Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH2:7])([O-:3])=[O:2].[C:14]([C:17]1[C:18](=[O:28])[O:19][C:20]([OH:27])=[C:21]([C:24](=O)[CH3:25])[C:22]=1[OH:23])(=[O:16])[CH3:15]>CO>[C:14]([C:17]1[C:18](=[O:28])[O:19][C:20](=[O:27])[C:21](=[C:24]([NH:7][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=2)[CH3:25])[C:22]=1[OH:23])(=[O:16])[CH3:15]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)C(=O)OC1=O

Procedure:
Following the procedures of Example 4, an equimolar mixture of 3,5-dinitroaniline and 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in methanol was reacted to give 5-acetyl-4-hydroxy-3-[1-(3,5-dinitrophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione. A solution of the latter (3.0 g., 0.008 mol) in 30 ml. of dimethylformamide was hydrogenated over 200 mg. of 10% palladium-on-carbon at 50 psi. When absorption stopped the catalyst was filtered and the filtrate poured into 200 ml. of ice-water. The resulting product was filtered, washed with water and dried to give 5-acetyl-4-hydroxy-3-[1-(3,5-diaminophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. above 350° C. (dec.).
Reaction SMILES: C([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH:25]=[C:26]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])C.[OH-].[Na+]>>[C:43]([CH2:42][CH2:41][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)[CH:25]=[C:26]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:29])=[O:30])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:48])=[O:3])([OH:45])=[O:44]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc(Cl)cc3)cc(S(=O)(=O)C(C)C)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CC(C)S(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(Cl)cc2)c1
Yield: 49.1 %

Procedure:
A similar procedure as described in Example 40, step 8 was used, starting from 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-(propane-2-sulfonyl)-4′-chloro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid ethyl ester (132 mg, 0.18 mmol) and 1.0 N aqueous sodium hydroxide (1.8 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(5-(propane-2-sulfonyl)-4′-chloro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (57 mg, 47%) as an amorphous white solid: ES(+)-HRMS m/e calcd for C34H41ClO8S (M+Na)+ 667.2103, found 667.2101.
Reaction SMILES: [CH:1]1([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH2:14])=[O:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CCO>[CH:1]1([C:7]2[N:14]=[C:12]([OH:13])[C:11]3[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1ccccc1NC(=O)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1nc(C2CCCCC2)nc2ccccc12

Procedure:
2-(Cyclohexylcarbonylamino)benzamide was stirred for 16 h in a mixture of excess 1 M NaOH and EtOH, and the resulting solution was treated with HCl to pH=7 causing the formation of a precipitate. The precipitate was collected by filtration, washed (with water and hexane), and dried under vacuum to give a nearly quantitative yield of 2-cyclohexyl-4-hydroxyquinazoline as a white solid, which was used immediately in the next step.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][CH2:4][CH:5]=[CH2:6].[CH2:8](O)[CH2:9][OH:10].C1(C)C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:1][C:2]1([CH2:3][CH2:4][CH:5]=[CH2:6])[O:10][CH2:9][CH2:8][O:7]1
Reactant: OCCO
Reactant: C=CCCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCCC1(C)OCCO1
Yield: 46.4 %

Procedure:
In a 200 mL RB flask, 5-hexen-2-one (37.18 g, 0.3788 mol) was mixed with ethylene glycol (23.49 g, 0.3788 mol), 0.72 g p-toluenesulfonic acid monohydrate and 40 mL toluene. A graduated water collector and a reflux condenser were connected to the flask. The mixture was refluxed overnight. The reaction was completed as shown by the amount of water collected (ca. 7 mL). After evaporation of toluene, the mixture was distilled under reduced pressure to gave 25 g of pure product. 1H NMR (CDCl3): δ 1.31 (s, 3H, —CH3); 1.72 (m, 2H, CH2═CHCH2CH2—); 2.13 (m, 2H, CH2═CHCH2CH2—); 3.92 (m, 4H, —OCH2CH2O—); 4.95 (m, 2H, CH2═CH—); 5.80 (m,1H, CH2═CH—).
Reaction SMILES: [CH:1]1([C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.Cl[C:16]1[N:25]=[C:24]([NH2:26])[C:23]2[C:18](=[CH:19][C:20]([O:29][CH3:30])=[C:21]([O:27][CH3:28])[CH:22]=2)[N:17]=1>>[NH2:26][C:24]1[C:23]2[C:18](=[CH:19][C:20]([O:29][CH3:30])=[C:21]([O:27][CH3:28])[CH:22]=2)[N:17]=[C:16]([N:12]2[CH2:11][CH2:10][N:9]([C:7]([CH:1]3[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]3)=[O:8])[CH2:14][CH2:13]2)[N:25]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(C1CC=CCC1)N1CCNCC1
Product: COc1cc2nc(N3CCN(C(=O)C4CC=CCC4)CC3)nc(N)c2cc1OC

