Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:12][N:11]3[C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26](F)[CH:25]=2)=[CH:4][CH:3]=1.[CH3:31][NH:32][CH3:33]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]4)=[N:12][N:11]3[C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:32]([CH3:33])[CH3:31])[CH:25]=2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)c(-c4ccnc(F)c4)n3n2)CC1
Solvent: O
Product: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)c(-c4ccnc(N(C)C)c4)n3n2)CC1
Temperature: 150 °C

Procedure:
0.10 g (0.25 mmol) of 2-(4-fluorophenyl)-3-(2-fluoropyrid-4-yl)-6-(4-methylpiperazin-1-yl)-imidazo[1,2-b]pyridazine and 10 mL of dimethylamine are introduced into an autoclave. The mixture is heated at 150° C. overnight and then cooled and poured into water. The product is extracted with chloroform, and the organic phase is dried over sodium sulfate and then concentrated under reduced pressure to give a solid. This solid is crystallized and recrystallized from acetonitrile to give 0.028 g of a white powder after cooling, filtering off and drying.
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH2:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[C:1]([O:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH:8][CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CCOC(CBr)OCC
Product: CCOC(CN[C@@H](C)C(=O)OC(C)(C)C)OCC

Procedure:
L-Alanine-t-butyl ester was allowed to react with 2-bromo-1,1-diethoxyethane in substantially the same manner as in Working Example 52 to afford the title compound as a yellowish brown oily product.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[C:10]([C:12]1[CH:33]=[CH:32][C:15]([C:16]([N:18]([CH3:31])[C:19]2[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][C:20]=2[N+:28]([O-:30])=[O:29])=[O:17])=[CH:14][CH:13]=1)#[N:11].Cl.[NH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40]>C(Cl)Cl>[CH3:42][O:41][C:39]([CH2:38][CH2:37][CH2:36][NH:35][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:18]([CH3:31])[C:16](=[O:17])[C:15]2[CH:32]=[CH:33][C:12]([C:10]#[N:11])=[CH:13][CH:14]=2)=[C:20]([N+:28]([O-:30])=[O:29])[CH:21]=1)=[O:40]
Reactant: CN(C(=O)c1ccc(C#N)cc1)c1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: COC(=O)CCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCNC(=O)c1ccc(N(C)C(=O)c2ccc(C#N)cc2)c([N+](=O)[O-])c1
Reaction time: 64 h

Procedure:
2.84 g of N-ethyl-diisopropylamine are added, with cooling to 0° C., to a mixture of 3.2 g of 4-[N-(4-cyano-benzoyl)-methylamino]-3-nitro-benzoylchloride, 1.68 g of methyl 4-aminobutyrate-hydrochloride and 50 ml of methylene chloride. The mixture is stirred for 64 hours and allowed to return to ambient temperature. The methylene chloride is evaporated off and the residue is purified over silica gel (eluant:ethyl acetate/ethanol=200:1). Yield: 3.9 g (100% of theory), Rf value: 0.62 (silica gel; ethyl acetate/ethanol=9:1)
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH:24]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CCO>[CH:24]1([CH2:30][NH:31][C:2]2[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:17])([F:16])[F:18])[CH2:9][C:10]([F:12])([F:13])[F:11])=[O:7])=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NCC1CCCCC1
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Solvent: CCO
Product: O=C(c1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
4-Fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (107 mg, 0.307 mmol) and cyclohexylmethylamine (0.050 mL, 0.368 mmol) were stirred in 3 mL of EtOH containing TEA (0.065 mL, 0.460 mmol) at 75° C. for 3 h. The mixture was concentrated. The residue was re-dissolved in EtOAc and washed with 5% KHSO4 solution, saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The title product was purified by flash chromatography using 9:1/hexanes:EtOAc. Yield: 113 mg (83%). 1H NMR (400 MHz, CDCl3) δ 1.05 (m, 2H), 1.24 (m, 4H), 1.69 (m, 2H), 1.75 (m, 2H), 1.83 (m, 1H), 3.17 (t, J=6.64 Hz, 2H), 4.23 (q, J=8.53 Hz, 4H), 6.91 (d, J=8.98 Hz, 1H), 7.51 (d, J=8.89 Hz, 1H), 8.28 (s, 1H), 8.39 (s, 1H).
