Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17].[Br:18][CH:19](Br)[CH3:20]>C(OCC)(=O)C.O>[Br:18][CH2:19][CH2:20][O:17][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:9]=1[F:8])[CH:13]=[O:14]
Reactant: CC(Br)Br
Reactant: O=Cc1ccc(F)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(F)c(OCCBr)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
Sodium hydride (1.14 g) was added to a DMF (30 mL) solution of 4-fluoro-3-hydroxybenzaldehyde (2.00 g) at room temperature., and the reaction solution was agitated for 30 minutes. Then, dibromoethane (2.46 mL) was added dropwise to the reaction solution, and the reaction solution was heated at 140° C. for 3 hours after the dropping ended. Water and ethyl acetate were added to the reaction solution under ice-cooling, and the organic layer was separated. The obtained organic layer was washed with a saturated sodium chloride solution, and the solvent was evaporated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (elution solvent:heptane-ethyl acetate 6:1), and 606 mg (20%) 3-(2-bromoethoxy)-4-fluoro benzaldehyde was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[O:7][CH:6]=[C:5]([CH:8]=O)[CH:4]=1.[C:12](Br)(Br)([Br:14])[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:13][C:12]([Br:14])=[CH:8][C:5]1[CH:4]=[C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])[O:7][CH:6]=1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[Si](C)(C)c1cc(C=C(Br)Br)co1

Procedure:
5-Trimethylsilyl-3-furaldehyde is treated with carbon tetrabromide and triphenylphosphine in dichloromethane at 0° to give 3-(2,2-dibromoethenyl)-5-trimethylsilylfuran. Treating with n-butyl lithium and 5-phenylpentyl iodide and hexamethylphosphoramide gives 3-(7-phenyl-1-heptynyl)-5-trimethylsilylfuran.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:37][CH2:38][CH2:39][CH2:40][CH:41]([OH:46])[CH2:42][CH2:43][CH2:44][CH3:45].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:46][CH:41]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:40][CH2:39][CH2:38][CH3:37])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: CCCCC(O)CCCC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(CCCC)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C
Yield: 74.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 5-nonanol (33 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (57 mg, yield 72%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:22]([F:25])([F:24])[F:23])[N:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[CH:8]=[CH:7][C:6]=12.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC.[C:55]([O:59][CH3:60])(=[O:58])[CH:56]=[CH2:57]>CN(C=O)C>[F:19][C:18]([F:20])([F:21])[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:5]([C:4]([C:22]([F:25])([F:24])[F:23])=[N:3][C:2]=3/[CH:57]=[CH:56]/[C:55]([O:59][CH3:60])=[O:58])[CH:10]=2)=[CH:16][CH:15]=1
Reactant: C=CC(=O)OC
Reactant: FC(F)(F)Oc1ccc(-c2ccc3c(Br)nc(C(F)(F)F)n3c2)cc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1nc(C(F)(F)F)n2cc(-c3ccc(OC(F)(F)F)cc3)ccc12
Temperature: 80 °C

Procedure:
1-bromo-6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)imidazo[1,5-a]pyridine (50.0 mg, 0.118 mmol), Pd(AcO)2 (2.6 mg, 0.0118 mmol, 0.1 equiv.) and P(o-tol)3 (14.4 mg, 0.0472 mmol, 0.4 equiv.) were placed in a 50 mL round bottomed flask under a nitrogen atmosphere. To the flask were added DMF (1 mL), a solution of Et3N (30.0 mg, 0.295 mmol, 2.5 equiv.) in DMF (1 mL) and a solution of methyl acrylate (50.8 mg, 0.59 mmol, 5.0 equiv.) were successively added. The mixture was heated at 80° C. for 19 h. And then, the solvent was removed from the reaction mixture to give a crude mixture. The crude mixture was purified by a column chromatography (SiO2=25 g, EtOAc/hexane=1:7 to 1:3, Rf=0.1 with EtOAc/hexane=1:7) to give (E)-methyl 3-(6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)imidazo[1,5-a]pyridin-1-yl)acrylate as light yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH3:12][O:13][C:14](=[O:25])[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:12][O:13][C:14](=[O:25])[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Br:1])[CH:3]=1
Reactant: COC(=O)CCCc1ccccc1N
Reactant: O=C(Cl)c1ccc(Cl)c(Br)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCc1ccccc1NC(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 101.9 %

