Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7](C(O)=O)[N:8]=[CH:9][N:4]2[CH:3]=1.O.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Br:1][C:2]1[S:6][C:5]2=[CH:7][N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: O=C(O)c1ncn2cc(Br)sc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Brc1cn2cncc2s1
Temperature: 105 °C
Reaction time: 19 h
Yield: 91.5 %

Procedure:
2-Bromoimidazo[5,1-b]thiazole-7-carboxylic acid (0.52 g, 2.10 mmol) was suspended in a mixed solvent composed of water (4.0 ml) and acetic acid (6.0 ml). Concentrated hydrochloric acid (0.30 g, 3.04 mmol) was added to the suspension at room temperature, and the mixture was stirred at 105° C. for about 19 hr. After the completion of the reaction, sodium carbonate (0.44 g, 4.15 mmol) was added to the reaction solution, and the mixture was concentrated by removal of the solvent by distillation under the reduced pressure. Water (10 ml) was added to the concentrate. Further, the solvent was removed by distillation under the reduced pressure, and water (10 ml) and ethyl acetate (5 ml) were again added thereto. The mixture was adjusted to pH 6 by the addition of a 2 M aqueous solution of sodium hydroxide with stirring. After the separation, the aqueous layer was extracted twice with 5 ml of ethyl acetate. Thereafter, the organic layers were combined and were washed with 15 wt % brine (5 ml). While concentrating the washed organic layers, the solvent was replaced with methanol (3 ml), and 10 ml of water was added thereto to crystallize 2-bromoimidazo[5,1-b]thiazole. The crystallizing liquid was cooled to 5° C. or below and was stirred overnight. The crystals were then collected by filtration. The resultant precipitate was dried under the reduced pressure to give 2-bromoimidazo[5.1-b]thiazole (0.39 g, yield 91.4%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:27])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:10]2)[C:5](F)=[N:6][CH:7]=1.[CH3:28][O-:29].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:27])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:10]2)[C:5]([O:29][CH3:28])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(Br)cnc2F)C[C@@H](C(F)(F)F)O1
Reactant: C[O-]
Agent: [Na+]
Product: COc1ncc(Br)cc1[C@]1(C)C[C@@H](C(F)(F)F)OC(NC(=O)OC(C)(C)C)=N1
Temperature: 50 °C
Yield: 97 %

