Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[C:6](=NNC(OC)=O)[CH3:7])[CH3:2].O.C(OCC)(=[O:28])C>CC(C)=O.[Cl-].[Cl-].[Cl-].[Ti+3]>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[C:6](=[O:28])[CH3:7])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C(Nc1cccc([N+](=O)[O-])c1)C(C)=NNC(=O)OC
Agent: [Ti+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(Nc1cccc([N+](=O)[O-])c1)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Titanium trichloride (10% solution in 20-30% HCl) was added to a solution of 3-(methoxycarbonylhydrazono)-2-(3-nitrophenylamino)butyric acid ethyl ester (compound 1c-51a) (5.0 g, 14.78 mmol) in acetone (50 mL), and the mixture was stirred at room temperature for 1 hour. Water was then added to the reaction mixture, extraction was performed with ethyl acetate, and the organic extract was washed with water and saturated saline. After drying over magnesium sulfate, it was concentrated under reduced pressure to yield a crude product, which was then purified by column chromatography to yield the title compound (3.75 g, 95%) as a yellow oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2[N:18]=[C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[C:24]3[O:28][N:27]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH:25]=3)[N:16]=[C:15]([NH:35][CH:36]3[CH:40]=[C:39]([CH3:41])[NH:38][N:37]3S(C3C=CC(C)=CC=3)(=O)=O)[CH:14]=2)(=O)=O)=CC=1.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>>[O:55]1[CH2:56][CH2:57][N:52]([CH2:12][C:13]2[N:18]=[C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[C:24]3[O:28][N:27]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH:25]=3)[N:16]=[C:15]([NH:35][C:36]3[CH:40]=[C:39]([CH3:41])[NH:38][N:37]=3)[CH:14]=2)[CH2:53][CH2:54]1
Reactant: CC1=CC(Nc2cc(COS(=O)(=O)c3ccc(C)cc3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)N(S(=O)(=O)c2ccc(C)cc2)N1
Reactant: C1COCCN1
Product: Cc1cc(Nc2cc(CN3CCOCC3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Temperature: 60 °C
Yield: 86.9 %

Procedure:
A mixture of 6-[(4-methylphenylsulphonyloxy)methyl]-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-2-N-[4-methylphenylsulphonyl]-1H-pyrazol-3-ylamino)pyrimidine (Method 52) (214 mg, 0.295 mmol) and morpholine (5 ml, 83.2 mmol) was heated at reflux for 2 hours. The volatiles were removed by evaporation and the residue was dissolved in methanol (10 ml) and 10M aqueous sodium hydroxide solution (3 ml). The mixture was heated at 60° C. for 1 hour. The volatiles were removed by evaporation and the residue dissolved in water, extracted with dichloromethane. The extracts were combined and the solvent removed by evaporation. The residue was purified by chromatography on silica gel, eluting with dichloromethane (100%) and then diethylether (100%). The purified product was triturated with diethylether and collected by filtration to give the title compound (125 mg).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][C:4](=[O:14])[C:3]=1[C:15](=O)[CH2:16][CH2:17][CH3:18].Cl.[CH2:21]([O:23][NH2:24])[CH3:22].O.O.O.C([O-])(=O)C.[Na+].C(O)(=O)C>C(O)C>[CH2:21]([O:23][N:24]=[C:15]([C:3]1[C:4](=[O:14])[CH2:5][CH:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:7][C:2]=1[OH:1])[CH2:16][CH2:17][CH3:18])[CH3:22]
Reactant: CCCC(=O)C1=C(O)CC(c2cccnc2)CC1=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCCC(=NOCC)C1=C(O)CC(c2cccnc2)CC1=O

