Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:9](=[O:11])N(CCCCCCCC)[C:7](=[O:20])[C:6]=2[C:5]([NH2:21])=[C:4]2[C:22](=[O:31])[C:23]3[C:28]([C:29](=[O:30])[C:3]=12)=[CH:27][CH:26]=[CH:25][CH:24]=3.[OH:32]S(O)(=O)=O.O=S(=O)=O.NC1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C(N)=C(C#N)C=1C#N>>[NH2:21][C:5]1[C:4]2[C:22](=[O:31])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29](=[O:30])[C:3]=2[C:2]([NH2:1])=[C:10]2[C:9]([O:32][C:7](=[O:20])[C:6]=12)=[O:11]
Reactant: O=S(=O)(O)O
Reactant: CCCCCCCCn1c(=O)c2c(N)c3c(=O)c4ccccc4c(=O)c3c(N)c2c1=O
Agent: N#Cc1c(N)c2c(c(N)c1C#N)C(=O)c1ccccc1C2=O
Agent: O=S(=O)=O
Product: Nc1c2c(=O)oc(=O)c2c(N)c2c(=O)c3ccccc3c(=O)c12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
(B-Cyan-4) Synthesis of 4,11-diamino-2-n-octyl-1H-naphth[2,3-f] isoindole-1,3,5,10(2H)-tetrone cyan dye. To 120 grams of 15 percent oleum (fuming sulfuric acid having 15 percent sulfur trioxide), 10.0 grams of 1,4-diamino anthraquinone-2,3-dinitrile were added at 30° C. and the mixture stirred for two hours. This reaction mixture was poured into 1,000 grams of ice water and the precipitates were filtered. The wet precipitates were added to 400 grams of cooled water and dissolved by the addition of sodium hydroxide, followed by adjusting pH to 12.5. The temperature was now raised to 100° C. and maintained for two hours. After that period, 20 grams of 50 percent sulfuric acid were added to the mixture and heating was continued for another one hour. The precipitate of 1,4-diamino anthraquinone-2,3-dicarboxylic acid anhydride thus obtained was collected by filtration, washed with water and dried. 3.2 Grams of 1,4-diamino anthraquinone-2,3-dicarboxylic acid anhydride (0.01 mole), 3.2 grams (0.025 mole) of n-octyl amine, and 50 milliliters of methanol were added to a 100 milliliter round-bottom flask equipped with a condenser and the contents refluxed for a period of 24 hours. The reaction mixture was cooled, filtered and washed twice with methanol (100 milliliters each time). The reaction product was dried in air to obtain 4,11-diamino-2-n-octyl-1H-naphth[2,3-f] isoindole-1,3,5,10(2H)-tetrone cyan dye.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C@@H:7]3[CH2:12][CH2:13][N:14](CC4C=CC=CC=4)[CH2:15][C@H:6]3[C:5]=2[CH:4]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C@@H:7]3[CH2:12][CH2:13][NH:14][CH2:15][C@H:6]3[C:5]=2[CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)[C@@H]1CN(Cc3ccccc3)CC[C@H]1N2
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)[C@@H]1CNCC[C@H]1N2
Yield: 77.8 %

Procedure:
A mixture of intermediate 8 (11.3 g) in methanol (250 ml) was hydrogenated with palladium-on-carbon (10%, 2 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was solidified in DIPE (30 ml). The precipitate was filtered off and dried, yielding 6.1 g (78%) of (±)-trans-2,3,4,4a,5,9b-hexahydro-8-methoxy-1H-pyrido[4,3-b]indole (intermediate 10).
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15]([N:23]=[C:24]=[O:25])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.[H-].[Na+].Cl>CN(C)C=O.O>[F:11][C:12]([F:26])([F:27])[C:13]1[CH:14]=[C:15]([NH:23][C:24]([CH:3]2[C:4](=[O:9])[CH:5]3[CH2:8][CH:1]([CH2:7][CH2:6]3)[C:2]2=[O:10])=[O:25])[CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CC(=O)C2CCC1C2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1C(=O)C2CCC(C2)C1=O

