Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[O:3].Cl.O1CCOCC1.[CH3:17][C:18]([OH:23])([CH2:21][CH3:22])[CH2:19][CH3:20]>ClCCl>[CH2:19]([C:18]([CH3:17])([O:23][C:2]([NH:1][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3])[CH2:21][CH3:22])[CH3:20]
Reactant: CCOC(=O)CN=C=O
Reactant: CCC(C)(O)CC
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)OC(C)(CC)CC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.500 ml (4.01 mmol) of ethyl isocyanatoacetate was dissolved in dichloromethane. 0.05 ml of 4 N hydrochloric acid/1,4-dioxane solution was added to the obtained solution, and they were stirred at room temperature for 5 minutes. 0.547 ml (4.41 mmol) of 3-methyl-3-pentanol was added to the reaction mixture, and they were stirred overnight. After the concentration under reduced pressure, ethyl acetate was added to the reaction mixture, and they were washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was washed with diethyl ether. The filtrate was concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][CH2:34][CH2:35][NH2:36].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:36][CH2:35][CH2:34][NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCNc1ccccn1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(Cc3ccccc3)c12
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1c(NCCNc2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)cn(Cc3ccccc3)c12
Temperature: 0 °C
Yield: 53.8 %

Procedure:
A solution of 5-amino-1-benzyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (400 mg, 1.11 mmol), N-2-pyridyl-1,2-ethanediamine (305 mg, 2.22 mmol) and triethylamine (0.310 mL, 2.22 mmol) in DMSO (4 mL) was stirred at 100° C. After 4 h the reaction mixture was poured into ice water and the resulting precipitate was removed by filtration, washed with ethanol, and dried to yield 5-amino-1-benzyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (285 mg, 54%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].II.[CH:11]([C:13]1[C:21]2[O:20][CH2:19][CH:18]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[C:17]=2[C:16]([CH3:31])=[C:15]([NH:32][C:33](=[O:39])[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:14]=1[CH3:40])=[O:12]>C1COCC1>[OH:12][CH:11]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]1[C:21]2[O:20][CH2:19][CH:18]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[C:17]=2[C:16]([CH3:31])=[C:15]([NH:32][C:33](=[O:39])[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:14]=1[CH3:40]
Reactant: Brc1ccccc1
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1C(O)c1ccccc1)OCC2c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.6 %

Procedure:
A solution of bromobenzene (770 mg, 4.91 mmol) in THF (10 mL) was added under an argon atmosphere to a mixture of magnesium (119 mg, 4.91 mmol) and a catalytic amount of iodine, and the resulting mixture was stirred at room temperature for 20 minutes. To the reaction solution was added dropwise a solution of N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (400 mg, 0.98 mmol) obtained in Example 20 in THF (5 mL) and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was added to ice and the product was extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 512 mg (yield: 99%) of the title compound. Yield: 99%. Oily matter.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][NH2:17].C(O)(=O)C>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([NH:17][CH3:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CCN(Cc2ccccc2)CC1=O
Reactant: CN
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC1CN(Cc2ccccc2)CCC1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.75 %

Procedure:
To a stirred solution of the product from Method E (3.81 grams/0.019 mol) and 38 mL of 2.0 M methylamine in THF was added 2.2 mL of acetic acid and the resulting mixture stirred at room temperature for 1.5 hours. Triacetoxysodiumborohydride (NaB(OAc)3H) (7.94 grams/0.038 mol) was added as a solid and the new mixture stirred at room temperature for 18 hours. The reaction was quenched with 2 N hydrochloric acid and the pH adjusted to 1. The reaction mixture was washed two times with ether, the aqueous layer then adjusted to pH of 12 with 6 N sodium hydroxide (aq) and extracted three times with dichloromethane The combined dichloromethane layers were dried over Na2SO4, filtered and evaporated to dryness in vacuo affording 3.51 grams (87.75%) of the title compound as dark yellow oil. LRMS: 219.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11](Cl)[C@H:10]1[OH:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:26])[CH2:22][CH:23]([CH3:25])[CH3:24].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:21]([NH:26][C@H:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:10]1[OH:20])[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@@H](Cl)[C@H]1O
Reactant: CC(C)CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CCN[C@H]1c2ccccc2C[C@@H](NC(=O)OC(C)(C)C)[C@H]1O

