Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH2:16][NH:17][O:18][CH3:19]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:17]([CH2:16][C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=2[F:13])[O:18][CH3:19])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccccc1F
Product: CON(Cc1ccccc1F)C(=O)C=C1OC(C)(C)OC1=O
Yield: 84 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(2-fluorobenzyl)-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as a white solid (84% yield): mp 109–111° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.72 (3H, s, OCH3), 4.92 (2H, s, NCH2), 6.40 (1H, s, CH), 7.03–7.12 (2H, m, aromatics), 7.24–7.30 (1H, m, aromatic), 7.4 (1H, m, aromatic). Anal. calcd. for C15H16FNO5: C, 58.25; H, 5.21; N, 4.52. Found: C, 58.47; H, 5.16; N, 4.66.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]3([OH:20])[CH2:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:24]>CO>[NH2:24][C:2]1[C:11]2[N:12]=[C:13]([CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]3([OH:20])[CH2:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCc1nc2c(Cl)nc3ccccc3c2n1CC1(O)CCC1
Reactant: N
Solvent: CO
Product: CCCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCC1
Temperature: 150 °C

Procedure:
1-[(4-Chloro-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol (1.56 g) was combined with a solution of ammonia in methanol (23 mL). The mixture was heated at 150° C. in a pressure vessel for 2 days. A portion of the solvent was removed under vacuum and then the mixture was diluted with additional methanol. A solid was isolated by filtration, washed with methanol, triturated with acetonitrile, and then dried. The material was suspended in water (70 mL). Concentrated hydrochloric acid (1.4 mL) was added and the mixture was heated at 90° C. for 30 minutes. The hot solution was neutralized with solid sodium bicarbonate. The solution was allowed to cool to ambient temperature. A precipitate was isolated by filtration, washed well with water, and then dried to provide 1-[(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol as a white powder, mp 228.0-229.0° C. Anal. Calcd for C18H22N4O C, 69.65; H, 7.14; N, 18.05. Found: C, 69.36; H, 7.24; N, 18.03.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.[CH2:16]([O:23][NH:24][CH2:25][CH3:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][N:24]([C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1)[CH2:25][CH3:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCNOCc1ccccc1
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Product: CCCNc1nc(NCCC)nc(N(CC)OCc2ccccc2)n1
Yield: 38 %

Procedure:
2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) and O-benzyl-N-ethyl-hydroxylamine (LXVII) were reacted as described in Example 13 to afford O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamine (LXVIII, 38% yield). 400 MHz 1H NMR (DMSO-d6, ppm) 7.51-7.45 (2H, m), 7.40-7.30 (3H, s), 6.97-6.85 (1H, m), 6.79-6.67 (1H, m), 4.97-4.87 (1H, m), 3.72-3.53 (2H, m), 3.23-3.11 (4H, m), 1.56-1.43 (4H, m), 1.13-1.00 (3H, m), 0.89-0.80 (6H, m). ESI-MS (m/z): 345 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:42]=[CH:41][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[CH:19][CH:18]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:42]=[CH:41][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:19][CH:18]=1
Reactant: CCOC(=O)CCCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCCCCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl E-7-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-7-phenylheptanoate (730 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-7-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-7-phenylheptanoic acid (569 mg, yield 82%) as colorless crystals. m.p. 84-85° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]1=[O:20].C([O-])=O.[NH4+]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:8][C:6]1[CH:5]=[C:4]([CH3:11])[C:3]([N:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]2=[O:20])=[C:2]([CH3:1])[CH:7]=1
Reactant: COc1cccn(-c2c(C)cc([N+](=O)[O-])cc2C)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cccn(-c2c(C)cc(N)cc2C)c1=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2.05 g (7.47 mmol) of the compound from Example 69A are dissolved in 70 ml of ethyl acetate and 70 ml of ethanol, 2.35 g (37.4 mmol) of ammonium formate and 0.39 g (0.37 mmol) of palladium/carbon (10%) are added and the mixture is stirred at 80° C. for 2 h. For work-up, the reaction solution is brought to room temperature and passed through a silica gel frit. The filter cake is washed with ethanol and the filtrate is concentrated under reduced pressure. The reaction product (1.65 g) is reacted without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][NH:20][CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][C:9]([N:20]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[CH3:19])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCc1c[nH]c2ccccc12
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 73.2 %