Procedure:
A solution of bicyclo[3,2,1]octane-2,4-dione (0.34 g, 2.5 mmole), 3,5-bis(trifluoromethyl)phenyl isocyanate (0.86 ml, 5.0 mmole), and 60% sodium hydride in mineral oil (0.11 g, 2.75 mmole) in dimethylformamide (100 mL) was stirred at 0° C. for 1 hour and heated at 45–50° C. under nitrogen for 24 hours. After cooling, the mixture was diluted with H2O and treated with 2N aqueous HCl until the mixture was clear. The clear solution was then extracted with dichloromethane. The organic layer was washed with H2O again, dried over anhydrous magnesium sulfate, and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel (30% dichloromethane/hexane) to give a clear oil as the expected product. The oily product was crystallized by triturated with hexane in a dry ice bath and collected at room temperature to give the title compound as a white solid, mp=88–90° C.; (−) ESI m/z=392 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])=[O:24])=[CH:21][CH:20]=1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2cccc(C(=O)C3CCN(C)CC3)c2)cc1
Yield: 101 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 4-methoxybenzoyl chloride (117 mg, 0.687 mmol), 81.5 mg (>100%) of the title compound were recovered.
Reaction SMILES: B1(C)[O:8][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H]2N1CCC2>C1(C)C=CC=CC=1.C(Cl)Cl.C1COCC1>[CH:20]1([CH2:15][C@@H:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[OH:8])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O[C@@H](CC1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
A solution of 2.7 mL of 1.0 M (R)-2-methyl-CBS-oxazaborolidine solution in toluene in 4 mL of CH2Cl2 at −25 °C. was treated with 1.4 mL of 2.0 M borane methyl sulfide complex in THF and stirred cold for 10 min. A solution of 501 mg (2.66 mmol) of cyclopentylmethylene phenyl ketone (from Step B) in 2 mL of CH2Cl2 was added over 25 min and the resulting mixture was stirred cold for an additional 45 min. The reaction was quenched by pouring it into cold (−25° C.) MeOH. The quenched reaction was warmed to rt and stirred for 45 min until gas evolution ceased. The mixture was concentrated and the residue dissolved in 20 mL of MeOH and concentrated again. Flash chromatography on silica gel using 17:3 v/v hexanes/EtOAc afforded 413 mg (81%) of the title compound: RF: 0.53 (4:1 v/v hexanes/ EtOAc); 1H NMR (300 MHz): δ1.10-1.17 (m, 2H), 1.47-1.89 (m, 9H), 4.69 (m, 1H), 7.25-7.35 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[Cl:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17]Cl>>[Cl:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[C:5]([I:11])=[N:6]1
Reactant: Clc1ccc2[nH]nc(I)c2c1
Reactant: ClCCOCCCl
Product: ClCCOCCn1nc(I)c2cc(Cl)ccc21
Yield: 54 %

Procedure:
The title compound was prepared from 5-chloro-3-iodo-indazole and bis(2-chloroethyl)ether in 54% yield according to the general procedure for Preparation 11A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 3.47 (2H, t, J=5.2 Hz), 3.60 (2H, t, J=5.2 Hz), 3.92 (2H, t, J=5.2 Hz), 4.56 (2H, t, J=5.2 Hz), 7.37 (1H, dd, J=2.0, 9.2 Hz), 7.44-7.46 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][C:24]([OH:26])=O)[N:22]=1)=[CH:5]2.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[N:22]=1)=[CH:5]2
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCOCC4)c3[nH]2)=N1
Reactant: C1COCCN1
Product: O=C(C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCOCC4)c3[nH]2)=N1)N1CCOCC1
Yield: 68 %

