Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Fc1ccc(C2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1ccc(F)cc1

Procedure:
The title compound, white solid, m.p. 118° C. and MS: m/e=339 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[N+]([O-])=O)[C:10](=[O:23])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:24][O:25][CH2:26][CH2:27][OH:28].[OH-].[K+]>O>[CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:28][CH2:27][CH2:26][O:25][CH3:24])[C:10](=[O:23])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1cccc2c1C(=O)c1c(cccc1[N+](=O)[O-])C2=O
Reactant: COCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COCCOc1cccc2c1C(=O)c1c(NC(C)C)cccc1C2=O
Reaction time: 1 h

Procedure:
15 g of 1-isopropylamino-8-nitro-anthraquinone are stirred into a solution of 60 ml of ethylene glycol monomethyl ether and 15 g of potassium hydroxide at 55° and the mixture is further stirred at 60°-65° (approx. 1 hour being required) until only a trace of the starting material remains chromatographically detectable. The mixture is diluted with 120 ml of water and the product is filtered off, washed with water until neutral and dried in vacuo at 60°. Yield: 16.7 g.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH:30]=O)=[CH:22]1>>[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:22]1
Reactant: Cn1cc(C=O)c2ccccc21
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: Cn1cc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c2ccccc21

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1-methylindole-3-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(1-methylindol-3-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]#[N:11])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([NH:22][C:23]1[S:27][C:26]2[CH2:28][CH2:29][CH2:30][CH2:31][C:25]=2[C:24]=1[C:32]([NH2:34])=[O:33])=[O:21]>CN(C=O)C.O>[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:19][C:20]([NH:22][C:23]2[S:27][C:26]3[CH2:28][CH2:29][CH2:30][CH2:31][C:25]=3[C:24]=2[C:32]([NH2:34])=[O:33])=[O:21])[N:2]=1)#[N:11]
Reactant: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Reactant: N#Cc1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1nn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)c2ccccc12
Temperature: 60 °C
Yield: 13 %

