Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][C:9](OCC)=[O:10])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C:3]=1[C:20]#[N:21].[Li]CCCC.O>C1COCC1>[O:10]=[C:9]1[CH2:8][CH2:7][N:6]2[N:5]=[C:4]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:3]([C:20]#[N:21])=[C:2]2[NH:1]1
Reactant: CCOC(=O)CCn1nc(-c2cccnc2)c(C#N)c1N
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(-c2cccnc2)nn2c1NC(=O)CC2
Temperature: -60 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 3-(5-amino-4-cyano-3-(pyridine-3-yl)-1H-pyrazol-1-yl)propanoate (213 mg, 0.75 mmol) in THF (5 mL) was added n-BuLi (0.6 mL, 1.49 mmol) at −60° C. The resulting mixture was stirred at −60° C. for 3 hours. 2 mL of water was added to quench the reaction and the THF was removed in vacuo. The residue was purified by HPLC to afford the desired product: MS (m/z): 240.1 [M+H]+, 1H NMR (DMSO, 400 MHz): δ11.79 (s, 1 H), 8.99 (s, 1 H), 8.65 (d, 1 H, J=5.2 Hz), 8.17 (d, 1 H, J=8.4 Hz), 7.57 (dd, 1 H, J=8.4 Hz, J=5.2 Hz), 4.38 (t, 2 H, J=7.6 Hz), 2.89 (t, 2 H, J=7.6 Hz).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12]S[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.C[N+]1([O-])CCOCC1.[S:22]([O-:25])(O)=[O:23].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[O:23]=[S:22]1(=[O:25])[CH2:10][CH2:9][CH:8]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:13][CH2:12]1
Reactant: O=S([O-])O
Reactant: Fc1ncccc1C1CCSCC1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=S1(=O)CCC(c2cccnc2F)CC1
Reaction time: 8 h

Procedure:
To a stirred mixture of 2-fluoro-3-(tetrahydro-2H-thiopyran-4-yl)pyridine (1.2 g, 6.08 mmol), 4-methylmorpholine 4-oxide (1.781 g, 15.21 mmol) in acetone/water (7:3, 30 mL) was added osmium(VIII) oxide (0.631 mL, 0.304 mmol). Stirring was continued at RT overnight. A saturated solution of sodium hydrogensulfite (10 mL) was added and stirred in 15 min., extracted with EtOAc (3×), dried over MgSO4, concentrated to give the tan solid. MS (M+1): 230.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 48.8 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 4-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.038 g (49%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C(=C(OC)C=CC=2)[O:40][C:39]=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([O:40][CH3:39])[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc2c(=O)c(I)c(-c3ccccc3)oc12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1cccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Yield: 98 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-8-methoxy-2-phenyl-chromen-4-one was reacted to give the title compound as a white solid (73 mg, 98%). LCMS (Method B): RT=4.84 min, [M+H]+=498.
Reaction SMILES: Br[CH:2]1[CH:11]([OH:12])[C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[S:4][CH2:3]1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(#N)C>O>[Cl:13][C:7]1[CH:8]=[CH:9][C:10]2[C@H:11]([OH:12])[C@H:2]([CH2:3][C:15]3[NH:14][CH:18]=[CH:17][N:16]=3)[S:4][C:5]=2[CH:6]=1
Reactant: OC1c2ccc(Cl)cc2SCC1Br
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CC#N
Product: O[C@H]1c2ccc(Cl)cc2S[C@H]1Cc1ncc[nH]1

