Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]2([CH2:36][CH3:37])[CH2:35][O:34][CH2:33]2)[NH:9]1)=[O:7])(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]3([CH2:36][CH3:37])[CH2:33][O:34][CH2:35]3)[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CCC1(CC2NC(C(=O)OC(C)(C)C)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)COC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1(CC2NC(C(=O)O)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)COC1
Yield: 91 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 113b (2 g, 3.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2 g, 91%).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]1[N:14]2[N:15]=[C:16]([NH2:18])[N:17]=[C:13]2[CH:12]=[C:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:10]=1>>[CH:1]1([NH:7][C:9]2[N:14]3[N:15]=[C:16]([NH2:18])[N:17]=[C:13]3[CH:12]=[C:11]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: Nc1nc2cc(-c3cccnc3)cc(Cl)n2n1
Product: Nc1nc2cc(-c3cccnc3)cc(NC3CCCCC3)n2n1

Procedure:
A mixture of cyclohexylamine (4 mL) and 5-chloro-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine, which may be produced as in Example 1A, (280 mg, 1.14 mmol) was microwaved at 155° C. for 1 h. On cooling, the product was triturated with toluene/cyclohexane, then taken up in CH2Cl2 and washed with aqueous Na2CO3. The organic layer was separated, dried (MgSO4), then concentrated to provide N5-cyclohexyl-7-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine. MS m/z 309 (M+H+).
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH2:15][CH3:16])[C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([OH:10])=O)[CH2:2][CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:29][C@@H:30]([CH2:46][C:47]1[CH:52]=[C:51]([F:53])[CH:50]=[C:49]([F:54])[CH:48]=1)[C@H:31]([OH:45])[CH2:32][NH:33][C:34]1([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]#[CH:44])[CH:38]=2)[CH2:36][CH2:35]1>ClCCl>[F:53][C:51]1[CH:52]=[C:47]([CH:48]=[C:49]([F:54])[CH:50]=1)[CH2:46][C@H:30]([NH:29][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][N:13]=[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:14][CH2:15][CH3:16])[CH:6]=1)[C@H:31]([OH:45])[CH2:32][NH:33][C:34]1([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]#[CH:44])[CH:38]=2)[CH2:36][CH2:35]1
Reactant: C#Cc1cccc(C2(NC[C@@H](O)[C@@H](N)Cc3cc(F)cc(F)c3)CC2)c1
Reactant: CCCN(CCC)c1cc(C(=O)O)ccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C#Cc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)c3ccnc(N(CCC)CCC)c3)CC2)c1
Reaction time: 8 h
Yield: 60 %

Procedure:
2-(Dipropylamino)isonicotinic acid (0.206 g) was dissolved in dichloromethane (10 mL). 1,1′-Carbonyldiimidazole was added (0.142 g) and the mixture was stirred for 2 h at room temperature, at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethynylphenyl)cyclopropyl]amino}butan-2-ol (0.284 g) in dichloromethane was added. The mixture was allowed to stir overnight and then was partitioned between dichloromethane, water, and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was chromatographed on silica gel using methanol/dichloromethane (4/96) to give N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethynylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-2-(dipropylamino)isonicotinamide (0.268 g). MS (ESI+) for C33H38F2N4O2+H1 m/z 561.30 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([OH:3])=O.[C:18]1([S:24]([NH2:27])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.O>[C:18]1([S:24]([N:27]=[C:1]([C:4]2[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:6][CH:5]=2)[OH:3])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1ccc(OCCn2ccnc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(N=C(O)c1ccc(OCCn2ccnc2)cc1)c1ccccc1

Procedure:
Treatment of 1-[2-(4-carboxyphenoxy)ethyl]imidazole with N,N'-carbonyldiimidazole followed by benzenesulphonamide as described in Example 36 above gave N-benzenesulphonyl-4-[2-(1-imidazolyl)ethoxy]benzenecarboximidic acid, m.p. 250°-252° C. (from N,N-dimethylformamide/H2O). Found: C, 58.17; H, 4.60; N, 11.08. C18H17N3O4S requires: C, 58.21; H, 4.61; N, 11.31%.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][C:30]#[N:31])=[CH:27][CH:26]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>ClC1C=CC=CC=1Cl>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][C:30]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:6]([Cl:12])=[CH:7][CH:8]=[CH:9][C:10]=3[Cl:11])[N:31]=2)=[CH:27][CH:26]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(Cl)cccc2Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: O
Product: Cn1nc(-c2c(Cl)cccc2Cl)nc1Cc1ccc(Cl)cc1
Temperature: 120 °C
Yield: 77.8 %

