Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:12][C:13]1[CH:38]=[CH:37][C:16]([CH2:17][N:18]([CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:19]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(#N)C.O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:2]3[C:3]4[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH2:25][CH2:26]2)=[O:20])=[CH:37][CH:38]=1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Reactant: CC(C)(C)OC(=O)NCCN(Cc1ccc(Cl)cc1)C(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)N(CCNC(=O)OC(C)(C)C)Cc4ccc(Cl)cc4)CC3)c21
Temperature: 80 °C
Yield: 30.2 %

Procedure:
(R)-4-Chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (46 mg, 0.27 mmol, 1.1 eq.) was added to a solution of the tert-butyl 2-(N-(4-chlorobenzyl)piperazine-1-carboxamido)ethylcarbamate (100 mg, 0.25 mmol) and Hunig's base (0.1 mL, 0.75 mmol, 3 eq.) in acetonitrile (3 mL). The resulting mixture was heated to 80° C. overnight. The reaction mixture was diluted with H2O and extracted with DCM, dried and concentrated to yield (R)-tert-butyl 2-(N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamido)ethylcarbamate (40 mg, 30%). MS (ESI) m/e (M+H+) 529.
Reaction SMILES: CN(C)C=O.CC(C)([O-])C.[Na+].[CH3:12][CH2:13][O:14][C:15]([CH:17](P(OCC)(OCC)=O)[CH3:18])=[O:16].[CH3:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1>O>[CH3:18][C:17](=[CH:32][C:31]1[CH:34]=[CH:35][C:28]([CH3:27])=[CH:29][CH:30]=1)[C:15]([O:14][CH2:13][CH3:12])=[O:16]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: Cc1ccc(C=O)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)=Cc1ccc(C)cc1
Temperature: -2.5 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To dimethylformamide (1802 ml) that had been cooled to −10° C. was added sodium tert-butoxide (528.6 g) and the solution was stirred at −5 to 0° C. for 30 min. Triethyl 2-phosphonopropionate (1310 g) was added dropwise thereto at 10° C. or below. The solution was stirred at 2 to 5° C. for 1 hr, and 4-methylbenzaldehyde (600.8 g) was added dropwise thereto at 10° C. or below and the solution was stirred at room temperature for 1 hr. Water was added thereto and the solution was extracted with toluene. The extract was washed with water and the solvent was distilled off to give the title compound as an oil (1009 g, yield 98.8%).
Reaction SMILES: C([Li])CCC.COB(OC)OC.Br[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH:21]([O:24][CH3:25])[O:22][CH3:23])[CH:15]=1.[C:26]([O:30][C:31](=[O:52])[NH:32][C:33]([C:35]1[S:36][C:37]([S:50][CH3:51])=[C:38]([S:40]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45](Br)[CH:44]=2)(=[O:42])=[O:41])[CH:39]=1)=[NH:34])([CH3:29])([CH3:28])[CH3:27].C([O-])([O-])=O.[Na+].[Na+].[CH3:59][O:60][CH:61]([O:72][CH3:73])[C:62]1[CH:67]=[C:66]([OH:68])[CH:65]=[CH:64][C:63]=1[B:69]([OH:71])[OH:70]>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.C1(C)C=CC=CC=1.C(O)C>[CH3:73][O:72][CH:61]([O:60][CH3:59])[C:62]1[CH:67]=[C:66]([OH:68])[CH:65]=[CH:64][C:63]=1[B:69]([OH:71])[OH:70].[C:26]([O:30][C:31](=[O:52])[NH:32][C:33]([C:35]1[S:36][C:37]([S:50][CH3:51])=[C:38]([S:40]([C:43]2[CH:44]=[C:45]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH:21]([O:24][CH3:25])[O:22][CH3:23])[CH:15]=3)[CH:46]=[CH:47][CH:48]=2)(=[O:42])=[O:41])[CH:39]=1)=[NH:34])([CH3:29])([CH3:28])[CH3:27]
Reactant: COC(OC)c1cc(Br)ccc1O
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COB(OC)OC
Agent: COC(OC)c1cc(O)ccc1B(O)O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(OC)c1cc(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)ccc1O
Yield: 28 %

