Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[N:13]=[N:12][NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].Br[CH2:19][CH2:20][CH3:21].O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[N:13]([CH2:19][CH2:20][CH3:21])[N:12]=[N:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1nn[nH]n1-c1ccc([N+](=O)[O-])cc1
Reactant: CCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1nnn(-c2ccc([N+](=O)[O-])cc2)c1=O
Temperature: 55 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a stirred solution of 1-(4-nitrophenyl)-5-tetrazolone (6 g) in anhydrous N,N-dimethylformamide (30 mL) was added powdered 85% potassium hydroxide (1.9 g) and 1-bromopropane (3.9 g). The mixture was stirred at 55° C. for 2 hours and then poured into 300 mL of water. The biphasic mixture was extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, ethyl acetate:hexane) to afford 7.2 g of the title compound as a pale yellow solid. 1H NMR (CDCl3) δ 8.32 (ABq, JAB =9.6 Hz, 4 H), 4.02 (t, J=7.2 Hz, 2 H), 1.93 (m, 2 H), 1.03 (t, J=7.5 Hz, 3 H); MS (CI) m/z 250 (MH+); Rf =0.6 (25% ethyl acetate/hexane).
Reaction SMILES: O=[O+][O-].[C:4]1([CH2:10][O:11][C:12](=[O:18])[CH:13]([CH3:17])[CH2:14][CH:15]=C)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O=O.C(O)(=[O:23])C>CO.[Zn]>[C:4]1([CH2:10][O:11][C:12](=[O:18])[CH:13]([CH3:17])[CH2:14][CH:15]=[O:23])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)O
Reactant: C=CCC(C)C(=O)OCc1ccccc1
Agent: O=O
Agent: O=[O+][O-]
Agent: [Zn]
Solvent: CO
Product: CC(CC=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A stream of ozone is passed through a -78° C. solution of 1.0 g of racemic 2-methyl-4-pentenoic acid phenylmethyl ester in 110 ml of methyl alcohol until the blue color persists. The excess zone is discharged by a stream of oxygen, followed by argon. One gram of zinc dust and 1.0 g of acetic acid is added and the resulting mixture allowed to warm to room temperature; followed by stirring for 1 hour. The excess zinc is removed by filtration and the filtrate is concentrated in vacuo. The residue is extracted with diethyl ether, filtered and the filtrate concentrated in vacuo. The residue is purified by pad filtration (silica gel, 50% diethyl ether/petroleum ether) to give 1.01 g of racemic 2-methyl-4-oxobutanoic acid phenylmethyl ester.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([C@@H:9]([NH:12][C:13]([C:15]2[C:16]3[CH:23]=[N:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:17]=3[CH:18]=[N:19][CH:20]=2)=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1.I([O-])(=O)(=O)=[O:32].[Na+]>CO>[CH3:1][S:2]([C:3]1[CH:8]=[C:7]([C@@H:9]([NH:12][C:13]([C:15]2[C:16]3[CH:23]=[N:22][N:21]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[C:17]=3[CH:18]=[N:19][CH:20]=2)=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1)=[O:32]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(SC)c1
Agent: [Na+]
Solvent: CO
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(S(C)=O)c1
Reaction time: 1.5 h

