Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH2:17][OH:18])=[C:12]2[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[O:5].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>ClCCl>[C:35]([O:18][CH2:17][C:13]1[CH:14]=[N:15][C:16]2[C:11]([C:12]=1[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:4](=[O:5])[C:3]1[C:24]([Cl:28])=[CH:25][CH:26]=[CH:27][C:2]=1[Cl:1])(=[O:37])[CH3:36]
Reactant: O=C(Nc1cccc2c(-n3ccnc3)c(CO)cnc12)c1c(Cl)cccc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1-n1ccnc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a suspension of 8-(2,6-dichlorobenzoylamino)-3-hydroxymethyl-4-(imidazol-1-yl)quinoline (250 mg) in dichloromethane (3 ml) were dropwise added pyridine (57.4 mg) and acetic anhydride (0.12 ml) at ambient temperature, and the mixture was stirred for 22 hours at ambient temperature. The mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate. The mixture was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (methanol-dichloromethane) to give 3-acetoxymethyl-8-(2,6-dichlorobenzoylamino)-4-(imidazol-1-yl)quinoline (270 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6](O)=[O:7].CC[N:18]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([NH2:18])=[O:7]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(Oc1ccc(Cl)cc1Cl)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(Oc1ccc(Cl)cc1Cl)C(N)=O
Reaction time: 18 h
Yield: 62.9 %

Procedure:
The reaction mixture of 3-(3-endo-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)benzonitrile hydrochloride (300 mg, 1.03 mmol), commercially available 2-(2,4-dichlorophenoxy)-2-methylpropanoic acid (310 mg, 1.24 mmol), EDCI (300 mg, 1.54 mmol), HOBT (210 mg, 1.54 mmol) and triethylamine (0.75 mL, 5.38 mmol) in CH2Cl2 (10 mL) was stirred 18 h. The resulting mixture was washed with satd. aq. NaHCO3 (5 mL) and brine (5 mL) successively, then dried over MgSO4, filtered and evaporated to give a residue which was purified by column chromatography (ethyl acetate: CH2Cl2=1:1) to give N-(8-(3-cyanobenzoyl)-8-azabicyclo[3.2.1]octan-3-endo-yl)-2-(2,4-dichlorophenoxy)-2-methylpropanamide (378 mg, 0.78 mmol, 76% yield) as a white foam. 1H NMR (CDCl3, 400 MHz): δ 1.55 (s, 6H), 1.85 (m, 2H), 2.00 (m, 3H), 2.20 (m, 3H), 2.50 (m, 1H), 4.04 (br s, 1H), 4.28 (q, 1H), 4.86 (br s, 1H), 7.05 (d, 1H), 7.22 (dd, 1H), 7.44 (d, 2H), 7.58 (m, 2H), 7.77 (m, 3H).
Reaction SMILES: COC1C=CC(C[O:8][C:9](=[O:29])[CH2:10][CH2:11][C:12]([CH3:28])([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[CH3:13])=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(OCC)C>[CH3:28][C:12]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)=[O:16])([CH3:13])[CH2:11][CH2:10][C:9]([OH:29])=[O:8]
Reactant: COc1ccc(COC(=O)CCC(C)(C)NC(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CCOCC
Product: CC(C)(CCC(=O)O)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-methyl-4-p-nitrobenzyloxycarbonylaminovaleric acid p-methoxybenzyl ester (25 g), anisole (25 g) and trifluoroacetic acid (125 ml) was stirred for 15 minutes at room temperature. Evaporation of trifluoroacetic acid gave an oily residue which was then dissolved in diethyl ether. The ether solution was extracted with aqueous sodium carbonate. The aqueous layer was washed with diether ether, acidified with dilute hydrochloric acid and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give 4-methyl-4-p-nitrobenzyloxycarbonylaminovaleric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=3)=[CH:16][C:15]=2[CH3:30])=[CH:12][C:11]([C:31]([O:33]C)=O)=[N:10]1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=3)=[CH:16][C:15]=2[CH3:30])=[CH:12][C:11]([C:31]([N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:33])=[N:10]1
Reactant: COC(=O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2C)n(-c2c(Cl)cccc2Cl)n1
Reactant: C1CCNC1
Product: Cc1cc(-c2cccc(S(C)(=O)=O)c2)ccc1-c1cc(C(=O)N2CCCC2)nn1-c1c(Cl)cccc1Cl
Temperature: 180 °C
Yield: 13.5 %

