Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.S(=O)(=O)(O)O.[OH-].[Na+].[C:20](OCC)(=O)[CH3:21]>C(O)C>[NH:1]1[C:5]2[CH:6]=[C:7]([C:10]([O:12][CH2:20][CH3:21])=[O:11])[CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: CCOC(C)=O
Reactant: O=C(O)c1ccc2nn[nH]c2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1ccc2nn[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1H-1,2,3-benzotriazole-6-carboxylic acid (6.0 g, 36.8 mmol) in ethanol (27.8 mL) was added sulfuric acid (1.5 mL, 28.1 mmol). The mixture was heated to 60 C. After 18 h, the mixture was cooled to ambient temperature. Aqueous sodium hydroxide (3N) and ethyl acetate was added and solid crashed out of the solution. The solid was filtered and dried under hi-vac to give the title compound (5.14 g): LC-MS [M+1]=192.1.
Reaction SMILES: [C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22]>CN(C)C=O>[C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:18][CH2:19][CH2:20][CH2:21][Cl:22])[C:10]2=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NCCN1N=Cc1ccccc1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(CCCCCl)CCN1N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
A stirred mixture of 1-phenylmethylenamino-2-imidazolidinone (27.6 g, 0.1458 mole) [prepared as in Example A, Part II] in dimethylformamide (500 ml) is treated portionwise with 60% NaH in mineral oil (5.8 g, 0.1458 mole) over 30 minutes. The resulting mixture is stirred at ambient temperature 30 minutes, then heated at 80°-90° C. for 30 minutes. The resulting thick mixture is cooled to ambient temperature, and 1-bromo-4-chlorobutane (50.0 g, 0.2916 mole, 2 eq) is added in one portion. The mixture is heated at 80°-90° C. After 30 minutes, a near-solution is formed followed, by gradual precipitation of a small amount of solid. The mixture is heated at 80°-90° C. temperature for 3 hours, then stirred at ambient temperature for 18 hours. The mixture is filtered (celite) removing a small amount of insoluble material. The filtrate is concentrated under reduced pressure to an oily residue. This residue is triturated with H2O giving a solid. The solid is collected and air-dried. This solid is triturated by stirring in anhydrous ether (350 ml) for one hour. The solid is collected and air-dried to give 36.4 g (0.130 mole) of 1-phenylmethyleneamino-3-(4-chlorobutyl)-2-imidazolidinone.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)(=O)=O.[I-:20].[Na+]>CC(C)=O>[I:20][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCCC(COS(C)(=O)=O)C1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(CI)C1
Temperature: 58 °C
Yield: 90.9 %

Procedure:
t-Butyl 3-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (Preparation 68, 609.22 g, 2.08 mol, 1 eq) was dissolved in acetone (3 L), and the reaction mixture was flushed with nitrogen. Sodium iodide (619.84 g, 4.16 mol, 2 eq) was added, and the reaction was stirred at reflux (58° C.) under nitrogen. The reaction mixture was cooled to room temperature, filtered, and the solvent removed under vacuum. The residue was re-dissolved in diethyl ether (1.5 L), and this solution was washed with water (500 mL), saturated sodium bicarbonate (400 mL), 5% sodium thiosulfate (400 mL), and brine (400 mL). The solution was dried over sodium sulfate, and the solvent removed under vacuum to afford title compound as a yellow oil (616 g, 1.89 mol, 91%).
Reaction SMILES: [BH4-].[Na+].[N:3]1([C:8]2([C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[O:12])[CH2:10][CH2:9]2)[CH:7]=[N:6][CH:5]=[N:4]1>CO>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH:11]([C:8]2([N:3]3[CH:7]=[N:6][CH:5]=[N:4]3)[CH2:10][CH2:9]2)[OH:12])=[CH:14][CH:15]=1
Reactant: O=C(c1ccc(F)cc1)C1(n2cncn2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(c1ccc(F)cc1)C1(n2cncn2)CC1
Yield: 88.6 %

