Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[NH:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:31][C:32]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:33].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(#N)C.O>[CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N:13]([CH2:31][C:32](=[O:33])[N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: CCOC(=O)c1ccc2c(C3CCCCC3)c3n(c2n1)CCNc1ccccc1-3
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(C3CCCCC3)c3n(c2n1)CCN(CC(=O)N1CCOCC1)c1ccccc1-3
Temperature: 90 °C
Yield: 63.2 %

Procedure:
To a solution of ethyl 12-cyclohexyl-6,7-dihydro-5H-5,7a,8-triazadibenzo[a,e]azulene-9-carboxylate (74 mg, 0.19 mmol) in N,N-dimethylformamide (2 ml) and acetonitrile (2 ml) were added 4-(2-chloroacetyl)morpholine (94 mg, 0.57 mmol), potassium iodide (64 mg, 0.38 mmol) and potassium carbonate (66 mg, 0.48 mmol), and the mixture was stirred with heating at 90° C. for 12 hr. The reaction mixture was allowed to cool to room temperature, and water was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel chromatography (ethyl acetate) to give ethyl 12-cyclohexyl-5-[2-oxo-2-(morpholin-4-yl)ethyl]-6,7-dihydro-5H-5,7a,8-triazadibenzo[a,e]azulene-9-carboxylate (62 mg, yield 63%).
Reaction SMILES: C[O-].[Na+].[Cl:4][CH2:5][C:6]1([CH3:24])[O:10][N:9]=[C:8]([S:11][CH2:12][C:13]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][N:16]([CH3:19])[C:17]=2F)[CH2:7]1.O.[C:26](OCC)(=[O:28])C>CO>[Cl:4][CH2:5][C:6]1([CH3:24])[O:10][N:9]=[C:8]([S:11][CH2:12][C:13]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][N:16]([CH3:19])[C:17]=2[O:28][CH3:26])[CH2:7]1
Reactant: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1F
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(CSC2=NOC(C)(CCl)C2)c(C(F)(F)F)nn1C

Procedure:
0.9 g (4.4 mmoles) of sodium methoxide (in the form of a 28% methanol solution) was added, at room temperature, into a solution of 1.0 g (2.9 mmoles) of 5-chloromethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline dissolved in 10 ml of methanol. The mixture was heated for refluxing for 5 hours, to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order, and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 3.3 g (yield: quantitative) of 5-chloromethyl-3-(5-methoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmeth-ylthio)-5-methyl-2-isoxazoline.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:24][C:23]2[C:25](=[O:26])[C:18](=[CH:19][C:20]([C:22]=2OC)=[O:21])[NH:17][C:15](=[O:16])[C:14]([CH3:29])=[CH:13][CH:12]=[CH:11][C@H:10]([O:30][CH3:31])[C@@H:9]([O:32][C:33]([NH2:35])=[O:34])[C:8]([CH3:36])=[CH:7][C@H:6]([CH3:37])[C@@H:5]([OH:38])[C@@H:4]([O:39][CH3:40])[CH2:3]1.[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][NH2:45].[ClH:47]>C(Cl)Cl.O1CCOCC1>[CH3:1][C@@H:2]1[CH2:24][C:23]2[C:25](=[O:26])[C:18](=[CH:19][C:20]([C:22]=2[NH:45][CH2:44][CH2:43][N:42]([CH3:46])[CH3:41])=[O:21])[NH:17][C:15](=[O:16])[C:14]([CH3:29])=[CH:13][CH:12]=[CH:11][C@H:10]([O:30][CH3:31])[C@@H:9]([O:32][C:33]([NH2:35])=[O:34])[C:8]([CH3:36])=[CH:7][C@H:6]([CH3:37])[C@@H:5]([OH:38])[C@@H:4]([O:39][CH3:40])[CH2:3]1.[ClH:47]
Reactant: CN(C)CCN
Reactant: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)C=C(C)[C@H](OC(N)=O)[C@@H](OC)C=CC=C(C)C(=O)NC(=CC1=O)C2=O
Agent: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)/C=C(\C)[C@H](OC(N)=O)[C@@H](OC)/C=C\C=C(/C)C(=O)NC(=CC1=O)C2=O
