Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]>CO>[CH2:7]([O:6][C:4](=[O:5])[C:3]1[CH:9]=[CH:10][C:11]([NH2:13])=[CH:12][C:2]=1[F:1])[CH3:8]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Solvent: CO
Product: CCOC(=O)c1ccc(N)cc1F
Reaction time: 0.67 h
Yield: 93.1 %

Procedure:
To a 250 mL round bottomed flask equipped with a magnetic stirrer were added 3.00 g of ethyl 2-fluoro-4-nitro-benzoate and 100 mL of MeOH. The solution was deoxygenated by bubbling nitrogen through for 10 min and then treated with 2.00 g of Raney nickel (Raney 3200, Davison Chemical, Chattanooga, Tenn. 37406) which had been washed with water and EtOH. The solution was subjected to hydrogenation at 1 atm with stirring for 40 min. The flask was purged with nitrogen and the catalyst was removed by filtration. The filtrate was concentrated in vacuo to afford 2.40 g (93%) of ethyl-4-amino-2-fluorobenzoate as a tan crystalline solid, m.p. 110-112° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]1[CH2:27][C@@:25]2([CH3:26])[C@@H:21]([CH2:22][CH2:23][C@@H:24]2[OH:28])[C@@:20]2([CH:29]=[CH2:30])[C@H:11]1[C:12]1[CH:13]=[CH:14][C:15]([OH:31])=[CH:16][C:17]=1[CH2:18][CH2:19]2>>[CH3:1][N:2]([CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]1[CH2:27][C@@:25]2([CH3:26])[C@@H:21]([CH2:22][CH2:23][C@@H:24]2[OH:28])[C@@:20]2([CH:29]=[CH2:30])[C@H:11]1[C:12]1[CH:13]=[CH:14][C:15]([OH:31])=[CH:16][C:17]=1[CH2:18][CH2:19]2
Reactant: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCBr)C[C@@]1(C)[C@H]2CC[C@@H]1O
Reactant: CNC
Product: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCN(C)C)C[C@@]1(C)[C@H]2CC[C@@H]1O

Procedure:
In the reaction with dimethylamine (2 M in tetrahydrofuran, 10 equivalents) analogously to instructions 17.2, 30 mg of bromide 30a yields 12 mg of amine 32a as a colorless foam (GC-MS: m/z theor.: 411, pract.: 411).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].C(#N)C.Br[CH2:14][CH:15]1[O:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][CH2:16]1>C(OCC)C>[O:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][CH2:16][CH:15]1[CH2:14][N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]=[CH:4]1
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCC1COc2ccccc2O1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOCC
Product: Clc1ncn(CC2COc3ccccc3O2)c1Cl
Temperature: 25 °C
Yield: 51.2 %

Procedure:
4,5-Dichloroimidazole (0.68 g, 5 mmol) and potassium hydroxide (0.28 g, 5 mmol) were added to a round bottom flask. Acetonitrile (2 mL) was added and the mixture was brought to reflux and stirred 30 min until all KOH was consumed. 2-(Bromomethyl)-1,4-benzodioxane (1.5 mL, 10 mmol) was added and the solution was returned to reflux overnight, during which time a white precipitate formed. The mixture was cooled to ambient temperature and filtered to remove the precipitate. The filtrate was concentrated via rotary evaporation at 75° C. until a yellow liquid remained. Upon cooling, the solution yielded a yellow solid. The solid was stirred in diethyl ether and filtered to yield a pale yellow solid (0.73 g, 52% yield).
Reaction SMILES: [CH:1]1([CH2:6][C:7](Cl)=[O:8])[CH2:5]CC[CH2:2]1.[NH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1.NC1C=CC(C(OC)=O)=CC=1>>[OH:16][CH:13]1[CH2:14][CH2:15][N:10]([C:7](=[O:8])[CH2:6][CH:1]([CH3:2])[CH3:5])[CH2:11][CH2:12]1
Reactant: OC1CCNCC1
Reactant: O=C(Cl)CC1CCCC1
Agent: COC(=O)c1ccc(N)cc1
Product: CC(C)CC(=O)N1CCC(O)CC1

