Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[CH:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N(C(C)C)CC)(C)C.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([SH:40])=[CH:36][CH:35]=1>ClCCl.C(N(CC)CC)C.S(Cl)(C)(=O)=O>[CH2:1]([O:8][C:9](=[O:21])[CH:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][S:40][C:37]1[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)NC(CO)C(=O)OCc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(SCC(NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Temperature: 4 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-t-butoxycarbonylamino-3-hydroxypropionic acid benzyl ester (29.5 g) in dichloromethane (300 ml), triethylamine (21 ml) and mesyl chloride (8.6 ml) were added and the reaction solution was stirred for 30 minutes at 4° C. The reaction solution was added to 1 N hydrochloric acid cooling with ice. The obtained yellow oil was dissolved into dichloromethane (300 ml), and diisopropylethylamine (17 ml) and 4-methoxybenzenethiol (12 ml) were added thereto at 4° C. and the reaction solution was stirred for 3 hours at room temperature and concentrated. The residue was purified by column chromatography (n-hexane:ethyl acetate=8:1) to give the title compound (24.8 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)=[CH:17][C:12]=1[C:13]([NH:15][CH3:16])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:10][C:11]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:17][C:12]=2[C:13]([NH:15][CH3:16])=[O:14])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CNC(=O)c1cc(N2CCN(C)CC2)ccc1N
Reactant: Clc1cc(I)c(Cl)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1cc(N2CCN(C)CC2)ccc1Nc1cc(Cl)ncc1Cl
Temperature: 100 °C

Procedure:
A mixture of 2,5-dichloro-4-iodopyridine (0.56 g, 2.04 mmol), 2-amino-N-methyl-5-(4-methylpiperazin-1-yl)benzamide (0.508 g, 2.04 mmol), 9,9-dimethyl-4,5-s bis(diphenylphosphino)xanthene (0.071 g, 0.12 mmol), cesium carbonate (1.332 g, 4.09 mmol) and palladium(II) acetate (0.018 g, 0.08 mmol) was suspended in DMA (15 mL). The mixture was heated at 100° C. for 1 hour in a microwave reactor and then allowed to cool to room temperature. The mixture was loaded onto an SCX column and the product eluted first using MeOH and then with a 7M solution of NH3 in MeOH. Fractions containing product were combined and evaporated to afford 2-[(2,5-dichloropyridin-4-yl)amino]-N-methyl-5-(4-methylpiperazin-1-yl)benzamide as a DMA adduct (0.990 g); 1H NMR spectrum: (300 MHz, DMSO) δ 2.23 (3H, s), 2.44-2.50 (4H, m), 2.73 (3H, d), 3.16-3.21 (4H, m), 6.90 (1H, s), 7.10-7.14 (1H, m), 7.20 (1H, d), 7.40 (1H, d), 8.19 (1H, s), 8.58 (1H, d), 9.67 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=394.09.
Reaction SMILES: [SnH3][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:11]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:16]=CC=C[CH:12]=1.[Li+].[Cl-].BrC(C)=C>CN(C=O)C.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:16]([C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:11]=[CH2:12]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: [SnH3]c1cc2ccccc2[nH]1
Agent: [Pd]
Agent: C=C(C)Br
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: C=CCc1cc2ccccc2[nH]1
Temperature: 100 °C