Procedure:
N-(3-cyclohexenylcarbonyl)piperazine (7.65 g., 0.04 mole) and 2-chloro-4-amino-6,7-dimethoxyquinazoline (9.6 g., 0.04 mole) are reacted according to the procedure of Example 1(a). The crude product crystallized from methanol affords analytically pure 4-amino-2-[4-(3-cyclohexenylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline, m.p. 211°-213° C. resolidifying and melting at 234.0° -236.0°C. (corr.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11]Br)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])[CH2:26][CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)NCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCCCCN1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
A solution of (4-bromobutyl)carbamic acid tert-butyl ester (3.75 g, 90%, 13.38 mmol) in acetone (10 mL) was added to a mixture of piperazine-1-carboxylic acid benzyl ester 15 (2.68 g, 12.16 mmol), sodium iodide (1.82 g, 12.16 mmol), and potassium carbonate (5.04 g, 36.47 mmol) in acetone (100 mL). The reaction mixture was stirred at reflux for 24 h. The mixture was concentrated in vacuo, the resulting residue was diluted with dichloromethane and insoluble inorganics were filtered off. The filtrate was concentrated in vacuo and the resulting residue was purified by Biotage silica gel column chromatography using methanol/dichloromethane (gradient 0% to 5%) to give 4-(4-tert-butoxycarbonylaminobutyl)piperazine-1-carboxylic acid benzyl ester (16) as a viscous, brown oil (3.26 g, 68%): 1H NMR (300 MHz, CDCl3) δ 1.40 (s, 9H), 1.51 (m, 4H), 2.49 (m, 6H), 3.10 (m, 2H), 3.51 (m, 4H), 5.10 (s, 2H), 5.25 (br, 1H), 7.32 (m, 5H); ESI MS m/z 392 [C21H33N3O4+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][OH:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[C:12]([CH3:22])=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:15]=1.O[C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[C:12]([CH3:22])=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:15]=1)[CH2:23][O:24][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:27]=1
Reactant: COc1cc(CO)ccc1OCc1cn(-c2ccccn2)nc1C
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1cn(-c2ccccn2)nc1C
Reaction time: 15 h
Yield: 31.5 %

Procedure:
To a mixture of {3-methoxy-4-[(3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)methoxy]phenyl}methanol (0.73 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.45 g), tributylphosphine (0.67 g) and tetrahydrofuran (80 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.83 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 3-({3-methoxy-4-[(3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as pale-yellow crystals (0.35 g, yield 32%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 179-180° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:5]=1[O:6][CH2:7][C:8]([NH:10][C@H:11]([CH2:18][F:19])[CH2:12][CH2:13][C:14]([O:16]C)=[O:15])=[O:9]>CO>[Cl:3][C:4]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:5]=1[O:6][CH2:7][C:8]([NH:10][C@H:11]([CH2:18][F:19])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9]
Reactant: COC(=O)CC[C@@H](CF)NC(=O)COc1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC[C@@H](CF)NC(=O)COc1ccc(Cl)cc1Cl

