Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([CH:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6]([OH:8])=[O:7])[CH3:4].[Cl-].Cl[C:15]([O:17][CH3:18])=[O:16]>O>[C:15](=[O:16])([O:17][CH3:18])[O:7][C:6](=[O:8])[CH:5]([CH2:3][CH3:4])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC(CC)C(=O)O
Reactant: COC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCC(CC)C(=O)OC(=O)OC
Yield: 100.2 %

Procedure:
To a well-stirred reaction vessel equipped with a thermometer and a pH electrode were added 45 g of water, 0.075 mole of a 33 wt % aqueous NaOH solution, 0.075 mole of 2-ethylhexanoic acid, and 0.23 g of Arquad CB50 (i.e. cocobenzyldimethylammonium chloride, ex Akzo Nobel) at 5° C. 0.075 mole of methyl chloroformate was dosed in 5 min at 5° C. The mixture was post-reacted for 30 min at 5° C. and a pH of 8. Then, the water layer was separated, giving 15.2 g of 2-ethylhexanoyl methyl carbonate having a content of 99.5% (determined by NMR) in a yield of 99.6%.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][C:8]=1[NH:25][C:26]([C:28]1[NH:29][C:30]2[C:35]([CH:36]=1)=[CH:34][C:33]([O:37][CH3:38])=[C:32]([O:39][CH3:40])[C:31]=2[O:41][CH3:42])=[O:27])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.CCOC(C)=O>[CH2:18]([O:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([CH2:6][CH2:5][OH:4])=[C:8]([NH:25][C:26]([C:28]2[NH:29][C:30]3[C:35]([CH:36]=2)=[CH:34][C:33]([O:37][CH3:38])=[C:32]([O:39][CH3:40])[C:31]=3[O:41][CH3:42])=[O:27])[CH:9]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc2cc(C(=O)Nc3cc(OCc4ccccc4)c4ccccc4c3CCOC(C)=O)[nH]c2c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2cc(C(=O)Nc3cc(OCc4ccccc4)c4ccccc4c3CCO)[nH]c2c(OC)c1OC
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a solution of 2-[4-benzyloxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl acetate (0.10 g, 0.18 mmol) in MeOH (2 mL) was added potassium carbonate (29.15 mg, 0.21 mmol) at room temperature and stirred overnight. The reaction mixture was diluted with AcOEt (50 mL) and washed with H2O (10 mL), saturated aqueous NaCl (20 mL), and then the organic layer was dried (Na2SO4) and concentrated under reduced pressure to yield as a yellow oil 2-[4-benzyloxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethanol (82 mg, 87%); 1H NMR (CDCl3, 500 MHz) δ 9.96 (s, 1H), 9.25 (s, 1H), 8.39 (d, 8.0, 1H), 7.85 (d, 8.5, 1H), 7.75 (s, 1H), 7.71 (dd, 3.5, 5.8, 1H), 7.57 (d, 7.5, 2H), 7.53 (m, 1H), 7.43 (t, 7.5, 2H), 7.36 (t, 7.0, 1H), 7.06 (s, 1H), 6.84 (s, 1H), 5.30 (s, 2H), 4.21 (t, 6.0, 2H), 4.08 (s, 3H), 3.95 (s, 3H), 3.91 (s, 3H), 3.37 (t, 5.0, 2H); EIMS m/z 527 (M+H+); IR (neat) νmax 3272, 2932, 1726, 1644, 1594, 1540, 1505, 1464, 1409, 1370, 1263, 1236, 1127, 1103, 1049, 997, 831, 760, 701 cm−1.
Reaction SMILES: C1(C[O:8][C:9]2[C:14]([O:15]CC3C=CC=CC=3)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36](=[O:40])[C:37]([OH:39])=[O:38])=[CH:32][CH:31]=2)C=CC=CC=1.Cl>C(O)(=O)C.O>[OH:8][C:9]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36](=[O:40])[C:37]([OH:39])=[O:38])=[CH:34][CH:35]=1
Reactant: O=C(O)C(=O)c1ccc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C(=O)c1ccc(OCCCCCCc2cccc(O)c2O)cc1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A mixture of 4-[6-[2,3-bis-(phenylmethoxy)phenyl]hexyloxy]-alpha-oxobenzeneacetic acid (0.3 g) in acetic acid (20 mL) containing concentrated hydrochloric acid (5 mL) was stirred at 80° C. for 2.5 hours. The cooled solution was diluted with water (100 mL) and extracted with three portions of ethyl acetate, then the combined extracts were dried (Na2SO4), and evaporated in vacuo. The residual oil was triturated in turn with cyclohexane and carbon tetrachloride to remove non polar impurities, then was crystallized from dichloromethane and recrystallized from dichloromethane-carbon tetrachloride to give 4-[6-(2,3-dihydroxyphenyl)hexyloxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 127°-130° C.
Reaction SMILES: C([O:8][C:9]1[CH:51]=[CH:50][C:12]([CH2:13][C@H:14]2[C@@H:18]([CH2:19][N:20]([CH2:33][CH:34]([CH3:36])[CH3:35])[S:21]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)(=[O:23])=[O:22])[O:17][C:16]([CH3:38])([CH3:37])[N:15]2[C:39]([O:41][C@H:42]2[C@H:49]3[C@H:45]([O:46][CH2:47][CH2:48]3)[O:44][CH2:43]2)=[O:40])=[CH:11][CH:10]=1)C1C=CC=CC=1.N.[H][H]>CO.[Pd]>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([N:20]([CH2:19][C@H:18]2[O:17][C:16]([CH3:37])([CH3:38])[N:15]([C:39]([O:41][C@H:42]3[C@H:49]4[C@H:45]([O:46][CH2:47][CH2:48]4)[O:44][CH2:43]3)=[O:40])[C@H:14]2[CH2:13][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:51][CH:50]=2)[CH2:33][CH:34]([CH3:36])[CH3:35])(=[O:22])=[O:23])=[CH:25][CH:26]=1
Reactant: [H][H]
Reactant: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: N
Solvent: CO
Product: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(O)cc1)S(=O)(=O)c1ccc(N)cc1
Yield: 54 %

