Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[CH2:6]1.COCO[C@H]1CCN([C@H](C2C=CC=CC=2)CO)C1.CN.CS(Cl)(=O)=O.[H-].[Na+].[Cl:46][C:47]1[CH:48]=[C:49]([CH:52]=[CH:53][C:54]=1[NH:55][CH3:56])[C:50]#[N:51].[NH4+].[OH-]>C(Cl)Cl.CN(C)C=O.O>[Cl:46][C:47]1[CH:48]=[C:49]([CH:52]=[CH:53][C:54]=1[N:55]([C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][N:7]1[CH2:8][CH2:9][C@H:5]([O:4][CH2:3][O:2][CH3:1])[CH2:6]1)[CH3:56])[C:50]#[N:51]
Reactant: CNc1ccc(C#N)cc1Cl
Reactant: COCO[C@H]1CCN(C[C@@H](O)c2ccccc2)C1
Agent: CN
Agent: COCO[C@H]1CCN([C@@H](CO)c2ccccc2)C1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COCO[C@H]1CCN(C[C@H](c2ccccc2)N(C)c2ccc(C#N)cc2Cl)C1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 61 %

Procedure:
To a stirred solution of the mixture of 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol (251 mg, 1.00 mmol) and methylamine (0.167 ml, 1.20 mmol) in CH2Cl2 (4 ml) was added methanesulfonyl chloride (0.093 ml, 1.20 mmol) dropwise at 0° C. (ice bath). After 15.5 h stirring at room temperature, the reaction mixture was washed with saturated NaHCO3 aqueous solution, brine, dried (Na2SO4), and concentrated to give 238 mg of brown viscous oil-(i). To a suspension of NaH (48 mg, 1.20 mmol) in N,N-dimethylformamide (2 ml) was added a solution of 3-chloro-4-methylaminobenzonitrile (200 mg, 1.20 mmol) at room temperature. After stirring for 45 min, to this mixture was added a solution of the above brown viscous oil-(i) in N,N-dimethylformamide (2 ml) at room temperature and the mixture was stirred at room temperature for 4.5 h. H2O was added to this mixture, basified with 25%-NH4OH and extracted with CH2Cl2. The extract was washed with water, brine, dried (Na2SO4), and concentrated to give brown oil, which was purified by column chromatography (silica gel 20 g, CH2C2/MeOH 100/1-50/1) to afford 244 mg (61%) of brown oil.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH2:6]([C:8]([CH3:20])([C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2)[OH:9])[CH3:7].C(N(CC)CC)C.O1CCCC1>O>[C:1]([O:9][C:8]([C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2)([CH3:20])[CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3]
Reactant: CCC(C)(O)C12CC3CC(CC(C3)C1)C2
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC(C)(CC)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
A total of 10 mmole of acryloyl chloride was added dropwise to a mixture of 10 mmole of the above-prepared α-ethyl-α-methyl-1-adamantanemethanol, 10 mmole of triethylamine and 40 ml of tetrahydrofuran over about 30 minutes. After the completion of addition, the resulting mixture was stirred at room temperature for 6 hours. After the addition of water, the reaction mixture was concentrated, and the concentrate was subjected to column chromatography on a silica gel to thereby yield the title compound in a yield of 74%.
Reaction SMILES: [SH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:19][C:20]1([CH3:35])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]2[CH:25]=[C:24]([C:32](Cl)=[O:33])[CH:23]=[CH:22][C:21]1=2.O>C1COCC1.CCCCCC.C(OCC)C>[CH3:19][C:20]1([CH3:35])[CH2:29][CH2:28][C:27]([CH3:30])([CH3:31])[C:26]2[CH:25]=[C:24]([C:32]([S:1][CH2:2][C:3]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=3)=[O:33])[CH:23]=[CH:22][C:21]1=2
Reactant: O=C(O)c1ccc(CS)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Cl)ccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C(=O)SCc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
1.68 g (10 mmol) of 4-mercaptomethylbenzoic acid, 2.8 ml (20 mmol) of triethylamine and 50 ml of THF are introduced into a round-bottomed flask. A solution of 2.5 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthoyl chloride in 50 ml of THF is added dropwise and the mixture is stirred at room temperature for four hours. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated. The residue obtained is ground in 50 ml of a mixture of ethyl ether and hexane (50:50) and then filtered off. 2.5 g (66%) of the expected acid, melting point 150-151° C, are obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][N:8]=[C:7]([CH3:10])[N:6]=1.[CH3:11][C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[C:21]([CH3:23])[C:20](O)=[C:19]([CH3:25])[CH:18]=2)[N:13]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:10][C:7]1[N:6]=[C:5]([CH2:4][CH2:3][CH2:2][O:1][C:20]2[C:19]([CH3:25])=[CH:18][C:17]([C:14]3[N:13]=[C:12]([CH3:11])[O:16][N:15]=3)=[CH:22][C:21]=2[CH3:23])[S:9][N:8]=1
Reactant: Cc1nsc(CCCO)n1
Reactant: Cc1nc(-c2cc(C)c(O)c(C)c2)no1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nsc(CCCOc2c(C)cc(-c3noc(C)n3)cc2C)n1
Temperature: 20 °C
Yield: 60.8 %

