Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.O1CCCC1.[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.6 %

Procedure:
In a 500 mL three-neck flask were put 16 g (90 mmol) of 4-bromoaniline, 11 g (108 mmol) of triethylamine, and 250 mL of tetrahydrofuran (THF), and the mixed solution was stirred. To this mixed solution, a mixed solution of 9.6 g (90 mmol) of isobutyryl chloride and 50 mL of THF was added dropwise under cooling with ice, and the mixture was stirred at room temperature for 12 hours. After the stirring, this mixture was dissolved in chloroform, and washed with water and a saturated aqueous solution of sodium hydrogen carbonate. After the washing, anhydrous magnesium sulfate was added to the organic layer for drying. The resulting mixture was subjected to gravity filtration, and the filtrate was concentrated to give a solid. This solid was washed with hexane to give 18 g of a white solid of N-(4-bromophenyl)isobutyramide in a yield of 82%. The reaction scheme of Step 1 is shown in (b-1) below.
Reaction SMILES: BrC1C=CC=CC=1C(Cl)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([F:33])[CH:27]=1.[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42]>C1(C)C=CC=CC=1.C(O)C>[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42].[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([NH:43][C:44]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([O:25][C:16]2[C:15]3[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=3)[N:19]=[CH:18][CH:17]=2)=[CH:27][C:28]=1[F:33])=[S:45])=[O:42]
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1ccccc1Br
Agent: O=C(N=C=S)c1ccccc1Br
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Br)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
2-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (73 mg, yield 83%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[CH2:26][CH2:27][O:28][CH3:29].[N:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[NH2:25][C:16]1[C:15]2[N:14]=[C:13]([CH2:26][CH2:27][O:28][CH3:29])[N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:36]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:37])[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)N1CCOCC1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
Under a nitrogen atmosphere, triethylamine (1.04 mL, 7.51 mmol) was added to a chilled (0°) solution of 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.01 mmol) in chloroform (75 mL). 4-Morpholinecarbonyl chloride (830 mg, 5.51 mmol) was added dropwise. The reaction was allowed to warm to ambient temperature and was maintained over the weekend. An equal volume of aqueous 1% sodium carbonate was added with vigorous stirring. A precipitate was isolated by filtration to provide 1.73 g of crude product as a white powder. This material was purified by column chromatography (silica gel eluting with a 0-5% methanol in chloroform gradient) and then triturated with diethyl ether to provide 1.6 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamide as a white powder, m.p. 194.0-196.0° C. Analysis: Calculated for C21H28N6O3: % C, 61.15; % H, 6.84; % N, 20.37. Found: % C, 60.82; % H, 6.94; % N, 20.34.
Reaction SMILES: S(O)(O)(=O)=O.[N:6]1[C:10]2[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=O)[CH2:14][C:9]=2[NH:8][CH:7]=1.S(Cl)(Cl)=O.[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[C:30]([O-:37])(=O)/[CH:31]=[CH:32]/[C:33]([O-])=O.[C:38](#N)[CH3:39]>C(Cl)(Cl)Cl.CO>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH3:24][C:23]1[O:37][C:30]2[CH:31]=[CH:32][CH:33]=[CH:39][C:38]=2[C:22]=1[C:15]([CH:13]1[CH2:12][CH2:11][C:10]2[N:6]=[CH:7][NH:8][C:9]=2[CH2:14]1)=[O:17]
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: CC#N
Reactant: O=C(O)C1CCc2nc[nH]c2C1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1oc2ccccc2c1C(=O)C1CCc2nc[nH]c2C1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
In 40 ml of acetonitrile was suspended 5.00 g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid sulfate, and 2.75 ml of thionyl chloride was added to the suspension. The suspension was stirred at 55° C. for 1 hour, and the solvent was distilled off under reduced pressure. To the residue was added 20 ml of nitrobenzene and 1.80 ml of 2-methylbenzofurane, and 2.20 ml of tin tetrachloride was then added thereto. After stirring at 85° C. for one night, 40 ml of 1M aqueous hydrochloric acid solution and 40 ml of ethyl ether were added thereto. The organic layer was removed, 40 ml of chloroform was added and then the solution was adjusted to a pH of 9 with 10% aqueous solution of sodium hydroxide. The reaction solution was filtered through celite and then extracted with chloroform containing 10% methanol. The organic layer was collected and the solvent was distilled off. To the free base of objective product obtained by treating the residue with silica gel column chromatography using chloroform/methanol was added calculated amount of fumaric acid to convert it to a fumarate and recrystallized from ethanol to obtain 0.14 g of 5-[(2-methylbenzofuran-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole fumarate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[O:14][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:16][N:17]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:12]([C:13]1[O:14][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:16][N:17]=1)=[O:11]
Reactant: CC(C)(C)c1cnc(CO)o1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)c1cnc(C=O)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
To a stirred solution of oxalyl chloride (45 mL, 90 mmole) at −78 deg C. under argon was added dropwise dimethyl sulfoxide (8.80 mL, 124 mmole). The reaction mixture was stirred at −78 deg C. for 10 min., and was treated with a solution of 2-hydroxymethyl-5-t-butyloxazole (11.7 g, 75.1 mmole) in anhydrous methylene chloride (30 mL) over 20 min. The mixture was stirred at this temperature for 1 hour, then triethylamine was added slowly (31.0 mL, 222 mmole), during which the reaction mixture became a yellowish slurry. After stirring at −78 deg C. for 20 min, the reaction mixture was warmed to room temperature, added with methylene chloride (100 mL) and stirred for 1 hour. The solid was filtered off and washed with EtOAc. The filtrate was washed with 5% aqueous citric acid (100 mL) and brine (50 mL), dried over MgSO4. Concentration and column chromatography (silica gel, EtOAc/hexane 1:4) afforded 2-formyl-5-t-butyloxazole as a light yellow oil (10.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13](CC4C=CC(OC)=CC=4)[N:14]=[C:15]([NH:16][CH:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[C:8]=23)=[C:4]([F:35])[CH:3]=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[C:48](=[O:49])[C:47]([C:50](O)=[O:51])=[CH:46][CH:45]=[N:44]2)=[CH:39][CH:38]=1.C([O-])(O)=O.[Na+]>>[F:35][C:4]1[CH:3]=[C:2]([NH:1][C:50]([C:47]2[C:48](=[O:49])[N:43]([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)[N:44]=[CH:45][CH:46]=2)=[O:51])[CH:34]=[CH:33][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][N:14]=[C:15]([NH:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:8]=12
Reactant: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CN1CCC(Nc2n[nH]c3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Yield: 96 %

