Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:15][CH2:16][C:17]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH2:18][C:19]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[O:29]C)([CH3:21])[CH3:20])[N:6]=1)=[O:4].B(Br)(Br)Br>>[CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:15][CH2:16][C:17]([OH:35])([C:31]([F:32])([F:33])[F:34])[CH2:18][C:19]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[OH:29])([CH3:21])[CH3:20])[N:6]=1)=[O:4]
Reactant: CNC(=O)c1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Agent: BrB(Br)Br
Product: CNC(=O)c1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3O)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 38, 97 mg (0.197 mmol) of 5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylamino]quinoline-2-carboxylic acid methylamide is reacted with 8.0 ml (8.0 mmol) of a 1 M boron tribromide solution. After working-up and purification on silica gel with hexane-ethyl acetate (0-70%), 18 mg (18% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][CH:5]([CH3:9])[C:6](O)=[O:7].CN(C=O)C.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH:5]([CH3:9])[C:6]([Cl:19])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)CC(C)C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)CC(C)C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 4-methoxy-2-methyl-4-oxobutanoic acid (1.2 g, 8.2 mmol) in oxalyl dichloride (15 mL) and DCM (15 mL) was added DMF (20 mg). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness to give the product as a yellow solid (1.3 g, 96% yield). 1H NMR (400 MHz, CDCl3): δ 3.71 (s, 3H), 3.35-3.30 (m, 1H), 2.87 (d, J=8.0 Hz, 0.5H), 2.82 (d, J=8.0 Hz, 0.5H), 2.56 (d, J=5.6 Hz, 0.5H), 2.52 (d, J=5.6 Hz, 0.5H), 1.37 (d, J=7.2 Hz, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:20][C:21]1[NH:25][N:24]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][CH:5]([C:3](=[O:4])[CH2:2][N:25]3[C:21]([CH3:20])=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24]3)[CH2:6][CH2:7]2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: COc1cc(N2CCC(C(=O)CCl)CC2)ccc1Cl
Reactant: Cc1cc(C(F)(F)F)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(N2CCC(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.4 %

Procedure:
A mixture of 2-chloro-1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)ethanone (580 mg, 1.919 mmol; see Example 1a, Step 2), 5-methyl-3-(trifluoromethyl)-1H-pyrazole (576 mg, 3.84 mmol), potassium carbonate (796 mg, 5.76 mmol) and acetonitrile (20 mL) was stirred at RT for 12 h. After this time, the solvent was removed under reduced pressure and the resultant residue was partitioned between EtOAc (100 mL) and water (50 mL). The organic phase was washed with brine, dried (Na2SO4) and concentrated on a rotary evaporator to yield a residue. The residue was purified by flash chromatography using a 40 g silica gel cartridge and gradient elution from 10:1 Hex/EtOAc to 1:1 Hex/EtOAc. The fractions containing the product were pooled and concentrated on a rotary evaporator to give 1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethanone (650 mg, 1.563 mmol, 81% yield) as clear oil. 1H-NMR (400 MHz, CDCl3) δ ppm 7.19 (1 H, d, J=8.57 Hz), 6.49 (1 H, d, J=2.42 Hz), 6.44 (1 H, dd, J=8.68, 2.53 Hz), 6.35 (1 H, s), 5.01-5.04 (2 H, m), 3.84-3.89 (3 H, m), 3.62-3.69 (2 H, m), 2.77 (2 H, td, J=12.03, 2.75 Hz), 2.58 (1 H, tt, J=11.29, 3.87 Hz), 2.21 (3 H, s), 1.99 (2 H, s), 1.80-1.91 (2 H, m).
Reaction SMILES: C([O:5][C:6](=[O:27])/[C:7](=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]2)=[C:15]([O:25][CH3:26])[CH:14]=1)/[CH2:8][CH2:9][CH2:10][Cl:11])(C)(C)C.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>C(Cl)Cl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[Cl:11][CH2:10][CH2:9][CH2:8]/[C:7](=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]2)=[C:15]([O:25][CH3:26])[CH:14]=1)/[C:6]([OH:27])=[O:5]
Reactant: COc1cc(/C=C(\CCCCl)C(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(/C=C(\CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a methylene chloride (20 mL) solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid tert-butyl ester (5 g), trifluoroacetic acid (10 mL) was added and the reaction solution was agitated at room temperature for 2 hours. After confirming disappearance of the starting materials, the reaction solution was concentrated under reduced pressure. The resulted solids were separated by filtering and 5.7 g of the title compound was obtained by washing with ethyl acetate further. The physical properties of the compound are as follows.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][CH2:15][OH:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17](Cl)([Cl:19])=[O:18]>C1(C)C=CC=CC=1.O1CCCC1>[Cl:19][C:17]([O:16][CH2:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:18]
Reactant: OCCC1c2ccccc2-c2ccccc21
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Cl)OCCC1c2ccccc2-c2ccccc21
Reaction time: 1 h

