Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([SH:35])=[CH:31][CH:30]=1>CCCCCC.C(OCC)(=O)C.CN1C(=O)CCC1>[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([S:35][C:2]2[CH:3]=[C:4]([C:8]3([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:31][CH:30]=1
Reactant: Nc1ccc(S)cc1
Reactant: N#CC1(c2cccc(Br)c2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCCCCC
Product: N#CC1(c2cccc(Sc3ccc(N)cc3)c2)CCOCC1
Temperature: 130 °C

Procedure:
A mixture of 4-(3-bromophenyl)tetrahydro-2H-pyran-4-carbonitrile (5.0 g, 18.79 mmol) (example 3), sodium carbonate (13.94 g, 131.58 mmol) and cesium carbonate (9.18 g, 28.19 mmol) was evacuated under vacuum for about 15 minutes. N-methyl pyrrolidinone (35 mL) and 4-aminothiophenol (2.8 g, 22.57 mmol) were added to this mixture under nitrogen atmosphere and heated at about 130° C. for about 15 hours. The reaction mixture was cooled to room temperature, poured over ice water and stirred. The mixture was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulphate, filtered and the solvent evaporated under vacuum to afford a brownish residue. Column chromatography over silica gel using ethyl acetate and hexane (3:2) yielded the title compound as a light yellow solid. Yield: 6.2 g.
Reaction SMILES: [OH-].[K+].[CH2:3]([S:6][CH:7]1[N:10]([CH2:11][C:12]([O:14]C)=[O:13])[C:9](=[O:16])[CH2:8]1)[CH:4]=[CH2:5].Cl>C(O)C.O>[CH2:3]([S:6][CH:7]1[N:10]([CH2:11][C:12]([OH:14])=[O:13])[C:9](=[O:16])[CH2:8]1)[CH:4]=[CH2:5]
Reactant: C=CCSC1CC(=O)N1CC(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCSC1CC(=O)N1CC(=O)O
Temperature: 25 °C

Procedure:
2.34 g of potassium hydroxide dissolved in a mixture of 285 ml of ethanol and 15 ml of water was added to 6.0 g of methyl 2-(4-allylthioazetidin-2-on-1-yl)acetate with stirring at room temperature. The solution was poured into 720 ml 1M hydrochloric acid, extracted into dichloromethane (2×650 ml), the organic layer extracted with saturated sodium bicarbonate solution and the aqueous phase acidified to pH 1 with 5M hydrochloric acid. This solution was extracted into dichloromethane (5×650 ml), dried with MgSO4 and evaporated to leave a colourless oil. Yield: 5.37 g (96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].[H-].[Na+].O([CH2:21][P:22]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])=[O:23])S(C(F)(F)F)(=O)=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][O:7][CH2:21][P:22](=[O:23])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(CO)c1
Reactant: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=O)(COCc1cccc(OC)c1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-methoxybenzyl alcohol (1 mmol) and sodium hydride (1.5 mmol) in 5 mL DMF was stirred at rt for 1 h and then added via cannula to a solution of diethylphosphonomethyl triflate (1 mmol) in 5 mL of DMF and the resulting mixture stirred at rt for 16 h. Extraction and chromatography provided diethyl 3-methoxyphenylmethoxymethylphosphonate as an oil.
Reaction SMILES: [O:1]=[C:2]([CH2:8][N:9]1[CH:12](SC)[CH2:11][C:10]1=[O:15])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Cl:16]Cl>C(Cl)(Cl)(Cl)Cl>[O:1]=[C:2]([CH2:8][N:9]1[CH:12]([Cl:16])[CH2:11][C:10]1=[O:15])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(=O)CN1C(=O)CC1SC
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)CC(=O)CN1C(=O)CC1Cl
Temperature: 25 °C