Procedure:
Prepared by a 2-step process from 4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine and 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (prepared as in Example 19, Step C) according to the procedure described for Example 21, Steps A and B, except that the crude was treated with aqueous NaHCO3). The crude was rinsed with Et2O to afford 34 mg (96%) of the desired product. LRMS (ESI pos) m/e 573.0 (M+1). 1H-NMR (400 MHz, CDCl3/CD3OD) δ 8.39 (d, 1H), 8.32 (d, 1H), 8.14 (d, 1H), 8.03 (dd, 1H), 7.66 (m, 2H), 7.48 (m, 1H), 7.39 (t, 1H), 7.28 (t, 2H), 6.12 (d, 1H), 3.76 (m, 1H), 3.25 (m, 2H), 2.51 (m, 2H), 2.46 (s, 3H), 2.25 (m, 2H), 1.73 (m, 2H); 19F-NMR (376 MHz, CDCl3/CD3OD) δ −113.8, −128.4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[S:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[N:18]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.CO.O.[SH-].[Na+]>O>[N:18]1[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[S:11][C:10]=1[C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc3ccncc3s2)c1
Agent: [Na+]
Agent: [SH-]
Solvent: CO
Solvent: O
Product: Nc1cccc(-c2nc3ccncc3s2)c1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
310 mg of 2-(3-nitrophenyl)thiazolo[5,4-c]pyridine (1.2 mmol) was mixed with 30 mL of MeOH along with 6 mL of water. Sodium hydrosulfide hydrate (6 eq, 7.24 mmol, 400 mg) was added and the reaction mixture was stirred under reflux for 3 hours. The reaction mixture was cooled to room temperature and concentrated. The aqueous layer was extracted with methylene chloride. The combined organic layers were dried (Na2SO4) and concentrated to afford 230 mg of 3-(thiazolo[5,4-c]pyridin-2-yl)benzenamine (84% crude yield) (MS, M++H=228).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:6]2=[N:7][CH:8]=1.CC[C:24]([O-:26])=[O:25].[OH-].[Na+]>C(O)C>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:24]([OH:26])=[O:25])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:6]2=[N:7][CH:8]=1
Reactant: Fc1cccc(Cn2ccc3cc(C(F)(F)F)cnc32)c1
Reactant: CCC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Yield: 99.7 %