Procedure:
0.77 ml of 1N aqueous sodium hydroxide solution was added to a stirred mixture of 0.27 g of 16 in 20 ml of methanol, the resulting mixture was stirred at reflux for one hour and then at room temperature over a week-end. The mixture then was filtered and the solvent evaporated from the filtrate. The residue was placed in water, ethyl acetate was added, then the mixture was acidified with 12N hydrochloric acid. The mixture was stirred for 30 minutes, then the organic phase was separated, dried (Na2SO4) and filtered. The solvent was evaporated from the filtrate to give a pale yellow oil. The oil was filtered through a florosil pad, eluted with ethyl acetate to give an oily solid, which was treated with methanol to give 17, as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:33])([C:23]([F:32])([F:31])[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[F:11][C:12]([F:33])([C:23]([F:31])([F:32])[C:24]([F:30])([F:29])[C:25]([F:26])([F:27])[F:28])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]=[O:22])=[CH:19][CH:20]=1
Reactant: OCc1ccc(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1ccc(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.8 %

Procedure:
To a solution of oxalyl chloride (80.2 μL, 0.93 mmol) in dichloromethane (8 mL) at −78° C., dimethyl sulfoxide (132.2 μL, 1.86 mmol) was added dropwise. After 15 minutes, 4-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)benzenemethanol (300 mg, 0.85 mmol) was added. After 30 minutes, triethylamine (590 μL, 4.23 mmol) was added. The reaction was then allowed to warm to room temperature. Saturated sodium bicarbonate solution was added. The mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 122 mg of 4-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)benzaldehyde; 1H NMR (300 MHz, CDCl3) δ 10.00 (s, 1H), 7.85 (d, 2H), 7.40 (d, 2H), 3.01 (m, 2H), 2.41 (m, 2H) ppm.
Reaction SMILES: [CH:1](O)([CH3:3])[CH3:2].CC(C)=O.[CH:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([CH:1]([CH3:3])[CH3:2])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)O
Reactant: c1ccccc1
Solvent: CC(C)=O
Product: CC(C)c1ccccc1

Procedure:
To reduce steps, Patent Literatures 2 to 4 disclose methods in which isopropanol from the hydrogenation of acetone is directly used as an alkylating agent without dehydration and is reacted with benzene to give cumene. Patent Literature 4 discloses that the process involves a trickle-bed reactor, but is silent on the flow rate of gas.
Reaction SMILES: C[C@@H]1O[C@@H](O[C@H]2[C@H](OC3C=C(O)C(C(CCC4C=CC(OC)=C(O)C=4)=O)=C(O)C=3)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@H](O)[C@H]1O.OC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(O)(=O)C(CC(O)=O)O.[C@@H]1(N2C3N=CN=C(O)C=3N=C2)O[C@H](C(C([O-])=O)O)[C@@H](O)[C@H]1O.[Na+:100].[Na+].[C@@H]1(N2C3N=CN=C(O)C=3N=C2)O[C@H](C(C([O-])=O)O)[C@@H](O)[C@H]1O.[CH:124]1[N:128]([C@@H:129]2[O:133][C@H:132]([CH2:134][O:135][P:136]([O-:139])([O-:138])=[O:137])[C@@H:131]([OH:140])[C@H:130]2[OH:141])[C:127]2[NH:142][C:143](N)=[N:144][C:145](=[O:146])[C:126]=2[N:125]=1.[Na+].[Na+]>O>[CH:143]1[NH:142][C:127]2[N:128]([C@@H:129]3[O:133][C@H:132]([CH2:134][O:135][P:136]([O-:139])([O-:138])=[O:137])[C@@H:131]([OH:140])[C@H:130]3[OH:141])[CH:124]=[N:125][C:126]=2[C:145](=[O:146])[N:144]=1.[Na+:100].[Na+:100]
Reactant: Nc1nc(=O)c2ncn([C@@H]3O[C@H](COP(=O)([O-])[O-])[C@@H](O)[C@H]3O)c2[nH]1
Agent: COc1ccc(CCC(=O)c2c(O)cc(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](O)[C@H]3O)cc2O)cc1O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(O)CC(O)C(=O)O
Solvent: O
Product: O=c1nc[nH]c2c1ncn2[C@@H]1O[C@H](COP(=O)([O-])[O-])[C@@H](O)[C@H]1O

