Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:3]=1.[C:17]([O:21][C:22]([CH2:24][CH2:25][CH2:26][S:27]([C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39](F)(F)F)[CH:38]=1)[C:33](O)=[O:34])(=[O:29])=[O:28])=[O:23])([CH3:20])([CH3:19])[CH3:18]>CCCCCCC.C(OCC)(=O)C>[C:17]([O:21][C:22](=[O:23])[CH2:24][CH2:25][CH2:26][S:27]([C:30]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:32]([C:33](=[O:34])[N:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH3:9])[CH:31]=1)(=[O:29])=[O:28])([CH3:18])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)CCCS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1nnc(Cl)cc1-c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1cc(C(=O)N(C)c2nnc(Cl)cc2-c2ccccc2C)cc(S(=O)(=O)CCCC(=O)OC(C)(C)C)c1
Yield: 14 %

Procedure:
The title compound was prepared in analogy to example 1, from (6-chloro-4-o-tolyl-pyridazin-3-yl)-methyl-amine (example 4, intermediate a) and 3-(3-tert-butoxycarbonyl-propane-1-sulfonyl)-5-trifluoromethyl-benzoic acid after a reaction time of 18 hours and using a gradient of n-heptane:ethyl acetate (100:0 to 30:70) for the chromatographic purification. Another purification step using preparative HPLC (Gemini NX column) with a gradient of methanol:water with 0.05% formic acid (80:20 to 98:2) yielded the desired compound as a colorless solid (14%). MS (ESI+): m/z=541.090 ([M+H]+).
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([O:19][C:20](=[O:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:15][C:16]([OH:18])=O.ON1C(=O)CCC1=O.[NH2:45][CH2:46][CH2:47][C:48]([NH:50][C@H:51]([C:55]([OH:57])=[O:56])[C@@H:52]([CH3:54])[OH:53])=[O:49].Cl>O1CCOCC1.CN(C)C=O.O.C(N(CC)CC)C>[CH3:36][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([O:19][C:20](=[O:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:15][C:16]([NH:45][CH2:46][CH2:47][C:48]([NH:50][C@H:51]([C:55]([OH:57])=[O:56])[C@@H:52]([CH3:54])[OH:53])=[O:49])=[O:18]
Reactant: C[C@@H](O)[C@H](NC(=O)CCN)C(=O)O
Reactant: CC(C)CCCCCCCCCCCC(=O)OC(CCCCCCCCCCCC(C)C)CC(=O)O
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)CCCCCCCCCCCC(=O)OC(CCCCCCCCCCCC(C)C)CC(=O)NCCC(=O)N[C@H](C(=O)O)[C@@H](C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
15-Methyl-3-(13-methyltetradecanoyloxy)hexadecanoic acid (140 mg) prepared by the method described in Preparation 1-(3) and N-hydroxysuccinimide (34 mg) were dissolved in dioxane (2.5 ml). N,N-Dicyclohexylcarbodiimide (63 mg) was added thereto under ice cooling. The mixture was reached to room temperature and stirred at ambient temperature overnight. The crystallized urea was filtered off and the filtrate was concentrated to give a residue which was dissolved in N,N-dimethylformamide (5 ml). To this solution was added a solution of β-alanyl-L-threonine (100 mg) and triethylamine (90 μl) in water (3 ml) at 0° C. The resulting mixture was reached to room temperature and stirred at ambient temperature overnight. The reaction mixture was acidified with 1 N hydrochloric acid, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. Ethyl acetate was distilled off to give a residue which was subjected to preparative thin layer chromatography (Merck, 0.25 mm×5) and eluted with a mixture of benzene, dioxane and acetic acid (10:5:1). The band containing the object compound was extracted with methanol and chloroform (3:7) and the solvent was evaporated off under reduced pressure to afford a wax of N-[N-[15-methyl-3-(13-methyltetradecanoyloxy)hexadecanoyl]-β-alanyl]-L-threonine (100 mg).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1[N:24]=[N+]=[N-])(=[O:3])[CH3:2].[H][H]>[Ni].C(OCC)(=O)C>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[NH2:24])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)OC[C@H]1O[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](N)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 60.9 %