Procedure:
Methyl 1-(2,6-dichlorophenyl)-5-(3-methyl-3′-(methylsulfonyl)biphenyl-4-yl)-1H-pyrazole-3-carboxylate (102 mg, 0.20 mmol) was suspended in pyrrolidine (0.6 mL, 7.2 mmol) and heated in the microwave at 180° C. for 10 minutes. The dark reaction mixture was concentrated under reduced pressure and azeotroped with toluene to remove most of the pyrrolidine. The resulting crude product was purified by preparative reverse phase HPLC eluting with MeCN/H2O with 0.05% TFA. The product fractions from the HPLC were made basic by the careful addition of saturated aqueous NaHCO3. The resulting mixture was concentrated to remove most of the MeCN. The resulting aqueous suspension was extracted with CH2Cl2 (3×), and the combined extracts were dried over Na2SO4 overnight, filtered and concentrated under reduced pressure to afford (1-(2,6-dichlorophenyl)-5-(3-methyl-3′-(methylsulfonyl)biphenyl-4-yl)-1H-pyrazol-3-yl)(pyrrolidin-1-yl)methanone (15 mg, 14% yield) as a brown solid. 1H NMR (400 MHz CDCl3): δ 8.10 (1H, m), 7.91 (1H, m), 7.83 (1H, m), 7.62 (1H, t), 7.49 (1H, d), 7.42-7.34 (2H, m), 7.33-7.21 (2H, m), 7.13 (1H, d), 7.06 (1H, s), 3.99 (2H, t), 3.71 (2H, t), 3.08 (3H, s), 2.50 (3H, s), 2.03-1.86 (4H, m). MS(ES): 554 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[N:30][CH:31]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:26]4[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[N:30][CH:31]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cncc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and 5-bromo-pyridine-3-sulfonic acid amide (59 mg, 0.25 mmol) (Example B.1) according to general procedure II. Obtained as a yellow solid (57 mg, 47%). MS (ISP) 484.0 [(M+H)+]; mp 276-277° C.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]([CH2:6][S:7][C:8]2[C:18]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13][C:12]=3[CH:11]=[CH:10][C:9]=2[Cl:26])=[CH:4][C:3]=1[F:29].[NH:30]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[ClH:26].[N:30]1([C:2]2[CH:28]=[CH:27][C:5]([CH2:6][S:7][C:8]3[C:18]4[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][C:12]=4[CH:11]=[CH:10][C:9]=3[Cl:26])=[CH:4][C:3]=2[F:29])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Br)c(F)c3)c2CC1
Reactant: C1CCCNCC1
Product: Cl
Product: Fc1cc(CSc2c(Cl)ccc3c2CCNCC3)ccc1N1CCCCCC1

Procedure:
Use a method similar to the Example 419 to react 6-(4-bromo-3-fluorobenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine with homopiperidine. Use a method similar to the General Procedure 14 to give the title compound as a white solid. MS (ES+) m/z: 419 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33](O)=[O:34])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][C:33]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)=[O:34])=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Reactant: O=C(O)CCc1ccc(Oc2ccccc2)cc1
Product: O=C(CCc1ccc(Oc2ccccc2)cc1)Nc1ccc2cnn(CCN3CCCC3)c2c1

