Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[N:27]([CH2:35][CH2:36][CH:37]([OH:39])[CH3:38])[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:34][C:30]1[CH:29]=[C:28]2[C:33]([C:25]([C:22]3[N:21]=[C:20]4[C:16]([C:14]([NH:13][C:10]([CH3:11])([CH3:12])[CH2:9][OH:8])=[O:15])=[CH:17][NH:18][C:19]4=[N:24][CH:23]=3)=[N:26][N:27]2[CH2:35][CH2:36][CH:37]([OH:39])[CH3:38])=[CH:32][CH:31]=1
Reactant: CC(O)CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(O)CCn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CO)c3n2)c2ccc(F)cc21
Reaction time: 1 h
Yield: 45 %

Procedure:
To a stirred solution of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1-(3-hydroxybutyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide in dichloromethane (2 mL) was added drop-wise trifluoroacetic acid (1 mL) at room temperature and the reaction mixture was stirred for 1 hour. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and washed with NaHCO3 (aqueous), The organic layer was concentrated, and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 36% acetonitrile/64% water (0.1% trifluoroacetic acid, v/v) initially, and then proceed to 42% acetonitrile/58% water (0.1% trifluoroacetic acid, v/v) in a linear fashion after just 9 min.) to give 2-(6-fluoro-1-(3-hydroxybutyl)-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (10 mg, 45% over three steps) as a white solid. LCMS: (M+H)+=441; 1H NMR (300 MHz, CD3OD): δ 9.15 (s, 1H), 8.58 (dd, 1H, J1=9. Hz, J2=5.4 Hz), 8.29 (s, 1H), 7.42 (d, 1H, J=7.8 Hz), 7.10 (d, 1H, J=7.2 Hz), 4.62-4.56 (m, 2H), 3.82 (s, 2H), 3.76 (brs, 1H), 2.19-2.13 (m, 2H), 2.04-1.99 (m, 2H), 1.55 (s, 6H), 1.22 (d, 3H, J=6.3 Hz).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[CH3:12][O:13][C:14](=[O:19])[C:15](Cl)=[N:16]O>C1(C)C=CC=CC=1>[CH2:8]([O:7][C:1]([C:2]1[C:15]([C:14]([O:13][CH3:12])=[O:19])=[N:16][O:4][C:3]=1[CH3:5])=[O:6])[CH3:9]
Reactant: COC(=O)C(Cl)=NO
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C(=O)OC)noc1C
Reaction time: 3 h

Procedure:
At room temperature, 39.0 g (0.3 mol) of ethyl acetoacetate in 100 ml of toluene was dripped into 9.9 g (0.33 mol) of NaH (80% strength suspension in white oil), and the mixture was stirred for 3 hours. Subsequently, 41.3 g (0.3 mol) of methyl-α-chloro-α-oximinoacetate in 100 ml of toluene was added and the mixture was stirred for 12 hours at room temperature. The reaction mixture was then transferred to a Soxhlet apparatus (extraction tube filled with 4 Å molecular sieve), 1 g of methanesulfonic acid was added and the mixture was refluxed for 1.5 hours. After the mixture had cooled, the organic phase was washed once with 200 ml of disodium bicarbonate solution and once with 200 ml of saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was stripped off under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19]C1C2C(=CC=CC=2)C=CC=1.C(N(CC)CC)C.N1C=CC=CC=1S([O-])(=O)=O>ClCCl.CS(C)=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH:18]=[O:19]
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCOc1cccc2ccccc12
Agent: O=S(=O)([O-])c1ccccn1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCC=O
Reaction time: 3 h