Procedure:
The title compound was prepared as described in Example 52A, substituting 3-methylbutanoyl chloride for 2-cyclopentylacetyl chloride and piperidin-4-ol for methyl 4-aminobenzoate.
Reaction SMILES: CN1C(=O)CCC1.[OH-].[Na+].Cl[C:11]1[CH:12]=[C:13]([C:20]([O-:22])=[O:21])[C:14](=[CH:18][CH:19]=1)[C:15]([OH:17])=O.[Na+]>[Ti].O>[C:20]1(=[O:21])[O:22][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:11][CH:12]=[C:13]12
Reactant: O=C([O-])c1cc(Cl)ccc1C(=O)O
Agent: [Ti]
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1OC(=O)c2ccccc21
Temperature: 250 °C

Procedure:
A titanium-lined autoclave was charged with 108 g of a poly(phenylene sulfide) (melt viscosity: 2800 poises) produced by Kureha Chemical Industry Co., Ltd., 500 g of NMP, 7 g of sodium hydroxide, 8.43 g (0.05 mole as S content) of hydrated sodium sulfide and 8.8 g of water. After the autoclave being purged with nitrogen gas, the contents were gradually heated up to 250° C. to react them for 30 minutes, thereby depolymerizing the poly(phenylene sulfide). Thereafter, the contents were cooled to room temperature. Then, 17.8 g (0.08 mole) of sodium hydrogen 4-chlorophthalate and 48.6 g of water were added to the autoclave, and the contents were heated up to 255° C. to react them for 2 hours.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.[OH-].[K+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(OC(=O)C)C>[N:19]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: c1ccc2[nH]ccc2c1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC1(C)CC(Nc2nccc(-n3ccc4ccccc43)n2)CC(C)(C)N1
Temperature: 120 °C
Yield: 27 %

Procedure:
A mixture of (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (200 mg, 0.74 mmol), indole (96 μl, 0.81 mmol), potassium hydroxide (63 mg, 1.10 mmol) and a few drops of Aliquat 336 were heated to 120° C. for 5 h. After cooling to room temperature the mixture was dissolved in ethylacetate, washed with water and brine and the crude product was purified by HPLC. Thus 71 mg (0.20 mmol, 27%) of the title compound were obtained.
Reaction SMILES: [O:1]=[C:2]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][NH:3]1.FC(F)(F)S(O[C:26]1[CH2:27][O:28][C:29](=[O:32])[C:30]=1[CH3:31])(=O)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:31][C:30]1[C:29](=[O:32])[O:28][CH2:27][C:26]=1[N:3]1[CH2:4][CH2:5][CH2:6][C:7]2([CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2=O)CC1
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)COC1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC1=C(N2CCCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Temperature: 90 °C

Procedure:
A microwave vial was charged with commercially available tert-butyl 1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (Shanghai AQ BioPharma Co., Ltd, catalog #ABP3640, 100 mg, 0.373 mmol), 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (110 mg, 0.447 mmol), Pd2(dba)3 (17 mg, 0.019 mmol), Xantphos (32 mg, 0.056 mmol), and cesium carbonate (182 mg, 0.559 mmol). The vial was sealed, degassed, and filled with toluene (1.5 mL). The reaction mixture was heated at 90° C. overnight, and was filtered through CELITE®. The filtrate was evaporated to give the crude product, which was purified by column chromatography (0-10% MeOH/DCM) to afford the title compound. LC/MS: [(M+1-56)]+=309
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2=[O:19].C(=O)([O-])[O-].[K+].[K+].[Br:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[C:29]([F:35])[CH:28]=1>CN(C)C=O>[Br:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:8]2[C:9]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=3)[C:5](=[O:19])[N:6]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7]2=[O:12])=[C:29]([F:35])[CH:28]=1
Reactant: CCOC(=O)Cn1c(=O)[nH]c2ccc(Cl)cc2c1=O
Reactant: Fc1cc(Br)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)c2cc(Cl)ccc2n(Cc2ccc(Br)cc2F)c1=O
Temperature: 0 °C
Yield: 72.2 %

Procedure:
Into 250 ml of dried dimethylformamide were dissolved 10 g of ethyl 6-chloro-1,4-dihydro-2,4-dioxo-3(2H)-quinazolineacetate, and 4.86 g of potassium carbonate were added and 10.40 g of 4-bromo-2-fluorobenzyl bromide were added under stirring. After stirring for 1 hour at 60° C., the reaction mixture was poured into 400 ml of ice water and the crystals were collected by filtration. They were recrystallized from ethanol to obtain 12.0 g of title compound. m.p. 145°-146° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=3)[CH2:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=2)=[CH:4][CH:3]=1.CCO>C1COCC1.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]([C:13]3[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=3)[NH2:19])[CH2:11][CH2:10][CH:9]2[C:22]2[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=2)[NH2:28])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(C2CCC(c3cccc([N+](=O)[O-])c3)N2c2ccc(F)cc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cccc(C2CCC(c3cccc(N)c3)N2c2ccc(F)cc2)c1
Reaction time: 20 h