Procedure:
According to the procedure for Example 49, 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine and 3-(4-phenoxy-phenyl)-propionic acid were processed to provide the title compound. MS (DCI/NH3) MS m/z 455 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ ppm 1.84 (m, 2 H), 2.00 (m, 2 H), 2.70 (t, J=7.64 Hz, 2 H), 2.94 (t, J=7.64 Hz, 2 H), 3.05 (m, 2 H), 3.53 (m, 2 H), 3.71 (q, J=5.82 Hz, 2 H), 4.68 (t, J=6.24 Hz, 2 H), 6.95 (m, 4 H), 7.09 (m, 2 H), 7.29 (m, 2 H), 7.36 (m, 2 H), 7.70 (m, 1 H), 8.08 (s, 1 H), 8.28 (s, 1 H), 9.62 (br s, N H).
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]([CH2:45][CH2:46][O:47][CH3:48])[CH3:44])=O>>[CH:34]([N:8]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:40][CH2:41][N:43]([CH2:45][CH2:46][O:47][CH3:48])[CH3:44])=[CH:38][CH:37]=1)[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=2[CH2:18]1)([CH3:36])[CH3:35]
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Reactant: COCCN(C)C(=O)CCl
Product: COCCN(C)CCOc1ccc(CN(c2cc(OC)ccc2C2CCc3cc(O)ccc3C2)C(C)C)cc1
Yield: 52.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (22 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (12 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>N1C=CC=CC=1>[CH2:24]([NH:26][C:27]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1)=[O:28])[CH3:25]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CCN=C=O
Solvent: c1ccncc1
Product: CCNC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.2 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (160 mg, 0.517 mmol) in pyridine (4.0 mL) was added ethyl isocyanate (409 μL, 5.17 mmol), and the mixture was stirred at room temperature for 24 hr. The solvent was evaporated under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the residue, and the aqueous layer was extracted three times with ethyl acetate. Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was filtrated, and washed with ethyl acetate/hexane to give the title compound (136 mg, 69%) as a white powder.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]1[O:13][CH:10]1[CH:11]=[CH2:12].Cl>CCOCC.C1COCC1>[C:1]1([CH2:12][CH:11]=[CH:10][CH2:9][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: C=CC1CO1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCC=CCc1ccccc1
Temperature: -10 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a -10° C. solution of phenylmagnesium bromide, 3M in ether (68 mL) was added a solution of cupric acetate (5.6 g) and butadiene monoxide (6.43 mL) in THF (200 mL) over 40 min while maintaining the reaction temperature below -5° C. The reaction was stirred at -10° C. for 1 h, room temperature for 16 h, refluxed for 15 min then cooled to room temperature. Aqueous HCl (10%, 100 mL) was added and the mixture extracted with ethyl acetate. The organic solution was washed with aqueous HCl (10%), NaHCO3 (saturated) and brine (saturated), dried (MgSO4) and concentrated to yield a blue liquid. The residue was chromatographed to yield the title compound (6.3 g, 30%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.C(NC(C)C)(C)C.[Li].[Br:21]C(F)(F)C(Br)(F)F>O1CCCC1>[Br:21][C:11]1[S:12][C:3]2[C:4](=[N:5][CH:6]=[C:7]([C:8]#[N:9])[C:2]=2[Cl:1])[CH:10]=1
Reactant: N#Cc1cnc2ccsc2c1Cl
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#Cc1cnc2cc(Br)sc2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol) in tetrahydrofuran (5.0 mL) is slowly added lithium diisopropylamine (0.7 mL, 1.40 mmol, 2M in tetrahydrofuran) at −78° C. over 5 minutes. After 30 minutes, 1,2-dibromo-1,1,2,2-tetrafluoroethane (0.16 mL, 1.3 mmol) is added slowly to the solution of the anion. The temperature is maintained at −78° C. for 4 hours then warmed to room temperature for 1 hour. The reaction mixture is poured into ice water, extracted with dichloromethane, dried over sodium sulfate, and concentrated in vacuo to afford a dark solid residue. The residue is purified by flash column chromatography eluting with a gradient of 2% ethyl acetate in hexane to 8% ethyl acetate in hexane to provide 103 mg of 2-bromo-7-chlorothieno[3,2-b]pyridine-6-carbonitrile as an off white solid, mp 190-191° C.; 1H NMR (DMSO-d6) δ 8.13 (s, 1H), 9.12 (s, 1H); MS 272.8, 274.8, 276.9 (M+H)+.
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[CH2:29]([C:31]1[N:32]=[C:33]([O:38][CH3:39])[C:34]([NH2:37])=[N:35][CH:36]=1)[CH3:30].C(N(C(C)C)CC)(C)C>C(#N)CCC>[CH2:29]([C:31]1[N:32]=[C:33]([O:38][CH3:39])[C:34]2[N:35]([C:2]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]4([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:12][CH2:13][CH2:14]4)=[CH:7][CH:6]=3)[N:37]=2)[CH:36]=1)[CH3:30]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: CCc1cnc(N)c(OC)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCC#N
Product: CCc1cn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c(OC)n1
Temperature: 120 °C

