Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[N:10]=2)[CH:7]=1.[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[N:10]=3)[CH:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CC1(C)C(=O)N=C2C=CC(Br)=CN21
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)C(=O)N=C2C=CC(c3cccc(Cl)c3)=CN21
Yield: 63.1 %

Procedure:
To a round-bottom flask was added 6-bromo-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one (60 mg, 0.25 mmol), 3-chlorophenylboronic acid (39 mg, 0.25 mmol), potassium carbonate (69 mg, 0.25 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), dioxane (5 mL) and water (1 mL). The mixture was heated at reflux until the starting material was consumed monitored by HPLC-MS. The solution was cooled and water was added. The reaction mixture was extracted twice with ethyl acetate and the combined organic layers were dried, filtered and concentrated. The residue was purified by column chromatography eluting with 5% methanol/dichloromethane to provide the desired product as an off-white solid (43 mg, 63%). 1H NMR (CDCl3) δ 7.84 (dd, J=1.8 and 9.1 Hz, 1H), 7.74 (s, 1H), 7.46-7.27 (m, 5H), 1.64 (s, 6H); MS (m/e): 273 (MH+); HRMS: calc'd MH+ for C15H13ClN2O 273.0794; found 273.0800.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([CH2:15][CH3:16])[C:9]=2[O:8][CH2:7][C:6]1=[O:17].[CH:18]1([CH2:21][O:22][CH:23]2[CH2:29][CH:28]3[NH:30][CH:25]([CH2:26][CH2:27]3)[CH2:24]2)[CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH:18]1([CH2:21][O:22][CH:23]2[CH2:24][CH:25]3[N:30]([CH2:2][CH2:3][CH2:4][N:5]4[C:10]5[CH:11]=[CH:12][CH:13]=[C:14]([CH2:15][CH3:16])[C:9]=5[O:8][CH2:7][C:6]4=[O:17])[CH:28]([CH2:27][CH2:26]3)[CH2:29]2)[CH2:20][CH2:19]1
Reactant: C1CC1COC1CC2CCC(C1)N2
Reactant: CCc1cccc2c1OCC(=O)N2CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cccc2c1OCC(=O)N2CCCN1C2CCC1CC(OCC1CC1)C2
Temperature: 60 °C
Reaction time: 90 h
Yield: 20.6 %

Procedure:
A 7 ml vial was charged with 4-(3-chloropropyl)-8-ethyl-4H-benzo[1,4]oxazin-3-one (0.21 g, 0.83 mmol), 3-cyclopropylmethoxy-8-aza-bicyclo[3,2,1]octane (0.16 g, 0.87 mmol), K2CO3 (0.23 g, 1.7 mmol), acetonitrile (4 ml) a shaken at 60° C. for 90 hours The reaction mixture was evaporated to dryness and purified by prep TLC (SiO2; heptanes/EtOAc 1:1) followed by Prep HPLC to give the title compound (0.068 g, 20.5%). 1H NMR (CDCl3) 1H NMR (CDCl3) d 7.05-6.84 (m, 3H), 4.56 (s, 2H), 4.04-3.98 (m, 2H), 3.53-3.49 (m, 1H), 3.19-3.11 (m, 4H), 2.67-2.59 (m,2H), 2.42-2.37 (m, 2H), 2.07-1.74 (m, 1OH), 1.21-1.15 (m, 3H), 1.06-0.93 (m, 1H), 0.51-0.44 (m, 2H), 0.21-0.14 (m, 2H); 13C NMR (CDCl3) d 164.60, 143.25, 133.02, 128.66, 123.99, 122.32, 113.20, 72.78, 72.23, 67.74, 58.59, 49.56, 39.83, 35.73, 26.45, 26.17, 23.03, 14.50, 11.04, 2.94.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[C:22]([CH2:21][N:12]1[C:8]2=[N:9][C:10]3[C:5]([C:6](=[O:19])[N:7]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]1=2)=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=3)([O:24][CH2:25][CH3:26])=[O:23]
Reactant: Cc1ccc2c(=O)n3c(nc2c1)[nH]c1ccccc13
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1c2ccccc2n2c(=O)c3ccc(C)cc3nc12

