Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[S:10](Cl)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11]>[OH-].[Na+]>[S:10]([NH:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CSCC[C@@H](N)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: CSCC[C@@H](NS(=O)(=O)c1ccc(C)cc1)C(=O)O

Procedure:
In Scheme 2, preparing enantiomerically pure (R)-azetidine alcohol 1 (R=Cbz) from D-methionine is as described in Abreo, et al., op. cit. First, D-methionine in aqueous sodium hydroxide solution is treated with tosyl chloride to form N-tosyl-D-methionine, which is treated with MeI followed by 1N sodium hydroxide to afford α-(N-p-tosyl-amino)-γ-butyrolactone according to the method of Sugano and Miyoshi, Bull. Chem. Soc. Japan, 1973, 46, 669. Further conversion to azetidine-2-carboxylic acid is carried out by the procedure of Miyoshi, et al., Chem. Lett. 1973, 5-6. The lactone in ethanol is treated with gaseous HBr to form N-tosyl-g-bromonorvaline ethyl ester. The bromoester in DMF solution with about four equivalents of H2O is treated with NaOH to form (R)-N-tosyl-azetidine-2-carboxylic acid (may be contaminated by the (S)-enantiomer as determined by 1H-NMR analysis of the amide derivative with α-methylbenzylamine)(Abreo, et al., op. cit.) Treating the N-tosylazetidine-2-carboxylic acid with sodium in liquid ammonia affords azetidine-2-carboxylic acid, which is subsequently treated with N-(benzyloxycarbonyl)oxy succinimide according to Abreo, et al., to afford N-Cbz-azetidine-2-carboxylic acid. To remove contaminating (S)-enantiomer, the N-Cbz derivative in MeOH is treated with D-tyrosine hydrazide to form an insoluble salt of the (R)-enantiomer, which is collected by filtration. The optical rotation of the subsequently liberated free acid is [α]D =+105.4 (c 4.0, CHCl3). Treating the free acid with borane.THF affords 1 (R=Cbz). The S-enantiomer ((S)-1) may be synthesized analogously starting from L-methionine. If needed for enantiomeric enrichment, the product may be optically resolved with D-tyrosine-hydrazide in analogy to the procedure described above. Other protecting groups, for example Boc, are readily incorporated by standard methods, e.g. by reacting the intermediate or Cbz deprotected azetidine-2-carboxylic acid with an appropriate standard reagent under prescribed conditions (Greene and Wuts, see above.).
Reaction SMILES: C(C1CCCCC1=O)(=O)C.C(C1CCCC1=O)(=O)C.[CH2:20]([O:22][C:23]([CH:25]1CC[CH2:27][C:26]1=[O:30])=[O:24])[CH3:21].C(CC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCOC(C1C(=O)CC(C)CC1)=O>>[C:23]([O:22][CH2:20][CH3:21])(=[O:24])[CH2:25][C:26]([CH3:27])=[O:30]
Reactant: CCOC(=O)C1CCCC1=O
Agent: CC(=O)C1CCCC1=O
Agent: CC(=O)C1CCCCC1=O
Agent: CCOC(=O)C1CCC(C)CC1=O
Product: CCOC(=O)CC(C)=O

Procedure:
Using the same apparatus and procedure as described in Example 1, the onset temperature for a one gram sample of 82.5% di-2-ethylhexyl peroxydicarbonate diluted in OMS was measured. The procedure was repeated with separate samples of the above solution to which ethyl-2-cyclohexanone carboxylate, 2-acetyl cyclohexanone, 2-acetyl cyclopentanone, methyl-2-cycloheptanone carboxylate, ethyl-2-oxocyclopentane carboxylate, dibenzoyl methane, and ethyl-4-methyl-2-cyclohexanone-1-carboxylate had been added. The results are shown in Table II. Results obtained with ethyl acetoacetate, which is disclosed in the prior art, are included for comparison.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16](=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28][NH:29][CH3:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([N:29]([CH3:30])[CH3:28])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Reactant: CNC
Agent: [H-]
Agent: [Na+]
Product: CN(C)c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1
Yield: 58.8 %

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloroquinol-2-one (74 mg, 0.2 mmol), sodium hydride (8 mg, 0.3 mmol), N-phenyl(trifluoromethylsulfon)imide (101 mg, 0.28 mmol), and dimethylamine (2 M in THF, 2 mL, 4.0 mmol) are treated according to method E yielding 46 mg of the 4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-7-chloro-2-dimethylaminoquinoline. This is treated with TFA-CH2Cl2 1:1 (0.6 mL) for 1 h and concentrated. The residue is converted into the title product with 4-fluorophenyl isocyanate (19 μL) and triethylamine (0.11 mL).
Reaction SMILES: C(OC([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][C:9]=2[CH3:16])=O)C.[OH-].[K+]>O.C(O)C>[Br:15][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH3:16])[CH:10]=1)[NH:7][CH:6]=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Br)cc(C)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(Br)cc2cc[nH]c12
Temperature: 25 °C

