Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16](OC(=O)C(F)(F)F)[C:17]2[C:18]([O:24][CH3:25])=[N:19][CH:20]=[CH:21][C:22]=2[Cl:23])=[C:11]([N+:33]([O-:35])=[O:34])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]2[C:18]([O:24][CH3:25])=[N:19][CH:20]=[CH:21][C:22]=2[Cl:23])=[C:11]([N+:33]([O-:35])=[O:34])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1nccc(Cl)c1C(Cc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-])OC(=O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: COc1nccc(Cl)c1/C=C/c1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
A solution of trifluoro-acetic acid 2-(4-tert-butoxycarbonylamino-2-nitro-phenyl)-1-(4-chloro-2-methoxy-pyridin-3-yl)-ethyl ester (crude 1.60 g, 3.08 mmol) in THF (10 mL) was added 8-diazabicyclo[5.4.0]undec-7-ene (1.33 g, 8,74 mmol) at 25° C. The reaction was allowed to stir at 70° C. for 3 hours. The reaction mixture was cooled to 25° C., and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (80/20 hexanes/ethyl acetate) afforded {4-[(E)-2-(4-chloro-2-methoxy-pyridin-3-yl)-vinyl]-3-nitro-phenyl}-carbamic acid tert-butyl ester (800 mg, 68%) as an oil. MH+ 406.0.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][C:18]2[N:19]=[C:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)[S:21][CH:22]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][NH2:39])[CH:33]=1>>[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH2:17][C:18]2[N:19]=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([C:27]([NH:39][CH2:38][C:34]4[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=4)=[O:28])=[CH:30][CH:31]=3)[S:21][CH:22]=2)(=[O:16])=[O:15])=[CH:12][CH:13]=1
Reactant: NCc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)Cc2csc(-c3ccc(C(=O)O)cc3)n2)cc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2csc(-c3ccc(C(=O)NCc4cccnc4)cc3)n2)cc1
Yield: 68.3 %

Procedure:
Method E. Reaction of oxalyl chloride (70 λL, 0.8 mmol) and benzoic acid 53 (200 mg, 0.54 mmol) with subsequent reaction with 3-pyridinylmethylamine (60 λL, 0.6 mmol) gave benzamide 54 (171 mg, 68%) as a white powder: mp (EtOAc) 178-181° C.; 1H NMR δ 9.19 (t, J=5.9Hz, 1 H, CONH), 8.57 (d, J=1.6Hz, 1 H, H-2″), 8.47 (dd, J=4.8, 1.5Hz, 1 H, H-6″), 7.97 (dd, J=6.7, 1.8Hz, 2 H, H-2 , H-6), 7.81 (dd, J=6.7, 1.8Hz, 2 H, H-3, H-5), 7.74 (ddd J=8.1, 2.1, 1.6Hz, 1 H, H-4″), 7.68 (s, 1 H, H-5′), 7.65 (dd, J=8.3, 1.7Hz, 2 H, H-2″, H-6″), 7.41 (br d, J=8.3Hz, 2 H, H-3″, H-5″), 7.36 (ddd, J=8.1, 4.8, 0.7Hz, 1 H, H-5″), 4.87 (s, 2 H, CH2SO2), 4.51 (d, J=5.9Hz, 2 H, CH2N), 2.40 (s, 3 H, CH3); 13C NMR δ 165.7, 165.5, 148.9, 148.1, 145.2, 144.3, 135.9, 135.3, 135.2, 135.0, 134.9, 129.5 (2), 128.2 (2), 128.1 (2), 125.9 (2), 123.4, 122.2, 57.0, 40.5, 21.0; MS m/z 464.8 (MH+, 100%). Anal. calcd for C24H21N3O3S2: C, 62.18; H, 4.57; N, 9.06. Found: C, 62.30; H, 4.55; N, 9.10%.
