Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[O:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[H-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].O>CN(C=O)C>[C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:20]3=[O:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: O=c1[nH]c2ccccc2n1C1CCN([C@@H]2Cc3cccc4cccc2c34)CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)n(C2CCN([C@@H]3Cc4cccc5cccc3c45)CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
(R)-1-[1-(Acenaphthen-1-yl)piperidin-4-yl]-1,3-dihydro-2H-benzoimidazol-2-one (2.3 g, 6 mmol) was dissolved in DMF (20 ml) and sodium hydride (300 mg, 60%) was added. The suspension was stirred at 50° C. for 30 min. After cooling to room temperature, ethyl bromoacetate (1.17 g, 7 mmol) was added and the mixture was stirred for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (2.6 g) as pale-yellow crystals.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH2:13][CH3:14])[C:7]=1[C:15](=[O:21])[C:16](OCC)=[O:17])[CH3:5]>CO>[CH2:4]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH2:13][CH3:14])[C:7]=1[C:15](=[O:21])[C:16]([NH:2][NH2:3])=[O:17])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)c1c(CC)cc(C)cc1CC
Solvent: CO
Solvent: O
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN
Temperature: 2 °C
Reaction time: 4 h
Yield: 39.8 %

Procedure:
To a 100 ml volume four-necked flask, methanol (22.91 g) and hydrazine hydrate (1.93 g) were added at room temperature, and cooled. Ethyl 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetate (9-a) (5.01 g) diluted with methanol (10.02 g) was added dropwise at 1° C. over 5 minutes. The resulting mixture was stirred at 2° C. for 4 hours, then the mixture was filtered. The resulting filtrate was concentrated, added tert-butyl methyl ether (41 g), and washed with brine (14 g). The resulting organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel: 40 g, hexane: ethyl acetate=1:1) to gave 1.88 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetohydrazide ((12-1)-(11)-39).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][C:3]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[SH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.O>CN(C)C=O>[F:15][C:10]1[C:9]([C:3]2[CH:4]=[C:5]([CH:7]=[O:8])[S:6][C:2]=2[S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=Cc1cc(-c2cccnc2F)c(Br)s1
Reactant: Sc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(-c2cccnc2F)c(Sc2ccccn2)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.6 %

Procedure:
A suspension of 5-bromo-4-(2-fluoropyridin-3-yl)thiophene-2-carbaldehyde (297 mg), potassium carbonate (171 mg) and 2-mercaptopyridine (129 mg) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound as a pale-yellow solid (yield 281 mg, yield 85%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1)([O-:16])=[O:15]>CN(C)C=O>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:25])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)=[CH:21][CH:22]=1)([O-:16])=[O:15]
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 4.88 g of ethyl 2-aminothiazol-4-ylglyoxylate, 5 g of p-nitrophenyl isocyanate and 30 ml of dimethylformamide. The resulting product was a pale yellow powder having the following physical properties.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:9]1)=[O:7])(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:10]([CH2:29][CH:30]([CH3:31])[CH3:32])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 46a (0.6 g, 1.3 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.6 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:9][CH2:10]1
Reactant: COC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
tert-Butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (35.71 g, 140 mmol) was dissolved in a mixture of ethyl acetate (110 mL) and methanol (110 mL). 50% wet 10% palladium on carbon (3.3 g) was added to the mixture. Reaction vessel was charged with 55 psi of hydrogen gas. Reaction shook on a Parr apparatus at room temperature for 16 hours. Reaction mixture was filtered to remove the catalyst. Filtrate was concentrated in vacuo. Title compound was obtained as clear colorless oil in 97% yield. 1H NMR (300 MHz, CDCl3): δ=4.04 (d, J=10.25, 2H), 3.64 (s, 3H), 2.68 (t, J=12.44, 2H), 2.21 (d, J=6.95, 2H), 1.98-1.77 (m, 1H), 1.64 (d, J=13.54, 2H), 1.41 (s, 9H), 1.25-0.99 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][Mg]Br.[Cl-].[NH4+]>C1COCC1.CCOCC>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-benzyl-4-piperidone (26.5 mmol, 5 g) in THF (50 mL) was cooled to −15° C. and a solution of methyl magnesium bromide in ether (3 M, 22 mL) was added. The mixture was stirred for 0.5 hours then allowed to warm to room temperature. Saturated aqueous ammonium chloride (50 mL) was added and the products were extracted into ethyl acetate, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum to give the title compound as a pale yellow solid (5.0 g) that was used directly without further purification.
Reaction SMILES: Br[CH:2]1[CH2:17][CH2:16][C:5]2=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:7][C:8]([S:9][CH3:10])=[C:4]2[C:3]1=O.[C:19]([NH2:27])(=[S:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)C>O>[CH3:10][S:9][C:8]1[S:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[C:4]=1[C:3]1[N:27]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:26][C:2]=1[CH2:17][CH2:16]2
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(Br)C2=O
Reactant: NC(=S)c1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1sc(SC)c2c1CCc1sc(-c3ccccc3)nc1-2
Yield: 33.9 %

