Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]=1[CH3:7].[H-].[Na+].Br[CH2:20][CH2:21][O:22][CH3:23]>CN(C)C(=O)C.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:16][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[C:6]=1[CH3:7]
Reactant: Cc1c(I)cnn1CC1(O)CCCCCC1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COCCOC1(Cn2ncc(I)c2C)CCCCCC1
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 151B (356 mg) in N,N-dimethylacetamide (6 mL) was added NaH (128 mg, 60% in mineral oil). The mixture was stirred for 30 minutes. Then, 1-bromo-2-methoxyethane (740 mg) was added to the mixture, which was stirred overnight. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with water, brine and dried over Na2SO4. After filtration and concentration, the residue containing the crude title compound was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([OH:14])[CH:2]([OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:15](=O)(OCC)[O:16]CC>[H-].[Na+].C1C=CC=CC=1>[CH2:3]([CH:2]1[CH2:1][O:14][C:15](=[O:16])[O:13]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCC(O)CO
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCCCCCCCC1COC(=O)O1
Yield: 108.1 %

Procedure:
A 125 ml round bottom flask equipped with a Dean-Stark trap was charged with 10 g of 1,2-dodecanediol, 7.1 g of diethyl carbonate and 50 ml of benzene. The solution was stirred until homogeneous and then 50 mg of 60% NaH was added. The reaction mixture was refluxed for 6 hours and then concentrated to afford 12.2 g of oil. This was taken up in 100 ml of pet. ether and allowed to crystallize in freezer whereupon 1.1 g of starting diol was recovered. Concentration of the filtrate gave 9.53 g (89.66%) of a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2[CH:13]=[C:12]([S:14][CH3:15])[N:11]=[C:10]([CH3:16])[N:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:26])[C:20]=2[CH:19]=[N:18]1>C(O)C.C([O-])(O)=O.[Na+]>[CH3:16][C:10]1[N:9]=[C:8]([C:3]2[C:2]([NH:26][C:21]3[C:20]4[CH:19]=[N:18][NH:17][C:25]=4[CH:24]=[CH:23][CH:22]=3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH:13]=[C:12]([S:14][CH3:15])[N:11]=1
Reactant: Nc1cccc2[nH]ncc12
Reactant: CSc1cc(-c2nccnc2Cl)nc(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CSc1cc(-c2nccnc2Nc2cccc3[nH]ncc23)nc(C)n1
Temperature: 160 °C
Yield: 45.9 %

Procedure:
A glass microwave reaction vessel was charged with 4-(3-chloropyrazin-2-yl)-2-methyl-6-(methylthio)pyrimidine (60 mg, 0.237 mmol) and 1H-indazol-4-amine (63.2 mg, 0.475 mmol, Bionet) in ethanol (2 mL). The reaction mixture was stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 160° C. for 30 min. The reaction mixture was diluted with saturated NaHCO3 (5 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give a yellow solid. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column eluting with 40% EtOAc/hexanes to provide N-(3-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-yl)-1H-indazol-4-amine (38 mg, 46% yield) as yellow solid. 1H NMR (300 MHz, d8-dioxane) δ 12.49 (s, 1H); 11.68 (s, 1H); 10.69 (s, 1H); 8.24 (s, 2H); 8.10 (d, J=7.60 Hz, 1H); 8.02 (s, 1H); 7.23 (t, J=7.97 Hz, 1H); 7.07 (d, J=8.18 Hz, 1H); 2.83 (s, 3H); 2.53 (s, 3H). m/z (ESI, +ve ion) 350 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:3]=1[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:31]=[CH:30][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[CH:16][C:15]=2[C:28]#[N:29])=[CH:11][CH:10]=1)=[O:8].C(O)(C(F)(F)F)=O>ClCCl>[C:28]([C:15]1[CH:16]=[C:17]([CH2:20][C:21]([OH:23])=[O:22])[CH:18]=[CH:19][C:14]=1[O:13][C:12]1[CH:30]=[CH:31][C:9]([C:7](=[O:8])[NH:6][CH2:5][CH2:4][C:3]2[C:2]([Cl:1])=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:36])=[CH:10][CH:11]=1)#[N:29]
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3c(Cl)cccc3Cl)cc2)c(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(CC(=O)O)ccc1Oc1ccc(C(=O)NCCc2c(Cl)cccc2Cl)cc1
Reaction time: 0.75 h
Yield: 111.5 %

