Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([CH3:16])([CH3:15])[CH2:4][CH2:3]1.[Cr]([O-])([O-])(=O)=[O:19]>C(O)(=O)C>[CH3:15][C:5]1([CH3:16])[C:6]2[C:14](=[CH:13][C:12]3[CH2:11][C:10](=[O:19])[CH2:9][C:8]=3[CH:7]=2)[C:2]([CH3:17])([CH3:1])[CH2:3][CH2:4]1
Reactant: O=[Cr](=O)([O-])[O-]
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)CCC3
Solvent: CC(=O)O
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)CC(=O)C3
Temperature: 70 °C
Yield: 94.2 %

Procedure:
A round bottom flask fit with a mechanical stirrer, condenser, thermometer, addition funnel, and nitrogen inlet was charged with 5,5,8,8-tetramethyl-5,6,7,8-tetrahydrobenz(f)indane (43.0 g, 0.0.19 mol) and 84 mL glacial acetic acid and heated to 70° C. While stirring chromate (56.7 g, 0.57 mol, Aldrich) was added slowly maintaining the temperature at about 110° C. After complete addition (30 minutes) the reaction was allowed to cool to room temperature for an additional 2½ hours. The reaction was quenched with 5% HCl/ice and extracted with diethyl ether. The combined ether extracts were washed with water and dried over anhydrous magnesium sulfate. Removal of the solvents by rotary evaporation gave 43.0 g of greenish solids which were washed with chilled acetone to give 16.0 g (98% pure by GC) of solids. The acetone wash was concentrated to give 15.0 g of more solids which were washed with hexane to give 8.7 g (79% pure by GC) of solids. The 16.0 g solids from the acetone wash and 8.7 g solids from the hexane wash were combined to give the crude 5,5,8,8-tetramethyl-5,6,7,8-tetrahydrobenz(f)indan-2one (total of 24.7 g). 1HNMR (CDCl3, 500 MHz) 6 7.75 (s, 1H); 7.43 (s, 1H); 3.08 (t, J=3.5 Hz, 2H); 2.66 (t, J=6 Hz, 2H); 1.71 (s, 4H); 1.32 (s, 6H); 1.30 (s, 6H).
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Na+].CN(C)P(N(C)C)(N(C)C)=O.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>C1COCC1>[CH2:19]([C:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCBr
Reactant: c1cc[cH-]c1
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC1=CC=CC1
Temperature: -55 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To a solution of sodium cyclopentadienide (71 mmole, 1.89 M in THF) in 20 ml of THF was added 10 ml of hexamethylphosphoramide. The solution was cooled to -55° C. and 1-bromopentane (10.5 g. 70 mmole) was added dropwise with stirring over a period of 30 min. After the addition was completed, the reaction mixture was stirred at -30°-40° C. for 30 minutes and at autogeneous temperature for 30 minutes, then poured into cold water and extracted with pentane, (3×80 ml). The pentane extracts were combined, washed with water (3×100 ml) dried over anhydrous sodium sulfate, filtered and concentrated in a rotary evaporator (water bath temperature 20° C.). The residue was distilled to give 8.1 g (85%) of pentylcyclopentadiene, b.p. 52°/8 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]2[OH:23].C(=O)([O-])[O-].[K+].[K+].C[N:31](C)C=O.C1(C)C=C(C)C=C(C)C=1S(NO)(=O)=O>C(Cl)Cl>[NH2:31][N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([F:12])[C:10]=2[CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5](=[O:23])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7]1
Reactant: CCOC(=O)c1cnc2c(COC(C)=O)c(F)c(F)cc2c1O
Reactant: CN(C)C=O
Agent: Cc1cc(C)c(S(=O)(=O)NO)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)c1cn(N)c2c(COC(C)=O)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
10.7 g (32.9 mmol) of ethyl 6,7-difluoro-4-hydroxy-8-acetoxymethylquinoline-3-carboxylate and 14.2 g (65.8 mmol) of anhydrous potassium carbonate were added to 130 ml of N,N-dimethylformamide, and the solution was stirred at room temperature for 4 hours. 14 g (NET 8.97 g, 49 mmol) of mesitylenesulfonylhydroxyamine was dissolved in 100 ml of methylene chloride, and after drying over sodium sulfate, while cooling on ice, this solution was dropped to the previous solution through 20 minutes. Then, the obtained solution was left overnight as it was. To this solution, 100 ml of water was added, and the solution was stirred at room temperature for 1 hour. The solution was extracted with methylene chloride, and the organic layer was washed. After drying over sodium sulfate, the solvent was removed under reduced pressure and ether was added to the crystal residue. The crystals were filtered off and washed with ether to obtain 6.4 g of the subject compound (97) in a 57% yield. The results of the analysis of this compound were as follows:
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH:9]2[CH2:14][CH:13]3[CH2:15][CH2:16][N:10]2[CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)CCN(C)C.C([Li])CCC.[C:36]1(=[O:41])[CH2:40][CH2:39][CH2:38][CH2:37]1>CCCCCC.C1CCCCC1>[N:10]12[CH2:16][CH2:15][CH:13]([CH2:12][CH2:11]1)[CH2:14][CH:9]2[CH2:8][C:7]([C:36]1([OH:41])[CH2:40][CH2:39][CH2:38][CH2:37]1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(C(CC2CC3CCN2CC3)c2ccccc2)cc1
Reactant: O=C1CCCC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: OC1(C(CC2CC3CCN2CC3)(c2ccccc2)c2ccccc2)CCCC1
Reaction time: 1.2 h

