Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[O:15][CH3:16])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[Cl:21][S:22](O)(=[O:24])=[O:23]>C(Cl)Cl>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:20]=[C:19]([S:22]([Cl:21])(=[O:24])=[O:23])[CH:18]=[CH:17][C:3]2=3)=[C:8]([O:15][CH3:16])[CH:9]=1)#[N:12]
Reactant: O=S(=O)(O)Cl
Reactant: COc1cc(C#N)ccc1N1CCOc2ccccc21
Solvent: ClCCl
Product: COc1cc(C#N)ccc1N1CCOc2cc(S(=O)(=O)Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.4 %

Procedure:
To a solution of 4-(2H-benzo[b][1,4]oxazin-4(3H)-yl)-3-methoxybenzonitrile (790 mg, 2.96 mmol) in DCM (10 mL) was added chlorosulfonic acid (0.79 mL, 11.8 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h. After completion, reaction mixture was poured into ice water (15 mL), quenched with solid sodium bicarbonate (pH˜9-10) and the aqueous layer was extracted with ethyl acetate (2×20 mL). The organic layer was dried over sodium sulfate and concentrated to get 4-(4-cyano-2-methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride as a sticky yellow solid (220 mg, 20.3%) which was used without further purification in the next step.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=5)[NH:15][C:14]4=[O:24])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[C:25]([O:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)(=[O:27])[CH3:26]>>[C:25]([O:28][CH:29]1[CH2:30][CH2:31][N:32]([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[C:10]4[C:5](=[CH:6][C:7]([C@H:11]5[C@@:13]6([C:21]7[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=7)[NH:15][C:14]6=[O:24])[CH2:12]5)=[CH:8][CH:9]=4)[NH:4][N:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(N5CCC(OC(C)=O)CC5)cc4)n[nH]c3c1)C(=O)N2
Yield: 40.4 %

Procedure:
The title compound was synthesized according to the method described for example A45 except reacting a (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (76 mg, 0.18 mmol) with 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl acetate (67 mg, 0.19 mmol). Crude product was purified by flash chromatography using EtOAc/Hexanes (2:3 to 1:0) to give the title compound as a yellow solid (38 mg, 41%). MS ESI 523.3[M+H]+, calcd for [C31H30N4O4+H]+ 523.23.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([C:14](Cl)=[O:15])=[CH:7][C:6]=1[O:17][CH2:18][CH3:19])[CH3:2].[S].N1C2C(=CC=CC=2)C=CC=1.[H][H]>[Pd]>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([CH:14]=[O:15])=[CH:7][C:6]=1[O:17][CH2:18][CH3:19])[CH3:2]
Reactant: CCOC(=O)c1c(OCC)cc(C(=O)Cl)cc1OCC
Reactant: [H][H]
Agent: [Pd]
Agent: [S]
Solvent: c1ccc2ncccc2c1
Product: CCOC(=O)c1c(OCC)cc(C=O)cc1OCC

Procedure:
A mixture of 12 g. of 4-(chloroformyl)-2,6-diethoxy-benzoic ethyl ester, 1.4 g. of palladium/barium sulfate catalyst (5%) and 0.2 ml. of quinoline sulfur regulator are heated under an atmosphere of nitrogen at 120° with stirring. Thereafter, hydrogen is passed through the reaction mixture at 120° until 90% of the theoretical amount of acid salt is freed. The reduction is stopped, and the suspension under an atmosphere of nitrogen is cooled to 25°. The catalyst is removed by filtration and the filtrate is evaporated to dryness under vacuum, whereby there is obtained 2,6-diethoxy-4-formylbenzoic acid ethyl ester as a colorless oil. A sample after recrystallization from low boiling petroleum ether yields pure 2,6-diethoxy-4-formylbenzoic acid ethyl ester having a m.p. of 45°-46°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N-:12][C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17]Cl)[C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10])([O-:3])=[O:2].[OH-].[Na+].Cl>O1CCCC1.O>[N+:1]([C:4]1[CH:5]=[C:6]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=[O:19])[C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10])([O-:3])=[O:2]
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1[N-]C(=O)CCCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c([N+](=O)[O-])cc1N1CCCCC1=O

Procedure:
77 g (0.27 mol) of N-(3-nitro-4,6-dimethylphenyl)-δ-chlorovaleroylamide are stirred vigorously in a mixture of 50 ml of tetrahydrofurane and 500 ml of 22% strength aqueous sodium hydroxide solution for 5 hours at 60°-65°. The reaction mixture is diluted with water, cooled and acidified with hydrochloric acid. The product which has precipitated is washed until neutral and dried in a desiccator at 70°. This gives 62.8 g (93%); melting point 134°-135° .
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[N:36][CH:37]=1)=[O:31].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:35]=[N:36][CH:37]=[C:32]([CH:33]=4)[C:30]([O:29][CH3:28])=[O:31])=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1cncc(B(O)O)c1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)c1cncc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)c1
Temperature: 100 °C
Yield: 74.4 %

