Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([OH:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](N1C2C(=C(Br)C=CC=2)C(O)=N1)=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[C:6]([OH:11])=[N:7]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)n1nc(O)c2c(Br)cccc21
Reactant: Oc1n[nH]c2cc(Br)ccc12
Product: CCOC(=O)n1nc(O)c2ccc(Br)cc21

Procedure:
6-Bromo-3-hydroxy-indazole-1-carboxylic acid ethyl ester CCXXXV was prepared from 6-bromo-1H-indazol-3-ol using the procedure described for preparation of 4-Bromo-3-hydroxy-indazole-1-carboxylic acid ethyl ester CLXXXIV (Example 37).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[C:10]1=[O:19].[CH:20](Br)([CH3:22])[CH3:21].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:20]([CH3:22])[CH3:21])=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[C:10]1=[O:19]
Reactant: CC(C)Br
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)ccc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1
Yield: 99.9 %

Procedure:
N-(2-Fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (VI) (20 g), isopropyl bromide (25 g), potassium iodide (5 g) and anhydrous potassium carbonate (11 g) were dissolved in a mixture of acetonitrile (135 g) and dimethylformamide (15 g), and the resultant solution was heated under reflux for 7 hours. After cooling, the reaction mixture was extracted with ethyl acetate. The extract was concentrated, and the precipitated crystals were collected by filtration to give 23.2 g of N-(2-fluoro-5-isopropoxyphenyl)-3,4,5,6-tetrahydrophthalimide (II: R=isopropyl). M.P. 62.8° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][C:6]1([CH2:29][OH:30])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12.[H-].[Na+].[CH3:37]I>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][C:6]1([CH2:29][O:30][CH3:37])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12
Reactant: CI
Reactant: COc1cc(-c2nnc3n2CCCC3(CO)Cc2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCC1(Cc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reaction time: 0.5 h

Procedure:
{8-(3,4-Difluorobenzyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}methanol (100 mg) was added to a suspension of sodium hydride (60%, 9.4 mg) in DMF (1 mL) under ice-cooling, and the mixture was stirred for 30 min. Methyl iodide (14.7 μL) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, and diluted with ethyl acetate, and the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (80.0 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C:21](=[N:23]O)[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].N>CO.O.[Ni].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@@H:21]([NH2:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=NO)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: [Ni]
Agent: [Pd]
Agent: N
Solvent: O
Solvent: CO
Product: C[C@H](N)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 0.03 h
Yield: 63.8 %

Procedure:
To a solution of 61E (3.6 g, 10.0 mmol) in methanol in a pressure vessel was added Raney Ni in water (˜0.2 g), 10% Pd/C (Degussa type, 200 mg), water (7.5 mL) and ammonia in methanol (2.0M, 5 mL). The reaction vessel was carefully evacuated under vacuum until the solvent bubbled gently. Hydrogen gas was then introduced to a pressure of 70 psi and the reaction was stirred for 2 min). The reaction vessel was again carefully evacuated under vacuum until the solvent bubbled gently. Hydrogen gas was then introduced to a pressure of 70 psi and the reaction was stirred for 18 h at rt. The reaction was filtered through a pad of celite, taking care to keep the captured catalyst wet with methanol at all times. The celite pad was washed with methanol until the product could no longer be detected in the eluent (TLC, 5% MeOH in CH2Cl2, stain with ninhydrin and heat). Solvent was removed under vacuum and purification by flash chromatography (110 g ISCO silica gel cartridge, step gradient 0%-5%-10% MeOH in CH2Cl2) gave the title compound (2.2 g): MS (ES) m/z 345.35 [M+H]+
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12](O)[CH:11]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[C:1]([O:9][C:12]1[CH:11]=[CH:10][C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1cccnc1
Reaction time: 1 h
Yield: 57 %

