Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]/[C:2](=[CH:10]/[CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[C:3]([O:5]C(C)(C)C)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.CCOCC>[Br:1]/[C:2](=[CH:10]/[CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)/[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)OC(=O)/C(Br)=C\CCC#Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C(O)/C(Br)=C\CCC#Cc1ccccc1
Yield: 76 %

Procedure:
A solution of t-butyl 2-bromo-7-phenyl-(2E)-hepten-6-ynoate (1.5 g, 4.48 mmol) and 4-toluenesulphonic acid (0.1 g) in dry benzene (15 ml) was heated under reflux under dry nitrogen for 2 hours. The cooled mixture was diluted with ether and the organic phase was extracted with aqueous sodium bicarbonate. The aqueous phase was acidified and extracted with ether. The organic phase was washed with brine and dried over magnesium sulphate. The solvents were removed to give 0.95 g (76% of theory) of 2-bromo-7-phenyl-(2E)-hepten-6-ynoic acid as a colourless solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@@H:12]([S:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:11]([OH:24])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([S:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11](=[O:24])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](SC(=O)c2ccccc2)[C@H](O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1CCC(SC(=O)c2ccccc2)C(=O)C1
Temperature: 5 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of thiobenzoic acid S-((1R, 2R, 4R)-4-tert-butoxycarbonylamino-2-hydroxy-cyclohexyl)ester+(1S, 2S, 4S)diasteromer (5 g, 14.2 mmol), 4 Å-molecular sieve (3 g) 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-one (6.33 g, 15 mmol) in 100 ml of dichloromethane was stirred under argon at 5° C. for 1 hour and 1 hour at room temperature. The mixture was filtered over celite, dried and concentrated under vacuum to give the crude product. After chromatography of the mixture (silica, toluene/ethyl acetate=7/1) the title compound (toluene/ethyl acetate=3/1, Rf=0.48, 4.18 g, 84% yield) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]=[CH2:10])[N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[O:15][CH3:16]>CCOC(C)=O.[Pd]>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH3:10])[N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[O:15][CH3:16]
Reactant: C=Cc1nc(C(=O)OC)c(OC)c(N)c1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1nc(C(=O)OC)c(OC)c(N)c1F
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To methyl 4-amino-5-fluoro-3-methoxy-6-vinylpicolinate (0.32 g, 1.42 mmol) in EtOAc (5 mL) was added 10% palladium on carbon (Pd/C, 0.16 g, 0.15 mmol). The mixture was stirred under an atmosphere of hydrogen overnight, filtered through Celite and concentrated to provide methyl 4-amino-6-ethyl-5-fluoro-3-methoxypicolinate (0.21 g, 0.92 mmol) as a white solid: mp 110.5-113.0° C.; 1H NMR (400 MHz, CDCl3) δ 4.41 (s, 2H), 3.96 (s, 3H), 3.90 (s, 3H), 2.81 (qd, J=7.6, 2.7 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 165.2, 148.6, 146.2, 144.2, 136.8, 136.1, 61.5, 52.7, 25.3, 12.9; 19F NMR (376 MHz, CDCl3) δ −142.6; EIMS m/z 228.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH2:8]([SH:13])[CH2:9][CH2:10][CH2:11][CH3:12].[NH2:14][C:15]1[N:23]=[C:22](Cl)[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>[Cl-].[Na+].O>[NH2:14][C:15]1[N:23]=[C:22]([S:13][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCCCCS
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 110 °C
Yield: 79.9 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (277 mg, 6.9 mmol, 60% in mineral oil) were added 1-pentanethiol (2 ml, 16 mmol) and 6-amino-9-benzyl-2-chloropurine (100 mg, 0.39 mmol) in order. The mixture was stirred under heating at 110° C. for 4 hours. Brine was added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (102 mg, yield 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.CN[CH:45]([CH3:53])[C:46]([O:48]C(C)(C)C)=[O:47].[CH3:54][N:55](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:55]([CH2:53][CH2:45][C:46]([OH:48])=[O:47])[CH3:54])=[O:25]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CNC(C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: CN(CCC(=O)O)C(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and tert.-butyl 2-methylamino-propanoate with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]5[N:43]([CH2:44][CH2:45][CH3:46])[N:42]=[N:41][CH:40]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][C:39]5[N:43]([CH2:44][CH2:45][CH3:46])[N:42]=[N:41][CH:40]=5)=[O:56])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cnnn4CCC)cc2)CCN3CCC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cnnn4CCC)cc2)CCN3CCC)cc1
Reaction time: 0.25 h
Yield: 46 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[(1-propyl-1,2,3-triazol-5-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.53 g) was dissolved in methylene chloride (15.9 ml), and to the solution was added dropwise a solution of m-chloroperbenzoic acid (0.21 g) in methylene chloride (10.6 ml) at −78° C. The mixture was stirred for 15 minutes, and an aqueous solution of saturated sodium thiosulfate was added to the mixture. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[(1-propyl-1,2,3-triazol-5-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 282) (0.25 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(N(CC)CC)C>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C@H:20]2[C:19]3[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=3[C:17]3[N:16]=[C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][N:36]5[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]5)=[CH:9][CH:10]=4)[N:24]=[CH:23][C:22]=3[CH2:21]2)=[CH:30][CH:29]=1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(F)cc2)C3)cc1
Solvent: CCN(CC)CC
Product: Fc1ccc([C@@H]2Cc3cnc(Nc4ccc(CCN5CCCCC5)cc4)nc3-c3ccccc32)cc1

