Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:17][CH2:18][N:19]([CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:20][CH2:21]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCNCC2)c1
Reactant: CC(C)CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(CCC(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of a mixture of 4-methyl-2-(5-piperidin-4-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester and methyl ester (68b) (57 mg, 0.13 mmol) in N,N-dimethylformamide (1.0 mL) was added Cs2CO3(85 mg, 0.26 mmol) and 1-iodo-3-methyl-butane (0.025 mL, 0.19 mmol). The mixture was stirred for 2 h at room temperature. The reaction was diluted with EtOAC (10 mL) and washed with saturated aqueous NaHCO3 solution, brine and water. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain 4-methyl-2-{5-[1-(3-methyl-butyl)-piperidin-4-yl]-4′-trifluoromethyl-biphenyl-3-yl}-pentanoic acid ethyl ester and methyl ester. Calcd for C30H40F3NO2 (M+H) 504.64, Found 504.4 (methyl ester) and Calcd for C31H42F3NO2 (M+H) 518.67, Found 518.7 (ethyl ester).
Reaction SMILES: O[C:2]([C:5]1[CH:6]=[C:7]([C:17]([CH3:21])([CH3:20])[C:18]#[N:19])[CH:8]=[C:9]([CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH:10]=1)([CH3:4])[CH3:3].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH:2]([C:5]1[CH:6]=[C:7]([C:17]([CH3:21])([CH3:20])[C:18]#[N:19])[CH:8]=[C:9]([CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1cc(Cn2cncn2)cc(C(C)(C)C#N)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc(Cn2cncn2)cc(C(C)(C)C#N)c1
Reaction time: 18 h

Procedure:
A solution of 2-[3-(1-hydroxy-1-methylethyl)-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-2-methylpropiononitrile (0.06 g) in trifluoroacetic acid (1 ml) was treated with triethylsilane (50 mg) and the solution kept at room temperature for 18 h and then evaporated to dryness under reduced pressure. The residue was treated with aqueous sodium hydrogen carbonate solution and the mixture was extracted twice with ethyl acetate. The combined extracts were dried and evaporated to dryness under reduced pressure, and the residue was purified by flash chromatography, using ethyl acetate as eluant, to give 2-[3-isopropyl-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-2-methylpropiononitrile. Nmr in deuteriochloroform: δ 8.1 (1H, s), 8.0 (1H, s), 7.32 (1H, m), 7.18 (1H, m), 7.05 (1H, m), 5.35 (2H, s), 2.92 (1H, m), 1.7 (6H, s), 1.24 (6H, d).
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]2[CH2:15][CH2:16][N:2]1[CH2:3][CH2:4]2.Br[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([CH3:28])[CH:22]=[CH:21]2>>[CH3:28][C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[CH:26][CH:27]=[C:18]([N:7]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14]4[CH2:1][N:2]5[CH2:3][CH2:4][CH:5]([C:6]3=4)[CH2:15][CH2:16]5)[CH:19]=2)[N:24]=1
Reactant: c1ccc2c3c([nH]c2c1)C1CCN(CC1)C3
Reactant: Cc1ccc2cc(Br)ccc2n1
Product: Cc1ccc2cc(-n3c4c(c5ccccc53)CN3CCC4CC3)ccc2n1

Procedure:
The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (212 mg, 1.0 mmol; Example 187A) and 6-bromo-2-methylquinoline (333 mg, 1.5 mmol; Oakwood) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.94-2.20 (m, 4H) 2.78 (s, 3H) 2.91-2.98 (m, 1H) 3.09-3.29 (m, 4H) 4.35 (s, 2H) 7.06-7.11 (m, 3H) 7.39-7.45 (m, 1H) 7.53 (d, J=8 Hz, 1H) 7.67 (dd, J=9, 2 Hz, 1H) 7.89 (d, J=2 Hz, 1H) 8.13 (d, J=9 Hz, 1H) 8.33 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 354 (M+H)+.
