Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:21]#[N:22])=[CH:16][CH:15]=2.C(=O)([O-])[O-].[K+].[K+]>O>[CH:8]([C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21]#[N:22])[CH:18]=2)[NH:13][C:12]=1[CH3:11])=[O:9]
Reactant: CN(C)C=O
Reactant: Cc1cc2cc(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1[nH]c2ccc(C#N)cc2c1C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under ice-cooling, 1.3 ml of phosphorus oxychloride was added to 7 ml of N,N-dimethylformamide at an inner temperature of from 10 to 20° C., followed by stirring at room temperature for 15 minutes. Under ice-cooling, 9 ml of an N,N-dimethylformamide solution of 2-methyl-1H-indole-5-carbonitrile was added to this solution at an inner temperature of from 10 to 20° C., followed by overnight stirring at room temperature. A 64 ml portion of water was added thereto at 0° C. and the pH was adjusted to 8 with potassium carbonate, followed by 2.5 hours of stirring at room temperature. The thus precipitated solid was collected by filtration, washed with water and then dried at 80° C. under a reduced pressure to obtain 1.73 g of 3-formyl-2-methyl-1H-indole-5-carbonitrile as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)(=O)C.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][C:17]([C:13]3[S:12][CH:16]=[CH:15][CH:14]=3)=[N:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccs1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc2oc(-c3cccs3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
15.4 g of 4-nitro-o-aminophenol and 11.2 g of thiophenecarboxaldehyde are dissolved in glacial acetic acid (450 ml) and heated to 85°. 44.4 g of lead tetraacetate is dissolved in 400 ml glacial acetic acid by warming and added to the above solution. Heating is continued for 0.5 hr and the solution is cooled to room temperature, diluted with an equal volume of water and the dark precipitate is collected and washed with additional water. The crude product is dissolved in CH2Cl2 (800 ml) and heated with 2.0 g of "Darco" G-60, followed by evaporation of the CH2Cl2. The resulting material is recrystallized from ethanol-chloroform (3:1) to yield 12.4 g of 5-nitro-2-(2-thienyl)benzoxazole, mp 186°-188°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[C:24](O)(=[O:28])[CH:25]([CH3:27])[OH:26]>>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:24](=[O:28])[C@@H:25]([OH:26])[CH3:27])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CC(O)C(=O)O
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Product: C[C@H](O)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (600 mg) was reacted with lactic acid via General Procedure B to give (S)-1-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH:6]([C:8]2[O:9][C:10]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)[OH:7])[CH2:5][CH2:4]1.I[CH3:20]>O1CCCC1>[CH:3]1([CH:6]([O:7][CH3:20])[C:8]2[O:9][C:10]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH2:4][CH2:5]1
Reactant: COc1cccc2cc(C(O)C3CC3)oc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2cc(C(OC)C3CC3)oc12
Reaction time: 0.08 h

Procedure:
To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 0.52 g) in tetrahydrofuran (60 ml) under an atmosphere of nitrogen was added slowly a solution of cyclopropyl-(7-methoxybenzofuran-2-yl)-methanol (1.88 g) in tetrahydrofuran (15 ml). After stirring for 5 minutes, iodomethane (1.6 ml) was added and the mixture concentrated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml), the organic layer washed with water (100 ml), separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with dichloromethane afforded the title compound as a yellow gum (1.62 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[C:10]3[S:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:8]([C:9]=23)=[N:7]1)[CH3:2].[OH:25]O>CC(C)=O>[OH2:25].[CH2:23]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[C:10]3[S:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:8]([C:9]=23)=[N+:7]1[O-:25])[CH3:24]
Reactant: CCN(CC)CCn1nc2c3c(c(C)ccc31)Sc1ccccc1-2
Reactant: OO
Solvent: CC(C)=O
Product: CCN(CC)CCn1c2ccc(C)c3c2c([n+]1[O-])-c1ccccc1S3
Product: O
Reaction time: 8 h

Procedure:
To a solution of 2-(2-(diethylamino)ethyl)-5-methyl-2H(1)benzothiopyrano[4,3,2-cd]indazole (0.17 g.) in acetone (4 ml.) was added 0.2 ml. of 30% aqueous hydrogen peroxide. The solution was left at room temperature overnight and then evaporated to dryness under reduced pressure. The residue was crystallized from acetone-ether to give 2-(2-(diethylamino)ethyl)-5-methyl-2H(1)benzothiopyrano[4,3,2-cd]indazole N-oxide monohydrate, m.p. 123°-124° (decomp.). This compound, when crystallized in the presence of hydrochloric acid, gave a water-soluble monohydrochloride salt which darkened and decomposed at temperatures above 150°.
