Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].C[PH3+].[CH3:4]C(C)([O-])C.[K+].[C:10]1([N:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1.ClCCl>[C:10]1([N:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[CH2:4])=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: C[PH3+]
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
19 g of methylphosphonium bromide is suspended in dried THF under protective gas, and 6 g of potassium tert-butoxide are added in portions at 0° C. An immediate colour change to orange occurs. 14 g of N,N-diphenyl-p-aminobenzaldehyde are added to the reaction solution at 0° C. The mixture is warmed to room temperature and stirred for a further 20 hours. The solvent is stripped off in vacuo, the residue is taken up in dichloromethane, and the solution is extracted with water dried over magnesium sulfate, filtered, and the solvent is stripped off in vacuo.
Reaction SMILES: C(C1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][N:4]=1)#N.[CH3:13][Mg]I.CC[O:18][CH2:19][CH3:20]>C1COCC1>[C:19]([C:20]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][N:4]=1)(=[O:18])[CH3:13]
Reactant: C[Mg]I
Reactant: N#Cc1ncccc1C(F)(F)F
Reactant: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1ncccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-cyano-3-trifluoromethylpyridine (179 g; 1.04 mol) and THF (1200 mL) are combined in a 5.0 liter flask and cooled with and ice and salt mixture. 3.0 M MeMgI/Et2O (694 mL) is added drop wise over a period of 90 minutes while maintaining the inside temperature of the reaction mixture below 5° C. After the addition, the reaction mixture is stirred at 0° C. for another 30 minutes, and is then slowly poured over 3.0 kg of crushed ice in a 12 liter vessel with stirring (6° C.). The undissolved magnesium salts from the original reaction vessel are quenched with ice (750 g) and transferred to the 12 liter vessel. The resulting mixture is acidified with 6.0 N aq. HCl to pH 2.0 and stirred for 30 minutes at <10° C. The mixture is then extracted with EtOAc (5×1 liters), and the combined extracts are washed with brine (1.5 liters) and dried with Na2SO4 (500 g). The dried extract is filtered and concentrated in vacuum at 40° C. to afford a dark brown oil. The crude product is distilled under vacuum to give 2-acetyl-3-trifluoromethylpyridine as a clear pale yellow liquid.
Reaction SMILES: O[NH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(OCCO)CCC.Cl>[Fe].O>[NH2:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)c2c(NO)cccc21
Agent: [Fe]
Agent: Cl
Solvent: CCCCOCCO
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 75 °C

Procedure:
50 Parts of 1-hydroxylaminoanthraquinone was stirred into a mixture of 500 parts of ethyleneglycol monobutyl ether, 200 parts of water and 60 parts of a 35 % aqueous hydrochloric acid. After heated to 75°C, the mixture was added with 17 parts of iron ribbon little by little over 1 hour and maintained at 75°C for additional 3 hours. After cooled to 25°C, the reaction mixture was filtered and the residue was washed with water and extracted with 500 parts of dimethylformamide to separate the resulting 1-aminoanthraquinone from unreacted metal. The extract was distilled for removal of dimethylformamide to obtain 42.5 parts of 1-aminoanthraquinone of a purity of 93 %.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:18][CH:19]=O.O>C(O)C>[N:1]1[CH:18]=[CH:19][N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]=12
Reactant: COC(=O)c1cccnc1N
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cccn2ccnc12

Procedure:
To a solution of methyl 2-amino-pyridine-3-carboxylate (5 g, 35 mmol, 1.0 eq) in ethanol (250 mL) was added NaHCO3 (5.08 g) and chloroacetaldehyde in water (35 mL of 45% in water, 148 mmol, 4.5 eq). The reaction mixture was heated at reflux for 18 h. Solvent was removed and the residue was basified with Na2CO3 and then extracted with DCM. Organic layers were combined and evaporated to give a residue, which was purified by column to give the titled compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.OC1C=CC(CC(=O)C)=CC=1.[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][CH:60](O)[CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:52])[CH3:51]>O1CCCC1>[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(=O)Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A solution of triphenylphosphine (18.5 g, 70.6 mmol) and 40% DEAD in toluene (12.3 g, 70.6 mmol) in 125.0 mL of tetrahydrofuran was cooled to 0° C. under N2 as a solution of 1-(4-hydroxy-phenyl)-propan-2-one (6.54 g, 43.6 mmol) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (10.7 g, 53.2 mmol) in 125.0 mL of tetrahydrofuran was added dropwise via addition funnel After stirred at rt overnight, the solvent was evaporated. The residue was stirred in hexane/EtOAc, the solid formed was filtered. The hexane/EtOAC solution was concentrated and purified by ISCO graduate chromatography (hexane-20% EtOAc in hexane) to give 4-[4-2-oxo-propyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (8.52 g, 59%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH:3]=1
Reactant: CC(C)=CCBr
Reactant: Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCSc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
25.00 g (132.0 mmol) of 3-bromothiophenol, 200 ml of DMF and 18.23 g (138.0 mmol) of potassium carbonate are introduced into a three-necked flask. 18.0 ml (157.0 mmol) of 1-bromo-3-methyl-2-butene are added dropwise and the mixture is stirred at room temperature for five hours. The reaction medium is poured into water and extracted with ethyl acetate, and the organic phase is separated out after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. 33.00 g (97%) of the expected compound are collected in the form of a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20]OS(C)(=O)=O)[CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[ClH:39].CO>CC(C)=O>[ClH:39].[ClH:39].[CH2:1]([O:8][C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20][N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Reactant: CN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: CN1CCN(Cc2ccc3c(c2)CN(C(=O)OCc2ccccc2)C3)CC1
Temperature: 15 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
The solid from Step 3 (assume 0.232 mol) was dissolved in acetone (700 mL) and this solution was added over 45 mins to a cooled (internal temp 15-17° C.) suspension of K2CO3 (48 g) and N-methylpiperazine (50 mL, 0.45 mol) in acetone (330 mL). The suspension was stirred at 15° C. for 3 h (complete removal of starting material by tlc) when the solution was evaporated to a small volume and the residue partition between EtOAc (1000 mL) and a mixture of water (500 mL) and saturated brine (50 mL). The organic phase was washed with a mixture of water (500 mL) and saturated brine (150 mL) and finally washed with saturated brine (300 mL). The solution was dried (MgSO4) and filtered and to this solution was added 1M-HCl in MeOH (430 mL, 0.43 mol). The suspension was cooled (0° C. for 30 mins) and the solid removed by filtration which was washed with EtOAc and then heptane on the sinter and the solid dried (oil-pump, RT 72 h) to give crop 1 of the title compound 66.34 g (65%) as a colourless solid. 1H NMR (400 MHz, Me-d3-OD): 7.64-7.51 (m, 2H), 7.51-7.29 (m, 6H), 5.23 (s, 2H), 4.79 (dd, J=16.2, 6.1 Hz, 4H), 4.49 (s, 2H), 3.66 (s, 8H), 3.03 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.Cl.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([C:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=2)[CH:20]=[CH:21][CH:22]=1.[OH-].[Na+].O>C(O)C>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][CH2:2][N:26]1[CH2:25][CH:24]=[C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:29])[F:30])[CH:18]=2)[CH2:28][CH2:27]1