Procedure:
To a solution of 1H-indazole-3-carbonitrile (11 mg, 0.077 mmol) in DMF (500 μL) was added potassium carbonate and the whole was stirred at RT for 30 min before 2-(2-bromoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (24 mg, 0.077 mmol) was added. The reaction mixture was heated to 60° C. and this temperature was maintained for 1.5 h before the reaction mixture was cooled to RT, then diluted with water (5 mL). The organics were extracted with diethyl ether (10 mL), EtOAc (10 mL) and DCM (10 mL), then combined and the suspension concentrated to dryness. The residue was dissolved in DMSO (1 mL) and purified by preparative reverse phase HPLC to give the title compound as a white solid (4 mg, 0.01 mmol, 14%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[Na].O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:10])[CH3:9])=[N:6][CH:7]=1
Reactant: CC(=O)c1ccc(F)cn1
Agent: [Na]
Solvent: O
Solvent: CO
Product: CC(O)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
1-(5-Fluoropyridin-2-yl)ethanone (Method 1; 11.3 g, (75% pure), 60.9 mmol) in MeOH was added sodium boronhydride (2.30 g, 60.9 mmol) potion wise at 0° C. After adding, the reaction was warmed to room temperature and stirred at room temperature for 1 hour. Water (10 ml) was added and the solution was extracted with ether (2×50 ml). The combined organic layers were dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (ether) to give the title compound as a clear oil (7.5 g, 87%). 1H NMR (400 MHz) 8.46 (d, J=3.2 Hz, 1H), 7.69 (ddd, J=3.2, 3.2 and 3.2 Hz, 1H), 7.55 (m, 1H), 5.44 (d, J=4.4 Hz, 111), 4.73 (m, 1H), 1.34 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([OH:26])=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[NH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([NH:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:26])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: NCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.1 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (60 mg, 0.16 mmol) in DMF (1 mL) were added 4-(2-aminoethyl)morpholine (32 mg, 0.25 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC. HCl) (38 mg, 0.20 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified using chromatography (silica gel, gradient 10% MeOH/ethyl acetate) yielding Compound 50 as a solid (10 mg).
Reaction SMILES: [ClH:1].C[NH:3]O.[CH3:5][O:6][CH:7]([O:17]C)[CH:8]([CH:12](OC)[O:13]C)[C:9]([O-])=[O:10]>O.Cl>[ClH:1].[CH3:5][O:6][C:7]([C:8]1[C:9](=[O:10])[NH:3][O:13][CH:12]=1)=[O:17]
Reactant: CNO
Reactant: COC(OC)C(C(=O)[O-])C(OC)OC
Agent: Cl
Solvent: O
Product: COC(=O)c1co[nH]c1=O
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2.21 g methylhyroxylamine-hydrochloride in 2.90 g water and 0.26 g concentrated aqueous HCl, 5.81 g 3,3-dimethoxy-2-dimethoxymethyl-propionate were fed over a period of 40 minutes. External cooling with an ice-bath was required in order to keep the temperature between 15° C. and 20° C. After stirring for an additional 15 minutes and cooling to 10° C., a non-stirrable white crystal-pap was gained. The needle-shaped crystals were isolated by suction-filtration, washing with a small amount of diisopropylether and drying in vacuo. Further product-fractions could be isolated by evaporation of part of the mother liquor, filtration, washing, and drying. The total amount of methyl-3-keto-isoxazole-4-carboxylate-hydrochloride obtained in this way was 4.60 g (91% theory based on 3,3-dimethoxy-2-dimethoxymethyl-propionate). Identification of the product was based on 1H-NMR-, 13C- and IR-spectra. The 1H-NMR-spectrum did not show any impurities.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:19]2[C:7]([CH2:8][C:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[NH:11][C:10]=3[CH2:18]2)=[C:6]([C:20]([O:22][CH3:23])=[O:21])[C:5]=1[C:24]([O:26][CH3:27])=[O:25].I[CH3:29].CO>CN(C=O)C>[CH3:3][C:4]1[N:19]2[C:7]([CH2:8][C:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[N:11]([CH3:29])[C:10]=3[CH2:18]2)=[C:6]([C:20]([O:22][CH3:23])=[O:21])[C:5]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1c(C(=O)OC)c2n(c1C)Cc1[nH]c3ccccc3c1C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1c(C(=O)OC)c2n(c1C)Cc1c(c3ccccc3n1C)C2
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (0.63 g, 26.5 mmol) in dry DMF (150 ml) was added portionwise dimethyl 3-methyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylate (6 g, 17.7 mmol) at 0° C. to 5° C. After being stirred for 15 min, iodomethane (2.5 g, 17.7 mmol) was added and the reaction mixture and was stirred for additional 1 h in an ice bath. After being stirred at room temperature for 9 h, methanol was added into the reaction mixture and then evaporated to dryness in vacuo. The residue was recrystallized from MeOH to give dimethyl 3,6-dimethyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylate, 5.8 g (94%); mp 240-241° C. 1H NMR (DMSO-d6) δ 2.45 (3H, s, Me), 3.73 (6H, s, COOMe and Me), 3.74 (3H, s, COOMe), 4.16 (2H, t, J=3.4 Hz, CH2), 5.27 (2H, t, J=3.4 Hz, CH2), 7.05-7.09 (1H, m, ArH), 7.17-7.21 (1H, m, ArH), 7.48 (1H, d, J=8.2 Hz, ArH), 7.53 (1H, d, J=7.8 Hz, ArH). Anal. Calcd for (C20H20N2O4): C, 68.17; H, 5.72; N, 7.95. Found: C, 67.79; H, 5.73; N, 7.84.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:22]2[CH:26]=[C:25]([C:27]3[C:28]4[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:29]=4[N:30]=[CH:31][N:32]=3)[CH:24]=[N:23]2)[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH:10]([CH3:21])[CH2:9]2)[CH2:5]1)#[N:2].Cl.O1CCOCC1>CO>[CH3:21][CH:10]1[CH2:9][CH:8]([N:6]2[CH2:7][C:4]([CH2:3][C:1]#[N:2])([N:22]3[CH:26]=[C:25]([C:27]4[C:28]5[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:42])([CH3:41])[CH3:43])[C:29]=5[N:30]=[CH:31][N:32]=4)[CH:24]=[N:23]3)[CH2:5]2)[CH2:13][CH2:12][NH:11]1
Reactant: CC1CC(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC1CC(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)CCN1
Temperature: 25 °C
Yield: 119.8 %

Procedure:
To a solution of tert-butyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-methylpiperidine-1-carboxylate (0.5 g) in methanol (2 mL) was added 10 mL of a 4.0 N solution of hydrogen chloride in 1,4-dioxane (40 mmol). The resulting solution was stirred at room temperature for an hour. The solvents were removed under reduced pressure to give 0.5 g (99%) of {1-(2-methylpiperidin-4-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile as a white solid. LC-MS: 507.1 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH2:28])[CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[NH:40]1[CH:44]=[C:43]([C:45](O)=[O:46])[N:42]=[CH:41]1>>[NH2:28][C:23]1[CH:22]=[C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:45]([C:43]2[NH:42][CH:41]=[N:40][CH:44]=2)=[O:46])[CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[O:4])(=[O:19])=[O:20])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(F)c(N)c1
Reactant: O=C(O)c1c[nH]cn1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)c1cnc[nH]1)S(=O)(=O)c1ccc(F)c(N)c1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(3-amino-4-fluoro-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (example 81) as described in general procedure E using 4-imidazolecarboxylic acid. The final product was obtained in 20% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.[NH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:26][N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CN1CCN(N)CC1
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCN(Nc2ncnc(Nc3ccc(P(C)(C)=O)cc3)n2)CC1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 L of triethylamine and 1-Amino-4-methyl-piperazine (13 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:28])[C:8](=[O:9])[N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)[C:6](=[O:22])[N:5]1[CH2:23][CH2:24][CH2:25][CH2:26][OH:27].[CH3:29]I.O>CN(C)C=O>[CH3:3][C:4]1([CH3:28])[C:8](=[O:9])[N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:19])([F:20])[F:21])[CH:11]=2)[C:6](=[O:22])[N:5]1[CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH3:29]
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCCO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(C)C
Reaction time: 0.33 h