Procedure:
A mixture of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (250 mg, 0.6 mmol), 5-(methoxycarbonyl)pyridin-3-ylboronic acid (163 mg, 0.9 mmol), PdCl2(PPh3)2 (50 mg, 20%) and aqueous Cs2CO3 solution (2 M, 2 mL) in 1,4-dioxane (6 mL) was heated to reflux at 100° C. overnight under N2. The mixture was filtered, and the filtrate was extracted with EtOAc for 3 times. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to the crude product, which was purified by preparative HPLC to give methyl 5-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate (220 mg, crude).
Reaction SMILES: [OH-].[Na+].[I:3][C:4]1[C:12]2[CH:11]=[CH:10][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][C:7]=2[N:6](S(C2C=CC(C)=CC=2)(=O)=O)[N:5]=1.C(OCC)(=O)C>O1CCCC1>[I:3][C:4]1[C:12]2[CH:11]=[CH:10][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][C:7]=2[NH:6][N:5]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(I)c3c2CC(c2ccccc2)(c2ccccc2)C=C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Ic1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Yield: 110 %

Procedure:
3 cm3 of aqueous 1N sodium hydroxide solution are added to a solution of 0.55 g of 3-iodo-6,6-diphenyl-1-(4-toluenesulphonyl)-6,7-dihydro-1H-indazole in 10 cm3 of tetrahydrofuran. After stirring for about 36 hours at a temperature in the region of 20° C., 30 cm3 of ethyl acetate are added. After separation of the phases by settling, the organic phase is washed with three times 15 cm3 of water, 20 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). 0.436 g of 3-iodo-6,6-diphenyl-6,7-dihydro-1H-indazole is obtained in the form of a solid, the characteristics 30′ of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[O:6].[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].N12CCN(CC1)CC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[C:12](=[CH2:13])[C:11]([O:15][CH3:16])=[O:14])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: C=CC(=O)OC
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: C=C(C(=O)OC)C(O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3,4-dichlorobenzaldehyde (17.5 g) and methyl acrylate (8.6 mL) in acetonitrile (100 ml) was added 1,4-diazabicyclo[2.2.2]octane (3.36 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (18.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32]3[CH2:31][CH2:30][CH2:29][NH:28][C:27]=3[CH:26]=[N:25]2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([N:28]2[CH2:29][CH2:30][CH2:31][C:32]3[N:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=4)[N:25]=[CH:26][C:27]2=3)=[O:11])=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14]
Reactant: CC(C(=O)O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
To a mixture of 2-[4-chloro-3-(trifluoromethyl)phenyl]propanoic acid (47 mg, 0.184 mmol) and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (40 mg, 0.184 mmol) in DMF (1 mL) was added Hunig's base (59 mg, 0.46 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uranium hexafluorophosphate methanaminium (HATU) (77 mg, 0.2 mmol). The mixture was stirred at room temperature for 1 hour, and then was partitioned between water (4 mL) and ethyl acetate (6 mL). The organic layer was washed with brine and dried (Na2SO4), filtered, concentrated in vacuo, and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the desired product as a white solid (24 mg, 29%). 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.48-7.42 (m, 4H), 7.16-7.11 (m, 2H), 4.11 (m, 1H), 3.76 (m, 1H), 3.52 (m, 1H), 2.77 (m, 2H), 1.96 (m, 1H), 1.80 (m, 1H), 1.55 (d, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C22H18ClF4N3O [M+H]+ 452.1, found 452.1.
Reaction SMILES: O[CH:2]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1>C(O)C>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17]
Reactant: COc1cccc(C(O)[C@@H]2CCCCC2=O)c1
Solvent: CCO
Product: COc1cccc(C[C@@H]2CCCCC2=O)c1
Reaction time: 4 h
Yield: 107.3 %

Procedure:
To a solution of (2S)-2-[1-hydroxy-1-(3-methoxyphenyl)methyl]cyclohexanone (0.8 g) in ethanol (20 ml) was added paradium on carbon (0.5 g). After being stirred for 4 hours under hydrogen atmosphere, the reaction mixture was filtered. The solvent was evaporated to give (2S)-2-(3-methoxybenzyl)cyclohexanone (0.8 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:15])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.[I:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[NH:22][C:21](=[O:28])[C:20]2=[CH:29]OC>CN(C)C=O>[OH:15][C:5]1[CH:4]=[C:3]([CH2:2][NH:1][CH:29]=[C:20]2[C:19]3[C:24](=[CH:25][CH:26]=[C:17]([I:16])[CH:18]=3)[C:23](=[O:27])[NH:22][C:21]2=[O:28])[CH:8]=[CH:7][C:6]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Reactant: NCc1ccc(-c2ccccc2)c(O)c1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Yield: 89.5 %

