Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]12(O)[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.S(=O)(=O)(O)O>ClCCl>[OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: O=Cc1ccc(O)cc1O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=Cc1cc(C23CC4CC(CC(C4)C2)C3)c(O)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 g (36.2 mmol) of 2,4-dihydroxybenzaldehyde, 5.8 g (38.1 mmol) of 1-adamantanol of 200 ml of dichloromethane were introduced into a round-bottomed flask. 2 ml of concentrated sulfuric acid were added and the mixture was stirred at room temperature for eight hours. The reaction mixture was evaporated to dryness, the residue was taken up in water, neutralized with sodium bicarbonate and extracted with ethyl ether and the extract was dried over magnesium sulfate and evaporated.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[C:3]#[C:4][CH3:5].[Li]CCCC.CCCCCC.Br[CH2:20][C:21]#[C:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>C1COCC1>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]#[C:21][CH2:20][CH2:5][C:4]#[C:3][Si:2]([CH3:7])([CH3:6])[CH3:1])=[CH:24][CH:25]=1
Reactant: Fc1ccc(C#CCBr)cc1
Reactant: CC#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)C#CCCC#Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of trimethyl(prop-1-ynyl)silane (2.19 g, 19.50 mmol) in 22 mL of THF at −78° C., was added dropwise n-BuLi 2.5M in hexane (7.8 mL, 20 mmol). After stiffing 2 hours at −78° C., 1-(3-bromoprop-1-ynyl)-4-fluorobenzene (1.40 g, 6.5 mmol) in 6 mL of THF was slowly added and the resulting mixture was stirred for 1h at −78° C. and warmed to room temperature for an additional 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated to afford 1.57 g of (6-(4-fluorophenyl)hexa-1,5-diynyl)trimethylsilane (99%) as a yellow oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:14][N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CNc1ccccc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: CN(c1ccccc1)S(=O)(=O)c1ccc(C(=O)O)cc1

Procedure:
4-(chlorosulfonyl)benzoic acid (500 mg, 2.27 mmol) was treated with N-methylaniline (729 mg, 6.8 mmol) using method A to give 4-(N-methyl-N-phenylsulfamoyl)benzoic acid as an off-white solid. Yield: 374 mg (57%). 1H-NMR: 8.09 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.38-7.28 (m, 3H), 7.13-7.08 (m, 2H), 3.17 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH:30]=1)([O-])=O.C(OCC)(=O)C>CO.[Pd]>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:10]3[O:11][C:7]4[CH:6]=[CH:5][C:4]([NH2:1])=[CH:30][C:8]=4[N:9]=3)=[CH:13][CH:14]=2)[CH:19]=[C:20]([O:28][CH3:29])[C:21]=1[O:26][CH3:27]
Reactant: COc1cc(-c2ccc(-c3nc4cc([N+](=O)[O-])ccc4o3)cc2)cc(OC)c1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(-c2ccc(-c3nc4cc(N)ccc4o3)cc2)cc(OC)c1OC
Reaction time: 4 h
Yield: 74.6 %

Procedure:
22 mg (0.0541 mmol) of 5-nitro-2-(3′,4′,5′-trimethoxy-[1,1′-biphenyl]-4-yl)benzo[d]oxazol e was dissolved in methanol, and then, 10% Pd/C was added thereto under hydrogen gas atmosphere. The mixed solution was stirred for 4 hours, and ethyl acetate was added thereto to filter with a celite pad. The filtered solution was concentrated under reduced pressure. Afterwards, the reaction solution was subjected to a silica gel column chromatography (ethyl acetate/normal-hexane at a volume ratio of 1:1) to obtain 15.2 mg (yield=74.6%) of 2-(3′,4′,5′-trimethoxy-[1,1′-biphenyl]-4-yl)benzo[d]oxazole-5-amine (Derivative #7).
Reaction SMILES: Br[C:2]1[CH:12]=[N:11][C:5]2[N:6]=[C:7]([Cl:10])[N:8]=[CH:9][C:4]=2[CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:10][C:7]1[N:8]=[CH:9][C:4]2[CH:3]=[C:2]([C:17]3[CH:16]=[C:15]([O:14][CH3:13])[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=3)[CH:12]=[N:11][C:5]=2[N:6]=1
Reactant: COc1cc(OC)cc(B(O)O)c1
Reactant: Clc1ncc2cc(Br)cnc2n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)cc(-c2cnc3nc(Cl)ncc3c2)c1
Temperature: 85 °C
Yield: 46.2 %