Procedure:
3-Hydroxy-5-(3-pyridyl)-2-butyrylcyclohex-2-en-1-one (1.0 g) was stirred with O-ethylhydroxylamine hydrochloride (1.1 equiv) and sodium acetate trihydrate (1.1 equiv) in ethanol (30 ml) at room temperature for 12 hr. The mixture was poured into a dilute acetic acid solution, which was subsequently extracted with ether. The dried (MgSO4) organic extract was evaporated to give 2-[1-(ethoxyimino)-butyl]-3-hydroxy-5-(3-pyridyl)cyclohex-2-en-1-one as an oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]([OH:18])=O)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[Si:33]([O:40][CH2:41][CH2:42][N:43]([C@H:51]1[C:59]2[C:54](=[C:55]([C:60](=[NH:63])[NH:61]O)[CH:56]=[CH:57][CH:58]=2)[CH2:53][CH2:52]1)[C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>CN(C=O)C>[Si:33]([O:40][CH2:41][CH2:42][N:43]([C@H:51]1[C:59]2[C:54](=[C:55]([C:60]3[N:63]=[C:16]([C:9]4[S:10][C:11]([C:12]([F:13])([F:14])[F:15])=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[O:18][N:61]=3)[CH:56]=[CH:57][CH:58]=2)[CH2:53][CH2:52]1)[C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])([C:36]([CH3:37])([CH3:38])[CH3:39])([CH3:35])[CH3:34]
Reactant: O=C(O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Reactant: CC(C)(C)OC(=O)N(CCO[Si](C)(C)C(C)(C)C)[C@@H]1CCc2c(C(=N)NO)cccc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(CCO[Si](C)(C)C(C)(C)C)[C@@H]1CCc2c(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cccc21
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
Prepared using General Procedure 2. To a solution of 4-phenyl-5-(trifluoromethyl)thiophene-2-carboxylic acid (0.109 g, 0.4 mmol) in DMF (3.0 mL) was added HOBt (0.088 g, 0.57 mmol) and EDC (0.109 g, 0.57 mmol) at room temperature. The reaction mixture was stirred for 0.5 h until the complete formation of the HOBt-acid complex. (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)carbamate INT-61 (0.200 g, 0.44 mmol) was added and the mixture was stirred at room temperature for 0.5 h until the formation of the intermediate (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(N-(4-phenyl-5-(trifluoromethyl)thiophene-2-carbonyloxy) carbamimidoyl)-2,3-dihydro-1H-inden-1-yl) carbamate was observed. The reaction mixture was heated at 85° C. for 4 h. Upon cooling, the mixture was extracted with DCM and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to produce a brown oil. The crude product was purified by silica gel flash chromatography (MeOH/DCM) to yield 0.108 g (40%) of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxa-diazol-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate INT-63 as a light yellow oil. LCMS-ESI (m/z) calculated for C35H42F3N3O4SSi: 685.9; found 411.0 [M+H−tert-butyl 2-(tert-butyldimethylsilyloxy)ethylcarbamate]+, tR=4.01 min.
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[C:19]3[C:10]([NH:11][C:12]4[C:13]([C:22]([OH:24])=[O:23])=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]3=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(C)=O>[C:1]1([C:7]2[CH:20]=[C:19]3[C:10]([N:11]=[C:12]4[C:17](=[CH:18]3)[CH:16]=[CH:15][CH:14]=[C:13]4[C:22]([OH:24])=[O:23])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2c(=O)c3cc(-c4ccccc4)ccc3[nH]c12
Solvent: CC(C)=O
Product: O=C(O)c1cccc2cc3cc(-c4ccccc4)ccc3nc12
Yield: 69 %

Procedure:
Reduction of the known [Denny et al., J. Med. Chem., 1987, 30, 658] 7-phenyl-9-oxoacridan-4-carboxylic acid as above gave 7-phenylacridine-4-carboxylic acid (69%), mp (acetone) 239-241° C. 1H NMR [(CD3)2SO] δ 7.49 (t, J=7.3 Hz, 1 H, H-4'), 7.60 (t, J=7.3 Hz, 2 H, H-3' and H-5'), 7.86 (dd, J=8.4, 7.1 Hz, 1 H, H-2), 7.96 (d, J=7.3 Hz, 2 H, H-2' and H-6'), 8.43 (br s, 2 H, H-6 and H-8), 8.58 (dd, J=8.5, 1.2 Hz, 1 H, H-1), 8.64 (br s, 1 H, H-5), 8.74 (br d, J=7.1 Hz, 1 H, H-3), 9.56 (s, 1 H, H-9), 16.93 (br s, 1 H, COOH). Anal. (C20H13NO2) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]2[N:18]=[CH:19][C:20]([C:22]4[CH:23]=[C:24]([NH2:28])[CH:25]=[CH:26][CH:27]=4)=[CH:21][C:12]3=2)=[CH:5][CH:4]=1.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]2[N:18]=[CH:19][C:20]([C:22]4[CH:23]=[C:24]([NH:28][S:35]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)(=[O:37])=[O:36])[CH:25]=[CH:26][CH:27]=4)=[CH:21][C:12]3=2)=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(-c2ccc3[nH]c4ncc(-c5cccc(N)c5)cc4c3c2)cc1
Solvent: c1ccncc1
Product: COc1ccc(-c2ccc3[nH]c4ncc(-c5cccc(NS(=O)(=O)c6ccccc6)c5)cc4c3c2)cc1
Reaction time: 3 h
Yield: 50 %

