Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[CH2:24][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][C:10]=3F)=[N+:2]=[N-:3].[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([OH:36])([C:34]#[CH:35])[CH3:33])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([C:34]2[N:1]([C@H:4]3[CH2:24][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:35]=2)([OH:36])[CH3:33])=[CH:30][CH:31]=1
Reactant: CCCOC(=O)Cc1c2n(c3c(F)cccc13)CC(N=[N+]=[N-])CC2
Reactant: C#CC(C)(O)c1ccc(F)cc1
Product: CC(O)(c1ccc(F)cc1)c1cnnn1[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 8 from propyl (7-azido-4-fluoro-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 2-(4-fluorophenyl)but-3-yn-2-ol. Separation of the resulting diastereoisomers was performed at the ester stage by flash chromatography using a gradient of 10-100% EA/Hex afforded 2 esters. The faster eluting enantiomeric mixture was resolved on chiral HPLC using a 4.6×250 mm Chiralcel OD column eluting with 20% iPrOH, 20% EtOH, 59.75% Hexanes and 0.25% Et3N at 1 mL/min and 254 nm. Retention times=6.9 and 8.4 min. The 2 resulting esters were hydrolyzed separately to afford EXAMPLE 31.1 and 31.2 respectively. The slower eluting enantiomeric mixture was resolved on chiral HPLC using a 4.6×250 mm Chiralcel OD eluting with 20% iPrOH, 20% EtOH, 60% Hexanes at 1 mL/min and 254 nm. Retention times=8.7 and 11.6 min. The 2 resulting esters were hydrolyzed separately to afford EXAMPLE 31.3 and 31.4 respectively. MS (+ESI) m/z: 453.1.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]([OH:9])=O)[CH2:2][CH2:3][CH3:4].[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:20])=[C:15]([N:17]=[C:18]=[S:19])[CH:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:5]1[CH2:6][C:7](=[O:9])[N:17]([C:15]2[CH:16]=[C:11]([Cl:10])[CH:12]=[CH:13][C:14]=2[CH3:20])[C:18]1=[S:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCC(=O)O
Reactant: Cc1ccc(Cl)cc1N=C=S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCN1CC(=O)N(c2cc(Cl)ccc2C)C1=S
Yield: 40.6 %

Procedure:
A mixture of N-butyl glycine (12.0 g), 5-chloro-2-methylphenyl-isothiocyanate (9.15 g), triethyl amine (12.0 g) and chloroform (200 mL) was heated at reflux for 5 hours. The solvent was evaporated. The residue was treated with diethyl ether (400 mL). The mixture was filtered. The solid was washed with diethyl ether then discarded. The filtrate was evaporated to dryness. Crystallization from ethanol afforded the title compound (6.0 g) as a tan solid, m.p. 102°-103° C. Anal. Calcd. for. C14H17Cl N2O S: C, 56.65; H, 5.77; N, 9.44. Found: C, 56.41; H, 5.97; N, 9.36. Mass spectrum (EI, M.+) m/z 296/298.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[CH3:12][C:11]([Si:8]([CH3:10])([CH3:9])[O:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7])([CH3:14])[CH3:13]
Reactant: O=C1NCC[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1=O
Reaction time: 8 h
Yield: 72.1 %

Procedure:
A mixture of 14 g of (S)-3-hydroxy-2-pyrrolidinone, 45 g of tert-butyldimethylsilyl chloride, 50 ml of triethylamine and 500 ml of dichloromethane was stirred overnight. The solution was washed four times with water, once with brine, dried and concentrated in vacuo. The residue was dissolved in 500 ml of methanol, refluxed overnight and concentrated in vacuo. The residue was purified by chromatography (silica gel), giving 21.5 g of (S)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pyrrolidinone; [α]D26° =-52° (dichloromethane); mp 48°-49° C.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Br:14])(=O)=O.[F:22][C:23]1([F:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:22][C:23]1([F:29])[CH2:28][CH2:27][N:26]([CH2:5][CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Br:14])[CH2:25][CH2:24]1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccccc2Br)cc1
Reactant: FC1(F)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC1(F)CCN(CCOc2ccccc2Br)CC1
Temperature: 60 °C