Reactant: BrCCc1ccc2ccccc2c1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1cccc(C2=CCN(CCc3ccc4ccccc4c3)CC2)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
A mixture of 12.5 g of 2-(2-bromoethyl)naphthalene, 14 g of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride, 4.34 g of sodium hydroxide, 135 ml of water and 95 ml of 95% ethanol is refluxed for 5 hours and the reaction mixture is then allowed to cool to room temperature overnight. It is cooled to below 25° C. and then filtered and the product isolated in this way is washed with water and dried under vacuum at 50° C. to give 1-[2-(naphth-2-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine base with a yield of 90%, calculated relative to the starting 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[O:37][CH3:38].C(#N)C>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[O:37][CH3:38])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 80.8 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1H-indazole (3.5 g, 16 mmol), K2CO3 (2.2 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (3.8 g, 16 mmol) and acetonitrile (90 ml) was refluxed for 16 hours. The reaction was poured into water and the resulting white solid, which precipitated from solution, was collected to afford 5.5 g of the desired product. The compound was recrystallized from dimethylformamide (twice) to afford 3.0 g (44%) of 1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]propoxy]-methoxyphenyl]ethanone as a white solid, m.p.=202°-204° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:20]=[CH:21][C:22]4[O:27][CH2:26][C:25](=O)[NH:24][C:23]=4[CH:29]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:20]=[CH:21][C:22]4[O:27][CH2:26][CH:25]=[N:24][C:23]=4[CH:29]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1COc2ccc(Nc3ncc(F)c(Nc4cccc([N+](=O)[O-])c4)n3)cc2N1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1cccc(Nc2nc(Nc3ccc4c(c3)N=CCO4)ncc2F)c1
Yield: 21.2 %

Procedure:
N4-(3-Nitrophenyl)-N2-[(2H)1,4-benzoxazin-3(4H)-one-6-yl]-5-fluoro-2,4-pyrimidinediamine (940 mg, 2.5 mmol) and Pd/C 10% (300 mg, 50% water content) were suspended in EtOH (7 mL) and 10% aqueous HCl (5 mL) and hydrogenated in a Parr apparatus for 3 hours (22° C., 60 psi). The suspension was filtered over celite and neutralized by addition of K2CO3. The solvents were removed and the resulting black slurry was suspended in MeOH. Silica gel (4 g) was added and the volatiles were removed under reduced pressure. The residue was subjected to column chromatography on silica gel (CHCl3-Acetone, 2:1) to give 186 mg of N4-(3-aminophenyl)-N2-(1,4-benzoxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine as brownish solid. 1H NMR (DMSO-d6): δ 8.92 (s, 1H), 8.64 (s, 1H), 7.95 (d, 1H, J=3.6 Hz), 7.11 (s, 1H), 6.84-6.95 (m, 3H), 6.66 (dd, 1H, J=2.4, 9.0 Hz); 6.46 (d, 1H, J=8.1 Hz), 6.28 (d, 1H, J=8.1 Hz), 5.62 (s, 1H), 4.98 (s, 2H), 4.03 (m, 2H), 3.31 (m, 2H); LCMS purity: 98.4%; MS (m/e): 352.7 (M+, 100).
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11](=[O:13])[CH:10]=[C:9]([C:14]([F:17])([F:16])[F:15])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]N1C(=O)CCC1=O>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[Br:18][C:10]1[C:11](=[O:13])[NH:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]=1[C:14]([F:16])([F:17])[F:15]
Reactant: O=c1cc(C(F)(F)F)nc(-c2ccccc2)[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: O=c1[nH]c(-c2ccccc2)nc(C(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To a solution of 1.0 g (3.94 mmol) of 2-phenyl-6-trifluoromethyl-4(3H)-pyrimidinone and 20 mL of glacial acetic add was added 1.0 g (5.6 mmol) N-bromosuccinimide and the mixture was left to stir at room temperature for 16 h. The reaction was poured onto ice water and vacuum filtered, washing well with water. The crude product was recrystallized from ethyl acetate to yield 1.05 g (83.5%) of 5-bromo-2-phenyl-6-trifluoromethyl-4(3H)-pyrimidinone, as a white solid. 1H-NMR (d6DMSO) δ 7.6(3H,m); 8.15(2H,m).