Procedure:
2-(9-Fluorenyl)ethyl chloroformate was prepared from a solution of 2-(9-fluorenyl)ethanol (1.26 g, 6.0 mmol) in 10 ml of toluene and 4 ml of tetrahydrofuran, which was added to 12 ml of phosgene solution (12.4 mol, [1.93M in toluene). The solution was stirred for 1 hour and put under vacuum to remove the phosgene. Concentration yielded 2-(9-fluorenyl)ethyl chloroformate (1.64 g, 6.0 mmol).
Reaction SMILES: N12CCCN=C1CCCCC2.[CH3:12][O:13][C:14]([C:16]1[C:17]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[S:30][CH:31]=[CH:32][C:33]=3[NH:34][S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[CH:25][CH:24]=2)=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1)=[O:15].[CH:41]([S:44](Cl)(=[O:46])=[O:45])([CH3:43])[CH3:42]>ClCCl>[CH3:12][O:13][C:14]([C:16]1[C:17]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[S:30][CH:31]=[CH:32][C:33]=3[NH:34][S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[CH:27][CH:28]=2)=[C:18]([NH:22][S:44]([CH:41]([CH3:43])[CH3:42])(=[O:46])=[O:45])[CH:19]=[CH:20][CH:21]=1)=[O:15]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: COC(=O)c1cccc(N)c1-c1ccc(-c2sccc2NS(=O)(=O)C(C)C)cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cccc(NS(=O)(=O)C(C)C)c1-c1ccc(-c2sccc2NS(=O)(=O)C(C)C)cc1
Yield: 19.4 %

Procedure:
Add 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) drop wise (0.51 mL, 3.6 mmol) to a suspension of 6-amino-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-2-carboxylic acid methyl ester (208 mg 0.48 mmol) in dichloromethane (9 ml) at 0° C., followed by drop wise addition of isopropylsulfonyl chloride (0.21 mL, 0.9 mmol) and stir the reaction at room temperature overnight. Remove solvent under reduced pressure. Purify with flash chromatography (Silica gel-hexane/EtOAc). Concentrate the desired fractions to provide 6-(propane-2-sulfonylamino)-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-2-carboxylic acid methyl ester (50 mg). MS (m/e): 535.1(M−1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:9][C:8]2[C:10]([Br:14])=[C:11]([CH3:13])[S:12][C:7]=2[CH:6]=1)=[O:4].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:9]([CH2:21][C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:25])[F:26])=[CH:24][CH:23]=2)[C:8]2[C:10]([Br:14])=[C:11]([CH3:13])[S:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1cc2sc(C)c(Br)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1cc2sc(C)c(Br)c2n1Cc1ccc(C(F)(F)F)cc1
Yield: 114.6 %

Procedure:
A solution of 3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid methyl ester (8.3 g), 4-trifluoromethybenzyl bromide (8.4 g) and Cs2CO3 (25 g) was stirred for 14 h at room temperature. The reaction mixture was then diluted with 200 ml of 1:1 hexane/EtOAc and filtered through a pad of silica gel. The filtrate was concentrated to give 15 g of the crude title compound which was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:6]([S:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=O)[CH:13]=[CH:12]3)[CH:7]=1.Cl.[NH2:28][OH:29]>>[F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:6]([S:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[N:28][OH:29])[CH:13]=[CH:12]3)[CH:7]=1
Reactant: NO
Reactant: COC1(c2cc(F)cc(Sc3ccc4c(c3)C=CC4=O)c2)CCOCC1
Agent: Cl
Product: COC1(c2cc(F)cc(Sc3ccc4c(c3)C=CC4=NO)c2)CCOCC1
Yield: 43 %

