Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH:14]=[CH:13]2.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([N:15]2[C:16]3[C:12](=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:18][CH:17]=3)[CH:13]=[CH:14]2)=[CH:20][CH:21]=1
Reactant: Fc1ccc(-n2ccc3cc(OCCCCCCCBr)ccc32)cc1
Reactant: C1CCNCC1
Product: Fc1ccc(-n2ccc3cc(OCCCCCCCN4CCCCC4)ccc32)cc1

Procedure:
In analogy to example 2.2, 5-(7-Bromo-heptyloxy)-1-(4-fluoro-phenyl)-1H-indole and piperidine were converted to yield 1-(4-Fluoro-phenyl)-5-(7-piperidin-1-yl-heptyloxy)-1H-indole as colorless gum, MS: 408 (MH+).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1)#[N:2].[OH-:38].[Na+].OO>CO.CS(C)=O.C(#N)C.CCOC(C)=O>[C:1]([C:3]1[N:4]=[CH:5][C:6]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[CH2:25]2)=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])=[CH:14][CH:15]=1)(=[O:38])[NH2:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
To a solution of (R)-tert-butyl 1-(5-cyano-6-(4-(morpholine-4-carbonyl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate (88) in MeOH (15 mL) and DMSO (1.5 mL) was added solid NaOH (200 mg) and 30% H2O2 (1.5 mL). The mixture was stirred at RT for 20 min, diluted with acetonitrile (10 mL), and EtOAc (200 mL) 10 min later. The organic phase was washed with water ×2, dried, and concentrated in vacuo. The residue was subjected to flash column chromatography with 0 to 7% MeOH in DCM to isolate (R)-tert-butyl 1-(5-carbamoyl-6-(4-(morpholine-4-carbonyl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate (89) (yield >95%). (R)-tert-butyl 1-(5-carbamoyl-6-(4-(morpholine-4-carbonyl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate (89) was treated with 4N HCl in dioxane (30 mL) for 40 min. The mixture was concentrated in vacuo to dryness to afford (R)-5-(3-aminopiperidin-1-yl)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamide hydrochloride (90).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:14])[CH:8]=2)[N:3]=1.[NH2:15][C@H:16]1[C@H:20]([OH:21])[CH2:19][N:18]([C:22](=[O:35])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=2)[CH2:17]1.O1CCOCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O.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]>[OH:21][C@H:20]1[C@H:16]([NH:15][C:2]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:14])[CH:8]=3)[N:3]=2)[CH2:17][N:18]([C:22](=[O:35])[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:28][CH:29]=2)[CH2:19]1
Reactant: COc1cc(Cl)nc2ccc(C)cc12
Reactant: N[C@@H]1CN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C[C@H]1O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(N[C@@H]2CN(C(=O)Cc3ccc(OC(F)(F)F)cc3)C[C@H]2O)nc2ccc(C)cc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a mixture of 2-chloro-4-methoxy-6-methylquinoline (0.12 g), Pd2(dba)3 (0.027 g), (±)-BINAP (0.056 g), 1-((3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.22 g), and 1,4-dioxane (2 mL) was added sodium t-butoxide (0.17 g) under nitrogen atmosphere, and the mixture was stirred at 70° C. for 1 h. The reaction mixture was diluted with ethyl acetate and water, then the interlayer was removed by Celite filtration, and the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, ethyl acetate, and NH silica gel, ethyl acetate/chloroform) to obtain white solid 1-((3R,4R)-3-hydroxy-4-(4-methoxy-6-methylquinolin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.16 g).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:26]=[CH:25][C:13]([O:14][CH:15]([CH3:24])[C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[BH4-].[Na+].O.C(Cl)Cl>C(O)C>[F:27][C:2]([F:1])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:26]=[CH:25][C:13]([O:14][CH:15]([CH3:24])[CH:16]([OH:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=2)=[N:7][CH:8]=1
Reactant: CCOC(=O)CC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 4-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]-3-oxopentanoate (175 mg, 0.44 mmol) in 5 ml of absolute ethanol at 0° is added sodium borohydride (32 mg, 0.84 mmol). The mixture is stirred for 15 minutes, after which it is poured into water and methylene chloride. The aqueous phase is separated and back-extracted with methylene chloride. The combined solvent extracts are washed with brine and dried. Solvent is removed by rotoevaporation, and the residue is purified by prep. thin layer chromatography (silica gel, 25% ethyl acetate/hexane) to yield ethyl 4-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]-3-hydroxypentanoate.
Reaction SMILES: N1CCCCC1.[C:7]([C:9]1[C:10](=[O:49])[NH:11][C:12](=[O:48])[N:13]([CH:47]=1)[C@@H:14]1[O:45][C@H:17]([CH2:18][O:19][C:20](=[O:44])[C@H:21]([C@H:40]([CH2:42][CH3:43])[CH3:41])[NH:22]C(OCC2C3CC4C(=CC=CC=4)C=3C=CC=2)=O)[C@@H:16]([F:46])[CH2:15]1)#[CH:8]>CN(C)C=O>[C:7]([C:9]1[C:10](=[O:49])[NH:11][C:12](=[O:48])[N:13]([CH:47]=1)[C@@H:14]1[O:45][C@H:17]([CH2:18][O:19][C:20](=[O:44])[C@H:21]([C@H:40]([CH2:42][CH3:43])[CH3:41])[NH2:22])[C@@H:16]([F:46])[CH2:15]1)#[CH:8]
Reactant: C#Cc1cn([C@H]2C[C@H](F)[C@@H](COC(=O)[C@@H](NC(=O)OCc3cccc4c3Cc3ccccc3-4)[C@@H](C)CC)O2)c(=O)[nH]c1=O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: C#Cc1cn([C@H]2C[C@H](F)[C@@H](COC(=O)[C@@H](N)[C@@H](C)CC)O2)c(=O)[nH]c1=O