Procedure:
5-Bromo-7-methyl-1H-indole-2-carboxylic acid ethyl ester (5.3 g, 18.7 mmol) was added to a potassium hydroxide solution in 1:1 water/ethanol mixture (20 mL) and heated at reflux for 12 h. After cooling to room temperature, the solvents were removed in vacuo and the resultant residue transferred to a 6N hydrochloric acid solution (20 mL). The white precipitate that formed was filtered, washed severally with water, and dried for several hours. The crude solid was dissolved in quinoline (14 mL) and heated at reflux for 4 h. After cooling to room temperature, the crude mixture was poured into a mixture of ice water (100 mL) and concentrated hydrochloric acid (16 mL), extracted with ethyl acetate (2×), brine (2×), dried over sodium sulfate, and concentrated. Attempts to recrystallize the desired product from isopropanol resulted in significant decomposition. The title compound was obtained by flash chromatography on silica get to afford 1.5 g (38%, 2 steps). LC/MS: tR=1.72 min, 210.05 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])[NH:6]2.Cl[CH2:20][C:21]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[O:23][N:22]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]([F:16])([F:17])[F:18])[N:6]2[CH2:20][C:21]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=2)[O:23][N:22]=1
Reactant: N#Cc1ccc2[nH]c(CCC(F)(F)F)cc2c1Cl
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Product: N#Cc1ccc2c(cc(CCC(F)(F)F)n2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1Cl

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-(3,3,3-trifluoropropyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.23 (d, J=7.8 Hz, 1H), 7.86 (d, J=7.9 Hz, 1 H), 7.67 (dd, J=7.8 Hz, 1H), 7.45 (s, 2H), 6.56 (s, 1H), 5.45 (s, 2H), 3.27 (t, 2H), 2.89-2.61 (m, 2H); MS (ES) m/z 499 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][C:24]([CH3:37])([CH3:36])[CH2:25][CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH2:28][CH2:27][CH2:26][CH2:25][C:24]([NH:23][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[NH:18][CH:19]=1)=[O:22])([CH3:36])[CH3:37]
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CCCNC(=O)OC(C)(C)C)c3n2)c2ccc(F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CCCN)c3n2)c2ccc(F)cc21
Reaction time: 2 h
Yield: 58 %

Procedure:
To a stirred solution of tert-butyl 4-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-4-methylpentylcarbamate (75 mg, 0.15 mmol) in 6 mL of dichloromethane was added trifluoroacetic acid (3 mL) in one portion at room temperature and the solution stirred for 2 hours. The solvent was evaporated at 40° C. under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 20% acetonitrile/80% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 45% acetonitrile/55% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give N-(5-amino-2-methylpentan-2-yl)-2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide 2,2,2-trifluoroacetate (35 mg, 58%) as a pale yellow solid. MS: (M+H)+=410; 1H NMR (300 MHz, DMSO): δ 12.98 (s, 1H), 9.11 (s, 1H), 8.49-8.42 (m, 2H), 7.88 (s, 1H), 7.74 (d, 1H, J=9.9 Hz), 7.60 (brs, 3H), 7.20 (t, 1H, J=9.0 Hz), 4.18 (s, 3H), 2.76 (brs, 2H), 2.00-1.94 (m, 2H), 1.61 (brs, 2H), 1.25 (s, 6H).
Reaction SMILES: FC1C=CC=CC=1NC(=S)NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(O)=O)C3)=CC=1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43](=[S:69])[NH:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[C:56](=[O:60])[N:55]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([O:64]C)=[O:63])[CH2:54]4)=[CH:47][CH:46]=2)=[CH:38][CH:37]=1>>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43](=[S:69])[NH:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[C:56](=[O:60])[N:55]([C@@H:61]([CH:66]([CH3:67])[CH3:68])[C:62]([OH:64])=[O:63])[CH2:54]4)=[CH:47][CH:46]=2)=[CH:40][CH:41]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccc(Cl)cc4)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=S)Nc4ccc(Cl)cc4)cc3)ccc2C1=O
Yield: 94 %

Procedure:
The compound of example 265 was prepared analogous to compound of example 257 by hydrolysis of compound of example 264.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].ClC(OCC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>>[Br:1][C:2]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Br)c1
Agent: CCOC(=O)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cncc(Br)c1