Procedure:
6-(Carboethoxymethyl)-3-methylbenzimidazo[2,1-b]-quinazolin-12(6H)one is prepared with 3-methylbenzimidazo[2,1-b]quinazoline-12(6H)one and ethyl bromoacetate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:31]N1C(=O)CCC1=O.O>C(Cl)Cl>[Cl:31][CH2:10][CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(C=CCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C=CCCl)cc1
Yield: 42.7 %

Procedure:
Compound 102-1 (2.50 g) was dissolved in methylene chloride (60 ml), triphenylphosphine (4.86 g) and N-chlorosuccinimide (2.84 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr. Triphenylphosphine (4.86 g) and N-chlorosuccinimide (2.84 g) were further added, and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate) to give the object product (1.20 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[NH2:11].[Cu][C:14]#[N:15]>CN1CCCC1=O.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([C:14]#[N:15])[CH:7]=[CH:6][C:5]=1[NH2:11]
Reactant: N#C[Cu]
Reactant: COC(=O)c1cc(Br)ccc1N
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cc(C#N)ccc1N
Temperature: 25 °C
Yield: 28.4 %

Procedure:
2-Amino-5-bromobenzoic acid methyl ester (4.6 g, 20 mmol) and copper (I) cyanide (3.6 g, 40 mmol) were heated at 200° C. in N-methylpyrrolidinone (20 ml) for 4 h. After cooling to room temperature, the solution was diluted with water, extracted with ethyl acetate, the aqueous extract acidified with 2N hydrochloric acid and filtered. The organic layer was separated, dried over magnesium sulphate and evaporated. The residue was purified by flash column chromatography on silica eluting with 50% ethyl acetate in hexane to yield the title compound as a colourless oil (1.0 g). MS (+EI) m /z 176 [M+ ].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: C1CCNC1
Reactant: O=Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1cc(Cl)ccc1N1CCCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
A 100 mL round-bottom flask was charged with 5-chloro-2-fluorobenzaldehyde (2.00 g, 12.6 mmol, 1.00 equiv), pyrrolidine (1.34 g, 18.8 mmol, 1.49 equiv), potassium carbonate (4.34 g, 31.4 mmol, 1.92 equiv), and dimethyl sulfoxide (10 mL). The resulting solution was stirred overnight at 100° C. in an oil bath and diluted with H2O (20 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with H2O (3×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/10) to yield 1.80 g (68% yield) of 5-chloro-2-(pyrrolidin-1-yl)benzaldehyde as brown oil. 1H NMR 300 MHz (CDCl3) δ 10.05 (s, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.267-7.31 (m, 1H), 6.76 (d, J=9.0 Hz, 1H), 3.29-3.37 (m, 4H), 1.95-2.04 (m, 4H). LCMS (ESI, m/z): 210 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl[CH2:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]2[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=2[N:14]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:12][C:13]3[N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16]4[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: ClCc1nc2ccccc2n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Clc1ncnc2c1ccn2Cc1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.62 g, 4.1 mmol), 2-(chloromethyl)-1-phenyl-1H-benzo[d]imidazole (1.0 g, 4.1 mmol) and K2CO3 (0.6 g, 4.3 mmol) in DMSO (20 mL) was stirred at room temperature overnight. Then the mixture was added H2O (50 mL) and extracted with EtOAc (20 mL×3). The combine organic layers were concentrated in vacuo to give 4-chloro-7-(1-phenyl-1H-benzoimidazol-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (1.2 g, yield 80%) as brown solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].[F:4][C:5]1[C:10](F)=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21]>CO>[F:4][C:5]1[C:10]([O:2][CH3:1])=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21]
Reactant: O=Cc1ccc(-c2ccc(F)cc2F)c(F)c1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1c(C=O)ccc(-c2ccc(F)cc2F)c1F
Temperature: 25 °C
Yield: 99.1 %

