Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=O.[OH-:13].[Na+].Cl.[CH3:16][C:17]([CH3:19])=O>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]=[C:17]([CH3:19])[CH:16]=[C:7]2[C:8]([OH:11])=[O:13]
Reactant: O=C1Nc2c(Br)cccc2C1=O
Reactant: [OH-]
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc(C(=O)O)c2cccc(Br)c2n1

Procedure:
A suspension of 7-bromoisatin (6.0 g) in acetone (27 ml) was treated with sodium hydroxide (4.6 g) in water (23 ml). The mixture was heated to reflux for 8 h, cooled and solvent reduced in volume at reduced pressure to approx. 25 ml. The residual aqueous phase was acidified with conc. HCl, extracted with ethyl acetate, the organic phase dried (MgSO4) and solvent removed at reduced pressure to give the title compound (7.2 g) as a yellow solid. 1H NMR δ: 2.85 (3H, s), 7.40 (1H, m), 7.90 (1H, s), 8.05 (1H, dd, J=1.2, 7.6 Hz), 8.79 (1H, dd, J=1.0, 8.5 Hz).
Reaction SMILES: [OH:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[Br:12]Br>C(Cl)(Cl)Cl>[CH3:11][O:10][C:8]([C:5]1[CH:4]=[N:3][C:2]([OH:1])=[C:7]([Br:12])[N:6]=1)=[O:9]
Reactant: COC(=O)c1cnc(O)cn1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cnc(O)c(Br)n1

Procedure:
A mixture of 2 g (13 mmol) methyl 5-hydroxypyrazine-2-carboxylate (commercially available), 0.192 g (0.65 mmol) FeBr3, 0.7 mL (14 mmol) Br2 in 20 mL CHCl3 was refluxed for 16 h. After evaporation of all volatiles the residue was used without further purification in the consecutive step.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:22][NH:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-:23].[Mn+2:24].[Cl-:25].[CH3:26]O>>[Cl:23][C:26]1([Cl:25])[CH2:22][NH:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][N:9]1[CH2:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[Mn+2:24]
Reactant: CO
Reactant: C1CCC(CC2CNCCNCCNCCNCCN2)CC1
Reactant: [Cl-]
Agent: [Mn+2]
Product: ClC1(Cl)CNCCNCCNCCNCCN1CCC1CCCCC1
Temperature: 0 °C
Yield: 65 %

Procedure:
A solution of 2-cyclohexylmethyl-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 7A (0.43 g, 1.4 mmole) and anhydrous manganese(II) chloride (0.17 g, 1.4 mmole) in anhydrous methanol (30 ml) was refluxed under a dry nitrogen atmosphere overnight. The solution was filtered and concentrated in vacuo to a volume of 3 ml. Ethyl ether (20 ml) was added. Upon cooling to 0° C., 0.39 g (65% yield) of the product was obtained as a white solid: FAB mass spectrum (NBA) m/z (relative intensity) 401/403 [(M-Cl)+, 100/33]: Anal. Calcd. for C17H37Cl2MnN5 : C, 46.69; H, 8.53; N, 16.09. Found: C, 45.87; H, 8.40; N, 15.55.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[NH:12][N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=1)=[O:7].C(N(CC)C(C)C)(C)C>C(#N)C>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:9]=[C:8]2[C:6](=[O:7])[NH:5][CH2:4][CH2:3][CH2:2][N:12]2[N:11]=1
Reactant: O=C(NCCCBr)c1cc(C(F)(F)F)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1NCCCn2nc(C(F)(F)F)cc21

Procedure:
A mixture of 400 mg (1.33 mmol) of N-(3-bromopropyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide, 350 mL (2 mmol) of N,N-diisopropylethylamine, and 8 mL of acetonitrile was stirred at reflux for 4.5 h. The cooled reaction mixture was concentrated, and the residue was flash chromatographed on silica gel [0-10% of (9:1 methanol:concentrated ammonium hydroxide) in dichloromethane]. Further purification by preparative HPLC (C18 reverse phase column, 10-50% acetonitrile in water containing 0.05% trifluoroacetic acid) separated the product from a major by-product, 2-[3-(trifluoromethyl)-1H-pyrazol-5-yl]-1,3-oxazinane, to give the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1.[O:19]1[CH2:21][CH:20]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:21][CH:20]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[OH:19])[C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: c1cncc(C2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(n(CC(O)c3cccnc3)c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.3 %