Procedure:
A mixture of 5-(3-hydroxypropyl)-3-methyl-1,2,4-thiadiazole (66 mg, 0.42 mmol), 4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenol (94 mg, 0.46 mmol), and DEAD (80 mg, 0.46 mmol) was dissolved in 5 mL of THF. To the above solution was added triphenylphosphine (120 mg, 0.46 mmol) at 0° C. and the mixture was allowed to warm to 20° C. overnight. The solvent was removed in vacuo, an aqueous sodium bicarbonate solution was added, and the mixture was extracted with methylene chloride (3×). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (20 cm column, ethyl acetate/hexane, from 1/6 to 1/4) followed by recrystallization from ethyl acetate/hexane to afford 88 mg (61%) of 3-methyl-5-[3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl]-1,2,4-thiadiazole, as a white crystalline solid, m.p. 67°-71° C.
Reaction SMILES: [C:1]([C:4]1[C:16]([NH2:17])=[C:15]([C:18]([CH3:20])=[CH2:19])[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1)([CH3:3])=[CH2:2]>C(O)C.[Pd].[Pt]>[CH:1]([C:4]1[C:16]([NH2:17])=[C:15]([CH:18]([CH3:20])[CH3:19])[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc2c(oc3ccccc32)c(C(=C)C)c1N
Agent: [Pd]
Agent: [Pt]
Solvent: CCO
Product: CC(C)c1cc2c(oc3ccccc32)c(C(C)C)c1N
Yield: 89.8 %

Procedure:
2,4-bis (isopropenyl)dibenzo[b,d]furan-3-amine (6.6 g, 25 mmol) was dissolved in ethanol (150 mL) and to it were added 10% Pd/C (1.5 g) and 5% Pt/C (1.5 g) and hydrogenated at 50 psi of H2 over night. GC indicated complete conversion of olefin to alkane. The reaction mixture was filtered through a Celite pad and washed with methylene chloride. The filtrate was concentrated to produce 6 g (90% yield) of desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:22]([F:24])[F:23])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]([CH:16]([CH3:20])[C:17](O)=[O:18])[C:10](=[O:21])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:22]([F:24])[F:23])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]([CH:16]([CH3:20])[C:17]([NH:25][C:26]3[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[CH:28][CH:27]=3)=[O:18])[C:10](=[O:21])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CC(C(=O)O)n1cc(C#N)c(-c2cc(Cl)ccc2C(F)F)cc1=O
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(-c2cc(Cl)ccc2C(F)F)cc1=O

Procedure:
88 mg (purity 92%, 0.23 mmol) of 2-{4-[5-chloro-2-(difluoromethyl)phenyl]-5-cyano-2-oxopyridin-1(2H)-yl}propanoic acid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 48 mg (36% of theory)
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][CH3:14])=[C:10]([Cl:15])[CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:20]([O:22]CC)=[O:21])[CH:6]([C:16]([F:19])([F:18])[F:17])[O:7]2.O.[OH-].[Li+].Cl>C1COCC1.C(O)C.O>[Cl:1][C:2]1[C:11]([O:12][CH2:13][CH3:14])=[C:10]([Cl:15])[CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:20]([OH:22])=[O:21])[CH:6]([C:16]([F:18])([F:19])[F:17])[O:7]2
Reactant: CCOC(=O)C1=Cc2c(cc(Cl)c(OCC)c2Cl)OC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1c(Cl)cc2c(c1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 80 °C
Yield: 70 %

