Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[OH:31])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.Br[CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:34]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[O:31][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: Oc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-{[(3,5-Bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenol (150 mg) is dissolved in N,N-dimethylformamide (4 ml), and thereto are added ethyl 4-bromo-butyrate (74 μl) and potassium carbonate (71 mg) and the mixture is stirred at 80° C. overnight. To the reaction solution are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=22:3→7:3) to give ethyl 4-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenoxy)-butyrate (123 mg). MS (m/z): 695 [M+H]+
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22](Cl)[CH:23]=1>CN1CCCC1=O>[Cl:17][C:18]1[CH:23]=[C:22]([C:9]2[N:8]([NH2:7])[C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:21]=[N:20][CH:19]=1
Reactant: Nn1ccc2ccccc21
Reactant: Clc1cncc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Nn1c(-c2cncc(Cl)c2)cc2ccccc21
Yield: 100.3 %

Procedure:
Potassium tert-butoxide (12.7) was added to a 0° C. solution of N-aminoindole (6.0 g) in 1-methyl-2-pyrrolidinone (150 ml). After stirring for thirty minutes, 3,5-dichloropyridine (7.5 g) was added and the resulting mixture was stirred at room temperature for five hours. The reaction mixture was quenched with water, diluted with ethyl acetate (500 ml) and washed with brine (3×500 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give an oil. Purification of the oil by flash chromatography (silica, 0-2% methanol/dichloromethane) afforded the title compound (11.1 g), m.p. 154°-156° C.
Reaction SMILES: Br[CH:2]([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1COCC1.[CH2:14]([CH:17]1[CH2:22][CH2:21][CH:20]([CH:23]=[O:24])[CH2:19][CH2:18]1)[CH2:15][CH3:16].Cl>[Zn].C(OCC)(=O)C>[F:8][CH:2]([CH:23]([OH:24])[CH:20]1[CH2:21][CH2:22][CH:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCC1CCC(C=O)CC1
Reactant: CCOC(=O)C(F)Br
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC1CCC(C(O)C(F)C(=O)OCC)CC1
Reaction time: 1 h
Yield: 112.6 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 1.7 g of well-dried zinc, 3.6 g of ethyl bromofluoroacetate (e-2) and 10 ml of THF were added, and the resultant mixture was cooled to 0° C. and stirred for 1 hour. The solution was slowly added dropwise in a temperature range of 20° C. to 25° C. to another reaction vessel under a nitrogen atmosphere in which 2.0 g of 4-propylcyclohexane carboaldehyde (e-8) and 10 ml of THF were put, and the resultant mixture was further subjected to heating reflux for 4 hours. After cooling the resultant reaction mixture to 25° C., 100 ml of 1 N HCl aqueous solution and 100 ml of ethyl acetate were added to separate the mixture into an organic layer and an aqueous layer, and an extraction operation was performed. Then, the resultant organic layer was isolated, and washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then the resultant solution was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, the resultant residue was purified by a preparative isolation operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 in a volume ratio) as an eluent and silica gel as a filler, the resultant product was dried, and thus 3.8 g of ethyl 2-fluoro-3-hydroxy-3-(4-propylcyclohexyl)propanoate (e-9) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[F:18])[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO>CN(C=O)C>[C:21]1([S:27]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[C:17]([F:18])[CH:16]=3)[CH:12]=[CH:13]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Fc1cc2[nH]ccc2cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=S(=O)(c1ccccc1)n1ccc2cc(OCc3ccccc3)c(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a stirred solution of 5-benzyloxy-6-fluoroindole (Intermediate 26, 2.0 g, 8.3 mmol) in dry DMF (30 mL) was sodium hydride (60% in mineral oil, 0.35 g, 8.7 mmol) added at 0° C. The solution was stirred for 30 minutes at room temperature and the reaction mixture was cooled to 0° C. and benzenesulfonyl chloride (1.17 mL, 9.12 mmol) was added dropwise. The reaction mixture was kept at 4° C. overnight, and a drop of methanol was added and the solvent was evaporated. The crude material was dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and evaporated. The crude material was purified by flash chromatography on silica gel using DCM as the eluent to give the title compound (2.88 g) as a light yellow oil. MS m/z 382 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](O)=O)=[C:4]([NH:12][C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:16]=[CH:15][CH:14]=2)[CH:3]=1.P(Cl)(Cl)([Cl:26])=O.[OH-].[Na+]>O>[Cl:26][C:6]1[C:5]2[C:4](=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=2)[N:12]=[C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:16]=[CH:15][C:14]=12
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1ccnn1-c1ccccn1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cc2nc3c(cnn3-c3ccccn3)c(Cl)c2cc1F
Temperature: 25 °C
Yield: 57 %