Procedure:
2-(2-Bromophenoxy)ethyl tosylate (1.86 g), 4,4-difluoropiperidine (0.73 g) and potassium carbonate (0.97 g) were mixed with dimethylformamide (30 ml) and heated to 60° C. for 18 h. The mixture was cooled and added to water (300 ml). The mixture was extracted with diethyl ether (×3), dried and evaporated. Purification was achieved using cation exchange chromatography eluting with ammonia/methanol/dichloromethane mixtures yielding, 4-difluoro-(2-(2-bromophenoxy)ethyl)piperidine (0.77 g).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:6][N:7]([CH3:18])[C:8]([C:10]1[C:15](Br)=[CH:14][N:13]=[C:12]([CH3:17])[N:11]=1)=[O:9].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:6][N:7]([CH3:18])[C:8]([C:10]1[C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:14][N:13]=[C:12]([CH3:17])[N:11]=1)=[O:9]
Reactant: OB(O)c1ccccc1
Reactant: Cc1ncc(Br)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ncc(-c2ccccc2)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Yield: 56.9 %

Procedure:
To a suspension of 0.456 g (1 mmol) 5-bromo-2-methyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, 0.034 g (0.2 mmol) tetrakis-(triphenylphosphin)palladium and 0.121 g (1 mmol) phenylboronic acid in 20 ml 1,2-dimethoxyethane a solution of 0.105 g (1 mmol) Na2CO3 in 8 ml H2O was added. The resulting reaction mixture was heated at reflux for 16 hrs. After evaporation of the 1,2-dimethoxyethan, the aqueous phase was extracted twice with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 40:1) and crystallised (Ethanol) to give 0.258 g (57%) 2-methyl-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as off-white crystalls, m.p. 149-152°.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([OH:20])=O)=[C:10]1[CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:41][CH2:42][C:43]1[C:44]([OH:51])=[N:45][C:46]([CH3:50])=[CH:47][C:48]=1[CH3:49]>ClCCl>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([NH:41][CH2:42][C:43]2[C:44]([OH:51])=[N:45][C:46]([CH3:50])=[CH:47][C:48]=2[CH3:49])=[O:20])=[C:10]1[CH3:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1c(C(=O)O)c2ccccc2n1C(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(C(=O)c3ccccc3)c3ccccc23)c(O)n1
Temperature: 20 °C
Reaction time: 13 h
Yield: 26.9 %

Procedure:
To a solution of 1-benzoyl-2-methyl-1H-indole-3-carboxylic acid (125 mg, 0.45 mmol), 1-hydroxybenzotriozole (122 mg, 0.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (173 mg, 0.9 mmol), triethylamine (0.4 mL) in dichloromethane (20 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (137 mg, 0.9 mmol). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the residue, which was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give 1-benzoyl-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide as a white solid (50 mg, 53%). LRMS (M+H+) m/z: calcd 413.17. found 413. HPLC Purity (214 nm): 96%. 1H NMR (300 MHz, do-DMSO): (11.57 (s, 1H), 8.13 (q, J=5.1 Hz, 1H), 7.74-7.70 (m, 4H), 7.60-7.58 (m, 2H), 7.20-7.00 (m, 3H), 5.88 (s, 1H), 4.32 (d, J=5.1 Hz, 2H), 2.37 (s, 3H), 2.267 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N+:3]=1[O-].O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:4]1[C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: [O-][n+]1cc(C(F)(F)F)ccc1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Heat a mixture of 2-chloro-5-trifluoromethylpyridine-N-oxide (40 g, 202.5 mmol) and POCl3 (200 mL) to 80° C. and stir for 16 hours. After cooling to room temperature, remove the excess POCl3 under vacuum. Pour the residue into ice water, and neutralize the mixture to pH=7 with solid NaHCO3. Extract the resulting mixture with diethyl ether (3×80 mL), dry the combined ether extracts (Na2SO4), filter, and evaporate to give a brown oil. Purification by column chromatography affords the title product as pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 1H), 7.41 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(O)(=O)C>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:30])[CH:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(=Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)OC
Yield: 101.2 %

