Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=1.[NH2:20][C@H:21]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH2:22][OH:23].CCN(C(C)C)C(C)C>CCCCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=[C:2]([NH:20][C@H:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH2:22][OH:23])[CH:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: N[C@@H](CO)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Nc1cc(C2CC2)[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=[N+]([O-])c1cnc(N[C@@H](CO)c2ccc(F)cc2)cc1Nc1cc(C2CC2)[nH]n1
Temperature: 195 °C
Yield: 69.7 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyridin-4-amine (Method 90, 0.15 g, 0.54 mmol), (R)-2-amino-2-(4-fluorophenyl)ethanol (0.10 g, 0.67 mmol), and DIEA (0.12 ml, 0.67 mmol) in n-BuOH (5 ml) was heated in a sealed tube at 195° C. for 52 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc) to give the title compound as a yellow solid (0.15 g, 72%). 1H NMR (400 MHz) 12.38 (s, 1H), 9.59 (b, 1H), 8.83 (s, 1H), 8.16 (b, 11H), 7.37 (m, 2H), 7.13 (m, 2H), 6.75 (b, 1H), 5.92 (b, 11H), 5.25 (b, 1H), 4.98 (m, 1H), 3.61 (t, J=6.4 Hz, 2H), 1.92 (m, 1H), 0.97 (m, 2H), 0.72 (m, 2H). MS: Calcd.: 398; Found: [M+H]+ 399.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[N:13][C:12](S(C)(=O)=O)=[N:11][C:10]=3[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:33][N:34]([CH2:36][CH2:37][NH2:38])[CH3:35].O>CS(C)=O>[Cl:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[N:13][C:12]([NH:38][CH2:37][CH2:36][N:34]([CH3:35])[CH3:33])=[N:11][C:10]=3[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Reactant: CN(C)CCN
Solvent: O
Solvent: CS(C)=O
Product: CN(C)CCNc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Yield: 40.7 %

Procedure:
The solution of 7-(3-chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-4-amine from Example 25 (50 mg, 0.1 mmol) and unsym-dimethylethylenediamine (100 mg, 1.1 mmol) in DMSO was irradiated by microwave at 150° C. for 10 min. The reaction mixture was poured into water and extracted by ethyl acetate. Solids between two phases were filtered out and this solid was dissolved in methanol and undissolved solid was filtered out. Filterate was concentrated to yield the product as beige powder (20 mg, 41%).
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][CH2:25][CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:11][O:10][C:3]1[C:2]([CH:24]([NH:23][S:21]([C:17]([CH3:19])([CH3:18])[CH3:20])=[O:22])[CH2:25][CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][N:4]=1
Reactant: COc1ccnc(OC)c1Br
Reactant: CCOC(=O)C(C)CC=NS(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(C)CC(NS(=O)C(C)(C)C)c1c(OC)ccnc1OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A cooled (−78° C.) solution of commercially available 3-bromo-2,4-dimethoxypyridine (1.390 g; 5.74 mmol) in anh. THF (70 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (3.60 ml; 5.74 mmol). The resulting solution was further stirred at −78° C. for 15 min. A solution of ethyl 4-((tert-butylsulfinyl)imino)-2-methylbutanoate (1.290 g; 5.22 mmol) in anh. THF (5 ml) was then added to the cooled reaction mixture, and stirring at −78° C. was continued for 30 min. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (35 ml), Et2O (75 ml) and water (20 ml). The separated organic layer was then washed with brine (30 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=30/1) afforded ethyl 4-(2,4-dimethoxypyridin-3-yl)-4-(1,1-dimethylethylsulfinamido)-2-methylbutanoate as a yellow oil. LC-MS (conditions B): tR=0.78 min. and [M+H]+: 386.68 g/mol; tR=0.80 min. and [M+H]+: 386.76 g/mol (mixture of diastereoisomers).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[N:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[N:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnn2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnn2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-oxo-3-(3-pyridazin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K27) (224 mg, 0.75 mmol) according to the general procedure M. Obtained as a white solid (250 mg, 67%).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@H:12]([O:13]C(=O)C2C=CC=CC=2)[C:11](=[CH2:22])[O:10][C@H:7]([O:8][CH3:9])[CH2:6]1)(=[O:3])[CH3:2].C[O-].[Na+].C1C=CC=CC=1.CC(C)=O>CO>[C:1]([NH:4][C@@H:5]1[C@H:12]([OH:13])[C:11](=[CH2:22])[O:10][C@H:7]([O:8][CH3:9])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=C1O[C@H](OC)C[C@H](NC(C)=O)[C@@H]1OC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: C=C1O[C@H](OC)C[C@H](NC(C)=O)[C@@H]1O
Reaction time: 12 h

