Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](/[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12]/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:23]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)([O-:25])=[O:24].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([O:16][C:15](=[O:17])/[CH:14]=[CH:13]/[CH:12]=[C:11](/[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCC/C(=C\C=C\C(=O)O)c1ccc(OC)c(OC)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC/C(=C\C=C\C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.2 %

Procedure:
As in Example 115, (E,E)-5-(3,4-dimethoxyphenyl)-2,4-decadienoic acid (3.08 g) and 4-nitrophenol (2.7 g) in 20 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (2.11 g). The mixture was stirred at room temperature for 3 days and after the usual word up crystallization of the crude ester from 2-propanol-hexane gave 2.98 g of (E,E)-5-(3,4-dimethoxyphenyl)-2,4-decadienoic acid 4-nitrophenyl ester, mp 95-°96.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[NH:22][CH:21]=3)=[O:19])[CH:17]=2)=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[N:22]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:21]=3)=[O:19])[CH:15]=[N:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)Nc1cncc(C(=O)c2c[nH]c3ncncc23)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 120.3 %

Procedure:
To a stirred solution of 2-(4-chlorophenyl)-N-[5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylcarbonyl)pyridin-3-yl]acetamide (Example 308, 250 mg, 0.638 mmol) in DMF (4 mL) was added Cs2CO3 (374 mg, 1.15 mmol) followed by methyl bromoacetate (73 uL, 0.766 mmol). The reaction was stirred at 25° C. for 3 hours and then quenched with water (10 mL) and extracted with EtOAc (3×10 mL). The organics were combined, washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to give a pale yellow oil (356 mg) which solidified on standing. Purification by column chromatography on silica gel (gradient of 0-100% 90:10:1 DCM/MeOH/NH3 in DCM) gave the title compound as a pale yellow solid in 70% yield, 208 mg. 1HNMR (400 MHz, CDCl3) δ 3.78 (s, 2H), 3.81 (s, 3H), 5.15 (s, 2H), 7.29-7.41 (m, 4H), 7.51 (s, 1H), 7.88 (s, 1H), 8.46 (m, 1H), 8.78-8.82 (m, 2H), 9.04 (s, 1H), 9.65 (s, 1H). LCMS (System 4): Rt=2.07 min; m/z 464 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[N:11]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30]1(=O)[O:35][C:33](=[O:34])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12>C1COCC1>[C:14]([O:13][C:12](=[O:18])[N:11]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:33](=[O:34])[C:32]3[C:31](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:30]2=[O:35])=[CH:3][CH:4]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (177.9 mg) and triethylamine (98 μL) in THF (2.94 mL) was added phthalic anhydride (105 mg). The mixture was stirred at room temperature overnight and the solvent was evaporated under reduced pressure. The residue was dissolved in acetic anhydride (3 mL), and the mixture was stirred at 80° C. for 5 hr. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (252.7 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][C:16]2[CH:25]=[C:24]([O:26][CH2:27][CH2:28][F:29])[CH:23]=[CH:22][C:17]=2[C:18]([O:20]C)=[O:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][C:16]2[CH:25]=[C:24]([O:26][CH2:27][CH2:28][F:29])[CH:23]=[CH:22][C:17]=2[C:18]([OH:20])=[O:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OCCF)cc1OCC1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(COc2cc(OCCF)ccc2C(=O)O)C1

Procedure:
Using a procedure similar to that of Example 26-C, the ester is hydrolyzed using LiOH.H2O (1.50 g, 2.2 equivalents), water (20 mL) and THF (60 mL) to afford the acid (2.93 g, 59% for the two steps).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][C:15]([CH3:17])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(O)(C(F)(F)F)=O>[CH3:14][C:15]1([CH3:17])[O:1][C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=2[C:4](=[O:6])[O:5]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Reactant: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)OC(=O)c2cc([N+](=O)[O-])ccc2O1
Reaction time: 1 h
Yield: 89.3 %

