Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH2:13][NH2:14])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH2:3]1.[S:15]([OH:19])([OH:18])(=[O:17])=[O:16].CS[C:22](=[NH:24])[NH2:23].CN(C)C=O>O>[S:15]([OH:19])([OH:18])(=[O:17])=[O:16].[OH:1][C:2]1([CH2:13][NH:14][C:22]([NH2:24])=[NH:23])[CH2:3][O:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[O:7][CH2:8]1
Reactant: NCC1(O)COc2ccccc2OC1
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: O
Product: N=C(N)NCC1(O)COc2ccccc2OC1

Procedure:
3-hydroxy-3-aminomethyl-3,4-dihydro-2H-1,5-benzodioxepin from Example 1, Step E, (1.95 g., 10 millimoles) and 2.78 g. (10 millimoles) of S-methylisothiourea sulfate in 15 mls. of dimethylformamide and 2 mls. of water is heated at 90°-100° C. for 5 hours. The solvent is evaporated in vacuo and the residue recrystallized from ethanol to give 3-hydroxy-3-guanidinomethyl-3,4-dihydro-2H-1,5-benzodioxepin sulfate.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([O:19]C)=[O:18].[OH-].[K+]>C(O)C>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: COC(=O)Cc1ccc2c(c1)Cc1ccccc1CO2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc2c(c1)Cc1ccccc1CO2

Procedure:
Reaction of methyl 6,11-dihydrodibenz[b,e]oxepin-2-acetate and potassium hydroxide in ethanol by the method described in Example 1c provides 6,11-dihydrodibenz[b,e]oxepin-2-acetic acid, m.p. 155°-157°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[N:15][OH:16])[CH2:10][CH2:11][CH2:12][C:13]#[N:14])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl[CH2:19][CH2:20][NH2:21].[OH-].[K+].CN(C)C=O>Cl>[ClH:1].[NH2:21][CH2:20][CH2:19][O:16][N:15]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH2:11][CH2:12][C:13]#[N:14]
Reactant: N#CCCCC(=NO)c1ccc(Cl)c(Cl)c1
Reactant: NCCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#CCCCC(=NOCCN)c1ccc(Cl)c(Cl)c1

Procedure:
5.0 mmol (1.29 g) of 3', 4'-dichloro-4-cyanobutyrophenone oxime (melting point 122°-123° C), 5.2 mmol (0.60 g) of 2-chloroethylamine hydrochloride and 0.7 g of powdered potassium hydroxide were added, in this sequence and while stirring at 10° C, to 12 ml of dimethylformamide (D.M.F). After stirring for 2 days at room temperature the D.M.F. was evaporated invacuo, the residue was brought in water and 2N hydrochloric acid was then added while stirring until pH 3. The remaining oxime was removed by means of ether. The acid aqueous solution was then rendered alkaline with 15 ml of 2N sodium hydroxide solution and then extracted three times with ether. After washing with a 5% sodium bicarbonate solution, drying over sodium sulphate and evaporating the ether, the free base was obtained. This was dissolved in alcoholic hydrochloric acid. After evaporating the ethonal, the above entitled compound was crystallized from isopropanol/ether (1 : 1). Melting point 129°-130° C.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[OH:13][C:14]1[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1.[OH-].[Na+]>O=S(Cl)Cl>[F:8][C:7]1[C:2]([O:13][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:23])[C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Reactant: CC(Oc1ccc(O)cc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2F)cc1)C(=O)O
Temperature: 115 °C

Procedure:
A fresh sample of 2-(4-((3-fluoro-5-(trifluoromethyl)-2-pyridinyl)oxy)phenoxy propanoic acid was prepared by the reaction of 2,3-difluoro-5-(trifluoromethyl)pyridine with 2-(4-hydroxyphenoxy)propanoic acid in the presence of 2 moles of sodium hydroxide as above described and 9.0 g (0.026 mole) was refluxed in excess SOCl2 for about 1/2 hour to prepare the corresponding acid chloride. The excess SOCl2 was removed by heating to 115° C. under an aspirator vacuum. The resulting acid chloride was added to a mixture of concentrated ammonium hydroxide (30 ml) and methanol (60 ml). The flask was rinsed with an additional 15 ml ammonium hydroxide mixed with about 25 ml of methanol and the two fractions were combined. The acid amide formed as a solid which was filtered out, rinsed with water, slurried in water, filtered, dried and analyzed. M.P. 140°-141° C.
Reaction SMILES: Cl[CH:2](P(=O)(OCC)OCC)[C:3]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=2[CH:4]=1.[CH:25]([C:27]1[CH:37]=[CH:36][C:30]([CH:31]=[CH:32][C:33]([OH:35])=[O:34])=[CH:29][CH:28]=1)=O>C(O)C>[CH3:13][C:9]1([CH3:14])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]2[CH:4]=[C:3]([C:2]#[C:25][C:27]3[CH:37]=[CH:36][C:30](/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])=[CH:29][CH:28]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(/C=C/C(=O)O)cc3)ccc21
Yield: 39.3 %