Procedure:
To a solution of 3-(6-(4-methoxyphenyl)-9H-pyrido[2,3-b]indol-3-yl)benzenamine (23 mg, 0.06 mmol, 1 equiv.), in anhydrous pyridine (0.300 ml), benzenesulfonyl chloride (0.009 ml) is added under argon. The reaction is carried out at room temperature for 3 hours and is then quenched with H2O (5 ml). The aqueous layer is extracted with AcOEt (3×5 ml) and CH2Cl2 (5 ml). The organic layers are dried over MgSO4 and concentrated under reduced pressure. The crude product is purified over silica gel chromatography (eluant CH2Cl2/AcOEt 7:3) to afford the product as a white solid (15 mg, 0.03 mmol) in 50% yield.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].Cl[CH:6]([O:8][C:9]([O:11][CH:12]([CH3:20])[CH2:13][NH:14][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])=[O:10])[CH3:7]>C1COCC1>[C:1]([O:4][CH:6]([O:8][C:9]([O:11][CH:12]([CH3:20])[CH2:13][NH:14][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])=[O:10])[CH3:7])(=[O:3])[CH3:2]
Reactant: C=C(C)C(=O)NCC(C)OC(=O)OC(C)Cl
Reactant: CC(=O)[O-]
Solvent: C1CCOC1
Product: C=C(C)C(=O)NCC(C)OC(=O)OC(C)OC(C)=O
Reaction time: 96 h
Yield: 24.8 %

Procedure:
A THF solution (100 ml) of TBA acetate (6.93 g, 23 mmol), prepared by freeze-drying an aqueous solution of equimolar TBA-OH and acetic acid, was added to a stirred solution of N-[2-(1-chloroethoxycarbonyloxy)propyl]methacrylamide (4.736 g, 19 mmol) in THF (100 ml) at room temperature. Following stirring for 4 days the solvent was removed under reduced pressure and the residue was dissolved in chloroform (100 ml) and washed with water (5×20 ml). The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. Flash chromatography (silicagel, hexane/ethyl acetate (3:4)) gave 1.29 g (25%) of the title product.
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10](Cl)[N:9]=[C:8]([Cl:14])[N:7]=1)=[O:5]>O1CCOCC1>[CH3:2][O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([NH2:1])[N:9]=[C:8]([Cl:14])[N:7]=1)=[O:5]
Reactant: COC(=O)c1nc(Cl)nc(Cl)c1Cl
Reactant: N
Solvent: C1COCCO1
Product: COC(=O)c1nc(Cl)nc(N)c1Cl
Yield: 87 %

Procedure:
Ammonia was bubbled through a solution of 2,5,6-trichloro-pyrimidine-4-carboxylic acid methyl ester (15.94 g, 66 mmol, see H. Gershon, J. Org. Chem. 1962, 27, 3507-3510 for preparation) in p-dioxane (150 mL) for 30 minutes. The solvent was then removed and the residue partitioned between ethyl acetate and water. The organic phase was dried and concentrated under vacuum. The product was purified by column chromatography to provide 6-amino-2,5-dichloropyrimidine-4-carboxylic acid methyl ester (12.74 g, 87% yield): mp 164-166° C.
Reaction SMILES: [Mg].[CH2:2](Br)[CH:3]=[CH2:4].[F:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH:13]=[O:14])=[CH:9][CH:8]=1.S(=O)(=O)(O)O>CCOCC.C(Br)C=C>[F:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH:13]([OH:14])[CH2:4][CH:3]=[CH2:2])=[CH:9][CH:8]=1
Reactant: O=CCOc1ccc(F)cc1
Reactant: C=CCBr
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: C=CCC(O)COc1ccc(F)cc1
Yield: 77.2 %