Procedure:
To a stirred solution of (3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (4S,5R)-4-[4-(benzyloxy)benzyl]-5-({isobutyl[(4-nitrophenyl)sulfonyl]amino}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate. (0.18 g, 0.25 mmol) in 6 mL of a 2M solution of ammonia in methanol was added 0.18 g of palladium (on charcoal, 10% Pd, Degussa type). The mixture was stirred under an atmospheric pressure of hydrogen for 12 hours. The catalyst was filtered, and the solvent was removed under reduced pressure. The residue was purified on silica gel using ethyl acetate-hexanes (7:3) as eluent to provide 81 mg (54%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([NH:18]C(=O)OC(C)(C)C)[CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[ClH:26].CO>CO>[ClH:26].[NH2:18][C:16]1[N:17]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([S:3]([NH:2][CH3:1])(=[O:4])=[O:5])=[CH:7][CH:8]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CNS(=O)(=O)c1ccc(-c2cccc(NC(=O)OC(C)(C)C)n2)cc1
Agent: Cl
Solvent: CO
Product: CNS(=O)(=O)c1ccc(-c2cccc(N)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of tert-butyl 6-(4-(N-methylsulfamoyl)phenyl)pyridin-2-ylcarbamate (8.5 g, 23.4 mmol) in MeOH (10 mL) was added HCl/MeOH (2M, 50 mL) at room temperature. The suspension was stirred at room temperature overnight. The solid product was collected by filtration, washed with MeOH, and dried to give 4-(6-aminopyridin-2-yl)-N-methylbenzenesulfonamide hydrochloride (5.0 g, 71%). 1H NMR (300 Hz, DMSO-d6) δ 8.12 (d, J=8.4 Hz, 2H), 7.91-7.96 (m, 3H), 7.58-7.66 (m, 1H), 7.31-7.53 (m, 1H), 7.27 (d, J=6.6, 1 H), 6.97 (d, J=9.0, 1 H), 2.43 (d, J=4.8 Hz, 3H). MS (ESI) m/z (M+H)+ 264.0.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][OH:11])[CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[F:19][C:20]([F:28])(S(F)(=O)=O)C(O)=O>CC#N.[Cu]I>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][CH:20]([F:28])[F:19])[CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4]
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: COC(=O)C1CC(CO)CN1C(=O)OC(C)(C)C
Agent: [Cu]I
Solvent: CC#N
Product: COC(=O)C1CC(COC(F)F)CN1C(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 3 h
Yield: 56.6 %

