Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[P:14]([O-:18])([O-:17])([O-:16])=[O:15].[Na+].[Na+].[Na+]>O>[P:14]([OH:18])([OH:17])([OH:16])=[O:15].[C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4]
Reactant: O=P([O-])([O-])[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: O
Product: O=P(O)(O)O

Procedure:
Combine 22.2 mL 0.1M citric acid (§3.A.) with 27.8 mL 0.2M sodium phosphate in 100 mL volumetric flask. Make volume to 100 mL with demineralized water.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCBr
Reactant: Clc1ccc(C(OC2CCNCC2)c2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCN1CCC(OC(c2ccc(Cl)cc2)c2ccccn2)CC1
Yield: 91.3 %

Procedure:
After 4.98 g (16.45 mmol) of 4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidine and 3.85 g (19.74 mmol) of ethyl 4-bromobutanoate were dissolved in 35 ml of acetone, 2.73 g (19.75 mmol) of potassium carbonate was added to the mixed solution, and the mixture was stirred under reflux by heating for 4 hours. The insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography using a solvent mixture of chloroform and methanol in the volume ratio of 30:1 as an eluent. The desired fraction was concentrated under reduced pressure to give 6.26 g (91%) of ethyl 4-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]-butanoate as an oil.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].II.[CH:24]([O:26][CH2:27][CH3:28])=[O:25].OS(O)(=O)=O>CCOCC>[CH:24]([O:26][CH:27]([CH2:1][CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:28][CH2:19][CH2:18][CH2:17]/[CH:16]=[CH:15]\[CH2:14]/[CH:13]=[CH:12]\[CH2:11]/[CH:10]=[CH:9]\[CH2:8]/[CH:7]=[CH:6]\[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[O:25]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCBr
Reactant: CCOC=O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC(CCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC)OC=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of arachidonyl bromide (II, 1 g, 3 mmol) in anhydrous ether (30 mL) was added Mg turnings (78 mg, 3.2 mmol) followed by one crystal of iodine. The resulting mixture was refluxed under nitrogen for 10 hours. The mixture was cooled to room temperature. To the cloudy mixture under nitrogen was added ethyl formate (0.25 mL), and the resulting mixture was stirred at room temperature overnight. To the mixture was added 20 mL of 10% H2SO4 aqueous solution. The ether phase was separated and aqueous phase extracted with ether (30 mL). The combined organic phase was washed with water (2×25 mL), brine (25 mL), and then dried over anhydrous Na2SO4. Evaporation of the solvent gave 1.1 g of pale oil as a crude product (III). The crude product was purified by column chromatography on silica gel (230-400 mesh, 40 mL) eluted with 0-3% ethyl acetate gradient in hexanes. This afforded 0.43 g (40%) of diarachidonylmethyl formate (III) as pale oil.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].Cl>>[C:1]([OH:10])(=[O:9])[C@H:2]([C@@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: Cl
Product: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Yield: 49.5 %

Procedure:
In the same way as shown in Example 1, utilizing Pseudomonas putida ATCC 17642, 40 g of DL-tartaric acid was put in the culture medium and the cultivation was carried out without adding hydrochloric acid. All L-(+)-tartaric acid was consumed in 8.5 hours and 19.8 g of D-(-)-tartaric acid was obtained. The value of OD550 was 5.1.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]([C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH:32]([CH3:34])[CH3:33])[C:30]=1[OH:31])[CH:26]=[O:27])([CH3:22])[CH3:21].O[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH:20]([C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH:32]([CH3:34])[CH3:33])[C:30]=1[O:31][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[CH:26]=[O:27])([CH3:22])[CH3:21]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1cc(C=O)cc(C(C)C)c1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 14.4 %

