Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:13][C:14]3[C:19]([N:20]=2)=[CH:18][C:17]([C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=3)[CH2:7][CH2:6]1)(=[O:4])=[O:3].CO.[OH-].[Na+]>ClCCl.O>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:13][C:14]3[C:19]([N:20]=2)=[CH:18][C:17]([C:21]([OH:23])=[O:22])=[CH:16][CH:15]=3)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(S(C)(=O)=O)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 3-(4-(methylsulfonyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylate (170 mg, 0.40 mmol, 1.00 equiv), methanol (15 mL) in dichloromethane (5 mL). This was followed by the addition of a solution of sodium hydroxide (190 mg, 4.75 mmol, 11.90 equiv) in water (10 mL). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum and diluted by 10 ml of H2O. The pH value of the aqueous solution was adjusted to 3 with hydrochloric acid. The resulting solids were collected by filtration. This resulted in 20 mg (12%) of 3-(4-(methylsulfonyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:6](B(O)O)=[CH:5][CH:4]=[N:3]1.Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)=[CH:12][CH:13]=1
Reactant: Cn1nccc1B(O)O
Reactant: Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(-c2ccnn2C)cc1
Reaction time: 3 h

Procedure:
A mixture of (1-methyl-1H-pyrazol-5-yl)boronic acid (C1) (60.0 g, 0.476 mol) and 1-bromo-4-methylbenzene (75.0 g, 0.438 mol) in a mixture of 1,2-dimethoxyethane (1.2 L) and 2 M aqueous sodium carbonate solution (550 mL) was degassed and purged with N2; this procedure was then repeated twice. Dichlorobis(triphenylphosphine)palladium(II) (3.1 g, 4.4 mmol) was added and the mixture was purged twice with N2. The reaction mixture was heated to reflux and stirred under N2 for 3 hours. The mixture was cooled and 1,2-dimethoxyethane was removed under reduced pressure; water (500 mL) was added to the residue, and the resulting mixture was extracted with dichloromethane (3×500 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Eluent: 100:1 petroleum ether/ethyl acetate) provided the product as a yellow liquid. Yield: 55.0 g, 319 mmol, 73%. 1H NMR (400 MHz, CDCl3) δ 2.42 (s, 3H), 3.89 (s, 3H), 6.29 (d, J=1.8 Hz, 1H), 7.29 (br AB quartet, JAB=8 Hz, ΔνAB=18 Hz, 4H), 7.52 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][CH3:11])[CH2:8][C:7](=[O:9])[O:6][C:4]1=[O:5])[CH3:2].[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([CH2:24][O:25][C:26]3[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=3)[NH2:29])=[N:21]2)=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([CH2:24][O:25][C:26]3[CH:27]=[C:28]([NH:29][C:7](=[O:9])[CH2:8][C:3]([CH2:10][CH3:11])([CH2:1][CH3:2])[C:4]([OH:6])=[O:5])[CH:30]=[CH:31][CH:32]=3)=[N:21]2)=[CH:16][CH:15]=1
Reactant: COc1ccc2ccc(COc3cccc(N)c3)nc2c1
Reactant: CCC1(CC)CC(=O)OC1=O
Product: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3ccc(OC)cc3n2)c1)C(=O)O

Procedure:
The title compound is prepared analogously to the compound described in Example 20 from 2,2-diethylsuccinic acid anhydride and 3-(7-methoxy-2-quinolinylmethoxy)aniline; colourless crystals of m.p. 163°-164°.
Reaction SMILES: Br[CH:2]([C:7](=[O:18])[C:8]([CH2:14][CH2:15][CH2:16][CH3:17])([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-].[K+]>CS(C)=O.O>[CH2:9]([C:8]1([CH2:14][CH2:15][CH2:16][CH3:17])[C:7](=[O:18])[CH:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[O:13]1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCC(O)(CCCC)C(=O)C(Br)CC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCC1(CCCC)OC(CC(C)C)C1=O
Temperature: 0 °C
Yield: 95 %