Reaction SMILES: [CH2:1]([NH:3][C@H:4]1[C@H:8]([S:9][CH3:10])[CH2:7][NH:6][CH2:5]1)[CH3:2].[Cl:11][C:12]1[C:13](F)=[C:14]([F:29])[CH:15]=[C:16]2[C:21]=1[N:20]([CH:22]1[CH2:24][CH2:23]1)[CH:19]=[C:18]([C:25]([OH:27])=[O:26])[C:17]2=[O:28]>>[Cl:11][C:12]1[C:13]([N:6]2[CH2:7][C@@H:8]([S:9][CH3:10])[C@H:4]([NH:3][CH2:1][CH3:2])[CH2:5]2)=[C:14]([F:29])[CH:15]=[C:16]2[C:21]=1[N:20]([CH:22]1[CH2:24][CH2:23]1)[CH:19]=[C:18]([C:25]([OH:27])=[O:26])[C:17]2=[O:28]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CCN[C@@H]1CNC[C@H]1SC
Product: CCN[C@@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)C[C@H]1SC

Procedure:
The reaction is carried out analogously to Example 13 with trans-3-ethylamino-4-methylthio-pyrrolidine and 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid to give 8-chloro-1-cyclopropyl-7-(trans-3-ethylamino-4-methylthio-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 217°-218° C. (with decomposition).
Reaction SMILES: [Na].Cl.[CH:3]([NH2:5])=[NH:4].[CH2:6]([N:13]1[CH2:19][CH2:18][C:17](Cl)=[C:16]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=O)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[CH2:6]([N:13]1[CH2:14][CH2:15][C:16]2[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:4][CH:3]=[N:5][C:17]=2[CH2:18][CH2:19]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(C1=C(Cl)CCN(Cc2ccccc2)CC1)c1ccccc1
Reactant: N=CN
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: c1ccc(CN2CCc3ncnc(-c4ccccc4)c3CC2)cc1
Temperature: 6 °C
Reaction time: 0.25 h
Yield: 39.5 %

Procedure:
16.8 g sodium was added to 500 mL ethanol at 10° C. Then, 48.5 g formamidine hydrochloride was added and the reaction was stirred 15 min at 6° C. 28 g (1-benzyl-5-chloro-2,3,6,7-tetrahydro-1H-azepin-4-yl)-phenyl-methanone was added and the reaction was stirred 17 h at RT and 1 h at 40° C. The mixture was filtered and the solvent was removed. The residue was dissolved in ethyl acetate. The layers were separated and the organic layer was washed with water and evaporated. The residue was crystallized with diethylether to yield 10.7 g of the desired product. Fp: 81-82° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2([CH2:15][CH2:14][CH2:13]2)[O:11][C:10]2[C:5](=[C:6]([CH3:19])[C:7]([OH:18])=[C:8]([CH3:17])[C:9]=2[CH3:16])[CH:4]=1.[H][H]>[Pd]>[OH:1][CH2:2][CH:3]1[C:12]2([CH2:15][CH2:14][CH2:13]2)[O:11][C:10]2[C:5](=[C:6]([CH3:19])[C:7]([OH:18])=[C:8]([CH3:17])[C:9]=2[CH3:16])[CH2:4]1
Reactant: Cc1c(C)c2c(c(C)c1O)C=C(CO)C1(CCC1)O2
Reactant: [H][H]
Agent: [Pd]
Product: Cc1c(C)c2c(c(C)c1O)CC(CO)C1(CCC1)O2

Procedure:
3-(Hydroxymethyl)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol was prepared by hydrogenation of 3-(hydroxymethyl)-5,7,8-trimethylspiro[chromene-2,1′-cyclobutan]-6-ol with hydrogen in the presence of Pd/C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH3:31][N:28]1[CH2:27][CH2:26][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:30][CH2:29]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CN1CCN(c2nnc3ccc(F)cn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a solution of Intermediate A (125 mg, 0.766 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 62 mg, 1.54 mmol) and the mixture stirred at RT for 0.5 h. A solution of Intermediate 68a (180 mg, 0.766 mmol) in DMF (3 mL) was added and the mixture stirred at 60° C. for 1.75 h. The cooled mixture was diluted with water and extracted with DCM (5×25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-20% [2M NH3 in MeOH] in DCM, to give the title compound as a pale brown gum (225 mg, 78%). LCMS (Method 3): Rt 0.44 min, m/z 379 [MH+].
