Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][CH2:46][NH2:47])[CH2:40][CH2:39]1.C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:47][CH2:46][CH2:45][CH2:44][N:41]3[CH2:40][CH2:39][N:38]([CH3:37])[CH2:43][CH2:42]3)=[O:29])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: CN1CCN(CCCN)CC1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)NCCCN4CCN(C)CC4)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl -1H-pyrrole-3-carboxylic acid and 3-(4-methylpiperazin-1-yl)propylamine using diethyl cyanophosphonate as a coupling reagent Mass: 648.20 (M+H).
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[S:9][C:8]2[CH2:10][CH2:11][N:12]([CH:14]([C:22]([CH:24]3[CH2:26][CH2:25]3)=[O:23])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[CH2:13][C:7]=2[CH:6]=1)=[O:3].[P:27](=[O:31])([OH:30])([OH:29])[OH:28]>C(OC)(=O)C>[CH3:1][C:2]([O:4][C:5]1[S:9][C:8]2[CH2:10][CH2:11][N:12]([CH:14]([C:22]([CH:24]3[CH2:26][CH2:25]3)=[O:23])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[CH2:13][C:7]=2[CH:6]=1)=[O:3].[P:27]([O-:31])([O-:30])([O-:29])=[O:28]
Reactant: O=P(O)(O)O
Agent: CC(=O)Oc1cc2c(s1)CCN(C(C(=O)C1CC1)c1ccccc1F)C2
Solvent: COC(C)=O
Product: O=P([O-])([O-])[O-]
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of prasugrel base (1.006 g) in 21.67 ml of methyl acetate/7.7% ethanol at 20-25° C., a dropwise solution of 99% phosphoric acid (329.9 mg) in 2 ml of methyl acetate was added. Crystallization occurred within 30 minutes. After 3 hours at 20-25° C., the suspension was cooled to 0-5° C. and stirred for about 2 hours at that temperature. The obtained crystals were filtered, washed with 4 ml of methyl acetate and dried at 40° C./vacuum for about 1.5 hours. Prasugrel phosphate Form P1 (0.883 g) was obtained.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.[CH3:9][C:10]([CH3:14])=[CH:11][CH:12]=[O:13]>C1COCC1>[OH:13][CH:12]([CH:11]=[C:10]([CH3:14])[CH3:9])[CH2:2][C:1]#[N:3]
Reactant: CC(C)=CC=O
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)=CC(O)CC#N
Temperature: -78 °C
Reaction time: 2 h
Yield: 108 %

Procedure:
Acetonitrile (11.5 mL, 219 mmol) in THF (300 mL) was cooled to −78° C. and n-BuLi (2.5 M in hexanes, 96 mL) was added slowly. The mixture was stirred at −78° C. for 2 h. 3-Methyl-2-butenal (25 mL, 262 mmol) dissolved in dry THF (50 mL) was added slowly and after 15 min the reaction was quenched with HCl (3N, 175 mL). After evaporation of the majority of solvents, the residue was extracted twice with diethylether. The combined ether extracts were dried (sodium sulfate), filtered and concentrated to give crude 3-hydroxy-5-methyl-hex-4-enenitrile (29.6 g, 100%) as a yellow oil.