Procedure:
The product of step 1 was dissolved in 5 mL THF and 1 mL ethanol. A solution of 61 mg of lithium hydroxide monohydrate in 6 mL of water was added to the organic solution. The vessel was capped and heated to 80° C. for 1 hour. After cooling to room temperature, the sample was concd using a nitrogen stream. The basic solution was then acidified with 3N HCl until the pH=2 and extracted 4 times with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and solvent removed. The sample was purified by reverse phase chromatography to afford 72.6 mg (70%) of a brown solid: 1H NMR (CDCl3, CD3OD/300 MHz) 1.46 (t, 3H, J=6.6 Hz), 4.08 (q, 2H, J=7.2 Hz), 5.71 (q, 2H, J=6.9 Hz), 7.01 (s, 1H), 8.08 (s, 1H); MS (ES+) 357 (M+1, 100), 359 (M+3, 68); LC-MS purity 100% at 3.166 min. (UV and ELSD); HRMS (ES−) m/z calcd for (M−1; C13H8O4Cl2F3) 354.9746, found 354.9744.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:9][S:10][C:11](SC)=[CH:12][N+:13]([O-:15])=[O:14]>CN(C=O)C.C(N(CC)CC)C>[NH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][C:11]([S:10][CH3:9])=[CH:12][N+:13]([O-:15])=[O:14]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: Nc1ccncc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSC(=C[N+](=O)[O-])Nc1cnccc1N
Yield: 13.1 %

Procedure:
3,4-Diaminopyridine (6.00 g, 55.0 mmol) and 1,1-bis(methylthio)-2-nitroethylene (10.0 g, 60.5 mmol) were dissolved in 60 ml of DMF and 10 ml of triethylamine, followed by reaction at 70° C. for 5 hours. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: chloroform:methanol=2:1 (v/v)] to obtain 1.63 g of the intended product (yield: 13.1%)
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5](C(OC(C)(C)C)=O)[CH2:4]1.[N+:27]([O-])([O-:29])=[O:28].[K+].N>OS(O)(=O)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=[CH:15][C:9]=3[C:8]([N+:27]([O-:29])=[O:28])=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1ccc1ccc(S(C)(=O)=O)cc21
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CS(=O)(=O)c1ccc2c([N+](=O)[O-])cc3c(c2c1)C(CCl)CN3
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69 %

Procedure:
Powdered 205 (350 mg, 0.88 mmol) was added to stirred conc. H2SO4 (4 mL) at 0° C. and the mixture was warmed to room temperature for 20 min. The resulting solution of amine was cooled to −5° C. and treated dropwise with a solution of KNO3 (98 mg, 0.97 mmol) in conc. H2SO4 (1 mL). The mixture was stirred at 0° C. for a further 5 min, then poured into ice/water and neutralized with dilute aqueous NH3. The resulting solid was filtered off, dissolved in CH2Cl2, and the solution was filtered through a column of silica gel and evaporated to dryness. Recrystallization from CH2Cl2/i-Pr2O followed by EtOAc gave 1-(chloromethyl)-8-(methylsulfonyl)-5-nitro-1,2-dihydro-3H-benzo[e]indole (206) (207 mg, 69%) as a red solid: mp 193-194° C.; 1H NMR [(CD3)2SO] δ 8.34 (d, J=1.5 Hz, 1H), 8.31 (d, J=9.1 Hz, 1H), 7.82 (s, 1H), 7.76 (dd, J=9.1, 1.9 Hz, 1H), 6.62 (br s, 1H), 4.37-4.28 (m, 1H), 3.93 (dd, J=11.1, 4.1 Hz, 1H), 3.87 (td, J=9.8, 2.3 Hz, 1H), 3.80-3.70 (1, 2H), 3.33 (s, 3H). Anal. (C14H13ClN2O4S) C, Ht N. The structure of 206 was confirmed by x-ray crystallography see FIG. 1.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][N:4]1[C:13]2[N:12]=[CH:11][N:10]=[C:9]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21]4=[O:29])[CH2:16][CH2:15]3)[C:8]=2[N:7]=[C:6](OC)[C:5]1=[O:32].Cl>CO>[CH3:3][N:4]1[C:6]([C:5]([OH:32])=[O:1])=[N:7][C:8]2[C:13]1=[N:12][CH:11]=[N:10][C:9]=2[N:14]1[CH2:15][CH2:16][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:18][CH2:19]1
Reactant: [OH-]
Reactant: COc1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n(C)c1=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cn1c(C(=O)O)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 589.5 %

