Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]1=[O:19])(C)(C)C.[O:21]=[C:22]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:30][CH2:29]1)[CH2:23][CH2:24][C:25](O)=[O:26].CN(C)C=O.Cl.C(N=C=NCCCN(C)C)C>C(#N)C>[CH3:18][O:17][C:15]([CH2:14][C@@H:10]1[N:11]([C:25](=[O:26])[CH2:24][CH2:23][C:22](=[O:21])[N:28]2[CH2:29][CH2:30][N:31]([C:34]3[N:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[CH2:32][CH2:33]2)[CH2:12][CH2:13][N:8]([CH2:7][C:6]([OH:5])=[O:20])[C:9]1=[O:19])=[O:16]
Reactant: O=C(O)CCC(=O)N1CCN(c2ncccn2)CC1
Reactant: COC(=O)C[C@@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)O)CCN1C(=O)CCC(=O)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.1 %

Procedure:
To a suspension of (S)-(3-methoxycarbonylmethyl-2-oxopiperazin-1-yl)acetic acid tert-butyl ester (0.45 g) and 4-oxo-4-(4-pyrimidin-2-ylpiperazin-1-yl)butanoic acid (0.46 g) produced in Reference Example 4 in acetonitrile (20 ml) and dimethylformamide (2 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.36 g) and the suspension was stirred for 15 hours at room temperature. The reaction mixture was concentrated under reduced pressure. To the solution was added saturated brine and the solution was extracted with ethyl acetate. The extract was dried over Na2SO4 and was concentrated under reduced pressure. To the produced ester derivative was added trifluoroacetic acid (10 ml) and the mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by CHP-20 column chromatography (H2O→30% acetonitrile aqueous solution). The objected fraction was concentrated and subjected to lyophilization to give the titled compound (0.45 g) as a white amorphous powdery product.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:8]1[S:9][C:10]([C:13]([O:22][CH3:23])([O:20][CH3:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH3:26]I.[Cl-].[NH4+]>CS(C)=O>[CH3:1][S:2][C:3]([C:8]1[S:9][C:10]([C:13]([O:20][CH3:21])([O:22][CH3:23])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)([CH3:26])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CI
Reactant: COC(=O)C(SC)c1ccc(C(OC)(OC)c2ccccc2)s1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COC(=O)C(C)(SC)c1ccc(C(OC)(OC)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
Methyl α-methylthio[5-(α,α-dimethoxybenzyl)-2-thienyl]acetate (1.162 g) was dissolved in 6 ml of anhydrous dimethyl sulfoxide, and 150 mg (65% content) of sodium hydride was added. The mixture was stirred at room temperature for 30 minutes. Methyl iodide (0.30 ml) was added, and the mixture was stirred at room temperature for 15 minutes. An aqueous solution of ammonium chloride (0.5 g/30 ml) was added, and the mixture was extracted three times with 20 ml of diethyl ether. The extract was washed twice with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a column of Florisil using benzene as an eluent to afford 932 mg of methyl α-methylthio-α-[5-(α,α-dimethoxybenzyl)-2-thienyl]propionate in a yield of 77% as colorless crystals.
Reaction SMILES: C(OC([N:6]1[CH:11](OCC)[CH2:10][CH:9](Cl)[C:8]([C:16]2[CH:21]=[C:20]([C:22]([O:24]C)=[O:23])[C:19]([NH:26]C(=O)C)=[CH:18][C:17]=2[C:30]([F:33])([F:32])[F:31])=[N:7]1)=O)C.[OH-].[K+].O>CCO>[NH2:26][C:19]1[CH:18]=[C:17]([C:30]([F:31])([F:32])[F:33])[C:16]([C:8]2[N:7]=[N:6][CH:11]=[CH:10][CH:9]=2)=[CH:21][C:20]=1[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)N1N=C(c2cc(C(=O)OC)c(NC(C)=O)cc2C(F)(F)F)C(Cl)CC1OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(C(F)(F)F)c(-c2cccnn2)cc1C(=O)O
Temperature: 110 °C
Yield: 74.1 %

