Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[CH3:31][O:32][C:33](=[O:43])[C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:38](=[O:39])[C:37]3[CH:36]=[CH:35][C:34]([C:33]([O:32][CH3:31])=[O:43])=[CH:42][CH:41]=3)=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)Nc2ccc(Cn3c(C(=O)OC)c(-c4ccccc4)c4cc(Br)ccc4c3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.9 %

Procedure:
To a solution of 2-(4-aminobenzyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (139 mg) in dichloromethane (5 ml) were added terephthalic acid monomethyl ester (65 mg), 1-hydroxy-1H-benzotriazole (64 mg) and dimethylpyridin-4-yl-amine (51 mg), and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (103 mg) was added at room temperature. The mixture was stirred at room temperature for 15 hrs. Dichloromethane was added, and the mixture was washed with 1N hydrochloric acid and saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol=1/0-+9/1) to give the title compound (103 mg, 55%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)=[CH:7][CH:6]=1.[O-:29][C:30]#[N:31].[K+]>C(O)(=O)C>[CH3:25][C:21]1[CH:20]=[C:19]([NH:18][C:16]2[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([CH2:4][NH:3][C:30]([NH2:31])=[O:29])=[CH:6][CH:7]=3)[N:17]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cccc(Nc2nc(Nc3ccc(CN)cc3)ncc2C(N)=O)c1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1cccc(Nc2nc(Nc3ccc(CNC(N)=O)cc3)ncc2C(N)=O)c1
Reaction time: 6 h
Yield: 32.3 %

Procedure:
A 20 ml acetic acid-10 ml THF mixed solution containing 500 mg of 2-{[4-(aminomethyl)phenyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamide dihydrochloride was mixed with 5.76 g of potassium cyanate, which was added by dividing into 6 portions, at room temperature, followed by stirring for 6 hours. The reaction mixture was concentrated and then poured into water, and the precipitated solid was collected by filtration and washed with acetonitrile. The resulting solid was purified by a silica gel column chromatography (chloroform:methanol) to obtain 150 mg of 4-[(3-methylphenyl)amino]-2-[(4-ureidomethylphenyl)amino]pyrimidine-5-carboxamide as a pale yellow solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[F:39][C:40]([F:56])([F:55])[C:41]1[CH:42]=[C:43]([S:51](Cl)(=[O:53])=[O:52])[CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1>O1CCCC1>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:51]([C:43]3[CH:44]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:46]=[C:41]([C:40]([F:39])([F:55])[F:56])[CH:42]=3)(=[O:53])=[O:52])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
Diisopropylethylamine (0.6 mL, 3.4 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 150 mg, 0.36 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 min. 3,5-Bis(trifluoromethyl)benzenesulfonyl chloride (available from Sigma-Aldrich; 169 mg, 0.54 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. Ethyl acetate was added and the mixture was washed with aqueous NaHCO3 (5 mL) and water (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using a Biotage purification system, eluting with 10% ethyl acetate/hexanes, to give {4-[1-(3,5-bis-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (87 mg, 42%) as an off-white solid. MS cald. for C26H23F7NO4S [(M+H)+]: 578, obsd. 578.4.
Reaction SMILES: O[C:2]1([C:18]2[C:19](=[O:26])[NH:20][C:21](=[O:25])[N:22]([CH3:24])[CH:23]=2)[C:8]2[N:9]=[C:10]([CH3:12])[S:11][C:7]=2[CH2:6][CH2:5][C:4]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:3]1=2>C(O)(=O)C>[CH3:24][N:22]1[CH:23]=[C:18]([CH:2]2[C:8]3[N:9]=[C:10]([CH3:12])[S:11][C:7]=3[CH:6]=[CH:5][C:4]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:3]2=3)[C:19](=[O:26])[NH:20][C:21]1=[O:25]
Reactant: Cc1ccc2c(c1)CCc1sc(C)nc1C2(O)c1cn(C)c(=O)[nH]c1=O
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C=Cc1sc(C)nc1C2c1cn(C)c(=O)[nH]c1=O