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid[(S)-1-(2-methylsulfanyl-pyridin-4-yl)-propyl]-amide (0.10 mg, 0.24 mmol) in MeOH (5 mL) was added an aqueous solution of sodium periodate (51 mg, 0.24 mmol). After 1.5 hours, a solid precipitated and additional MeOH (3 mL) was added. After 5 days, mixture was concentrated and partitioned between water (5 mL) and EtOAc (50 mL). The organic phase was separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by reversed-phase HPLC (Sunfire PrepC 18 OBD 5 mM 30×150 mm column) eluting with a gradient of 15-75% acetonitrile in water (0.1% TFA). The fractions from the column were concentrated to remove acetonitrile, made basic with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated to afford the title compound as a white solid.
Reaction SMILES: S[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=2[N:6]=1.C1(C)C=CC(S([O:22][CH3:23])(=O)=O)=CC=1.[CH3:25][N:26]([CH3:50])[CH2:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]=[C:38]2[N:42]([C:43]3O[CH:45]=[CH:46][CH:47]=3)[C:41](=[O:48])[CH:40]([CH3:49])[S:39]2)[CH:32]=1)=[O:29]>>[CH3:25][N:26]([CH3:50])[CH2:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]=[C:38]2[N:42]([CH2:43][C:47]3[O:22][CH:23]=[CH:45][CH:46]=3)[C:41](=[O:48])[C:40](=[C:49]3[N:6]([CH3:2])[C:5]4[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=4[S:3]3)[S:39]2)[CH:32]=1)=[O:29]
Reactant: CC1SC(=Nc2cccc(NC(=O)CN(C)C)c2)N(c2ccco2)C1=O
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc2sc(S)nc2c1
Product: COc1ccc2c(c1)N(C)C(=C1SC(=Nc3cccc(NC(=O)CN(C)C)c3)N(Cc3ccco3)C1=O)S2

Procedure:
In a manner similar to Example 45, 2-mercapto-5-methoxybenzothiazole was alkylated with methyl p-toluenesulfonate and then condensed with 2-dimethylamino-N-[3-(3-furan-2-yl methyl-4-oxothiazolidin-2-ylideneamino)-phenyl]acetamide. MS(ESI): 550 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[CH:2].I[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:16][CH:15]=1>CN(C=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:24]([NH:23][CH:21]([CH3:22])[CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:2]#[C:1][C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])=[CH:15][CH:16]=1)(=[O:26])[CH3:25]
Reactant: C#Cc1cccc(C(=O)OC)c1
Reactant: CC(=O)NC(C)Cc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C#Cc2ccc(CC(C)NC(C)=O)cc2)c1
Temperature: 25 °C

Procedure:
To 10.0 g (63.4 mmol) methyl 3-ethynylbenzoate (J. Org. Chem. 1981, 46, 2280-6) and 7.00 g (23.1 mmol) N-(1-(4-iodo-phenyl)propan-2-yl)acetamide (I52.1) in 80 mL DMF are added 100 mL TEA, 250 mg (1.31 mmol) CuI and 1.20 g (1.71 mmol) bis(triphenylphosphine)-palladium (II) chloride. After stirring over night r.t. the solvents are removed under reduced pressure. The residue is partitioned between EtOAc and diluted aq. NH4Cl solution. The organic layer is separated and the aq. layer is extracted with EtOAc (2×). The org. layers are combined, washed with brine, dried with Na2SO4 and the solvent is removed in vacuo. The residue is purified by column chromatography (silica gel, EtOAc 100%).
Reaction SMILES: C(C1C=CC(C(Cl)=O)=CC=1)CCC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=1[F:36].[CH2:37]([C:41]1[CH:46]=[CH:45][C:44]([C:47]([N:49]=[C:50]=[S:51])=[O:48])=[CH:43][CH:42]=1)[CH2:38][CH2:39][CH3:40]>C1(C)C=CC=CC=1.C(O)C>[CH2:37]([C:41]1[CH:46]=[CH:45][C:44]([C:47]([N:49]=[C:50]=[S:51])=[O:48])=[CH:43][CH:42]=1)[CH2:38][CH2:39][CH3:40].[CH2:37]([C:41]1[CH:46]=[CH:45][C:44]([C:47]([NH:49][C:50]([NH:33][C:32]2[CH:34]=[CH:35][C:29]([O:28][C:19]3[C:18]4[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=4)[N:22]=[CH:21][CH:20]=3)=[C:30]([F:36])[CH:31]=2)=[S:51])=[O:48])=[CH:43][CH:42]=1)[CH2:38][CH2:39][CH3:40]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: CCCCc1ccc(C(=O)Cl)cc1
Agent: CCCCc1ccc(C(=O)N=C=S)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
4-Butyl-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-butyl-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-butyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (66 mg, yield 78%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:20]=[C:19](F)[CH:18]=[CH:17][C:16]=3[Br:22])[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1.BrC1C=CC=CC=1CBr>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Br:22])[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1
Reactant: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2cc(F)ccc2Br)c1=O
Agent: BrCc1ccccc1Br
Product: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2ccccc2Br)c1=O

