Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[N+:6]([O-])[CH:5]=2)[CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cc(C2CC2)c2ccccc2c1
Product: Clc1ncc(C2CC2)c2ccccc12
Yield: 5.76 %

Procedure:
A solution of 4-cyclopropylisoquinoline-2-oxide (0.3 g, 1.620 mmol) in POCl3 (15 ml) was refluxed for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get the desired compound (0.02 g, 5.76%) as oil. 1H NMR (400 MHz, CDCl3): δ ppm 8.37-8.35 (d, J=8 Hz, 2H), 8.08 (s, 1H), 7.81 (t, J=8 Hz, 1H), 7.70 (t, J=4 Hz, 1H), 2.18 (m, 1H), 1.11 (t, J=4 Hz, 2H), 0.80 (t, J=8 Hz, 2H); MS: MS m/z 204.28 (M++1).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][C:28](=O)[CH2:27]1>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[C:28]3[CH2:29][CH2:30][CH2:31][C@@H:26]([CH3:25])[CH2:27]3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: C[C@@H]1CCCC(=O)C1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CCCC(=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)C1
Temperature: 25 °C

Procedure:
The product of Example 268D (0.073 g, 0.2 mmol) was reacted with (3R)-3-methylcyclohexanone (1.12 g, 10.0 mmol) in N,N-dimethylacetamide (2 mL) in a sealed tube at 135° C. for 45 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether (3 mL) and filtered to give the title compound.
Reaction SMILES: [Cl:1][S:2]([C:5]1[C:6]([O:17][CH3:18])=[CH:7][C:8]([O:14][CH2:15][CH3:16])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[N+](=[CH2:21])=[N-]>O1CCCC1.CCOCC>[CH3:21][O:11][C:10](=[O:12])[C:9]1[CH:13]=[C:5]([S:2]([Cl:1])(=[O:4])=[O:3])[C:6]([O:17][CH3:18])=[CH:7][C:8]=1[O:14][CH2:15][CH3:16]
Reactant: CCOc1cc(OC)c(S(=O)(=O)Cl)cc1C(=O)O
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1cc(OC)c(S(=O)(=O)Cl)cc1C(=O)OC
Reaction time: 0.17 h