Procedure:
tert-Butyl ((4S,6S)-4-(5-bromo-2-fluoropyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)carbamate (5k, 0.500 g, 1.096 mmol, as described in Example 31, Method G, Step 9) was treated with sodium methanolate 25% MeOH (3 mL). The reaction was heated at 50° C. for 40 min. The reaction was quenched with water and methanol was removed by reduced pressure. The resulting mixture was extracted with EtOAc three times. The combined organic layers were dried on sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography using a gradient of 0-30% EtOAc/hexane to give tert-Butyl ((4S,6S)-4-(5-bromo-2-methoxypyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)carbamate (0.49 g, 97% yield). MS m/z=469.9 [M+H]+. Calculated for C17H21BrF3N3O4: 468.3
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]3[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22][N:21]3[C:17]=2[C:16]2[C:11](=[CH:12][C:13]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:14][CH:15]=2)[N:10]=1>ClCCl>[CH2:34]([O:33][C:13]1[CH:12]=[C:11]2[C:16]([C:17]3[N:21]4[CH2:22][CH2:23][NH:24][CH2:25][C:20]4=[N:19][C:18]=3[C:9]([NH2:8])=[N:10]2)=[CH:15][CH:14]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nc3c(N)nc4cc(OCc5ccccc5)ccc4c32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2cc(OCc3ccccc3)ccc2c2c1nc1n2CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (10 mL of a 10% solution in dichloromethane) was added to tert-butyl 6-amino-3-benzyloxy-10,11-dihydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate (0.550 g, 1.23 mmol), and the reaction was stirred at ambient temperature overnight. The solvent was removed under reduced pressure, and the residue was treated with hydrogen chloride (4 N in 1,4-dioxane). The solvent was removed under reduced pressure, and the residue was dissolved in methanol. Ammonia gas was bubbled through the resulting solution for 15 minutes, and then the solvent was removed under reduced pressure. The residue was dried overnight under vacuum to provide 3-benzyloxy-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine in a crude mixture, which was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:34])[NH:6]2.ClC(Cl)(Cl)[C:37]([N:39]=C=O)=[O:38]>N1C=CC=CC=1.CO>[C:37]([N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][CH2:25][O:24][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:10]4[C:2]([F:1])=[C:3]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([CH3:34])=[CH:4]5)=[N:13][CH:14]=[N:15]3)=[CH:20][C:19]=2[O:22][CH3:23])[CH2:29][CH2:30]1)(=[O:38])[NH2:39]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCNCC1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(C(N)=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinazoline (240 mg, 0.52 mmol), (prepared as described for the starting material in Example 15), was dissolved in pyridine (5 ml) and cooled to 0° C. Trichloroacetyl isocyanate (61 μl, 0.52 mmol) was added and the mixture stirred at ambient temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue dissolved in 7N ammonia in methanol and stirred at 45° C. for 2.5 hours. Aqueous ammonia (1 ml) was added and the mixture was stirred at 60° C. for 1.5 hours and then at ambient temperature overnight. The solvent was removed under reduced pressure. Column chromatography of the residue using methylne chloride/methanol (90/10) followed by methylene chloride/methanol (saturated with ammonia) (90/10) gave a solid which was suspended in methanol and filtered to give 7-(3-[4-carbamoylpiperazin-1-yl]propoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (120 mg, 46%) as a pale yellow solid.
Reaction SMILES: [OH:1]O.[NH2:3][C:4]1[C:5]([C:14]#[N:15])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[OH-].[Na+].CO>O>[NH2:3][C:4]1[C:5]([C:14]([NH2:15])=[O:1])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=1
Reactant: OO
Reactant: N#Cc1ncc(C(F)(F)F)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)c1ncc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 ml of a 30% aqueous hydrogen peroxide solution was added to a mixture of 100 mg of 3-amino-2-cyano-5-trifluoromethylpyridine, 2 ml of a 10% aqueous sodium hydroxide solution and 6 ml of methanol, under ice cooling, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with a 10% aqueous sodium thiosulfate solution and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 100 mg of 3-amino-5-trifluoromethylpyridine-2-carboxylic acid amide.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:6]([F:18])=[CH:5][C:4]=1[C:19]1[CH:27]=[C:26]2[C:22]([C:23]([C:34]#[N:35])=[N:24][N:25]2[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)=[CH:21][CH:20]=1)[CH3:2].[CH3:36][O-:37].[Na+]>CO>[CH3:36][O:37][C:34]([C:23]1[C:22]2[C:26](=[CH:27][C:19]([C:4]3[CH:5]=[C:6]([F:18])[C:7]([O:9][CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:15])[CH3:16])=[CH:8][C:3]=3[CH2:1][CH3:2])=[CH:20][CH:21]=2)[N:25]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[N:24]=1)=[NH:35]
Reactant: C[O-]
Reactant: CCc1cc(OCOCC[Si](C)(C)C)c(F)cc1-c1ccc2c(C#N)nn(C3CCCCO3)c2c1
Agent: [Na+]
Solvent: CO
Product: CCc1cc(OCOCC[Si](C)(C)C)c(F)cc1-c1ccc2c(C(=N)OC)nn(C3CCCCO3)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
To a solution of 6-[2-ethyl-5-fluoro-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carbonitrile (Preparation 6, 37.42 g, 75.6 mmol) in methanol (700 mL) was added sodium methoxide (12.21 g, 226.8 mmol) and the reaction mixture was then stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was partitioned between EtOAc (1 L) and water (500 mL). The organic layer was washed with water (500 mL), dried over MgSO4 and concentrated in vacuo to give the title compound as a gum (37.26 g) in a 94% yield.
Reaction SMILES: Br[CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]1=O.[CH3:10][NH:11][C:12]([NH2:14])=[S:13]>N1C=CC=CC=1>[CH3:10][NH:11][C:12]1[S:13][C:2]2[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=2[N:14]=1
Reactant: CNC(N)=S
Reactant: O=C1CCCC(=O)C1Br
Solvent: c1ccncc1
Product: CNc1nc2c(s1)C(=O)CCC2
Yield: 42.7 %

