Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([O:13][C:14](=[O:28])[CH:15]([CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16](=O)[CH3:17])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:19]=[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:10])[CH3:9])[CH:3]=2)[C:16]=1[CH3:17])=[O:28])[CH3:12]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: CC(=O)c1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(C(C)=O)c2)c1C

Procedure:
3′-Aminoacetophenone (5 mmol, 0.7 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was purified over silica and yielded the named product as a solid (m.p. 102° C.-104° C.).
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][CH2:4][C@@H:5]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[N:12](COCC[Si](C)(C)C)[CH:11]=1)=[O:9])[CH3:6].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[F:38][CH:2]([F:1])[O:3][CH2:4][C@@H:5]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[NH:12][CH:11]=1)=[O:9])[CH3:6]
Reactant: C[C@@H](COC(F)F)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](COC(F)F)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 26.6 %

Procedure:
In a 10 mL round-bottom flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-difluoromethoxy-1-methyl-ethyl)-amide (10 mg, 0.018 mmol) and TFA (0.5 ml, 6.5 mmol) were combined with dichloromethane (1.5 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (1 mL) and ethylenediamine (30 ul, 0.46 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (dichloromethane) to afford 2 mg (32%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-difluoromethoxy-1-methyl-ethyl)-amide as an off-white solid. MS: [M+H]+=419; 1H NMR (300 MHz, DMSO-d6) δ: 12.86 (br. s., 1H), 9.11 (s, 1H), 8.47 (s, 1H), 8.49 (dd, J=9.1, 5.3 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H), 7.70 (dd, J=9.8, 2.3 Hz, 1H), 7.15 (td, J=9.2, 2.1 Hz, 1H), 6.70 (t, J=75.2 Hz, 1H), 4.36-4.54 (m, 1H), 4.16 (s, 3H), 4.00 (d, J=4.5 Hz, 2H), 1.37 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12](N(OC)C)=[O:13])=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]([CH:12]=[O:13])=[CH:4][C:5]([C:8]([F:9])([F:10])[F:11])=[N:6][CH:7]=1
Reactant: CON(C)C(=O)c1cc(C(F)(F)F)ncc1Br
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1cc(C(F)(F)F)ncc1Br
Temperature: -10 °C
Reaction time: 0.67 h
Yield: 76.9 %

Procedure:
To 5-bromo-N-methoxy-N-methyl-2-(trifluoromethyl)pyridine-4-carboxamide (21 g, 67.1 mmol) in THF (200 mL) was added DIBAL-H in toluene (1M, 73.8 mL, 73.8 mmol) through a syringe at −78° C. The reaction was stirred for 40 minutes while it was warmed to −10° C. The reaction was diluted with EtOAc (100 mL) and was quenched with 1N HCl solution (150 mL). The reaction mixture was filtered on a Celite and silica gel bed. The layers were separated and the organic layer was partitioned with saturated. NaHCO3 and then brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction was purified by column chromatography to yield 5-bromo-2-(trifluoromethyl)pyridine-4-carbaldehyde (13.1 g, 51.6 mmol). 1H NMR (500 MHz, CDCl3) δ10.2 (s, 1H), 9.04 (s, 1H), 8.84 (s, 1H).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH:3]([OH:12])[CH2:2]1.[CH3:13][O:14][C:15]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22](O)[CH:23]=2)[CH:18]=1)=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH2:5]1[C:6]2([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:1][CH2:2][CH:3]([O:12][C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:15]([O:14][CH3:13])=[O:16])[CH:26]=[CH:25]3)[CH2:4]1
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Reactant: OC1CCC2(CCCCC2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1