Procedure:
To 3-bromo-4-chloro-benzoyl chloride (1.09 g, 4.3 mmol) in DCM (30 mL) cooled with an ice bath, was added 4-(2-amino-phenyl)-butyric acid methyl ester (0.85 g, 4.4 mmol), followed by addition of diisopropylethylamine (1 mL, 5.6 mmol) slowly. Upon the completion of the addition, ice bath was removed and the mixture was stirred at room temperature for 12 hrs. The mixture was further diluted with DCM, washed with saturated NaHCO3, 1N HCl, brine and dried over Na2SO4 and concentrated to yield 4-[2-(3-bromo-4-chloro-benzoylamino)-phenyl]-butyric acid methyl ester (1.8 g). MS [M+H]+: 411.7; tR=2.45 min. (method 1)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([CH2:10][Cl:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.B.C1(C2(C3C=CC=CC=3)OBN3CCC[C@H]23)C=CC=CC=1.CO>O1CCCC1>[Cl:11][CH2:10][CH:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)[OH:9]
Reactant: O=C(CCl)c1cccc(Cl)n1
Agent: B
Agent: B1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: CO
Solvent: C1CCOC1
Product: OC(CCl)c1cccc(Cl)n1
Reaction time: 3.5 h
Yield: 97.2 %

Procedure:
A solution of chloromethyl 6-chloro-2-pyridyl ketone (8.126 g) in tetrahydrofuran (32 ml) and a solution of borane in tetrahydrofuran (1.0M, 25.7 ml) were added simultaneously to a mixture of a solution (R)-tetrahydro-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]-oxazaborole in tetrahydrofuran (ca. 0.335M, 8.9 ml) and a solution of borane in tetrahydrofuran (1.0M, 4.3 ml) at -5° C. under nitrogen atmosphere over 0.5 hour and the whole was stirred for 3.5 hours. Methanol (10.4 ml) was added dropwise to the mixture at 0° C. and the whole was stirred at ambient temperature overnight. The mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with chloroform as an eluent to give (-)-2-chloro-1-(6-chloro-2-pyridyl)ethanol (7.98 g) as an oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH2:28]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH:41]([CH2:45][CH:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)[C:42]([OH:44])=O)=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH2:29][CH2:30][CH3:31].[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:28]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH:41]([CH2:45][CH:46]2[CH2:47][CH2:48][CH2:49][CH2:50]2)[C:42]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:44])=[CH:37][CH:36]=1)(=[O:33])=[O:34])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 65.9 %

Procedure:
A solution of triphenylphosphine (99 mg, 0.37 mmol) and N-bromosuccinimide (76 mg, 0.42 mmol) in methylene chloride (1.26 mL) cooled to 0° C. was treated with 2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-propionic acid (85 mg, 0.25 mmol) in methylene chloride. The reaction mixture was stirred at 25° C. for 45 min. At this time, the reaction was treated with 2-aminothiazole (33 mg, 0.32 mmol) and pyridine (0.03 mL, 0.37 mmol). The reaction was stirred at 25° C. for 18 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. At this time, the reaction was diluted with water (50 mL) and extracted with chloroform (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 50/50 hexanes/ethyl acetate) afforded 2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide (69.3 mg, 65.6%) as an off-white solid: mp 163-165° C.; EI-HRMS m/e calcd for C21H28N2O3S2 (M+) 420.1541 found 420.1535.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[N:12][NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)[C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:26]1CCOCC1>COCCOC>[C:1]1([CH2:7][C:8](=[N:12][NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)[C:9]([NH2:26])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(Cc1ccccc1)=NNc1nc(-c2ccccc2)cs1
Reactant: CN1CCOCC1
Solvent: COCCOC
Product: NC(=O)C(Cc1ccccc1)=NNc1nc(-c2ccccc2)cs1
Reaction time: 0.33 h

