Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH:6]([C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1)[CH:7]([CH3:9])[CH3:8].O>ClCCl>[Cl:3][CH:6]([C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1)[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)C(O)c1ccc2c(c1)CCO2
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)C(Cl)c1ccc2c(c1)CCO2

Procedure:
Thionyl chloride (2.02 cm3, 0.265 mol) was added dropwise to a stirred solution of 2,3-dihydro-5-(1-hydroxy-2-methyl-1-propyl)benzofuran (5.10 g, 0.0265 mol) pyridine (2.16 cm3, 0.0265 mol) in dichloromethane (45 cm3) at 0°-5° C., and the mixture was heated to reflux for 3 hr. The mixture was poured into water and separated. The organic layer was washed with hydrochloric acid (2 N, 20 cm3), water, dried (Na2SO4), filtered and the solvent was removed. The residue was subjected to column chromatography on silica using toluene as the eluant. The appropriate fractions were combined and the solvent was removed to give 5-(1-chloro-2-methyl-1-propyl)-2,3-dihydrobenzofuran. (5.43 g, 0.028 mol, 97.2%) RF 0.68.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:22])[CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26].[N:37]1([CH2:43][C:44]2[CH:45]=[C:46]([CH:52]=[CH:53][CH:54]=2)[O:47][CH2:48][CH2:49][CH2:50][NH2:51])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:25]([NH:51][CH2:50][CH2:49][CH2:48][O:47][C:46]2[CH:52]=[CH:53][CH:54]=[C:44]([CH2:43][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:45]=2)=[O:26])[CH3:22])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(CCCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Product: CN(CCCCNC(=O)NCCCOc1cccc(CN2CCCCC2)c1)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.45 g (1.0 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,4-butanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 3-[3-(piperidinomethyl)phenoxy]propylamine as starting materials. Chromatographic working-up analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=605 ([M+H]+, 8), 109 (100); IR (KBr): 1641 cm-1 (C=O). For further analysis, a portion of the compound is converted into the tartaric acid salt and recrystallised from isopropanol/ether/petroleum ether; m.p.: 69° C. (isopropanol/ether/petroleum ether).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18](O)[CH:19]([CH2:45][CH2:46]O)[CH2:20][C:21]3[CH:22]=[C:23]([O:27][Si:28]([C:41]([CH3:44])([CH3:43])[CH3:42])([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:24]=[CH:25][CH:26]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[S:50](Cl)(=O)=O.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH:19]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][Si:28]([C:41]([CH3:44])([CH3:43])[CH3:42])([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:22]=4)[CH2:45][CH2:46][S:50]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](Oc1cccc(CC(CCO)C(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](Oc1cccc(CC2CCSC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-[3-(4,5-diphenyloxazol-2-yl)-3-hydroxy-2-(2-hydroxyethyl)propyl]-1-(t-butyldiphenylsilyloxy)benzene (3.0 g) and methanesulfonyl chloride (1.1 ml) and triethylamine (2.6 ml) in THF (50 ml) was stirred at room temperature for 1 hour. The solution was diluted with ethyl acetate and washed with sat. NaHCO3 and brine, dried over MgSO4, and evaporated. The residue was dissolved in DMF (40 ml) and to the solution was added Na2S (600 mg). After being stirred for 30 minutes at 80° C., the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, sat. NaHCO3, and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to afford 2-(4,5-diphenyloxazol-2-yl)-3-(3-t-butyldiphenylsilyloxybenzyl)tetrahydrothiophene (3.2 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:5][CH:4]=[CH:3]1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>C(Cl)Cl.C(O)C.O>[N:28]([CH:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH2:7][CH:2]([CH3:1])[CH:3]1[OH:25])=[N+:29]=[N-:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1C=CC=C(c2ccncc2[N+](=O)[O-])C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CC1CC(c2ccncc2[N+](=O)[O-])=CC(N=[N+]=[N-])C1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
To a solution of (+/−)-4-(5-methylcyclohexa-1,3-dienyl)-3-nitropyridine (1.0 equiv.) in DCM (0.1 M) at 0° C. was added m-CPBA (1.1 equiv.) and the reaction was allowed to warm to room temperature. After 3 hours, the mixture was quenched with saturated NaHCO3, extracted with DCM, and the organic phase was dried with sodium sulfate, filtered, and concentrated to give a yellow oil. The crude was dissolved in ethanol and water (3:1, 0.1 M), and sodium azide (2.0 equiv.) and ammonium chloride (2.0 equiv.) were added. The reaction was stirred for 4 hours, then concentrated in vacuo. To the crude was added ethyl acetate and water, the organic phase was washed with brine, dried with sodium sulfate, filtered, and concentrated. The crude material was purified via silica gel column chromatography eluting with ethyl acetate and hexanes (1:1) to afford (+/−)-2-azido-6-methyl-4-(3-nitropyridin-4-yl)cyclohex-3-enol as an oil in 49% yield. LC/MS=276.1 (M+H), Rt=0.71 min.
Reaction SMILES: C(O)(=O)C.[N+:5]([O-:8])(O)=[O:6].[CH2:9]([S:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([OH:20])[N:14]=1)[CH2:10][CH3:11]>O>[N+:5]([C:16]1[C:15]([OH:20])=[N:14][C:13]([S:12][CH2:9][CH2:10][CH3:11])=[N:18][C:17]=1[OH:19])([O-:8])=[O:6]
Reactant: O=[N+]([O-])O
Reactant: CCCSc1nc(O)cc(O)n1
Solvent: CC(=O)O
Solvent: O
Product: CCCSc1nc(O)c([N+](=O)[O-])c(O)n1
Reaction time: 1 h