Procedure:
This was synthesized by using (S)-4-(6-(4-fluorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, piperidine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=185-188° C. 1H NMR (CDCl3) 400 MHz δ 12.19 (brs, 1H), 10.89 (brs, 1H), 8.36 (brs, 1H), 8.01 (brs, 1H), 7.69 (d, J=6.6 Hz, 2H), 7.58-7.59 (m, 2H), 7.35 (d, J=6.2 Hz, 2H), 7.26 (d, J=2.7 Hz, 1H, 7.11-7.12 (m, 1H), 7.01-7.11 (m, 3H), 4.14 (s, 1H), 3.63 (d, J=10.5 Hz), 3.31-3.33 (m, 3H), 3.12-3.17 (m, 3H), 2.74 (d, J=11.2 Hz, 2H), 2.36 (d, J=12.1 Hz, 2H), 2.09 (s, 1H), 1.92-1.95 (m, 3H), 1.43-1.46 (m, 1H). LCMS m/e 479 [M+H].
Reaction SMILES: [CH:1]([O:4]/[C:5](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[O:21])[CH:13]=1)/[C:6]([O:8]CC)=[O:7])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[CH:1]([O:4]/[C:5](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=2)=[O:21])[CH:13]=1)/[C:6]([OH:8])=[O:7])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)OC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C=C(\OC(C)C)C(=O)O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 60.8 %

Procedure:
77 mg of ethyl (Z)-2-isopropoxy-3-[4-methoxy-3-({[4-(trifluoromethyl)benzyl]amino}carbonyl)phenyl]-2-propenoate was dissolved in 2 ml methanol, and 1 ml of 1N sodium hydroxide was added, and the mixture was stirred at room temperature for 22 hours. The reaction mixture was ice-cooled and neutralized with 1N hydrochloric acid, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was evaporated, to give 44 mg of (Z)-2-isopropoxy-3-[4-methoxy-3-({[4-(trifluoromethyl)benzyl]amino}carbonyl)phenyl]-2-propenoic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:19]=[C:18]([C:20]([NH:22][C:23]([NH2:25])=[NH:24])=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:19]=[C:18]([C:20]([NH:22][C:23]([NH2:25])=[NH:24])=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: N=C(N)NC(=O)c1cc(-c2cccc([N+](=O)[O-])c2)nc2ccccc12
Agent: [Pd]
Solvent: CO
Product: N=C(N)NC(=O)c1cc(-c2cccc(N)c2)nc2ccccc12
Yield: 123.5 %

Procedure:
2-(3'-Nitrophenyl)quinoline-4-carbonylguanidine (0.40 g) formed in Example 19 was dissolved in 40 ml of methanol, and hydrogenated under normal pressure for 5.5 hours in the presence of 0.3 g of Pd/C (purity 10%). The catalyst was filtered off from the reaction solution, and the filtrate was concentrated to obtain 0.45 g of the above-mentioned compound as a brown crystal. m.p. 209°-210° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]#[N:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][CH2:15][C:16]1OC(=O)[S:18][N:17]=1.O>CCCCCCCCCCCC>[CH3:13][O:14][CH2:15][C:16]1[N:12]=[C:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[S:18][N:17]=1
Reactant: COCc1nsc(=O)o1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Solvent: CCCCCCCCCCCC
Solvent: O
Product: COCc1nsc(S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 150 °C

