Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[N:37][CH:38]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([S:39]([NH:42][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:4]3[C:5]([CH3:13])=[C:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:2]([CH3:1])=[N:3]3)=[CH:19][CH:18]=2)=[O:24])(=[O:40])=[O:41])=[N:37][CH:38]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cn1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(Cl)cn3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 5-chloro-2-pyridinesulfonamide (DK Patent 107422): 1H-NMR (CDCl3) δ 8.59 (1H, d, J=1.8 Hz), 8.00-7.90 (2H, m), 7.46-7.22 (9H, m), 6.52 (1H, br.s), 3.48-3.41 (2H, m), 2.85-2.80 (2H, m), 2.33 (3H, s), 2.24 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH:10]=[CH:9]1.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[C:11]=2[CH:10]=[CH:9]1
Reactant: NCCCO
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(C)cccc3c21
Product: Cc1ccccc1-n1ccc2c(NCCCO)nc3c(C)cccc3c21
Yield: 50.6 %

Procedure:
1-(2-Methylphenyl)-4-chloro-6-methylpyrrolo[3,2-c]quinoline (1.0 g) and 3-aminopropanol (3.0 g) were heated to 150° C. for 3 hours. Chromatography (silica gel, 2% methanolic ammonia in dichloromethane) and recrystallisation from ethyl acetate/petroleum ether yielded 1-(2-methylphenyl)-4-(3-hydroxypropylamino)-6-methylpyrrolo[3,2-c]quinoline (0.57 g), m.p. 135°-137°.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH2:12][C:13]([OH:15])=[O:14])[CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(=O)(O)[O-].[Na+].[CH2:27](O)[CH3:28]>Cl>[CH2:27]([O:14][C:13](=[O:15])[CH2:12][CH:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][NH:2][CH2:1]2)=[CH:6][CH:7]=1)[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH3:28]
Reactant: CCO
Reactant: O=C(O)CC(c1ccncc1)c1ccc2c(c1)CNCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)CC(c1ccncc1)c1ccc2c(c1)CNCC2
Reaction time: 8 h

Procedure:
A solution of 3-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-3-(pyrid-4-yl)-propionic acid, enantiomer A {Reference Example 18(a)} in ethanol (50 mL) was treated with concentrated hydrochloric acid (two drops) and then heated at reflux temperature, under nitrogen, for 8 hours. The pH of the reaction mixture was adjusted to ˜5 by dropwise addition of sodium bicarbonate solution (5%) and this mixture was then evaporated to give the title compound which was used without further purification.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.[N:14]1(CCO)[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:3]1([CH2:8][C:9]([O:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)CN1CCCC1
Reactant: OCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Product: O=C(CN1CCCC1)OCCN1CCCC1
Temperature: 225 °C

Procedure:
To a mixture of 1.3 g of sodium hydride (in the form of a 60% by weight suspension in mineral oil) and 100 g (0.64 mol) of ethyl 1-pyrrolidineacetate was added 91 g of 2-(1-pyrrolidinyl)ethanol. The mixture was heated slowly to about 225° C., and the ethanol by-product was collected in a Dean-Stark trap. The reaction mixture was cooled to about 25° C., then 12 g of 1-bromopropane was added to react any alkoxide present. The sodium bromide by-product was removed by filtration. The desired product 2-(1-pyrrolidinyl)ethyl 1-pyrrolidineacetate was purified by distillation at 95° C. at a pressure of 250 μmHg. The structural assignment was confirmed by mass spectral analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>ClCCl>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:3][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(F)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(F)cn1
Reaction time: 3 h

Procedure:
To a stirred solution of 2-amino-5-fluoropyridine (50.0 g, commercially available) and triethylamine (93 ml) in dichloromethane (600 ml) was added pivaloyl chloride (56 ml) at ambient temperature. The slurry that formed was stirred for 3 hours, stored for 18 hours then washed with water (200 ml), brine (100 ml) then dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the required product as a brown oil, 86 g. 1H NMR (CDCl3) δ: 8.30 (1H, dd), 8.10 (1H, d), 8.00 (1H, bs), 7.42 (1H, m), 1.30 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:31][N:32]([CH3:38])[CH2:33][CH2:34][CH2:35][NH:36][CH3:37]>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:36]([CH2:35][CH2:34][CH2:33][N:32]([CH3:38])[CH3:31])[CH3:37])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: CNCCCN(C)C
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N(C)CCCN(C)C
Yield: 66.4 %

