Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27]Cl)=[CH:21][CH:20]=1>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][O:18][CH2:27][C:26]#[C:25][C:22]2[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: ClCC#Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCOCC#Cc2ccccc2)CC1
Temperature: 0 °C

Procedure:
Sodium hydride (0.912 g, 23 mmol, 60% oil disp.) which had been rinsed with hexanes (3×10 mL), and dry N,N-dimethylformamide (50 mL) were cooled to 0° C. with stirring under a nitrogen atmosphere. A solution of 1-t-butyloxycarbonyl-4-hydroxyethylpiperidine (4.3 g, 19 mmol) in dry DMF (15 mL) was added, and the mixture stirred for 1 hour. 3-Phenylpropargyl chloride (2.8 g, 19 mmol) was added, and the mixture was heated to reflux for 24 hours. After cooling, the solvent was removed by distillation under reduced pressure. The residue was u dissolved in ethyl acetate and extracted with water (3×100 mL), brine (100 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with 5% ethyl acetate in hexanes, and concentrated under reduced pressure to yield 1-t-butyloxycarbonyl-4-[(3-phenyl-2-propynyloxy)ethyl]piperidine (1.02 g, 16% dark oil. 1H NMR (300 MHz, CDCl3 /TMS, δ): 7.5(m,2H),
Reaction SMILES: [OH:1][C:2]1[C:3]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=1.F[C:15]1[CH:20]=[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])[C:18]([F:34])=[CH:17][C:16]=1[N+:35]([O-:37])=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:34][C:18]1[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:20][C:15]([O:1][C:2]2[C:3]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=2)=[C:16]([N+:35]([O-:37])=[O:36])[CH:17]=1
Reactant: COC(=O)COc1ncccc1O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2 h
Yield: 115.8 %

Procedure:
To a mixture of 0.29 g of 3-hydroxy-2-(methoxycarbonyl)methoxypyridine, 0.23 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene, and 3.2 ml of N,N-dimethylformamide was added 0.11 g of potassium carbonate, and the mixture was stirred at 70° C. for 2 hours. Another 0.12 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyri midin-1-yl]nitrobenzene and another 0.05 g of potassium carbonate were added, and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was cooled to room temperature and then poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.39 g of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrim idin-1-yl]-2-nitrophenoxy}-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: OCC1[O:8][C:7]2=[C:9]([C:17]([O:19]CC)=[O:18])[S:10][C:11]([C:12]([O:14]CC)=[O:13])=[C:6]2[O:5]C1.[OH-:22].[K+].CN1CCC(=[C:29]2[C:43]3[C:38](=[CH:39][CH:40]=CC=3)[CH:37]=[CH:36]C3C2=CC=CC=3)CC1>O>[CH2:37]([C:38]1([CH2:39][CH3:40])[CH:43]([CH2:29][OH:22])[O:5][C:6]2=[C:11]([C:12]([OH:14])=[O:13])[S:10][C:9]([C:17]([OH:19])=[O:18])=[C:7]2[O:8]1)[CH3:36]
Reactant: [OH-]
Reactant: CCOC(=O)c1sc(C(=O)OCC)c2c1OCC(CO)O2
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: [K+]
Solvent: O
Product: CCC1(CC)Oc2c(C(=O)O)sc(C(=O)O)c2OC1CO
Temperature: 25 °C
Yield: 90 %

Procedure:
In a 500 mL round bottom flask equipped with a reflux condenser 11.3 g (0.0357 mol) diethyl 2,3-dihydro-2-(hydroxymethyl)thieno[3,4-b][1,4]dioxine-5,7-dicarboxylate was combined with 12.0 g (0.214 mol) potassium hydroxide in 250 mL water. The reactin mixture was refluxed and the progress of the reaction tracked by TLC. Upon completion of the hydrolysis the reaction was concentrated to ˜100 mL. The mixture was cooled to 0 C then acidified with concentrated HCl. After allowing to warm to room temperature overnight the white solid was filtered and washed with a small amount of water. Drying under high vacuum gave 8.5 g (90%) of product as a white solid. Structure and purity were confirmed by 1H/13C NMR and LC-MS.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[OH2:30]>>[CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@@H:21]([OH:30])[CH2:22][C@@H:23]([OH:28])[CH2:24][C:25]([OH:27])=[O:26])[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4]
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Reactant: O
Product: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21

