Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[O:5][C:6]=1[CH3:7].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C:43]1[CH:59]=[CH:58][C:46]([O:47][CH2:48][CH2:49][NH:50]C(=O)OC(C)(C)C)=[C:45]([C:60]2[N:64]([CH3:65])[N:63]=[CH:62][CH:61]=2)[CH:44]=1.Cl.CCOCC>ClCCl>[NH2:50][CH2:49][CH2:48][O:47][C:46]1[CH:58]=[CH:59][C:43]([NH:42][C:8]([C:4]2[O:5][C:6]([CH3:7])=[C:2]([CH3:1])[CH:3]=2)=[O:10])=[CH:44][C:45]=1[C:60]1[N:64]([CH3:65])[N:63]=[CH:62][CH:61]=1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Reactant: Cc1cc(C(=O)O)oc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)oc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.3 %

Procedure:
4,5-dimethylfuran-2-carboxylic acid (12.65 mg, 1.2 eq), triethylamine (26.21 μL, 3.0 eq) and HATU (34.32 mg, 1.2 eq) were dissolved in 1 mL of dichloromethane and stirred at room temperature for 20 minutes. At this time tert-butyl 2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (25.0 mg, 75.2 μmol) dissolved in 0.5 mL of dichloromethane was added and the reaction was stirred at room temperature for 18 hr. The solvent was evaporated under a stream of nitrogen and the residue was dissolved in 0.5 mL of ethyl acetate. To this was added 2.0M hydrochloric acid in ether (376 μL, 5 eq) and the reaction was stirred at room temperature overnight. The solvent was evaporated under a stream of nitrogen and the residue was dissolved in 1 mL of dimethylsulfoxide and purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a pale yellow solid in 47.3% yield. LCMS m/z (%)=355 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.98 (s, 3 H), 2.30 (s, 3 H), 3.11-3.20 (m, 2 H), 3.71 (s, 3 H), 4.16 (t, J=5.31 Hz, 3 H), 6.36 (s, 1 H), 7.10 (s, 1 H), 7.21 (d, J=9.09 Hz, 1 H), 7.49 (d, J=2.02 Hz, 1 H), 7.49 (d, J=2.02 Hz, 1 H), 7.68 (d, J=3.03 Hz, 1 H), 7.84 (dd, J=9.09, 2.53 Hz, 1 H), 7.86-7.98 (m, 2 H), 10.01 (s, 1 H).
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C.C[C:22]1(C)[O:29][C:27](=[O:28])[CH2:26][C:24](=[O:25])O1.N1C=CC=CC=1>C(Cl)Cl>[O:25]=[C:24]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:26][C:27]([O:29][CH3:22])=[O:28]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)CC(=O)OC

Procedure:
270 ml of stearoyl chloride were added dropwise at a maximum of 150° C. to a solution of 117 g of Meldrum's acid and 131 ml of pyridine in 1.5 l of methylene chloride. After stirring the reaction mixture was washed with 4N hydrochloric acid, the aqueous phase was back-extracted with methylene chloride and the methylene chloride phase was dried and concentrated. The residue was taken up in methanol and stirred under reflux. After cooling the separated crystals were filtered off, dissolved in methylene chloride and chromatographed on silica gel with methylene chloride. There were obtained 175 g of methyl 3-oxoeicosanoate, m.p. 52°-54° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[N:9]=[CH:10][C:11]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:12][C:13]=1[O:14][CH3:15].[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][C:35]([F:38])([F:37])[F:36])[CH:31]=[CH:30][C:29]=1B(O)O>C1(C)C=CC=CC=1.[OH-].[Na+].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>[CH3:15][O:14][C:13]1[N:12]=[C:11]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:10]=[N:9][C:8]=1[C:29]1[CH:30]=[CH:31][C:32]([O:34][C:35]([F:37])([F:38])[F:36])=[CH:33][C:28]=1[O:27][CH3:26]
Reactant: COc1ccc(CNc2cnc(Br)c(OC)n2)cc1