Procedure:
Methyl 3-oxo-4-(2-oxo-4-methylthioazetidin-1-yl)butyrate (300 mg) was dissolved in dry carbon tetrachloride (10 ml) and the solution was stirred and ice-cooled with exclusion of moisture while chlorine (90 mg) in dry carbon tetrachloride (1.5 ml) was added in one portion. After addition, the mixture was warmed to room temperature and stirred for 3 minutes. The solvent was then evaporated under reduced pressure. The residue was dissolved in fresh carbon tetrachloride (5 ml) and again the solvent was removed under reduced pressure. The title compound was thus obtained as a yellow gum (300 mg).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[CH:7][C:6]=1[F:13])=O.[NH2:14][C:15]([NH2:17])=[S:16]>CCO>[F:13][C:6]1[CH:7]=[C:8]([F:12])[CH:9]=[C:10]([F:11])[C:5]=1[C:3]1[N:14]=[C:15]([NH2:17])[S:16][CH:2]=1
Reactant: O=C(CCl)c1c(F)cc(F)cc1F
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc(-c2c(F)cc(F)cc2F)cs1
Yield: 97 %

Procedure:
A mixture of 2-chloro-1-(2,4,6-trifluorophenyl)ethanone (9.04 g, 43.5 mmol) and thiourea (3.51 g, 46.1 mmol) in 95% EtOH (50 mL) was heated at reflux overnight. The solution was concentrated and mixed with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The solids were filtered and dried under vacuum to give 4-(2,4,6-trifluorophenyl)thiazol-2-amine (9.71 g) as pink-white solids in 97% yield: 1H NMR (500 MHz, DMSO-d6) δ 7.26-7.22 (m, 2 H), 7.09 (s, 2 H), 6.77 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4].Cl.[O-:14][C:15]#[N:16].[K+]>>[CH3:1][C:2]([CH3:12])([CH3:11])[CH:3]([NH:4][C:15]([NH2:16])=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)C(N)c1ccccc1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Product: CC(C)(C)C(NC(N)=O)c1ccccc1

Procedure:
In a manner simnilar to that described for Intermediate 16B, 2,2-dimethyl-1-phenylpropan-1-amine was reacted with HCl and potassium cyanate to provide 1-(2,2-dimethyl-1-phenylpropyl)urea. MS: [M+H]+ m/z 207.
Reaction SMILES: [BH4-].[Li+].[CH2:3]([N:10]1[C:14](=[O:15])[CH2:13][CH:12]([C:16](OC)=[O:17])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(=O)C>C1COCC1>[CH2:3]([N:10]1[CH2:11][CH:12]([CH2:16][OH:17])[CH2:13][C:14]1=[O:15])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1CC(CO)CN1Cc1ccccc1
Temperature: 10 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
200 ml of a 2M solution of lithium borohydride in THF were added dropwise to a stirred solution of 100 g of methyl 1-benzyl-5-oxo-3-pyrrolidinecarboxylate in 600 ml of THF under a nitrogen atmosphere. After 3 hours, the mixture was cooled to 10° C. and treated with 200 ml of 50% aqueous acetic acid. The solvents were removed under reduced pressure and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic extracts were dried and evaporated to dryness to give 92 g of 1-benzyl-4-(hydroxymethyl)-2-pyrrolidinone. This was dissolved in 200 ml of pyridine and the solution was treated with 95 g p-toluenesulphonyl chloride. The solution obtained was stirred for 18 hours and then concentrated. The residue was partitioned between dichloromethane and 2M hydrochloric acid. The organic phase was washed with water, dried and evaporated to dryness. Crystallization of the residue from diethyl ether/n-hexane gave 115 g of 1-benzyl-4-(p-toluenesulphonyloxy)-2-pyrrolidinone of melting point 83°-84° C.
Reaction SMILES: C(OC(N=[C:7]=[S:8])=O)C.[O:9]([C:16]1[N:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]2[N:25]=[CH:26][NH:27][C:28]=2[C:29]([NH2:31])=[O:30])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl>[O:9]([C:16]1[N:21]=[CH:20][C:19]([CH2:22][N:23]2[C:24]3[N:25]=[CH:26][NH:27][C:28]=3[C:29](=[O:30])[NH:31][C:7]2=[S:8])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)N=C=S
Reactant: NC(=O)c1[nH]cnc1NCc1ccc(Oc2ccccc2)nc1
Solvent: ClCCl
Product: O=c1[nH]c(=S)n(Cc2ccc(Oc3ccccc3)nc2)c2nc[nH]c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 12.3 %