Procedure:
Lovastatin shows poor solubility under the aqueous conditions necessary for enzymatic activity. Alternatively, in one aspect, a suspension of lovastatin in water is raised to pH>12 to effect a rapid hydrolysis of the lactone ring resulting in the in-situ formation of the more soluble lovastatin acid salt. In practice, a suspension of lovastatin in water/MeOH is treated with a solution of 1 mole equivalent of NaOH in water and stirred until dissolution is complete. The pH of the reaction mixture is then readjusted to a range suitable for the enzymatic reaction and the enzyme is added.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.C1(=O)[O:14][C:12](=[O:13])CCC1.C1C2C(CO)C3C(=CC=CC=3)C=2C=CC=1>>[C:12]([OH:14])(=[O:13])[CH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C1CCCC(=O)O1
Reactant: O=C1CCC(=O)O1
Agent: OCC1c2ccccc2-c2ccccc21
Product: O=C(O)CCCC(=O)O

Procedure:
The mixed diesters (E) are readily prepared in two stages from succinic anhydride (r=2) or glutaric anhydride (r=3). In the first stage, the appropriate cyclic anhydride is reacted with 0.5 equivalents of 9-fluorenyl methanol to form the fluorenylmethyl mono-ester of succinic or glutaric acid. In the second stage, reaction of the mono-ester with pentafluorophenol under standard esterification conditions affords the mixed diester.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([CH3:25])([CH3:24])[C:19](=[O:23])[NH:20]2)=[CH:16][C:15]=1[NH:26][CH3:27]>O1CCOCC1>[CH3:27][N:26]1[C:15]2[CH:16]=[C:17]3[C:18]([CH3:24])([CH3:25])[C:19](=[O:23])[NH:20][C:21]3=[CH:22][C:14]=2[N:13]=[C:1]1[OH:2]
Reactant: CNc1cc2c(cc1N)NC(=O)C2(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: Cn1c(O)nc2cc3c(cc21)C(C)(C)C(=O)N3
Temperature: 25 °C

Procedure:
9.8 g. 1,1'-Carbonyldiimidazole are added to 6.1 g. 6-amino-5-methylamino-3,3-dimethylindolin-2-one in 250 ml. dioxan and the reaction mixture is heated under reflux for 2 hours. The solution is evaporated to dryness in a vacuum and the reddish oil remaining behind is boiled under reflux for 2 hours with 20% aqueous hydrochloric acid. The mixture is cooled to ambient temperature and neutralised with aqueous ammonia solution, while cooling with ice. The precipitate is filtered off with suction and recrystallised from methanol. There are obtained 2.0 g. of the title compound; m.p. 364°-367° C.
Reaction SMILES: C(O[CH:5]([O:12][C:13](=[O:36])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]([C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:16]=1[CH3:35])C1C=CC=CC=1)(=O)C.[C:37]([OH:40])(=[O:39])C>[C].[Pd]>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]([N:17]2[C:18]3[C:23](=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:15]([CH2:14][C:13]([O:12][CH2:5][C:37]([OH:40])=[O:39])=[O:36])=[C:16]2[CH3:35])=[O:34])=[CH:28][CH:29]=1
Reactant: CC(=O)O
Reactant: COc1ccc2c(c1)c(CC(=O)OC(OC(C)=O)c1ccccc1)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: [Pd]
Product: COc1ccc2c(c1)c(CC(=O)OCC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1

Procedure:
25.4 g (0.050 mol) of [1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetoxy]-benzyl acetate were dissolved in 400 ml of glacial acetic acid and hydrogenated on 2.0 g of palladium carbon at room temperature. After the absorption of hydrogen had finished (1 hour), the catalyst was filtered off, the filtrate was concentrated by evaporation under vacuum and the compound was caused to crystallise by adding petroleum ether. The compound melted at 149.5°-150.5°C (determined on the micro-Kofler bench); the yield was 19.4 g which corresponds to 93% of the theoretical yield.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[NH:11][C:12]2[C:17]([C:18]=1[CH:19]=O)=[CH:16][CH:15]=[CH:14][CH:13]=2.[S:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27]>>[CH2:1]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]([CH:19]=[C:25]2[S:21][C:22](=[O:27])[NH:23][C:24]2=[O:26])=[C:10]1[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: BrCc1ccccc1
Reactant: Cc1[nH]c2ccccc2c1C=O
Product: Cc1c(C=C2SC(=O)NC2=O)c2ccccc2n1Cc1ccccc1