Reaction SMILES: ClS([N:5]=[C:6]=O)(=O)=O.[Br:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.CN(C)C=O.Cl>C(Cl)Cl>[Br:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:6]#[N:5]
Reactant: Cc1ccc(-n2cccc2)c(Br)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(-n2cccc2C#N)c(Br)c1
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
Chlorosulfonyl isocyanate (1.2 ml) in methylene chloride (12 ml) was added dropwise to a stirred solution of 1-(2-bromo-4-methylphenyl)pyrrole (2.5 g) in methylene chloride (25 ml) kept about -20° C. under nitrogen atmosphere. The reaction mixture was stirred at -20° C. for 30 minutes and at room temperature for 1.5 hours, and then was added dropwise dimethylformamide (1.7 ml) keeping at about -20° C. The reaction mixture was stirred at -20° C. for 30 minutes and at room temperature for an hour. To the reaction mixture was added 4N-hydrochloric acid at 0° C., and stirred at 0° C. for 30 minutes. The organic layer was washed with water and saturated sodium hydrogencarbonate solution, and dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography with a mixture of ethyl acetate and n-hexane (1:10) as eluent to give 1-(2-bromo-4-methylphenyl)pyrrole-2-carbonitrile (2.4 g).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([OH:14])=[CH:9][CH:8]=1.[Cl:15][CH2:16][C:17]([CH3:19])=[CH2:18]>O>[Br:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([OH:14])=[C:9]([C:17]([CH3:19])([CH3:18])[CH2:16][Cl:15])[CH:8]=1
Reactant: Cc1cc(O)ccc1Br
Reactant: C=C(C)CCl
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(O)c(C(C)(C)CCl)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
Concentrated sulfuric acid (1.75 g, 17.8 mmol) was added drop wise to a cooled (ice bath) mixture of 4-bromo-5-methyl-phenol (Compound 45, 10 g, 53.46 mmol) and 3-chloro-2-methyl-propene (5.28 mL, 53.46 mmol). The dark reaction mixture was allowed to warm to ambient temperature and stirred a total of 2 hours. The reaction mixture was diluted with water, and extracted with diethylether. The combined organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to an oil. Flash column chromatography using 3% ethyl acetate in hexanes as the eluent afforded the title compound (6.2 g, 48%) as a green solid; 4-bromo-5-methyl-phenol was recovered. 1H NMR (300 MHz, CDCl3): δ 7.35 (s, 1H), 6.54 (s, 1H), 5.02 (s, 1H), 3.96 (s, 2H), 2.28 (s, 3H), 1.44 (s, 6H).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:53]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[C:55]([C:63]2[CH:64]=[C:65]([NH2:69])[CH:66]=[CH:67][CH:68]=2)[CH:54]=1>CN(C=O)C>[N:53]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[C:55]([C:63]2[CH:64]=[C:65]([NH:69][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:66]=[CH:67][CH:68]=2)[CH:54]=1
Reactant: Nc1cccc(-c2cnc3ccccc3c2)c1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cnc3ccccc3c2)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 67.9 %

Procedure:
DIEA (0.013 mL, 0.075 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.019 g, 0.068 mmol) and HATU (0.028 g, 0.075 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-quinolin-3-yl-phenylamine (0.015 g, 0.068 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.022 g of product in 68% yield: LCMS (ESI) m/z 477 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([C:13]1([C:16]2[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=2)[C:19]([NH:21][C:22]2[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=2[CH3:29])=[O:20])[CH2:15][CH2:14]1)#[N:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:11]([C:13]1([C:16]2[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=2)[C:19]([NH:21][C:22]2[CH:27]=[C:26]([O:28][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=3)[CH:25]=[CH:24][C:23]=2[CH3:29])=[O:20])[CH2:15][CH2:14]1)#[N:12]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1ccc(O)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 103.6 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (3.25 g, 20.5 mmol) and 3-(1-cyanocyclopropyl)-N-(5-hydroxy-2-methylphenyl)benzamide (6.0 g, 20.5 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (7.08 g, 51.3 mmol), and the mixture was stirred at 60° C. for 12 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (300 mL), washed with water (300 mL), 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→30/70). The obtained solution was concentrated under reduced pressure to give the title compound (8.8 g, quantitative) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[C:32](=[O:33])[CH2:31][CH2:30][C@H:29]1[C:34]([NH:36][C@H:37]([C:44]([NH:46][C@H:47]([C:58]([NH:60][C@H:61]([C:64](O)=[O:65])[CH2:62][OH:63])=[O:59])[CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)=[O:45])[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)=[O:35].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:27])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[NH:11][C:62](=[O:63])[C@H:61]([CH2:64][OH:65])[NH:60][C:58](=[O:59])[C@H:47]([CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)[NH:46][C:44](=[O:45])[C@H:37]([CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)[NH:36][C:34](=[O:35])[C@@H:29]1[CH2:30][CH2:31][C:32](=[O:33])[NH:28]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC[C@@H](C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)N[C@@H](CO)C(=O)O)N1
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CC[C@@H](C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)OCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
O-Benzyl-L-tyrosine benzyl ester (VIII) hydrochloride (0.397 g) and L-pyroglutamyl-L-histidyl-L-tryptophyl-L-serine (VII) (0.539 g) in dry dimethylformamide (50 ml) is treated with triethylamine (0.14 ml) and dicyclohexylcarbodiimide (0.227 g) in dry dimethylformamdie (5 ml) at 0° C. After stirring at room temperature for 24 hours, the reaction mixture is evaporated to dryness. The residue is triturated in methanol and the dicyclohexylurea is removed by filtration. The filtrate is concentrated to L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-O-benzyl-L-tyrosine benzyl ester (IX).