Procedure:
Acetic acid (125 ml) and fuming nitric acid (42.5 ml) were placed in a clean and dry reaction assembly, followed by the addition of 2-propylthio-pyrimidine-4,6-diol (50 g) over a period of 60 minutes at 30-35° C. and with stirring for 1 hour. After completion of the reaction, monitored by TLC, the reaction mass was slowly added to water (250 ml) with maintaining the temperature at below 25° C. The resulting slurry was stirred for 1 hour at 20-25° C. The product was isolated by filtration and washed successively with water (3×100 ml). The wet product was dried under reduced pressure at 40-45° C. to produce 48.28 g of 5-nitro-2-propylthiopyrimidine-4,6-diol as a off-white powder (Purity by HPLC: 99.02 area-%).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[C:11]([NH:14][C@@H:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16](O)=[O:17])(=[O:13])[CH3:12].CCN=C=NCCCN(C)C.Cl.[NH2:38][C@@H:39]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([N:55]2[CH2:59][C:58](=[O:60])[N:57]([CH2:61][C:62]3[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=3)[S:56]2(=[O:71])=[O:70])[CH:50]=1)[C:40]([NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:41]>C(Cl)Cl>[C:11]([NH:14][C@@H:15]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:16]([NH:38][C@H:39]([C:40](=[O:41])[NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([N:55]2[CH2:59][C:58](=[O:60])[N:57]([CH2:61][C:62]3[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=3)[S:56]2(=[O:70])=[O:71])[CH:50]=1)=[O:17])(=[O:13])[CH3:12]
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCCCCNC(=O)[C@@H](N)Cc1cccc(N2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCCNC(=O)[C@H](Cc1cccc(N2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)c1)NC(=O)[C@H](Cc1ccccc1)NC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HOBt (40.5 mg, 0.264 mmol), (S)-2-acetylamino-3-phenyl-propionic acid (54.7 mg, 0.264 mmol) and EDCl (50.6 mg, 0.264 mmol) are added to a solution of the title G compound, (S)-2-amino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-N-pentyl-propionamide (129 mg, 0.264 mmol) in CH2Cl2 (5 mL) and stirred at RT for 2 h. The reaction is concentrated and the product is taken up in EtOAc, washed with 1N aqueous HCl, saturated aqueous NaHCO3 and brine, dried over magnesium sulfate, filtered and concentrated to yield (S)-2-acetylamino-N-((S)-2-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-3-phenyl-propionamide as a white solid: [M+1]+=678.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCC(O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCC(OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85.2 %

Procedure:
4-Hydroxy-N-methylpiperidine (200 μL, 1.70 mmol) was dissolved in methylene chloride (10 mL) and then cooled to 0° C. Triethylamine (296 μL, 2.13 mmol) was added, followed by the addition of methanesulfonyl chloride (145 μL, 1.87 mmol). After 1.5 hours, the reaction was quenched with water, and extracted with methylene chloride. The combined organic layers were dried over MgSO4, then concentrated under vacuum to give the desired product (280 mg, 88%). LCMS calculated for C7H16NO3S (M+H)+: m/z=194.1. Found: 194.1.
Reaction SMILES: [OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[CH:3]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1>>[OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[C:3]=1[CH:14]([C:24]1[NH:25][C:26]2[C:31]([C:23]=1[CH3:22])=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1c[nH]c2ccccc12
Reactant: O=C1C=C(O)C(c2ccccc2)C1
Product: Cc1c(C(C2=C(O)C(c3ccccc3)CC2=O)c2ccccc2)[nH]c2ccccc12