Procedure:
To a solution of 3-Phenyl-2-[(4-phenyl-thiazol-2-yl)-hydrazono]-propionic acid (4b) (1.0 mmol, 337 mg) in DME (5 mL) at −15° C., were added NMM (1.1 mmol, 121 μL), then IBCF (1.1 mmol, 147 μL). Then, a solution of NH4OH concentrated was added and the mixture was stirred for 20 minutes. 5 mL of water was added and the precipitate was filtered and washed with H2O and hexane to give the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].CI.[C:14](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([O:10][CH3:14])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(Br)cc(F)c1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(F)cc(Br)cc1C=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
928 mg of 5-bromo-3-fluoro-2-hydroxybenzaldehyde was dissolved in 3 ml of N,N-dimethylformamide, and 0.5 ml of methyl iodide and 1 g of potassium carbonate were successively added, followed by stirring for 1 hour at 50° C. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated, to give 926 mg of 5-bromo-3-fluoro-2-methoxybenzaldehyde. This crude product was dissolved in 4 ml of ethanol and 2 ml of tetrahydrofuran, and 200 mg of sodium tetrahydroborate was added, followed by stirring for 0.5 hours at room temperature. The reaction was quenched with 1 N-hydrochloric acid, followed by extracting with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 3:1), to give 907 mg of 5-bromo-3-fluoro-2-methoxybenzyl alcohol.
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]=1[CH3:3].[OH:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1/[CH:15]=[CH:3]/[C:2]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccccc1O
Reactant: Cc1ccc2ccccc2n1
Product: CC(=O)Oc1ccccc1/C=C/c1ccc2ccccc2n1
Temperature: 130 °C
Yield: 97 %

Procedure:
Quinaldine (2.84 mL, 3.00 g, 21.0 mmol, 1.0 eq.) and 2-hydroxybenzaldehyde (2.23 mL, 2.56 g, 21.0 mmol, 1.0 eq.) were dissolved in acetic anhydride (25 mL). The resulting mixture was heated at 130° C. for 16 h. The mixture was allowed to cool down to r.t. and was poured onto water (150 mL) and was stirred vigorously. The mixture was extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with saturated aqueous ammonium acetate (2×75 mL) and brine (75 mL), dried over sodium sulfate and concentrated under reduced pressure which gave the crude product as a red oil. The crude product was purified by column chromatography (SiO2, 1:4 ethyl acetate-cyclohexane) which yielded the product (5.88 g, 97% yield) as a clear yellow oil which crystallised upon standing.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([N:27]1[CH2:31][CH2:30][C@H:29]([C:32]([OH:34])=O)[CH2:28]1)[CH3:26].CN1CCOCC1.[NH2:42][CH2:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=1[S:51]([NH:54][C:55]1[C:64]([C:65]([O:67][CH3:68])=[O:66])=[C:63]2[C:58]([CH:59]3[CH2:69][CH:60]3[CH2:61][O:62]2)=[CH:57][CH:56]=1)(=[O:53])=[O:52]>CN(C=O)C.O>[CH2:25]([N:27]1[CH2:31][CH2:30][C@H:29]([C:32]([NH:42][CH2:43][C:44]2[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=2[S:51]([NH:54][C:55]2[C:64]([C:65]([O:67][CH3:68])=[O:66])=[C:63]3[C:58]([CH:59]4[CH2:69][CH:60]4[CH2:61][O:62]3)=[CH:57][CH:56]=2)(=[O:52])=[O:53])=[O:34])[CH2:28]1)[CH3:26]
Reactant: CCN1CC[C@H](C(=O)O)C1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CN)ccc2c1OCC1CC21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCN1CC[C@H](C(=O)NCc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1
Reaction time: 0.25 h
Yield: 58.1 %