Procedure:
Using a procedure similar to that described in Example 6b, 16.5 g (44 millimoles) of diethyl 1-chloro-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)methylphosphonate (about 85% strength), 7.8 g (44 millimoles) of 4-formylcinnamic acid and 15.5 g (137 millimoles) of potassium tert.-butylate were converted to 6.2 g (39%) of the title compound of melting point 256°-258° C. (from ethanol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)=[N:8][C:7]=23)[CH:28]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: Brc1cccnc1
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4cccnc4)c3n2)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (355 mg, 1.0 mmol) and commercially available 3-bromo-pyridine (158 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (211 mg, 49%). MS (EI) 432.2 [(M)+]; mp 173° C.
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:8]=[C:7]([CH:9]=[O:10])[NH:6][C:5]=1[C:11]([O:13]C)=[O:12]>C1COCC1.CO>[Cl:3][C:4]1[CH:8]=[C:7]([CH:9]=[O:10])[NH:6][C:5]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1[nH]c(C=O)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=Cc1cc(Cl)c(C(=O)O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.6 %

Procedure:
LiOH (2 mL, 2 mmol) was added to a solution of methyl 3-chloro-5-formyl-1H-pyrrole-2-carboxylate (0.050 g, 0.26 mmol) in THF (2 mL) and methanol (2 mL). The solution was stirred at room temperature overnight. The solvents were evaporated and the residue was partitioned between EtOAc and 1 N HCl. The organic layer was separated, dried over MgSO4, filtered and evaporated to a solid to afford the title compound (0.0517 g) as a crude product which was used with no further purification. 1H NMR (400 MHz, Acetone-d6) δ ppm 11.87 (br. s., 1H), 9.72 (s, 1H), 7.02 (s, 1H). LCMS: m/z 174.2 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH:9]1[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)=O)(C)(C)C.[NH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1>>[NH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]([CH2:28][C@@H:9]2[NH:8][CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([C:21]4[CH:26]=[CH:25][N:24]=[C:23]([NH:38][CH2:39][CH2:40][C:41]5[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=5)[N:22]=4)[CH:18]=[CH:19][CH:20]=3)[CH2:10]2)=[CH:30]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC1Cc1c[nH]c2ccccc12
Reactant: NCCc1ccc(O)cc1
Product: Oc1ccc(CCNc2nccc(-c3cccc(CN4CCN[C@@H](Cc5c[nH]c6ccccc56)C4)c3)n2)cc1

Procedure:
Intermediate 109 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 520. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.51 (s, 1H), 8.29 (d, 2H), 7.81 (d, 1H), 7.55 (m, 3H), 7.34 (d, 1H), 7.25 (s, 1H), 7.02 (m, 4H), 6.69 (s, 2H), 4.54 (m, 2H), 4.08 (m, 1H), 3.90 (m, 2H), 3.61 (m, 4H), 3.25 (m, 4H), 2.92 (t, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20]([F:23])([F:22])[F:21])=[C:13]([O:17][CH2:18][CH3:19])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:24]>>[ClH:24].[CH2:18]([O:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[C:20]([F:23])([F:21])[F:22])[CH2:9][NH:8][CH2:16]2)[CH3:19]
Reactant: CCOc1cc2c(cc1C(F)(F)F)CN(C(=O)OC(C)(C)C)C2
Agent: Cl
Product: CCOc1cc2c(cc1C(F)(F)F)CNC2

Procedure:
Prepared in analogy to Example A3(e) from 5-ethoxy-6-trifluoromethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. White solid. MS (m/e): 232.1 ([M+H]+, 100%).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O)[CH:2]=[C:3]([CH3:5])[CH3:4].[NH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][CH3:30]>>[CH2:29]([N:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[CH2:23][NH:22][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:15][C:7]=1[O:6][CH2:1][CH:2]=[C:3]([CH3:4])[CH3:5])[CH3:30]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCOc1ccc(C(=O)O)c(OCC=C(C)C)c1
Product: CCN1CCCC1CNC(=O)c1ccc(OCC=C(C)C)cc1OCC=C(C)C
Yield: 98 %