Procedure:
A solution of 3.15 g (8.6 mmol) of 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-ethyl carboxylate obtained in Stage 1.2 in 100 mL of ethanol and of 26 mL of 2N sodium hydroxide is stirred for four hours under reflux. After this time, the reaction mixture is concentrated at reduced pressure, and then is taken up in 40 mL of water. The reaction mixture is acidified to pH 3 by successive additions of 1N hydrochloric acid. The precipitate is collected by filtration, washed with water and then dried at reduced pressure. Thus, 2.9 g of the expected product is isolated in the form of a white powder, which is used as it is in the next stage.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH2:25])=[N:17][C:18]([NH2:24])=[N:19]3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[F:26][C:27]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Br>CN(C)C=O>[F:26][C:27]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][N:11]1[CH2:12][CH2:13][N:8]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH2:25])=[N:17][C:18]([NH2:24])=[N:19]3)[CH2:9][CH2:10]1
Reactant: Cc1cccc(CBr)c1F
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(CN2CCN(c3cccc4nc(N)nc(N)c34)CC2)c1F
Temperature: 60 °C
Yield: 50.5 %

Procedure:
In an 8 mL vial with stir bar, triethylamine (40 mg; 0.4 mmol) was added to a mixture of 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2-fluoro-3-methylbenzyl bromide (54 mg; 0.27 mmol) in dimethylformamide and heated to 60° C. for 16 hours. Mixture was quenched with 1 mL of 1N NaOH and after 1.5 hours solids were collected by filtration and triturated with ethanol to obtain 37 mg of title compound. (51% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 7.2 (m, 3H), 7.07 (t, J=7.6 Hz, 1H), 6.95 (dd, J=8.4, 0.8 Hz, 1H), 6.84 (dd, J=7.6, 0.8 Hz, 1H), 5.90 (br s, 2H), 3.59 (s, 2H), 2.98 (d, J=11.2 Hz, 2H), 2.89 (d, J=12.0 Hz, 2H), 2.81 (t, J=9.6 Hz, 2H), 2.313 (t, J=9.2 Hz, 2H), 2.24 (s, 3H). ESIMS+367.6 m/z
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[K+].O.NN>C(O)CO>[C:8]1([C:3]2([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:2]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)CCC1(c2ccccc2)CCCCC1=O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: O=C(O)CCC1(c2ccccc2)CCCCC1
Temperature: 130 °C
Yield: 93 %

Procedure:
A mixture of 3-(2-oxo-1-phenylcyclohexyl)propanoic acid (1 g, 4.06 mmol), potassium hydroxide (0.770 g, 13.72 mmol), hydrazine monohydrate (0.348 mL, 6.09 mmol), and ethylene glycol (5 mL) was heated to 130° C. for 1.5 h. The condenser was removed and the mixture was heated to 200° C. for 30 min. The reaction mixture was then heated under reflux with a reflux condenser for additional 1.5 h. The reaction mixture was cooled to room temperature and diluted with 1N HCl to a total reaction volume of 25 mL. The precipitated product was collected by filtration, washed several times with water, and dried in vacuo to obtain 3-(1-phenylcyclohexyl) propanoic acid as a white solid (Int. 2, 923 mg, 93% yield). HPLC: tR=3.7 min, Chromolith SpeedRod 4.6×50 mm, 4 min gradient, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH-0.2% H3PO4; Final solvent: 90% aq. MeOH-0.2% H3PO4. LC/MS: m/e 215.19 (M+H-H2O)+.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=O)=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C[O:29]CC1>>[OH:29][N:7]1[NH:6][N:5]=[CH:24][N:23]1[C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:18][CH:19]=1
Reactant: O=C=Nc1ccc(OCc2ccccc2)cc1
Reactant: C1CCOC1
Reactant: [N-]=[N+]=[N-]
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: ON1NN=CN1c1ccc(OCc2ccccc2)cc1

