Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([C:19]([OH:21])=[O:20])[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH:2]=[CH2:3].[Li].[CH2:23](I)C=C.[Cl-].[NH4+]>C1COCC1.CCCCCC.C1COCC1>[CH2:1]([C:4]1([C:19]([O:21][CH3:23])=[O:20])[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCI
Reactant: C=CCC1(C(=O)O)CCCN1C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OC)CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Synthesis of (RS)-2-allyl-N-(benzyloxycarbonyl)proline ##STR5## N-benzyloxycarbonylproline methyl ester (13 g) in THF (20 ml) was added dropwise to lithium dilsopropylamide (27.5 ml, 2M in hexane/THF) in THF (100 ml) at -78° C. under nitrogen. The mixture was stirred for 30 minutes and then allyl iodide (5.5 ml) was added dropwise and the mixture stirred for a further 30 minutes and then allowed to warm to ambient temperature. The mixture was then added to aqueous ammonium chloride (200 ml) and extracted with ether (2×200 ml). The ether layer was evaporated and the residue was purified by chromatography on silica using a gradient of hexane increasing to 20% ethyl acetate:hexane. The appropriate fractions, evaporated to dryness, gave methyl (RS)-2-allyl-N-(benzyloxycarbonyl)prolinate (9 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=O)=[C:4]([F:15])[CH:3]=1.[NH:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[NH2:17].C(O)(=O)C>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=[N:17][NH:16][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:4]([F:15])[CH:3]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(c1ccc(Br)cc1F)C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NN=C(c1ccc(Br)cc1F)C1CCOC1
Yield: 91.3 %

Procedure:
A mixture of ((4-bromo-2-fluorophenyl)(tetrahydro-3-furanyl)methanone (Intermediate 7, 850 mg) 1,1-dimethylethyl hydrazinecarboxylate (616 mg) and acetic acid (1 mL) in methanol (5 mL) was stirred at reflux under nitrogen for 20 h. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic phase was washed with sodium bicarbonate (1M, 10 mL), dried using a hydrophobic filter tube and concentrated under vacuum to give the title compound as a brown oil (1.1 g).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1.[OH-].[Na+].Cl>C1COCC1>[F:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:22])=[O:2])=[N:7][CH:8]=2)=[O:21])=[CH:19][CH:18]=1
Reactant: COC(=O)COc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Yield: 871.5 %

Procedure:
To a solution of [5-(4-fluoro-phenylcarbamoyl)-pyridin-2-yloxy]-acetic acid methyl ester (0.052 g, 0.17 mmol) in THF (1.2 mL) was added an aqueous solution of sodium hydroxide (0.34 mL of a 1 M solution, 0.34 mmol). After 30 minutes the reaction was acidified to pH 3 with 6N HCl and the solvent removed in vacuo. The solids were washed with cold water and the volatiles removed to yield 0.43 g (82%) of the titled product as a white solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:30][C:31]=1[CH3:32])[CH2:6][O:7][C:8]1[C:12]([C:13](O)=[O:14])=[CH:11][N:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:9]=1.Cl.C([N:42]=C=NCCCN(C)C)C.CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[O:30][C:31]=1[CH3:32])[CH2:6][O:7][C:8]1[C:12]([C:13]([NH2:42])=[O:14])=[CH:11][N:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:9]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2C(N)=O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
A mixture of 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-4-carboxylic acid (0.80 g), 1-hydroxy-1H-1,2,3-benzotriazole ammonia complex (0.27 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.34 g) and N,N-dimethylformamide (10 mL) was stirred overnight at room temperature. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-4-carboxamide (0.78 g, yield 98%) as colorless crystals. The crystals were recrystallized from acetone-hexane. melting point: 190-191° C.
Reaction SMILES: [CH2:1]([SH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]2>>[O:6]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:1][S:7][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]2
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: SCc1ccco1
Product: O=C1CCc2cc(OCCCCSCc3ccco3)ccc2N1

Procedure:
Prepared analogous to Example 1 from furfuryl-mercaptan and 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH3:10][O:11][CH2:12]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][O:11][CH3:12])=[C:4]([F:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Into acetone (300 ml), 4-bromo-2-fluorophenol (30 g, 157 mmol) was dissolved, to which chloromethyl methyl ether (18 ml, 237 mmol) and potassium carbonate (43 g, 235 mmol) were added, followed by stirring at room temperature for two hours. Impurities were filtered off and the filtered solution was washed with acetone. The filtrate was concentrated under reduced pressure and the residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-85:15, V/V) to give the desired title compound (36.5 g, yield 82%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14].[OH-].[Na+]>O1CCCC1.O>[CH2:16]([O:15][C:13]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:14])[CH:17]=[CH2:18]
Reactant: CCOC(=O)[C@@H]1COCCN1
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CCOC[C@H]1C(=O)OCC