Procedure:
A solution of 20.4 parts 2-(2,2-diphenylethyl)-1-azabicyclo[2.2.2]octane, 10.5 parts by volume of N,N,N',N'-tetramethylethylenediamine, 48 parts by volume of a 1.6 M solution of butyllithium in hexane in 500 parts by volume of cyclohexane is heated to reflux while being stirred for 1.2 hours under nitrogen. The reaction mixture is cooled to 10 and 6.8 parts by volume of cyclopentanone is added during 5 minutes. It is washed four times with water and one time with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residual solid is triturated with 40 parts diethyl ether and filtered. The filtrate is evaporated under reduced pressure to give residual solid and oil. This residue is put on a 25 mm volume of Woelm silica gel and eluted with a mixed solvent of ethanol, concentrated ammonia and toluene (ratio 2:0.25:98) under a pressure to maintain a flow rate of 8 ml per minute. The desired fraction is evaporated under reduced pressure giving residual oil which solidifies. The solid is washed with n-pentane and recrystallized from diethylether giving the product as a white solid: (XI) 1-[2-(1-azabicyclo [2.2.2]octan-2-yl)-1,1-diphenylethyl]cyclopentanol m.p. 178°-179.5°, MW 376. The hydrochloride of this compound is crystallized from a mixed solvent of isopropanol and diethyl ether: 1-[2-(1-azabicyclo[2.2.2]octan-2-yl)-1,1-diphenylethyl] cyclopentanol hydrochloride (XVII); m.p. 247°-249°; MW 412.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]1[NH:24][C:23]([C@@H:25]3[CH2:29][C@H:28]([CH3:30])[CH2:27][N:26]3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:22][CH:21]=1)[CH:14]=[CH:13]2>CN(C=O)C>[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]1[N:24]=[C:23]([C@@H:25]3[CH2:29][C@H:28]([CH3:30])[CH2:27][N:26]3[C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[NH:22][C:21]=1[Cl:8])[CH:14]=[CH:13]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@H]1C[C@@H](c2ncc(-c3ccc4cc(Br)ccc4c3)[nH]2)N(C(=O)OC(C)(C)C)C1
Solvent: CN(C)C=O
Product: C[C@H]1C[C@@H](c2nc(-c3ccc4cc(Br)ccc4c3)c(Cl)[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 50 °C
Yield: 37.4 %