Procedure:
To a 100 mL recovery flask was added THF (20 mL) and a stirbar. The flask was cooled to 0° C. whereupon AlCl3 (751 mg, 5.63 mmol, 1.1 eq.) was added. The solution was stirred for 15 min whereupon NaN3 (1.00 g, 15.4 mmol, 3.0 eq.) and 4-benzyloxy-phenylisocyanate 51 (1.15 g, 5.12 mmol, 1.0 eq.) was added. The reaction mixture was refluxed overnight. The reaction mixture was quenched with 1N HCl (50 mL) and diluted with EtOAc (100 mL). The organic phases were washed with brine and the combined aqueous phases were extracted with EtOAc (3×50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give an off-white solid that was used in subsequent reactions without further purification. (515 mg, 37%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[CH3:8].ClC1C=CC(NC2N(C)C3C=CC(O[C:31]4C=CN=[C:33]([C:37](NC)=[O:38])[CH:32]=4)=CC=3N=2)=CC=1[N+]([O-])=O.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[C:33]1[CH:32]=[CH:31][O:38][CH:37]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Reactant: CNC(=O)c1cc(Oc2ccc3c(c2)nc(Nc2ccc(Cl)c([N+](=O)[O-])c2)n3C)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccc([N+](=O)[O-])cc1-c1ccoc1
Temperature: 80 °C
Yield: 78.5 %

Procedure:
A suspension of 3-bromo-4-methyl nitrobenzene 1 (421 mg, 2.0 mmol), 3-furan boronic acid 2 (452 mg, 4.0 mmol), diisopropylethylamine (1.4 mL, 8.0 mmol), and Pd(dppf)Cl2—CH2Cl2 (162 mg, 0.2 mmol) in dry NMP (10 mL) was sparged with Ar for 20 min. The reaction mixture was heated to 80° C. and maintained at that temperature for 16 h. The reaction was allowed to cool to rt and was then partitioned with water and EtOAc. The resulting mixture was filtered through Celite and the phases partitioned and separated. The aqueous portion was extracted with EtOAc (3×) and the combined organic phases were washed with brine, dried (MgSO4), and concentrated. The crude residue was adsorbed onto SiO2 and purified by flash chromatography (9:1 hexanes-EtOAc) to furnish 319 mg (1.57 mmol, 80%) of an off-white solid as 3: 1H NMR (300 MHz, CD3OD) δ 8.16 (d, J=2.5 Hz, 1H), 8.04 (dd, J=2.5, 8.5 Hz, 1H), 7.77 (dd, J=0.8, 1.7 Hz, 1H), 7.63 (app t, J=1.9 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 6.72 (dd, J=0.8, 1.9 Hz, 1H), 2.48 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:4]=1[CH:21]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[CH:24]=1)O.C(O)(C(F)(F)F)=[O:34].C([O-])([O-])=O.[K+].[K+].CO>C(Cl)Cl.O>[CH3:32][O:31][C:25]1[CH:24]=[C:23]([CH:21]2[C:4]3[C:5](=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=3[O:2][CH3:1])[CH:11]([OH:34])[CH:12]2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(C=Cc2cc(OC)cc(OC)c2C(O)c2cc(OC)cc(OC)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C2C(O)c3cc(OC)cc(OC)c3C2c2cc(OC)cc(OC)c2)cc1
Temperature: -20 °C
Reaction time: 5 h
Yield: 75.3 %

