Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:18]=[N:19][C:20](I)=[CH:21][CH:22]=2)=[O:16])[CH2:11][CH2:10]1.[CH3:24][C@@H:25]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[NH:26]1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:18]=[N:19][C:20]([N:26]3[C@H:25]([CH3:24])[CH2:29][CH2:28][S:27]3(=[O:31])=[O:30])=[CH:21][CH:22]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)nc3)CC2)c(C)c1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](C)CCS4(=O)=O)nc3)CC2)c(C)c1
Yield: 29.4 %

Procedure:
Using [4-(2,4-dimethylphenyl)piperazin-1-yl](6-iodopyridin-3-yl)methanone (341 mg) described in Preparation Example 162 and (R)-3-methylisothiazolidine 1,1-dioxide (123 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 1, the title compound (102 mg) was obtained.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][CH:3]=1.[CH:10](OC)([O:13][CH3:14])[O:11][CH3:12]>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:12][O:11][CH:10]([O:13][CH3:14])[C:5]1[CH:8]=[CH:9][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: COC(OC)OC
Reactant: O=Cc1ccc(I)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(OC)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A solution of 4-iodobenzaldehyde (1 g, 4.31 mmol) in MeOH (50 mL) was mixed with trimethyl orthoformate (4 mL, 36.10 mmol) and p-toluenesulfonic acid (5 mg). The reaction was stirred at room temperature for 3 h and then quenched by adding excess of sodium bicarbonate solid and stirred for 1 h. The solid was removed by filtration and the filtrate was concentrated to yield 1-dimethoxymethyl-4-iodo-benzene (1.2 g, 100%). A mixture of 1-dimethoxymethyl-4-iodo-benzene (1.2 g, 4.31 mmol), cesium carbonate (1.4 g, 4.31 mmol), morpholine (0.375 g, 4.31 mmol), and palladium tetrakis(triphenyl)phosphine (0.25 g, 0.216 mmol) in toluene (60 mL) and tert-butanol (10 mL) was thoroughly degassed and stirred at 110° C. for 28 h. The reaction was quenched by adding water (50 mL), extracted with DCM (3×100 mL), concentrated to afford a solid residue. Purification by column chromatography left 4-(4-dimethoxymethyl-phenyl)-morpholine (0.61 g, 60%). A solution of 4-(4-dimethoxymethyl-phenyl)-morpholine (0.61 g, 2.58 mmol) in THF (20 mL) was mixed with HCl in ether (10 mL, 10 mmol) and stirred at room temperature for 2 h. The reaction mixture was then neutralized with 1 N sodium bicarbonate aqueous to pH 9 and extracted with DCM (3×100 mL), to afford 4-morpholin-4-yl-benzaldehyde (0.37 g, 75%).
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1.[Cl:16][CH2:17][CH2:18][CH2:19]I.[NH4+].[Cl-]>C1COCC1.[Cu]I>[Cl:16][CH2:17][CH2:18][CH2:19][C:8]1[O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]=1[CH3:6]
Reactant: ClCCCI
Reactant: Cc1coc2ccccc12
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(CCCCl)oc2ccccc12
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 6 %

Procedure:
n-BuLi in heptanes (1.5 ml, 2.4 mmol, 1.6M) was added drop wise to 3-methylbenzofuran (264 mg, 2.0 mmol) in THF (5 ml) at −20° C. under argon. The reaction mixture was stirred at −15° C. for 30 min, then 1-chloro-3-iodopropane (322 μl, 3.0 mmol) and copper (I) iodide (38 mg, 0.2 mmol) were added. The reaction was stirred at −15° C. for 1 h, then NH4Cl (sat'd aq., 5 ml) was added. The product was extracted with diethyl ether (2×30 ml) and the organic layer was washed with brine, (10 ml) dried (K2CO3), filtered and concentrated in vacuo. The product was purified by column chromatography (0-1% diethyl ether in heptanes) to give 2-(3-chloro-propyl)-3-methylbenzofuran (25 mg, 6%). 1H NMR (CDCl3): δ2.19 (tt, 2H), 2.22 (s, 3H), 2.94 (t, 2H), 3.57 (t, 2H), 7.22 (m, 2H), 7.38 (m, 1H), 7.44 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:16]=[O:17])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4].[O-:18][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCn1cc(C=O)c2ccc(C(=O)OC)cc21
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCn1cc(C(=O)O)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.4 %