Procedure:
Under argon a solution of (1R,2S,3R)-3-tert-butoxycarbonylamino-1-chloro-1,2,3,4-tetrahydro-2-naphthalenol (BOC-amino-cis-chlorohydrin) (500 mg) in anhydrous tetrahydrofuran was refluxed with isoamylamine (1.0 ml) and triethylamine (250 μl) for 5 hours at 90° C. The mixture was poured in aqueous 5% sodium bicarbonate and extracted with methylene chloride. The organic solution was dried over magnesium sulfate and evaporated under vacuum to yield an oil. Crystallization of this oil in hexane yielded the title compound as a white solid (270 mg).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.C(O[C:10](=[NH:17])[CH2:11][C:12](OCC)=[O:13])C.[NH:18]1[C:22]([NH2:23])=[CH:21][CH:20]=[N:19]1>C(OCC)(=O)C.C(O)C>[NH2:17][C:10]1[NH:23][C:22]2[N:18]([N:19]=[CH:20][CH:21]=2)[C:12](=[O:13])[CH:11]=1
Reactant: Nc1ccn[nH]1
Reactant: CCOC(=N)CC(=O)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(=O)n2nccc2[nH]1
Temperature: 0 °C

Procedure:
Sodium bicarbonate (3.9 g, 46.2 mmol) is added in small portions to a mixture of ethyl 3-ethoxy-3-iminopropanoate hydrochloride (Z-1) (8.6 g, 44.0 mmol) in crushed ice (100 g) and ethyl acetate (50 mL) until the pH value reaches 8-9. The organic layer is separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers are dried over anhydrous MgSO4 and filtered. The filtrate is concentrated in vacuo to afford a colourless oil which is added to a solution of 1H-pyrazol-5-amine (3.65 g, 44.0 mmol) in ethanol (100 mL). The resulting mixture is then degassed and backfilled with argon (three cycles) and stirred at reflux overnight. The mixture is then filtered while it was still warm. The solid is rinsed with cold ethanol (25 mL) and ether (2×25 mL), and then dried in vacuo to afford 5-aminopyrazolo[1,5-a]pyrimidin-7(4H)-one (Z-2).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[CH:4]1.[C:10]([O:16][CH2:17]Cl)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]>O1CCCC1.CN(C=O)C>[C:10]([O:16][CH2:17][N:3]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[CH:4]1)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1cnc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a suspension of sodium hydride (60% in oil, 1.0 g, 26 mmol) in tetrahydrofuran (10 ml) was added dropwise a solution of 1H-imidazole-4-carbaldehyde (1.92 g, 20 mmol) in DMF (5 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. Chloromethyl pivalate (3.92 g, 26 mmol) was further added dropwise at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with 6% aqueous sodium hydrogen carbonate solution and saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (100 g), and eluted with hexane-ethyl acetate (4:1-1:2, v/v) to give the title compound (4.11 g, 98%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[N:23]=[C:24]=[O:25]>C(Cl)Cl>[C:11]([C:3]1[NH:4][C:5]([C:7]([CH3:10])([CH3:8])[CH3:9])=[CH:6][C:2]=1[NH:1][C:24]([NH:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[Cl:15])=[O:25])([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1[nH]c(C(C)(C)C)cc1N
Reactant: O=C=Nc1cccc(Cl)c1Cl
Solvent: ClCCl
Product: COC(=O)c1[nH]c(C(C)(C)C)cc1NC(=O)Nc1cccc(Cl)c1Cl