Procedure:
To the solution of allene (48. mg, 0.230 mmol) in 1:1 solution of t-BuOH and pH 7.4 buffer (3.0 ml) at rt was added NMO (60. mg, 0.460 mmol) and 4 wt % OsO4 in water (0.300 ml, 0.046 mmol). NBS (77. mg, 0.460 mmol) was dissolved in 1:1:1 solution of t-BuOH, water and acetone (3.00 ml) and added to the reaction mixture via syringe pump over 5 h at rt. After the complete consumption of allene as judged by TLC (5 h), the reaction was quenched by a saturated solution of sodium sulfite (3.00 ml). The reaction was diluted by water and the organic layer was extracted in EtOAc (3×10.0 ml), dried over anhydrous Na2SO4, filtered, concentrated and purified by flash column chromatography (4% EtOAc/Hexane) to obtain 4-bromo-6-butyl-6-hydroxy-2-methyldecan-5-one (63. mg, 85% yield) as colorless oil. The 4-bromo-6-butyl-6-hydroxy-2-methyldecan-5-one (63. mg, 0.196 mmol) was dissolved in DMSO (3.92 ml) and cooled to 0° C. To the reaction at 0° C. was added KOH (0.180 ml, 0.216 mmol) dropwise. Upon the completion of reaction as judged by TLC (10 min), the reaction was diluted with water and the organic layer was extracted in EtOAc (3×5.00 ml), dried over anhydrous Na2SO4, filtered, concentrated and purified by flash column chromatography (2% EtOAc/Hexane) to obtain 2,2-dibutyl-4-isobutyloxetan-3-one (45. mg, 95% yield) as colorless oil.
Reaction SMILES: CN(C=O)C.O=S(Cl)Cl.[Cl:10][C:11]1[N:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][C:12]=1[I:20].CCN(C(C)C)C(C)C.[F:30][C:31]([F:41])([F:40])[O:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.C1COCC1.CC(OC)(C)C>[Cl:10][C:11]1[C:12]([I:20])=[CH:13][C:14]([C:17]([NH:37][C:36]2[CH:38]=[CH:39][C:33]([O:32][C:31]([F:30])([F:40])[F:41])=[CH:34][CH:35]=2)=[O:19])=[CH:15][N:16]=1
Reactant: O=C(O)c1cnc(Cl)c(I)c1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(I)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
DMF (1.927 mL, 24.89 mmol) and SOCl2 (18.17 mL, 249 mmol) were added to a suspension of 6-chloro-5-iodo-3-pyridinecarboxylic acid (24 g, 83 mmol) in toluene (165 mL) and the RM was stirred at 80° C. for 1 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in THF (165 mL). DIPEA (29.0 mL, 166 mmol) was added and the mixture was cooled down to −15° C., treated dropwise with a solution of 4-(trifluoromethoxy)aniline (15.43 g, 87 mmol) in THF (165 mL) and was stirred at RT for 1 h. The solvent was off under reduced pressure and the residue was dissolved in TBME (500 mL), washed with 1N HCl, a sat. aq. solution of NaHCO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure and the product was recrystallized from EtOAc/n-heptane to afford the title compound as a white solid. UPLC-MS (Condition 2) tR=1.23 min, m/z=440.8 [M−H]−.
Reaction SMILES: C(OC(=O)C)(=O)C.[NH:8]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][C:12](=[O:14])[NH2:13].[C:28]1([C:34]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.S(=O)(=O)(O)O>C(O)(=O)C.O>[NH:8]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][C:12](=[O:14])[NH:13][C:34]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(CC[C@H](NC(=O)OCc1ccccc1)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
1.1 ml of acetic anhydride (12 mmol) are added to a mixture of 2.8 g of Z-Gln-OH (10 mmol), 5.2 g of triphenylmethanol (20 mmol) in 30 ml of acetic acid, and the mixture is stirred at 50° for 15 minutes. Then 0.05 ml of conc. sulfuric acid (about 1 mmol) is added, resulting in a clear yellow solution after a few minutes. After 2 hours, the solution is added dropwise to 500 ml of water, while stirring and cooling in ice, and the precipitate is filtered off and thoroughly washed with water. The moist material is dissolved in ethyl acetate, the aqueous phase is separated off, and the organic phase is washed once with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to 20 g. Z-Gln(Trt)-OH is crystallized by addition of hexane in portions, m.p. 161°-162°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[CH2:19][C:18]1=[O:26]>>[CH3:1][O:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]([CH:7]=[C:19]2[C:20]3[C:25](=[N:24][CH:23]=[CH:22][CH:21]=3)[NH:17][C:18]2=[O:26])=[CH:9][CH:10]=1
Reactant: O=C1Cc2cccnc2N1
Reactant: COc1ccc(C=O)cc1-c1ccccc1
Product: COc1ccc(C=C2C(=O)Nc3ncccc32)cc1-c1ccccc1