Procedure:
A mixture of spiro[5.5]undecan-3-ol (0.999 g, 0.00593 mol), 6-hydroxy-naphthalene-2-carboxylic acid methyl ester (1.00 g, 0.00494 mol) and triphenylphosphine (1.56 g, 0.00593 mol) in toluene (10 mL, 0.1 mol) was heated to reflux. Diisopropyl azodicarboxylate (1.17 mL, 0.00593 mol) was then added dropwise and the resulting mixture was refluxed for 6 hours. The mixture was then diluted with dichloromethane and subjected to chromatographic purification with ethyl acetate:hexane (0:100 to 40:60) to give methyl 6-(spiro[5.5]undecan-3-yloxy)-2-naphthoate as a white solid. (1.09 g, 62%). 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.01 (dd, J=8.7, 1.7 Hz, 1H), 7.84 (d, J=9.6 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.17 (m, 2H), 4.45 (m, 1H), 3.97 (s, 3H), 1.93-1.28 (m, 18H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].O1CCCC1.C([Li])CCC.[CH2:25]([N:28]=[CH:29][C:30]1[S:31][CH:32]=[CH:33][C:34]=1[CH3:35])[CH2:26][CH3:27]>CCCCCC.O>[CH3:12][C:10]([CH3:11])([CH3:13])[C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:1][CH:29]([C:30]1[S:31][CH:32]=[CH:33][C:34]=1[CH3:35])[NH:28][CH2:25][CH2:26][CH3:27])=[O:14]
Reactant: CCCN=Cc1sccc1C
Reactant: Cc1ccccc1NC(=O)C(C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCNC(Cc1ccccc1NC(=O)C(C)(C)C)c1sccc1C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a stirred, chilled (-10° C.) solution of 10.14 g of N-[(2-methyl)-phenyl]-2,2-dimethylpropanamide and 80 ml of tetrahydrofuran, was added over 45 min 48 ml of 2.5M n-butyllithium in hexane, maintaining the temperature below 0° C. The solution was stirred for 2 hr, with cooling. To the suspension, was added a solution of 10.6 g of 3-methyl-2-thiophene carboxaldehyde-n-propylimine and 45 ml of tetrahydrofuran, with stirring and cooling over 15 min. The solution was stirred for 1.5 hr, with cooling, and then 150 ml of water was added. The mixture was concentrated. The residue was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue was accomplished by Preparative HPLC (Water Associates Prep LC/System 500, silica gel, eluted with ethyl acetate, flow rate 200 ml/min, Gow Mac model 80-800 UV detector). The appropriate fractions were combined and concentrated to give 15.2 g of product, as an oil.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1.N1CC[O:21]CC1.[F:24][C:25]([F:29])=[C:26](F)F.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:24][CH:25]([F:29])[C:26]([N:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1)=[O:21]
Reactant: C1COCCN1
Reactant: FC(F)=C(F)F
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(F)F)s1
Temperature: 50 °C
Reaction time: 13 h
Yield: 98 %

Procedure:
A solution of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1.29 g, 5.0 mmol) and morpholine (0.96 g, 11.0 mmol) in N,N-dimethylformamide (10 ml) charged in a reaction flask was reacted with tetrafluoroethylene, which was made to flow into the flask (ca. 0.7 liter/hr), with vigorous stirring at 50° C. for 13 hours. After cooling to an ambient temperature, the reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution (100 ml), and extracted twice with toluene (100 ml×2). The toluene layer was washed twice with 5% hydrochloric acid (50 ml×2) and water (50 ml) and then brine (50 ml), and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography, which afforded 2-difluoroacetylimino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1.64 g, 4.9 mmol, yield 98%).
Reaction SMILES: [CH:1]([Si:4]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[CH2:7])([CH3:3])[CH3:2].C1C(=O)N([Cl:27])C(=O)C1.CCOCC>C1COCC1>[Cl:27][CH:7]=[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[O:5][Si:4]([CH:1]([CH3:2])[CH3:3])([CH:14]([CH3:16])[CH3:15])[CH:17]([CH3:19])[CH3:18]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=C(O[Si](C(C)C)(C(C)C)C(C)C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)[Si](OC(=CCl)c1ccccn1)(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
Crude 2-{1-[(triisopropylsilyl)oxy]vinyl}pyridine (131.5 g, assumed 0.413 mmol) is placed in a 2 L, 1N round bottom flask and dissolved in anhydrous THF (Aldrich Sure Seal, 0.6 L). The flask is equipped with a reflux condenser and the apparatus is placed under nitrogen. NCS (60.66 g, 0.454 mol, 1.1 eq.) is added and the mixture is heated to reflux and maintained at reflux for 2 hours. The reaction mixture is cooled to room temperature, poured into a 4 L separatory funnel containing ether (1.5 L), and is washed with saturated aq. NaHCO3 (2×0.7 L). The organic phase is separated, dried (Na2SO4), and concentrated in vacuo affords the target (117.5 g, 91%) as a yellow-orange oil. The crude material is not further purified, but is immediately carried into the next step.
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3](=[O:12])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6]1.N1C=CC=CC=1.S(Cl)([Cl:29])=O.C(OCC)(=O)C>C(Cl)Cl>[CH3:1][N:2]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3](=[O:12])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([CH2:10][Cl:29])=[CH:6]1
Reactant: O=S(Cl)Cl
Reactant: CN(CCc1ccccc1)C(=O)Cn1ccc(CO)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CN(CCc1ccccc1)C(=O)Cn1ccc(CCl)c1
Reaction time: 18 h