Procedure:
A 20% solution of piperidine in dry dimethylformamide (5 ml) was added to 2',3'-dideoxy-5-ethynyl-5'-O-(N-fluorenylmethoxycarbonyl-L-isoleucinyl)-3'-fluorouridine (0.57 g, 0.96 mmol) and after 4 minutes at room temperature, the solvents were evaporated rapidly under high vacuum with minimal heating. Trituration of the residue with several portions of ether afforded a crop of the title compound containing ~5% of N,N'-dicyclohexylurea.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[C:7]=2[O:6]1)=[N+]=[N-]>[Pd]>[CH3:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]2[C:7]3[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=3[CH:10]=[CH:11][CH:12]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(-c2cccc3c2OC(CN=[N+]=[N-])C3)cc1
Agent: [Pd]
Product: Cc1ccc(-c2cccc3c2OC(CN)C3)cc1
Yield: 75 %

Procedure:
Treatment of (±)-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.01 g, 2.56 mmol) with sodium azide (0.664 g, 10.24 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.03 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.528 g (75%) of (±)-1-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 231-232° C.; Anal. calcd. for C16H17NOHCl: C, 69.69; H, 6.58; N, 5.08. Found: C, 66.26; H, 7.0; N, 4.73.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:32])[CH2:11][C@H:12]([C:22]1[O:23][CH:24]=[C:25]([C:27]([O:29]CC)=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCOCC1.O>[CH2:1]([O:8][NH:9][C:10](=[O:32])[CH2:11][C@H:12]([C:22]1[O:23][CH:24]=[C:25]([C:27]([OH:29])=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(C(=O)O)co1)NOCc1ccccc1
Reaction time: 3.5 h
Yield: 61.1 %

