Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[NH:6][C:5]([C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:3]1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:2]1[S:3][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]([C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[N:6]=1
Reactant: CCOC(=O)c1sc(=O)[nH]c1C(F)(F)C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1sc(Cl)nc1C(F)(F)C(F)(F)F
Yield: 71 %

Procedure:
To a stirred mixture of 65 g (0.4995 mole) of ethyl acetoacetate, 200 ml. of methanol and 100 ml. of saturated sodium acetate at 50° C. was introduced 100 g (0.769 mole) of pentafluoropropionitrile in 3 hours. The reaction mixture was poured into 1200 ml. of water. An oil separated from the reaction mixture. The aqueous solution was extracted with ether. The ether solution was combined with the oil, dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 40 g (37%) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate. A mixture of 21.8 g (0.0790 mole) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 75 ml. of 58% ammonium hydroxide was stirred for 66 hours. The reaction mixture was extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 16.3 g (88%) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate, nD25 =1.4011. A well stirred mixture of 54 g (0.23 mole) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 31 g (0.237 mole) of chlorocarbonylsulfenyl chloride was held at 100° C. for 1 hour. The reaction mixture was cooled and triturated with hexane. The solid precipitate was washed with water and recrystallized from hexane-ether to give 31 g (46%) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, m.p. 95°-97° C. A mixture of 10 g (0.0344 mole) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, 4 g (0.0506 mole) of pyridine and 150 ml. of phosphorus oxychloride was held at reflux for 18 hours. Excess phosphorus oxychloride was removed under reduced pressure. The residue was treated with water and extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 7.5 g (71%) of ethyl 2-chloro-4-pentafluoroethyl-5-thiazolecarboxylate, nD25 =1.4460.
Reaction SMILES: [C:1]([NH:20][C@H:21]([CH2:24][CH3:25])[CH:22]=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([Mg]Br)[CH3:27].O>CCOCC>[C:1]([NH:20][C@@H:21]([CH2:24][CH3:25])[CH:22]([OH:23])[CH2:26][CH3:27])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC[Mg]Br
Solvent: CCOCC
Solvent: O
Product: CCC(O)[C@H](CC)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (R)-2-(trityl-amino)-butyraldehyde (1.5 g, 1 eq, 4.53 mmol) in Et2O (150 mL) under an argon atmosphere at −78° C., was added ethylmagnesium bromide (3 M in Et2O, 1.51 mL, 1 eq, 4.53 mmol) dropwise. The solution was stirred at −78° C. for 2 h, then allowed to warm to room temperature over 16 h. The mixture was recooled to 0° C., H2O (150 mL) added, and the organic phase separated. The aqueous phase was extracted with more Et2O (2×50 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane:ether (90:10) to afford the title compound as a light yellow oil. Yield: 1.19 g (73%). (65% de 3R,4S: 35% de 3S,4S). 1H-NMR (d6-DMSO, 250 MHz): δ 0.46+0.69 (t & m, 6H, J=7.34 Hz, —NHCH(CH2CH3)CH(CH2CH3)OH), 1.13-1.29 (m, 4H, —NHCH(CH2CH3)CH(CH2CH3)OH), 2.17 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 2.55 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.20-3.39 (m, 1H, —NHCH(CH2CH3)CHCH2CH3)OH), 4.29 & 4.39 (2×d, 1H, J=4.74 & 5.53 Hz, —NHCH(CH2CH3)CH(CH2CH3)OH), 7.15-7.52 (m, 15H, 3×Ph).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6](=[O:15])[N:5]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:4](=[O:23])[C:3]=1[N:24]=O.C1(CN2C(N)=C(N)C(=O)N(CC3CCCCC3)C2=O)CCCCC1.[CH:50]([C:52]1[CH:53]=[C:54]([CH:60]=[CH:61][CH:62]=1)[CH:55]=[CH:56][C:57]([OH:59])=[O:58])=O>>[CH:17]1([CH2:16][N:5]2[C:4](=[O:23])[C:3]3[N:24]=[C:50]([C:52]4[CH:53]=[C:54]([CH:60]=[CH:61][CH:62]=4)/[CH:55]=[CH:56]/[C:57]([OH:59])=[O:58])[NH:1][C:2]=3[N:7]([CH2:8][CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:6]2=[O:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=Cc1cccc(C=CC(=O)O)c1
Reactant: Nc1c(N=O)c(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Agent: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O
Product: O=C(O)/C=C/c1cccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)c1
Yield: 49 %