Procedure:
Add 3-bromo-7-chlorothiochroman-4-ol (5.27 gms., 18.8 mmols) and imidazole (12.8 gms., 188 mmols) to acetonitrile (100 ml.), and heat at reflux temperature for 4 hours. Pour the reaction mixture into water (500 ml.), and extract with chloroform (500 ml.). Wash the organic layer with water (500 ml.), dry the organic layer over anhydrous magnesium sulfate, filter and evaporate in vacuo. Triturate the resultant residue with anhydrous ether, filter and recrystallize from acetonitrile to give cis-6-chloro-2,3-dihydro-3-hydroxy-2-(1'-imidazolylmethyl)benzo(b)thiophene.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH2:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].C(O)C.C([BH3-])#N.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:24][CH2:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Reactant: NCC(F)(F)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCC(F)(F)C(=O)O)ccc3c2)CC1
Temperature: 25 °C

Procedure:
A solution of 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (150 mg, 0.483 mmol) and 3-amino-2,2-difluoro-propionic acid (60.4 mg, 0.483 mmol) in ethanol (0.7 mL, 10 mmol) was heated to reflux for 2 h. The yellow solution was then cooled to room temperature and sodium cyanoborohydride (36.4 mg, 0.580 mmol) was added to the stirring solution. The resulting mixture was heated to reflux for 1 h. After cooling to room temperature, citric acid was added, and the solvent removed under vacuum. The resulting solid was suspended in water and collected via filtration. The filtrate was washed thoroughly with water (4×), ether (3×), and hexane (3×). The resulting solid was dried on the filter to give the title compound as a white solid (128.8 mg, 64%). 1H NMR (400 MHz, CDCl3) δ: 7.92 (s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.82 (d, J=9.1 Hz, 1H), 7.52 (dd, J=8.4, 1.8 Hz, 1H), 7.30 (d, J=2.2 Hz, 1H), 7.19 (dd, J=9.0, 2.4 Hz, 1H), 4.45 (s, 2H), 4.40 (m, 1H), 3.61 (t, J=13.8 Hz, 2H), 2.28˜2.31 (m, 2H), 1.92-1.95 (m, 2H), 1.49-1.14 (m, 5H), 0.94 (s, 9H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[CH2:16][C:17](O)=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:32][OH:33]>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[CH2:16][C:17]([NH:32][OH:33])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC1CCCC1
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(C(CC(=O)NO)N2C(=O)c3ccccc3C2=O)cc1OC1CCCC1
Yield: 93.1 %

Procedure:
3-(3-Cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide was prepared by the procedure of Example 1 from 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-phthalimidopropanoic acid (1.50 g, 3.67 mmol), N,N′-carbonyldiimidazole (653 mg, 4.03 mmol) and hydroxylamine hydrochloride (308 mg, 4.43 mmol) in tetrahydrofuran (5 mL) to afford 3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide as a white solid (1.45 g, 93% yield): mp, 169.0-171.0° C.; 1H NMR (DMSO-d6) δ1.54-1.85 (m, 8H, C5H8), 3.09 (d, J=7.9 Hz, 2H, CH2), 3.69 (s, 3H, CH3), 4.70-4.72 (m, 1H, CH), 5.67 (t, J=7.9 Hz, 1H, NCH), 6.87 (br s, 2H, Ar), 7.01 (br s, 1H, Ar), 7.79-7.87 (m, 4H, Ar), 8.78 (br s, 1H, OH), 10.58 (1H, NH); 13C NMR (DMSO-d6) δ23.51, 32.17, 34.23, 50.19, 55.53, 79.57, 112.08, 114.16, 119.69, 123.11, 131.16, 131.20, 134.59, 146.73, 149.17, 166.01, 167.63; Anal Calcd for C23H24N2O6: C, 65.08; H, 5.70; N, 6.60. Found: C, 64.73; H, 5.60; N, 6.53.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3]([C:9]1[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=1)=[CH:2]2.Cl[CH2:19][CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2.C([O-])([O-])=O.[K+].[K+]>CC#N>[NH:26]1[C:27]2[C:23](=[C:22]([O:21][CH2:20][CH2:19][N:8]3[CH:5]4[CH2:6][CH2:7][CH:1]3[CH:2]=[C:3]([C:9]3[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:11][CH:10]=3)[CH2:4]4)[CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:25]1
Reactant: C1=C(c2c[nH]c3ccccc23)CC2CCC1N2
Reactant: ClCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C1=C(c2c[nH]c3ccccc23)CC2CCC1N2CCOc1cccc2[nH]ccc12
Temperature: 80 °C
Yield: 61 %