Reactant: COc1cc(OC(F)(F)F)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2cnc(-c3ccc(OC(F)(F)F)cc3OC)c(OC)n2)cc1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (100 mg) and potassium carbonate (2.0 M, 2.0 mL) are added to a stirred solution of (5-bromo-6-methoxypyrazin-2-yl)[(4-methoxyphenyl)methyl]amine (0.80 g, 2.50 mmol) and 2-methoxy-4-trifluoromethoxy benzeneboronic acid (1.75 g, 7.5 mmol) in toluene (25 mL). The mixture is heated to 85 C for 8 hours, cooled to room temperature, diluted with 2.0 M sodium hydroxide and extracted twice with 1:1 hexane-ethyl ether. The combined extracts are dried (sodium sulfate), filtered and concentrated. The residue is purified by flash chromatography, eluting with 60% hexanes in ether to give {6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2yl}[(4-methoxyphenyl)methyl]amine (967 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:15])=[N:11][N:10]=1.Cl[C:24]1[N+:29]([O-:30])=[CH:28][C:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>CC(O)(CC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([C:24]3[N+:29]([O-:30])=[CH:28][C:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:26][CH:25]=3)[CH2:21][CH2:22]2)=[O:15])=[N:11][N:10]=1
Reactant: COC(=O)Cc1ccc(Cl)[n+]([O-])c1
Reactant: O=C(NC1CCNCC1)c1nnc(Nc2ccccc2F)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)(C)O
Product: COC(=O)Cc1ccc(N2CCC(NC(=O)c3nnc(Nc4ccccc4F)o3)CC2)[n+]([O-])c1
Yield: 32.2 %

Procedure:
5-[(2-Fluorophenyl)amino]-N-piperidin-4-yl-1,3,4-oxadiazole-2-carboxamide (Intermediate 101) (100 mg, 0.33 mmol) and methyl (6-chloro-1-oxidopyridin-3-yl)acetate (67 mg, 0.33 mmol) were heated with sodium hydrogen carbonate (56 mg, 0.66 mmol) in 2-methyl-2-butanol (4 mL) at 100° C. for 22 h. The reaction mixture was concentrated by evaporation and the residue was dissolved in DMSO then filtered and purified by preparative HPLC to give the title compound (50 mg, 32%) as a gum; 1H NMR δ 1.94-1.74 (m, 4H), 2.58-2.43 (m, 2H), 2.95-2.84 (m, 2H), 3.65 (s, 3H), 4.07-3.93 (m, 3H), 7.21-7.12 (m, 2H), 7.35-7.23 (m, 2H), 7.45-7.40 (m, 1H), 8.06-7.98 (m, 1H), 8.25-8.20 (m, 1H), 9.13 (d, 1H), 10.64 (s, 1H); MS m/e MH+ 471.
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:11][N:10](C(OC(C)(C)C)=O)[C@H:9]([C@H:19]([C:21]3[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=3[Cl:28])[OH:20])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1CCCC1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[CH:1]1([C@H:7]2[CH2:11][NH:10][C@H:9]([C@H:19]([C:21]3[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=3[Cl:28])[OH:20])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](C2CCCCC2)C[C@H]1[C@@H](O)c1c(Cl)cncc1Cl
Solvent: ClCCl
Solvent: C1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: O[C@@H](c1c(Cl)cncc1Cl)[C@@H]1C[C@@H](C2CCCCC2)CN1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.1 %

Procedure:
(2S,4S)-tert-butyl 4-cyclohexyl-2-((S)-(3,5-dichloropyridin-4-yl)(hydroxy)methyl)pyrrolidine-1-carboxylate (1.20 g, 2.79 mmol) and its epimer at C2 of the pyrrolidine was treated with DCM (10 mL) and TFA (7 mL, 91 mmol) and allowed to stir at room temperature for 1.5 h. The reaction mixture was concentrated on the rotovap and the crude residue purified on an ISCO Combiflash™ RF (40 g Grace Reveleris column, using a gradient of 0-20% 2M NH3/MeOH in DCM) affording (S)-((2S,4S)-4-cyclohexylpyrrolidin-2-yl)(3,5-dichloropyridin-4-yl)methanol 2,2,2-trifluoroacetate (755 mg, 1.705 mmol, 61% yield) along with its epimer at C2 of the pyrrolidine as a light tan-colored foam. MS (ESI) 329.0, 331.1 [M+H]+.