Procedure:
N-(Benzyloxycarbonyloxy)succinimide (8.9 g, 35.7 mmole) was added to a solution of 3-(methylaminomethyl)-1H-indole (5.2 g, 32.5 mmole), from Preparation 16, and triethylamine (5.0 mL, 65.7 mmole) in DMF (100 mL) at RT. The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with water and the mixture was extracted with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (33% ethyl acetate/hexanes) gave the title compound (7.0 g, 74%) as an off-white solid: MS (ES) m/e 295 (M+H)+.
Reaction SMILES: [CH2:1]([SH:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].[H-].[Na+].Br[CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27].[NH4+].[Cl-]>CN(C=O)C.CCCCCCC.O>[CH2:1]([S:21][CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CCOC(=O)C(Br)CC
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCS
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCCC
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCSC(CC)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a solution of (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaene-1-thiol (305 mg, 1.00 mmol) in dry DMF (10 mL) at 0° C. under inert atmosphere was added NaH (60% in mineral oil, 44 mg, 1.1 mmol). After fifteen minutes ethyl bromobutyrate (154 μL, 1.05 mmol) was added. The mixture was stirred for 1 hour at 0° C. Sat. aq. NH4Cl (20 mL), water (20 mL) and heptane (50 mL) were added. The phases were separated and the water phase was extracted with heptane (2×25 mL). The combined organics were washed with water (25 mL) and brine (25 mL), dried (MgSO4), filtered and evaporated to give 379 mg of the title compound as a crude oil. Purification by flash chromatography on silica gel using gradient elution (starting pure heptane and increasing stepwise to heptane:EtOAc 95:5) afforded 345 mg (82% yield) of the title compound as oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]#[N:16])[N:5]([NH:7]C(=O)OC(C)(C)C)[CH:6]=1.O1CCOCC1.[ClH:23].O1CCOCC1.CCOC(C)=O.CCCCCC>C(OCC)C>[ClH:23].[NH2:7][N:5]1[CH:6]=[C:2]([Br:1])[CH:3]=[C:4]1[C:15]#[N:16]
Reactant: CC(C)(C)OC(=O)Nn1cc(Br)cc1C#N
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1cc(Br)cn1N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 1 L, 3-neck RB flask was fitted with a mechanical stirrer, nitrogen inlet, thermocouple/JKEM thermocontroller, cooling bath and an addition funnel. tert-Butyl (4-bromo-2-cyano-1H-pyrrol-1-yl)carbamate (19 g, 66 mmol) was added and dissolved with 1,4-dioxane (50 mL), then the stirred orange solution was cooled to 0° C. and HCl/dioxane (4 N, 100 mL, 8 eq.) was slowly added from the addition funnel, maintaining an internal temperature around 25° C. After 2 hours the solution became cloudy and stirring @ room temperature was continued for 7 hours; the reaction was monitored for completion by TLC (silica gel, GHLF, 1:3 EtOAc/hexane, UV; Note: the free base may be observed as a high-Rf spot and can be misinterpreted as incomplete reaction). The reaction mixture was diluted with diethyl ether (150 mL) and the precipitated solids were collected by suction filtration and washed with ether (200 mL). Drying (vacuum oven @ 50° C.) afforded the desired product as 10.9 g (93%) of a white solid. 1H-NMR (DMSO): δ 7.24 (d, 1H, J=2 Hz), 6.93 (d, 1H, J=2 Hz), 6.2 (bs, 3H, J=2.8, 4.4 Hz).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=O)[N:7]([CH2:11][CH:12]2[O:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][CH2:13]2)[CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[O:17]1[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][CH2:13][CH:12]1[CH2:11][N:7]1[CH2:8][CH2:9][CH:5]([CH2:3][OH:2])[CH2:6]1
Reactant: COC(=O)C1CC(=O)N(CC2COc3ccccc3O2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCN(CC2COc3ccccc3O2)C1
Temperature: 25 °C