Reaction SMILES: C(O[C:4](=[O:23])[CH2:5][N:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]([CH3:16])[N:15]=2)[C:7]1=[O:22])C.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.[C-]#N.[Na+]>ClCCl>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:4](=[O:23])[CH2:5][N:6]2[CH2:10][CH2:9][N:8]([C:11]3[S:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]([CH3:16])[N:15]=3)[C:7]2=[O:22])=[CH:27][CH:26]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)CN1CCN(c2nc(C)c(C(=O)OCC)s2)C1=O
Agent: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1sc(N2CCN(CC(=O)NCc3ccc(F)cc3)C2=O)nc1C
Temperature: 80 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
A mixture of ethyl 2-(3-(2-ethoxy-2-oxoethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate (0.43 g, 1.25 mmol), 4-fluorobenzylamine (3 mL) and catalytic amount of sodium cyanide was stirred at 80° C. for 16 h. The reaction mixture was allowed to cool to ambient temperature, diluted with dichloromethane (25 mL) and filtered. The solid was washed with dichloromethane and hexanes on the filter. The filtrate was filtered again, and the solid was washed with hexanes. The combined material was dried to afford the title compound as a colorless solid (0.45 g, 86%): 1H NMR (300 MHz, CDCl3) δ 7.28-7.20 (m, 2H), 7.05-6.97 (m, 2H), 6.42 (br s, 1H), 4.42 (d, J=5.7 Hz, 2H), 4.29 (q, J=7.1 Hz, 2H), 4.19-4.10 (m, 2H), 3.99 (s, 2H), 3.77-3.70 (m, 2H), 2.62 (s, 3H), 1.34 (t, J=7.1 Hz, 3H); MS (ES+) m/z 421.2 (M+1).
Reaction SMILES: C(CCCCC1C=C(/[C:14](=[CH:47]\[CH:48]=[C:49]2\[N:50]([CH2:72][CH2:73][CH2:74][S:75]([O-:78])(=[O:77])=[O:76])[C:51]3[CH:52]=[CH:53][C:54]4[C:63]([S:64]([O-:67])(=[O:66])=[O:65])=[CH:62][C:61]([S:68]([O-:71])(=[O:70])=[O:69])=[CH:60][C:55]=4[C:56]=3[C:57]\2([CH3:59])[CH3:58])/[CH:15]=[CH:16]/[C:17]2[C:25]([CH3:27])([CH3:26])[C:24]3[C:23]4[CH:28]=[C:29]([S:36]([O-:39])(=[O:38])=[O:37])[CH:30]=[C:31]([S:32]([O-:35])(=[O:34])=[O:33])[C:22]=4[CH:21]=[CH:20][C:19]=3[N+:18]=2[CH2:40][CH2:41][CH2:42][S:43]([O-:46])(=[O:45])=[O:44])C=CC=1)(O)=O.[Na+:79].[Na+].[Na+].[Na+].[Na+].B([C:87]1[CH:88]=[C:89]([CH:95]=[C:96]([F:98])[CH:97]=1)[O:90][CH2:91][C:92]([OH:94])=[O:93])(O)O>>[C:92]([CH2:91][O:90][C:89]1[CH:88]=[C:87](/[C:14](=[CH:47]\[CH:48]=[C:49]2\[N:50]([CH2:72][CH2:73][CH2:74][S:75]([O-:78])(=[O:77])=[O:76])[C:51]3[CH:52]=[CH:53][C:54]4[C:63]([S:64]([O-:67])(=[O:66])=[O:65])=[CH:62][C:61]([S:68]([O-:71])(=[O:69])=[O:70])=[CH:60][C:55]=4[C:56]=3[C:57]\2([CH3:59])[CH3:58])/[CH:15]=[CH:16]/[C:17]2[C:25]([CH3:26])([CH3:27])[C:24]3[C:23]4[CH:28]=[C:29]([S:36]([O-:39])(=[O:37])=[O:38])[CH:30]=[C:31]([S:32]([O-:35])(=[O:33])=[O:34])[C:22]=4[CH:21]=[CH:20][C:19]=3[N+:18]=2[CH2:40][CH2:41][CH2:42][S:43]([O-:46])(=[O:44])=[O:45])[CH:97]=[C:96]([F:98])[CH:95]=1)([OH:94])=[O:93].[Na+:79].[Na+:79].[Na+:79].[Na+:79].[Na+:79]
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCCCC(=O)O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
Reactant: O=C(O)COc1cc(F)cc(B(O)O)c1
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cc(F)cc(OCC(=O)O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21

Procedure:
Compound 36 was prepared analogously to compound 8 (Example 8), except that 2-(3-borono-5-fluorophenoxy)acetic acid is used as a starting material.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:23]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26].Cl.[NH2:38][CH2:39][C@H:40]([N:45]1[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][CH2:46]1)[C:41]([O:43][CH3:44])=[O:42].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:23]([O:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:38][CH2:39][C@H:40]([N:45]2[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][CH2:46]2)[C:41]([O:43][CH3:44])=[O:42])=[O:34])=[CH:35][CH:36]=1)[C:24]#[C:25][CH3:26]
Reactant: CC#CCOc1ccc(C(=O)O)cc1
Reactant: COC(=O)[C@H](CN)N1CCN(S(C)(=O)=O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(C(=O)NC[C@@H](C(=O)OC)N2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 101.2 %

Procedure:
210 mg (1.5 mmol) of 1-hydroxybenzotriazole and 290 mg (1.5 mmol) of 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride are added to a solution of 260 mg (1.9 mmol) of 4-but-2-ynyloxybenzoic acid (prepared as described in example 1-5) in 10 ml of dimethylformamide. The reaction medium is stirred for 15 minutes and a mixture of 420 mg (1.4 mmol) of methyl (S)-3-amino-2-(4-methanesulphonylpiperazin-1-yl)propanoate hydrochloride and 390 mg (2.8 mmol) of triethylamine in 3 ml of dimethylformamide are added. The reaction medium is stirred at ambient temperature for 1 h 30 min, heated to 50° C., over 1 h 30 min then hydrolysed with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase is washed with an aqueous solution of sodium hydrogen carbonate then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated. The crude product obtained is purified by chromatography over silica gel eluted with a 98/2 dichloromethane/methanol mixture. 620 mg (100%) of methyl (S)-3-(4-but-2-ynyloxybenzoylamino)-2-(4-methanesulphonylpiperazin-1-yl)propanoate are obtained in the form of a colourless oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4]OC1=O.[CH3:7][C:8]1([CH3:20])[C:12]([CH3:14])([CH3:13])[O:11][B:10]([C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)[O:9]1.[OH-].[Na+].C>CN(C)C=O>[CH3:7][C:8]1([CH3:20])[C:12]([CH3:13])([CH3:14])[O:11][B:10]([C:15]2[CH:19]=[N:18][N:17]([CH2:4][CH2:5][OH:1])[CH:16]=2)[O:9]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=C1OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CCO)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A solution of 1,3-dioxolan-2-one (2.496 g, 28.3 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5 g, 25.8 mmol) and sodium hydroxide (0.103 g, 2.58 mmol) in N,N-Dimethylformamide (DMF) (18 mL) was stirred at 140° C. for 16 h. then cooled to room temperature and treated with activated charcoal (200 mg). The resulting mixture was stirred at room temperature for 1 h then filtered through celite (10 g). The insoluble were washed with EtOAc (50 mL) and EtOH (50 mL). The combined filtrate and washings were concentrated in vacuo. Purification of the residue by flash chromatography on silica gel using a 50 G silica cartyridge (gradient: 0 to 40% MeOH in DCM) gave a residue which was further purified by SP4 using a 100 G silica cartridge (eluant: 0 to 20% MeOH in DCM) to give 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanol (5.58 g, 23.44 mmol, 91% yield) as a colourless oil which was used in the next step without further purification.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[CH:7]=[C:6]([C:20]([O:22]CC)=[O:21])[C:5]2=[O:25].[CH2:26]([NH:28][C:29](=[O:49])[NH:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[C:33]([C:40]2[S:41][CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[N:44]=2)[CH:32]=1)[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Li+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:26]([NH:28][C:29](=[O:49])[NH:30][C:31]1[N:36]=[CH:35][C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[N:10][CH:11]=2)[N:8]([CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:7]=[C:6]([C:20]([OH:22])=[O:21])[C:5]3=[O:25])=[C:33]([C:40]2[S:41][CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[N:44]=2)[CH:32]=1)[CH3:27]
Reactant: CCOC(=O)c1cn(CC2CCN(C)CC2)c2ncc(I)cc2c1=O
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)O)cn3CC2CCN(C)CC2)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 7.4 %

Procedure:
To a solution of ethyl 6-iodo-1-((1-methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 1, 952 mg, 2.32 mmol) and 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 9, 834 mg, 2.32 mmol) in 1,4-dioxane (7.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (268 mg, 0.23 mmol) followed by a solution of cesium carbonate (1.51 g, 4.63 mmol) in water (2 mL). The reaction mixture was stirred at 100° C. for 2 h. 2 M lithium hydroxide (2.32 mL, 4.63 mmol) was then added and the mixture was stirred at 100° C. for 12 h. The reaction mixture was diluted with water, and the precipitate was washed with water and hexanes and then dried. The compound was purified via reverse phase HPLC (C18, 0-95% acetonitrile/water, gradient) and concentrated under reduced pressure to give 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-((1-methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid as a light yellow solid (106.1 mg, 7%).