Reaction SMILES: [OH-:1].[K+].[C:3]1(=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O.Br[CH2:12][C:13](=O)[C:14]([O:16]CC)=[O:15].[OH-].[Na+].Cl>CO.O>[O:10]=[C:3]1[C:4]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][O:1][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: O=C1CCCCC1=O
Reactant: [OH-]
Reactant: CCOC(=O)C(=O)CBr
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1coc2c1C(=O)CCC2
Temperature: 0 °C
Reaction time: 14.5 h
Yield: 50.5 %

Procedure:
4-Oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid is prepared according to the following procedure. Potassium hydroxide (345 g, 6.15 mol) is dissolved in methyl alcohol (1.2 L) then cooled in an ice water bath. A solution of cyclohexanedione (714 g, 6.15 mol) in methyl alcohol (1.2 L), dissolved using gentle heat, is added dropwise to the cold, stirred KOH solution over 2 h. A solution of ethyl bromopyruvate (1200 g, 6.15 mol) in methyl alcohol (1.5 L) is then added dropwise over 3 h. The reaction mixture is allowed to reach ambient temperature and stirred an additional 14.5 h. While cooling the reaction mixture via a water bath, a solution of sodium hydroxide (492 g, 12.4 mol) in water (984 mL) is added dropwise over 2.5 h. After stirring at ambient temperature for 15.5 h, the reaction mixture is cooled in an ice water bath, 500 g of ice added, and the resulting mixture is then acidified with concentrated hydrochloric acid (ca 1 L) to pH 1. Be reaction mixture is concentrated in vacuo, 1 L of ice is added and the precipitate filtered, washed with ice water (3×200 mL), and then dried in a vacuum oven at 75° C. to afford 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (560 g). m.p. 137-138° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([N:12]([CH3:22])[C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])[CH2:4][C:5]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CCN(CC)CC.[Si:30](Cl)([CH3:33])([CH3:32])[CH3:31].Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:37]>C(Cl)Cl>[CH3:22][N:12]([CH:3]([CH2:2][NH:1][C:36]([O:38][C:39]1[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=1)=[O:37])[CH2:4][C:5]1([O:11][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])=[O:14]
Reactant: CN(C(=O)OCC[Si](C)(C)C)C(CN)CC1(O)CCCCC1
Reactant: C[Si](C)(C)Cl
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OCC[Si](C)(C)C)C(CNC(=O)Oc1ccc([N+](=O)[O-])cc1)CC1(O[Si](C)(C)C)CCCCC1
Reaction time: 1 h

Procedure:
To a solution of 1-(3-amino-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-propyl)cyclohexanol (21 mg, 0.064 mmol) in CH2Cl2 (2 mL) were added Et3N (0.2 mL) and Me3SiCl (13.9 mg, 16 μL, 0.13 mmol). The resulting solution was stirred for 1 h and evaporated under vacuum. The residue was dissolved in CH2Cl2 (2 mL) and pyridine (0.05 mL) was added, followed by 4-nitrophenyl chloroformate (15 mg, 0.077 mmol). The mixture was stirred for 30 min to afford a solution of 1-(2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-(p-nitrophenoxycarbonylamino)propyl)-1-(trimethylsilyloxy)cyclohexane which was used directly without isolation.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[CH3:9][O:10][C:11]1[S:15][C:14]([N:16]=[C:17]=[O:18])=[CH:13][CH:12]=1.O>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:9][O:10][C:11]1[S:15][C:14]([NH:16][C:17]([N:8]=[C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:2]2[CH3:1])=[O:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(N=C=O)s1
Reactant: CN1CC(=O)N=C1N
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)N=C2NC(=O)CN2C)s1
Temperature: 65 °C
Yield: 3.2 %

Procedure:
To a stirred suspension of 3.0 g (26 mM) of creatinine in 25 ml of anhydrous DMF was added a solution of 4.1 g (26 mM) of 5-methoxy-2-thienyl isocyanate in 20 ml of toluene. The resulting mixture was heated at 65° C. for 4.5 hrs., cooled, and poured into 200 ml of water. The mixture was extracted with ethyl acetate, and the combined extracts dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate and then ethanol. Final purification was accomplished by chromatography over silica gel (ethyl acetate as eluant), decolorizing the product with charcoal, concentration and recrystallization from acetone-hexane to give 0.23 g of the above urea as a light brown solid, m.p. 180°-182° C. (dec.).