Procedure:
The title compound was prepared from compound 1 used the procedures described in the synthesis of compound 10, except that 2-bromo benzyl bromide was used in the place of 2-bromo-5-fluoro-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): δ 7.45 (d, J=7.8 Hz, 1H), 7.16 (t, J=7.5 Hz, 1H), 7.03 (t, J=7.2 Hz, 1H), 6.80 (d, J=7.3 Hz, 1H), 5.28 (s, 1H), 4.93-5.05 (ABq, 2H, J=36.4, 16.4 Hz), 3.22 (m, 1H), 3.19 (m, 3H), 3.09 (m, 1H), 2.84 (d, J=12.6 Hz, 1H), 2.63 (t, J=10.5 Hz, 1H), 2.42 (t, J=10.9 Hz, 1H), 1.97 (d, J=11.1 Hz, 1H), 1.58-1.69 (m, 1H), 1.38-1.48 (m, 2H). MS (ES) [m+H] calc'd for C17H22BrN4O2, 393.1; found, 393.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[OH-].[Na+].[CH:13](O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][CH:13]=[N:9][C:4]=2[C:3]=1[Cl:10]
Reactant: O=CO
Reactant: Nc1ccc(Br)c(Cl)c1N
Agent: [Na+]
Agent: [OH-]
Product: Clc1c(Br)ccc2[nH]cnc12
Yield: 78 %

Procedure:
A mixture of 4-bromo-3-chloro-benzene-1,2-diamine (CASRN 1008361-80-5, 27 g, 0.1221 mol) and formic acid (80 mL) was heated to reflux for 1.5 h. After the completion of the reaction, 10% NaOH was added until the solution basic. The resulting solid was filtered and washed well with water then dried over night over suction to afford 22 g (78%) of 5-bromo-4-chloro-1H-benzoimidazole (128) as pale yellow solid which was used without additional purification.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:10])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[H-].[Na+].Br[CH2:14][CH:15]([CH2:20]Br)[C:16]([O:18][CH3:19])=[O:17].O>CN(C)C=O.C(OCC)(=O)C>[CH3:19][O:18][C:16](=[O:17])[C:15]([CH2:20][N:2]1[C:3](=[O:10])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1]1)=[CH2:14]
Reactant: O=c1[nH]nc2ccccn12
Reactant: COC(=O)C(CBr)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(Cn1nc2ccccn2c1=O)C(=O)OC
Reaction time: 0.5 h

Procedure:
After dissolving 2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (CAS 6969-71-7) (1.0 g) in N,N-dimethylformamide (50 ml), sodium hydride (60% in oil) (355 mg) was added while stirring on ice. After stirring for 20 minutes, methyl 3-bromo-2-(bromomethyl)propionate (2.11 ml) was added dropwise. Stirring was continued for 1 hour and 30 minutes, and then sodium hydride (60% in oil) (200 mg) was added and the mixture was stirred for 3 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography to obtain the title compound (400 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:33])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)[CH:21]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=4)[CH:21]=3)[CH2:17][C:16](=[O:33])[NH:15][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)ccc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4ccc(Cl)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M67) (0.40 g, 0.83 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (239 mg, 79%).
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:25])[C:23]#[N:24])=[C:18]([F:26])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2(CCC3C=CC(C4(C#N)CCC4)=C(F)C=3)CC(O)=C(CC3N=C4N=C(C)C=C(C)N4N=3)C(=O)O2)CCCC1.[CH3:67][C:68]1[CH:69]=[N:70][C:71]2[N:72]([N:74]=[C:75]([CH:77]=O)[N:76]=2)[CH:73]=1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:25])[C:23]#[N:24])=[C:18]([F:26])[CH:17]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:77][C:75]3[N:76]=[C:71]4[N:70]=[CH:69][C:68]([CH3:67])=[CH:73][N:72]4[N:74]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cnc2nc(C=O)nn2c1
Reactant: CC(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Agent: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(C5(C#N)CCC5)c(F)c4)(C4CCCC4)OC3=O)nc2n1
Product: Cc1cnc2nc(CC3=C(O)CC(CCc4ccc(C(C)C#N)c(F)c4)(C4CCCC4)OC3=O)nn2c1