Procedure:
To 9.85 g, 80 mmoles, nicotinic acid and 13.35 g, 96 =moles p-nitrophenol in 250 ml DMF was added 16.5 g, 80 mmoles DCC with stirring in ice-bath. After 1 hour at 0° C. and 3 hours at room temperature the urea was filtered off and the product was precipitated by the addition of an equal volume of water. Filtration, drying in vacuo and recrystallization from i-PrOH gave 11.22 g, 57% of white needles, m.p. 172.5°-173° C. (24)
Reaction SMILES: BrC1SC=CC=1.Br[C:8]1[S:12][C:11]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.CCN(CC)CC.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28]>C1COCC1.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.[Cu]I>[F:15][C:14]([F:17])([F:16])[C:13]([C:11]1[S:12][C:8]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])=[CH:9][CH:10]=1)=[O:18]
Reactant: C#C[Si](C)(C)C
Reactant: O=C(c1ccc(Br)s1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Brc1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(C(=O)C(F)(F)F)s1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-thiophene Example 3, C2 (1.0 eq), Pd(PPh3)2Cl2 (0.025 eq), CuI (0.05 eq) and Et3N (28.7 eq) in THF (0.25 M) was degassed with a stream of Ar for 30 min. Trimethylsilylacetylene (1.5 eq) was added and the mixture was stirred O/N at RT. Evaporation of the solvent gave a residue which was purified by flash column chromatography on silica using 0-5% EtOAc/Petroleum ether to yield the desired compound as a yellow oil. 1H NMR (300 MHz, CDCl3, 300K) δ 7.83-7.78 (1H, m), 7.25 (1H, bs), 0.28 (9H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:24](O)([CH3:26])[CH3:25])[N:9]=2)=[CH:4][CH2:3]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:24]([CH3:26])([N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)[CH3:25])[N:9]=2)=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2nc(C(C)(C)O)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN1CCN(C(C)(C)c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCC(C)(C)CC3)n2)CC1

Procedure:
The title compound is prepared from 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-6-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-amide (as prepared in Example 56, step (e)), N-methylpiperizine and thionyl chloride in DCM solvent according to the procedure in Example 14, step (e).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1([CH3:25])[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]2[CH2:24][CH2:23][NH:22][CH2:21]2)[CH:14]=1>>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([N:22]2[CH2:23][CH2:24][CH:20]([O:19][C:15]3[CH:14]=[C:13]([CH3:25])[CH:18]=[CH:17][CH:16]=3)[CH2:21]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: Cc1cccc(OC2CCNC2)c1
Product: COC(=O)c1cc(Cl)cnc1N1CCC(Oc2cccc(C)c2)C1
Yield: 49.3 %

Procedure:
The title compound (D96) (200 mg) was prepared according to the experimental procedure described in Description 62 starting from methyl 2,5-dichloronicotinate (241.37 mg, 1.17 mmol) and 3-(m-tolyloxy)pyrrolidine (D61) (247.7 mg, 1.39 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.N1C=CC=CC=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](Cl)=[O:33])=[CH:27][CH:26]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([NH:11][C:32](=[O:33])[CH2:31][C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)[N:10]=2)[CH:7]=1
Reactant: Nc1nc2ccc(F)cn2c1-c1ccccc1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Cc1ccc(F)cc1)Nc1nc2ccc(F)cn2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-amine (compound l, 0.075 g, 0.00033 mol) was dissolved in tetrahydrofuran (5.0 mL) and pyridine (29 uL, 0.00036 mol) was added. Rxn cooled to 0° C. and 4-fluorophenylacetyl chloride (48 uL, 0.00036 mol) was added. The reaction was stirred at 0° C. for 30 minutes. The solvent was removed and the crude product was partioned between water (25 mL) and EtOAc (25 mL). The layers were separated and the organic layer was washed 3×20 mL with water. The organic layer was dried (magnesium sulfate) then chromatographed on silica (70% ethyl acetate/hexanes) to give N-(6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide Rf 0.37, 70% ethyl acetate/hexanes; MS m/z 364 (M+H). SH-SY5Y_EC50 (μM): 0.7321.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[Mg].[CH2:11]([O:17][C:18](=[O:28])[C:19](OCC/C=C\CC)=[O:20])[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH3:16].[NH4+].[Cl-]>C1COCC1>[O:20]=[C:19]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1)[C:18]([O:17][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH3:16])=[O:28]
Reactant: CC/C=C\CCOC(=O)C(=O)OCC/C=C\CC
Reactant: C=Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=Cc1ccc(C(=O)C(=O)OCC/C=C\CC)cc1
Temperature: 25 °C
Yield: 37.8 %