Procedure:
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (92 mg, 3.83 mmol) in 5 mL of DMF, 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.3 g, 1.27 mmol) was added and stirred at RT for 5 min. 3-(Oxiran-2-yl)pyridine (232 mg, 1.92 mmol) in DMF (5 mL) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture quenched with ice water, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by reverse phase chromatography to afford 250 mg of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-3-yl)ethanol as the TFA salt.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)=[O:10])=[C:4]([Cl:19])[CH:3]=1.I[CH3:21]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:21])[C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)=[O:10])=[C:4]([Cl:19])[CH:3]=1
Reactant: Cn1cc(C(=O)Cc2ccc(Br)cc2Cl)ccc1=O
Reactant: CI
Product: CC(C(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1Cl

Procedure:
In analogy to Example 1, steps 4 and 5, 5-[2-(4-bromo-2-chloro-phenyl)-acetyl]-1-methyl-1H-pyridin-2-one was alkylated with iodomethane to give 5-[2-(4-bromo-2-chloro-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one which was further converted to the title compound. Colorless foam. MS (m/e, ISP neg. ion)=421.8 [M−H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[CH2:10][C:11]([O:13][CH3:14])=[O:12].O.O.O.C([O-])(=O)C.[Na+].CO>O>[CH3:14][O:13][C:11](=[O:12])[CH2:10][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Br:1])[CH:3]=1
Reactant: COC(=O)CCl
Reactant: Nc1cccc(Br)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CNc1cccc(Br)c1

Procedure:
A mixture of 3-bromoaniline (88.6 g), methyl chloroacetate (44 ml), sodium acetate trihydrate (114 g) and methanol (70 ml) was heated under reflux for 18 h. The mixture was poured into water (500 ml) and extracted with dichloromethane (3×250 ml). The combined, dried organic extracts were evaporated and the residue was treated with 10% concentrated sulphuric acid in methanol (250 ml). After 3 h the solution was poured carefully into 8% sodium bicarbonate (1200 ml). The resulting solid was filtered off, dissolved in dichloromethane (1000 ml), and this solution was dried and evaporated to give a solid (94 g). A portion of this solid (1 g) was purified by FCC eluting with System A (1:1) to give a semi-solid which was recrystallised from System A to give the title compound, m.p. 66°-68°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[C:34]([F:36])[CH:35]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[S:37]([C:32]2[CH:31]=[C:30]([F:29])[CH:35]=[C:34]([F:36])[CH:33]=2)(=[O:39])=[O:38])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(S(=O)(=O)c4cc(F)cc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure VII as described above, the sulphonylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 3,5-difluorobenzenesulfonyl chloride gave the title compound. ES-MS m/e (%): 575.3 (M+H+).
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[C:8]=1Cl)(=[O:6])=[O:5])[CH3:2].[H-].[Na+].[OH2:20]>>[CH2:1]([NH:3][S:4]([C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[C:8]=1[OH:20])(=[O:6])=[O:5])[CH3:2]
Reactant: CCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-ethyl-2,6dichloro-3-nitrobenzenesulfonamide (1.16 g, 3.88mmol), 60% NaH (466 mg, 11.64 mmol) and water (70 μL, 3.88 mmol) were reacted. The crude product (1.34 g) was carried on to the next step without purification. 1H NMR (MeOD-d4): δ 8.07 (d, 1H), 7.25 (d, 1H), 3.05 (q, 2H), 1.12 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]([CH3:18])=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:16]([CH3:18])[CH3:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 72.7 %