Procedure:
To a solution of ethyl (3S)-morpholine-3-carboxylate (3.80 g) in a mixture of tetrahydrofuran (40 ml) and water (40 ml) was added a solution of allyl chloroformate (3.36 ml), in tetrahydrofuran (3 ml) under ice-cooling with stirring, keeping the pH between 8.5 and 9.5 with 4N aqueous sodium hydroxide. After stirring for 30 minutes, the mixture was extracted with ethyl acetate (100 ml), dried over magnesium sulfate, and evaporated to give ethyl (3S)-4-allyloxycarbonylmorpholine-3-carboxylate (5.83 g) as a syrup.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:3].CN(C)C=O.[N:29]([CH2:32][CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[N+:30]=[N-:31]>[Cu]I.CO>[CH3:3][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[N:31]=[N:30][N:29]([CH2:32][CH2:33][NH:34][C:35]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:41])[CH:18]=3)[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:1]
Reactant: C#Cc1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Reactant: CC(C)(C)OC(=O)NCCN=[N+]=[N-]
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)N1c2ccc(-c3cn(CCNC(=O)OC(C)(C)C)nn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A flask was charged with 1-methylethyl[(2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 58) (80 mg, 0.254 mmol) and copper(I) iodide (2.423 mg, 0.013 mmol) then filled with N,N-dimethylformamide (DMF) (1.8 mL) and methanol (0.200 mL). 1,1-Dimethylethyl (2-azidoethyl)carbamate (for a preparation, see Intermediate 78) (95 mg, 0.509 mmol) was added and the resulting mixture was stirred under microwave irradiation at 100° C. for 2 h then cooled to room temperature. The reaction mixture was partitioned between EtOAc and brine and the layers were separated. The aqueous phase was extracted with EtOAc (3×) and the combined organic phases were washed with brine, dried over a Na2SO4 cartridge and concentrated in vacuo. Purification of the residue on SP4 using a 10 G silica cartridge (gradient: 5 to 25% (10% MeOH in DCM) in DCM) gave 1-methylethyl((2S,4R)-1-acetyl-6-{1-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1H-1,2,3-triazol-4-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (108 mg, 0.216 mmol, 85% yield) as a pale yellow foam. LCMS (method A): Retention time 0.95 min, [M+H]+=501.26
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[NH:6][C:5](=[O:16])[CH:4]=1.[F-].[Cs+].I[CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[NH2:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[C:5]([O:16][CH:22]([CH3:24])[CH3:23])[CH:4]=[C:3]2[C:2]([F:18])([F:17])[F:1]
Reactant: O=c1cc(C(F)(F)F)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CC(C)I
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C(F)(F)F)c2cc(N)ccc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
In a 250-mL r.b. flask, a solution of 4-trifluoromethyl-6-nitroquinolinone (structure 1 of Scheme I) (3.78 g, 14.6 mmol) in DMF (75 mL) was treated with CsF (12.41 g, 73 mmol, 5.0 equiv.) and 2-iodopropane (11.09 g, 73 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature (rt) for 18 h. The reaction mixture was quenched with H2O (100 mL) and extracted with EtOAc (3×200 mL). The combined EtOAc extracts were washed with saturated aqueous NH4Cl solution (300 mL), H2O (300 mL) and brine (300 mL). Dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 5×20 cm, 2% EtOAc in hexane as eluent) to afford 3.94 g (90%) of the 2-isopropoxyquinoline as a white solid. Rf 0.81 (SiO2, 10% EtOAc-hexane). 1H NMR (400 MHz, CDCl3) 8.93 (s, 1H), 8.47 (dd, 1H, J=9.2, 2.5), 7.98 (d, 1H, J=9.2), 7.32 (s, 1H), 5.62 (septet, 1H, J=6.2), 1.45 (d, 1H, J=6.2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C)[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][O:30][C:31](=[O:46])[CH:32]([O:41][CH2:42][CH2:43][O:44][CH3:45])[CH2:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:29][O:30][C:31](=[O:46])[CH:32]([O:41][CH2:42][CH2:43][O:44][CH3:45])[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:17][CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:14][CH:13]=2)=[CH:38][CH:39]=1
Reactant: COCCOC(Cc1ccc(O)cc1)C(=O)OC
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(N(C)C(=O)OC(C)(C)C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COCCOC(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(=O)OC
Yield: 57 %