Procedure:
Following the procedure used to prepare Example 27, 150 mg (0.34 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile is reacted with 238 mg (2.05 mmol) of N, N, N′-trimethyl-1,3-propanediamine in 1 mL of 1-methyl-2-pyrrolidinone at 105° C. for 16 hours to yield 121 mg of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-7-{[3-(dimethyl)aminopropyl]-methylamino}-6-methoxyquinoline-3-carbonitrile as a tan solid, mp 196-201° C.
Reaction SMILES: C(OC([N:8]([C:10]1([C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:12][CH2:11]1)[CH3:9])=O)(C)(C)C.C(N(CC)CC)C.F[C:26]1[C:35]([CH3:36])=[C:34]2[C:29]([C:30](=[O:44])[C:31]([C:41]([OH:43])=[O:42])=[CH:32][N:33]2[C@@H:37]2[CH2:39][C@@H:38]2[F:40])=[CH:28][CH:27]=1>CS(C)=O>[F:40][C@H:38]1[CH2:39][C@H:37]1[N:33]1[C:34]2[C:29](=[CH:28][CH:27]=[C:26]([N:15]3[CH2:16][CH2:17][C@@H:13]([C:10]4([NH:8][CH3:9])[CH2:11][CH2:12]4)[CH2:14]3)[C:35]=2[CH3:36])[C:30](=[O:44])[C:31]([C:41]([OH:43])=[O:42])=[CH:32]1
Reactant: Cc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CN(C(=O)OC(C)(C)C)C1([C@@H]2CCNC2)CC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CNC1([C@@H]2CCN(c3ccc4c(=O)c(C(=O)O)cn([C@@H]5C[C@@H]5F)c4c3C)C2)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine (118 mg, 436 mmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (1 ml, 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (122 mg, 436 μmol) was added thereto and heated under reflux in an oil bath of 100° C. for 18 hours under a nitrogen atmosphere. After concentrating the reaction solution under a reduced pressure, the residue was dissolved in chloroform (100 ml). After washing the organic layer with a 10% aqueous citric acid solution (100 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (2 ml) to the residue while cooling with ice, it was stirred at room temperature for 30 minutes. After adding 1 mol/l hydrochloric acid (2 ml) to the reaction solution and washing the yellow acidic aqueous solution with chloroform (50 ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was then purified by a preparative chromatography (developed into the lower layer of a 7:3:1 mixture of chloroform:methanol:water), purified further by recrystallization from ethanol, and then dried under a reduced pressure. 72.8 mg (42%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [C:1](O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][CH:22]([CH:25]([OH:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:23][OH:24]>C(OCC)(=O)C.CCCCCCC>[C:1]([NH:21][CH:22]([CH:25]([OH:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:23][OH:24])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCC(O)C(N)CO
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCCCCCCCCCCCCCCC(=O)NC(CO)C(O)CCCCCCCCCCCCCCC
Yield: 72 %

Procedure:
6.2 g (0.022 mol) of stearic acid and 6 g (0.022 mol) of 2-aminooctadecane-1,3-diol were mixed in a tube and irradiated with the apparatus used in Example 1, under the same frequency and power conditions. After an irradiation of 18 minutes at 140° C.±5° C., the reaction mixture was solubilized in a mixture of 80 ml of ethyl acetate and 40 ml of heptane. The precipitate obtained was recrystallized from ethanol and 8.1 g of expected pure product were obtained with a yield of 72%.
Reaction SMILES: [BrH:1].[OH:2][C:3]1[C:16]2[CH2:15][CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][CH2:11][NH:12]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>FC(F)(F)C(O)=O>[BrH:1].[C:17]([O:2][C:3]1[C:16]2[CH2:15][CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][CH2:11][NH:12]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: Oc1cccc2c1CC[C@@H]1NCCC[C@@H]21
Reactant: CC(C)(C)C(=O)Cl
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)Oc1cccc2c1CC[C@@H]1NCCC[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-trans-7-Hydroxy-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)quinoline hydrobromide (50 mg, 0.17 mmol) was dissolved in trifluoroacetic acid (1 ml). Pivaloyl chloride (0.2 ml) was added and the mixture was stirred at room temperature overnight. After evaporation of the solvent, the residue was partitioned between H2O and CH2Cl2. The organic layer was concentrated and applied to a SiO2 column and the product was eluted with CH2Cl2 -MeOH. Fractions containing the product were collected. The solvent was evaporated yielding 20 mg of an oil. GC-MS: M+ at m/e 287.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20]([OH:22])=O)=[C:16]([CH3:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[I-].ClC1C=CC=C[N+]=1C>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:22])=[C:16]([CH3:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc2c(cc1C(=O)O)SCC[C@@H]2NC(=O)OC(C)(C)C
Reactant: Nc1ccncc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Product: Cc1cc2c(cc1C(=O)Nc1ccncc1)SCC[C@@H]2NC(=O)OC(C)(C)C
Yield: 87.4 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 53 using (S)-4-(tert-butoxycarbonylamino)-6-methylthiochromane-7-carboxylic acid (1.00 g), 4-aminopyridine (321 mg) and 2-chloro-1-methylpyridinium iodide (949 mg), the objective (S)-4-(tert-butoxycarbonylamino)-6-methyl-N-(4-pyridyl)thiochromane-7-carboxamide (1.08 g) was obtained as a pale-brown amorphous solid.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]([CH2:43][C:44]([OH:47])([CH3:46])[CH3:45])[C:39](=[O:48])[CH:38]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]([CH2:43][C:44]([OH:47])([CH3:45])[CH3:46])[C:39](=[O:48])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(C)(O)Cn1ccc(Br)cc1=O
Product: C[C@@H](c1ccc(-c2ccn(CC(C)(C)O)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 4-bromo-1-(2-hydroxy-2-methyl-propyl)-1H-pyridin-2-one following a procedure analogous to that described in Example 75. Mass spectrum (ESI+): m/z=519 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]([CH2:18]Cl)=[CH2:17]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][C:16]([CH3:18])=[CH:17][C:4]=2[CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: C=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc2cc(Br)ccc2s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 115.9 %

