Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH:5](=[C:12]1[NH:16][C:15](=[O:17])[CH:14]=[C:13]1[OH:18])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(=O)C>[CH:5](=[C:12]1[NH:16][C:15](=[O:17])[C:14](=[N:1][OH:3])[C:13]1=[O:18])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=N[O-]
Reactant: O=C1C=C(O)C(=Cc2ccccc2)N1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=Cc2ccccc2)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of 1.1 mmol (0.075 g) sodium nitrite was added dropwise to an ice-cooled solution of 2 mmol 5-benzylidene 4-hydroxy-1,5-dihydropyrrol-2-one (prepared in accordance with H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, 331, 389-394) and H.-D. Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 5 ml glacial acetic acid, while stirring. The resulting solution was then stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is purified by recrystallization from ethanol. The yield of 5-benzylidene-pyrrolidine-2,3,4-trione 3-oxime was 65%, with a melting point of 205° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:16][CH2:15][CH2:14][CH2:13][O:11][C:3]1[CH:4]=[CH:5][C:6]([C:8](=[O:9])[CH3:10])=[CH:7][C:2]=1[CH3:1]
Reactant: ClCCCBr
Reactant: CC(=O)c1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCCCCl)c(C)c1
Yield: 95.1 %

Procedure:
A mixture of 25 g (0.166 mole) of 4-hydroxy-3-methylacetophenone, 45.8 g (0.33 mole) of 1-bromo-3-chloropropane and 69.1 g (0.5 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for 20 hr. The mixture was cooled, filtered, and the filtrate concentrated under reduced pressure to give an oil as residue. The oil was crystallized in petroluem ether. The solid was collected by filtration, washed with petroleum ether and dried to yield 35.8 g (95%) of an off-white powder. An analytical sample, m.p. 41.5°-42.5° C. was prepared from petroleum ether.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:15][C@H:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[OH:21])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])[CH3:3].CC(C1C=C(S[C@@H]2CC[CH2:39][C@H:38]2[OH:42])C=C(C(C)(C)C)C=1)(C)C.CC(C1C=C(C(C)(C)C)C=CC=1S[C@H]1CCC[C@H]1[OH:63])(C)C>C(Cl)(Cl)Cl>[CH3:14][C:11]([C:9]1[CH:8]=[C:7]([S:15][C@H:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[O:21][CH2:39][C:38]([OH:42])=[O:63])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:10]=1)([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(S[C@H]2CCC[C@H]2O)c(C(C)(C)C)c1
Reactant: CC(C)(C)c1cc(S[C@H]2CCC[C@H]2O)cc(C(C)(C)C)c1
Reactant: CC(C)(C)c1cc(S[C@@H]2CCC[C@H]2O)cc(C(C)(C)C)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(S[C@H]2CCC[C@H]2OCC(=O)O)cc(C(C)(C)C)c1

