Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3I)=[CH:13][CH:12]=2)[CH:5]=1.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)CCC>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[CH:13][CH:12]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(Cc2ccc(COc3ccc(C(C)=O)c(O)c3I)cc2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Cc2ccc(COc3ccc(C(C)=O)c(O)c3-c3ccccn3)cc2)c1
Temperature: 100 °C
Yield: 60.9 %

Procedure:
A mixture of 3-[4-(4-acetyl-3-hydroxy-2-iodo-phenoxymethyl)-benzyl]-benzoic acid methyl ester (417 mg, 0.808 mmol), 2-tributylstannanyl-pyridine (1.72 g, 4.67 mmol), and tetrakis(triphenylphosphine)palladium(0) (111 mg, 0.096 mmol) in toluene (19 mL) is thoroughly degassed, placed under nitrogen and heated at 100° C. for 16 hours. After cooling to room temperature, the reaction mixture is concentrated in vacuo. The residue thus obtained is purified by flash chromatography (20% to 40% ethylacetate in hexanes) to give 230 mg of the title compound as a yellow oil: MS (m/z): 468 (M+1); 1H NMR (CDCl3) δ 8.74 (m, 1H), 7.87 (m, 2H), 7.78 (m, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.36-7.27 (m, 3H), 7.17 (d, J=8.0 Hz, 2H), 7.11 (d, J=8.0 Hz, 2H), 6.60 (d, J=9.0 Hz, 1H), 5.14 (s, 2H), 3.99 (s, 2H), 3.89 (s, 3H), 2.61 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:17])[CH2:13][C:14]([CH3:16])=O.[CH:25]([NH:28][C:29](=[O:34])/[CH:30]=[C:31](\[NH2:33])/[CH3:32])([CH3:27])[CH3:26]>C(O)C>[CH3:32][C:31]1[NH:33][C:14]([CH3:16])=[C:13]([C:12]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:17])[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])[C:30]=1[C:29]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:34]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CCCCCCOC(=O)CC(C)=O
Reactant: C/C(N)=C/C(=O)NC(C)C
Solvent: CCO
Product: CCCCCCOC(=O)C1=C(C)NC(C)=C(C(=O)NC(C)C)C1c1ccccc1[N+](=O)[O-]
Yield: 29.9 %

Procedure:
o-Nitrobenzaldehyde (3.8 g, 0.025 mole), n-hexyl acetoacetate (4.6 g, 0.025 mole) and 3-aminocrotonic isopropylamide (3.5 g, 0.025 mole) are dissolved in ethanol (50 ml), and the mixture is refluxed for 8 hours. After the reaction, the solvent is distilled off under reduced pressure. The residue is dissolved in elution solvent [chloroform:carbon tetrachloride:ethyl formate:formic acid:ethanol (10:10:8:1:2)] (30 ml) and subjected to column chromatography [silica gel 60 Art. 9385 (Manufactured by Merck Co.), 300 g, φ40 mm×50 cm]. The fraction containing the desired compound is regulated to pH 10 with 28% aqueous ammonia, and the organic layer is separated, washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue is recrystallized from 80% ethanol to give the title compound (3.31 g, yield 29.9%) as yellow prisms, m.p. 175°-178° C.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]([CH2:36][O:37][C:38](=[O:41])[CH:39]=[CH2:40])([CH2:14][O:15][CH2:16][C:17]([CH2:30][O:31]C(=O)C=C)([CH2:24][O:25][C:26](=[O:29])[CH:27]=[CH2:28])[CH2:18][O:19][C:20](=[O:23])[CH:21]=[CH2:22])[CH2:8][O:9][C:10](=[O:13])[CH:11]=[CH2:12])(=[O:4])[CH:2]=[CH2:3].[CH2:42]([C:44]([CH3:46])=[O:45])[CH3:43]>>[C:20]([O:19][CH2:18][C:17]([CH2:30][OH:31])([CH2:16][O:15][CH2:14][C:7]([CH2:8][O:9][C:10](=[O:13])[CH:11]=[CH2:12])([CH2:36][O:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:24][O:25][C:26](=[O:29])[CH:27]=[CH2:28])(=[O:23])[CH:21]=[CH2:22].[C:44]1(=[O:45])[CH2:46][CH2:2][CH2:1][CH2:43][CH2:42]1
Reactant: CCC(C)=O
Reactant: C=CC(=O)OCC(COCC(COC(=O)C=C)(COC(=O)C=C)COC(=O)C=C)(COC(=O)C=C)COC(=O)C=C
Product: C=CC(=O)OCC(CO)(COCC(COC(=O)C=C)(COC(=O)C=C)COC(=O)C=C)COC(=O)C=C
Product: O=C1CCCCC1