Procedure:
tert-Butyl 2-(4-(4-((2,6-dichlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)acetate (34 mg, 0.065 mmol) was dissolved in dichloromethane (1 ml) and TFA (1 ml) was added. After stirring for 45 minutes, the mixture was concentrated under reduced pressure to give 2-(3-cyano-4-(4-(2,6-dichlorophenethylcarbamoyl)phenoxy)phenyl)acetic acid (0.034 g).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[NH:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[N:33]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:26])[CH3:23]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C1CCCCC1NC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1CCCCC1N(C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1)C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.333 g, 1.0 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). 2-Cyclohexylamino-cyclohexanecarboxylic acid ethyl ester (0.253 g, 1.0 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.201 g, 1.05 mmol). Then N-methylmorpholine (212 mg, 2.1 mmol) was added. The mixture was stirred at 25° C. for 5 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, 2-{cyclohexyl-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclohexanecarboxylic acid ethyl ester (0.48 g, 0.845 mmol, 84.5%), as a yellow oil. LC-MS (ESI) calcd for C25H36N4O7S2 568.20, found 569.3 [M+H+].
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([CH2:23][OH:24])[CH:22]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=1)=[O:9])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:27].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:23]([OH:27])=[O:24])[CH:22]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=1)=[O:9])([CH3:3])[CH3:2]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CC(C)Oc1cc(CO)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(C(=O)O)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Reaction time: 0.75 h
Yield: 87.2 %

Procedure:
To 2-(3-isopropoxy-5-hydroxymethyl-benzoyl) amino-5-pyridine carboxylic acid (0.33 g, 1.0 mM) in THF (20 ml) under argon, Dess-Martin periodinane (0.46 g, 1.1 mM) was added in one portion. After 45 mins satd. potassium carbonate (20 ml) was added and the THF removed in vacuo. Residue was stirred with 2.0M Na2S2O3 (3.5 ml, 7 mM) for 35 mins then acidified cautiously to pH=1 with 2M HCl. Resulting suspension was filtered, washed with water, diethyl ether, DCM and dried under high-vacuum to give 2-(3-isopropyloxy-5-carboxy-benzoyl) amino-5-pyridine carboxylic acid as a pale yellow solid (0.3 g, 93%); 1H NMR δ (d6-DMSO): 1.32 (d, 6H), 4.82 (m, 1H), 7.58 (m, 1H), 7.84 (m, 1H), 8.11 (s, 1H), 8.29 (s, 2H), 8.87 (s, 1H), 10.02 (s, 1H), 11.34 (bs, 1H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[N:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[ClH:13].[CH3:14][O:15][C:16]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=2[C:19]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([C:38]3C=CC(C(N4CCN(C/C=C/C5C=CC=CC=5)CC4)=O)=CC=3)[N:28]=2)=[CH:18][CH:17]=1>>[ClH:13].[ClH:13].[CH3:14][O:15][C:16]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=2[C:19]([C:27]2[C@H:36]3[C@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([CH2:38][C:34]3[CH:35]=[CH:36][C:31]([C:30]([N:4]4[CH2:5][CH2:6][N:1]([C:7]5[CH:12]=[N:11][CH:10]=[CH:9][N:8]=5)[CH2:2][CH2:3]4)=[O:37])=[CH:32][CH:33]=3)[N:28]=2)=[CH:18][CH:17]=1
Reactant: c1cnc(N2CCNCC2)cn1
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(Cc3ccc(C(=O)N4CCN(c5cnccn5)CC4)cc3)C(=O)[C@H]3CC=CC[C@@H]23)c2c1OC(C)(C)C2

