Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].[CH3:38][O:39][CH2:40][C:41](O)=[O:42]>>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:41](=[O:42])[CH2:40][O:39][CH3:38])[CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Reactant: COCC(=O)O
Product: COCC(=O)N[C@@H](Cc1cccc2ccccc12)C(=O)NCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (product of example 8) as described in general procedure E using methoxyacetic acid. The final product was obtained in 30% yield.
Reaction SMILES: C(OCC1CSC2N(C(=O)C2NC(=O)CC2N=C(C3C=CC=CC=3O)SC=2)C=1C(O)=O)(=O)C.C1(C([O:47][C:48]([C:50]2[N:51]3[CH:54]([S:55][CH2:56][C:57]=2[CH3:58])[CH:53]([NH:59][C:60](=[O:75])[CH2:61][C:62]2[N:63]=[C:64]([C:67]4[C:72]([OH:73])=[CH:71][CH:70]=[CH:69][C:68]=4[OH:74])[S:65][CH:66]=2)[C:52]3=[O:76])=[O:49])C2C=CC=CC=2)C=CC=CC=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O>C(Cl)CCl>[OH:73][C:72]1[CH:71]=[CH:70][CH:69]=[C:68]([OH:74])[C:67]=1[C:64]1[S:65][CH:66]=[C:62]([CH2:61][C:60]([NH:59][CH:53]2[C:52](=[O:76])[N:51]3[CH:54]2[S:55][CH2:56][C:57]([CH3:58])=[C:50]3[C:48]([OH:49])=[O:47])=[O:75])[N:63]=1
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3csc(-c4c(O)cccc4O)n3)C2SC1
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ccccc4O)n3)C2SC1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4c(O)cccc4O)n3)C2SC1
Yield: 98 %

Procedure:
The procedure used for the preparation of 9a was repeated with 8h (169 mg, 0.276 mmol), Et3SiH (0.441 mL, 2.76 mmol), and trifluoroacetic acid (0.849 mL, 11.0 mmol) in dry ClCH2CH2Cl (6 mL) at 0° C. under nitrogen to give 9h (121 mg, 98%) as a white solid after crystallization from THF/hexane. mp 155° C. (dec); IR (KBr) 3500-2500 (br), 1768, 1670, 1467 cm-1 ; 1H NMR (DMSO-d6) δ1.97 (3H, s, CH3), 3.31 (1H, d, J=18.0 Hz), 3.51 (1H, d, J=18.0 Hz), 3.76 (2H, s, CH2), 5.00 (1H, d, J=4.5 Hz), 5.57 (1H, dd, J=8.0 and 4.5 Hz), 6.42 (2H, d, J=8.1 Hz), 7.07 (1H, t, J=8.1 Hz), 7.41 (1H, s), 9.07 (1H, d, J=8.0 Hz, NH), 12.20 (2H, br s, OH), 13.20 (1H, br s, CO2H); FDMS m/z 448 (M+ +1); HRMS m/z Calcd for C19H18N3O6S2 (M+ +1): 448.0637, Found: 448.0607.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].[F:19][C:20]([F:39])([F:38])[C:21]1[CH:22]=[C:23]([C:31]2[O:35][N:34]=[C:33]([CH2:36]Cl)[N:32]=2)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC#N>CCOC(C)=O>[F:39][C:20]([F:19])([F:38])[C:21]1[CH:22]=[C:23]([C:31]2[O:35][N:34]=[C:33]([CH2:36][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:1][CH2:2][CH3:3])[N:32]=2)[CH:24]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:26]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 80.1 %