Reaction SMILES: CC(C)CC=[C:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:6][O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH2:10][CH2:9]1.[O:32]=[O+][O-]>ClCCl>[O:32]=[C:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:6][O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH2:10][CH2:9]1
Reactant: O=[O+][O-]
Reactant: CC(C)CC=C(CO[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1)c1ccccc1
Solvent: ClCCl
Product: O=C(CO[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1)c1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of 2 g of trans-2-[4-(5-methyl-2-phenyl-hex-2-enyloxy)-cyclohexyl]-isoindole-1,3-dione in 100 mL of dichloromethane cooled to −78° C. was dispersed a stream of ozone from an ozone generator until a blue color persisted. The excess ozone was purged with nitrogen until the blue color dissipated, and 5 mL of methyl sulfide was added. After warming to room temperature over 30 min, the solution was concentrated under reduced pressure. Chromatography over silica gel eluting with a gradient of 2%-30% ethyl acetate in hexane gave 1.8 g of product as a white crystalline solid: 1H NMR (400 MHz, CDCl3) 8.0 (d, 2H), 7.8 (m, 2H), 7.6 (t, 1H), 7.5 (t, 2H), 4.8 (s, 2H), 4.18 (m, 1H), 3.5 (m, 1H), 2.35 and 2.25 (overlapping dd and d, 4H), 1.8 (d, 2H), 1.5 (dd, 2H).
Reaction SMILES: C(OC([C:6]1[N:10]([OH:11])[C:9]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:8]=2[N:7]=1)=O)C.[ClH:19]>>[ClH:19].[N+:16]([C:13]1[CH:14]=[CH:15][C:8]2[N:7]=[CH:6][N:10]([OH:11])[C:9]=2[CH:12]=1)([O-:18])=[O:17]
Reactant: CCOC(=O)c1nc2ccc([N+](=O)[O-])cc2n1O
Agent: Cl
Product: O=[N+]([O-])c1ccc2ncn(O)c2c1
Temperature: 25 °C

Procedure:
A mixture of 1-hydroxy-6-nitro-1H-benzoimidazole-2-carboxylic acid ethyl ester (3) (5 g, 20 mmol) and concentrated HCl (100 mL) was refluxed for 3 hours. After cooling the mixture to room temperature, the resulting solid was collected by filtration. Yield 1.9 g (44%) of the HCl salt.
Reaction SMILES: Cl.[N:2]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11](N)=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=2)[CH:6]=[CH:5][N:4]=[CH:3]1.N([O-])=O.[Na+].[Cu][C:29]#[N:30].[C-]#N.[Na+].C([O-])([O-])=O.[Na+].[Na+].[NH4+].[OH-]>ClC(Cl)Cl.O>[N:2]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:29]#[N:30])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=2)[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1[N+](=O)[O-]
Reactant: N#C[Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(C(c2ccccc2)n2ccnc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
To 200 ml of cooled (0°-5° C.) HCl 5N were added 19.3 parts of intermediate 51, namely 4-[(1H-imidazol-1-yl)phenylmethyl]-2-nitrobenzenamine, while stirring. When a homogeneous solution was obtained, there was added dropwise a solution of 4.75 parts of sodium nitrite in 40 parts of water at 0°-5° C. Stirring at 0°-5° C. was continued for 1/2 hour and then the mixture was added dropwise to a cooled (0°-5° C.) solution of 5.8 parts of copper(I)cyanide, 6.42 parts of sodium cyanide and 127.1 parts of Na2CO3 (aq.) in a mixture of 700 parts of water and 298 parts of trichloromethane. The whole was left overnight to warm up to room temperature and then there were added NH4OH (aq.) and 447 parts of trichloromethane. After heating at 50° C. for 15 min. and subsequent cooling, the organic layer was separated, dried, filtered and evaporated. The residue was purified twice by column chromatography (silica gel; CHCl3 /CH3OH (NH3) 97.5:2.5; CHCl3 /CH3OH 97.5:2.5). The eluent of the desired fractions was evaporated, yielding 14.6 parts (73.2%) of 4-[(1H-imidazol-1-yl)phenylmethyl]-2-nitrobenzonitrile (interm. 52).