Procedure:
1.2 g of sodium borohydride were added to a solution of 13.8 g (0.06 mol) of 4-fluorophenyl 1-(1, 2, 4-triazol-1-yl)-cyclopropyl ketone in 50 ml of methanol, the mixture was refluxed for 1 hour, and 12.4 g (89%) of the title compound, melting point 104°-106° C., were isolated by working up using dichloromethane/water.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:14][CH:13]=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:11]=2.C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:36][CH2:37][C:38](Cl)=[O:39].C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:36][CH2:37][C:38]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:14][CH:13]=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:11]=2)=[O:39]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3N)[nH]c2c1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3NC(=O)CCl)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a suspension of methyl 2-(2-aminophenyl)-3-cyclohexyl-1H-indole-6-carboxylate (6.48 g, 18.6 mmol), sodium acetate (1.68 g, 20.5 mmol) and acetic acid (1.17 ml, 20.5 mmol) in tetrahydrofuran (60 ml) was added dropwise chloroacetyl chloride (1.63 ml, 20.5 mmol), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was m washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 2-[2-(2-chloroacetylamino)phenyl]-3-cyclohexyl-1H-indole-6-carboxylate (7.90 g, yield 100%).
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19][C:20]2[CH:27]=[CH:26][C:25]([B:28]3[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]3)=[CH:24][C:21]=2[C:22]#[N:23])[CH2:14][CH2:13]1>ClCCl>[C:1]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19][C:20]2[CH:27]=[CH:26][C:25]([B:28]3[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]3)=[CH:24][C:21]=2[C:22]#[N:23])[CH2:14][CH2:13]1)(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(OCC3CCNCC3)c(C#N)c2)OC1(C)C
Reactant: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C#N)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 134.6 %

Procedure:
Glacial acetic acid (2.1 g, 0.035 mol), triethylamine (3.5 g, 0.035 mol) and 1-propanephosphonic anhydride (60% w/w in ethyl acetate) (11 ml, 0.0174 mol) are added to a solution of 2-(piperidin-4-ylmethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (4.0 g, 0.0116 mol) in dichloromethane (40 ml) at 0° C. under nitrogen. The reaction is stirred at room temperature for 15 h. The solution is evaporated and poured into water (200 ml). The mixture is extracted with dichloromethane (100 ml×2) and evaporated in a rotary evaporator. The crude product is purified by chromatography, giving 6.0 g of the desired product as colourless oil;
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[O:13]([CH2:20][CH2:21][OH:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(N(CC)CC)C>[O:13]([CH2:20][CH2:21][O:22][C:1](=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:22][CH2:21][CH2:20][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:7])=[CH:4][CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCOc1ccccc1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: O=C(OCCOc1ccccc1)c1ccc(C(=O)OCCOc2ccccc2)cc1

Procedure:
In a typical laboratory setting, bis(aryloxyalkyl)terephthalates are made by reacting terephthaloyl chloride with the corresponding aryloxyalkanol. For example, the reaction of terephthaloyl chloride with 2-phenoxyethanol in the presence of excess triethylamine and a solvent, followed by an organic workup to remove the ammonium salt, concentration, and recrystallization provides bis(2-phenoxyethyl)-terephthalate (see Scheme 1, compound 2 and Synthetic Examples 1 and 2 in U.S. Pat. Appl. Publ. No. 2009/0087764). Unfortunately, the lab procedure is impractical on a commercial scale because of the cost of terephthaloyl chloride and, among other issues, the need to recover a solvent and dispose of the ammonium salt.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1.[Cl:24][C:25]1[O:29][C:28]([CH:30]=O)=[CH:27][CH:26]=1>C(O)C.C(O)(C(F)(F)F)=O>[Cl:24][C:25]1[O:29][C:28]([CH:30]2[C:5]3=[C:6]4[C:11](=[C:12]([C:13]5[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=5)[N:4]3[CH2:3][CH2:2][NH:1]2)[C:10](=[O:20])[N:9]([CH3:21])[C:8](=[O:22])[N:7]4[CH3:23])=[CH:27][CH:26]=1
Reactant: O=Cc1ccc(Cl)o1
Reactant: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(CCN)cc2n(C)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Cn1c(=O)c2c(-c3cccc(Cl)c3)n3c(c2n(C)c1=O)C(c1ccc(Cl)o1)NCC3
Temperature: 50 °C