Procedure:
1-Ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (800 mg, 3.5 mmol), prepared as shown in example 1P, step A, is dissolved in acetone (98 mL). A solution of KMnO4 (655 mg, 4.15 mmol) in H2O (31 mL) is added. The reaction mixture is stirred at room temperature for 90 minutes. Another addition of KMnO4 (108 mg) in H2O (6 mL), followed by stirring for another 45 minutes is required to drive the reaction to completion. The reaction mixture is then quenched with 10% H2O2 (1.5 mL). The mixture is filtered through celite. The filtrate is stripped down under vacuum to roughly ⅓ of the volume. The residue is acidified with 6N HCl, and is extracted into ethyl acetate. The solids isolated from the ethyl acetate layer are triturated with acetone to yield 1-ethyl-1H-indole-3,6-dicarboxylic acid 6-methyl ester (696 mg, 79%) as a light orange solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][C:5]=1[F:13])[CH3:2].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27](SC2C=CC=CC=2)=[O:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].S1C=CC=C1C([O-])=O.[Cu+]>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27](=[O:28])[C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([F:13])[CH:6]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOc1ccc(B(O)O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Sc2ccccc2)CC1
Agent: [Cu+]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCOc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Yield: 82.6 %

Procedure:
To a mixture of 4-ethoxy-3-fluorophenylboronic acid (0.86 g, 4.67 mmol), ligand TFP (0.144 g, 0.62 mmol), Pd2dba3 (0.29 g, 0.31 mmol), copper (I) thiophene-2-carboxylate (0.89 g, 4.7 mmol) was added a solution of 4-phenylsulfanylcarbonyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 3.11 mmol) in 10 mL of THF while purging with N2 at 50° C. After 18 hours the reaction mixture was diluted with ethyl acetate, filtered through celite then concentrated in vacuo. Purification by flash chromatography gave the title compound (0.95 g, 2.57 mmol). MS (ESI) m/z 352.0 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.42 min.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[S:7][C:8]([CH3:11])=[CH:9][CH:10]=1)(=[O:5])[CH3:4].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(O)C>[CH3:11][C:8]1[S:7][C:6]([C:3](=[O:5])[CH:4]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: CC(=O)c1ccc(C)s1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C(=O)C=Cc2ccccc2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
A stirred solution of 2.2 grams (0.055 mole) of sodium hydroxide in 20 ml of ethanol was cooled to 0° C. and a mixture of 4.0 grams (0.03 mole) of 2-acetyl-5-methylthiophene and 3.1 grams (0.03 mole) of benzaldehyde in 5 ml of ethanol was added dropwise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it stirred for 16 hours. The reaction mixture was poured into aqueous 1N hydrochloric acid and extracted with methylene chloride. The extract was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 4.6 grams of 1-(5-methyl-2-thienyl)-3-phenyl-2-propen-1-one as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH2:4][CH2:5][N:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:7][C:8]=1[C:9]1[N:13]([CH:14]([CH3:16])[CH3:15])[N:12]=[CH:11][CH:10]=1.[OH:24][C:25]1[C:30]([CH:31]=[O:32])=[CH:29][C:28]([O:33][CH3:34])=[N:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.CCOC(C)=O>[CH:31]([C:30]1[CH:29]=[C:28]([O:33][CH3:34])[N:27]=[CH:26][C:25]=1[O:24][CH2:2][C:3]1[CH2:4][CH2:5][N:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:7][C:8]=1[C:9]1[N:13]([CH:14]([CH3:16])[CH3:15])[N:12]=[CH:11][CH:10]=1)=[O:32]
Reactant: CC(C)n1nccc1C1=C(CBr)CCN(C(=O)OC(C)(C)C)C1
Reactant: COc1cc(C=O)c(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C=O)c(OCC2=C(c3ccnn3C(C)C)CN(C(=O)OC(C)(C)C)CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
To a solution of tert-butyl 4-(bromomethyl)-5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (18 mg, 0.05 mmol) and 5-hydroxy-2-methoxyisonicotinaldehyde (10 mg, 0.06 mmol) in DMF (1 mL) was added K2CO3 (14 mg, 0.1 mmol). After stirred at room temperature for 1 h, it was diluted with water and EtOAc, organic layer was separated, and the aqueous layer was extracted with EtOAc, organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=2:1) to give tert-butyl 4-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)-3-(1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (7.2 mg). 1H NMR (400 MHz, CDCl3) (ppm) 10.39 (s, 1H), 7.79 (s, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.05 (s, 1H), 6.11 (d, J=1.6 Hz, 1H), 4.40 (s, 2H), 4.38 (m, 1H), 4.01 (s, 2H), 3.88 (s, 3H), 3.66 (bs, 2H), 2.46 (bs, 2H), 1.48 (s, 9H), 1.43 (d, 6.4 Hz, 6H). MS (ESI) m/z 457.3 [M+H]+.
Reaction SMILES: COC(=O)C1C=CC(C=O)=CC=1OCC1C=CC=CC=1.[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][C:25]=1[C:32](F)(F)F.COC(=O)C1C=C(C(F)(F)F)C=C(C=O)C=1>>[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][C:25]=1[CH3:32]
Reactant: COC(=O)c1ccc(C=O)cc1C(F)(F)F
Agent: COC(=O)c1cc(C=O)cc(C(F)(F)F)c1
Agent: COC(=O)c1ccc(C=O)cc1OCc1ccccc1
Product: COC(=O)c1ccc(C=O)cc1C