Reaction SMILES: O.[C:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[OH-].[K+].[CH3:10][N:11]([CH3:15])[CH2:12]CO>CO>[CH3:10][N:11]([CH2:15][CH2:4][O:3][C:2](=[O:7])[O:5][CH2:6][CH2:10][N:11]([CH3:15])[CH3:12])[CH3:12]
Reactant: CN(C)CCO
Reactant: COC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)CCOC(=O)OCCN(C)C
Temperature: 80 °C

Procedure:
Into a flask equipped with a reflux cooler, a water separator and a dropping funnel, there were charged 113.5 grams (1.25 moles) of dimethyl carbonate. The substance was heated to 80° C. A solution of 1.4 grams (0.025 moles) of potassium hydroxide in 225.0 grams (2.5 moles) of dimethylethanolamine was then added in drops over a period of 30 minutes. The methanol formed during the reaction was removed by azeotropic distillation using cyclohexane as an entraining agent.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:45]([OH:48])(=[S:47])[CH3:46]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([S:47][C:45](=[O:48])[CH3:46])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CC(O)=S
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)S[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 18 h
Yield: 89.2 %

Procedure:
3 g (16 mmol) (R)-3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester and 4.63 g Triphenylphosphine were dissolved in 70 ml THF. Over a period of 10 min 2.8 ml (17.6 mmol) Diethylazodicarboxylate were added at 0° C. After 10 min 1.26 ml (17.6 mmol) Thioacetic acid was added and the mixture was allowed to come to RT and stirring was continued for 18 h. After evaporation the residue was purified over silica gel (heptane to 20% ethyl acetate in heptane) to give 3.5 g of the expected compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:19]4[CH:20]=[N:21][N:22]([CH2:24][C:25]([OH:28])([CH3:27])[CH3:26])[CH:23]=4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:29]=1.[C:30]([C:32]1([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33]1)#[CH:31]>>[OH:28][C:25]([CH3:27])([CH3:26])[CH2:24][N:22]1[CH:23]=[C:19]([C:13]2[N:8]3[CH:9]4[CH2:12][CH:11]([C:5]5[CH:4]=[CH:3][C:2]([C:31]#[C:30][C:32]6([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33]6)=[CH:29][C:6]=5[C:7]3=[N:15][C:14]=2[C:16]([NH2:18])=[O:17])[CH2:10]4)[CH:20]=[N:21]1
Reactant: C#CC1(O)CCCC1
Reactant: CC(C)(O)Cn1cc(-c2c(C(N)=O)nc3n2C2CC(C2)c2ccc(Br)cc2-3)cn1
Product: CC(C)(O)Cn1cc(-c2c(C(N)=O)nc3n2C2CC(C2)c2ccc(C#CC4(O)CCCC4)cc2-3)cn1

Procedure:
10-bromo-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-5,7 methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with 1-ethynylcyclopentanol via General Procedure E to afford 20 mg (14.5%) of 3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-10-((1-hydroxycyclopentyl)ethynyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide following reverse phase purification. M+1=486.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([NH:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([CH3:23])[N:16]=1)=[S:13])(=[O:10])=[O:9].BrBr>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]=[C:12]1[S:13][N:16]2[C:17]([CH3:23])=[CH:18][C:19]([O:21][CH3:22])=[N:20][C:15]2=[N:14]1)(=[O:10])=[O:9]
Reactant: COc1cc(C)nc(NC(=S)NS(=O)(=O)c2ccccc2Cl)n1
Agent: BrBr
Solvent: c1ccncc1
Product: COc1cc(C)n2sc(=NS(=O)(=O)c3ccccc3Cl)nc2n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 70.4 %

Procedure:
A solution of 2.0 g of N-(2-chlorophenylsulfonyl)-N'-(4-methoxy-6-methyl-2-pyrimidinyl) thiourea in 30 ml of pyridine is cooled to -6° C.~-8° C., to which 0.9 g of bromine is dropwise added. After stirring for 1.5 hours, at the same temperature, the reaction mixture is poured into 150 ml of ice water and the precipitate is collected by filtration. It is then washed with water, dried, and recrystallized from acetonitrile to give 1.4 g of title compound as white needles. mp 191°~192° C. (decomp.)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([C:18]4[CH:19]=[N:20][CH:21]=[N:22][CH:23]=4)=[CH:11][CH:12]=3)[C:7]([CH:25]=[CH2:26])(O)[C:6]=2[CH:5]=1.[NH2:27][C:28]([NH2:30])=[S:29]>CC(O)=O>[CH3:2][O:3][C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([C:18]4[CH:23]=[N:22][CH:21]=[N:20][CH:19]=4)=[CH:11][CH:12]=3)[C:7]3([CH2:25][CH2:26][S:29][C:28]([NH2:30])=[N:27]3)[C:6]=2[CH:5]=1
