Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Br[C:10]1[N:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1>CN(C=O)C>[Br:16][C:13]1[CH:12]=[N:11][C:10]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])=[N:15][CH:14]=1
Reactant: Brc1cnc(Br)nc1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
To sodium hydride (303 mg) under an argon atmosphere at 0° C. was added dropwise 2,2,2-trifluoroethanol (775 μl) and the mixture was then stirred at RT for 90 min. A solution of 2,5-dibromopyrimidine (1.5 g) in DMF (8 ml) was then added and stirring continued at RT for 2 hours. The reaction mixture was poured into ice (50 mL) and extracted with EtOAc (2×50 mL). The organic layers were dried over MgSO4 and concentrated in vacuo to afford 5-bromo-2-(2,2,2-trifluoro-ethoxy)-pyrimidine (790 mg, 49%) as a yellow oil which was used in the next step without further purification. MS (EI): 258 ([{81Br}M]+), 256 ([{79Br}M]+), 189 ([{81Br}M−CF3]+), 187 ([{79Br}M−CF3]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]1[O:20][CH2:19][CH2:18][O:8]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCCO
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc(OCc2ccccc2)c(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 5-bromo-2-benzyloxybenzaldehyde, prepared from commercial 5-bromosalicylicaldehyde by benzylation according to the method given in Reference example 22a), (25 g, 74.6 mmol) in toluene (250 ml) was treated with ethylene glycol (5 ml), and p-toluenesulfonic acid (0.24 g). The reaction was heated to reflux with azeotropic removal of water (Dean Stark trap). After 2.5 hrs, no further water was collected. The reaction was cooled to ambient temperature and washed with saturated aqueous NaHCO3, dried (MgSO4 and evaporated to give 2-(2-benzyloxy-5-bromophenyl)-1,3-dioxolane as a pale orange solid (26.8 g). This material was used without purification.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24]([OH:26])=[O:25])[CH:20]=[CH:21][CH:22]=1.Br[CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>O1CCCC1>[Br:16][C:17]1[CH:18]=[C:19]([CH:23]([CH2:28][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[C:24]([OH:26])=[O:25])[CH:20]=[CH:21][CH:22]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(CC(C(=O)O)c2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a solution of n-butyl lithium (95 ml, 15% solution in hexane, 147 mmol) and 2,2,6,6-tetramethylpiperidine (24.9 ml, 147 mmol) in tetrahydrofurane (220 ml) was added a solution of (3-bromo-phenyl)-acetic acid (15.05 g, 70 mmol) in tetrahydrofuran (80 ml) at −78° C. The reaction mixture was stirred for 60 minutes at that temperature. Then 4-bromomethyl-benzonitrile (13.72 g, 70 mmol) in tetrahydrofuran (160 ml) was added. The reaction mixture was stirred for 2 hours at −78° C., then warmed up to room temperature and quenched with ammonium chloride solution (240 ml), 3 N hydrochloric acid (50 ml), and ethyl acetate (300 ml). The organic layer was washed with ammonium chloride solution and brine, dried, and evaporated in vacuo. The residue was solved in ethyl acetate and stirred with methyl-tert-butylether. The precipitate was sucked off and dried in vacuo to give 19.0 g of the desired product (82% yield).
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].Br[CH2:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11].O>CS(C)=O>[N+:1]([CH2:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])([O-:3])=[O:2]
Reactant: O=N[O-]
Reactant: C[Si](C)(C)CCCCBr
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C[Si](C)(C)CCCC[N+](=O)[O-]
Reaction time: 3 h
Yield: 44.8 %

Procedure:
4-Nitrobutyltrimethylsilane was prepared as follows: To a solution of 1.9 g (0.028 mol) of sodium nitrite in 30 ml of dimethyl sulfoxide was added 2.92 g (0.014 mol) of 4-bromobutyltrimethylsilane. After 3 hrs, 30 ml of water was added and the mixture was extracted with three 15 ml portions of carbon tetrachloride. The carbon tetrachloride solution was washed with 10 ml of water and dried over magnesium sulfate. The NMR spectrum showed 30% nitrite ester (CH2ONOδ4.57), and 70% nitro compound. Distillation gave 1.1 g (45%) of 4-nitrobutyltrimethylsilane, bp 54°-6° (0.9 mm).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:14]([CH:17]=2)[C:15]#[N:16])[CH:5]=[CH:4][N:3]=1.C1N2CCN(CC2)C1.C(=O)([O-])[O-:39].[K+].[K+].O1CCOCC1>O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][O:8][C:6]3[NH:7][C:2](=[O:39])[N:3]=[CH:4][CH:5]=3)=[CH:17][C:14]=2[C:15]#[N:16])=[CH:20][C:21]=1[C:26]([F:29])([F:28])[F:27]
Reactant: N#Cc1cc(COc2ccnc(Cl)n2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: C1CN2CCN1CC2
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(COc2ccnc(=O)[nH]2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 70 °C
Yield: 90.8 %