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [Int-1-A] (288 mg, 0.55 mmol, 1.0 eq), 5-ethyl-3-methoxypyrazin-2-amine (84.4 mg, 0.55 mmol, 1 eq.; see step 2) and diisopropylethylamine (0.110 mL, 0.61 mmol, 1.1 eq) in 3.9 mL butyronitrile was heated at 120° C. for 20 hours. The reaction mixture was concentrated in vacuo. The crude mixture was purified via MPLC (Isolera, 50 g Snap-cartridge, eluent:hexane→hexane/ethyl acetate 1/1) to deliver 128 mg (25%) of the title compound in approximately 50-60 purity (UPLC). The title compound observed this way was forwarded to the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11](Cl)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:39])[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11]([N:36]1[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][N:30]([CH3:39])[CH3:29])[CH2:34][CH2:35]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCN1CCNCC1
Reactant: CC(C)c1cc(C(=O)Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(=O)N2CCN(CCN(C)C)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
2,4-Bis-benzyloxy-5-isopropyl-benzoyl chloride (200 mg, 0.5 mmol) was dissolved in DCM (5 ml), treated with 1-(2-dimethylaminoethyl)piperazine (83.6 mg, 0.53 mmol) and triethylamine (0.2 ml, then stirred for 1 hour at room temperature. The reaction mixture was diluted with DCM, washed with water and, dried (MgSO4) and evaporated to give 0.25 g of the title compound. MS: [M+H]+ 516.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=1[CH3:10])=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[NH:25][C:26]([NH2:28])=[S:27]>>[BrH:1].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[NH:25][C:26]1[S:27][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=2[CH3:10])[N:28]=1
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Reactant: COc1ccc(OC)c(NC(N)=S)c1
Product: Br
Product: COC(=S)c1cc(-c2csc(Nc3cc(OC)ccc3OC)n2)c(C)s1
Yield: 89.6 %

Procedure:
Methyl 4-{2-[(2,5-dimethoxyphenyl)amino](1,3-thiazol-4-yl)}-5-tethylthiothiophene-2-carboxylate hydrobromide: Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (49.4 mg, 0.15 mmol) was allowed to react with 2,5-dimethoxy phenyl thiourea (37.2 mg) as described in Example 154, step (a), to give 65.5 mg (87% yield) of methyl 4-{2-[(2,5-dimethoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide. 1H NMR (DMSO-d6, 300 MHz) δ 2.66 (s, 3H), 3.76 (s, 3H), 3.81 (s, 3H), 3.83 (s, 3H), 6.49 (dd, 1H, J=3.0, 8.8 Hz), 6.92 (d, 1 H, J=8.9 Hz), 7.26 (s, 1H), 8.17 (s, 1H), 8.37 (d, 1H, J=3.1 Hz), 9.70 (s, 1H); Mass Spectrum (ESI) m/z calcd. for C18H18N2O4S3, 422.54 (M+H), found 423.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)CCl>[C:12]1([NH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:3]([O:2][CH3:1])=[O:4])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1ccccc1
Solvent: ClCCCl
Product: COC(=O)C=C(Nc1ccccc1)C(=O)OC
Reaction time: 1 h