Reactant: NC(N)=S
Reactant: C=CC1(O)c2cc(OC)ccc2Oc2ccc(-c3cncnc3)cc21
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C1(CCSC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A vial charged with Pd2(dba)3 (0.150 g, 0.164 mmol), XPhos (0.391 g, 0.819 mmol), 5-(tributylstannyl)pyrimidine (1.81 g, 4.92 mmol), 2-bromo-7-methoxy-9H-xanthen-9-one (1.000 g, 3.28 mmol) and dioxane (10 mL). The reaction mixture was evacuated and backfilled with nitrogen. The reaction mixture was heated to 100° C. overnight. The reaction mixture was cooled to RT and diluted with water and EtOAc. A grey solid precipitated out, which was filtered off. The solid was washed with EtOAc and water. The grey solid dried under reduced pressure to afford 2-methoxy-7-(pyrimidin-5-yl)-9H-xanthen-9-one) (0.600 g, 60.2% yield). Step 2: A solution of vinylmagnesium chloride (1.6M solution in THF; 0.82 mL, 1.314 mmol) was added dropwise to a solution of 2-methoxy-7-(pyrimidin-5-yl)-9H-xanthen-9-one (200 mg, 0.657 mmol) in THF (10 mL) at −78° C. After 30 min, the reaction mixture was allowed to warm to −10° C. and was then quenched with saturated aqueous ammonium chloride. The reaction was extracted with EtOAc, and the organic phase was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography to give 2-methoxy-7-(pyrimidin-5-yl)-9-vinyl-9H-xanthen-9-ol as a pale yellow gum. Step 3: 2 N HCl (3 mL) was added to solution of 2-methoxy-7-(pyrimidin-5-yl)-9-vinyl-9H-xanthen-9-ol (50 mg, 0.150 mmol) and thiourea (9.25 μL, 0.171 mmol) in HOAc (5 mL). The reaction mixture was allowed to stir overnight at rt and concentrated under reduced pressure. The residue was treated with of TFA (4 mL). The reaction mixture was stirred overnight at rt. The reaction mixture was concentrated under reduced pressure and the residue was treated with aqueous, half-saturated sodium bicarbonate, extracted with EtOAc, and concentrated under reduced pressure. The residue was purified by chromatography (DCM/MeOH 20:1 to 5:1) to give 2′-methoxy-7′-(pyrimidin-5-yl)-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-amine as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[CH2:27][CH3:28].C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[CH2:27][CH3:28])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: O=c1[nH]c(-c2cc(Cl)ccc2F)nc2nccnc12
Reactant: CCc1cnccc1N
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: CCc1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2nccnc12

Procedure:
The title product was synthesized by reaction of the 2-(5-chloro-2-fluorophenyl)-pteridin-4-one with 4-amino-3-ethylpyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][C:5]([O:12][CH2:13][O:14][CH3:15])=[CH:4][C:3]=1[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C)[CH:27]=[O:28].O.CO>C(OCC)C>[CH2:18]([O:17][CH2:16][C:3]1[CH:4]=[C:5]([O:12][CH2:13][O:14][CH3:15])[CH:6]=[C:7]([O:8][CH2:9][O:10][CH3:11])[C:2]=1[CH:27]=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COCOc1cc(COCc2ccccc2)c(Br)c(OCOC)c1
Reactant: CN(C)C=O
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: COCOc1cc(COCc2ccccc2)c(C=O)c(OCOC)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
The above-obtained 2-bromo-1-(benzyloxymethyl)-3,5-bis(methoxymethoxy)benzene (1.6 g, 4.3 mmol) was dissolved in diethylether (25 mL) and cooled to −78° C. The obtained solution was added with 1.52 mol/L n-butyllithium-hexane solution (4.0 mL, 6.1 mmol) and stirred at −78° C. for 1 hour. Then, N,N-dimethylformamide (1.0 mL, 13 mmol) was added thereto and stirred at a room temperature for 3 hours. The reaction mixture was added with water and methanol, and then extracted with chloroform 3 times. The organic layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1 to 5/1 to 3/1) to obtain 2-(benzyloxymethyl)-4,6-bis(methoxymethoxy)benzaldehyde (0.99 g, 72%).