Procedure:
A mixture of 5-{[(2-chloro-4-pyrimidinyl)oxy]methyl}-2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}benzo-nitrile (2.30 g, 2.61 mmol), DABCO (0.147 g, 1.31 mmol) and potassium carbonate (1.08 g, 7.84 mmol) in a mixed solvents of 1,4-Dioxane (10 mL) and water (10 mL) was heated at 70° C. for 3 h, then concentrated and diluted with ethyl acetate (100 mL) and water (100 mL). Separated organic part was washed with water and brine, dried over sodium sulfate, concentrated. Purification via mass-directed autopreparation afforded the title product (1.0 g). LC-MS (ESI): m/z 420 [M−H]+; 3.89 min (ret time).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:12]=O.N1CCCCC1>C(O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:12]=[C:5]1[S:1][C:2](=[O:7])[NH:3][C:4]1=[O:6]
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2ccc([N+](=O)[O-])c(O)c2)S1
Temperature: 0 °C
Yield: 44.2 %

Procedure:
To a solution of 2,4-thiazolidinedione (3.50 g, 30.0 mmol) in ethanol (120 mL) was added 3-hydroxy-4-nitrobenzaldehyde (5.00 g, 30.0 mmol) and piperidine (0.44 mL, 4.50 mmol). The mixture was stirred at reflux for 15 hours and then cooled to 0° C. The resulting precipitate was collected and washed with cold ethanol to afford 3.53 g of the desired compound as a brown solid. Further concentration and precipitation of the mother liquor afforded an additional 3.1 g of the product. This was used without further purification in the next reaction. 1H NMR (CDCl3)·8.20 (1H, d, J=8.8 Hz), 7.75 (1H, s), 7.26 (1H, s), 7.12 (1H, d, J=8.8 Hz).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6](O)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH3:15][O:16][C:17](=[O:47])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39]S(C)(=O)=O)[C:25]=1[CH2:44][CH2:45][CH3:46].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:15][O:16][C:17](=[O:47])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:25]=1[CH2:44][CH2:45][CH3:46]
Reactant: CCCc1c(OCCCCCC(=O)OC)ccc(C(C)=O)c1OCCOCCOS(C)(=O)=O
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCOCCOc2c(C(C)=O)ccc(OCCCCCC(=O)OC)c2CCC)ccc(C(C)=O)c1O
Yield: 76.6 %

Procedure:
A mixture of 1.14 g (0.0059 mole) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.87 g (0.0059 mole) of 6-[4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]-2-propylphenoxy]hexanoic acid methyl ester and 1.62 g (0.012 mole) of anhydrous potassium carbonate in 50 ml of anhydrous acetone and 25 ml of anhydrous dimethylformamide was stirred at reflux for 17 hours. The solvents were removed in vacuo and the residue was purified by HPLC using 35% ethyl acetate-hexane to yield 2.65 g (77% yield) of 6-[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]hexanoic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:20])=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([N+:21]([O-])=O)[CH:3]=1>C(O)(=O)C.CCOC(C)=O.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]2[C:6]([F:20])=[N:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:12])=[O:13])[C:9]=2[CH:10]=1
Reactant: O=[N+]([O-])c1cc(Br)cc2c1c(F)nn2S(=O)(=O)c1ccccc1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc(Br)cc2c1c(F)nn2S(=O)(=O)c1ccccc1
Reaction time: 0.08 h
Yield: 44 %