Procedure:
To a solution containing 130 mg (0.45 mmol) of 1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester in dry tetrahydrofuran (4 mL) was added 68 mg (1.79 mmol) of LiAlH4. The reaction mixture was stirred at room temperature for 2½ h, and subsequently refluxed for 2 h. After the reaction mixture was cooled to room temperature, it was quenched with water and 1 M NaOH. The solution was filtered through celite and the filtrate was evaporated to dryness. Purification by column chromatography (silica gel, triethylamine/ethyl acetate, 1:99) afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19]C(=O)C)=[C:15]([O:23][CH3:24])[CH:14]=2)C(O)=O)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].CC1NC=CN=1>C(O)COCCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:23][CH3:24])[CH:14]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(C=C(C(=O)O)c2ccc(Cl)cc2)ccc1OC(C)=O
Agent: Cc1ncc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCOCCO
Product: COc1cc(C=Cc2ccc(Cl)cc2)ccc1O
Yield: 89 %

Procedure:
A mixture of α-(4′-chlorophenyl)-4-acetyloxy-3-methoxy cinnamic acid (0.0083 mol), NaHCO3 (10%, 5 mL) and methylimidazole (2 mL) and diethylene glycol (8 mL) were taken in a 100 ml round bottom flask fitted with a condenser. The flask was shaken well and placed inside the microwave oven and irradiated (200 W, 180° C.) for 9 minutes in parts. After completion of reaction, the reaction mixture was worked (yield 89%) as in example I; solid, (m.p. 121-124° C.); 1H NMR (CDCl3) δ 7.35 (2H, d, J=8.48 Hz), 7.25 (2H, d, J=8.07 Hz), 6.96 (3H, m), 6.87 (2H, d, J=8.07 Hz), 5.72 (1H, s), 3.87 (3H, s); 13C NMR (CDCl3) δ 146.8, 145.8, 136.1, 132.7, 129.6, 129.2, 128.8, 127.4, 125.1, 120.6, 114.6, 108.3 and 55.9. HREIMS data: m/z [M+H]+ for C15H14O2Cl, calculated=261.7229; observed=261.7228.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].O[CH2:10][C:11]1[C:17](O)=[C:16]([CH2:19][CH3:20])[CH:15]=[C:14]([CH2:21]O)[C:12]=1[OH:13].Cl>O>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[CH2:21][C:14]1[CH:15]=[C:16]([CH2:19][CH3:20])[CH:17]=[C:11]([CH2:10][C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[OH:5])[C:12]=1[OH:13]
Reactant: Oc1cccc(O)c1
Reactant: CCc1cc(CO)c(O)c(CO)c1O
Agent: Cl
Solvent: O
Product: CCc1cc(Cc2ccc(O)cc2O)c(O)c(Cc2ccc(O)cc2O)c1
Reaction time: 8 h
Yield: 46.6 %

Procedure:
To a 2 liter round bottom flask was added 800 ml of de-mineralized water, 825.0 g resorcinol and 45.58 g of 2,6-bis(hydroxymethyl)-4-ethylresorcinol. 6.5 ml of concentrated hydrochloric acid was added and the mixture stirred overnight at ambient conditions. The reaction mixture was then added to 12 L of de-mineralized water and slowly stirred at room temperature for 24 hours. The precipitate was isolated by vacuum filtration and washed with de-mineralized water. It was air dried for 24 hours and then vacuum oven dried at 60° C. for 18 hours. About 39.3 g of product was obtained having a purity of about 91% as determined by HPLC analysis.
Reaction SMILES: [OH:1][N:2]1[C:8](=[O:9])[N:7]2[CH2:10][C@H:3]1[CH2:4][CH2:5][C@H:6]2[C:11]([O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:12].[S:28](=[O:31])(=[O:30])=[O:29].N1C=CC=CC=1>N1C=CC=CC=1>[O:9]=[C:8]1[N:7]2[CH2:10][C@@H:3]([CH2:4][CH2:5][C@H:6]2[C:11]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[O:12])[N:2]1[O:1][S:28]([OH:31])(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)CC1
Reactant: O=S(=O)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)O)CC1
Reaction time: 8 h