Procedure:
A mixture of 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.040 g, 0.16 mmol), 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole (0.058 g, 0.17 mmol), Cs2CO3 (0.057 g, 0.17 mmol) and CH3CN (4 mL) was stirred at 75° C. for 1.5 h. The mixture was diluted with EtOAc (25 mL), washed with water (15 mL), and brine (15 mL). The organic portion was dried (MgSO4), filtered, and concentrated. The concentrated material was treated with 10% Et2O in hexanes (10 mL) and stirred for 2 h. The resulting solid was filtered, rinsed with hexanes, and dried to afford the title compound (0.070 g, 81%) as a light tan solid: 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 2H), 8.50 (s, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 6.59 (s, 1H), 5.90 (s, 2H), 2.90 (t, J=7.5 Hz, 2H), 1.79-1.70 (m, 2H), 0.98 (t, J=7.4 Hz, 3H); MS m/z 547 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)s2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-[5,6-dihydro-5,5-dimethyl-8-(5-methyl-2-thienyl)-2-naphthalenyl)ethynylbenzoate (Compound 33) (35.0 mg, 0.082 mmol) in 2 ml of EtOH and 1 ml THF at room temperature was added aqueous NaOH (1 ml, 1 M, 1 mmol). The resulting solution was stirred at room temperature overnight and then acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (d6-acetone): δ 8.03 (2H, d, J=8.6 Hz), 7.63 (2H, d, J=8.6 Hz), 7.54-7.48 (3H, m), 6.89 (1H, m), 6.18 (1H, t, J=4.7 Hz), 2.49 (3H, s), 2.35 (2H, d, J=4.7 Hz), 1.32 (6H, s).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][NH:35][CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[CH3:23][N:20]1[CH2:21][CH2:22][CH:17]([C:14]2[CH:15]=[CH:16][C:11]([C:4]3[N:3]=[C:2]([C:32]4[CH:33]=[N:34][NH:35][CH:36]=4)[N:7]4[CH:8]=[CH:9][N:10]=[C:6]4[CH:5]=3)=[CH:12][CH:13]=2)[CH2:18][CH2:19]1
Reactant: CN1CCC(c2ccc(-c3cc4nccn4c(Cl)n3)cc2)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: [K+]
Solvent: O
Solvent: COCCOC
Product: CN1CCC(c2ccc(-c3cc4nccn4c(-c4cn[nH]c4)n3)cc2)CC1
Temperature: 100 °C
Yield: 23.6 %

Procedure:
5-Chloro-7-(4-(1-methylpiperidin-4-yl)phenyl)imidazo[1,2-c]pyrimidine (0.120 g, 0.367 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.107 g, 0.551 mmol) and potassium carbonate (0.152 g, 1.10 mmol) were suspended in a mixture of DME (5 mL) and water (2 mL) and purged with argon for 5 minutes. Tetrakis(triphenylphosphine)palladium (0) (0.02121 g, 0.01836 mmol) was added and the reaction sealed and heated at 100° C. for 18 hours. The reaction mixture was cooled to ambient temperature and diluted with water and filtered. The solids were washed with acetone and then dried under high vacuum to afford 7-(4-(1-methylpiperidin-4-yl)phenyl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.0310 g, 0.0865 mmol, 23.55% yield). MS (apci) m/z=359.2 (M+H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].C1C=CC=CC=1>O1CCCC1>[CH2:1]([NH:8][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[I:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C(Cl)c1ccccc1I
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)c1ccccc1I

Procedure:
A solution of 15 ml of benzylamine in 20 ml of tetrahydrofuran was reacted with a solution of 8.0 g of o-iodobenzoyl chloride in 20 ml of tetrahydrofuran in accordance with the procedure of Example 3. There was obtained by recrystallization from benzene 9.1 g of N-benzyl-o-iodobenzamide, m.p. 122°-123°, Rf 0.78.
Reaction SMILES: N1C=CC=CC=1[C:7]1[CH:12]=[CH:11]C=CN=1.[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].C1(C(Br)C)C=CC=CC=1>C1COCC1>[CH:13]([O:17][CH2:18][CH:12]([CH3:11])[CH3:7])=[CH2:14].[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15]
Reactant: c1ccc(-c2ccccn2)nc1
Agent: CC(Br)c1ccccc1
Solvent: C=CC(=O)OC
Solvent: C1CCOC1
Product: C=COCC(C)C
Temperature: 50 °C