Procedure:
A mixture of 2-hydroxy-5-nitrobenzoic acid (50.0 g. 0.27 mol), acetone (40 mL, 0.54 mol) and trifluoroacetic anhydride (100 mL, 0.71 mol) in TFA (300 mL) was heated at reflux. After 1 hour, a supplementary amount of acetone (60 mL, 0.82 mol) was added and the reaction mixture was refluxed for 48 hours. The solvents were evaporated under reduced pressure. The residual brown solid was dissolved in DCM (800 mL) and washed with a mixture of saturated aqueous NaHCO3 (400 mL) and water (400 mL). The aqueous layer was extracted with DCM (2×400 mL). The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The residual brown oil was taken up in cold pentane (300 mL, 0° C.) and a yellow solid precipitated off. Filtration and washing with pentane gave 53.8 g (88%) of the title compound as a yellow solid. HPLC, Rt: 2.9 min (purity: 99.8%). 1H NMR (CDCl3) δ: 8.88 (d, J=2.8 Hz, 1H), 8.44 (dd, J=9.0, 2.8 Hz, 1H), 7.14 (d, J=9.0 Hz, 1H), 1.80 (s, 6H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@@H:20]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22]>>[CH3:25][N:23]([CH3:24])[C:21]([C@@H:20]([NH:19][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:26][CH:27]([CH3:28])[CH3:29])=[O:22]
Reactant: CC(C)C[C@H](N)C(=O)N(C)C
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: CC(C)C[C@H](NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)N(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42 a) and (2S)-2-amino-N,N,4-trimethyl-pentanamide hydrochloride (1:1) (CAN 207595-81-1) as starting materials, LC-MS (UV peak area/ESI) 100%, 374.2240 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:21])OC(C)=C)[CH:10]=2)=[CH:6][CH:5]=[C:4]([NH:22][C:23]([NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:24])[N:3]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CN1CCCC1>O1CCOCC1>[CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:21])[CH:10]=2)=[CH:6][CH:5]=[C:4]([NH:22][C:23]([NH:25][C:26](=[O:31])[C:27]([CH3:29])([CH3:30])[CH3:28])=[O:24])[N:3]=1
Reactant: C1COCCN1
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2C)ccn1
Agent: CN1CCCC1
Solvent: C1COCCO1
Product: Cc1nc(NC(=O)NC(=O)C(C)(C)C)ccc1Oc1ccnc(NC(=O)N2CCOCC2)c1
Temperature: 80 °C
Yield: 12 %

Procedure:
A mixture of prop-1-en-2-yl (4-((2-methyl-6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)carbamate (0.164 g, 0.384 mmol), morpholine (0.067 g, 0.767 mmol) and N-methylpyrrolidine (3.27 mg, 0.038 mmol) in dioxane (4 mL) was heated at 80° C. overnight. The mixture was cooled to RT, concentrated to dryness and purified twice via silica gel chromatography (MeOH/DCM, then MeOH/EtOAc). The material was treated with satd. NaHCO3, extracted with DCM (4×) and the combined organics were dried over Na2SO4, concentrated to dryness and further purified via silica gel chromatography (MeOH/DCM) to afford N-(4-((2-methyl-6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)morpholine-4-carboxamide (21 mg, 12%). 1H NMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H), 10.39 (s, 1H), 9.27 (s, 1H), 8.11 (d, J=5.7 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.27 (d, J=2.3 Hz, 1H), 6.57 (dd, J=5.7, 2.4 Hz, 1H), 3.53 (m, 4H), 3.38 (m, 4H), 2.23 (s, 3H), 1.21 (s, 9H); MS (ESI) m/z: 457.2 (M+H+).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][NH:35][CH:36]([CH3:38])[CH3:37])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][N:35]([CH:36]([CH3:38])[CH3:37])[C:1](=[O:5])[CH2:2][OH:3])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CC(C)NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C(O)CO
Product: CC(C)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)CO
Yield: 11 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(isopropylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 9, preparation of starting materials) to give the title compound in 11% yield; NMR spectrum (DMSO-d6) 1.19 (d, 6H), 3.81 (t, 2H), 3.93-4.01 (m, 1H), 4.14-4.18 (m, 2H), 4.35-4.47 (m, 3H), 5.31 (s, 2H), 7.21-7.29 (m, 2H), 7.32-7.40 (m, 2H), 7.56-7.63 (m, 2H), 7.70-7.76 (m, 1H), 7.86-7.91 (m, 1H), 8.04 (s, 1H), 8.47 (s, 1H), 8.60 (d, 1H), 10.02 (s, 1H); Mass spectrum MH+ 522.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=[O:15].[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21](Cl)=[O:22]>CN(C)C=O.CN(C)C1C=CN=CC=1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]([C:21]([C:17]2[O:16][CH:20]=[CH:19][CH:18]=2)=[O:22])[C:7]1=[O:15]
Reactant: O=C(Cl)c1ccco1
Reactant: O=C1Cc2ccccc2N1c1nccs1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: O=C(c1ccco1)C1C(=O)N(c2nccs2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 64 %