Procedure:
t-Butyl-piperidin-4-ylcarbamate (3 g, 15 mmol) obtained in Preparation Example 2-ii was dissolved in methanol (30 ml) in a 100 ml vessel, and acetone (7.70 ml, 105 mmol) and acetic acid (0.45 ml, 7.5 mmol) were added thereto while stirring. To the resulting mixture, NaCNBH3 (1.88 mg, 30 mmol) was added dropwise in 4-divided portions and reacted for 18 hrs. After the completion of reaction, ice water was poured to the reaction product while stirring, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with an aqueous sodium bicarbonate solution and brine in order, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 2.644 g of the title compound as a white solid (yield 73.3%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][CH:18]([CH3:20])[CH3:19])=[C:15]([C:21]([OH:23])=O)[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:27]2N(O)N=[N:30][C:28]=2[CH:29]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:28]1([NH:30][C:21]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:8]=[CH:7][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=3)[C:16]=2[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:23])[CH2:29][CH2:27]1
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CC(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CC(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 194.8 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-isobutyl-1H-1,2,3-triazole-4-carboxylic acid (510 mg, 1.61 mmol) obtained in Example 93b), HOBt (110 mg, 0.806 mmol, 0.5 eq.) and cyclopropylamine (0.150 ml, 2.10 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 8.0 ml), WSC (378 mg, 1.93 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate-hexane (4:1, 50 ml) and washed with 2% aqueous sodium carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (2:1, 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and ethyl acetate and diethyl ether were added to the residue. The precipitate was collected by filtration, washed with ethyl acetate-diethyl ether (1:3) and diethyl ether and dried to give the title compound as a white powder (559 mg, 1.57 mmol, 98.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([N:7]([CH3:11])[C:8](=[O:10])[CH3:9])=[CH:5][CH:4]=1.C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH2:34]([N:41]1[CH2:46][CH2:45][C:44](=[O:47])[CH2:43][CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O.O1CCCC1>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([N:7]([CH3:11])[C:8](=[O:10])[CH2:9][C:44]2([OH:47])[CH2:45][CH2:46][N:41]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:42][CH2:43]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N(C)C(C)=O)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N(C)C(=O)CC2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
A solution of 4′-methoxy-N-methylacetanilide (12 g) in an anhydrous tetrahydrofuran (30 mL) was added to a solution in an anhydrous tetrahydrofuran (100 mL) of lithium diisopropylamide prepared from diisopropylamine (10.5 mL) and n-butyl lithium (1.53M hexane solution; 48 mL) at below −65° C., and the mixture was stirred at −78° C. for 15 minutes. An anhydrous tetrahydrofuran solution (20 mL) of 1-benzylpiperidin-4-one (12.7 g) was then added to this reaction mixture at below −65° C., and the resulting mixture was stirred at −78° C. for 10 minutes. After increasing the temperature to room temperature, water was added to the mixture, and the mixed solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. The residue obtained was recrystallized from ether-hexane to obtain the titled compound (17.2 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:14])OCC(Cl)(Cl)Cl)=[N:2]1.[C:15]1([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]([N:29]2[CH2:30][CH2:31][N:26]([C:24]3[S:23][N:22]=[C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:25]=3)[CH2:27][CH2:28]2)=[O:14])=[N:2]1
Reactant: O=C(Nc1ccon1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccon1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 18.8 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl isoxazol-3-ylcarbamate (192 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 49.5 mg (18.8%) of the desired product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[Cl:9].[N+:10]([O-])([OH:12])=[O:11]>>[Br:1][C:2]1[C:3]([Cl:9])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([Cl:8])[CH:7]=1
Reactant: Clc1ccc(Cl)c(Br)c1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc(Cl)c(Br)cc1Cl
Temperature: 0 °C
Yield: 95 %

Procedure:
A solution of 2-bromo-1,4-dichlorobenzene (1.000 g, 4.443 mmol, Aldrich, used as received) in fuming HNO3 (7.0 mL) was stirred at 50° C. for 1.5 h and poured into ice (80 g). The yellowish precipitate was filtered, washed with water (10 mL) and dried under vacuum to give 1.14 g (95%) of pure title compound as a yellowish powder; m.p. 50°-53° C.; 1H NMR (CDCl3): 7.863 (s, 1H), 8.030 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].CI.[C:26](OCC)(=O)C>CN(C=O)C.[Ag-]=O>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][CH3:26])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CCOC(C)=O
Agent: O=[Ag-]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 14 %

Procedure:
(3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester (100 mg, 0.32 mmol) was dissolved in DMF (3 mL). Then, molecular sieves (4 A), silver(I)oxide (355 mg, 1.53 mmol) and methyl iodide (0.40 ml, 6.38 mmol) was added and the black suspension stirred at room temperature for 48 hour. The reaction mixture was filtrated through celite and the filtrate evaporated. The crude yellow residue was subjected to silica gel flash chromatography (ISCO Companion CombiFlash; 40 g Gold silica gel cartridge, heptane/ethyl acetate gradient; ethyl acetate: 2% (2 min), 2-20% (3 min), 20% (8 min), 20-30% (2 min), 30% (8 min), 30-50% (3 min) and 50% (8 min) to yield (3aR,4S,7aR)-4-methoxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester (15 mg, 0.04 mmol, 14% yield) as colorless oil. MS [2M+Na]677; RT=8.147 min HPLC Method III
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH2:9][C:10]([C:12]2([CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:37][NH2:38]>C(O)C>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][C:12]([CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])([C:10]2[NH:38][N:37]=[C:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:9]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO[Si](C)(C)C(C)(C)C)(C(=O)CC(=O)Cc2ccccc2)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CCO[Si](C)(C)C(C)(C)C)(c2cc(Cc3ccccc3)n[nH]2)CC1
Temperature: 85 °C
Yield: 71.5 %