Procedure:
The 2-stannylindole 23-1 (1.280 g, 2.34 mmol; prepared using methods described in WO 03/010141), triphenylphosphine (0.065 g, 0.25 mmol), Cul (0.045 g, 0.24 mmol), LiCl (0.200 g, 4.72 mmol) and 2-bromopropene (0.444 mL, 5.00 mmol) were dissolved in DMF (6 mL) and the suspension degassed by bubbling Ar for 20 min. Pd2(dba)3 (0.035 g, 0.034 mmol) was added and after degassing for an additional 10 min, the reaction mixture was heated to 100° C. overnight. The suspension was then diluted with TBME (100 mL) and washed with brine (2×25 mL). The extract was dried (MgSO4) and concentrated under reduced pressure to give a residue that was purified by flash chromatography using 5-10% EtOAc in hexane as eluent. The desired 2-(2-propenyl)indole 23-2 was obtained as beige solid (0.57 g, 81% yield): MS-ES m/z 298.1 (MH+). The methyl ester 23-2 was saponified in the usual way (NaOH/DMSO) to give the corresponding carboxylic acid 23-3 in 96% yield: MS-ES m/z 284.1 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:27]([O:30][CH2:31][C:32]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[CH:34][C:33]=1[N:47]1[CH2:59][CH2:58][N:50]2[C:51]3[CH2:52][CH2:53][CH2:54][CH2:55][C:56]=3[CH:57]=[C:49]2[C:48]1=[O:60])(=[O:29])[CH3:28].CC(O[Na])=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC#N.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].O>[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[CH2:59][CH2:58][N:50]3[C:51]4[CH2:52][CH2:53][CH2:54][CH2:55][C:56]=4[CH:57]=[C:49]3[C:48]2=[O:60])=[CH:34][CH:35]=[CH:36][C:37]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)nn1CCO[Si](C)(C)C(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)O[Na]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C)n(CCO[Si](C)(C)C(C)(C)C)n3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 17.7 %

Procedure:
A mixture of 161a (750 mg, 1.7 mmol), 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (882 mg, 1.9 mmol), CH3COONa (309 mg, 3.8 mmol), PdCl2(dppf) (153 mg, 0.19 mmol) and K3PO4 (1 g, 3.8 mmol) suspended in CH3CN (30 mL) and H2O (2 mL) was heated at 110° C. for 12 h under argon atmosphere. After reaction the mixture was evaporated and the residue was purified by reverse phase Combi-flash eluting with 0.3% NH4HCO3 in 1:4 water/CH3CN to give 161b as a brown solid (210 mg, 18%). LCMS: [M+H]+ 699.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1.[NH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25].C(NC(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: COC(=O)CN
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)CNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(6-chloropyrimidine-4-carboxamido)-3-methylbenzene-1-sulfonyl chloride (Intermediate 30, 1.2 g; 3.47 mmol) in THF (100 ml) was treated with methyl 2-aminoacetate (540 mg; 4.34 mmol) and diisopropylamine (2 ml; 14.3 mmol). After stirring at RT for 18 hours the solvent was removed in vacuo and the residue redissolved in DCM and washed with water. The organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc. The title product was obtained as a white solid (1.05 g, 76%).
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.[OH-].[Na+].S(OC)(OC)(=O)=O.CCOCC>O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([S:3][CH3:2])[C:5]=1[NH2:6]
Reactant: Nc1nc2c(Cl)cccc2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CSc1cccc(Cl)c1N
Reaction time: 4.5 h

Procedure:
A mixture of 36.0 g (196 mmol) of 2-amino-4-chlorobenzothiazole, 108 g (2.8 mmol) of sodium hydroxide, and 480 mL of water was heated at reflux with stirring for 4.5 hours. The resulting mixture was cooled and diluted with 180 mL of water. Six drops of tetrabutylammonium hydroxide were added and then 22.5 mL (235 mmol) of dimethyl sulfate dissolved in 50 mL of toluene was added dropwise over a 20-min period with stirring. The mixture was stirred another 30 min at ambient temperature. Ether was added and the phases were separated. The aqueous phase was extracted with ether. The combined organic phase and extract were treated with dimethylamine to destroy excess dimethyl sulfate, washed with water, dried, and concentrated by evaporation under reduced pressure. The residual liquid was distilled at 1 mm (millimeter) Hg (130 Pascals) pressure and the 18 g (53 percent of theory) colorless liquid fraction boiling at 100° C. was collected and shown to be the title compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[N:11]1.Cl[C:20]([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)=[O:21].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.O1CCCC1.O>[N:10]1([C:20]([N:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]2)=[O:21])[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[N:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Reactant: c1cnc2nn[nH]c2c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)n2nnc3ncccc32)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
1.39 ml (8.40 mmol) of diisopropylethylamine are added to a suspension of 0.840 g (7 mmol) of 1H-[1,2,3]triazolo[4,5-b]pyridine, of 1.741 g (7 mmol) of tert-butyl 4-chlorocarbonylpiperazine-1-carboxylate (Bioorg. Med. Chem. Lett. 2000, 10, 2357) and of 0.042 g (0.35 mmol) of 4-dimethylaminopyridine in 14 ml of tetrahydrofuran. The mixture is stirred at ambient temperature for 4 hours and then 80 ml of ethyl acetate and 20 ml of water are added. The organic phase is separated by settling out and is then washed with 3×20 ml of water and 20 ml of a saturated aqueous solution of sodium chloride. The product is dried over sodium sulfate and evaporated to dryness. The residue is recrystallized from isopropanol, so as to obtain 1.70 g (5.1 mmol) of product in the form of white crystals.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[C:35]4[C:30](=[CH:31][C:32]([O:38][CH3:39])=[C:33]([O:36][CH3:37])[CH:34]=4)[N:29]=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][C:26]3[C:35]4[C:30](=[CH:31][C:32]([O:38][CH3:39])=[C:33]([O:36][CH3:37])[CH:34]=4)[N:29]=[CH:28][CH:27]=3)=[CH:23][CH:24]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(OCc5ccccc5)cc4)cc3)c2cc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(O)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.7 %