Procedure:
A solution of 3-(4-acetylamino-5-methoxycarbonyl-2-trifluoromethyl-phenyl)-4-chloro-6-ethoxy-5,6-dihydro-4H-pyridazine-1-carboxylic acid ethyl ester (400 mg, 0.81 mmol) in EtOH (20 mL) containing KOH (227 mg, 4.05 mmol) was heated to 110° C. for 18 h. Water (2 mL) was added and the reaction was heated to 110° C. for 8 h. The solution was poured onto ice/water/2 N aq HCl (2.5 mL) then extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4) and the solvent was removed in vacuo to give the title compound (170 mg, 74%). API-ES: m/z 284.0 [M+H]+, rt 2.78 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]([NH:15][C:16]2[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][C:17]=2[NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]2[N:24]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:17]3[CH:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:16]=3[N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(NC2CCCCC2)c(NC(=O)c2ccc(OCc3ccccc3)cc2)c1
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A solution of compound 11 (2.08 g, 4.89 mmol) in acetic acid (15 mL) was refluxed for 4.5 h. The reaction mixture was cooled to rt and concentrated on a rotary evaporator. The residue was dissolved in ethyl acetate and washed with saturated NaHCO3 (2×) and water (1×). The organic layer was dried (MgSO4) and concentrated on a rotary evaporator. The residue was recrystallized from hexane/ethyl acetate to give compound 12 as a tan solid (1.8 g, 90%). ESI-MS m/e 408.3 (M+1).
Reaction SMILES: [C@H:1]1([C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:4][C@@H:3]([C:5]([O:7]CC2C=CC=CC=2)=[O:6])[CH2:2]1>CO.[C].[Pd]>[C@H:1]1([C:15]([OH:17])=[O:16])[CH2:4][C@@H:3]([C:5]([OH:7])=[O:6])[CH2:2]1
Reactant: O=C(OCc1ccccc1)[C@H]1C[C@@H](C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@H]1C[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.8 %

Procedure:
To a solution of dibenzyl cis-cyclobutane-1,3-dicarboxylate (5.29 g, 16.31 mmol) in MeOH (100 mL) was added 10% palladium-carbon (500 mg, 50%, wet), and the mixture was stirred at room temperature for 5 hr under hydrogen atmosphere (1 atm). The catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The residue was solidified with hexane to give crude cis-cyclobutane-1,3-dicarboxylic acid (2.23 g, 15.47 mmol, 95%) as a white solid.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)(OCC)=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:30]([C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=O>C1COCC1>[CH3:17][O:16][C:14]([C:13]1[CH:12]=[CH:11][C:10](/[CH:9]=[CH:30]/[C@@H:32]2[CH2:36][CH2:35][CH2:34][N:33]2[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[CH:19][CH:18]=1)=[O:15]
Reactant: CCOP(=O)(Cc1ccc(C(=O)OC)cc1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Yield: 61.6 %

Procedure:
To a solution of the product of Example 149A (4.02 g, 14.05 mmol) dissolved in THF (50 mL) and cooled to −78° C. was added lithium bis(trimethylsilyl)amide (1.0M in THF, 12.05 mL, 12.05 mmol) dropwise and the resultant solution stirred at −78° C. for 1 additional hour. Afterwards a solution of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate (2.0 g, 10.04 mmol) in THF (20 mL) was added dropwise, the cooling bath was then removed and after the reaction reached room temperature it was maintained at this temperature for an additional 3 hours. The solution had EtOAc added to it and the mixture extracted with water. The organic extract was then dried, filtered, concentrated and purified by chromatography (silica gel, 10-50% EtOAc in hexanes) to afford 2.05 g (62%) of the title compound. MS (ESI) m/z 332 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:13]1[C:14](=[O:23])[O:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:12])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12>CN(C=O)C>[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH:63][C:10]([C:13]3[C:14](=[O:23])[O:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:12])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12
Reactant: O=C(O)c1cc2ccccc2oc1=O
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2ccccc2oc1=O
Temperature: 25 °C
Yield: 84.3 %

Procedure:
DIEA (50.4 μL, 0.29 mmol) was added to 3-carboxy-coumarin (50.0 mg, 0.26 mmol) and HATU (110.0 mg, 0.29 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (55.0 mg, 0.26 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 83.6 mg of product in 85% yield: LCMS (ESI) m/z 382 (MH+).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][O:8][C:9]2[N:14]=[C:13]([NH:15][C@H:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)[CH3:17])[N:12]=[C:11]([NH:25][C:26]3[CH:30]=[C:29]([O:31][CH:32]([CH3:34])[CH3:33])[NH:28][N:27]=3)[C:10]=2[F:35])[CH2:4][O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[F:35][C:10]1[C:9]([O:8][CH2:7][C@@H:5]([OH:6])[CH2:4][OH:3])=[N:14][C:13]([NH:15][C@H:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=2)[CH3:17])=[N:12][C:11]=1[NH:25][C:26]1[CH:30]=[C:29]([O:31][CH:32]([CH3:34])[CH3:33])[NH:28][N:27]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)nc(OC[C@@H]3COC(C)(C)O3)c2F)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)nc(OC[C@@H](O)CO)c2F)n[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.8 %