Procedure:
To a solution of 1.0 g of N-methyl-N-(p-toluenesulfonyl)-2,6-dichlorobenzohydrazonoyl chloride in 10 ml of o-dichlorobenzene at room temperature, were added 0.46 g of p-chlorobenzyl cyanide and 0.41 g of anhydrous aluminum chloride. The reaction mixture was heated at 120° C. for 30 minutes. Aster cooling, the section mixture was poured into iced-water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 0.7 g of 5-(4-chlorobenzyl)-3 (2,6-dichlorophenyl)-1-methyl-1H-1,2,4-triazole. m.p.112°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:40])=[C:6]([N:8]2[C:15](=[O:16])[C:14]3[N:13]=[C:12]([C:17]4[CH:18]=[C:19]([CH2:25][C:26]([OH:28])=O)[CH:20]=[N:21][C:22]=4[O:23][CH3:24])[N:11]([CH:29]([CH3:31])[CH3:30])[C:10]=3[CH:9]2[C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=2)[CH:7]=1.Cl.[CH3:42][NH2:43]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:40])=[C:6]([N:8]2[C:15](=[O:16])[C:14]3[N:13]=[C:12]([C:17]4[CH:18]=[C:19]([CH2:25][C:26]([NH:43][CH3:42])=[O:28])[CH:20]=[N:21][C:22]=4[O:23][CH3:24])[N:11]([CH:29]([CH3:31])[CH3:30])[C:10]=3[CH:9]2[C:32]2[CH:33]=[CH:34][C:35]([C:38]#[N:39])=[CH:36][CH:37]=2)[CH:7]=1
Reactant: CN
Reactant: COc1ncc(CC(=O)O)cc1-c1nc2c(n1C(C)C)C(c1ccc(C#N)cc1)N(c1cc(Cl)ccc1C)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)Cc1cnc(OC)c(-c2nc3c(n2C(C)C)C(c2ccc(C#N)cc2)N(c2cc(Cl)ccc2C)C3=O)c1

Procedure:
The title compound was prepared in analogy to the procedure described for example 147 but using the product from example 146 and methylamine hydrochloride. tR: 0.97 min (LC-MS 2); ESI-MS: 569.3/571.3 [M+H]+ (LC-MS 2); Rf=0.15 (CH2Cl2/MeOH, 20:1).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][C:12]1([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:20]2[C:15](=[CH:16][C:17]([C:21]#[N:22])=[CH:18][CH:19]=2)[CH2:14][O:13]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OC(=O)C)C>[OH:8][CH2:9][CH2:10][CH2:11][C:12]1([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:20]2[C:15](=[CH:16][C:17]([C:21]#[N:22])=[CH:18][CH:19]=2)[CH2:14][O:13]1
Reactant: COc1ccc(C2(CCCO[Si](C)(C)C(C)(C)C)OCc3cc(C#N)ccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2(CCCO)OCc3cc(C#N)ccc32)cc1
Reaction time: 2 h
Yield: 60 %

Procedure:
34.1 g (80.8 mmol) of the 1-(3-tert-butyldimethylsilyloxypropyl)-1-(4-methoxyphenyl)-1,3-dihydro-5-isobenzofurancarbonitrile prepared in step 4 was dissolved in 200 ml of tetrahydrofuran. 121.1 ml (121.1 mmol) of 1 M tetrabutylammonium fluoride tetrahydrofuran was added dropwise to the solution at room temperature, and the mixture was stirred for 2 hrs. The reaction mixture was diluted in ethylacetate, and washed with water and saturated NaCl solution. An organic layer was dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified using column chromatography to afford 15.0 g of the pale yellow target compound (yield: 60%).
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:32])[C@H:16]([CH2:28][C:29](=[O:31])[NH2:30])[NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[OH:26])[CH2:11][CH2:10]1)C1C=CC=CC=1.CCOCC>[H][H].[C].[Pd]>[ClH:1].[OH:26][C:20]1[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=1[C:18]([NH:17][C@H:16]([C:15]([N:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1)=[O:32])[CH2:28][C:29](=[O:31])[NH2:30])=[O:27]
Reactant: NC(=O)C[C@H](NC(=O)c1ccc(O)cc1O)C(=O)N1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Product: NC(=O)C[C@H](NC(=O)c1ccc(O)cc1O)C(=O)N1CCNCC1
Yield: 77.4 %