Procedure:
HATU (0.234 g) was added to a mixture of (S)-1-ethylpyrrolidine-3-carboxylic acid (Intermediate 189, 0.089 g) and NMM (0.068 mL) in DMF (4 mL) and the mixture was stirred for 15 minutes. Methyl (1aRS,7bSR)-5-(2-aminomethyl-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 102, 0.250 g) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 solution, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of 2M ammonia in methanol and DCM with a gradient of 0-15% to give methyl (1aRS,7bSR)-5-(2-{[((S)-1-ethylpyrrolidine-3-carbonyl)amino]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.190 g) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[C:11]([O-])(O)=O.[Na+]>C(O)=O.O>[CH3:1][C:2]1[C:3]2[N:10]=[CH:11][NH:9][C:4]=2[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)c(N)c(N)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: Cc1cc(C)c2nc[nH]c2c1

Procedure:
Intermediate 179.1 (275 mg) in 3 mL formic acid was irradiated in a microwave reactor at 150° C. for 5 min. The mixture was diluted with water, neutralized with sat. NaHCO3, then extracted with EtOAc (3×). The organic phase was washed with water and brine, dried (Na2SO4) and concentrated to afford 245 mg of Intermediate 179.2 as an orange solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[N:8][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:10][CH:11]=1)=O)C.C(OC(=O)C(C(=O)C1C=CC(C)=CC=1)=[CH:32][N:33](C)[CH3:34])C.Cl.FC1C=CC(CC(N)=N)=CC=1.CCN(CC)CC>CCO.O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:9]2[N:8]=[C:7]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[C:6]([CH2:4][N:33]([CH3:34])[CH3:32])=[CH:11][N:10]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1cnc(Cc2ccc(F)cc2)nc1-c1ccc(C)cc1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(C)cc1
Agent: Cl
Agent: N=C(N)Cc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2nc(Cc3ccc(F)cc3)ncc2CN(C)C)cc1
Yield: 74 %

Procedure:
2-(4-Fluoro-benzyl)-4-p-tolyl-pyrimidine-5-carboxylic acid ethyl ester. To solution of 3-dimethylamino-2-(4-methyl-benzoyl)-acrylic acid ethyl ester (Tetrahedron, 2002, 58, 8581-8589; 0.567 g, 2.15 mmol) in EtOH (10 mL) was added 2-(4-fluoro-phenyl)-acetamidine hydrochloride (0.405 g, 2.15 mmol) and Et3N (0.90 mL, 6.5 mmol). The mixture was heated at reflux for 18 h, and then was diluted with water and extracted with EtOAc (2×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO2 chromatography (5-20% EtOAc/hexanes) to give 0.560 g (74%) of the title compound. MS (ESI): exact mass calcd. for C21H19FN2O2, 350.14; m/z found, 351.4 [M+H]+. 1H NMR (CDCl3): 8.97 (s, 1H), 7.51 (d, J=8.2, 2H), 7.38-7.35 (m, 2H), 7.27-7.26 (m, 2H), 7.01-6.97 (m, 2H), 4.32 (s, 2H), 4.23 (q, J=7.1, 2H), 2.42 (s, 3H), 1.16 (t, J=7.1, 3H). Step B. [2-(4-Fluoro-benzyl)-4-p-tolyl-pyrimidin-5-yl]-methanol. To a 0° C. solution of the product from Step A (0.606 g, 1.73 mmol) in THF (8 mL) was added DIBAL-H (1.5 M in toluene; 2.5 mL, 3.8 mmol). The mixture was allowed to warm to rt, and was stirred for 18 h. The mixture was diluted with 20% aq. sodium potassium tartrate and extracted with EtOAc (2×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO2 chromatography (40-60% EtOAc/hexanes) to give 0.330 g (62%) of the title compound. MS (ESI): exact mass calcd. for C19H17FN2O, 308.13; m/z found, 309.4 [M+H]+. 1H NMR (CDCl3): 8.77 (s, 1H), 7.58 (d, J=8.0, 2H), 7.38-7.35 (m, 2H), 7.29 (d, J=7.9, 2H), 6.99-6.96 (m, 2H), 4.70 (s, 2H), 4.29 (s, 2H), 2.42 (s, 3H). Step C. The title compound was prepared using the methods described in Example 112, Step C. MS (ESI): exact mass calcd. for C21H22FN3, 335.18; m/z found, 336.4 [M+H]+. 1H NMR (CDCl3): 8.67 (s, 1H), 7.69 (d, J=8.1, 2H), 7.40-7.36 (m, 2H), 7.29 (d, J=7.9, 2H), 7.01-6.96 (m, 2H), 4.29 (s, 2H), 3.36 (s, 2H), 2.42 (s, 3H), 2.22 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.CO.C[O-].[Na+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:15]([O:8][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: CC1(C)OCC(CO)O1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1(C)OCC(COCc2ccccc2)O1
Temperature: 80 °C

