1ccc(Cl)cc1)c1cc2c3c(c1)c(-c1cccc(Cl)c1)cc(=O)n3CO2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1c(S)nnc1C(O)(c1ccc(Cl)cc1)c1cc2c3c(c1)c(-c1cccc(Cl)c1)cc(=O)n3CO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 1.4 %

Procedure:
nBuLi 1.6M in hexane (0.0086 mol) was added at −78° C. to a solution of 2,4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione (0.0043 mol) in THF (25 ml) under N2 flow. The mixture was stirred at 0° C. for 1 hour, then cooled to −78° C. 8-(4-chlorobenzoyl)-6-(3-chlorophenyl)-2H,4H-oxazolo[5,4,3-ij]quinolin-4-one (0.0024 mol) described in International Publication WO98/40383, was added portionwise. The mixture was stirred at room temperature for 4 hours, poured out into ice water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (1.38 g) was purified by column chromatography over silica gel (15-40 μm) (eluent: CH2Cl2/CH3OH/NH4OH97/3/0.1). The pure fractions were collected and the solvent was evaporated. A part of the residue (0.049 g) was purified by column chromatography over silica gel (10 μm) (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 0.018 g (1%) of 6-(3-chlorophenyl)-8-[(4-chlorophenyl)hydroxy(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2H,4H-oxazolo[5,4,3-ij]quinolin-4-one, melting point: 193° C. (intermediate 13).
Reaction SMILES: C1C2C(C[O:15][C:16]([N:18]([CH2:31][C:32]3[N:36]([CH3:37])[C:35]4[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=4[N:33]=3)[CH2:19][CH2:20][NH:21][C@@H:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([O:25][CH3:26])=[O:24])=O)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C.C(=O)(OC1C=CC([N+]([O-])=O)=CC=1)OC1C=CC([N+]([O-])=O)=CC=1>CN(C)C=O.ClC(Cl)C>[CH3:30][C:27]([CH3:29])([CH3:28])[C@H:22]([N:21]1[CH2:20][CH2:19][N:18]([CH2:31][C:32]2[N:36]([CH3:37])[C:35]3[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=3[N:33]=2)[C:16]1=[O:15])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)[C@@H](NCCN(Cc1nc2ccccc2n1C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C
Agent: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC(Cl)Cl
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](N1CCN(Cc2nc3ccccc3n2C)C1=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.2 %

Procedure:
A solution of the product of Example 148D (0.19 g) in N,N-dimethylformamide (3.5 mL) was treated with diethylamine (0.35 mL), stirred at 25° C. for 1.5 hours and concentrated. A solution of the residue in dichloroethane (7 mL) was treated with bis-(p-nitrophenyl) carbonate (0.128 g, 1.2 equivalents), stirred at 60° C. for 16 hours and concentrated. The residue was chromatographed on silica gel, eluting with ethyl acetate:dichloromethane (3:2) to give 80 mg (64%) of the title compound.
Reaction SMILES: [C:1]([Cu])#N.C[Li].[Cl:6][C:7]1[CH:12]=[C:11]([C:13]2[N:18]([CH2:19][C:20]#[CH:21])[C:17](=[O:22])[C:16]([CH2:23][CH3:24])=[C:15](OS(C(F)(F)F)(=O)=O)[N:14]=2)[CH:10]=[C:9]([Cl:33])[N:8]=1>C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]2[N:18]([CH2:19][C:20]#[CH:21])[C:17](=[O:22])[C:16]([CH2:23][CH3:24])=[C:15]([CH3:1])[N:14]=2)[CH:10]=[C:9]([Cl:33])[N:8]=1
Reactant: N#C[Cu]
Reactant: C#CCn1c(-c2cc(Cl)nc(Cl)c2)nc(OS(=O)(=O)C(F)(F)F)c(CC)c1=O
Agent: [Li]C
Solvent: C1CCOC1
Product: C#CCn1c(-c2cc(Cl)nc(Cl)c2)nc(C)c(CC)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
To a stirred, cold (-78° C.) solution of CuCN (1.91 g, 20 mmol) in 100 mL of THE was added methyllithium (30 mL, 42 mmol, 2.1 equiv, 1.4M in diethyl ether) over 10 min. After stirring for 15 min, this solution was added over 10 min via a canula to a cold (-78° C.) solution of 2-(2,6-dichloro-4-pyridyl)-5-ethyl-3-propargyl-6 -trifluoromethanesulfonyloxy-4(3H)-pyrimidinone in 20 mL of THF. The reaction mixture was stirred for 30 min, quenched with 15 mL of 10% concentrated NH4OH/saturated NH4Cl, diluted with 200 mL of ethyl acetate and warmed to room temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give a semi oil. The crude product was purified by flash chromatography (silica gel, ethyl acetate/hexane, 2/8) to afford 2.29 g (71%) of 2-(2,6-dichloro-4-pyridyl)-5-ethyl-6-methyl-3-propargyl-4(3H)-pyrimidinone as a white solid: mp 143°-144° C.; IR (KBr) 3220, 2125, 1668, 1584, 1541, 1515, 1367 cm-1 ; 1H NMR (270 MHz, CDCl3) δ 1.16 (t, J=7.6 Hz, 3H), 2.35 (s, 3H), 2.43 (t, J=2.6 Hz, 1H), 2.62 (q, J=14.8 Hz, 2H), 4.56 (d, J=2.6 Hz, 2H), 7.60 (s, 2H).