Procedure:
The manner in which certain 5-substituted-3-pyridyl compounds of the present invention can be synthetically produced can vary. For example, 3-(5-bromo-3-pyridyl)-containing compounds can be prepared using a combination of synthetic techniques known in the art. 2-[3-(5-bromopyridiyl)]- substituted analogs of the 1-azatricyclo[3.3.1.13,7 ]decanes can all be prepared starting from 5-bromonicotinic acid, which is commercially available from Aldrich Chemical Co. The 5-bromonicotinic acid is converted to the mixed anhydride with ethyl chloroformate and reduced with lithium aluminum hydride/tetrahydrofuran (TIIF) at -78° C., to afford 5-bromo-3-hydroxymethylpyridine, as reported by Ashimori et al., Chem. Pharm. Bull. 38:2446 (1990). Alternatively, the 5-bromonicotinic acid is esterified in the presence of sulfuric acid and ethanol, and the intermediate ester is reduced with sodium borohydride to yield 5-bromo-3-hydroxymethylpyridine, according to the techniques reported in C. F. Natatis, et al., Org. Prep. and Proc. Int. 24:143 (1992). The resulting 5-bromo-3-hydroxymethylpyridine can then be converted to the 5-bromo-3-aminomethylpyridine utilizing a modification of the techniques of O. Mitsunobu, Synthesis 1 (1981), or via treatment of 5-bromo-3-hydroxymethylpyridine with thionyl chloride and reaction of the resulting 5-bromo-3-chloromethylpyridine with aqueous ammonia/ethanol, according to North et al., WO 95/28400. 5-Bromo-3-aminomethylpyridine can be converted to 1-aza-2-[5-bromo-(3-pyridyl)]tricyclo[3.3.1.13,7 ]decane using procedures analogous to those described hereinbefore for the preparation of 1-aza-2-(3-pyridyl)tricyclo[3.3.1.13,7 ]decane.
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][C:6]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][C:20]3[N:21]=[C:22]4[N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][CH2:24][N:23]4[CH:35]=3)=[CH:16][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]([F:40])([F:39])[F:38].[C:41]1([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[ClH:58].O1CCOCC1>>[ClH:58].[O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([O:12][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:11])[CH2:7][C:6]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][C:20]3[N:21]=[C:22]4[NH:27][CH2:26][CH2:25][CH2:24][N:23]4[CH:35]=3)=[CH:16][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]([F:38])([F:39])[F:40]
Reactant: OCCCCCCCCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCn2cc(CCOc3ccc4c(c3)CN(CC(F)(F)F)C(=O)[C@H](CC(=O)O)C4)nc21
Agent: Cl
Solvent: C1COCCO1
Product: O=C(C[C@@H]1Cc2ccc(OCCc3cn4c(n3)NCCC4)cc2CN(CC(F)(F)F)C1=O)OCCCCCCCCCCc1ccccc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
984 mg (1.74 mmol) of (4S)-3-oxo-8-[2-(8-tert-butoxycarbonyl-5,6,7,8-tetra-hydroimidazo[1,2-a]pyrimidin-2-yl)ethoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetic acid obtained in Example 5-(a) and 2.12 g (8.68 mmol) of 10-phenyl-1-decyl alcohol were mixed, 17.4 mL (69.6 mmol) of 4N hydrogen chloride/1,4-dioxane solution was added to the mixture, and the resulting mixture was stirred under nitrogen gas atmosphere at 50° C. for 4 hours.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=3)=[CH:11][CH:12]=2)[N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[N:4]=1.C([O-])([O-])=O.[K+].[K+].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CC#N>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:5]1[C:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:14]=3)=[CH:11][CH:12]=2)=[CH:7][C:3]([CH2:2][N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[N:4]1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(CBr)nn3-c3ccccc3Cl)s2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(CN4CCOCC4)nn3-c3ccccc3Cl)s2)c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 97.3 %

Procedure:
A mixture of 3-bromomethyl-1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-thiophen-2-yl]-1H-pyrazole (51 mg, 0.1 mmol), K2CO3 (42 mg, 0.3 mmol), KI (10 mg), and morpholine (0.3 mmol) in anhydrous MeCN (5 mL) was stirred at 90° C. for 6 h under N2. The solid was filtered off, and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography (0-80% EtOAc/hexanes) to give the title compound as a pale-yellow solid (50 mg, 96%). 1HNMR (CDCl3): δ 8.04 (m, 1H), 7.82 (m, 1H), 7.72 (m, 1H), 7.57-7.43 (m, 5H), 7.20 (d, 1H), 6.75 (d, 1H), 6.66 (s, 1H), 3.77 (m, 4H), 3.66 (s, 2H), 3.07 (s, 3H), 2.60 (m, 4H). MS(ES): 514 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:14](Cl)(C)=O>CO.CCOC(C)=O>[CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:14])=[O:6]
Reactant: CC(=O)Cl
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Reaction time: 20 h