Procedure:
To a solution of Compound VII (5 g, 16.4 mmoles) in absolute methanol (30 ml) was added M sodium methoxide (0.5 ml), and the mixture was kept for 12 hours at 25° C, at which point, t.l.c. (2:3 benzene-acetone) indicated that saponification was complete. The solution was passed through a small bed (250 × 20 mm) of silica gel in a column, and the effluent was evaporated in vacuo to give Compound VIII as a syrup, yield 3.2 g (97%); this was subjected, without delay, to the hydrogenation step of Example 8.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:12][CH2:13][CH:14]=[CH2:15]>O1CCCC1>[CH2:15]([P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4])[CH2:14][CH:13]=[CH2:12]
Reactant: CCOP([O-])OCC
Reactant: C=CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCP(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.8 %

Procedure:
Diethyl phosphite (4.14 g, 0.03 mol) was added to a suspension of 60% sodium hydride (1.2 g, 0.03 mol) in dry tetrahydrofuran (60 ml) at ambient temperature. The mixture was stirred for 5 minutes until a pale yellow solution was obtained. 4-Bromobut-1-ene (4.5 g, 0.033 mol) was added dropwise and the reaction mixture heated at reflux for 3 hours. After cooling to ambient temperature and filtering, the filtrate was concentrated under reduced pressure to give an oil. The oil was chromatographed on silica gel (eluting with ethyl acetate-hexane, 50:50) to yield the title compound as a colorless oil (3.85 g, 67%). IR: υmax (film) 3080, 3000, 2940, 2920, 2880, 1645, 1450, 1390, 1260, 1165, 1060, 1030, 970, 820, 790 cm-1. 1H NMR: δH (CDCl3) 1.35 (6H, t, J=7Hz, (OCH2CH3)2), 1.50-2.70 (4H, m, CH2CH2P), 4.10 (4H, m, (OCH2CH3)2) 4.85-5.28 (2H, m, CH2 =CH), 5.5-6.28 (1H, m, CH2 =CH--CH2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)nc3N21
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCC4CCCCC4)nc3N21

Procedure:
This compound was prepared in analogy to Example 15 intermediate c), from (4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and (bromomethyl)cyclohexane.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][O:6][C:5]2([CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[O:4][CH2:3]1.[NH3:15].[H][H]>CO.[Ni]>[CH3:1][C:2]1([CH3:14])[CH2:7][O:6][C:5]2([CH2:12][CH2:11][CH:10]([NH2:15])[CH2:9][CH2:8]2)[O:4][CH2:3]1
Reactant: CC1(C)COC2(CCC(=O)CC2)OC1
Reactant: N
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CC1(C)COC2(CCC(N)CC2)OC1