Procedure:
To a solution of 1-(2-thiazolyl)-2-oxindole (0.6 g, 2.7 mM) in dimethylformamide (8 ml) at 0° C. was added 4-dimethylaminopyridine (0.847 g, 2.2 eq.) and the mixture stirred for 5 minutes. Then, a solution of 2-furoyl chloride (0.31 ml, 3.04 mM, 1.1 eq.) in dimethylformamide (2 ml) was added dropwise and the mixture stirred for 15 minutes at 0° C. and then at room temperature for 2 hours. The reaction was poured onto about 100 ml of ice/2N HCl, and the resulting yellow precipitate recovered by filtration, washed with water and air-dried. Recrystallization from toluene-hexane (1:1) afforded 0.585 g (64%) of title product as yellow needles; m.p. 156°-157° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([CH3:15])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+]>>[CH2:16]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:4])=[N:14][C:13]=2[CH3:15])[CH:8]=[C:9]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]1=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1nc(C)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(Cc3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 38.3 %

Procedure:
A mixture of 1,3-dibenzyl-5-hydroxy-8-methyl-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.097 mmol), glycine (2.90 g, 38.6 mmol) and NaOMe solution (58 mL, 29 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH about 2, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was further purified by silica gel chromatography (0-60% EtOAc/hexanes+2% AcOH) to give 17 mg of the title compound MS: (+) m/z 458.17 (M+1).
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:19]3[C:18](=[O:20])[CH2:17][CH2:16][CH2:15][C:14]=3[N:13]([CH2:21][C:22]([O:24]CC)=[O:23])[C:12]=2[CH3:27])=[CH:6][CH:5]=1>C1COCC1.CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:19]3[C:18](=[O:20])[CH2:17][CH2:16][CH2:15][C:14]=3[N:13]([CH2:21][C:22]([OH:24])=[O:23])[C:12]=2[CH3:27])=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c1CCCC2=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Sc2ccc(Cl)cc2)c2c(n1CC(=O)O)CCCC2=O
Reaction time: 1 h

Procedure:
A solution of LiOH (1.79 g, 1.77 g corrected for assay, 42.2 mmol) was added to a stirred solution of ethyl [3-(4-chlorophenylsulfanyl)-2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl]acetate (7.5 g, 5.33 g corrected for assay, 14.1 mmol) in a mixture of THF (27 mL) and MeOH (27 mL). The mixture was stirred for 1 h. The solvents were removed in vacuo (45 mbar) at 45° C. until the volume of the mixture was ˜20 mL. Water (27 mL) and CH2Cl2 (27 mL) was added and the mixture stirred for 5 mins. The layers were allowed to separate, concentrated aqueous hydrochloric acid (5 mL) was added to the aqueous layer and the resulting solid product was collected by filtration and washed with water (5 mL). This crude damp product was slurried in a mixture of EtOAc (20 mL), CH5Cl2 (20 mL) and heptane (20 mL) at r.t. The product was dried briefly on the filter to give the title compound; 4.64 g; assay by 1H NMR: 89.3% w/w; yield corrected for assay: 4.14 g (84%); purity by LC 99.1 area %; m/z: 350 (MH+); 1H NMR: 1.99-2.05 (2H, m), 2.16 (3H, s), 2.26-2.31 (2H, t), 2.73-2.77 (2H, t), 4.83 (2H, s), 6.95-6.99 (2H, d), 7.23-7.27 (2H, d).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CS([O:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47]C[CH2:45][CH2:44]1)(=O)=O.O>CN(C=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:45][CH2:44][N:43]4[CH2:42][CH2:41][O:40][CH2:47][CH2:48]4)=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3ccc(O)cc3)nn3ccnc23)n1
Reactant: CS(=O)(=O)OCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCCN1c1cccc(Nc2cc(-c3ccc(OCCN4CCOCC4)cc3)nn3ccnc23)n1
Temperature: 50 °C
Yield: 80.1 %