Reaction SMILES: CO.[NH:3]([C:10]1[CH:18]=[C:17]([C:19](O)=[O:20])[C:16]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:15][C:11]=1[C:12](O)=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[Cl-].C([N+](CCCCCCCCCCCCCCCCCC)(C)C)CCCCCCCCCCCCCCCCC.O>[CH:26]1[CH:27]=[C:28]2[C:19]([C:17]3[C:16]([NH:22][C:23]2=[CH:24][CH:25]=1)=[CH:15][C:11]1[C:12]([C:9]2[C:4]([NH:3][C:10]=1[CH:18]=3)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:13])=[O:20]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
225 parts of polyphosphoric acid (P2O5 content 85.5%) are heated to 50° C. 3.75 parts of methanol are then added dropwise in the course of 10 minutes. After stirring for 30 minutes the mixture is raised to 100° C. and is stirred at this temperature for 2 hours. It is then raised to 120° C. On reaching this temperature 50 parts of 2,5-dianilinoterephthalic acid are added with stirring in the course of 1 hour. After the mixture has been stirred at 120° C. for a further hour 1 part of distearyldimethylammonium chloride is added, and the mixture is stirred at 120° C. for a further hour. The melt is then hydrolyzed with 300 parts of ice and 375 parts of water. The crude quinacridone is separated off by filtration and is washed with water until neutral. The water-moist crude quinacridone is suspended in 300 parts of water and 75 parts of 10% strength potassium hydroxide solution are added. The suspension thus obtained is bulked to 750 parts with water and is then boiled with stirring for 7 hours. The suspended particles are then filtered off and washed with water until neutral. The isolated neutral moist quinacridone is suspended in 300 parts of 80% strength isobutanol, the suspension is stirred at 150° C. in a sealed vessel for 5 hours, and the quinacridone is then isolated as described in Example 1. Drying produces 44.5 parts of bluish red pigment of the pure γ-crystal modification. To measure the gloss, a casting was prepared on plastic film and measured, both steps being carried out as described in Example 1. The gloss value is 52.1.
Reaction SMILES: [CH2:1]([N:8]([CH3:30])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:26])([CH2:23][C:24]#[N:25])[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][C:10]=1[N+:27]([O-:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn]([N:44]=[N+:45]=[N-:46])(CCCC)CCCC)CCC>>[CH2:1]([N:8]([CH3:30])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:26])([CH2:23][C:24]2[NH:46][N:45]=[N:44][N:25]=2)[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][C:10]=1[N+:27]([O-:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CN(Cc1ccccc1)c1ccc(C(C)(CC#N)C(=O)N2CCCC2)cc1[N+](=O)[O-]
Product: CN(Cc1ccccc1)c1ccc(C(C)(Cc2nnn[nH]2)C(=O)N2CCCC2)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to Example 4g from 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-cyano-1-pyrrolidino-propan-1-one and tributyl tin azide.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10]#N)=[N:8][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:6]1.[C:22](=O)([O-])[O-:23].[Cs+].[Cs+].Cl.C[OH:30]>>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10]([O:23][CH3:22])=[O:30])=[N:8][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:6]1
Reactant: O=C([O-])[O-]
Reactant: CO
Reactant: N#Cc1nc(-c2ccccn2)nn1Cc1ccccc1F
Agent: Cl
Agent: [Cs+]
Product: COC(=O)c1nc(-c2ccccn2)nn1Cc1ccccc1F
Temperature: 25 °C
Reaction time: 3.75 h
Yield: 99 %

Procedure:
To a solution of 1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carbonitrile (I-33, 120 mg, 0.430 mmol) in methanol (2.0 mL) was added cesium carbonate (280 mg, 0.859 mmol). After stirring at room temperature for 3.75 h, aqueous 0.1 N hydrochloric acid (10 mL) was added, followed by aqueous 1 N hydrochloric acid (˜1 mL) until pH ˜3. After stirring for 45 min, the methanol was removed in vacuo, and the crude residue was brought up in ethyl acetate (75 mL) and saturated aqueous sodium bicarbonate (50 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organics were washed with brine (50 mL), dried over magnesium sulfate, filtered, and the solvent was removed in vacuo to give the crude product as white solid. Purification by silica gel chromatography (20-80% ethyl acetate in hexanes) gave methyl 1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carboxylate (99% yield) as a white solid.