Procedure:
To a solution of N-methyl-N-phenethyl-2-[3-hydroxymethylpyrrol-1-yl]acetamide and pyridine in methylene chloride is added dropwise 2 molar equivalents of thionyl chloride. The resulting mixture is stirred at room tenperature for 18 hours and ethyl acetate is added. The solution is washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue obtained is purified by a silica gel flash column to give N-methyl-N-phenethyl-2-[3-chloromethylpyrrol-l-yl]acetamide which is used directly in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]([CH3:26])[C:15]([CH2:17][NH:18][C:19]3[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:36].C(O)C.C(=O)([O-])[O-].[NH4+:44].[NH4+]>ClCCl.CO>[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]([CH3:26])[C:15]([CH2:17][NH:18][C:19]3[S:20][C:21]([C:24](=[NH:44])[NH2:25])=[CH:22][N:23]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ncc(C#N)s1)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ncc(C(=N)N)s1)n2C)c1ccccn1

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(5-cyano-thiazol-2-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: % of theory, C24H26N8O3S (506.6) Rf value: (silica gel; dichloromethane/methanol=4:1)
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].O.[NH2:16][NH2:17].C(O)(=O)C>CS(C)=O>[NH:16]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12])[NH2:17]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: NN
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: NNc1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 5 h

Procedure:
7.5 g (36 mmol) of 4-fluoro-3-trifluoromethylbenzoic acid is dissolved in 12 mL dimethylsulfoxide and, after the addition of 15 mL (0.24 mol) of hydrazine hydrate (80%), stirred for 5 hours at 100° C. After cooling, it is combined with ice and acidified with glacial acetic acid. The precipitated product is suction filtered and dried. Yield: 5.3 g (66%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7](=[N:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:18][I:19]>C1C=CC=CC=1>[I-:19].[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7](=[N+:9]([CH3:18])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CI
Reactant: Clc1ccc2sc(=Nc3ccccc3)sc2c1
Solvent: c1ccccc1
Product: C[N+](c1ccccc1)=c1sc2ccc(Cl)cc2s1
Product: [I-]

Procedure:
A solution of 5-chloro-N-phenyl-1,3-benzodithiol-2-imine (6.0g) and methyl iodide (50 ml, excess) in 200 ml of dry benzene is heated at 50° C for 72 hours. The reaction mixture is filtered and the resultant solid is washed several times with pentane. The solid product is recrystallized from n-amyl alcohol to yield 4.0g of the title compound, melting point 205°-207° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[Cl:5][C:6]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([F:15])[C:7]=1[CH2:8][Br:9]>CC(=O)CC>[BrH:9].[Cl:5][C:6]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([F:15])[C:7]=1[CH2:8][S:3][C:2](=[NH:4])[NH2:1]
Reactant: NC(N)=S
Reactant: Fc1ccc(Cl)c(Cl)c1CBr
Solvent: CCC(C)=O
Product: Br
Product: N=C(N)SCc1c(F)ccc(Cl)c1Cl
Temperature: 100 °C

Procedure:
A mixture of thiourea (1.52 g) and 2,3-dichloro-6-fluorobenzyl bromide (commercially available) (5.16 g) in 2-butanone (20 ml) was heated to 100° C. for 5 minutes in the microwave. The reaction mixture was cooled to ambient temperature and filtered. The white solid was washed with diethyl ether to give 2-(2,3-dichloro-6-fluoro-benzyl)-isothiourea hydrobromide (5.14 g). 1H-NMR (400 MHz, CD3OD): 7.61-7.65 (m, 1H), 7.22-7.27 (m, 1H), 4.64 (m, 2H) ppm.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH2:10]([NH2:13])[CH2:11][CH3:12]>CO>[S:6]1[C:2]([NH:13][CH2:10][CH2:11][CH3:12])=[N:3][N:4]2[CH:9]=[CH:8][N:7]=[C:5]12
Reactant: Brc1nn2ccnc2s1
Reactant: CCCN
Solvent: CO
Product: CCCNc1nn2ccnc2s1
Temperature: 175 °C