Procedure:
4-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (584 mg, 2.25 mmol) and CuI (86 mg, 0.45 mmol) were suspended in MeCN (10 mL). The reaction mixture was heated to 45° C. and difluoro-fluorosulfonyl-acetic acid (0.465 mL, 4.5 mmol) was added dropwise over the course of 30 min. Stirring was continued for another 3 h, after which the reaction mixture was cooled to RT and concentrated. The residue was taken up in EtOAc and washed with saturated aqueous NaHCO3 and brine then dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (19% to 40% EtOAc/Hex) to afford the title compound (394 mg, 57%).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C(N(CC)CC)C.[Cl:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C1C=CC=CC=1>[Cl:15][CH2:16][CH2:17][CH2:18][C:19]([NH:1][C:2]1[O:3][CH:4]=[C:5]([CH3:7])[N:6]=1)=[O:20]
Reactant: Cc1coc(N)n1
Reactant: O=C(Cl)CCCCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1coc(NC(=O)CCCCl)n1
Temperature: 25 °C
Yield: 23.92 %

Procedure:
2-Amino-4-methyloxazole (5.0 g., 0.0509 mol) was dissolved in dry benzene (100 mls.) and triethylamine (5.70 g., 0.0563 mol) was added. The mixture was stirred vigorously at room temperature and 4-chlorobutyrylchloride (7.88 g., 0.0558 mol) in dry benzene (50 mls.) was added rapidly. After the addition the mixture was heated under reflux for 2 hours. The mixture was then cooled and filtered. The filtrate was placed in a separating funnel and washed successively with water (1 × 100 mls.), 10% Na2CO3 (2 × 100 mls.) and water (3 × 100 mls.). The organic layer was dried over magnesium sulphate and evaporated under vacuum. The product was recrystallised from ethyl acetate/hexane. Wt. = 2.47 g.m.p. 98° C. (Yield = 23.92%).
Reaction SMILES: Cl.C1(C[N:9]2[CH2:14][CH2:13][CH:12]([C:15]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[OH:16])[CH2:11][CH2:10]2)C=CC=CC=1.C(O)C.[H][H]>CO.[Pd]>[F:36][C:33]([F:34])([F:35])[C:30]1[CH:29]=[CH:28][C:27]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=2)([OH:16])[CH:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)=[CH:32][CH:31]=1
Reactant: OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
A mixture of 10.0 grams (0.019 mole) of N-phenylmethyl-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine hydrochloride (prepared as in Steps A and B of Example 3) and 3.0 grams of 5% palladium (catalyst) on charcoal in about 200 mL of 1:1 methanol:ethanol was shaken in a Parr hydrogenator for five to six hours at about 85° C., until the theoretical amount of hydrogen gas was taken up. The mixture was cooled to ambient temperature where it stood for about 18 hours. The mixture was filtered and concentrated under reduced pressure to a residue, which was stirred with ethyl acetate and an aqueous solution saturated with sodium bicarbonate until the residue dissolved. The organic layer was separated and passed through phase-separation paper to remove aqueous material. The organic layer was concentrated under reduced pressure, yielding about 7.0 grams of 4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([CH2:11][NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)([OH:10])[C:6]([F:9])([F:8])[F:7])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]([CH3:48])[C:40]=1[C:41](Cl)=[O:42]>ClCCl>[CH2:1]([N:3]([CH2:4][C:5]([CH2:11][NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)([OH:10])[C:6]([F:8])([F:9])[F:7])[C:41](=[O:42])[C:40]1[C:44]([CH3:48])=[CH:45][CH:46]=[CH:47][C:39]=1[CH3:38])[CH3:2]
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: Cc1cccc(C)c1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(Ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}methyl)-2-propanol (25 mg, 0.063 mmol) was dissolved in anhydrous dichloromethane (0.15 ml). N,N-diisopropylethylamine (0.011 ml, 0.13 mmol) was then added followed by 2,6-dimethylbenzoyl chloride in DCM (10.6 mg, 0.065 mmol as a 100 μl aliquot of 80.8 mg in 0.76 ml DCM) and the mixture stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed successively with aqueous sodium bicarbonate and water and then dried through a hydrophobic frit and evaporated and the crude product purified by mass directed autopreparation (System B). Product containing fractions were partitioned between dichloromethane and aqueous sodium bicarbonate. The aqueous layer was re-extracted with dichloromethane and the combined organic extracts were washed successively water and brine, dried through a hydrophobic frit and evaporated in vacuo to give the title compound (13.1 mg).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5](N)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[I:13]I.N(OC(C)(C)C)=O.O>C(#N)C.[Cu]I>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([I:13])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: II
Reactant: Cc1cc(F)cc([N+](=O)[O-])c1N
Agent: [Cu]I
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: CC#N
Product: Cc1cc(F)cc([N+](=O)[O-])c1I
Yield: 46.5 %

