Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[NH:7][C:6](=[O:17])[N:5]([CH3:18])[C:4]=2[N:3]=1.Cl.[NH2:20][CH2:21][C:22]([CH3:25])([SH:24])[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:20][CH2:21][C:22]([S:24][C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[NH:7][C:6](=[O:17])[N:5]([CH3:18])[C:4]=2[N:3]=1)([CH3:25])[CH3:23]
Reactant: CC(C)=CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(C)(S)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(SC(C)(C)CN)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A mixture of 80 mg of 8-bromo-3-methyl-7-(3-methylbut-2-enyl)-3,7-dihydropurine-2,6-dione, 90 mg of 1-amino-2-methyl-2-propanethiol hydrochloride, 2 ml of DMF and 200 mg of cesium carbonate was stirred at 70° C. for 5 hours.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[CH:49]=[C:50]([C:58]([NH:60][C:61]2[CH:62]=[C:63](/[CH:67]=[CH:68]/[C:69]([O:71]CC)=[O:70])[CH:64]=[CH:65][CH:66]=2)=[O:59])[C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][CH:52]=2.[NH:74]1[CH2:79][CH2:78][O:77][CH2:76][CH2:75]1.CC(C)([O-])C.[K+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[N:74]1([C:48]2[CH:49]=[C:50]([C:58]([NH:60][C:61]3[CH:62]=[C:63](/[CH:67]=[CH:68]/[C:69]([OH:71])=[O:70])[CH:64]=[CH:65][CH:66]=3)=[O:59])[C:51]3[C:56]([CH:57]=2)=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH2:79][CH2:78][O:77][CH2:76][CH2:75]1
Reactant: C1COCCN1
Reactant: CCOC(=O)/C=C/c1cccc(NC(=O)c2cc(Br)cc3ccccc23)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)/C=C/c1cccc(NC(=O)c2cc(N3CCOCC3)cc3ccccc23)c1

Procedure:
A Biotage Process Vial (5-20 mL) was charged with (BINAP) (0.47 mmol), Pd2(dba)3 (0.11 mmol), ethyl(E)-3-[3-[(3-bromonaphthalene-1-carbonyl)amino]phenyl]prop-2-enoate (23) (1.17 mmol), morpholine (3.53 mmol), and potassium tertbutoxide (2.35 mmol). The vial was charged with DMF (5 mL) and irradiated at 100-130° C. for 1 h, using the microwave reactor Smith Synthesizer. After irradiation, the sample was cooled and diluted with water and extracted with ethyl acetate (3×50 mL). The organic layer was washed with water, brine and dried over Na2SO4 and the solvent evaporated to dryness to afford crude 28, which was purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17]CC4C=CC=CC=4)=[C:13]([F:25])[CH:12]=3)[N:6]=[CH:5][C:4]=2[C:3]=1[OH:26]>C(O)C.[Pd]>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:25])[CH:12]=3)[N:6]=[CH:5][C:4]=2[C:3]=1[OH:26]
Reactant: Oc1c(F)ccc2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(-n2ncc3c(O)c(F)ccc32)cc1F

Procedure:
A solution of 5-fluoro-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-1H-indazol-4-ol (D17) (610 mg, 1.731 mmol) in ethanol (20 mL) was hydrogenated with 10% palladium on carbon (0.25 g, 2.349 mmol) at room temperature for 2 hrs. The mixture was filtered, concentrated and chromatographed (0-100% EtOAc in hexane) to give the title compound (E10) as an off white solid (290 mg)
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.NC1C=CC=CC=1.[O:35]=[C:36]1[NH:41][CH2:40][CH2:39][N:38]([CH2:42][C:43]2[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=2)[CH2:37]1>>[O:35]=[C:36]1[NH:41][CH2:40][CH2:39][N:38]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([NH:47]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:48][CH:49]=2)[CH2:37]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(CN2CCNC(=O)C2)cc1
Solvent: Nc1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCNC(=O)C2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(3-oxo-piperazin-1-yl-methyl)-aniline aniline Rf value: 0.46 (silica gel, methylene chloride/methanol=9:1) C28H26N4O4
Reaction SMILES: O[CH:2]([CH:12]([CH3:14])[CH3:13])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.CCOCC>[CH3:13][CH:12]([CH3:14])/[CH:2]=[CH:3]/[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(C)C(O)CC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(C)/C=C/C(=O)c1ccccc1
Yield: 91.1 %