Procedure:
The title compound was prepared by the method described in Example 77, except that the title product of Example 83 was substituted for the title product of Example 75, Compound A. The structure was supported by NMR, optical rotation (CHCl3, 25° C.; 589 nm -64.0°±2.80°; 365 nm -208.1°±6.04) and elemental analysis.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9])#[N:2].[OH-].[Na+].Cl>O1CCOCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([OH:10])=[O:9])#[N:2]
Reactant: COC(=O)c1cc(C#N)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C#N)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
Methyl 5-cyano-2-methoxybenzoate (2 g) obtained in step A of Example 1-3-1 was dissolved in 28 mL of 1,4-dioxane, and 21 mL of an aqueous solution of 2.5 mols of sodium hydroxide was added. After stirring for 30 minutes at room temperature, the reaction mixture was cooled in an ice bath, and neutralized with the use of 50 mL of 1 M hydrochloric acid. The resulting aqueous solution was extracted 6 times with methylene chloride. The respective organic layers were combined, whereafter the combined organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and washed with methylene chloride. The filtrate and the. washings were combined, and methylene chloride was distilled off under reduced pressure. The resulting solid was dried under reduced pressure to obtain 1.6 g (87%) of 5-cyano-2-methoxybenzoic acid.
Reaction SMILES: [S:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[CH3:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[S:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:18][C:17]2[CH:19]=[CH:20][C:14]([CH3:13])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(N=Cc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-sulfamoylbenzaldehyde and 4-methylaniline as starting materials, the title compound was obtained as a yellow powder (yield 82%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:13](OC)(=[O:17])[C:14]([CH3:16])=[CH2:15].CC(C)([O-])C.[K+].Cl>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:13](=[O:17])[C@@H:14]([CH3:16])[CH2:15][C@@H:8]2[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1cccc(F)c1
Reactant: C=C(C)C(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](C)C(=O)c2ccc(F)cc21
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 3-fluorophenylacetate (prepared from 3 fluorophenylacetic acid (Aldrich Chem. Co., Madison, Wis.) via esterification with methanol catalyzed by gaseous HCl) in anhydrous N,N-dimethylformamide (40 mL) warmed to 70° C. was added methyl methacrylate (5.8 mL) and potassium tertbutoxide (0.55 gm). After 15 minutes, aqueous 1N HCl (75 mL) was added, and the mixture extracted with diethyl ether. The organic extracts were washed with H2O, brine, dried (Na2SO4, filtered and evaporated. The residue was dissolved in concentrated H2SO4 (80 mL)/H2O (20 mL), and warmed to 70° C. for 3 hours, then poured onto crushed ice, and the mixture extracted with ethyl acetate. The extracts were washed with H2O, brine, dried (Na2SO4, filtered and evaporated. The oily residue was dissolved in methanol (250 mL), and the solution saturated with gaseous HCl. After 30 minutes, the mixture was purged with nitrogen, and concentrated under reduced pressure. The oily residue was partitioned between H2O (500 mL), and ethyl acetate, and the organic layer washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo to yield the title compound (10.9 gm, Rf (1:1 diethyl ether/SiO2)=0.4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si](C)(C)N[Si](C)(C)C.[Na].[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:28](=O)[O:27][CH2:26]2>C(COC)OC.CN(C=O)C>[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:28](=[C:5]1[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:6]1=[O:11])[O:27][CH2:26]2
Reactant: Nc1ccc2c(c1)COC2=O
Reactant: O=C1Cc2cc(Cl)ccc2N1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)COC2=C1C(=O)Nc2ccc(Cl)cc21
Reaction time: 0.13 h
Yield: 31.3 %

Procedure:
To a solution of 5-chlorooxindole (0.629 g, 3.78 mmol) in 10.0 mL monoglyme was added 7.51 mL sodium hexamethyldisilazane (1.0 M in THF) over 3 min. After stirring a troom temperature for 8 min, a solution of 5-aminophthalide (0.561 g, 3.78 mmol) in 3.0 mL of DMF was added over 1 min. The mixture was stirred for 40 min and then quenched into 4% aqueous HCl solution. The aqueous solution was neutralized to pH 7 with 1 M NaOH and then made basic with saturated NaHCO3. The solid was filtered and washed with H2O and then partitioned between EtOAc and saturated NaHCO3 (heated to dissolve the solid). The organic phase was washed with H2O, brine and then dried with Na2SO4. The solvent was removed in vacuo and the residue triturated with MeOH to give the title compound (353 mg, 31%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([OH:21])(=[O:20])[CH2:16]C(O)=O.C([O-])(=O)C.[NH4+:26]>CCCCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:26])([CH2:16][C:15]([OH:21])=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C(O)CC(=O)O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCC(N)(CC(=O)O)CC1
Yield: 35.3 %