Procedure:
Sodium methoxide (28% methanol solution, 5.64 g) was added at room temperature to a methanol (120 mL) solution of 2,2′,3,4′-tetrafluorobiphenyl-4-carbaldehyde (4.95 g), and the mixture was heated to reflux for 16 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and then, the solvent was distilled off under reduced pressure. The obtained residue was diluted with ethyl acetate and water, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (5.14 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[C:13](=[O:14])OC(=O)[NH:10][C:9]=2[CH:16]=1)(=[O:4])=[O:3].[CH:17]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)([CH2:19][CH3:20])[CH3:18]>CN(C)C=O.O>[NH2:10][C:9]1[CH:16]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=1[C:13]([NH:25][C:24]1[CH:26]=[CH:27][C:21]([CH:17]([CH2:19][CH3:20])[CH3:18])=[CH:22][CH:23]=1)=[O:14]
Reactant: CS(=O)(=O)c1ccc2c(=O)oc(=O)[nH]c2c1
Reactant: CCC(C)c1ccc(N)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(NC(=O)c2ccc(S(C)(=O)=O)cc2N)cc1
Temperature: 25 °C

Procedure:
A solution of 7-methanesulfonyl-1H-benzo[d][1,3]oxazine-2,4-dione (0.98 g, 3.8 mmol) and 4-sec-butylaniline (0.57 g, 3.8 mmol) in N,N-dimethylformamide (30 mL) was stirred at 115° C. for 16 hours, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (2×100 mL), and concentrated using a rotary evaporator. The residue was further purified by column chromatography (SiO2, hexane/ethyl acetate=2:1) to provide 2-amino-N-(4-sec-butyl-phenyl)-4-methanesulfonyl-benzamide. Yield: 0.466 g (33%).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])/[C:2](=[CH:4]\[CH3:5])/[CH3:3].[CH3:9][C:10](=[CH2:14])[CH2:11]CO.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCCCCCC)CCCCCCC.C([O-])(=O)CCCCCCCCCCC>C1(C)C=CC=CC=1>[C:1]([O:7][CH2:8][CH2:11][C:10]([CH3:14])=[CH2:9])(=[O:6])/[C:2](=[CH:4]\[CH3:5])/[CH3:3]
Reactant: C=C(C)CCO
Reactant: C/C=C(/C)C(=O)OC
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCCCCCC[Sn+2]CCCCCCCC
Solvent: Cc1ccccc1
Product: C=C(C)CCOC(=O)/C(C)=C\C

Procedure:
A mixture of 20.0 g. of methyl angelate, 22.65 g. of 3-methyl-3-butenyl alcohol, 100 ml. of toluene and 0.8 g. of dioctyltin laurate was reacted under the same conditions as in Example 6. The reaction mixture was subjected to single distillation to obtain 39.5 g. of a distillate boiling at 104° C. (32 mmHg).
Reaction SMILES: [CH:1]1([N:7]2[CH:14]=[CH:13][C:11]([NH2:12])=[N:10][C:8]2=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15]([NH:18][C:19]1[CH:28]=[CH:27][C:22]([S:23](Cl)(=[O:25])=[O:24])=[CH:21][CH:20]=1)(=[O:17])[CH3:16].Cl.C1(C2(C=CC(C3N=CC=CN=3)(N)CC2=O)S(N)(=O)=O)CCCCC1>O.N1C=CC=CC=1>[C:15]([NH:18][C:19]1[CH:28]=[CH:27][C:22]([S:23]([NH:12][C:11]2[CH:13]=[CH:14][N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:8](=[O:9])[N:10]=2)(=[O:25])=[O:24])=[CH:21][CH:20]=1)(=[O:17])[CH3:16]
Reactant: Nc1ccn(C2CCCCC2)c(=O)n1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: NC1(c2ncccn2)C=CC(C2CCCCC2)(S(N)(=O)=O)C(=O)C1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccn(C3CCCCC3)c(=O)n2)cc1