Procedure:
Using general procedure D, rac-3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) was reacted with benzaldehyde and 3-methyl-1H-indole to give the title compound as a red solid. MS: 394.1 ([M+H]+).
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C:15](=O)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C:15](=[CH2:1])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
To a suspension consisting of methyl triphenylphosphonium bromide (18 g, 51 mmol) and THF (200 mL) at 0° C. was added n-butyl lithium (1.6 M solution in hexanes, 32 mL). The resulting orange solution was stirred at 0° C. for 5 min, then a solution of 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (9.0 g, 48 mmol) in THF (40 mL) was added via cannula. The reaction mixture was stirred at 0° C. for 90 min, then warmed to rt and stirring was continued for 1 h. The reaction mixture was then cooled to 0° C., quenched with sat. NH4Cl, and extracted with Et2O. The organic layer was dried (MgSO4) and concentrated. The crude residue was suspended in hot hexanes and filtered. The filtrate was concentrated and purified (FCC) to give the title compound (4.4 g, 50%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C:12](=[O:14])[CH3:13])=[CH:4][C:3]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23].[CH3:24][Mg]Cl.C1COCC1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C:12]([CH3:24])([OH:14])[CH3:13])=[CH:4][C:3]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23]
Reactant: C[Mg]Cl
Reactant: CC(=O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Yield: 96 %

Procedure:
To a stirred solution of 1-(6-Bromo-5-(2,4-difluorophenoxy)-1H-indazol-1-yl)propan-2-one (3.81 g, 10.0 mmol) in toluene (100 mL) at 21° C. was added a 3.0 M solution of methylmagnesium chloride in THF (5.0 mL, 15 mmol) in one portion. The temperature of the resulting solution rose to 34° C. and was stirred without any temperature control. After a total of 60 min the reaction mixture was quenched by addition of saturated ammonium chloride (50 mL). The resulting mixture was vigorously stirred for 20 min, then transferred to a separatory funnel and shaken. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure to afford the title compound as an orange oil (3.79 g, 96%) that slowly crystallized on standing.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[CH2:13][CH3:14].C([Li])CCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.Cl>C1COCC1.CCCCCC.O>[CH2:13]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][O:10][CH2:11][CH3:12])=[CH:7][C:2]=1[B:20]([OH:25])[OH:21])[CH3:14]
Reactant: CCOCOc1ccc(CC)c(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOCOc1ccc(CC)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
12 g (49 mmol) of 1-bromo-2-ethyl-5-ethoxymethoxybenzene are placed in 200 ml of dry THF in a round-bottomed flask and under a stream of nitrogen. The reaction medium is cooled to −78° C. and 23 ml (58 mmol) of 2.5M n-butyllithium in hexane are added dropwise. 20 minutes later, 13.6 ml (59 mmol) of triisopropyl borate are added slowly. Stirring is continued for 1 hour at −78° C. The mixture is then poured into a solution of water and hydrochloric acid and is then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (50/50). After evaporating off the solvents, 6.7 g (65%) of the expected product are obtained in the form of white crystals.
Reaction SMILES: [O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[CH:11]\[C:12]1[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[C:15]3[NH:21]C(=O)OC(C)(C)C)=[CH:8][CH:7]=[CH:6][CH:5]=2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:21][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([CH:11]=[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[NH:3][C:2]3=[O:1])[CH:13]=2)[NH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)Nc1n[nH]c2ccc(/C=C3/C(=O)Nc4ccccc43)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1n[nH]c2ccc(C=C3C(=O)Nc4ccccc43)cc12
Reaction time: 3 h

Procedure:
To a solution of (E)-tert-butyl 5-((2-oxoindolin-3-ylidene)methyl)-1H-indazol-3-ylcarbamate (14 mg, 0.04 mmol) in CH2Cl2 (1 mL) was added TFA (0.25 mL) and the reaction was stirred for 3 h. The solution was concentrated to dryness and purified by preparatory HPLC to give the title compound as a 3:2 mixture of E/Z isomers. ESI 277.0 [M+H]+, calcd for [C16H12N4O+H]+ 277.1.
Reaction SMILES: [CH3:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>[Cu](I)I.C(OCC)(=O)C>[CH3:1][CH2:2][C:3]([N:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: Ic1ccccc1
Reactant: CCC(=O)Nc1ccccc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(=O)N(c1ccccc1)c1ccccc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 2-methylacetanilide (4.5 g), iodobenzene (6.8 ml), potassium carbonate (8.3 g), and copper iodide (574 mg) was stirred overnight at 150° C. After the mixture was allowed to cool, water and ethyl acetate were added thereto, and the mixture was further stirred. The mixture was then filtered with celite. Filtrate was collected, and an aqueous phase was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The resulting solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, ethyl acetate:hexane=1:2.5) to obtain 2-methyl-N-phenylacetanilide (4.96 g; yield, 73%) as a light brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[O:11]1[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:18]1[CH2:19][CH2:20][C:15]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:16][CH2:17]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: COc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cccc(CN2CCC3(CC2)OCCO3)c1
Reaction time: 19 h
Yield: 94.7 %