Procedure:
A suspension of Pd/C (0.0527 g, 0.050 mmol) in THF (2 mL) was added to a solution of Example 55D (0.45 g, 1.105 mmol) in THF (7 mL)/EtOH (7 mL) under N2. The flask was flushed with H2 and stirred under 1 atm H2 for 20 hours. The reaction was filtered through a celite plug, rinsed with ˜100 mL (1:1 EtOH:THF) and solvent was removed under vacuum. The material was used without purification. MS (DCI) m/z 348 (M+H)+.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(Cl)(=O)C1C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:34]=[C:35]([O:37][CH3:38])[N:36]=1)[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[C:4]([NH:20][C:21]1[CH:22]=[C:23]([CH:34]=[C:35]([O:37][CH3:38])[N:36]=1)[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])(=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1
Reactant: COc1cc(C(=O)NCc2ccccc2)cc(N)n1
Reactant: O=C(Cl)c1ccccc1F
Solvent: O=C(Cl)c1ccccc1
Product: COc1cc(C(=O)NCc2ccccc2)cc(NC(=O)c2ccccc2)n1
Yield: 14 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with benzoyl chloride to react with 2-amino-N-benzyl-6-methoxyisonicotinamide, 2-benzamido-N-benzyl-6-methoxyisonicotinamide was obtained as a colorless solid in 14% yield: mp 132-133° C.; 1H NMR (300 MHz, CDCl3) 8.43 (s, 1H), 8.15 (s, 1H), 7.84 (d, J=7.5 Hz, 2H), 7.57-7.43 (m, 3H), 7.34-7.23 (m, 5H), 6.98 (s, 1H), 6.87 (s, 1H), 4.57 (d, J=5.1 Hz, 2H), 3.86 (s, 3H); 13C NMR (300 MHz, CDCl3) δ 165.6, 165.3, 163.6, 149.8, 147.0, 137.6, 133.8, 132.4, 128.9, 128.7, 127.9, 127.6, 127.1, 105.2, 102.4, 54.0, 44.1; MS (ES+) m/z 362.5 (M+1).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](OCC)CN(C3SC=CN=3)C2)=NC=1CC.Br[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.[CH2:40]([O:42][C@H:43]1[CH2:47][NH:46][CH2:45][C@H:44]1[NH:48][C:49]1[C:54]([CH2:55][CH3:56])=[N:53][C:52]([C:57]2[C:58]([C:65]([F:68])([F:67])[F:66])=[N:59][C:60]([O:63][CH3:64])=[CH:61][CH:62]=2)=[C:51]([CH2:69][CH3:70])[N:50]=1)[CH3:41]>>[CH2:40]([O:42][C@H:43]1[CH2:47][N:46]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:45][C@H:44]1[NH:48][C:49]1[C:54]([CH2:55][CH3:56])=[N:53][C:52]([C:57]2[C:58]([C:65]([F:68])([F:67])[F:66])=[N:59][C:60]([O:63][CH3:64])=[CH:61][CH:62]=2)=[C:51]([CH2:69][CH3:70])[N:50]=1)[CH3:41]
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C(F)(F)F)nc1CC
Reactant: Brc1ccccn1
Agent: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(c2ccccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C(F)(F)F)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl}-3,6-diethylpyrazin-2-amine but substituting 2-bromopyridine and starting with N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethyl-5-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]pyrazin-2-amine provided the title compound as an amorphous solid. 1H NMR (CDCl3) δ 1.15, 1.30, 2.44, 2.70, 3.43, 3.58, 3.75˜3.85, 4.05, 4.27, 4.90, 5.32, 6.46, 6.62, 6.97, 7.52, 7.56, 8.20; IR (diffuse reflectance) 2352 (w), 2338 (w), 2257 (w), 2175 (w), 2025 (w), 1600 (s), 1559, 1475 (s), 1443 (s), 1397, 1339, 1277, 1239, 1174, 1137 (s) cm−1 HRMS (ESI) calcd for C26H31N6O2F3+H1 517.2538. found 517.2533.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.[CH2:27]([O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:21][CH2:22][CH:23]([O:26][C:40](=[O:41])[C:39]3[CH:38]=[CH:37][C:36]([O:35][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:44][CH:43]=3)[CH2:24][CH2:25]2)=[CH:16][CH:15]=1
Reactant: CCCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: OC1CCC(c2ccc(OCCCCCCCCCCCBr)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(C(=O)OC2CCC(c3ccc(OCCCCCCCCCCCBr)cc3)CC2)cc1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
3 g (7.05 mmol) of 4-[4-(11-Bromo-undecyloxy)-phenyl]-cyclohexanol obtained in Step 2 and 2.02 g (7.52 mmol) of 4-Octyloxy-benzoyl chloride are dissolved in 100 mL of dry CH2Cl2. 0.95 g (7.52 mmol) of DMAP are added. The mixture is stirred at room temperature over night. The solvent is distilled off and then the resulting product is purified by column chromatography on silica gel using CH2Cl2 as eluent to give a pure product as a white solid (3.8 g, 82% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:27])([F:26])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH:23][CH:24]=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[CH3:24][NH:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([C:8]([F:27])([F:7])[F:26])=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: O=CNCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CNCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 100.1 %

