Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.[H-].[Na+].Cl.[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18]Cl>CN(C)C=O>[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][N:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(C)cn1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(CCN(C)C)c1ccc(C)cn1
Reaction time: 0.5 h

Procedure:
N-(5-Methyl-2-pyridyl)acetamide (75.0 g, 0.5 mole) is dissolved in 1000 ml of dry dimethylformamide and a 50% suspension of sodium hydride in mineral oil (24.0 g, 0.5 mole) is added under nitrogen with stirring in two portions over 1/2 hour. The temperature rises to 40° and then is increased to 50°-55° to keep the salt in addition. Additional sodium hydride suspension (28.8 g, 0.6 mole) is added over 10 minutes followed by 2-dimethylaminoethyl chloride hydrochloride (86.5 g, 0.6 mole) added in small portions over 1/2 hour. The temperature is moderated at 70° with occasional ice bath cooling. Then the mixture is stirred overnight at steam bath temperature. The reaction mixture is cooled and filtered. Removal of the dimethylformamide under reduced pressures gives a dark liquid. The product distills as a pale yellow liquid at 124°-128° at 0.6 mm, n25D 1.5216. Weight obtained is 78 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20](=[O:30])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:30])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: CCOC(=O)COc1cccc(N)c1
Product: CCOC(=O)COc1cccc(NC(=O)c2cccc(-c3cccc(Cl)c3)n2)c1

Procedure:
Carboxylic acid (136) (44 mg, 0.19 mmol) was coupled with aniline (64) (40 mg, 0.2 mmol) using Method D. The residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[CH3:29][O:30][CH2:31][CH2:32][NH:33][CH3:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[CH3:29][O:30][CH2:31][CH2:32][N:33]([CH3:34])[C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([CH:15]2[CH2:14][CH2:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:3]([C:2]([F:27])([F:1])[F:28])=[N:4][N:5]=4)[N:8]=3)[CH2:17][CH2:16]2)=[CH:19][CH:20]=1
Reactant: CNCCOC
Reactant: O=C(O)c1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
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: CC(=O)N(C)C
Product: COCCN(C)C(=O)c1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
A mixture of 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzoic acid (79 mg, 0.20 mmol), N-(2-methoxyethyl)methylamine (21 mg, 0.24 mmol), DIPEA (0.105 mL, 0.61 mmol) and HATU (92 mg, 0.24 mmol) in DMA (3 mL) was stirred at ambient temperature for 16 hours. The reaction mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give N-(2-methoxyethyl)-N-methyl-4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzamide (77 mg, 82%) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[N:10]1.[CH3:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH3:18])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[N:10]1
Reactant: COC(=O)c1ccn(-c2ccc(O)cc2O)n1
Reactant: COCCOCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOCCOc1ccc(-n2ccc(C(=O)OC)n2)c(O)c1
Reaction time: 8 h

Procedure:
To a solution of methyl 1-(2,4-dihydroxyphenyl)-1H-pyrazole-3-carboxylate 3 (200 mg, 0.855 mmol, 1.00 equiv) in THF (5 mL), 2-(2-methoxyethoxy)ethanol (103 mg, 0.855 mmol, 1.00 equiv) was added Ph3P (223 mg, 0.855 mmol, 1.00 equiv), and DEAD (149 mg, 0.855 mmol, 1.00 equiv) at 0° C. The resulting solution was stirred overnight. The solvent was concentrated under vacuum, the residue was applied onto a silica gel column and eluted with PE/EA (1/1). This resulted in 70 mg (50%) of methyl 1-(2-hydroxy-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-1H-pyrazole-3-carboxylate 4 as a green oil.
Reaction SMILES: [C:1]([CH:6]=[CH:7][C@H:8]1[O:12][C@@H:11]([N:13]2[CH:21]=[C:19]([CH3:20])[C:17](=[O:18])[NH:16][C:14]2=[O:15])[CH2:10][C@@H:9]1[N:22]=[N+]=[N-])([O:3][CH2:4][CH3:5])=[O:2]>CO.[Pd]>[C:1]([CH2:6][CH2:7][C@H:8]1[O:12][C@@H:11]([N:13]2[CH:21]=[C:19]([CH3:20])[C:17](=[O:18])[NH:16][C:14]2=[O:15])[CH2:10][C@@H:9]1[NH2:22])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C=C[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1N
Reaction time: 24 h
Yield: 95.4 %