Procedure:
A mixture of 3-hydroxy-4-methyl-1-phenyl-1-pentanone (8.400 gm, 43.7 mmol) and p-toluenesulfonic acid (820 mg, 4.3 mmol) in benzene (210 ml) was refluxed in a Dean-Stark apparatus for 10 minutes. The solution was cooled, diluted with Et2O, and washed with saturated NaHCO3 and brine. Filtration and removal of the solvent afforded a yellow oil which was subsequently distilled (P=2.0 mm, 97°-100° C.) to give the (E)-4-methyl-1-phenyl-2-penten-1-one (6.94 gm) as a colorless liquid. 1H-NMR analysis showed the distillate to be 78% the desired product and 22% the β, δ-unsaturated isomer. The material was used directly for the next reaction.
Reaction SMILES: C(N(CC)CC)C.F[C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([C:13](=[O:27])[C:14]([C:24]([OH:26])=[O:25])=[CH:15][N:16]2[C@@H:20]2[CH2:22][C@@H:21]2[F:23])=[CH:11][CH:10]=1.C(OC([NH:35][C@:36]12[CH2:44][NH:43][CH2:42][C@@H:41]1[CH2:40][CH2:39][CH2:38][CH2:37]2)=O)(C)(C)C>CS(C)=O.C(OCC)(=O)C.Cl>[NH2:35][C@:36]12[CH2:44][N:43]([C:9]3[C:18]([CH3:19])=[C:17]4[C:12]([C:13](=[O:27])[C:14]([C:24]([OH:26])=[O:25])=[CH:15][N:16]4[C@@H:20]4[CH2:22][C@@H:21]4[F:23])=[CH:11][CH:10]=3)[CH2:42][C@@H:41]1[CH2:40][CH2:39][CH2:38][CH2:37]2
Reactant: CC(C)(C)OC(=O)N[C@@]12CCCC[C@H]1CNC2
Reactant: Cc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1c(N2C[C@@H]3CCCC[C@@]3(N)C2)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 75 °C
Reaction time: 288 h
Yield: 33.5 %

Procedure:
Triethylamine (0.277 mL, 1.98 mmol) and 7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (185 mg, 0.663 mmol) were added to a solution of (1S,6S)-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0]nonane (175 mg, 0.728 mmol) in dimethyl sulfoxide (1.33 mL) in a nitrogen atmosphere, and the mixture was stirred at 75° C. for 12 days. The reaction solution was diluted with ethyl acetate (45 mL) and then washed with a 10% citric acid solution (40 mL), water (40 mL), and a saturated sodium hydroxide solution (40 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2). 260 mg (0.578 mmol) of the resulting residue was dissolved in concentrated hydrochloric acid (2.5 mL) under ice-cooling, and the solution was stirred at room temperature for 10 minutes. After washing with chloroform (50 mL×2), the aqueous layer was adjusted to pH 12 with a saturated sodium hydroxide solution. The basic solution was adjusted to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (100 mL×2) and chloroform/methanol=10/1 (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by PTLC (developed with the lower layer of chloroform/methanol/water=7/3/1). After the fluorescent part was collected, the lower layer of chloroform/methanol/water=7/3/1 (70 mL) was added. After ultrasonic treatment, the silica gel was filtered off. The filtrate was concentrated under reduced pressure and then vacuum dried. Ethanol (1 mL), diethyl ether, and 2-propanol were added to the residue. Diethyl ether was added. After repeating ultrasonic treatment and ice-cooling several times, the mixture was stirred at 40° C. for 30 minutes. After stirring at room temperature for two hours, the crystals were collected by filtration and dried under reduced pressure to give 88.7 mg of the title compound as pale yellow crystals.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:13]([S:17][CH3:18])[C:14]([OH:16])=O)=[CH:7][CH:6]=2.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([NH:23][C:14](=[O:16])[CH:13]([O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[CH:3][C:2]([I:1])=[CH:11]2)[S:17][CH3:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)N
Reactant: CSC(Oc1ccc2ncc(I)cc2c1)C(=O)O
Product: CSC(Oc1ccc2ncc(I)cc2c1)C(=O)NC(C)(C)C