Procedure:
A solution of 2-bromo-cyclohexane-1,3-dione (8.0 g, 41.9 mmol) and methyl thiourea (3.77 g, 41.9 mmol) in pyridine (63 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum, extracted with CH2Cl2 /10% aq NaCl solution, dried, filtered, and concentrated under vacuum. Crystallization from EtOAc afforded the title compound as yellow crystals (3.26 g, 43%): mp 180-182° C. Anal. RP-HPLC: tR 8.4 min (0-60% MeCN, purity 100%). 1H-NMR (CDCl3): δ 7.90 (s, 1H, NH), 2.99 (s, 3H, CH3), 2.72 (t, 2H, J 6.1, CH2), 2.49 (t, 2H, J 6.1, CH2), 2.10 (qu, 2H, J 6.1, CH2). 13C-NMR (CDCl3): δ 191.0, 176.6, 168.0, 120.0, 37.5, 32.5, 27.7, 23.2. MS: (ESI+) m/z 183.07 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1([F:31])[CH2:17][CH2:16][CH:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([CH:15]1[CH2:14][CH2:13][C:12]([F:31])([F:11])[CH2:17][CH2:16]1)[C:21]1[CH:26]=[N:25][C:24]([C:27]([F:28])([F:29])[F:30])=[N:23][CH:22]=1)=[O:6]
Reactant: NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1)c1ccccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=448.1, tR (minutes, Method F)=2.95. [α]D20==+28.00 (c=1.5 mg/mL,CHCl3)
Reaction SMILES: [O:1]1[CH2:24][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH:13]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[S:14]1.[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>C(O)C>[C:25]([NH:29][CH2:24][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH:13]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[S:14]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: COc1ccc(OCC2CO2)c(C2Sc3ccccc3NC2=O)c1
Reactant: CC(C)(C)N
Solvent: CCO
Product: COc1ccc(OCC(O)CNC(C)(C)C)c(C2Sc3ccccc3NC2=O)c1
Yield: 93 %

Procedure:
3,4-Dihydro-2-[2-(2,3-epoxypropoxy)-5-methoxyphenyl]-3-oxo-2H-1,4-benzothiazine (compound No. 10, 0.8 g) and tert-butylamine (2.5 ml) are dissolved in ethanol (15 ml). The solution is refluxed for 1.5 hours, and after cooling, concentrated in vacuo. The residue is dissolved in chloroform, and the solution is washed with 2N HCl, water and N NaOH. The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo to give 0.9 g (93%) of the titled compound.
Reaction SMILES: [Na].Cl.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[C:12](#[N:15])[CH:13]=[CH2:14]>C(O)C>[NH2:15][C:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][CH:6]=2)[N:11]=1
Reactant: C=CC#N
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1ccc(N2CCC(N)=N2)cc1
Reaction time: 0.08 h

Procedure:
A 2.8 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 15.86 g. of p-methylphenylhydrazine hydrochloride is added followed in 5 minutes by 5.5 g. of acrylonitrile. The reaction mixture is refluxed for 18 hours, then is evaporated to dryness in vacuo. Water is added and the separated solid is collected by filtration. The solid is dissolved in dichloromethane and passed through a short column of a hydrous magnesium silicate. The effluent is refluxed with the gradual addition of hexane to separate a crystalline product. The entire crystallization step is repeated to give 3.4 g. of the product of the Example as colorless plates, m.p. 142°-143° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:22]I>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:22])[N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CI
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3[nH]ncc3c2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc2cc(Oc3ccc([N+](=O)[O-])cn3)ccc21
Reaction time: 3.5 h