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH3:13][CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22].O>C(OCC)(=O)C>[CH3:13][CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:12][CH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1)=[O:22]
Reactant: CC(C)CCCCCCC(=O)O
Reactant: COc1cc(CCO)ccc1O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(CCOC(=O)CCCCCCC(C)C)ccc1O
Temperature: 50 °C
Yield: 93.4 %

Procedure:
Homovanillyl alcohol (769 mg, 4.57 mmol), 8-methylnonanoic acid (751 mg, 4.35 mmol) and Novozyme 435 (51 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr without plugging the flask. After stirring with heating for 2 to 3 hr, attachment of water onto the upper wall of the flask was observed. The reaction mixture was allowed to cool to room temperature, ethyl acetate (25 ml) was added, and Novozyme 435 and the precipitated insoluble material were removed by filtration. Ethyl acetate (50 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2), saturated brine (25 ml), 5% aqueous sodium hydrogen carbonate solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (preparative thin layer chromatography) (n-hexane:ethyl acetate=3:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give homovanillyl 8-methylnonanoate (1.31 g, yield 93.2%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][N:10]1[C:14]([C:15]#[N:16])=[CH:13][CH:12]=[C:11]1B(O)O.[F-].[K+]>CCOC(C)=O.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].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:11]2[N:10]([CH3:9])[C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:3][CH:4]=1
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: Nc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: Cn1c(C#N)ccc1-c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.7 %

Procedure:
4-Bromoaniline (5.00 g, 29.0 mmol), 1-methyl-5-cyano-2-pyrroleboronic acid (5.2 g, 34.8 mmol), KF (5.55 g, 95.7 mmol), and Pd2(dba)3 (332 mg, 0.36 mmol) were added to a 200 mL round bottom flask under nitrogen. The flask was sealed and purged with nitrogen for 5 min. THF (72 mL) was added and the mixture was purged with nitrogen for an additional 5 min. A solution of tri-t-butylphosphine (10 wt % in hexanes) (2.15 mL, 0.73 mmol) was added via syringe and the mixture was stirred vigorously at 25° C. for 5 h. The mixture was diluted with 250 mL of EtOAc, filtered through a plug of silica gel, washed through with 200 mL of EtOAc and concentrated to give a crude brown/black semi-solid. Purification by silica gel flash chromatography (20% acetone/hexane) afforded 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (3.3 g) as an off-white solid.
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.O[C:23]1[CH:58]=[CH:57][C:26]([CH2:27][N:28]([CH2:49][C:50]([O:52]C(C)(C)C)=[O:51])[C:29](=[O:48])[C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:47])[CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)=[CH:32][CH:31]=2)=[CH:25][CH:24]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][C:23]3[CH:58]=[CH:57][C:26]([CH2:27][N:28]([CH2:49][C:50]([OH:52])=[O:51])[C:29](=[O:48])[C:30]4[CH:31]=[CH:32][C:33]([NH:36][C:37](=[O:47])[CH2:38][C:39]5[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=5)=[CH:34][CH:35]=4)=[CH:25][CH:24]=3)=[O:12])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)cc2)cc1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(OC(=O)c4ccc(C5CCCCC5)cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
Prepared using General Procedures 2 and 8: To a stirring solution of 4-cyclohexylbenzoic acid (24 mg, 0.119 mmol) in DCM (0.5 mL) were added DMF (1 drop) and oxalyl chloride (0.011 mL, 0.127 mmol). The reaction mixture was stirred at room temperature for 2 h. To this mixture was added a solution of tert-butyl 2-(N-(4-hydroxybenzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-7 (40 mg, 0.079 mmol) and TEA (0.022 mL, 0.159 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 18 h then TFA (1 mL) was added. After stirring for 2 h, the solvent was concentrated and the product was purified by preparative HPLC to provide to afford 22.2 mg (44%) of 2-(N-(4-((4-cyclohexylbenzoyl)oxy)benzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido) acetic acid 39. LCMS-ESI (m/z) calculated for C38H38N2O7: 634; found 633 [M−H]−, tR=8.92 min (Method 4). 