Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[O:24]=[C:23]1[NH:22][N:21]=[C:20]([CH2:25][CH2:26][CH3:27])/[C:19]/1=[C:11]1/[NH:12][C:13]2[C:18]([C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:7][CH:6]=3)=[CH:10]/1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)c3ccccc3)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and benzoyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.71 (t, J=7.33 Hz, 3H) 1.29-1.39 (m, 2H) 2.26 (t, J=6.82 Hz, 2H) 6.80 (s, 1H) 7.55-7.67 (m, 4H) 7.76 (d, J=8.59 Hz, 2H) 7.85-7.94 (m, 2H) 7.98 (d, J=7.07 Hz, 2H) 8.11 (d, J=8.59 Hz, 2H) 8.17 (d, J=8.08 Hz, 1H) 10.62 (s, 1H); ESI-MS: m/z calc'd for C28H24N4O2S 480.58. found 481.2 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=4)=[CH:23][CH:22]=3)[CH:12]=[N:11][C:10]=12)=[O:5])C.[Li+].[OH-].Cl>O1CCCC1>[CH:15]1([C:14]2[N:9]3[N:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]3[N:11]=[CH:12][C:13]=2[C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)=[CH:25][CH:26]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)c1cnn2c(C3CCCCC3)c(-c3ccc(-c4cccc(OC)c4)cc3)cnc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc(-c3cnc4c(C(=O)O)cnn4c3C3CCCCC3)cc2)c1
Yield: 34.1 %

Procedure:
To a solution of 47 mg (0.103 mmol) of 7-cyclohexyl-6-(3′-methoxy-biphenyl-4-yl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester in 3 mL of tetrahydrofuran was added 0.62 mL (0.62 mmol) of 1 M LiOH solution, and the resulting mixture was heated at reflux overnight. The reaction mixture was then acidified with 1 M HCl solution to pH=2, and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, and concentrated to give a residue which was purified via reverse-phase chromatography to afford (after lyophilization) 15 mg (34% yield) of 7-cyclohexyl-6-(3′-methoxy-biphenyl-4-yl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (446) as a solid (90% purity) as indicated by 1H NMR; LC-MS—calcd for C26H25N3O3 [M++H]+: 428.19, found: 428.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5](=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:8]=1[N+:19]([O-:21])=[O:20])[CH3:2].[O-]CC.[K+].[C:28]([O:33][CH2:34][CH2:35]Br)(=[O:32])[C:29]([CH3:31])=[O:30]>C1COCC1.O.CCOCC>[CH2:1]([O:3][C:4](=[O:23])[C:5](=[O:22])[CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[C:8]=1[N+:19]([O-:21])=[O:20])[CH2:31][C:29](=[O:30])[C:28]([O:33][CH2:34][CH3:35])=[O:32])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1cccc(N2CCCCC2)c1[N+](=O)[O-]
Reactant: CC(=O)C(=O)OCCBr
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=O)CC(C(=O)C(=O)OCC)c1cccc(N2CCCCC2)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 3-(2-nitro-3-piperidin-1-yl-phenyl)-2-oxo-propionic acid ethyl ester (ii) in THF is treated with potassium ethoxide (“KOEt”) (1 eq), followed by bromoethyl pyruvate (1.05 eq), at 0° C. The reaction is allowed to warm to room temperature over 90 min. The reaction is diluted with water and ether, partitioned, and the aqueous layer is washed with ether. The combined organic layers are dried over MgSO4, filtered and concentrated. Chromatography gives 3-(2-nitro-3-piperidin-1-yl-phenyl)-2,5-dioxo-hexanedioic acid di ethyl ester (iii).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[S:9][C:10]=1[CH3:11])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[CH3:11][C:10]1[S:9][C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[N:7][C:6]=1[CH2:5][CH2:4][NH2:1]
Reactant: Cc1ccc(-c2nc(CCN=[N+]=[N-])c(C)s2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: Cc1ccc(-c2nc(CCN)c(C)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
4-(2-Azidoethyl)-5-methyl-2-p-tolylthiazole (160 mg, 619 μmol), triphenylphosphine polymer bound (270 mg, 803 μmol) and water (2 drops, 8 μL, 444 μmol) were combined at RT to give a brown suspension. The mixture was stirred at RT overnight. The suspension was filtered and the liquid was evaporated to give the product as light yellow oil (151 mg, 617 μmol, 99.7%) which was used without further purification for the next step.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[OH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]2[O:29][CH2:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)=[CH:12][CH:11]=1>O.C(O)(=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][C:8]([OH:2])=[O:7])=[CH:11][CH:12]=2)[CH:17]([O:29][CH2:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[CH2:18]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCO)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CC(=O)O)cc2)C(OCc2ccc3ccccc3c2)C1
Reaction time: 48 h
Yield: 50.5 %