Procedure:
A solution of ethyl 2-((1R)-1-{2-[(benzyloxy)amino]-2-oxoethyl}4-cyclohexylbutyl)-1,3-oxazole4-carboxylate (Preparation 64) (1.31 g, 2.96 mmol) in 1,4-dioxane:water (10 ml:5 ml) was treated with lithium hydroxide monohydrate (0.19 g, 4.44 mmol) and stirred in a cold water bath for 3.5 hours. The mixture was diluted with water (100 ml) and washed with ethyl acetate. The layers were separated and the aqueous layer was acidified with solid citric acid then extracted with ethyl acetate. The layers were separated and the organic layer was dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a white solid (0.75 g).
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:20])[C:14]([C:18]#[N:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])CCC.[BH4-].[Li+]>C(O)C.C(OCC)C>[C:18]([C:14]1[C:13]([CH3:20])=[C:12]2[C:17](=[CH:16][CH:15]=1)[CH:8]([CH2:7][CH2:6][OH:5])[N:9]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:10][CH2:11]2)#[N:19]
Reactant: CCCCOC(=O)CC1c2ccc(C#N)c(C)c2CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: CCOCC
Product: Cc1c(C#N)ccc2c1CCN(C(=O)OC(C)(C)C)C2CCO
Reaction time: 1.5 h
Yield: 96.6 %

Procedure:
To a solution of 1,1-dimethylethyl 1-[2-(butyloxy)-2-oxoethyl]-6-cyano-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 18; 2.15 g, 5.56 mmol) in ethanol (10 ml) and diethyl ether (40 ml) was added lithium borohydride (2M solution in tetrahydrofuran, 4.17 ml; 8.34 mmol) at 25° C. under nitrogen. After 1.5 h at 25° C., the solvent was removed, and the residue dissolved in ethyl acetate. The solution was washed with 1N hydrochloric acid, and the aqueous layer further extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, dried over MgSO4 and concentrated in vacuo to give the title compound (1.70 g) as a white foam.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H][H].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CCOC(C)=O.C(Cl)Cl.[Pd]>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CC=C(c2cccc(C(F)(F)F)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1CCC(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
To a solution of Intermediate 3C (650 mg, 2.71 mmol) in EtOAc (10 mL) was added Pd/C (0.15 g, 0.27 mmol) in a pressure bottle. The mixture was stirred under 45 psi of hydrogen for 16 h. The catalyst was carefully filtered under nitrogen and the solvent was removed under vacuum. The residue was dissolved in DCM (10 mL) and Dess-Martin periodinane (1.26 g, 2.98 mmol) was added as one single portion. The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with DCM, washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified by flash chromatography on a 24 g cartridge with 0 to 100% EtOAc in hexanes over 15 min to give Intermediate 3D (276 mg, 1.14 mmol, 42.1% yield). LCMS, RT=2.01 min (Method B).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][CH:6]=1)=[NH:4].Cl.[Cl:18]CCN>Cl>[ClH:18].[CH3:1][N:2]([CH3:16])[C:3]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[NH:4]
Reactant: CCOC(=O)c1ccc(C(=N)N(C)C)cc1
Reactant: NCCCl
Agent: Cl
Product: CN(C)C(=N)c1ccc(C(=O)O)cc1

Procedure:
Ethyl 4-(N,N-dimethylamidino)benzoate (compound of step 1 in Example 7) was heated under reflux in 6 N hydrochloric acid for 6 hours, and then the solvent was distilled off to obtain the title compound.
Reaction SMILES: O[C:2]1([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1>S(=O)(=O)(O)O>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][CH2:3][CH:2]2[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1cccc2c1CCCC2(O)CN1CCCCC1
Agent: O=S(=O)(O)O
Product: COc1cccc2c1C=CCC2CN1CCCCC1
Temperature: 0 °C

Procedure:
The hydroxy compound of Step 2 (75 g) is dissolved in 20% (w/w) sulfuric acid (375 ml) and refluxed under nitrogen for 18 hours. The cooled mixture is poured into ice-water, extracted with ether and the aqueous layer made strongly alkaline. The precipitated oil is extracted into ether which is washed, dried, filtered and evaporated in vacuo yielding the desired product as an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si]([C:11]#[C:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])(C)C>C(O)C>[C:12]([C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[CH:11]
Reactant: CCOC(=O)c1cccc(C#C[Si](C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#Cc1cccc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
Potassium carbonate (583 mg, 4.22 mmol) was added to an ethanol solution (10 ml) of ethyl 3-[(trimethylsilyl)ethynyl]benzoate (1.04 g, 4.22 mmol), and stirred at room temperature for 2 h. The mixture was concentrated, and the residue was dissolved in ethyl acetate. The organic layer was washed with water and then brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=30/1) to give ethyl 3-ethynylbenzoate (96%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(-c2cnc3[nH]cc(I)c3n2)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3c(n2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94.3 %