Procedure:
To 200 mg (0.89 mmol) 3-(8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-1H-indole, 174 mg (0.89 mmol) 4-(2-chloroethoxy)-1H-indole and 10 mL MeCN is added 246 mg (1.78 mmol) K2CO3. After heating at 80° C. for 12 h, the reaction mixture is cooled to 23° C., filtered through celite and evaporated to a light yellow oil. Flash chromatography on SiO2 gel, eluting with CHCl3/MeOH (20/1 to 10/1), gives 208 mg (0.54 mmol, a 61% yield) of the title compound as an off-white solid. The corresponding oxalate salt is prepared by combining the title compound with 1 equivalent of oxalic acid in EtOH/Et2O. The oxalate salt of the title compound precipitates as an off-white solid. Recrystallization from EtOH/Et2O gives the oxalate salt of the title compound as an off-white solid. mp: 135-138° C.; MS (ES) m/z 384 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[CH3:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:31]1[CH2:32][CH2:33][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:29][CH2:30]1)=[O:20])=[N:5]2
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(F)c(F)cc2nc1OC
Product: COc1nc2cc(F)c(F)cc2nc1NC(=O)N1CCN(c2cccc(C)c2)CC1
Yield: 66 %

Procedure:
Ethyl N-(6,7-difluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-methylphenyl)piperazine were reacted by the same way with the example 169 to obtain the titled compound (yield, 66%). 1H NMR (300 MHz, CDCl3) δ 2.34 (s, 3H), 3.27-3.29 (m, 4H), 3.75-3.77 (m, 4H), 4.15 (s, 3H), 6.75-6.78 (m, 4H), 7.18-7.21 (m, 1H), 7.49-7.53 (m, 1H), 7.58-7.62 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:9]([OH:10])=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=[C:6]([CH3:15])[C:3]=1[CH2:4]Br.[CH:16]1([P:22]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)([SH:24])=[S:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([P:22]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)([S:24][CH2:4][C:3]2[C:6]([CH3:15])=[CH:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[C:9]([OH:10])[C:2]=2[CH3:1])=[S:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CBr
Reactant: S=P(S)(C1CCCCC1)C1CCCCC1
Product: Cc1cc(C(C)(C)C)c(O)c(C)c1CSP(=S)(C1CCCCC1)C1CCCCC1