1H NMR (400 MHz, DMSO) δ 10.30 (s, 1H), 8.04 (d, J=7.7 Hz, 2H), 7.64 (d, J=8.2 Hz, 2H), 7.45 (t, J=7.0 Hz, 3H), 7.39-7.26 (m, 3H), 7.24 (d, J=8.4 Hz, 4H), 6.88 (d, J=8.1 Hz, 2H), 4.62 (d, J=36.7 Hz, 2H), 3.94 (d, J=31.7 Hz, 2H), 3.72 (s, 2H), 3.57 (s, 3H), 2.63 (t, J=10.7 Hz, 1H), 1.76 (dd, J=36.3, 11.5 Hz, 5H), 1.53-1.16 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:16][CH2:15][CH2:14][C@:13]([CH2:23][C:24]3([CH3:27])[CH2:26][O:25]3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:16][CH2:15][CH2:14][C@:13]([CH2:23][C:24]([OH:25])([CH3:26])[CH3:27])([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CCC[C@](CC2(C)CO2)(c2ccccc2)OC1=O
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
To a solution of (7S)-3-((S)-1-(4-bromophenyl)ethyl)-7-((2-methyloxiran-2-yl)methyl)-7-phenyl-1,3-oxazepan-2-one (280 mg, 0.63 mmol) in THF (10 mL) was added dropwise 1 M LiEt3BH in THF (Super-hydride, 6.3 mL, 6.3 mmol) at 0° C. under N2 for 30 min. The resulting solution was stirred at room temperature for 1 h, quenched with H2O2 (7 mL), diluted with (CH3)3COCH3 (30 mL), washed with water, 30% aq Na2S2O3 and brine. The organic phase was dried over Na2SO4, and concentrated to give the crude product, which was purified by prep TLC afford (S)-3-((S)-1-(4-bromophenyl)ethyl)-7-(2-hydroxy-2-methylpropyl)-7-phenyl-1,3-oxazepan-2-one (150 mg, 53%). (S)-3-((S)-1-(4-bromophenyl)ethyl)-7-(2-hydroxy-2-methylpropyl)-7-phenyl-1,3-oxazepan-2-one. LC-MS Method 30-90 tR=1.199 min, m/z=470; 1H NMR (CDCl3) d 0.83 (s, 3H), 1.05 (m, 1H), 1.13 (s, 3H), 1.42 (m, 1H), 1.48 (d, 3H), 2.1-2.35 (m, 4H), 2.72 (m, 1H), 3.13 (m, 1H), 3.95 (s, 1H), 5.50 (m, 1H), 7.02 (d, 2H), 7.22 (m, 1H), 7.30 (m, 2H), 7.32-7.48 (m, 4H).
Reaction SMILES: O.O.O.[I-].[Li+].C[O:7][C:8]1[CH:9]=[C:10]([CH2:16][CH2:17][NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[CH:12][C:13]=1[O:14]C>C(OCC)(=O)C.O>[OH:7][C:8]1[CH:9]=[C:10]([CH2:16][CH2:17][NH:18][C:19](=[O:24])[C:20]([CH3:22])([CH3:21])[CH3:23])[CH:11]=[CH:12][C:13]=1[OH:14]
Reactant: COc1ccc(CCNC(=O)C(C)(C)C)cc1OC
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)C(=O)NCCc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Mix 2.2 g. of lithium iodide trihydrate and 0.53 g. of N-[β-(3,4-dimethoxyphenyl)-ethyl]-2,2-dimethylpropionamide, as prepared in Example 5, step A, heat under nitrogen to 180° and hold for 6 hours. Allow the melt to cool to room temperature, then dissolve the solid mixture by shaking with an ethyl acetate-water mixture. Separate the layers and wash the ethyl acetate layer with 2N hydrochloric acid, water, saturated aqueous sodium thiosulfate, saturated sodium bicarbonate and water in the order set forth. Dry the ethyl acetate solution over anhydrous sodium sulfate, filter and evaporate to a residue. Crystallize the residue from a 9:1 mixture of toluene:ethanol to obtain the title product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=2)=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.[Br:21]Br>C(Cl)Cl>[Br:21][C:6]1[S:5][C:4]([C:7]([O:9][CH3:10])=[O:8])=[C:3]([C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=2)[C:2]=1[CH3:1]
Reactant: BrBr
Reactant: COC(=O)c1scc(C)c1-c1ccc(S(N)(=O)=O)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(Br)c(C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a stirred suspension of methyl 4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 7b, 8.80 g, 27.0 mmol) in DCM (150 ml), bromine (5.19 g, 1.67 ml, 32.0 mmol) was added at 0° C. in a drop wise manner. The reaction mixture was stirred at 25° C. for 2 hr and the progress of the reaction was monitored by TLC. The reaction mixture was then concentrated completely and again dissolved in DCM (250 ml). The organic layer so obtained was washed with water (2×50 ml), brine (1×50 ml) and dried over sodium sulfate and concentrated under reduced pressure to obtain crude product as semi-solid (10.2 g), which was then purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (20% ethyl ester as trans esterified product was observed) (9.0 g, 82.34%).