Procedure:
Ethanolic solution (20 ml) of 1-benzyl-4-(2,4-dihydroxybenzoyl-L-asparaginyl)piperazine.hydrochloride (340 mg) was subjected to catalytic reduction in the presence of 10% palladium-carbon (300 mg) for 18 hours at room temperature and under atmospheric pressure in hydrogen stream. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a colorless oily product. This product was powdered with addition of ether and then collected by filtration to obtain 1-(2,4-dihydroxybenzoyl-L-asparaginyl)piperazine.hydrochloride (212 mg).
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@:12]3([CH3:24])[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:5][C:4]=2[CH:3]=1>CCCCCC.C(O)C>[Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C:12]3([CH3:24])[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:5][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)c1nc2cc(Br)sc2c(=O)[nH]1
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCCC1(C)c1nc2cc(Br)sc2c(=O)[nH]1

Procedure:
tert-Butyl 2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-methylpyrrolidine-1-carboxylate (180 mg) was fractionated by high performance liquid chromatography (column: CHIRALPAK AD (50 mm i.d.×500 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (900/100), flow rate: 80 mL/min, column temperature: 30° C.). Under the above-mentioned high performance liquid chromatography conditions, the fraction solution containing an optically active form having a shorter retention time was concentrated to give tert-butyl (2R)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-methylpyrrolidine-1-carboxylate (88 mg, 9.25 min, >99.9% ee). In addition, the fraction solution containing an optically active form having a longer retention time was concentrated to give tert-butyl (2S)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-methylpyrrolidine-1-carboxylate (85 mg, 19.3 min, >99.9% ee). The analysis was performed by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mm i.d.×250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (900/100), flow rate: 1.0 mL/min, column temperature: 30° C., detection 220 nm). The absolute configuration was determined by comparison to tert-butyl (2S)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-methylpyrrolidine-1-carboxylate produced in Example 103, step A.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[CH2:19]([N:21]1[C:25]([NH2:26])=[CH:24][CH:23]=[N:22]1)[CH3:20].C(O)(=O)C>CN(C=O)C>[CH2:19]([N:21]1[C:25]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]([NH2:18])=[O:17])=[CH:24][CH:23]=[N:22]1)[CH3:20]
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Reactant: CCn1nccc1N
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCn1nccc1Nc1c(C(N)=O)cnc2cc(OC)c(OC)cc12
Temperature: 100 °C
Yield: 32.7 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g, 0.17 mmol), 1-ethyl-5-aminopyrazol (0.030 g, 0.27 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100° C. for 7.5 h. The DMF was evaporated under reduced pressure and the residue was dissolved in a mixture of MeCN and water (1:7) containing 0.1% trifluoroacetic acid. Preparative HPLC using a gradient (containing 0.1% trifluoroacetic acid) of 10→40% MeCN in water as eluent gave, after evaporation, the title compound as the trifluoroacetic acid salt. The product was suspended in saturated aqueous NaHCO3 and absorbed on a short SPE column [ISOLUTE™ C18 (EC)] pre-conditioned subsequently with methanol and water. The column was washed extensively with water until the pH of the eluent was neutral. The product was then eluted with methanol, the solvent evaporated and the residue crystallized from ethanol to give the title compound (19 mg, 32%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH:17]=[CH2:18].[B-](F)(F)(F)F.CC([PH+](C(C)(C)C)C(C)(C)C)(C)C.C1(CNCC2CCCCC2)CCCCC1>O1CCOCC1>[C:21]([O:20][C:16](=[O:19])[CH:17]=[CH:18][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=2)[CH:7]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)c1cnc2ccc(Br)cn12
Reactant: C=CC(=O)OC(C)(C)C
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2ccc(C=CC(=O)OC(C)(C)C)cn12
Temperature: 95 °C