Procedure:
To a solution of tert-butyl 4-(4-phenyl-1,3-dioxobut-1-yl)-4-(2-(tert-butyldimethylsilyloxy)eth-1-yl)piperidine-1-carboxylate (343 mg, 0.68 mmol) from Step G in ethanol (7 mL) was added hydrazine hydrate (0.040 mL, 0.82 mmol). The reaction was heated at 85° C. for 3 h and was then concentrated in vacuo. The residue was purified by flash chromatography (30% ethyl acetate in hexanes) to afford the title product (243 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:30](O)[CH3:31]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH2:30][CH3:31])=[O:16])=[CH:18][CH:19]=1
Reactant: CCO
Reactant: O=C(O)c1ccc(CCCc2ccccc2Br)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(CCCc2ccccc2Br)cc1
Reaction time: 40 h

Procedure:
To a solution of 4-[3-(2-bromophenyl)propyl]benzoic acid (2.0 g) in a mixture of chloroform (50 ml) and ethanol (50 ml) was added dropwise, with stirring, concentrated sulphuric acid (98% w/v, 5.0 ml) and the resulting solution allowed to stand for 40 hours at 20° C. The solution was poured onto a stirred mixture of chloroform (100 ml) and saturated sodium bicarbonate. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated to give ethyl 4-[3-(2-bromophenyl)propyl)benzoate (2.3 g).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([OH:30])([C:9]2[S:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:11][CH:10]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: c1ccc(-c2cccs2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(-c3ccccc3)s2)CC1
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 76.4 %

Procedure:
To a solution of 2-phenylthiophene (1.35 g, 9.1 mmol) in tetrahydrofuran (40 ml) at -40° C. under a nitrogen atmosphere was added a solution of n-butyllithium (1.6M in hexanes, 6 ml, 95 mmol) keeping the temperature below -40° C. The reaction was stirred at -40° C. for 10 minutes, allowed to warm to 0° C. and stirred at 0° C. for 30 minutes. The reaction was cooled to -78° C. and a solution of 1-tert-butoxycarbonyl-4-piperidone (1.8 g, 9.1 mmol) in tetrahydrofuran (20 ml) added, keeping the temperature below -50° C. When addition was complete, the reaction was stirred at -60° C. for 30 minutes and at room temperature for 1 hour. The reaction was cooled to 0° C. and quenched by addition of saturated aqueous ammonium chloride (10 ml), poured into water (100 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo to an oil. Purification by chromatography on silica eluting with ethyl acetate/hexane (1:2) gave the title compound as a foam, (2.5 g, 76%). δH (CDCl3) 1.41 (9H, s, OC(CH3)3), 1.84-1.97 (2H, m, piperidinyl H), 2.36 (1H, t, J 9.0 Hz, piperidinyl H), 3.20-3.28 (2H, m, piperidinyl H), 3.64 (1H, t, J 8.9 Hz, piperidinyl H), 3.82 (2H, m, piperidinyl H), 6.86-6.91 (1H, m, ArH), 7.09 (1H, m, ArH), 7.09 (1H, d, J 5.3 Hz, ArH), 7.16-7.33 (3H, m, ArH), 7.46-7.51 (2H, m, ArH).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17]2.C(N(C(C)C)CC)(C)C.[CH2:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][NH:40]1>ClCCl>[CH2:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][N:40]1[C:5]([NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17]2)=[O:11]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(N)cc2C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1ccc2c(c1)CNC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2ccc(NC(=O)N3Cc4ccccc4C3)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 250 mL round bottom flask was mixed at room temperature triphosgene (234 mg, 0.790 mmol) in anhydrous dichloromethane (25 mL). To this solution was added dropwise over 15 minutes, a slurry of tert-butyl 5-aminoisoindoline-2-carboxylate (500 mg, 2.134 mmol) and diisopropylethylamine (0.410 ml, 2.347 mmol) in anhydrous dichloromethane (20 mL). The mixture was stirred overnight at room temperature. A solution of isoindoline (0.242 ml, 2.134 mmol) and diisopropylethylamine (0.410 ml, 2.347 mmol) in anhydrous dichloromethane (20 mL) was added in one portion. The reaction stirred overnight at room temperature. The solvent was removed and the residue was purified by normal phase flash chromatography to provide the title compound.