Procedure:
A mixture of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.5 g, 17.55 mmol) (Sigma-Aldrich), malonic acid (2.0 g, 19.30 mmol) and ammonium acetate (3.1 g, 40.36 mmol) in n-BuOH was refluxed for 3 h. After cooled, white solid was collected, rinsed with EtOAc and dried in vacuo to provide the title compound 1.61 g (6.2 mmol) in 36% yield. 1H NMR (200 MHz) in D2O, δ ppm: 3.66 (br m, 2H), 3.10 (br m, 2H), 2.45 (s, 2H), 1.69 (br m, 4H), 1.28 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[I:10]Cl.[OH-].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([I:10])=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(N)nc(N)n1
Reactant: ClI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(N)nc(N)c1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
A solution of 8.0 grams (0.064 mole) of 2,4-diamino-6-methylpyrimidine in 30 mL of glacial acetic acid is stirred, and a solution of 13.5 grams (0.083 mole) of iodine monochloride in 20 mL of glacial acetic acid is added dropwise during a 5 minute period. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about 18 hours. After this time the reaction mixture is diluted with 100 mL of water and then is made basic with 10% aqueous sodium hydroxide. The mixture is then extracted with three 75 mL portions of ethyl acetate. The combined extracts are washed with one 75 mL portion of an aqueous solution saturated with sodium chloride. The organic layer is dried with sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 11.7 grams of 2,4-diamino-5-iodo-6-methylpyrimidine. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [NH2:1][CH:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1.Cl>CC(C)=O.O>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:1][CH:2]([CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[C:13]([OH:15])=[O:14])=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC(Cc1c[nH]c2ccccc12)C(=O)O)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
10 Grams of DL-tryptophane was dissolved in a mixture of 100 ml of acetone with 20 ml of water, then to this solution was added 6 g of potassium carbonate. Under an ice-cooled condition, 9 g of 4-chlorobenzoyl chloride was added dropwise to the above-mentioned mixture, and the reaction mixture was stirred at the same temperature for 2 hours. Then, acetone was removed by evaporation, to the residue thus obtained was added water, and mixture was acidified by adding concentrated hydrochloric acid, the crystals formed were collected by filtration, and washed with water. Recrystallized from ethanol to obtain 14 g of 2-(4-chlorobenzoylamino)-3-(indol-3-yl)propionic acid. White powdery substance.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][CH2:13][C:14]2[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=2[O:16][CH2:17][CH2:18][NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])[NH:4][CH:3]=1.Cl.[OH-:29].[Na+]>C(O)C.O>[CH3:21][C:20]([NH:19][CH2:18][CH2:17][O:16][C:15]1[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=1[CH2:13][CH2:12][CH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:2][C:3](=[O:29])[NH:4]2)([CH3:23])[CH3:22]
Reactant: [OH-]
Reactant: CC(C)(C)NCCOc1ccccc1CCCc1cccc2[nH]cc(Cl)c12
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)NCCOc1ccccc1CCCc1cccc2c1CC(=O)N2
Reaction time: 19 h

Procedure:
A mixture of 3.76 g of the product of Step A in 94 ml of 94% ethanol and 94 ml of aqueous N hydrochloric acid was stirred under an inert atmosphere for 19 hours and was diluted with water and iced. The mixture was made alkaline by addition of 32% sodium hydroxide solution and was extracted with ethyl acetate. The organic phase was washed with water, dried over a deshydrant, filtered and evaporated to dryness. The residue was chromatographed over silica and eluted with a 9-1 ethyl acetate-triethylamine mixture to obtain 2.18 g of 1,3-dihydro-4-[3-(2-{2-[1,1-dimethylethylamino]-ethoxy}-phenyl)-propyl]-2H-indol-2-one.
Reaction SMILES: ClC1C=CC([CH:6](OC2CNC2)[C:7]2[CH:12]=[CH:11][C:10](Cl)=[CH:9][CH:8]=2)=CC=1.[N-]=[C:22]=O.Cl[C:25]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:26]=1[CH:27]([O:35][CH:36]1[CH2:39][N:38]([C:40]([NH:42]C(C)(C)C)=[O:41])[CH2:37]1)[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1>>[Cl:51][C:49]1[CH:48]=[CH:47][C:26]([CH:27]([O:35][CH:36]2[CH2:37][N:38]([C:40]([NH:42][CH2:22][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([CH3:6])[CH:12]=3)=[O:41])[CH2:39]2)[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[CH:25][CH:50]=1
Reactant: CC(C)(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccc(Cl)cc2Cl)C1
Reactant: Clc1ccc(C(OC2CNC2)c2ccc(Cl)cc2)cc1
Reactant: [N-]=C=O
Product: Cc1cccc(CNC(=O)N2CC(OC(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
This material was prepared from 3-(4,4′-dichlorobenzhydryloxy)azetidine (36) and the corresponding commercially available isocyanate, using the procedure described for compound (5).
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N)C#C.C(N(CC)CC)C.[O:20]1CCCC1>C(OCC)C>[CH3:3][CH2:2][O:4][C:5](/[C:6](/[Cl:1])=[N:7]\[OH:20])=[O:8]
Reactant: C1CCOC1
Reactant: CCOC(=O)CN
Reactant: Cl
Agent: C#CCN
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)/C(Cl)=N\O
Reaction time: 8 h