Procedure:
A mixture of ethyl 5-bromo-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (6.99 g), thiobenzamide (5.49 g) and ethanol (150 ml) was refluxed under heating for 3 hours, after which it was poured over water (500 ml) and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with chloroform-hexane (1:1, v/v) to yield ethyl 4,5-dihydro-8-methylthio-2-phenylthieno[3,4-e]benzothiazole-6-carboxylate (2.63 g, 33.9%), which was then recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 153-154° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[C:5]2[O:10][C:9]3[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:8]=3[C:6]=2[N:7]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>N1C=CC=CC=1>[Cl:15][C:13]1[CH:12]=[CH:11][C:9]2[O:10][C:5]3[C:4]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:3][C:2]([NH:30][CH2:29][C:28]4[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)=[N:7][C:6]=3[C:8]=2[CH:14]=1
Reactant: COc1ccc(CN)cc1
Reactant: CN1CCN(c2nc(Cl)nc3c2oc2ccc(Cl)cc23)CC1
Solvent: c1ccncc1
Product: COc1ccc(CNc2nc(N3CCN(C)CC3)c3oc4ccc(Cl)cc4c3n2)cc1
Temperature: 200 °C

Procedure:
To a solution of 2,8-dichloro-4-(4-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidine (1.3 g, 3.0 mmol) in pyridine (4 mL) was added 4-methoxybenzylamine (4 mL, 30 mmol). After heating at 200° C. for 1 h in the microwave, the resulting mixture was concentrated and the residue was purified by FCC (CH2Cl2/MeOH) to give [8-chloro-4-(4-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-(4-methoxy-benzyl)-amine. The intermediate was then dissolved in TFA (7 mL) and heated at 65° C. for 3 h. The mixture was diluted with CH2Cl2 (20 mL) and H2O (20 mL). The product was extracted with CH2Cl2 (2×20 mL). The combined organic layers were washed with 1 N NaOH (20 mL), dried, and concentrated. The residue was purified by reverse-phase chromatography to afford the desired product (523 mg, 55%). MS: 318.1. 1H NMR (CDCl3): 7.99 (d, J=1.99 Hz, 1H), 7.48-7.47 (m, 2H), 4.76 (s, 2H), 4.08-4.06 (m, 4H), 2.57-2.55 (m, 4H), 2.37 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([CH3:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>CN(C)C=O.C(Cl)Cl>[CH3:1][C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([CH3:13])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C(=O)O)c(C)c(C)c1C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(=O)Cl)c(C)c(C)c1C
Reaction time: 3.5 h
Yield: 142.8 %

Procedure:
A 3 L 3-necked flask is equipped with a condenser, argon inlet, thermowell, magnetic stirrer. The flask is purged with argon then charged with 2,3,4,5-tetramethylbenzoic acid (138.3 g, 0.776 mol), methylene chloride (1.5 L), thionyl chloride (73.5 mL, 1.01 mol) and N, N-dimethylformamide (2.0 mL, 0.026 mol). The resulting suspension is heated to reflux, after a clear solution is formed, heating is continued for 3.5 hours. The solution is allowed to cool then concentrated in vacuo. Last traces of thionyl chloride are removed by co-distillation with toluene (2×100 mL). The remaining oil is dried under high vacuum then used without further purification. Additional reactions are carded out to produce a total of 218 g of 2,3,4,5-tetramethylbenzoyl chloride.
Reaction SMILES: F.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[CH:7][CH:8]=1.[C:10](OC)(=[O:19])/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]2[C:4]=1[CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][C:10]2=[O:19]
Reactant: COC(=O)/C=C/c1ccccc1
Reactant: Cc1ccc(C)cc1
Agent: F
Product: Cc1ccc(C)c2c1C(=O)CC2c1ccccc1
Temperature: 70 °C
Reaction time: 17 h
Yield: 90 %