Procedure:
To 0.11 g (6.68×10−4 mole) 2,2′-bipyridyl and 0.036 g (2.34×10−4 mole) CuBr in a glass tube, were added 1.8 ml (1.65×−10−2 mole) IBVE, 0.5 ml (0.55×10−2 mole) methyl acrylate and 0.034 ml (2.34×10−4 mole) 1-phenylethyl bromide under argon atmosphere. The glass tube was sealed under vacuum, and the reaction mixture was warmed at 50° C. for 12 hours. The reaction mixture was then dissolved in THF, and the conversion of MA and IBVE as determined by GC were 100%. The polymer was then precipitated in methanol (three times), filtered, dried at 60° C. under vacuum for 48 h and weighed. The content of IBVE in the copolymer was 75%, and Mn=8710, Mw/Mn=2.00 (Mth=9090). The glass transition temperatures of the product as determined by DSC were −44.3° C. and 7.1° C.
Reaction SMILES: O=[C:2]([CH3:12])[CH2:3][CH:4]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]1=[O:11].[NH2:13][CH2:14][C:15]([OH:17])=[O:16].O>C(O)(=O)C>[CH3:12][C:2]1[N:13]([CH2:14][C:15]([OH:17])=[O:16])[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:11])[C:4]=2[CH:3]=1
Reactant: CC(=O)CC1C(=O)CCCC1=O
Reactant: NCC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2c(n1CC(=O)O)CCCC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred mixture of 2-(2-oxopropyl)cyclohexane-1,3-dione (prepared by evaporation of an ethanolic solution to dryness under vacuum) (20.0 g, 119 mmol) and glycine (17.9 g, 238 mmol) in acetic acid (100 mL) was heated under reflux for 1.5 h then allowed to cool to r.t. Water (100 mL) was then added and the mixture evaporated to a thick oil in vacuo. Acetone (200 mL) and water (40 mL) were added to the residue and the mixture stirred for 30 mins at r.t., after which the solid was collected by filtration and the filtrates retained. The solid was slurried with further acetone (100 mL) and water (20 mL) at r.t. then removed by filtration. The combined filtrates were concentrated in vacuo then dissolved in aqueous sodium hydroxide (1M, 200 mL), adding a small amount of 10M sodium hydroxide to bring the pH to 14. After washing with ethyl acetate (2×100 mL), the mixture was acidified by the addition of aqueous hydrochloric acid (5M, 60 mL) then sodium chloride (50 g) was added. After stiffing for 4 h, the solid product was collected by filtration, washed with acetone (2×25 mL) then dried under vacuum at 40° C. to afford the title compound as an orange-brown solid; 7.45 g (30%); purity 99.1 area % by HPLC; m/z: 208 (MH+); 1H-NMR: 13.2 (1H, br s), 6.02 (1H, s), 4.67 (2H, s), 2.65 (2H, t, J=6.2 Hz), 2.29-2.24 (2H, m), 2.10 (3H, s), 2.02-1.95 (2H, m).
Reaction SMILES: N1(CCN2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)CCCCCC1.NC1C=C[C:37]([CH2:38][N:39]([CH3:46])[CH:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=CC=1>>[CH3:46][N:39]([CH2:38][C:37]1[CH:11]=[CH:12][C:13]([NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[C:25]([O:28][CH2:29][CH:30]([CH3:31])[CH3:32])[CH:24]=[CH:23][CH:22]=3)=[O:18])=[CH:14][CH:15]=1)[CH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Product: CC(C)COc1cccc2[nH]c(C(=O)Nc3ccc(CN(C)C4CCOCC4)cc3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8) and (4-Amino-benzyl)-methyl-(tetrahydro-pyran-4-yl)-amine (WO9932468).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[C:5]=12.[I:12]N1C(=O)CCC1=O>ClCCl>[I:12][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[C:5]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1cccn2ccnc12
Solvent: ClCCl
Product: N#Cc1cccn2c(I)cnc12
Yield: 79.8 %

Procedure:
To a stirred solution of imidazo[1,2-a]pyridine-8-carbonitrile (1.2 g, 8.38 mmol) in dichloromethane (10 mL) was added N-iodosuccinimide (1.89 g, 8.38 mmol). LCMS monitored the reaction until the starting material consumed completely. The reaction mixture was diluted with dichloromethane and water. The separated organic layer was dried sodium sulfate, filtered and concentrated to give 3-iodoimidazo[1,2-a]pyridine-8-carbonitrile (1.8 g, 6.69 mmol, 80% yield) as a brown solid. MS (ES+) C8H8IN3 requires: 269. found: 270 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:14]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=1)[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)#[N:2].O1CCCC1.[OH-].[Na+]>C(O)C>[C:1]([C:3]1[C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:14]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=1)[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)#[N:2]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OC)cc3c2C#N)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2oc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C#N)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To a mixture of ethyl 3-{[(4-{[(3-cyano-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (253 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (218 mg, 91%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:36])[C@@H:15]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][CH:26]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:37][C:38]([F:51])([F:50])[C:39]1[CH:49]=[CH:48][CH:47]=[CH:46][C:40]=1/[CH:41]=[CH:42]/[C:43](O)=[O:44]>>[CH2:16]([C@H:15]([N:23]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:29][CH:30]=1)[C:43](=[O:44])[CH:42]=[CH:41][C:40]1[CH:46]=[CH:47][CH:48]=[CH:49][C:39]=1[C:38]([F:50])([F:51])[F:37])[C:14]([N:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1)=[O:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Reactant: CCCCCc1ccc(CN[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Product: CCCCCc1ccc(CN(C(=O)C=Cc2ccccc2C(F)(F)F)[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Yield: 61.3 %