Procedure:
6-(2-Amino-ethyl)-5-(3-chloro-phenyl)-1,3-dimethyl-1,6-dihydro-pyrrolo[3,4-d]pyrimidine-2,4-dione (Intermediate B) (150 mg, 0.451 mmol) and 5-chlorofuran-2-carbaldehyde (commercially available, 58.8 mg, 0.451 mmol) were suspended in ethanol (1.2 ml). The mixture was heated at 50° C. under microwave irradiation for 1 hour. TFA (4 drops) was added to the reaction mixture and heating continued at 60° C. for a further 30 mins under microwave irradiation. The reaction mixture was diluted with ethanol (0.5 mL) and purified using mass directed HPLC. The product containing fractions were combined and evaporated under reduced pressure to afford a white solid which was dried under vacuum at 50° C. for 16 h to afford the title compound as a pale tan solid;
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][CH:27]=1>C(OCCO)C>[C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][CH:27]=1)=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)#[N:17]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: NC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc(C(N)=O)cc3)c2cc1OC
Yield: 73.4 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 163.4 mg (1.2 mmol) of 4-amino-benzamide to give 255.7 mg (73.4%) of the product as a light yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 348.9.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH:19]1([CH:22]([NH2:26])[CH2:23][O:24][CH3:25])[CH2:21][CH2:20]1>>[Cl:1][C:2]1[N:3]=[C:4]([NH:26][CH:22]([CH:19]2[CH2:21][CH2:20]2)[CH2:23][O:24][CH3:25])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: COCC(N)C1CC1
Product: COCC(Nc1nc(Cl)nc2c1CCC2c1ccc(F)cc1)C1CC1

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) was reacted as described in Preparation Hr with 1-cyclopropyl-2-methoxyethanamine to afford 2-chloro-N-(1-cyclopropyl-2-methoxyethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Hw) as a mixture of 4 diasteriomers. LC-MS (M+H)+=362.1.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]([F:33])([F:32])[C@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[NH2:25]>>[F:33][C:23]([F:22])([F:32])[C@@H:24]([NH:25][C:18]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[N:8]=1)=[O:20])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: O=C(O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Reactant: N[C@@H](c1ccccn1)C(F)(F)F
Agent: Cl
Product: O=C(N[C@@H](c1ccccn1)C(F)(F)F)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 155 g) and (S)-2,2,2-trifluoro-1-(pyridin-2-yl)ethanamine hydrochloride (CAN 336105-45-4) as starting materials. MS (EI): m/e=430.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:11]([C@H:12]([OH:15])[CH2:13]O)=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7].N1C=CC=CC=1.[S:22](Cl)([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23].Cl>CN(C1C=CC=CN=1)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.C(OCC)(=O)C>[CH3:1][C:2]1[O:3][C:4]2[C:11]([C@H:12]([OH:15])[CH2:13][S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1oc2c([C@H](O)CO)cccc2c1C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)C[C@@H](O)c2cccc3c(C)c(C)oc23)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
14 g (67.96 mmol) of (+)-2,3-dimethyl-7-(2-hydroxy-1(S)-hydroxyethyl)benzofuran and 250 ml of pyridine are introduced into a 500 ml three-necked flask. The mixture is cooled to 0° C. and 11.62 g (61.16 mmol) of tosyl chloride and then 0.5 g of dimethylaminopyridine are added. The reaction mixture is stirred for 2 h at room temperature, 0.645 g of tosyl chloride is added and stirring is continued for 16 h. The mixture is cooled to 0° C. and 300 ml of ethyl acetate and then 250 ml of a hydrochloric acid solution (4M) are added. Extraction is carried out with ethyl acetate (2×400 ml). The organic phases are combined, washed with 2×250 ml of a hydrochloric acid solution (4M), dried over magnesium sulphate and concentrated. The residue is purified by silica column chromatography (elution solvent: 25% ethyl acetate in cyclohexane). 15 g of (+)-2,3-dimethyl-7-(2-para-methylphenylsulphonyl-1(S)-hydroxyethyl)benzofuran are obtained in the form of a white solid--M.p.: 90° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12](O)=[O:13])[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].ClC(OCC(C)C)=O.CN1CCOCC1.Cl.[NH2:45][CH2:46][C:47]([NH2:49])=[O:48]>CC(N(C)C)=O.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH:45][CH2:46][C:47]([NH2:49])=[O:48])=[O:13])[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: NCC(N)=O
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
To a cooled (0° C.) solution of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (from Step 3) (0.25 g, 0.61 mmol) in DMA (2 mL) was added isobutyl chloroformate (0.96 mL stock solution prepared 0.1 mL in 0.9 mL DCM, 0.74 mmol) and 4-methylmorpholine (0.88 mL stock solution prepared 0.1 mL in 0.9 mL DMA, 0.80 mmol). Stirred at 0° C. for 5 min, ambient temperature for 30 min. Added NMM (0.1 mL, 0.92 mmol), glycineamide HCl (0.10 g, 0.92 mmol), and DMAP (0.01 g, 0.06 mmol) and stirred at ambient temperature for 1.5 h. Removed DMA under reduced pressure. Purified crude product by preparatory HPLC using a 10-90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=463) were combined and concentrated to approximately 20 mL under reduced pressure. Added 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as an off-white solid (77 mg, 27%). 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.96 (m, 1H), 7.80 (s, 1H), 7.61 (m, 1H), 7.54 (m, 1H), 7.01 (m, 2H), 5.60 (m, 2H), 4.01 (s, 2H), 2.20 (s, 3H). ESHRMS m/z 463.0990 (M+H calculated for C21H18ClF2N4O4 requires 463.0979).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([NH2:14])=[O:13])[CH2:11][CH2:10]1.Br[CH:16]([CH3:29])[C:17]([C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=1[Cl:28])=O>CN(C=O)C>[Cl:28][C:20]1[CH:21]=[C:22]([O:26][CH3:27])[C:23]([CH3:25])=[CH:24][C:19]=1[C:17]1[N:14]=[C:12]([C:9]2([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH2:11][CH2:10]2)[O:13][C:16]=1[CH3:29]
Reactant: NC(=O)C1(c2ccc(Cl)cc2Cl)CC1
Reactant: COc1cc(Cl)c(C(=O)C(C)Br)cc1C
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(-c2nc(C3(c4ccc(Cl)cc4Cl)CC3)oc2C)cc1C
Temperature: 80 °C