Procedure:
The title compound was prepared analogously to example A(236) substituting 2-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-propionitrile from example A(241) in place of 1-(4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5 -a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclobutanecarbonitrile and 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in place of 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. 1H NMR (400 MHz, CDCl3) δ: 1.66–2.00 (m, 8H), 2.30 (s, 2H), 2.36 (s, 2H), 2.49–2.62 (m, 4H), 2.69–2.85 (m, 3H), 3.49–3.59 (m, 1H), 3.89–3.94 (m, 1H), 4.01–4.08 (m, 2H), 4.18 (s, 1H).
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[Cl:11][C:12]1[S:16][C:15]([CH2:17][C@H:18]2[CH2:22][NH:21][C@H:20]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)=[O:24])[CH2:19]2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:21]2[CH2:22][C@H:18]([CH2:17][C:15]3[S:16][C:12]([Cl:11])=[CH:13][CH:14]=3)[CH2:19][C@H:20]2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:28][CH:27]=2)=[O:24])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)s2)CN1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)s2)CN1C(=O)Cn1cncn1
Yield: 28 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4S)-4-((5-chlorothien-2-yl)methyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 67, (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-((5-chlorothien-2-yl)methyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (23.1 mg, 28%). 1H-NMR (400 MHz, CDCl3): σ 9.01 (s, 1H), 8.24 (s, 1H), 7.99 (s, 1H), 7.42 (d, 2H), 7.00 (t, 2H), 6.95-6.90 (m, 4H), 6.75 (d, 1H), 6.63 (d, 1H), 5.03 (dd, 2H), 4.83 (d, 1H), 3.76 (dd, 1H), 3.27 (t, 1H), 3.06-2.93 (m, 2H), 2.85-2.79 (m, 1H), 2.71 (dd, 1H), 1.73-1.66 (m, 1H). MS (EI) for C26H23ClFN5O3S. found 540.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[O:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.C1C(=O)N([Br:20])C(=O)C1>CN(C=O)C.C(OCC)(=O)C.O>[Br:20][C:12]1[C:2]([Br:1])=[CH:3][C:4]2[NH:9][C:8](=[O:10])[CH2:7][O:6][C:5]=2[N:11]=1
Reactant: O=C1COc2ncc(Br)cc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1COc2nc(Br)c(Br)cc2N1
Yield: 79.3 %