Procedure:
N-(4-Benzyloxyphenyl)-N'-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}urea (228 mg) was dissolved in N,N-dimethylformamide/ethyl acetate (15 ml/20 ml), after the addition of triethylamine (4 ml), 20% palladium hydroxide (1.18 g) was added, and the admixture was stirred at room temperature under hydrogen for 15 hours. The reaction mixture was filtered using Celite, after which the filtrate was concentrated, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 188 mg of the title compound (yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[CH:9][N:10]=2)[N:7]=1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: OCc1cnc2ccc(Cl)nn12
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a solution of (6-chloro-imidazo[1,2-b]pyridazin-3-yl)-methanol (1.3 g, 7.1 mmol) in DCM (50 mL) was added active MnO2 (3 g, 34.5 mmol). The mixture was stirred at rt overnight and then filtered. The filtrate was concentrated under vacuum and the residue was washed with EtOAc to afford 6-chloro-imidazo[1,2-b]pyridazine-3-carbaldehyde (0.7 g) in 54% yield. 1H-NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 8.42 (s, 1H), 8.08 (d, 1H), 7.38 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[CH3:28][O:29][C:30]([CH3:39])([CH3:38])[CH2:31][N:32]1[CH:36]=[CH:35][C:34]([NH2:37])=[N:33]1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[C:13]([NH:37][C:34]2[CH:35]=[CH:36][N:32]([CH2:31][C:30]([O:29][CH3:28])([CH3:38])[CH3:39])[N:33]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CC(=O)C2)C(=O)O)cc1Cl
Reactant: COC(C)(C)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(C)(C)Cn1ccc(NC(=O)[C@H](CC2CC(=O)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 50.8 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclobutyl)-propionic acid (65 mg, 0.20 mmol) in methylene chloride (8 mL) was cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 120 μL, 0.24 mmol) and N,N-dimethylfomamide (one drop) which was then stirred at 0° C. for 20 minutes and 40 min at 25° C. After this time, the reaction was concentrated in vacuo and azeotroped with methylene chloride (10 ml). In a separate flask a solution of 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (36 mg, 0.22 mmol), 2,6-lutidine (34 μL, 0.29 mmol) in methylene chloride (8 mL) was cooled to 0° C. in an ice bath. To this solution was then added the solution of the prepared acid chloride in methylene chloride (5 mL) dropwise. After addition was complete the reaction was then stirred at 0° C. for 15 min and at 25° C. for 18 h. After this time the reaction was concentrated in vacuo. Purification on an AnaLogix Intelliflash system (40 g column, 50% ethyl acetate/hexanes to 100% ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(3-oxo-cyclobutyl)-propionamide (49 mg, 52%) as an off-white solid: [α]29589=−14.0° (c=0.55, CHCl3); 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04, 1.05 (2×s, 6H, 2×CH3), 1.93-2.40 (m, 3H, CH and CH2), 2.69-2.84 (m, 2H, 2×CH or 2×CH2), 2.99-3.12 (m, 2H, 2×CH or 2×CH2), 3.14 (s, 3H, OCH3), 3.34 (s, 3H, SO2CH3), 3.88 (t, J=7.8 Hz, 1H, ArCHCO2), 3.98 (s, 2H, NCH2), 6.47 (d, J=2.3 Hz, 1H, Ar), 7.49 (d, J=2.3 Hz, 1H, Ar), 7.61 (dd, Jm=1.2 Hz, Jo=8.3 Hz, 1H, Ar), 7.73 (d, Jm=1.2 Hz, 1H, Ar), 8.02 (d, Jo=8.3 Hz, 1H, Ar), 10.84 (s, 1H, NH).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.F[C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C:27](=[O:29])[CH3:28].C(O[K])(C)(C)C.O>CN(C)C(=O)C>[CH3:26][C:25]1[C:20]([O:18][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]=[CH:10][N:9]=[C:8]3[NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[C:21]([C:27](=[O:29])[CH3:28])[CH:22]=[CH:23][CH:24]=1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: CC(=O)c1cccc(C)c1F
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)c1cccc(C)c1Oc1ccc2ncnc(Nc3ccn(C)n3)c2c1
Temperature: 130 °C
Reaction time: 5 h
Yield: 5.4 %