Procedure:
To a 1000 ml round-bottom flask fitted with a thermometer, a nitrogen-introducing tube, and a stirrer were added 132.2 g (1.0 mol) of 2,2-dimethyl-1,3-dioxolane-4-methanol, 231.4 g (1.2 mol) of a 28% methanol solution of sodium methoxide, and 500 ml of toluene. With introducing nitrogen thereinto, the toluene was refluxed under reduced pressure for 1 hour to remove the methanol by distillation. With maintaining the solution at 80° C., 126.6 g (1.0 mol) of benzyl chloride was added dropwise over a period of 2 hours using a dropping funnel, followed by further 2 hours of the reaction. The reaction solution was subjected to solvent removal and purification by distillation (b.p. 93-95° C./266 Pa) to obtain 4-(benzyloxymethyl)-2,2-dimethyl-1,3-dioxolane.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[Br:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[Br:13][C:14]1[CH:19]=[C:18]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[Cl:1])[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: OB(O)c1cccc(Br)c1
Product: O=Cc1c(Cl)n(-c2cccc(Br)c2)c2ccccc12
Yield: 87 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 3-bromophenylboronic acid as described in Step 1 of Example 29 to afford 1-(3-bromophenyl)-2-chloro-1H-indole-3-carboxaldehyde (87% yield) as a cream solid. ESI/MS 334 (M), 375 [(M+2+CH3CN) adduct]; RT=3.59 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:46])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:45]=[CH:44][C:34]([CH2:35][NH:36]C(=O)OC(C)(C)C)=[CH:33][CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:36][CH2:35][C:34]1[CH:44]=[CH:45][C:31]([NH:30][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:46])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[CH:32][CH:33]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(CNC(=O)OC(C)(C)C)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(CN)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
To a solution of rac tert-butyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzylcarbamate (64 mg, example XC31) in CH2Cl2 (4 ml) was added TRIFLUOROACETIC ACID (5.92 g, 4 mL) and the reaction was stirred at 0 C for 1.5 hrs. The crude reaction mixture was concentrated in vacuo and the taken up in CH2Cl2 (80 mL) and washed with sat Na2CO3 (2×15 mL), water (2×15 mL) and concentrated to give rac-(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-aminomethyl-phenyl)-amide as a white solid (54.3 mg, 99%). HRMS (ES+) m/z Calcd for C30H31Cl2F2N4O [(M+H)+]: 571.1838. found: 571.1837.
Reaction SMILES: CON(C)[C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[CH3:14][Mg+].[Br-]>C1COCC1>[N:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4](=[O:12])[CH3:14])=[CH:7][CH:8]=1
Reactant: C[Mg+]
Reactant: CON(C)C(=O)Cc1ccncc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)Cc1ccncc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
To a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of argon, was added THF (70 mL) and N-methoxy-N-methyl-2-(pyridin-4-yl)acetamide (7.0 g, 0.039 mol, 1.0 equiv). The mixture was cooled to 0° C. and CH3MgBr (3M in THF, 65 mL, 5.0 equiv) was added dropwise. The resulting solution was warmed to ambient temperature and stirred for 16 h. The reaction mixture was cooled to 0° C. and quenched by the addition of saturated NH4Cl (aq, 100 mL). The resulting solution was extracted with EtOAc (3×200 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by flash chromatography (silica gel, CH2Cl2/CH3OH (20:1)) to yield 2.7 g (51%) of the title compound as yellow oil. 1H-NMR (400 MHz, CDCl3): δ ppm 8.58 (m, 2H), 7.17 (d, J=0.4 Hz, 2H), 3.75 (s, 2H), 2.24 (s, 3H).