Procedure:
2-Dimethoxymethyl-4-hydroxyl phenylboronic acid (212 mg. 1.0 mmol) was prepared using the procedure described in Example 1: step b using butyllithium (2.5M, 2.8 mL, 7 mmol), trimethylborate (0.812 mL, 5.6 mmol), 4-bromo-2-dimethoxymethyl-phenol (685 mg, 2.8 mmol, Example 26: step a) in THF (5 mL) and was used in the next step without purification. The procedure described in Example 1: step c was followed using {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (100 mg, 0.21 mmol, Example 27: step c), Pd(PPh3)4 (47 mg, 0.04 mmol), aqueous Na2CO3 (2M, 0.8 mL, 1.6 mmol), ethanol (0.8 mL), toluene (1.6 mL) and 2-dimethoxymethyl-4-hydroxy-phenylboronic acid (212 mg, 1.0 mmol). Purification by preparative SiO2 TLC (33% EtOAc in hexanes) of the residue yielded the title compound (37 mg, 28%) as a white solid. ESI-MS (m/z): Calcd. for C26H30N2O7S3: 579.1 (M+1); found: 579.9.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[I:12]I>CO.O>[OH:1][C:2]1[C:3]([I:12])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: II
Reactant: Oc1ccc2ncccc2c1
Solvent: CO
Solvent: O
Product: Oc1ccc2ncccc2c1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
6-Hydroxyquinoline (0.5 g) and iodine (1.24 g) were dissolved in methanol/water (15 ml/7.5 ml) to prepare a solution which was then stirred at room temperature for 2 hr. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was washed with ethyl acetate to give 6-hydroxy-5-iodo-quinoline (419 mg, yield 45%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[H-].[Na+].CC1C=CC(S(O[CH2:24][CH2:25][C@H:26]([OH:28])[CH3:27])(=O)=O)=CC=1.[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:24][CH2:25][C@H:26]([OH:28])[CH3:27])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H](C)O)cc1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC[C@@H](C)O)cc(C)c1Br
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To 4-bromo-3,5-dimethylphenol (5.4 g) in dehydrated N,N-dimethylformamide (60 mL), sodium hydride (1.1 g) was added under ice-cooling and the resultant reaction mixture was stirred for 30 minutes. To the reaction mixture, (R)-3-hydroxybutyl 4-methylbenzenesulfonate (5.0 g) was added and the resultant reaction mixture was stirred at room temperature for 45 minutes. To the reaction mixture, a saturated ammonium chloride aqueous solution was added, followed by extracting the reaction mixture with ethyl acetate. The organic phase was washed with a saturated saline and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluate: n-hexane:ethyl acetate-95:5 to 80:20) to obtain the subject compound (4.2 g) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][N+:12]([O-:14])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25]>O1CCCC1>[C:22]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][N+:12]([O-:14])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1)(=[O:26])[CH2:23][CH2:24][CH3:25]
Reactant: Nc1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Reactant: CCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 7.5 %

Procedure:
(4-Aminophenylsulphonyl)nitromethane (1.62 g, 7.5 mmol) was dissolved in dry tetrahydrofuran (35 ml) under an atmosphere of argon. Triethylamine (1.14 g, 11.25 mmol) was added, followed by butyryl chloride (0.88 g, 8.25 mmol). The mixture was stirred for 2 hours. The precipitated triethylamine hydrochloride was removed by filtration and the filtrate concentrated in vacuo. The brown oil obtained was purified by MPLC, eluting with dichloromethane/methanol (99:1 v/v) to give (4-butyramidophenylsulphonyl)nitromethane (0.16 g, 7.5% yield) as a solid, m.p. 155 156° C.; microanalysis, found: C, 45.8; H, 4.8; N, 9.6%; C11H14N2O5S requires: C, 46.1; H, 4.9; N, 9.8%.
Reaction SMILES: [CH:1]([Li])=[CH2:2].[C:4]1([CH:14]=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.CO.CCOCC>C1COCC1>[C:4]1([CH:14]([OH:15])[CH:1]=[CH2:2])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: [Li]C=C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: C=CC(O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of vinyl lithium (2.04 g, 0.06 mole, 2.5 ml) in dry THF (30 ml) under N2 with stirring, at -60° was added dropwise a solution of naphthaldehyde (4.68 g, 0.03 mole) in 10 ml THF. The reaction was kept at -60° for 30 min, the flask was then warmed to room temperature and 5 ml MeOH added cautiously with rigorous stirring, followed by 100 ml of ether. The ethereal solution was washed with brine and dried over MgSO4. After evaporation of the solvent, the residue was chromatographed through Florisil (250 g), eluted first with hexane and then a mixture 20% ether in hexane, giving the expected product. 4.77 g (86% yield). b.p. 92-105°/10μ.
Reaction SMILES: C([O-])C.[Na+].C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:14][C:13]=2[CH:23]=1)(=O)C>C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:14][C:13]=2[CH:23]=1
Reactant: CCOC(=O)C1=COc2ccc(OC(C)=O)cc2O1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=COc2ccc(O)cc2O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
Add 0.5 cm3 of a molar solution of sodium ethanolate in ethanol to a solution of 1 g (3.78 mmol) of ethyl 7-acetoxy-1,4-benzodioxin-2-carboxylate in 15 cm3 of anhydrous ethanol under a nitrogen atmosphere. Stir for 18 hours at room temperature and then neutralise with Dowex X-8 resin, acid form, which has been washed beforehand with ethanol. After filtration and concentration to dryness under partial pressure, the crude product obtained is purified by chromatography on a silica column (eluant: petroleum ether/diethyl ether, 80:20). Ethyl 7-hydroxy-1,4-benzodioxin-2-carboxylate is thereby obtained in a yield of 96%.
Reaction SMILES: C1(N[C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])C=CC=CC=1.[F-].[Cs+].[CH3:19][CH:20]1[CH2:24]OC(=O)[O:21]1>CS(C)=O>[C:11]1([N:10]2[CH2:19][CH:20]([CH3:24])[O:21][C:8]2=[O:9])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC1COC(=O)O1
Reactant: O=C(Nc1ccccc1)Nc1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: CC1CN(c2ccccc2)C(=O)O1
Temperature: 140 °C
Reaction time: 30 h
Yield: 74.3 %