Procedure:
A solution of 4,5-difluoro-2-[[1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (7.00 g, 22.1 mmol) in phosphorous oxychloride (10.3 mL, 111 mmol) was heated under reflux for 1 hour. The solution was allowed to cool to room temperature, and poured into iced water. After neutralization by addition of a sodium hydroxide solution, the organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform) to give the title compound (3.99 g, 57% yield).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[CH2:6][C:7]([O-:9])=[O:8].[Na+]>O>[C:7]([CH2:6][NH:3][CH2:2][CH2:1][NH:4][CH2:6][C:7]([OH:9])=[O:8])([OH:9])=[O:8]
Reactant: O=C([O-])CCl
Reactant: NCCN
Agent: [Na+]
Solvent: O
Product: O=C(O)CNCCNCC(=O)O
Yield: 99.9 %

Procedure:
Into a four-necked flask containing ethylenediamine (3 g, 0.05 mol) and water (50 g), an aqueous sodium chloroacetate solution (11.7 g, 0.1 mol) was added dropwise over 30 minutes. The contents were mixed at 60° C. for 2 hours, and then washed with ethanol to give 8.8 g of N,N'-bis(carboxymethyl) ethylenediamine (separation yield: 88 wt %).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:33])[F:34])=[CH:29][CH:28]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccc(OC(F)(F)F)cc2)CC1
Yield: 93.9 %

Procedure:
Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (0.400 g, 1.34 mmol) in toluene (2.68 mL). Add 4-(trifluoromethoxy)phenylboronic acid (0.303 g, 1.47 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (0.077 g, 0.067 mmol). Add ethanol (2.68 mL), followed by a 2 N aqueous sodium carbonate solution (2.68 mL). Reflux reaction for 18 hr. Cool reaction to room temperature and concentrate. Add ethyl acetate and wash with water. Extract water layer one time with ethyl acetate. Dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 20:80 ethyl acetate:hexanes), to give 3′-(4-trifluoromethoxyphenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (534 mg, 94%). MS (ES): m/z=425 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.CCN(C(C)C)C(C)C.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.Cl.O1CCOCC1>C(Cl)Cl>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([S:32]([C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:36])[F:37])=[CH:31][CH:30]=2)(=[O:34])=[O:33])[CH2:7]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82.8 %

Procedure:
To a solution of 1,1-dimethylethyl (2R)-2-methyl-1-piperazinecarboxylate (2.95 g, 14.73 mmol) in DCM (120 ml) was added DIPEA (5.40 ml, 30.9 mmol) and then 4-(trifluoromethyl)benzenesulfonyl chloride (3.96 g, 16.20 mmol). The reaction mixture was stirred 2.5 hours at room temperature then washed with water (250 ml), dried on a phase separation cartridge and concentrated in vacuo. The obtained product was dissolved in 1,4-dioxane (60 ml) and treated with 4M aq. HCl in 1,4-dioxane (18.41 ml, 73.6 mmol) overnight. The mixture was concentrated under vacuo then dissolved in EtOAc (150 ml), washed with 2N aq. NaOH solution (200 ml) then dried on a phase separation cartridge and concentrated in vacuo. The product was then dissolved in EtOAc (100 ml) and extracted with 2M aq. HCl (2×200 ml). 2M aq. NaOH solution was added to the aqueous layer until basic pH then the product was extracted with EtOAc (500 ml). The organic layer was dried on a phase separation cartridge and concentrated under vacuo to give the title compound (3.76 g).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2].[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(O)C.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>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:30]3[CH:29]=[N:28][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH:31]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2]
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
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
Solvent: CCO
Product: COCCn1cc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cn1
Reaction time: 8 h