Procedure:
A solution of the product from example 18 step (iii) (0.111 g) in glacial acetic acid (5 ml) was stirred at 100° C. for 3 h and evaporated. Purification of the residue was by flash chromatography, eluting with 40% acetone in isohexane to give the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([C:23]#[CH:24])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+].Br[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[Cl:45]>CN(C)C=O.[Pd].[Cu]I>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([C:23]#[C:24][C:43]1[CH:42]=[CH:41][C:40]([Cl:45])=[CH:39][CH:44]=1)=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: Clc1ccccc1Br
Reactant: C#Cc1ccc2[nH]c3cnc(C(=O)OC(C)C)c(COC)c3c2c1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(C#Cc4ccc(Cl)cc4)cc3c12

Procedure:
250 mg of 6-ethinyl-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester is mixed in 8 ml of dimethylformamide with 2 ml of triethylamine, 118 mg of anhydrous potassium carbonate, 22 mg of tetrakis (triphenylphosphine)-palladium(O), 7 mg of copper(I)iodide and 149 mg of 4-bromochlorobenzone and then the mixture is heated for 4 hours to 110° C. Then bromochlorobenzene, copper(I)iodide and palladium catalyst are added again and heated for 3 hours to 120° C. solution temperature. After concentration by evaporation it is taken up in ethyl acetate, washed in succession with saturated sodium carbonate and common salt solution each, dried, filtered and concentrated by evaporation. The residue is chromatographed twice in succession on silica gel, first with the mobile solvent toluene:ethanol:water=80:20:1 and then with the mobile solvent methylene chloride:ethanol=12:1, and the corresponding fractions are combined and used in the next chromatography. 120 mg of 6-(4-chlorophenylethinyl)-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester, melting point of 220°-221° C., is obtained.
Reaction SMILES: [C:1]([CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:22]([CH3:23])[N:21]=[CH:20][C:19]=2[NH:24][C:25]([C:27]2[N:28]=[C:29](Br)[S:30][C:31]=2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:26])[C@@H:13]([NH2:41])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH:42]1([C:45]2[CH:46]=[C:47]([CH3:63])[C:48]([F:62])=[C:49](B3OC(=O)CN(C)CC(=O)O3)[CH:50]=2)[CH2:44][CH2:43]1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:22]([CH3:23])[N:21]=[CH:20][C:19]=2[NH:24][C:25]([C:27]2[N:28]=[C:29]([C:49]3[CH:50]=[C:45]([CH:42]4[CH2:43][CH2:44]4)[CH:46]=[C:47]([CH3:63])[C:48]=3[F:62])[S:30][C:31]=2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:26])[C@@H:13]([NH2:41])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCCC(C(=O)OCc2ccccc2)C[C@@H]1N
Reactant: Cc1cc(C2CC2)cc(B2OC(=O)CN(C)CC(=O)O2)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(C2CC2)cc(-c2nc(C(=O)Nc3cnn(C)c3N3CCCC(C(=O)OCc4ccccc4)C[C@@H]3N)c(NC(=O)OC(C)(C)C)s2)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
In a microwave reaction vessel, (R)-tert-butyl 4-(5-(4-Cbz-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate (130 mg, 0.2 mmol), 2-(5-cyclopropyl-2-fluoro-3-methylphenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (167 mg, 0.55 mmol), S-Phos (13.2 mg, 0.032 mmol) and palladium acetate (3.6 mg, 0.016 mmol) were dissolved in 1,4-dioxane (4.0 mL). The cap was closed and the reaction vessel was vacuum purged with nitrogen three times. Potassium phosphate (3.0M aq., 0.27 mL, 0.81 mmol, degassed before use) was added and mixture was stirred at room temperature for 10 min before heated under microwave at 120° C. for 20 min. The mixture was diluted with methanol and filtered through a pad of Celite and washed with copious amount of methylene chloride. The filtrate was concentrated in vacuo and purified on flash chromatography (Isco Co.) eluted with 0 to 5% methanol in methylene chloride to give (R)-tert-butyl 4-(5-(4-Cbz-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(5-cyclopropyl-2-fluoro-3-methylphenyl)thiazol-5-ylcarbamate (82 mg, 57%).
Reaction SMILES: C([C:4]1[NH:12][C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=1)CC.[H-].[Na+].C(OC(C1C=CC=CC=1C1C=CC(CBr)=CC=1)=O)(C)(C)C>O>[NH:12]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1
Reactant: CCCc1cc2cccnc2[nH]1
Agent: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: c1cnc2[nH]ccc2c1
Reaction time: 0.33 h