Procedure:
In the manner of step (d) of Example 1, 6-amino 1,3-bis(cyclohexylmethyl)-5-nitrosouracil (from step (c) example 1, 2.79 g, 8.00 mmol) was reduced to 1,3-bis(cyclohexylmethyl)-5,6-diaminouracil, which was condensed with 3-formylcinnamic acid (T. Higa, A. J. Krubsack, J. Org. Chem. 1975, 40: 3037-3045, 1.424 g, 8.00 mmol) to give (E)-3-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic acid as an off-white solid (1.947 g, 49%), m.p. >350° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)C(=O)C)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5]1.Cl.[C:34]([O-])(O)=O.[Na+]>CCO>[CH3:1][O:2][CH2:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:22][CH2:26][C:27]3[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:5][CH2:34][CH2:6]1
Reactant: COCC1(c2ccc(NC(=O)c3ccccc3N(Cc3ccncc3)C(C)=O)cc2)CC1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COCC1(c2ccc(NC(=O)c3ccccc3NCc3ccncc3)cc2)CCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of N-[2-(N-{4-[(methoxymethyl)-cyclopropyl]phenyl}carbamoyl)-phenyl]-N-(4-pyridylmethyl)acetamide (100 mg) and 20% HCl (5 ml) in EtOH (15 ml) was stirred at 80° C. overnight. The solution was basified with NaHCO3 and evaporated with silica gel and purified by column chromatography to give the title compound. Mass: (M+1), 402.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1.[F:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][N:6]([C:20]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:13])[CH:21]=3)[C@H:5]2[CH:9]([CH3:10])[CH3:11])[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(F)cc1F
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC(C)[C@@H]1N(c2ccc(C#N)c(F)c2)CC[C@@]1(O)C1CC1

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3R)-3-cyclopropyl-2-isopropylpyrrolidin-3-ol 0.5 oxalate (215 mg), 2,4-difluorobenzonitrile (139 mg) and lithium carbonate (163 mg), the title compound was obtained as a pale-brown solid (yield: 114 mg, yield: 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH2:15](Cl)[CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: COc1ccccc1N1CCN(CCCO)CC1
Temperature: 0 °C
Reaction time: 10 h
Yield: 76.8 %

Procedure:
46 g of 1-(2-methoxyphenyl)-piperazin and 24.5 g of trimethylene chlorohydrine are dissolved in 200 ml of ethanol, and 25 g of potassium carbonate are added to the solution. The mixture is refluxed for 30 hours, thereafter it is cooled to 0° C, diluted with 50 ml of ethyl ether, filtered, and the filtrate is evaporated. The residue is dissolved in 100 ml of 50° C benzene, the solution is cooled to 0° C, and allowed to stand for 10 hours. The separated crystals are filtered off and dried. 46 g (77%) of 3-[4-(2-methoxyphenyl)-piperazine-1-yl]-1-hydroxy-propane are obtained; m.p.: 92°-93° C.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([CH:9]1[C:22]3[CH:21]=[CH:20][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[NH:29][C:30](=[O:32])[CH3:31])=[CH:18][C:17]=3[O:16][C:15]3[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:2]2.C(=O)([O-])[O-].[K+].[K+].[CH2:39](Br)[CH:40]=[CH2:41]>CN(C=O)C>[CH2:41]([N:8]1[CH:1]2[CH2:7][CH2:6][CH:5]1[CH2:4][CH:3]([CH:9]1[C:22]3[CH:21]=[CH:20][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[NH:29][C:30](=[O:32])[CH3:31])=[CH:18][C:17]=3[O:16][C:15]3[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:2]2)[CH:40]=[CH2:39]
Reactant: CC(=O)Nc1ccccc1-c1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C1)N2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN1C2CCC1CC(C1c3ccccc3Oc3cc(-c4ccccc4NC(C)=O)ccc31)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
To a solution of N-{2-[9-(8-Aza-bicyclo[3.2.1]oct-3-yl)-9H-xanthen-3-yl]-phenyl}-acetamide, 7b (53 mg, 0.125 mmol) in DMF (0.5 mL) at 0° C. were added potassium carbonate (18 mg, 0.13 mmol) and allyl bromide (10.6 μL, 0.122 mmol). The mixture was stirred overnight at rt, and poured onto H2O. The solid was separated via filtration and washed with H2O. The solid was purified via reverse phase HPLC (eleuent gradient: 10% to 90% CH3CN in H2O containing 0.1% TFA) to yield 25 mg (36%) of N-{2-[9-(8-allyl-8-aza-bicyclo[3.2.1]oct-3-yl)-9H-xanthen-3-yl]-phenyl}-acetamide, 18b. MS 18b: m/z: 464.9 (MH+).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:27]2([CH2:32][NH2:33])[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:27]2([CH2:32][NH:33][C:8](=[O:10])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:28][CH2:29][CH2:30][CH2:31]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C2(CNC(=O)C(c3ccccc3)c3ccccc3)CCCC2)cc1OC
Reaction time: 16 h
Yield: 15.5 %