Procedure:
To a mixture of ether (50 ml.) and magnesium turnings (4.49 g., 0.185 mole) is added a small amount of allyl bromide (ca. 0.5 g.). The mixture is stirred until Grignard reagent is formed (reflux of ether is a good sign). A solution of allyl bromide (24.2 g., 0.20 mole) and 4-fluorophenoxyacetaldehyde (19.0 g., 0.123 mole) in ether (110 ml.) is then added at such a rate as to maintain the reflux of ether. The resulting mixture is heated at reflux for another hour, cooled in an ice bath, and treated with dilute sulfuric acid (1.6 M, 70 ml.). The organic phase is separated and the aqueous phase is extracted with ether three times. The combined extracts are washed with 5% sodium bicarbonate, dried over anhydrous magnesium sulfate and finally concentrated on a rotary evaporator. The oil residue is vacuum distilled at 73° C./0.03 mm. to afford the desired product (18.6 g., 0.095 mole, 77%). ir (neat) 2.90, 3.22, 3.40, 6.05, 6.20, 6.62, 8.00, 8.25, 10.87, 12.10, 13.14μ; pmr (CCl4)δ2.32 (2H, t, J=6Hz), 2.54 (1H, m), 3.6-4.1 (3H, m), 4.8-5.05(1H, m), 5.05-5.25 (1H, m), 5.4-6.3 (1H, m), 6.6-7.1 (4H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:14][CH2:13]1.[C:29](Cl)(=[O:33])[CH2:30][CH2:31][CH3:32]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:16][CH2:17]1)[C:29](=[O:33])[CH2:30][CH2:31][CH3:32]
Reactant: CCC(=O)N(c1ccccc1)C1CCN(CCNc2c(C)cccc2C)CC1
Reactant: CCCC(=O)Cl
Product: CCCC(=O)N(CCN1CCC(N(C(=O)CC)c2ccccc2)CC1)c1c(C)cccc1C

Procedure:
Using the same procedure but starting from 1-[2-(2,6-dimethyl phenylamino)-ethyl]-4-(N-phenyl N-propionylamino) piperidine and butyroyl chloride, 1-[2-(N-(2,6-dimethyl phenyl) N-butyrylamino)-ethyl]-4-(N-phenyl N-propionylamino) piperidine is produced.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[CH2:14][CH2:13][NH:12]2)[CH2:10][CH2:9]1.CO.C=O.[C:28]([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[CH2:14][CH2:13][N:12]2[CH3:28])[CH2:9][CH2:10]1
Reactant: COc1cc2c(cc1C)CCNC2C1(c2ccccc2Cl)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc2c(cc1C)CCN(C)C2C1(c2ccccc2Cl)CC1
Reaction time: 0.25 h
Yield: 77.6 %

Procedure:
A mixture of 1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-6-methyl-1,2,3,4-tetrahydroisoquinoline (6.2 g), methanol (160 ml) and 37-40% aqueous formaldehyde solution was stirred for 15 minutes. Sodium cyanoborohydride (5.13 g) was added and the mixture was stirred for a further 10 minutes. The reaction was then neutralised with acetic acid and stirred for 45 minutes. The methanol was removed in vacuo and the residue treated with aqueous sodium hydroxide solution. The product was extracted with ethyl acetate. The extracts were washed with aqueous ammonia solution, water and brine, then dried over magnesium sulphate. Concentration yielded 1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-2,6-dimethyl-1,2,3,4-tetrahydroisoquinoline as a gum (5.02 g).
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)#[N:14].N12CCCN=C1CCCCC2.[ClH:34].C1(=O)NC(=O)C2=CC=CC=C12.O.NN>CN1C(=O)CCC1.C(O)C>[ClH:34].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:1][NH2:2])=[CH:17][CH:16]=1)#[N:14]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cl
Agent: NN
Agent: O=C1NC(=O)c2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Solvent: CCO
Product: N#Cc1ccc(CON)cc1
Temperature: 25 °C
Reaction time: 1.08 h