Procedure:
To a solution of 5-(5-Nitro-pyridin-2-yloxy)-1H-indazole (1.0 g, 3.9 mmol) in 15 mL of DMF is added sodium hydride (3.9 mmol) and methyl iodide (20 mmol). The resulting mixture is stirred at room temperature to 50° C. for 1-6 hours. The mixture is diluted with water, extracted 3× with ethyl acetate, and the combined organic layers are dried over sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography eluting with ethyl acetate-hexanes, affords 5-(5-Nitro-pyridin-2-yloxy)-1-methyl-1H-indazole.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([CH:11]([CH3:15])[CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:16][C:17]1[C:22]([C:23](O)=[O:24])=[C:21]([CH3:26])[N:20]=[CH:19][N:18]=1>>[O:4]1[C:5]2([CH2:6][CH2:7][N:8]([CH:11]([CH3:15])[CH2:12][CH2:13][NH:14][C:23]([C:22]3[C:17]([CH3:16])=[N:18][CH:19]=[N:20][C:21]=3[CH3:26])=[O:24])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: CC(CCN)N1CCC2(CC1)OCCO2
Reactant: Cc1ncnc(C)c1C(=O)O
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC2(CC1)OCCO2
Yield: 69.7 %

Procedure:
Using general procedure E with 3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-butylamine (4.50 g, 21.0 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (3.20 g, 21.0 mmol), followed by purification by column chromatography on silica gel (2-10% MeOH/CH2Cl2) gave 4,6-dimethyl-pyrimidine-5-carboxylic acid [3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-butyl]-amide (5.10 g, 73%).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:19][C:20]3[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=3)=[CH:13][C:9]=2[C:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].CO>O>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:19][C:20]3[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=3)=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: Cn1cncc1CC(Oc1ccc(CCc2ccc(F)cc2)c(C(=O)[O-])c1)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1cncc1CC(Oc1ccc(CCc2ccc(F)cc2)c(C(=O)O)c1)c1ccc(F)cc1
Yield: 73.2 %

Procedure:
A mixture of 2-(4-fluorophenethyl)-5-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]benzoate (1.5 g.), sodium hydroxide (0.62 g.), methanol (200 ml.) and water (30 ml.) was stirred at reflux for 16 hours. The mixture was then cooled, the methanol evaporated away and the residue diluted with water (100 ml.). It was then washed with dichloromethane and the aqueous phase separated, acidified with 1M aqueous citric acid (25 ml.) and extracted with dichloromethane. The extracts were dried and evaporated to dryness to give 2-(4-fluorophenethyl)-5-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]benzoic acid as a white foam (1.1 g).
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([NH2:24])(=[O:23])[CH2:21][CH3:22].CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>CC(O)C>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[CH2:11][CH2:10][C:9]=1[NH:24][C:20](=[O:23])[CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc2C1Cc1ccccc1
Reactant: CCC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCC(=O)NC1=C(Cc2ccccc2)c2cc(Br)ccc2CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
In a three-necked flask equipped with a Dean-Stark apparatus, heating mantle and magnetic stirrer were charged 1-benzyl-7-bromo-3,4-dihydronaphthalen-2(1H)-one (23.50 g, 74.6 mmol), propionamide (13.62 g, 186 mmol) and 4-methylbenzenesulfonic acid (1.284 g, 7.46 mmol) followed by toluene (200 ml). The resulting solution was heated to reflux overnight and monitored by HPLC (<6% starting material remained). The reaction mixture was cooled to r.t. and a suspension formed. To the mixture was added IPA and the resulting suspension was cooled to 0° C., stirred at 0° C. for 2 hours and filtered. The filtrate was concentrated and the residue was suspended in IPA/EtOH (50 ml/50 ml) at 0° C. for 1 hr and filtered to give additional product as a white solid. HPLC analysis indicated that both crops have similar purity. The solids were combined and further dried to give 22.5 g product as white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:21](CC2C=CC(OC)=CC=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:37]1([NH2:44])[CH2:42][CH2:41][C@H:40]([NH2:43])[CH2:39][CH2:38]1>C(O)(C(F)(F)F)=O>[NH2:43][C@H:40]1[CH2:41][CH2:42][C@H:37]([NH:44][C:2]2[CH:3]=[C:4]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=4)=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:38][CH2:39]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C(=O)Nc4ccnc(C)c4)cnc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NC(=O)c2cnc3c(Nc4ccccc4)cc(N[C@H]4CC[C@H](N)CC4)nn23)ccn1
Temperature: 70 °C