Agent: CO[C@H]1/C=C\C=C(/C)C(=O)NC2=CC(=O)C(NCCN(C)C)=C(C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)/C=C(\C)[C@@H]1OC(N)=O)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CO[C@H]1C=CC=C(C)C(=O)NC2=CC(=O)C(NCCN(C)C)=C(C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)C=C(C)[C@@H]1OC(N)=O)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of geldanamycin (15 g, 26.75 mmol) (SAIC-Frederick, Lot No. 3155-28-1) and N,N-dimethyl-ethylenediamine (15 mL, 37.83 mmol) (Aldrich, Lot No. HN04216AL) in dry methylene chloride (300 mL) (Mallinckrodt, Lot No. 4881KVJP) was stirred at room temperature for 1 hour and subsequently poured into ice water (500 mL). After the organic layer and aqueous layer became visually separated, the aqueous layer was extracted with methylene chloride (2×100 mL). The combined methylene chloride solution was washed with water (2×100 mL), dried with MgSO4 (Spectrum, Lot No. HJ302), and evaporated in a diaphragm pump. The remaining residue (16.5 g, 26.75 mmol) was dissolved in methylene chloride (130 mL). Dissolved hydrogen chloride (1.1 eq, 29.43 mmol) (Matheson, Lot No. T410242) in dioxane (Aldrich, Lot No. 16619CQ) was added to the solution resulting in immediate precipitation. After stirring for 30 minutes, the solids were collected, rinsed with methylene chloride (50 mL), and air-dried for 18 hours to give the crude hydrochloride salt (17.2 g). A solution of the crude product (17.2 g) in aqueous alcohol (50% v/v, 200 mL) (Aaper Alcohol, Lot. No. 97A28UARAT) was heated to reflux, filtered, and allowed to cool for 30 minutes. After cooling on ice for an additional 30 minutes, the solids were collected, washed with cold anhydrous alcohol (50 mL), and air-dried for 1 hour. The product was dried further at 70° C./0.1 mmHg for 17 hours to give pure target compound. Approximately 13.4 g of 17-Demethoxy-17-[[2(dimethylamino)ethyl]amino]geldanamycin hydrochloride (82%) was isolated as a violet crystalline solid and used in Examples 1 and 2.
Reaction SMILES: [NH2:1][C:2](=[O:38])[CH:3]([OH:37])[CH:4]([NH:12][C:13]([C:15]1[C:16]([N:21]2[CH:29]=[C:28]3[C:23]([CH2:24][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:27]3)=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O.C(#N)C>[NH2:1][C:2](=[O:38])[C:3](=[O:37])[CH:4]([NH:12][C:13]([C:15]1[C:16]([N:21]2[CH:29]=[C:28]3[C:23]([CH2:24][N:25]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:26][CH2:27]3)=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ncccc3C(=O)NC(Cc3ccccc3)C(O)C(N)=O)nc2C1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cn(-c3ncccc3C(=O)NC(Cc3ccccc3)C(=O)C(N)=O)nc2C1
Yield: 49.5 %

Procedure:
Oxidation of tert-butyl 2-(3-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-ylcarbamoyl)pyridin-2-yl)-4,5-dihydro-2H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (170 mg, 0.327 mmol) as described in example 1.4 and purification by chromatography over Chromabond RP-C18 (eluent: water/acetonitrile) gave 84 mg of an amorphous solid; ESI-MS [M+H]+: 519.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (4.4 g) obtained in Example 2 was suspended in dimethyl sulfoxide (250 ml), and to the suspension was added potassium carbonate (4.5 g). The mixture was stirred at room temperature for 30 minutes, and t-butyl bromoacetate (2.1 ml) was added. The mixture was stirred at room temperature for 12 hours, and the reaction mixture was poured into ice water (300 ml) and extracted with methylene chloride. The methylene chloride layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride containing 3% methanol) to produce the title compound (3.4 g, 63%).