Procedure:
4-Aminomethyl-biphenyl-2-ol (80 mg, 0.4 mmol) and 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (110 mg, 0.34 mmol) is stirred in N,N-dimethylformamide (5 mL). After which N,N-dimethylformamide is removed under vacuum and the residue is triturated with MeOH. The precipitate thus formed is collected and washed with MeOH and dried to provide the title compound (151 mg, 89%). MS (ESI): 495.1 (M−1)−1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][C:16]([C:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20][N:19]=2)=[O:17])=[CH:4][C:5]([F:14])=[C:6]([CH2:8][C:9]([O:11]CC)=[O:10])[CH:7]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[C:3]([NH:15][C:16]([C:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20][N:19]=2)=[O:17])=[CH:4][C:5]([F:14])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2nsc3ccccc23)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1cc(Cl)c(NC(=O)c2nsc3ccccc23)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
Methyl 4-amino-5-chloro-2-fluorophenylacetate (753 mg, 3.25 mmol), benzo(d)isothiazole-3-carboxylic acid (583 mg, 3.25 mmol), HOBt (834 mg, 6.18 mmol), EDC HCl (934 mg, 4.88 mmol) and DMAP (catalytic amount) were dissolved in DMF (16 ml). The resulting solution was stirred for 10 hours at 80° C. After cooling, the reaction mixture was poured in 1M HCl, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (middle pressure, n-hexane/ethyl acetate 9:1, 15 ml/min, φ 50×300 mm) to give ethyl (5-chloro-2-fluoro-4-((3-benzo(d)isothiazolylcarbonyl)amino)phenyl)acetate. The resulting ester was dissolved in THF/methanol (4 ml, 3:1), and to the resulting solution was added 1M NaOH (1 ml). The mixture was stirred for 18 hours at room temperature. The solvent was distilled off under reduced pressure, and the residue was poured in 1M HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (5-chloro-2-fluoro-4-((3-benzo(d)isothiazolylcarbonyl)amino)phenyl)acetic acid (354 mg, 30%) as a colorless solid.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([O:17][C:18](=[O:26])[C:19](=[O:25])[C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)[CH2:10]2.[Cl-].[NH4+].CCOCC>C1COCC1.N#N>[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([O:17][C:18](=[O:26])[C:19]([C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)([OH:25])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:10]2
Reactant: Br[Mg]c1ccccc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1ccco1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1ccccc1)c1ccco1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
Phenylmagnesium bromide, 0.0057 mol (5.7 ml of a solution 1M in THF), was added to a solution of 1.3 g (0.0052 mol) of oxofuran-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-4e-) dissolved in 15 ml of THF, at −701C in N2 atmosphere. The mixture was stirred at this temperature for 10 minutes, and then warmed to room temperature. After 1 hour, the reaction mixture was treated with a saturated solution of ammonium chloride and extracted three times with ethyl acetate The organic phases were combined, washed with water and dried over Na2SO4. After removal of the solvent, the solid obtained was treated with ether and filtered to yield 0.67 g (40%) of a product whose structure was confirmed by 1H-NMR. This compound was also prepared as is described in Example I-1a (Method c). The diastereomers were separated by crystallization from acetonitrile and distinguished by 1H-NMR.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25]>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([NH:27][CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CC(C)CN
Solvent: CS(C)=O
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example B5) (5.00 g, 14.7 mmol), isobutyl-amine (7.36 mL, 73.4 mmol) in DMSO (35 mL) at RT according to the general procedure C. Obtained as a yellow solid (5.39 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH:7]2[O:9][CH2:8]2)=[CH:5][C:4]=1[O:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.[C:22]1([CH2:28][CH2:29][CH:30]([NH2:32])[CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH:7]([OH:9])[CH2:8][NH:32][CH:30]([CH3:31])[CH2:29][CH2:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:5][C:4]=1[O:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: CC(N)CCc1ccccc1
Reactant: COc1ccc(C2CO2)cc1OCCOC1CCCCO1
Solvent: CCO
Product: COc1ccc(C(O)CNC(C)CCc2ccccc2)cc1OCCOC1CCCCO1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 34.9 %