Procedure:
Acylation of 1-(4-benzyl-piperazin-1-yl)-(S)-2-(4-pentyl-benzylamino)-3-phenyl-propan-1-one (43.5 mg, 0.09 mmol) according to the procedure described for the preparation of Example 1 with trans-2-trifluoromethyl-cinnamic acid (21.4 mg, 0.099 mmol) gave 37.6 mg (60%) of N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-(4-pentyl-benzyl)-3-(2-trifluoromethyl-phenyl)-acrylamide. LC-MS: tR=1.04 min; [M+H]+=682.49.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].S(C1C=CC(C)=CC=1)([O:13][CH2:14][CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=1)[CH3:17])(=O)=O>CN(C)C=O.O>[CH2:25]([O:24][C:20]1[CH:19]=[C:18]([CH:16]([CH3:17])[CH2:15][CH2:14][O:13][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)c2cccc(OCc3ccccc3)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCOc1ccccc1)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of phenol (4.56 g., 48.6 mmole) in dimethylformamide (40 ml.) is added under a nitrogen atmosphere to a suspension of sodium hydride (2.32 g., 48.6 mmole) of 50% previously washed with pentane) in dimethylformamide (70 ml.) at 60° C. The reaction mixture is stirred for one hour at 60°-70° C., after which a solution of 3-(3-benzyloxyphenyl)butyl tosylate (18.9 g., 46 mmole) in dimethylformamide (80 ml.) is added. The reaction mixture is stirred at 80° C. for a half hour and is then cooled to room temperature, diluted with cold water (2500 ml.) and extracted with ether (4 × 400 ml.). The combined extracts are washed successively with cold 2N hydrochloric acid (2 × 300 ml.) and saturated sodium chloride solution (3 × 300 ml.) and then dried (Na2SO4). Removal of the solvent under reduced pressure affords the product as an oil. The oily residue is dissolved in benzene and filtered through silica gel (100 g.). Concentration of the filtrate under reduced pressure gives the product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[C:14]([CH2:17][CH2:18]OS(C)(=O)=O)[CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[CH:24]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[C:14]([CH2:17][CH2:18][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[CH:24]=1
Reactant: CS(=O)(=O)OCCc1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1Nc2cc(CCN3CCOCC3)ccc2Nc2cc(Cl)ccc21
Temperature: 50 °C