Procedure:
Prepared from intermediate product A11 and 3,4,5,6-Tetrahydro-2H-[1,2′]bipyrazinyl as described for compound 8. M.p. 124–126° C.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([F:17])[CH:11]=2)[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.O>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH2:6][CH:5]([CH2:4][NH2:1])[O:9][N:8]=2)=[CH:11][C:12]=1[F:17]
Reactant: [N-]=[N+]=NCC1CC(c2ccc(Br)c(F)c2)=NO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: NCC1CC(c2ccc(Br)c(F)c2)=NO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.3 %

Procedure:
5-(Azidomethyl)-3-(4-bromo-3-fluorophenyl)-4,5-dihydroisoxazole (8.046 g, 26.9 mmol) was dissolved in a mixture of acetonitrile (40 ml) and water (4 ml). Triphenylphosphine (8.48 g, 32.3 mmol) was added and the reaction mixture stirred at room temperature for 48 hours. The reaction mixture was then poured onto a silica gel chromatography column (400 ml). The product was eluted with 10% to 20% water/acetonitrile, then freeze dried to yield 2.67 g of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:17])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[CH:7]2.[C:18]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19]1.ClC(Cl)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C([O-])(O)=O.[Na+]>[CH:18]1([NH:1][C:2]2[CH:3]=[C:4]([CH3:17])[CH:5]=[C:6]3[C:10]=2[NH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:7]3)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1cc(N)c2[nH]c(-c3ccccn3)cc2c1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Cc1cc(NC2CCCC2)c2[nH]c(-c3ccccn3)cc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.8 %

Procedure:
7-Amino-5-methyl-2-(pyridin-2-yl)-1H-indole (5 g, 22.4 mmol) prepared in Step A and cyclopentanone (1.88 g, 22.4 mmol) were added to dichloroethane (50 mL). NaBH(OAc)3 (9.5 g, 44.8 mmol) was added thereto, and the mixture was stirred for 12 h at room temperature. After completion of the reaction, the reaction mixture was diluted with saturated aqueous NaHCO3 solution, and extracted with dichloromethane and EtOAc. The extracted organic material was washed with water and aqueous NaCl solution, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (eluent EtOAc/n-Hex=1/5) to give the title compound (3.77 g, Yield 58%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][C:3]=1[N+:13]([O-])=O.C.[H][H]>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][C:3]=1[NH2:13]
Reactant: CCCCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: [H][H]
Solvent: CO
Product: CCCCOc1ccc(N)c(N)c1

Procedure:
2.1 G. of 1-amino-4-n-butoxy-2-nitrobenzene, prepared according to Example XXXV, and 1 g. of 5% palladized charcoal in 100 ml. methanol are treated with hydrogen at atmospheric pressure until the theoretical uptake of hydrogen has occurred. The mixture is filtered and the filtrate evaporated to give 1,2-diamino-4-n-butoxybenzene. This is treated, in 60 ml. acetone, with 7.0 g. methoxycarbonyl isothiocyanate. The mixture is kept at room temperature overnight and then concentrated under vacuum. The residue is stirred with water, filtered and recrystallized from dichloromethane/benzene yielding 1,2-bis-(3-methoxycarbonyl-2-thioureido)-4-n-butoxybenzene.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.C(O)(C(F)(F)F)=O.[CH3:20][O:21][C:22]([C:24]1[CH:50]=[CH:49][C:27]([C:28]([NH:30][CH2:31][C:32]2[CH:48]=[CH:47][C:35]([C:36]([NH:38][NH:39]C(OC(C)(C)C)=O)=[O:37])=[CH:34][CH:33]=2)=[O:29])=[CH:26][CH:25]=1)=[O:23]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:39][NH:38][C:36]([C:35]1[CH:47]=[CH:48][C:32]([CH2:31][NH:30][C:28]([C:27]2[CH:26]=[CH:25][C:24]([C:22]([O:21][CH3:20])=[O:23])=[CH:50][CH:49]=2)=[O:29])=[CH:33][CH:34]=1)=[O:37]
Reactant: COC(=O)c1ccc(C(=O)NCc2ccc(C(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C(=O)NCc2ccc(C(=O)NN=C3C(=O)Nc4ccc(I)cc43)cc2)cc1
Temperature: 100 °C
Yield: 86 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFA was added tert-butyl 2-[4-({[4-(methoxycarbonyl)benzoyl]amino)methyl)benzoyl]hydrazinecarboxylate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 70° C. for 15 hrs gave 614 mg of the title compound (86%) as a yellow solid in 97.9% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]2[C:10]([CH3:15])=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[S:7][N:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:15][C:10]1[C:9]2[C:5]([CH2:3][OH:2])=[N:6][S:7][C:8]=2[CH:13]=[C:12]([CH3:14])[CH:11]=1
Reactant: COC(=O)c1nsc2cc(C)cc(C)c12
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(CO)nsc2c1
Reaction time: 1 h