Procedure:
In a similar procedure to Stage 2 of Example 1, (3-iodo-quinolin-6-yloxy)-methylsulfanyl-acetic acid was condensed with t-butylamine to give N-tert-butyl-2-(3-iodo-quinolin-6-yloxy)-2-methylsulfanyl-acetamide as a white solid (MH+ 431).
Reaction SMILES: C([N:4]([C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])C=C.[C:22]([Mg]Cl)(C)([CH3:24])[CH3:23].Cl>C1(C)C=CC=CC=1>[CH2:24]([C@@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([NH:4][CH:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:15])=[O:13])[CH:22]=[CH2:23]
Reactant: CC(C)(C)[Mg]Cl
Reactant: C=CCN(C(=O)CCCCCCC)[C@H](C)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: C=CC[C@@H](CCCCCC)C(=O)NC(C)c1ccccc1
Reaction time: 6 h
Yield: 54.9 %

Procedure:
To a solution of 24.0 g (83.0 mmol) of (R)-N-allyl-N-octanoyl-1-phenylethylamine in 240 ml of toluene was added dropwise 61.5 ml (98.0 mmol) of tert-butylmagnesium chloride (1.6 M) at room temperature and, after completion of the addition, the reaction was allowed to proceed at 70° C. for 6 hours. After completion of the reaction, the reaction mixture was added dropwise to 240 ml of 1 N aqueous hydrochloric acid on an ice bath. The resulting mixture was extracted with 300 ml of hexane, and the organic layer was washed with 100 ml of a saturated aqueous solution of sodium chloride and then concentrated under reduced pressure to give 25.0 g of a crude product. The crude product was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1) to give 13.1 g (76%, (1R,2S):(1R,2R)=80:20) of N-[(R)-2-allyloctanoyl]-1-phenylethylamine.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[CH:29]([N:32]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=2)[C:33]1=[O:50])([CH3:31])[CH3:30]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:37]3[CH:38]=[C:39]4[C:34](=[CH:35][CH:36]=3)[C:33](=[O:50])[N:32]([CH:29]([CH3:31])[CH3:30])[CH2:40]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CC(C)N1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CN(C(C)C)C5=O)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 2-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=465.2.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([S:7][CH3:8])[CH2:5][NH:4][CH2:3]1.[CH:9](=O)[C:10]([CH3:13])([CH3:12])[CH3:11]>CO>[CH3:9][C:10]([CH3:13])([CH3:12])[CH:11]=[N:1][C@H:2]1[C@H:6]([S:7][CH3:8])[CH2:5][NH:4][CH2:3]1
Reactant: CC(C)(C)C=O
Reactant: CS[C@@H]1CNC[C@H]1N
Solvent: CO
Product: CS[C@@H]1CNC[C@H]1N=CC(C)(C)C
Reaction time: 0.5 h

Procedure:
1.32 g (10 mmol) of trans-3-amino-4-methylthio-pyrrolidine are initially introduced into 5 ml of methanol, and 1.23 ml (11 mmol) of 97% strength pivalaldehyde are added dropwise, after which the temperature rises from 25° to 36° C. The mixture is subsequently stirred for a further 30 minutes, without cooling, the batch is then concentrated and the residue is distilled. Yield: 1.50 g (75% of theory),
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.O.O.[Sn](Cl)Cl>CCO>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: COc1ccc([N+](=O)[O-])cc1OCCN1CCOCC1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(N)cc1OCCN1CCOCC1
Temperature: 60 °C
Reaction time: 19 h
Yield: 47.2 %