Procedure:
To a solution of ethyl 7-bromo-3-(4-hydroxypropyl)-1H-indole-2-carboxylate (EXAMPLE 1C) (3.4 g) and triethylamine (8.5 ml) in dichloromethane (100 ml) and dimethylsulfoxide (10 mL), cooled to 0° C., was added pyridine-2-sulfonate (9.54 g). The mixture was stirred for 3 hours and diluted with ethyl acetate (300 ml) and washed with 5% HCl, water, and brine. After drying the combined organic layers over Na2SO4, the filtrate was concentrated and the crude product was purified by flash chromatography on a silica gel, eluting with 10% ethyl acetate in hexane.
Reaction SMILES: O.[NH2:2][C:3]1[C:4](=[O:13])[N:5]([CH3:12])[C:6](=[O:11])[N:7]([CH3:10])[C:8]=1[NH2:9].[C:14]([CH2:16][C:17](O)=[O:18])#[N:15]>CC(C)=O>[C:14]([CH2:16][C:17]([NH:2][C:3]1[C:4](=[O:13])[N:5]([CH3:12])[C:6](=[O:11])[N:7]([CH3:10])[C:8]=1[NH2:9])=[O:18])#[N:15]
Reactant: N#CCC(=O)O
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Solvent: CC(C)=O
Solvent: O
Product: Cn1c(N)c(NC(=O)CC#N)c(=O)n(C)c1=O
Temperature: 25 °C

Procedure:
A mixture of 5,6-diamino-1,3-dimethyluracil hydrate (19.0 g, 0.11 mole) and cyanoacetic acid (19.0 g, 0.22 mole) is heated to 120°-130° C. under a nitrogen atmosphere. The mixture melts and resolidifies within thirty minutes. The resolidified residue is cooled to room temperature and is taken up in acetone. The residue is collected on a filter, recrystallized in water using decolorizing carbon, dried, and triturated under vacuum to yield 5-cyanoacetamido-6-amino-1,3-dimethyluracil as a solid (14.2 g; 54%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[C:8]([F:11])([F:10])[F:9].Cl.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](Cl)=[O:20]>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([NH:7][C:19](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)=[N:4][C:3]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Nc1nc(C(F)(F)F)c(Br)s1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1nc(C(F)(F)F)c(Br)s1)c1ccccn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of 5-bromo-4-(trifluoromethyl)thiazol-2-amine (0.204 g, 0.826 mmol) ethyldiisopropylamine (0.36 mL, 2.1 mmol) in methylene chloride (4 mL) at 0° C. was added picolinoyl chloride hydrochloride (0.162 g, 0.908 mmol) and the reaction mixture was stirred at room temperature for 15 h. The reaction mixture was diluted with methylene chloride and washed with saturated NaHCO3, dried, filtered and concentrated under vacuum to give the crude product. The residue was purified by column chromatography eluting with ethyl acetate/hexanes 0 to 30% to give the product.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[SH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Cl)s1
Reactant: Sc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2ccccn2)s1
Temperature: 130 °C
Yield: 75.6 %

Procedure:
A mixture of 2-acetylamino-5-chlorothiazole (5.3 g), 2-mercaptopyridine (3.5 g) and potassium carbonate (6.2 g) in N,N-dimethylformamide (50 ml) was heated at 130° C. for 3.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-acetylamino-5-(2-pyridylthio)thiazole (5.70 g, yield: 76.0%). mp: 185°-188° C. (dec.)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([NH2:14])=[O:13])=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[CH2:15](OC(OCC)OCC)C>>[F:10][C:8]([F:11])([F:9])[C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:15][NH:14][C:12](=[O:13])[C:3]=2[N:4]=1
Reactant: NC(=O)c1nc(C(F)(F)F)ccc1N
Reactant: CCOC(OCC)OCC
Product: O=c1[nH]cnc2ccc(C(F)(F)F)nc12
Yield: 95.37 %