Procedure:
NCS (203 mg, 1.52 mmol) was added to a solution of (2S,4S)-tert-butyl 2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (560 mg, 1.39 mmol) in dry DMF (15 mL) and the mixture was heated at 50° C. for 16 h. The solvent was removed by nitrogen purge and the residue was purified with a Thompson 90 g silica gel cartridge (gradient elution 5%-100% B over 2 L; Solvent B=ethyl acetate and Solvent A=hexanes) to yield (2S,4S)-tert-butyl 2-(4-(6-bromonaphthalen-2-yl)-5-chloro-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (255 mg) as a tan foam. For purpose of characterization, approximately 20 mg was dissolved in methanol (2 mL) and subject to prep HPLC (gradient 0-100% B over a 25 min at 40 ml/min) on a PHENOMENEX® Luna column (30×100 mm, 10u); Solvent B=95% CH3CN-5% H2O-10 mM NH4OAc and A=5% CH3CN-95% H2O-10 mM NH4OAc. LC-MS retention time 2.61 min; calcd. for C23H26BrClN3O2: 492.09 m/z. found 492.03 [M+H]. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min and an analysis time of 5 min where Solvent A was 5% methanol/95% water/0.1% TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 8.18 (s, 1H), 8.09 (s, 1H), 7.91 (br. s, 2H), 7.83 (d, J=8.6 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 4.79-4.75 (m, 1H), 3.78 (t, J=8.9 Hz, 1H), 3.19 (t, J=10.4 Hz, 1H), 2.49 (quin, J=6.1 Hz, 1H), 2.36-2.32 (m, 1H), 1.78 (q, J=11.9 Hz, 1H), 1.45/1.24 (s, 9H), 1.15 (d, J=6.1 Hz, 3H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[S:9])=[CH:3][CH:2]=1.CI.[CH2:19](O)C>O>[CH3:19][S:9][C:8](=[N:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCO
Reactant: S=C(Nc1ccccc1)Nc1ccccc1
Solvent: CI
Solvent: O
Product: CSC(=Nc1ccccc1)Nc1ccccc1
Temperature: 25 °C

Procedure:
To a 2 l flask were added 342 g of thiocarbanilide, 240 g of methyl iodide and 350 cc of ethanol and the mixture was refluxed for 2 hours. After cooling the mixture to a room temperature, a small amount of water was added and the mixture was allowed to stand to precipitate the raw product, which was then filtered off and dissolved in 12 l of hot water. After filtration, the filtrate was converted to an alkaline solution by addition of NaOH to precipitate the product. The product was filtered and washed well until the filtrate became neutral. After drying, the product was recrystalized in 1 l of ethanol to give S-methyl-N,N'-diphenylisothiourea.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[S:12][CH:13]=[C:14]([C:16]([N:18]2[CH2:23][C:22]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[O:21][CH2:20][CH2:19]2)=[O:17])[N:15]=1)([CH3:10])[CH3:9].[F:29][C:30]1[C:39]([F:40])=[C:38]([CH2:41][CH2:42][OH:43])[CH:37]=[CH:36][C:31]=1[O:32][CH2:33][CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1CCCC1=O.C(O)(=O)C>[F:29][C:30]1[C:39]([F:40])=[C:38]([CH2:41][CH2:42][OH:43])[CH:37]=[CH:36][C:31]=1[O:32][CH2:33][CH2:34][N:26]1[CH2:25][CH2:24][C:22]2([O:21][CH2:20][CH2:19][N:18]([C:16]([C:14]3[N:15]=[C:11]([CH:8]([CH3:10])[CH3:9])[S:12][CH:13]=3)=[O:17])[CH2:23]2)[CH2:28][CH2:27]1
Reactant: O=CCOc1ccc(CCO)c(F)c1F
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCOc4ccc(CCO)c(F)c4F)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2-Isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.5 g) was added to a solution of 2-(2,3-difluoro-4-(2-hydroxyethyl)phenoxy)acetaldehyde (example 77, step d) (0.31 g) in N-methyl-2-pyrrolidinone (10 mL) and acetic acid (0.07 mL). The resulting mixture was stirred for 30 min then cooled in an ice bath. Sodium triacetoxyborohydride (0.38 g) was then added and the reaction was allowed to warm to RT and stirred overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous phase was basified with saturated sodium hydrogen carbonate solution and the layers separated. The aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic solutions were washed with water (100 mL) and brine (100 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography, eluting with 47.5:47.5:5 isohexane:ethylacetate:triethylamine to 5% triethylamine in ethyl acetate. The fractions containing product were combined and evaporated to give the subtitled compound as a clear gum. Yield 0.41 g.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[N:15]1([C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(O)C>[O:14]=[C:5]1[NH:4][C:3]([NH:25][C:24]2[CH:23]=[CH:22][C:21]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:27][CH:26]=2)=[N:8][CH:7]=[C:6]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Nc1ccc(N2CCCCC2)cc1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccc(N3CCCCC3)cc2)[nH]c1=O
Temperature: 80 °C