Procedure:
Triphenylphosphine (5.14 g, 19.58 mmol) was added to a solution of 3,5-diisopropyl-4-hydroxybenzaldehyde (4 g, 19.58 mmol) in tetrahydrofuran (40 ml) followed by addition of 2-hydroxyethylmorpholine (2.57 g, 19.58 mmol) and then the dropwise addition of diethylazodicarboxylate (3.41 g, 19.58 mmol). The mixture was stirred at room temperature for 12 hours. The reaction was concentrated under reduced pressure and partitioned between 2N hydrochloric acid (200 ml) and ethyl acetate (150 ml). The aqueous layer was extracted with ethyl acetate (2×150ml), basified to pH 9 with solid sodium bicarbonate and extracted with ethyl acetate (3×150 ml). The organic layers were combined, dried over magnesium sulfate and concentrated to afford 900 mg (14%) of 3,5-diisopropyl-4-(2-morpholin-4-ylethoxy)-benzaldehyde as a yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=O.S(Cl)(Cl)=O.C1N2CCN(CC2)C1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:10][CH:11]=1)[C:7](=[O:9])[O:14][C:12]2=[O:13]
Reactant: COc1ccc(C(=O)O)c(C(=O)O)c1
Agent: C1CN2CCN1CC2
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)OC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
To a mixture of 4-methoxy-phthalic acid (1.8 g, 9.18 mmol), thionyl chloride (1.4 mL, 19.79 mmol) in CH2Cl2 (15 mL) is added DABCO (1.1 g, 9.81 mmol). The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with CH2Cl2 (100 mL), washed with H2O (75 mL×2), dried with Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to afford 5-methoxy-isobenzofuran-1,3-dione (950 mg, 58%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:15][O:16][P:17](OC)([O:19][CH3:20])=[O:18]>>[CH3:15][O:16][P:17]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)(=[O:18])[O:19][CH3:20]
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: COP(=O)(OC)OC
Product: COP(=O)(Cc1ccc(-c2ccccc2)cc1)OC
Yield: 72.8 %

Procedure:
A solution of 4-(chloromethyl)biphenyl (4.12 g, 0.020M) in trimethylphosphate (10 mL, 10.5 g, 0.085M) is heated at reflux temperature for 60 hours. The excess trimethylphosphite is removed under reduced pressure and the solid residue is chromatographed (400 g of 40-63 μm silica gel, 50 mL fractions). The sample is applied to the column in a minimum amount of EtOAc and the column is eluted with 50% EtOAc-hexane (1.2 L), 75% EtOAc-hexane (2 L), and with EtOAc. Fractions 88-136 contained the dimethyl ester (4.98 g, 0.0180M, 90%) which is crystallized from ether-pentane to give 4.09 g of title compound as white crystals, mp 70°-71° C.(fused), 76.5°-77.5° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[O:16]1[C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=[N:17]1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:21]([C:20]4[O:16][N:17]=[CH:18][CH:19]=4)=[O:22])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: O=C(Cl)c1ccno1
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1ccno1

Procedure:
The title compound was prepared following procedure described for example 19, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and isoxazole-5-carbonyl chloride (49 mg; 0.37 mmol; 1.5 eq.) as a white powder (19.4 mg, 26%). HPLC, Rt: 2.62 min. (purity 95.3%). LC/MS, M+(ESI): 296.4, M−(ESI): 294.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH:13]([C:15](=O)[CH3:16])[CH3:14])[C:9]2=O)=[CH:5][CH:4]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:30][CH2:31][C@H:32]([OH:34])[CH3:33]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8]3[C:13]([CH3:14])=[C:15]([CH3:16])[N:30]([CH2:31][C@H:32]([OH:34])[CH3:33])[C:9]=32)=[CH:5][CH:4]=1
Reactant: C[C@@H](O)CN
Reactant: COc1ccc2c(c1)C(=O)C(C(C)C(C)=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)-c1c(c(C)c(C)n1C[C@@H](C)O)C2
Reaction time: 1.42 h
Yield: 70.2 %

Procedure:
A solution of 1.5 g of rac-6-methoxy-2-(3-oxo-2-butyl)-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 1.94 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 85 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 2:3). 1.23 g (70%) of (R)-1-(7-methoxy-2,3-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([Cl:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2].[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][C:12]([Cl:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2]
Reactant: CCCCN
Reactant: CCOC(=O)c1cnc2c(OC)cc(Cl)cc2c1Cl
Product: CCCCNc1c(C(=O)OCC)cnc2c(OC)cc(Cl)cc12