Procedure:
N,N′-Diphenylurea (20.7 g, 98.0 mmol) was dissolved in dimethyl sulfoxide (40 mL), and thereto were added cesium fluoride (1.48 g, 9.80 mmol) and 4-methyl-1,3-dioxolan-2-one (10.0 g, 98.0 mmol), in order. The mixture was stirred for 30 hours at 140° C. under an atmosphere of argon. After filtering off the insoluble materials, the filtrate was condensed in vacuo, and the residue was recrystallized from ethanol to give the subject 3-phenyl-5-methyloxazolidin-2-one (12.9 g, yield 74.3%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].C(Cl)(Cl)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)(OC1C=CC=CC=1)N.N[CH2:44][CH2:45][N:46]1[C:55]2[C:50](=[CH:51][CH:52]=[C:53]([NH:56][CH2:57][C:58]3[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:66])[F:65])[CH:59]=3)[CH:54]=2)[N:49]=[C:48]([CH3:68])[C:47]1=[O:69].CN1CCOCC1>C1COCC1>[CH3:68][C:48]1[C:47](=[O:69])[N:46]([CH2:45][CH2:44][NH:1][C:2]([NH2:4])=[O:3])[C:55]2[C:50]([N:49]=1)=[CH:51][CH:52]=[C:53]([NH:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:66])[F:65])[CH:59]=1)[CH:54]=2
Reactant: NC(N)=O
Reactant: Cc1nc2ccc(NCc3cccc(C(F)(F)F)c3)cc2n(CCN)c1=O
Agent: NC(=O)Oc1ccccc1
Agent: O=C(Cl)Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1nc2ccc(NCc3cccc(C(F)(F)F)c3)cc2n(CCNC(N)=O)c1=O

Procedure:
Compounds of Formula I in which R1 includes a urea moiety can be synthesized from primary amines in a variety of ways using phosgene, triphosgene, carbonyldiimidazole, and others as coupling reagents. One preferred way includes the use of the reagent phenyl carbamate (Young, R. J. et al, Bioorg. Med. Chem. Lett. 2006, 16, 5953-7). Starting material 1-(2-aminoethyl)-3-methyl-7-(3-(trifluoromethyl)benzyl-amino)quinoxalin-2(1H)-one (50 mg) was heated to reflux in THF for 2 h in the presence of N-methyl morpholine (0.16 mmol) and phenyl carbamate (0.16 mmol). The reaction mixture was concentrated and purified by chromatography using 6% MeOH in dichloromethane as eluent. Product 1-(2-(3-methyl-2-oxo-7-(3-(trifluoromethyl)benzyl-amino)quinoxalin-1(2H)-yl)ethyl)urea was isolated as off-white solid.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)[CH:17]=[CH:16][C:15]=1[OH:29]>>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)[CH:17]=[CH:16][C:15]=1[O:29][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: BrCc1cc2ccccc2o1
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCc1cc2ccccc2o1
Yield: 29 %