Procedure:
To 315.0 g of a dipentaerythritol pentaacrylate and dipentaerythritol hexaacrylate mixture (DPHA, produced by Nippon Kayaku Co., Ltd.), 450.0 g of a methyl ethyl ketone dispersion solution of silica fine particle (MEK-ST, solid concentration: 30 mass %, produced by Nissan Chemicals Industries, Ltd.), 15.0 g of methyl ethyl ketone, 220.0 g of cyclohexanone and 16.0 g of a photopolymerization initiator (Irgacure 907, produced by Nippon Ciba Geigy) were added and stirred. The resulting solution was filtered through a polypropylene-made filter having a pore size of 0.4 μm to prepare a coating solution for hard coat layer.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O.C(OC(=O)C)C>[O:13]=[C:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:14]([O:16][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])[CH2:10]1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a stirring solution of a mixture of (S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (2.85 g, 12.43 mmol) and potassium carbonate (4.33 g, 24.87 mmol) in anhydrous N,N-dimethylformamide (60 mL) was added benzyl bromide (4.25 g, 24.87 mmol). The mixture was stirred at room temperature overnight. The resulting crude mixture was diluted with ethylacetate and the organic layer was washed with 10% sodium carbonate and brine. The organic layer was dried over sodium sulfate and volatiles were removed in-vacuo. The residue was purified on normal phase column to yield 2.82 g (71%) of desired product.
Reaction SMILES: [NH2:1][C@H:2]([CH3:12])[CH2:3][NH:4]C(=O)OC(C)(C)C.[CH:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([Cl:26])(=[O:25])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.C(N(CC)CC)C>ClCCl>[ClH:26].[ClH:26].[NH2:4][CH2:3][C@H:2]([NH:1][S:23]([C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[CH:13]=[N:14][CH:15]=[CH:16]2)(=[O:25])=[O:24])[CH3:12]
Reactant: C[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc2cnccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](CN)NS(=O)(=O)c1ccc2cnccc2c1
Product: Cl

Procedure:
(R)-tert-butyl 2-aminopropylcarbamate (338 mg) synthesized according to the method described in PCT publication No. WO2010/006085 was condensed with isoquinoline-6-sulfonyl chloride prepared in Reference Example 1 in the presence of triethylamine (0.538 mL) in dichloromethane to obtain a crude product. Subsequently, 252 mg of the title compound was obtained as a white solid (38%) with reference to the methods of Steps 2 and 3 of Example 1.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]1[C:16](=[O:17])[C:15](=[O:18])[C:14]=1OCC)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH3:22]>>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]1[C:16](=[O:17])[C:15](=[O:18])[C:14]=1[NH2:22])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOc1c(CNCCP(=O)(OCC)OCC)c(=O)c1=O
Reactant: N
Product: CCOP(=O)(CCNCc1c(N)c(=O)c1=O)OCC
Reaction time: 18 h
Yield: 77 %