Procedure:
2-{4-[2-(4-Methanesulfonyloxyphenyl)ethoxy]benzylidene}malonic acid dimethyl ester (described in Example 10) (2.31 g; 5.32 mmole) was hydrogenated for 2.5 hours at atmospheric pressure in ethyl acetate (140 ml) and acetic acid (5 ml) using Pd/C (0.8 g) as catalyst and then filtered through hyflo. The solvent was evaporated in vacuo, dichloromethane and diluted sodium bicarbonate solution were added and the phases were separated. The organic phase was washed with brine, dried (sodium sulfate), filtered and evaporated in vacuo to give 2.35 g (yield 100%) of 2-{4-[2-(4-methanesulfonyloxyphenyl)ethoxy]benzyl}malonic acid dimethyl ester.
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br>>[C:1]1([C:12]2[CH:13]=[CH:14][C:9]([OH:15])=[CH:10][CH:11]=2)([C:12]2[CH:13]=[CH:14][C:9]([OH:15])=[CH:10][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccccc1
Reactant: O=C1CCCCCC1
Agent: Br
Product: Oc1ccc(C2(c3ccc(O)cc3)CCCCCC2)cc1

Procedure:
Into a solution of 112.7 parts by weight (1.0 partmole) cycloheptanone and 470 parts by weight (5.0 partmole) phenol there was introduced gaseous hydrobromic acid. The mildly exothermic reaction was moderated by external cooling, keeping the reaction temperature between 30° and 37° C. After ca. 1.5 hours of reaction time, the red colored mixture thickened and solids began to form. After an additional four hour contact with a slow stream of hydrobromic acid, all acid was removed by placing the stirred mixture under water aspirator vacuum and the solid phase removed by vaccum filtration. Washing the solids with hot water and recrystallizing them by charcoaling from aqueous menthol, yielded white crystals of 4,4'-cycloheptylidenediphenol, melting point 208°-209° C., that were 99.1% pure by gas chromatography analysis (retention time: 25.35 min.; p-cumylphenol reference retention time: 16.47 min.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:25]=1.[C:26](Cl)(=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:14][CH:15]=3)=[C:7]([C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:6]=2[CH:25]=1
Reactant: CCN(CC)CCCOc1ccc(-c2cc3cc(Cl)ccc3o2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)CCCOc1ccc(-c2oc3ccc(Cl)cc3c2C(=O)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of the product from Example 4(i) (1 g, 2.8 mmol) in dry DCM was stirred at 0° C. under nitrogen. Anisoyl chloride (4.9 mmol) was added followed by a solution of SnCl4 (1M DCM, 4.9 mmol). An immediate red colour occurred and stirring was continued for 2 hours. The reaction mixture was added carefully to 100 ml of ice-water and the aqueous was extracted with ethylacetate (3×100 Ml). The organic extracts were combined, dried (Na2SO4) and evaporated to give a bright yellow oil. This was purified by flash chromatography (silica flash) to give the title compound as a pale yellow solid. (0.8 g 58%).
Reaction SMILES: [O-]CC.[Na+].[CH3:5][S:6][C:7]([CH3:17])([CH3:16])[CH2:8][CH2:9][CH2:10][CH:11]([CH3:15])[CH2:12][CH:13]=O.[CH2:18]([O:20][C:21]([CH:23]=[C:24]([CH3:34])[CH2:25]P(=O)(OCC)OCC)=[O:22])[CH3:19]>CN(C)C=O>[CH3:5][S:6][C:7]([CH3:17])([CH3:16])[CH2:8][CH2:9][CH2:10][CH:11]([CH3:15])[CH2:12][CH:13]=[CH:25][C:24]([CH3:34])=[CH:23][C:21]([O:20][CH2:18][CH3:19])=[O:22]
Reactant: CCOC(=O)C=C(C)CP(=O)(OCC)OCC
Reactant: CSC(C)(C)CCCC(C)CC=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(C)C=CCC(C)CCCC(C)(C)SC
Reaction time: 1.5 h