Procedure:
6.95 g (44 mmol) of powdered potassium permanganate dissolved in a mixture of 100 ml of water and 100 ml of glacial acetic acid as well as 0.73 g (2 mmol) of tetrabutylammonium iodide were added to a solution of 5.0 g (10.83 mmol) of tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethyl)-phenyl]-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate in 500 ml of benzene. The reaction mixture was stirred intensively for 48 hours. For the working-up, the phases were separated. The organic phase was washed with 100 ml of saturated sodium thiosulphate solution. The aqueous phase was decolorized by the addition of saturated sodium thiosulphate solution and subsequently extracted twice with 100 ml of ethyl acetate and 100 ml of methylene chloride each time. The organic phases were combined, dried over sodium sulphate and evaporated under reduced pressure. For purification, the crude material was chromatographed on silica gel using a 9:1 mixture of methylene chloride and methanol as the eluent after the column had previously been prepared with a 90:10:0.1 mixture of methylene chloride, methanol and ammonia. There were obtained 2.6 g (50% of theory) of (3RS,4RS)-[4-(1-tert-butoxycarbonyl-3-naphthalen-2-ylmethoxy-piperidin-4-yl)-phenyl]-acetic acid as a colourless, amorphous solid; MS: 476 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]#[CH:10])(=O)=O.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])(O)=O.[Na+]>ClCCCl>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:6][CH2:7][CH2:8][C:9]#[CH:10])[CH2:14][CH2:13]1
Reactant: C#CCCCOS(C)(=O)=O
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C#CCCCN1CCN(C)CC1
Temperature: 80 °C

Procedure:
A mixture of pent-4-ynyl methanesulfonate (887 mg) and N-methyl piperazine (607 μL) was heated to 80° C. for 4.5 h, diluted with 1,2-dichloroethane (5 mL) and heated to 70° C. for 18 h. Saturated aq. NaHCO3 was added (10 mL) and the mixture was extracted with DCM (3×40 mL), dried over Na2SO4, and concentrated to afford 1-methyl-4-(pent-4-ynyl)piperazine (0.23 g).
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([C:7]([OH:9])=O)=[N:4][C:3]=1[CH3:10].[CH3:11][N:12](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:13].F[P-](F)(F)(F)(F)F.Cl.CNC.C(N(CC)CC)C>CN(C)C=O.CCOC(C)=O>[I:1][C:2]1[NH:6][C:5]([C:7]([N:12]([CH3:13])[CH3:11])=[O:9])=[N:4][C:3]=1[CH3:10]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1nc(C(=O)O)[nH]c1I
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)N(C)C)[nH]c1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 5-iodo-4-methyl-1H-imidazole-2-carboxylic acid (compound 239.3, 200 mg, 0.79 mmol) in N,N-dimethylformamide (4 mL). HBTU (602 mg, 1.59 mmol), dimethylamine hydrochloride (96 mg, 1.18 mmol) and triethylamine (552 μL, 3.96 mmol) were added to the reaction. The reaction mixture was stirred for 3 h at room temperature, then diluted with 50 mL of EtOAc. The organic layer was washed with 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 150 mg (68%) of the title compound as yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:16]P(OCC)(OCC)=O)=[N:11][C:12]=2[CH:13]=[CH:14][CH:15]=1)=[O:5])C.[CH:25]([C:27]1[N:28]=[C:29]2[C:34]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:33][CH:32]=[N:31][N:30]2[C:41]=1[C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=1)=O>>[C:46]([C:45]1[CH:48]=[CH:49][C:42]([C:41]2[N:30]3[N:31]=[CH:32][CH:33]=[C:34]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[C:29]3=[N:28][C:27]=2/[CH:25]=[CH:16]/[C:10]2[CH:9]=[CH:8][C:7]3[C:6]([C:4]([OH:3])=[O:5])=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=2)=[CH:43][CH:44]=1)#[N:47]
Reactant: N#Cc1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1
Reactant: CCOC(=O)c1cccc2nc(CP(=O)(OCC)OCC)ccc12
Product: N#Cc1ccc(-c2c(/C=C/c3ccc4c(C(=O)O)cccc4n3)nc3c(N4CCOCC4)ccnn23)cc1