Procedure:
A mixture of 4.4 grams (0.026 mole) of 4-fluoro-2-nitro-6-methylaniline, 13.2 grams (0.052 mole) of iodine, and 5.5 grams (0.029 mole) of copper(I) iodide in 125 mL of acetonitrile was stirred, and a solution of 4.6 mL (0.039 mole) of tert-butyl nitrite in 25 mL of acetonitrile was added dropwise during a 10 minute period. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 16 hours. After this time the reaction mixture was poured into 300 mL of water. Excess iodine was destroyed using sodium meta-bisulfite. The mixture was then extracted with two 250 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 1:3 methylene chloride: petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.4 grams of 4-fluoro-2-nitro-6-methylphenyl iodide. The NMR spectrum was consistent with the proposed structure. The reaction was repeated to obtain more product.
Reaction SMILES: [OH-:1].[Na+].[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>C(O)C>[CH2:4]([O:1][C:7]1[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCBr
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCOc1ccc(Br)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 164.4 %

Procedure:
50.0 g (0.290 mol) of p-bromophenyl was dissolved in 300 ml of ethanol and 14.2 g (0.340 mol) of sodium hydroxide and 49.5 g (0.300 mol) of 1-bromohexane were added thereto. The resulting solution was stirred at 70° C. for 4 hours to complete the reaction and the solvent was removed by distillation. Then 150 ml of water was added and the organic layer was extracted with 200 ml of hexane. The hexane was removed by distillation thereafter. The residue was distilled under reduced pressure to yield 63.4 g of 4-hexyloxybromobenzene having a b.p. 139° C./7 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:13][C:14]([O-:16])=[O:15].[Na+].O.Cl>CS(C)=O>[C:10]([CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:13][C:14]([OH:16])=[O:15])#[N:11]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])CCl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Yield: 66 %

Procedure:
A mixture of 18.6 g (0.10 mol) of 3,4-dichlorophenylacetonitrile and 12 g (1.03 mol) of dry sodium chloroacetate is reacted for 5 hours at room temperature in 150 ml of dry dimethyl sulfoxide, in the presence of 0.5 g (1.05 mol) of sodium tert-butylate. After the reaction, the reaction mixture is poured into 1 liter of iced water and acidified to pH<3 with hydrochloric acid. The cyanoacid is extracted with ethyl acetate, which is washed to pH>3, dried over magnesium sulfate and concentrated to dryness. The residue is solidified in 1,2-dichloroethane to give 16.1 g of the expected compound (III), which is characterized by proton NMR.
Reaction SMILES: [C:1]([O:4][C:5]12[CH2:9][C:7]([NH2:10])([CH2:8]1)[CH2:6]2)(=[O:3])[CH3:2].[C:11](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[C:1]([O:4][C:5]12[CH2:9][C:7]([NH:10][CH3:11])([CH2:8]1)[CH2:6]2)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)OC12CC(N)(C1)C2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNC12CC(OC(C)=O)(C1)C2