Procedure:
An ethanolic solution (40 mL) of [2-[(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)methylamino]ethyl]phosphonic acid diethyl ester (3.00 g, 9.40 mmol) was combined with ethanolic ammonia solution (70 mL) and left for 18 hours. After concentrating in vacuo, the solid was recrystallized twice from methanol in ethyl acetate (final volume=50 mL) to yield [2-[(2-amino-3,4-dioxo-1-cyclobuten-1-yl)methylamino]ethyl]phosphonic acid diethyl ester as a solid (2.10 g, 77%, mp 130°-132° C.); IR (KBr, cm-1): 3320, 3160, 1800, 1670, 1650, 1640; MS (+FAB): 291 (MH+, 100), 196 (22), 109 (20); 1H NMR (DMSO, 400 MHz): δ 7.61 (br s NH2), 4.02-3.94 (m, 4H), 3.74 (br s, 2H), 3.13 (br s, 3H), 2.13 (d of t, J= 18 and 7.5 Hz, 2H), 1.22 (t,J=7 Hz, 6H).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]1([C:3]2[C:2]([N:33]3[CH2:32][CH2:31][N:30]([C:27]4[CH:26]=[CH:25][C:24]([C:23]([F:36])([F:37])[F:22])=[CH:29][CH:28]=4)[CH2:35][CH2:34]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(C(F)(F)F)cc4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv) in DMF (8 mL), 1-(4-(trifluoromethyl)phenyl)piperazine (202 mg, 0.88 mmol, 2.00 equiv), DIEA (170.3 mg, 1.32 mmol, 3.00 equiv) were placed in a 20-mL sealed tube and stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 4×50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate followed by filtration to remove solids. The resulting mixture was concentrated under vacuum, resulting in 177.4 mg (78%) of methyl 2-phenyl-3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: FC(F)(F)[C:3]([O-:5])=[O:4].[CH:8]1([C@H:14]2[C:47](=[O:48])[N:46]3[CH2:49][C@@H:43]([CH2:44][C@H:45]3[C:50](=[O:67])[NH:51][C@:52]3([C:57](=[O:66])[NH:58][S:59]([C:62]4([CH3:65])[CH2:64][CH2:63]4)(=[O:61])=[O:60])[CH2:54][C@H:53]3[CH:55]=[CH2:56])[O:42][C:26]3=[N:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=4[C:34]([O:35][CH:36]4[CH2:41][CH2:40][NH2+:39][CH2:38][CH2:37]4)=[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[CH2:68][C@H:18]3[O:17][C:16](=[O:69])[NH:15]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:85][C:86]([F:89])([F:88])[F:87])(=O)=O>C(#N)C>[CH:3]([O-:5])=[O:4].[CH:8]1([C@H:14]2[C:47](=[O:48])[N:46]3[CH2:49][C@@H:43]([CH2:44][C@H:45]3[C:50](=[O:67])[NH:51][C@:52]3([C:57](=[O:66])[NH:58][S:59]([C:62]4([CH3:65])[CH2:63][CH2:64]4)(=[O:61])=[O:60])[CH2:54][C@H:53]3[CH:55]=[CH2:56])[O:42][C:26]3=[N:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=4[C:34]([O:35][CH:36]4[CH2:37][CH2:38][NH+:39]([CH2:85][C:86]([F:89])([F:88])[F:87])[CH2:40][CH2:41]4)=[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[CH2:68][C@H:18]3[O:17][C:16](=[O:69])[NH:15]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C([O-])C(F)(F)F
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CC[NH2+]CC1)O2)C(=O)NS(=O)(=O)C1(C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CC[NH+](CC(F)(F)F)CC1)O2)C(=O)NS(=O)(=O)C1(C)CC1
Product: O=C[O-]
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To a solution of the product from Step 1 (101 mg, 0.102 mmol) in acetonitrile (5 mL) was added Hunig's base (0.089 mL, 0.511 mmol) followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (71.1 mg, 0.306 mmol). The reaction was stirred at 55° C. for 3 hours after which it was quenched with water and extracted with EtOAc. Purification by PTLC (3% MeOH in CH2Cl2) followed by reverse phase HPLC (0 to 90% acetonitrile in water; with 0.1% HCOOH) provided the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C@@H:12]1[CH2:17][NH:16][CH2:15][C@H:14]([CH3:18])[NH:13]1>C(#N)C>[CH3:11][C@H:12]1[NH:13][C@@H:14]([CH3:18])[CH2:15][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:17]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CC#N
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@H](C)N1