Reaction SMILES: [C:1]([O:6][C@H:7]([C:9]1[N:14]=[C:13](O)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.S(Cl)(C)(=O)=O.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(Cl)Cl>[C:1]([O:6][C@H:7]([C:9]1[N:14]=[C:13]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: C1CNCCN1
Reactant: CCCC(=O)O[C@@H](C)c1nccc(O)n1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)O[C@@H](C)c1nccc(N2CCNCC2)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
To an ice cold solution of 1-(S)-(4-hydroxy-pyrimidin-2-yl)-ethyl butyrate (0.42 g, 2.0 mmol) and triethylamine (0.20 g, 2.2 mmol) in methylene chloride (10 mL) was added mesyl chloride (0.25 g, 2.1 mmol) dropwise and stirred for 1.5 h. The mixture was washed successively with saturated bicarbonate and water, and the organic layer dried over anhydrous magnesium sulfate. It was, filtered and evaporated to give 1-(S)-(4-methanesulfonyloxy-pyrimidin-2-yl)-ethyl as an oil. The oil was dissolved in tetahydrofuran (10 mL), and to the solution was added piperazine (0.69 g, 8.0 mmol) and stirred at ambient temperature for 4 hr. The mixture was filtered and the filtrate was concentrated to obtain a crude product which was purified by flash chromatography (9:1 methylene chloride/methanol) to give the title compound as a oil 0.50 g (90%). 1H NMR (CDCl3, 300 MHz) δ0.95 (t, 3H), 1.51 (d, 3H) 1.68 (m, 2), 2.66 (t, 2H), 2.83 (m, 4H), 3.63 (m, 4H), 5.54 (q, 1H), 6.38 (d, 1H), 8.24 (d, 1H); MS (Cl) 251 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:9]=[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:11]([Cl:14])=[N:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1.[CH3:25][O:26][CH2:27][C:28](Cl)=[O:29]>>[C:19]1([S:16]([NH:15][C:10]2[CH:9]=[C:8]([C:4]3[S:3][C:2]([NH:1][C:28](=[O:29])[CH2:27][O:26][CH3:25])=[N:6][C:5]=3[CH3:7])[CH:13]=[N:12][C:11]=2[Cl:14])(=[O:18])=[O:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1nc(N)sc1-c1cnc(Cl)c(NS(=O)(=O)c2ccccc2)c1
Reactant: COCC(=O)Cl
Product: COCC(=O)Nc1nc(C)c(-c2cnc(Cl)c(NS(=O)(=O)c3ccccc3)c2)s1

Procedure:
Using an analogous method to that described in Example 51, N-[5-(2-amino-4-methyl-1,3-thiazol-5-yl)-2-chloropyridin-3-yl]benzenesulfonamide was reacted with 2-methoxyacetyl chloride. The reaction product was purified by preparative HPLC (Method A) to give the title product (retention time 7.0 minutes); 1H NMR Spectrum: (DMSOd6+D2O) 8.59 (1H, d); 8.14 (1H, d); 8.03 (2H, d); 7.83 (1H, t); 7.70 (2H, t); 4.01 (1H, d); 3.72 (1H, d); 3.18 (3H, s); 2.27 (3H, s); Mass Spectrum: M+H+ 453.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24](O)=[O:25])=[CH:9][N:8]=1)[CH2:2]2.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([NH:33][CH2:32][C:31]3[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=3)=[O:25])=[CH:9][N:8]=1)[CH2:2]2
Reactant: NCc1ccc(F)cc1
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCc2ccc(F)cc2)cc1Cl
Reaction time: 18 h
Yield: 15.6 %

Procedure:
In THF (10 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-pyrimidine-5-carboxylic acid (150 mg, 0.40 mmol), 4-fluorobenzylamine (56 mg, 0.45 mmol) and triethylamine (101 mg, 1 mmol). The reaction mixture was cooled in an ice bath and HATU (266 mg, 0.70 mmol) was added. The reaction was conducted at ambient temperature for 18 h. The reaction mixture was concentrated, followed by addition of water and extraction with ethyl acetate. The organic phase was dried, concentrated, and purified by silica gel column chromatography (DCM/methanol=20/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-(4-fluorobenzyl)pyrimidine-5-formamide (30 mg, 16% yield).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([NH:8][C:9]([NH:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[N:15]=[CH:14][N:13]=1)=[O:10])([CH3:7])[CH3:6])C.[Li+].[OH-]>C1COCC1.O>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:9](=[O:10])[NH:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:26])=[O:3])[CH:17]=1