Procedure:
2-[4-{tert-Butoxycarbonyl(methyl)amino}phenyl]ethyl-4-methylbenzenesulfonate (described in Example 40a) (0.50 g; 1.26 mmole), 3-(4-hydroxyphenyl)-2-(2-methoxyethoxy)propanoic acid methyl ester(0.32 g; 1.26 mmole) and potassium carbonate (0.35 g; 2.64 mmole) were mixed in acetonitrile (20 ml) and refluxed over night. Water was added, acetonitrile evaporated and the residue extracted three times with ethyl acetate. The organic phase was dried with magnesium sulfate and evaporated. Purification of the crude product with preparativ HPLC (Kromasil C8, 7 μm, 50×250 mm) using acetronitrile (50-70%) in ammonium acetate buffer (pH 7) as mobil phase gave 0.34 g (58% yield) of 3-[4-(2-(4-tert-butoxycarbonylaminophenyl}ethoxy)phenyl]-2-(2-methoxyethoxy)propanoic acid methyl ester
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[CH:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(Cl)(=O)C>>[CH:17]1([C:23]([NH:1][C:2]2[N:3]=[CH:4][N:5]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[C:7]([NH2:9])=[O:8])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CC(=O)Cl
Product: NC(=O)c1c(NC(=O)C2CCCCC2)ncn1Cc1ccccc1
Yield: 49 %

Procedure:
An amidation reaction and a post-treatment were carried out according to the conditions of Example 18, using 2.2 g (10 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide prepared in Reference Example 2 and cyclohexanecarbonyl chloride separately prepared according to a conventional method, instead of acetyl chloride, to obtain a crude crystals. The crude crystals were purified by suspension in hot methanol to obtain 1.62 g of 4-cyclohexylcarbonylamino-1-benzyl-5-imidazolecarboxamide (yield 49%).
Reaction SMILES: [C:1]([C:9]1[CH:31]=[CH:30][C:12]([O:13][CH2:14][C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([O:28][CH3:29])[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][OH:33]>C(O)C>[OH:33][N:32]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:31]=[CH:30][C:12]([O:13][CH2:14][C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([O:28][CH3:29])[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1
Reactant: NO
Reactant: CO[C@@H](Cc1ccc(C#CCOc2ccc(C(=O)c3ccccc3)cc2)cc1)C(=O)O
Solvent: CCO
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc(C(=NO)c3ccccc3)cc2)cc1)C(=O)O
Reaction time: 8 h

Procedure:
(2S)-3-{4-[3-(4-Benzoyl-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-propionic acid (0.01 mmol, 1 eq) (Example 2) was mixed with Hydroxylamine chlorydrate (4 eq), pyrydine (10 eq) and Ethanol (2 ml) and the mixture reaction was stirred overnight. The ethanol was evaporated under vacuo and HCl 0.5% was added to the residue to pH=3. Extracted with Ethyl Acetate and concentrated to give the title product as a mixture of two oximes. MS(ES) for C26H23NO5 [M+H]+: 430.2, [M−H]−: 428.2.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1>>[CH3:22][N:21]([CH3:23])[C:19](=[O:20])[CH2:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:3][C:2]([C:34]4[CH:33]=[N:32][C:31]([CH3:30])=[CH:36][CH:35]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1
Reactant: CN(C)C(=O)CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(CC(=O)N(C)C)CC4)cc3n2)cn1

Procedure:
2-[4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-N,N-dimethyl-acetamide (Example 80) was reacted with 2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine in General Procedure A. Purification on silica yielded 174. (400 MHz CDCl3): 2.54 (8H, m, CH2), 2.55 (3H, s, CH3), 2.87 (3H, s, CH3), 3.00 (3H, s, CH3), 3.12 (2H, s, CH2), 3.76 (2H, s, CH2), 3.81-3.83 (4H, m, CH2), 3.96-3.99 (4H, m, CH2), 7.16 (1H, m, ar), 7.23 (1H, s, ar), 8.48 (1 h, dd(J=8.06, 2.23), ar), 9.43 (1H, d(J=1.87), ar). MH+ 496.37
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N+:15]([O-:17])=[O:16])[C:9]2=[O:18])=[CH:5][CH:4]=1.[CH2:21]=[O:22].C[O-].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:21][OH:22])=[C:10]([N+:15]([O-:17])=[O:16])[C:9]2=[O:18])=[CH:5][CH:4]=1
Reactant: C=O
Reactant: COc1ccc(Cn2ccc(C)c([N+](=O)[O-])c2=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(Cn2ccc(CCO)c([N+](=O)[O-])c2=O)cc1
Reaction time: 2 h
Yield: 59.2 %