Procedure:
1-Fluoro-4-nitrobenzene (10 g, 70.87 mmol) and (2R,6S)-2,6-dimethylpiperazine (17 g, 148.83 mmol) were heated in acetonitrile (25 ml) at 70° C. for 2 h. The solution was concentrated in vacuo, then the residue was partitioned between DCM and water+sat. sodium hydrogen carbonate. The organic extract was washed with water (4 times), brine, dried and concentrated to give the title compound as a yellow solid which was dried in vac oven overnight at 50° C. (16.13 g, 97%). NMR (400 MHz) 1.04 (d, 6H), 2.39 (m, 2H), 2.77 (m, 2H), 3.89 (dd, 2H), 7.02 (d, 2H), 8.03 (d, 2H); m/z 236.
Reaction SMILES: C([O:5][C:6](=O)[C@@H:7]([O:10][C:11]1[CH:34]=[CH:33][C:14]2[C:15]3[N:19]([CH2:20][CH2:21][O:22][C:13]=2[CH:12]=1)[CH:18]=[C:17]([C:23]1[N:24]([CH2:28][C:29]([F:32])([F:31])[F:30])[N:25]=[CH:26][N:27]=1)[N:16]=3)[CH2:8][CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C[N:44](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[CH2:28][N:24]1[C:23]([C:17]2[N:16]=[C:15]3[C:14]4[CH:33]=[CH:34][C:11]([O:10][C@@H:7]([CH2:8][CH3:9])[C:6]([NH2:44])=[O:5])=[CH:12][C:13]=4[O:22][CH2:21][CH2:20][N:19]3[CH:18]=2)=[N:27][CH:26]=[N:25]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC[C@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
To a solution of (S)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-butyric acid tert-butyl ester in DCM (3 mL) was added TFA (0.5 mL) and the reaction mixture stirred at RT for 16 h. The reaction mixture was concentrated in vacuo, and the residue dissolved in DMF (3 mL). HATU (217 mg, 0.56 mmol), ammonium chloride (46 mg, 0.85 mmol) and triethylamine (119 μL, 0.85 mmol) were added and the reaction mixture stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (10 mL) and the mixture washed with water extracting with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2 gradient 0-10% methanol in EtOAc) then reverse phase preparative HPLC (C-18 column, 10-90% MeCN in water, 0.1% formic acid, 25 min gradient) to yield 494 as a white solid (49 mg, 39%). LCMS: RT=3.78 min, [M+H]+=437; 1H NMR (400 MHz, d6-DMSO) 8.22 (1H, d, J=8.9 Hz), 8.03 (1H, s), 7.96 (1H, s), 7.50 (1H, br s), 7.24 (1H, br s), 6.74 (1H, dd, J=8.9, 2.5 Hz), 6.51 (1H, d, J=2.5 Hz), 5.86 (2H, q, J=8.9 Hz), 4.52-4.39 (5H, m), 1.79 (2H, pent, J=7.2 Hz), 0.92 (3H, t, J=7.2 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][C:18]1=[O:23]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:20]2[CH2:21][CH2:22][NH:17][C:18](=[O:23])[CH2:19]2)=[CH:4][CH:3]=1
Reactant: O=C1CNCCN1
Reactant: BrCc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CN(Cc2ccc(Br)cc2)CCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine (0.84 mL, 6.0 mmol) and piperazin-2-one (0.81 g, 8.0 mmol) in THF (20 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the resultant residue diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound (1.0 g, 93%). 1H NMR (CDCl3, 300 MHz): δ 7.49-7.43 (m, 2H); 7.24-7.16 (m, 2H); 6.20 (s, 1H); 3.53 (s, 2H); 3.38-3.32 (m, 2H); 3.15 (s, 2H); 2.66-2.59 (m, 2H).). LCMS (Method G): RT=2.54 min, M−H+=268.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.Cl.[NH2:25][C:26]([CH3:31])([CH2:29][CH3:30])[C:27]#[CH:28]>O.O1CCCC1>[CH3:31][C:26]([NH:25][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([Cl:11])[C:2]([NH2:1])=[N:3][CH:4]=1)([CH2:29][CH3:30])[C:27]#[CH:28]
Reactant: C#CC(C)(N)CC
Reactant: Nc1ncc(C(=O)O)cc1Cl
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C#CC(C)(CC)NC(=O)c1cnc(N)c(Cl)c1
Temperature: -30 °C
Yield: 43 %

Procedure:
In a 300 mL, three-necked, round-bottomed flask fitted with a mechanical stirrer, nitrogen inlet and thermometer were placed 5 g (0.03 mole) of 6-amino-5-chloronicotinic acid, 150 mL of tetrahydrofuran and 6.67 g (0.066 mole) of triethylamine. The resulting well-stirred mixture was cooled to -30° C. and 2.24 ml (0.03 mole) of methane sulfonyl chloride were added dropwise keeping the reaction temperature at -30° C. The resulting suspension was stirred at -30° C. during 30 minutes, after which 4.01 g (0.03 mole) of 3-amino-3-methyl-1-pentyne hydrochloride were added slowly over a 20 minute period. After the addition was completed, the reaction mixture was stirred at -30° C. for an additional 30 minutes. The reaction mixture was poured into water and extracted with methylene chloride (3×450 ml). The combined organic phases were washed with water (1×200 ml), and dried over anhydrous magnesium sulfate. The solvent was removed using a rotary evaporator, yielding the crude product. After purification by chromatographic column (silica gel, 1:1 ethyl acetate:hexane), 3.25 g N-(3-methylpent-1-yn-3-yl)-6-amino-5-chloronicotinamide were obtained as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:1][CH2:2][CH:3]2[CH2:12][N:7]3[CH2:8][CH2:9][N:10]([C:17]4[N:16]=[N:15][C:14]([Cl:13])=[CH:19][CH:18]=4)[CH2:11][CH:6]3[CH2:5][CH2:4]2)=[CH:24][CH:23]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: OCC1CCC2CNCCN2C1
Reactant: Oc1ccc(F)cc1
Product: Fc1ccc(OCC2CCC3CN(c4ccc(Cl)nn4)CCN3C2)cc1