Reactant: CCOC(=O)C(C)(C)NC(=O)Nc1cc(-c2ccccc2OC)ncn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1-c1cc(NC(=O)NC(C)(C)C(=O)O)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-ureido}-2-methyl-propionic acid ethyl ester (LVI) (370 mg, 1.03 mmol) in a mixture of THF and water (1:1) was added a solution of LiOH (87.0 mg, 2.06 mmol) in water at ice bath temperature over 10 min and then allowed to stir for two hours at room temperature. THF was evaporated and the aqueous solution was acidified with 2N HCl. This aqueous phase was then extracted with ethyl acetate (2×100 ml), the combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in a vacuum rotavapor to afford 2-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-ureido}-2-methyl-propionic acid as a white solid. Yield: 235 mg, 69.1%.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[CH:13]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Oc2nc(Cl)ncc2Br)c1
Temperature: 0 °C
Reaction time: 7 h
Yield: 91.2 %

Procedure:
To a mixture of 5-bromo-2,4-dichloropyrimidine (300 mg, 1.32 mmol) and 3-methoxyphenol (163.4 mg, 1.32 mmol) in DMF (5 mL) at 0° C. was added K2CO3 (363 mg, 2.63 mmol). The resulting mixture was stirred at 0° C. for 7 h. The reaction was quenched with H2O and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with H2O (5×30 mL), brine, dried and concentrated. The crude product was purified by preparative TLC using 100% of CH2Cl2 as eluting solvent to afford the title compound (380 mg, 92%). 1HNMR (CDCl3, 400 MHz): 8.57 (s, 1H), 7.37 (dd, 1H), 6.88-6.84 (dd, 1H), 6.72-6.79 (dd+d, 2H), 3.83 (s, 3H). MS (ESI) m/z: Found: 315.0 (M++1), 317.0 (M++3); Calc. 314.0 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:18][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Br
Reactant: OCc1ccc(Cl)cc1
Product: O=[N+]([O-])c1ccncc1OCc1ccc(Cl)cc1
Yield: 25.3 %

Procedure:
In accordance with the same procedures as in Steps 3 and 4 of Preparation 1, except for using 3-bromo-4-nitropyridin-N-oxide prepared in Step 2 of Preparation 1 and 4-chlorobenzyl alcohol, the titled compound was obtained as a white solid. (Yield: 25.3% )
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]#[CH:21])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:22]([C@@H:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)[CH3:26])=[N+:23]=[N-:24].[Na].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.O>O1CCOCC1.C(O)(C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]2[N:24]=[N:23][N:22]([C@@H:25]([C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=3)[CH3:26])[CH:21]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1ccc([C@@H](C)N=[N+]=[N-])cc1
Reactant: C#CC[C@@H]1C(=O)NC=CN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc([C@@H](C)n2cc(C[C@@H]3C(=O)NC=CN3S(=O)(=O)c3ccc(Cl)c(Cl)c3)nn2)cc1
Reaction time: 0.08 h

Procedure:
To a solution of (R)-4-(3,4-dichlorobenzenesulfonyl)-3-(prop-2-ynyl)-3,4-dihydro-pyrazin-2(1H)-one (1.46 g, 4.24 mmol) and (R)-methyl 4-(1-azidoethyl)benzoate (0.870 g, 4.24 mmol) in dioxane (80 mL) and tert-butanol (120 mL) were added CuSO4.5H2O (1.11 g, 4.46 mmol in 8.0 mL H2O) and sodium-L-ascorbate (0.880 g, 4.44 mmol in 8.0 mL H2O). After 5 min, H2O (40 mL) was added and the reaction mixture was stirred for 16 h. The solvent was concentrated to approximately 40 mL under reduced pressure and diluted with 200 mL EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (1×100 mL). The extracts were washed with 5% NaHCO3 (200 mL×2), brine (200 mL×2), dried over Na2SO4 and concentrated under reduced pressure. The crude product was chromatographed on silica (100% CH2Cl2 to 10% MeOH in CH2Cl2) to yield the title compound.