Reaction SMILES: [C:1]1([S:7]([C:9]2[C:10]([CH2:15][O:16]C(=O)C)=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[C:1]1([S:7]([C:9]2[C:10]([CH2:15][OH:16])=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OCc1ncccc1S(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: O=S(c1ccccc1)c1cccnc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
To a solution of the crude Acetic acid 3-benzenesulfinyl-pyridin-2-ylmethyl ester (268 mg) in anhydrous MeOH (4 mL) was added powdered K2CO3 (254 mg, 1.84 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with CH2Cl2 (30 mL), filtered by vacuum filtration, and the filtrate was concentrated. Purification by flash chromatography on silica gel (Hexanes/EtOAc, 20:80 then 0:100) provided (3-Benzenesulfinyl-pyridin-2-yl)-methanol (128 mg, 42% over 2 steps) as a colorless oil. 1H NMR (CDCl3) δ 4.18 (t, 1H, J=5.7 Hz), 4.58 (dd, 1H, J=14.8, 4.3 Hz), 4.88 (dd, 1H, J=14.9, 5.3 Hz), 7.45-7.53 (m, 4H), 7.59-7.66 (m, 2H), 8.33 (dd, 1H, J=7.9, 1.4 Hz), 8.66 (dd, 1H, J=5.3, 1.8 Hz).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[CH:18]=[C:17]([CH3:19])[C:16]([O:20][CH3:21])=[C:15]2[C:7]=1[CH:8]1[CH:13]([CH:14]2O)[CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)(Cl)Cl>[CH3:5][C:6]1[CH:18]=[C:17]([CH3:19])[C:16]([O:20][CH3:21])=[C:15]2[C:7]=1[CH:8]1[C:13](=[CH:14]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COc1c(C)cc(C)c2c1C(O)C1CCCCC21
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COc1c(C)cc(C)c2c1C=C1CCCCC12
Reaction time: 2 h
Yield: 88.9 %

Procedure:
5.5 Milliliters of thionyl chloride was added dropwise to a chloroform solution containing 16.1 g of 5,7-dimethyl-8-methoxy-9-hydroxy-1,2,3,4,4a,9a-hexahydrofluorene under ice-cooling. After completion of the addition, reaction was effected at the same temperature for 2 hours. The reaction mixture was washed successively with water twice, saturated aqueous sodium chloride solution and saturated sodium bicarbonate solution and dried with magnesium sulfate. Then, the solvent was distilled off and the residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:20) to obtain 13.26 g of 5,7-dimethyl-8-methoxy-2,3,4,4a-tetrahydro-1H-fluorene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:7]([C:11]3[CH:16]=[CH:15][C:14]([C:17](=[CH2:22])[CH2:18][CH2:19][CH2:20][OH:21])=[CH:13][CH:12]=3)=[CH:6][N:5]2[CH:23]=1.FC1C=C2C(=O)NC(C3C=CC(/C(/C)=C/CCO)=CC=3)=CN2C=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:7]([C:11]3[CH:12]=[CH:13][C:14]([C:17]4([CH3:22])[CH2:18][CH2:19][CH2:20][O:21]4)=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:23]=1
Reactant: C=C(CCCO)c1ccc(-c2cn3cc(F)cc3c(=O)[nH]2)cc1
Agent: C/C(=C\CCO)c1ccc(-c2cn3cc(F)cc3c(=O)[nH]2)cc1
Product: CC1(c2ccc(-c3cn4cc(F)cc4c(=O)[nH]3)cc2)CCCO1

Procedure:
7-fluoro-3-[4-(4-hydroxy-1-methylene-butyl)-phenyl]-2H-pyrrolo[1,2-a]pyrazin-1-one (contains some of the isomer 7-fluoro-3-[4-((E)-4-hydroxy-1-methyl-but-1-enyl)-phenyl]-2H-pyrrolo[1,2-a]pyrazin-1-one); HPLC/MS 2.32 (B), [M+H] 313; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.98 (s, 1H), 7.69-7.53 (m, 3H), 7.53-7.43 (m, 3H), 6.75 (m, 1H), 6.45-6.39 (m, 2H), 4.41 (t, J=5.2 Hz, 1H), 3.45 (td, J=6.4, 5.0 Hz, 2H), 2.29-2.19 (m, 2H), 1.66-1.54 (m, 2H).