Procedure:
To a mixture of 2-propyl-1H-pyrrolo[2,3-b]-pyridine prepared in Example 1 step 3 (0.1M in DMF) is added NaH (1.1 equivalent of an 80% dispersion in oil, 0.271 mmol). After 20 min, 2-t-butoxycarbonyl-4'-bromomethylbiphenyl (1.1 equivalent) is added and the mixture is stirred for 30 min. Water is added and the mixture extracted with EtOAc. Purification by flash chromatography (SiO2, 25% EtOAc/hexanes) gives 2-propyl-1-[(2'-t-butoxycarbonyl)-[1,1']-biphenyl-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[CH:34]([N:37]([CH:41]([CH3:43])[CH3:42])[CH2:38][CH2:39]Cl)([CH3:36])[CH3:35].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:39][CH2:38][N:37]([CH:41]([CH3:43])[CH3:42])[CH:34]([CH3:36])[CH3:35])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N(CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21)C(C)C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.458 g) is dissolved in DMF (10 mL), and K2CO3 (0.69 g) and 2-(diisoproplyamino)ethyl chloride hydrochloride (0.50 g) are added. The reaction mixture is heated to 90° C. for 2 h, then allowed to stir at room temperature overnight. A drop of water is added and the mixture is heated for 20 h. An additional equivalent of 2-(diisoproplyamino)ethyl chloride hydrochloride (0.25 g, 1.25 mmol) is added and the mixture is heated at 100° C. for 5 h, and then stirred at room temperature overnight. Water is added and an oily solid formed, which is isolated by decanting the liquid. Column chromatography (elution with 1-2% MeOH/CHCl3) gave 0.45 g of a solid. Crystallization by dissolving in CH2Cl2 with a few drops of MeOH and adding to a 1:1 solution of pentane/Et2O gave 0.22 g of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[CH:4][CH:3]=1.[C:23]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24]1.O>C(COC)OC>[C:19]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:23](=[O:30])[CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:3][CH:4]=2)[CH:13]=[C:12]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:11]=1[OH:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C1CCCC(=O)O1
Reactant: CC(C)(C)c1cc(-c2ccc(N)cc2)cc(C(C)(C)C)c1O
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)c1cc(-c2ccc(NC(=O)CCCC(=O)O)cc2)cc(C(C)(C)C)c1O
Reaction time: 1 h

Procedure:
To a hot (70° C.) solution of 10.0 g (0.0336 mole) of the known compound 4'-amino-3,5-di-tertiary-butyl-4-hydroxybiphenyl in 100 ml of glyme was added 5.0 g (0.044 mole) of glutaric anhydride. After stirring for one hour, the mixture was cooled and poured into water. The precipitate was separated by filtration and recrystallized from a chloroform-hexane mixture to provide tan needles of N-(3',5'-di-tertiary-butyl-4'-hydroxy-4-biphenylyl)-glutaramic acid, m.p. 217.5°-219° C. Analysis: Calculated for C25H33NO4 : % C, 73.0; % H, 8.1; % N, 3.4; Found: % C, 72.6; % H, 8.1; % N, 3.1.
Reaction SMILES: [C:1]1(CC[C@H](C2C=CC=C(OCCCC(=O)NOC(C)(C)C)C=2)O)[CH:6]=CC=C[CH:2]=1.[O:29]=[C:30]([N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][C@H:39]1[C:44]([OH:46])=[O:45])[C:31](=[O:37])[C:32]([CH3:36])([CH3:35])[CH2:33][CH3:34].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:36][C:32]([CH3:35])([CH2:33][CH3:34])[C:31](=[O:37])[C:30]([N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][C@H:39]1[C:44]([O:46][CH2:2][CH2:1][CH3:6])=[O:45])=[O:29]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O
Reactant: CC(C)(C)ONC(=O)CCCOc1cccc([C@H](O)CCc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCOC(=O)[C@@H]1CCCCN1C(=O)C(=O)C(C)(C)CC
Reaction time: 8 h
Yield: 176.2 %