Procedure:
In a manner identical to Example 15, 2,4-diprenyloxybenzoic acid (1.45 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.96 g (98%) of the aimed compound.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23].O>N1C=CC=CC=1>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH:2]([CH3:1])[CH2:3][CH2:4][O:5][C:20](=[O:24])[CH2:21][CH2:22][CH3:23])=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(CCO)c1ccc(OCc2ccccc2)cc1
Reactant: CCCC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCC(=O)OCCC(C)c1ccc(OCc2ccccc2)cc1
Yield: 95 %

Procedure:
2.56 (10 millimols) of (+)-3-methyl-3-(4benzyloxyphenyl)propanol (XI-1) obtained in Preparation Example (starting material compound (V)) 1, was dissolved in 20 ml of pyridine and 1.38 g (13 millimols) of butyrylchloride was added at 30°-40° C. and reacted for 2 hours. The reaction mixture was poured into 200 ml of water and extracted with 200 ml of toluene and separated and then washed with, in the order, 1N aqueous solution of hydrochloric acid, water, 5% aqueous solution of sodium bicarbonate and water, and thereafter dried on anhydrous magnesium sulfate. After the solvent was distilled out under the reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: toluene-ethyl acetate) to provide 3.1 g (yield: 95%) of (+)-4-benzyloxy-l-(1-methyl-3-butyryloxypropyl) benzene (VIII-9).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].CC1C(C)=CC(C)=C([OH:15])C=1O>>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:15])[C:5]([CH3:9])=[CH:4][C:3]=1[OH:10]
Reactant: Cc1cc(C)c(O)c(O)c1C
Reactant: Cc1cc(C)c(C)c(O)c1
Product: Cc1cc(O)c(C)c(C)c1O

Procedure:
By following in the same manner as in Example 56 except that 100 g. (735 m.moles) of 2,3,5-trimethylphenol was used instead of 3,5-dimethylphenol, 2.16 g. (14.2 m.moles) of 3,4,6-trimethylcatechol and 0.71 g. (4.7 m.moles) of 2,3,5-trimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 44.9%.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:21])[CH2:4][C@H:3]1[CH2:22][NH:23]C(=O)OCC1C=CC=CC=1>[OH-].[OH-].[Pd+2]>[NH2:23][CH2:22][C@H:3]1[C@@H:2]([OH:1])[CH2:6][N:5]([CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:21])[CH2:4]1
Reactant: COc1ccc2ccc(=O)n(CCN3C[C@@H](CNC(=O)OCc4ccccc4)[C@@H](O)C3)c2c1
Agent: [Pd+2]
Agent: [OH-]
Product: COc1ccc2ccc(=O)n(CCN3C[C@@H](CN)[C@@H](O)C3)c2c1
Reaction time: 18 h
Yield: 99.3 %

Procedure:
To a solution of phenylmethyl [((3R,4R)-4-hydroxy-1-{2-[7-(methyloxy)-2-oxo-1(2H)-quinolinyl]ethyl}-3-pyrrolidinyl)methyl]carbamate (337 mg, 0.746 mmol) was added 20% Pd(OH)2/C, degassed and placed under 1 atm of H2 for 18 h. The reaction mixture was filtered through Celite and concentrated to obtain the title compound as a yellow oil (235 mg, 100%).
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[N:8]2[CH:25]=[C:26]([Cl:28])[CH:27]=[C:7]2[C:6]=1[OH:29])=[O:4].[NH2:30][C@H:31]([C:33]([OH:35])=[O:34])[CH3:32].C[O-].[Na+]>>[C:16]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[C:10](=[O:11])[C:5]([C:3]([NH:30][C@@H:31]([CH3:32])[C:33]([OH:35])=[O:34])=[O:4])=[C:6]([OH:29])[C:7]3=[CH:27][C:26]([Cl:28])=[CH:25][N:8]23)=[CH:18][CH:17]=1
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(-c3ccccc3)cc2)c1=O
Agent: C[O-]
Agent: [Na+]
Product: C[C@H](NC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(-c3ccccc3)cc2)c1=O)C(=O)O