Procedure:
To a stirred mixture of 1-(4-methoxybenzyl)-4-methyl-3-nitro-2-pyridone (1.38 g, 5.0 mmol) and paraformaldehyde (0.152 g) in dimethylsulfoxide (8 mL) was added sodium methoxide (0.018 g). After 2 hours, the mixture was diluted with ethyl acetate and washed with water. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was dried, filtered and evaporated. The residual solid was triturated with chloroform/ethyl acetate (10 mL, 1/1) and 1-(4-methoxybenzyl)-4-hydroxyethyl-3-nitro-2-pyridone was collected by filtration (0.496 g). Fractionation of the supernatant over silica gel (chloroform/ethyl acetate to ethyl acetate/methanol 99/1) gave additional product (0.404 g) (total yield, 2.96 mmol, 59%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([SH:10])[CH:7]=[CH:8][CH:9]=1.[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16](F)[C:13]=1[C:14]#[N:15]>CN(C=O)C>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([S:10][C:6]2[CH:5]=[C:4]([CH3:3])[CH:9]=[CH:8][CH:7]=2)[C:13]=1[C:14]#[N:15]
Reactant: N#Cc1c(F)cccc1F
Reactant: Cc1cccc(S)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Sc2cccc(F)c2C#N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
To a cold (ice water) suspension of sodium hydride (316 mg; 7.9 mmol) in anhydrous DMF (10 mL) is added a solution of 3-methylbenzenethiol (941 uL; 7.9 mmol) in anhydrous DMF (5 mL) over 10 minutes. After allowing to room temperature over 30 minutes, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (1 g; 7.2 mmol) in anhydrous DMF (15 mL), and allowed to room temperature over 3 hours. The reaction mixture is poured into ice water with vigorous stirring and the resulting precipitate is removed by filtration and dried under vacuum overnight to give 1.74 grams of 2-fluoro-6-m-tolylsulfanylbenzonitrile.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[N:21]=[C:20]([NH:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]3)[N:19]=[C:18]3[C:14]=1[N:15]=[CH:16][N:17]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:8][CH2:7]2)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[N:21]=[C:20]([NH:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([NH:29][C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])[CH2:25][CH2:24]3)[N:19]=[C:18]3[C:14]=1[N:15]=[CH:16][N:17]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:8][CH2:7]2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc([N+](=O)[O-])ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(N)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1

Procedure:
12.65 g of product obtained in stage 3 above in 130 ml of methanol are introduced into a round-bottomed hydrogenation flask; 500 mg of Pd/C are added and the mixture is stirred under a pressure of 1400 mbar of hydrogen for 12 hours. The mixture is filtered over clarcel and the solvent is then evaporated off. The residue is chromatographed on 600 g of silica, with 60/40 dichloromethane/ethyl acetate as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:15]([O:17]CC)=O)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1.[C:21]([NH:34][NH2:35])(=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:15]([NH:35][NH:34][C:21](=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:17])[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCC(=O)NN
Reactant: CCOC(=O)c1c(O)c2ccc(Cl)cc2n(CC)c1=O
Product: CCCCCCCCCCCC(=O)NNC(=O)c1c(O)c2ccc(Cl)cc2n(CC)c1=O

Procedure:
Reagents: Comp 40 (0.5 mmols, 0.15 g); dodecanoyl hydrazine (0.56 mmols, 0.124 g). Yield: 0.221 g (95%), white solid, m.p.=138° C.-139° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[O:8][N:7]=1.C(N(CC)CC)C.[C:25](Cl)(Cl)=[S:26]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([N:17]=[C:25]=[S:26])=[CH:13][CH:12]=2)[O:8][N:7]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(-c2nc(-c3ccco3)no2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: S=C=Nc1ccc(-c2nc(-c3ccco3)no2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.3 %

Procedure:
To a solution of 3-(2-furyl)-5-(4-aminophenyl)-1,2,4-oxadiazole (5.1 g, 0.02 mole) in 150 ml of dry tetrahydrofuran containing 3.1 ml of triethylamine, thiophosgene 2.53 g (0.02 mole) is added and the mixture is stirred at room temperature for 4 hours. After filtration, the solvent is evaporated in vacuo and the product is crystallized from petroleum ether to give 4.0 g (68%) of the title compound, m.p. 136°-137°.
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH2:22]([N:24]=[C:25]=[S:26])[CH3:23].O>CN(C=O)C>[CH2:22]([NH:24][C:25](=[S:26])[O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([S:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:7][CH:8]=1)[CH3:23]
Reactant: CCN=C=S
Reactant: CCC(C)Sc1ccc(OCCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=S)OCCOc1ccc(SC(C)CC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the above alcohol (2.16 g, 10.0 mmol) and potassium carbonate (1.66 g, 12.0 mmol) in 10 ml of DMF is cooled to 5° and ethyl isothiocyanate (1.10 ml, 12.0 mmol) in 10 ml of DMF is added dropwise. After addition is complete, the mixture is allowed to warm to RT and is stirred at RT overnight. Water is added and the aqueous phase is extracted with ether. The combined organic layers are washed with water and brine, dried, and the solvent removed, and the residue is purified by column chromatography to give O-2-[4-(1-methylpropylthio)phenoxy]ethyl N-ethylthiocarbamate.