Procedure:
100 g (5 mol) of anhydrous hydrogen fluoride were added to 10.6 g (100 mmol) of p-xylene (99% purity) and 17 g (105 mmol) of methyl trans-cinnamate, and the mixture was stirred at 70° C. for 17 hours. Work-up carried out analogously to Example A gave 23.6 g of a yellowish solid. The purity of the product is 96% (GC). (96% of theory). After recrystallization once from an ethyl acetate/hexane mixture (1:1), a virtually white solid was obtained in a yield of 90%. The purity after this step is greater than 98% (GC).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11]Cl.[CH3:14][CH:15]1[CH2:20][NH:19][CH2:18][CH:17]([CH3:21])[NH:16]1.C(NC(C)C)(C)C>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11][N:19]1[CH2:18][CH:17]([CH3:21])[NH:16][CH:15]([CH3:14])[CH2:20]1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: CC1CNCC(C)N1
Solvent: CCO
Solvent: CC(C)NC(C)C
Product: Cc1cccc(C)c1NC(=O)CN1CC(C)NC(C)C1

Procedure:
To a solution of compound 3 (5 g, 25.2 mmol) in ethanol (100 mL) was added 2,6-dimethylpiperazine 4 (2.1 g, 25.0 mmol) and N,N-diisopropylamine (3.2 g, 25.2 mmol). The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography (10:1, DCM:MeOH) to afford compound 5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH:18]=[O:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]([Mg]Br)#[CH:21]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH:18]([OH:19])[C:20]#[CH:21])=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C#C[Mg]Br
Reactant: O=Cc1c(-c2cccc(Br)c2)nn2c(Cl)cccc12
Product: C#CC(O)c1c(-c2cccc(Br)c2)nn2c(Cl)cccc12
Yield: 64.8 %

Procedure:
In a similar manner as described in Example 46 from 2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridine-3-carbaldehyde (1.0 g, 2.9 mmol) and ethynylmagnesium bromide (6.4 mL, 0.5 M in tetrahydrofuran, 3.2 mmol) at 0 ° C., was obtained 1-[2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (0.68 g, 68%) as a white solid. 1H NMR (DMSO-d6): δ 8.04 (m, 2 H), 7.87 (d, 1 H), 7.67 (d, 1 H), 7.49 (t, 1 H), 7.38–7.29 (m, 2 H), 6.27 (bs, 1 H), 5.69 (s, 1 H), 3.49 (d, 1 H).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:9]=1)=[O:7])(C)(C)C.O[Li].O>O1CCCC1.O>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:11][C:12]=1[OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Yield: 76.3 %

Procedure:
To a solution of 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (344) (3.9 g, 7.64 mmol) in tetrahydrofuran (60 mL) and water (12 mL) was added LiOH.H2O (3.2 g, 76.4 mmol) and the reaction mixture heated to reflux for 20 h (the reaction was monitored by LC-MS), tetrahydrofuran was removed from the reaction mixture under vacuum and the residue was diluted with water (50 mL). The aqueous layer was washed with ethyl acetate (2×50 mL) and then acidified with 1N HCl to pH 3. A white solid was separated by filtration and dried in vacuum to get pure 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (345) (2.65 g, 76%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[S:5][C:6]=1[CH2:7][CH3:8].[Cu](C#N)[C:16]#[N:17].[C-]#N.[Na+]>CN(C)C=O>[CH2:7]([C:6]1[S:5][C:4]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])=[CH:3][C:2]=1[C:16]#[N:17])[CH3:8]
Reactant: N#C[Cu]C#N
Reactant: CCc1sc(C(=O)OC(C)C)cc1Br
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1sc(C(=O)OC(C)C)cc1C#N
Yield: 52.9 %

Procedure:
A stirred solution of 4 g (14.4 mmol) of isopropyl 4-bromo-5-ethylthiophene-2-carboxylate was refluxed in dry dimethylformamide (50 mL) with copper cyanide (1.94 g, 22 mmol) for 8 hours. The cooled mixture was poured into 0.1 M sodium cyanide (500 mL) and extracted with diethyl ether (4×50 mL). The organic layers were washed twice with brine (50 mL) and dried over anhydrous sodium sulfate. The solvents were removed in vacuo. Column chromatography on silica gel (400 g), eluting with hexanes:ethyl acetate 9/1 (v:v) gave isopropyl 2-ethyl-3-cyano-thiophene-5-carboxylate (1.7 g, 53%) as a pale yellow oil. 1H-NMR (DMSO-d6; 300 MHz) δ8.03 (s, 1H), 5.10 (septet, 1H, J=6.2 Hz), 3.04 (q, 2H, J=7.5 Hz), 1.31 (t, 3H, J=7.5 Hz), 1.30 (d, 6H, J=6.2 Hz). Mass spectrum (ESI m/z): Calcd. for C11H13NO2S 224.1 (M+H), found 224.0.
Reaction SMILES: [Cl-].C(CC[N+:7]1[CH:12]=[CH:11][C:10](C#N)=[CH:9][CH:8]=1)(=O)N.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[OH-].[Na+].[OH-].[Na+]>O>[N:15]1([C:10]2[CH:9]=[CH:8][N:7]=[CH:12][CH:11]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: N#Cc1cc[n+](CCC(N)=O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1cc(N2CCCC2)ccn1