Reaction SMILES: [F:1][CH:2]([F:12])[CH2:3][N:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[N:5]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl:23]C(Cl)(Cl)C(Cl)(Cl)Cl.[Cl-].[NH4+]>C1COCC1.O>[Cl:23][C:8]1[N:4]([CH2:3][CH:2]([F:1])[F:12])[N:5]=[CH:6][C:7]=1[N+:9]([O-:11])=[O:10]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnn(CC(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cnn(CC(F)F)c1Cl
Temperature: -70 °C
Reaction time: 0.67 h
Yield: 40.4 %

Procedure:
To a stirred solution of 1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole (1.0 g, 5.13 mmol) in dry THF (20 mL) cooled to −70° C. was added dropwise a solution of lithium hexamethyldisilazide (1 M in THF, 8.47 mL, 8.47 mmol). After stirring at −70° C. for 40 min, the reaction mixture was allowed to warm to −55° C. over 20 min. After recooling to −70° C., a solution of perchloroethane (1.74 g, 7.34 mmol) in THF (10 mL) was added slowly and the reaction mixture was stirred at −70° C. for 1.5 hr. Saturated aqueous ammonium chloride solution (30 mL) was added followed by water (15 mL) and the mixture was extracted with EtOAc (3×100 mL). The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure. Purification of the residue by silica gel column chromatography (0-100% EtOAc/isohexane) gave 5-chloro-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole as an off-white solid (438 mg, 37%). 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 6.18 (tt, J=54.8, 4.2 Hz, 1H), 4.58 (td, J=12.8, 4.2 Hz, 2H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([O:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][C@H:27]([OH:31])[CH2:26]4)=[N:21][CH:20]=[N:19][C:18]=3[O:17][C:16]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:11][CH:10]=1.[C:38](#[N:41])[CH:39]=[CH2:40]>C1COCC1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:23]3[C:22]([O:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][C@H:27]([O:31][CH2:40][CH2:39][C:38]#[N:41])[CH2:26]4)=[N:21][CH:20]=[N:19][C:18]=3[O:17][C:16]=2[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:13][CH:14]=1
Reactant: C=CC#N
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@@H]4CCC[C@H](O)C4)c23)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@@H]4CCC[C@H](OCCC#N)C4)c23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add a solution of 10 mg of potassium tert-butoxide in 0.5 ml of THF dropwise to a solution of 150 mg (0.36 mmol) of (+/−)-cis-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclohexanol in 1 ml of acrylonitrile. Stir the reaction mixture with exclusion of light at RT for approx. 2 h. After dilution with dichloromethane, wash successively with 1N hydrochloric acid, satd. sodium hydrogencarbonate solution and satd. sodium chloride solution, and concentrate the organic phase under reduced pressure. After purification of the residue by means of preparative RP-HPLC (eluent: acetonitrile/water gradient), 136.9 mg of the target product are obtained (81% of theory).