Procedure:
Preparation 84A: 2-Benzyloxy-4-formyl-benzoic acid methyl ester (384 mg, 86%), LC-ES/MS m/e 293.0 (M+23); Preparation 84B: 4-Formyl-2-trifluoromethyl-benzoic acid methyl ester (1.29 g, 92%), LC-ES/MS m/e 233.3 (M+1); Preparation 84C: 3-Formyl-5-trifluoromethyl-benzoic acid methyl ester (0.5 g, 78%), 1HNMR (CDCl3) (ppm): 3.95 (3H, s), 8.25 (1H, s), 8.5 (1H, s), 8.7 (1H, s), 10.1 (1H, s).
Reaction SMILES: [CH3:1][Si:2]([CH3:48])([CH3:47])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=2)[CH:9]=1.C1C(=O)N([Br:56])C(=O)C1>C(#N)C>[CH3:46][Si:43]([CH3:45])([CH3:44])[CH2:42][CH2:41][O:40][CH2:39][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:47])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:33]=2)[C:9]=1[Br:56]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)cc1
Solvent: CC#N
Product: COC(=O)Cc1ccc(Cc2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 2-(4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)phenyl)acetate (150 mg, 0.22 mmol) was dissolved in ACN (10 mL). NBS (40 mg, 0.22 mmol) was added and the mixture was stirred at room temperature for 1 h. After concentration, the product that resulted, methyl 2-(4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)phenyl)acetate was used in the next step without further purification HPLC-MS tR=2.66 min (UV254 nm); mass calculated for formula C37H48BrN5O4Si2 761.2, observed LCMS m/z 762.2 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([C:21]1[CH:35]=[CH:34][C:24]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[O:26])=[CH:23][CH:22]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[N:13]2)=[CH:8][CH:7]=1.O1CCCC1.[OH-].[Na+]>CO>[CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([C:21]1[CH:35]=[CH:34][C:24]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:22]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[N:13]2)=[CH:10][CH:11]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(Cc2ccc(-n3cc(C(F)(F)F)cn3)cc2)CC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC(Cc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.6 %

Procedure:
Methyl 3-(4-(4-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-yl)phenyl)pentan-2-yl)benzamido)propanoate (4.2 mg, 0.0080 mmol) was dissolved in 1:1 methanol:tetrahydrofuran (0.50 mL). 1N NaOH (0.024 mL) was added and the reaction was stirred at room temperature for 18 hours. The reaction was concentrated to dryness. The crude residue was taken up in water and acidified to pH=2 with 1N HCl. This solution was extracted three times with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated to give (+/−)-3-(4-(4-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pentan-2-yl)benzamido)propanoic acid (4.0 mg, 100%), as a white solid. 1H NMR (400 MHz, CD3OD, δ): 8.62 (s, 1H), 7.91 (s, 1H), 7.69-7.64 (m, 2H), 7.58-7.53 (m, 2H), 7.22-7.17 (m, 2H), 7.14-7.09 (m, 2H), 3.62-3.55 (m, 2H), 3.09-2.96 (m, 2H), 2.90-2.81 (m, 1H), 2.60 (t, J=6.9 Hz, 2H), 1.78-1.68 (m, 1H), 1.52 (ddd, J=13.7, 9.2, 4.9 Hz, 1H), 1.39-1.25 (m, 1H), 0.83 (dd, J=6.4, 4.7 Hz, 6H). MS (M+1): 488.4.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[K+].Cl.[NH2:13]O.C(=O)(O)[O-].[Na+]>C(O)C.O>[NH2:9][C:8]1[CH:7]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[O:6][N:13]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(N)no1
Reaction time: 1 h