Procedure:
Diphenyl-acetic acid (42.4 mg, 0.200 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (47.1 g, 0.200 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (83.6 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (76.0 mg, 0.200 mmol) was added and the solution was allowed to stir for 16 hours. The mixture was then purified by reverse phase preparative liquid chromatography to yield the pure product (13.3 mg, 0.0310 mmol, 15.5%) ESI-MS m/z calc. 429.2, found 430.2 (M+1)+. Retention time of 3.47 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH2:15][CH3:16])[C:13]4[CH:17]=[CH:18][C:19]([C:21](O)=[O:22])=[CH:20][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH2:26]([O:28][CH2:29][CH2:30][NH2:31])[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:26]([O:28][CH2:29][CH2:30][NH:31][C:21]([C:19]1[CH:18]=[CH:17][C:13]2[N:14]([CH2:15][CH3:16])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:25]=[CH:24][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:20]=1)=[O:22])[CH3:27]
Reactant: CCOCCN
Reactant: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2CC
Yield: 44.2 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (79.0 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (150.0 mg), 2-ethoxy-ethylamine (53.0 mg), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 445; and 1H NMR (DMSO-d6, 400 MHz): δ 8.47 (1H, br. s), 8.08 (1H, br. s), 7.92 (1H, br. s), 7.76-7.63 (2H, m), 7.52 (1H, m), 7.40-7.38 (1H, m), 4.22 (2H, m), 3.53-3.41 (6H, m), 1.34-1.30 (3H, t), 1.14-1.11 (3H, t), —NH proton signal was not observed.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])=[CH:21][CH:20]=1)[CH3:18]>>[F:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH:17]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])=[CH:21][CH:20]=3)[CH3:18])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CC(=O)NCc1ccc(C(C)Cl)cc1
Agent: Cl
Product: CC(=O)NCc1ccc(C(C)N2CCN(c3ccc(F)cc3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(4-fluorophenyl)piperazine dihydrochloride instead of phenylpiperazine and N-(4-(1-chloroethyl)phenylmethyl)acetamide instead of N-(4-chloromethylphenylmethyl) acetamide, the title compound was obtained as white crystals, m.p.=128-130° C.
Reaction SMILES: [NH:1]1[CH:8]=CC(N)=[N:4][C:2]1=[O:3].FF.[F:11][C:12](F)(F)[CH2:13][OH:14]>>[F:11][C:12]1[C:13](=[O:14])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: OCC(F)(F)F
Reactant: Nc1cc[nH]c(=O)n1
Agent: FF
Product: O=c1[nH]cc(F)c(=O)[nH]1

Procedure:
The reaction and the treatment were carried out in the same manner as in Example 1 but using a solution of cytosine (1.11 g) in 2,2,2-trifluoroetanol (100 ml) and blowing the fluorine gas therein at 20° C. to give 5-fluorouracil (0.72 g). Yield, 55%.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([C:5](=[O:14])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[C:3]#[N:4].[C-]#N.[Na+].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][C:21]=1[O:28][CH3:29].C(=O)([O-])O.[Na+]>CN(C=O)C.O>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([C:24](=[O:25])[CH:7]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH2:6][C:5](=[O:14])[C:2]([CH3:15])([CH3:1])[C:3]#[N:4])=[CH:22][C:21]=1[O:28][CH3:29]
Reactant: COc1cc(C=O)ccc1Cl
Reactant: CC(C)(C#N)C(=O)C=Cc1ccncc1
Agent: O=C([O-])O
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)C(CC(=O)C(C)(C)C#N)c2ccncc2)ccc1Cl
Reaction time: 0.25 h
Yield: 222.9 %