Procedure:
Compound 73d (55.0 mg, 0.165 mmol) was reacted under Horner-Emmons coupling conditions with compound 76a (58.0 mg, 0.165 mmol) using the procedures described in Example 74, Step B to afford compound 76b. Mass spectrum (LCMS, ESI pos.) Calcd. For C29H22N6O3: 503.2 (M+H). found 503.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:27])=[CH:8][C:9]=1[N:10]([C:18]([CH:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:4].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:27])=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:12][CH2:13][CH:14]([OH:17])[CH2:15][CH2:16]1)[C:18]([CH:20]1[CH2:21][CH2:22][CH:23]([CH3:26])[CH2:24][CH2:25]1)=[O:19])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)C1CCC(C)CC1)C1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc(Br)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
5-Bromo-3-[(4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (473 mg, 1.04 mmol) was dissolved in methanol (10.4 ml), cooled to 0° C. and treated with sodium borohydride (43 mg, 1.14 mmol). After 30 minutes of stirring at 0° C., the reaction was left stirring at room temperature for 30 min and quenched with a 10% solution of hydrochloric acid (20 ml). The aqueous phase was extracted with ethyl acetate (3×10 mL) and the combined ethyl acetate layer was dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using EtOAc:hexanes as eluent to furnished 5-Bromo-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (365 mg, 77% yield) as a solid. 1H NMR (CDCl13, 400 MHz): 6.82 (s, 1H), 4.56 (m, 1H), 3.82 (s, 3H), 3.45 (m, 1H), 2.08-1.72 (m, 4H), 1.75 (m, 1H), 1.68-1.23 (m, 11H), 0.98 (m, 1H), 0.80 (d, 3H), 0.68 (m, 2H).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C@@H:7]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[CH:15]=1)[CH:10]([CH3:12])[CH3:11])[OH:6])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]([C@@H:7]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[CH:15]=1)[CH:10]([CH3:12])[CH3:11])[OH:6]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN=[N+]=[N-])C(C)C)ccc1OC
Agent: [Pd]
Solvent: CO
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN)C(C)C)ccc1OC

Procedure:
The solution of 0.185 g of tert-butyl {1(S)-(2-azido-1(S)-hydroxyethyl)-3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl}carbamate in 6 ml of methanol is hydrogenated in the presence of 0.037 g of 10% Pd/C over 2 hours. The reaction mixture is clarified by filtration and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a slightly greyish oil. Rf=0.08 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=15.47 (gradient II).
Reaction SMILES: [CH2:1]([S:5][C:6]1[N:10]=[CH:9][NH:8][N:7]=1)[CH:2]([CH3:4])[CH3:3].[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15](Cl)=[O:16])[CH:12]=[CH2:13].O1CCCC1.C(N(CC)CC)C>CCOCC>[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[N:7]1)=[O:16])[CH:12]=[CH2:13]
Reactant: CC(C)CSc1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(SCC(C)C)n1