Procedure:
4,6-Dichloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.84 mmol) was treated with butylamine following general procedure B to afford 4-butylamino-6-chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (230 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (155 mg) following general procedure E. The above ethylamide (155 mg, 0.45 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 1-butyl-9-chloro-3-ethyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (87 mg). LCMS: m/z 362 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[CH3:27][C:28]([S:33]([CH3:36])(=[O:35])=[O:34])([CH3:32])[C:29](O)=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>O1CCCC1>[CH3:27][C:28]([S:33]([CH3:36])(=[O:35])=[O:34])([CH3:32])[C:29]([O:26][CH:23]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:24][CH3:25])=[O:30]
Reactant: CC(C)(C(=O)O)S(C)(=O)=O
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC(OC(=O)C(C)(C)S(C)(=O)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.3 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (100 mg, 0.243 mmol), 2-methyl-2-(methylsulfonyl)propanoic acid (65.6 mg, 0.395 mmol) and triphenylphosphine (104 mg, 0.397 mmol) in tetrahydrofuran (5.0 mL) was added a solution of diethylazodicarboxylate in toluene (2.2 M, 0.18 mL, 0.396 mmol) at 0° C. After stirring at room temperature for 20 hr, the mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-60% ethyl acetate/n-hexane gradient mixture to give the title compound (83.0 mg, 0.149 mmol, 61%) as a colorless amorphous.
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:14][C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][C:17](=[O:18])[C:12]=2[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9]2)[CH:2]=[CH2:3].[H][H]>C(O)C.[Pd]>[O:18]=[C:17]1[CH:16]=[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:14][C:13]2[C:4]([CH2:1][CH2:2][CH3:3])=[C:5]3[C:10](=[CH:11][C:12]1=2)[CH2:9][CH2:8][CH2:7][CH2:6]3
Reactant: C=CCc1c2c(cc3c(=O)cc(C(=O)OCC)oc13)CCCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1c2c(cc3c(=O)cc(C(=O)OCC)oc13)CCCC2
Yield: 49.7 %

Procedure:
A solution of the product of step (a) (20 g), in ethanol (120 ml), was treated with a 5% palladium on charcoal catalyst (100 mg), and shaken in a hydrogen atmosphere at 45 psi for 2 hours at room temperature. The catalyst was subsequently filtered off and the filtrate was evaporated. The residue solidified upon trituration with a little diethyl ether and the solid was twice crystallised from aqueous ethanol to give as white crystals, ethyl 6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate (10 g), mp 98°-99.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1.[C:15]1([CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](O)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH:10][C:22](=[O:23])[CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:7][CH:6]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: Nc1ncc(Cc2ccccc2Cl)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ncc(Cc2ccccc2Cl)s1)C(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
5-(2-Chloro-benzyl)-thiazol-2-ylamine (45 mg, 0.20 mmol) and diphenyl-acetic acid (42 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (10.3 mg, 0.0246 mmol, 12%), ESI-MS m/z calc. 418.1, found 419.2 (M+1)+ Retention time 3.85 minutes. 1H NMR (400 MHz, DMSO-d6) δ 4.19 (s, 2H), 5.30 (s, 1H), 7.23-7.47 (m, 15H).
Reaction SMILES: [OH-].[K+].[CH3:3]N(N=O)C(N)=O.[Cl:10][C:11]1[N:12]=[CH:13][N:14]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:15]=1[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([O:27][C:28]2[CH:33]=[C:32]([CH:34]=[CH2:35])[CH:31]=[C:30]([C:36]#[N:37])[CH:29]=2)[C:21]=1[F:38])=[O:17].C(Cl)Cl>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:10][C:11]1[N:12]=[CH:13][N:14]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:46])[CH3:45])[C:15]=1[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([O:27][C:28]2[CH:33]=[C:32]([CH:34]3[CH2:3][CH2:35]3)[CH:31]=[C:30]([C:36]#[N:37])[CH:29]=2)[C:21]=1[F:38])=[O:17]
Reactant: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Reactant: CN(N=O)C(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(C3CC3)c2)c1F
Temperature: 0 °C

Procedure:
To a mixture of 30% aqueous KOH (30 mL) and diethyl ether (30 mL) was added N-methyl-N-nitrosourea (0.264 g, 2.56 mmol) in one potion with stirring and cooling at 0° C. and the reaction mixture was maintained at this temperature for 20 min. The organic phase was isolated, dried over KOH pellets and added dropwise to a solution of 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethenylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.144 g, 0.256 mmol) and palladium(II) acetate (5.8 mg, 0.026 mmol) in diethyl ether (30.0 mL) with stirring and cooling at 0° C. DCM (20 mL) was added to the reaction mixture to achieve complete solution and the reaction mixture was stirred at 0° C. for 1 h at which time LC-MS indicated complete conversion to desired product. Water and a small amount of acetic acid were added to the reaction mixture and stirred vigorously at room temperature for 1 h. The organic phase was isolated, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 20 to 60% EtOAc/hexanes to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.132 g, 0.230 mmol, 90% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.79 (t, J=5.68 Hz, 1H), 8.00 (s, 1H), 7.36-7.54 (m, 2H), 7.28 (s, 1H), 7.11 (s, 1H), 7.05 (s, 1H), 5.51 (s, 2H), 4.50 (d, J=5.68 Hz, 2H), 3.40 (t, J=8.10 Hz, 2H), 1.92-2.05 (m, 1H), 0.95-1.05 (m, 2H), 0.71-0.82 (m, 4H), −0.07 (s, 9H). LC-MS (ES−) m/z 575.13, 575.05 [M−1]. LC-MS (ES+) m/z 575.11, 577.12 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[C:5]([C:7](=[CH:13][NH:14][CH:15]1[CH2:17][CH2:16]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>>[Cl:1][C:2]1[C:20]([F:21])=[CH:19][CH:18]=[C:4]2[C:3]=1[N:14]([CH:15]1[CH2:17][CH2:16]1)[CH:13]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2=[O:6]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1ccc(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)ccc2c1=O