Procedure:
1-(2,4-Dichloro-phenyl)-cyclopropanecarboxylic acid amide (46 mg, 0.2 mmol) and 2-Bromo-1-(2-chloro-4-methoxy-5-methly-phenyl)-propan-1-one (58 mg, 0.2 mmol) were combined in DMF (1 mL) at 0.2 M and the mixture heated to 80° C. overnight. The reaction was then cooled to room temperature. The desired product was purified by reversed phase HPLC/MS using an acetonitrile/water gradient and C18 stationary phase. Yield: 1 mg (2%) [MH]+ 424.2, 422.2, 426.0 (small).
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[C:8]([C:11]2[NH:15][N:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O[CH2:17][C@@H:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19]>>[NH2:20][C@@H:18]([CH3:19])[CH2:17][N:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=2[F:10])=[N:15]1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(-c2ccn[nH]2)c(F)c1Cl
Product: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1
Yield: 53.8 %

Procedure:
The title compound was prepared from 2-chloro-3-fluoro-4-(1H-pyrazol-5-yl)benzonitrile (0.075 g, 0.34 mmol) and (S)-tert-butyl (1-hydroxypropan-2-yl)-carbamate (0.059 g, 0.34 mmol) using the method of Example 34(c) to afford 0.051 g of the title product. 1H NMR (400 MHz; CDCl3): δ 1.15 (d, 3H), 1.34 (bs, 2H), 3.49 (m, 1H), 3.95 (dd, 1H), 4.16 (dd, 1H), 6.79 (dd, 1H), 7.48 (m, 1H), 7.52 (d, 1H), 8.07 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@H:18]([OH:19])[C@H:17]([CH3:20])[O:16][C@H:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[C@H:4]1[OH:21].[H][H].ClCCl.CO>CO.[Pt](=O)=O>[CH3:1][O:2][C@@H:3]1[C@H:18]([OH:19])[C@H:17]([CH3:20])[O:16][C@H:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=2)[C@H:4]1[OH:21]
Reactant: [H][H]
Reactant: CO[C@H]1[C@H](O)[C@@H](Oc2ccc([N+](=O)[O-])cc2)O[C@@H](C)[C@H]1O
Agent: O=[Pt]=O
Solvent: CO
Solvent: ClCCl
Product: CO[C@H]1[C@H](O)[C@@H](Oc2ccc(N)cc2)O[C@@H](C)[C@H]1O

