Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]([O:10]CC)=[O:9])[N:6]=1.CO.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCCCCCON=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCON=C(C(=O)O)c1csc(N)n1
Yield: 91 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)2-n-hexyloxyiminoacetate (syn isomer, 29.1 g.), methanol (97.2 ml.), 2 N aqueous solution of sodium hydroxide (97.2 ml.) and tetrahydrofuran (50 ml.) were treated in a similar manner to that of Example F-(4) to give 2-(2-aminothiazol-4-yl)-2-n-hexyloxyiminoacetic acid (syn isomer, 24.0 g.), mp. 174° C. (dec.).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH:15]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:16][O:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)[CH2:11][CH2:10]1)C.C(O)C.[OH-].[Na+].Cl>O>[F:28][C:25]([F:26])([F:27])[C:23]1[CH:24]=[C:19]([CH:20]=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:22]=1)[CH2:18][O:17][CH2:16][CH:15]([N:12]1[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:39])=[O:3])[CH2:14][CH2:13]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)CCCCN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 75.1 %

Procedure:
In a round-bottomed flask fitted with a reflux condenser and a thermometer 2.48 g (4 mmoles) of 5-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-pentanoic acid ethyl ester (compound 140 prepared at example 1.4.1 above), 45 ml of ethyl alcohol, 4 ml of water, and 6.6 ml of a 1N solution of sodium hydroxide in water were introduced. The mixture was stirred at room temperature for 22 hours, and 6.6 ml of a 1N solution of hydrochloric acid in water was added. The volatile substances were removed under reduced pressure, water and methylene chloride were added, the aqueous layer was extracted with methylene chloride, and the combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 35 ml of methylene chloride, 3.96 ml of a 1.96 N solution of hydrochloric acid in diethyl ether were added, and the volatile substances were removed under reduced pressure. The residue was recristallized from acetonitrile, affording 1.6 g of 5-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-pentanoic acid (compound 233) as a solid. Yield: 61%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:2]2[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=2)=[CH:12][CH:11]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: Nc1ccc(F)cc1
Product: Nc1cc(Nc2ccc(F)cc2)ncn1

Procedure:
The title compound is prepared analogously as described in Example 114A from 6-chloro-pyrimidin-4-ylamine and 4-fluoroaniline.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[OH:47][CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:47][CH:48]1[CH2:53][CH2:52][N:51]([C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:10]([N:7]2[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]2)=[O:11])=[CH:20][CH:19]=3)=[O:23])[CH2:50][CH2:49]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(O)CC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-hydroxy piperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].C([Li])CCC.[NH2:12][C:13]1[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[C:20]([O:27][CH3:28])=[CH:19][C:14]=1[C:15](OC)=[O:16].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.CCCCCC>[NH2:12][C:13]1[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[C:20]([O:27][CH3:28])=[CH:19][C:14]=1[C:15](=[O:16])[CH2:6][S:3](=[O:5])(=[O:4])[NH:2][CH3:1]
Reactant: CNS(C)(=O)=O
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNS(=O)(=O)CC(=O)c1cc(OC)c(OC)c(OC)c1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-methylmethanesulphonamide (13.6 g) in dry tetrahydrofuran (160 ml) at -70° to -60° was added a solution of n-butyl lithium in hexane (2.5M; 100 ml) under argon. The mixture was stirred at -78° for 1 hour and a solution of methyl 2-amino-3,4,5-trimethoxybenzoate (10 g) in dry tetrahydrofuran (50 ml) was added at -70° to -60°. The mixture was stirred for 2 hours, during which time the temperature rose to 10°. The mixture was poured on to ice (500 g), acidified to pH 1 with 5N HCl, and then neutralised to pH 7 with saturated aqueous sodium bicarbonate. The solid product was extracted into dichloromethane (3×500 ml). The extract was dried and evaporated to give a residue. This residue was triturated with ether to give a solid which was collected, dried and crystallised from ethyl acetate to give the novel compound 1-(2-amino-3,4,5-trimethoxyphenyl)-2-(N-methylsulphamoyl)ethanone, m.p. 125°-127°.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[N:6]=[CH:7][C:8]([C:11]([O:13][CH3:14])=[O:12])=[N:9][CH:10]=1.O>CN(C)P(N(C)C)N(C)C>[CH3:1][S:2][C:5]1[N:6]=[CH:7][C:8]([C:11]([O:13][CH3:14])=[O:12])=[N:9][CH:10]=1
Reactant: C[S-]
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: CN(C)P(N(C)C)N(C)C
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cnc(SC)cn1
Reaction time: 0.5 h
Yield: 7.3 %