Procedure:
4-Bromobenzenethiol (10.0 g, 52.8 mmol) was dissolved in acetone (100 ml), and anhydrous potassium carbonate (8.8 g, 63 mmol), and 2,3-dichloropropene (7.0 g, 63 mmol) were added. The mixture was stirred at room temperature for 14 hr. Acetone was distilled away under reduced pressure and toluene and water were added to the residue. The toluene layer was separated. The organic layer was washed with water, and dried over anhydrous sodium sulfate. The desiccant was filtered away and the filtrate was concentrated under reduced pressure to give a pale-yellow oil (13.9 g). This oil was dissolved in diethyl aniline (45 ml), and the mixture was stirred at 205° C. for 50 hr with heating. Diethyl aniline was distilled away under reduced pressure, and 3N hydrochloric acid and toluene were added to the residue. After the toluene layer was separated, the organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residual crystalline oil was dissolved in hexane, and the insoluble oil was removed by decantation. After concentration under reduced pressure, the residue was recrystallized from a small amount of hot hexane to give the objective compound (5.9 g, 58%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2)=[O:15].[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([NH:16][C:14](=[O:15])/[CH:13]=[CH:12]/[C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)=[CH:25][CH:24]=2)[CH:20]=[CH:21]1
Reactant: O=C(/C=C/c1ccc(C(F)(F)F)cc1Br)Nc1ccc2[nH]ccc2c1
Reactant: OB(O)c1ccncc1
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1-c1ccncc1)Nc1ccc2[nH]ccc2c1

Procedure:
Analogous to the procedure used to prepare Example 100, (2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide, Example 97, (120 mg, 0.29 mmol) and pyridine-4-boronic acid (72 mg, 0.59 mmol, Frontier Scientific) provided, after purification by silica gel chromatography (gradient: 0-60%EtOAc in hexane), the title product as a yellow solid. MP 229-234° C. MS (ESI, pos. ion) m/z: 408 (M+1).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([S:9][C:10]1C=[CH:17][CH:16]=[CH:15][C:11]=1C(O)=O)[CH3:8].CN(C=O)C>C(Cl)Cl>[CH2:7]([S:9][C:10]1[CH:11]=[CH:15][CH:16]=[CH:17][C:1]=1[C:2]([Cl:4])=[O:3])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCSc1ccccc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCSc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Oxalyl chloride (113 μL, 1.3 mmol) was added slowly to a stirring suspension of 2-(ethylthio)benzoic acid (1-A) (182 mg, 1.0 mmol) and 3 μL DMF in methylene chloride (2 mL). After stirring for 3.5 h at room temperature, the mixture was concentrated in vacuo to give 2-(ethylthio)benzoyl chloride (1-B).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[N:5][N:6]([CH2:8]Cl)[CH:7]=1.[F:10][C:11]([F:20])([F:19])[CH2:12][CH2:13][CH:14]([C:17]#[N:18])[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:2][C:3]1[CH:4]=[N:5][N:6]([CH2:8][C:14]([CH2:13][CH2:12][C:11]([F:10])([F:19])[F:20])([C:15]#[N:16])[C:17]#[N:18])[CH:7]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: ClCn1cc(Br)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(Br)cn1
Yield: 72.4 %