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([N:7]1[C:15]2[C:10](=[CH:11][C:12](/[CH:16]=[C:17](/[C:19](=[O:24])[NH:20][CH2:21][CH2:22][CH3:23])\[CH3:18])=[CH:13][CH:14]=2)[C:9]([CH2:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][C:27]=2[O:36][CH3:37])=[CH:8]1)[CH:5]=[CH2:6]>O.CO>[CH2:4]([N:7]1[C:15]2[C:10](=[CH:11][C:12](/[CH:16]=[C:17](/[C:19](=[O:24])[NH:20][CH2:21][CH2:22][CH3:23])\[CH3:18])=[CH:13][CH:14]=2)[C:9]([CH2:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][C:27]=2[O:36][CH3:37])=[CH:8]1)[CH:5]=[CH2:6]
Reactant: C=CCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(/C=C(\C)C(=O)NCCC)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCn1cc(Cc2ccc(C(=O)O)cc2OC)c2cc(/C=C(\C)C(=O)NCCC)ccc21
Reaction time: 18 h
Yield: 88 %

Procedure:
A solution of lithium hydroxide monohydrate (0.16 g) in water (2 ml) was added to a stirred solution of methyl E-4[1-allyl-5-[2-(propylcarbamoyl)- 1-propenyl]indol-3-ylmethyl]-3-methoxybenzoate (0.34 g) in methanol (5 ml), and the mixture was stirred for 18 hr under an atmosphere of nitrogen. The solution was concentrated to remove methanol, acidified with 1M hydrochloric acid (30 ml), diluted with water (30 ml), and the precipitate which formed (0.31 g) was isolated by filtration and dried. The product was dissolved in methanol (2 ml) and water (2 ml), and triethylamine (0.1 ml) was added. The salt that formed was purified by reverse-phase flash chromatography on octadecylsilyl (ODS, J. T. Baker) 40 micron packing material (40 g), eluting with 1:1 methanol:water. The fraction containing the purified salt was evaporated and acidified with 1M hydrochloric acid, extracted with methylene chloride (3×50 ml), and the organic phase washed with 1M hydrochloric acid and brine, and dried (MgSO4). The solvent was evaporated to give the title compound (0.29 g, 88%) as a solid glass, mp 84°-90°.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH:14]([CH3:17])[CH2:15][F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH:25]1[CH2:27][CH2:26]1)([CH3:24])[CH2:20][C:21]([NH2:23])=[O:22]>>[NH2:23][C:21](=[O:22])[CH2:20][C:19]([NH:18][C:10](=[O:12])[C:7]1[CH:6]=[C:5]([O:13][CH:14]([CH3:17])[CH2:15][F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)([CH:25]1[CH2:27][CH2:26]1)[CH3:24]
Reactant: CC(CF)Oc1cc(C(=O)O)ncc1C1CC1
Reactant: CC(N)(CC(N)=O)C1CC1
Product: CC(CF)Oc1cc(C(=O)NC(C)(CC(N)=O)C2CC2)ncc1C1CC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(1-fluoropropan-2-yloxy)picolinic acid (enantiomer B) (example 289b) and 3-amino-3-cyclopropyl-butanamide (example 270c) as starting materials and isolated (85.4 mg, 80%); MS (ESI, m/z): 364.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@@H:11]1[CH2:16][CH2:15][CH2:14][O:13][CH2:12]1)[C:7]([O:9]C)=[O:8])=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@@H:11]1[CH2:16][CH2:15][CH2:14][O:13][CH2:12]1)[C:7]([OH:9])=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)OC)[C@@H]1CCCOC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)O)[C@@H]1CCCOC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.6 %

Procedure:
To a solution of (S)-methyl 2-(methoxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetate (126 mg, 0.545 mmol) in THF (4 mL) stirring at rt was added a solution of 1M LiOH (1.090 mL, 1.090 mmol) in water. The reaction was stirred at rt for 3 h, neutralized with 1M HCl (1.1 mL) and extracted with EtOAc (3×10 mL). The organics were dried, filtered and concentrated to yield (S)-2-(methoxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetic acid (Cap-177a) (125 mg) as a clear colorless oil. LC-MS retention time 0.44 min; m/z 218.00 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, chloroform-d) δ ppm 5.28 (d, J=8.8 Hz, 1 H), 4.38 (dd, J=8.7, 5.6 Hz, 1 H), 3.96-4.04 (m, 1 H), 3.91 (d, J=11.0 Hz, 1 H), 3.71 (s, 3 H), 3.33-3.41 (m, 1 H), 3.24-3.32 (m, 1 H), 2.10-2.24 (m, 1 H), 1.74-1.83 (m, 1 H), 1.63-1.71 (m, 2 H), 1.35-1.49 (m, 1 H).