Procedure:
Sodium methanethiolate (44.6 mg) was added to a solution of methyl 5-chloropyrazine-2-carboxylate (87 mg) in hexamethylphosphorous triamide (1 mL) at room temperature, followed by stirring for 13 hours and 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (6.8 mg).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:22]([OH:24])=[O:23])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=O)C1C=CC=CC=1>C(O)C.[Pd].C1CCCCC=1>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@@H:12]([C:22]([OH:24])=[O:23])[NH2:11])=[CH:19][CH:18]=1
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COc1ccc(C[C@H](N)C(=O)O)cc1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
N-Benzyloxycarbonyl-O-methyl-L-tyrosine (5.7g, 17.3 mmol) was dissolved in ethanol (50 ml) and the solution added to a suspension of 10% palladium on charcoal (100 mg) in cyclohexene (10 ml). The reaction was then heated at reflux for 1 h, allowed to cool to ambient temperature, filtered, and the filtrate concentrated to give O-methyl-L-tyrosine (1.4 g, 43%) as a white solid which was used directly in the next step.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:10])[C@:5]([CH3:9])([CH2:7][CH3:8])[NH2:6]>CO>[ClH:1].[CH3:2][O:3][C:4](=[O:10])[C@@:5]([CH3:9])([CH2:7][CH3:8])[NH2:6]
Reactant: CC[C@](C)(N)C(=O)OC
Agent: Cl
Solvent: CO
Product: CC[C@@](C)(N)C(=O)OC

Procedure:
In a 2-liter round-bottomed flask equipped with a condenser and a magnetic stirrer were placed 70 g of the (R)-N-chloroacetylisovaline obtained from the enzymatic resolution of racemic N-chloroacetylisovaline, 696 ml of water, and 696 ml of concentrated hydrochloric acid. The resulting mixture was heated at reflux for 2.25 hours. The mixture was then cooled to room temperature and the solvent was removed using rotary evaporation yielding a solid residue. the residue was washed with dry acetone and then dried in a vacuum oven at 40° C. yielding a crude product. The crude product was esterified with methanol using the above-described procedure for preparation of (S)-isovaline methyl ester hydrochloride to give 47.52 g of the corresponding (R)-isovaline methyl ester hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[F:15][C:16]([F:40])([F:39])[CH2:17][NH:18][C:19]([C:21]1([CH2:34][CH2:35][CH2:36][CH2:37]Br)[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20]>>[F:15][C:16]([F:39])([F:40])[CH2:17][NH:18][C:19]([C:21]1([CH2:34][CH2:35][CH2:36][CH2:37][N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:10][CH2:11]2)[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)cc1

Procedure:
Prepared analogously to Example 2 b from 1-(4-methoxy-phenyl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: C[Si](C)(C)O[C:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH:5]=1.BrN1C(=O)CCC1=O.[NH2:24][C:25]([NH2:27])=[S:26]>O1CCCC1>[NH2:27][C:25]1[S:26][C:5]2[CH2:6][CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:9][C:4]=2[N:24]=1
Reactant: NC(N)=S
Reactant: COC(=O)C1CC=C(O[Si](C)(C)C)CC1
Agent: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COC(=O)C1CCc2nc(N)sc2C1

Procedure:
The procedure of M. E. Jung, et al, Journal of the American Chemical Society, Volume 103, pages 6177-6185 (1981), is followed to prepare (±)-methyl 4-[(trimethylsilyl)oxy]-3-cyclohexene-1-carboxylate. A solution of 100 g of this compound in 500 ml of dry tetrahydrofuran is cooled in an ice bath under nitrogen and treated sequentially with N-bromosuccinimide (92.91 g) and 20 minutes later with thiourea (39.73 g). The mixture is refluxed under nitrogen for two hours. The solvent is removed in vacuo and the residue is partitioned between chloroform and a dilute solution of ammonium hydroxide. The organic phase is washed with brine and dried over magnesium sulfate. Evaporation of the solvent gives 82.7 g of the title compound; mp 148°-168° C.
Reaction SMILES: B.[CH2:2]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>O1CCCC1>[CH2:2]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][OH:21])=[CH:23][CH:24]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Agent: B
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCOc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 22 h