Procedure:
Prepared according to the reaction condition used in Example 19 step a) from 1-biphenyl-4-ylmethyl-6-chloro-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester, L-alanine and NaOMe. ESI (m/z): 466 (M+H)+.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([SH:12])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(O[CH:17]1[NH:20][C:19](=[O:21])[CH2:18]1)(=O)C>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([S:12][CH:17]2[NH:20][C:19](=[O:21])[CH2:18]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CC(=O)OC1CC(=O)N1
Reactant: COc1ccc(S)cc1OC
Agent: [Na]
Solvent: CCO
Product: COc1ccc(SC2CC(=O)N2)cc1OC
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
Sodium (0.9 g, 39 mmol) was dissolved in ethanol (150 ml) and 3,4-dimethoxythiophenol (5.9 g, 35 mmol) added dropwise over 20 minutes keeping the temperature between 20° C.-25° C. whilst bubbling nitrogen through the mixture. After 15 minutes, the reaction was cooled to 5° C. and a solution of 4-acetoxyazetidin-2-one (4.3 g, 33 mmol) in ethanol (50 ml) was added dropwise over 15 minutes whilst maintaining the temperature at 5° C. The mixture was stirred at room temperature for 60 minutes and evaporated to dryness under reduced pressure. Water (400 ml) was added, the mixture extracted with dichloromethane (2×300 ml), the extracts dried (MgSO4) and evaporated under reduced pressure to an oil. The oil was cooled to -20° C. and titurated with ether (400 ml) to give a white solid which was isolated by filtration (4.1 g, 52%) m.p. 145-6° C. 1H NMR δ (CDCl3) 2.85 (1H, m, H3a), 3.31 (1H, m, H3b), 3.88 (3H, s, O--CH3), 3.89 (3H, s, O--CH3), 4.92 (1H, dd, J=4.92, 2.30 Hz, H4), 6.30 (1H, br. singlet, N--H), 6.85 (1H, d, J=8.30 Hz, Ph--H), 7.00 (1H, d, J=2.04 Hz, Ph--H), 7.09 (1H, dd, J=8.25, 2.06 Hz, Ph--H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[CH:4]=[O:5].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1c(Cl)cccc1N1CCCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A 100 mL round-bottom flask was charged with 2-chloro-6-fluorobenzaldehyde (2.00 g, 12.6 mmol, 1.00 equiv), pyrrolidine (1.34 g, 18.8 mmol, 1.49 equiv), potassium carbonate (4.34 g, 31.4 mmol, 2.49 equiv), and dimethyl sulfoxide (20 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. Then diluted with H2O (20 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with H2O (3×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/15) to yield 1.40 g (53% yield) of 2-chloro-6-(pyrrolidin-1-yl)benzaldehyde as a yellow solid. 1H NMR 300 MHz (CDCl3) δ 10.49 (s, 1H), 7.20-7.25 (m, 1H), 6.73-6.78 (m, 2H), 3.14-3.19 (m, 4H), 1.94-2.02 (m, 4H). LCMS (ESI, m/z): 210 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10]([OH:14])[CH2:11][C:12]#[CH:13].C(N(CC)CC)C>C1COCC1>[OH:14][CH2:10][CH2:11][C:12]#[C:13][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(Br)c1
Reactant: C#CCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=Cc1cccc(C#CCCO)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
A 1-L, 3-necked round-bottom flask was equipped with a magnetic stirring bar, a condenser with a nitrogen inlet, and two stoppers. The vessel was charged with 3-bromobenzaldehyde (18.5 g), 3-butyn-1-ol (10.5 g), triethylamine (100 mL), and THF (100 mL). To this mixture was then added PdCl2 (PPh3)2 (1.4 g) and CuBrMe2S (0.405 g). The reaction mixture was heated to reflux using a heating mantle. After 4 h when TLC showed complete consumption of the bromide, the mixture was allowed to cool to room temperature, transferred to a 1-L round-bottom flask and concentrated under reduced pressure. The residue was dissolved in 250 mL of ethyl acetate. The solution was washed with water and brine, dried over MgSO4, and filtered. The solvents were removed from the filtrate under reduced pressure to obtain the title compound as pale yellow oil (16.8 g).
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:25]=[C:24](N)[CH:23]=2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:36][S:37]SC>C(Cl)(Cl)Cl>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:25]=[C:24]([S:37][CH3:36])[CH:23]=2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1ccc(-n2nc(N)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Reactant: CSSC
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(-n2nc(SC)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of t-butyl nitrite (1.14 ml) in CHCl3 (3 ml) was added dropwise to a solution of 5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-3-amino-1H-pyrazole (1.5 g) and dimethyldisulfide (1.15 ml) in CHCl3 (10 ml). After all of t-butyl nitrite solution was added, the temperature of reaction mixture began to rise and reached to reflux. After the reflux ceased, the mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluted with AcOEt/n-hexane=25% to give 5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-3-(methylthio)-1-H-pyrazole (635.2 mg) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[OH:19][C@H:20]([CH3:23])[CH2:21][NH2:22]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:22][CH2:21][C@@H:20]([OH:19])[CH3:23])=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: C[C@@H](O)CN
Product: C[C@H](O)CNC(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-[(2S)-2-hydroxypropyl]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.3 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.4 mmol of 2-(R)-hydroxypropylamine. LC/MS [8.40 min; 416 (M+1)]
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[C:15](=[O:19])[NH:16][N:17]([CH3:18])[C:13]=3[NH:12][C:11]3[CH2:20][O:21][CH2:22][C:23](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([N:16]1[C:15](=[O:19])[C:14]2[CH:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=3)[C:10]3[C:23](=[O:24])[CH2:22][O:21][CH2:20][C:11]=3[NH:12][C:13]=2[N:17]1[CH3:18])(=[O:27])[CH3:26]
Reactant: Cn1[nH]c(=O)c2c1NC1=C(C(=O)COC1)C2c1ccc(F)c(Br)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)n1c(=O)c2c(n1C)NC1=C(C(=O)COC1)C2c1ccc(F)c(Br)c1