Procedure:
4-Methoxy-3-phenylbenzaldehyde was condensed with 7-aza-2-oxindole to give 0.25 g of 3-(6-methoxybiphenyl-3-ylmethylene)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one as a yellow-orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.[CH3:10][S:11]([NH2:14])(=[O:13])=[O:12].C(O)(=O)C.C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:14][S:11]([CH3:10])(=[O:13])=[O:12])[CH:5]=[N:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: O=Cc1cncc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCc1cncc(Br)c1
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-3-pyridine-carboxaldehyde (1.5 g, 7.9 mmol), methanesulfonamide (0.5 g, 5.3 mmol), acetic acid (0.637 g, 10.6 mmol), triethylamine (1.07 g, 10.6 mmol) in DCE (50 mL) at ambient temperature is added NaBH(OAc)3 (3.14 g, 14.84 mmol). The reaction mixture is stirred overnight. Aqueous NaHCO3 (20 mL) is added and the organic phase is separated. The aqueous phase is extracted with dichloromethane and the combined organic phase is dried over Na2SO4. Concentration affords a residue which is purified by silica gel flash chromatography with a methanol in dichloromethane gradient to afford N-(5-bromo-pyridin-3-ylmethyl)-methanesulfonamide as a solid. MS (ESI) m/z 266.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[CH:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[CH:14]1([C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([OH:13])=[C:6]3[C:11]=2[NH:10][C:9](=[O:12])[CH2:8][CH2:7]3)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Nc1ccc(O)c2c1NC(=O)CC2
Reactant: O=C(Cl)C1CCCCC1
Solvent: c1ccncc1
Product: O=C1CCc2c(O)ccc(NC(=O)C3CCCCC3)c2N1
Temperature: 25 °C
Yield: 38.1 %

Procedure:
10.7 g of 8-amino-5-hydroxy-3,4-dihydrocarbostyril was dissolved in 100 ml of pyridine, and 10.0 g of cyclohexylcarbonyl chloride was added to the solution while vigorously stirring at room temperature followed by stirring at 50° C. for 30 minutes. The precipitated crystals were recovered by filtration, washed with ethanol, dried and dissolved in 200 ml of a 10% aqueous sodium hydroxide solution. Activated carbon was added to the solution, and the mixture was stirred and filtered. The filtrate was rendered acidic with hydrochloric acid under ice cooling, and the precipitated crystals were recovered by filtration, washed with water and dried. Recrystallization from methanol yielded 6.6 g of 8-cyclohexylcarbonylamino-5-hydroxy-3,4-dihydrocarbostyril as colorless amorphous crystals having a melting point of 304.2°-304.8° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4](Cl)=[O:5].[CH2:7]([OH:11])[CH2:8][CH2:9][CH3:10]>CCOCC>[Cl:1][CH2:2][CH2:3][S:4]([O:11][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5]
Reactant: CCCCO
Reactant: O=S(Cl)CCCl
Solvent: CCOCC
Product: CCCCOS(=O)CCCl

Procedure:
2-Chloroethanesulfinyl chloride (16.2 w), prepared as in Example I was dissolved in dry ether (130 v) and the solution was cooled to -15°. Normal butanol was added dropwise under a nitrogen atmosphere to the cooled solution. Upon completion of the addition period the reaction mixture was allowed to warm to ambient temperatures and the solvent was removed by distillation in a vacuum to yield a colorless liquid, butyl 2-chloroethanesulfinate (18.5 w).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C@@:5]([OH:33])([CH3:32])[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[F:31])=[CH:20][CH:19]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])[CH3:2].[CH2:35](O)[CH2:36][CH2:37][CH2:38][CH2:39]CC.Cl.O1CCOCC1>>[CH2:1]([O:3][C:4](=[O:34])[C@@:5]([OH:33])([CH3:32])[CH2:6][N:7]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[F:31])=[CH:22][CH:23]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])[CH2:2][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCOC(=O)[C@](C)(O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(O)no1
Reactant: CCCCCCCO
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCCCOC(=O)[C@](C)(O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(O)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
(R)-3-[N-(5′-Chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-hydroxy-isoxazole-5-carbonyl)-hydrazino]-2-hydroxy-2-methyl-propionic acid ethyl ester (100 mg, 0.2 mmol) was dissolved in 1-heptanol (6 g, 50 mmol), followed by the addition of 4 M HCl in dioxane (1 mL, 4 mmol). The resulting mixture was stirred at room temperature for 8 hours, then evaporated under reduced pressure and purified (Interchim reverse phase chromatography column). The pure fractions were lyophilized to yield the title compound (27 mg, 95% purity). MS m/z [M+H]+ calc'd for C28H33ClFN3O6, 562.20; found 562.2.
Reaction SMILES: [CH2:1]([CH:8]([CH2:13][S:14]([N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)(=[O:16])=[O:15])[C:9]([O:11]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Na+].C(O)(C)C>CC(C)=O>[CH2:1]([C@H:8]([CH2:13][S:14]([N:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)(=[O:16])=[O:15])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccccc1)CS(=O)(=O)N1CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CN1CCN(S(=O)(=O)C[C@@H](Cc2ccccc2)C(=O)O)CC1
Temperature: 75 °C
Reaction time: 18 h
Yield: 19.7 %