Procedure:
Methanol (25 mL) and aqueous 2M sodium hydroxide solution (25.4 mmol, 12.7 mL, 10 equiv) were added to 8-methyl-6-(methyloxy)-4-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]pteridin-7(8H)-one (1.00 g, 2.54 mmol, 1 equiv) in a 100 mL single-necked round bottomed flask fitted with a Teflon stirrer. The resulting stirred slurry was then heated to 80° C. and the reaction was monitored by LC/MS. The reaction mixture gradually became clear and homogenous. LC/MS indicated that the reaction was complete after 12 hours. The new product peak was characterized by a 394 (MH+) molecular ion and a 350 (MH+−44 (—CO2) decarboxylation fragmentation peak. The reaction mixture was then allowed to cool to room temperature. The stirred reaction mixture was then acidified to pH 2 by the gradual addition of aqueous 3M hydrochloric acid, resulting in the precipitation of a white solid. The resulting slurry was then stirred for 30 minutes and then filtered off. The solid was washed with cold water (2×10 mL) and dried at reduced pressure to give 5.89 g (82% yield) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.89 (broad s, 1H), 8.33 (s, 1H), 7.17 (dd, 1H), 6.91 (m, 3H), 5.40 (v broad s, 2H), 4.56 (t, 1H), 3.22 (broad s, 2H), 2.33 (d, 2H), 1.85 (d, 2H). MS (EI) for C18H17N7O3: 394 (MH+), 350 (MH+−44 (—CO2).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH:2]12.[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31](ON3C(=O)CCC3=O)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[N:1]1([C:31]([O:30][CH2:29][CH:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:28]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:32])[CH2:5][CH2:4][CH:3]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH:2]12
Reactant: CC(C)(C)OC(=O)N1CC2CCNC2C1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)C2C1

Procedure:
A solution of tert-butyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (424 mg, 2 mmol), N-(9-fluorenylmethoxycarbonyloxy) succinimide (600 mg, 1.8 mmol) and DIPEA (310 mg, 2.4 mmol) in dioxane (20 mL) was stirred at room temperature overnight and then concentrated in vacuo. The residue was treated with EtOAc/H2O, separated, and the aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound. MS (m/z): 355 (M-boc+H)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:12]([CH2:20][CH2:21][OH:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)[CH3:11]>CC(C)=O.N1C=CC=CC=1>[CH3:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[N:12]([CH2:10][CH3:11])[CH2:20][CH2:21][O:22][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN(CCO)c1cccc(C)c1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCN(CCOC(=O)c1ccccc1)c1cccc(C)c1

Procedure:
Benzoylchloride (3.3 g) was added to a mixture of N-ethyl-N-hydroxyethyl-3-methylaniline (2.1 g) in acetone (25 cm3) and pyridine (1 cm3) and stirred at reflux for 1 hour. The reaction mixture was cooled and used directly in iv) below.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C@H:18]2[NH:28]C(=O)OCC[Si](C)(C)C)[C:13]1=[O:38])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>ClCCl>[C:24]([NH:23][C@@H:20]1[CH2:21][CH2:22][C@H:17]([N:14]2[CH2:15][CH2:16][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:13]2=[O:38])[C@H:18]([NH:28][S:54]([CH3:53])(=[O:56])=[O:55])[CH2:19]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](NC(=O)OCC[Si](C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](NS(C)(=O)=O)C1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A sample of 2-(trimethylsilyl)ethyl (1R,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexylcarbamate and its 5S diastereomer (100 mg, 0.183 mmol; see Example 11, Step 4) was dissolved in dichloromethane (2 ml) prior to the addition of trifluoroacetic acid (2.54 ml, 32.9 mmol). After 30 min, the solution was concentrated in vacuo. The residue was dissolved in dichloromethane (3 ml) prior to the addition of triethylamine (0.100 ml, 0.720 mmol) and methanesulfonyl chloride (0.018 ml, 0.234 mmol). After 2 h, this was washed with sat NaHCO3 solution and the organic layer was dried (Na2SO4), filtered and concentrated to afford benzyl (S)-1-((1S,2R,4R)-4-(tert-butylamino)-2-(methylsulfonamido)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate as a mixture with its 4S diastereomer (66 mg, 0.137 mmol, 76% yield). LC/MS found [M+H]+=481.22.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:27])[CH2:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH3:26])=[CH:4][C:3]=1[CH3:28].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:28][C:3]1[CH:4]=[C:5]([C:8](=[O:27])[CH2:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH3:26])[CH:6]=[CH:7][C:2]=1[O:1][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: Cc1cc(C(=O)CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(C(=O)CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 55 °C