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a solution of methyl 3-amino-5-tert-butylpyrrole-2-carboxylate (0.99 g, 5.00 mmol) in anh. CH2Cl2 (50 ml) at room temp. was added a solution of 2,3-dichlorophenyl isocyanate (0.948 g, 5.00 mmol) in CH2Cl2 (10 mL) and the resulting mixture was allowed to stir overnight. The resulting white precipitate formed overnight was separated and washed with CH2Cl2 to give the desired urea (1.39 g, 67%) as a white powder: mp 200-201° C.; 1H-NMR (DMSO-d6) δ1.23 (s, 9H), 3.78 (s, 3H), 6.50 (d, J=2.95 Hz, 1H), 7.26-7.30 (m, 2H), 7.88-7.91 (m, 1H), 9.12 (s, 1H), 9.40 (s, 1H), 10.91 (br s, 1H); FAB-LRMS m/z 384 (M+H). Anal. Calcd for C17H19N3O3Cl2: C, 53.14; H, 4.98; N, 10.94. Found: C, 53.03; H, 4.79; N, 10.86.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.[C-]#N.[Na+].CN(C)[CH:14]=[O:15]>O>[CH:14]1([O:15][C:4]2[CH:8]=[CH:7][S:6][CH:5]=2)[CH2:7][CH2:8][CH2:4][CH2:5]1
Reactant: Brc1ccsc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: c1cc(OC2CCCC2)cs1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a solution of cyclocentanol (8.75 ml, 95.8 mmol) in N,N-dimethylformamide (250 mL) was added sodium hydride (60% dispersion in mineral oil, 3.84 g, 95.8 mmol) at 0-5° C. under nitrogen. After 10 minutes, the mixture was allowed to reach room temperature and stirred for 40 minutes. 3-Bromothiophene (3.59 mL, 38.3 mmol) was added followed by cuprous iodide (14.63 g, 76.8 mmol). The mixture was heated at 120° C. for 22 hours. After cooling to about 10° C., a solution of sodium cyanide (12.1 g, 0.25 mol) in water (200 mL) was added under vigorous stirring. The mixture was stirred for additional 10 minutes then filtered. The filtrate was extracted with hexane. The extract was washed with water, dried (Na2SO4) and concentrated to dryness. Distillation (100° C., 8 mm Hg) gave 3-cyclopentyloxythiopene (4.52 g, 70%) as a slightly pale yellow oil; 1H NMR (300 Mz, CDCl3) δ 7.15 (dd, J=5.2, 3.1 Hz, 1H), 6.72 (dd, J=5.2, 15 Hz, 1H) 6.19 (dd, J=3.1, 1.5 Hz, 1H), 4.65 (quintet, J=4.2 Hz), 1H), 1.55-1.95 (m, 8H). MS m/e (%): 168 (M+; 17).
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])[C:23]([Cl:37])=[CH:22][N:21]=1>>[Cl:37][C:23]1[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])=[N:25][C:20]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([F:1])[F:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:21][CH:22]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(F)F)CC2
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(F)F)CC3)ncc1Cl

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in an analogous manner to Example 61e. Product isolated as an off-white solid (0.005 g, 5%). MP: 169-172° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 11.23 (br s, 1H), 8.58 (d, 1H, J=8.6 HZ), 8.06 (s, 1H), 7.97 (br s, 1H), 7.50 (d, 1H, J=7.8 Hz), 7.38 (t, 1H, J=7.8 Hz), 7.10 (t, 1H, J=7.6 Hz), 6.66 (s, 1H), 6.26 (br s, 1H), 6.20-5.87 (m, 1H), 3.86 (s, 3H), 3.15-2.75 (m, 14H). MS: 517 (MH)+.
Reaction SMILES: Cl.[NH2:2]O.C([O:6][C:7](=O)[CH2:8][C:9](=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])C>>[CH2:10]([C:9]1[O:21][N:2]=[C:7]([OH:6])[CH:8]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: NO
Reactant: CCCCCCCCCCCC(=O)CC(=O)OCC
Agent: Cl
Product: CCCCCCCCCCCc1cc(O)no1