Procedure:
A mixture of 29.0 g. of 1-cyclohexylcytosine, 90 ml. of pyridine and 35.1 g. of N-acetylsulfanilyl chloride was stirred overnight, poured into 900 ml. of water, and acidified by addition of 80 ml. of concentrated hydrochloric acid. After several hours of vigorous stirring, the precipitated product solidified to yield 33.3 g. of N4 -acetyl-N1 -(1-cyclohexyl-1,2-dihydro-2-oxo-4-pyrimidinyl-sulfanilamide, m.p. 219°-234°. A sample purified by two recrystallizations from ethanol melted at 247°-250°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[C:8]([OH:15])=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].C(=O)([O-])[O-].[Na+].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CC(C)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[C:8]([O:15][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11]
Reactant: COc1c(C)c(Cc2cccc(C=O)c2O)c(OC)c(OC)c1OC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1c(C)c(Cc2cccc(C=O)c2OCc2ccccc2)c(OC)c(OC)c1OC
Yield: 82.6 %

Procedure:
3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzaldehyde (1.16 g, 3.35 mol) was dissolved in acetone (5 ml) and after adding thereto anhydrous sodium carbonate (1.02 g, 7.38 mmol) and benzyl bromide (0.69 g, 4.02 mmol), the solution was refluxed under heating for 3 hours. The reaction solution was filtered, the filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=2:1) to obtain the titled compound (1.45 g, 3.32 mmol, 99%).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].CCCCCC.C([O:14][CH:15](OCC)[C:16]1[CH:21]=[C:20](Br)[CH:19]=[CH:18][C:17]=1[O:23][CH3:24])C.COB(OC)OC>C1COCC1>[CH2:2]([C:20]1[CH:19]=[CH:18][C:17]([O:23][CH3:24])=[C:16]([CH:21]=1)[CH:15]=[O:14])[CH2:3][CH2:4][CH3:5]
Reactant: [Li]CCCC
Reactant: CCOC(OCC)c1cc(Br)ccc1OC
Agent: COB(OC)OC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCc1ccc(OC)c(C=O)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
n-BuLi in hexane (1.6M, 15.4 mL, 24.6 mmol) was added dropwise over 15 min to a -70° C. solution of 5-bromo-2-methoxybenzaldehyde diethylacetal in 50 mL of THF. Once the addition was complete, the mixture was stirred and allowed to warm up to 0° C. over 1.5 h. The mixture was then cooled to -70° C. and a solution of trimethylborate (5.4 mL, 48 mmol) in 25 mL of THF was added rapidly through a double-ended needle. The reaction was kept at -70° C. for 4 h and was then allowed to warm to 0° C. slowly before being quenched by the addition of 70 mL of 2.0N aqueous hydrochloric acid. After the mixture had been stirred for 1 h, the layers were separated and the aqueous layer was extracted with 3×100 mL of ethyl acetate. The combined organic layers were dried (sodium sulfate), decanted, and evaporated. The residue was then dissolved in ethyl acetate (100 mL) and extracted with 4×44 mL of 2.0N sodium hydroxide. The ethyl acetate layer was dried (sodium sulfate), decanted, and evaporated. The crude material was purified by flash column chromatography on silica gel, eluting with 10-20% dichloromethane in hexane to yield 5-butyl-2-methoxybenzaldehyde (1.87 g, 43% yield) as an amber liquid.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:14]3([CH2:18][C:19]#[N:20])[CH2:17][NH:16][CH2:15]3)[CH:13]=2)[N:6]2[CH:21]=[CH:22][N:23]=[C:5]2[CH:4]=1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O>CN(C=O)C>[Cl:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:14]3([CH2:18][C:19]#[N:20])[CH2:17][N:16]([CH2:39][C:40]([F:43])([F:42])[F:41])[CH2:15]3)[CH:13]=2)[N:6]2[CH:21]=[CH:22][N:23]=[C:5]2[CH:4]=1
Reactant: N#CCC1(n2cc(-c3nc(Cl)cc4nccn34)cn2)CNC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CCC1(n2cc(-c3nc(Cl)cc4nccn34)cn2)CN(CC(F)(F)F)C1
Yield: 61.4 %