Procedure:
The compound (44 mg, 0.11 mmol) prepared in Example 31 and morpholine instead of methylamine were reacted according to the same procedure as Example 82 to give the title compound (35 mg, Yield 68%).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[C:15]([S:16]([CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])(=[O:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:8][CH2:9][C:10]1[C:15]([S:16]([CH2:19][C:20]([OH:23])([CH3:21])[CH3:22])(=[O:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(O)CS(=O)(=O)c1cccnc1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(O)CS(=O)(=O)c1cccnc1CN

Procedure:
A solution of 121 mg (0.35 mmol) 2-tert-butoxycarbonylaminomethyl-3-(2-hydroxy-2-methylpropanesulfonyl)pyridine, 10 mL 4M HCl/dioxane and 5 mL methanol was stirred at room temperature for 2 hours. The reaction was evaporated to dryness. The residue was treated with triethylamine and purified by chromatography on SiO2 using 0:100 to 5:95 methanol-chloroform yielding a yellow oil: 1H NMR (CDCl3): δ1.44 (s, 6H), 3.56 (s, 2H), 4.41 (s, 2H), 7.43 (dd, 1H), 8.32 (dd, 1H), 8.79 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C@H:12]([CH2:16][CH3:17])[C:13]([OH:15])=[O:14])[CH2:7][CH2:6]2.[C:18]([O-])(O)=O.[Na+].CI.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C@H:12]([CH2:16][CH3:17])[C:13]([O:15][CH3:18])=[O:14])[CH2:7][CH2:6]2
Reactant: CC[C@H](C(=O)O)[C@@H]1CCc2cc(OC)ccc21
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H](C(=O)OC)[C@@H]1CCc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
A suspension of acid prepared in Example 4 (220.0 g, 0.94 mol), NaHCO3 (237.0 g, 2.82 mol), CH3I (200 g, 1.41 mol) in 2.0 L DMF was stirred under Ar at rt for 18 hours. NMR analysis showed 95% reaction. Adding CH3I (100 g), and stirring for additional 24 hours at rt caused completion of the reaction. The reaction mixture was poured into 4.0 L water, and extracted with EtOAc (2×2 L). The organic layer was sequentially washed with water (2×1 L), 1 L of 1N NaOH solution, water (2×1 L), and 500 mL brine, and dried over Na2SO4. The product (233 g, 99%) was obtained as a light yellow oil after solvent removal and vacuum drying. 1H NMR (DMSO-d6) δ 6.90(d, 1H), 6.78(d, 1H), 6.66(dd, 1H), 3.70(s, 3H), 3.60(s, 3H), 3.20(m, 1H), 2.80(m, 2H), 2.40(m, 1H), 2.08(m, 1H), 1.80(m, 1H), 1.58(m, 1H), 1.40(m, 1H), 0.80(t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:19]([CH3:22])=[N:20][O:21][C:11]=3[CH:10]([NH2:23])[N:9]=2)=[CH:4][CH:3]=1.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25].C(N(CC)CC)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:19]([CH3:22])=[N:20][O:21][C:11]=3[CH:10]([NH:23][C:27]([NH:26][CH2:24][CH3:25])=[O:28])[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=NC2N
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)NC1N=C(c2ccc(Cl)cc2)c2ccccc2-c2c(C)noc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To a round bottomed flask was added 6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-amine (218 mg, 0.67 mmol). The flask was purged with nitrogen, MeCN was added (7 mL), and the solution was cooled to 0° C. Ethyl isocyanate (128 μL, 1.62 mmol) and triethylamine (244 μL, 1.75 mmol) were added and the reaction was allowed to warm to ambient temperature and stirred for 2 h. The reaction was quenched with a 1:1 mixture of sat. aq. NaHCO3:brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated and purified on a Biotage (isocratic elution 40% EtOAc: 60% Hexanes) to provide the title compound as white solid (220 mg). LC/MS m/z 395 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2=[CH:13][S:14][CH:15]=[C:4]2[C:3]1=[O:16].[C:17](Cl)(=[O:19])[CH3:18]>C1C=CC=CC=1>[C:17]([N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:16])[C:4]2=[CH:15][S:14][CH:13]=[C:5]12)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: CN1C(=O)c2cscc2Nc2ccccc21
Solvent: c1ccccc1
Product: CC(=O)N1c2cscc2C(=O)N(C)c2ccccc21
Reaction time: 3 h