Procedure:
A mixture of 6-bromo-2-chloropyrido[2,3-d]pyrimidine (800 mg, 3.3 mmol), 3,5-dimethoxyphenylboronic acid (655 mg, 3.6 mmol), bis(tri-tert-butylphosphine)palladium (83 mg, 0.16 mmol) and cesium carbonate (1.06 g, 3.3 mmol) in THF (30 mL) and water (6 mL) was degassed with nitrogen for three times and then heated at 85° C. for 0.5 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/ethyl acetate=3/1) to get the title product as a yellow solid (460 mg, 47%) as a yellow solid. MS (ES+) C15H12ClN3O2 requires: 301, 302, found: 302, 304 [M+H]+.
Reaction SMILES: Cl.C(OC([N:9]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:11]([C:16]([OH:18])=[O:17])[CH2:10]1)=O)(C)(C)C>O1CCOCC1>[O:15]=[C:14]1[NH:9][CH2:10][C@@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)CCC1=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CC[C@H](C(=O)O)CN1
Yield: 144.5 %

Procedure:
A solution of HCl in dioxane (6M, 10 mL) was added to a solution of (S)-1-(tert-butoxycarbonyl)-6-oxopiperidine-3-carboxylic acid (700 mg, 2.90 mmol) in dioxane (5 mL) at 0° C. with stirring. The reaction mixture was stirred for 4 h and concentrated to dryness. The residue was azeotroped three times with MeOH (10 mL for each portion) to afford (S)-6-oxopiperidine-3-carboxylic acid (600 mg, quantitative) as a colorless solid. (R)-6-oxopiperidine-3-carboxylic acid was made in similar manner.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][CH:8]([CH3:10])[O:9][C:4]=2[CH:3]=1.Cl[CH2:14][CH:15]1[O:17][CH2:16]1>>[O:17]1[CH:15]([CH2:14][O:1][C:2]2[CH:12]=[CH:11][C:5]3[CH2:6][CH2:7][CH:8]([CH3:10])[O:9][C:4]=3[CH:3]=2)[CH2:16]1
Reactant: CC1CCc2ccc(O)cc2O1
Reactant: ClCC1CO1
Product: CC1CCc2ccc(OCC3CO3)cc2O1

Procedure:
Starting from 7-hydroxy-2-methyl-3,4-dihydro-2H-1-benzopyrane, using 1-chloro-2,3-epoxypropane reagent and following the process of example 9 (b), 1,2-epoxy-3-(2-methyl-3,4-dihydro-2H-1-benzopyrane-7-yloxy)-propane was obtained (m.p. 67°-69° C.).
Reaction SMILES: [NH2:1][OH:2].[C:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C@H:13]2[CH2:18][C@H:17]([C:19]([O:21]C)=O)[C@@H:16]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)=[O:24])[CH2:15][CH2:14]2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]>CO>[C:3]([N:6]1[CH2:7][CH2:8][CH:9]([O:12][C@H:13]2[CH2:18][C@H:17]([C:19]([NH:1][OH:2])=[O:21])[C@@H:16]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)=[O:24])[CH2:15][CH2:14]2)[CH2:10][CH2:11]1)(=[O:5])[CH3:4]
Reactant: COC(=O)[C@H]1C[C@H](OC2CCN(C(C)=O)CC2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: NO
Solvent: CO
Product: CC(=O)N1CCC(O[C@@H]2CC[C@H](C(=O)N3CCN(c4ccccc4)CC3)[C@@H](C(=O)NO)C2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 M of H2NOH in MeOH (0.75 ml) was added into a solution of methyl (1S,2S,5R)-5-[(1-acetylpiperidin-4-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexane-carboxylate (0.1 mmol, 0.0001 mol) in 0.5 ml of MeOH. It was stirred at rt for 2 hrs. It was purified by Prep-HPLC. LCMS: (M+H)+=473.1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C(#N)C.[CH2:10]([O:12][C:13](Cl)=[O:14])[CH3:11]>C(N(CC)CC)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:13]([O:12][CH2:10][CH3:11])=[O:14]
Reactant: CCOC(=O)Cl
Reactant: Cn1ccnc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1nccn1C
Temperature: -20 °C
Yield: 59.9 %