Procedure:
7-bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (1.5 g, 6.55 mmol) and NBS (5.83, 32.7 mmol) were heated to 80° C. in DMF (30 ml) for 2 hours. The resulting reaction mixture was diluted with ethyl acetate (30 ml) and water (30 ml). The aqueous phase was extracted with fresh ethyl acetate (50 ml×3) and the combined organic layers were washed with brine (50 ml), dried on anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to give the title compound (1.6 g, 79%). It was used for the next step without further purification. LCMS (Method D): RT=0.91 min, M+1=309.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:9]([CH2:16][CH2:17][CH3:18])[CH2:10][C:11](OCC)=[O:12].[C:19]1(C)C=CC=CC=1>>[CH3:19][N:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]([CH2:16][CH2:17][CH3:18])=[CH:10][C:11]1=[O:12]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: Nc1ccccc1
Reactant: Cc1ccccc1
Product: CCCc1cc(=O)n(C)c2ccccc12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Aniline (1 ml) and toluene (66 ml) were added to ethyl 3-oxohexanoate (2.1 ml) and stirred at 120° C. overnight. After removing the solvent, sulfuric acid (40 ml) was added to the residue and stirred at 80° C. for seven hours. The reaction solution was put into ice and adjusted to pH=3, and the precipitated crystals were filtered out. Methyl iodide (3 ml), potassium carbonate (1.9 g) and DMF (20 ml) were added to the residue and stirred at room temperature for 26 hours. After removing the solvent, the reaction mixture was diluted with dichloromethane, washed with 1N hydrochloric acid and saturated sodium bicarbonate water and dried over magnesium sulfate to remove the solvent. The residue was purified with a silica gel chromatography (dichloromethane-methanol) to obtain 1-methyl-4-propyl-2(1H)-quinolinone (800 mg).
Reaction SMILES: [CH2:1]([C:4]1[C:25]([CH2:26][CH2:27][CH3:28])=[CH:24][C:23]2[C:6](=[CH:7][C:8]3[C:9](=[O:36])[C:10]4[C:19]([C:20](=[O:29])[C:21]=3[CH:22]=2)=[CH:18][C:17]2[C:12](=[CH:13][C:14]([CH2:33][CH2:34][CH3:35])=[C:15]([CH2:30][CH2:31][CH3:32])[CH:16]=2)[CH:11]=4)[CH:5]=1)[CH2:2][CH3:3].C([BH-](CC)CC)C.[Li+].Cl>C1COCC1>[OH:29][CH:20]1[C:19]2[C:10](=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([CH2:30][CH2:31][CH3:32])=[C:14]([CH2:33][CH2:34][CH3:35])[CH:13]=3)[CH:9]([OH:36])[C:8]2[CH:7]=[C:6]3[C:23]([CH:24]=[C:25]([CH2:26][CH2:27][CH3:28])[C:4]([CH2:1][CH2:2][CH3:3])=[CH:5]3)=[CH:22][C:21]1=2
Reactant: CCCc1cc2cc3c(cc2cc1CCC)C(=O)c1cc2cc(CCC)c(CCC)cc2cc1C3=O
Agent: CC[BH-](CC)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCc1cc2cc3c(cc2cc1CCC)C(O)c1cc2cc(CCC)c(CCC)cc2cc1C3O

Procedure:
A solution of 357 mg of 2,3,9,10-tetra(n-propyl)-6,13-pentacenequinone dissolved in 50 mL of THF was added to 11 mL of a 1 mol/1000 mL THF solution of lithium triethylborohydride, and the mixture was heated for 24 hours under reflux in a nitrogen atmosphere. The resulting solution was neutralized with diluted aqueous hydrochloric acid, and the organic phase was separated, concentrated and dried under a vacuum to produce 6,13-dihydro-6,13-dihydroxy-2,3,9,10-tetra(n-propyl)penta cene almost stoichiometrically.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([OH:8])[CH2:3]1.C[O:10][C:11](=O)[C:12]([OH:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na]>C1CCCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([O:8][C:11](=[O:10])[C:12]([OH:25])([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:3]1
Reactant: COC(=O)C(O)(c1ccccc1)c1ccccc1
Reactant: CN1CCC[C@@H](O)C1
Agent: [Na]
Solvent: C1CCCCC1
Product: CN1CCC[C@@H](OC(=O)C(O)(c2ccccc2)c2ccccc2)C1
Temperature: 50 °C