Procedure:
1-Methylethyl [(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for preparation see Intermediate 1) (185 mg), 1-[2-(methyloxy)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (for a preparation see Journal of Heterocyclic Chemistry, 41(6), 931-939; 2004) (151 mg), potassium carbonate (90 mg) and tetrakis(triphenylphosphine)palladium(0) (28.9 mg) were combined in ethanol and toluene under nitrogen and heated to 80° C. for 18 h. The reaction was concentrated, the residue partioned between ethyl acetate (10 ml) and water (10 ml) and the aqueous layer was extracted with ethyl acetate (10 ml). The combined organics were washed with brine (25 ml), dried with sodium sulphate, filtered and concentrated. The residue was purified by MDAP (formate ×2) and the collected product dissolved in 1,4-dioxane (0.5 ml) and cooled in a CO2 bath then left on a freeze dryer overnight. The resulting white solid was dried at 40° C. under vacuum overnight to give 1-methylethyl ((2S,4R)-1-acetyl-2-methyl-6-{1-[2-(methyloxy)ethyl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (84.7 mg). LCMS (formate), Rt 0.84 min, MH+ 415
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[CH:2].[CH3:13][O:14][C:15](=[O:45])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[C:27][C:28]2[CH:33]=[C:32]([C:34]#[C:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:31]=[C:30](Br)[CH:29]=2)=[CH:20][C:19]=1[CH3:44]>CN(C=O)C.C(N(CC)CC)C.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>[CH3:13][O:14][C:15](=[O:45])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[C:27][C:28]2[CH:33]=[C:32]([C:34]#[C:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:31]=[C:30]([C:2]#[C:1][C:3]3[CH:4]=[CH:5][C:6]([S:9]([CH3:12])(=[O:10])=[O:11])=[CH:7][CH:8]=3)[CH:29]=2)=[CH:20][C:19]=1[CH3:44]
Reactant: C#Cc1ccc(S(C)(=O)=O)cc1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#CCN3CCOCC3)c2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccc(S(C)(=O)=O)cc3)c2)cc1C
Temperature: 65 °C

Procedure:
A mixture of 1-ethynyl-4-methanesulfonyl-benzene (346 mg, 1.92 mmol), (4-{3-[3-bromo-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (123 mg, 0.24 mmol, example 6), Pd(PPh3)2Cl2 (17 mg, 0.024 mmol), CuI (12 mg, 0.067 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 1 hour at 65° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using methylene chloride/THF mixtures to give (4-{3-[3-(4-methanesulfonyl-phenylethynyl)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester in 50 mg (34%) yield.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([CH:16]=[N:17][OH:18])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].BrN1C(=O)[CH2:25][CH2:24][C:23]1=O.ClC(C)=C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:20][C:2]([F:1])([F:19])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([C:16]3[CH:23]=[C:24]([CH3:25])[O:18][N:17]=3)=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N1CCc2ccc(C=NO)cc2CC1)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: C=C(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccc3c(c2)CCN(C(=O)C(F)(F)F)CC3)no1
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 36.4 %