Procedure:
A solution of 20.0 g (0.1 mol) of 3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-9-one in 250 ml of methanol which contained 38 g of ammonia was hydrogenated at 100° C. and a hydrogen pressure of 100 bar in the presence of 3 g of Raney nickel. The catalyst was filtered off and the solvent was stripped off in vacuo. The crude product was purified by means of a thin film evaporator (140° C./0.8 bar). This gave 16 g (80% of theory) of distillate which solidified upon standing.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:37])[C:10]=1[CH2:11][S:12][C:13]1[N:14]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:15]([C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[CH:22]=2)([CH3:20])[CH3:19])=[CH:16][N:17]=1)[C:5]([OH:7])=O.[NH2:38][C@@H:39]([CH2:47][CH2:48][CH2:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:54]([O:53][C:51]([NH:50][CH2:49][CH2:48][CH2:47][C@H:39]([NH:38][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([F:37])[C:10]([CH2:11][S:12][C:13]2[N:14]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:15]([C:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[CH:22]=3)([CH3:20])[CH3:19])=[CH:16][N:17]=2)=[C:2]([Cl:1])[CH:3]=1)[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:52])([CH3:56])([CH3:57])[CH3:55]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)O)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)OC(C)(C)C
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: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a 0° C. solution of 3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluoro-phenyl)-1H-imidazol-2-ylthio)methyl)-5-fluorobenzoic acid (0.94 g, 0.17 mmol), (S)-tert-butyl 2-amino-5-(tert-butoxycarbonylamino)pentanoate (0.050 g, 0.18 mmol) and HATU (0.067 g, 0.18 mmol) in DMF (4 mL) was added DIPEA (0.058 mL, 0.33 mmol). The ice bath was removed and the reaction was stirred for 2 h at room temperature. The reaction was quenched with satd NaHCO3 and diluted with EtOAc. The organic layer was washed with H2O (2×5 mL), brine, and dried with Na2SO4. The solvent was removed in vacuo and the residue was purified by column chromatography to afford 114 mg of (S)-tert-butyl 5-(tert-butoxycarbonylamino)-2-(3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-5-fluorobenzamido)pentanoate. The compound was then dissolved in 4N solution of HCl in dioxane and stirred for 2 h, when the reaction was determined to be complete by LCMS. Ether was added to the reaction mixture. Then the solids were collected by filtration and dried under vacuum to afford the title compound (75 mg). 1H-NMR (DMSO6, 400 MHz) δ 9.00 (d, J=8.3 Hz, 1H), 8.01 (s, 3H), 7.93 (s, 1H), 7.82-7.75 (m, 2H), 7.23 (d, J=8.5 Hz, 1H), 7.06-6.99 (m, 2H), 6.67-6.64 (m, 1H), 6.61-6.57 (m, 1H), 6.53-6.52 (m, 1H), 6.50-6.47 (m, 1H), 4.43-4.38 (m, 1H), 4.19 (s, 2H), 3.70 (s, 3H), 2.84-2.80 (m, 2H), 1.97-1.80 (m, 2H), 1.75-1.66 (m, 2H), 1.51 (m, 6H); MS (ES): 677 [M]+.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.O1C(CC)C1.[Cl:17]Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:17][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCl
Agent: CCC1CO1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 150 ml. of methylene chloride were added 7.35 g. (0.05 mole) of phthalimide, 21.5 ml. (5 equiv.) of 1,2-epoxybutane, and 0.061 g. (0.5 mmoles) of 4-dimethylaminopyridine. The mixture was cooled to 0° C. and saturated with chlorine. The resulting mixture was stirred for 20 hours at room temperature. A sample of the reaction mixture, analyzed by thin-layer chromatography (TLC), indicated that the reaction was not yet complete. The mixture was allowed to stir for an additional 24 hours, and the resulting clear yellow solution was evaporated to obtain crystalline N-chlorophthalimide. The product was vacuum dried to afford 7.7 g. (84.8%) of product. Analysis: (1) Percent Cl+ : Theory: 19.6; Found: 18.3. (2) Percent total chlorine: 18.1.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[NH:21][C:20](=[O:23])[C:19]([CH3:24])=[N:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:25]([C:29]1[CH:33]=[C:32]([N:34]=[C:35]=[O:36])[N:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([C:29]1[CH:33]=[C:32]([NH:34][C:35]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][C:13]3[C:22]4[NH:21][C:20](=[O:23])[C:19]([CH3:24])=[N:18][C:17]=4[N:16]=[CH:15][CH:14]=3)=[CH:4][CH:3]=2)=[O:36])[N:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Reactant: Cc1nc2nccc(Oc3ccc(N)c4ccccc34)c2[nH]c1=O
Product: Cc1nc2nccc(Oc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c4ccccc34)c2[nH]c1=O
Yield: 41 %