Procedure:
This compound was prepared in analogy with the compound described in example 200 from benzyl bromide and 2-methylindole-3-carbaldehyde, followed by reaction with thiazolidine-2,4-dione resulting in 50 mg of the title compound.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=O)=[N:5]1)([CH3:3])[CH3:2].[NH2:16][C@H:17]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:20]([CH2:30][C:31]2([OH:37])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O>[OH:37][C:31]1([CH2:30][C@H:20]2[CH2:19][CH2:18][C@@H:17]([NH:16][C:13]([C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=3)=[O:15])[CH2:22][N:21]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: CC(C)n1nc(C(=O)O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)CC[C@@H]1CC1(O)CCOCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)n1nc(C(=O)N[C@@H]2CC[C@H](CC3(O)CCOCC3)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Reaction time: 18 h
Yield: 94.2 %

Procedure:
To a stirred solution of 1-isopropyl-1H-indazole-3-carboxylic acid (126 mg, 0.619 mmol), tert-butyl cis-5-amino-2-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidine-1-carboxylate (234 mg, 0.743 mmol, step 5 of Example 2), N,N-diisopropylethylamine (96 mg, 0.743 mmol) in N,N-dimethylformamide (3 mL) was added diethyl cyanophosphonate (121 mg, 0.743 mmol) at room temperature, and the mixture was stirred at the same temperature for 18 h. The mixture was concentrated under reduced pressure and the resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (1:1) to give 292 mg (94%) of the title compound as a colorless oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Si:8]([O:15][C@H:16]1[C@H:21]([NH:22]C(=O)OC(C)(C)C)[CH2:20][CH2:19][N:18]([C:30]2[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([NH:38][C:39]3[N:44]=[C:43]([N:45]([CH:55]4[CH2:57][CH2:56]4)[CH2:46][C:47]4[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=4)[C:42]4=[N:58][CH:59]=[C:60]([C:61]#[N:62])[N:41]4[N:40]=3)[C:31]=2[Cl:63])[CH2:17]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C1(OC)C=CC=CC=1>ClCCl>[NH2:22][C@@H:21]1[CH2:20][CH2:19][N:18]([C:30]2[C:31]([Cl:63])=[C:32]([NH:38][C:39]3[N:44]=[C:43]([N:45]([CH:55]4[CH2:56][CH2:57]4)[CH2:46][C:47]4[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=4)[C:42]4=[N:58][CH:59]=[C:60]([C:61]#[N:62])[N:41]4[N:40]=3)[CH:33]=[C:34]([C:36]#[N:37])[CH:35]=2)[CH2:17][C@H:16]1[O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[NH2:22][C@@H:21]1[CH2:20][CH2:19][N:18]([C:30]2[C:31]([Cl:63])=[C:32]([NH:38][C:39]3[N:44]=[C:43]([NH:45][CH:55]4[CH2:56][CH2:57]4)[C:42]4=[N:58][CH:59]=[C:60]([C:61]#[N:62])[N:41]4[N:40]=3)[CH:33]=[C:34]([C:36]#[N:37])[CH:35]=2)[CH2:17][C@H:16]1[O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:9])[CH3:10]
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1N
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](N)[C@H](O[Si](C)(C)C(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (25% in 1,2-dichloroethane, 3 mL, 9.73 mmol) was added to a solution of (+/−)-tert-butyl ((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamate (Example 20B, 180 mg, 0.225 mmol) and anisole (0.098 mL, 0.901 mmol) in dichloromethane (1 mL) and the resulting reaction mixture was stirred at room temperature for 1 h. LCMS showed consumption of starting material and formation of two product (desired product and loss of Boc and PMB by-product). The reaction mixture was diluted with dichloromethane, washed cold saturated sodium bicarbonate/1N aqueous sodium hydroxide (pH 10). The layers were separated and aqueous layer was extracted with dichloromethane two more times. The combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 1-3% methanol/dichloromethane) to give (+/−)-2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (114 mg) and (+/−)-2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (30 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[NH:19]1[CH:23]=[C:22]([C:24]#[N:25])[N:21]=[CH:20]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:19]2[CH:23]=[C:22]([C:24]#[N:25])[N:21]=[CH:20]2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: N#Cc1c[nH]cn1
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(-n2cnc(C#N)c2)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 8.8 %