Procedure:
To a mixture of about 3.0 grams of 2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl azide, 0.5 grams Raney nickel catalyst, and 40 ml. ethyl acetate, is vigorously agitated with hydrogen at atmospheric pressure, at a temperature of about 25° C. for a period of about 6.5 hours. The reaction mixture is filtered through diatomaceous silica, and the filtered solution is evaporated in vacuo to a syrup which crystallizes upon standing at a temperature of about 5° C. The crystalline product is recrystallized from 2-propanol to give about 1.7 grams of 2,3,4,6-tetra-O-acetyl-β-D-mannopyranosylamine; m.p. 145°-147° C.; [α]D25 -9.8° (c 1.02, methanol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:3][CH:2]=1.I[CH2:17][CH2:18][CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1>>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH:19]1[CH2:18][CH2:17][N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:5][CH2:6]1
Reactant: ICCC1Cc2ccccc2C1
Reactant: c1ccc2[nH]c(-c3ccncc3)cc2c1
Product: C1=C(c2cc3ccccc3[nH]2)CCN(CCC2Cc3ccccc3C2)C1

Procedure:
Prepared from 27a and 24a. Mp 175-176  C. 1H NMR (CDCl3) δ1.75-1.85 (m, 2H), 2.45-2.55 (m, 1H), 2.55-2.60 (m, 2H), 2.60-2.70 (m, 4H), 2.70-2.80 (m, 2H), 3.05-3.15 (m, 2H), 3.25 (broad s, 2H), 6.05 (broad s, 1H), 6.45 (s, 1H), 7.05 (t, 1H), 7.10-7.25 (m, 5H), 7.35 (d, 1H), 7.55 (d, 1H), 8.10 (broad s, 1H). MS m/z (%): 343 (MH+, 8%), 174 (32%), 143 (100%).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]2[CH:14]2[CH:21]3[CH2:22][C:17]4([C:24]([O:26]C)=[O:25])[CH2:18][CH:19]([CH2:23][CH:15]2[CH2:16]4)[CH2:20]3)=[CH:4][CH:3]=1.O.[Na].Cl>O1CCCC1CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:10]([CH3:11])([CH3:12])[C:9](=[O:13])[N:8]2[CH:14]2[CH:21]3[CH2:22][C:17]4([C:24]([OH:26])=[O:25])[CH2:18][CH:19]([CH2:23][CH:15]2[CH2:16]4)[CH2:20]3)=[CH:28][CH:29]=1
Reactant: COC(=O)C12CC3CC(C1)C(N1C(=O)C(C)(C)N1Cc1ccc(F)cc1)C(C3)C2
Agent: Cl
Agent: [Na]
Solvent: OCC1CCCO1
Solvent: O
Product: CC1(C)C(=O)N(C2C3CC4CC2CC(C(=O)O)(C4)C3)N1Cc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
A solution of methyl 4-[2-(4-fluorobenzyl)-3,3-dimethyl-4-oxo-1,2-diazetidin-1-yl]adamantane-1-carboxylate (40.0 mg, 0.100 mmol) in tetrahydrofuran-methanol (1:1, 1 mL) was added with 2M aqueous solution of sodium hydrate (1 mL) at room temperature, and the resultant was stirred at 80° C. for 30 minutes. The reaction solution was neutralized with 4M hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was purified using Preparative Thin-Layer chromatography (hexane:ethyl acetate=1:2), and the title compound (24.5 mg, 63.4%) was obtained as a white crystalline powder.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([CH3:11])[CH:5]=1>[OH-].[Na+].C1COCC1>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:12])=[O:2])=[CH:5][C:6]=1[CH3:11]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of methyl-4-bromo-3-methylbenzoate (400 mg) in 2N NaOH aqueous solution (3 mL) and THF (5 mL) was stirred at room temperature for 16 h. The mixture was washed with Et2O. The aqueous layer was acidified with 4N HCl aqueous solution, extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-bromo-3-methyl-benzoic acid as white powder: MS (m/z) 215 (M+1); 1H NMR (CD3OD, 400 MHz) δ 7.95 (s, 1H), 7.76 (d, 1H), 7.64 (d, 1H), 2.47 (s, 3H).
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]2[N:28]([CH:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)[CH:29]=[C:30]([CH3:31])[C:9]=12.C(O)(C(F)(F)F)=O.O>>[F:27][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([C:16]1[CH:15]=[N:14][N:13]3[C:8]([NH2:7])=[C:9]4[C:30]([CH3:31])=[CH:29][N:28]([CH:32]5[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]5)[C:10]4=[N:11][C:12]=13)=[CH:26]2
Reactant: Cc1cn(C2CCN(C(=O)OC(C)(C)C)CC2)c2nc3c(-c4cnc5ccc(F)cc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cn(C2CCNCC2)c2nc3c(-c4cnc5ccc(F)cc5c4)cnn3c(N)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., tert-butyl 4-(8-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)-7-methyl-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate (95 mg, 0.12 mmol) was treated with 80% TFA/H2O (5 mL). After stirring at room temperature for 30 min, concentration afforded crude 3-(6-fluoroquinolin-3-yl)-7-methyl-5-(piperidin-4-yl)-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidin-8-amine which was used for next step without further purification. LCMS is =0.69 Min (5 min run, UV254nm), Mass calculated for M+415.2, observed m/z 416.2 (M+H).
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][C:3]([NH2:5])=[O:4].[O-]CC.[Na+].[F:12][CH:13]([F:19])[C:14](OCC)=O.Cl.[Cl-].[NH4+]>CO>[F:12][CH:13]([F:19])[C:14]1[N:5]=[C:3]([OH:4])[CH:2]=[C:1]([OH:6])[N:7]=1
Reactant: NC(=O)CC(N)=O
Reactant: CCOC(=O)C(F)F
Agent: CC[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: Oc1cc(O)nc(C(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of malonamide (5.1 g) and sodium ethoxide (20% ethanol solution, 34.3 g) in methanol (125 mL) was stirred at room temperature for 1 hour. To the mixture was added ethyl 2,2-difluoroacetate (6.31 mL), and the mixture was heated at reflux for 10 hours, and then stirred at room temperature overnight. To the mixture was added 1 mol/L hydrochloric acid until the pH became 3. The mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate thrice. The extracts were washed with brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residual solids were suspended in a mixed solvent (n-hexane/ethyl acetate=2/1), and collected by filtration. The collected solids were dried under reduced pressure to give 2-difluoromethyl-4,6-dihydroxypyrimidine (2.36 g). The title compound was prepared in a similar manner to that described in Reference Example 177 using this material instead of 4,6-dihydroxy-2-methylpyrimidine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]#[CH:11])=[CH:4][N:3]=1.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]#[C:11][C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:22])([F:21])[F:12])=[CH:15][CH:16]=2)=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: C#Cc1cnc(N)c(C#N)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1nc(C#Cc2ccc(C(F)(F)F)cc2)cnc1N