Procedure:
14.7 g of 4-methoxy-3-[2-(tetrahydro-2-pyranyloxy)ethoxy]styrene oxide was dissolved in 770 ml of ethanol, and 55 g of 4-phenyl-2-butylamine was added. The mixture was stirred at 90° C. for 40 minutes. After the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to afford 7.73 g (yield 34.9%) of 1-[4-methoxy-3-[2-(tetrahydro-2-pyranyloxy)ethoxy]phenyl]-2-(1-methyl-3-phenylpropyl)aminoethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21])=O.N1C=CC=CC=1.C[CH:29]([C:33](Cl)=[O:34])[C:30](Cl)=[O:31].Cl>C(Cl)Cl>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([OH:21])=[C:14]([C:12]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:4]=3)[NH:1][C:30](=[O:31])[C:29]=2[CH2:33][OH:34])[CH:19]=1
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)c1cc(Cl)ccc1O
Reactant: CC(C(=O)Cl)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=c1[nH]c2ccc(C(F)(F)F)cc2c(-c2cc(Cl)ccc2O)c1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [2-amino-5-(trifluoromethyl)phenyl](5-chloro-2-hydroxyphenyl)methanone (0.5 g, 1.58 mmol) and pyridine (0.25 mL, 3.17 mmol) in methylene chloride (15 mL), a solution of methyl malonyl chloride (0.34 mL, 3.17 mmol) in methylene chloride (10 mL) was added dropwise at 0° C. The reaction mixture was then allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was acidified with 1N HCl and the organic layer was separated. It was then washed with saturated NaHCO3 twice, water, brine and dried (MgSO4). Evaporation of the solvent gave the title compound as a yellowish oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:19]([OH:21])=O)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:23][NH:24][O:25][CH3:26].CN1CCOCC1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]([C:19]([N:24]([O:25][CH3:26])[CH3:23])=[O:21])[NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of O-benzyl-N-(tert-butoxycarbonyl)serine (5.9 g, 20.0 mmol) in CH2Cl2 (20 mL) was added N,O-dimethylhydroxylamine hydrochloride (1.95 g, 20.0 mmol) followed by N-methylmorpholine (2.20 mL, 19.98 mmol). The mixture was cooled to 0° C. and treated with a 1 M solution of N,N-dicyclohexylcarbodiimide in CH2Cl2 (20.0 mL, 20.0 mmol). The mixture was allowed to warm to ambient temperature while stirring under inert atmosphere for 18 h. The mixture was filtered, washing the solid residue with excess CH2Cl2, and the filtrate was concentrated in vacuo. The resulting oil was suspended in EtOAc, stirred for 20 min, and filtered once more, washing with EtOAc. The filtrate was concentrated to an orange oil which was purified by silica gel chromatography (20% to 60% EtOAc/hexanes) to afford the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.35-7.25 (m, 5H), 5.44 (d, J=8.4 Hz, 1H), 4.88 (d, J=3.2 Hz, 1H), 4.53 (dd, J=12.4, 28.8 Hz, 2H), 3.71 (s, 3H), 3.69-3.64 (m, 2H), 3.21 (s, 3H), 1.44 (s, 9H). ES MS (M+1−100, for loss of BOC group)=239.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[N:7]=[C:8]([NH:22][NH2:23])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:10]=1[CH3:11])=[O:4].C(N(CC)CC)C.Cl[C:40]([O:42][CH2:43]C)=[O:41]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=2)[N:7]=[C:8]([NH:22][NH:23][C:40]([O:42][CH3:43])=[O:41])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(NN)=NC1c1ccc(C#N)cc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)NNC1=NC(c2ccc(C#N)cc2)C(C(=O)OC)=C(C)N1c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 5.9 %

Procedure:
Intermediate 2 (724 mg, 1.7 mmol) was dissolved in THF (20 mL) and cooled to 0° C. before addition of triethylamine (362 μL, 2.6 mmol) and ethyl chloroformate (191 μL, 2 mmol). The reaction mixture was stirred at 0° C. for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (Na2SO4) and evaporated in vacuo. The resultant residue was triturated with EtOAc, filtered and the solid collected to yield the title compound as a white solid (49 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[CH2:29][OH:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[CH2:29][O:30][C:41](=[O:42])[N:40]([CH3:44])[CH3:39])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(S(=O)(=O)c3cccc(F)c3)cc2CO)C1
Reactant: CN(C)C(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)OCc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
3-[4-(3-Fluoro-benzenesulfonyl)-2-hydroxymethyl-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (74 mg, 0.170 mmol) was dissolved in 25 ml of THF and the mixture was cooled to −78° C. LDA (0.102 ml, 0.204 mmol) was added and allowed to stir for 30 minutes. Dimethylcarbamoyl chloride (0.023 ml, 0.255 mmol) was added and the mixture was allowed to warm to room temperature over 3 hours. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2/MeOH 95/5) to give 83 mgs (96%) of 3-[2-Dimethylcarbamoyloxymethyl-4-(3-fluoro-benzenesulfonyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a clear oil.