Procedure:
To a mixture of 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(piperidin-1-yl)ethyl methanesulfonate (25 mg, 0.12 mmol). The mixture was heated at 50° C. for 16 h. After cooling, the mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography (silica, EtOAc) to give N-(6-(2-Methylpyrrolidin-1-yl)pyridin-2-yl)-6-(4-(2-morpholinoethoxy)phenyl)imidazo[1,2-b]pyridazin-8-amine (40 mg, 80%). 1H NMR (300 MHz, CDCl3): δ 8.63 (s, 1H), 8.05-7.90 (m, 4 h), 7.57 (s, 1H), 7.42 (t, 1H, J=8.0 Hz), 7.04-7.01 (m, 2H), 6.22 (d, 1H, J=7.5 Hz), 6.04 (d, 1H, J=8.4 Hz), 4.30-4.19 (m, 3H), 3.80-3.77 (m, 4 h), 3.70-3.64 (m, 1H), 3.51-3.48 (m, 1H), 2.87 (t, 2H, J=5.7 Hz), 2.65-2.62 (m, 4 h), 2.17-2.05 (m, 3H), 1.78 (brs, 1H), 1.26 (d, 3H, J=6.3 Hz). LC/MS: 500 [M+H]+, tR=1.11 min. HPLC: 99.73% at 214 nm, 99.60% at 254 nm, tR=99.73% min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[CH:2]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1)=[O:1]
Reactant: OCc1ccc2cc[nH]c2c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 6-hydroxymethyl indole (4.9 g, 33.3 mmol) in dry dichloromethane (200 ml) was added a solution of pyridinium dichromate (15.97 g, 42.5 mmol) in dry dichloromethane (100 ml) and the suspension stirred at room temperature for 5 hours. The suspension was diluted with diethyl ether and filtered through a pad of silica to give an orange solution, which was evaporated in vacuo. The crude solid was purified by flash chromatography on silica, eluting with 50% diethyl ether in hexane, to yield a pale orange solid. Recrystallisation from diethyl ether/40°-60° C. petrol gave a pale orange crystalline solid, m.p. 126°-128° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[CH3:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9])=[O:18]
Reactant: COCCCCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCCCCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (5.77 g, 40.0 mmol) and 4-dimethylaminopyridine (5.86 g, 44.0 mmol) in 100 ml of CH2Cl2 was added dropwise the solution of crude 5-methoxyvaleric chloride (6.00 g, 39.9 mmol) in 10 ml of CH2Cl2 at 0° C. The mixture was stirred at 0° C. for 1 hr then at room temperature for an additional 1 hr. The solution was washed with 1N aqueous HCl (100 ml) and brine (250 ml). After dried over Na2SO4 and evaporation of solvent, 5-(5-methoxypentanoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was obtained as a light pink oil (9.20 g, 89%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1>CO.O=[Pt]=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3occc3c2)CC1
Agent: O=[Pt]=O
Solvent: CO
Product: O=C(O)C1(c2ccc3c(c2)CCO3)CC1
Reaction time: 72 h
Yield: 46.6 %

