Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:15])([O:4][CH:5]1[O:10][C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH:6]1[OH:14])[CH3:3].N1C=CC=CC=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>Cl>[CH3:3][C:2]([CH3:15])([O:4][CH:5]1[O:10][C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH:6]1[O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH3:1]
Reactant: CC(C)(C)OC1OC(=O)CC(C)(C)C1O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC1OC(=O)CC(C)(C)C1OS(C)(=O)=O
Reaction time: 2 h

Procedure:
A mixture of the product of Step A, 5 ml of pyridine and 1 ml of methanesulfonyl chloride was stirred for 31/2 hours and was then diluted with N hydrochloric acid. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The 677 mg of residue was chromatographed over silica and was eluted with a 7-3 mixture of hexane-ethyl acetate to obtain 410 mg of 6-(1,1-dimethylethoxy)-5-methylsulfonyloxy-4,4-dimethyl-tetrahydro-pyr-2-one melting at 64° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([N:28]1[C:32]([OH:33])=[CH:31][CH:30]=[N:29]1)[CH3:27].C1(N=C=NC2CCCCC2)CCCCC1>C(O)(CC)(C)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=[CH:7][C:3]=1[C:4]([C:31]1[CH:30]=[N:29][N:28]([CH2:26][CH3:27])[C:32]=1[OH:33])=[O:6]
Reactant: COCCOc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Reactant: CCn1nccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(OCCOC)c2Cl)c1O

Procedure:
1.2 g of the crude product of 2-chloro-4-methanesulfonyl-3-(2-methoxy)ethoxybenzoic acid, 0.3 g of potassium carbonate, 0.45 g of 1-ethyl-5-hydroxypyrazole and 0.77 g of N,N'-dicyclohexyl carbodiimide were put into 40 ml of t-amyl alcohol, and the mixture was stirred under heating at a temperature of from 80° to 90° C. for from 4 to 5 hours. The solvent was distilled off, and a dilute potassium carbonate aqueous solution was added to the residue. The mixture was washed with chloroform. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain a crude product of the above identified compound. The crude product was recrystallized from ethanol to obtain 0.3 g of the desired product. Melting point: 159°-160° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C=O)C>[Cl:15][C:12]([F:13])([F:14])[C:6]1[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1N1CCCC1
Yield: 83.8 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 2.1 ml (0.026 mol) of pyrrolidine in 30 ml of DMF were reacted at room temperature for 16 hours affording 4.69 g of solid. Recrystallization in hot hexane-ether gave 4.36 g (77.9%) of product as a white solid; mp 72°-73.5° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]=[C:11]=[S:12])[CH3:2].[CH:13]([NH:16][CH2:17][C:18](O)=[O:19])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]1[C:18](=[O:19])[CH2:17][N:16]([CH:13]([CH3:15])[CH3:14])[C:11]1=[S:12])[CH3:2]
Reactant: CCc1cccc(C)c1N=C=S
Reactant: CC(C)NCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1cccc(C)c1N1C(=O)CN(C(C)C)C1=S
Yield: 47.1 %