Procedure:
A stirring mixture of ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (24s) (500 mg, 1.86 mmol), tert-butyl acrylate (408 uL, 2.79 mmol), tris(dibenzylideneacetone)diplalladium(0) (51 mg, 0.056 mmol), [(t-Bu)3PH]BF4 (27 mg, 0.093 mmol) and N,N-dicyclohexylmethylamine (738 uL, 3.48 mmol) in anhydrous 1,4-dioxane (5 mL) was heated at 95° C. overnight. The reaction was cooled to room temperature and filtered. The solvent was concentrated and the crude product was purified by silica chromatography to yield ethyl 6-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)imidazo[1,2-a]pyridine-3-carboxylate (70). MS m/z 317.14 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.COC1C=CC(C[NH2:20])=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:20])[CH:6]=[CH:5]2
Reactant: Clc1ccc2cc(Br)ccc2n1
Reactant: COc1ccc(CN)cc1
Product: Nc1ccc2cc(Br)ccc2n1
Temperature: 140 °C

Procedure:
6-Bromo-2-chloro-quinoline (3.34 g, 13.8 mmol) was dissolved in p-methoxybenzylamine (5 mL) and heated to 140° C. for 1 hour. The mixture was cooled to room temperature, filtered, and concentrated. The residue was purified by silica gel chromatography, and the isolated material was refluxed in TFA (6 mL) for 1 hour. The mixture was concentrated and purified by silica gel chromatography to give the desired product, 8a.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:18](=[O:19])[N:17]([CH3:16])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(OCc2ccccc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-benzyloxy-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized (ethanol/water) (83%, white crystals). HPLC-MS m/z=334.2 (M+1), Rt: 4.88 min.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17]C=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[CH2:12]([O:11][CH:4]([O:3][CH2:1][C:2]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:15]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:13]1[CH:15]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)CC(OCC)OCC
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)CC(OCc1ccccc1)OCc1ccccc1
Temperature: 80 °C
Yield: 99.6 %

Procedure:
To a 1000 mL round-bottomed flask was added ethyl 3,3-diethoxypropionate (20.0 g, 0.1051 mole), benzyl alcohol (22.7 g, 0.2102 mole), p-toluenesulfonic acid monohydrate (0.5 g, 0.0026 mole) and benzene (350 mL). Heating the mixture at 80° C., the solvent was distilled from the reaction mixture in 1.5 h period. The resulting residue was dissolved in ether (@ 300 mL) and washed with saturated sodium bicarbonate solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous magnesium sulfate and the solvent removed in vacuo to give ethyl 3,3-dibenzyloxypropionate (9) as a colorless oil (32.9 g, 99.5% yield): 1H NMR (CDCl3) d 1.22 (t, 3H, J=7.2 Hz), 2.79 (d, 2H, J=5.9 Hz), 4.12 (q, 2H, J=7.2 Hz), 4.60 (d, 2H, J=11.6 Hz), 4.70 (d, 2H, J=11.6 Hz), 5.22 (t, 1H, J=6 Hz), 7.27-7.36 (m, 10H); IR (Neat) 3100, 3080, 3040, 2990, 2940, 2920, 2885, 1740, 1630, 1458, 1375, 1315, 1190, 1120, 1050, 1030, 740, 700. ##STR8##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.[N:16]1([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2B(O)O)(=[O:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[F:15][C:4]1[CH:3]=[C:2]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[S:22]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:24])=[O:23])[CH:7]=[CH:6][C:5]=1[C:8]1[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1
Reactant: O=S(=O)(c1ccccc1B(O)O)N1CCCCC1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCCCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 42 using 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine and (2-(piperidin-1-ylsulfonyl)phenyl)boronic acid. MS (ESI): mass calcd. for C21H21FN4O2S, 412.14; m/z found, 413.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.40-8.30 (m, 2H), 8.10-8.06 (m, 1H), 7.98 (m, 1H), 7.79-7.73 (m, 1H), 7.71-7.64 (m, 1H), 7.62-7.56 (m, 1H), 7.43-7.39 (m, 1H), 7.34-7.28 (m, 1H), 2.86 (d, J=5.3, 4H), 1.50-1.38 (m, 6H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[N:17]=[CH:16]3)=[CH:11][CH:10]=2)O1.[CH3:25][O:26][C:27]([C:29]1[N:30]([CH3:35])[C:31](Br)=[N:32][CH:33]=1)=[O:28].C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][O:26][C:27]([C:29]1[N:30]([CH3:35])[C:31]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[N:17]=[CH:16]3)=[CH:13][CH:14]=2)=[N:32][CH:33]=1)=[O:28]
Reactant: COC(=O)c1cnc(Br)n1C
Reactant: CC1(C)OB(c2ccc(-n3cnc4ccccc43)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1cnc(-c2ccc(-n3cnc4ccccc43)cc2)n1C
Temperature: 90 °C
Yield: 36 %