Procedure:
A solution of alcohol 2 (385 mg, 1.0 mmol) in CH2Cl2 (3 mL) was treated with (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylic acid (23, 255 mg, 1.0 mmol, prepared from L-pipercolic acid in 4 steps following literature procedures by Holt et al. J. Amer. Chem. Soc., 1993, 115, 9925-9938), followed by 1,3-dicyclohexylcarbodiimide (DCC, 247 mg, 1.2 mmol), and 4-(dimethylamino)-pyridine (DMAP, 85 mg, 0.70 mmol) under a nitrogen atmosphere. The resulting bright yellow suspension was allowed to stir overnight. The mixture was then filtered through glass wool and chromatographed (silica gel, 20% EtOAc/hexanes) to give (1R)-3-Phenyl-1-[3-9(3-tert-butyloxycarbamylpropyl)oxy)phenyl]-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarboxylate (524 mg, 84%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) (single diastereomer, mixture of rotamers) 7.35-6.90 (m, 9 H), 5.80 (t, J=5.9 Hz, 1 H), 5.32 (d, J=5.0 Hz, 0.82 H, pipercolate α-H of rotamer A), 4.80 (br. s, 1 H), 4.02 (t, J=6.1 Hz, 2 H), 3.40-3.25 (m, 3 H), 3.12 (td, J=13.0, 3.3 Hz, 1 H), 2.60 (m, 2 H), 2.35 (d, J=14 Hz, 1 H), 2.28 (m, 1 H), 2.07 (m, 1 H), 1.96 (t, J=6.3 Hz, 2 H), 1.80-1.60 (m, 5 H), 1.43 (s, 9 H), 1.22 (s, 3 H), 1.20 (s, 3 H), 0.88 (t, J=7.4 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) (single diastereomer, mixture of rotamers) 208.2, 170.1, 167.6, 159.4, 156.4, 141.7, 141.3, 130.1, 128.9, 128.7, 126.5, 119.4, 114.7, 113.2, 113.0, 66.1, 57.1, 51.7, 47.1, 44.5, 38.3, 32.9, 32.1, 30.0, 28.8, 26.8, 25.4, 24.9, 24.0, 23.8, 23.5, 21.6, 9.1. MS(FAB): (M+Na)+ 645, (M+H)+ 623.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]=[C:10]([C:16](=[O:18])[CH3:17])[C:11]([O:13]CC)=O>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[C:16]([C:10]1[C:11](=[O:13])[C:4]2[C:3](=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)[NH:8][CH:9]=1)(=[O:18])[CH3:17]
Reactant: CCOC(=O)C(=CNc1ccccc1Br)C(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CC(=O)c1c[nH]c2c(Br)cccc2c1=O
Temperature: 250 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To Dowtherm (20 ml) at apx 200° C. was added solid ethyl 2-(((2-bromophenyl)amino) methylene)-3-oxobutanoate (3 g, 9.61 mmol). The reaction was heated to 250° C. and stirred for 1 h. LCMS showed consumption of starting material and formation of desired product along with an unknown biproduct of lower mass. The reaction was allowed to cool to room temperature and was them poured into 150 mL of hexanes. The mixture was stirred for 15 min, then the precipitate was collected by filtration and dried to afford 3-acetyl-8-bromoquinolin-4(1H)-one (1.77 g, 6.65 mmol, 69.2% yield) as a light brown solid. LCMS: (M+H)+: 265.9.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Cl:7].C1COCC1.[CH2:13]([CH:15]([C:18]1[C:19]2[N:20]([C:25](I)=[C:26]([CH3:28])[N:27]=2)[N:21]=[C:22]([CH3:24])[CH:23]=1)[CH2:16][CH3:17])[CH3:14]>[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:25]1[N:20]2[N:21]=[C:22]([CH3:24])[CH:23]=[C:18]([CH:15]([CH2:13][CH3:14])[CH2:16][CH3:17])[C:19]2=[N:27][C:26]=1[CH3:28]
Reactant: Clc1ccsc1Br
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sccc3Cl)c(C)nc12
Yield: 104.2 %

Procedure:
To a flask of 2-bromo-3-chloro-thiophene (Lemaire et. el., Synth. Commun., 1994, 24, 95) (2.53 g, 12.82 mmol) is added 0.05 g/mL Reike® zinc in THF (25 mL, 19.24 mmol). The solution is heated at a reflux for 2 hours. The excess zinc is allowed to settle and the solution transferred to a flask containing 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (example KW1-A03735-193) (2.01 g, 6.41 mmol) and PdCl2(dppf) (0.23 g, 0.32 mmol). The solution is heated at a reflux overnight, quenched with sat. NH4Cl (25 mL) and extracted with EtOAc (2×25 mL). The combined organic layers are dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (2%-15% EtOAc/hexane gradient) furnish the title compound (1.32 g, 6.68 mmol, 62%). 1H NMR (CDCl3), δ 0.87 (t, J=7.5 Hz, 6H), 1.74-1.91 (m, 4H), 2.48 (s, 3H), 2.49 (s, 3H), 3.37-3.36 (m, 1H), 6.67 (s, 1H), 7.07 (d, J=5.4 Hz, 1H), 7.48 (d, J=5.4 Hz, 1H). LC/MS (m/z): calcd. for C17H20ClN3S (M+H)+: 334.1; found: 334.1.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O:13]C)=[O:12])(=[O:4])=[O:3].[OH-].[Na+].Cl>C1COCC1>[CH3:1][S:2]([NH:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([OH:13])=[O:12])(=[O:3])=[O:4]
Reactant: COC(=O)c1sccc1NS(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccsc1C(=O)O
Temperature: 80 °C
Yield: 99.3 %