Procedure:
A solution of 3.2 grams (0.022 mole) of 2-amino-3-cyano-5-ethynylpyrazine, 8.4 grams (0.031 mole) of 4-trifluoromethylphenyl iodide, 10.7 grams (0.077 mole) of triethylamine, 0.5 gram (catalyst)of bis(triphenylphosphine)palladium(II) chloride, and 0.5 gram (catalyst) of copper iodide in 100 mL of acetonitrile is stirred at ambient temperature for about 18 hours. After this time the reaction mixture is concentrated under reduced pressure to a residue. The residue is partitioned between ethyl acetate and aqueous 1N hydrochloric acid. The two-layered mixture is filtered to remove a solid. The aqueous layer and the organic layer are separated, and the aqueous layer is washed with ethyl acetate. The ethyl acetate wash is combined with the organic layer, and the combination is washed with an aqueous solution of 10% lithium chloride. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is triturated with methylene chloride and filtered. The filtrate is subjected to column chromatography on silica gel. Elution is accomplished using methanol/methylene chloride combinations. The product-containing fractions are combined and concentrated under reduced pressure, yielding 2-amino-3-cyano-5-[(4-trifluoromethylphenyl)ethynyl]pyrazine.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH:17]=[CH:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[N-:29]=[N+:30]=[N-:31].[Na+].Cl.N1C=CC=CC=1>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH:17]=[CH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]3[NH:31][N:30]=[N:29][N:24]=3)=[CH:25][CH:26]=2)=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C(=Cc1ccc(-c2nnn[nH]2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 100 °C