Procedure:
A mixture of 7 g. of 4,9-dihydro-9-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2.7 g. of acetyl chloride in 75 ml. of benzene is heated under reflux with stirring for 3 hours. The reaction mixture is cooled in an ice bath and two crops of brown crystals are collected, washed with benzene, dried and combined. Concentration of the benzene provides a third crop which is combined with the first two crops, heated to boiling in 250 ml. of ethyl acetate and filtered while hot. An equal amount of hexane is added, the mixture is cooled and the solid is collected, washed with hexane and dried, giving the desired product, mp. 197°-199° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1F)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][CH:6]2[C:16]([O:18][CH3:19])=[O:17])#[N:2].C([O-])([O-])=O.[K+].[K+].[Cl:26][C:27]1[CH:44]=[CH:43][C:30]([CH2:31][CH2:32][NH:33][C:34](=[O:42])[C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)=[CH:29][CH:28]=1>CN1CCCC1=O>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][CH2:32][NH:33][C:34]([C:35]2[CH:40]=[CH:39][C:38]([O:41][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:7][C:8]([CH3:15])([CH3:14])[O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:37][CH:36]=2)=[O:42])=[CH:43][CH:44]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Reactant: COC(=O)C1CC(C)(C)Oc2cc(F)c(C#N)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)C1CC(C)(C)Oc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3)c(C#N)cc21
Temperature: 110 °C
Yield: 5.4 %

Procedure:
Methyl 6-cyano-7-fluoro-2,2-dimethylchroman-4-carboxylate (19 mg, 0.072 mmol) was diluted with N-methylpyrrolidone (2 mL) followed by the addition of K2CO3 (25 mg, 0.18 mmol) and N-(4-chlorophenethyl)-4-hydroxybenzamide (20 mg, 0.072 mmol). The reaction was bubbled with argon for 10 minutes and then heated at 110° C. for 6 hours. After cooling, the reaction mixture was loaded directly onto a Biotage 25 column and eluted with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield the title compound (2.0 mg, 5.3% yield).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C:8]1([C:21](OC)=[O:22])[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1>C1COCC1>[NH2:7][C:8]1([CH2:21][OH:22])[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1
Reactant: COC(=O)C1(N)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC1(CO)CCN(Cc2ccccc2)CC1
Temperature: 0 °C

Procedure:
To a 1 L 4-neck round bottom flask was added LAH (9.42 g, 248 mmol) in dry THF (1000 mL) and the reaction mixture was cooled to 0° C. A solution of methyl 4-amino-1-benzylpiperidine-4-carboxylate (47.0 g, 165 mmol) in dry THF (250 ml) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was cooled to 0° C. and quenched with water and filtered. The solid was washed with 50 ml of ethyl acetate. The organic layer of the filtrate was separated, washed with 2×200 ml portions of water and 200 ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [NH2:1][C@@:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH:17]3[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:18]3)[CH:12]=2)[CH:7]=1)([CH3:5])[CH2:3][OH:4].[OH-].[Li+].C(O)C.O>>[NH2:1][C@@:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C@H:17]3[CH2:18][CH2:19][C@H:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22]3)[CH:12]=2)[CH:7]=1)([CH3:5])[CH2:3][OH:4]
Reactant: CCCCC1CCC(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCC[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1