Procedure:
4-[(1-Methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (71 mg; 0.295 mmol) and 90 mg (0.592 mmol) of 1-(2-fluoro-3-methylphenyl)ethanone were added to a solution of 82 mg (0.732 mmol) of tert-butoxy potassium in 5 ml of N,N-dimethylacetamide and the mixture was stirred at 130° C. for 5 hours. Water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was dried and concentrated and the resulting residue was purified by a silica gel chromatography (chloroform:methanol=12:1) to give 6 mg (yield: 5%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[I-:9].[Na+].[OH-].[Na+].Cl[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>CO.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1
Reactant: Cc1ccc(O)cc1
Reactant: [I-]
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(O)c(I)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
4-Methylphenol (2.69 g, 24.86 mmol) was dissolved in 50 mL of methanol, and then sodium iodide (3.84 g, 25.60 mmol) and sodium hydroxide (1.16 g, 29.00 mmol) were added. Under nitrogen atmosphere, the solution was cooled down to 0° C. One equivalent of sodium hypochlorite (5.0% NaOCl, 40.0 mL) was added drop wise adjusting the drip rate to maintain a reaction temperature of 0-3° C. A red color appeared and faded instantly when sodium hypochlorite hit the solution. After complete addition, the mixture was stirred for 1 hr at 0-3° C. Then, 10% aqueous sodium thiosulfate solution (28.0 mL) was added and the pH was adjusted to 3-4 using 5% hydrochloric acid or until a white suspension came out. The reaction mixture was extracted with diethyl ether 3×50 mL. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was removed in vacuo to afforded light yellow oil, which solidified upon standing. The crude solid was purified by column chromatography (hexane:dichloromethane, 1:3 as the eluent) to afford a white solid (4.54 g, 77.9% yield). 1H NMR δ 2.24 (s, 3H), 5.16 (s, 1 H), 6.85 (d, J=8.3, 1H), 7.01 (dd, J=8.3, and 2.1, 1H), 7.46 (dd, J=1.5, 1H). m.p.: 34.5-35.5° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][CH3:13])=[CH:7]2.[NH2:14][CH2:15][CH2:16][N:17]1[CH:22]=[C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:19][C:18]1=[O:28]>CC(O)C>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:14][CH2:15][CH2:16][N:17]3[CH:22]=[C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH:20]=[CH:19][C:18]3=[O:28])=[CH:3][CH:4]=[N:5]2)=[N:10][CH:9]=1
Reactant: NCCn1cc(-c2cccs2)ccc1=O
Reactant: COc1cnc2c(Cl)ccnc2c1
Solvent: CC(C)O
Product: COc1cnc2c(NCCn3cc(-c4cccs4)ccc3=O)ccnc2c1
Temperature: 100 °C