Procedure:
N-methylimidazole (16) (320 g, 3.9 mol) was combined with 2 liters of acetonitrile and 1 liter of triethylamine in a flask equipped with a mechanical stirrer and the solution was cooled to −20° C. Ethylcloroformate (1000 g, 9.2 mol) was added with stirring, keeping the temperature between −20° C. and −25° C. The reaction was allowed to slowly warm to room temperature and stir for 36 hours. Precipitated triethylamine hydrochloride was removed by filtration and the solution was concentrated in vacuo at 65° C. The resulting oil was purified by distillation under reduced pressure (2 torr, 102° C.) to provide (17) as a white solid (360 g, 82% yield). TLC (7:2 benzene/ethyl acetate) Rf 0.2; 1H NMR (DMSO-d6) δ 7.44 (d, 1H, J=2.8 Hz), 7.04 (d, 1H, J=2.8 Hz), 4.26 (q, 2H, J=3.5 Hz) 3.91 (s, 3H), 1.26 (t, 3H, J=3.5 Hz); 13C NMR (DMSO-d6) δ 159.3, 129.1, 127.7, 61.0, 36.0, 14.5; IR (KBr) 3403, 3111, 2983, 1713, 1480, 1422, 1262, 1134, 1052, 922, 782, 666; FABMS m/e 155.083 (M+H 155.083 calc. for C7H11N2O).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=1[O:35][CH2:36][C:37]([F:40])([F:39])[F:38]>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:22][CH2:23][N:24]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[CH2:25][CH2:26]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncnc(Cl)c1OCC(F)(F)F
Reactant: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Product: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4OCC(F)(F)F)CC3)n2)ccn1

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “1” by using 4-[1-(2-azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H -imidazol-4-yl]-2-isopropyl-pyridine and 6-chloro-5-(2,2,2-trifluoro-ethoxy)-pyrimidin-4-ylamine as the starting materials. LC-MS (M+H=545, obsd=545).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16](I)[C:17]([NH2:20])=[N:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[C:16]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:11][CH3:12])[C:17]([NH2:20])=[N:18][CH:19]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: Nc1ncc(Cl)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1-c1cc(Cl)cnc1N
Temperature: 25 °C
Yield: 45.8 %

Procedure:
Mixture of 5-chloro-2-methoxyphenylboronic acid (5.0 g, 26.8 mmol), 5-chloro-3-iodopyridin-2-amine (6.83 g, 26.8 mmol), sodium carbonate (8.53 g, 80.5 mmol in 50 mL of water), Pd(PPh3)4 (621 mg, 2 mol. %) and 100 mL of toluene was refluxed overnight under N2. reaction mixture was cooled down to room temperature, organic layer was separated and concentrated in vacuum. The residue was subjected to column chromatography on silica gel with hexane/ethyl acetate gradient mixture as eluent, providing 3.3 g (46% yield) of 5-chloro-3-(5-chloro-2-methoxyphenyl)pyridin-2-amine.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[C:16]([N:18](C)[C:19](=O)C)[CH:15]=[CH:14][N:13]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:23]>O.O1CCOCC1>[ClH:23].[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]3[CH:17]=[C:16]([NH:18][CH3:19])[CH:15]=[CH:14][N:13]=3)[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)N(C)c1ccnc(N2CCN(C3CCCC3)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CNc1ccnc(N2CCN(C3CCCC3)CC2)c1
Temperature: 25 °C
Yield: 72 %