Procedure:
A Grignard reagent prepared from 4-bromostyrene (6.95 g, 38.0 mmol) and magnesium (0.97 g, 39.9 mmol) in THF (100 mL) was added dropwise (during a period of 20 min) to a stirred solution of bis[(Z)-3-hexenyl]oxalate (9.20 g, 36.2 mmol) in THF (35 mL) at −60° C. The mixture was left warming to room temperature and poured into a mixture of ice (100 g) and a saturated solution of NH4Cl (100 mL). Extraction with diethyl ether (200 mL, 2×), washing with a saturated solution of NaCl (50 mL, 4×, pH 7), drying (Na2SO4) and concentrating afforded 11.47 g of the crude compound as a brownish oil. Bulb-to-bulb distillation of 8.68 g of the crude product (0.06 mbar, 60° C.) and column chromatography (SiO2, heptane/ether 95:5, then 1:1, then pure ether) gave 3.53 g (50%) of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:17]=[C:13]([C:14]([OH:16])=[O:15])[C:12]([OH:18])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].Cl.[OH-].[NH4+].[CH4:26]>CO.CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:17]=[C:13]([C:14]([O:16][CH3:26])=[O:15])[C:12]([OH:18])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([F:20])([F:21])[F:22]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)c(Cl)c2)ccc1O
Reactant: C
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Oc2ccc(C(F)(F)F)c(Cl)c2)ccc1O
Reaction time: 8 h

Procedure:
A chilled solution of 5-[(2-chloro-α,α,α-trifluoro-p-tolyl)oxy]salicylic acid (148 g, 0.45 mol) in methanol is saturated with hydrogen chloride gas, warmed to and held at room temperature overnight and poured onto ice. The aqueous mixture is adjusted to about pH 7.5 with concentrated ammonium hydroxide solution and extracted with methylene chloride. The combined organic extracts are washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, treated with 10 g of silica gel, filtered and concentrated in vacuo to obtain a dark gum. The gum is dissolved in a methanol-water solution, treated with charcoal, filtered and crystallized to give the title product as an offwhite solid (102.3 g 66.2% mp 62°-64° C.).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][OH:5].C(N(CC)CC)C.[N:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1>C(Cl)Cl>[OH:5][CH2:4][CH:3]([NH:2][S:30]([C:27]1[CH:26]=[CH:25][C:24]([O:23][C:20]2[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=2)=[CH:29][CH:28]=1)(=[O:31])=[O:32])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccncc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CO)NS(=O)(=O)c1ccc(Oc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled mixture of 6.84 g (44 mmol) of D, L-serine, methyl ester hydrochloride and 21.4 (144 mmol) of triethylamine in 90 ml of CH2Cl2 was added a solution of 10.78 g (40 mmol) of 4-(4-pyridinyloxy)benzenesulfonyl chloride in 50 ml of CH2Cl2. The mixture was stirred at room temperature overnight, diluted with 50 ml of CH2Cl2 and the solution washed with H2O, 1N NaHCO3, 2N citric acid, brine and dried (with Na2SO4). The solvent was removed under vacuum to give a solid. The aqueous 2N citric acid wash was made basic with saturated NaHCO3 and then extracted with CH2Cl2. The solvent was removed to give a solid. The two crops of solid were combined, washed with H2O and then hexane. The solid was dried at 80° C. to give 10.95 g of methyl 3-hydroxy-2-[4-(4-pyridinyloxy)-benzenesulfonylamino]propionate as white crystals, mp. 137-139° C.
Reaction SMILES: [NH:1]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([N:25]([CH3:41])[C@H:26]([C:34]([NH:36][NH:37][C:38]([NH2:40])=[O:39])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.OO.CC[O:53]CC.CN(C=O)C>C(O)(=O)C>[NH:1]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([N:25]([CH3:41])[C@H:26]([C:34]([NH:36][NH:37][C:38]([NH2:40])=[O:39])=[O:35])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24])=[O:20])[CH2:15][CH2:16][S:17]([CH3:18])=[O:53])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N(C)[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Reactant: CCOCC
Agent: OO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN(C(=O)CNC(=O)[C@@H](CCS(C)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Reaction time: 0.17 h