Procedure:
50 mg of sodium hydride were added in several lots to 370 mg of the product of Example 58 in solution in 3 ml of dimethylformamide and the mixture was stirred for 20 minutes. 0.06 ml of methyl iodide were added and the mixture was stirred for one hour. A further 50 mg of sodium hydride were added and then after 20 minutes, 0.06 ml of methyl iodide were added. The reaction medium was poured into water and extracted with ether. The extracts were washed with water, dried and the solvent was evaporated. The residue was chromatographed on silica (eluant: methylene chloride--acetone 98-2) to obtain 135 mg of the expected product melting at 80°-81° C.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[C:12]([O:15][CH2:16]Cl)(=[O:14])[CH3:13]>CC(N(C)C)=O>[C:12]([O:15][CH2:16][N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[N:4]([CH2:16][O:15][C:12](=[O:14])[CH3:13])[C:5]1=[O:8])(=[O:14])[CH3:13]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CC(=O)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)OCn1cc(F)c(=O)n(COC(C)=O)c1=O
Yield: 6.6 %

Procedure:
In 70 ml of dimethylacetamide was dissolved 2.60 g (0.02 mol) of 5-fluorouracil. To this solution were added 0.96 g (0.02 mol) of 50% sodium hydride and then a solution of 2.16 g (0.02 mol) of chloromethyl acetate in 10 ml of dimethylacetamide. The mixture was reacted together at room temperature for 5.5 hours. After completion of the reaction, the reaction liquid was filtered to remove a precipitate and then the dimethylacetamide used as solvent was removed from the filtrate by distillation. The residue was taken up in 100 ml of ether and the ethereal solution was filtered to remove insoluble matters. The ether was removed by distillation and the residue was subjected to an adsorption treatment using a column packed with silica gel. The adsorbed substance was elutriated with a mixture (1:1 in mixing ratio) of benzene and ethyl acetate to isolate at first 180 mg of 1,3-bis(acetoxymethyl)-5-fluorouracil in a yield of 3.2%. This product was a viscous liquid and exhibited in IR-absorption spectral analysis characteristic absorption bands at 3120, 2970, 1755(s), 1704(s), 1690(s), 1478, 1375, 1285, 1230(s), 1170, 1087, 1035(s), 980, 842, 790 and 772 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=O)=[N:6][CH:7]=1.Cl.[O:28]([NH2:30])[CH3:29]>CCO>[CH3:29][O:28][N:30]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1)[C:10]1[N:19]=[C:18]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)cn3)nc3ccccc23)n[nH]1
Reactant: CON
Agent: Cl
Solvent: CCO
Product: CON=C(c1ccc(F)cn1)c1nc(Nc2cc(C)[nH]n2)c2ccccc2n1
Temperature: 60 °C

Procedure:
To a 0.3 M solution of (5-fluoropyridin-2-yl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 1 in EtOH is added methoxylamine hydrochloride (2 equiv) and the mixture is heated to 60° C. for 30 min or until the reaction is substantially complete. The mixture is concentrated under reduced pressure and the residue is purified by chromatography to afford (5-fluoropyridin-2-yl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone O-methyl oxime. LC-MS (ESI) m/z 377 (M+H)+.
Reaction SMILES: C([O:4][C@@H:5]([CH3:32])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17](=[O:29])[CH:18]=[C:19]([CH3:28])[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]=2[N:12]([CH3:30])[C:11]1=[O:31])(=O)C.Cl.C(=O)(O)[O-].[Na+]>CO>[CH2:21]([N:20]1[C:13]2[N:12]([CH3:30])[C:11](=[O:31])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@@H:5]([OH:4])[CH3:32])[C:15](=[O:16])[C:14]=2[C:17](=[O:29])[CH:18]=[C:19]1[CH3:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)O[C@@H](C)CCCCn1c(=O)c2c(=O)cc(C)n(Cc3ccccc3)c2n(C)c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(=O)c2c(=O)n(CCCC[C@H](C)O)c(=O)n(C)c2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.2 %