Procedure:
The product of Example 4B (69 kg, 202 mol) in acetone (420 kg)/water (960 kg) was adjusted to pH 8.0 using 1N sodium hydroxide. Alcalase™ (Novo Industries, Denmark (Subtilisin Carlsberg) (6.9 liters) was added and the pH was maintained between 7.9 and 8.4 by the addition of 1N sodium hydroxide. When 80% of the theoretical amount of sodium hydroxide had been consumed, the reaction was quenched by the addition of ethyl acetate. The reaction mixture was concentrated to half the original volume under reduced pressure and then washed with ethyl acetate (2×700 kg). The volume of the aqueous phase was concentrated by half and the pH adjusted to 5.2. The reaction mixture was treated with XAD-16 resin (50 kg), stirred for 18 hours, and applied to an XAD-16 resin column (50 kg). The column was eluted with water (500 kg) and then 35% ethanol in water (1000 kg) to afford a residue which was treated with isopropanol (270 kg) and warmed to 75° C. Upon cooling to room temperature and subsequently to -5° C., crystalline material was obtained. The solid was removed by filtration, washed with cold isopropanol (30 kg) and dried at 50° C. to afford the title compound (13 kg, 49%). MS (DCI/NH3) m/e 327 (M+H)+. This compound can be recrystallized from 1:1 isopropanol/water.
Reaction SMILES: Cl.[CH2:2]([C:5]1[S:6][C:7]([C:10]([OH:12])=[O:11])=[CH:8][N:9]=1)[CH2:3][CH3:4].[CH2:13](O)[CH3:14]>>[CH2:2]([C:5]1[S:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:9]=1)[CH2:3][CH3:4]
Reactant: CCO
Reactant: CCCc1ncc(C(=O)O)s1
Agent: Cl
Product: CCCc1ncc(C(=O)OCC)s1

Procedure:
A current of hydrochloric acid gas was passed with stirring through a solution of 30 g of 2-propyl-thiazole-5-carboxylic acid in 400 ml of absolute ethanol overnight and the ethanol was then evaporated off. The oily residue was taken up in ether containing 10% of potassium carbonate and the mixture was extracted with ether. The ether extracts were washed with water until a pH of 6 was obtained and the resulting yellow oil was purified by distillation to obtain 31.2 g of ethyl 2-propyl-thiazole-5-carboxylate with a boiling point of 139°-140°C at 16 mmHg.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:33])[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([CH2:21][N:22]3C(=O)C4C(=CC=CC=4)C3=O)[N:12]=2)=[CH:6][C:5]=1[F:34])[CH3:2].ClCC1N=C(N(C2C=CC(OCC)=C(F)C=2)C)C2C(=CC=CC=2)N=1.C1(=O)NC(=O)C2=CC=CC=C12.[K]>CN(C=O)C.CCOC(C)=O>[NH2:22][CH2:21][C:13]1[N:12]=[C:11]([N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([F:34])[CH:6]=2)[CH3:33])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: CCOc1ccc(N(C)c2nc(CN3C(=O)c4ccccc4C3=O)nc3ccccc23)cc1F
Agent: CCOc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1F
Agent: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(N(C)c2nc(CN)nc3ccccc23)cc1F
Temperature: 70 °C
Yield: 91 %

Procedure:
2-{4-[(4-Ethoxy-3-fluoro-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione: A suspension of (2-chloromethyl-quinazolin-4-yl)-(4-ethoxy-3-fluoro-phenyl)-methyl-amine (179.1 mg, 0.52 mmol) and potassium phthalimide (104 mg, 0.56 mmol) in DMF (2 mL) was heated to 70° C. for 2 h. The reaction was cooled to rt, diluted with EtOAc, washed with 5% NaOH and H2O, dried (MgSO4), filtered and concentrated. The residue was purified by gradient MPLC (SiO2, EtOAc/hexanes, 0-100%) to provide 215 mg (91%) of the title compound. 1H NMR (CDCl3) δ 7.90-7.92 (m, 2H), 7.67-7.80 (m, 3H), 7.50-7.57 (m, 3H), 6.83-7.05 (m, 4H), 6.75-6.81 (m, 1H), 5.14 (s, 2H), 4.11 (q, 2H), 3.24 (s, 3H), 1.47 (t, 3H); LC-MS (ESI+; 457 ([M+H]+)).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]([F:42])([F:41])[C:31]1[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][NH:33][N:32]=1>C(Cl)Cl.CN(C=O)C>[CH3:17][CH:16]([S:13]([NH:12][C@H:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][N:33]3[CH:34]=[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:31]([C:30]([F:29])([F:41])[F:42])=[N:32]3)[CH:4]=2)[CH2:8]1)(=[O:15])=[O:14])[CH3:18]
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reactant: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(CO)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cn(Cc2ccc3c(c2)C[C@H](NS(=O)(=O)C(C)C)C3)nc1C(F)(F)F
Temperature: 25 °C
Yield: 85.7 %