Procedure:
To a solution of 6-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-5-fluoro-N2-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (Example 25; 0.21 g, 0.415 mmol) in methanol (5 ml) was added a few drops of water and then p-toluenesulfonic acid (0.119 g, 0.623 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was subjected to silica gel chromatographic purification (by ISCO Combiflash with gradient EtOAc/hexanes) to afford the desired product as a white solid (0.075 g, yield 40%). LC-MS, 466 (M+1); 1H NMR δ 9.85 (br s, 1H), 8.30 (s, 1H), 7.60 (m, 1H), 7.30 (m, 1H), 5.25 (s, 1H), 4.80-4.90 (m, 2H), 4.60 (m, 2H), 4.0 (br s, 2H), 3.55 (m, 1H), 1.35 (d, 3H), 1.15 (d, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:13]1([C:2]2[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1N1CCNCC1
Yield: 59.8 %

Procedure:
68 g (0.3 mol) of 2,4,5-Trichloronitrobenzene and 77.4 g (0.9 mol) of piperazine were stirred in 100 ml of a dimethylformamide in the presence of 31 g of anhydrous potassium carbonate for one hour at a room temperature of 25° C. to 40° C. and then for one hour at 70° to 80° C. to obtain 49.5 g of 2-piperazino-4,5-dichloronitrobenzene. This compound was reacted with 2-ethylhexanoyl chloride in a solvent of acetonitrile in the presence of pyridine to obtain 2-[N-(2-hexanoyl)piperazino]-4,5-dichloronitrobenzene.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:13]#[N:14])[C:11]#[N:12].Cl.S1C2C=CC=CC=2[NH:18]C1=C(C#N)C(=N)[O-].N>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:13]#[N:14])[C:11]([NH2:18])=[NH:12]
Reactant: N#CC(C(=N)[O-])=C1Nc2ccccc2S1
Reactant: N#CC(C#N)=C1Nc2ccccc2S1
Agent: Cl
Agent: N
Product: N#CC(C(=N)N)=C1Nc2ccccc2S1

Procedure:
In the first step, the benzothiazole 10 [L is a leaving group, as in Reaction Scheme 4] reacts with malononitrile in the presence of a strong base, such as sodium ethoxide in ethanol, to give the 2-[benzothiazol-2(3H)-ylidene]malononitrile 17. Reaction of this nitrile in suspension in a polar solvent with gaseous hydrogen chloride gives the 2-[benzothiazol-2(3H)-ylidene]-2-cyanoacetimidate 18, and reaction of the imidate with ammonia gives the corresponding 2-[benzothiazol-2(3H)-ylidene]-2-cyanoacetamidine 19. Compound 19 is then reacted with a β-diketone or equivalent, such as 2,4-pentanedione or ethyl 3-oxo-4,4,4-trifluorobutyrate, to form the pyrimidine ring [substituents not shown] of the compound of formula 6, in the presence of a base such as sodium ethoxide in an aprotic solvent under strong (e.g. microwave) heating. Finally, the compound of formula 6 is hydrolyzed to a compound of formula 8, as in Reaction Scheme 1. If the order is reversed, so that the hydrolysis is performed before the coupling, the hydrolysis proceeds as in Reaction Scheme 1, and the coupling may take place under milder conditions.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:13]([C:14]2[CH2:18][CH2:17][O:16][N:15]=2)=[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7]>CO>[Cl:3][C:4]1[C:13]([C:14]2[CH2:18][CH2:17][O:16][N:15]=2)=[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOCC2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1C1=NOCC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A solution of 32.8 g of sodium hydroxide, dissolved in 330 ml of methanol, was slowly added dropwise to a mixture of 170.0 g (0.54 mol) of methyl 2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoate and 1 l of methanol at 40-45° C. The suspension was stirred for 5 hours at 50° C. After the solvent had been distilled off, the residue was taken up in 1.5 l of water, and the aqueous phase was extracted three times with ethyl acetate. The aqueous phase was acidified with hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were subsequently washed to neutrality with water, dried and concentrated. This gave 148.8 g (91% of theory) of 2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][N:13]3[CH3:18])[C:5]([C:19]([O:21]CC)=[O:20])=[CH:4][N:3]=1.[Li+].[OH-]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][N:13]3[CH3:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1Nc1cccc2c1ccn2C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1ccc2c(Nc3nc(Cl)ncc3C(=O)O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-chloro-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxylate (crude from step 1) in THF (4 mL), aq. 1N LiOH (2.25 mL, 2.25 mmol) was added. The mixture was stirred at room temperature overnight. Upon acidification of the mixture with 1N HCl, white solids precipitated out, which were collected, and dried on vacuum to give 2-chloro-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxylic acid (325 mg). MS 303.3, 305.3 (M+H, Cl pattern)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][O:7][C:6]=1[CH3:10])=[O:4].[Br:11]N1C(=O)CCC1=O>C1(C)C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([Br:11])[O:7][C:6]=1[CH3:10])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccoc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Br)oc1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
2-Methyl-furan-3-carboxylic acid methyl ester (2.0 g, 14.3 mmol) was dissolved in toluene followed by addition of 2,2′-azobis(2-methylpropionitrile) (10 mg, 0.06 mmol). The mixture was cooled to 0° C. by an ice-water bath followed by addition of N-bromosuccinimide (2.8 g, 15.7 mmol). Upon completion of the addition, the ice-water bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 5-bromo-2-methyl-furan-3-carboxylic acid methyl ester 53a (1.9 g, yield 61%) as a colourless oil.
Reaction SMILES: [BH4-].[Na+].C12CCC(CC1)C([CH2:11][OH:12])C2.[ClH:13].[CH3:14][N:15]([CH2:17][CH:18]1[CH:23]2[CH2:24][CH2:25][CH:20]([CH2:21][CH2:22]2)[CH:19]1[C:26]1[CH:31]=[CH:30][C:29]([N+]([O-])=O)=[CH:28][CH:27]=1)[CH3:16]>>[ClH:13].[CH3:14][N:15]([CH2:17][CH:18]1[CH:23]2[CH2:24][CH2:25][CH:20]([CH2:21][CH2:22]2)[CH:19]1[C:26]1[CH:31]=[CH:30][C:29]([O:12][CH3:11])=[CH:28][CH:27]=1)[CH3:16]
Reactant: OCC1CC2CCC1CC2
Reactant: CN(C)CC1C2CCC(CC2)C1c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(C2C3CCC(CC3)C2CN(C)C)cc1