Procedure:
Sodium ethoxide (prepared from 0.2 g. of sodium and 12 ml. of ethanol) is slowly added to a mixture of 1.1 g. of 7-methylthio-3,7-dimethyloctan-1-al, diethyl 3-ethoxycarbonyl-2-methyl-prop-2-enyl-phosphonate (1.6 g.) and 50 ml. of dimethylformamide, with stirring, under nitrogen, at 0°. The reaction is stirred for 1.5 hours after addition is complete and then worked up by extraction with ether to yield ethyl 11-methylthio-3,7,11-trimethyldodeca-2,4-dienoate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](=O)[CH3:4].[NH2:8][C:9]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:10](Br)[C:11]#[N:12]>C(O)(=O)C.O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:9]2[NH:8][C:3]([C:2]([F:7])([F:6])[F:1])=[CH:4][C:10]=2[C:11]#[N:12])=[CH:19][CH:18]=1
Reactant: N#CC(Br)=C(N)c1ccc(Cl)cc1
Reactant: CC(=O)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A solution of trifluoroacetone (3.36 g, 2.7 mL,0.03 mol) in acetic acid is added dropwise at 100° C. to a solution of β-amino-α-bromo-p-chlorocinnamonitrile, (E)- or (Z)- (5.15 g, 0.02 mol) in acetic acid over 41/2 hours. The reaction mixture is heated at 100° C. overnight, diluted with water and extracted with ethyl acetate. The combined organic extracts are washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo to obtain a gum. The gum is flash chromatographed using silica gel and a 15% ethyl acetate in heptane solution to give the title product as a yellow solid (1.8 g, mp 129°-131° C.) which is identified by 1H and 19FNMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[N:7]=1.[CH:28]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)=[CH2:29]>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2[N:6]([C:8]([CH:29]=[CH:28][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: C=Cc1ccncc1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(I)cnc23)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C=Cc4ccncc4)cnc23)cc1
Temperature: 25 °C
Yield: 64.1 %

Procedure:
6-chloro-3-iodo-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (120 mg, 0.25 mmol) from (1a), 4-vinylpyridine (54 μL, 0.50 mmol) and Pd(OAc)2 (23 mg, 0.1 mmole) in acetonitrile (1 mL) were heated at 85° C. for 2 h. After cooling to room temperature, the mixture was partitioned between EtOAc (200 mL) and water (20 mL) and the organic layer was washed with water, brine, then dried over MgSO4 and concentrated. The resulting residue was purified by flash chromatography to provide 6-chloro-N-(4-methoxybenzyl)-N-phenyl-3-(2-(pyridin-4-yl)vinyl)imidazo[1,2-b]pyridazin-8-amine as a yellow solid (75 mg, 66%). LCMS [M+H]+ 468.
Reaction SMILES: C(NCCS[C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:17])[C@H:12]2[CH2:15][CH3:16])[C:9]=1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:19])(=O)C.N12CCC1CC=C2.C(N(C(C)C)CC)(C)C.[C:47]([NH:50][CH2:51][CH2:52]S)(=[O:49])[CH3:48]>C(#N)C>[C:47]([NH:50][CH2:51][CH2:52][C:8]1[CH2:14][CH:13]2[N:10]([C:11](=[O:17])[CH:12]2[CH2:15][CH3:16])[C:9]=1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:19])(=[O:49])[CH3:48]
Reactant: CC[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(C)=O)C[C@H]12
Reactant: CC(=O)NCCS
Agent: C1=CN2CCC2C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(CCNC(C)=O)CC12
Reaction time: 0.25 h