Procedure:
Neohesperidin dihydrochalcone (10 g) and sorbitol (50 g) were mixed together and were heated to 140° C. to 170° C. (water or alcohol in appropriate quantities may be used to assist dissolution of the starting material). The liquified mixture was cooled to about 60° C. to 70° C., and the pH of the solution was adjusted to 5.5 to 6.0 by the addition of citric acid or malic acid. Then a mixture of disodium 5'--inosinate and disodium 5'--guanylate (0.016 g), which is commercially obtained as ribotide, was added and the entire mixture was dried by conventional methods. The dried mixture was ground into a fine powder. The resulting composition had excellent solubility in aqueous solution and gave an immediate sweet taste with no methanol-like aftertaste. This composition may be used to sweeten beverages and other food products.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9][CH2:10][C:11]([O:13]C)=O)[CH:5]=[N:6][CH:7]=1.[NH3:15]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9][CH2:10][C:11]([NH2:15])=[O:13])[CH:5]=[N:6][CH:7]=1
Reactant: N
Reactant: COC(=O)CSCc1cncc(Br)c1
Product: NC(=O)CSCc1cncc(Br)c1
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of methyl 2-((5-bromopyridin-3-yl)methylthio)acetate (1.2 g, 4.5 mmol) in NH3 (2.0 M in MeOH, 40 mL) was heated at 80° C. in a sealed vessel for 2 h. After this time, the reaction mixture was allowed to cool to room temperature and then the solvent was evaporated under reduced pressure. The resulting residue was recrystallized from EtOAc/hexanes to provide 2-((5-bromopyridin-3-yl)methylthio)acetamide (0.8 g, 72% yield). LCMS Method W: retention time 1.08 min; [M+1]=263.0.
Reaction SMILES: [CH3:1][C:2]1[O:9][C:5]([CH:6](O)[CH3:7])=[CH:4][CH:3]=1.C([O-])(=[O:12])C.[Na+]>O>[CH3:7][CH:6]1[C:2]([OH:9])([CH3:1])[CH:3]=[CH:4][C:5]1=[O:12]
Reactant: Cc1ccc(C(C)O)o1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC1C(=O)C=CC1(C)O
Yield: 78 %

Procedure:
In the same apparatus as in Example 1, 5-methyl-α-methyl-furfuryl alcohol (35 parts), water (1050 parts) and sodium acetate (0.07 part) were charged, and the resultant mixture was stirred at 100° C. in a nitrogen stream while maintaining the pH at 5.0 to 5.7 until the starting compound was consumed. The reaction mixture was treated as in Example 1 to give 2-methyl-3-hydroxy-3-methyl-4-cyclopentenone in a yield of 78 %.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[C:5]([C:11](O)=[O:12])[C:4](=[O:14])[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH2:21][C:22]1[CH:43]=[CH:42][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]3[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]4[CH2:41][CH2:40]4)=[O:38])[N:35]=3)[CH:32]=2)=[C:24]([F:44])[CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1.CN(C)C=O>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:42]=[CH:43][C:22]([NH:21][C:11]([C:5]5[C:4](=[O:14])[N:3]([C:15]6[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=6)[N:2]([CH3:1])[C:6]=5[C:7]([F:10])([F:9])[F:8])=[O:12])=[CH:23][C:24]=4[F:44])=[CH:32][N:31]3[CH:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Cn1c(C(F)(F)F)c(C(=O)O)c(=O)n1-c1ccccc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)c(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 48.9 %

Procedure:
A mixture of 1-methyl-3-oxo-2-phenyl-5-(trifluoromethyl)-2,3-dihydro-1H-pyrazole-4-carboxylic acid (450 mg, 1.6 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (360 mg, 1.1 mmol), HATU (590 mg, 1.6 mmol), diisopropylethylamine (430 mg, 3.3 mmol) and N,N-dimethylformamide (7 mL) was stirred at room temperature for 13 hr. Ethyl acetate/tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution were added to the mixture, and the aqueous layer was extracted 4 times with ethyl acetate/tetrahydrofuran. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=40/60→100/0) to give the title compound (320 mg, 48%) as a pale-yellow solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[Cl:9][C:10]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:11]=1[CH:12]=O.N1CCCCC1.C(O)(=O)C>O1CCCC1>[Cl:9][C:10]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:11]=1[CH:12]=[C:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)CC#N
Solvent: C1CCOC1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=Cc1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
29.7 g (300 millimoles) of ethyl cyanoacetate were added to a solution of 55.7 g (300 millimoles) of 2-chloro-5-nitrobenzaldehyde in 200 ml of tetrahydrofuran, after which 1 ml of piperidine was added as a catalyst at 0° C. The mixture was stirred for 16 hours at room temperature, neutralized with acetic acid and then worked up in a conventional manner to give a product of melting point 83°-85° C. in 71% yield.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.F[C:8]1[CH:18]=[CH:17][C:11]([C:12](OCC)=[O:13])=[CH:10][C:9]=1[CH3:19]>>[CH3:19][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:8]=1[N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1])[CH2:12][OH:13]
Reactant: Cc1ncc[nH]1
Reactant: CCOC(=O)c1ccc(F)c(C)c1
Product: Cc1cc(CO)ccc1-n1ccnc1C