Reaction SMILES: [K].[C:2]([O:5][C:6]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([OH:27])(=O)=[O:25])=[CH:20][CH:19]=2)=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:4])[CH3:3].CN(C)C=O.S(Cl)([Cl:35])=O.[OH-].[Na+]>ClCCl.O>[C:2]([O:5][C:6]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([Cl:35])(=[O:27])=[O:25])=[CH:20][CH:19]=2)=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:4])[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc(C=Cc2ccc(S(=O)(=O)O)cc2)ccc1OC(C)=O
Agent: [K]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C=Cc2ccc(S(=O)(=O)Cl)cc2)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 2-acetyloxy-5-[2-(4-sulfophenyl)ethenyl]benzoate potassium salt (42.4 g, 0.104 mol) was suspended in dichloromethane. Dimethylformamide (5 ml) and thionyl chloride were added, and the mixture refluxed with sniffing for 3 h. After cooling to room temperature, water (15 ml) was added. By careful addition of 5M sodium hydroxide, the pH of the aqueous phase was adjusted to about 7. The phases were separated and the organic phase washed with water. The solution was dried (MgSO4), treated with activated carbon and filtered. After evaporation of the solvent, the solid residue was recrystallized from a toluene and petroleum ethermixture. Yield 29.3 g (71%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[OH:40][C@@H:41]([C:45]([CH3:48])([CH3:47])[CH3:46])[C:42](O)=[O:43].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:42](=[O:43])[C@@H:41]([OH:40])[C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC(C)(C)[C@H](O)C(=O)O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.3 %

Procedure:
A solution of the product of Example 2C (0.020 g, 0.038 mmol) in tetrahydrofuran (0.40 mL) was treated with (s)-(−)-2-hydroxy-3,3-dimethylbutyric acid (0.006 g, 0.045 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.201 mmol), stirred at 25° C. for 2 hours and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic layer was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with ethyl acetate to give the title compound (0.005 g, 21% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.70 (s, 9 H), 0.79 (s, 9 H), 1.42-1.54 (m, 2 H), 2.71-2.76 (m, 3 H), 3.42 (d, J=5.9 Hz, 1 H), 3.48 (s, 3 H), 3.61-3.67 (m, 1 H), 3.82 (d, J=9.9 Hz, 1 H), 4.10-4.21 (m, 2 H), 4.98 (d, J=5.5 Hz, 1 H), 5.33 (d, J=5.8 Hz, 1 H), 6.65 (d, J=9.6 Hz, 1 H), 7.09-7.24 (m, 9 H), 7.28-7.32 (m, 1 H), 7.80 (d, J=8.5 Hz, 1 H), 7.84-7.89 (m, 4 H), 8.62 (m, 1 H).
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[CH:4]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:7][C:8]=1[F:9].[Cl:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[C:30]2[CH2:34][CH3:35])[N:24]=[N:25][CH:26]=1>>[ClH:20].[F:19][CH:2]([F:1])[C:3]1[CH:4]=[C:5]([C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[C:30]3[CH2:34][CH3:35])[N:24]=[N:25][CH:26]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CCc1nccn1CCc1cc(Cl)cnn1
Reactant: CC1(C)OB(c2ccc(F)c(C(F)F)c2)OC1(C)C
Product: CCc1nccn1CCc1cc(-c2ccc(F)c(C(F)F)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=333.3 (M+H+), was prepared from 2-(3-difluoromethyl-4-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-ethyl-imidazol-1-ylethyl)-pyridazine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[CH:4][N:3]=1.Cl.[F:11][C:12]1([F:17])[CH2:16][CH2:15][NH:14][CH2:13]1.C(N(C(C)C)C(C)C)C.FC(F)(F)C(O)=O.CN([CH:37]=[C:38]([N:44]1[CH:48]=[C:47]([C:49]#[N:50])[N:46]=[CH:45]1)[C:39](OCC)=[O:40])C.Cl>O>[F:11][C:12]1([F:17])[CH2:16][CH2:15][N:14]([C:2]2[N:3]=[CH:4][N:5]=[C:6]([N:8]3[C:39](=[O:40])[C:38]([N:44]4[CH:48]=[C:47]([C:49]#[N:50])[N:46]=[CH:45]4)=[CH:37][NH:9]3)[CH:7]=2)[CH2:13]1
Reactant: NNc1cc(Cl)ncn1
Reactant: CCOC(=O)C(=CN(C)C)n1cnc(C#N)c1