Procedure:
Ethoxycarbonyl isothiocyanate (0.096 mL, 0.85 mmol) was added to 4-{[(6-phenoxypyridin-3-yl)methyl]amino}-1H-imidazole-5-carboxamide (0.25 g, 0.81 mmol, obtained from Example 25(a)) in anhydrous dichloromethane (3.0 mL). After stirring for 2.5 h at ambient temperature the mixture was concentrated to dryness. Sodium hydroxide (10 mL, 2% w/v) was added and the solution was heated at 50° C. over night. After cooling, the pH was adjusted to 4-5 using 2N HCl. The solid was collected by filtration and recrystallized from DMSO/water to give a white crystalline material. A portion of this material was recrystallized from MeOH to give 35 mg (0.10 mmol, 12% yield) of the title compound.
Reaction SMILES: [C:1]([C:4]1[S:12][C:11]2[CH:10]=[N:9][C:8]([NH:13][C:14]3[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)[CH:15]=3)=[N:7][C:6]=2[C:5]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42])(=[O:3])[NH2:2].[ClH:43]>O1CCOCC1>[ClH:43].[CH3:42][O:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:5]1[C:6]2[N:7]=[C:8]([NH:13][C:14]3[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:15]=3)[N:9]=[CH:10][C:11]=2[S:12][C:4]=1[C:1]([NH2:2])=[O:3]
Reactant: COc1ccccc1-c1c(C(N)=O)sc2cnc(Nc3cc(C4CCN(C(=O)OC(C)(C)C)CC4)nn3C(C)C)nc12
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccccc1-c1c(C(N)=O)sc2cnc(Nc3cc(C4CCNCC4)nn3C(C)C)nc12
Reaction time: 0.5 h

Procedure:
Note 3: Example I-61 was prepared from Example I-52 according to the following method: 140 mg of 2-methylpropan-2-yl 4-[5-{[6-carbamoyl-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidin-2-yl]amino}-1-(propan-2-yl)-1H-pyrazol-3-yl]piperidine-1-carboxylate are added to a solution of 4 ml of 4N hydrochloric acid in dioxane at a temperature of about 20° C. and the mixture is left to stir for 30 minutes. After concentration of the mixture under reduced pressure, a solid is obtained which is washed successively with ethyl ether, with dichloromethane, with dioxane and to finish with dichloromethane. The solid is dried under reduced pressure, so as to obtain 112 mg of 7-(2-methoxyphenyl)-2-{[3-(piperidin-4-yl)-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}thieno[3,2-d]pyrimidine-6-carboxamide hydrochloride.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Sn](C)(C)C)=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:3]1.Br[C:23]1[S:27][C:26]([C:28]2[CH2:32][CH:31]([CH2:33][OH:34])[O:30][N:29]=2)=[CH:25][CH:24]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[OH:34][CH2:33][CH:31]1[O:30][N:29]=[C:28]([C:26]2[S:27][C:23]([C:10]3[CH:11]=[CH:12][C:7]([N:6]4[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:3][C:2]4=[O:1])=[CH:8][CH:9]=3)=[CH:24][CH:25]=2)[CH2:32]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc([Sn](C)(C)C)cc2)C(=O)O1
Reactant: OCC1CC(c2ccc(Br)s2)=NO1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NOC(CO)C4)s3)cc2)C(=O)O1
Temperature: 90 °C
Yield: 42.1 %