Procedure:
Method F2 was used with 8-(4-aminonaphthalen-1-yloxy)-3-methylpyrido[2,3-b]pyrazin-2(1H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound as a white solid (50 mg, 41%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:30](=[O:31])[C:27]3[CH:28]=[CH:29][C:24]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:25][CH:26]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (11 mg) with 4-biphenylcarbonyl chloride (16 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [F:1][C@:2]1([CH3:19])[C@H:6]([OH:7])[C@@:5]([F:10])([CH2:8][OH:9])[O:4][C@H:3]1[N:11]1[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]1=[O:18].C([Mg]Cl)(C)(C)C.Cl[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[O:37][P:38](=[N:40][C@@H:41]([CH3:48])[C:42]([O:44][CH:45]([CH3:47])[CH3:46])=[O:43])=[O:39].CO>C1COCC1>[CH:45]([O:44][C:42](=[O:43])[C@@H:41]([N:40]=[P:38]([O:37][C:28]1[CH:29]=[CH:30][C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]=1[O:9][CH2:8][C@:5]1([F:10])[C@@H:6]([OH:7])[C@:2]([F:1])([CH3:19])[C@H:3]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[O:4]1)=[O:39])[CH3:48])([CH3:46])[CH3:47]
Reactant: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@](F)(CO)[C@H]1O
Reactant: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1ccc2ccccc2c1Cl
Agent: CC(C)(C)[Mg]Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1ccc2ccccc2c1OC[C@@]1(F)O[C@@H](n2ccc(=O)[nH]c2=O)[C@](C)(F)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a solution of chiral 1-((2R,3R,4S,5S)-3,5-difluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (60 mg, 216 μmol) prepared in Preparation 6 in THF (8 ml) was added a THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (539 μl, 539 μmol) dropwise. The mixture was stirred at room temperature for 15 min. followed by the addition of THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(naphthalen-2-yloxy)phosphorylamino)propanoate (1.08 mL, 539 μmol). The reaction mixture was stirred at room temperature for 1 h, then additional THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (270 μl, 270 μmol) and THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(naphthalen-2-yloxy)phosphorylamino)propanoate (0.54 mL, 270 μmol) were added. The reaction mixture was then stirred at room temperature for 18 h. Methanol (2 mL) was added to quench the reaction. The mixture was purified by flash chromatography (silica gel, 1-18% MeOH in DCM) and dried in vacuo to give the title compound as a white solid (75 mg, 58%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH3:16])[CH:12]=[C:11]2[C:6]=1[N:7]=[C:8](Cl)[C:9](Cl)=[N:10]2.[O:19]1[CH2:23]CCC1>C(OCC)(=O)C>[NH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH3:16])[CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([O:19][CH3:23])[C:9]([O:2][CH3:1])=[N:10]2
Reactant: Cc1cc2nc(Cl)c(Cl)nc2c(N)c1C
Reactant: C1CCOC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1nc2cc(C)c(C)c(N)c2nc1OC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 77 %