Procedure:
In a 100 ml. round bottom 3-neck flask there was placed 2 g. of pivalyl acetonitrile, 0.9 g. of potassium hydroxide, 25 ml. of ethanol, and 35 ml. of water. The mixture was heated to refluxing, and an aqueous solution of hydroxylamine hydrochloride was added. After the addition was complete, the mixture showed a pH of 5.6. The pH was immediately adjusted to 6.2 by adding aqueous saturated sodium bicarbonate solution. The pH of the reaction mixture after 1 hour was 6.3. After 2 hours, the pH of the reaction mixture was 6.4. After 3 hours, the pH of the reaction mixture was 6.5. The reaction mixture was allowed to reflux overnight, and the following morning the pH was 6.8. The reaction mixture was cooled and the ethanol stripped on the rotovapor. The white solid which separated was filtered off and dried. The solid weighed 0.8 g., and was determined by vpc to contain 91.9% 3-amino-5-(t-butyl)isoxazole and 5.7% of 5-amino-3-(t-butyl)isoxazole. Yield of desired isomer was 48%.
Reaction SMILES: Cl[C:2]([CH3:17])([CH3:16])[CH:3]([N:14]=[O:15])[CH2:4][N:5]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]1[N+:11]([O-:13])=[O:12].[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([CH3:30])([CH3:29])[C:24](=[N:27][OH:28])[CH2:25]C.CCN(C(C)C)C(C)C>C(#N)C>[CH3:16][C:2]([CH3:17])([NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([CH3:30])([CH3:29])[C:24](=[N:27][OH:28])[CH3:25])[C:3](=[N:14][OH:15])[CH2:4][N:5]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]1[N+:11]([O-:13])=[O:12]
Reactant: CCC(=NO)C(C)(C)NCCCN
Reactant: Cc1cn(CC(N=O)C(C)(C)Cl)c([N+](=O)[O-])n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=NO)C(C)(C)NCCCNC(C)(C)C(Cn1cc(C)nc1[N+](=O)[O-])=NO
Temperature: 50 °C
Reaction time: 2 h