Procedure:
Preparation of trans (±)-3-[[2-(acetylamino)ethyl)thio]-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, (4-nitrophenyl)methyl ester (XVII, R=CH3CH2 --, R'"=CH3CONH--CH2 --CH2 --, R4 = ##STR19## A solution of the bicyclic keto ester obtained in step (c) above (XV R=CH3CH2 --) (2.49 g) in acetonitrile (15 ml) is cooled to 0° C. and diisopropylethylamine (1.42 ml) is added. Then chlorodiphenylphosphate (1.72 ml) is added drop by drop keeping the temperature at 0°/-2° C. Stirring is continued for 15 minutes at 0° C., after which thin layer chromatography confirms the complete transformation of the bicyclic keto ester XV into the enol phosphate derivative XVI (R=CH3CH2 --). An additional portion of diisopropylethylamine (1.55 ml) is added followed by the slow addition of N-acetylcysteamine (1.07 g) dissolved in acetonitrile (5 ml). The reaction mixture is then stirred at 0° C. for 30 minutes and the solid which precipitates is filtered, washed with cold acetonitrile (10 ml) and diethyl ether (20 ml), and dried in vacuo at room temperature yielding 2.03 g of trans (±)-3-[[2 -(acetylamino)ethyl]-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, (4-nitrophenyl)methyl ester which melts at 174°-76° C. Additional 0.46 g of equally pure product is obtained on cooling the filtrate to -20° C. for 2 hours.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12](O)=[O:13])=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.[NH3:23]>O1CCCC1.CN(C)C=O>[F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([NH2:23])=[O:13])=[CH:6][CH:5]=1
Reactant: O=C(O)C=Cc1ccc(OC(F)(F)F)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)C=Cc1ccc(OC(F)(F)F)cc1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
To a suspension of 4.90 g (21.1 mmol) 3-(4-Trifluoromethoxy-phenyl)-acrylic acid in 30.0 ml tetrahydrofuran and 0.3 ml N,N-dimethyl formamide a solution of 2.70 ml (32.0 mmol) oxalyl chloride in 5.0 ml tetrahydrofuran was added dropwise at 0° C. within 10 min. Stirring was continued at 0-5° C. for 30 min. and 2 h at room temperature thereafter. The resulting solution was cooled to 0-5° C. again and then added within 15 min. to 75 ml of a 25% aqueous ammonia solution. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo. 4.48 g (92%) 3-(4-Trifluoromethoxy-phenyl)-acrylamide.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CN(C)C=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:42][C:43]1([CH3:60])[C:47]2[C:48]([O:52][C:53]3[N:58]=[CH:57][C:56]([NH2:59])=[CH:55][N:54]=3)=[CH:49][CH:50]=[CH:51][C:46]=2[O:45][CH2:44]1>C(OCC)(=O)C>[CH3:42][C:43]1([CH3:60])[C:47]2[C:48]([O:52][C:53]3[N:54]=[CH:55][C:56]([NH:59][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:13][CH3:14])=[O:12])=[CH:57][N:58]=3)=[CH:49][CH:50]=[CH:51][C:46]=2[O:45][CH2:44]1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1(C)COc2cccc(Oc3ncc(N)cn3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2cccc3c2C(C)(C)CO3)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15 %

Procedure:
To a solution of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (20.14 mg, 0.099 mmol) in N,N-dimethylformamide (1.5 mL) DIPEA (0.029 mL, 0.165 mmol) and TBTU (33.9 mg, 0.106 mmol) were added. The mixture reaction was stirred during 15 minutes at room temperature, then 2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinamine (Intermediate 65, 17 mg) was added. The reaction mixture was stirred during 48 hours at room temperature. The mixture was diluted with ethyl acetate (5 ml) and washed with brine (3×5 ml). The organic layer was separated, dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel flash chromatography using a 10 g-SNAP column and cyclohexane/ethyl acetate from 100/0 to 40/60 as eluent to afford the title compound as a white solid (4.4 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[Cl-].[NH4+]>CCCCCC.CCOCC>[CH2:23]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: c1ccoc1
Reactant: CCCCCCCCCCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCCCCCCCCCc1ccco1

Procedure:
A mixture of 68.1 g (1.0 mole) of furan and 500 ml of anhydrous ether is stirred at -20° C. after which 1.1 moles (458 ml of a 2.4 molar hexane solution) of butyllithium is added slowly with stirring. The reaction mixture is stirred for 1 hour, then 284 g (1.2 moles) of 1-bromododecane is added. The reaction mixture is stirred at room temperature for 4 hours after which it is poured into a saturated ammonium chloride solution. The organic layer is separated and washed with water and brine, dried over sodium sulfate and distilled under reduced pressure to give 2-dodecylfuran.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.O>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Clc1ccc2ccccc2n1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Nitrophenol (41 moles, 5.1 g) was dissolved in DMF (500 ml) and treated with sodium hydride (41 mmoles previously washed with hexane). After stirring at room temperature for 1 hr, 2-chloroquinoline (40 moles, 6.5 g) was added dropwise and stirred for 16 hr at room temperature followed by refluxing for 6 hr. Water was added to the cooled solution and the product was extracted with ethyl acetate. The ethyl acetate solution was washed with water, and 5N NaOH, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with ethyl acetate/hexane to yield 2-(4-nitrophenoxy)quinoline. 3.1 mmoles, 8%. Mass Spec (FD) 266. Calcd for C15H10N2O3 : C, 67.45; H, 3.84; N, 10.40. Found: C, 65.84; H, 3.88; N, 8.47.