Procedure:
A mixture of 3-methoxybenzaldehyde (10.0 g, 73.4 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (10.5 g, 73.4 mmol), sodium triacetoxyborohydride (20.2 g, 95.3 mmol), and acetic acid (4.2 mL), in methylene chloride (400 mL), was stirred at ambient temperature. After 19 h, a 2 N aqueous sodium carbonate solution (220 mL) was added portionwise. After stirring for 15 min, the aqueous layer was separated and extracted with methylene chloride (100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to provide 8-(3-methoxybenzyl)-1,4-dioxa-8-azaspiro[4.5]decane (18.3 g, 95%) as a yellow oil: 1H NMR (CDCl3, 500 MHz) δ 7.25-7.19 (m, 1H), 6.91-6.89 (m, 2H), 6.80-6.77 (m, 1H), 3.94 (s, 4H), 3.80 (s, 3H), 3.50 (s, 2H), 2.53-2.49 (m, 4H), 1.76-1.72 (m, 4H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH2:25][C:24]1=[O:43])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44]I>>[Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH:25]([CH3:44])[C:24]1=[O:43])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CI
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)C(C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a −78° C. solution of 98.2 g (156 mmol) of (5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 185, Step C) and 10.0 mL (160 mmol) of methyl iodide in dry, degassed THF (400 mL) was added 200 mL (200 mmol) of a degassed 1 M solution of lithium bis(trimethylsilyl)amide in THF slowly over 20 min. The orange solution was stirred at −78° C. for 1.5 h and then warmed to 0° C. and stirred for an additional 1.5 h. The reaction was quenched with saturated aqueous ammonium chloride, and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by chromatography on silica gel (Biotage® Snap™ column; Biotage, LLC, Charlotte, N.C.), 5-55% EtOAc/hexanes, gradient elution) provided the title compound as a light yellow foam.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:14](Cl)=[O:15])=[CH:8][CH:7]=1>C(Cl)Cl>[CH2:12]([O:13][C:14]([N:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)=[O:15])[C:9]1[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1CCNC1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC=CC1
Reaction time: 14 h
Yield: 97.5 %

Procedure:
Commercially-obtained pyrrolidine 5 (6.7 g, 96 mmol) was dissolved in DCM (100 ml) at 0° C. Cbz-Cl (13.6 g, 80 mmol) was added slowly, and the reaction was allowed to stir for 14 hours. The solvent was removed under vacuum, and the residue was taken up in ethyl acetate. This ethyl acetate was washed with 0.5 N HCl two times, saturated sodium bicarbonate solution once, brine and dried over MgSO4. The solvent was removed under vacuum to yield the title product 6 (15.9 g (99%), 78 mmol). 1H NMR (DMSO-d6): δ 7.24 (m, 5H), 5.61 (m, 2H), 5.35 (s, 2H), 3.62 (d, J =4.3 Hz, 2H). MS (ESI-POS): [M+H]+=204.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].Cl[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C1(C2(C3C=CC=CC=3)CC2(P(C(C)(C)C)C(C)(C)C)C)C=CC=CC=1>[C:8]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: COc1ccc(Cl)cc1
Agent: CC(C)(C)P(C(C)(C)C)C1(C)CC1(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
To a solution of diphenylamine (0.34 g, 2.0 mmol) in 4 ml of toluene were added sodium tert-butoxide (0.23 g, 2.4 mmol), 4-chloroanisole (0.27 ml, 2.2 mmol), (π-allyl)palladium chloride (3.7 mg, 0.01 mmol) and 2,2-diphenyl-1-(di-tert-butylphosphino)-1-methylcyclopropane (14.1 mg, 0.04 mmol) obtained in Example 4 under a nitrogen atmosphere and the mixture was stirred for 3 hours at 100° C. The reaction mixture was cooled, washed with water, and dried over anhydrous magnesium sulfate. Then, the solvent was removed under reduced pressure, and the concentrate was purified by column chromatography to give the title compound (0.53 g, 95%) as white crystal.