Procedure:
Lithium aluminum hydride (237 mg, 6.25 mmol) was suspended in THF (20 ml), which was stirred while cooling in an ice-bath. To which a solution of N-{2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]ethyl}-formamide (942 mg, 3.13 mmol) prepared in Reference Example 155 in THF (10 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours and then heated under reflux for 2 hours. The reaction mixture was allowed to return to room temperature, to which water and a 15% sodium hydroxide aqueous solution were added carefully. To the mixture, sodium sulfate was added, and the resulting mixture was vigorously stirred and filtered through Celite. The filtrate was concentrated under reduced pressure to afford N-methyl-{2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]ethyl}-amine (900 mg, yield 100%) as a yellow oil.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:22]=[CH:23][CH:24]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-])=O)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1>[NH2:19][C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:22]=[CH:23][CH:24]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=2)[CH:17]=[CH:16][C:15]=1[CH3:18]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Temperature: 100 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of the above-mentioned crude product of 3-(1-cyano-1-methylethyl)-N-(4-methyl-3-nitrophenyl)benzamide in tetrahydrofuran (300 mL) was added an aqueous solution (500 mL) of sodium dithionite (78.1 g, 629 mmol), and the mixture was stirred at 100° C. for 2 hr. The organic layer of the reaction mixture was separated, and the aqueous layer was extracted with ethyl acetate (2×150 mL). The combined organic layer was washed with saturated brine (150 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=98/2→0/100), and the fractions containing the object product were concentrated under reduced pressure to give the title compound (5.60 g, 38%) as a yellow solid.
Reaction SMILES: C[C@:2]1([O:11][C:10]([CH2:14][OH:15])([CH2:12][OH:13])[C@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[OH:5])O>S(=O)(=O)(O)O>[OH:13][CH2:12][C@@:10]12[CH2:14][O:15][C@@H:2]([O:11]1)[C@H:4]([OH:5])[C@@H:6]([OH:7])[C@H:8]2[OH:9]
Reactant: C[C@@]1(O)OC(CO)(CO)[C@H](O)[C@H](O)[C@H]1O
Agent: O=S(=O)(O)O
Product: OC[C@@]12CO[C@@H](O1)[C@H](O)[C@@H](O)[C@H]2O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 39.6 %

Procedure:
Methyl 5-C-hydroxymethyl-α-L-arabino-hexopyranose (3) (59.0 g, 0.263 moles) is dissolved in 0.70M sulfuric acid (260 ml), and stirred at 100° C. for 90 minutes. The solution is cooled to room temperature and neutralized using an ion exchange resin (Amberlite IRA-400 (OH--). The resin is filtered off, and the filtrate is refluxed for 15 minutes with activated carbon (4.0 g). Carbon is removed with a glass fiber filter, and the filtrate is evaporated to dryness with ethanol. The white waxy residue is refluxed for 15 minutes with methanol (50 ml). The solution is stored overnight at 0° C. The product is filtered to yield 20.0 g (39.6%) of 1,6-anhydro-5-C-hydroxymethyl-β-L-altropyranose (4).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:31])[C@@H:16]([N:18]2[CH2:23][CH2:22][C:21]([OH:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].O>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([OH:31])[C@@H:16]([N:18]2[CH2:19][CH2:20][C:21]([OH:30])([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][CH2:23]2)[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](C(=O)c1ccc(OCc2ccccc2)cc1)N1CCC(O)(c2ccccc2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Product: C[C@@H]([C@@H](O)c1ccc(OCc2ccccc2)cc1)N1CCC(O)(c2ccccc2)CC1
Temperature: 22.5 °C
Reaction time: 0.33 h
Yield: 86.9 %