Procedure:
A solution of the product of Example 1 Step 1 (4.0 g, 20.0 mmol) in DMF (7 ml) was added to a solution of sodium cyanide (300 mg, 6.12 mmol) in DMF (7 ml) over 15 minutes at room temperature. After stirring for a further 15 minutes, a solution of 4-chloro-3-methoxy-benzaldehyde (F. Claudi et al., J. Med. Chem., 1992, 35, 4408) (640 mg, 3.75 mmol) in DMF (6 ml) was added dropwise. The mixture was stirred at room temperature for 18 hours and then diluted with water and the pH of the solution adjusted to 9 with aqueous sodium hydrogen carbonate solution. The mixture was extracted with chloroform and the organic phase washed with water and brine, dried and concentrated in vacuo. The residue was chromatographed on silica gel eluting with chloroform/ethanol/0.880 ammonia solution (90:9:1) to give the title compound (3.1 g, 42%); MS (ES+) m/e 371, 373 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2.[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.[Cu-]=O>[CH:14]1([C:12]([N:8]2[C:9]3[C:4](=[C:3]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:2]([N:25]4[CH:29]=[CH:28][CH:27]=[N:26]4)=[CH:11][CH:10]=3)[CH2:5][CH2:6][C@@H:7]2[CH3:17])=[O:13])[CH2:16][CH2:15]1
Reactant: c1cn[nH]c1
Reactant: C[C@H]1CCc2c(ccc(Br)c2Oc2ccccc2)N1C(=O)C1CC1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1CCc2c(ccc(-n3cccn3)c2Oc2ccccc2)N1C(=O)C1CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 17.2 %

Procedure:
A mixture of (S)-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1 (2H)-yl)(cyclopropyl)methanone (0.300 g, 0.78 mmol), 1H-pyrazole (0.053 g, 0.78 mmol), copper (I) oxide (0.056 g, 0.39 mmol), cesium carbonate (0.508 g, 1.56 mmol) in N,N-dimethylformamide (5 mL) stirred for 18 h at 100° C. The resulting mixture was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 1:10, ethyl acetate/petroleum ether) to afford (S)-cyclopropyl(2-methyl-5-phenoxy-6-(1H-pyrazol-1-yl)-3,4-dihydroquinolin-1 (2H)-yl)methanone (0.050 g, 17%) as a yellow solid. MS (ESI, pos. ion) m/z 374 [M+H]+.
Reaction SMILES: [C-]#N.[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.Cl[CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.OCCCC1C=C[N:47]=[CH:46]C=1>C(#N)C>[C:46]([CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)#[N:47]
Reactant: OCCCc1ccncc1
Reactant: ClCCCc1ccncc1
Agent: [C-]#N
Agent: [K+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CC#N
Product: N#CCCCc1ccncc1