Reaction SMILES: [C:1]1([P:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=O)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>>[C:1]1([P:7]([Cl:18])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(O)(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Product: O=P(Cl)(c1ccccc1)c1ccccc1

Procedure:
Thirteen grams (0.064 m) of diphenylphosphinic acid was combined with 50 ml of thionyl chloride and the mixture heated at reflux for 2.5 hours. The diphenylphosphinic chloride was purified by distillation, bp 140° C. at 0.1 torr.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C@@:8]12[C:24](=O)[CH2:23][CH2:22][C@H:21]1[C:20]1[C@@H:11]([C:12]3[CH:13]=[CH:14][C:15]([OH:26])=[CH:16][C:17]=3[CH2:18][CH:19]=1)[CH2:10][CH2:9]2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH2:1]=[C:24]1[CH2:23][CH2:22][C@H:21]2[C:20]3[C@H:11]([CH2:10][CH2:9][C@:8]12[CH3:7])[C:12]1[CH:13]=[CH:14][C:15]([OH:26])=[CH:16][C:17]=1[CH2:18][CH:19]=3
Reactant: C[C@]12CC[C@H]3C(=CCc4cc(O)ccc43)[C@@H]1CCC2=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=C1CC[C@H]2C3=CCc4cc(O)ccc4[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphonium bromide (1.9967 g, 5.5892 mmol) and potassium t-butoxide (627.2 mg, 5.589 mmol) suspended in 6.1 mL of anh. DMSO under argon were 1 h in an oil bath (71-83° C., after which equilin (300.0 mg, 1.118 mmol) in 6.1 mL of anh. DMSO was added via syringe. See FIG. 18. After stirring a further 70 min., the reaction mixture was poured into 40 mL of ice water and extracted three times with 25 mL portions of ether. The combined organic extracts were washed with 25 mL of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 mL of ether and the combined filtrates were concentrated under reduced pressure. Flash chromatography (15% ethyl acetate/hexanes on silica gel) followed by preparative TLC (20% ethyl acetate/hexanes on silica gel GF, 1000μ thickness) gave an opaque white film (162.3 mg, 0.6093 mmol, 54%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:29])[CH:27]=[CH2:28])[CH:22]=[CH:23][CH:24]=3)[N:17]=2)[N:12](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:11]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:29])[CH:27]=[CH2:28])[CH:22]=[CH:23][CH:24]=3)[N:17]=2)[NH:12][CH:11]=1
Reactant: C=CC(=O)Nc1cccc(-c2cnc3c(n2)c(-c2cc4ccccc4[nH]2)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: C=CC(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cc5ccccc5[nH]4)c3n2)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A solution of compound 13 (90 mg, 1.449 mmol) in chloroform was added trifluoroacetic acid. The reaction was stirred overnight at 45° C., distilled off TFA and diluted with water and pH was adjusted to 9-10 with 1M NaOH solution at 20-25° C. The aqueous layer was extracted with dichloromethane (25 mL) twice. The organic layer was dried over sodium sulphate, filtered and concentrated to get the crude. The resulting oil was purified via silica gel chromatography using gradient of 50% Ethyl acetate in hexane to afford brown colour solid Compound 14. MS-ES+379.41, 1H NMR (400 MHz, DMSO-D6-d6) 14: 11.36 (d, 1H), 10.40 (d, 1H), 8.89 (d, 1H), 8.54 (d, 1H), 8.38 (d, 1H), 7.94 (d, 2H), 7.55 (d, 2H), 7.43 (d, 2H), 7.13 (d, 2H), 6.56 (d, 1H), 6.36 (d,1H), 5.83 (d, 1H), 5.31 (d, 1H).