Procedure:
To a solution of aldol adduct 11 (0.150 g, 0.344 mmol, 1.0 equiv) in CH2Cl2 (10 mL) at −78° C. was added in a single portion a solution of TFA (0.027 mL, 0.344 mmol, 1.0 equiv) in CH2Cl2 (0.2 mL). The resultant dark purple reaction mixture was then warmed slowly to −20° C. over the course of 30 min and stirred for 5 h at −20° C. Upon completion, the reaction mixture was quenched sequentially with solid K2CO3 (0.475 g, 3.44 mmol, 10 equiv) and MeOH (10 mL), warmed to 25° C., and stirred for 15 min at 25° C. The reaction contents were then poured into water (15 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL), dried (MgSO4), and concentrated. The resultant brown oil was purified by flash column chromatography (silica gel, EtOAc/hexanes, 2:1) to give alcohol 15 (0.113 g, 75% yield) as an amorphous white solid. 15: Rf=0.41 (silica gel, EtOAc/hexanes, 1:1); IR (film) νmax 2935, 1597, 1512, 1463, 1304, 1248, 1203, 1151, 1060, 829; 1H NMR (300 MHz, CDCl3) δ 7.09 (d, J=8.7 Hz, 2H), 6.83 (d, J=8.7 Hz, 2H), 6.65 (d, J=2.1 Hz, 1H), 6.42 (d, J=2.1 Hz, 1H), 6.27 (t, J=2.3 Hz, 1H), 6.17 (d, J=2.4 Hz, 2H), 5.13 (app t, J=5.7 Hz, 1H), 4.19 (d, J=6.9 Hz, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.68 (s, 3H), 3.59 (s, 3H), 3.18 (d, J=6.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 161.7, 160.4, 158.5, 157.1, 146.9, 146.3, 134.0, 128.7, 122.9, 113.9, 105.5, 99.7, 99.4, 99.3, 98.0, 82.5, 66.1, 55.6, 55.3, 55.2, 54.7; HRMS (MALDI-FTMS) calculated for C26H21O6+ [M+] 436.1886. found 436.1870.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([C:7]2[S:8][C:9](=[CH:13][C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[C:34]([F:37])([F:36])[F:35])[N:18]=[CH:17]4)[C:10](=[O:12])[N:11]=2)[C@@H:4]([CH2:38][OH:39])[CH2:3]1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>>[F:35][C:34]([F:37])([F:36])[C:25]1[CH:26]=[C:27]([C:30]([F:33])([F:31])[F:32])[CH:28]=[CH:29][C:24]=1[CH2:23][N:19]1[C:20]2[C:16](=[CH:15][C:14]([CH:13]=[C:9]3[S:8][C:7]([N:5]4[C@@H:4]([CH2:38][OH:39])[CH2:3][C@@H:2]([NH:1][C:40](=[O:42])[CH3:41])[CH2:6]4)=[N:11][C:10]3=[O:12])=[CH:22][CH:21]=2)[CH:17]=[N:18]1
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H]1C[C@H](CO)N(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C1
Product: CC(=O)N[C@@H]1C[C@H](CO)N(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C1

Procedure:
N-{(3R,5R)-1-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(hydroxymethyl)pyrrolidin-3-yl}acetamide was prepared from 2-[(2R,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl]-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one (example 258) and acetic anhydride.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:25][C:26](C)([O-:28])C.[K+].BrCCO>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][OH:28])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccccc1Nc1c(C(=O)C(C)C)cnc2c(O)cccc12
Agent: OCCBr
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1Nc1c(C(=O)C(C)C)cnc2c(OCCO)cccc12
Reaction time: 48 h
Yield: 39.6 %

Procedure:
To a solution of 3-isobutyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (5 g, 15.6 mmol) in dry tetrahydrofuran (250 ml) was added potassium t-butoxide (2.63 g, 23.4 mmol), followed by 2-bromoethanol (3.9 g, 31.2 mmol). The stirred mixture was heated under reflux for 16 hours, then a further quantity of potassium t-butoxide (2.63 g, 23.4 mmol) and 2-bromoethanol (3.9 g, 31.2 mmol) added, and heating continued for 2 days. The solvent was evaporated, and the residue treated with aqueous sodium bicarbonate and extracted into dichloromethane. The extracts were dried and evaporated to an oil, which was purified by flash chromatography (silica gel, dichloromethane/methanol) and recrystallization from 40-60 petroleum ether to yield 3-isobutyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)-quinoline (2.25 g), m.p. 154°-156°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[O:5][CH2:6][C:7]([OH:9])=O.[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[C:31]([CH3:40])[CH:30]=1>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[O:5][CH2:6][C:7]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[C:31]([CH3:40])[CH:30]=1)=[O:9]
Reactant: Cc1cc(CN)ccc1NS(C)(=O)=O
Reactant: O=C(O)COc1ccc(C(F)(F)F)c(Cl)c1
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: Cc1cc(CNC(=O)COc2ccc(C(F)(F)F)c(Cl)c2)ccc1NS(C)(=O)=O
Yield: 66.5 %

Procedure:
[3-Chloro-4-(trifluoromethyl)phenoxy]acetic acid (127 mg, 0.5 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (97 mg, 0.6 mmol), triethylamine (0.33 ml) and N{4-(aminomethyl)-2-methylphenyl]methanesulfonamide hydrochloride (151 mg, 0.6 mmol) were treated in the same procedure described in Example 2(b). The crude residue was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and ethyl acetate (3/1 to 1/1) to furnish 150 mg (67% yield) of the title compound as a white solid.