Procedure:
2,6-Dimethyl-3-hydroxy-4-t-butylbenzyl bromide was reacted with the ammonium salt of dicyclohexylphosphinodithioic acid to obtain 2,6-dimethyl-3-hydroxy-4-t-butylbenzyl dicyclohexylphosphinodithioate, m.p. 113°-116° C, which on testing lasted 150 hours longer than the control. The total number of hours required to reach failure was 1.3 times that of the control.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@@H:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21]([NH2:23])=[O:22]>>[C:21]([C@@H:20]([NH:19][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:22])[NH2:23]
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 15, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) and (S)-2-amino-3-phenyl-propionamide hydrochloride (1:1) (CAN 5241-58-7, 118.84 mg, 0.64 mmol) as starting materials, and isolated (60 mg, 37.03%) as colorless sticky solid; LC-MS (UV peak area, ESI) 100%, 381.4 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](N)=[O:10])=[C:7]([OH:14])[N:6]=1)[CH2:2][CH:3]=[CH2:4].Cl.[OH-:16].[K+]>>[CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:16])=[O:10])=[C:7]([OH:14])[N:6]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCc1ccc(C(N)=O)c(O)n1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: C=CCCc1ccc(C(=O)O)c(O)n1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of b1 (12.38 g, 70.1 mmol) in 10% aqueous KOH (350 mL) was heated to reflux for 20 h and subsequently cooled to room temperature. The reaction mixture was acidified with 12 M HCl to pH 2-3, and the resulting precipitate was filtered, washed with water (2×50 mL), and dried under vacuum to afford c1 as a yellow solid (12.46 g, 92%): mp=151-155° C.; IR(cm−1) 2905 (br), 1736, 1652; 1H NMR (DMSO-d6) δ 2.34-2.29(m, 2H), 2.73 (t, 2H, J=7.6), 4.96-5.07 (m, 2H), 5.72-5.85 (m, 1H), 6.56 (d, 1H, J=7.5), 8.28 (d, 1H, J=7.5), 13.26 (s, br, 1H), 14.64 (s, br, 1H); Anal. C10H11NO3·0.10H2O: C, H, N.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:13][OH:14])=[CH:8][CH:7]=1)[CH3:4].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][C:21]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:14][CH2:13][CH:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:3][CH3:4])=[CH:11][CH:10]=2)[C:15]([F:16])([F:17])[F:18])=[CH:22][C:21]=1[O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOc1ccc(C(CO)C(F)(F)F)cc1
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(COCc2ccc(F)c(Oc3ccccc3)c2)C(F)(F)F)cc1
Reaction time: 15 h
Yield: 63.7 %

Procedure:
Under a nitrogen atmosphere, 113 mg of sodium hydride (60% oil dispersion) was added to 20 ml of dry DMF. A solution of 0.60 g of 2-(4-ethoxyphenyl)-3,3,3-trifluoropropanol and 0.65 g of 4-fluoro-3-phenoxybenzyl bromide in 5 ml of dry DMF was then added at room temperature, and the reaction solution was stirred at that temperature for 15 hours. Thereafter, the reaction mixture was poured into dilute HCl-ice water and extracted twice with diethyl ether. The ether layers were combined, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure, and the residue was subjected to column chromatography on silica gel [eluted with n-hexane/ethyl acetate (25:1) mixture] to obtain 0.64 g of the desired compound.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[K+].S(O[CH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:31][CH2:30]1)(C1C=CC(C)=CC=1)(=O)=O>C1(C)C(C)=CC=CC=1>[CH3:5][C:4]([CH3:7])([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][O:11][CH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[CH2:31][CH2:30]1)=[O:2])[CH3:6]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To BOC-L-prolinol (10 mmol) in xylene (10 mL) was added KOH (20 mmol), 4-tosyloxymethyl-N-carbobenzyloxy piperidine (11 mmol) and the reaction was heated to reflux for 3 hours. The reaction mixture was stirred at room temperature for 16 hours, quenched with NH4Cl, extracted with ethyl acetate and purified by column chromatography to provide the title ether.
Reaction SMILES: N1C=CC=CC=1.[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18](=[O:20])[CH3:19])[C@@H:13]([CH3:21])[CH2:12][NH:11]2.[Cl:22][C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[C:18]([N:14]1[C:15]2[C:10](=[CH:9][C:8]([Br:7])=[CH:17][CH:16]=2)[N:11]([C:23]([Cl:22])=[O:25])[CH2:12][C@@H:13]1[CH3:21])(=[O:20])[CH3:19]
Reactant: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1c2ccc(Br)cc2N(C(=O)Cl)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pyridine (0.150 mL, 1.86 mmol) was added to a solution of (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)ethanone (0.500 g, 1.86 mmol) in dichloromethane (6.6 mL). Triphosgene (0.197 g, 0.663 mmol) was then added in portions over ten minutes, and the reaction mixture stirred for 2 h at room temperature. The reaction was diluted with dichloromethane and washed with 1 N aqueous HCl solution. The organic phase was separated and washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated in a Genevac to afford (S)-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carbonyl chloride, which was dissolved in 1,2-dichloroethane (9.0 mL) to afford a 0.2 M solution.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:34]=[CH:33][C:11]([O:12][CH2:13][CH2:14][N:15]3[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]4[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=4)[CH2:17][CH2:16]3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][N:15]3[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=4)[CH2:17][CH2:16]3)=[CH:33][CH:34]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(CN2CCCN(CCOc3ccc(Cc4ccccc4)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CN2CCCN(CCOc3ccc(Cc4ccccc4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 86.2 %