Procedure:
Ethyl trans-2-p-methylphenylbicyclo[2,2,2]octane-3-carboxylate (0.025 mole) was added to lithium aluminium hydride (0.03 mole) in tetrahydrofuran (60 ml.) at 0°C. and after 3 hours, water was added and the mixture extracted with ether. Evaporation of the ether extract gave the corresponding bicyclo[2,2,2]oct-3-yl methanol as an oil. The latter was dissolved in dichloromethane (50 ml.) and methylamine (10 ml.) and methanesulphonyl chloride (3.6 g.) added at 0°C. After 2 hours, dimethylamine (25 ml. of a 33% solution in water) was added to the resultant methyl sulphonate and the mixture refluxed for 1 week. A large excess of water was added and the mixture extracted with ether. Evaporation of the dried ether extract yielded a solid which, on addition of ethanolic hydrochloric acid, gave N,N-dimethyl-2-p-methylphenylbicyclo[2,2,2]oct-3-yl methylamine hydrochloride as a white solid (2 g.) which had a satisfactory C, H, N and Cl analysis. Similarly, N,N-dimethyl-2-p-methoxyphenylbicyclo[2,2,2]oct-3-yl methylamine hydrochloride was prepared. Also by reduction of trans-2-p-nitrophenylbicyclo[2,2,2]octane-3-carboxyaldehyde, using sodium borohydride, followed by treatment of the resultant methanol as described above, N,N-dimethyl-2-p-nitrophenylbicyclo[2,2,2]oct-3-yl methylamine hydrochloride was obtained.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[C:19]([NH:29][CH2:30][C:31](O)=[O:32])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.CN(C=O)C>[CH2:22]([O:21][C:19]([NH:29][CH2:30][C:31]([C@@:7]1([N:6]2[CH:16]=[C:2]([F:1])[C:3](=[O:18])[NH:4][C:5]2=[O:17])[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9])=[O:32])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(NCC(=O)[C@@]1(n2cc(F)c(=O)[nH]c2=O)O[C@H](CO)[C@@H](O)[C@H]1O)OCc1ccccc1
Reaction time: 48 h
Yield: 26.5 %