Procedure:
A mixture of 1.15 g (3.17 mmol) of 4-(4-(2-quinolinylmethyloxy)styryl)benzonitrile 1.03 q (15.86 mmol) of sodium azide, and 1.83 (15.86 mml) of pyridine hydrochloride in 15 ml of DMF is heated at 100° C. for 48 hours and then poured into ice water. The precipitate that forms is filtered off and suspended in hot methanol and filtered to give 5-(4-(4- (2-quinolinylmethyloxy)styryl)phenyl)tetrazole. (M.P. 241° C.-243° C.)
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:8][CH:7]=1.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.[Li]CCCC>C1COCC1>[CH3:16][O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:2]=2[B:22]([OH:27])[OH:23])=[CH:7][CH:8]=1
Reactant: COCCOc1ccc(OCc2cc(Cl)ccc2Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOc1ccc(OCc2cc(Cl)ccc2B(O)O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
In a flask, 1.8 g (4.8 mmol) of the compound obtained in Step 2 was dissolved in 10 ml of anhydrous THF, and 1.34 ml (5.8 mmol) of triisopropyl borate was added thereto. The flask was cooled to −78° C. over a dry ice-acetone bath, 2.3 ml (5.8 mmol) of 2.5 M n-BuLi (in hexane) was added dropwise to the mixture over 15 min. After the reaction mixture was kept for 1 hour, the dry ice-acetone bath was removed, and 5 ml of 2 N HCl was added to the mixture. After stirring the mixture for 1 hour, the water layer was separated and extracted twice with 10 ml portions of ethyl acetate. The organic layers were combined, washed with a brine solution, dried over anhydrous MgSO4, and filtered under a reduced pressure to remove the solvent. The residue was recrystallized from ethyl acetate/hexane to obtain 1.12 g (yield 69%) of 2-((4-(2-methoxyethoxy)phenoxy)methyl)-4-chlorophenylboronic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]([C:9]([O:11]N2C(=O)CCC2=O)=O)=[CH:7][C:6]=1[CH3:21])=[O:4].[OH:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27].C(N(CC)CC)C>CN(C)C=O>[OH:22][C:23]1[CH:24]=[C:25]([CH2:26][NH:27][C:9]([C:8]2[CH:19]=[CH:20][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]([CH3:21])[CH:7]=2)=[O:11])[CH:28]=[CH:29][CH:30]=1
Reactant: NCc1cccc(O)c1
Reactant: COC(=O)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1C
Yield: 91.3 %

Procedure:
A solution of 1-[[4-(methoxycarbonyl)-3-methylbenzoyl]oxy]-2,5-pyrrolidinedione (Example 6; 6.00 g, 20.6 mmol), 3-hydroxybenzylamine (2.92 g, 23.7 mmol) and triethylamine (2.61 g, 25.8 mmol) in N,N-dimethyl-formamide (100 mL) was stirred at room temperature overnight. The solvent was evaporated (<0.5 mm Hg, 40° C.) and ethyl acetate (200 mL) was added. The solution was washed with 0.5N hydrochloric acid (200 mL), brine (200 mL), saturated sodium bicarbonate solution (2×150 mL) and brine (200 mL). Each aqueous layer was back-extracted in turn with ethyl acetate (100 mL). The combined organic layers were dried (MgSO4), filtered, and evaporated to give 4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-2-methylbenzoic acid, methyl ester (5.63 g, 91%) as an orange liquid that solidified on standing, mp 100–103° C.
Reaction SMILES: Cl.[C:2](=[NH:10])([O:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH2:5][CH3:6].N[NH:12][C:13]([NH2:15])=[S:14].C(Cl)Cl.CO>CN(C=O)C>[C:2](=[N:10][NH:12][C:13]([NH2:15])=[S:14])([O:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(=N)OCC
Reactant: NNC(N)=S
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCC(=NNC(N)=S)OCC
Reaction time: 2.5 h

Procedure:
A solution of 10.79 g (65 mmol) of ethyl valerimidate hydrochloride [prepared by method of A. J. Hill and I. Rabinowitz, J. Am. Chem. Soc., 48, 734 (1926)] in 130 ml of dry DMF was stirred at room temperature as 5.91 g (65 mmol) of thiosemicarbazide was added. Stirring was continuted under N2. After 2.5 hours, by which time TLC (19:1 CH2Cl2 -MeOH) indicated complete conversion of thiosemicarbazide to a higher Rf product, the mixture was partitioned between 1 L of H2O, then dried over MgSO4, filtered, and concentrated in vacuo. The residual oil, upon drying in vacuo (<1 mm) overnight, solidified to yield 11.05 g (84%) of nearly white solid, mp 73°-74.5° C.; homogeneous by TLC in 97:3 CH2Cl2 -MeOH. NMR indicated a mixture of syn and anti isomers.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[F:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:2]([O:15][C:12]1[CH:13]=[CH:14][C:9]([Br:8])=[C:10]([F:16])[CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCBr
Reactant: Oc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCOc1ccc(Br)c(F)c1