Procedure:
In 1.5 mL of DMF were combined 2-(3-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (0.059 g, 0.14 mmol), DIEA (0.15 mL, 0.84 mmol), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.049 g, 0.21 mmol) and allowed to proceed at ambient temperature with stirring. After 2 hours the DMF was removed under reduced pressure with heating and the crude was purified by means of silica gel chromatography eluting with 1:1 EtOAc/hexanes containing 0.25% NH4OH to afford 2-(3-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoro ethyl)azetidin-3-yl)acetonitrile (0.034 g, 0.086 mmol, 62% yield). MS (apci) m/z=396.1 (M+H).
Reaction SMILES: [OH:1][CH:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl.[CH3:40][N:41]([CH3:47])[CH2:42][CH2:43][C:44](O)=[O:45].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:40][N:41]([CH3:47])[CH2:42][CH2:43][C:44]([O:21][CH:3]([C:2](=[O:1])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:45]
Reactant: CN(C)CCC(=O)O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)C(O)CCCCCCC/C=C\C/C=C\CCCCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)C(CCCCCCC/C=C\C/C=C\CCCCC)OC(=O)CCN(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
To a solution of (6Z,9Z,27Z,30Z)-19-hydroxyhexatriaconta-6,9,27,30-tetraen-18-one (1.0 g, 1.9 mmol), 3-(dimethylamino)propanoic acid hydrogen chloride (876 mg, 5.7 mmol) and EDCI (1.2 g, 6.3 mmol), in dichloromethane (20 mL) was added DIPEA (1.0 mL, 5.7 mmol) and DMAP (20 mg). The solution was stirred at room temperature for 16 hours under nitrogen. Upon completion, the reaction was diluted with dichloromethane (50 mL) and washed with sodium bicarbonate solution (50 mL). The dichloromethane layer was dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography (100% ethyl acetate) to afford the title compound as a colorless oil (675 mg, 57%). 1H NMR (400 MHz, CDCl3): δ 5.43-5.28 (m, 8H), 5.03-4.98 (m, 1H), 2.80-2.75 (m, 4H), 2.74-2.56 (m, 4H), 2.54-2.36 (m, 2H), 2.28 (s, 6H), 2.09-2.01 (m, 8H), 1.82-1.64 (m, 2H), 1.63-1.52 (m, 2H), 1.42-1.23 (m, 30H), 0.93-0.86 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].Br[CH2:26][C:27]#[C:28][Si:29]([CH3:32])([CH3:31])[CH3:30]>C1CCCCC1.C(Cl)Cl>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([CH2:26][C:27]#[C:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2
Reactant: C[Si](C)(C)C#CCBr
Solvent: ClCCl
Solvent: C1CCCCC1
Product: COC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CC#C[Si](C)(C)C)(c1ccccc1)C2
Yield: 74 %

Procedure:
Reaction of methyl (6,7-dichloro-1-oxo-2-phenyl-5-indanyloxy)acetate with 1-bromo-3-(trimethylsilyl)-2-propyne according to Example 1, STEP (b), affords the title compound, m.p. 125.5°-127° (from cyclohexane-methylene chloride) in 74% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][F:17].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23](Cl)=[O:24]>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][CH2:16][F:17])[C:23](=[O:24])[C:22]1[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=[C:20]([C:19]([F:18])([F:33])[F:34])[CH:21]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: FCCNc1cnccc1-c1ccccc1Cl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(CCF)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-yl]-(2-fluoro-ethyl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification to give a first batch of compound (light yellow solid). A second chromatographic purification of the remaining impure fractions and mother liquor gave a second batch of compound. Yellow solid (25% overall). MS (ESI): m/z=491.08 [M+H]+.
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.CCCCCCC>CC(O)COC>[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: CCCCCCC
Solvent: COCC(C)O
Product: C[C@H]1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 90 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
3 g (10.67 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 30 mL of PGME and 4.75 mL (43 mmole) of N-methyl piperazine. The reaction mixture was heated to reflux for 23 hours until completion of the reaction. During that time, the reaction mixture became soluble. The mixture was then cooled to 90° C. and n-Heptane (10 mL) was added at this temperature. The reaction mixture was then cooled to 0° C. and the precipitation occurred around 65° C. The reaction was left at 0° C. for 3 hours, filtrated under vacuum and dried overnight to obtain 2.98 g (77.3%) of levofloxacin.