Procedure:
A solution of 1-(4-hydroxy-3-methylphenyl)-3-{4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}propan-1-one (intermediate 10, 0.28 g) in dry acetonitrile (15 ml) was treated with ethyl bromoacetate (0.076 ml) and cesium carbonate (0.449 g) and heated at 55° C. for 18 hours. The reaction was filtered, and the filtrate evaporated to give material which was further purified by flash column chromatography using cyclohexane:ethyl acetate (3:1) as eluent to give the title compound as a white solid.
Reaction SMILES: [N:1]1([CH2:6][C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].Cl>CO>[OH:8][CH:7]([CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)[CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CN2CCCC2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C(O)CN2CCCC2)CC1

Procedure:
Tert-butyl 4-(2-pyrrolidin-1-ylacetyl)piperidinecarboxylate (0.33 g, 1.1 mmol) prepared according to Reference Example 12 was dissolved in methanol (5.0 mL), and was mixed with sodium borohydride (0.13 g, 3.3 mmol) added with stirring under ice-cooling, followed by stirring at room temperature for one hour. Diluted hydrochloric acid (1.0 mol/L, 0.5 mL) was added dropwise to the reaction mixture under ice-cooling, and the solvent was distilled off. The residue was diluted with water and was extracted with ethyl acetate. The organic layer was washed with brine, was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was dried under reduced pressure and thereby yielded tert-butyl 4-(1-hydroxy-2-pyrrolidin-1-ylethyl)piperidinecarboxylate (0.24 g, 73%).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][C:5]=1[OH:13].[CH3:14][N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][CH2:21]OS(C)(=O)=O.CN1CCCC1CCO.CS(Cl)(=O)=O>CO.C(Cl)Cl.C(N(CC)CC)C.CS(C)=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][C:5]=1[O:13][CH2:21][CH2:20][CH:16]1[CH2:17][CH2:18][CH2:19][N:15]1[CH3:14]
Reactant: N#CCc1ccc(Br)c(O)c1
Reactant: CN1CCCC1CCOS(C)(=O)=O
Agent: CN1CCCC1CCO
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN1CCCC1CCOc1cc(CC#N)ccc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A suspension of KCN (16.0 g, 238.3 mmol) in DMF (100 mL) was heated at 60° C. for 30 min. The slurry was cooled to room temperature and treated with a solution of 2-bromo-5-bromomethylphenol 72 (4.16 g, 15.7 mmol) in DMF (50 mL). The resultant mixture stirred at room temperature for 23 h, and then was diluted with water and extracted with ethyl acetate (5×). The organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (hexanes:EtOAc, 3:1) to afford impure (4-bromo-3-hydroxy-phenyl)acetonitrile 73. To a solution of KOH (26.5 mg) in MeOH (1.5 mL) was added (4-bromo-3-hydroxy-phenyl)-acetonitrile 73 (100.0 mg), the resulting mixture was stirred at room temperature for 10 min then conentrated in vacuo. DMSO (3 mL) and methanesulfonic acid 2-(1-methyl-pyrrolidin-2-yl)-ethyl ester, (prepared from 2-(1-methyl-pyrrolidin-2-yl)-ethanol, methane sulfonyl chloride in presence of triethylamine) were added. The reaction mixture was stirred at room temperature overnight. DCM (80 mL) was added and the organics washed with saturated aqueous NaHCO3 solution (20 mL) and brine (20 mL). The organic layer was dried with MgSO4. The residue was purified by silica gel column chromatography (eluent: DCM/MeOH, 4/1) to give 74. MS (EI) m/z (M+H+) 324.
Reaction SMILES: C([NH:4][C:5]1[C:6]([N+:19]([O-:21])=[O:20])=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[CH2:10][CH:9]([NH:15][C:16](=[O:18])[CH3:17])[CH2:8]2)(=O)C.S(=O)(=O)(O)O>O>[NH2:4][C:5]1[C:6]([N+:19]([O-:21])=[O:20])=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[CH2:10][CH:9]([NH:15][C:16](=[O:18])[CH3:17])[CH2:8]2
Reactant: CC(=O)Nc1c(Br)cc2c(c1[N+](=O)[O-])CC(NC(C)=O)C2
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)NC1Cc2cc(Br)c(N)c([N+](=O)[O-])c2C1
Temperature: 90 °C
Yield: 80 %

Procedure:
N-(5-Acetylamino-6-bromo-4-nitro-indan-2-yl)-acetamide (1 g, 2.8 mmol) was suspended in a 2:1 mixture of sulfuric acid and water (30 mL) and heated at 90° C. for 12 h. The mixture was poured onto ice and the resulting yellow solid was collected by filtration and dried in vacuo to give (0.7 g, 80% yield).