Procedure:
A mixture of 7.85 g. 3-isobutylthio-1,2,4-triazole, 10.97 g. diallylcarbamoyl chloride, 100 ml. dry tetrahydrofuran and 11 ml. dry triethylamine was refluxed under anhydrous conditions for 48 hours. The reaction mixture was worked up as described in Example 1, using ether in place of methylene dichloride. An oily residue was obtained which was distilled under reduced pressure to give 1-diallylcarbamoyl-3-isobutylthio-1,2,4-triazole, b.p. 116° - 118°C./0.5 mm. (96.0% 1-isomer by GLC assay).
Reaction SMILES: ClC1N=C(OC)N=C(OC)N=1.[F:12][C:13]([F:38])([F:37])[C:14]1[CH:36]=[CH:35][CH:34]=[CH:33][C:15]=1[C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[N:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].CN1CCOCC1.[Cl:46][C:47]1[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=1>C1COCC1.C(OCC)(=O)C>[Cl:46][C:47]1[CH:53]=[CH:52][C:50]([NH:51][C:30]([C:27]2[N:28]=[N:29][C:24]([N:21]3[CH2:20][CH2:19][N:18]([C:16](=[O:17])[C:15]4[CH:33]=[CH:34][CH:35]=[CH:36][C:14]=4[C:13]([F:37])([F:12])[F:38])[CH2:23][CH2:22]3)=[CH:25][CH:26]=2)=[O:32])=[CH:49][CH:48]=1
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: Nc1ccc(Cl)cc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
2-Chloro-4,6-dimethoxy-1,3,5-triazine (0.105 g, 0.60 mmol) was added to a cooled (0° C.) solution of 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (0.190 g, 0.50 mmol) and methylmorpholine (0.07 mL, 0.63 mmol) in THF (10 mL). The reaction mixture was stirred at 0° C. for 15 min, and then at ambient temperature for 1 h. 4-Chloroaniline (0.0765 g, 0.60 mmol) was then added. After stirring at ambient temperature for 20 h, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water, brine, dried over anhydrous Na2SO4 and concentrated. Purification by flash chromatography and recrystallization from ethyl acetate/hexanes afforded the title compound in 67% yield (0.164 g). 1H NMR (300 MHz, CDCl3) δ 9.79, 8.08, 7.82-7.55, 7.36-7.28, 7.02, 4.10-4.00, 3.93-3.68, 3.35. 13C NMR (75 MHz, CDCl3) δ 167.6, 160.7, 160.0, 144.8, 136.2, 134.2, 132.4, 129.5, 129.2, 129.1, 127.2, 126.9, 126.8, 126.7, 125.4, 121.8, 120.7, 112.6, 46.3, 44.5, 44.3, 41.2. MS (ES+) m/z 490.1 (M+1).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH2:20][CH2:19][C:18]4[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=4[CH:16](O)[CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:26].[OH-].[Na+]>O1CCOCC1>[ClH:26].[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH:14]3[CH:15]=[CH:16][C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19][CH2:20]3)[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1CC(CN2CCC(c3ccccc3)CC2)CCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C1=CC(CN2CCC(c3ccccc3)CC2)CCc2ccccc21

Procedure:
0.2 g (0.6 mmol) of (±)-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol were dissolved in 5 mL of 1,4-dioxane and 16 mL of 37% HCl and heated to reflux for 2 h. The reaction mixture was then basified with NaOH and extracted with CH2Cl2. The organic phase was dried and the solvent was removed in vacuo. The resulting crude product was purified by chromatography, eluting with a mixture CH2Cl2/MeOH 100:2 respectively; The compound was dissolved in Et2O and brought to acidic pH with Et2O/HCl. The resulting white solid was triturated with Et2O, filtered and dried, yielding 0.02 g of the title compound. m.p.=268-270° C.
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[N:9]=[C:8]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:16]=2[C:22]2[O:26][CH:25]=[N:24][CH:23]=2)[N:7]=1.C(N(CC)CC)C.[CH:34]1([N:40]=[C:41]=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>O>[CH3:13][O:12][C:10]1[CH:11]=[C:6]([O:5][CH3:4])[N:7]=[C:8]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:41](=[O:42])[NH:40][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:16]=2[C:22]2[O:26][CH:25]=[N:24][CH:23]=2)[N:9]=1
Reactant: COc1cc(OC)nc(Oc2cccc(O)c2-c2cnco2)n1
Reactant: O=C=NC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(OC)nc(Oc2cccc(OC(=O)NC3CCCCC3)c2-c2cnco2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To methylene chloride solution containing 0.15 g 5-[2-(4,6-dimethoxypyrimidine-2-yloxy)-6-hydroxyphenyl]oxazole, was added 0.07 g triethylamine. The solution reacted was stirred at room temperature for 15 min., then 0.08 g cyclohexyl isocyanate was added thereto. The solution was further stirred for 1.5 hours, and the solution reacted was then added with water and extracted with ethyl acetate. The organic layer obtained was washed with water and saturated saline solution in turn and then dried by using anhydrous magnesium sulfate. The solvent used was removed by distillation under reduced pressure, and the oily substance obtained was recrystallized in a mixed-solvent consisting of n-hexane and diethyl ether, affording the objective substance in an amount of 0.17 g.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[C:15]1([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[C:23]2[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=2)[NH:17][C:16]1=[O:25].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:15]([NH:1][C:2]3[C:10]([O:11][CH2:12][CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)[C:16](=[O:25])[NH:17]2)=[CH:22][CH:21]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Reactant: CCOc1cccc(C(=O)O)c1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cccc(C(=O)O)c1NC1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reaction time: 8 h
Yield: 26 %