Procedure:
To a solution of 4,6-dimethyl-benzo[d]isothiazole-3-carboxylic acid methyl ester (100 mg, 0.45 mmol) in THF (10 mL) was added lithium aluminum hydride (LiAlH4) (34 mg, 0.9 mmol) at 0° C. under nitrogen atmosphere. The solution was stirred at the same temperature for 1 hour. Sat. NaHCO3 was added and the solution was extracted with EtOAc. The combined organic layer was dried with MgSO4 and filtered. The filtrate was concentrated and the residue was used in the next step of the synthesis without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:9][CH2:10][C:11](Cl)=[O:12]>[OH-].[Na+].ClCCl>[Cl:9][CH2:10][C:11]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([CH3:1])[CH:3]=1)=[O:12]
Reactant: Cc1cccc(N)c1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cccc(NC(=O)CCl)c1
Reaction time: 18 h
Yield: 76.1 %

Procedure:
3-Methylaniline (1 g, 9.3 mmol) in 2N aqueous sodium hydroxide (30 mL) was treated with chloroacetyl chloride (0.82 mL, 10.27 mmol) dropwise at room temperature as a solution in dichloromethane. After 18 hours, the reaction mixture was quenched with water and the layers separated. The organic phase was washed with an aqueous solution of 1N HCl and dried over MgSO4, filtered and the filtrate concentrated under reduced pressure to provide 1.3 g (76%) of the title compound as a white solid. 1H NMR (300 MHz, CDCI3) δ 2.35 (s, 3H), 4.20 (s, 2H), 7.00 (s, 1H), 7.22 (m, 1H), 7.35-7.45 (m, 2H), 8.15 (br s, 1H); MS (DCI/NH3) m/e 201 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])=[CH:13][CH:12]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([CH:23]=[O:24])=[CH:5][NH:6]2.Cl([O-])=[O:26].[Na+].P([O-])(O)(O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C(O)(C)(C)C.CC(=CC)C.O>[F:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])=[CH:15][CH:16]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([C:23]([OH:26])=[O:24])=[CH:5][NH:6]2
Reactant: [O-][Cl+][O-]
Reactant: CC(C)(CO)c1ccc(-c2c(F)cc3[nH]cc(C=O)c3c2F)cc1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: O=S([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC#N
Product: CC(C)(CO)c1ccc(-c2c(F)cc3[nH]cc(C(=O)O)c3c2F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.7 %