Reaction SMILES: C(O[C:4](=[O:25])[CH2:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])C.[C:26]1([NH:32][C:33]([NH:35][C:36]([NH2:38])=[NH:37])=[NH:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH2:7]([C:6]1[N:37]=[C:36]([NH:35][C:33]([NH:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[NH:34])[NH:38][C:4](=[O:25])[CH:5]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCCCCC(=O)CC(=O)OCC
Reactant: N=C(N)NC(=N)Nc1ccccc1
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCc1cc(=O)[nH]c(NC(=N)Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
In a 50 milliliter round-bottom flask, 3-oxoeicosanoic acid ethyl ester (2.25 grams, 6.60 mmol, prepared as described in Part B of this Example) was added at room temperature to a solution of 1-phenylbiguanide (1.17 grams, 6.60 mmol, prepared as described in Part D of this Example) in anhydrous ethanol (20 milliliters). The mixture was heated at reflux and stirred for 16 hours. Cooling the resulting yellow solution to room temperature gave a colorless precipitate. The precipitate was isolated by filtration and thoroughly washed with water, then with cold ethanol (0° C.), and finally with pentane. The resulting powder was then recrystallized from anhydrous ethanol, recovered by filtration, and dried under reduced pressure to give the targeted N-(4-heptadecyl-6-oxo-1,6-dihydropyrimidin-2-yl)-N′-phenylguanidine as a colorless solid (1.79 grams, 58 percent yield): mp=164° C.; 1H NMR (DMSO-d6, 303 K) δ: 11.16 (s, 1H), 9.04 (s, 1H), 8.5-6.5 (br, 2H), 7.66 (d, 2H, 3J=7.9 Hz), 7.25 (m, 2H), 6.99 (t, 1H, 3J=7.4 Hz), 5.56 (s, 1H), 2.32 (t, 2H, 3J=7.5 Hz), 1.56 (m, 2H), 1.33-1.17 (m, 28H), 0.85 (t, 3H, 3J=6.8 Hz); Exact mass calculated for C28H45N5O=467.3624. Measured Low Resolution Mass Spectrum (MAB/LR/N2)=468.2. Anal. Calcd for C28H45N5O: C, 71.91; H, 9.70; N, 14.97. Found: C, 72.02; H, 9.96; N, 14.92.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:15][O:16][CH3:17])[C:12]([OH:14])=O)[N:10]=1)=[O:4].C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[NH2:31][CH:32]1[C:44](=[O:45])[N:34]2[C:35]([C:41]([OH:43])=[O:42])=[C:36]([CH3:40])[CH:37]([CH3:39])[S:38][C@H:33]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.O.CN(C)C=O>[F:18][C:2]([F:1])([F:19])[C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:15][O:16][CH3:17])[C:12]([NH:31][CH:32]2[C:44](=[O:45])[N:34]3[C:35]([C:41]([OH:43])=[O:42])=[C:36]([CH3:40])[CH:37]([CH3:39])[S:38][C@H:33]23)=[O:14])[N:10]=1)=[O:4]
Reactant: CON=C(C(=O)O)c1csc(NC(=O)C(F)(F)F)n1
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1C
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C)C(C)S[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Reaction time: 0.67 h
Yield: 81.1 %

Procedure:
2-{2-(2,2,2-Trifluoroacetamido)-4-thiazolyl}-2-methoxyiminoacetic acid (syn isomer, 0.65 g.) was added at 0° C. to Vilsmeier reagent which had been prepared from dimethylformamide and phosphorus oxychloride in ethyl acetate (10 ml.), and the mixture was stirred at the same temperature for 40 minutes to prepare the activated acid solution. The activated acid solution was added dropwise to a solution of 7-amino-2,3-dimethyl-3-cephem-4-carboxylic acid (5.0 g.) and trimethylsilylacetamide (1.73 g.) in ethyl acetate (30 ml.) at -20° C., and the mixture was stirred at the same temperature for 40 minutes. To the resultant mixture was added water (10 ml.), and the ethyl acetate layer was separated from the mixture and washed with water. Water (30 ml.) was added to the solution and the mixture was adjusted to pH 7.5 with sodium bicarbonate under ice-cooling. After shaking the mixture, the aqueous layer was separated. Ethyl acetate (50 ml.) was added to the aqueous solution, and the mixture was adjusted to pH 2 with dilute hydrochloric acid with stirring, and the ethyl acetate layer was separated, washed with water and a saturated aqueous solution of sodium chloride in turn, treated with activated charcoal, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was pulverized with diisopropyl ether to give 7-[2-{2-(2,2,2-trifluoroacetamido)-4-thiazolyl}-2-methoxyiminoacetamido]-2,3-dimethyl-3-cephem-4-carboxylic acid (syn isomer, 0.9 g.).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH:9]([CH3:12])[CH2:10][OH:11])[CH:6]=[CH:7][N:8]=1)[CH2:2][CH3:3].[CH2:13]([O:15][C:16](=[O:22])[CH2:17][C:18]([CH2:20]Cl)=[O:19])[CH3:14].Cl>O1CCCC1>[CH2:1]([C:4]1[N:5]([CH:9]([CH3:12])[CH2:10][O:11][CH2:20][C:18](=[O:19])[CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:22])[CH:6]=[CH:7][N:8]=1)[CH2:2][CH3:3]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CCCc1nccn1C(C)CO
