Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]([CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)=[CH2:4].[CH3:11][C:12]([Si:15]([CH3:23])([CH3:22])[O:16][C@@H:17]([CH3:21])[C:18](Cl)=[O:19])([CH3:14])[CH3:13]>O1CCCC1.C(Cl)Cl>[CH3:13][C:12]([Si:15]([CH3:23])([CH3:22])[O:16][C@@H:17]([CH3:21])[C:18]([N:9]1[C@H:5]([CH:3]=[CH2:4])[CH2:6][CH2:7][C:8]1=[O:10])=[O:19])([CH3:11])[CH3:14]
Reactant: C=CC1CCC(=O)N1
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C[C@@H]1CCC(=O)N1C(=O)[C@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 52.3 %

Procedure:
To 60% sodium hydride (336 mg, 10 mmol) in mineral oil) in tetrahydrofuran (20 mL) at 0° C. was added dropwise a solution of 5-vinylpyrrolidin-2-one (1.0 g, 9.0 mmol) in tetrahydrofuran (10 mL) over a 5 minute period. The cooling bath was removed and the solution was allowed to warm to 25° C. to ensure complete anion generation. To the anion at 25° C. was added dropwise a solution of (2S)-2-((1,1-dimethylethyl)dimethylsilyloxy)propanoyl chloride (2.23 g, 10 mmol) in tetrahydrofuran (10 mL) over a 5 minute period. TLC indicated that the reaction was complete upon addition of the acid chloride (silica gel plates; hexane and ethyl acetate, 9:1). The solvent was removed by rotary evaporation affording a thick slug. The slug was dissolved in methylene chloride (75 mL) and washed with water (1×50 mL) and dried (MgSO4). Concentration and purification by flash chromatography on silica gel (EM 60, 0.040-0.063 partical size, 230-400 Mesh, column size: 4.5 cm diameter×15 cm length) using hexane and ethyl acetate (19:1) afforded 1.40 g (47%) of (5S)-N-((2S)-2-((1,1-dimethylethyl)dimethylsilyloxy)propanoyl)-5-ethenylpyrrolidin-2-one (9a) as clear liquid: 1H NMR (CDCl3) δ0.0300 (s,3 H), 0.0656 (s, 3 H), 0.877 (s, 9 H), 1.37 (d, J=6.5 Hz, 3 H), 1.82-1.88 (m, 1 H) 2.21 (p, J=10.7 Hz, 1 H), 2.34-2.47 (m, 1 H), 2.60 (p, J=9.8 Hz, 1 H), 4.88 (br, 1 H), 5.05-5.11 (m, 2 H), 5.36-5.38 (m, 1 H), 5.70-5.79 (m, 1 H); 13C NMR (CDCl3) δ174.86, 174.77, 135.5, 115.4, 66.8, 57.9, 31.6, 25.5, 24.4, 21.1, 18.1, -4.87, -5.16.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@H:16]1[C@@H:20]([CH3:21])[CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:17]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:9]([NH:15][C@H:16]3[C@@H:20]([CH3:21])[CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:17]3)=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)nc2c1Cl
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)nc12
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 2-bromo-8-chloroimidazo[1,2-b]pyridazine-7-carboxamide (2.198 g, 7.98 mmol), (3S,4S)-benzyl 3-amino-4-methylpyrrolidine-1-carboxylate (2.15 g, 9.18 mmol) and Hunig's Base (4.18 ml, 23.94 mmol) in DMF (7.9 ml) in a reaction vial was stirred at 90° C. for 2 h. After cooling to room temperature, the reaction solution was added slowly to a stirred ice-water resulting in a light tan precipitate. The suspension was stirred for 30 min. (3S,4S)-Benzyl 3-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-4-methylpyrrolidine-1-carboxylate (3.78 g, 7.98 mmol, 100% yield) was collected as a light tan solid via filtration. ESI-MS (analytical LCMS Method A): m/z 473, 475 ([M+H]+). HPLC (analytical HPLC Method A) Rt: 3.808 min.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.[OH-].[Na+]>CO.O>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:8][C:5]2[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][OH:10])[O:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=c1cc(CO)occ1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1cc(CO)occ1OCc1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