Procedure:
The above-identified compound was synthesized according to the process of (Example 1) using hydroxylamine hydrochloride and dodecanoylacetic acid ethylester as raw materials.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(Cl)(Cl)=O.Cl[CH:19](Cl)C>>[Cl:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:19])=[O:10])=[CH:12][CH:13]=1)(=[O:4])=[O:3]
Reactant: CC(Cl)Cl
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
4-Chlorosulfonyl benzoic acid (5 g, 23 mmol) and thionyl chloride (20 mL) in dichloroethane (10 mL) was heated to 80° C. for 2 hr. The reaction mixture was concentrated via rotary evaporation to give a brownish solid. The solid was chilled on ice for 5 minutes and ice-cold methanol (40 mL) was added with stirring at 0° C. for 5 minutes. The reaction mixture was allowed to warm to ambient temperature and stirred an additional 10 min. The addition of ice-cold water (40 mL), produced a white solid that was collected by filtration and dried under vacuum to afford pure methyl 4-(chlorosulfonyl)benzoate (4.5 g, 84%). NMR (400 MHz, DMSO-d6): δ, ppm: 3.84 (s, 3H), 7.70 (d, 2H, J=8.4 Hz), 7.93 (d, 2H, J=8.4 Hz).
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Si:14]([O:21][CH2:22][C:23]1[CH:49]=[CH:48][C:26]([C:27]([NH:29][NH:30][C:31](=[O:47])[C@H:32]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[C:39]([Cl:45])[C:38]=2[CH3:46])[C@@H:33]([OH:35])[CH3:34])=[O:28])=[CH:25][CH:24]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>CN(C=O)C>[Si:10]([O:35][C@@H:33]([CH3:34])[C@@H:32]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[C:39]([Cl:45])[C:38]=1[CH3:46])[C:31]([NH:30][NH:29][C:27](=[O:28])[C:26]1[CH:48]=[CH:49][C:23]([CH2:22][O:21][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])=[CH:24][CH:25]=1)=[O:47])([C:7]([CH3:9])([CH3:8])[CH3:6])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)[C@H](C)O)ccc(C#N)c1Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 135 %

Procedure:
Imidazole (3.99 g, 58.55 mol) and TBDMS-Cl (5.29 g, 35 mmol) were added sequentially to a pre-cooled (0° C.) solution of 4-((tert-butyldimethylsilyloxy)methyl)-N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)benzohydrazide (6.22 g, 11.71 mmol) in DMF (300 mL). The reaction mixture was allowed to warm to room temperature and stirred for 18 h, whereupon the solution was poured into H2O (120 mL). The white precipitate was filtered, washed with H2O (30 mL) and taken up in CH2Cl2 (200 mL). This organic layer was washed with brine (1×100 mL), dried (Na2SO4), filtered and concentrated to provide the title compound (10.2 g). This crude product was used directly in the next step.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C@@H:28]1[O:32][N:31]=[C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([N:45]4[CH2:49][C@H:48]([CH2:50][NH:51][C:52](=[O:54])[CH3:53])[O:47][C:46]4=[O:55])=[CH:41][CH:40]=3)=[CH:35][CH:34]=2)[CH2:29]1)(C(C)(C)C)(C)C.C(OCC)(=O)C>C1COCC1>[OH:26][CH2:27][C@@H:28]1[O:32][N:31]=[C:30]([C:33]2[CH:34]=[CH:35][C:36]([C:39]3[CH:40]=[CH:41][C:42]([N:45]4[CH2:49][C@H:48]([CH2:50][NH:51][C:52](=[O:54])[CH3:53])[O:47][C:46]4=[O:55])=[CH:43][CH:44]=3)=[CH:37][CH:38]=2)[CH2:29]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NO[C@@H](CO[Si](C)(C)C(C)(C)C)C4)cc3)cc2)C(=O)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NO[C@@H](CO)C4)cc3)cc2)C(=O)O1
Reaction time: 2 h
Yield: 59.7 %