Procedure:
A suspension of 8-chloro-3-methoxy-1,5-naphthyridine (35 mg, 182 μmol) and 1-(2-aminoethyl)-5-(thiophen-2-yl)pyridin-2(1H)-one (40 mg, 182 μmol) in iPrOH (0.5 mL) was heated to 100° C. overnight. The mixture was partitioned between CH2Cl2 (10 mL) and 1M NaOH (5 mL). The aqueous was further extracted with CH2Cl2 (2×5 mL) and combined organics dried over MgSO4 then purified on silica (12 g) eluting with 15-60% of 5% (MeOH/CH2Cl2). MS (ESI pos. ion) m/z (MH+): 379. Calc'd exact mass for C20H18N4O2S: 378. 1H NMR (400 MHz, Chloroform-d) 8 ppm 3.09 (br. s., 1H) 3.85 (q, J=6.13 Hz, 2H) 3.93 (s, 3H) 4.28 (t, J=5.97 Hz, 2H) 6.57 (d, J=5.48 Hz, 1H) 6.65 (d, J=9.59 Hz, 1H) 6.81 (d, J=2.74 Hz, 1H) 6.91-7.00 (m, 2H) 7.10-7.15 (m, 1H) 7.34 (d, J=2.54 Hz, 1H) 7.50-7.58 (m, 2H) 8.40 (d, J=2.74 Hz, 1H) 8.45 (d, J=5.48 Hz, 1H).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:31])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][C:27]([C:29]#[CH:30])=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.C(OC[N:41]=[N+:42]=[N-:43])(=O)C(C)(C)C.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[OH-].[Na+]>CC(O)(C)C.O.CO.[O-]S([O-])(=O)=O.[Cu+2]>[F:32][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:31])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][C:27]([C:29]6[N:41]=[N:42][NH:43][CH:30]=6)=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1
Reactant: C#Cc1ccn2c(C(=O)Nc3cc(-c4noc(C5CC(F)(F)C5)n4)ccc3C)cnc2c1
Reactant: CC(C)(C)C(=O)OCN=[N+]=[N-]
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2cc(-c3c[nH]nn3)ccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-7-ethynylimidazo[1,2-a]pyridine-3-carboxamide (53) (10 mg, 0.023 mmol), azidomethyl pivalate (3.64 mg, 0.023 mmol), CuSO4(2 μL of 0.5M aqueous solution, 0.001 mmol) and sodium ascorbate (1.4 mg, 0.007 mmol) in tBuOH/H2O (1 mL, 2:1) was stirred at room temperature overnight. Then the reaction mixture was diluted and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated to afford a residue which was dissolved in MeOH (1 mL). Aqueous NaOH (0.6 mL, 1N) was added and the reaction mixture was stirred for 30 minutes. The above mixture was purified by HPLC to give N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-7-(1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (F65). MS m/z 477.1 (M+1)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH3:10].[CH3:11][O:12][CH:13](Cl)Cl.O>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:11][O:12][C:13]1[C:4]([CH3:10])=[CH:5][C:6]([CH3:9])=[CH:7][C:8]=1[CH:3]=[O:2]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(C)cc1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1c(C)cc(C)cc1C=O
Reaction time: 0.33 h
Yield: 97.5 %

Procedure:
To a solution of 1-methoxy-2,4-dimethylbenzene (8.00 g, 58.7 mmol) and 1,1-dichloromethyl methyl ether (7.40 g, 64.7 mmol) in methylene chloride (30 mL) was added titanium tetrachloride (20.0 g, 105 mmol) at 0° C. and the mixture was stirred at that temperature for 20 minutes. This reaction mixture was poured into iced water and the organic layer was taken, washed with saturated aqueous sodium hydrogen carbonate solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 9.40 g of the title compound. Yield 98%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[S:17][CH:18]=[C:19]([CH2:21][C:22](OCC)=[O:23])[N:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[C:12]([C:9]1[CH:8]=[C:7]([C:16]2[S:17][CH:18]=[C:19]([CH2:21][CH2:22][OH:23])[N:20]=2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCOC(=O)Cc1csc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(-c2nc(CCO)cs2)cc(C(C)(C)C)c1O
Yield: 99.4 %

Procedure:
The compound of Step D 5.0 g (13.33 mmole), was dissolved in 95 ml tetrahydrofuran with stirring, under nitrogen. Solid lithium aluminum hydride, 760 mg (20 mmole), was cautiously added. There was much bubbling. The mixture was stirred under nitrogen for 1 hour. Water, 0.76 ml H2O, was cautiously added followed by 0.76 ml 15% sodium hydroxide, followed by 2.3 ml water. The inorganics were filterer off and the filtrate was stripped, dissolved in ethyl acetate, washed once with 1 N hydrochloric acid, twice with brine, and stripped to give 4.42 g (99%) product which was used without further purification.