Procedure:
A solution of 5-chlorosulfonyl-2-ethoxy-4-methoxybenzoic acid (13 g, 44 mmol) in tetrahydrofuran was cooled to 5° C. and treated with excess diazomethane in ether solution (prepared from N-methyl-N-nitroso-p-toluenesulfonamide, Aldrich) and stirred for 10 min. Solvent and excess diazomethane was removed by rotary evaporation. The resulting residue was dissolved in dichloromethane and filtered through a plug of silica gel and evaporated. The solids were triturated with ether/hexane to give 13 g of 5-chlorosulfonyl-2-ethoxy-4-methoxy-benzoic acid methyl ester as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: C1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Br)cc1)N1CCCC1
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 4-bromobenzoyl chloride (3 g, 13.7 mmol)) in dichloromethane (25 mL) was cooled to 0° C. and treated with pyrrolidine (2.5 mL, 30.3 mmol) and triethylamine (2 mL, 14.4 mmol). The mixture was warmed to ambient temperature over 3 hours and concentrated. The residue was purified by flash chromatography on silica gel using 10-60% hexane/ethyl acetate to provide the title compound (3.1 g, 89%). MS (ESI) m/e 256 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].[F:7][C:8]([F:15])([F:14])[C:9](=[CH2:13])[C:10](Cl)=[O:11].O>CN(C=O)C>[CH3:1][N:2]1[CH2:13][CH:9]([C:8]([F:15])([F:14])[F:7])[C:10](=[O:11])[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: CNC(=O)NC
Reactant: C=C(C(=O)Cl)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC(C(F)(F)F)C(=O)N(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A solution of 1,3-dimethylurea (423 mg; 4.8 mmoles) in DMF (5 ml) was cooled to 0° C., and α-trifluoromethylacryloyl chloride (792 mg; 5.0 mmoles) was added dropwise. The mixture was stirred at room temperature for 1 hour. Then, water (20 ml) was added, and the mixture was extracted with methylene chloride (20 ml×1, 10 ml×2). The combined extracts were dried over anhhdrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by a column chromatography on silica gel (chloroform) to give 508 mg (yield: 50%) of 1,3-dimethyl-5-trifluoromethyl-5,6-dihydrouracil (OF-1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.S(=O)(=O)(O)O.[C:24](=O)([O-])O.[Na+]>CO>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH3:24])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: O=C([O-])O
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
To a solution of [3,5-bis(trifluoromethyl)phenyl]acetic acid (10 g) in methanol (50 mL) was added concentrated sulfuric acid (0.5 mL), and the mixture was stirred at 80° C. for 14 hr. The reaction mixture was cooled, basified with saturated aqueous sodium hydrogen carbonate solution, and concentrated under reduced pressure. The residue was diluted with ethyl acetate, and washed with saturated brine. The aqueous layer was extracted again with ethyl acetate, and the combined extract was dried, and concentrated to give methyl [3,5-bis(trifluoromethyl)phenyl]acetate (10.8 g, 100%) as a colorless oil.
Reaction SMILES: [N:1]1[NH:2][CH:3]=[C:4]2[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5]=12.[H-].[Na+].[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23]Cl>CN(C=O)C>[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23][N:2]1[CH:3]=[C:4]2[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5]2=[N:1]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)OC(=O)N1Cc2c[nH]nc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2cn(COCC[Si](C)(C)C)nc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (20 g, 96 mmol) in DMF (200 mL) at 0° C. was added sodium hydride (4.21 g, 105 mmol). After stirring for 1 h at RT, 2-trimethylsilylethoxymethyl chloride (SEM-Cl) (4.65 mL, 26.3 mmol) was added. The resulting mixture was stirred at RT overnight. The mixture was quenched with saturated NH4OH, and the solvents were removed. The residue was diluted with ethyl acetate (500 mL), washed with water, brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on a silica gel Biotage 65i® column, eluting with 0 to 20% ethyl acetate in hexanes to give the title compound as a colorless gum. LC-MS: 340.1 (M+H)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](Cl)=[O:13])=[C:7]([O:15][CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][NH:18][CH3:19]>C(Cl)Cl.O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([N:18]([CH3:19])[CH3:17])=[O:13])=[C:7]([O:15][CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C(C)(C)C)ccc1CC(=O)Cl
Reactant: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)C)ccc1CC(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of Step B was dissolved in 20 mL CH2Cl2 and 5.0 mL of a 2 M solution of dimethylamine in tetrahydrofuran was added. The reaction mixture was stirred overnight at room temperature, and then concentrated in vacuo. The residue was partitioned between 50 mL EtOAc, 20 mL water and 10 mL of 5 N sodium hydroxide. The aqueous layer was separated and re extracted with EtOAc, then the organic layers were combined, dried Na2SO4), filtered and evaporated in vacuo to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: OCCc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: OCCc1ccc(-c2ccc(F)cc2)cc1

Procedure:
To a 2-5 mL microwave vial was added 2-(4-bromophenyl)ethanol (603 mg, 3.0 mmol), (4-fluorophenyl)boronic acid (462 mg, 3.3 mmol), sodium carbonate (973 mg, 9.0 mmol), palladium acetate (33.7 mg, 0.15 mmol), 1,4dioxane (4.5 mL) and water (4.5 mL). The mixture was irradiated in a CEN microwave at 120° C. for 10 minutes. The reaction mixture was biphasic upon reaction completion. The reaction mixture was extracted into ethyl acetate (2×150 mL) dried over Na2SO4 then filtered through a pad of celite. The organics were concentrated in vacuo and the crude material was purified by chromatography on silica gel (gradient: 70:30 heptanes:EtOAc). Isolated material still contained 2-(4-bromophenyl)ethanol, therefore, the material was triturated in heptanes to furnish the title compound as a white solid. (430 mg, 45%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([Si:9]([CH3:12])([CH3:11])[CH3:10])#[CH:8]>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>[CH3:10][Si:9]([CH3:12])([CH3:11])[C:7]#[C:8][C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: Brc1nccs1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1nccs1