Procedure:
A solution of 1-bromohexane (9.33 g) in acetone (20 ml) is added dropwise to a stirred mixture of 4-bromo-3-fluorophenol (9.00 g) and potassium carbonate (13.5 g) in acetone 75 ml) at room temperature. The stirred mixture is heated under reflux for 21 h (i.e. until glc analysis revealed a complete reaction). The product is extracted into ether twice, and the combined ether extracts are washed with water, 10% sodium hydroxide, water and dried (MgSO4). The solvent is removed under vacuo and the residue is distilled (bp 100°-105° C. at 0.1 mm Hg) to yield a colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[F:20].[I-:21].OS([O-])=O.[Na+]>S([O-])([O-])(=O)=O.[Ag+2].CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[C:16]([I:21])[C:15]([O:18][CH3:19])=[CH:14][C:13]=1[F:20]
Reactant: [I-]
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2F)c(Cl)c1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Agent: O=S([O-])O
Solvent: CO
Product: COC(=O)c1ccc(-c2cc(I)c(OC)cc2F)c(Cl)c1

Procedure:
methyl 2-chloro-2′-fluoro-4′-methoxybiphenyl-4-carboxylate (550 mg, 1.87 mmol), methanol (8 mL), iodide (474 mg, 1.87 mmol) and silver sulfate (583 mg, 1.87 mmol) were stirred at room temperature for 2 hours. Reaction crude was worked up with NaHSO3 (aq). Volatiles were removed under reduced pressure. The pot residue was worked up with brine, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated to afford a light brown solid. This solid was purified by SiO2 (Biotage Horizon Flash system, 40+M cartridge, 0-20% EtOAc/hexanes, v/v) to afford the title compound. LCMS (ESI) calc.=419.94; found=420.86 (M+1)+.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:28])[CH2:12][N:13]3[CH2:18][CH2:17][C:16]4([C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][C:19]4=[O:27])[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.IC.[C:31]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:28])[CH2:12][N:13]3[CH2:18][CH2:17][C:16]4([C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]([CH3:31])[C:19]4=[O:27])[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C([O-])[O-]
Reactant: O=C(CN1CCC2(CC1)C(=O)Nc1ccccc12)N1CCN(C2CCC2)CC1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C2(CCN(CC(=O)N3CCN(C4CCC4)CC3)CC2)c2ccccc21
Temperature: 65 °C

Procedure:
A mixture of 1′-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]spiro[indole-3,4′-piperidin]-2(1H)-one (0.136 mmol), iodomethane (0.544 mmol) and Cs2CO3 (177 mg, 0.544 mmol) in DMF (3 ml) is heated in a sealed tube at 65° C. overnight. DMF is removed in vacuo and the residue is partitioned between water (5 ml) and EtOAc (10 ml). The layers are separated and the aqueous layer is extracted with EtOAc (10 ml). The combined extracts are washed with brine (20 ml), dried over Na2SO4 and evaporated. Purification of the residue with PTLC gives the title compound as a white solid. LC-MS (M+1): 396.3.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][CH2:15][OH:16].[CH3:17][C:18]1[N:19]=[C:20]([N:33]2[C:37](=[O:38])[NH:36][N:35]=[CH:34]2)[S:21][C:22]=1[C:23]([NH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:24]>>[OH:16][CH2:15][CH2:14][N:36]1[C:37](=[O:38])[N:33]([C:20]2[S:21][C:22]([C:23]([NH:25][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:24])=[C:18]([CH3:17])[N:19]=2)[CH:34]=[N:35]1
Reactant: Cc1nc(-n2cn[nH]c2=O)sc1C(=O)NCc1cccnc1
Reactant: OCCBr
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: Cc1nc(-n2cnn(CCO)c2=O)sc1C(=O)NCc1cccnc1
Yield: 76 %

Procedure:
Following the procedure as described in Example 19, making variation as required to replace 4-(trifluoromethyl)benzyl bromide with 2-bromoethanol to react with 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 76% yield: mp 201-202° C. (ethyl acetate/hexane); 1H NMR (300 MHz, DMSO-d6) δ 8.87 (t, J=5.8 Hz, 1H), 8.71 (s, 1H), 8.51 (br s, 1H), 8.47-8.39 (m, 1H), 7.73-7.66 (m, 1H), 7.37-7.30 (m, 1H), 4.83 (t, J=5.8 Hz, 1H), 4.40 (d, J=5.8 Hz, 2H), 3.78 (t, J=5.5 Hz, 2H), 3.68-3.58 (m, 2H), 2.53 (s, 3H); MS (ES+) m/z 361.2 (M+1).