Procedure:
4-(2-(2-methoxy-5-nitrophenoxy)ethyl)morpholine (350 mg, 1.2 mmol, 1 eq.) and tin (II) chloride dihydrate (1.4 g, 6.20 mmol, 5 eq.) were placed in EtOH (12.3 mL). The reaction mixture was heated at 60° C. and stirred for 19 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with a 1N NaOH aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 4-methoxy-3-(2-morpholinoethoxy)aniline (143 mg, 46%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[CH2:15][CH2:16][C:17]2[C:25]3[C:24](=[O:26])[CH2:23][CH2:22][CH2:21][C:20]=3[NH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:27]=[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH2:15][CH2:16][C:17]1[C:25]2[C:24](=[O:26])[CH2:23][CH2:22][CH2:21][C:20]=2[NH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCc2c[nH]c3c2C(=O)CCC3)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCCc2[nH]cc(CCC(=O)N3CCNCC3)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[3-(4-Oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionyl]-piperazine-1-carboxylic acid tert-butyl ester (37.5mg, 0.1 mmol) was added to 3 ml of dichloromethane at 0° C. followed by the addition of 1 ml of 20% trifluoroacetic acid. The reaction mixture was stirred at room temperature for 8 hours. The reaction solution was rotary evaporated and diluted with 1,4-dioxane. The reaction solution was concentrated at 30° C. till dryness then purified by flash chromatography and eluting with (chloroform: methanol: ammonia 20/1/0.1, 15/1/0.1) to provide 3-(3-oxo-3-piperazin-1-yl-propyl)-1,5,6,7-tetrahydro-indol-4-one.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:3]1.I[CH2:28][CH2:29][CH2:30][CH2:31][B:32]1[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[O:1]=[C:2]1[O:3][C@@H:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@H:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:7]1[CH2:28][CH2:29][CH2:30][CH2:31][B:32]1[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:39])([CH3:40])[O:33]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)O[C@@H](c2ccccc2)[C@H]1c1ccccc1
Reactant: CC1(C)OB(CCCCI)OC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H](CCCCB2OC(C)(C)C(C)(C)O2)C(=O)O[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A solution of (2S,3R)-tert-butyl 6-oxo-2,3-diphenylmorpholine-4-carboxylate (4.69 g, 13.27 mmol) and 2-(4-iodobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (d 1.38, 5.96 mL, 8.23 g, 26.5 mmol, 2 equiv) in THF (66 mL, 0.2 M) and HMPA (6.6 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (14.6 mL, 1.0 M, 1.1 equiv) drop wise over 5 min and stirred for 1 h. After warming to room temperature and stirring for an additional 2 h, the solution was cooled to 0° C. and quenched with 0.5 N HC (2-3 equiv). The resulting solution was diluted with heptane and washed successively with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-60% ethyl acetate in heptane over 6 CV) gave (3R,5R,6S)-tert-butyl 2-oxo-5,6-diphenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)morpholine-4-carboxylate as a white solid (6.66 g, 94%); ESI-LCMS m/z calcd for C31H42BNO2: expected 535.3. found 536.4 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.O>[CH2:15]([N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CCN2
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc2c(c1)CCN2Cc1ccccc1
Reaction time: 2 h
Yield: 72.4 %

Procedure:
A solution of methyl 2,3-dihydro-1H-indole-5-carboxylate HCl salt 55a (88.6 mg, 0.42 mmol), and benzaldehyde 23a (0.060 mL, 0.55 mmol) in CH2Cl2 (4 mL) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (159 mg, 0.75 mmol) was added to the mixture and stirring was continued for 2 h. Water was added to the resulting mixture at 0° C., and pH of the solution was adjusted to ˜8 with 1N aqueous NaOH. The mixture was extracted with CH2Cl2 and the organic layer was washed with brine and dried over Na2SO4. The solution was concentrated and purified by flash column chromatography (silica gel, 10-25% EtOAc/Heptanes) to give 55e (81.3 mg). MS m/z (M+H+) 268.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]1([CH3:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[C:21]([F:38])=[C:22](/[CH:26]=[C:27](/[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[F:37])\[C:28]#[N:29])[CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[CH:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[C:21]=2[F:38])[C:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[F:37])([C:28]#[N:29])[CH:9]([CH2:10][C:11]2([CH3:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[NH:8]1)=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C/C=N/CC(=O)OC(C)(C)C)CCCCC1
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)(C)O
Product: CC1(CC2NC(C(=O)OC(C)(C)C)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)CCCCC1
Yield: 66.5 %