Procedure:
5-Fluorouridine (0.300 g, 1.144 mmol, Sigma) was suspended in 4.0 mL of anhydrous tetrahydrofuran under nitrogen. Dry DMF (0.25 mL) was added. Slowly, the solid dissolved. Cbz glycine (0.239 g, 1.142 mmol, Aldrich), triphenylphosphine (0.300 g, 1.144 mmol), and DIAD (0.220 g, 1.088 mmol) were added. The yellow solution was stirred for 48 h. The solution was concentrated under reduced pressure and chromatographed eluting successively with 1:20 MeOH:CHCl3, 1:10 MeOH:CHCl3, then 1:5 MeOH:CHCl3 to provide 0.137 g (27%) of the title compound as a colorless oil. (The same reaction without the DMF as a cosolvent resulted in an isolated yield of only 13%): IR (TF) 3300 (br), 1710, 1670 cm-1 ; 1H NMR (300 MHz, methanol-d4) δ3.95 (s, 2H, NHCH2 CO), 4.05-4.20 (m, 3H, ribose H-2',3', 4'), 4.35-4.50 (m, 2H, ribose H-5'), 5.09 (s, 2H, benzylic H), 5.81 (m, 1 H, ribose H-1'), 7.25-7.40 (m, 5H, aromatic H), 7.83 (m, 1 H, vinylic H); 13C NMR (75 MHz, methanol-d4) δ43.41, 64.90, 67.82, 70.65, 74.99, 82.85, 91.43, 125.95 (d, J=34.7 Hz, C 4), 128.77, 128.97, 129.40, 137.86, 141.74 (d, J=234.3 Hz, C5), 150.74, 158.96, 159.24 (d, J=26.2, C4), 171.55; TLC (methanol-chloroform, 1:5) Rf =0.35; exact MS (El) calcd for C19H20N3O9F: m/z 453.1184. Found: m/z 453.1174.
Reaction SMILES: C([O:3][C@@H:4]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@H:6]([CH2:7][C:8](=[O:38])[C@@H:9]3[C@@H:29]2[CH2:28][C@H:27]([O:34]C=O)[C@@:26]2([CH3:37])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:25])[CH2:15][CH2:16][C:17]([NH:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])=[O:18])[CH2:5]1)=O.[OH-].[K+]>>[OH:3][C@@H:4]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@H:6]([CH2:7][C:8](=[O:38])[C@@H:9]3[C@@H:29]2[CH2:28][C@H:27]([OH:34])[C@@:26]2([CH3:37])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:25])[CH2:15][CH2:16][C:17]([NH:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])=[O:18])[CH2:5]1
Reactant: C[C@H](CCC(=O)NC(C)(C)CO)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](OC=O)CC[C@]4(C)[C@H]3C[C@H](OC=O)[C@]12C
Agent: [K+]
Agent: [OH-]
Product: C[C@H](CCC(=O)NC(C)(C)CO)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C

Procedure:
The diformyl amide obtained in Example 2 (2 g) was hydrolyzed with 5% methanolic KOH (reflux, 1 hr). Dilution with water and extraction with ethyl acetate gave chromatographically pure 2-(3α,12α-dihydroxy-7-oxo-5β-cholan-24-amido)-2-methyl-1-propanol which was recrystallized from ethyl acetate (colorless prisms), melting at 229°-231° C. PMR (δ ppm): 0.70 (3H, s, 18--CH3), 1.09 (3H, d, J=6 Hz, 21--CH3), 1.16 (3H, s, 19--CH3), 1.52 (6H, s, --C(CH3)2 --), 3.65 (1H, m, 3β--H), 3.86 (2H, s, --CH2OH), 4.09 (1H, m, 12β--H), 7.54 (1H, s, --NH--).
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C@@H:21]4[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)(Cl)Cl>[CH3:31][S:32]([O:28][CH2:27][C@H:24]1[CH2:23][CH2:22][C@@H:21]([N:19]2[CH:20]=[C:16]([C:15]3[C:10]4[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:30])([CH3:29])[CH3:1])[C:11]=4[N:12]=[CH:13][N:14]=3)[CH:17]=[N:18]2)[CH2:26][CH2:25]1)(=[O:34])=[O:33]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](CO)CC4)c3)ncnc21
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](COS(C)(=O)=O)CC4)c3)ncnc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethanol was dissolved in chloroform (3.00 mL) and was cooled to 0° C. To the reaction was added TEA (0.10 mL, 0.00072 mol) and methanesulfonyl chloride (0.05 mL, 0.0006 mol) and this mixture was stirred at 0° C. for 2 hours at which time LCMS analysis showed mainly the product present in the mixture. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. LC/MS (M+H)+: 506