Procedure:
To a solution of 4,6-difluoro-5-[4-(1-hydroxy-2-methylpropan-2-yl)phenyl]-1H-indole-3-carbaldehyde (40 mg, 0.122 mmol) in acetonitrile (2.3 mL), t-butanol (2.3 mL) and 2-methyl-2-butene (1.5 mL) was added a solution of sodium chlorite (164 mg, 2.43 mmol) and sodium dihydrogen phosphate (335 mg, 2.43 mmol) in water (2.3 mL) at 0° C. The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with a solution of sodium sulfite (337 mg, 2.68 mmol) in water (5.0 mL), and extracted with ethyl acetate (10 mL×3). The organic layers were washed with brine (10 mL) and dried over sodium sulfate, filtered and concentrated to give a crude residue, which was purified by reverse phase HPLC to give the title compound (14.6 mg, 42%) as a white solid.
Reaction SMILES: [NH:1]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[C:5](=[O:6])[NH:4][C:2]1=[O:3].FC(F)(F)C(O[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=O>N1C=CC=CC=1>[OH:3][C:2]1[N:4]=[C:5]([OH:6])[C:7]([C:9]([O:11][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[O:10])=[CH:8][N:1]=1
Reactant: O=C(O)c1c[nH]c(=O)[nH]c1=O
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Solvent: c1ccncc1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1cnc(O)nc1O
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
Uracil-5-carboxylic acid (1.0 g) is dissolved in dry pyridine (20 ml) under heating. p-Nitrophenyl trifluroacetate (1.8 g) is added to the solution which is subsequently stirred at 45° C for 30 minutes. Then, the solution is concentrated to dryness under reduced pressure, and the cyrstals thus obtained are washed with chloroform and then acetone to give the active ester, i.e. p-nitrophenyl 2,4-dihydroxypyrimidine-5-carboxylate (1.16 g). M.P. 298°-299° C (decomp.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][P:21](=[O:29])([O:25][CH:26]([CH3:28])[CH3:27])[O:22][CH2:23][CH3:24])=[CH:16][C:15]=1[O:30][CH3:31].C(N(C(C)C)CC)(C)C>ClC(Cl)C.C(O)(C)(C)C.[Cl-].[Cl-].[Zn+2]>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][P:21](=[O:29])([O:25][CH:26]([CH3:28])[CH3:27])[O:22][CH2:23][CH3:24])=[CH:16][C:15]=2[O:30][CH3:31])[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CCOP(=O)(Cc1ccc(N)c(OC)c1)OC(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2,4-dichloro-5-trifluoromethyl-pyrimidine (7.5 g, 34.7 mmol) in dichloroethane and t-butanol (1:1, 10 mL) was treated with ZnCl2 (1M solution in ether, 35 mL) and stirred for half an hour at RT. The reaction mixture was cooled to 0° C. and a solution of ethyl propan-2-yl [(4-amino-3-methoxyphenyl) methyl]phosphonate (Compound 72E, 5 g, 16.28 mmol) in dichloroethane and t-butanol (1:1, 10 mL) followed by diisopropylethylamine (6 mL, 34.7 mmol) were added drop wise while stirring was continued for 24 hrs. The resulting white precipitate was filtered. The solid was dissolved in dichloromethane, washed with water (2×50 mL), dried over magnesium sulfate, filtered and evaporated to give 6.3 g of pure required isomer. 1H NMR (400 MHz, CDCl3) δ 8.6 (s, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.04 (s, 1H), 7.04 (s, 1H), 6.89 (d, J=8 Hz, 1H), 4.73-4.76 (m, 1H), 4.08-4.11 (m, 2H), 3.95 (s, 3H), 3.23 (d, J=21 Hz, 2H), 1.24-1.33 (9H).
Reaction SMILES: [CH3:1][C:2]([CH:4]([CH2:10][CH:11]=[C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[Cl:21])[CH3:13])[C:5](OCC)=[O:6])=O.Cl.[NH2:23][C:24]([NH2:26])=[NH:25].[H-].[Na+]>C(O)C>[NH2:26][C:24]1[N:25]=[C:5]([OH:6])[C:4]([CH2:10][CH:11]=[C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[Cl:21])[CH3:13])=[C:2]([CH3:1])[N:23]=1
Reactant: CCOC(=O)C(CC=C(C)c1cc(Cl)ccc1Cl)C(C)=O
Reactant: N=C(N)N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CC(=CCc1c(C)nc(N)nc1O)c1cc(Cl)ccc1Cl
Reaction time: 18 h
Yield: 96.6 %