Reaction SMILES: Br[C:2]1[C:3]([F:10])=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[Cu][C:12]#[N:13].O.[OH-].[NH4+]>CN1CCCC1=O>[NH2:7][C:6]1[C:5]([CH3:9])=[CH:4][C:3]([F:10])=[C:2]([CH:8]=1)[C:12]#[N:13]
Reactant: N#C[Cu]
Reactant: Cc1cc(F)c(Br)cc1N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(F)c(C#N)cc1N
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
The starting 5-bromo-4-fluoro-2-methylaniline (1) (20 g, 98 mmol) was dissolved in anhydrous 1-methylpyrrolidinone (100 mL), and copper (I) cyanide (17.6 g, 196 mmol) was added. The reaction was heated to 180° C. for 3 hours, cooled to room temperature, and water (300 mL) and concentrated ammonium hydroxide (300 mL) added. The mixture was stirred for 30 minutes and extracted with EA (3×200 mL). The combined extracts were dried over magnesium sulfate, and the solvent was removed under reduced pressure. The oily residue was washed with hexanes (2×100 mL), and the solid dissolved in dichloromethane and loaded onto a silica gel column. Eluting with 0 to 25% EA in hexanes gradient provided 5-amino-2-fluoro-4-methylbenzonitrile (10.06 g, 67.1 mmol). LC/MS (m/z:151 M+1).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][NH:21][C:20](=[N:23][NH2:24])[C@H:19]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:18][CH2:17]1.[F:33][C:34]([F:40])([F:39])[CH2:35][C:36](O)=O.C(Cl)CCl.ON1C2N=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:36]([CH2:35][C:34]([F:40])([F:39])[F:33])=[N:24][N:23]=[C:20]2[C@H:19]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:18][CH2:17]1
Reactant: O=C(O)CC(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=NN
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21
Reaction time: 18 h

Procedure:
Triethylamine (0.259 mL, 1.86 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-hydrazonoazepan-3-ylcarbamate from Step A (548 mg, 1.55 mmol), 3,3,3-trifluoropropionic acid (0.205 mL, 2.32 mmol), EDC (356 mg, 1.86 mmol), and 1-hydroxy-7-azabenzotriazole (253 mg, 1.86 mmol) in dichloromethane (55 mL). After 18 h, saturated aqueous NaHCO3 was added and the mixture was extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 96:4, to give the title compound. MS: m/z=447 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15].[CH3:19]N(C)C=O>>[CH3:19][O:9][C:8]([C:5]1[CH:4]=[N:3][C:2]([CH:1]=[CH:13][N:14]([CH3:16])[CH3:15])=[CH:7][N:6]=1)=[O:10]
Reactant: Cc1cnc(C(=O)O)cn1
Reactant: COC(OC)N(C)C
Reactant: CN(C)C=O
Product: COC(=O)c1cnc(C=CN(C)C)cn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A solution of 5-methylpyrazine-2-carboxylic acid (5.0 g, 36.2 mmol), N,N-dimethylformamide dimethyl acetal (15 mL, 113 mmol) and N,N-dimethylformamide (15 mL) was heated with stirring in an oil-bath at 90° C. under argon for 60 min. The temperature of the oil-bath was raised to 120° C., and the heating and stirring continued for an additional 120 min. The reaction mixture was then cooled to 25° C. and concentrated in vacuo to a volume of about 10 mL. The oily residue was partitioned with water (50 mL) and ethyl acetate (50 mL). The aqueous phase was further extracted with ethyl acetate (2×50 mL), and each organic extract was washed with a portion of a saturated aqueous sodium chloride solution (25 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to a dark oil. The residue was treated with a solution of diethyl ether/hexanes (50 mL, 3:2) to produce an orange solid. The solid was collected by filtration and washed with a mixture of diethyl ether/hexanes (25 mL, 1:1) to afford 5-(2-dimethylamino-vinyl)-pyrazine-2-carboxylic acid methyl ester (4.94 g, 66%) as a bright orange solid.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].I([Cl:26])(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClC(Cl)C.CO>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:4]([C:1](=[O:3])[CH2:2][Cl:26])=[C:5]2[C:10]=1[NH:9][C:8](=[O:22])[CH:7]=[CH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=I(=O)Cl
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CC(Cl)Cl
Solvent: CO
Product: O=C(CCl)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reaction time: 8 h

Procedure:
25.2 g (86 mmol) 5-acetyl-8-benzyloxy-1H-quinolin-2-one (European Journal of Medicianl Chemistry 1984, 19(4), 341) and 50 g (142 mmol) benzyltrimethylammonium dichloriodate in 500 mL dichloroethane and 300 mL methanol are stirred overnight at reflux temperature. The reaction mixture is evaporated down and the residue is stirred overnight in THF and 1 N hydrochloric acid. After the THF has been distilled off the precipitated solid is suction filtered, washed with diethyl ether and dried.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.OC1CCC(C(OCC)=O)CC1.[Cr](O)(O)(=O)=O.C(O)(C)C>CC(C)=O>[O:1]=[C:2]1[CH2:12][CH2:11][CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=[Cr](=O)(O)O
Agent: CCOC(=O)C1CCC(O)CC1
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CCOC(=O)C1CCC(=O)CC1
Temperature: 0 °C

Procedure:
Ethyl 4-hydroxybenzoate is reduced to ethyl 4-hydroxycyclohexanecarboxylate according to the procedure described in R. A. Finnegan and P. L. Bachman, Journal of Organic Chemistry, Volume 30, pages 4145-4150 (1965). The crude material obtained in this reduction (190 g) is dissolved in 1200 ml of reagent grade acetone. The solution is cooled to 0° C. and 152 ml of a 8 N chromic acid solution (prepared from concentrated sulfuric acid and chromium trioxide) is added dropwise to the mechanically stirred reaction mixture. Enough isopropanol is added to the mixture to discharge its red color and it is then filtered through Celite. The salts are washed with several portions of acetone. The filtrate is evaporated in vacuo. The residue is dissolved in 750 ml of diethyl ether and washed with sodium bicarbonate and brine solutions. After drying, the solvent is evaporated and the residue is distilled to yield the title compound; bp12 125 ° C.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[I-].[K+].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>C(Cl)Cl.[Ag]=O>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:4][CH2:3][CH2:2][CH2:1][OH:5])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCO
Agent: O=[Ag]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.5 %

Procedure:
1.45 mL (corresponding to 20.0 mmol) of 1,3-propanediol was dissolved in 200 mL of methylene chloride. To this solution under an ice bath, 6.96 g (corresponding to 30.0 mmol) of silver oxide, 666 mg (corresponding to 4.0 mmol) of potassium iodide and 4.21 g (corresponding to 22.0 mmol) of p-toluenesulfonyl chloride were added. The resulting mixture was stirred at room temperature for 3 hours. Insoluble matters were filtered out of the reaction mixture, and were washed with ethyl acetate. The washings were combined with the filtrate, and the mixture was concentrated. The resulting crude product was purified with flash silica gel column chromatography (elution solvent: hexane/ethyl acetate=3/2 to 1/1) to obtain 2.47 g (corresponding to 10.7 mmol) of 1,3-propanediol mono-p-toluenesulfonate (FIG. 1, Step 6).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[F:21][CH:22]([F:28])[C:23](OCC)=[O:24]>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:23](=[O:24])[CH:22]([F:28])[F:21])[CH:15]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)C(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(c1cc(Br)ccc1F)C(F)F
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 91.6 %

Procedure:
A solution of diisopropylamine (12.7 g, 17.9 ml, 126 mmol) and tetrahydrofuran (375 ml) was cooled to −78° C. and n-BuLi (1.6 M in hexane) (78.6 ml, 126 mmol) was added dropwise. After stirring for 10 min commercially available 1-bromo-4-fluorobenzene {CAS[460-00-4]} (20 g, 12.4 ml, 114 mmol) was added dropwise at max. −60° C. Stirring was continued at −70° C. for 2.5 hours. Then ethyl difluoroacetate (17.0 g, 13.7 ml, 137 mmol) was added dropwise and the mixture was warmed to −10° C. and then quenched by pouring the mixture onto 1 M HCl. The mixture was extracted twice with ethyl acetate, dried over sodium sulphate, filtered and evaporated to give a yellow liquid (34 g; 118%). The residue was chromatographed on 200 g silica gel with cyclohexane/ethyl acetate 3:1 to give 1-(5-bromo-2-fluorophenyl)-2,2-difluoroethanone (26.5 g, 105 mmol, 91.6% yield) as a yellow liquid. MS (EI): m/z=252.0 [M]+ and 254.0 [M+2]+.