Procedure:
3.27 g of 4-bromo-1-(chloromethyl)-1H-pyrazole hydrochloride and 2.29 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 28 ml of N,N-dimethylformamide. 3.89 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.28 g of [(4-bromo-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (21), hereinafter) shown by below formula.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:29]=[CH:28][C:10]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5].C(N(CC)CC)C>C(Cl)Cl>[C:4]([NH:6][C:7]1[CH:29]=[CH:28][C:10]([C:11]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[CH2:17][CH2:18]2)=[O:12])=[CH:9][CH:8]=1)(=[O:5])[CH:3]=[CH2:2]
Reactant: O=C(CCCl)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
0.5 g of 1-[4-(3-chloropropionylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine and 0.4 g of triethylamine are dissolved in 20 ml of methylene chloride, and the solution is boiled under reflux for 4 hours and then concentrated by evaporation, yielding 1-(4-acryloylaminobenzoyl)-4-[2-(4-chlorophenyl)ethyl]piperazine having a melting point of 163°-165°.
Reaction SMILES: [CH3:1][CH:2]1[O:10][C:5]2([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[O:6][CH:7]([CH3:9])[CH2:8][N:4]2[CH2:3]1.C(N(CC)CC)C.[C:24](Cl)(=[O:28])[C:25]([CH3:27])=[CH2:26]>C(Cl)(Cl)Cl>[CH3:1][CH:2]1[O:10][C:5]2([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:24](=[O:28])[C:25]([CH3:27])=[CH2:26])[O:6][CH:7]([CH3:9])[CH2:8][N:4]2[CH2:3]1
Reactant: C=C(C)C(=O)Cl
Reactant: CC1CN2CC(C)OC2(CCCCCO)O1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCC12OC(C)CN1CC(C)O2
Temperature: 0 °C
Yield: 462 %

Procedure:
In an oven dried 100 mL round-bottom flask equipped with a pressure equalizing addition funnel and a reflux condenser were added 5-(2,6-Dimethyl-tetrahydro-oxazolo[2,3-b]oxazol-7a-yl)-pentan-1-ol (22.9 g, 0.01 mol) followed by chloroform 50 mL and triethylamine 12.12 g, 0.12 mol). The reaction content was cooled to 0° C. under nitrogen. While stirring a solution of methacryloyl chloride (11.44 g, 0.11 mol) in chloroform was added slowly. After completion of the acid chloride the reaction was stirred one hour at 0° C., then allowed to warmed to room temperature and then stirred over night at room temperature. The triethylamine salt was filter off through Celite® (World Minerals, Santa Barbara, Calif.), the filtrate concentrate at reduced pressure. NMR (proton) showed this material to be the desired material contaminated with triethyl amine salt. This material was then washed with hexanes (2×125 ml), the hexanes washes combined concentrated giving 13.74 g of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCCCc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCCCc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 16.3 g. of ethyl 4-[3-(p-chlorophenyl)propylamino]benzoate, 16.3 g. of potassium hydroxide and 200 ml. of 95% ethanol is refluxed for 3 hours. The mixture is diluted with 100 ml. of water and brought to pH 6 with concentrated hydrochloric acid. Chilling and filtering gave 15 g. of white crystals. Recrystallization from ethanol gave 8.6 g. of white crystals, m.p. 191°-192° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:11]O>CC(O)=O.C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N+:6]=1[O-:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccn1
Reactant: OO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)c1cccc[n+]1[O-]
Yield: 71.5 %

Procedure:
Preparation C3, Step 1: 2-tert-butylpyridine (2.00 g, 14.8 mmol, 1 eq.) was dissolved in HOAc (10 mL) and 30% hydrogen peroxide (1.68 mL, 14.8 mmol, 1 eq.) at room temperature then the reaction was refluxed for 20 hours. The reaction was stripped to obtain an amber oil which was dissolved in methylene chloride (10 mL) then dried over sodium sulfate and stripped to obtain 2-tert-butylpyridine-N-oxide (1.60 g) as an amber oil. Yield=71.5%. LCMS detects (M+H)+=152.09.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C(N(CC)CC)C.FC(F)(F)S(O[Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])(=O)=O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[CH:7][CH:6]=[CH:5]2
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O=C1CCCc2cc(Br)ccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](Oc1cccc2cc(Br)ccc12)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To a solution of 6-bromo-1-tetralone (10.6 g, 47.1 mmol) in dichloromethane (145 mL) cooled to 0° C. were sequentially added triethylamine (12 mL, 86.1 mmol) and triisopropylsilyl trifluoromethanesulfonate (15.3 mL, 56.7 mmol). After stirring for ten minutes, the ice bath was removed and the reaction was allowed to warm to room temperature for 30 minutes. The reaction was diluted with 1:1 ethyl acetate:hexanes and the organic layer was washed with water and brine. The organics were dried (MgSO4), concentrated, and the resulting material was used without further purification. The crude enolsilane was dissolved in tetrahydrofuran (470 mL) and cooled to 0° C. To the solution was added solid 2,3-dichloro-5,6-dicyanobenzoquinone (16 g, 70.5 mmol) and the reaction was warmed to room temperature. After 30 minutes the reaction was concentrated and the crude material was purified by flash column chromatography (hexanes) to afford (6-bromonaphthalen-1-yloxy)triisopropylsilane (17.1 g, 96% over 2 steps).