Procedure:
6-Bromo-3-fluoro-4-nitro-1-(phenylsulfonyl)-1H-indazole (5.9 g, 14.74 mmol) was suspended in acetic acid (60 ml) and to it added iron powder (4.12 g, 73.7 mmol). The suspension was heated to reflux for 2 h, then the reaction mixture was cooled, diluted with 100 ml EtOAc and filtered through celite. The filter cake was washed well with ethyl acetate then the filtrate basified till the colour moved from the aqueous layer to the organic (around pH 8-9). The biphasic system was then stirred for around 5 minutes and the aqueous layer turned cloudy. The layers were then separated, the aqueous washed with ethyl acetate and the combined organics washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was dry loaded onto a 330 g silica cartridge, purified on a 0-100% EtOAc/Cyclohexane gradient and the relevant fractions combined and concentrated to yield the title compound as a yellow solid (2.4 g).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[Cl:5][C:6]1[C:11]([OH:12])=[CH:10][C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:8]([F:26])[CH:7]=1>C(N(CC)CC)C.C(Cl)Cl>[CH3:1][NH:2][C:3](=[O:4])[O:12][C:11]1[CH:10]=[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[N:15]([CH3:24])[C:14]2=[O:25])[C:8]([F:26])=[CH:7][C:6]=1[Cl:5]
Reactant: CN=C=O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
0.51 g of methyl isocyanate and subsequently one drop of triethylamine are added at room temperature while stirring to a solution of 2.00 g of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione in 20 ml of methylene chloride. The reaction mixture is stirred for one hour and evaporated to dryness under reduced pressure. The residue is purified by chromatography on a silica gel column using diethyl ether-n-hexane (2:1) as the eluent. There is obtained 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorophenyl methylcarbamate, 1H-NMR (CDCl3, 400 MHz): 7.33 ppm (d,1H), 7.24 ppm (d,1H), 6.34 ppm (s,1H), 5.21 ppm (q,1H), 3.54 ppm (d,3H), 2.88 ppm (d,3H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:17][C:18](=[O:29])[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:28][C:25]3[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][CH2:19][C:18]([OH:29])=[O:17])=[CH:27][CH:26]=3)=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCCC1
Reactant: CCOC(=O)CCCc1ccc(O)cc1
Product: O=C(O)CCCc1ccc(OCc2cccnc2SC2CCCC2)cc1
Yield: 92.7 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.020 g, 0.09 mmol) obtained in Step C of Preparation Example 8 and 4-(4-hydroxy-phenyl)-butyric acid ethyl ester (0.018 g, 0.09 mmol) obtained in Step E of Preparation Example 13 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.031 g, 94%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:12])=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:13][NH2:14]>CO>[CH3:13][NH:14][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:12])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1ncccc1OCCCCl
Reactant: CN
Solvent: CO
Product: CNCCCOc1cccnc1C
Temperature: 100 °C
Yield: 61 %

Procedure:
The 3-chloro-1-(2-methyl(3-pyridyloxy))propane (2.00 g, 10.8 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (25 mL) was added to the residue. The pH of the solution was adjusted to 6, and the mixture was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was basified to pH 10 with 10% NaOH solution and extracted with chloroform (4×50 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated to give 1.19 g (61.0%) of an oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N1C2C(=CC=CC=2)C=C1.[CH3:29][O:30]C1NC2C(C=1)=CC=CC=2>>[O:4]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:30][CH3:29])[CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: COc1cc2ccccc2[nH]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Agent: c1ccc2[nH]ccc2c1
Product: COc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Yield: 82 %

Procedure:
This compound was prepared in the manner described above for intermediate 1a by replacing indole with 5 methoxy indole (5 g, 34 mmol) in 82% yield (7.95 g) as a white solid: mp 161-162° C.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:32])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][NH2:42])=[CH:35][CH:34]=1>O1CCCC1>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:42][CH2:41][CH2:40][CH2:39][C:36]2[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=2)=[O:32])=[CH:25][CH:26]=1
Reactant: NCCCc1ccncc1
Reactant: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=C/C=C/C(=O)NCCCc2ccncc2)c2ccc(OC)cc2)cc1
Yield: 92.7 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (0.647 g) and 4-pyridinepropanamine (0.204 g) in tetrahydrofuran (5 mL) was stirred for 3 hours at room temperature. After the usual work up, the crude product was purified by HPLC (ethyl acetate) and then was crystallized from ethyl acetate to provide 0.595 g of (E)-5,5-bis(4-methoxyphenyl)-N-[3-(4-pyridinyl)propyl]-2,4-pentadienamide, mp 90°-92° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4].C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29][NH:30][CH3:31]>O1CCOCC1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29][N:30]([CH3:31])[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: CNCc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(CC(=O)c1cccc([N+](=O)[O-])c1)Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-bromo-1-(3-nitrophenyl)ethanone (2 g, 8.23 mmol, 1.00 equiv), triethylamine (3.4 g, 4.00 equiv), (2,4-dichlorophenyl)-N-methylmethanamine (1.9 g, 10.05 mmol, 1.20 equiv), 1,4-dioxane (50 mL). The resulting solution was stirred for 2 h at room temperature at which time it was judged to be complete by LCMS. The mixture was concentrated under vacuum and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100˜1:50). This resulted in 1.5 g (50%) of 2-((2,4-dichlorobenzyl)(methyl)amino)-1-(3-nitrophenyl)ethanone as a yellow solid.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([CH2:10][OH:11])[CH:8]=[CH:9][C:2]=12.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:11][CH2:10][C:7]1[CH:8]=[CH:9][C:2]2[C:3]([CH:6]=1)=[N:4][O:5][N:1]=2)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc2nonc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc2nonc2c1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 99.7 %