Procedure:
In 3 ml of acetic acid is dissolved 0.35 g of BOC-Tyr-(D)-Met-Gly-MePhe-NHNHCONH2 followed by addition of 0.082 ml of 30% aqueous H2O2. The solution is stirred for 10 minutes, treated with 100 ml of ether and filtered to obtain a powder. Yield 0.35 g (88%); m.p. 110°-115° C.; [α]D24 -35.1° (c=1.04, DMF); Rf1 0.05.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH2:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[C:18]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:19]2[N:20]([C:22]([C:25]([NH:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[O:26])=[CH:23][N:24]=2)[N:21]=1>CO.C(O)(C(F)(F)F)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:16]2[CH:17]=[C:18]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[C:19]3[N:20]([C:22]([C:25]([NH:27][C:28]4[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=4)=[O:26])=[CH:23][N:24]=3)[N:21]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccncc1)c1cnc2c(Nc3ccccn3)cc(Cl)nn12
Reactant: N[C@H]1CCCN(Cc2ccccc2)C1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccncc1)c1cnc2c(Nc3ccccn3)cc(N[C@H]3CCCN(Cc4ccccc4)C3)nn12
Temperature: 170 °C
Yield: 7.1 %

Procedure:
A vial containing a mixture of (S)-1-benzylpiperidin-3-amine (0.385 g, 2.021 mmol) and 6-chloro-8-(pyridin-2-ylamino)-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 37A (0.08 g, 0.135 mmol) was heated to 170° C. overnight. The mixture was dissolved in 3 mL methanol and 3 mL Solvent B (90% MeOH, 10% water, 0.1% TFA). One drop of TFA was added to the solution, the sample was split into 4 equal volumes and purified by reverse phase preparative HPLC on a Phenx Luna Axia Column 5u (21.2×100 mm) Solvent A (10% MeOH, 90% water, 0.1% TFA), Solvent B (90% MeOH, 10% water, 0.1% TFA) 20-100% solvent B gradient, 20 mL/min, 220 nM UV detection to provide (S)-6-(1-benzylpiperidin-3-ylamino)-8-(pyridin-2-ylamino)-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (0.0082 g, 9.52 μmol, 7.06% yield). 1H NMR (500 MHz, CD3OD) δ ppm 8.42 (2H, m), 8.02-7.68 (5H, m), 7.49 (1H, m), 7.29-6.76 (9H, m), 4.2-3.95 (2H, m), 3.73-3.58 (1H, m), 3.37 (1H, m), 3.06-2.64 (2H, m), 2.32-1.78 (3H, m). LC/MS: HPLC Retention time: 2.15 min, MS: 520 (M+1) (Shimidazu LC, Waters Sunfire C-18 column (4.65×50 mm, 5 um, 0-100% Solvent B, 4 min gradient, 4 mL/min, 220 UV detection. Solvent A: 10% MeOH/90% Water/0.1% TFA, Solvent B 90% MeOH/10% Water/0.1% TFA.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]=[C:7]([CH2:11]O)[C:6]=2[CH:13]=1.N1C=CC=CC=1.S(Cl)([Cl:22])=O>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]=[C:7]([CH2:11][Cl:22])[C:6]=2[CH:13]=1
Reactant: OCC1=CCOc2ccc(Cl)cc21
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: ClCC1=CCOc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 2.86 g of 6-chloro-4-hydroxymethyl-2H-1-benzopyrane in 50 ml of ether is reacted with 2 ml of pyridine. To the resulting mixture are then slowly added dropwise, with cooling by ice/water, 1.71 g of thionylchloride in 10 ml of diethylether. Reaction is continued for 5 hours at room temperature, the mixture poured onto ice/water and the ether phase separated. This is then washed with saturated aqueous NaHCO3 and water, dried over MgSO4 and concentrated by evaporation. The product is used directly for further reaction.