Procedure:
A solution of methyl 4-[[hexahydro-4-[2-[4-(phenylmethyl)phenoxy]ethyl]-1H-1,4-diazepin-1-yl]methyl]benzoate (55 mg, 0.12 mmol) in methanol (4 mL) was stirred as a solution of aqueous sodium hydroxide (0.60 mL, 2 M) was added. The reaction was stirred for 17 hours at ambient temperature. The reaction was concentrated under reduced pressure. The residue was diluted with water, adjusted to pH 8 with 1 M aqueous hydrochloric acid, and extracted with butanol. The combined organic layers were concentrated under reduced pressure. Flash chromatography gave 46 mg of 4-[[hexahydro-4-[2-[4-(phenylmethyl)phenoxy]ethyl]-1H-1,4-diazepin-1-yl]methyl]benzoic acid; 1H NMR (300 MHz, CD3OD) δ 7.94 (d, 2H), 7.36 (d, 2H), 7.21 (dd, 2H), 7.13 (d, 2H), 7.12 (dd, 1H), 7.07 (d, 2H), 6.82 (d, 2H), 4.08 (t, 2H), 3.82 (s, 2H), 3.75 (s, 2H), 3.05 (t, 2H), 2.99 (m, 4H), 2.81 (m, 2H), 2.80 (m, 2H), 1.88 (m, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[OH:12][NH2:13].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:13][OH:12])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 115.4 %

Procedure:
4-Methoxybenzaldehyde (10.0 g, 73.4 mmol) was dissolved in 200 mL of ethanol. A solution of hydroxyamine hydrochloride (6.38 g, 91.8 mmol) in 50 mL of H2O was added followed by a solution of sodium acetate (12.1 g, 146.8 mmol) in 50 mL of H2O. The mixture was stirred at room temperature under N2 for 12 h. The ethanol was removed in vacuo and the aqueous mixture was extracted with EtOAc. The EtOAc solution was washed with brine, dried over MgSO4, and concentrated to afford 12.8 g of light yellow oil. 1H NMR showed it was 80% pure (92% yield). This material was taken into the next step without further purification. (CDCl3): δ2.15 (s, 1H); 3.83 (s, 3H); 6.92 (d, 2H); 7.50 (d, 2H); 8.10 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][O:14][CH3:15]>CCOC(C)=O.C(O)C.[Pt]>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][O:14][CH3:15])[NH2:8]
Reactant: COCCOc1ccc([N+](=O)[O-])cc1Cl
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COCCOc1ccc(N)cc1Cl
Reaction time: 16 h
Yield: 97.6 %

Procedure:
2-Chloro-1-{[2-(methyloxy)ethyl]oxy}-4-nitrobenzene (1.0 g) was dissolved in a 1:1 solution of EtOAc and ethanol (30 mL). Pt/C (0.15 g of 10% by weight) was added and the resulting mixture was placed under 50 psi of H2 for 16 h. The reaction was then filtered through celite and the resulting organics were concentrated in vacuo to obtain 0.85 g of the compound. 1H NMR (300 MHz, DMSO-d6): δ 6.88 (d, 1H), 6.66 (m, 1H), 6.50 (m, 1H), 4.00 (m, 2H), 3.63 (m, 2H), 3.33 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:31]4[CH2:32][CH2:33][N:28]([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=5)[CH2:29][CH2:30]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2ccccn2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1-pyridin-2-yl-piperazine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=449.