Procedure:
N-({(5S)-2-Oxo-3-[4-(trimethylstannyl)phenyl]-1,3-oxazolidin-5-yl}methyl)acetamide (500 mg, 1.26 mM), [3-(5-bromothien-2-yl)-4,5-dihydroisoxazol-5-yl]methanol (330 mg, 1.26 mM), tris(dibenzylideneacetone)dipalladium (0)-chloroform adduct (130 mg, 0.126 mM) and tri-2-furylphosphine (58 mg, 0.252 mM) were placed in a flask. The solids were degassed and placed under nitrogen. Anhydrous dioxane (10 ml) was added and the suspension was heated at 90° C. for 16 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title compound (220 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].Cl[C:24]1[N:29]=[CH:28][N:27]=[C:26]2[NH:30][N:31]=[CH:32][C:25]=12.C(N(C(C)C)CC)(C)C>C(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([N:13]3[CH2:14][CH2:15][N:16]([C:24]4[N:29]=[CH:28][N:27]=[C:26]5[NH:30][N:31]=[CH:32][C:25]=45)[CH2:17][CH2:18]3)=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:20])[F:21]
Reactant: Fc1ccc(-c2cnc(N3CCNCC3)[nH]2)cc1C(F)(F)F
Reactant: Clc1ncnc2[nH]ncc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-c2cnc(N3CCN(c4ncnc5[nH]ncc45)CC3)[nH]2)cc1C(F)(F)F
Yield: 79.7 %

Procedure:
Combine 1-[5-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperazine (195 mg, 1.00 equiv; 0.620 mmoles); 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine (1.00 equiv; 0.620 mmoles; 96 mg); isopropyl alcohol (3 mL); diisopropylethylamine (1 mL) and heat in a microwave reactor at 80° C. for 60 min. Evaporate the reaction mixture and purify on silica gel with 5% MeOH/DCM. Combine the fractions to give 213.2 mg (0.494 mmol, 80%) of 4-{4-[5-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine. Dissolve the free base in DCM/MeOH and add 1.0 eq 1M HCl in ether. Concentrate the mixture to give 237.2 mg 4-{4-[5-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine hydrochloride.
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])C.[OH-].[Na+]>>[C:42]([CH2:41][CH2:40][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:33]3[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:29])=[O:30])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:47])=[O:3])([OH:44])=[O:43]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc(Cl)cc3)cc(S(=O)(=O)CC)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(Cl)cc2)c1
Yield: 98.8 %

Procedure:
A similar procedure as described in Example 40, step 8 was used, starting from 4-[3-[6-(5-ethanesulfonyl-4′-chloro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (116 mg, 0.17 mmol) and 1.0 N aqueous sodium hydroxide (1.7 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(5-ethanesulfonyl-4′-chloro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (106 mg, 99%) as an amorphous white solid: ES(+)-HRMS m/e calcd for C33H39ClO8S (M+Na)+ 653.1946, found 653.1948.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:8]([CH:9]=[O:10])=[C:7](Cl)[N:6]=[CH:5][N:4]=1>C1(C)C=CC=CC=1.O>[NH2:1][C:7]1[C:8]([CH:9]=[O:10])=[C:3]([Cl:2])[N:4]=[CH:5][N:6]=1
Reactant: N
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ncnc(Cl)c1C=O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
NH3 (g) was blown through a solution of 4,6-dichloro-pyrimidine-5-carbaldehyde Compound 1a (50 g, 282.5 mmol) in toluene (565 mL, 0.5M) for 3 mins using a 12C glass frit, then the mixture was warmed at 60° C. with stirring for 30 min. NH3 (g) was blown through the reaction mixture a second time for 3 min and the reaction was heated for 30 mins. NH3 (g) was blown through the reaction mixture a third time for 3 min and the reaction was heated for a final 20 mins. The reaction mixture was diluted with H2O (1 L), and extracted with EtOAc (1×750 mL, 3×500 mL). The organic extracts were washed with brine (4×) and dried (Na2SO4), then concentrated to afford 4-amino-6-chloro-pyrimidine-5-carbaldehyde Compound 1b (38.5 g, 87%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.74 (br s, 1H), 8.58 (br s, 1H), 8.42 (s, 1H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:24](=[O:25])[N:5]2[C:6]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH2:10][Cl:11])[CH2:8][S:9][C@H:4]12.[CH:26](=O)[C:27]1[C:28](=[CH:30][CH:31]=[CH:32][CH:33]=1)[OH:29].C(N(CC)CC)C>CO>[OH:29][C:28]1[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=1[CH:26]=[N:2][C@@H:3]1[C:24](=[O:25])[N:5]2[C:6]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH2:10][Cl:11])[CH2:8][S:9][C@H:4]12
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Reactant: O=Cc1ccccc1O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](N=Cc4ccccc4O)C(=O)N23)cc1
Reaction time: 5 h
Yield: 90.1 %