Procedure:
The product from Example 26C (0.1 g) was heated for 15 minutes on a steam bath with 5 mL of acetic anhydride. The reaction mixture was evaporated under reduced pressure and the residue was chromatographed on silica gel eluting with 5% ethanol/methylene chloride to provide 0.035 g of the title compound as the more polar compound. 1H NMR (DMSO-d6) δ 2.12 (s, 3H), 3.55 (s, 3H), 4.0 (m, 2H), 4.56 (q, 2H), 4.89 (s, 1H), 7.15 (m, 1H), 7.22 (t, 1H), 7.35 (dd, 1H), 10.18 (s, 1H); MS (ESI−) m/z 436 (M−H)−; Anal. Calcd for C18H15N3BrFO4: C, 49.58; H, 3.47; N, 9.63. Found: C, 49.31; H, 3.32; N, 9.62.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13](=[O:53])[C@@H:14]([NH:39][S:40]([C:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45][CH:44]=1)(=[O:42])=[O:41])[CH2:15][NH:16][C:17]1[C:18]2[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]3[NH:33][CH2:34][CH2:35][CH2:36][N:37]=3)[C:19]=2[N:20]=[C:21]([CH3:23])[N:22]=1)(C)(C)C>C(Cl)Cl>[CH3:23][C:21]1[N:22]=[C:17]([NH:16][CH2:15][C@H:14]([NH:39][S:40]([C:43]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH:46]=[CH:45][CH:44]=2)(=[O:41])=[O:42])[C:13]([OH:53])=[O:12])[C:18]2[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]3[NH:33][CH2:34][CH2:35][CH2:36][N:37]=3)[C:19]=2[N:20]=1
Reactant: Cc1nc(NC[C@H](NS(=O)(=O)c2cccc3ccccc23)C(=O)OC(C)(C)C)c2ccn(CCCC(=O)NC3=NCCCN3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(NC[C@H](NS(=O)(=O)c2cccc3ccccc23)C(=O)O)c2ccn(CCCC(=O)NC3=NCCCN3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 ml of TFA were added to a solution of 75 mg of (2S)-3-(2-methyl-7-[3-(1,4,5,6-tetrahydro-pyrimidin-2-ylcarbamoyl)-propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-(naphthalene-1-sulfonylamino)-propionic acid tert-butyl ester (example 3c) in 5 ml of DCM and stirred for 2 h at room temperature. Solvent and TFA were removed in vacuo, the residue was lyophilized from AcOH/H2O (1:1). Yield: 84 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:21]([NH2:23])=O>O>[F:18][C:17]([F:20])([F:19])[C:16]1[C:11]([C:9]2[CH:10]=[C:2]3[C:3]([C:4]([OH:6])=[N:23][CH:21]=[N:1]3)=[CH:7][CH:8]=2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cc(-c2ncccc2C(F)(F)F)ccc1C(=O)O
Reactant: NC=O
Solvent: O
Product: Oc1ncnc2cc(-c3ncccc3C(F)(F)F)ccc12
Temperature: 25 °C

Procedure:
Stir the mixture of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzoic acid (1.95 mmol) in HCONH2 (10 mL) for 4 hours at 145° C. Cool to room temperature, dilute with 20 ml of water, and collect the precipitate to give 7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ol.