Procedure:
6-Chloro-8-((4-methoxybenzyl)(phenyl)amino)-N-(2-methylpyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (100 mg, 0.201 mmol) and (trans)-cyclohexane-1,4-diamine (9459 mg, 4.016 mmol) were heated at 160° C. for 1 hour. The reaction mixture was dissolved in TFA (5 mL) and heated at 70° C. for 2 hours. The reaction mixture was concentrated, dissolved in methanol and purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA) to afford 6-((trans-4-aminocyclohexyl)amino)-8-anilino-N-(2-methyl-4-pyridinyl)imidazo[1,2-b]pyridazine-3-carboxamide (39 mg, 48.5% yield) as a white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=1.320 minutes, [M+H]=457.28. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.35-11.58 (1H, m), 9.33 (1H, s), 8.48-8.74 (1H, m), 8.14 (1H, s), 7.93-8.04 (1H, m), 7.87 (3H, d, J=4.28 Hz), 7.59-7.81 (1H, m), 7.31-7.52 (3H, m), 7.07-7.26 (1H, m), 6.87-7.06 (1H, m), 6.29 (1H, s), 3.53-3.77 (1H, m), 2.93-3.22 (1H, m), 2.65 (3H, s), 2.05-2.25 (2H, m), 1.87-2.09 (2H, m), 1.09-1.52 (4H, m).
Reaction SMILES: [N:1]1([C:10]2[C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:12][C:13]3[C:18]([N:19]=2)=[CH:17][C:16]([C:20]([O:22]C)=[O:21])=[CH:15][CH:14]=3)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+]>CO.O>[N:1]1([C:10]2[C:11]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[N:12][C:13]3[C:18]([N:19]=2)=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][CH:14]=3)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(-n3ccc4ccccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-n3ccc4ccccc43)nc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(1H-indol-1-yl)-2-phenylquinoxaline-6-carboxylate (40 mg, 0.11 mmol, 1.00 equiv) in methanol (10 mL). A solution of sodium hydroxide (21.1 mg, 0.53 mmol, 5.00 equiv) in H2O (2 mL) was added. The resulting solution was stirred for 2 hrs at 50° C. in an oil bath. The resulting mixture was concentrated in vacuo. The resulting solution was diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with aq. 1N hydrogen chloride. The resulting solids were collected by filtration. The crude product (50 mL) was further purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, H2O/CH3CN=100:1 increasing to H2O/CH3CN=100:60 within 40 min; Detector, UV 254 nm. This resulted in 15 mg (38%) of 3-(1H-indol-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][CH:10]1[C:40]1[C:48]2[O:47][CH2:46][CH2:45][C:44]=2[C:43]([Cl:49])=[C:42]([CH2:50]Br)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:58][O:59][C:60]1[CH:65]=[CH:64][C:63](B(O)O)=[CH:62][CH:61]=1>CC(C)=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:49][C:43]1[C:44]2[CH2:45][CH2:46][O:47][C:48]=2[C:40]([CH:10]2[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:11]2)=[CH:41][C:42]=1[CH2:50][C:63]1[CH:64]=[CH:65][C:60]([O:59][CH3:58])=[CH:61][CH:62]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Clc1c(CBr)cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2c1CCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)CCO3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a mixture of compound 49 (623 mg, 0.81 mmol), K2CO3 (447 mg, 3.24 mmol) and 4-methoxyphenyl boronic acid (306 mg, 2.02 mmol) in acetone (7.5 mL) and H2O (2.5 mL) was added bis(triphenylphosphine)palladium chloride (56 mg, 0.08 mmol) at 0° C. under atmosphere of nitrogen. The mixture was stirred at 0° C. for 30 min and then, stirred at room temperature for 16 hours. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 50 (407 mg, 62%) as colorless oil.