Procedure:
Sodium methoxide (25% solution in methanol, 13.9 ml, 61 mmol) was added over 12 minutes to a stirred solution of 5-amino-2,3-dichloro-6,7-dimethylquinoxaline (6.15 g, 25.4 mmol) in dry tetrahydrofuran (250 ml) under nitrogen at 0° C. The mixture was stirred at 0° C. for 20 minutes, and at room temperature for 72 hours. The mixture was diluted with ethyl acetate (750 ml), washed with water (2×250 ml) and brine (250 ml), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane/dichloromethane) to give 5-amino-2,3-dimethoxy-6,7-dimethylquinoxaline (4.55 g, 77%) as a white solid, mp 166°-167° C.
Reaction SMILES: O.FC(F)(F)C(O)=O.C([O:11][CH:12](OCC)[CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])C>C(Cl)(Cl)Cl>[O:24]=[C:15]1[C:16]2[C:17](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:19])[N:14]1[CH2:13][CH:12]=[O:11]
Reactant: CCOC(CN1C(=O)c2ccccc2C1=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.8 %

Procedure:
Water (50 mL) and trifluoroacetic acid (50 mL) were added to a solution of phthalimidoacetaldehyde diethyl acetal (30.0 g, 114 mmol) in chloroform (200 mL), and the reaction mixture was stirred at room temperature for 48 hours. The aqueous layer was separated, adjusted to pH 7 with the addition of sodium carbonate, and extracted with several portions of dichloromethane. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 14.2 g of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetaldehyde as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[F:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:29])[C:26](O)=[O:27])[CH2:21][CH2:20]2)=[CH:16][CH:15]=1>C(OCC)C>[F:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25](=[O:29])[C:26]([NH:1][C:2]3[CH:12]=[CH:11][C:5]4[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=4[CH:3]=3)=[O:27])[CH2:23][CH2:24]2)=[CH:16][CH:15]=1
Reactant: Nc1ccc2c(c1)OCC(=O)N2
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: O=C1COc2cc(NC(=O)C(=O)N3CCC(Cc4ccc(F)cc4)CC3)ccc2N1

Procedure:
The title compound is prepared from 7-amino-4H-benzo[1,4]oxazin-3-one [J. Med. Chem., 32, 1627. (1989)] and [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) according to the method described in Example 2. Melting Point: 209-212° C. (diethylether)
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.[CH3:26][C:27](=[CH2:30])[CH2:28][NH2:29]>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:29][CH2:28][C:27]([CH3:30])=[CH2:26])=[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: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Reactant: C=C(C)CN
Solvent: CO
Product: C=C(C)CNC1=C(C)C(=O)C2=C(C1=O)C(CO)C1(OC)C3NC3CN21
Product: NC(=O)O
Reaction time: 2 h
Yield: 107 %

Procedure:
A solution of 50 mg mitomycin A (0.138 mmol) in 8 ml. of anhydrous methanol was stirred with 29 mg of 2-methylallylamine. The progress of the reaction was periodically checked by TLC and, after 2 hours, the solvent was removed by evaporation under reduced pressure and the residue was purified by column chromatography using silica-gel as adsorbent and ethyl acetate as the eluant. Recrystallization from a mixture of chloroform and hexane gave 30 mg (55% yield) of the desired product as purple crystals having a melting point of >250° C. (decomposing) and providing the following analysis:
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[C:19]([O:23][C:24]([N:26]1[CH2:33][CH:32]2[CH:28]([CH2:29][NH:30][CH2:31]2)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.CCOC(C)=O>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH:28]2[CH:32]([CH2:31][N:30]([CH2:2][C:3]3[S:11][C:10]4[C:9]([N:12]5[CH2:17][CH2:16][O:15][CH2:14][CH2:13]5)=[N:8][C:7]([Cl:18])=[N:6][C:5]=4[CH:4]=3)[CH2:29]2)[CH2:33]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (175 mg, 0.50 mmol) in DMF (5 mL) were added hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (160 mg, 0.754 mmol) and potassium carbonate (136 mg, 0.984 mmol). The resulting mixture was stirred at RT for 2 h, then diluted with water and EtOAc. The organic layer was isolated, then washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography to give the title compound as an off-white solid (218 mg, 90%).