Procedure:
Under a nitrogen atmosphere, a solution of 5.0 grams (0.015 mole) of ethyl 2-methylcarbonyl-5-(2,5-dichlorophenyl)-4-hexenoate in 70 mL of ethanol is stirred, and 3.1 grams (0.032 mole) of guanidine hydrochloride is added. To this is then added dropwise a mixture of 1.5 grams (0.038 mole) of sodium hydride (60% in mineral oil) in 30 mL of ethanol. Upon completion of addition, the reaction mixture is warmed to reflux where it is stirred for about 18 hours. After this time the reaction mixture is cooled and concentrated under reduced pressure to a residual oil. The oil is stirred with 40 mL of aqueous 10% acetic acid, and the acid wash is decanted from the oil. This is repeated with an additional 40 mL of aqueous 10% acetic acid, and then with two 30 mL portions of water. The oil is dissolved in hot ethanol and the solution is placed in a refrigerator. The resultant solid is collected by filtration, yielding 4.7 grams of 2-amino-4-hydroxy-6-methyl-5-[3-(2,5-dichlorophenyl)-2-butenyl]pyrimidine, mp>250° C. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].ICl>CC(C)=O>[CH3:2][C:3]1([CH3:5])[O:6][C@H:5]2[C@@H:7]3[O:8][C:9]([CH3:11])([CH3:7])[O:10][C@:9]3([CH2:11][OH:12])[O:4][C@H:3]2[CH2:2][O:1]1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: ClI
Solvent: CC(C)=O
Product: CC1(C)OC[C@@H]2O[C@@]3(CO)OC(C)(C)O[C@H]3[C@@H]2O1
Temperature: 60 °C
Reaction time: 6 h
Yield: 150.9 %

Procedure:
To 200 ml of acetone were added 10.0 g of L-sorbose and 81.5 mg of iodine monochloride and the mixture was refluxed with stirring in a water bath at 60° C. for 6 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the cooling jacket. The reaction mixture was then subjected to an after-treatment similar to that described in Example 11 to give 10.9 g (75.8%) of 2,3:4,6-di-O-isopropylidene-L-sorbofuranose (purity ≥97%).
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]([O:19][CH2:20][CH3:21])=[CH:7][C:6]=1[N+:22]#[N:23])[CH3:3].[F:24][C:25]([F:36])([S:32]([OH:35])(=[O:34])=[O:33])[CH:26]([F:31])[C:27]([F:30])([F:29])[F:28]>O>[F:36][C:25]([F:24])([S:32]([O-:35])(=[O:33])=[O:34])[CH:26]([F:31])[C:27]([F:28])([F:30])[F:29].[CH2:2]([O:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:8]([O:19][CH2:20][CH3:21])=[CH:7][C:6]=1[N+:22]#[N:23])[CH3:3]
Reactant: O=S(=O)(O)C(F)(F)C(F)C(F)(F)F
Agent: CCOc1cc(Sc2ccc(C)cc2)c(OCC)cc1[N+]#N
Agent: [Cl-]
Solvent: O
Product: O=S(=O)([O-])C(F)(F)C(F)C(F)(F)F

Procedure:
50 g of 2,5-diethoxy-4-p-tolylmercaptobenzenediazonium chloride 1/2 ZnCl2 were dissolved in 1.5 1 of water. 20 ml of 1,1,2,3,3,3-hexafluoropropanesulfonic acid were then added dropwise to the filtered solution while stirring vigorously. The product, which precipitates as oily drops, solidified after a few minutes, was filtered off by suction, suspended in 1 1 of water while stirring vigorously, again filtered off by suction and, finally, dried. 56.5 g of 2,5-diethoxy-4-p-tolylmercaptobenzenediazonium 1,1,2,3,3,3-hexafluoropropanesulfonate were obtained as a fine, light brown powder.