Procedure:
The title compound was prepared by the procedure described in Example 45 using 17.7 g of 2-ethyl-6-methylphenyl-isothiocyanate, 21.2 g of N-isopropyl glycine, 21.0 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethanol afforded the title compound (13.0 g) as a light yellow solid, m.p. 132°-134° C. Anal. Calcd. for. C15H2O N2O S: C, 65.18; H, 7.29; N, 10.14. Found: C, 65.06; H, 7.37; N, 10.20. Mass spectrum (El, M.+) m/z 276.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:20]=[O:21])[O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:22][C:23]1[C:24]([NH:40][NH2:41])=[N:25][C:26]([CH3:39])=[N:27][C:28]=1[N:29]1[CH2:32][C:31]([CH3:38])([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:30]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH:1]1([CH2:6][C@@H:7]([C:8]([NH:41][NH:40][C:24]2[C:23]([F:22])=[C:28]([N:29]3[CH2:30][C:31]([CH3:38])([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[CH2:32]3)[N:27]=[C:26]([CH3:39])[N:25]=2)=[O:10])[CH2:11][N:12]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH:20]=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nc(NN)c(F)c(N2CC(C)(N3CCCC3)C2)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c(F)c(N2CC(C)(N3CCCC3)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
A mixture of (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (107 mg, 0.357 mmol), 5-fluoro-4-hydrazino-2-methyl-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]pyrimidine (100 mg, 0.357 mmol), EDC (82 mg, 0.428 mmol), HOAt (53 mg, 0.393 mmol), and NMM (0.20 mL, 1.79 mmol) in DMF (5 ml) was stirred at room temperature overnight. The reaction mixture was then purified via RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]-4-pyrimidinyl}hydrazino)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (118 mg, 58%). LCMS: (M+H)+: 562.2.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[CH2:14](O)[CH3:15]>>[ClH:3].[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: CCO
Reactant: NCCCCCC(=O)O
Product: CCOC(=O)CCCCCN
Product: Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Anhydrous ethanol (400 mL) was cooled to −78° C., and thionyl chloride (63.34 mL, 868.4 mmol) was added. The reaction was stirred for one hour at −78° C., and solid 6-aminocaproic acid (100.0 g, 723.7 mmol) was then added. The reaction was allowed to warm to ambient temperature slowly, stirred overnight, and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate:diethyl ether to provide 137 g of ethyl 6-aminocaproate hydrochloride as a white solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].Br[C:18]1[S:19][CH:20]=[CH:21][C:22]=1[CH3:23]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[CH3:23])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: Cc1ccsc1Br
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCSc1ncc(C(=O)c2sccc2C)c(N)n1

Procedure:
The compound was prepared from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 2-bromo-3-methyl-thiophene (Aldrich) in an analogous manner as described in Example 169.
Reaction SMILES: [C:1]([NH:3][C:4]([NH2:6])=[NH:5])#[N:2].[CH3:7][C:8](=O)[CH2:9][C:10](=O)[CH3:11].Cl>O>[C:1]([NH:3][C:4]1[N:6]=[C:10]([CH3:11])[CH:9]=[C:8]([CH3:7])[N:5]=1)#[N:2]
Reactant: CC(=O)CC(C)=O
Reactant: N#CNC(=N)N
Agent: Cl
Solvent: O
Product: Cc1cc(C)nc(NC#N)n1
Temperature: 120 °C
Yield: 69.9 %

Procedure:
A mixture of 42 g (0.5 mole) of cyanoguanidine ("dicyandiamide") and 50 g (0.5 mole) of 2,4-pentanedione ("acetylacetone") is heated at 120° C. for 15 hours. After the reaction mixture has cooled, 500 ml of water are added and the solution is acidified with hydrochloric acid at 0° C. to 10° C. The product thereby obtained as crystals is isolated by filtration with suction. 51.8 g (70% of theory) of 2-cyanoamino-4,6-dimethyl-pyrimidine of melting point 205° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH2:15]([O:17][NH2:18])[CH3:16].Cl>CO>[CH2:15]([O:17][N:18]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH3:16]
Reactant: COC(=O)CC(=O)c1ccc(O)cc1
Reactant: CCON
Agent: Cl
Solvent: CO
Product: CCON=C(CC(=O)OC)c1ccc(O)cc1
Temperature: 65 °C

Procedure:
A mixture of methyl 3-(4-hydroxyphenyl)-3-oxopropanoate (1 g) and EtONH2.HCl (600 mg) in methanol (10 mL) was heated at 65° C. for 2 h. Methanol was removed in vacuo, and saturated sodium bicarbonate was added to the residue. The aqueous solution was extracted with ethyl acetate (×4), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo to give the title compound as a colorless oil, which was used directly in Step B. HPLC retention time: 1.51 min (method A). MS (ESI) (M+H)+ 238.09.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:15]2[N:19]=[CH:18][N:17](/[CH:20]=[CH:21]\[C:22]([NH:24][NH2:25])=[O:23])[N:16]=2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)([CH3:3])[CH3:2].[CH3:26]OC(OC)OC.CS(O)(=O)=O.CCOC(C)=O.CCCCCC>C1COCC1>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:15]2[N:19]=[CH:18][N:17](/[CH:20]=[CH:21]\[C:22]3[O:23][CH:26]=[N:25][N:24]=3)[N:16]=2)[CH:8]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:10]=1)([CH3:3])[CH3:2]
Reactant: COC(OC)OC
Reactant: CC(C)Oc1cc(-c2ncn(/C=C\C(=O)NN)n2)cc(C(F)(F)F)c1
Agent: CS(=O)(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Oc1cc(-c2ncn(/C=C\c3nnco3)n2)cc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 13.4 %