Procedure:
A solution of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester (3.2 g, 11.98 mmol), 1H-imidazole-4-carbonitrile (2.017 g, 14.37 mmol) and ethyl-diisopropyl-amine (8.4 ml, 47.9 mmol) in 10 ml of dioxane is heated to reflux for 24 hours. The solution is allowed to cool to room temperature and evaporated. The residue is chromatographed on silica gel using gradients of dichloromethane and methanol to give 0.36 g (1.05 mmol, 8.8%) of amorphous 5-(4-cyano-imidazol-1-yl)-2-nitro-4-trifluoromethyl-benzoic acid methyl ester, ES-MS: m/z 341 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:24])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[NH2:5].[CH3:25][CH:26]([C:31](=O)[CH2:32][CH3:33])[C:27](OC)=[O:28].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH2:32]([C:31]1[C:26]([CH3:25])=[C:27]([OH:28])[C:6]2[C:4](=[CH:3][C:2]([CH3:1])=[C:8]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=3)[C:7]=2[CH3:24])[N:5]=1)[CH3:33]
Reactant: CCC(=O)C(C)C(=O)OC
Reactant: Cc1cc(N)cc(C)c1OCCCOc1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCc1nc2cc(C)c(OCCCOc3ccc(C(F)(F)F)cc3)c(C)c2c(O)c1C
Yield: 91.6 %

Procedure:
A solution of 1.18 g of 3,5-dimethyl-4-(3-(4-trifluoromethylphenoxy)propoxy)aniline, 1.35 g of methyl 2-methyl-3-oxopentanoate, and 0.7 g of p-toluenesulfonic acid dissolved in 38 mL of xylene was heated under reflux for 7 hr. This reaction solution was cooled, and ethyl acetate and sodium bicarbonate water were added thereto, followed by separation. The ethyl acetate layer was washed with brine and was further concentrated under the reduced pressure to give 1.38 g of 2-ethyl-4-hydroxy-3,5,7-trimethyl-6-(3-(4-trifluoromethylphenoxy)propoxy)quinoline. Next, 1.38 g of the product thus obtained was added to 15 mL of dimethylacetamide, and 0.26 g of 60% sodium hydride and 0.6 g of methyl chloroformate were added thereto at room temperature. The reaction solution was stirred at room temperature for 2 hr, and ethyl acetate and distilled water were then added thereto. The organic layer was washed with brine and was concentrated under the reduced pressure. The crude product was purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane/ethyl acetate) and was then recrystallized from n-hexane /ethyl acetate to give 1.13 g of 4-methoxycarbonyloxy-2-ethyl-3,5,7-trimethyl-6-(3-(4-trifluoromethylphenoxy)propoxy)quinoline (yield 72.2%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][NH:18][C:17](=[O:20])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[F:23][C:24]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br.C(OCC)(=O)C>CN(C)C=O.C1OCCOCCOCCOCCOC1.O1CCCC1>[F:23][C:24]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:18]1[CH2:19][CH:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)[CH2:16][C:17]1=[O:20]
Reactant: COc1ccc(C2CNC(=O)C2)cc1OC1CCCC1
Reactant: Fc1cccc(CBr)c1F
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(C2CC(=O)N(Cc3cccc(F)c3F)C2)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (110 mg, 0.4 mmol) in 2 ml of N,N-dimethylformamide and 110 μl of 15-crown-5 is treated with sodium hydride (20 mg, 0.5 mmol) under nitrogen at ambient temperature. After 3 hours, the mixture is cooled to 0° C. and treated with 2,3-difluorobenzyl bromide (166 mg, 0.8 mmol) in 2 ml of tetrahydrofuran. The resulting mixture is allowed to stir at ambient temperature for 6 hours. 100 ml of ethyl acetate is added, followed by 100 ml of ice cold water. After usual aqueous work up, the crude product is purified by flash column chromatography (ethyl acetate/hexane 2:1) to give 112 mg (70%) of 1-(2,3-difluorobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone: 1H NMR (300 MHz, CDCl3) δ 7.18-6.98 (m, 3H), 6.79 (d, J=8.1 Hz, 1H), 6.90 (d, J=8.1 Hz, 1H), 6.68 (s, 1H) 4.71-4.69 (m, 1H), 4.60 (s, 2H), 3.81 (s, 3H), 3.68 (t, J=9.0 Hz, 1H), 3.66-3.54 (m, 1H), 3.29 (dd, J=9.6, 7.2 Hz, 1H), 2.84 (dd, J=16.8, 9.0 Hz, 1H), 2.57 (dd, J=16.8, 8.4 Hz, 1H), 2.00-1.75 (b, 6H), 1.70-1.52 (b, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:20][CH3:21])=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]3[CH2:16][CH2:17][CH2:18][C:11]=3[C:10]=2[CH:19]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)([OH:36])[CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1.CC(C)=O.C([O-])(=O)/C=C/C([O-])=O>O.CC(OC)(C)C>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:37]2[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=2)([OH:36])[CH:30]2[CH2:31][CH2:32][N:33]([CH2:2][CH2:3][CH2:4][O:5][C:6]3[C:7]([O:20][CH3:21])=[CH:8][C:9]4[O:14][C:13](=[O:15])[C:12]5[CH2:16][CH2:17][CH2:18][C:11]=5[C:10]=4[CH:19]=3)[CH2:34][CH2:35]2)=[CH:25][CH:24]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCl)CCC3
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)=O
Solvent: O
Solvent: COC(C)(C)C
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1)CCC3
Yield: 67 %