Reaction SMILES: [CH:1]12[CH:7]([CH2:8][CH2:9][NH:10][C:11]([C:13]3[S:17][C:16]([O:18][CH:19]4OC(C)(C)N(C(C)(C)C)[C:20]4=[CH2:30])=[N:15][CH:14]=3)=[O:12])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[OH-:31].[Na+]>C(OCC)(=O)C>[CH:1]12[CH:7]([CH2:8][CH2:9][NH:10][C:11]([C:13]3[S:17][C:16]([O:18][CH2:19][CH:20]([OH:31])[CH3:30])=[N:15][CH:14]=3)=[O:12])[CH:4]([CH2:3][CH2:2]1)[CH2:5][CH2:6]2
Reactant: C=C1C(Oc2ncc(C(=O)NCCC3C4CCC3CC4)s2)OC(C)(C)N1C(C)(C)C
Reactant: [OH-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(O)COc1ncc(C(=O)NCCC2C3CCC2CC3)s1
Reaction time: 0.5 h

Procedure:
This example illustrates methods of converting the compounds of formula E into the compounds of formula C. In this example 1 g. of 5-(5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]thiazol-2-yloxy)-methylene-N-t-butyl-2,2-dimethyloxazolidine is dissolved in 50 ml. of ethyl acetate and this solution is treated with aqueous 5% sodium hydroxide (20 ml.) at 20° C. The mixture is allowed to stand for 0.5 hours, washed three times with water, dried over magnesium sulfate and then evaporated to dryness affording 1-t-butyl-3-(5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]thiazol-2-yloxy-propan-2-ol.
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-])=O)=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)=[CH:11][C:10]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)C1C=CC=CC=1>[Pd]>[NH2:24][C:20]1[CH:21]=[C:22]([CH3:23])[C:14]([O:13][C:12]2[CH:27]=[CH:28][C:9]([OH:8])=[C:10]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[CH:11]=2)=[C:15]2[C:19]=1[CH2:18][CH2:17][CH2:16]2
Reactant: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(Cc3ccc(F)cc3)c1)CCC2
Agent: [Pd]
Product: Cc1cc(N)c2c(c1Oc1ccc(O)c(Cc3ccc(F)cc3)c1)CCC2

Procedure:
The title compound was prepared in a similar manner to those described in Reference Example 34 using 4-[4-benzyloxy-3-(4-fluorobenzyl)phenoxy]-5-methyl-7-nitroindane instead of 4-(4-benzyloxy-3-iodophenoxy)-5-methyl-7-nitroindane and using Pd/C instead of Pt/C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:25][C:26](OC(C)=O)=[O:27]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[CH2:5][N:4]([C:26](=[O:27])[CH3:25])[CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CNCc2cc([N+](=O)[O-])ccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1Cc2cc([N+](=O)[O-])ccc2C(C)(C)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-(dimethylamino)pyridine (0.125 g, 1.02 mmol), 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydro-isoquinoline (0.21 g, 1.02 mmol), DIEA (0.53 mL, 3.06 mmol), and Ac2O (0.19 mL, 2.04 mmol) in 7 mL of CH2Cl2 was stirred at RT under N2 for two days. The volatiles were removed under vacuum. The residue was partitioned between EtOAc and brine, and the organic portion was dried with Na2SO4, filtered, and concentrated. The crude material was purified by flash column chromatography (2-3% MeOH in CH2Cl2), to yield the desired compound as a light yellowish solid. MS (ES+): 249.3 (M+H)+. Calc'd for C13H16N2O3-248.28.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]([CH2:15][CH2:16][C:17](Cl)=[O:18])([O:12][CH2:13][CH3:14])=[O:11].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH2:13]([O:12][C:10](=[O:11])[CH2:15][CH2:16][C:17](=[O:18])[C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[CH3:14]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: COc1ccc(C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CCC(=O)c1cc(C)ccc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of p-methylanisole (100 g, 0.81 mole), β-carbethoxypropionylchloride (96%, 230 g, 1.22 mole), and CH2Cl2 (800 mL) was stirred under N2 at 0° as AlCl3 (131 g, 0.94 mole) was added over 2 hours. The reaction mixture was stirred at room temperature for 20 hours, then was poured onto ice and the layers were separated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, saturated aqueous NaHCO3, 1N KOH, H2O, saturated aqueous NaCl, dried (MgSO4), filtered, and evaporated (in-vacuo) to obtain a yellow oil.