Procedure:
5-Benzofurazanmethanol (0.6 g, 4 mmol) and triethylamine (0.84 mmol, 0.61 g, 6 mmol) were dissolved in dichloromethane (20 ml) and cooled to -20° C. Methanesulfonyl chloride (0.37 ml, 0.55 g, 4.8 mmol) was added dropwise and the mixture was stirred at -20° C. for 20 minutes, diluted with dichloromethane (30 ml), washed with water (30 ml), dried (Na2SO4), and evaporated under reduced pressure to give the benzofurazan as a white solid (0.91 g, 99%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:28]([CH3:29])[C:9]2=[N:10][C:11]([O:14][C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([O:22][C:23](=[O:25])[CH3:24])=[C:17]([CH3:26])[C:16]=3[CH3:27])=[CH:12][CH:13]=[C:8]2[N:7]=1)(=O)C.C[O-].[Na+].O>CO>[C:23]([O:22][C:18]1[C:19]([CH3:21])=[CH:20][C:15]([O:14][C:11]2[N:10]=[C:9]3[N:28]([CH3:29])[C:6]([CH2:5][OH:4])=[N:7][C:8]3=[CH:13][CH:12]=2)=[C:16]([CH3:27])[C:17]=1[CH3:26])(=[O:25])[CH3:24]
Reactant: CC(=O)OCc1nc2ccc(Oc3cc(C)c(OC(C)=O)c(C)c3C)nc2n1C
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)Oc1c(C)cc(Oc2ccc3nc(CO)n(C)c3n2)c(C)c1C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To 500 ml of a solution of 26.0 g of 2-acetoxymethyl-5-(4-acetoxy-2,3,5-trimethylphenoxy)-3-methyl-3H-imidazo[4,5-b]pyridine in methanol, a 1.2 ml solution (28%) of sodium methoxide in methanol was added dropwise at −18° C., followed by stirring at the same temperature for one hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was crystallized from ethanol. The crystals were collected by filtration, whereby 20.5 g of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15](=[O:21])[C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=3)([OH:21])[C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1
Reactant: Clc1cccc([Mg]Br)c1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Solvent: C1CCOC1
Product: O=C1Nc2cc(Cl)ccc2C1(O)c1cccc(Cl)c1
Temperature: -25 °C
Reaction time: 2 h

Procedure:
A solution of 3-chlorophenyl magnesium bromide in tetrahydrofuran (0.5 M, 50 mL, 25 mmol) (Aldrich) was added dropwise with magnetic stirring to a suspension of 6-chloroisatin (1.82 g, 10 mmol) in tetrahydrofuran (20 mL) under argon with cooling in a −25° C. bath at such a rate that reaction temperature was kept below −10° C. (approximately 30 minutes). Cooling bath was then removed and mixture allowed to warm to room temperature. After stirring for an additional 2 hour, 15% aqueous ammonium chloride solution (25 mL) and water (50 mL) were added and mixture extracted with ethyl acetate (2×75 mL). Ethyl acetate layers were then washed with water (75 mL), brine (75 mL), combined, dried (MgSO4), filtered and concentrated. Residue was stirred in dichloromethane (100 mL) at room temperature for 15 minutes and filtered to give crude rac-6-chloro-3-(3-chloro-phenyl)-3-hydroxy-1,3-dihydro-indol-2-one as an off-white powder. This was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:9]1[C@H:14]([O:15][CH3:16])[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32].CCN(C(C)C)C(C)C>CCOC(C)=O>[C:6]([N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:9]1[C@H:14]([O:15][CH3:16])[CH2:13][CH2:12][N:11]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:10]1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CO[C@@H]1CCNC[C@H]1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1CCN(c2ccncc2[N+](=O)[O-])C[C@H]1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 59 %