Procedure:
Using an analogous procedure to that described in Example 50, 5-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]inden-1-one was reacted with hydroxylamine hydrochloride to give 5-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]inden-1-one oxime in 43% yield, m.p.124°-136° C., as a 11:9 mixture of the (E)- and (Z)-isomers;
Reaction SMILES: [CH2:1]([C:8]([CH3:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][C:12]([CH2:14]Cl)=[CH2:13]>>[CH3:13][C:12]([CH2:14][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8](=[O:9])[CH3:10])=[CH2:11]
Reactant: C=C(C)CCl
Reactant: CC(=O)Cc1ccccc1
Product: C=C(C)CC(C(C)=O)c1ccccc1

Procedure:
Reaction of methyl benzyl ketone with β-methallyl chloride in accordance with the foregoing process yields 2-methyl-4-phenyl-hex-1-en-5-one of boiling point 85° C./3 mmHg; nD20 =1.5151.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[F:10].[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[F:10][C:4]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=1[CH2:2][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cc(F)ccc1F)OCC
Temperature: 160 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
A mixture of 2-(bromomethyl)-1,4-difluorobenzene (3 g, 14.49 mmol) and triethyl phosphite (7.72 ml, 43.5 mmol) was heated to 160° C. with stirring for 4 hours, cooled to ambient temperature and concentrated under high vacuum to remove most triethyl phosphite. The resulting residue was purified by column chromatography (20% to 30% EtOAc/Toluene) providing diethyl 2,5-difluorobenzylphosphonate (3.76 g, 13.52 mmol, 93% yield) as colorless oil. 1H NMR (500 MHz, DMSO-d6) δ 7.30-7.10 (m, 3H), 4.05-3.91 (m, 4H), 3.31-3.20 (m, 2H), 1.18 (t, J=7.0 Hz, 6H). MS Anal. Calcd. for [M+H]+ C11H16F2O3P: 265.2. found 265.3.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[H-].[Na+].[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18]>CN(C)C=O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccccc1F
Yield: 62.6 %

Procedure:
Using 0.19 g of 2-fluorobenzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.17 g of 2-(2-fluorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (75)).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][NH:14][CH2:15][CH2:16][NH:17][CH3:18].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:13][N:14]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH2:15][CH2:16][NH:17][CH3:18]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CNCCNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNCCN(C)Cc1ccc(C(=O)OC)cc1
Yield: 62 %

Procedure:
A mixture of methyl 4-(bromomethyl)benzoate (2 g, 8.73 mmol) and N,N′-dimethylethan-1,2-diamine (7.5 mL, 70 mmol) was heated with triethylamine (9.8 mL, 70 mmol) in tetrahydrofuran (80 mL) to reflux for two hours. After cooling, the mixture was treated with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 1.28 g of methyl 4-[(methyl(2-(methylamino)ethyl)amino)methyl]benzoate, 1H NMR (300 MHz, CD3OD) δ 7.97 (d, 2H), 7.45 (d, 2H), 3.59 (s, 2H), 2.67 (m, 2H), 2.54 (m, 2H), 2.35 (s, 3H), 2.22 (s, 3H) ppm.
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([OH:19])[CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[CH:34][N:35]=2)[N:32]=1.C(=O)(O)[O-].[Na+]>>[C:20]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([OH:19])[CH2:17][NH:18][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([N:33]=[CH:34][N:35]=4)[N:32]=3)[CH2:11][CH2:10]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Clc1ccc2ncnn2n1
Reactant: NCC(O)CN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: OC(CNc1ccc2ncnn2n1)CN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 56 %

Procedure:
0.675 g of 3-[4-(diphenylmethoxy)piperidino]-2-hydroxypropylamine and 0.335 g of 6-chloro[1,2,4]triazolo [1,5-b]pyridazine were stirred at 135-140° C. for 3 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate-tetrahydrofuran (2:1); the extract was washed with saline and dried with sodium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (90:10:1). The desired fraction was collected, recrystallized from ethyl acetate and dried to yield 0.509 g of the title compound.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:19]
Reactant: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 3 h
Yield: 102.8 %