Reaction SMILES: [C:1]([O:9][CH:10]([CH2:57][CH:58]=[CH2:59])[CH:11]1[CH:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:14]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:13]([CH2:41][O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:12]1[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:60].[Na+].OO.O>O1CCCC1>[C:1]([O:9][CH:10]([CH:11]1[CH:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:14]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:13]([CH2:41][O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:12]1[CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[CH2:57][CH2:58][CH2:59][OH:60])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC(OC(=O)c1ccccc1)C1C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C(COCc2ccccc2)N1Cc1ccccc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OC(CCCO)C1C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C(COCc2ccccc2)N1Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of Compound (XIV) (1.80 g; 2.29 mmoles) in tetrahydrofuran (25 mL), cooled at 0° C., was added a 1.0M solution of borane-dimethylsulfide complex in tetrahydrofuran (1.5 mL). The reaction was warmed to room temperature and kept for 20 hours. After cooling to 0° C., 3N NaOH solution (15 mL) and 30W% hydrogen peroxide (0.5 mL) were added, and the suspension was heated under reflux for 1 hour. Upon cooling to room temperature, the suspension was mixed with water (10 mL) and extracted with ether (2×40 mL). The combined organic solution was washed with saturated sodium chloride solution, dried over magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the crude residual oil was purified via flash chromatography (silica gel; 1:2 ethyl acetate:hexane) to yield the primary alcohol, 1-[3,4,5-tris(phenylmethoxy)-6[(phenylmethoxy) methyl]-1-(phenylmethyl)-2-piperidinyl]-1,4-butanediol 1-benzoate (XV), as a clear, colorless oil (1.05 g; 56.9%) and the 1,4-diol, 1-[3,4,5-tris (phenylmethoxy)-6-[(phenylmethoxy)methyl]-1-(phenylmethyl) -2-piperidinyl]-1,4-butanediol (XVIII), as a yellow oil (0.41 g; 24.9%). Compound (XV): IR(neat) 1720 cm-1 (C=0); MS (FAB-MNBA) 806 (MH+), 788 (MH+H2O); 1H nmr (CDCl3) δ 1.5-1.9 (m, 2H), 2.8 (t, 1H), 3.4 (t, 2H), 3.5 (m, 1H), 3.7-4.2 (m, 7H), 4.3-4.4 (m, 1H), 4.4 (s, 2H), 4.5-4.9 (m, 7H), 5.4-5.5 (m, 1H), 7.0-7.4 (m, 27H), 7.5 (m, 1H), 8.1 (m, 2H).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][C:16](=[O:21])[C:15]([C:22]([OH:24])=O)=[CH:14]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12>CN(C=O)C>[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:15]3[C:16](=[O:21])[O:17][C:18]4[C:13]([CH:14]=3)=[CH:12][C:11]([OH:10])=[CH:20][CH:19]=4)=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: O=C(O)c1cc2cc(O)ccc2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cc(O)ccc2oc1=O
Temperature: 25 °C
Yield: 85 %

Procedure:
DIEA (46.5 μL, 0.27 mmol) was added to 6-hydroxy-3-carboxy-coumarin (50.0 mg, 0.24 mmol) and HATU (101.4 mg, 0.27 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (50.8 mg, 0.24 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 81.1 mg of product in 85% yield: LCMS (ESI) m/z 398 (MH+).