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1nccn1C(C)COCC(=O)CC(=O)OCC
Reaction time: 4 h
Yield: 40.2 %

Procedure:
2-(2-propylimidazol-1-yl)propan-1-ol (from Preparation 1 above) (5.4 g) was added and the suspension was sonicated until there was no further gas evolution. Ethyl-4-chloroacetoacetate (4.83 g) in tetrahydrofuran (10 ml) was added over 5 minutes with sonication and sonication continued at 25°-35° C. for a further 4 hours. The suspension was poured into 2N hydrochloric acid (30 ml) and the tetrahydrofuran removed under reduced pressure. The aqueous solution was washed with toluene (30 ml) and then neutralised with potassium carbonate. The aqueous solution was extracted with dichloromethane (3×100 ml), the combined organic extracts dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was chromatographed over silica eluting with a mixture of methanol and ethyl acetate (1:9) yielding the title compound as a pale red oil 3.5 g (40%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH3:32][O:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>CS(C)=O.CO>[CH3:31][O:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([S:19][C:16]3[CH:17]=[CH:18][C:13]([NH:12][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]([N:37]5[CH2:38][CH2:39][CH:34]([O:33][CH3:32])[CH2:35][CH2:36]5)=[N:3][N:4]=4)=[CH:14][CH:15]=3)=[CH:21][CH:22]=[N:23]2)=[N:28][CH:27]=1
Reactant: COC1CCNCC1
Reactant: COc1cnc2c(Sc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Solvent: CS(C)=O
Solvent: CO
Product: COc1cnc2c(Sc3ccc(Nc4nnc(N5CCC(OC)CC5)c5ccccc45)cc3)ccnc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 15 ml sealed pressure tube was charged with 4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine (120 mg, 0.269 mmol) and 4-methoxypiperidine (620 mg, 5.382 mmol), in 0.3 ml of DMSO. The sealed tube was placed in a preheated oil bath at 100° C. where it was stirred for 16 hours. The reaction was cooled to ambient temperature, diluted with 2 ml of MeOH, and the solution purified using Gilson Reverse Phase HPLC. The fractions containing the desired product was neutralized with saturated sodium bicarbonate and extracted with 10 ml of DCM (3×). The organics were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to afford N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)-4-(4-methoxypiperidin-1-yl)phthalazin-1-amine as a yellow solid. MS [M+H]+=525.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CC(C)=O>[O:13]([CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1ccccc1)C(=O)OCC
Yield: 76.8 %

Procedure:
22.1 g (160 mmol) of potassium carbonate were suspended in 30 ml of acetone, 7.5 g (80 mmol) of phenol in 100 ml of acetone were added, and the mixture was refluxed for 1 hour. 15.5 g (80 mmol) of diethyl 2-chloromalonate in 100 ml of acetone were subsequently added dropwise, the mixture was refluxed for 10 hours and evaporated in vacuo, and the residue was taken up in methylene chloride. The organic phase was washed with saturated NaHCO3 solution and saturated NaCl solution, dried over magnesium sulfate and evaporated. Column chromatography (silica gel, heptane/diethyl ether 2:1) of the residue gave 15.5 g (77% of theory) diethyl 2-phenoxymalonate as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:29](O)=[O:30])=[N:22][N:23]([CH2:25][CH:26]([F:28])[F:27])[CH:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:21]3[C:20]([Cl:19])=[CH:24][N:23]([CH2:25][CH:26]([F:28])[F:27])[N:22]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1nn(CC(F)F)cc1Cl