Procedure:
6.8 g (0.0332 mol, 1 eq) of 3-amino-6-trifluoromethyl-pyridine-2-carboxylic acid amide in 170 ml of triethylorthoformate under nitrogen was heated at 145° C. for 8 h. Excess triethylorthoformate was removed under reduced pressure and the solid product obtained was washed with pet-ether and dried under vacuum to get 6.8 g (95.37%) of white solid. 1H NMR (CDCl3, 400 MHz): 8.11 (1H, d), 8.35 (1H, d), 12.28 (1H, bs). MS 216 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:27])[CH:8]=2)[N:3]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1.C(O)(=O)C>CN1CCCC1=O.CN(C)C1C=CN=CC=1>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:35][C:2]2[N:11]=[C:10]([NH:12][C@H:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]3[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:27])[CH:8]=3)[N:3]=2)=[CH:32][CH:31]=1
Reactant: Cc1ccc2nc(Cl)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Reactant: COc1ccc(CN)cc1
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: COc1ccc(CNc2nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c3cc(C)ccc3n2)cc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 101.4 %

Procedure:
To a solution of 4.00 g of tert-butyl (1R,2S)-2-[(2-chloro-6-methylquinazolin-4-yl)amino]cyclohexylcarbamate and 5.91 g of 4-methoxybenzylamine in 30 ml of N-methyl-2-pyrrolidone, 100 mg of 4-dimethylaminopyridine was added, and then the mixture was stirred at 110° C. for 24 hours. The reaction solvent was mixed with an aqueous 5% acetic acid solution and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain 5.10 g of the desirable compound.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([S:17]([CH2:20][C@@H:21]([N:25]1[C@H:30]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C@@H:29]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=2)[CH2:28][C@@:27]([CH2:46][C:47]([OH:49])=O)([CH3:45])[C:26]1=[O:50])[CH:22]1[CH2:24][CH2:23]1)(=[O:19])=[O:18])([CH3:16])([CH3:15])[CH3:14].[NH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[C:13]([S:17]([CH2:20][C@@H:21]([N:25]1[C@H:30]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C@@H:29]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=2)[CH2:28][C@@:27]([CH2:46][C:47]([NH:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[O:49])([CH3:45])[C:26]1=[O:50])[CH:22]1[CH2:23][CH2:24]1)(=[O:18])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)S(=O)(=O)C[C@H](C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(C)(C)S(=O)(=O)C[C@H](C1CC1)N1C(=O)[C@@](C)(CC(=O)Nc2ccccc2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC, 0.117 g, 0.612 mmol) was added to a solution of 2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (0.118 g, 0.204 mmol, Example 1, Step H) and aniline (0.020 mL, 0.225 mmol) at 0° C. After the addition was complete, the reaction mixture was removed from the ice bath and stirred at room temperature for 19 hours. The reaction mixture was diluted with ice-cold 1 M hydrochloric acid to adjust the pH to 1 and the solution was extracted twice with ether. The combined organic layer was washed with brine, dried over sodium sulfate, decanted and concentrated under a vacuum to provide an orange oil. Purification by flash chromatography (12 g SiO2 column, gradient elution of 15% to 100% ethyl acetate in hexanes provided the title compound as a white foam.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH2:7][CH:6]([C:21]([O:23]C)=[O:22])[CH2:5]1)(=[O:3])[CH3:2].CC(C)([O-])C.[K+]>CO>[C:1]([N:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([F:18])([F:20])[F:19])=[CH:12][CH:11]=2)[CH2:7][CH:6]([C:21]([OH:23])=[O:22])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(C)=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)N1CC(C(=O)O)CC(c2ccc(CC(F)(F)F)cc2)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 1.32 g (3.27 mmol) of the compound from Example 63A in methanol (73 ml) were added, at RT, 3.67 g (32.7 mmol) of potassium tert-butoxide. The mixture was stirred at 60° C. overnight. For workup, the methanol was removed under reduced pressure, and the residue was admixed with water and acidified (pH=1) with aqueous 1 N hydrochloric acid solution. The mixture was extracted with ethyl acetate, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 1.19 g (99% of theory)
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[N+:13]([O-])([OH:15])=[O:14].N>S(=O)(=O)(O)O>[N+:13]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:4]=1[O:3][C:2]([F:11])([F:12])[F:1])[NH2:8])([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: N
Agent: O=S(=O)(O)O
Product: Nc1ccc(OC(F)(F)F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 63 %