Procedure:
N-Hydroxyphthalimide (3.30 g, 20.2 mmol) was dissolved in NMP (50 ml) and 4-cyanobenzyl bromide (4.35 g, 22.2 mmol) was added followed by drop-wise addition of 1,8-diazabicyclo[5,4,0]-undec-7-ene (DBU) (3.0 ml, 20.1 mmol). After complete addition of DBU (ca. 15 min.) the reaction mixture was stirred at room temperature for 65 min. The mixture was poured into ice cooled 1M aqueous hydrochloric acid (500 ml) and the precipitated material was collected by filtration and washed with water and dried under high vacuum. This phthalimide derivative (5.31 g, 19.1 mmol) was suspended in ethanol (40 ml) and a solution of hydrazine monohydrate (0.93 ml, 19.1 mmol) in ethanol (10 ml) was added drop wise. The reaction mixture was heated to reflux and stirred for 2.5 hours. The mixture was cooled to room temperature and the solid material removed by filtration and washed with ethanol. The combined filtrates were evaporated under reduced pressure. The residue was resuspended in EtOAc and the undissolved material was removed by filtration. The EtOAc filtrate washed with saturated aqueous NaHCO3, and water, dried (MgSO4) and evaporated under reduced pressure. The residue was suspended in diethyl ether (150 ml) and concentrated hydrochloric acid (50 ml) was added and the resulting slurry was stirred at room temperature for 30 min. The precipitated product was isolated by filtration, washed with diethyl ether and dried in vacuo, affording the title compound (2.24 g) as a white powder. 1H-NMR (DMSO-d6) δ 11.26 (bs, 3H), 7.90 (d, 2H), 7.63 (d, 2H), 5.17 (s, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@:13]1([CH3:19])[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[CH:7]=[CH:6]2.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@:13]1([CH3:19])[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@]3(C)COC(=O)N3)ccc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(R)-4-(6-Methoxy-naphthalen-2-yl)-4-methyl-oxazolidin-2-one (215 mg, 0.836 mmol) was dissolved in methylene chloride (5.4 mL) and, at −78° C., 2.5 mL of 1.0 M boron tribromide in methylene chloride was added and was stirred under N2 to rt. After 5 h, TLC and LCMS showed no starting material (1.34, 213.92, 100%) but only product (1.02, 200.02, 100%). The reaction was quenched with water (10 mL) and extracted with ether (100 mL) and EtOAc (3×10 mL). The organic layer was washed with brine and dried over Na2SO4. After concentration, a white solid was obtained (200 mg, 99%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:2]1.[Si:14]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:29]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:2]1)(=[O:31])[CH3:30].[C:25]([Si:22]([O:21][Si:14]([CH3:16])([CH3:15])[C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: OCCCc1c[nH]c2ccccc12
Agent: CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)n1cc(CCCO)c2ccccc21

Procedure:
A solution of the indole 2 (29 g, 86 mmol), CH2Cl2 (450 mL), 1,8-diazobicyclo[5.4.0]undec-7-ene (38 mL, 0.26 mol), 4-dimethylaminopyridine (1.0 g, 8.5 mmol), and acetic anhydride (32 mL, 0.34 mol) was stirred for 1 week at ambient temperature. The reaction mixture was concentrated and then diluted with ether. The ether was then washed with H2O, 5% KHSO4 and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 5% ethyl acetate/hexanes) gave the acylated product 3 (27 g) as a yellow oil. TLC Rf=0.56 (20% ethyl acetate/hexanes).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]([CH2:10][CH:11]=[CH2:12])[CH2:8][OH:9])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=[N:3]1.[H-].[Na+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([O:9][CH2:8][CH:7]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[N+:13]([O-:15])=[O:14])[CH2:10][CH:11]=[CH2:12])[CH:19]=[CH2:18]
Reactant: C=CCC(CO)c1c([N+](=O)[O-])cnn1C
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCC(CC=C)c1c([N+](=O)[O-])cnn1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.6 %