Procedure:
Alkylation of 2-bromomethyl-benzofuran with 2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol was carried out according to Example 136, Step 3, to give 2-[2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-benzofuran in 29% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.3 (s, 12 H) 3.9 (s, 3 H) 5.3 (s, 2 H) 6.8 (d, J=0.8 Hz, 1 H) 7.0 (d, J=8.1 Hz, 1 H) 7.2 (m, 1 H) 7.3 (m, 2 H) 7.4 (dd, J=8.0, 1.4 Hz, 1 H) 7.5 (dd, J=8.1, 0.8 Hz, 1 H) 7.5 (dd, J=8.0, 1.1 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1)=[CH:11][CH:10]=3.[CH3:27][C:28]([CH3:41])([CH3:40])/[CH:29]=[CH:30]/B1OC(C)(C)C(C)(C)O1.CC(N)CC1C=CC=CC=1.OP(O)(O)=O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:27][C:28]([CH3:41])([CH3:40])/[CH:29]=[CH:30]/[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:21]1[CH:26]=[N:25][CH:24]=[N:23][CH:22]=1)=[CH:11][CH:10]=3
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1cnc(Cl)cc12
Reactant: CC(C)(C)/C=C/B1OC(C)(C)C(C)(C)O1
Agent: CC(N)Cc1ccccc1
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)/C=C/c1cc2c(cn1)Oc1ccc(-c3cncnc3)cc1[C@@]21COC(N)=N1
Temperature: 130 °C

Procedure:
A mixture of (S)-3-chloro-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (0.967 g, 2.64 mmol), trans-(3,3-dimethylbutenyl)boronic acid pinacol ester (1.389 g, 6.61 mmol), AmPhos (0.094 g, 0.132 mmol), and potassium phosphate hydrate (1.218 g, 5.29 mmol) in 10 mL dioxane/water (1:1) was heated in the microwave at 130° C. for 1 h. After cooling to rt, the reaction was concentrated and the residue purified by silica gel chromatography using 0-5% MeOH/DCM to give (S,E)-3-(3,3-dimethylbut-1-enyl)-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine. Found MS: MH+=414.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[C:35]([CH3:40])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[F:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])=[CH:34][C:35]=1[CH3:40]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: Cc1cc([C@H](N)CN(C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)ccc1F
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(F)c(C)c1

Procedure:
Compound 67 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(4-fluoro-3-methyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound. LC/MS [355 (M+H)]1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 9.07 (s, 1H), 8.99 (d, 1H), 8.54 (s, 1H), 8.38 (d, 1H), 8.17 (s, 1H), 7.38 (m, 1H), 7.30 (m, 1H), 7.07 (m, 1H), 5.45 (s, 1H), 3.15 (dd, 1H), 2.89 (dd, 1H), 2.32 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[OH:6][CH2:7][CH2:8][CH:9]1[N:14]2[CH:15]=[C:16]([I:18])[CH:17]=[C:13]2[C:12](=[O:19])[NH:11][CH2:10]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:4][S:1]([O:6][CH2:7][CH2:8][CH:9]1[N:14]2[CH:15]=[C:16]([I:18])[CH:17]=[C:13]2[C:12](=[O:19])[NH:11][CH2:10]1)(=[O:3])=[O:2]
Reactant: O=C1NCC(CCO)n2cc(I)cc21
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1CNC(=O)c2cc(I)cn21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Mesyl chloride (0.172 g, 1.50 mmol) was added to an ice-cooled stirred solution of 4-(2-hydroxyethyl)-7-iodo-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (0.230 g, 0.75 mmol) and DIPEA (0.291 g, 2.25 mmol) in DCM (5 ml). The reaction mixture was stirred at room temperature under N2 for 1 h and then it was portioned between DCM and saturated NaHCO3 solution. The title compound was isolated by precipitation from the organic layer as a white solid (0.202 g, 0.52 mmol, 70%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([CH2:16][OH:17])[NH:14][C:13]1=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClS([N:23]=[C:24]=[O:25])(=O)=O.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([CH2:16][O:17][C:24](=[O:25])[NH2:23])[NH:14][C:13]1=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1CO)OCc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)OC[C@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
In 16 ml of dry dichloromethane is dissolved 0.50 g of (3S,4S)-3-benzyloxycarbonylamino-4-hydroxymethyl-2-azetidinone obtained in Example 37 and, on cooling at -15° C., 0.368 g of chlorosulfonyl isocyanate is added, followed by stirring for 30 minutes. A 15-ml aqueous solution of 0.72 g of sodium sulfite is added and the solution is warmed to room temperature, followed by stirring for 1 hour. The dichloromethane is distilled off under reduced pressure and the residue is extracted twice with ethyl acetate-tetrahydrofuran (3:1, v/v). The extract is washed with aqueous sodium chloride, dried over mangesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography [eluent: chloroform-ethyl acetate-methanol (40:55:5, v/v/v)] to give 0.323 g of (3S,4S)-3-benzyloxycarbonylamino-4-carbamoyloxymethyl-2-azetidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=O.O>C1(C)C=CC=CC=1.CCCCO.CCCCO.CCCCO.CCCCO.[Ti]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: C[C@@H](N)c1ccc(Cl)cc1
Agent: [Ti]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCO
Product: CC(=N[C@H](C)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 65.8 %