Procedure:
To a suspension of 3-methyl-2-nitro-benzoic acid (1.0 eq.) in MeOH (0.4 M) at 0° C. was added dropwise AcCl (3.0 eq.). The reaction mixture was stirred for 20 hr at reflux. The solvent was reduced in vacuo and the residue was dissolved in EtOAc and washed several times with sat. aq. NaHCO3 solution, brine and dried (Na2SO4). Evaporation of the solvent gave (A1) as a white solid which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3, 300K) δ 7.86 (1H, d, J=7.5 Hz), 7.53-7.42 (2H, m), 3.89 (3H, s), 2.36 (3H, s). MS (ES) C9H9NO4 requires: 195. found: 218 (M+Na)+.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.C(Cl)(=O)C(Cl)=O.[C:18]([NH:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>ClCCl.CN(C)C=O>[C:18]([N:22]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:1](=[O:3])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)NCCC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCN(C(=O)c1ccc(C=O)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
N,N-dimethylformamide (25 μL) was added to a room temperature suspension of 4-carboxybenzaldehyde (2.0 g, 13 mmol) and oxalyl chloride (1.14 mL, 13.3 mmol) in dichloromethane (50 mL). The reaction was stirred at room temperature 30 minutes, then heated to reflux for 5 hours. The reaction mixture was concentrated. A solution of tert-butyl 3-(tert-butylamino)propanoate (2.68 g, 13.3 mmol) and triethylamine (1.9 mL, 13 mmol) in dichloromethane (50 mL) was added to the crude acid chloride. The mixture was stirred at room temperature overnight. The reaction was washed with water, then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give tert-butyl 3-(N-tert-butyl-4-formylbenzamido)propanoate (4.47 g, 100%). 1H NMR (400 MHz, CDCl3, δ): 10.01 (s, 1H), 7.86-7.91 (m, 2H), 7.45-7.49 (m, 2H), 3.46-3.54 (m, 2H), 2.34-2.41 (m, 2H), 1.52 (s, 9H), 1.31 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Br-].[CH2:14]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+].Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:14]\[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Br-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(/C=C\c2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a suspension of 4-chloro-3-nitrobenzaldehyde (1 g) and benzyltriphenylphosphonium bromide (2.34 g) in toluene (35 mL) was added sodium hydride (55%, 0.28 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with methylene chloride. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give 2-chloro-5-((Z)-2-phenylvinyl)-1-nitrobenzene (0.79 g). The obtained 2-chloro-5-((Z)-2-phenyl -vinyl)-1-nitrobenzene (0.16 g) was dissolved in ethanol (6 mL) -methanol (2 mL). To the solution was added 5% rhodium-carbon powder (20 mg) and morpholine (5 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give the title compound (87 mg).
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=O)[S:11][CH:12]=2)[N:4]([CH3:16])[N:3]=1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=3)[CH2:19][N:20]3[C:21](=[O:30])[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:28]3=[O:29])=[O:15])[S:11][CH:12]=2)[N:4]([CH3:16])[N:3]=1
Reactant: Cc1c(Cl)nn(C)c1-c1csc(C(=O)O)c1
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)nn(C)c1-c1csc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (238 mg, 0.93 mmol) [prepared according to the procedure of Example 176], 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (355 mg, 0.92 mmol) [prepared according to the procedure of Preparation 6, except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (5.0 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (532 mg, 1.13 mmol) in chloroform (9.5 mL). DIEA (820 μL, 4.70 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (448 mg, 0.72 mmol, 78%): LC-MS (ES) m/z=587 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([C:27]1[C:28]([O:39][CH3:40])=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:31][CH:32]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)O)C1C=CC=CC=1.[PH2](O)=O>C(#N)C>[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:19]([C:27]2[C:28]([O:39][CH3:40])=[C:29]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]=1[OH:8])([CH3:18])([CH3:16])[CH3:17]
Reactant: COc1c(-c2ccccc2)cccc1C(O)(c1ccccc1)c1cccc(C(C)(C)C)c1OCc1ccccc1
Agent: O=[PH2]O
Solvent: CC#N
Product: COc1c(-c2ccccc2)cccc1C(c1ccccc1)c1cccc(C(C)(C)C)c1O
Yield: 84.6 %

Procedure:
A solution of 15 (1.02 g, 1.93 mmol) in acetonitrile (24 mL) was treated with 50% aqueous hypophosphorous acid (11 mL) and stirred at reflux for 1.5 hr. After cooling, the acetonitrile was removed on a rotary evaporator. The residue was diluted with water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was washed with water (100 mL), saturated sodium bicarbonate (100 mL) and water (100 mL). The organic layer was dried over sodium sulfate and stripped. The crude product was purified by chromatography on silica (60 g) with 1% ethyl acetate in hexane (2 L). The relevant fractions were stripped and the residue was taken up in ethanol (12 mL) and stirred at 60° C. on a water bath for 30 min. The resulting slurry was allowed to cool overnight. The crystals were collected by filtration, washed with cold ethanol and dried in a vacuum oven at 65° C. to produce pure B4 (0.69 g, 85%).