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3nn(CC(F)F)cc3Cl)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 4-chloro-1-(2,2-difluoro-ethyl)-1H-pyrazole-3-carboxylic acid following procedure I yielded the title compound. MS (ISP): m/z=452.1 [M+H]+.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3]Cl.[Na+].[I-].O=C(C1C=CC=CC=1)C[O:14][C:15](=[O:43])[C@H:16]([OH:42])[CH2:17][N:18]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)=[CH:31][CH:30]=1)[NH:19][C:20]([C:22]1[O:26][N:25]=[C:24]([OH:27])[CH:23]=1)=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].CC(O)=O>CC(C)=O.[Zn]>[Cl:41][C:37]1[CH:36]=[C:35]([C:32]2[CH:31]=[CH:30][C:29]([CH2:28][N:18]([CH2:17][C@@H:16]([OH:42])[C:15]([OH:43])=[O:14])[NH:19][C:20]([C:22]3[O:26][N:25]=[C:24]([O:27][CH2:3][O:2][C:1]([O:5][CH2:6][CH3:7])=[O:8])[CH:23]=3)=[O:21])=[CH:34][CH:33]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)OCCl
Reactant: O=C(COC(=O)[C@H](O)CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CCOC(=O)OCOc1cc(C(=O)NN(Cc2ccc(-c3cccc(Cl)c3)cc2)C[C@@H](O)C(=O)O)on1
Temperature: 60 °C
Reaction time: 1 h
Yield: 7.6 %

Procedure:
A mixture of chloromethyl ethyl carbonate (22.7 mg, 164 μmol) and NaI (24.5 mg, 164 μmol) in acetone (2.0 mL, 27 mmol) was stirred at 60° C. for 1 hour, then cooled to room temperature and added to a mixture of (R)-3-[N-(3′-chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid 2-oxo-2-phenylethyl ester (30.0 mg, 54.5 μmol) and cesium carbonate (17.8 mg, 0.054.5 μmol) in acetone (1 mL). The resulting mixture was stirred at room temperature for 2 hours, concentrated, dissolved in AcOH (2 mL), filtered, and purified by reverse phase preparative HPLC. The desired fractions were combined and concentrated. Zinc (178 mg, 2.7 mmol) and AcOH (1.0 mL, 18 mmol) were added and the resulting mixture was stirred at room temperature for 2 hours. The mixture was filtered and purified by reverse phase preparative HPLC to yield the title compound (2.2 mg). MS m/z [M+H]+ calc'd for C24H24ClN3O9, 534.12. found 534.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]#[C:25][CH2:26][CH3:27])[CH2:6][O:7][N:8]1C(=O)C2C(=CC=CC=2)C1=O.O.NN.Cl.O>CO.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]#[C:25][CH2:26][CH3:27])[CH2:6][O:7][NH2:8]
Reactant: CCC#CCOc1ccc(CON2C(=O)c3ccccc3C2=O)cc1OC
Agent: Cl
Agent: NN
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CCC#CCOc1ccc(CON)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(3-Methoxy-4-pent-2-ynyloxy-benzyloxy)-isoindole-1,3-dione (27 g, 74 mmol) is suspended in a mixture of 500 ml of methanol and 50 ml of N,N-dimethylformamide. After heating this mixture to +60° C., hydrazine hydrate (8.5 g, 0.17 mol) is added. The reaction is stirred for 3 hours at +60° C. and subsequently cooled down to room temperature. A mixture of 28 ml of concentrated hydrochloric acid and 80 ml of water is added to acidify the resulting suspension. Then it is filtered to remove a precipitation and the solid is washed with water/methanol. The filtrate is concentrated in vacuo to one third of its original volume. Sodium hydroxide (18 g, mol in 90 ml water) is added to the remainder and this mixture is extracted with diethyl ether. The combined organic layer is washed with water and brine, dried over magnesium sulfate and evaporated to give O-(3-methoxy-4-pent-2-ynyloxy-benzyl)-hydroxylamine as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH:22]2[CH2:24][CH2:23]2)[C:9]2[N:10]=[CH:11][C:12]3[N:17]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:25][C:26]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:19]([NH:18][C:16]1[S:15][C:13]2[N:14]=[C:9]([N:8]([CH:22]3[CH2:24][CH2:23]3)[C:4]3[CH:3]=[C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([F:36])([F:37])[F:38])[C:26]=4[Cl:25])[CH:7]=[CH:6][CH:5]=3)[N:10]=[CH:11][C:12]=2[N:17]=1)(=[O:21])[CH3:20]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: CC(=O)Nc1nc2cnc(N(c3cccc(N)c3)C3CC3)nc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(N(c3cccc(NC(=O)c4cccc(C(F)(F)F)c4Cl)c3)C3CC3)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
A solution of N-{5-[(3-aminophenyl)(cyclopropyl)amino][1,3]thiazolo[5,4-d]pyrimidin-2-yl}acetamide (120 mg, 353 μmol) produced in Example D21(v), 2-chloro-3-(trifluoromethyl)benzoic acid (84 mg, 371 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (161 mg, 424 μmol) in pyridine (3 mL) was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=10/90→0/100), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (124 mg, 64%) as colorless crystals.