Procedure:
A mixture of Example 767A (360 mg, 0.98 mmol) in DMF (5 mL) was treated with morpholine (200 μL) and heated at 50° C. for 24 hours. The mixture was then cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by column chromatography on silica gel to provide the desired product. MS (ESI) m/e 358 (M+H)+; 1H NMR (300 MHz, DMSO-d.6 □ 9.84 (s, 1H), 7.97 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.91 (dd, J=8.5, 2.0 Hz, 1H), 6.81-6.89 (m, 3H), 3.55-3.58 (m, 4H), 2.57-2.62 (m, 2H), 2.37-2.45 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1.[CH:15](OCC)(OCC)OCC>>[Cl:1][C:2]1[C:11]2[N:10]([CH:15]=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2
Reactant: CCOC(OCC)OCC
Reactant: NNc1nc2cc(F)ccc2nc1Cl
Product: Fc1ccc2nc(Cl)c3nncn3c2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture consisting of 10 g. (0.047 mole) of 2-chloro-6-fluoro-3-hydrazinoquinoxaline and 80 ml. (0.47 mole) of triethyl orthoformate was heated under a nitrogen atmosphere with mechanical stirring in a preheated oil bath at 100° C. overnight (~16 hours). The resulting mixture was cooled to room temperature, and the precipitate which formed was subsequently recovered by means of suction filtration, washed with three-50 ml. portions of ethanol and air-dried to constant weight to ultimately afford 9.42 g. (91%) of pure 4-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 310°-312° C. (decomp.). Mass Spectrum: m/e, 224, 223, 222 (P+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: ClCCN1CCCCC1
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A suspension of 6-nitro-3,4-dihydroquinolin-2(1H)-one (400 mg, 2.08 mmol), 1-(2-chloroethyl)piperidine hydrochloride(421 mg, 2.29 mmol) and potassium carbonate(862 mg, 6.24 mmol) in 10 mL DMF was stirred at room temperature overnight. After this time, the mixture was poured into 20 mL H2O then extracted with 2×50 mL CH2Cl2. The organic layer was separated, washed with brine and concentrated to give a yellow brown solid which was subjected to flash chromatography on silica gel using 5% MeOH/CH2Cl2 to give a yellow viscous oil (560 mg, 88.7%). 1H-NMR (CDCl3) δ: 8.14 (dd, J=2.7, 9 Hz, 1H), 8.06-8.05 (m, 1H), 7.24 (d, J=9.0 Hz, 1H), 4.11 (t, J=7.2 Hz, 2H), 3.02-2.95 (m, 2H), 2.73-2.67 (m, 2H), 2.57-2.48 (m, 6H), 1.59-1.44 (m, 6H).
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=[O:3].OC1C(=O)[N:10]([CH2:21][CH2:22][O:23][CH3:24])[S:11](=[O:20])(=[O:19])[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:6][C:1]1[C:2](=[O:3])[N:10]([CH2:21][CH2:22][O:23][CH3:24])[S:11](=[O:19])(=[O:20])[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCCN1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Solvent: ClCCl
Product: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Yield: 92.3 %

Procedure:
Oxalyl chloride (0.185 g, 1.46 mmol) was added dropwise to a solution of 4-hydroxy-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.250 g, 0.88 mmol) in DCM (15 mL). The mixture was refluxed for 2 days and then evaporated. The residue was dissolved in water and extracted 3 times with DCM. The combined organic layer was washed 2 times with water, dried through a phase separator and evaporated to give the title compound (0.245 g, 92%) as a solid; 1H NMR (500 MHz, CD3OD): δ 7.94-7.97 (m, 2H), 7.58-7.67 (m, 3H), 3.94 (t, 2H), 3.70 (t, 2H), 3.38 (s, 3H).
Reaction SMILES: C([O:4][CH:5]([CH3:7])[CH3:6])(C)C.[Cl-].[Cl-].[Cl-].[Al+3].[N+:12]([C:15]1[C:21]([OH:22])=C[CH:19]=[CH:18][C:16]=1[OH:17])([O-:14])=[O:13].C(OC(=O)C)(=O)C.Cl>[N+](C1C=CC=CC=1)([O-])=O.C(OCC)C>[OH:22][C:21]1[C:15]([N+:12]([O-:14])=[O:13])=[C:16]([OH:17])[CH:18]=[CH:19][C:7]=1[C:5](=[O:4])[CH3:6]
Reactant: CC(C)OC(C)C
Reactant: O=[N+]([O-])c1c(O)cccc1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(=O)c1ccc(O)c([N+](=O)[O-])c1O
Temperature: 5 °C

Procedure:
The extraction solvent can be changed from diethyl ether to di-isopropyl ether. For example: Nitrobenzene (87.5 mL) was added to aluminium trichloride (46.33 g). 2-nitroresorcinol (25 g), in nitrobenzene (112.5 mL) was added. The mixture was cooled to 5° C. and acetic acid anhydride (15.68 mL) added maintaining the internal temperature below 20° C. The mixture was heated to 100° C. for 2 h then cooled to 5° C. Cold (3° C.) 3M aqueous hydrogen chloride (200 mL) was charged. The mixture was heated to 20° C. then di-isopropylether (200 mL) charged. The aqueous phase was removed and the organic phase extracted with 2 M aqueous sodium hydroxide (200 mL). The aqueous phase was washed with di-isopropylether (200 mL). The aqueous phase was removed and heated to 50° C. 3 M aqueous hydrogen chloride (467.5 mL) was charged and the mixture cooled to 20° C. The suspension was filtered, washed with water (50 mL) and dried under vacuum to yield the title compound (31.14 g).