Procedure:
Prepared from 2-methylimidazole and ethyl 4-fluoro-3-methylbenzoate.
Reaction SMILES: [Na].[F:2][C:3]([F:13])([F:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O-:5].[CH2:14]([O:16][C:17](=[O:21])[CH:18](Br)[CH3:19])[CH3:15]>>[CH2:14]([O:16][C:17](=[O:21])[CH:18]([O:5][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([F:12])([F:13])[F:2])[CH3:19])[CH3:15]
Reactant: CCOC(=O)C(C)Br
Reactant: [O-]C(c1ccccc1)C(F)(F)F
Agent: [Na]
Product: CCOC(=O)C(C)OC(c1ccccc1)C(F)(F)F

Procedure:
Using the same procedure as in Example I, Step B, starting from 10.3 g sodium-2,2,2-trifluoro-1-phenylethanolate and 9.4 g ethyl-2-bromopropionate, 6.2 of the title compound is isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[N:34]([CH3:38])[C:33](=[O:39])[CH:32]=[C:31]3[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([OH:27])[C:9]2[N:10]=[C:11]([Si](CC)(CC)CC)[N:12]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:13]=2)=[CH:4][CH:3]=1.[NH4+].[OH-]>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[N:34]([CH3:38])[C:33](=[O:39])[CH:32]=[C:31]3[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)([OH:27])[C:9]2[N:10]=[CH:11][N:12]([S:14]([N:17]([CH3:18])[CH3:19])(=[O:15])=[O:16])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC[Si](CC)(CC)c1nc(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2ccccc2)cc(=O)n3C)cn1S(=O)(=O)N(C)C
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CN(C)S(=O)(=O)n1cnc(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2ccccc2)cc(=O)n3C)c1
Temperature: 110 °C
Yield: 11.2 %

Procedure:
A mixture of intermediate (3-a) (26 g) in sulfuric acid (2.5 ml) and water (250 ml) was stirred and heated at 110° C. for 2 hours. The mixture was poured into ice, basified with NH4OH and extracted with DCM. The organic layer was dried, filtered off and evaporated till dryness. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 99/1/0.2). The pure fractions were collected and evaporated, yielding 2.4 g (11%) of (±)-4-[(4-chlorophenyl)(1,2-dihydro-1-methyl-2-oxo-4-phenyl-6-quinolinyl)hydroxymethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide (interm. 3-b).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:15][C:14]=3[F:27])=[O:9])=[CH:4][CH:3]=1.CO.C#C>C(Cl)Cl.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:15][C:14]=3[F:27])=[O:9])=[CH:28][CH:29]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#CCCCO)cc2c1O
Agent: [Pd]
Agent: C#C
Solvent: ClCCl
Solvent: CO
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CCCCCO)cc2c1O
Yield: 55.7 %

Procedure:
A mixture of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(5-hydroxy-1-pentynyl)-3-quinolinecarboxamide from Example 107 (230 mg) and Pd/C (10%, 46.0 mg) is dissolved in 3:1 CH2Cl2 :MeOH. The reaction mixture is placed under the Parr hydrogenator at 38 psi H2 and monitored by mass spectroscopy for complete reduction of the acetylene. The reaction is complete in 11/2 h and filtered over celite to remove the palladium. The filtrate is condensed to afford 129.3 mg (56%) of the title compound as a white solid.