Procedure:
A solution of the ester of Example 7 (16; 700 mg, 2.09 mM) in methanol (15 ml) was subjected to hydrogenation in a Parr apparatus (30 psi) in the presence of 10% Pd/C (210 mg; 30 wt %). The hydrogenation reaction was completed after 24 hours. The catalyst was filtered and the filtrate evaporated to give 620 mg (96%) of the title compound. Rf =0.3(5% saturated. NH3 in MeOH in EtOAc). FAB-MS: MH+=312.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:33])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:31][CH3:32])=[C:16]([CH2:19][N:20]([CH3:30])[C:21]4([C:27]([OH:29])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:34]=O>>[Cl:1][C:2]1[C:3]([F:33])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:31][CH3:32])=[C:16]([CH2:19][N:20]([CH3:30])[C:21]4([C:27]([OH:29])=[O:28])[CH2:26][CH2:25][N:24]([CH3:34])[CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(=O)O)CCNCC1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(=O)O)CCN(C)CC1

Procedure:
4-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-carboxylic acid was reacted with para-formaldehyde using an analogous method to that described for the equivalent step in Example 11 to give 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-1-methylpiperidine-4-carboxylic acid; 1H NMR Spectrum: (DMSO-d6+CD3COOD) 2.04 (m, 2H); 2.17 (m, 2H); 2.27 (s, 3H); 2.45-2.55 (m, 3H+ DMSO); 2.68 (m, 2H); 3.06 (m, 2H); 3.72 (s, 2H); 3.95 (s, 3H); 7.20 (s, 1H); 7.28 (t, 1H); 7.48 (t, 1H); 7.57 (t, 1H); 8.32 (s, 1H); 8.42 (s, 1H); Mass Spectrum: (M+H)+ 488.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[C:22](#[N:25])[CH2:23][OH:24].Cl>C1(C)C=CC=CC=1>[N+:12]([C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([F:8])=[CH:7][C:2]=1[O:24][CH2:23][C:22]#[N:25])([O-:14])=[O:13]
Reactant: N#CCO
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(F)cc1F
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#CCOc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a solution of 1,5-difluoro-2,4-dinitrobenzene (7.4 g) and triethylamine (4.4 g) in toluene (74 g) kept at room temperature, a mixture of glycolonitrile (3.1 g) and toluene (6.2 g) was dropwise added, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into 5% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and concentrated to give 2,4-dinitro-5-fluorophenoxyacetonitrile (8.2 g; yield, 93.8%). M.P., 112°-113° C. (recrystallized from ethyl acetate-hexane).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(O[K])(C)(C)C.F[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24].CCOC(C)=O>CS(C)=O>[N+:23]([C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([O-:25])=[O:24]
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: CC(C)(C)O[K]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1-n1ccnc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of imidazole (0.997 g, 14.65 mmol) and tert-BuOK (1.722 g, 15.35 mmol) was put under Ar in a 100 mL and dissolved in dry DMSO (15 mL) to give a colorless solution. After 5 min, 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (2.04 mL, 14.58 mmol) was added within 30 s, immediately leading to a darkening of the rm to black. A temperature rise was also noted. The black solution was stirred at RT for 20 min. Ice water (60 mL) and EtOAc (50 mL) were added, the organic layer was isolated, and the aqueous phase was extracted twice with 20 mL EtOAc. The organic layer was washed with H2O (2×30 mL), brine, dried, filtered and evaporated to give the title compound as an orange oil. Yield: 3.66 g (97%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:21]=[C:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[S:16][C:1]([C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(=O)Nc1cccc(C#N)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(-c2nc(=O)c3ccccc3s2)c1
Yield: 1.8 %