Procedure:
In a 25-mL, 3N round-bottomed flask equipped with nitrogen inlet, and a rubber septum, (Z)-3-(3-(3-isopropoxy-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.29 g, 1.0 eq.) was dissolved in THF (7.5 mL, 26V), added trimethylorthoformate (0.095 g, 1.1 eq) and added methanesulphonic acid (0.048 g, 0.5 eq). The Reaction mixture was refluxed at 70° for 2-3 h. The progress of the reaction was followed by TLC analysis on silica gel with 50% EtOAc-hexane as mobile phase. SM Rf=0.40 and Product Rf=0.5. Reaction mixture was poured in to ice water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with Brine solution. (3×15 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation (25° C., 20 mmHg) to afford 0.28 g of crude compound. The crude reaction mixture was purified by column chromatography using silica 60/120 using ethyl acetate:hexane as mobile phase. The column (5×10 cm) was packed in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection (25-mL fractions) from 35% to 40% ethyl acetate in hexane. Compound started eluting with 35% ethylacetate in hexane. Fraction containing such TLC profile was collected together to obtain pure compound (40 mg), Yield (13.42%). 1H NMR (400 MHz, CDCl3) δ8.46-8.54 (d, 1H), 8 (t, 2H), 7.89 (s, 1H), 7.38-7.42 (d, 1H), 7.28 (d, 1H), 7.01-7.23 (d, 1H), 4.72-4.75 (d, J=11.6 Hz, 1H), 1.59 (d, 6H): LCMS for C16H14F3N5O2 [M+1]+ 365.31 found 365.89 at 3.986 min(LCMS 95.75%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[C:8]3[N:16]=[N:15][N:14]([CH2:17][C:18]4[CH:23]=[C:22]([N+:24]([O-])=[O:25])[CH:21]=[CH:20][N:19]=4)[C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+]>CCO.CO.O.[Zn]>[OH:25][NH:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([CH2:17][N:14]2[C:9]3[N:10]=[C:11]([NH2:13])[N:12]=[C:7]([C:5]4[O:6][C:2]([CH3:1])=[CH:3][CH:4]=4)[C:8]=3[N:16]=[N:15]2)[CH:23]=1
Reactant: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cc([N+](=O)[O-])ccn2)o1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Solvent: CCO
Product: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cc(NO)ccn2)o1
Reaction time: 1 h
Yield: 69.5 %

Procedure:
A solution of 7-(5-methyl-2-furyl)-3-(4-nitro-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (60 mg, 0.17 mmol) in EtOH (40 mL), MeOH (20 mL) and water (15 mL) was treated with ammonium chloride (280 mg, 5.23 mmol) and zinc (138 mg, 2.05 mmol), stirred for 1 h, filtered through Celite, concentrated in vacuo to −20 mL, diluted with brine (20 mL), extracted with EtOAc (3×20 mL) and the combined organic phase dried (MgSO4) and concentrated in vacuo to give the title compound (40 mg, 73%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C:4]([OH:7])([CH3:6])[CH3:5].O([Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])S(C(F)(F)F)(=O)=O.N1C(C)=CC=CC=1C.O>C(Cl)Cl>[Si:17]([O:7][C:4]([CH3:6])([CH3:5])[C:3]([O:2][CH3:1])=[O:8])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)C(C)(C)O
Solvent: ClCCl
Solvent: O
Solvent: Cc1cccc(C)n1
Product: COC(=O)C(C)(C)O[Si](C)(C)C(C)(C)C
Yield: 78.5 %