Procedure:
To a solution of 3-Trifluoracetyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-carbaldehyde oxime (17.2 g) in chloroform (700 ml) was added N-bromosuccinimide (11.8 g), portionwise over 5 min., and the mixture stirred for 1.5 h. 2-Chloropropene (30.3 ml) was added and the reaction cooled to −20° C. Triethylamine (25.1 ml) in chloroform was added over 10 min. and the reaction stirred at room temperature for 18 h. The solution was washed with 2M HCl, dried and evaporated and the residue chromatographed on Si gel, gradient eluting with 10-20% EtOAc in hexane to give the title compound (7.1 g) as a yellow oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)O1.[Cl:19][C:20]1[N:24]=[C:23](Cl)[S:22][N:21]=1.O.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[Cl:19][C:20]1[N:24]=[C:23]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[S:22][N:21]=1
Reactant: Clc1nsc(Cl)n1
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
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: COCCOC
Solvent: O
Product: Clc1nsc(-c2ccc3[nH]ccc3c2)n1
Temperature: 85 °C
Yield: 35.1 %

Procedure:
To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (2 g, 8.23 mmol, Aldrich) and 3,5-dichloro-1,2,4-thiadiazole (1.27 g, 8.23 mmol, Aldrich) in 1,2-dimethoxy ethane (30 mL)/H2O (10 mL) was added K2CO3 (2.27 g, 16.46 mmol) and Pd(PPh3)4 (0.95 g, 0.82 mmol). N2 gas was purged for 15 min through the mixture. The reaction was heated at reflux at 85° C. for 6 h. The mixture was cooled to RT and quenched with H2O (100 mL) and was extracted with EtOAc (2×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica-gel column chromatography (eluent: 5% EtOAc in petroleum ether) to give 3-chloro-5-(1H-indol-5-yl)-1,2,4-thiadiazole (680 mg, 35.5%) as an off white solid. MS (ESI, pos. ion) m/z: 236 (M+1); 1H-NMR (300 MHz, CDCl3): δ 8.5 (brs, 1H), 8.29 (d, J=0.8 Hz, 1H), 7.78 (dd, J=8.4, 1.8 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.32-7.31 (m, 1H), 6.67 (t, J=2.1 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:15])=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](I)[CH3:23]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:15][CH2:22][CH3:23])=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2[nH]ncc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2[nH]ncc2c1OCC
Reaction time: 10 h