Procedure:
Method 1 was followed using trans(+/−)-3-(bis(tert-butoxycarbonyl)amino)-4-methoxypiperidine (1.0 equiv.), 4-chloro-3-nitropyridine (1.2 equiv.), and DIEA (4.0 equiv.) to give trans(+/−)-N,N-di-BOC-4-methoxy-1-(3-nitropyridin-4-yl)-piperidin-3-amine after column chromatography (EtOAc and hexanes, 50%) in 59% yield for two steps. LCMS (m/z): 453.2 (MH+), LC Rt=3.24 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([NH:23][C@H:24]([C:30]([OH:32])=O)[CH2:25][C:26]([F:29])([CH3:28])[CH3:27])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1.[NH2:33][CH:34]([C:45]#[N:46])[CH2:35][C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][C:37]=1[Cl:44]>>[Cl:44][C:37]1[CH:38]=[C:39]([C:40]#[N:41])[CH:42]=[CH:43][C:36]=1[CH2:35][CH:34]([NH:33][C:30](=[O:32])[C@@H:24]([NH:23][C@@H:18]([C:15]1[CH:14]=[CH:13][C:12]([C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=2[Cl:1])=[CH:17][CH:16]=1)[C:19]([F:21])([F:20])[F:22])[CH2:25][C:26]([F:29])([CH3:28])[CH3:27])[C:45]#[N:46]
Reactant: N#Cc1ccc(CC(N)C#N)c(Cl)c1
Reactant: CC(C)(F)C[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2Cl)cc1)C(F)(F)F)C(=O)O
Product: CC(C)(F)C[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2Cl)cc1)C(F)(F)F)C(=O)NC(C#N)Cc1ccc(C#N)cc1Cl

Procedure:
(S)-2-[(S)-1-(2′-Chloro-4′-methanesulfonyl-biphenyl-4-yl)-2,2,2-trifluoro-ethylamino]-4-fluoro-4-methyl-pentanoic acid [2-(2-chloro-4-cyano-phenyl)-1-cyano-ethyl]-amide was prepared from N-{(1S)-1-[2′-chloro-4′-(methylsulfonyl)biphenyl-4-yl]-2,2,2-trifluoroethyl}-4-fluoro-L-leucine and 4-(2-amino-2-cyanoethyl)-3-chlorobenzonitrile by following procedures as in step 4 of Example 2.
Reaction SMILES: [Na].CCO.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[CH2:11][CH2:10]2.S([CH2:27][N+:28]#[C-])(C1C=CC(C)=CC=1)(=O)=O>COCCOC>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]([C:27]#[N:28])[CH2:11][CH2:10]2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc2c(c1)CCC2=O
Agent: [Na]
Solvent: COCCOC
Solvent: CCO
Product: COc1ccc2c(c1)CCC2C#N
Temperature: -5 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
Dissolve sodium metal (1.51 g, 66.0 mmol) in abs. EtOH (50 ml) and DME (100 ml) and add the resulting solution drop-wise to a mixture of 5-methoxy-1-indanone (3.57 g, 22.0 mmol), tosylmethyl isocyanide (6.45 g, 33.0 mmol) and DME (150 ml) cooled to −5° C. under nitrogen. After addition is complete (ca. one hour), allow mixture to slowly obtain ambient temperature and stir overnight. After cooling to 0° C., carefully quench with water and extract with EtOAc (2×). Wash the combined extracts with water and brine, dry (MgSO4) and concentrate. Purify on silica gel (toluene) to give 5-methoxy-indan-1-carbonitrile (2.55 g) as a yellow oil. 1HNMR (CDCl3): 7.31 (d, 1H), 6.80 (m, 2H), 4.05 (t, 1H), 3.80 (s, 3H), 3.07 (m, 1H), 2.93 (m, 1H), 2.56 (m, 1H), 2.39 (m, 1H).