Procedure:
4-Methylbenzenesulfonyl cyanide (16.26 g) was added to an emulsion of 5-methoxymethyl-1,3,4-oxathiazol-2-one (6.6 g) in dodecane (60 cm3). The reaction mixture was stirred and heated at 150° C. for 18 hours, then cooled. Water was added and the product extracted into ethyl acetate. The combined organic phases were dried (MgSO4) and ethyl acetate was removed by evaporation under reduced pressure. The residue separated into a brown liquid and a clear dodecane layer which was removed and discarded. Chromatography of the brown liquid on silica gel (Sorbsil C30) using 3:7 ethyl acetate:hexane as eluant give a pale orange oil which solidified on standing (6.94 g). M+ =284; 1H NMR: δ 2.40(3H,s); 3.45(3H,s); 4.7(2H,s); 7.4(2H,d); 8.0(2H,d); (mp 43.4-45-4° C.).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:17][C:18](=[O:29])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([F:28])[CH:22]=1)C>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:27][C:24]3[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][C:18]([OH:29])=[O:17])=[CH:22][C:23]=3[F:28])[CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccc(SC2CCCC2)n1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1
Product: O=C(O)CCc1ccc(OCc2cccc(SC3CCCC3)n2)c(F)c1
Yield: 85.6 %

Procedure:
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (0.032 g, 0.14 mmol) obtained in Step C of Preparation Example 27 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.045 g, 84%).
Reaction SMILES: [CH:1]1[C:13]2[C:12]3([C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:19]4[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:26]Br.S([O-])(O)=O.[Na+]>[Fe](Cl)(Cl)Cl.O>[Br:26][C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]3([C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:14]=2[CH:15]=1
Reactant: c1ccc2c(c1)-c1ccccc1C21c2ccccc2-c2ccccc21
Reactant: BrBr
Agent: Cl[Fe](Cl)Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: Brc1ccc2c(c1)C1(c3ccccc3-c3ccccc31)c1ccccc1-2
Reaction time: 3 h
Yield: 97.2 %

Procedure:
In a two-liter flask having four openings equipped with a stirrer, a thermometer, a dropping funnel, and a reflux condenser, respectively, 1 L of water, three drops of a surfactant, 10.7 g (0.0395 mol) of anhydrous iron (III) chloride, and 253 g (0.8 mol) of 9,9′-spirobifluorene were placed and stirred to mix. By adding 102 g (0.638 mol) of bromine into the mixture, a reaction was started. After the reaction had been conducted at room temperature for 3 hours, unreacted bromine was decomposed with an aqueous solution of sodium hydrogen sulfite. The reaction product, which was a solid, was filtered and washed with water. Thus, 298 g of a crude product was obtained. The crude product was recrystallized using dioxane, thus resulting in 245 g (0.62 mol, yield of 78%) of a white solid, which is the target product. This product was subjected to gas chromatography and the purity of the product was 99%.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.Cl[CH2:33][C:34](=[O:44])[C:35]12[CH2:42][CH:41]3[CH2:43][CH:37]([CH2:38][CH:39]1[CH2:40]3)[CH2:36]2.C1C2CC3(C(O)=O)CC1CC3C2>C1COCC1>[O:44]=[C:34]([C:35]12[CH2:42][CH:41]3[CH2:43][CH:37]([CH2:38][CH:39]1[CH2:40]3)[CH2:36]2)[CH2:33][N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([N:16]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5]
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(CCl)C12CC3CC(CC1C3)C2
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C(O)C12CC3CC(CC1C3)C2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC1C3)C2
Yield: 72.6 %

Procedure:
Using the procedure described in Example 5, a solution of L-proline-L-isoleucine benzylamide (167 mg, 0.52 mmol), and triethylamine (367 uL, 5.0 eq) in THF (2 mL), was treated with 209 mg (1.2 eq) of 1-chloro-2-oxo-2-tricyclo[3.3.1.0 3,7 ]non-3-yl-ethane (prepared from 3-noradamantanecarboxylic acid using the procedure described in example 1) to provide 181 mg of L-isoleucine, N-[1-(2-oxo-2-tricyclo[3.3.1.0 3,7 ]non-3-yl-ethyl)-L-prolyl] benzylamide as a colorless residue.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]([NH2:22])=[O:21].C([O-])([O-])=O.[K+].[K+].F[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=1[CH2:39][CH2:40]O>CN(C=O)C>[N+:36]([C:33]1[CH:34]=[CH:35][C:30]2[N:6]3[N:5]=[C:4]([C:7]4[CH:8]=[CH:9][C:10]([O:13][C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)=[CH:11][CH:12]=4)[C:3]([C:20]([NH2:22])=[O:21])=[C:2]3[NH:1][CH2:40][CH2:39][C:31]=2[CH:32]=1)([O-:38])=[O:37]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Reactant: O=[N+]([O-])c1ccc(F)c(CCO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCc1cc([N+](=O)[O-])ccc1-2
Temperature: 80 °C
Reaction time: 16 h
Yield: 11.3 %