Procedure:
A mixture of N-(3-cyanophenyl)acetamide (2.00 g, 13 mmol), methyl thiosalicylate (3.20 g, 19 mmol), triethylamine (2.30 g, 23 mmol) and toluene (15 ml) was heated and refluxed for 25 hours under a nitrogen flow. The solvent was concentrated under reduced pressure. After washing with isopropyl ether and ethanol, the residue was recrystallized from tetrahydrofuran-ethyl acetate to give the title compound (0.07 g, 2%) as crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[O:40][CH3:41])(=[O:31])=[O:30])[CH2:25][CH2:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:41][O:40][C:33]1[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:32]=1[S:29]([N:26]1[CH2:25][CH2:24][N:23]([S:20]([C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:2]3[C:11]4[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH2:28][CH2:27]1)(=[O:30])=[O:31]
Reactant: COc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(N)cc3)CC2)c(OC)c1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Product: COc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(Nc4ccnc5cc(Cl)ccc45)cc3)CC2)c(OC)c1

Procedure:
In the manner given in Example 1C, 4,7-dichloroquinoline is heated with 1-[(p-aminophenyl)sulfonyl]-4-[(2,4-dimethoxyphenyl)sulfonyl]piperazine to give 1-[(2,4-dimethoxyphenyl)sulfonyl]-4-[[4-[[7-chloro-4-quinolinyl]amino]phenyl]sulfonyl]piperazine.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([NH2:8])(=[O:7])=[O:6].CCN=C=NCCCN(C)C.Cl.[C:21]([O:25][C:26]([NH:28][CH2:29][CH2:30][N:31]([CH3:60])[C@@H:32]1[CH2:39][N:38]2[C:40]3[CH:41]=[C:42]([C:53](O)=[O:54])[CH:43]=[CH:44][C:45]=3[C:46]([CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)=[C:37]2[C:36]2[CH:56]=[CH:57][CH:58]=[CH:59][C:35]=2[O:34][CH2:33]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:53]([C:42]1[CH:43]=[CH:44][C:45]2[C:46]([CH:47]3[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]3)=[C:37]3[C:36]4[CH:56]=[CH:57][CH:58]=[CH:59][C:35]=4[O:34][CH2:33][C@H:32]([N:31]([CH3:60])[CH2:30][CH2:29][NH:28][C:26](=[O:27])[O:25][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:39][N:38]3[C:40]=2[CH:41]=1)=[O:54])(=[O:7])=[O:6]
Reactant: CN(CCNC(=O)OC(C)(C)C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Reactant: NS(=O)(=O)CCCCl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(CCNC(=O)OC(C)(C)C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)CCCCl)cc3n2C1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
3-chloropropane-1-sulfonamide (1.8 eq), DMAP (2.9 eq) and EDAC.HCl (1.8 eq) were added to a solution of (7R)-7-[{2-[(tert-butoxycarbonyl)amino]ethyl}(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (prepared as described in Example 1, Step 7) (0.025 M) in DCM. The reaction was stirred under N2 at 40° C. for 2 h, before being allowed to cool. Volatiles were removed in vacuo to leave the crude product as a yellow gum which could be taken on without further purification. (ES+) m/z 687 (M+H)+; 689 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].Cl[C:11]1[C:12](=[O:26])[NH:13][C:14](=[O:25])[C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1.CN1CCCC1=O>Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]2[C:12](=[O:26])[NH:13][C:14](=[O:25])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: O=C1NC(=O)C(c2cccc([N+](=O)[O-])c2)=C1Cl
Reactant: Cc1ccc(N)cc1Br
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1ccc(NC2=C(c3cccc([N+](=O)[O-])c3)C(=O)NC2=O)cc1Br
Temperature: 200 °C

Procedure:
A mixture of 3-bromo-4-methylaniline (0.220 g, 1.18 mmol), 3-chloro-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione (0.100 g, 0.40 mmol) and 1-methyl-2-pyrrolidinone (1.0 mL) was heated in an oil bath at 200° C., for 51 minutes. The mixture was diluted with aqueous hydrochloric acid (5 mL) and extracted with ethyl acetate (5 mL). The combined organic solutions were evaporated and the residue chromatographed on silica gel using dichloromethane as eluent to afford the title compound, a solid, following trituration with dichloromethane-hexane (90:10 v/v).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([CH3:19])([CH3:18])[C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[CH:4][C:3]=1[CH3:20].[OH-].[Na+]>CO.O>[Br:1][C:2]1[S:6][C:5]([C:7]([CH3:18])([CH3:19])[C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[CH3:20]
Reactant: Cc1cc(C(C)(C)C(=O)OCc2ccccc2)sc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(C)(C)C(=O)O)sc1Br