Procedure:
To a solution of the product of Step 2 (50 mg, 0.13 mmol) in dry pyridine (1 mL) was added pyridine sulfur trioxide (104 mg, 0.652 mmol) at room temperature under nitrogen. The reaction mixture was stirred overnight then filtered (collected solid was washed well with dichloromethane). The filtrate was concentrated under vacuum to afford the title compound which was used without purification in the next step.
Reaction SMILES: C[O:2][C:3](=[O:44])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:42][CH3:43])[S:24]([C:27]2[CH:32]=[CH:31][C:30]([N:33]([CH3:41])[C:34]3[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=3)=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:6]=1.[OH-].[Li+].Cl>C1COCC1>[CH2:42]([N:23]([CH2:22][C:13]1[CH:14]=[C:15]([C:18]([F:21])([F:19])[F:20])[CH:16]=[CH:17][C:12]=1[O:11][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:44])=[O:2])[CH:10]=[CH:9][CH:8]=1)[S:24]([C:27]1[CH:28]=[CH:29][C:30]([N:33]([CH3:41])[C:34]2[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=2)=[CH:31][CH:32]=1)(=[O:25])=[O:26])[CH3:43]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1)S(=O)(=O)c1ccc(N(C)c2cccc(C)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1)S(=O)(=O)c1ccc(N(C)c2cccc(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude {3-[2-({ethyl-[4-(methyl-m-tolyl-amino)-benzenesulfonyl]-amino}-methyl)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid methyl ester (0.013 mmol) in THF was added aqueous lithium hydroxide (3 mL), and the reaction was stirred overnight at room temperature. The mixture was acidified with 1N aqueous HCl and extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by preparative HPLC to give the title compound. M+H=613.
Reaction SMILES: CN(C)C=O.BrCCBr.Cl[Si](C)(C)C.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19]Br.[C:25]([C:27]1[C:28](I)=[C:29]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[S:30][C:31]=1[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)#[N:26]>[Zn].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:24][C:23]1[CH:22]=[CH:21][C:18]([CH2:19][C:28]2[C:27]([C:25]#[N:26])=[C:31]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[S:30][C:29]=2[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:17][C:16]=1[F:15]
Reactant: Fc1cc(CBr)ccc1Cl
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1I
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: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1Cc1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame-dried scintillation vial, to a suspension of zinc (0.0998 g, 1.53 mmol) in N,N-dimethylformamide (1.36 mL, 17.6 mmol) were added 1,2-dibromoethane (0.003279 mL, 0.03805 mmol) and chlorotrimethylsilane (0.004830 mL, 0.03805 mmol). Stirred at room temperature for 15 min, at which point a solution of 3-fluoro-4-chlorobenzylbromide (0.341 g, 1.53 mmol) in N,N-dimethylformamide (1.36 mL, 17.6 mmol) was added. The resulting suspension was stirred at room temperature for 16 hours. A scintillation vial containing ethyl 4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylate (199 mg, 0.507 mmol and bis(tri-t-butylphosphine)palladium(0) (12.96 mg, 0.02537 mmol) was purged via vacuum/backfilling with argon. To this was added the organozinc solution from above, and the resulting solution was stirred at 45° C. for 6 hours, at which point LC/MS showed complete conversion to a single new peak with mass representing desired product. The reaction mixture was transferred to a separatory funnel containing saturated NaHCO3 (aq., 10 mL) and water (10 mL), and then diluted with EtOAc (40 mL). The layers were separated, and the aqueous layer was extracted 2×30 mL with EtOAc. The combined organic layers were washed 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford crude ethyl 3-(4-chloro-3-fluorobenzyl)-4-cyano-5-morpholin-4-ylthiophene-2-carboxylate as a brown oil that was used without further purification. LCMS: (FA) ES+ 409, 411
Reaction SMILES: [CH2:1]([O:6][CH:7]=[CH:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:2]([CH2:4][OH:5])[OH:3]>[Pd]>[CH2:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:2]([CH2:4][OH:5])[OH:3]
Reactant: CCCCC=CC=COCC(O)CO
Agent: [Pd]
Product: CCCCCCCCOCC(O)CO
Temperature: 47.5 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
In a 500-mL autoclave were added 100 g of the resulting octadienyl glyceryl ether and 5 g of 5% Pd—C (product of NE Chemcat Corporation). The mixture was stirred at 25 to 70° C. for 6 hours under a hydrogen atmosphere of a pressure of 1 to 5 MPa. After completion of the reaction, the catalyst was filtered off, whereby 102 g of octyl glyceryl ether was obtained as a colorless transparent oil. Gas chromatography(GC) analysis showed that the monooctyl glyceryl ether content was 99%, and the dioctyl glyceryl ether content was 1% or less.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][OH:19])[CH2:13]2)([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[SH:21][CH2:22][CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[OH:25][CH2:24][CH2:23][CH2:22][S:21][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][OH:19])[CH2:13]2)([CH3:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)c1ccc(Cl)cc1)N1CCCC(CO)C1
Reactant: OCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C(=O)c1ccc(SCCCO)cc1)N1CCCC(CO)C1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
22.4 g of 1-(4-chloro-phenyl)-2-(3-hydroxymethyl-piperidin-1-yl)-2-methyl-propan-1-one, 8.39 g of 3-mercaptopropanol and 21.0 g of potassium carbonate are mixed in 75 ml of dried dimethylacetamide. After stirring for 18 h at 80° C., the mixture is filtered to remove solids and poured into ice-water. The crude product is extracted with ethyl acetate, washed with saturated NaCl solution and dried over MgSO4. After ethyl acetate is distilled off, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (40:60) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.02 (m, 1H), 1.29 (s, 3H), 1.30 (s, 3H), 1.52-1.77 (m, 6H), 1.95 (m, 2H), 2.05 (t, 1H), 2.27 (t, 1H), 2.67 (d, 1H), 2.86 (d, 1H), 3.12 (t, 2H), 3.44 (m, 2H), 3.78 (m, 2H), 7.28 (d, 2H), 8.48 (d, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1>[NH2:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=1[NH:10][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1N
Temperature: 5 °C
Yield: 62.3 %