Procedure:
4.1 g of 4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.02 mol), 5.6 g of potassium carbonate (0.04 mol) and 3.5 g of ethyl iodide (0.022 mol) are heated in 30 ml of dimethylformamide with stirring for 10 hours at 60°. After this time, the excess potassium carbonate is filtered off and 30 ml of water is added. 4-Ethoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester precipitates and is recrystallized from methanol, yield 2 g (42.5%), m.p. 180°.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH2:12]([NH2:15])[CH2:13][CH3:14]>>[OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:15][CH2:12][CH2:13][CH3:14])=[O:6]
Reactant: CCCN
Reactant: COC(=O)c1ccccc1O
Product: CCCNC(=O)c1ccccc1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
The crude methyl 2-hydroxybenzoate was dissolved in n-propylamine (400 mL). The reaction mixture in a sealed reactor was stirred at 80° C. overnight. The reaction mixture was concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography to afford 120 g (84%) of 2-hydroxy-N-propylbenzamide. LCMS ESI (+) m/z 180 (M+1) detected.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:15]([O:16]C(=O)C2C=CC=CC=2)[C@H:14]([O:25]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:34][O:35]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[O:44][C@H:45]1[C@H:50]([O:51]C(=O)C2C=CC=CC=2)[C@@H:49]([CH2:60][O:61]C(=O)C2C=CC=CC=2)[O:48][C@H:47]([O:70][C@H:71]2[C@H:114]([O:115]C(=O)C3C=CC=CC=3)[C@@H:113]([CH2:124][O:125]C(=O)C3C=CC=CC=3)[O:112][C@H:73]([O:74][CH2:75][CH2:76][CH2:77][N:78]3[CH:82]=[C:81]([CH2:83][O:84][C@H:85]4[CH2:109][CH2:108][C@@:107]5([CH3:110])[CH:87]([CH2:88][CH2:89][C@@H:90]6[C@@H:106]5[CH2:105][CH2:104][C@@:103]5([CH3:111])[C@H:91]6[CH2:92][CH2:93][C@@H:94]5[C@H:95]([CH3:102])[CH2:96][CH2:97][CH2:98][CH:99]([CH3:101])[CH3:100])[CH2:86]4)[N:80]=[N:79]3)[C@H:72]2[O:134]C(=O)C2C=CC=CC=2)[C@H:46]1[O:143]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C[O-].[Na+]>C1COCC1.CO>[C@H:11]1([O:44][C@H:45]2[C@H:50]([OH:51])[C@@H:49]([CH2:60][OH:61])[O:48][C@H:47]([O:70][C@H:71]3[C@H:114]([OH:115])[C@@H:113]([CH2:124][OH:125])[O:112][C@H:73]([O:74][CH2:75][CH2:76][CH2:77][N:78]4[CH:82]=[C:81]([CH2:83][O:84][C@H:85]5[CH2:109][CH2:108][C@@:107]6([CH3:110])[CH:87]([CH2:88][CH2:89][C@@H:90]7[C@@H:106]6[CH2:105][CH2:104][C@@:103]6([CH3:111])[C@H:91]7[CH2:92][CH2:93][C@@H:94]6[C@H:95]([CH3:102])[CH2:96][CH2:97][CH2:98][CH:99]([CH3:101])[CH3:100])[CH2:86]5)[N:80]=[N:79]4)[C@H:72]3[OH:134])[C@H:46]2[OH:143])[O:12][C@H:13]([CH2:34][OH:35])[C@@H:14]([OH:25])[C@H:15]([OH:16])[C@@H:10]1[OH:9]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@@H](OCc5cn(CCCO[C@H]6O[C@H](COC(=O)c7ccccc7)[C@@H](OC(=O)c7ccccc7)[C@H](O[C@H]7O[C@H](COC(=O)c8ccccc8)[C@@H](OC(=O)c8ccccc8)[C@H](O[C@H]8O[C@H](COC(=O)c9ccccc9)[C@@H](OC(=O)c9ccccc9)[C@H](OC(=O)c9ccccc9)[C@@H]8OC(=O)c8ccccc8)[C@@H]7OC(=O)c7ccccc7)[C@@H]6OC(=O)c6ccccc6)nn5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@@H](OCc5cn(CCCO[C@H]6O[C@H](CO)[C@@H](O)[C@H](O[C@H]7O[C@H](CO)[C@@H](O)[C@H](O[C@H]8O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]8O)[C@@H]7O)[C@@H]6O)nn5)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 48 h

Procedure:
The perbenzoate 58 (70 mg, 0.0341 mmol) was dissolved in anhydrous THF (2 mL) and MeOH (2 mL). The mixture was treated with a solution of 11M NaOMe in MeOH (0.2 mL, 2.2 mmol). After stirring at r.t for 2 days, the white suspension was neutralized by addition of AG50WX8 resin (H+ form). The clear solution was separated from the resin by filtration. The resin was washed with MeOH (3×2 mL). The combined filtrate and washings were evaporated to dryness and dried in vacuum dessicator under P2O5 o/n to give the polyol 59, used directly in the next step.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=O)=[CH:15][CH:14]=1.[NH2:35][C:36]1[NH:37][CH2:38][CH2:39][CH2:40][N:41]=1>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][C:23](=[O:25])[NH:35][C:36]2[NH:41][CH2:40][CH2:39][CH2:38][N:37]=2)=[CH:17][CH:18]=1
Reactant: NC1=NCCCN1
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](Nc2nc3ccccc3s2)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)Nc1nc2ccccc2s1
Reaction time: 24 h
Yield: 28.2 %

Procedure:
The ester 7-2 (80 mg) is mixed with 2-amino-1,4,5,6-tetrahydropyrimidine (40 mg) in 5 ml of CH2Cl2 and agitation is carried out at ambient temperature for 24 hours. After evaporating under reduced pressure, purifying the dry extract obtained by chromatography eluting with a CH2Cl2/MeOH mixture (100/0→90/10), 25 mg of the expected product 7-3 is obtained.