Procedure:
A solution of 1-(2-carbamoylethyl)-4-cyanopyridinium chloride (21.2 g; 0.1 mole) dissolved in 15 ml of deionized water was prepared and charged to the dropping funnel. This solution was then added to the pyrrolidine/sodium hydroxide solution at a rate which permitted maintenance of the reaction temperature with stirring at below 5° C. It was held there for an additional hour, after which 14 g (0.175 mole) of a 50% (w/w) sodium hydroxide solution was added dropwise with continued maintenance of the reaction temperature below 5° C. (approximately 45 minutes). The mixture was then heated to reflux and maintained for two hours and then allowed to cool.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([F:29])[F:28])[CH:21]=1>>[F:28][CH:27]([F:29])[O:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][N:16]1[CH:11]([C:4]2[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]1=[O:17]
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: FC(F)Oc1cccc(CBr)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(OC(F)F)c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-3-(difluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions D): tR=1.05 min.; [M+H]+: 392.75 g/mol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][C:20](=O)[N:19]([CH:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:25])[C:18]=3[CH:31]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1.COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][C:20](=[S:41])[N:19]([CH:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:25])[C:18]=3[CH:31]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C)N1C(=O)COc2ccc(OC3(C)CN(C(=O)OC(C)(C)C)C3)cc21
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: CCOC(=O)C(C)N1C(=S)COc2ccc(OC3(C)CN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Yield: 36.7 %

Procedure:
To a solution of 3-[4-(1-ethoxycarbonyl-ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.250 g, 0.575 mmol) in toluene (5 mL) and DME (5 mL) was added Lawesson reagent (0.372 g, 0.920 mmol) and the mixture was heated to reflux for 4 h. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5% to 10% EtOAc in petroleum ether) to give 3-[4-(1-ethoxycarbonyl-ethyl)-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.095 g, 36.6%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ 6.90 (d, J=8.8 Hz, 1H), 6.67 (brs, 1H), 6.38 (m, 1H), 6.31 (s, 1H), 4.85 (d, J=15.2 Hz, 2H), 4.14 (m, 4H), 3.87 (m, 2H), 1.64 (d, J=7.2 Hz, 3H), 1.59 (s, 3H), 1.42 (s, 9H), 1.13 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[N:14]=[C:15]([N:28]2[CH2:33][CH2:32][CH:31]([CH2:34][OH:35])[CH2:30][CH2:29]2)[C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][S:19][C:17]=2[N:18]=1>ClCCl>[Cl:12][C:13]1[N:14]=[C:15]([N:28]2[CH2:29][CH2:30][CH:31]([CH:34]=[O:35])[CH2:32][CH2:33]2)[C:16]2[C:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][S:19][C:17]=2[N:18]=1
Reactant: OCC1CCN(c2nc(Cl)nc3scc(-c4ccccc4)c23)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CC1CCN(c2nc(Cl)nc3scc(-c4ccccc4)c23)CC1
Reaction time: 2 h
Yield: 100.5 %

Procedure:
Pyridinium chlorochromate (898 mg, 4.17 mmol) was added to a stirred solution of [1-(2-chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-4-piperidyl]methanol (1 g, 2.78 mmol) in dry dichloromethane (ml) at room temperature. The resulting mixture was stirred for 2 h and then eluted through a pad of silica (eluting ethyl acetate). The solvent was evaporated to give the 1-(2-chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)piperidine-4-carbaldehyde as a pale yellow solid (1 g, quantitative yield). Product was used in the subsequent reaction without further purification. LCMS: (M+H)+358, RT=4.98 min.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([O:22][CH3:23])=[N:10][CH:11]=[C:12]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26]I.O>CN(C)C=O>[CH2:1]([C:8]1[C:9]([O:22][CH3:23])=[N:10][CH:11]=[C:12]([N:14]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH3:26])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: COc1ncc(NC(=O)OC(C)(C)C)cc1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(N(C)C(=O)OC(C)(C)C)cc1Cc1ccccc1
Temperature: 25 °C

Procedure:
970 mg of 3-benzyl-5-tert-butoxycarbonylamino-2-methoxypyridine was dissolved in 10 ml of N,N-dimethylformamide, followed by. adding 200 mg of 60% oily sodium hydride thereto. After stirring at room temperature, 0.192 ml of methyl iodide was added thereto in an ice bath. After the returned to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated, to give 920 mg of the target compound.