Procedure:
The mixture of carbamate (Example 7; 360 mg 0.00094 mol, cis and trans mixture) and lithium hydroxide (248 mg, 0.0104 mol) in ethanol (6.0 mL, 0.10 mol) and water (2.0 mL, 0.11 mol) was heated to reflux for overnight. LCMS showed reaction completed. The solvent was removed under vacuum and the residue was partitioned between water/CH2Cl2. The aqueous layer was extensively extracted with CH2Cl2. The combined organic phase was dried over Na2SO4. The concentrated residue was taken up into DCM and subjected to chromatographic purification with CH2Cl2/MeOH (10:90 to 80:20) to give the product (220 mg, 66%). Separation on ChiralPak-ADH (5μ, 4.6 mm×250 mm, 2 mL/min, 25% (0.3% DEA in MeOH) in CO2, 100 bar, 36° C.) gave peak 1, Rf=8.373 min, 87 mg (87.9% yield, 96.4% ee), and peak 2, Rf=12.479 min, 74 mg (74.7% yield, 97.0% ee). Peak 1 was purified on Si gel (0-100% MeOH/DCM) to give 26.2 mg; peak 2 was purified on Si gel (0-100% MeOH/DCM) to give 44.3 mg. LCMS 339.71 ([M−NH2]+, 100%). 1H NMR (400 MHz, CD3OD) δ ppm 0.93 (t, J=6.9 Hz, 3H), 1.14 (ddd, J=14.7, 13.4, 3.0 Hz, 2H), 1.24-1.39 (m, 7H), 1.45 (ddd, J=14.7, 12.5, 3.3 Hz, 2H), 1.56 (s, 3H), 1.89 (br d, J=13.0 Hz, 2H), 2.22 (brd, J=12.5 Hz, 2H), 3.70 (d, J=10.9 Hz, 1H), 3.76 (d, J=10.9 Hz, 1H), 4.37 (m, 1H), 7.11 (dd, J=9.0, 2.6 Hz, 1H), 7.21 (d, J=2.5 Hz, 1H), 7.55 (dd, J=8.7, 2.0 Hz, 1H), 7.74 (d, J=6.6 Hz, 1H), 7.76 (d, J=6.9 Hz, 1H), 7.84 (d, J=1.9 Hz, 1H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Li]CCCC.[C:12](=[O:14])=[O:13].CC(C)=O>C1COCC1>[C:12]([OH:14])(=[O:13])[C:3]1[CH:2]=[CH:1][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCC
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=C(O)c1ccccc1
Reaction time: 0.5 h

Procedure:
After the inside of a 2-liter four-necked flask equipped with a magnetic stirrer, dropping funnel, 3-way cock and thermometer was replaced with nitrogen gas, the flask was charged with 117 ml (0.55 mol) of HN(Si(CH3)3)2 and 200 ml of TFE. After cooling in dry ice/acetone bath, 328 ml (0.525 mol) of 1.6 N hexane solution of n-BuLi was added dropwise over 45 minutes so that the solution temperature did not exceed −50° C. Further after stirring for 30 minutes, thereto was added dropwise over 45 minutes a solution prepared by dissolving, in 200 ml of THF, 136 g (0.5 mol) of benzoic acid (1,1,1,3,3,3-hexafluoro-2-propyl) obtained by usual preparation process so that the solution temperature did not exceed 50° C., followed by 30-minute stirring. 300 Gram of ice and 150 ml of concentrated hydrochloric acid were put in a 3-liter beaker, followed by stirring, and to the obtained slurry was added the reaction solution gradually. Then an organic layer was separated in the dropping funnel and water layer was extracted two times with 300 ml of n-hexane. The organic layer obtained by two extractions was washed with saturated brine, followed by drying with MgSO4, concentrating with an evaporator and refining by distillation under reduced pressure. Thereby 107.3 g of benzoic acid (1, 1,1,3,3-pentafluoro-2-propenyl) was synthesized (boiling point: 71° to 73° C./24 mmHg).
Reaction SMILES: C(OC([N:11]([CH2:28][C:29]([N:31]1[CH2:35][C@@H:34]([F:36])[CH2:33][C@H:32]1[C:37]#[N:38])=[O:30])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([N:22]3[CH2:27][CH2:26]C[CH2:24][CH2:23]3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=O)C1C=CC=CC=1.[H][H]>C(O)C.ClCCl.[C].[Pd]>[N:22]1([C:20]([C:15]23[CH2:18][CH2:19][C:12]([NH:11][CH2:28][C:29]([N:31]4[CH2:35][C@@H:34]([F:36])[CH2:33][C@H:32]4[C:37]#[N:38])=[O:30])([CH2:13][CH2:14]2)[CH2:17][CH2:16]3)=[O:21])[CH2:23][CH2:24][CH2:26][CH2:27]1
Reactant: [H][H]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)N3CCCCC3)(CC1)CC2
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)N3CCCC3)(CC1)CC2
Yield: 70.6 %