Procedure:
A solution of 2-Bromothiazole (Aldrich, 5.0 g, 30.5 mmol), ethynyl-trimethyl-silane (Aldrich, 3.0 g, 30.5 mmol), PdCl2(PPh3)2 (Aldrich, 500 mg, 0.71 mmol) and CuI (Aldrich, 400 mg, 1.52 mmol) in THF (20 mL) was treated with TEA (5 mL) at room temperature for 20 min. The reaction was heated at 60 for 4 hours. The solid was filtered off through a pad of celite and the filtrate was concentrated to give yellow solid, which was then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as yellow oil.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH:37]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccc[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(Nc1ccc(N2CCN(Cc3ccc[nH]3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (310 mg) in 1,2-dichloroethane (20 mL) was added 1H-pyrrole-2-carboxaldehyde (95 mg) and acetic acid (67 mg). The solution was cooled at 0° C. and sodium triacetoxy borohydride (317 mg) was added portionwise and the mixture was stirred at room temperature for 16 hours. The solution was then washed with a saturated solution of NaHCO3, with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with CH2Cl2/MeOH (95/5) and the solid obtained was recrystallized from EtOH to give the title compound (180 mg) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O>C1COCC1.O1CCOCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][OH:15])=[CH:17][CH:18]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
LiAl4 (227 mg, 5.97 mmol) was slurried in a mixture of THF (5 mL) and dioxane (5 mL) and cooled to 0° C. under an atmosphere of N2. 4-(tert-Butoxycarbonylamino-methyl)-benzoic acid was dissolved in a mixture of THF (5 mL) and dioxane (5 mL) and added to the chilled solution drop-wise over 15 min. The reaction mixture was allowed to warm to r.t and stirred for 16 h. Water (1 mL) was added to the reaction mixture which was then filtered through celite. The filtrate was evaporated to dryness and the residue partitioned between EtOAc (25 mL) and water (25 mL). The aqueous layer was extracted with EtOAC (2×25 mL), the organic layers combined, dried (Na2SO4) and evaporated to dryness to afford the desired product (460 mg, 100%). m/z 260 [M++Na]+
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[F:20])=[C:10]([CH3:21])[C:9](=[O:22])[N:8]([CH3:23])[C:7]=1[CH2:24]Br)=O)C.[NH3:26]>CO>[F:20][C:14]1[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=1[NH:12][C:11]1[C:6]2[C:4](=[O:3])[NH:26][CH2:24][C:7]=2[N:8]([CH3:23])[C:9](=[O:22])[C:10]=1[CH3:21]
Reactant: CCOC(=O)c1c(Nc2ccc(C)cc2F)c(C)c(=O)n(C)c1CBr
Reactant: N
Solvent: CO
Product: Cc1ccc(Nc2c3c(n(C)c(=O)c2C)CNC3=O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of 2-bromomethyl-4-(2-fluoro-4-methylphenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (0.016 g, 0.040 mmol) in MeOH (0.50 mL) was added ammonia (0.006 mL, 0.040 mmol, 7 M solution in MeOH). After stirring for 2 hours at room temperature, the reaction mixture was heated to 40° C. for 8 hours. The resulting white precipitate was filtered to yield clean desired product (0.005 g, 46%). MS ESI (+) m/z 303 (M+1) detected; 1H NMR (400 MHz, DMSO) δ 8.16 (br s, 1H), 8.04 (br s, 1H), 6.81-6.94 (m, 3H), 4.33 (s, 2H), 3.45 (s, 3H), 2.33 (s, 3H), 1.63 (s, 3H). 19F (376 MHz, DMSO) −127.1 (s, 1F).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=O)=[CH:4][CH:3]=1.[CH3:15][NH2:16].CO>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:16][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCc1ccc(N)cc1
Reactant: CN
Solvent: CO
Product: CNC(=O)CCCc1ccc(N)cc1
Yield: 95 %