Procedure:
A mixture of the benzyl 2-(5-bromo-4-methyl-2-thienyl)-2-methylpropanoate and sodium hydroxide (0.33 g, 8.3 mmol) in methanol (10 ml) and water (2.5 ml) was heated under reflux for 1 hour. The solvent was evaporated and the residue triturated with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate and then evaporated to leave 2-(5-bromo-4-methyl-2-thienyl)-2-methylpropanoic acid as a yellow gum which was used in the next step without purification. 1H NMR (CDCl3): 2.09 (s, 6H), 2.13 (s, 3H), 6.69 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[N:25]1([CH:30]2[CH:39]3[CH:34]([CH2:35][CH2:36][CH2:37][NH:38]3)[CH2:33][CH2:32][CH2:31]2)[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:38]2[CH:39]3[CH:34]([CH2:33][CH2:32][CH2:31][CH:30]3[N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:35][CH2:36][CH2:37]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: C1CNC2C(C1)CCCC2N1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCCC2CCCC(N3CCCC3)C21
Reaction time: 4 h

Procedure:
A solution of 1.98 g of 3,4-dichlorophenyl acetic acid and 1.56 g of carbonyldiimidazole in 17 ml of tetrahydrofuran was stirred at 20° to 22° C. for one hour and the, 1.679 g of [4aRS(4aα, 8α, 8aβ)](±)-decahydro-8-(1-pyrrolidinyl)-quinoline (preparation given at the end of Example (4) were added in solution in 5 ml of tetrahydrofuran. The solution was stirred for 4 hours at 20° to 22° C. and the tetrahydrofuran was eliminated under reduced pressure at less than 45° C. The residue was triturated in 15 ml of ether and in 5 ml of a saturated solution of sodium bicarbonate, then separated and rinsed, first with water then with ether. After drying under reduced pressure, 2.320 g of [4aRS(4aα, 8α, 8aβ)](±)-decahydro-1-[(3,4-dichlorophenyl)-acetyl]-8-(1-pyrrolidinyl)-melting at 138° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.[C:16](O)(=[O:18])[CH3:17].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:18][C:16](=[C:11]1[C:10](=[O:15])[CH2:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:13][C:12]1=[O:14])[CH3:17]
Reactant: Cc1ccccc1C1CC(=O)CC(=O)C1
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: CC(O)=C1C(=O)CC(c2ccccc2C)CC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.8 %

Procedure:
To a solution of 5-(2-methylphenyl)cyclohexane-1,3-dione (1.0 g), acetic acid (0.27 g) and dimethylaminopyridine (0.60 g) in dimethylformamide (45 ml) was added dicyclohexylcarbodiimide (1.0 g), and the mixture was stirred at room temperature for 12 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate. The organic layer was washed with potassium hydrogensulfate aqueous solution, and insoluble materials were filtered, to which was added 1N sodium hydroxide solution. The aqueous layer was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give, the residue was recrystallized from ethyl acetate-hexane to give colorless crystals of 2-(1-hydroxyethylidene)-5-(2-methylphenyl)cyclohexane-1,3-dione (0.69 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:16][CH:17]=1)([CH3:23])([CH3:24])[CH3:22]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared in accordance with Example 8(c) from 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester (see Example 1(a)) and 4-chlorophenylboronic acid, followed by ester hydrolysis in accordance with the procedure described in Example 35, Method 3, step (b).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].Cl.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(OCC)(=O)C>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:36][CH2:35][N:34]([CH2:2][C:3]([NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]4[CH:21]=[N:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]=4)[CH:7]=3)=[O:4])[CH2:33][CH2:32]2)=[CH:29][CH:30]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(CN1CCN(c2ccc(Cl)cc2)CC1)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 36.4 %