Procedure:
7-Iodo-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (371 mg, 0.9 mmol) was suspended in 5 ml of THF and cooled to 0° C. in an ice bath. Sodium hydride, 60% dispersion in mineral oil (43 mg, 1.08 mmol) was added and the suspension was stirred for 20 minutes. 4-Methyl-benzenesulfonyl chloride (189 mg, 0.99 mmol) was added, the ice bath was removed, and the reaction was stirred at room temperature for 3 hours. The solvent was evaporated on a rotary evaporator. The residue was triturated with 1M potassium hydroxide. The solid was filtered, washed with water, and dried to yield 480 mg of 7-iodo-5-(toluene-4-sulfonyl)-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine which was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:9]([NH:12][C:13]#[N:14])(=[O:11])[CH3:10].[Na]>CN(C)C=O>[CH2:2]([N:12]([C:13]#[N:14])[C:9](=[O:11])[CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)NC#N
Reactant: CCCCCCCBr
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCCCCCN(C#N)C(C)=O

Procedure:
36.0 g (0.20 mol) of 1-bromoheptane are added dropwise to a solution of 21.2 g (0.20 mol) of sodium acetylcyanamide in 50 ml of dimethylformamide at 85° C. The mixture is allowed to after-react for 2 hours and the NaBr is filtered off with suction at room temperature. The filtrate is treated with 50 ml of H2O and the mixture is extracted with cloroform. The solvent is separated off on a rotary evaporator and the crude product is distilled over a rotating belt column to give 24.3 g (66.7% of theory) of pure product of boiling point 124° C./18 mbar.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][Si:22]([CH3:26])([CH3:25])[CH2:21][CH2:20]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+].O>CN(C=O)C>[N:28]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][Si:22]([CH3:26])([CH3:25])[CH2:23][CH2:24]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: C[Si]1(C)CCN(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si]1(C)CCN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To the Mesyl compound 18 (250 mg, 0.59 mmol) in DMF, NaN3 (78 mg, 1.20 mmol) is added and stirred at 60° C. for 2 h. Water (5 mL) is then added and extracted with DCM (2×5 mL), dried and concentrated. The crude (220 mg) is used for further steps without purification.
Reaction SMILES: C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[I:34][C:35]1[O:36][CH:37]=[CH:38][C:39]=1[C:40]([OH:42])=O.[CH3:43][CH:44]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[NH2:55])[CH2:45][CH:46]([CH3:48])[CH3:47]>C(#N)C.O>[CH3:43][CH:44]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[NH:55][C:40]([C:39]1[CH:38]=[CH:37][O:36][C:35]=1[I:34])=[O:42])[CH2:45][CH:46]([CH3:47])[CH3:48]
Reactant: CC(C)CC(C)c1ccccc1N
Reactant: O=C(O)c1ccoc1I
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)CC(C)c1ccccc1NC(=O)c1ccoc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.2 %

Procedure:
Under protective gas (argon), 0.56 ml (3.38 mmol) of N,N-diisopropylethylamine and 1.18 g (2.5 mmol) of bromotrispyrrolidinophosphonium hexafluorophosphate (PyBrop) are added to a solution of 483 mg (2.02 mmol) of 2-iodofuran-3-carboxylic acid and 300 mg (1.7 mmol) of 2-(1,3-dimethylbutyl)phenylamine in 10 ml of acetonitrile. The reaction mixture is stirred at room temperature for 24 hours and, for work-up, added to water, extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. Column chromatography (cyclohexane/ethyl acetate gradient) gives 130 mg (18% of theory) of N-[2-(1,3-dimethylbutyl)phenyl]-2-iodo-3-furamide [log P (pH 2.3)=3.88].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:20][CH2:21][OH:22]>CCO.C(#N)C>[OH:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:18])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: OCCCl
Reactant: O=c1cc(-c2ccc(O)cc2)oc2ncccc12
Solvent: CCO
Solvent: CC#N
Product: O=c1cc(-c2ccc(OCCO)cc2)oc2ncccc12
Temperature: 25 °C
Yield: 32.1 %