Procedure:
To a mixture of (R)-1-methyl-piperidine-3-ol (4.61 g, 0.040 mol) and hydroxy-diphenyl-acetic acid methyl ester (9.63 g, 0.040 mol) in cyclohexane (50 ml) is added preactivated 4A molecular sieves and the mixture heated to 50° C. Sodium metal (50 mg) is then added and the resulting mixture heated to reflux. After 1 hour further sodium (50 mg) is added and reflux maintained for 5 hours. Concentration, re-dissolution in chloroform and washing with water followed by brine, drying over magnesium sulphate, filtration and evaporation gives a crude product. Purification by vacuum flash silica chromatography (gradient elution: DCM to DCM:methanol 20:1) gives, after evaporation, the title product as a foam.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[F:18][CH:19]([C:24]([F:27])([F:26])[F:25])[C:20]([O:22][CH3:23])=[O:21].C(N(C(C)C)CC)(C)C.[CH:37](=[O:39])[CH3:38]>ClCCl>[F:18][C:19]([C:24]([F:27])([F:26])[F:25])([CH:37]([OH:39])[CH3:38])[C:20]([O:22][CH3:23])=[O:21]
Reactant: CC=O
Reactant: COC(=O)C(F)C(F)(F)F
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(F)(C(C)O)C(F)(F)F
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
Dibutylboron triflate (5 g) was added to a stirred solution of methyl 2,3,3,3-tetrafluoropropionate (2.9 g) in dichloromethane at 0° C. under nitrogen. After 15 minutes, the solution was cooled to -10° C. and diisopropylethylamine (3.8 ml) was added in portions. After 30 minutes, freshly distilled acetaldehyde (2 ml) was added in small portions, keeping the temperature at -10° C. The reaction was stirred at -10° C. for 1 hour before quenching with a mixture of pH7 phosphate buffer (60 ml), aqueous hydrogen peroxide (100 vol; 15 ml) and crushed ice and stirring for 1.5 hours. The organic phase was separated and the aqueous layer further extracted with dichloromethane. The combined organic phases were washed with aquesous sodium metabisulphite and with brine, dried (MgSO4) and concentrated under reduced pressure to give a pink oil (2.2 g) which was distilled using a Kugelrohr apparatus. The fraction distilling at 40° C. (air bath temperature) and at 0.05 mmHg was collected; 1H NMR (270 MHz; CDCl3) (signals recorded for a 50:50 mixture of diastereomers) δ 1.34 (1.5H,d), 1.42 (1.5H,d), 2.2(1H,bs), 3.91(1.5H,bs), 3.94(1.5H,s), 4.35-4.52(1H,m) ppm.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:19][C:20](=[O:42])[C:21]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([O:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:25][CH:24]=2)=O)[C:8]([O:17][CH3:18])=[C:9]([CH:16]=1)[C:10]([NH:12][CH:13]1[CH2:15][CH2:14]1)=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH2:43]([O:45][C:46]([NH:48][NH2:49])=[O:47])[CH3:44].[CH3:50]CO>CC(O)=O>[CH2:43]([O:45][C:46]([NH:48][N:49]=[C:21]([C:20](=[O:42])[NH:19][C:7]1[CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:16]=[C:9]([C:10](=[O:11])[NH:12][CH:13]([CH2:14][CH3:50])[CH3:15])[C:8]=1[O:17][CH3:18])[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([O:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:25][CH:24]=1)=[O:47])[CH3:44]
Reactant: CCO
Reactant: CCOC(=O)NN
Reactant: COc1c(NC(=O)C(=O)c2ccc(OCCN3CCOCC3)c3ccccc23)cc(C(C)(C)C)cc1C(=O)NC1CC1
Solvent: CC(=O)O
Product: CCOC(=O)NN=C(C(=O)Nc1cc(C(C)(C)C)cc(C(=O)NC(C)CC)c1OC)c1ccc(OCCN2CCOCC2)c2ccccc12
Temperature: 120 °C
Reaction time: 15 h

Procedure:
Compound 30 (44 mg, 0.077 mmol) was dissolved in EtOH (1 mL) and hydrazinecarboxylic acid ethyl ester (24 mg, 0.231 mmol) and 1 drop of AcOH were added. The reaction mixture was stirred at 120° C. for 15 hrs, after which the crude mixture was purified by LC/MS. The isomers separated and the desired isomer was taken on into the next step. Calculated mass=660. Observed mass=660.