Reaction SMILES: C(ON=O)(C)(C)C.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10](N)[CH:9]=1.B(F)(F)[F:20].CCOCC>C1C(Cl)=CC=C(Cl)C=1>[F:20][C:10]1[CH:9]=[N:8][C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: Nc1cnc2ccccc2c1
Reactant: FB(F)F
Agent: CC(C)(C)ON=O
Solvent: Clc1ccc(Cl)cc1
Solvent: CCOCC
Product: Fc1cnc2ccccc2c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Tert-butylnitrite (4.6 ml, 38.7 mmol) was added dropwise over 15 min to a solution of quinolin-3-amine (4.61 g, 32.0 mmol) and borontrifluoride-etherate (6 ml, 47.3 mmol) in dichlorobenzene (100 ml). The solution was heated to 100° C. After stirring for 1 h, the solution was cooled to ambient temperature and the dichlorobenzene was decanted leaving 3-fluoroquinoline as a black residue. Method [8] retention time 3.28 min by HPLC (M+ 148).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:6]([C:7]#[CH:8])[O:5][C:4](=[O:9])[NH:3]1.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19](I)[CH:20]=2)[N:15]=[CH:14][N:13]=1.C(NC(C)C)(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:8]#[C:7][CH:6]3[O:5][C:4](=[O:9])[NH:3][C:2]3([CH3:10])[CH3:1])[CH:20]=2)[N:15]=[CH:14][N:13]=1
Reactant: C#CC1OC(=O)NC1(C)C
Reactant: Clc1ncnc2ccc(I)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC1(C)NC(=O)OC1C#Cc1ccc2ncnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
A mixture of 4,4-Dimethyl-5-ethynyl-2-oxazolidinone (1.10 g, 7.90 mmol), 4-chloro-6-iodoquinazoline (1.63 g, 5.60 mmol), dichlorobis(triphenylphosphine)palladium(II) (200 mg, 0.28 mmol), copper iodide (53 mg, 0.28 mmol), and diisopropylamine (0.57 g, 5.60 mmol) in anhydrous THF (30 mL) was stirred at room temperature under nitrogen for 4 hours. After concentration, the residue was dissolved in CH2Cl2 (80 mL), washed with aqueous NH4Cl and brine, dried over sodium sulfate, and concentrated to give the crude product as brown oil. Purification by silica gel column using 50-70% EtOAc in hexane afforded 1.22 g (72%) of yellow solid: 1H NMR (CDCl3) δ 1.49 (s, 3H), 1.53 (s, 3H), 5.14 (s, 1H), 5.57 (br s, 1H), 7.95 (dd, 1H), 8.04 (d, 1H, J=8.8 Hz), 8.38 (d, 1H, J=2.0 Hz), 9.05 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1Cl.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C.O>[C:10]1([C:3]2[C:2]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:6]=[CH:5][N:4]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ncnc(Cl)c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: c1ccc(-c2ncnc(-c3ccccc3)c2-c2ccccc2)cc1
Yield: 46 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were put 4.25 g of 5-bromo-4,6-dichloropyrimidine, 6.84 g of phenylboronic acid, 5.95 g of sodium carbonate, 0.16 g of bis(triphenylphosphine)palladium (II) dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. Here, into the flask were further put 2.28 g of phenylboronic acid, 1.98 g of sodium carbonate, 0.053 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of acetonitrile, and the mixture was heated again by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. After that, the precipitated solid was suction-filtered and washed with water. The obtained residue was purified by flash column chromatography using dichloromethane and ethyl acetate as a developing solvent in a ratio of 10:1, so that a pyrimidine derivative Htppm, which was the objective substance, was obtained (white powder, yield of 46%). Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme (1-1) of Step 1 is shown below.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.C(N(C(C)C)C=O)(C)C.[CH2:16]([C:18]1[CH:31]=[CH:30][C:21]([O:22][C:23]2[C:24](=O)[NH:25][CH:26]=[N:27][CH:28]=2)=[CH:20][CH:19]=1)[CH3:17].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:4][C:24]1[C:23]([O:22][C:21]2[CH:30]=[CH:31][C:18]([CH2:16][CH3:17])=[CH:19][CH:20]=2)=[CH:28][N:27]=[CH:26][N:25]=1
Reactant: CCc1ccc(Oc2cnc[nH]c2=O)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: CC(C)N(C=O)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1ccc(Oc2cncnc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of oxalyl chloride (Aldrich) (1.97 g, 15.2 mmoles) in dichloromethane (6 mL) was added in several portions to a stirred, ice-bath cooled solution of diisopropylformamide (Aldrich) (2.00 g, 15.17 mmoles) in dichloromethane (25 mL). The ice-bath was removed, and the solution was stirred at ambient temperature for 10 minutes. Solid 5-(4-ethylphenoxy)pyrimidin-4(3H)-one (1.00 g, 4.62 mmoles) was added, and the mixture was refluxed with stirring for 45 minutes. The solution was cooled and poured into a cold solution of vigorously stirred, saturated aqueous sodium bicarbonate (80 mL). The organic layer was washed with cold saturated aqueous sodium bicarbonate (80 mL), with cold water (80 mL) and then dried over sodium sulfate. The dry solution was spin evaporated in vacuo to give the intermediate 4-chloro-5-(4-ethylphenoxy)pyrimidine as an orange liquid. The liquid was dissolved in ethanol (50 mL) and trans-4-hydroxycyclohexylamine hydrochloride (Aldrich) (1.79 g, 11.45 mmoles) was added. A solution of sodium ethoxide, which had been prepared from sodium hydride (60% in mineral oil) (Aldrich) (0.41 g, 10.25 mmoles) and ethanol (15 mL) was added. The flask was rinsed with ethanol (10 mL), and the reaction was refluxed with stirring for 65 hours. The volatiles were removed by spin evaporate in vacuo to a small volume, and the residue was triturated with water (100 mL). The gummy residue was extracted with dichloromethane (150 mL). The solution was washed with water (80 mL), dried over sodium sulfate and spin evaporated in vacuo. This material was dissolved in ethyl acetate-hexanes and chromatographed on Silica Gel 60 (E. M. Science, 230-440 mesh) (13×4 cm column bed) using ethyl acetate as the eluent for the first 1.2 L and then with 5% ethanol in ethyl acetate. The fractions that contained homogeneous product were spin evaporated in vacuo to give a syrup. The pure 5-(4-ethylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine was converted to the hydrochloride by the same procedure described in Example 4. The residue was triturated under ethyl acetate to give a white solid which was collected, washed with ethyl acetate and dried in vacuo to give 1.25 g (77% yield) of 5-(4-ethylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine hydrochloride as a white solid, mp 245-243° C.