Procedure:
In a 100 mL dry round bottom flask with reflux condenser and magnetic stirrer was placed 2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one (1.0 g, 4.18 mmol) in EtOH (10 mL) and acetonitrile (50 mL). 2-Chloroethanol (2.05 g, 25.0 mmol) was added slowly and the reaction mixture was refluxed for 48 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography, using 2% MeOH in dichloromethane to afford 2-(4-(2-hydroxyethoxy)phenyl)-4H-pyrano[2,3-b]pyridine-4-one (380 mg, 32% yield). MS (ES) m/z: 284.94 (M+1), 283.95 (M); MP 157-159° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[ClH:21].[NH3:22]>C(O)C>[ClH:21].[F:1][C:2]([F:19])([F:20])[CH:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]([NH2:22])=[NH:16])=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: N
Reactant: CCCCCCC(Oc1ccc(C#N)cc1)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: CCCCCCC(Oc1ccc(C(=N)N)cc1)C(F)(F)F

Procedure:
Into 20 ml of dry ethanol containing 3.76 g of oa p-(1-trifluoromethyl-heptyloxy)-benzonitrile, about 1 g of dry hydrogen chloride was introduced under stirring at a temperature below 10° C. After stirring at room temperature for 3 days, solvent was distilled off to obtain any oily product To this, were added slowly 20 ml of dry ethanol containing about 2 g of ammonia under cooling with ice, followed by stirring at room temperature for 3 days. Ethanol and ammonia were removed to obtain 3.40 g of oily oa p-(1-trifluoromethyl-heptyloxy)-benzamidine hydrochloride. This oily hydrochloride was solidified by trituration in hexane to use the following reaction.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([O:18]CC)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.C1COCC1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([OH:18])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3ccccc3F)cccn12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nc2c(OCc3ccccc3F)cccn2c1C(=O)O
Reaction time: 96 h
Yield: 100.7 %

Procedure:
To 2.16 g of ethyl 8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate were added 20 ml of THF, 40 ml of ethanol, and 20 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring for 4 days. The solvent was evaporated under reduced pressure, and water and 1 M hydrochloric acid were added thereto. The insoluble material was collected by filtration and dried to obtain 1.99 g of 8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]C#N)=[C:4]([C:12](=O)[C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:3]=1.[OH-].[NH4+:22]>CO>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[S:9][N:22]=[C:12]([C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=3)[C:4]=2[CH:3]=1
Reactant: [NH4+]
Reactant: Cc1cccnc1C(=O)c1cc(N)c(F)cc1SC#N
Agent: [OH-]
Solvent: CO
Product: Cc1cccnc1-c1nsc2cc(F)c(N)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
A mixture of 4-amino-5-fluoro-2-(3-methylpicolinoyl)phenyl thiocyanate(3.06 g, 0.0112 mole), concentrated ammonium hydroxide (300 ml) and methanol (300 ml) is stirred overnight at room temperature. The methanol is removed in vacuo and the resultant mixture is filtered to afford the title compound as a green solid (1.93 g, 66.6%) which is identified by NMR spectral analysis.
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1>>[CH2:4]1[C:8]2([CH:13]=[CH:12][C:11](=[O:14])[CH:10]=[CH:9]2)[CH2:7][CH2:6][CH2:5]1
Reactant: Oc1ccc(CCCCCl)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C1C=CC2(C=C1)CCCC2
Temperature: 190 °C
Yield: 47.8 %

Procedure:
A 25% sodium hydroxide aqueous solution, 4.8 g, was added to 5.5 g of p-(4-chlorobutyl)phenol and stirred. The mixture was slowly heated under reduced pressure while removing water (until 120° C. at 50 Pa) and subsequently heated to 180-200° C., at which a distillate was collected. There was obtained 2.11 g (yield 47%) of spiro[4.5]deca-6,9-dien-8-one.