Procedure:
To a solution of 1-(benzofuran-5-yl)cyclopropanecarboxylic acid (700 mg, 3.47 mmol) in MeOH (10 mL) was added PtO2 (140 mg, 20%) at room temperature. The stirred reaction mixture was hydrogenated under hydrogen (1 atm) at 10° C. for 3 days. The reaction mixture was filtered. The solvent was evaporated under vacuum to afford the crude product, which was purified by preparative HPLC to give 1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid (330 mg, 47%). 1H NMR (400 MHz, CDCl3) δ 7.20 (s, 1H), 7.10 (d, J=10.8 Hz, 1H), 6.73 (d, J=11.2 Hz, 1H), 4.57 (t, J=11.6 Hz, 2H), 3.20 (t, J=11.6 Hz, 2H), 1.67-1.63 (m, 2H), 1.25-1.21 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([NH2:9])=[C:7]([CH3:10])[CH:6]=[CH:5][CH:4]=1)[CH3:2].[C:11]([OH:15])(=[O:14])[CH:12]=O>CO>[NH2:9][C:8]1[C:3]([CH2:1][CH3:2])=[CH:4][C:5]([CH:12]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]([NH2:9])=[C:7]([CH3:10])[CH:6]=2)[C:11]([OH:15])=[O:14])=[CH:6][C:7]=1[CH3:10]
Reactant: O=CC(=O)O
Reactant: CCc1cccc(C)c1N
Solvent: CO
Product: CCc1cc(C(C(=O)O)c2cc(C)c(N)c(CC)c2)cc(C)c1N
Temperature: 25 °C

Procedure:
A mixture of 6-ethyl-2-methylaniline (30.0 parts) and methanol (100 parts) was stirred at ambient temperature. Glyoxylic acid 50% w/v (16.5 parts) was added and the mixture was stirred for 24 hours at ambient temperature. The precipitated product was isolated by filtration, washed with methanol (20 parts) and dried to yield di(4-amino-5-ethyl-3-methylphenyl)acetic acid (31.0 parts).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[I:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[O:17][CH2:18][CH2:19][C:12]=12>>[I:10][C:11]1[C:16]([N+:1]([O-:4])=[O:2])=[CH:15][N:14]=[C:13]2[O:17][CH2:18][CH2:19][C:12]=12
Reactant: O=[N+]([O-])O
Reactant: Ic1ccnc2c1CCO2
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cnc2c(c1I)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
A solution of fuming nitric acid (15.0 mL, 358 mmol) in concentrated sulfuric acid (15.0 mL, 281 mmol) was added slowly over a period of 15 min. to a stirred solution of 4-iodo-2,3-dihydrofuro[2,3-b]pyridine (2.237 g, 9.055 mmol) in sulfuric acid (10.0 mL, 188 mmol) at −10° C. The reaction mixture was allowed to warm to room temperature, and stirred for a further 16 h. The reaction mixture was quenched by pouring onto crushed ice and was then extracted with EtOAc (6×100 mL). The organic extracts were combined and washed with saturated aq. NaHCO3 (2×300 mL) and brine (300 mL), then dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a pale yellow solid (2.43 g, 92%). LCMS calc. for C2H61N2O3 (M+H)+: m/z=292.9. found 293.0.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH2:8]Cl)=[O:7])(=[O:3])[CH3:2].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C(N(CC)CC)C>COC(C)(C)C>[C:1]([O:4][CH2:5][C:6]([CH2:8][S:17][C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: Cc1ccc(S)cc1
Reactant: CC(=O)OCC(=O)CCl
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CC(=O)OCC(=O)CSc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
To a solution of 1-acetoxy-3-chloroacetone (5.0 g, 33.2 mmol) and 4-methylthiophenol (4.12 g, 33.2 mmol) in tert-butyl methyl ether (100 ml) was slowly added triethylamine (5.1 ml, 36.6 mmol) under ice-cooling. The solution was stirred at room temperature for 30 minutes. The reaction solution was washed with water, saturated aqueous sodium hydrogen carbonate solution, then saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give 7.72 g of 1-acetoxy-3-(4-methylphenylthio)acetone (yield: 97%) as oil.