Procedure:
(2S,4S)-1-[[N-Benzyloxycarbonyl-N-[4-(piperidin-1-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) and 10% palladium carbon (3.0 mg) were dissolved in ethanol (1.0 mL) and dichloromethane (0.5 mL). The mixture was stirred at room temperature for 8 hours in a hydrogen atmosphere. The mixture was then filtered through a Celite pad and the solvent was concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluant:dichloromethane:methanol=10:1) to give (2S,4S)-1-[[N-[4-(pyrrolidin-1-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (15.2 mg).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:11][C:12]([CH3:17])=[CH:13][C:14](Cl)=[O:15].C(OCC)(=O)C>O1CCCC1.[Cl-].[Na+].O.CCCCCC>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:14](=[O:15])[CH:13]=[C:12]([CH3:17])[CH3:11])=[CH:6][CH:5]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)=CC(=O)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)=CC(=O)Oc1ccc(Br)cc1
Reaction time: 4 h
Yield: 58.8 %

Procedure:
To a stirred, cooled (ice bath) suspension of sodium hydride (2.4 g, 100 mmol) in anhydrous tetrahydrofuran (200 mL), 4-bromo phenol (17.3 g, 100 mmol) was added followed by 3,3,-dimethyl acryloyl chloride (11.14 mL, 100 mmol). After 4 hours at ambient temperature, the reaction mixture was poured into brine and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 2% ethyl acetate in hexane as the eluent to afford the title compound (15 g, 59%).
Reaction SMILES: [Si]([O:18][C:19]1[CH:56]=[CH:55][C:22]([O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:53]=[CH:52][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([C:43]4[C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[NH:45][CH:44]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:54][C@H:25]([CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([OH:18])=[CH:56][CH:55]=1)[CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:53]=[CH:52][C:33]([NH:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]([C:43]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[NH:45][CH:44]=3)=[O:42])[CH2:37][CH2:36]2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)c4c[nH]c5ccccc45)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(c1c[nH]c2ccccc12)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 83 %

Procedure:
{4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinyl}(1H-indol-3-yl)methanone (0.148 g, 0.182 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.087 g, 0.151 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([Br:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CCCCCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH2:1][Br:17])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)cc(Br)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Br)cc(CBr)c1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
A mixture of 3,5-dimethylbromobenzene (70 g, 0.378 M), NBS (67.3 g, 0.373 M), and benzoyl peroxide (2.27 g, 0.009 M) in carbon tetrachloride (300 mL) was refluxed for 3 hr. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated in vacuo to give a pale brown oil. The crude product was dissolved in hexane and filtered through a short silica gel pad (diameter: 9.5 cm, height: 7 cm). The silica gel pad was washed with hexane until the product eluted completely. The filtrate was evaporated in vacuo to give 94 g of 1-bromo-3-(bromomethyl)-5-methylbenzene (contaminated with starting material and 1-bromo-3,5-bis-bromomethylbenzene) as a pale brown oil, which solidified on standing at room temperature. The mixture was used directly in the next reaction without further purification.