Procedure:
In 50 ml of methanol was dissolved 4.05 g(10 mmol) of 4-methoxybenzyl 7 β-amino-3-chloromethyl-ceph-3-em-4-carboxylate hydrochloride, and 1.28 ml(12 mmol) of salicylaldehyde and 1.39 ml(10 mmol) of triethylamine were added thereto. The reaction mixture was stirred for 5 hours. The resulting precipitate was filtered, washed with 50 ml of methanol and dried to give 4.26 g of the desired compound(90%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:17]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:8]([O:10][CH3:17])=[O:9])=[N:6][CH:7]=1
Reactant: Cc1cc(O)cnc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ncc(O)cc1C
Temperature: 95 °C
Reaction time: 24 h

Procedure:
A sealable reaction vessel was charged with 5-hydroxy-3-methylpicolinic acid (0.651 g, 4.25 mmol) and MeOH (35 mL). The reaction vessel was placed in a water bath, and concentrated sulfuric acid (0.854 mL, 15.94 mmol) was added. The vessel was sealed and heated in a 95° C. oil bath. After 24 h, the reaction mixture was concentrated and the residue was taken up in 30 mL of 0.5M aqueous Na2CO3. The aqueous phase was extracted with 10% MeOH-EtOAc (100 mL). The aqueous layer was separated and saturated with NaCl. The aqueous phase was extracted with 10% MeOH-EtOAc (7×100 mL). The combined organic fractions were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography, eluting with 3% to 4% MeOH-DCM to afford the title compound (593 mg). MS m/z=168 (M+H)+.
Reaction SMILES: [CH3:1]/[C:2](=[CH:5]\[CH2:6][C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]=1[CH3:15])/[CH2:3]O.[Br:16]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:16][CH2:3]/[C:2](/[CH3:1])=[CH:5]/[CH2:6][C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]=1[CH3:15]
Reactant: BrC(Br)(Br)Br
Reactant: CC1=C(C/C=C(\C)CO)C(C)(C)CCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1=C(C/C=C(\C)CBr)C(C)(C)CCC1
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of (2E)-2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butenol (Chem. Abstr., 94, 65904 h) (4.15 g) and tetrabromomethane (7.0 g) in dichloromethane (40 ml) is added over 20 min a solution of triphenylphosphine (5.51 g) in dichloromethane (30 ml). The mixture is stirred overnight under nitrogen, the solvent is removed, and the residue is triturated with hexane. The mixture is filtered, and the filtrate concentrated in vacuo to provide (2E)-1-bromo-2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butene (5.25 g) as an orange oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH3:17])[C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([F:16])[CH2:12]1)=[O:10])(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>ClCCl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[NH2:7][C@H:8]([CH3:17])[C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([F:16])[CH2:12]1)=[O:10]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)C(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
[(R)-2-((S)-3-Fluoro-pyrrolidin-1-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (43 mg, 0.127 mmol) was dissolved in dichloromethane (1.6 ml) and cooled in an ice bath. Trifluoroacetic acid (0.8 ml) was slowly added and the reaction was stirred at room temperature for 3 h then evaporated and dried under high vacuum to afford (R)-2-amino-1-((S)-3-fluoro-pyrrolidin-1-yl)-propan-1-one trifluoroacetate which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH2:15][CH3:16])[CH:8]=1)[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH:36]2[CH2:38][CH2:37]2)=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:19][C:20]2[C:21]([CH:36]3[CH2:38][CH2:37]3)=[N:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:30][CH:31]=3)=[N:24][CH:25]=2)=[C:9]([O:14][CH2:15][CH3:16])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(O)c(OCC)c1
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Product: CCOC(=O)CCc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c(OCC)c1