Procedure:
A mixture of tert-butyl {2-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate 42 (0.21 g, 0.48 mmol) and Pd/C (0.063 g) in methanol (10 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through celite pad and concentrated to provide 43 (0.17 g, quant. yield) as a light yellow foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:15]2[NH:14][CH:13]3[CH2:16][CH2:17][N:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH:12]3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].[H-].[Na+].[C:27](Cl)(=[O:29])[CH3:28]>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[O:29]=[C:27]1[N:14]2[CH:13]3[CH2:16][CH2:17][N:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH:12]3[C:11]3[C:15]2=[C:7]([CH:8]=[CH:9][CH:10]=3)[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:28]1
Reactant: CCOC(=O)Nc1cccc2c1NC1CCN(C(=O)OCC)CC21
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2C(=O)CN3C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.6 %

Procedure:
To a solution of ethyl 6-[(ethoxycarbonyl)amino]-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate (2.2 g, 6.6 mmol) in DMF (20 mL) at 0° C. was added NaH (660 mg, 16.5 mmol), DMAP (878 mg, 7.2 mmol), acetyl chloride (0.6 mL, 7.2 mmol) and stirred at rt for 16 hours. The solution was diluted with water (30 mL), and extracted with EtOAc (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford diethyl 1-oxo-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (1.1 g, 57%) as a clear oil. MS [M+H]+374. 1H NMR (CDCl3, 300 MHz): δ 6.75 (t, 1H, J=7.7 Hz), 6.59 (m, 1H), 6.45 (m, 1H), 4.05 (m, 1H), 3.60-4.00 (m, 7H), 3.40 (m, 1H), 3.00 (m, 3H), 1.92 (m, 2H), 0.91 (m, 1H), 0.85 (m, 6H) ppm.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[H-].[Na+].[NH:10]1[C:21](=[O:22])[C:20]2[N:18]([CH3:19])[CH:17]=[N:16][C:15]=2[N:13]([CH3:14])[C:11]1=[O:12].O>CS(C)=O>[CH2:2]([N:10]1[C:21](=[O:22])[C:20]2[N:18]([CH3:19])[CH:17]=[N:16][C:15]=2[N:13]([CH3:14])[C:11]1=[O:12])[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: C=CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 43 h
Yield: 98.2 %

Procedure:
1-(5,6-Oxidohexyl)-3,7-dimethylxanthine (CT1541) was synthesized and used as an intermediate for synthesizing CT1517 and CT1595 as described in examples 2 and 3 below. A mixture of 1-bromo-5-hexene (10.7 g, 66 mmol), sodium hydride (1.58 g, 66 mmol), and theobromine (11.9 g, 66 mmol) in dimethylsulfoxide (100 ml) was stirred for 43 hr. The solution was treated with water (200 ml) and then extracted with dichloromethane (3×80 ml). The combined extracts were washed with water (3×100 ml), dried over magnesium sulfate, and then the solvent was evaporated under vacuum to give 1-(5-hexenyl)-3,7-dimethylxanthine (CT1539) (17 g, 98% yield) as a white powder.
Reaction SMILES: [CH:1]([C:3]1[CH2:4][S:5][C@@H:6]2[CH:13](NC(=O)CC3SC=CC=3)[C:12](=[O:23])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10])=[O:2].[C:24]1([C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N+]=[N-])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH:30]([O:11][C:9]([C:8]1[N:7]2[C:12](=[O:23])[CH2:13][C@H:6]2[S:5][CH2:4][C:3]=1[CH:1]=[O:2])=[O:10])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: C1CCOC1
Product: O=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C[C@H]2SC1
Reaction time: 0.5 h
Yield: 130 %