Procedure:
A mixture of 3.3 g (11 mmol) N-[2-(4-cyclopentyl-piperazin-1-yl)-pyridin-4-yl]-N-methyl-acetamide and 12 ml 4N HCl in 5 ml water and 25 ml dioxane was stirred at room temperature. After evaporation of the volatiles the residue was triturated with a mixture formed from acetone and dioxane and dried under vacuum to yield 2.3 g (72%) of the title compound (intermediate 10) as off-white solid. MS: (m/e): 261.2 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[C:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][C:21]1[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]2)([CH3:16])([CH3:17])[CH3:18]
Reactant: BrCc1cccc2ccccc12
Reactant: CCOC(=O)c1cc2cc(C(C)(C)C)ccc2[nH]1
Product: CC(C)(C)c1ccc2c(c1)cc(C(=O)O)n2Cc1cccc2ccccc12

Procedure:
Using general procedure B, 5-tert-butyl-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a pale brown solid. MS: 356.3 ([M−H]−).
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.N1C=CC=CC=1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([C:27]2([OH:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>O1CCCC1>[OH:33][C:27]1([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:35])([F:19])[F:34])[CH:22]=2)[CH2:32][CH2:31][N:30]([C:7]([Cl:10])=[O:6])[CH2:29][CH2:28]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Cl)N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 8 h
Yield: 203.6 %

Procedure:
A solution of triphosgene (3.26 g, 0.011 mol) and anhydrous tetrahydrofuran (1000 mL) cooled to −20° C. was treated with pyridine (4.45 mL, 0.055 mol). The resulting cloudy suspension was slowly treated with a solution of 4-(3-trifluoromethyl-phenyl)-piperidin-4-ol (9 g, 0.036 mol) in anhydrous tetrahydrofuran (45 mL) while the internal temperature was maintained between −20° C. to −30° C. The resulting mixture was transferred to an ice bath which was allowed to come to 25° C. overnight to give a light brown solution with a small amount of brown precipitates. The reaction mixture was then concentrated in vacuo to give a brown solid. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 4-hydroxy-4-(3-trifluoromethyl-phenyl)-piperidine-1-carbonyl chloride (6.89 g, 61%) as a clear, viscous oil. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[CH:23]([OH:26])[CH2:24][CH3:25].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[C:23](=[O:26])[CH2:24][CH3:25]
Reactant: CCC(O)c1cc(I)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Solvent: O
Solvent: CS(C)=O
Product: CCC(=O)c1cc(I)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 4 %

Procedure:
1-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-iodophenyl}-1-propanol was dissolved in anhydrous dimethylsulfoxide (1 ml) to prepare a solution. A sulfur trioxide trimethylamine complex (70 mg) was added to the solution at 0° C., and the mixture was stirred at room temperature for 18 hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give the title compound (9 mg, yield 4%).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH:12]([OH:15])([CH3:14])[CH3:13]>>[CH:12]([O:15][C:4]([C:3]1[C:2]([C:1]([OH:6])=[O:11])=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])([CH3:14])[CH3:13]
Reactant: CC(C)O
Reactant: O=C1OC(=O)c2ccccc21
Product: CC(C)OC(=O)c1ccccc1C(=O)O

Procedure:
To a suitable reaction vessel there is charged phthalic anhydride and a 2.0X molar excess of isopropyl alcohol. The charge is heated to reflux temperature for about one hour. At the end of this time period an aliquot of the reaction mixture shows an absence of anhydride by infra-red analysis. The solvent is removed under vacuum and the residue recrystallized from toluene to obtain 1,2-benzene dicarboxylic acid mono-isopropyl ester (M.P. 73°-77° C.).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([S:18][CH3:19])=[N:16][CH:17]=1)=[O:11])[CH3:8]>C(Cl)Cl>[CH2:7]([O:9][C:10]([C:12]1[C:17]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:16][C:15]([S:18][CH3:19])=[N:14][CH:13]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: NC1CCCC1
Solvent: ClCCl
Product: CCOC(=O)c1cnc(SC)nc1NC1CCCC1
Reaction time: 72 h
Yield: 105.5 %