Procedure:
20 g (112.9 mmol) of 4-trifluoromethoxyaniline were dissolved in 50 ml of concentrated sulfuric acid at a temperature of 0 to 5° C., treated with 30 ml of a 4/1 mixture of sulfuric acid and nitric acid. The mixture was stirred for 5 hours at 0° C. and then poured into an ice-cold water mixture and made alkaline with 200 ml of concentrated aqueous ammonia solution. Extraction with EE, drying with sodium sulfate, evaporation to dryness and recrystallization from ethyl acetate/heptane gave 15.5 g (63%) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[C:16]([NH2:22])[N:15]=2)=[N:6]1.Cl[C:28]([O:30][CH3:31])=[O:29]>C(O)(C)C>[NH2:22][C:16]1[C:17]([NH:21][C:28](=[O:29])[O:30][CH3:31])=[C:18]([NH2:20])[N:19]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[F:1])[N:6]=2)[N:15]=1
Reactant: COC(=O)Cl
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1N
Solvent: CC(C)O
Product: COC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 35 °C
Yield: 90.8 %

Procedure:
In a reaction vessel, 1.50 kg of the compound of the formula (VI) were initially charged in 14.25 l of isopropanol, and the mixture was heated with stirring to 35° C. 531 g of methyl chloroformate were, at a steady rate, metered in over a period of 30 min, rinsing with 750 ml of isopropanol, and the mixture was stirred at 35° C. for 16 h. The mixture was then heated to 50° C. and 3.85 l of methanol and 606 g of triethylamine were metered in with stirring at 50° C., rinsing with 450 ml of methanol. The mixture was then stirred at 50° C. for 1 h, cooled to RT and stirred at RT for 1 h. The suspended solid was filtered off with suction, washed twice with in each case 3.0 l of isopropanol/methanol (4:1) and once with 3.0 l of isopropanol and sucked dry. The moist product was dried at 50° C. for 1 h and then at 100° C. for 22 h in a vacuum drying cabinet. The weight of the product obtained was 1.793 kg or 103.3% of theory. The product of the formula (VI) contained 6.45% of isopropanol virtually unremovable by drying (partially, an isopropanol solvate was present), and the analytical content was 87.9% by weight (HPLC). Based on this content, the yield was 90.8% of theory.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][C:21]1([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[OH-].[Na+]>C(O)C.O>[CH2:1]([O:3][CH2:4][C:5]1[N:19]([CH2:20][C:21]2([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(CNc2c(N)cnc3ccccc23)CCCCC1
Reactant: CCOCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(NC(=O)OC(C)(C)C)CCCCC1
Yield: 37 %