Procedure:
To a solution of 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-benzoimidazole (0.43 g, 1.5 mmol) and 2-bromo-3-methyl-3H-imidazole-4-carboxylic acid methyl ester (0.25 g, 1.15 mmol) in DME (9 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.07 g, 0.057 mmol) and 2 M aqueous potassium carbonate (1.4 mL) and the reaction mixture was heated at 90° C. for 12 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The reaction mixture was filtered and the filtrate washed with water, dried (Na2SO4), and the solvent removed under reduced pressure. Purification by flash column chromatography (silica, petroleum ether:ethyl acetate 7:3→1:1 then dichloromethane:methanol 99:1→97:3) provided the title compound (36%). LCMS (ESI+) 332.2 (MH+).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:29][C:30]1[N:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][CH:31]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:36][C:33]3[CH:34]=[N:35][C:30]([Br:29])=[CH:31][CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccc(Br)nc4)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 6-bromopyridine-3-carbaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 548.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:5][N:4]2[C:18]([CH:21]=[O:22])=[CH:19][CH:20]=[C:3]12.[BH4-].[Na+]>C(O)C.O1CCCC1>[OH:22][CH2:21][C:18]1[N:4]2[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][CH:9]=3)[NH:7][C:2](=[O:1])[C:3]2=[CH:20][CH:19]=1
Reactant: O=Cc1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)cn12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)cn2c(CO)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
A mixture of 1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carbaldehyde (0.02 g, 65.3 μmol) in ethanol (0.25 mL) and tetrahydrofuran (0.25 mL) cooled to 0° C. was treated with sodium borohydride (3 mg, 79.3 μmol). The reaction was stirred at 0° C. for 1 h and then was stored in the refrigerator overnight. At this time, the reaction was concentrated in vacuo. The remaining solid was triturated with water, collected by filtration, washed with water and dried in vacuo to afford 6-hydroxymethyl-3-(4-trifluoromethyl-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one (10 mg, 50%) as an off-white solid. 1H NMR (DMSO-d6) δ ppm 7.87-7.96 (m, 3H), 7.79-7.87 (m, 2H), 7.40 (s, 1H), 6.87 (s, 1H), 5.03 (t, J=5.4 Hz, 1H), 4.50 (d, J=5.0 Hz, 2H). LC-MS calcd. for C15H12F3N2O2 [(M+H)+] 309, obsd. 309.0.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:21][CH2:22][CH3:23])[C:5]#[C:6][C:7](=[N:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:8]([F:11])(F)F)[CH3:2].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCCC1>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]2[C:8]([F:11])=[C:7]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:6]=[C:5]([CH:4]([O:3][CH2:1][CH3:2])[O:21][CH2:22][CH3:23])[N:30]=2)=[CH:27][CH:26]=1
Reactant: CCOC(C#CC(=Nc1ccc(OC)cc1)C(F)(F)F)OCC
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(OCC)c1cc(Nc2ccc(OC)cc2)c(F)c(-c2ccc(Cl)cc2)n1
Temperature: 80 °C

Procedure:
In a typical reaction, N-(5,5-diethoxy-1,1,1-trifluoro-pent-3-yn-2-ylidene)-4-methoxyaniline is mixed with about a 2.5 to 3 fold excess of p-chlorobenzylamine and about a 2.5 to 3 fold excess of cesium carbonate in anhydrous tetrahydrofuran. The mixture is heated at about 80° C. until the reaction is complete. After cooling, an extraction solvent like a halogenated hydrocarbon is added to the mixture along with water. The organic layer is recovered, washed with brine and dried. The solvent is evaporated to provide crude 2-(4-chlorophenyl)-6-(diethoxymethyl)-3-fluoro-N-(4-methoxyphenyl)pyridin-4-amine.