Reaction SMILES: [NH4+]=[S:2].C(O)C.[CH2:6]([N:10]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([C:20]#[N:21])[N:12]=[C:11]1[N:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)[C:7]#[C:8][CH3:9].C(OCC)(=O)C>O>[CH2:6]([N:10]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([C:20](=[S:2])[NH2:21])[N:12]=[C:11]1[N:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:24][CH2:23]1)[C:7]#[C:8][CH3:9]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C#N)c1C(=O)OCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(N)=S)c1C(=O)OCC
Temperature: 60 °C

Procedure:
5 ml of an aqueous solution of 50% ammonium sulfide was added to a 20-ml ethanol solution containing 0.80 g of t-butyl 4-[1-(2-butynyl)-4-cyano-5-ethoxycarbonyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the mixture was heated at 60° C. for 14 hours. 100 ml of ethyl acetate and 50 ml of water were added to the mixture, and the organic layer was washed successively with 50 ml of water and 50 ml of a saturated sodium chloride solution. The reaction solution was dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.58 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3:2).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([CH:9]([CH2:13][CH3:14])[C:10](Cl)=[O:11])[CH3:8].[F:15][C:16]([F:50])([F:49])[C:17]1[CH:18]=[C:19]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:20][N:21]([C@@H:28]1[C:34]2=[CH:35][C:36]3[CH2:37][O:38][CH2:39][C:40]=3[CH:41]=[C:33]2[NH:32][CH2:31][CH2:30][CH2:29]1)[C:22]1[N:23]=[N:24][N:25]([CH3:27])[N:26]=1.O>ClCCl>[F:50][C:16]([F:15])([F:49])[C:17]1[CH:18]=[C:19]([CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=1)[CH2:20][N:21]([C:22]1[N:23]=[N:24][N:25]([CH3:27])[N:26]=1)[C@@H:28]1[C:34]2=[CH:35][C:36]3[CH2:37][O:38][CH2:39][C:40]=3[CH:41]=[C:33]2[N:32]([C:10](=[O:11])[CH:9]([CH2:13][CH3:14])[CH2:7][CH3:8])[CH2:31][CH2:30][CH2:29]1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3cc4c(cc32)COC4)n1
Reactant: CCC(CC)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCC(CC)C(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc3c(cc21)COC3
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Add pyridine (0.35 mmol) followed by 2-ethyl-butyryl chloride (0.35 mmol) to a solution of (S)-(3,5-Bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (Example 73, Step 7) (0.17 mmol) in dichloromethane (3 mL). After stirring at room temperature for 14 h, dilute the reaction with dichloromethane (10 mL) followed by water (10 mL). Separate the organic phase and wash the aqueous with dichloromethane (2×10 mL). Dry the combined organics over sodium sulfate, filter, and remove solvent in vacuo. Chromatograph the crude product over silica gel using ethyl acetate/hexane (10-50%) to elute to obtain the title compound as a colorless foam. MS (ES+): 611 (M+H).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[CH2:17][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([OH:16])[C:10]=3[C:8](=[O:9])[C:4]2=[C:5]([OH:7])[CH:6]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>C1(C)C=CC=CC=1>[OH:16][C:15]1[C:10]2[C:8](=[O:9])[C:4]3[C:3](=[CH:2][CH:1]=[CH:6][C:5]=3[OH:7])[CH:17]([C:24](=[O:26])[CH3:25])[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: O=C1c2c(O)cccc2Cc2cccc(O)c21