Kojic acid (637, 5.00 g, 35.2 mmol) and 4-chlorobenzyl bromide (557, 7.95 g, 38.7 mmol) were suspended in methanol (40 mL) in an 80 mL scaled tube. Sodium hydroxide in water (12 M, 2.93 mL) was added. The reaction was heated at 80° C. overnight. The resulting suspension was concentrated. Water was added and the mixture was filtered and washed with water to provide a brown solid. Washing with minimal methanol on the filter removed the brown color. A white solid (638, 7.58 g, 80%) was isolated. 1H-NMR was consistent with the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O>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.COCCOC>[CH2:26]1[O:27][C:21]2[CH:20]=[CH:19][C:24]([C:2]3[CH:3]=[CH:4][C:5]4[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=4[CH:16]=3)=[CH:23][C:22]=2[O:25]1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2OCC1
Reactant: [O-]B([O-])Oc1ccc2c(c1)OCO2
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: COCCOC
Solvent: O
Product: COC(=O)C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2OCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a mixture of methyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (0.57 g), 3,4-methlenedioxy-phenyl borate (0.47 g) and sodium carbonate (0.42 g) were added water (2 ml) and 1,2-dimethoxyethane (12 ml). Under argon atmosphere, the mixture was stirred at room temperature for 30 minutes, and to the mixture was added tetrakistriphenylphosphinepalladium (0.16 g). The mixture was stirred at 80° C. for 14 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/hexane) to give methyl 7-(3,4-methlenedioxyphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (0.43 g).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[O:10][CH2:9][CH2:8][NH:7][CH2:6]1)[CH3:3].[NH2:11][C:12]1[CH:19]=[C:18](F)[C:15]([C:16]#[N:17])=[CH:14][N:13]=1.C(N(CC)CC)C>>[NH2:11][C:12]1[CH:19]=[C:18]([N:7]2[CH2:8][CH2:9][O:10][CH:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH2:6]2)[C:15]([C:16]#[N:17])=[CH:14][N:13]=1
Reactant: CN(C)CC1CNCCO1
Reactant: N#Cc1cnc(N)cc1F
Solvent: CCN(CC)CC
Product: CN(C)CC1CN(c2cc(N)ncc2C#N)CCO1
Temperature: 60 °C

Procedure:
A mixture of racemic 2-dimethylaminomethylmorpholine (670 mg, 4.65 mmol), 6-amino-4-fluoronicotinonitrile (intermediate 21, 637 mg, 4.65 mmol) and triethylamine (2.59 ml, 18.6 mmol) was heated at 60° C. in a septum sealed reaction vessel under argon for 10 h. The reaction mixture was evaporated, partitioned between aq. hydrochloric acid (2 M) and DCM (2×), the aqueous layer basified with aqueous NaHCO3, extracted a further 10× with DCM containing 10% MeOH, the combined DCM layers from the basic extraction, dried over Na2SO4 and evaporated. The residue was applied to a 24 g RediSep® silica column as a DCM solution and purified by normal phase chromatography, eluting with a gradient from DCM to 20% MeOH in DCM. Product containing fractions were combined and evaporated to give the title compound as a beige foam. (UPLC-MS 6) tR 0.28; ESI-MS 262.2 [M+H]+.
Reaction SMILES: C[Si](C)(C)C1C=C(C=CC=1)N.Cl[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][N:14]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:19][C:18]1[C:13]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1cccnc1Cl
Reactant: C1CNCCN1
Agent: C[Si](C)(C)c1cccc(N)c1
Product: Clc1cccnc1N1CCNCC1
Yield: 86.8 %

Procedure:
Compound A-11 can be synthesized according to method 1. Just of Scheme 1, R1 is —Cl; R2 is —H; R3 is m-SiMe3. More specifically, compound 1 is 2,3-dichloro pyridine (2 g); compound 2 is piperazine; the synthesized compound 3 is 1-(3-chloro-2-pyridyl)piperazine (2.3 g, yield about 86.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12](F)[C:11]([F:15])=[CH:10][C:3]=1[C:4]([O:6][CH2:7][C:8]#[CH:9])=[O:5].[CH2:16]([OH:19])[C:17]#[CH:18].[H-].[Na+].Cl>CN(C=O)C>[Cl:1][C:2]1[CH:13]=[C:12]([O:19][CH2:16][C:17]#[CH:18])[C:11]([F:15])=[CH:10][C:3]=1[C:4]([O:6][CH2:7][C:8]#[CH:9])=[O:5]
Reactant: C#CCO