Procedure:
A slurry of 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (100 mg, 0.336 mmol), 1-(4-chlorophenyl)piperazine dihydrochloride (100 mg, 0.367 mmol) and K2CO3 (149 mg, 1.075 mmol) in MeCN (5 mL) was heated at reflux for 24 hrs. The reaction mixture was diluted with ethyl acetate (20 mL), and the organic phase washed with water (20 mL) and then brine (20 mL), dried over MgSO4 and evaporated in vacuo. The residue was triturated with diethyl ether and dried in vacuo at 50° C. to afford 2-[4-(4-chlorophenyl)piperazin-1-yl]-N-(3-(quinoxalin-2-yl)phenyl)acetamide (56 mg, 36% yield). LCMS calculated for C26H24ClN5O (M+H): 458.17. found 458.21. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.00 (1H, br. s), 9.51 (1H, s), 8.55 (1H, m), 8.15-8.10 (2H, m), 8.05 (1H, d, 1=7.5 Hz), 7.95-7.80 (3H, m), 7.55 (1H, m), 7.21 (2H, d, J=7.5 Hz), 6.90 (2H, d, J=7.5 Hz), 3.21 (4H, m), 2.61 (4H, m).
Reaction SMILES: C([O:8][C:9](=[O:50])[C@@H:10]([NH:35][C:36](=[O:49])[C@@H:37]([NH:45][C:46](=[O:48])[CH3:47])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[S:19]2(=[O:34])=[O:33])=[CH:14][CH:13]=1)C1C=CC=CC=1>CCOC(C)=O.CCO.[Pd]>[C:46]([NH:45][C@@H:37]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:36]([NH:35][C@@H:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[S:19]2(=[O:34])=[O:33])=[CH:16][CH:17]=1)[C:9]([OH:50])=[O:8])=[O:49])(=[O:48])[CH3:47]
Reactant: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](NC(=O)[C@H](Cc4ccccc4)NC(C)=O)C(=O)OCc4ccccc4)cc3)S2(=O)=O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](NC(=O)[C@H](Cc4ccccc4)NC(C)=O)C(=O)O)cc3)S2(=O)=O)cc1
Reaction time: 1.5 h

Procedure:
The title B compound, (S)-2-((S)-2-acetylamino-3-phenyl-propionylamino)-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid benzyl ester (104.3 mg, 0.149 mmol) is dissolved in EtOAc:EtOH (50:50; 250 mL) and put in a Parr Shaker bottle along with 10% Palladium on carbon (30 mg). This gas in the bottle is evacuated and replaced with hydrogen at 45 psi and shaken for 1.5 h. The reaction mixture is filtered through celite and concentrated to yield (S)-2-((S)-2-acetylamino-3-phenyl-propionylamino)-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid as a light yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12]2[CH:17]=[C:16](F)[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12]2[CH:17]=[C:16]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(Nc1cc(F)ccc1[N+](=O)[O-])c1cc(Cl)cc(Cl)c1
Reactant: C1CNCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(N2CCNCC2)ccc1[N+](=O)[O-])c1cc(Cl)cc(Cl)c1
Yield: 19 %

Procedure:
N-(1-(3,5-dichlorophenyl)ethyl)-5-fluoro-2-nitrobenzenamine (1.62 mmol), piperazine (8.1 mmol), N,N-diisopropylethylamine (0.58 mmol) were stirred at 60° C. in dry acetonitrile (20 mL) for 3 days. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 20% ethyl acetate in hexanes to afford the title compound (19% yield). 1H NMR (400 MHz, CDCl3): δ 9.31 (d, 1H), 7.63 (d, 1H), 7.25 (s, 1H), 7.22 (s, 2H), 6.18 (d, 1H), 5.53 (s, 1H), 4.48 (m, 1H), 3.48 (m, 4H), 3.25 (m, 4H), 1.60 (d, 3H), 1.47 (s, 9H); MS (ESI) m/z: Calculated for C18H20O2N4O2: 395.28; Observed: 396.3 (M++1).