Procedure:
A mixture of methyl 3-(methylsulfonamido)thiophene-2-carboxylate (Int. 37) (193 mg, 0.820 mmol) in aqueous 2M NaOH (4.10 ml, 8.20 mmol) and THF (4.1 ml) was heated under microwaves irradiation at 80° C. for 30 minutes. 2N HCl was added (pH=2) and the mixture was extracted with EtOAc (×3). The combined organic layers were dried over Na2SO4 and evaporated to dryness affording 3-(methylsulfonamido)thiophene-2-carboxylic acid (Int. 38) (180 mg, 0.814 mmol, MS/ESI+221.8 [MH]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[NH2:9][C@@H:10]([C:13]([OH:15])=[O:14])[CH2:11][SH:12]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:9][C@@H:10]([C:13]([OH:15])=[O:14])[CH2:11][S:12]2)[CH:2]=1
Reactant: N[C@H](CS)C(=O)O
Reactant: O=Cc1cccnc1
Solvent: CCO
Product: O=C(O)[C@H]1CSC(c2cccnc2)N1
Temperature: 25 °C
Yield: 53.8 %

Procedure:
A solution of 1.07 g of pyridine-3-aldehyde and 1.21 g of D-cysteine in 60% v/v aqueous ethanol was heated under reflux for 4 hours. The mixture was cooled to room temperature and the resulting solid material was removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, and 5 ml of ethanol were added to the resulting residue. Collecting the precipitated crystals by filtration gave 1.13 g (yield 54%) of the title compound, melting at 138°-139° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=2[C:24](N)=[O:25])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[CH3:32][CH:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[C:43]([O:48][CH3:49])[CH:42]=2)[CH2:37][CH2:36]1)[CH3:34].[I-].[K+].Cl>C(O)C(F)(F)F.O1CCOCC1.C(=O)(O)[O-].[Na+].C(Cl)Cl>[F:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:22]2[C:23]=1[C:24](=[O:25])[N:3]1[C:2]([NH:47][C:44]3[CH:45]=[CH:46][C:41]([N:38]4[CH2:39][CH2:40][N:35]([CH:33]([CH3:32])[CH3:34])[CH2:36][CH2:37]4)=[CH:42][C:43]=3[O:48][CH3:49])=[N:7][C:6]3[N:8]([S:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]=3[C:4]1=[N:21]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(N)=O)nc(Cl)nc32)cc1
Reactant: COc1cc(N2CCN(C(C)C)CC2)ccc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: OCC(F)(F)F
Product: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c2nc3cccc(F)c3c(=O)n12
Temperature: 80 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
To a solution of 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (5.50 g, 11.98 mmol), [4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amine (4.5 g, 18 mmol, 1.50 equiv.), and potassium iodide (<20 mg) in trifluoroethanol (200 mL) in a 300 mL sealed tube was added hydrochloric acid as a 4.0M solution in dioxane (12 mL, 48 mmol, 4 equiv.). The vessel was sealed and the resulting suspension was stirred rapidly at 80° C. for 12 hours. TLC/LCMS analysis indicates starting material still remains, so additional hydrochloric acid (5 mL as a 4.0M solution in dioxane) and potassium iodide (<20 mg) were added and heating was continued. Three such reactions were cooled and poured directly in saturated sodium bicarbonate/methylene chloride. The organic layer was collected, concentrated under reduced pressure, and then resuspended in diethylether. Sonication for 10 minutes was followed by filtration to give crude 8-fluoro-5-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one as an orange solid with sufficient purity for use in the next transformation (23.5 g, ca 99% yield, purity 85-90%). ESIMS (M+H)+=655.