Procedure:
Over 20 minutes, (2S)-1-(4-benzyloxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanone (75 g, 0.18 mol) was added to a suspension of lithium borohydride (3.15 g, 0.15 mol) in ethanol (0.75 L) maintained under a nitrogen atmosphere at 20 to 25° C. After stirring for about 5 minutes, a mild exotherm occurred raising the temperature to 27° C. The slurry was stirred for 42 hours at 20 to 25° C. when HPLC indicated that the reaction was complete. Water (37.5 mL) was added and the slurry was granulated for 1 hour at 20 to 25° C. The white solid was filtered and then washed with ethanol (75 mL), water (150 mL), and finally ethanol (75 mL). The product was dried in vacuo at 40 to 45° C. for 20 hours to give 65.3 g of the title compound. The (1S,2S) amino alcohol product was obtained in 78.3% yield and contained only 2.3% of diastereomers. M.p. 158-161° C., [α]D25+38.7 (c 6.1, CH3OH)
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([O:18][CH3:19])[CH:12]=[C:13]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:7]=2[O:6]1)=[N+]=[N-]>[Pd]>[C:14]([C:13]1[C:7]2[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=2[CH:10]=[C:11]([O:18][CH3:19])[CH:12]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: COc1cc2c(c(C(C)(C)C)c1)OC(CN=[N+]=[N-])C2
Agent: [Pd]
Product: COc1cc2c(c(C(C)(C)C)c1)OC(CN)C2
Yield: 40 %

Procedure:
Treatment of 2-tert-butyl-4-methoxyphenol and 3-tert-butyl-4-methoxyphenol (18.25 g, 0.101 mol) with potassium carbonate (55.28 g, 0.400 mol) and allyl bromide (14.69 g, 0.121 mol) followed by treatment of the resultant allyl ether in refluxing mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-tert-butyl-4-methoxyphenol and 2-allyl-5-tert-butyl-4-methoxyphenol. Treatment of the phenol with 3-chloroperoxybenzoic acid (49.58 g, 0.287 mol, 77%) and potassium carbonate (33.0 g, 0.238 mol) generally according to the procedure described for Intermediate 9 gave 3.23 g (14%) of (±)-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanol as a white solid. Treatment of the benzofuran with p-toluenesulfonyl chloride (2.86 g, 0.015 mol) generally according to the procedure described for Intermediate 10 afforded (±)-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (1.46 g, 22.5 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.14 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 1.5 g (40%) of (±)-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methylamine) as a white solid, hydrochloride salt. mp 174-176° C.; Anal calcd. for C14H21O2NHCl: C, 61.87; H, 8.16; N, 5.15. Found C, 61.67; H, 8.37; N, 4.93.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C(N(CC)CC)C.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C@@:19]2([CH3:52])[C:23](=[O:24])[N:22]([CH2:25][C:26]([O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)=[O:27])[C:21](=[O:40])[N:20]2[CH2:41][C:42]2[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=2)=[CH:15][CH:14]=1)#[N:12]>C(O)C>[NH2:12][C:11](=[N:3][OH:2])[C:13]1[CH:18]=[CH:17][C:16]([C@@:19]2([CH3:52])[C:23](=[O:24])[N:22]([CH2:25][C:26]([O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)=[O:27])[C:21](=[O:40])[N:20]2[CH2:41][C:42]2[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=2)=[CH:15][CH:14]=1
Reactant: C[C@]1(c2ccc(C#N)cc2)C(=O)N(CC(=O)OCc2ccc3ccccc3c2)C(=O)N1Cc1ccc2ccccc2c1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@]1(c2ccc(C(N)=NO)cc2)C(=O)N(CC(=O)OCc2ccc3ccccc3c2)C(=O)N1Cc1ccc2ccccc2c1
Yield: 86.4 %

Procedure:
1.67 g (24 mmol) of hydroxylammonium chloride and 5.04 ml (36 mmol) of triethylamine were added to a solution of 6.64 g (12 mmol) of 2-naphthylmethyl ((S)-4-(4-cyanophenyl)-3-(2-naphthylmethyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate in 120 ml of absolute ethanol and the mixture was heated under reflux for 2.5 h. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The phases were separated and the water phase was extracted with ethyl acetate. The combined organic phases were washed with water and dried over magnesium sulfate. After filtration, the solvent was removed in vacuo and 6.08 g (86%) of the title compound were obtained.