Procedure:
Ethyl chloroximidoacetate is prepared starting from glycine ethyl ester hydrochloride according to a literature procedure (G. S. Skinner, J. Am. Chem. Soc. 46 (1924), 731). 14.55 g (0.096 mol) of this product are added dropwise, dissolved in 100 ml of tetrahydrofuran, at room temperature to a solution of 17.07 g (0.11 mol) of the protected propargylamine from a) and 11.14 g (0.11 mol) of triethylamine in 400 ml of diethyl ether during the course of 5 hours. The mixture is stirred overnight, washed with dil. ammonium chloride solution and water, dried and concentrated in vacuo. Yield: 25 g. The product ethyl 5-tert.-butoxycarbonyaminomethylisoxazole-3-carboxylate can be further purified by crystallization from ethyl acetate/petroleum ether, resulting in a melting point of 72° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:13][C:14]1[N:15]([CH2:22][CH2:23][CH:24]2[CH2:26][O:25]2)[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[N:18]=1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC.O>[Cl:13][C:14]1[N:15]([CH2:22][CH2:23][CH:24]([OH:25])[CH2:26][O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[N:18]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: O=[N+]([O-])c1cn(CCC2CO2)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1cn(CCC(O)COc2ccc(OC(F)(F)F)cc2)c(Cl)n1
Temperature: 81 °C
Reaction time: 12 h
Yield: 67.2 %

Procedure:
4-Trifluoromethoxyphenol (0.375 mL, 2.89 mmol) was added to a mixture of epoxide 129 (250 mg, 1.15 mmol) and powdered K2CO3 (558 mg, 4.04 mmol) in anhydrous 2-butanone (3 mL) under N2, and the mixture was stirred at 81° C. for 12 h. The resulting cooled mixture was diluted with water (50 mL) and extracted with CH2Cl2 (4×50 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-25% EtOAc/petroleum ether firstly gave foreruns, and then further elution with 25-33% EtOAc/petroleum ether gave 4-(2-chloro-4-nitro-1H-imidazol-1-yl)-1-[4-(trifluoromethoxy)phenoxy]-2-butanol (130) (306 mg, 67%) as a pale yellow oil; 1H NMR (CDCl3) δ 7.85 (s, 1H), 7.16 (br dd, J=9.1, 0.8 Hz, 2H), 6.88 (dt, J=9.2, 3.0 Hz, 2H), 4.37-4.24 (m, 2H), 4.02-3.93 (m, 2H), 3.86 (dd, J=10.0, 7.8 Hz, 1H), 2.47 (dd, J=4.2, 1.1 Hz, 1H), 2.13-1.98 (m, 2H); HRESIMS calcd for C14H14ClF3N3O3 m/z [M+H]+ 398.0540, 396.0569. found 398.0538, 396.0567.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]#N)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[OH-:13].[K+].Cl.[OH2:16]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:16])=[O:13])[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: [OH-]
Reactant: O
Reactant: COc1ncc(CC#N)cc1Br
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: COc1ncc(CC(=O)O)cc1Br
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
To a suspension of (5-bromo-6-methoxy-pyridin-3-yl)-acetonitrile (Step AM1) (6.61 mmol) in EtOH (19 mL) was added a solution of KOH (26.7 mmol) in H2O (19 mL) and the mixture was stirred at 80° C. for 45 min. After cooling to rt, the pH was adjusted to 3-4 with 1M aqueous HCl and the mixture was extracted with CH2Cl2 (2×). The combined organic layers were dried (MgSO4), filtered and concentrated to afford the title compound. ESI-MS: tR=0.75 min, [M+H]+ 246/248 (LC-MS 1).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([C:23]3[CH2:24][CH2:25][C@:26]([CH3:32])([C:28](OC)=[O:29])[N:27]=3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH3:46]>CO>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([C:23]3[CH2:24][CH2:25][C@:26]([CH3:32])([C:28]([NH2:46])=[O:29])[N:27]=3)=[N:21][CH:22]=2)=[O:15])[CH:4]=[C:3]([C:2]([F:44])([F:45])[F:1])[CH:8]=1
Reactant: COC(=O)[C@@]1(C)CCC(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)=N1
Reactant: N
Solvent: CO
Product: Cc1cc(F)ccc1-c1cc(C2=N[C@@](C)(C(N)=O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Methyl (2R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)pyridin-2-yl]-2-methyl-3,4-dihydro-2H-pyrrole-2-carboxylate (Intermediate 23 1.06 Kg) was suspended in 20.44 L of 7M ammonia in methanol. The mixture was gently stirred for at least 5 days at 20° C. The mixture was concentrated by half by distillation at atmospheric pressure. The solution obtained was then cooled to 40° C. and stirred for 1 h. The slurry obtained was then cooled to 0° C. over 3 h and aged at 0° C. for 2 h. The title compound was then isolated by filtration and the cake washed with ice cold methanol (1.1 L). The wet cake was dried at 40° C./vacuum to yield the title compound (841.3 g).
Reaction SMILES: [NH2:1][CH2:2][P:3]([OH:6])(=[O:5])[OH:4].[F:7][C:8]([F:21])([F:20])[C:9]1[CH:10]=[C:11]([N+:17]([O-:19])=[O:18])[C:12](Cl)=[CH:13][C:14]=1[Cl:15]>O.C(O)C>[N+:17]([C:11]1[CH:10]=[C:9]([C:8]([F:7])([F:20])[F:21])[C:14]([Cl:15])=[CH:13][C:12]=1[NH:1][CH2:2][P:3]([OH:6])(=[O:4])[OH:5])([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Cl
Reactant: NCP(=O)(O)O
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1NCP(=O)(O)O
Temperature: 120 °C
Yield: 68.2 %