Procedure:
Ethyl 2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (200 mg, 0.934 mmol) was added to 4-(piperidin-1-yl)aniline (158 mg, 0.934 mmol) dissolved in ethanol. The solution was heated in an oil bath to 80° C., while stiffing, in reflux, for 72 hours. The sample was filtered and dried. 1H-NMR confirmed the product (HGN-0034) (15 mg, 0.447 mmol).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[N+:7]([C:10]1[C:18]2[NH:17][C:16](=[O:19])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)([O-:9])=[O:8].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[N+:7]([C:10]1[C:18]2[NH:17][C:16](=[O:19])[N:15]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=c1[nH]c2cccc([N+](=O)[O-])c2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2c([N+](=O)[O-])cccc21
Reaction time: 18 h

Procedure:
Cesium carbonate (1.75 g, 5.4 mmol) was added to a solution of 4-nitro-1,3-dihydro-2H-benzimidazol-2-one (800 mg, 4.5 mmol, described in Intermediate 26) and tert-butyl bromoacetate (0.791 mL, 5.4 mmol) in DM (15 mL). After 18 h, the reaction was quenched with H2O (100 mL) and the solid precipitate was collected by filtration. The crude product was purified by silica gel chromatography, eluting with CH2Cl2:MeOH—95:5, to give the title compound. MS: m/z=294 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[C:12](#[N:16])/[CH:13]=[CH:14]/[CH3:15].Cl>C(O)(C)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9](=[O:11])[CH3:10])[CH:14]([CH3:15])[CH2:13][C:12]#[N:16])=[CH:6][CH:7]=1
Reactant: CC(=O)Cc1ccc(Cl)cc1
Reactant: C/C=C/C#N
Agent: Cl
Solvent: CC(C)(C)O
Product: CC(=O)C(c1ccc(Cl)cc1)C(C)CC#N
Temperature: 65 °C

Procedure:
Triton B (5.85 ml) was added dropwise to 4-chlorophenylacetone (21.8 grams) in 78 ml of tert.butanol. Next crotononitrile (9.17 grams) was likewise added with initial cooling to lower the temperature to about 20° C. Since the reaction was not exothermic, no additional cooling was necessary after the desired temperature was reached. The reaction was then heated to 65° C. for 21/2 hours and, after chilling in an ice bath, 262 ml of 1N HCl was added in portions. Next the reaction mixture was extracted with ether, washed with water, dried, and evaporated in vacuo. An oil resulted which was distilled under vacuum, yield 18.6 grams, b.p. 130°-131° C.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:8]([C:9]([CH3:12])=[CH:10][CH:11]=1)=[N:7][C:6](=[O:13])[C:5]([CH3:15])([CH3:14])[CH:4]=2.Cl[CH2:17][C:18]([CH3:20])=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>CCOCC>[CH3:19][C:18](=[CH2:17])[CH2:20][C:11]1[CH:10]=[C:9]([CH3:12])[C:8]2[C:3](=[CH:4][C:5]([CH3:15])([CH3:14])[C:6](=[O:13])[N:7]=2)[C:2]=1[OH:1]
Reactant: C=C(C)CCl
Reactant: Cc1ccc(O)c2c1=NC(=O)C(C)(C)C=2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: C=C(C)Cc1cc(C)c2c(c1O)=CC(C)(C)C(=O)N=2
Yield: 54.9 %

Procedure:
Using 5-hydroxy-3,3,8-trimethylcarbostyril (1.99 g, 9.69 mmol), 3-chloro-2-methyl-1-propene (1.08 g, 12.0 mmol), and potassium carbonate (2.67 g, 19.38 mmol), the procedure of Reference Example 41 was followed (reaction and post-treatment) to obtain 2.43 g of a crude ether. The obtained crude (2.43 g) was allowed to react and post-treated in a manner similar to that Reference Example 47, followed by purifying by silica gel column chromatography(ether:hexane =1:1). As a result, 1.37 g of the title compound was obtained as a colorless solid (54.4%).
Reaction SMILES: [N+:1]([C:4]1[CH:50]=[CH:49][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:37][N:38]2C(=O)C3=CC=CC=C3C2=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O.NN>ClCCl.CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][C@H:13]2[CH2:37][NH2:38])=[O:11])=[CH:49][CH:50]=1)([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: NC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 91 %