Procedure:
(R)—N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (2.82 mmol, 760 mg) was dissolved in DCM (20 mL) and Thionyl Chloride (5.64 mmol, 0.409 mL, 671 mg) added and the solution stirred at room temperature. After 45 min the mixture was concentrated then azeotroped with DCM (4×10 mL) to give a yellow oil. To this oil was added DMF (10 mL) and potassium carbonate (8.46 mmol, 1170 mg) followed by ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (2.82 mmol, 587 mg). The mixture was heated to 60° C. with stirring for 1 h. The reaction was concentrated to remove DMF before partitioning between EtOAc/Water. The phases were mixed and separated and the aqueous phase further washed with EtOAc (×2). Combined organics were dried and concentrated to give a light yellow oil which was purified on silica eluting with 25% EtOAc/heptane. Desired fractions were collected and concentrated to give (R)-ethyl 1-((2-(1-methylethylsulfonamido)-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate as a colourless solid (1.11 g, 86%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[C:15](=[O:33])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[C:18]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:17]=1)[C:9](O)=[O:10])[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)C(Cl)=O.[CH:40]([NH2:43])([CH3:42])[CH3:41].Cl>C(Cl)Cl.O.C(OCC)(=O)C.CN(C)C=O>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15](=[O:33])[C:14]2[CH:13]=[CH:12][C:8]([C:9]([NH:43][CH:40]([CH3:42])[CH3:41])=[O:10])=[CH:7][C:6]=2[O:5][CH2:1][CH:2]([CH3:3])[CH3:4])=[CH:17][C:18]=1[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: COC(=O)CCc1cc(C(=O)c2ccc(C(=O)O)cc2OCC(C)C)ccc1OCC(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cc(C(=O)c2ccc(C(=O)NC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 2.5 ml of methylene chloride is dissolved 0.25 g of 3-isobutoxy-4-[4-isobutoxy-3-(3-methoxy-3-oxopropyl)benzoyl]benzoic acid. At ambient temperature, 60 μl of oxalyl chloride is added and then 20 μl of N,N-dimethylformamide is added, and the mixture thus obtained is stirred at ambient temperature for one hour. The reaction mixture is cooled with ice water, 0.12 ml of isopropylamine is dropwise added thereto, and the mixture thus obtained is stirred at ambient temperature for one hour. Ethyl acetate and water are added to the reaction mixture, pH is adjusted to 2 with 2 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain 0.12 g of methyl 3-(2-isobutoxy-5-{2-isobutoxy-4-[(isopropylamino)carbonyl]benzoyl}-phenyl)propanoate as a white solid product.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6](=O)[CH:7]([O:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[N:13][CH:12]=1)[CH3:8])=[O:4].C([O-])(=O)C.[NH4+:24]>C(O)C>[CH3:1][O:2][C:3](=[O:4])[CH2:5][C:6]1[N:24]=[C:10]([C:11]2[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[O:9][C:7]=1[CH3:8]
Reactant: COC(=O)CC(=O)C(C)OC(=O)c1ccc(Cl)nc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: COC(=O)Cc1nc(-c2ccc(Cl)nc2)oc1C
Temperature: 80 °C
Yield: 28.2 %

Procedure:
A mixture of 6-chloro-nicotinic acid 3-methoxycarbonyl-1-methyl-2-oxo-propyl ester (16.3 g, 57.1 mmol) and ammonium acetate (18.5 g, 240 mmol) in ethanol (150 mL) is heated at 80° C. for 2 h, concentrated. The residue is taken into acetic acid (330 mL) and heated to reflux overnight, concentrated. The residue is taken into ethyl acetate and washed with water, dried, concentrated, purified by column giving [2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-acetic acid methyl ester (4.3 g).