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cn(-c2c[nH]n(-c3cc(N4CCC(F)(F)C4)ncn3)c2=O)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 200 mg (1.4 mmol) of the compound from Example 11A, 238 mg (1.7 mmol) of 3,3-difluoropyrrolidine hydrochloride and 289 μl (215 mg, 1.7 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine in 3 ml of water is stirred at 100° C. for 16 h. Following the addition of 53 μl (79 mg, 0.7 mmol) of trifluoroacetic acid and 324 mg (1.4 mmol) of the compound from Example 6A, the reaction mixture is stirred at 100° C. for 16 h. 1 ml of 1 N hydrochloric acid is added to the reaction mixture. The resulting precipitated hydrochloride of the crude product is filtered off, washed with diethyl ether and dried. The crude product still contains unreacted starting material (compound from Example 11A). Accordingly, the crude product is reacted with 108 μl (80 mg, 0.6 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine, 10 mg (0.1 mmol) of 3,3-difluoropyrrolidine hydrochloride and 2 ml of water in a single mode microwave (Emrys Optimizer) at 170° C. for 15 min The reaction solution purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 30 mg (6% of theory)
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH3:19][Si:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:22])[CH3:21].CI>C1COCC1>[CH3:19][Si:20]([CH3:22])([CH3:21])[CH:23]([CH3:1])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C[Si](C)(C)C
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To a solution of 21.8 mL (0.156 mole) of diisopropylamine in 100 mL of THF at 0° was added 0.156 mole of butyl lithium/hexane. After 30 minutes at 0°, the solution was cooled to -78°, and 25 g (0.156 mole) of ethyl trimethylsilylacetate was added. After 30 minutes at -78°, 22.7 g (10 mL, 0.16 mole) of methyl iodide was added. After warming to room temperature, the mixture was filtered, and the filtrate was evaporated. The residue was treated with hexane and filtered under argon The hexane layer of the filtrate was concentrated and distilled in a small Vigreux column to give 12 g of ethyl 2-trimethylsilylpropionate, b.p. 61.4°/15 mm.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[CH:11]=[C:10](I)[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.C([Sn](CCCC)(CCCC)[C:18]1[N:22]([CH3:23])[CH:21]=[N:20][C:19]=1[I:24])CCC>CN(C=O)C.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>[I:24][C:19]1[N:20]=[CH:21][N:22]([CH3:23])[C:18]=1[C:10]1[S:9][C:5]2[N:6]=[CH:7][N:8]=[C:3]([S:2][CH3:1])[C:4]=2[CH:11]=1
Reactant: CSc1ncnc2sc(I)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(I)ncn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CSc1ncnc2sc(-c3c(I)ncn3C)cc12
Temperature: 100 °C
Yield: 67.3 %

Procedure:
4-Methylthio-6-iodo-thieno[2,3-d]pyrimidine (Intermediate 91) (949 mg), 5-tributylstannyl-4-iodo-1-methyl-1H-imidazole (Intermediate 92) (2.76 g) and tetrakis(triphenylphosphine)palladium(0) (178 mg) were stirred in anhydrous DMF (50 mL), degassed with nitrogen for 10 min, then heated to 100° C. for 18 hours under an inert atmosphere. The reaction mixture was concentrated in vacuo and the crude product triturated with DCM (20 mL) to afford the title compound as a yellow solid (805 mg, 67%);
Reaction SMILES: C([O-])(=O)C.[Na+].[N+:6]([C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][NH:13]2)([O-:8])=[O:7].C(Cl)(Cl)Cl.[Br:22]Br>C(O)(=O)C>[Br:22][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[N+:6]([O-:8])=[O:7])[NH:13][N:12]=1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a flask equipped with a mechanical stirrer was added sodium acetate (26.4 g, 0.306 mol), 4-nitro-1H-indazole (50 g, 0.306 mol), 300 mL of acetic acid and 300 mL of chloroform. Bromine (51.4 g, 0.322 mol) in 60 mL of acetic acid was added to the reaction mixture over 3.5 hours, while the temperature was kept under 25° C. The reaction mixture was stirred for two hours, then concentrated under reduced pressure. Water (500 mL) was added to the resulting solids. The solids were collected by filtration, washed with 500 mL of water, and dried under vacuum to give 68 g (92%) of 3-bromo-4-nitro-1H-indazole.