Procedure:
A mixture of (S)-3-(5-acetoxyhexyl)-8-benzyl-1,7-dimethylpyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (1.2 g, 2.7 mmol), methanol (10 ml) and 37% aqueous hydrochloric acid (2 ml) was stirred at room temperature for 18 hours. The mixture was treated with saturated aqueous sodium bicarbonate solution (20 ml). The solid was filtered, rinsed with water, and air dried to afford (S)-8-benzyl-1,7-dimethyl-3-(5-hydroxyhexyl)pyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (850 mg, 89% yield) as a white fluffy powder. 1H NMR (300 MHz, CDCl3) δ 1.17 (d, 3H), 1.38-1.6 (m, 6H), 2.47 (s, 3H), 3.63 (s, 3H), 3.78 (m, 1H), 4.05 (t, 2H), 5.28 (s, 2H), 6.56 (s, 1H), 7.23-7.57 (m, 5H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)[CH3:3].Cl[C:13]1[N:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=1>>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([NH:11][C:13]2[CH:14]=[C:15]([NH2:19])[N:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:1]
Reactant: Nc1cc(Cl)ncn1
Reactant: CN(C)Cc1cccc(N)c1
Product: CN(C)Cc1cccc(Nc2cc(N)ncn2)c1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
The title compound is prepared as described in Example 152A but using 3-dimethylaminomethyl-phenylamine, 6-chloro-pyrimidin-4-ylamine, and stirring the reaction mixture for 2 h at 150° C. The crude product is purified by trituration in diethyl ether followed by silica gel column chromatography (DCM/MeOH+1% NH3aq, 92:8) of the resulting beige solid to afford the title compound as a white solid. ESI-MS: 242.1 [MH]−; tR=0.95 min (purity: 100%, gradient J); TLC: Rf=0.11 (DCM/MeOH+1% NH3aq, 92:8).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(N(CC)C(C)C)(C)C.[NH2:32][C:33]1[S:34][C:35]([C:38]([NH2:40])=[O:39])=[CH:36][N:37]=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:32][C:33]2[S:34][C:35]([C:38]([NH2:40])=[O:39])=[CH:36][N:37]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Reactant: NC(=O)c1cnc(N)s1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)Nc2ncc(C(N)=O)s2)cc1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 12.1 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 96 mg, 0.28 mmol), N,N-diisopropylethylamine (145 μL, 0.83 mmol) and 2-amino-thiazole-5-carboxylic acid amide (prepared as in Example 12, 48 mg, 0.34 mmol) were combined in acetonitrile (1.4 mL) and cooled to 0° C. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) was added and the cooling bath was removed. After stirring 16 h, the reaction mixture was treated with saturated aqueous sodium bicarbonate solution (30 mL) and extracted with 10% methanol/chloroform (3×35 mL). The combined organic phases were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 2% methanol/chloroform) to afford (E)-2-[2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-acetylamino]-thiazole-5-carboxylic acid amide (16 mg, 12%) as a white solid after lyophilization from aqueous dioxane: LC-MS (ESI) m/e calcd for C18H19ClN4O5S2 [M+] 470.05, found 471 [M+H+]: H1-NMR (400 MHz, CD3OD) δ ppm 1.66 (m, 4 H, 2×CH2), 1.92 (m, 4 H, 2×CH2), 3.34 (s, 3 H, SO2CH3), 5.04 (m, 1 H, OCH), 7.66 (dd, Jo=8.2, Jm=1.6 Hz, 1 H, Ar), 7.78 (d, Jm=1.6 Hz, 1 H, Ar), 8.05 (s, 1H, Ar), 8.17 (d, Jo=8.2 Hz, 1 H, Ar).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([O:27]C)=[O:26])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:29](=[O:31])[NH2:30])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([OH:27])=[O:26])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:29](=[O:31])[NH2:30])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cc(C)cc(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C)cc(Cn2c3cccc(OCC(=O)O)c3c3c(C(N)=O)cccc32)c1
Temperature: 25 °C
Reaction time: 42 h
Yield: 69 %

Procedure:
A suspension of the {9-[(3,5-dimethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (18 mg, 0.043 mM) and 0.043 mL (0.043 mM) of 1 N NaOH in 5 mL of ethanol was stirred for 42 hours at 25° C. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH, then dried in vacuo to afford 12 mg (67%) of the {9-[(3,5-dimethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (DMSO-d6) δ 7.6 (d, 1H, J=8 Hz), 7.5-7.3 (m, 4H), 7.1 (m, 2H), 6.9 (s, 1H), 6.8 (s, 2H), 6.6 (d, 1H, J=8 Hz), 5.65 (s, 2H), 4.35 (s, 2H), and 2.2 (s, 6H). IR (KBr, cm−1) 3385, 1663, 1616, 1575, 1498, 1456, 1412, and 1330. MS (ES) m/e 401, 403.