Procedure:
A solution of compound 27 (450 mg, 2.33 mmol) in CH3NH2/CH3OH (29, 50 mL) was stirred at room temperature for overnight. The reaction mixture was concentrated to dryness to give compound 30 (450 mg, 95%) as a white solid. The crude product was used directly for the next step without purification. 1H NMR (400 MHz, CDCl3) δ6.95 (d, 2H, J=8.3 Hz), 6.61 (d, 2H, J=8.3 Hz), 5.30 (br s, 1H), 3.50 (br s, 2H), 2.78 (d, 3H, J=4.8 Hz), 2.54 (t, 2H, J=7.4 Hz), 2.14 (t, 2H, J=7.4 Hz), 1.85-1.95 (m, 2H).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I[C:18]1[CH:19]=[C:20]([O:24][CH3:25])[CH:21]=[CH:22][CH:23]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([NH:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc(I)c1
Reactant: NCc1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)O
Product: COc1cccc(NCc2ccccc2)c1
Yield: 80.2 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (425 mg, 2.00 mmol), benzylamine (131 μL, 1.20 mmol), 3-iodoanisole (119 μl, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). Column chromatography using a solvent mixture (hexane/ethyl acetate=10/1, Rf=0.4) afforded N-(3-methoxyphenyl)benzylamine (171 mg, 80% isolated yield) as white solid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity. See Ali, M. H.; Buchwald, S. L. J. Org. Chem. 2001, 66, 2560–2565.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.Cl[CH2:17][C:18](=O)[CH3:19]>CN(C)C=O>[CH3:19][C:18]1[C:11]2[C:10](=[O:15])[CH2:9][CH:8]([C:4]3[S:3][CH:7]=[CH:6][CH:5]=3)[CH2:13][C:12]=2[O:14][CH:17]=1
Reactant: O=C1CC(=O)CC(c2cccs2)C1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1coc2c1C(=O)CC(c1cccs1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
In dimethylformamide (10 ml) was suspended 60% sodium hydride (0.44 g, washed with hexane thrice), and to the suspension was added 5-(2-thienyl)cyclohexane-1,3-dione (1.9 g) and then was added chloroacetone (0.92 g). The mixture was stirred at room temperature for 1 hour and then at 150° C. for 13 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane). The resulting crystals were recrystallized from hexane to give colorless crystals of 3-methyl-6-(2-thienyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.34 g).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CC(O)C>CCCCCCC>[CH3:10][C@@H:7]1[N:6]2[C:5]3[C:14]([C:13]([C:12]([C:17]([OH:19])=[O:18])=[CH:11]2)=[O:16])=[CH:15][C:2]([F:1])=[C:3]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[C:4]=3[O:9][CH2:8]1
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CN1CCNCC1
Solvent: CC(C)O
Solvent: CCCCCCC
Product: C[C@H]1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 80 °C
Yield: 76.2 %

Procedure:
5 g (17.79 mmole) of (S)-(−)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de][1,4]benzoxazine-6-carboxylic acid was put in suspension in 6.8 mL (0.06 mole) of N-methyl piperazine. The reaction mixture was heated to reflux for 40 minutes until completion of the reaction. The mixture was then cooled to 80° C. IPA (10 mL) and n-heptane (10 mL) were added at this temperature. The solid was filtrated under vacuum and rinsed with n-heptane. The mother liquor also gave a precipitate after addition of n-heptane. Both precipitates were filtrated under vacuum and dried overnight to yield 4.9 g (76%) levofloxacin.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][CH:43]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O.CN(C)C=O>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][CH:43]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A dimethylformamide solution (15 ml) of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (700 mg, 1.30 mmol), 4-bromobenzoic acid (313 mg, 1.56 mmol), tris(dibenzylideneacetone) dipalladium (29.7 mg, 0.0324 mmol), X-Phos (61.8 mg, 0.130 mmol) and potassium phosphate (881 mg, 4.15 mmol) was degassed under ultrasonic irradiation, and stirred at 100° C. for 16 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, 6M hydrochloric acid (2 ml) and water (15 ml) were added, followed by stirring at room temperature for 1 hour. The precipitated solid was filtered, and ethyl acetate (10 ml) was added, followed by irradiation of ultrasonic wave. The solid was filtered, and washed with ethyl acetate, whereby 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid was obtained as a yellow solid (855 mg, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:27]1[C:28](=O)[C:29]2[C:34](C=1C1C=CC=CC=1)=[CH:33][CH:32]=[C:31](O)[CH:30]=2.C1(CCO)CCCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[CH:29]1([CH2:28][CH2:27][O:18][C:14]2[CH:13]=[C:12]3[C:17]([C:9]([C:4]4[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=4)=[C:10]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:11]3=[O:19])=[CH:16][CH:15]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: OCCC1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCC3CCCCC3)cc21
Reaction time: 48 h
Yield: 26 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 64 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 2-cyclohexylethanol (2.0 eq) instead of 4-(2-hydroxyethyl)morpholine, using 2 equivalents of PPh3 and DIAD, being stirred for 48 h, and being purified by prep. HPLC (20% H2O/CH3CN) to provide the title compound (26%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[OH-].[NH4+:16].O.CCOC(C)=O>C1COCC1>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([NH2:16])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: [NH4+]
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc2nnc(C(F)(F)F)n2n1
Temperature: 60 °C

Procedure:
A mixture of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (1.14 g, 5.1 mmol) and ammonium hydroxide (10 mL) in THF (10 mL) was heated to 60° C. for 18 h. The reaction mixture was cooled to room temperature and water and EtOAc were added. The aqueous layer was extracted with EtOAc (4×), the organics were combined, dried over sodium sulfate, and evaporated to dryness to afford 1 g of 3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine as beige solid. 1H NMR (300 MHz, DMSO-d6) δ 8.12 (d, 1H), 7.23 (s, 2H), 6.97 (d, 1H).