Procedure:
3-Chloro-3-methyl-2-nitroso-1-(4-methyl-2-nitro-1H-imidazol-1-yl)butane (3.41 g, 13.09 mmol) was added in portions to a stirred solution of N-(3-aminopropyl)-1-amino-1,1-dimethyl-2-butanone oxime (2.0 g, 11.56 mmol, Example 1) and (i-Pr)2NEt (1.64 g, 13.09 mmol) in dry acetonitrile (20 mL) at 50° C. under a nitrogen atmosphere. After the addition the reaction mixture was stirred for an additional 2 hours at 50° C. and cooled to room temperature. The solid which formed was filtered and recrystallized from acetonitrile to provide the title product as a light yellow colored solid. Yield: 3.08 g (59.4%); mp. 140°-141° C. ; 1H NMR (DMSO-d6) δ 1.12 & 1.19[2s, 6H, C(CH3)2), 1.33(m, 2H, CH2CH2CH2), 1.70's, 3H, C(=N)CH3 ], 1.79(bs, 2H, NH), 2.15(s, 3H, imi-CH3), 2,19(m, 4H, NHCH2), 5.19[s, 2H, NCH2C(=N)], 7.05(s, 1H, imi-CH) and 10.33 & 11.36(2s, 2H, NOH). MS m/e 398 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([O:10][C:11](=[O:26])[NH:12][C:13]([CH3:25])([CH3:24])[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[CH3:23])([CH3:9])([CH3:8])[CH3:7].C(=O)(O)[O-].[Na+]>CN(C)C(=O)C>[C:6]([O:10][C:11](=[O:26])[NH:12][C:13]([CH3:25])([CH3:24])[CH2:14][N:15]([C:3](=[O:4])[CH2:2][Br:1])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[CH3:23])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=C(Br)CBr
Reactant: Cc1c(F)cccc1NCC(C)(C)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1c(F)cccc1N(CC(C)(C)NC(=O)OC(C)(C)C)C(=O)CBr
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
1.4 ml of bromoacetyl bromide (16.1 mmol) was added to a solution of 3.97 g of [1,1-dimethyl-2-(3-fluoro-2-methylphenylamino)ethyl]carbamic acid t-butyl ester obtained in Example (67a) (13.4 mmol) in N,N-dimethylacetamide (67 ml) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Hexane was added to the residue, and the solid was collected by filtration to obtain 4.23 g of the title compound (yield: 76%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[C:12]([CH:26]=[CH:27][C:28]=2[NH:29]CC2C=C(OC)C(OC)=C(OC)C=2)[C:13]([NH:15][CH:16]2[C:21]([CH3:23])([CH3:22])[C@H:20]3[CH2:24][C@:17]2([CH3:25])[CH2:18][CH2:19]3)=[O:14])(=[O:9])=[O:8])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>>[NH2:29][C:28]1[CH:27]=[CH:26][C:12]([C:13]([NH:15][CH:16]2[C:21]([CH3:22])([CH3:23])[C@H:20]3[CH2:24][C@:17]2([CH3:25])[CH2:18][CH2:19]3)=[O:14])=[CH:11][C:10]=1[S:7]([N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:9])=[O:8]
Reactant: COc1cc(CNc2ccc(C(=O)NC3C(C)(C)[C@@H]4CC[C@@]3(C)C4)cc2S(=O)(=O)N2CCOCC2)cc(OC)c1OC
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(NC(=O)c2ccc(N)c(S(=O)(=O)N3CCOCC3)c2)[C@@]2(C)CC[C@@H]1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
3-(Morpholinosulfonyl)-4-(3,4,5-trimethoxybenzylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide (2.5.AaBa, 0.36 g, 0.00060 mol) was dissolved in trifluoroacetic acid (7 mL, 0.09 mol). The reaction was stirred overnight at room temperature. The reaction was evaporated to dryness and the residue underwent aqueous workup. Prep-HPLC was performed to isolate the desired product, a white, crystalline solid 2H in 40% yield. MS analysis (m+1)=422.6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:22][CH2:23][O:24][CH3:25])[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15]CCOC)=[O:14])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]([CH2:22][CH2:23][O:24][CH3:25])[C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOC(=O)c1ccc(N(CCOC)C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCN(C(=O)OC(C)(C)C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 2-methoxy-ethyl 4-[tert-butoxycarbonyl-(2-methoxyethyl)-amino]-benzoate (compound E6) (1.37 g, 3.9 mmol) in methanol (60 mL) is added aqueous 2N NaOH (30 mL, 60 mmol) and the solution is stirred 16 h at ambient temperature. By using an aqueous 2N hydrochloric acid solution the pH is adjusted to 4, methanol is evaporated and the water phase is extracted with CH2Cl2 (4×15 mL). After drying (MgSO4) and evaporation the crude product is transferred to the next step without any further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([F:50])[CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][N:53]=1>C(Cl)Cl>[Br:58][C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:35](=[O:36])[CH:34]([C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([F:50])[CH:39]=2)[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[N:53][CH:54]=1
Reactant: Nc1ccc(Br)cn1
Reactant: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)O)cc1F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(Br)cn2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A solution of triphenylphosphine (288 mg, 1.1 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (196 mg, 1.1 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with 3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionic acid (prepared in Example 1, 175 mg, 0.55 mmol). The clear solution was stirred for 15 min at 0° C. and then allowed to warn to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-amino-5-bromopyridine (476 mg, 2.75 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and water (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×25 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/1 hexanes/ethyl acetate) afforded N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionamide (190 mg, 73%) as a white solid: mp 73-78° C.; EI-HRMS m/e calcd for C21H22BrFN6O (M+) 472.1022, found 472.1022.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][C:14]=2[N+:21]([O-:23])=[O:22])[CH:3]=1.[Li+].[Br-].P(Br)(Br)[Br:27]>CN(C=O)C>[Br:27][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])=[C:14]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: COC(=O)c1ccc(Cl)cc1Nc1ccc(CO)cc1[N+](=O)[O-]
Reactant: BrP(Br)Br
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)cc1Nc1ccc(CBr)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 97 %

Procedure:
A mixture of Example 569B (0.336 g, 1.0 mmol) and LiBr (0.1 g) in 3 mL of DMF was treated with PBr3 (0.1 mL) at 0° C. The solution was stirred for additional two hours, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum to give 0.38 g of the title compound (97%). MS (DCI) m/e 401 (M+H)+; 1H NMR (300 MHz, DMSO-d6) □ 10.94 (s, 1H), 8.29 (d, J=2.03 Hz, 1H), 7.98 (d, J=8.82 Hz, 1H,) 7.70-7.75 (m, 2H), 7.54 (d, J=2.03 Hz, 1H), 7.18 (dd, J=8.48, 2.03 Hz, 1H), 4.80 (s, 2H), 3.89 (s, 3H).