Reactant: C#CCOC(=O)c1cc(F)c(F)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOC(=O)c1cc(F)c(OCC#C)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 129.4 %

Procedure:
To a mixture of 150 ml of DMF, 12.7 g of 2-propynyl 2-chloro-4,5-difluorobenzoate and 3.4 g of propargyl alcohol was added 2.4 g of 60% sodium hydride (oily) under ice-cooling. The reaction mixture was stirred at room temperature overnight. Hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The resulting organic layer was washed sequentially with water and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and 19 g of 2-propynyl 2-chloro-5-fluoro-4-(2-propynyloxy)benzoate was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[C:9]3[C:14]([C:15]=2/[C:16](=[N:18]/[OH:19])/[NH2:17])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:27])[O:4][N:3]=1.[H-].[Na+].[CH:30](OCC)=O>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)[C:9]3[C:14]([C:15]=2[C:16]2[N:17]=[CH:30][O:19][N:18]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1c(/C(N)=N/O)c2ccccc2n1-c1ccc(O)cc1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1c(-c2ncon2)c2ccccc2n1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(Z)-2-(3,5-Dimethylisoxazol-4-yl)-N′-hydroxy-1-(4-hydroxyphenyl)-1H-indole-3 carboximidamide (Example 11) was dissolved in THF containing 4-Å powdered molecular sieves. The mixture was stirred for 30 min under N2. NaH (60% dispersion in mineral oil, 7.0 mg, 2.1 eq,) was added and the mixture was stirred at 60° C. for 20 min. After cooling to room temperature, ethyl formate (25.6 mg, 2.5 eq) in THF was added dropwise. The resulting mixture was heated at reflux for 1 h and then cooled to room temperature. The mixture was filtered and concentrated. The residue was filtered through silica and then purified using reversed phase HPLC to give 4-(2-(3,5-dimethylisoxazol-4-yl)-3-(1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)phenol as a white powder: ES/MS m/z: 395.17 (M−H), 393.19 (M−H); 1H NMR (acetone-d6, 500 MHz): 9.21 (s, 1H), 8.40 (m, 1H), 7.37-7.31 (m, 2H), 7.26-7.22 (m, 3H), 6.98 (m, 2H), 2.17 (s, 3H) and 1.98 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1OC(F)(F)F)N1CCCC1
Yield: 64.9 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and pyrrolidine (0.21 mL, 2.57 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 1-{[4-bromo-2-(trifluoromethoxy)phenyl]sulfonyl}pyrrolidine (0.25 g, 65%) was provided after purification. MS (ESI) m/z 374. HPLC purity 100.0% at 210-370 nm, 10.1 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1)[CH3:2].S(Cl)(Cl)=O.[CH2:16](OC1C=CC(CO)=CC=1)[CH2:17][CH2:18][CH2:19]CC>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1)[CH2:2][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCOc1ccc(CCl)cc1
Reactant: CCCCCCOc1ccc(CO)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCCOc1ccc(CCl)cc1

Procedure:
This molecule was synthesized following the same general procedure as that for the preparation of 4-ethoxybenzyl chloride; thionyl chloride (7.17 g, 60.3 mmol), 4-hexyloxybenzyl alcohol (11.3 g, 54.3 mmol), CH2Cl2 (150 mL).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11].C([Li])CCC.C(Cl)(Cl)(Cl)Cl.C(=O)=O.[CH:26](=[O:28])[CH3:27].Cl>O1CCCC1>[Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[C:8]([CH:26]([CH3:27])[OH:28])[S:7][C:6]=2[C:10]=1[Cl:11]
Reactant: CC=O
Reactant: Oc1cc2ccsc2c(Cl)c1Cl
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Reaction time: 4 h

Procedure:
To a solution of 25 g of 6,7-dichloro-5-hydroxybenzo[b]thiophene in 145 ml of dried tetrahydrofuran at -25° to -30° is added 110 ml of 2.5 M n-butyllithium maintaining a temperature below -21°. After the addition, the carbon tetrachloride-dry ice bath is replaced with an ice-water bath and the mixture is stirred at 0°-5° for 4 hrs. A solution of 7.5 ml of freshly distilled acetaldehyde in 10 ml tetrahydrofuran is added dropwise. And additional 2 ml of acetaldehyde is added and the solution is stirred for 1 hr. The solution is poured onto 500 ml of a cold 5% hydrochloric acid solution and the mixture is extracted with ethyl ether. The ether extracts are washed, dried over anhydrous magnesium sulfate, filtered and solvent is removed to give a solid. Recrystallization from ethyl acetate and hexane gives 20 g of 6,7-dichloro-5-hydroxy-α-methylbenzo[b]thiophene-2-methanol, mp 173°-174°.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[C:6]([Cl:8])[CH:7]=1.[C:10]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C.[Cl-].[NH4+]>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH3:10])[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=c1[nH]nc(Cl)cc1Br
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nc(Cl)cc(Br)c1=O
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of 4-bromo-6-chloropyridazin-3(2H)-one (1.0 equiv.) and Cs2CO3 (1.2 equiv.) in DMF (0.07 M) was added iodomethane (1.5 equiv.) drop-wise over 20 min. The resulting mixture was stirred for 3 h. The reaction mixture was then diluted with ammonium chloride, then extracted with ethyl acetate, dried over MgSO4 and concentrated in vacuo to yield as a brown solid. The oil was further purified via silica gel column chromatography eluting with 100% heptanes to 80% ethyl acetate:heptanes to yield 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one as an off-white solid in 79% yield. LCMS (m/z) (M+H)=222.9/224.9, Rt=0.54 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 3.77-3.86 (m, 3H) 7.56-7.69 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:6])[CH3:5].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:17][C:18]1[CH:25]=[C:24](F)[C:21]([C:22]#[N:23])=[CH:20][N:19]=1>CN1C(=O)CCC1>[NH2:17][C:18]1[CH:25]=[C:24]([O:6][CH:4]([CH3:5])[CH2:3][O:2][CH3:1])[C:21]([C:22]#[N:23])=[CH:20][N:19]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: COCC(C)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COCC(C)Oc1cc(N)ncc1C#N
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
1-methoxypropan-2-ol (329 mg, 3.65 mmol) was treated at room temperature with KHMDS (1M in THF, 1.82 ml, 1.82 mmol). The reaction mixture was stirred for 10 min. Then, the mixture was added to a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 50 mg, 0.365 mmol) in NMP (0.5 ml). The solution was then heated at 50° C. for 1 h. The reaction mixture was quenched with water and diluted in EtOAc. The layers were separated and the aq. layer was extracted 3× with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100). The product containing fractions were concentrated; the obtained oil was dissolved in water and lyophilized to give the title compound as a white solid. (UPLC-MS 3) tR 0.57 min; ESI-MS 208.1 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=O)[CH3:2].[NH2:9][C:10]([NH2:12])=[S:11]>ClCCl.CO.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[NH2:12][C:10]1[S:11][CH:2]=[C:1]([C:4]2[O:5][CH:6]=[CH:7][CH:8]=2)[N:9]=1
Reactant: CC(=O)c1ccco1
Reactant: NC(N)=S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CO
Solvent: ClCCl
Product: Nc1nc(-c2ccco2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
2-Acetylfuran (5.1 g, 46.0 mmol) was dissolved in a mixed solvent of dichloromethane (50 mL) and methanol (50 mL), and tetra(n-butyl)ammonium bromide (22.3 g, 46.0 mmol) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was dissolved in acetonitrile (60 mL), thiourea (3.5 g, 46.0 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. The precipitated solid was collected by filtration, and the resulting solid was dissolved in a mixed solvent of a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate, and subjected to liquid-liquid separation. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=3:1) to afford 2-amino-4-(2-furyl)thiazole (1.53 g, 20%).