Procedure:
Ethoxyacetyl chloride (9.00 g, 73.4 mmol) was reacted with tert-butyl 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclohexylcarbamate (27.2 g, 73.4 mmol) according to the method described in Part E of Example 9 and the resulting product was treated according to the method described in Part E of Example 9. After the solvent was removed to yield an oil, the oil was dissolved in ethanol (300 mL) and water (30 mL). Sodium hydroxide (4.3 g, 108 mmol) was added and the solution was heated at reflux for 6 h. The volatiles were removed under reduced pressure and the resulting brown oil was partitioned between dichloromethane (500 mL) and water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a brown oil. Purification by flash chromatography (silica gel, 30% ethyl acetate/hexanes) provided tert-butyl 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexylcarbamate as a brown solid (11.9 g, 38%).
Reaction SMILES: [CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[O:21][C:20]=2[CH2:34][O:35][CH2:36][CH3:37])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[O:21][C:20]=2[CH2:34][O:35][CH2:36][CH3:37])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)OC)cc1)C1CCCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of cyclohexyl{2-(methoxymethyl)-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methanol (574 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (274 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (0.7 mL) and 1,1′-(azodicarbonyl)dipiperidine (757 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give methyl 4-(cyclohexyl{2-(ethoxymethyl)-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methoxy)benzoate as an amorphous compound. The obtained methyl 4-(cyclohexyl{2-(ethoxymethyl)-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methoxy)benzoate was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL). 2N Lithium hydroxide (1.0 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (289 mg, 38%) as an amorphous compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:36]([N:37]2[N:46]=[CH:45][C:44]3[C:39](=[C:40]([F:51])[CH:41]=[C:42]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH:43]=3)[C:38]2=[O:52])=[CH:35][CH:34]=[CH:33][C:32]=1[B-](F)(F)F)(=[O:28])[CH3:27].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O.C(O)CCC>[C:47]([C:42]1[CH:43]=[C:44]2[C:39](=[C:40]([F:51])[CH:41]=1)[C:38](=[O:52])[N:37]([C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([C:2]3[CH:3]=[C:4]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([CH2:18][N:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)=[CH:14][N:13]=4)[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[N:7]=3)[C:31]=1[CH2:30][O:29][C:26](=[O:28])[CH3:27])[N:46]=[CH:45]2)([CH3:48])([CH3:49])[CH3:50]
Reactant: CC(=O)OCc1c(-n2ncc3cc(C(C)(C)C)cc(F)c3c2=O)cccc1[B-](F)(F)F
Reactant: CN1CCN(Cc2ccc(Nc3cc(Cl)nn4ccnc34)nc2)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCCCO
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(CN4CCN(C)CC4)cn3)c3nccn3n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 100 °C

Procedure:
In a 50 mL test tube, 6-chloro-N-(5((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (170 mg, 475 μmol, Eq: 1.00) and potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate (225 mg, 475 μmol, Eq: 1.00) were combined with BuOH (10 ml) to give an orange solution. Water (2.5 ml) was added. X-PHOS (22.6 mg, 47.5 μmol, Eq: 0.1) and potassium phosphate tribasic (202 mg, 950 μmol, eq: 2) were added. Bis(dibenzylideneacetone)palladium (13.7 mg, 23.8 μmol, Eq: 0.05) was added. The tube was purged with argon and sealed. The solution was warmed in an oil bath at 100° C. for 1.5 hours. The solution was cooled to room temperature. The reaction mixture was poured into 75 mL H2O and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 50% to 100% (60:10:1 DCM:MeOH:NH4OH)/DCM gradient) to give a residue. The residue was triturated with Et2O. LC/MS analysis showed that the crude material was a mix of products: 12% 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{8-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-imidazo[1,2-b]pyridazin-6-yl}-phenyl)-2H-phthalazin-1-one and 88% acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{8-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-imidazo[1,2-b]pyridazin-6-yl}-benzyl ester by UV. (157 mg, 48%). The mixture was taken into the next reaction “as is.” LC/MS-ESI observed [M+H]+ 648 and 690.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]2[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=3)[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][NH:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClC(Cl)C>[CH2:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][N:28]1[CH2:25][C:21]1[CH:20]=[C:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([NH:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)[CH:14]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1cc(Nc2cccc(-c3cccc(C=O)c3)c2)c2ccccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cc(Nc2cccc(-c3cccc(CN4CCc5ccccc5C4)c3)c2)c2ccccc2n1
Reaction time: 19 h
Yield: 54.7 %

Procedure:
To a solution of 73 (102 mg, 0.301 mmol) in dichloroethane (3.0 mL) under N2 was added 40 (0.04 mL, 0.315 mmol). The reaction was stirred for 24 minutes before the sequential addition of NaBH(OAc)3 (94 mg, 0.444 mmol) and AcOH (0.02 mL, 0.349 mmol). The reaction was stirred for 19 hours and then extracted with ethyl acetate (2×30 mL). The ethyl acetate extracts were washed with 2 N NaOH (aq. 15 mL), brine (15 mL), dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (dichloromethane to 30:1 to 20:1 dichloromethane/methanol) to give the desired product as a yellow solid (75 mg, 55%).