Procedure:
3.81 g (12.73 nmmol) of p-nitrophenyl 3-O-methyl-β-L-fucopyranoside are dissolved in methanol and, after addition of platinum dioxide, hydrogenated in a hydrogen atmosphere at a slight overpressure. After filtering off the catalyst and precipitating with ether, 3 g (88%) of the target product are obtained. [TLC: dichloromethane/methanol 9:1 Rf =0.53].
Reaction SMILES: [CH2:1]([N:3]([CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:4](=[O:7])[CH:5]=[CH2:6])[CH3:2].[CH3:15][C:16]([C:19]1[CH:24]=[C:23]([SH:25])[CH:22]=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]=1[OH:30])([CH3:18])[CH3:17]>C(N(CC)CC)C>[CH3:29][C:26]([C:21]1[CH:22]=[C:23]([S:25][CH2:6][CH2:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[O:7])[CH:24]=[C:19]([C:16]([CH3:18])([CH3:17])[CH3:15])[C:20]=1[OH:30])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)N(CC)Cc1ccncc1
Solvent: CCN(CC)CC
Product: CCN(Cc1ccncc1)C(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The title compound was prepared according to the method of Example 4 from N-ethyl-N-(4-pyridinylmethyl)-2-propenamide (1.5 g, 0.00788 mole,), 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (2.06 g, 0.00867 mole,) and triethylamine (1 ml) to provide 3.0g of product, m.p. ca. 121°-123° C. Analysis calc. for C25H36N2O2S(428.63): Calc.: C, 70.05; H, 8.47; N, 6.54; S, 7.48. Found: C, 70.23; H, 8.55; N, 6.34; S, 7.55.
Reaction SMILES: [CH2:1]([C:3]1[S:30][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][C:15]=3[O:28][CH3:29])[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)=[O:34].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:30][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][C:15]=3[O:28][CH3:29])[C:8](=[O:12])[N:9]([CH2:32][C:33]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)=[O:34])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3OC)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3OC)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-3′-methoxybiphenyl-2-carbonitrile (1.9 g), 2-bromo-1-(4-methoxyphenyl)ethanone (1.3 g) and N,N-dimethylformamide (19 mL) was added 60% sodium hydride (0.28 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as pale-yellow crystals (1.2 g, 46%).
Reaction SMILES: [C:1]([O:4][C@H:5]([C:7]#[C:8][CH:9]=[O:10])[CH3:6])(=[O:3])[CH3:2].CC(=CC)C.[O-:16]Cl=O.[Na+]>CC(O)(C)C.O>[C:1]([O:4][C@@H:5]([CH3:6])[C:7]#[C:8][C:9]([OH:16])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C)C#CC=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(=O)O[C@@H](C)C#CC(=O)O
Reaction time: 0.33 h
Yield: 100.6 %

Procedure:
To a solution of 9 (133 mg, 0.949 mmol) and 2-methyl-2-butene (1.20 mL, 14.2 mmol) in tBuOH (1.9 mL) was added the mixture of NaClO2 (257 mg, 2.84 mmol) and NaH2PO4 (393 mg, 2.84 mmol) in H2O (1.9 mL) at 23° C. The resulting mixture was stirred for 20 min at the same temperature and quenched by 1 N aqueous HCl (3 mL) at 0° C. The mixture was poured into a separatory funnel and diluted with EtOAc (3 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×4 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue via flash chromatography (silica gel 15 mL; 50→100% EtOAc in hexanes containing 1.0% acetic acid) afforded acid 10 (149 mg, quantitative yield) as a pale yellow oil.