Procedure:
To a stirred solution of 3.5 g of 3-formyl-7-thienylacetamido-3-cephem-4-carboxylic acid in 100 ml of tetrahydrofuran is added 2.3 g of diphenyldiazomethane, and the stirring is continued for 30 min. The solvent is distilled off under reduced pressure, and the residue is washed with petroleum ether to give 4.9 g of the corresponding 3-formyl-3-cephem-4-carboxylic acid benzhydryl ester.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][C@@H:18]([O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[CH2:17][C@H:16]1[CH2:31][O:32][C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1)=O)(C)(C)C>C(Cl)Cl>[CH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[O:20][C@@H:18]1[CH2:19][NH:15][C@H:16]([CH2:31][O:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH2:17]1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.2 %

Procedure:
Trifluoroacetic acid (6 ml) was added to a solution of methyl 4-((2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylmethoxy)benzoate (870 mg, 1.74 mmol) in methylene chloride (24 ml). The resulting mixture was stirred overnight at room temperature. To the residue obtained by concentrating the reaction mixture under reduced pressure was added 1N NaOH under ice cooling to make the residue alkaline, followed by extraction with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 100 g), whereby from hexane/ethyl acetate (2/1) eluate fractions, the title compound (750 mg, 100%) was obtained as a black oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]([F:22])=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[CH3:23][NH2:24]>CO>[F:22][C:15]1[CH:16]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:11]2[O:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][NH:24][CH3:23])=[CH:4][CH:5]=3)=[N:13][C:12]=2[CH:14]=1
Reactant: COC(=O)c1cc(F)cc2nc(-c3ccc(CBr)cc3)oc12
Reactant: CN
Solvent: CO
Product: CNCc1ccc(-c2nc3cc(F)cc(C(=O)OC)c3o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
To the solution of methyl 2-(4-(bromomethyl)phenyl)-5-fluorobenzo[d]oxazole-7-carboxylate (350 mg, 0.96 mmol) in methanol (20 mL), methylamine (6 mL) was added, the mixture was stirred at room temperature for 1 hr, then heated to 30° C. for 30 min; the solvents were evaporated and the residue was purified by pre-HPLC to obtain methyl 5-fluoro-2-(4-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate as a white solid (25 mg, yield 8%). LC-MS (ESI) m/z 315 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[C:15](Cl)([N:17]=[C:18]=[O:19])=[O:16]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[O:14][C:18](=[O:19])[NH:17][C:15](=[O:16])[C:10]=3[CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C=NC(=O)Cl
Reactant: O=C1CCCCC1c1ccc(F)cc1
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccc(F)cc1)CCC2
Yield: 19.62 %

Procedure:
2-(4-fluorophenyl)cyclohexanone and carbonisocyanatidic chloride (0.966 mL, 12 mmol) was reacted as in Intermediate AC(1) to provide 8-(4-fluorophenyl)-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (415.0 mg, 1.689 mmol, 19.62% yield) as white solid and 4a-(4-fluorophenyl)-4-a,5,6,7-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (746.4 mg, 3.04 mmol, 35.3% yield) as white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([CH2:17][CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:16].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]3([CH2:17][CH3:18])[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CCC1(CCCCCCl)C(=O)Nc2ccccc21
Product: CCC1(CCCCCN2CCN(c3ccc(Cl)cc3)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 from 3-(5-chloropentyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(4-chlorophenyl)-piperazine.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19].[CH3:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(Cl)(Cl)Cl>O>[CH3:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[N:5]=[C:4]([Cl:11])[C:3]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[CH2:23][CH2:22]1
Reactant: Fc1cccc(Cl)c1-c1c(Cl)nc2nccn2c1Cl
Reactant: CC1CCNCC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1CCN(c2c(-c3c(F)cccc3Cl)c(Cl)nc3nccn23)CC1
Reaction time: 0.17 h
Yield: 96.7 %

Procedure:
Under ice-cooling, 0.63 g of 5,7-dichloro-6-(2-chloro-6-fluorophenyl)imidazo[1,2-a]pyrimidine and 0.79 g of 4-methylpiperidine were mixed. The reaction mixture was allowed to stand at room temperature for 10 minutes, and chloroform and water were added thereto. The separated organic layer was with water, dried over sodium sulfate and concentrated. The residue was subjected to silica gel chromatography to give 0.73 g of 5-(4-methylpiperidin-1-yl)-6-(2-chloro-6-fluorophenyl)-7-chloroimidazo[1,2-a]pyrimidine.