Procedure:
3 g of tetrabutyl ortho-titanate are added to a solution of 52 g (0.35 mol) of (R)-1-(4-chlorophenyl)-ethylamine (97% ee) and 51.7 g (0.353 mol) of 4-chloroacetophenone in 300 ml of toluene at room temperature with stirring, and then the mixture is refluxed for 2 hours at the water separator. A further 2 g of tetrabutyl ortho-titanate are added, and the mixture is refluxed for a further 6 hours. A further 2 g of tetrabutyl ortho-titanate are then added, and the mixture is then refluxed for 3 hours. The reaction mixture is then filtered. The filtrate is evaporated under reduced pressure to give 67.3 g (66% of theory) of (R)-[1-(4-chlorophenyl)-ethyl]-[1-(4-chlorophenyl)-ethylidene]-amine.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]2[N:15]([CH2:27][C:28]([O:30]CC)=[O:29])[C:16](=[O:26])[N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[CH2:18][C:12]2=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>CO.O.C(OCC)(=O)C.O>[CH2:1]([S:8][C:9]1[N:14]=[C:13]2[N:15]([CH2:27][C:28]([OH:30])=[O:29])[C:16](=[O:26])[N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[CH2:18][C:12]2=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN1C(=O)N(c2ccccc2Cl)Cc2cnc(SCc3ccccc3)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=C(O)CN1C(=O)N(c2ccccc2Cl)Cc2cnc(SCc3ccccc3)nc21
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of 7-benzylthio-3-(2-chlorophenyl)-1-(ethoxycarbonylmethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (1.435 g, 3.36 mmol) and lithium hydroxide monohydrate (481 mg, 11.5 mmol) in methanol (10 mL) and water (30 mL) were refluxed for 48 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate/water. The aqueous layer was adjusted to pH 4 and extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated in vacuo to give 1.2 g of 7-benzylthio-3-(2-chlorophenyl)-1-(hydroxycarbonylmethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[C:8]1[C:14](=O)[C:13]2[N:16]3[C@@](OC)([C@H](COC(N)=O)[C:12]=2[C:10](=[O:11])[C:9]=1[O:30][CH3:31])[C@H]1N[C@H]1C3>>[CH2:31]1[O:30][C:9]2[CH:8]=[CH:14][C:13]([NH2:16])=[CH:12][C:10]=2[O:11]1
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+]
Product: Nc1ccc2c(c1)OCO2

Procedure:
This compound was prepared by the procedure described in Example 1, except that the potassium carbonate was omitted. From 80 mg. of mitomycin A and 0.1 ml. of 3,4-methylenedioxyaniline was obtained 50 mg. (48% yield) of the desired product having a melting point of 86°-88° C. (decomposition) and providing the following analysis:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[OH:19].C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Cc1ccc(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C)c(Oc2ccc(Br)cc2C=O)c1
Yield: 98.3 %

Procedure:
In a manner similar to the method described in Example 50a, 5-bromo-2-fluorobenzaldehyde (2.1 g, 10 mmol) (Alfa) was reacted with 2,5-dimethylphenol (1.4 g, 11 mmol) and K2CO3 in N,N-dimethylacetamide to give 5-bromo-2-(2,5-dimethyl-phenoxy)-benzaldehyde as an orange oil (Yield 3 g, 98%).