Procedure:
To a stirred, chilled (0° C.) solution of methyl-2-hydroxyisobutyrate (20.0 g) in dry CH2Cl2 was added TBDMS triflate (45 g) dropwise, followed by anhydrous 2,6-lutidine (19.3 g). The mixture was stirred at 0° C. for 1 hour before 150 ml water was added. Stirring was continued for a further hour, the organic layer separated, dried (Na2SO4), and concentrated to dryness at reduced pressure. The crude product was purified by dry flash silica gel chromatography eluting with CH2Cl2 to yield the title compound as a colorless oil (30.9 g). δH (360 MHz, CDCl3) 0.07 (6H, s, Si(CH3)2), 0.87 (9H, s, C(CH3)3), 1.41 (6H, s, C(CH3)2), 3.69 (3H, s, CH3O). m/z 233 (M+1)+, 100%, CI+) 217 (30), 174 (40), 164 (45), 106 (30).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])[C:3]=1[CH2:23][OH:24].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1>[C:32]([O:24][CH2:23][C:3]1[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1CO)C3=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCc1c(Cl)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 199c (7.0 g, 20.2 mmol, 1.0 eq.), triethylamine (4.08 g, 40.4 mmol, 2.0 eq.), and THF (50 mL). To the mixture was added the solution of acetyl chloride (2.36 g, 30.3 mmol, 1.5 eq.) in THF (20 mL) dropwise. The reaction mixture was stirred at room temperature for one hour. After the reaction was completed, it was quenched with ice water and evaporated under reduced pressure. The residue was extracted with dichloromethane. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was washed with 1:8 ethyl acetate/petroleum to afford 199d as a white solid (5.9 g, 76%). MS-ESI: [M+H]+ 388.3.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[N:30]1([C:35]([C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[NH2:39])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:39][C:38]2[CH:40]=[CH:41][CH:42]=[CH:43][C:37]=2[C:35]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:36])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: Nc1ccccc1C(=O)N1CCCC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)N3CCCC3)n2)c(OC)c1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and the commercially available 2-(pyrrolidin-1-ylcarbonyl)aniline.MS (ES+): m/z 608.35 (100) [MH+]; HPLC: tR=1.07 min (UPLC, purity).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[S:30]1[C:34]([CH2:35]O)=[CH:33][N:32]=[CH:31]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:35][C:34]5[S:30][CH:31]=[N:32][CH:33]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: OCc1cncs1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1cncs1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(1,3-thiazol-5-ylmethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and thiazol-5-ylmethanol following General Procedure J.
Reaction SMILES: [NH2:1][C:2]1([CH3:13])[C:7](=[O:8])[N:6]([CH2:9][CH3:10])[C:5](=[O:11])[NH:4][C:3]1=[O:12].[F:14][C:15]1[C:16]([F:28])=[C:17]([F:27])[C:18]([F:26])=[C:19]2[C:24](=O)[O:23][C:21](=[O:22])[C:20]=12>CC(O)=O>[CH2:9]([N:6]1[C:7](=[O:8])[C:2]([CH3:13])([N:1]2[C:21](=[O:22])[C:20]3[C:19](=[C:18]([F:26])[C:17]([F:27])=[C:16]([F:28])[C:15]=3[F:14])[C:24]2=[O:23])[C:3](=[O:12])[NH:4][C:5]1=[O:11])[CH3:10]
Reactant: CCN1C(=O)NC(=O)C(C)(N)C1=O
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Solvent: CC(=O)O
Product: CCN1C(=O)NC(=O)C(C)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O
Temperature: 25 °C