Procedure:
To a solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (30 mg, 0.10 mmol) in DMF (5.0 mL) was added K2CO3 (28 mg, 0.20 mmol), followed by 2-(2-fluoro-5-nitrophenyl)ethanol (37 mg, 0.20 mmol). The mixture was warmed to 80° C. stirred for about 16 hr. After cooling down to RT, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (15 mL) and water (15 mL), the aqueous was extracted with ethyl acetate (3×10 mL). The combined organic phases were washed brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by Pre-TLC (DCM/CH3OH=20/1) to afford the product about 5.0 mg (11.1%). 1H NMR (400 MHz, DMSO-d6) δ 8.35 (t, J=4.0 Hz, 1 H), 8.28 (d, J=2.8 Hz, 1 H), 8.22 (dd, J=2.8, 9.2 Hz, 1 H), 8.12 (d, J=9.2 Hz, 1 H), 7.64-7.60 (m, 2 H), 7.45-7.41 (m, 2 H), 7.22-7.17 (m, 1 H), 7.14-7.09 (m, 4 H), 3.72-3.65 (m, 2 H), 3.29-3.24 (m, 2 H). MS (ESI) m/e [M+1]+ 442.
Reaction SMILES: [CH:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:27]([NH2:29])=[O:28])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])=[CH2:2].[OH-:30].[Na+]>CS(C)=O>[OH:30][CH2:2][CH2:1][S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:27]([NH2:29])=[O:28])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4]
Reactant: [OH-]
Reactant: C=CS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Agent: [Na+]
Solvent: CS(C)=O
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCO)CC3)c[nH]c12
Temperature: 80 °C
Yield: 59 %

Procedure:
The mixture of 3-[1-(ethenylsulfonyl)-4-piperidinyl]-5-phenyl-1H-indole-7-carboxamide (26 mg, 0.063 mmol) and aqueous 6M NaOH (0.2 mL) in DMSO was heated to 80° C. overnight. After which time the reaction mixture was filtered and purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 3-70%) to give the title compound (16 mg, 59%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[C:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:30]([CH3:33])([O-:32])=[O:31]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[C:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:10]=1[CH:11]=[CH:33][N+:30]([O-:32])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1cc(OCc2ccccc2)c(C=O)c(C(C)(C)C)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(OCc2ccccc2)c(C=C[N+](=O)[O-])c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a mixture of 1.5 g (4.6 mmol) of the product of Step A and 2.0 g of ammonium acetate in 25 mL acetic acid was added 3 mL nitromethane. The reaction mixture was refluxed for 5 h, then cooled to room temperature and the volatiles were removed in vacuo. The residue was partitioned between EtOAc and water, then separated. The aqueous layer was re-extracted with EtOAc, the organic layers were combined, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 0-20% CH2Cl2-hexane. Combination of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH:12]=O)(=[O:3])[CH3:2].[C:14](Br)(Br)([Br:16])[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCCC>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH:12]=[C:14]([Br:16])[Br:15])(=[O:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(=O)Oc1cc(C)ccc1C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: CC(=O)Oc1cc(C)ccc1C=C(Br)Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To a stirred mixture of 2-formyl-5-methylphenyl acetate (12.8 g, 71.8 mmol), carbon tetrabromide (47.6 g, 144 mmol), and 150 mL of DCM at 0° C. (translucent clear/yellow solution) under nitrogen was added a solution of triphenylphosphine (75 g, 287 mmol) in 140 mL of DCM dropwise over 15 min. A clear orange solution results initially. After 1 hr a purplish suspension results. The reaction was stirred for 2 hr at RT. After 2 hr 100 mL of heptane was added. The mixture was filtered to remove solids and the collected filtrate was concentrated under reduced pressure to give a dark brown gum. This was dissolved in minimal DCM and filtered through a silica gel plug which was flushed with 70% Heptane/30% EtOAc. The combined washes from the silica plug were concentrated under reduced pressure to give a yellow oil, 2-(2,2-dibromovinyl)-5-methylphenyl acetate (16.7 g). 1H NMR (400 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.31 (s, 3H), 7.01 (s, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.48 (s, 1H), 7.54 (d, J=8.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[C:8]([CH:12]([CH3:14])[CH3:13])[O:9]2)=[CH:4][CH:3]=1.[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:11]([Br:23])=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)=[C:8]([CH:12]([CH3:13])[CH3:14])[O:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)c1oc2cc(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC(C)c1oc2c(Br)c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Reaction time: 0.33 h

Procedure:
A stirred solution of 7-amino-3-(4-chlorophenyl)-2-isopropyl-chromen-4-one (0.36 g, 1.15 mmol) in chloroform (10 ml) is treated at room temperature with N-bromosuccinimide (0.21 g, 1.2 mmol, 1.05 eq.). After stirring for 20 min, the mixture is partitioned between water (150 ml) and ethyl acetate (50 ml). The organic phase is washed with brine (100 ml), dried (magnesium sulfate) and filtered, and the solvent is removed by evaporation in vacuo to afford the title compound as an orange solid. The product is used in the next step without further purification.