Procedure:
To 200 ml. of 1.0 M borane in tetrahydrofuran, chilled in an ice bath is added dropwise over 30 minutes 32.0 g. of p-tridecyloxybenzoic acid in 450 ml. of tetrahydrofuran. After 22 hours at room temperature, the mixture is poured onto ice. After the ice melts, the solid is filtered and washed with water to give white crystals, m.p. 72°-75° C. Recrystallization from ethanol gives white crystals, m.p. 74°-75° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)[S:7]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[C:24]2[CH:25]=[N:26][N:27](COC)[CH:28]=2)=[CH:12][C:11]=1[F:32])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.Cl>CO.ClCCl>[F:32][C:11]1[CH:12]=[C:13]([O:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)[C:14]([CH3:16])=[CH:15][C:10]=1[S:7]([NH:6][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)(=[O:8])=[O:9]
Reactant: COCn1cc([C@@H]2CCCC[C@H]2Oc2cc(F)c(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3ccncn3)cc2C)cn1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@@H]1CCCC[C@H]1c1cn[nH]c1
Yield: 52.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 147e by using the N-(2,4-dimethoxybenzyl)-2-fluoro-4-({(1R,2S)-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (144 mg, 0.230 mmol) prepared in Example 170a, triethylsilane (0.184 mL), dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL), methanol (15 mL) and 6 M hydrochloric acid (5.0 mL), to yield the title compound (51.7 mg, 52%) as a colorless solid.
Reaction SMILES: C(NCC1C=CN=C(NCC2[N:17]3[CH:18]=[C:19](C)[CH:20]=[CH:21]C3=NC=2C2C=CC(F)=CC=2)N=1)C.[Cl:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([C:37]([CH2:47][NH:48][C:49]3[N:54]=[C:53]([CH:55]=O)[CH:52]=[CH:51][N:50]=3)=[C:38]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)[N:39]=2)[CH:36]=1.N1CCCC1>>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([C:37]([CH2:47][NH:48][C:49]3[N:54]=[C:53]([CH2:55][N:17]4[CH2:18][CH2:19][CH2:20][CH2:21]4)[CH:52]=[CH:51][N:50]=3)=[C:38]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)[N:39]=2)[CH:36]=1
Reactant: CCNCc1ccnc(NCc2c(-c3ccc(F)cc3)nc3ccc(C)cn23)n1
Reactant: O=Cc1ccnc(NCc2c(-c3ccc(F)cc3)nc3ccc(Cl)cn23)n1
Solvent: C1CCNC1
Product: Fc1ccc(-c2nc3ccc(Cl)cn3c2CNc2nccc(CN3CCCC3)n2)cc1
Yield: 33 %

Procedure:
The title compound was prepared in the same fashion as that described for compound 196 from 2-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methylamino)pyrimidine-4-carbaldehyde and pyrrolidine. (0.040 g, 33% yield). M/e+ 437.1 for C23H22ClFN6 (M+H)+; 1H-NMR (500 MHz, CDCl3, δ) 8.54 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 7.77-7.75 (m, 2H), 7.57 (dd, J=9.5. 0.5 Hz, 1H), 7.20-7.15 (m, 3H), 6.81 (d, J=5.0 Hz, 1H), 5.32-5.26 (m, 1H), 5.05 (d, J=5.5 Hz, 2H), 3.64 (s, 2H), 2.64 (br s, 4H), 1.84 (br s, 4H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:3]=1.[C:28]([N:32]1[CH2:37][CH:36]=[C:35]([Sn](C)(C)C)[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29]>O1CCOCC1>[C:28]([N:32]1[CH2:33][CH:34]=[C:35]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]3[C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])=[C:4]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[N:3]=2)[CH2:36][CH2:37]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)N1CC=C([Sn](C)(C)C)CC1
Reactant: O=c1ccc2c(-c3ccccc3Cl)nc(Br)cc2n1-c1c(Cl)cccc1Cl
Solvent: C1COCCO1
Product: CC(C)(C)N1CC=C(c2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1
Reaction time: 8 h