Procedure:
At room temperature, 2-Amino-3-ethoxy-benzoic acid (0.59 g, 3.26 mmol), 3-Bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (1.21 g, 3.26 mmol) and DIPEA (0.68 ml) were mixed in about 6 ml CH2Cl2. After stirred overnight, the solution was concentrated and the crude product was purified by chromatography to obtain 400 mg solid rac-2-[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-3-ethoxy-benzoic acid. MS: 471 (M+H)+.
Reaction SMILES: [CH:1]1([CH:6]2[C:31](=[O:32])[N:30]3[CH2:33][CH:27]([CH2:28][CH:29]3[C:34]([O-:36])=[O:35])[O:26][C:25]3[N:20]([C:21](=[O:37])[CH:22]=[CH:23][CH:24]=3)[CH2:19][CH:18]=[CH:17][CH2:16][CH2:15][CH:14]3[CH:10]([CH2:11][CH2:12][CH2:13]3)[O:9][C:8](=[O:38])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:39](O)C>>[CH:1]1([C@H:6]2[C:31](=[O:32])[N:30]3[CH2:33][C@@H:27]([CH2:28][C@H:29]3[C:34]([O:36][CH3:39])=[O:35])[O:26][C:25]3[N:20]([C:21](=[O:37])[CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[O:9][C:8](=[O:38])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCO
Reactant: O=C1NC(C2CCCC2)C(=O)N2CC(CC2C(=O)[O-])Oc2cccc(=O)n2CC=CCCC2CCCC2O1
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCCCCn1c(cccc1=O)O2
Yield: 94 %

Procedure:
The title compound was prepared in a similar manner as Example 13 Step 1, utilizing methyl (1R,10E, and 10Z,14S,18R,22S,25S)-22-cyclopentyl-7,20,23-trioxo-2,19-dioxa-8,21,24-triazatetracyclo[22.2.1.03,8.014,18]heptacosa-3,5,10-triene-25-carboxylate and replacing THF with ethanol as the solvent to give a 94% yield. LCMS (ES+) m/z 544.3 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:20]1([CH3:32])[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28](Cl)(=[O:30])=[O:29]>CN(C1C=CN=CC=1)C.C(#N)C>[C:20]1([CH3:32])[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28]([NH:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([CH:2]=[CH2:1])=[CH:8][CH:7]=1)(=[O:11])=[O:10])(=[O:29])=[O:30]
Reactant: C=Cc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=Cc1ccc(S(=O)(=O)NS(=O)(=O)c2c(C)cc(C)cc2C)cc1
Yield: 64.7 %

Procedure:
Using 55.0 g (0.3 mol) of p-styrenesulfonamide, 3.7 g (0.03 mol) of 4-(N,N-dimethylamino)pyridine, 82.0 g (0.81 mol) of triethylamine, 91.8 g (0.42 mol) of 2-mesitylenesulfonyl chloride, and 500 ml of acetonitrile, reaction was conducted in the same manner as in Synthesis Example 1. As a result, 70.9 g of N-(2-mesitylenesulfonyl) -p-styrenesulfonamide was obtained (yield, 64.7%; light-yellow crystals; m.p., 146.5-147° C.).
Reaction SMILES: Br[C:2]1[C:3]([O:20][CH3:21])=[C:4]([CH:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:15]([O:14][C:13]([NH:12][CH:10]([C:4]1[C:3]([O:20][CH3:21])=[C:2](/[CH:24]=[CH:23]/[C:22]([O:26][CH3:27])=[O:25])[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)[CH3:11])=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1Br
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1c(C)c(Cl)cc(C(C)NC(=O)OC(C)(C)C)c1OC
Temperature: 130 °C
Yield: 68.1 %

Procedure:
Into a sealed tube was placed a suspension of tert-butyl[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]carbamate [from Example 113, step 1, peak 2] (1.0 g, 2.6 mmol) in DMF (15 mL) that was degassed with nitrogen and treated with methyl acrylate (0.83 mL, 9.2 mmol), triphenylphosphine (97 mg, 0.37 mmol), and palladium acetate (59 mg, 0.26 mmol). Lastly, triethylamine (1.1 mL, 7.9 mmol) was added and the reaction mixture was heated at 130° C. for 16 hours. After cooling to room temperature, the mixture was filtered over Celite and the Celite was washed with EtOAc (100 mL). The EtOAc was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated to a crude foam. The crude material was dissolved in 2:1 hexane/dichloromethane and purified by flash column chromatography using EtOAc in hexanes (0%-30% over 30 min) to give the desired product (0.68 g, 68%) as a white foam. LCMS for C14H16ClO3 (M−NHBoc)+: m/z=267.1. Found: 266.9.