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)C1c2cccc(O)c2C(=O)c2c(O)cccc21
Temperature: 25 °C
Yield: 31.3 %

Procedure:
To a solution of 56.5 g of purified anthralin (0.25 mole) in 1750 cm3 of anhydrous toluene, there are added, with stirring at ambient temperature, 27.3 cm3 of anhydrous pyridine (0.34 mole). There are then slowly added, using a dropping funnel, 21.4 cm3 of acetyl chloride (0.3 mole). There is produced during the course of this addition a slight exothermicity. After the end of the addition, the temperature of the reaction mixture is raised to 90° C. for about 1 hour. After cooling the reaction mixture there are added at 30°-35° C., 27.3 cm3 of pyridine and then slowly 21.4 cm3 of acetyl chloride. The mixture is stirred for 1 hour at 85°-90° C. After having verified that the anthralin has been transformed into the 10-acetyl derivative, the reaction mixture is brought to ambient temperature, then washed three times with water (250 cm3). The toluene phase is decanted, dried on sodium sulfate and then concentrated to about 300 cm3. This solution is then introduced into a silica gel column and eluted with toluene and a 1:1 toluene-methylene chloride mixture. The first fractions are collected and concentrated under a vacuum. The resulting solid is then recrystallized in toluene, yielding 21 g of bright yellow crystals of 1,8-dihydroxy-10-acetyl anthrone having a melting point of 146° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.FC1C(F)=CC=CC=1CSC1N=C(NS(N2CCC2)(=O)=O)C=C([O:43][CH:44](CO)[CH2:45][OH:46])N=1.C(O)CO.[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=[C:2]([O:43][CH2:44][CH2:45][OH:46])[CH:7]=1
Reactant: O=S(=O)(Nc1cc(OC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: OCCO
Product: OCCOc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine ((the product of example 1 step 5 g) and ethylene glycol (1.517 g) in THF (100 ml) was added NaH (1.3 g) slowly and the reaction was then allowed to stir overnight at RT. The reaction mixture was then partitioned between EtOAc (200 ml) and H2O (200 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×200 ml). Organics were combined, dried (MgSO4) and reduced in vacuo and the resulting residue was purified by column chromatography on silica gel 10% EtOAc/90% iso-Hex to give the subtitle compound as a clear oil. Yield: 2.4 g
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[O:11][C:12]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:43][C:44]1[CH:45]=[CH:46][C:47]([CH3:63])=[C:48]([NH:50][C:51]2[CH:52]=[C:53]3[C:58](=[CH:59][CH:60]=2)[N:57]=[CH:56][N:55]([CH3:61])[C:54]3=[O:62])[CH:49]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[O:11][C:12]=2[C:13]([NH:43][C:44]2[CH:45]=[CH:46][C:47]([CH3:63])=[C:48]([NH:50][C:51]3[CH:52]=[C:53]4[C:58](=[CH:59][CH:60]=3)[N:57]=[CH:56][N:55]([CH3:61])[C:54]4=[O:62])[CH:49]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: O=C(O)c1oc(C(F)(F)F)nc1-c1ccc(F)cc1
Reactant: Cc1ccc(N)cc1Nc1ccc2ncn(C)c(=O)c2c1
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2oc(C(F)(F)F)nc2-c2ccc(F)cc2)cc1Nc1ccc2ncn(C)c(=O)c2c1
Reaction time: 1 h
Yield: 67 %

Procedure:
To a flask containing DCM (3 mL) on ice was added 4-(4-fluorophenyl)-2-(trifluoromethyl)oxazole-5-carboxylic acid (S-41) (76 mg, 0.28 mmol), EDC (47.2 mg, 0.3 mmol), HOAt (48.9 mg, 0.36 mmol), and DIPEA (0.193 mL, 1.10 mmol). The resulting solution was stirred for 1 hr followed by the addition of 6-((5-amino-2-methylphenyl)amino)-3-methylquinazolin-4(3H)-one (HGM-7) (77.4 mg, 0.28 mmol). The reaction was stirred for 18 hours at ambient temperature at which point the solution was made basic by the addition of saturated sodium bicarbonate (10 mL) which was then extracted with DCM (2×10 mL) and EtOAc (2×10 mL). The organic extracts were washed with brine, combined, dried over Na2SO4, and concentrated. The crude material was fractionated by SiO2 chromatography (stepwise gradient of DCM to 90% DCM/10% MeOH, desired product elutes in 5% MeOH)(101 mg, 67% yield). 1HNMR (400 MHz, CDCl3): d 8.9 (s, 1H), 7.82 (m, 2H), 7.80 (s, 1H), 7.55 (d, 1H, J=2.4 Hz), 7.50 (s, 1H), 7.41 (d, 1H, J=8.4 hz), 7.27 (m, 2H), 7.03 (d, 1H, J=8.4 Hz), 6.95 (t, 2H, J=8.8 Hz), 3.44 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:11]=[C:10]([CH:12]=[C:13]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH:30]([C:33]1[NH:37][C:36]2[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=2[N:34]=1)([CH3:32])[CH3:31].CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:30]([C:33]1[N:34]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[N:11]=[C:10]([CH:12]=[C:13]4[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:16]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CC(=Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)C1
Reactant: CC(C)c1nc2ccccc2[nH]1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)ccc2n1

Procedure:
To a microwave vial was added tert-butyl 3-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methylene)azetidine-1-carboxylate, 2-isopropyl-1H-benzo[d]imidazole (1.05 eq), sodium tert-butoxide (2 eq), Palladium Acetate (0.1 eq) and Bis(tri-t-butylphosphine)palladium (0.1 eq). The tube was flushed with nitrogen for 10 minutes before adding Toluene (8 mL). The reaction was microwaved at 145° C. for 20 minutes. The crude was purified by flash column chromatography to afford 0.22 g of tert-butyl 3-((2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methylene)azetidine-1-carboxylate.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]([NH2:13])=[S:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][CH2:15][C:16](=O)[CH2:17]Cl>C(O)C>[C:1]([O:9][CH2:10][C:11]1[S:12][CH:17]=[C:16]([CH2:15][Cl:14])[N:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)COC(=O)c1ccccc1
Reactant: O=C(CCl)CCl
Solvent: CCO
Product: O=C(OCc1nc(CCl)cs1)c1ccccc1
Yield: 70 %

Procedure:
A mixture of 2-amino-2-thioxoethyl benzoate (7.6 g), 1,3-dichloro-2-propanone (7.6 g) and ethanol (100 mL) was heated under reflux for 4 hrs. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:5, v/v) to give (4-chloromethyl-1,3-thiazol-2-yl)methyl benzoate as a brown oil (7.3 g, yield 45%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C(OC([NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27]2[CH:28]=[C:29]([N:39]([CH:49]3[CH2:51][CH2:50]3)CC3C=CC(OC)=CC=3)[C:30]3[N:31]([C:33]([C:36](O)=[O:37])=[CH:34][N:35]=3)[N:32]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(O)(C(F)(F)F)=O>CN(C=O)C>[C:9]([NH:8][C:4]1[CH:3]=[C:2]([NH:1][C:36]([C:33]2[N:31]3[N:32]=[C:27]([NH:26][C@H:23]4[CH2:24][CH2:25][C@H:20]([NH2:19])[CH2:21][CH2:22]4)[CH:28]=[C:29]([NH:39][CH:49]4[CH2:51][CH2:50]4)[C:30]3=[N:35][CH:34]=2)=[O:37])[CH:7]=[CH:6][CH:5]=1)(=[O:11])[CH3:10]