Procedure:
In a manner similar to the method described in Example 100b, [2-(1-methyl-cyclohexyl)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 101a (2.55 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 52a, AgF (1.55 g, 12.3 mmol), and triethylamine (2.8 mL, 20 mmol) in dichloromethane (150 mL) at room temperature for 18 h, followed by the reaction with DBU (10 ml) in tert-butanol (50 mL) at 100° C. for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow solid (3 g, 66%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Br:5][C:6]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9].B(F)(F)F.CCOCC.Cl>CCOCC.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[Br:5][C:6]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:7]=1[C:8]1([NH2:9])[CH2:2][CH2:1]1
Reactant: CC[Mg]Br
Reactant: N#Cc1ccc(F)cc1Br
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Product: NC1(c2ccc(F)cc2Br)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.4 %

Procedure:
Add ethylmagnesium bromide (3 N, 53.9 mL, 74.9 mmol) to a solution of 2-bromo-4-fluorobenzonitrile(15 g, 73.5 mmol) and tetraisopropoxytitanium (23 mL, 162 mmol) in ether (25 mL) at −70° C. under N2. After stirring at the temperature for 10 min, let it warm-up to RT and stir for one hour. Add boron trifluoride etherate (BF3OEt2) (16.8 mL, 147 mmol) to the solution slowly and stir for another hour. After adding 1 N HCl (200 mL) and ether (150 mL), separate the ether layer. Add 10% NaOH (150 mL) to the aqueous solution and extract it with ether. Separate the organic layer and dry over magnesium sulfate. Filter and concentrate in vacuo to give a residue. Purify the residue by column chromatography (diethylether) to give the title compound (7.5 g, 44%). MS (ES) m/z 230 [M+1]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[CH2:16][C:17]([OH:19])=O)([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:23])=O>CN(C)C=O>[CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[CH2:16][C:17]([Cl:23])=[O:19])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)O)c(C(C)C)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(C)C)c(CC(=O)Cl)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 2,4,6-triisopropylphenylacetic acid (6.03 g, 0.023 mol), oxalyl chloride (20 mL), and dimethylformamide (3 drops) was stirred vigorously at room temperature and then allowed to stand overnight at room temperature. The reaction mixture was then concentrated to give the product as an off-white solid 6.5 g, 100%. This was used directly in the next step.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:28][C:29]1[CH:30]=[C:31]([N:35]2[C:39]([C:40]([F:43])([F:42])[F:41])=[C:38]([C:44]([OH:46])=O)[CH:37]=[N:36]2)[CH:32]=[CH:33][CH:34]=1.[F:47][C:48]([F:58])([F:57])[C:49]1[CH:50]=[C:51]([CH:54]=[CH:55][CH:56]=1)[CH2:52][NH2:53].C(N(CC)CC)C>O1CCCC1>[F:47][C:48]([F:57])([F:58])[C:49]1[CH:50]=[C:51]([CH:54]=[CH:55][CH:56]=1)[CH2:52][NH:53][C:44]([C:38]1[CH:37]=[N:36][N:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[CH:30]=2)[C:39]=1[C:40]([F:41])([F:42])[F:43])=[O:46]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (0.083 g; 0.189 mmol) was added to a solution of 1-(3-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.050 g; 0.172 mmol), 3-trifluoromethyl benzylamine (0.030 g; 0.206 mmol) and triethylamine (0.072 mL; 0.516 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 4 h, concentrated and the crude product purified by column chromatography on silica gel to give 1-(3-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 3-trifluoromethyl-benzylamide. LCMS m/z=448.8 (M+H)+.