Procedure:
A mixture of 100 mg of 7-bromo-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one (COMPOUND HHH2) and 94 mg of 1-tert-butyl-4-(trimethylstannyl)-1,2,3,6-tetrahydropyridine (COMPOUND PPA-2) in 2 mL of dry dioxane was evacuated and purged three times with Ar. Pd(Ph3P)4 (23 mg) was added and the mixture was evacuated and purged again with Ar. The mixture was heated to reflux and stirred at this temperature overnight, then filtered through Celite and concentrated. The residue was purified by preparative thin-layer chromatography, eluting with 95:5 CH2Cl2-2M NH3 in MeOH, to yield the title compound. The HCl salt was prepared by dissolving this compound in CH2Cl2, adding 1 eq 1M HCl in Et2O, and concentrating. Mass spectrum (ESI) 540 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:34]=[CH:33][C:8]([CH2:9][C:10]2[N:18]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]3[C:16](=[O:27])[NH:15][C:14](=[O:28])[N:13]([CH2:29][CH2:30][CH2:31][CH3:32])[C:12]=3[N:11]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].N12CCCN=C1CCCCC2.Br[CH2:47][C:48]1[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:49]=1[F:57].C(OCC)(=O)C>C(#N)C>[C:1]([NH:4][C:5]1[CH:34]=[CH:33][C:8]([CH2:9][C:10]2[N:18]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:24])([CH3:25])[CH3:23])[C:17]3[C:16](=[O:27])[N:15]([CH2:47][C:48]4[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:49]=4[F:57])[C:14](=[O:28])[N:13]([CH2:29][CH2:30][CH2:31][CH3:32])[C:12]=3[N:11]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)c(CBr)c1
Reactant: CCCCn1c(=O)[nH]c(=O)c2c1nc(Cc1ccc(NC(C)=O)cc1)n2COC(=O)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCn1c(=O)n(Cc2cc([N+](=O)[O-])ccc2F)c(=O)c2c1nc(Cc1ccc(NC(C)=O)cc1)n2COC(=O)C(C)(C)C
Temperature: 50 °C
Reaction time: 18 h
Yield: 33.1 %

Procedure:
A solution of 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-3-butyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (104 mg, 0.22 mmol) in acetonitrile (2.0 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.03 mL, 0.24 mmol) and 2-bromomethyl-1-fluoro-4-nitro-benzene (56.6 mg, 0.24 mmol). The resulting solution was heated to 50° C. for 6 h. At this time, another portion of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.03 mL, 0.24 mmol) was added. The reaction was stirred at 25° C. for 18 h. At this time, the reaction was poured into ethyl acetate (200 mL) and was washed with a 1N aqueous hydrochloric acid solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1:1 ethyl acetate/petroleum ether) afforded 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-3-butyl-1-(2-fluoro-5-nitro-benzyl)-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (45.3 mg, 33%) as a tan solid: FAB-HRMS m/e calcd for C31H35N6O7F (M+H)+ 623.2630, found 623.2631.
Reaction SMILES: [CH2:1]1[O:21][C:20]2[C:3](=[CH:4][CH2:5][C:6]([O:22][CH3:23])([CH:19]=2)[CH2:7][CH:8]([C:14]([O:16]CC)=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:2]1.[OH-].[K+]>C(O)C.O>[CH2:1]1[O:21][C:20]2[C:3](=[CH:4][CH2:5][C:6]([O:22][CH3:23])([CH:19]=2)[CH2:7][CH:8]([C:14]([OH:16])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:2]1
Reactant: CCOC(=O)C(CC1(OC)C=C2OCOC2=CC1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CC1(OC)C=C2OCOC2=CC1)C(=O)O
Yield: 87.9 %

Procedure:
To a solution of the diethyl 2-(4,5-methylenedioxy-1-methoxybenyl)-malonate (20.0 g, 0.066 mol) of in ethanol (50 ml) was added a solution of potassium hydroxide (3.5 g, 0.066 mol) in water (25 ml). The solution stirred at reflux for 6 h. After concentrating the aqueous layer was washed with ether and acidified with concentrated HCl to pH 1 and extracted with ethyl acetate. The organic extracts were dried (Na2SO4) and concentrated to afford the title compound as a yellow solid (17.3 g, 89%).
Reaction SMILES: B(F)(F)F.CCOCC.CN(C(F)(F)C(F)F)C.FC(F)C(=O)CC(OCC)=O.N1C=CC=CC=1.Cl.[C:37]([NH:41][NH2:42])([CH3:40])([CH3:39])[CH3:38].[OH-].[K+].[F:45][CH:46]([F:62])[C:47]([C:49](=[C:55](N(C)C)[CH:56]([F:58])[F:57])[C:50]([O:52][CH2:53][CH3:54])=[O:51])=O>ClCCl.C(#N)C.CO>[CH2:53]([O:52][C:50]([C:49]1[C:47]([CH:46]([F:45])[F:62])=[N:42][N:41]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:55]=1[CH:56]([F:58])[F:57])=[O:51])[CH3:54]
Reactant: CC(C)(C)NN
Reactant: CCOC(=O)C(C(=O)C(F)F)=C(C(F)F)N(C)C
Agent: CCOC(=O)CC(=O)C(F)F
Agent: CN(C)C(F)(F)C(F)F
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1c(C(F)F)nn(C(C)(C)C)c1C(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30 %