Procedure:
In analogy to the procedures described in examples 8A] and 31B], 3-(3-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl ester [Eur. Pat. Appl. (1996), EP 710659/A1] was reacted with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) to give 3-{4-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-3-ethoxy-phenyl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[CH3:27])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:29]\[OH:30])=[CH:4][CH:3]=1
Reactant: Cc1cc(F)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-(3-(4-bromophenyl)-3-(4-fluoro-2-methylphenyl)propanoyl)-1-methylpyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 10% of the corresponding Z isomer as a colorless foam, MS (ESI+): m/z=443.08 [M+H]+.
Reaction SMILES: [I-].[Li+].[CH3:3][C:4]1([CH3:33])[S:9][CH2:8][CH2:7][N:6]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C@H:5]1[C:29]([O:31]C)=[O:30]>>[CH3:3][C:4]1([CH3:33])[S:9][CH2:8][CH2:7][N:6]([S:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:18]=2)(=[O:11])=[O:12])[C@H:5]1[C:29]([OH:31])=[O:30]
Reactant: COC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#Cc3ccccc3)cc2)CCSC1(C)C
Agent: [I-]
Agent: [Li+]
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#Cc3ccccc3)cc2)[C@H]1C(=O)O
Yield: 79.1 %

Procedure:
According to the procedure of Example 250, lithium iodide mediated ester cleavage of 0.282 g (0.61 mmol) of methyl (3S)-2,2-dimethyl-4-({4-[(3-phenyl-2-propynyl)oxy]phenyl}sulfonyl)-3-thiomorpholinecarboxylate provided 0.215 g (79%) of (3S)-2,2-dimethyl-4-({4-[(3-phenyl-2-propynyl)oxy]phenyl}sulfonyl)-3-thiomorpholine carboxylic acid as a white solid. Electrospray Mass Spec: 446.0 (M+H)+
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[CH:17][C:15]([NH2:16])=[N:14][C:12]2=[O:13])[CH2:5]1)=[N+]=[N-].[H][H]>[Pd]>[NH2:1][C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[CH:17][C:15]([NH2:16])=[N:14][C:12]2=[O:13])[CH2:5]1
Reactant: [H][H]
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1CO
Agent: [Pd]
Product: Nc1ccn([C@H]2C[C@H](N)[C@@H](CO)O2)c(=O)n1

Procedure:
An alternate synthesis of compound (XIII) involves treatment of 3,-azido-5'-0-acetyl-2',3'-dideoxyuridine (X) with 4-chlorophenylphosphorodichloridate and 1,2,4-triazole in pyridine at room temperature for 3 days to give the 4-trizolylpyrimidinone derivative. Subsequent treatment with aqueous ammonia in dioxane (1:3 v/v) for 4 hours, then saturated methanolic ammonia overnight at room temperature, yields the 3'-azido analog (XII). Compound (XII) is then reduced under 50 psi of hydrogen in the presence of 10% palladium on charcoal at room temperature for 6 hours to obtain the desired 3'amino-2',3'-dideoxycytidine derivative (XIII).