Procedure:
1.5 g of 2-bromo-imidazo[2,1-b][1,3,4]thiadiazole were dissolved in 10 ml methanol and 10 ml of propylamine were added to the solution. The resulting mixture was heated in a microwave oven at 175° C. for 15 min. The resulting suspension was evaporated and dissolved in ethylacetate. It was washed with water, dried with sodium sulphate and evaporated. Silica-gel chromatography with petroleum ether-ethylacetate gave 519 mg of the desired product as solid material.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]2[CH:7]=[C:6](/[C:16](=[CH:20]\[CH:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)/[C:17](O)=[O:18])[CH:5]=[CH:4][C:3]1=2.[CH3:29][N:30]1[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1>CN(C)C=O.C(OCC)(=O)C>[O:28]=[S:2]1(=[O:1])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]2[CH:7]=[C:6](/[C:16](=[CH:20]\[CH:21]3[CH2:22][CH2:23][C:24](=[O:27])[CH2:25][CH2:26]3)/[C:17]([NH:35][C:32]3[CH:33]=[CH:34][N:30]([CH3:29])[N:31]=3)=[O:18])[CH:5]=[CH:4][C:3]1=2
Reactant: O=C1CCC(/C=C(/C(=O)O)c2ccc3c(c2)Nc2ccccc2S3(=O)=O)CC1
Reactant: Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ccc(NC(=O)/C(=C/C2CCC(=O)CC2)c2ccc3c(c2)Nc2ccccc2S3(=O)=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
276 mg of (E)-2-(5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-3-(4-oxocyclohexyl)acrylic acid, 101 mg of commercial 1-methyl-1H-pyrazol-3-ylamine and 0.61 ml of N,N-diisopropylethylamine are dissolved in 10 ml of dimethylformamide. 318 mg of HATU and 114 mg of HOAT are added, and the mixture stirred at room temperature for two hours. The reaction mixture is then diluted by addition of 100 ml of ethyl acetate and washed five times with in each case 30 ml of water. The organic phase is dried over MgSO4, and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane (100%)=>:ethyl acetate (100%). This gives 134 mg of (E)-2-(5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(4-oxocyclohexyl)acrylamide.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1)([CH3:3])[CH3:2].[Br:10]Br.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:10][C:8]1[S:7][C:6]([NH2:9])=[N:5][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(N)n1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)c1nc(N)sc1Br
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 4-isopropyl-thiazol-2-ylamine (2.0 g, 14 mmol) in 30 mL CHCl3 was added dropwise to a stirring solution of bromine ((2.697 g, 17 mmol) in 15 mL CHCl3. The reaction mixture was stirred for 60 hours at room temperature. The reaction mixture was poured into saturated aqueous NaHCO3, and extracted with methylene chloride. The combined organic extracts were washed with saturated aqueous NaHCO3 and brine, dried (MgSO4), filtered and concentrated under reduced pressure to give 2.05 g of 5-bromo-4-isopropyl-thiazol-2-ylamine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].CI.[C:14](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([O:10][CH3:14])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(F)cc(Cl)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1c(Cl)cc(F)cc1C=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
5-Fluoro-2-hydroxy-3-chlorobenzaldehyde (2.0 g, 11.01 mmol) was dissolved in N,N-dimethylformamide (30 mL) and to the solution was added methyl iodide (1.1 mL, 18.11 mmol) and potassium carbonate (4.4 g, 30.21 mmol). The mixture was stirred at 100° C. for one hour, cooled to room temperature and then diluted with water (40 mL). After extraction twice with ethyl acetate (40 mL) the combined organic layer was washed with brine and then dried over Na2SO4. The solvent was removed and the solid residue was treated with methanol. After filtration and drying desired compound was obtained 2.0 g (99%). 1H NMR (400 MHz, CDCl3): δ 10.21 (s, 1H), 7.25 (dd, 1H), 7.12 (dd, 1H), 3.75 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](N3CCN(CCS(C)(=O)=O)CC3)=[O:21])[C:10]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([CH3:49])([CH3:48])[C:41]([N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])=[O:42])=[CH:36][C:35]=3[O:50][CH2:51][CH3:52])=[N:9]2)=[CH:4][CH:3]=1.[N:53]1([C:59](=[O:67])[CH2:60][N:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:64]3[CH2:63][CH2:62][N:61]([CH2:60][C:59]([N:53]4[CH2:54][CH2:55][O:56][CH2:57][CH2:58]4)=[O:67])[CH2:66][CH2:65]3)=[O:21])[C:10]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([CH3:49])([CH3:48])[C:41]([N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])=[O:42])=[CH:36][C:35]=3[O:50][CH2:51][CH3:52])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)C(=O)N(CC)CC)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: CCOc1cc(C(C)(C)C(=O)N(CC)CC)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1
Yield: 84.6 %