Procedure:
A mixture of (7RS,9aSR)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (U.S. Pat. No. 5,326,874) and 3,6-di-chloropyridazine were combined according to Preparation 3. The product from this reaction was coupled with 4-fluorophenol according to Example 1 to give the title compound. mp (—HCl) 255° C. (dec). HRMS calc for C19H22ClFN4O: 376.1461, found: 376.1458.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.[H][H]>[Ni].CC(N(C)C)=O.CO>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: CN(C)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [Ni]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CN(C)c1ccc(N)c(C(=O)O)c1

Procedure:
A mixture of 18 g. of 2-nitro-5-dimethylaminobenzoic acid, 1.0 liter of a 50:50 mixture of dimethylacetamide/methanol and 18 g. of Raney Nickel is hydrogenated at a hydrogen pressure of 40-50 psi for 2 hours. The resulting mixture is filtered, washed with methanol and the total filtrate evaporated to a solid which is broken up, washed with ether and dried to obtain 2-amino-5-dimethylaminobenzoic acid, m.p. 231°-234° C. (decomp.).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17]C3C4NC(=NC(=O)C(F)(F)F)SC=4C=C(OC(F)(F)F)C=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.CS(OCC[N:46]1[C:50]2[CH:51]=[CH:52][C:53]([O:55][C:56]([F:59])([F:58])[F:57])=[CH:54][C:49]=2[S:48][C:47]1=[N:60][C:61](=[O:66])[C:62]([F:65])([F:64])[F:63])(=O)=O.Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1>C1(C)C=CC=CC=1>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:46]3[C:50]4[CH:51]=[CH:52][C:53]([O:55][C:56]([F:59])([F:57])[F:58])=[CH:54][C:49]=4[S:48][C:47]3=[N:60][C:61](=[O:66])[C:62]([F:63])([F:64])[F:65])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)OCCn1c(=NC(=O)C(F)(F)F)sc2cc(OC(F)(F)F)ccc21
Reactant: COc1ccc(N2CCN(CCc3cc(OC(F)(F)F)cc4sc(=NC(=O)C(F)(F)F)[nH]c34)CC2)cc1
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1ccc(N2CCN(CCn3c(=NC(=O)C(F)(F)F)sc4cc(OC(F)(F)F)ccc43)CC2)cc1

Procedure:
3-{2-[4-(4-Methoxyphenyl)-1-piperazinyl]ethyl-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride may be prepared in the following manner: a mixture of 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)ethyl methanesulphonate (4.52 g), toluene (120 cc) and the base liberated from 4-(p-methoxyphenyl)piperazine dihydrochloride (10.56 g) is heated to reflux for 1 hour, cooled to +4° C. and then drained. The toluene filtrate is evaporated under reduced pressure and then treated with 1.2N aqueous hydrochloric acid solution (45 cc). The hydrochloride separates in amorphous form and then crystallizes on grinding with ethanol (50 cc). After draining, washing with ethanol (15 cc) and drying at 50° C. at 20 mmHg, 3-{2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl}-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride (1.7 g) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)SC)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:26][CH:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[NH:26][CH:27]([CH3:28])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CSC(Nc1cccc(C#N)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(N)C(C)(C)C
Product: CC(NC(Nc1cccc(C#N)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1)C(C)(C)C
Yield: 25 %

Procedure:
2-(4-Chlorophenylsulfonyl)-3-(3-cyanophenylamino)-3-methylsulfanyl-2-propenenitrile (0.300 g, 0.6 mmol) was stirred in 2-amino-3,3-dimethylbutane (1 ml) for 48 h at 100° C. under nitrogen in a sealed flask. The reaction mixture was concentrated and the residue dissolved in dichloromethane, washed twice with 1N aqueous HCl, once with brine, and once with water. The organic phase was dried (sodium sulphate) and concentrated. The residue was trituated with ether to afford a white crystalline substance which was further purified by flash chromatography (SiO2) using heptane/ethyl acetate (1:1) to yield 85 mg(25%) of the title compound. Mp 80-82° C. 1H NMR (200 MHz, CDCl3): δ=0.90 (s, 9H), 1.02 (d, 3H), 3.02 (m, 1H), 7.27 (s, 2H), 7.47 (d, 2H), 7.51 (d,2H), 7.81 (d, 2H);