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nn3c(C(=O)O)cnc23)C2CC2)cc1
Reactant: CC(=O)Nc1cccc(N)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(NC(=O)c2cnc3c(NC4CC4)cc(N[C@H]4CC[C@H](N)CC4)nn23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-(3-aminophenyl)acetamide (4.09 mg, 0.027 mmol), 83C (10 mg, 0.018 mmol) and DIEA in DMF (0.5 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (16.06 mg, 0.036 mmol) and the reaction was stirred at room temperature overnight. One mL of TFA was added to the reaction mixture and heated at 60° C. After 1 hr, the reaction mixture was concentrated under reduced pressure and purified using preparative HPLC containing TFA to isolate N-(3-acetamidophenyl)-6-((trans)-4-aminocyclohexylamino)-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (4 mg, 5.02 μmol, 27.6% 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=1.3 minutes. [M+H]=463.23. 1H NMR (500 MHz, METHANOL-d3) δ ppm 10.99 (1H, s), 7.92 (1H, d, J=1.83 Hz), 7.62 (1H, d, J=8.25 Hz), 7.37 (2H, t, J=8.25 Hz), 7.16 (1H, d, J=8.25 Hz), 6.08 (1H, s), 3.80 (1H, t, J=4.35 Hz), 3.09-3.26 (1H, m), 2.51-2.72 (1H, m, J=6.76, 6.76, 3.67, 3.44 Hz), 2.35 (2H, d, J=10.08 Hz), 2.11-2.24 (3H, m), 1.98-2.14 (2H, m), 1.67-1.89 (2H, m, J=12.72, 12.43, 12.43, 3.21 Hz), 1.37-1.53 (2H, m), 1.20-1.38 (1H, m), 0.82-1.00 (2H, m), 0.58-0.76 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[I:34])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[I:34])[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: [N-]=[N+]=NCCNC(=O)c1ccccc1I
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)c3ccccc3I)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.083 g, 0.299 mmol) was reacted with N-(2-azidoethyl)-2-iodobenzamide (0.095 g, 0.299 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(2-iodobenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.74 (d, 2H), δ 7.57 (t, 1H), δ 7.36 (s, 1H), δ 7.22 (s, 2H0, δ 6.97 (m, 1H0, δ 6.39 (s, 1H), δ 5.97 (s, 2H), δ 4.48 (t, 2H0, δ 3.85 (m, 2H0, δ 2.44 (t, 2H), δ 2.18 (t, 2H), δ 1.45 (m, 13H, δ 1.18 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 170.3, 150.4, 149.5, 148.2, 141.8, 139.9, 138.7, 131.3, 128.4, 128.3, 122.3, 106.5, 92.8, 84.9, 49.2, 40.5, 29.2, 28.9, 28.3, 28.2, 28.0, 25.5 ppm; HRMS (ESI) calcd for C24H32IN7O3 (M+) 593.1611. found 593.1603, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-2-iodobenzamide hydrochloride (0.125 g, 79% yield). 1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), δ 7.88*d, 1H), δ 7.45 (t, 1H), δ 7.34 (d, 1H), δ 7.15 (t, 1H), δ 6.47 (s, 1H), δ 4.78 (s, 2H), δ 3.99 (s, 2H), δ 2.83 (s, 2H), δ 2.44 (t, 2H), δ 1.76 (s, 2H), δ 1.64 (s, 2H), δ 1.29 (s, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 171.6, 159.2, 147.3, 142.1, 139.8, 131.2, 128.2, 127.7, 124.4, 92.1, 52.2, 40.8, 39.4, 31.2, 28.3, 28.1, 27.7, 24.1, 20.9, 15.9, 10.7 ppm; HRMS (ESI) calcd for C19H24IN7O (M+) 493.1087. found 493.1085.