Procedure:
To an anhydrous DMF (5 mL) solution of 3-aminobicyclo[1.1.1]pentan-1-yl acetate (1 mmol; prepared as described in Example 1, Step 2) is potassium carbonate (3 mmol) followed by the addition of methyl iodide (1 mmol) by syringe at room temperature. The reaction is monitored by LCMS and TLC. After consumption of starting material, the reaction mixture is quenched by adding water (3 mL) and extracted with ethyl acetate (3×). The organic layers are combined, dried (magnesium sulfate), filtered, and concentrated. The crude residue is subjected to flash chromatography (silica gel, EtOAc/hexanes) to afford 3-(methylamino)bicyclo[1.1.1]pentan-1-yl acetate.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:2]([NH:1][C:13]([NH:12][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=4)[N:22]=3)=[CH:19][CH:20]=2)=[S:14])[CH2:3][OH:4])=[CH:6][CH:7]=1
Reactant: NC(CO)c1ccc(F)cc1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1ccc(F)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-fluorophenyl)ethanol and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an off-white solid (1.42 g, 81%): 1H NMR (300 MHz, CDCl3) δ 7.96 (s, 1H), 7.72-7.57 (m, 2H), 7.27 (s, 1H), 7.23-7.14 (m, 2H), 6.87-6.72 (m, 4H), 6.64-6.56 (m, 2H), 6.38-6.22 (m, 3H), 5.05 (s, 1H), 3.47-3.28 (m, 2H), 3.20 (s, 3H); ESIMS m/z 530 ([M+H]+).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][CH2:11]2.CS(C)=O.[Br:26]N1C(=O)CCC1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([Br:26])[CH2:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: C1=Cc2c(cccc2-c2ccccc2-c2ccccc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CS(C)=O
Product: BrC1=Cc2c(cccc2-c2ccccc2-c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A cold solution (5° C.) of compound 8 (40 g, 149 mmol, 1 equiv), dimethyl sulfoxide (400 mL) and water (5 mL) was treated in one portion with N-bromosuccinimide (39.8 g, 224 mmol, 1.5 equiv). The bath was removed and the reaction allowed to stir at room temperature overnight. The reaction was poured into water (1 L) and extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with saturated brine (1 L), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in 500 mL of toluene and p-toluenesulfonic acid (5.6 g, 29.4 mmol, 0.2 equiv) was added. This mixture was refluxed for 20 h while removing water with a Dean-Stark trap. The reaction was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified over silica gel (1 Kg), eluting with heptanes to give compound 9 (39 g, 75% yield) as a light yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:13][O:12][CH:11]([CH2:14][NH:15][CH2:16][CH3:17])[O:10][C:9]=2[CH:18]=1)(=[O:4])=[O:3].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOC(C)=O>[CH2:19]([N:15]([CH2:14][CH:11]1[O:10][C:9]2[CH:18]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[CH:7][C:8]=2[CH2:13][O:12]1)[CH2:16][CH3:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CCNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN(Cc1ccccc1)CC1OCc2ccc(S(C)(=O)=O)cc2O1
Yield: 89.5 %

Procedure:
N-{[7-(methylsulfonyl)-4H-1,3-benzodioxin-2-yl]methyl}ethanamine (0.93 g, 3.4 mmol), benzylbromide (0.43 ml, 3.6 mmol), potassium carbonate (0.61 g, 4.4 mmol) and ACN (20 ml) were heated at 70° C. for 2 h. EtOAc (50 ml) was added before the reaction mixture was filtered and concentrated. Purification by flash chromatography (isooctane/EtOAc 1:1) afforded the title compound (1.1 g). 1H-NMR (400 MHz, MeOH): δ 7.47 (1H, dd, J1 8 Hz, J2 1.6 Hz), δ 7.31 (7H, m), δ 5.18 (1H, t, J 5.2 Hz), δ 4.97 (2H, dd, J1 41 Hz, J2 15 Hz), δ 3.09 (3H, s), δ 2.90 (2H, m), δ 2.70 (2H, m), δ 1.12 (3H, t, J 7.2 Hz).
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(O[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[N:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)=O.Cl>CCOCC>[C:17]1([CH2:16][N:15]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]2[C:1]#[N:2])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)OC1CCCCC1N(Cc1ccccc1)Cc1ccccc1
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: N#CC1CCCCC1N(Cc1ccccc1)Cc1ccccc1

Procedure:
To 100 mL of ether is added 10 g (0.2 mol) of sodium cyanide and 37.3 g (0.1 mol) of 2-[bis(phenylmethyl)amino]-cyclohexanol methanesulfonate. Reflux the reaction and monitor by thin-layer chromatography. Upon completion add 1N HCl until gas evolution ceases. Remove the solvent in vacuo and add saturated aqueous sodium bicarbonate and 100 mL methylene chloride. Dry the organic phase over Na2SO4. Filter off the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:21]=[CH:22]/[C:23]([OH:25])=O)[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[CH:10]=2)[CH:8]=1.[CH3:26][NH2:27]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:21]=[CH:22]/[C:23]([NH:27][CH3:26])=[O:25])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[CH:10]=2)[CH:8]=1
Reactant: COc1cc(/C=C/C(=O)O)cc(-c2ccc3cc(OC)ccc3c2)c1
Reactant: CN
Product: CNC(=O)/C=C/c1cc(OC)cc(-c2ccc3cc(OC)ccc3c2)c1
Yield: 53 %

Procedure:
The compound was prepared by reaction of (E)-3-[3-methoxy-5-(6-methoxynaphthalene-2-yl)phenyl]acrylic acid (300 mg, 0.89 mmol, 1 eq) with 33% methylamine (1 eq) according to method D. Purification by column chromatography with hexane/ethyl acetate 2/1 as the eluent yielded the desired product in a yield of 53%, 200 mg.