Procedure:
BF3.OEt2 (2.7 ml, 22.0 mmol) was added to a solution of TFEDMA (2.5 ml, 22.0 mmol) in dry dichloromethane (20 ml) under argon in a Teflon flask. The solution was stirred at room temperature for 15 min, before the dichloromethane was removed under reduced pressure. The residue was then taken up in dry acetonitrile (20 ml). In a second Teflon flask, ethyl 4,4-difluoroacetoacetate (2.8 ml, 20.0 mmol) was added to a solution of pyridine (7.1 g, 90.0 mmol) in dry acetonitrile (40 ml) and the mixture was stirred at room temperature for 15 min. To this were added dropwise, at −30° C., the contents of the first flask. The reaction mixture was brought to room temperature in the cold bath and stirred overnight. tert-Butyl hydrazine hydrochloride (3.74 g, 30.0 mmol) was added to a solution of potassium hydroxide (1.68 g, 30 mmol) in methanol (10 ml) and the mixture was stirred at room temperature for 30 minutes. This mixture was then added to the previously prepared intermediate (ethyl 2-(2,2-difluoroacetyl)-3-(dimethylamino)-4,4-difluorobut-2-enoate) and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1). N-tert-Butyl-3,5-di(difluoromethyl)-4-pyrazolecarboxylic acid ethyl ester (1.77 g, 5.98 mmol, 30%) was isolated as an orange oil.
Reaction SMILES: [O:1]=[C:2]([CH3:27])[CH:3]=C1CCP(C2C=CC=CC=2)C1(C1C=CC=CC=1)C1C=CC=CC=1.[CH:28]([C:30]1[C:31]([CH3:44])=[C:32]([CH:37]=[CH:38][C:39]=1[S:40]([CH3:43])(=[O:42])=[O:41])[C:33]([O:35][CH3:36])=[O:34])=O>C1C=CC=CC=1>[CH3:43][S:40]([C:39]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([CH3:44])[C:30]=1[CH:28]=[CH:3][C:2](=[O:1])[CH3:27])(=[O:42])=[O:41]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1C
Reactant: CC(=O)C=C1CCP(c2ccccc2)C1(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C=CC(C)=O)c1C
Reaction time: 1 h

Procedure:
30 ml of benzene and then 3.85 g (0.012 mol) of 2-oxopropylidenetri phenylphospholane were added to 3.1 g (0.012 mol) of methyl 3-formyl-4-methanesulfonyl-2-methylbenzoate, followed by stirring for 1 hour under heating reflux. After the solution was allowed to cool, insoluble substance was removed by filtration, and the solvent was concentrated under reduced pressure to obtain methyl 4-methanesulfonyl-3-(3-oxo-1-butenyl)-2-methylbenzoate. Methyl 4-methanesulfonyl-3-(3-oxo-1-butenyl)-2-methylbenzoate thus obtained was dissolved in a solvent of 10 ml of ethanol and 10 ml of pyridine, and 1.1 g (0.016 mol) of hydroxyamine hydrochloride was added, followed by stirring for 1 hour under heating reflux. The resulting reaction mixture was poured into ice water, and extraction was carried out with ethyl acetate. Afterward, the resulting ethyl acetate layer was washed with 1N hydrochloric acid and subsequently with saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. Next, the solvent was distilled off under reduced pressure. The thus obtained methyl 4-methanesulfonyl-3-(3-hydroxyimino-1-butenyl)-2-methylbenzoate was dissolved in 15 ml of THF, and 15 ml of water containing 1.4 g (0.017 mol) of sodium hydrogencarbonate was added to the solution. Next, an aqueous solution obtained by dissolving 2.5 g (0.015 mol) of potassium iodide and 1.1 g (0.05 mol) of iodine in 12 ml of water was added, and the solution was heated under reflux for 3 hours under a condition that light was blocked. The reaction mixture was poured into ice water, and sodium hydrogen sulfite was then added, followed by extraction with ethyl acetate. The resulting organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. Next, the solvent was distilled off under reduced pressure. The resulting residue was purified through silica gel column chromatography to obtain 0.84 g of methyl 4-methanesulfonyl-2-methyl-3-(3-methyl-1,2-isoxazol-5-yl)benzoate. Yield=23%.