Procedure:
Cyclopentylamine (12.7 mL, 129.3 mmol) was added to solution of 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (10 g, 43.10 mmol) in DCM (250 mL) at RT and the resulting mixture was stirred for 3 days. The reaction mixture was washed 3 times with water; the aqueous extracts were combined and extracted twice with DCM. The combined organic extracts were dried over Na2SO4, filtered, and evaporated under reduced pressure to give 12.8 g of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester as a crude oil without further purifications.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[CH:10])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:16][C:17]([CH3:19])=[O:18]>COC(C)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[C:10][C:17]([CH3:19])([OH:18])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: C#Cc1ccc(Cl)nc1C
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: Cc1nc(Cl)ccc1C#CC(C)(C)O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
6-Chloro-3-ethynyl-2-methylpyridine (Example 432, Step 1) (200 mg, 1.32 mmol) was taken up in 4 ml tert-butyl methyl ether and added to a dry flask under argon. The flask was cooled to −78° C. and allowed to stir for 20 min. Butyllithium (0.99 ml of 1.6 M in hexanes, 1.58 mmol) was added to the reaction mixture dropwise over 30 minutes, and the mixture was allowed to stir as such for 30 min. Acetone (0.13 ml, 1.72 mmol) was taken up in 1 ml tert-butyl methyl ether and added dropwise over 30 min. The reaction mixture was allowed to warm to 0° C. and was stirred as such for 90 minutes. The reaction mixture was then allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was quenched with aqueous sodium bicarbonate and extracted twice with diethyl ether. All organic fractions were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography (0-50% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13]>CCO>[CH3:12][NH:13][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1ccncc1[N+](=O)[O-]
Reactant: CN
Solvent: CCO
Product: CNc1ccncc1[N+](=O)[O-]
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
4-Methoxy-3-nitropyridine (8.17 g, 53.0 mmol) was transferred to a bomb in EtOH (5-10 mL). To this was added a solution of methylamine in EtOH (26.4 mL, 8.03M, 0.212 mol). The bomb was sealed and lowered into an oil bath at 120° C. The bath temperature fell to 90° C. and remained that way for 2 hours. The temperature was raised to 140° C. over 0.5 hour and held there 0.5 hour. The contents were transferred to a flask with EtOH (not very soluble) and the solvent was evaporated. Flash chromatography on silica gel with a gradient of CH2Cl2 /CH3OH gave 7.17 g (88%) of 4-methylamino-3-nitropyridine as a yellow solid: mp 155°-158° C.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO>[CH2:19]([O:18][C:10]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=[CH:14][C:9]=1[NH2:8])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc([N+](=O)[O-])c1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1cccc([N+](=O)[O-])c1OCc1ccccc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 96.9 %

Procedure:
N-tert-Butoxycarbonyl-2-benzyloxy-3-nitroaniline (9.37 g, 27.2 mmol) was dissolved in methanol (150 ml), p-toluenesulfonic acid monohydrate (7.84 g, 45.5 mmol) was added thereto and the mixture was stirred at 50° C. for 12 hours. The reaction solution was neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by a silica gel column chromatography (50 g of silica gel; developing solvent, hexane:ethyl acetate=6:1) to provide 6.44 g (yield 96.9%) of 2-benzyloxy-3-nitroaniline as pale yellowish brown oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1.CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1)(=[O:34])=[O:33]
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCO)c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCOS(C)(=O)=O)c2)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice-cooled solution of N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide (178 mg, 0.57 mmol) in DCM (8 mL), Et3N (0.24 mL, 1.71 mmol) was added. After stirring for 5 min at 0° C., methanesulfonyl chloride (0.11 mL, 1.43 mmol) was added dropwise, and the resulting suspension was stirred at 0° C. for 1 h 15, then quenched with water and extracted with DCM (2×). The combined org. layers were washed with brine, dried (MgSO4) and concentrated in vacuo to obtain the title compound as an oil. LC-MS conditions A: tR=0.90 min, [M+H]+=391.03.