Procedure:
To a stirred solution of dimethylacetylenedicarboxylate (DMAD, 0.10 mol) in 50 mL of ethylene dichloride (EDC), is slowly added a solution of aniline (0.10 mol) in 15 mL of EDC. The temperature of the reaction mixtures is maintained below 30° C. and stirring is continued for about one hour until the reaction is essentially complete. The EDC is then removed under vacuum to afford the dimethyl 3-phenylaminobut-2-ene-dioate.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8]O.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8][N:21]1[C:17](=[O:27])[C:18]2[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20]1=[O:22]
Reactant: CC(C)(CO)C(=O)NCc1ccccc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(CN1C(=O)c2ccccc2C1=O)C(=O)NCc1ccccc1Cl
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of N-(2-chlorobenzyl)-3-hydroxy-2,2-dimethylpropanamide (0.50 g, 2.07 mmol) in THF (5 mL) were added phthalimide (0.457 g, 3.10 mmol, 1.5 equiv.) and PPh3 (0.813 g, 3.10 mmol, 1.5 equiv.). DIAD (600 μL, 3.10 mmol, 1.5 equiv.) was added dropwise into the reaction mixture. The resulting mixture was stirred overnight. LC/MS indicated that starting material was consumed. The reaction mixture was concentrated. The resulting residue was purified on silica gel column a mixture of hexanes and ethyl acetate to give N-(2-chlorobenzyl)-3-(1,3-dioxoisoindolin-2-yl)-2,2-dimethylpropanamide (0.50 g, 65%). LRMS (M+H+) m/z 371.1.
Reaction SMILES: [C:1]([NH:4][N:5]=[C:6]([C:14]#[N:15])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)(=[NH:3])[NH2:2].C([OH:19])CC>CS(C)=O>[NH2:3][C:1]1[N:4]=[N:5][C:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[C:14]([NH2:15])[N:2]=1.[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([C:14]#[N:15])=[O:19])=[CH:8][CH:9]=1
Reactant: N#CC(=NNC(=N)N)c1ccc(Cl)cc1
Reactant: CCCO
Solvent: CS(C)=O
Product: N#CC(=O)c1ccc(Cl)cc1
Product: Nc1nnc(-c2ccc(Cl)cc2)c(N)n1

Procedure:
The title compound was prepared as in Example 2(a) from 4-chlorobenzoyl cyanide amidinohydrazone obtained in Example 7. The solvent for the ring closure was a mixture of 1-propanol and dimethyl sulfoxide (4:1). Total yield (from 4-chlorobenzoyl cyanide): 72%; m.p. 219-221° C. (uncorrected).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH3:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21].C(O)C>CCOCC>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)C(c1ccccc1)c1ccccc1
Reactant: COC(OC)N(C)C
Solvent: CCOCC
Solvent: CCO
Product: CN(C)C=CC(=O)C(c1ccccc1)c1ccccc1
Temperature: -10 °C

Procedure:
A mixture of 21.0 g of 1,1-diphenylacetone and 40 ml of N,N-dimethylformamide dimethyl acetal in a 300 ml round bottom flask was heated in an oil bath at 120° C. for 8 hours with ethanol being distilled over. The reaction mixture was cooled and evaporated in vacuo to give an oil. The oil was boiled up in 50 ml of ether then cooled at -10° C. and gave a heavy precipitate. The precipitate was collected, washed with ether, then air dried and gave 21.5 g of crude product. A 5.0 g portion was recrystallized from 50 ml of 2-propanol, then cooled at room temperature. The material was collected and dried at 60° C. and gave 1.7 g of the desired product, mp 93°-94° C.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:11](=O)[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14]>O>[CH:11](=[N:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14]
Reactant: O=Cc1ccccc1O
Reactant: NNC(=O)c1ccccc1
Solvent: O
Product: O=C(NN=Cc1ccccc1O)c1ccccc1
Temperature: 25 °C
Yield: 79.1 %

Procedure:
A reaction vessel was charged with 13.6 g (0.10 mole) of benzhydrazide and 50 ml of water, and the vessel contents were agitated as 13.4 g (0.11 mole) of salicylaldehyde was added. Heat was evolved and the mixture was stirred at room temperature for an additional hour, then warmed briefly on a steam bath. The precipitate which had formed was filtered off, washed with water and ether, and dried under vacuum. It was then placed in 300 ml of ethanol for several hours and the remaining solid, crystalline in appearance, was filtered off and dried under vacuum. The filtrate was then diluted with water and cooled, forming additional precipitate which was then filtered off and dried. Both precipitates were combined to yield 19.0 g (79% of theoretical yield) of salicylidene benzhydrazide, with a melting point range of 172°-174° C.
Reaction SMILES: C(OC([NH:8][C:9]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][O:11][CH2:10]1)=O)(C)(C)C.[ClH:17]>>[ClH:17].[NH2:8][C:9]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCOC1
Agent: Cl
Product: NC1(C(=O)O)CCOC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.5 g (15.1 mmol) 3-tert.-butoxycarbonylamino-tetrahydro-furan-3-carboxylic acid are dissolved in 150 ml of 1-molar hydrochloric acid and stirred for 1 h at room temperature. Then the reaction mixture is lyophilised.