Procedure:
Method B (38 h at 60° C.); starting materials: 8-(3-chloropropoxy)-2,3-dihydro-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 83) and 4-[bis(4-fluorophenyl)hydroxy-methyl]piperidine; yield 67%; fusion point 91° C. (decomposes; from acetone and TBME). Fumarate (×0.5 C4H4O4): method E; yield 70%; fusion point 191° C. (decomposes; from water).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7](Cl)(=[O:9])[CH3:8].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2.O>O1CCOCC1>[C:7]([N:1]1[CH:6]=[CH:5][CH:4]([C:15]2[C:14]3[C:18](=[CH:19][CH:20]=[C:12]([Cl:11])[CH:13]=3)[NH:17][CH:16]=2)[CH:3]=[CH:2]1)(=[O:9])[CH3:8]
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: c1ccncc1
Reactant: CC(=O)Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1C=CC(c2c[nH]c3ccc(Cl)cc23)C=C1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
27 ml of redistilled pyridine were added at an interior temperature of 8° to 15° C. to a mixture of 11.2 ml of acetyl chloride and 120 ml of dioxane cooled in an ice bath and a mixture of 22 g of 5-chloro-1H-indole in 120 ml of dioxane was added to the resulting suspension at 10° to 15° C. The mixture was stirred in the dark at room temperature for 7 hours and the suspension was poured into 500 ml of water. The mixture was stirred for 5 minutes and another 500 ml of water were added. The mixture was filtered and the recovered solid was empasted with 40 ml of acetonitrile, was filtered, rinsed with acetonitrile and once with ether to obtain 13.5 g of 3-(1-acetyl-1,4-dihydro-4-pyridyl)-5-chloro-1H-indole in the form of a pale yellow solid melting at 202° C.
Reaction SMILES: [N:1]1([C:7]2[NH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][N:11]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:15][O:14][C:12]([C:9]1[NH:8][C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])[CH2:3][CH2:2]2)=[N:11][N:10]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1nnc(N2CCNCC2)[nH]1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nnc(N2CCN(C(=O)OC(C)(C)C)CC2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of methyl 5-(piperazin-1-yl)-4H-1,2,4-triazole-3-carboxylate (1.0 g, 4.44 mmols) in DCM (10 mL) was added (BOC)2O (0.970 g, 4.44 mmol), DMAP (0.050 g, 0.41 mmol), DIEA (3.9 mL, 22.4 mmol). The reaction was stirred at RT overnight. Reaction concentrated and ISCO purification (0-5% MeOH in DCM) to obtain tert-butyl 4-(5-(methoxycarbonyl)-4H-1,2,4-triazol-3-yl)piperazine-1-carboxylate (0.580 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH2:12].N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CCOCC.O>[CH2:23]([O:22][C:20](=[O:21])[NH:12][C:3]1[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=1[Br:1])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)Nc1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine 2-bromo-5-trifluoromethylphenylamine (27.06 g, 112.74 mmol) and 200 mL of pyridine. Cool in an ice bath and add ethyl chloroformate (18.35 g, 169.11 mL, 1.5 eq). After addition was complete, allow the reaction to gradually warming to room temperature. After 18 hours, evaporate it vacuo to give a residue. Dissolve the residue in Et2O/water and transfer to a separatory funnel. Separate the layer and extract the aqueous layer with Et2O (2×300 mL), combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give N-(2-bromo-5-trifluoromethylphenyl)carbamic acid ethyl ester which may be used without further purification.