Procedure:
To a solution of 2-(2-methyl-4-nitro-pyrazol-3-yl)pent-4-en-1-ol (91 mg, 0.43) in anhydrous DMF (5 mL) was added at 0° C. sodium hydride (20 mg, 0.49 mmol, 60 mass %). After stirring at 0° C. for 15 min, allyl bromide (79, 0.64 mmol) was added slowly, stirred at 0° C. for 10 min then warm to room temperature for 2 h. The reaction was quenched with water (10 ml) and extracted with EA (3×50 ml). Combined organic layer was washed with brine (10 ml) and concentrated to dryness. The residue was purified via silica gel chromatography (0-100% EtOAc/heptane) to afford 5-[1-(allyloxymethyl)but-3-enyl]-1-methyl-4-nitro-pyrazole (84 mg, 78%).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]([NH:15][C@@H:16]([CH2:24][NH:25]C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>FC(F)(F)C(O)=O.ClCCl>[NH2:25][CH2:24][C@H:16]([NH:15][C:13]([O:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)=[O:14])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCC12CC3CC(CC(C3)C1)C2)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCC12CC3CC(CC(C3)C1)C2
Yield: 93.7 %

Procedure:
A solution of 8.7 g (19.22 mmol) of tert-butyl (S)-2-(1-adamantylmethyloxycarbonylamino)-3-tert-butoxycarbonylamino-propionate in 180 ml of trifluoroacetic acid/dichloromethane (1:1) was added after 1 min to 1.5 l of ice-cold NaHCO3 solution, the mixture was extracted three times with dichloromethane and the dichloromethane phases were then dried over sodium sulfate. After filtration and removal of the solvent in vacuo, 6.35 g (94%) of tert-butyl (S)-3-amino-2-(1-adamantylmethyloxycarbonylamino)propionate were obtained as a colorless solid.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[CH:8]=[C:9]([Cl:26])[CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=[C:12]2[C:24]#[N:25])[CH3:6].[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2([CH2:50][OH:51])[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]2)=[CH:33][CH:32]=1>ClCCl>[Cl:26][C:9]1[CH:10]=[C:11]2[C:15](=[C:7]([CH:5]([O:51][CH2:50][C:37]3([C:34]4[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=4)[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[CH2:41][CH2:42]3)[CH3:6])[CH:8]=1)[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=[C:12]2[C:24]#[N:25]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2c(C#N)cn(COCC[Si](C)(C)C)c12
Solvent: ClCCl
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c(C#N)cn(COCC[Si](C)(C)C)c12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 38.1 %

Procedure:
Fluoroboric acid diethylether complex (0.015 g, 0.095 mmol) was added to a 0° C. solution of (±)-1-(5-chloro-3-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)ethyl 2,2,2-trichloroacetimidate (0.945 g, 1.907 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.59 g, 1.907 mmol) in Dichloromethane (10 mL) and was stirred for 20 min at 0° C. TLC indicated the reaction was complete, and the reaction was quenched with aqueous sodium bicarbonate (10 mL). The reaction was extracted with ethyl acetate (3×10 mL) and the organic phase was dried with MgSO4 and evaporated. The residue was purified by chromatography on SiO2 with 15%-20% ethyl acetate/hexanes to give (±)-tert-butyl 4-((1-(5-chloro-3-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (466 mg, 0.726 mmol, 38.0% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 7.60 (d, J=2.0 Hz, 1H), 7.49 (s, 1H), 7.15 (m, 2H), 7.05 (d, J=2.0 Hz, 1H), 6.94 (app t, J=8.6 Hz, 2H), 5.22 (m, 2H), 5.07 (m, 1H), 3.66 (m, 2H), 3.33 (app t, J=8.3 Hz, 2H), 3.22 (d, J=8.8 Hz, 1H), 3.11 (d, J=8.8 Hz, 1H), 3.02 (m, 2H), 2.07 (m, 2H), 1.79 (m, 2H), 1.42 (d, J=6.3 Hz, 3H), 0.65-0.90 (m, 2H), −0.08 (s, 9H).