Procedure:
4-Nitro-o-phenylenediamine (30.6 g; 0.2 mole) was nearly dissolved in pyridine (ca. 500 ml). The mixture was chilled to 5° C. and methanesulfonyl chloride (22.8 g; 0.2 mole) was added dropwise, while stirring, at <10° C. After the addition, the solution was left stirring at the ice bath temperature for about one hour. The reaction solution was poured into ice cold water (~2 liter) and stirred while scratching vigorously. The product was filtered and dried to yield 28.8 g (62 percent) beige solid, m.p. 201° to 204° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]5[O:34][CH:33]=[N:32][CH:31]=5)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[CH2:40][C:41](Cl)=[O:42].C(O)C(N)(CO)CO>C1COCC1>[O:34]1[C:30]([C:26]2[CH:25]=[C:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:41](=[O:42])[CH2:40][C:36]6[S:35][CH:39]=[CH:38][CH:37]=6)[CH:7]=[CH:6][CH:5]=5)=[N:9][N:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=45)[CH:22]=[CH:21][N:20]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:31][N:32]=[CH:33]1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Reactant: O=C(Cl)Cc1cccs1
Agent: NC(CO)(CO)CO
Solvent: C1CCOC1
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Reaction time: 0.25 h
Yield: 35.9 %

Procedure:
To a stirred solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[3-(1,3-oxazol-5-yl)phenyl]-2-pyrimidinamine (100 mg, 0.22 mmol) in 1 mL THF was added 2-thiopheneacetyl chloride (40 mg, 0.25 mmol). After 15 min. LC/MS indicated the reaction was complete and several equivalents of PS-trisamine were added and the mixture was stirred for 16 h followed by addition of 25 mg of TEA. The mixture was filtered and the resin washed well with THF. The filtrate was concentrated and the crude purified by HPLC (Agilent, 50-90% gradient over 15 min.) to give the title compound (45 mg, 36% yield). 1H NMR (400 MHz, d6-DMSO) δ 10.34 (s, 1H), 9.71 (s, 1H), 8.81 (d, J=6.8 Hz, 1H), 8.49 (d, J=8.6 Hz, 1H), 8.18-8.37 (m, 3H), 7.87 (s, 1H), 7.67-7.72 (m, 2H), 7.54 (s, 1H), 7.24-7.42 (m, 6H), 7.09 (t, J=6.9 Hz, 1H), 6.93-6.95 (m, 2H), 6.49 (d, J=5.3 Hz, 1H), 3.84 (s, 2H) ppm. ES-LC/MS m/z=570 [M+H]+