Procedure:
Reaction of 3-chloro-2,4-difluoro-benzoyl chloride with diethyl malonate gives diethyl (3-chloro-2,4-difluoro-benzoyl)-malonate, and partial hydrolysis and decarboxylation lead to ethyl (3-chloro-2,4-difluoro-benzoyl)-acetate, which is reacted with ethyl orthoformate/acetic anhydride to give ethyl 2-(3-chloro-2,4-difluorobenzoyl)-3-ethoxy-acrylate; further reaction with cyclopropylamine leads to ethyl 2-(3-chloro-2,4-difluoro-benzoyl)-3-cyclopropylaminoacrylate, which is cyclized with potassium carbonate/dimethylformamide to give ethyl 8-chloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3 -quinolinecarboxylate; hydrolysis then finally leads to the corresponding carboxylic acid. The reaction sequence described can be represented by the following equation: ##STR4##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Si:20]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:45]O)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(C=P(CCCC)(CCCC)CCCC)#N.CO>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:20]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:45][CH:11]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[F:19])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([C:33]([CH3:36])([CH3:35])[CH3:34])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](OCc1ccccc1CO)(c1ccccc1)c1ccccc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCc1ccccc1CC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Yield: 86.4 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (600 mg, 1.98 mmol) obtained in Example 5 and [2-[(t-butyldiphenylsilyloxy)methyl]phenyl]methanol (1.00 g, 2.66 mmol) were dissolved in toluene (20 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (640 mg, 2.65 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, 2-[(t-butyldiphenylsilyloxy)methyl]phenyl]methanol (400 mg, 1.06 mmol) and cyanomethylenetri-n-butylphosphorane (400 mg, 1.66 mmol) were added. Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, the residue obtained by concentrating the mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=15:1 eluate was concentrated under reduced pressure, whereby the title compound (1.13 g, 1.71 mmol, 86%) was obtained as a pale yellowish brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([O:18]CC)=[O:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.[OH-].[K+].Cl>C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: CCOC(=O)c1cnn2c(-c3cccnc3)ccnc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 0.10 mole of ethyl 7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate and 0.50 mole of potassium hydroxide in 50 ml. of ethanol-water (9:1) is heated at reflux temperature for 4 hours. The mixture is brought to pH 7 with concentrated hydrochloric acid, concentrated and filtered to give 7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid. The preceding product in tetrahydrofuran is added dropwise to a solution of 0.2 mole of diborane in tetrahydrofuran chilled in an ice bath. The mixture is stirred for one hour and the bath removed. After standing 16 hours at room temperature the mixture is poured onto ice to give the product of the example.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[C:4]2[CH:10]=[C:9](I)[NH:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH:28]=[C:29]([C:9]2[NH:8][C:5]3=[N:6][CH:7]=[C:2]([Br:1])[C:3]([Cl:12])=[C:4]3[CH:10]=2)[CH2:30][CH2:31]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Clc1c(Br)cnc2[nH]c(I)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)c(Br)cnc3[nH]2)CC1

Procedure:
To a mixture of 5-bromo-4-chloro-2-iodo-1H-pyrrolo[2,3-b]pyridine (46 mg, 0.12 mmol), potassium carbonate (36 mg, 0.25 mmol), dichlorobis-(triphenylphosphine)palladium (9 mg, 0.01 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (42 mg, 0.13 mmol) were added degassed dioxane (4 mL) and water (1 mL), and the mixture was heated to reflux for 5 h. The reaction was evaporated under reduced pressure and the residue was dissolved in DCM and filtered. The DCM filtrate was evaporated and the crude product obtained was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with DCM:methanol 100:0→99.5:0.5], yielding the title compound. MS (ES+): m/z 413.84 (100) [MH+]; HPLC: tR=6.95 min (ZQ2000, nonpolar—15 min).