Procedure:
A mixture of 5-amino-1-ethyl-5-methylbarbituric acid (0.28 g, 1.50 mmol) and tetrafluorophthalic anhydride (0.40 g, 1.80 mmol) in glacial AcOH (111 mL) was stirred under reflux for 3 hours. The yellow solution was then allowed to cool down to room temperature and evaporated to dryness under reduced pressure. The oily residue was recrystallized from EtOH to give 1-ethyl-5-methyl-5-(tetrafluorophthalimido)barbituric acid (19f) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][C@H:12]([C:15]3[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=3[F:23])[C@@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:10]2)=[N:6][C:7]=1[NH2:8].O=[C:33]([CH3:36])[CH:34]=O.C(=O)(O)[O-]>CO.C(Cl)Cl>[CH3:36][C:33]1[N:8]=[C:7]2[N:6]=[C:5]([N:9]3[CH2:14][CH2:13][C@H:12]([C:15]4[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=4[F:23])[C@@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH2:10]3)[CH:4]=[CH:3][C:2]2=[N:1][CH:34]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(c2ccc(N)c(N)n2)CC[C@@H]1c1cc(F)c(F)cc1F
Reactant: CC(=O)C=O
Agent: O=C([O-])O
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc2ccc(N3CC[C@H](c4cc(F)c(F)cc4F)[C@@H](NC(=O)OC(C)(C)C)C3)nc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 40 mg (0.09 mmol) of the product of Step B in 2 mL of methanol was added 0.07 mL (0.46 mmol) of 2-oxopropanal solution (40 wt. % in water) and stirred at ambient temperature for 1 h. The reaction mixture was then, diluted with 10 mL of methylene chloride and poured into 10 mL of a saturated aqueous bicarbonate solution. The layers were separated and the aqueous layer extracted with three 10 mL portions of methylene chloride and the combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to yield a tan solid which was purified by preparative thin layer chromatography using an Analtech® 1500 micron plate (1:3 hexane/ethyl acetate solvent) to give the title compound as a tan crystalline solid. LC/MS 474.1 (M+1).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[CH:10][C:11]=2[Cl:13])[NH:6][C@@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[Cl:13][C:11]1[CH:10]=[C:9]([Cl:14])[CH:8]=[C:7]2[C:12]=1[C@@H:3]([NH:2][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:4][C@H:5]([C:15]([O:17][CH3:18])=[O:16])[NH:6]2
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H]1C[C@H](N)c2c(Cl)cc(Cl)cc2N1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@H](NS(C)(=O)=O)c2c(Cl)cc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To a suspension of trans-4-amino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline hydrochloride (0.15 g, 0.482 mmol) in dichloromethane (15 ml) was added triethylamine (0.14 ml, 1.01 mmol) and the mixture was stirred under an atmosphere of nitrogen at room temperature until dissolution was complete. To this solution was added methanesulphonyl chloride (0.039 ml, 0.50 mmol) and the resulting mixture was stirred at room temperature under an atmosphere of nitrogen for 2.5 h. A further portion of methanesulphonyl chloride (0.039 ml, 0.50 mmol) was added and stirring was continued for 2 h after which time more triethylamine (0.07 ml, 0.50 mmol) was added and the mixture was stirred for a further 18 hours. The solvent was removed in vacuo and the residue obtained was partitioned between dilute citric acid solution (50 ml) and ethyl acetate (100 ml). The organic layer was washed with saturated sodium hydrogen carbonate (2×50 ml), brine (1×50 ml), dried (MgSO4) and evaporated to give the title compound as colourless crystals (0.14 g, m.p. 143°-146° C.); δ (250 MHz, CDCl3) 1.69 (1H, m, CHACHBHCCHD), 2.90 (1H, dm, J=13.6 Hz, CHACHBHCCHD), 3.17 (3H, s, --SO2CH3), 3.83 3H, s, CO2CH3), 4.26 (2H, m, CHACHBHCCHD) and CHNHSO2CH3), 4.84 (1H, m, CHACHBHCCHD), 6.57 (1H, d, J=1.9 Hz, 6-H or 8-H), 6.73 (1H, d, J=1.9 Hz, 6-H or 8-H); m/e 353 (M+), 198 (100% M-NHSO2CH3, CO2CH3 and H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]=[C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][N:13]3[C:12](=[O:19])[S:11]2)=[CH:4][C:3]=1[N:20]1[C:25](=[O:26])[NH:24][C:23](=[O:27])[N:22]([CH3:28])[C:21]1=[O:29].C(=O)([O-])[O-].[K+].[K+].[CH2:36](Br)[CH:37]=[CH2:38].O>CC(C)=O>[CH2:36]([N:24]1[C:23](=[O:27])[N:22]([CH3:28])[C:21](=[O:29])[N:20]([C:3]2[CH:4]=[C:5]([N:9]=[C:10]3[N:14]4[CH2:15][CH2:16][CH2:17][CH2:18][N:13]4[C:12](=[O:19])[S:11]3)[C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[C:25]1=[O:26])[CH:37]=[CH2:38]
Reactant: Cn1c(=O)[nH]c(=O)n(-c2cc(N=c3sc(=O)n4n3CCCC4)c(F)cc2Cl)c1=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCn1c(=O)n(C)c(=O)n(-c2cc(N=c3sc(=O)n4n3CCCC4)c(F)cc2Cl)c1=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
A mixture of 1-{2-chloro-4-fluoro-5-[(tetrahydro-3-oxo-1H,3H-[1,3,4]thiadiazolo[3,4-a]pyridazin-1-ylidene)-amino]phenyl}-3-methyl-s-triazine-2,4,6(1H,3H,5H)-trione (1.00 g, 2.27 mmol), potassium carbonate (0.627 g, 4.54 mmol) and allyl bromide (0.329 g, 2.72 mmol) in acetone is stirred overnight at 40° C. and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as a white glass (0.8 g) which is identified by NMR spectral analyses.