Procedure:
A solution of tetrabutylammonium fluoride in THF (1M, 0.69 ml, 0.69 mM) was added to a solution of N-[((5S)-3-{4′-[(5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4,5-dihydroisoxazol-3-yl]-1,1′-biphenyl-4-yl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (300 mg, 0.57 mM) in THF (5 ml). After approximately 2 hours, ethyl acetate was added and the resulting suspension was filtered. The filter cake was washed with water and ethyl acetate to give 140 mg of the title product.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)[C@H:8]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(OCCN2CCCCC2)cc1

Procedure:
In an manner analogous to that described in step 5 for Example 10, (±)-cis-7-methoxy-3-phenyl-4-(4-(2-piperidinoethoxy)phenyl)chromane (0.89 g, 2.0 mmol) was de-methylated by heating with pyridine hydrochloride to give the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:10]O)=[CH:4][CH:3]=1.Cl.NC(C1C=CN=C([Cl:41])C=1)C(C1C=CC(F)=CC=1)=O>>[ClH:41].[NH2:10][CH:9]([C:12]1[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH:19]([CH3:21])[CH3:20])[CH:13]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:22]
Reactant: NC(C(=O)c1ccc(F)cc1)c1ccnc(Cl)c1
Reactant: CC(C)Oc1cc(C(=NO)C(=O)c2ccc(F)cc2)ccn1
Agent: Cl
Product: CC(C)Oc1cc(C(N)C(=O)c2ccc(F)cc2)ccn1

Procedure:
23c was prepared from 22c (2.0 g; 7.6 mmol) using the method described in the synthesis of 23a.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:34])([CH3:33])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:12]([O:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])=[O:13])(=[O:7])=[O:6].[N-:35]=[N+:36]=[N-:37].[Na+]>CS(C)=O>[N:35]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:34])([CH3:33])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:12]([O:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])=[O:13])(=[O:7])=[O:6])=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CO[C@@H](C(=O)O[C@H](C)c2ccccc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CO[C@@H](C(=O)O[C@H](C)c2ccccc2)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-])cc1

Procedure:
Following the general procedure for the preparation of azides of Description 16, (1R)-1-phenylethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (34a) (0.42 g, 0.82 mmol) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 75 mg (1.15 mmol) of sodium azide (NaN3). After work-up, the crude title compound (34b) was used in the next step without further purification. MS (ESI) m/z 542.02 (M+Na)+.
Reaction SMILES: [O:1]=[C:2]([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=[O:5].Cl>C1COCC1>[CH2:7]([C:2]1[O:5][C:4](=[O:6])[C:3]([C:2](=[O:1])[CH2:7][CH3:8])=[C:4]([OH:5])[CH:3]=1)[CH3:8]
Reactant: CCC(=O)CC(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: CCC(=O)c1c(O)cc(CC)oc1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
3-Oxopentanoic acid (II in Scheme 1; Example 1.1; 2 g; 17.2 mmol) was dissolved in 30 ml THF and cooled to 0° C. To the solution, was added dicarbodiimidazole (3.6 g; 22.2 mmol; Aldrich). The reaction mixture was stirred for 18 h at 25° C., neutralized with 2% HCl, extracted with 3×30 ml EtOAc, dried with anhydrous Na2SO4, and evaporated to a white solid. The product was purified via silica chromatography (20% EtOAc in hexanes).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(CN2CCOCC2)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
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: CCO
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCOCC2)cc1
Temperature: 120 °C
Yield: 19.6 %

Procedure:
100 mg of 4-(4-Bromo-benzyl)-morpholine was combined with 111 mg of 2-(Trifluoromethyl)phenyl boronic acid, 23 mg of tetrakis(triphenylphosphine)palladium(0), 1.3 mL of 2M sodium carbonate solution, 3.6 mL toluene and 1.7 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was purified by flash chromatography using flash chromatography followed by reverse phase HPLC. 24.6 mg of product is obtained. ES MS (+) m/z 322