Procedure:
To a solution of (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-phthalimidomethyl-4-tritylthiopyrrolidine (10.46 g: 15.31 mmole) in a mixture of dichloromethane (80 ml) and methanol (160 ml), hydrazine hydrate (1.53 ml: 2 eq.) is added, and the mixture is concentrated to remove dichloromethane by warming and refluxed for 3 hours and 15 minutes. The reaction mixture is concentrated in vacuo. The residue is diluted with dichloromethane and filtered to remove solid. The filtrate is washed with water, dried over magnesium sulfate, and concentrated in vacuo to give crude (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-aminomethyl-4-tritylthiopyrrolidine (7.71 g). Yield: 91%.
Reaction SMILES: CN(C=O)C.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=[O:16])=[CH:7]1.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][O:23][CH3:24]>CCOCC>[CH3:24][O:23][CH2:22][CH2:21][CH2:20][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=[O:16])=[CH:7]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: COCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCCCn1cc(C=O)c2ccccc21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a DMF (0.1 M) solution of indole-3-carbaldehyde (1 eq) was added sodium hydride (60% (w/w) dispersion in oil, 1.1 eq.) at 0° C. followed by 1-bromo-3-methoxypropane (1.5 eq.). The reaction mixture was stirred at 50° C. for 4 h. The mixture was then diluted with ether, washed with water and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 1:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]2[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[C:6]([OH:19])[C:5]([N+:20]([O-])=O)=[CH:4][CH:3]=1.[H][H]>[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:20])=[C:6]([OH:19])[C:7]=1[S:8]([N:11]1[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13][CH2:12]1)(=[O:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCS(=O)(=O)CC2)c1O
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)(=O)CC2)c1O

Procedure:
Following the general hydrogenation procedure outlined in example 15, 6-chloro-1-(1,1 -dioxidothiomorpholinosulfonyl)-2-hydroxy-3-nitrobenzene (220 mg, 0.60 mmol) was reduced with hydrogen and 10% Pd/C (100 mg) to give the desired (186 mg, 92%). 1H NMR (MeOD-d4): δ 6.88 (m, 2H), 3.85 (t, 4H), 3.22 (t, 4H).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([CH3:30])[CH:17]=1.Cl>O1CCCC1>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:5]([C:4](=[O:3])[CH2:11][CH2:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:17][C:18]=1[CH3:30])#[N:29]
Reactant: Cc1cc(CBr)ccc1-c1ccccc1C#N
Reactant: CCCC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c(C)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a solution (15 mL) of 4′-(hydroxymethyl)-2′-methylbiphenyl-2-carbonitrile (4.12 g) in toluene was added phosphine tribromide (6.00 g) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The obtained ethyl acetate solution was washed with saturated aqueous sodium hydrogen carbonate and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (5.08 g, 96%). To a mixture of 60% sodium hydride in oil (1.10 g) and tetrahydrofuran (20 mL) was added dropwise a mixture of ethyl 3-oxohexanoate (5.62 g) in tetrahydrofuran (20 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Then, 4′-(bromomethyl)-2′-methylbiphenyl-2-carbonitrile (5.08 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 M hydrochloric acid (50 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (4.53 g, 70%).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH2:32])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:40](OC(=O)C)(=[O:42])[CH3:41]>O1CCCC1.ClCCl>[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH:32][C:40](=[O:42])[CH3:41])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:16]1)=[O:14])([CH3:10])([CH3:9])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(Cl)c2)CO1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](Cc1cc(F)cc(Cl)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
Add triethylamine (138 μL, 0.99 mmol) to a solution of (2R,5R)-5-[(1S,2S)-2-amino-3-(3-chloro-5-fluorophenyl)-1-hydroxypropyl]-2-(2,2-dimethylpropoxy)-morpholine-4-carboxylic acid tert-butyl ester (0.428 g, 0.901 mmol) in tetrahydrofuran (5 mL) followed by acetic anhydride (91 μL, 0.991 mmol). Stir at room temperature for 30 minutes, dilute with dichloromethane, wash with 0.1 N hydrochloric acid (30 mL), saturated aqueous sodium chloride (30 mL), dry (sodium sulfate), filter and purify (silica gel chromatography, eluting with 2:98 to 10:90 methanol:dichloromethane) to give the title compound as a white foam (0.212 g, 45%).