Reaction SMILES: [CH3:1]OC(OC)N(C)C.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[C:23][C:24]3[CH:25]=[CH:26][C:27]([O:31][CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[C:28]([NH2:30])[CH:29]=3)=[N:20][CH:21]=2)=[CH:12][CH:11]=1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[C:23][C:24]3[CH:25]=[CH:26][C:27]([O:31][CH2:32][CH2:33][N:34]4[CH2:35][CH2:36][CH2:37][CH2:38]4)=[C:28]([NH:30][CH3:1])[CH:29]=3)=[N:20][CH:21]=2)=[CH:12][CH:11]=1
Reactant: Nc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Reactant: COC(OC)N(C)C
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Under a nitrogen atmosphere 178 μL (1.35 mmol) N,N-dimethylformamide dimethylacetal are added to a solution of 100 mg (0.24 mmol) 5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-phenylamine in 2 mL DMF, the reaction mixture is stirred for 5 h at 60° C. and cooled to RT overnight. Then 32 mg (0.85 mmol) NaBH4 are added and the mixture is again heated to 60° C. for 1 h. To complete the reaction a further 32 mg NaBH4 are added and the mixture is heated to 60° C. for a further 4 h. After cooling it is combined with saturated NaHCO3 solution, exhaustively extracted with EtOAc and the organic phase is dried over MgSO4. After the desiccant and solvent have been eliminated the residue is purified by HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([CH3:12])[CH3:11].[I:14]([O-])(=O)=O.[K+].II.Cl>C(O)C.O>[OH:1][C:2]1[C:7]([I:14])=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)C(=O)c1ccc(O)cc1O
Reactant: [O-][I+2]([O-])[O-]
Agent: Cl
Agent: II
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)C(=O)c1ccc(O)c(I)c1O
Temperature: 25 °C
Yield: 558.3 %

Procedure:
Mechanically stir suspensions of 1-(2,4-dihydroxy-phenyl)-2-methyl-propan-1-one (818 g, 4.54 mol) in ethanol (3 L) and water (6 L) in two separate 22-L Morton flasks. Treat each suspension with potassium iodate (170 g, 794 mmol) and iodine (410 g, 1.62 mol) and allow to stir over night at room temperature. Dilute the mixtures with water (2 L), adjust pH to 4 by adding 5N hydrochloric acid, then extract twice with 4 L of ethyl acetate. Wash organic layers once with dilute aqueous sodium bisulfite, brine, dry with magnesium sulfate, filter, combine both filtrates, and evaporate to 2.6 Kg of a black solid. Chromatograph 500 g portions of the solid on 3.5 Kg of silica gel, eluting with 80% dichloromethane in heptane to provide the title compound (1357 g, 49% yield) in approximately 97% purity (HPLC shows 97% purity, with 3% 3,5-diiodo analog; LCMS confirms both. HPLC Rt=4.75 min; 1H NMR (CDCl3) δ 14.07 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 6.02 (s, 1H), 3.53 (hept, J=8.0 Hz, 1H), 1.24 (d, J=8.0 Hz, 6H); MS (m/z): 307.0 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1N2CN3CN(C2)CN1C3.[C:29](O)(C(F)(F)F)=[O:30].Cl>O.CO>[CH:29]([C:17]1[C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:30]
Reactant: CCCCCCCc1cc(=O)c2ccccc2[nH]1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCCCCCc1[nH]c2ccccc2c(=O)c1C=O
Reaction time: 1 h
Yield: 40 %

Procedure:
A mixture of 2-heptyl-4(1H)-quinolone (5 mmol), hexamine (2.5 mmol), and TFA (7.5 ml) was stirred at reflux under nitrogen for 30 hours. MeOH (15 ml) and water (15 ml) were added, and heating was continued for 1 hour. 3 M HCl (5 ml) was added and the heating was continued for a further period of 30 minutes. The mixture was cooled and the precipitate removed by filtration and washed with water. The solid on trituration with acetone afforded the title compound in 40% yield. Recrystallisation from MeOH/EtOAc gave colourless needles, mp 245-248° C. (dec).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:10].[C:17]([O:21][C:22]([NH:24][C@H:25]1[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28][NH:27][C:26]1=[O:33])=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([O:21][C:22]([NH:24][C@H:25]1[CH2:31][CH2:30][C@@H:29]([O:32][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:10])[CH2:28][NH:27][C:26]1=[O:33])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CNC1=O
Reactant: CCCCCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCOC(=O)O[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)C(=O)NC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
Triethylamine (2 mL, 15 mmol) is added to a solution of pentyl chloroformate (1.8 g, 12.2 mmol), (3S 6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-hydroxy-2H-azepin-2-one (1.5 g, 6.1 mmol) and 20 mL of CH2Cl2 at 5° C. The reaction mixture is stirred at room temperature overnight. The reaction mixture is then partitioned with water, and the organic layer is dried (Na2SO4), and concentrated by rotary evaporation. The resulting residue is chromatographed (5% EtOAc-CH2Cl2) to give 1.3 g (60%) of (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-([[pentyloxy]carbonyl]oxy)-2H-azepin-2-one as a pale yellow solid: 1H NMR (CDCl3): δ 5.90 (d, J=6 Hz, 1H), 5.77 (t, J=6 Hz, 1H), 4.79 (m, 1H), 4.30 (m, 1H), 4.12 (m, 3H), 3.53 (m, 2H), 2.24 (m, 1H), 1.92 (m, 2H), 1.66 (m, 1H), 1.44 (s, 9H), 1.34 (m, 5H), 0.91 (m, 3H).