Procedure:
3.3 g (30 mmol) of aminomethanephosphonic acid in 120 ml of water and 120 ml of ethanol are introduced together with 3.37 g (31.8 mmol) of soda and mixed with 7.8 g (97%, 30 mmol) of 3-trifluoromethyl-4,6-dichloronitrobenzene, and it is refluxed for 4 hours at 120° C. bath temperature. After removing the ethanol in a rotary evaporator, it is extracted three times with 100 ml of ethyl acetate. The organic phase is washed with a little water. It contains starting material and is discarded. The collected aqueous phase is adjusted acidic with 4 N hydrochloric acid to pH 1 and extracted three times with 100 ml of ethyl acetate each. The organic phase is washed with water, dried, filtered and concentrated by evaporation. 6.85 g (68% of theory) of N-(2-nitro-4-trifluoromethyl-5-chloro-phenyl)-aminomethanephosphonic acid of melting point 207.3° C. is obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[S:18][C:17]([CH2:19][CH2:20][CH3:21])=[N:16][C:10]=3[C:11]([NH2:15])=[N:12][C:13]=2[CH:14]=1)(=O)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.BrCC[N:36]1[CH:40]=[CH:39][CH:38]=[CH:37]1>ClCCl>[CH2:19]([C:17]1[S:18][C:9]2[C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH2:2][N:36]4[CH:40]=[CH:39][CH:38]=[CH:37]4)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:15])[C:10]=2[N:16]=1)[CH2:20][CH3:21]
Reactant: BrCCn1cccc1
Reactant: CCCc1nc2c(N)nc3cc(OC(C)=O)ccc3c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCc1nc2c(N)nc3cc(OCCn4cccc4)ccc3c2s1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 40.6 %

Procedure:
A mixture of 4-amino-2-propylthiazolo[4,5-c]quinolin-7-ol acetate (318 mg, 1.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), and DMF (20 mL) was stirred at 75° C. for 10 minutes. 1-(2-Bromoethyl)pyrrole (200 mg, 1.1 mmol) was added dropwise over a period of 10 minutes. After 3 hours an additional equivalent of cesium carbonate was added in a single portion followed by the dropwise addition of an equivalent of 1-(2-bromoethyl)pyrrole. The reaction mixture was stirred overnight and then an additional equivalent of both cesium carbonate and 1-(2-bromoethyl)pyrrole were added. After 1 hour the heat source was removed; the reaction mixture was diluted with water (250 mL), stirred for 1 hour, and then filtered. The isolated solid was rinsed with water and then dried to provide a brown powder. This material was dissolved in dichloromethane and then purified by HPFC eluting with a gradient of 0-15% CMA in chloroform over 1500 mL. The resulting solid was recrystallized from acetonitrile to provide 143 mg of 2-propyl-7-[2-(pyrrol-1-yl)ethoxy]thiazolo[4,5-c]quinolin-4-amine as an off-white solid, mp 158.0-160.0° C. MS (ESI) m/z 353 (M+H)+; Anal. calcd for C19H20N4OS: C, 64.75; H, 5.72; N, 15.90. Found C, 64.86; H, 5.38; N, 16.00.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:10]([NH2:14])[CH:11]([CH3:13])[CH3:12].CCCCCC>CO.CCOC(C)=O>[Br:1][C:2]1[C:3]([NH:14][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CC(C)CN
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: CC(C)CNc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (14.0 mmol) in methanol (30 ml) is added isobutylamine (28.0 mmol) at room temperature. The mixture is stirred at room temperature for one day and diluted with AcOEt. The organic layer is washed with water and brine, dried over sodium sulfate and concentrated. Chromatography on silica gel (n-hexane and n-hexane:AcOEt=25:1) gives the product in 78% yield. Rf=0.52 (n-hexane:AcOEt=4:1)