Procedure:
4,5-Bis-(4-chloro-phenyl)-2-[4-(1-diethylcarbamoyl-1-methyl-ethyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (27 mg, 0.0439 mmol, example 157) was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (14 mg, 0.0659 mmol, Oakwood Products) using the procedure described in example 25 to give cis-2-(4-{4,5-bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-phenyl)-N,N-diethyl-isobutyramide (29.4 mg, 85% yield) as white solids. HR-MS (ES, m/z): observed 791.3445, calculated for C42H52Cl2N6O5 [(M+H)+] 791.3449.
Reaction SMILES: C1C=CC2N([OH:10])N=NC=2C=1.[CH2:11]1[CH2:16][CH2:15][CH:14]([N:17]=[C:18]=[N:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:13][CH2:12]1>CN(C=O)C.C(OCC)(=O)C>[CH:20]1([NH:19][C:18]([NH:17][CH:14]2[CH2:13][CH2:12][CH2:11][CH2:16][CH2:15]2)=[O:10])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: On1nnc2ccccc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 8 h

Procedure:
L-valyl-L-tyrosyl-O-benzyl-thioamide (2 mmol) was dissolved in anhydrous DMF (0.5 ml) at 0° C. under N2 and α-N-Boc-L-aspartyl-β-benzyl ester (2 mmol) was added to the solution with stirring. HOBt (2 mmol) and DCC (2 mmol) were added slowly at 0° C. and stirring was allowed to continue overnight. The mixture was diluted with 8 volumes of ethyl acetate and the N,N'-dicyclohexylurea so formed was filtered away from the solution. The filtrate was transferred to a separatory funnel and washed successively with 5% aqueous sodium bicarbonate, 5% aqueous citric acid, and saturated brine. The organic phase was collected and dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromotography on silica gel employing a 1:1 hexane-ethyl acetate solvent mixture as an eluant to afford the α-N-Boo-L-aspartyl-β-benzyl ester-L-valyl-L-tyrosyl-O-benzyl ether-benzyl ester-3-thioamide in good yield (74%). The following physical characteristics were recorded for the compound: Melting point 112°-114° C. and UV (CHCl3) lambdamax 271.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[CH3:29][C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[CH2:35][CH2:36][CH2:37]O>C1(C)C=CC=CC=1.O1CCCC1>[NH3:15].[CH3:29][C@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[CH2:35][CH2:36][CH2:37][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H]1CCCN1CCCO
Reactant: N#CC1(c2ccc(O)cc2)CCOCC1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@H]1CCCN1CCCOc1ccc(C2(C#N)CCOCC2)cc1
Product: N
Temperature: 85 °C
Yield: 42.6 %

Procedure:
A solution of 4-(4-hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (203 mg, 1.0 mmol) and tri-n-butylphosphine (299 μL, 1.20 mmol) in toluene (6 mL) were added to a solution of 3-[(2R)-2-methylpyrrolidin-1-yl]propan-1-ol (172 mg, 1.20 mmol) in toluene (6 mL) and tetrahydrofuran (2 mL) at ambient temperature. 1′1-azobis(N,N-dimethylformamide) (206 mg, 1.20 mmol) was added and the reaction heated to 85° C. overnight. The reaction mixture was concentrated in vacuo followed by addition on dichloromethane (30 mL). The organic solution was then washed with NaOH (2.0M, 2×20 mL), dried with Na2SO4 and concentrated in vacuo. The compound was purified by column chromatography on Biotage® silica gel, eluting with dichloromethane:methanol:ammonia, 98:2:0.2 to 96:4:0.4 to give the title compound as a pale yellow oil (70 mg, 21%). HRMS (ESI+) 329.2224 (M+H)+.