Procedure:
Potassium cyanide (11.18 g) and dibenzo-18-crown-6 (1.0 g) are added to a solution of 4-(3-chloropropyl)-pyridine (6.68 g) prepared from 4-(3-hydroxypropyl)pyridine, in 300 ml of dry acetonitrile under nitrogen. The mixture is refluxed for 24 hours, the solvent evaporated and the residue partitioned between methylene chloride and water. The aqueous phase is further extracted with methylene chloride (3×100 ml) and the combined extracts are dried over sodium sulfate, decolorized with charcoal and evaporated to yield 4-(3-cyanopropyl)pyridine as a colorless oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:34]([O:38][C:39](=[O:46])[NH:40][C@@H:41]1[CH2:45][CH2:44][NH:43][CH2:42]1)([CH3:37])([CH3:36])[CH3:35].[Br:47][C:48]1[CH:49]=[N:50][C:51]([N:54]2[C:62]3[C:57](=[CH:58][CH:59]=[C:60]([C:63](O)=[O:64])[CH:61]=3)[C:56]([S:66][CH3:67])=[CH:55]2)=[N:52][CH:53]=1>CN(C=O)C>[Br:47][C:48]1[CH:49]=[N:50][C:51]([N:54]2[C:62]3[C:57](=[CH:58][CH:59]=[C:60]([C:63]([N:43]4[CH2:44][CH2:45][C@@H:41]([NH:40][C:39](=[O:46])[O:38][C:34]([CH3:37])([CH3:35])[CH3:36])[CH2:42]4)=[O:64])[CH:61]=3)[C:56]([S:66][CH3:67])=[CH:55]2)=[N:52][CH:53]=1
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)O)ccc12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
HATU (2.41 g, 6.363 mmol), diisopropylethylamine (3.02 ml, 17.355 mmol) and (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (1.18 g, 6.363 mmol) were added to an ice cooled suspension of 223a) (2.1 g, 5.787 mmol) in DMF (20 mL). The resulting mixture was stirred at room temperature for 16 h and then diluted with ice cold water (40 mL). The precipitate was filtered off, washed with water and hexane (3 times) and dissolved in dichloromethane. The solution was successively washed with saturated ammonium chloride solution (2×30 mL), saturated sodium hydrogen solution (2×30 mL), and brine (30 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was triturated with ether. White solid. Yield: 3 g (97% of theory)
Reaction SMILES: [F:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:14]([CH3:17])([O-:16])=[O:15].CN(C)C(N(C)C)=N>CCOC(C)=O.O>[F:1][C:2]1[C:7]([CH:8]([CH2:17][N+:14]([O-:16])=[O:15])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)/C=C/c1cccnc1F
Agent: CN(C)C(=N)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CC(C[N+](=O)[O-])c1cccnc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To (E)-methyl 3-(2-fluoropyridin-3-yl)acrylate (0.945 g, 5.22 mmol) was added nitromethane (10.0 mL, 186 mmol) and 1,1,3,3-tetramethylguanidine (0.120 mL, 0.956 mmol). The reaction mixture was stirred at room temperature for 30 min, heated to 50° C. for 1 h, and diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (2×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (20% to 60% EtOAc in hexanes) gave methyl 3-(2-fluoropyridin-3-yl)-4-nitrobutanoate (0.996 g, 4.11 mmol, 79% yield) as a colorless oil. MS (ESI, pos. ion) m/z: 243.1 (M+1).
Reaction SMILES: [F:1][C@H:2]1[CH2:4][C@H:3]1[N:5]1[C:14]2[C:9](=[C:10]([CH3:18])[C:11]([F:17])=[C:12]([F:16])[C:13]=2[F:15])[C:8](=[O:19])[C:7]([C:20]([O:22]CC)=[O:21])=[CH:6]1.Cl.C(O)(=O)C>O>[F:1][C@H:2]1[CH2:4][C@H:3]1[N:5]1[C:14]2[C:9](=[C:10]([CH3:18])[C:11]([F:17])=[C:12]([F:16])[C:13]=2[F:15])[C:8](=[O:19])[C:7]([C:20]([OH:22])=[O:21])=[CH:6]1
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(F)c(F)c(F)c(C)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Yield: 104.5 %

Procedure:
A mixture of 1.00 g of ethyl 1-[-(1R,2S)-2-fluorocyclopropyl]-6,7,8-trifluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate, 10 ml of concentrated hydrochloric acid, and 20 ml of acetic acid was heated under reflux for 1 hour and, after allowing to cool, water was added thereto. The precipitated crystals were collected by filtration, washed with water and ethanol, and dried to yield 960 mg of the titled compound as a pale yellow powderous crystal, which was then recrystallized from a mixed solvent of ethanol and chloroform.
Reaction SMILES: [CH3:1][NH2:2].F[C:4]1[N:9]=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:6][CH:5]=1>>[CH3:1][NH:2][C:4]1[N:9]=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:6][CH:5]=1
Reactant: NS(=O)(=O)c1cccc(F)n1
Reactant: CN
Product: CNc1cccc(S(N)(=O)=O)n1

Procedure:
To 10 ml of condensed methylamine was added 1.86 g (10 mmol) of 6-fluoropyridine-2-sulfonamide. The mixture was allowed to reflux under a dry-ice condenser for 4 hr, then excess amine was allowed to evaporate overnight. The residue was crystallized with water to yield 1.64 g of tan solid, m.p. 124° C. to 26° C.
Reaction SMILES: [K].CC(C)([O-])C.[I-].[CH:8]1([CH2:14][CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH2:35]([O:37][C:38](=[O:49])[C:39]([C:41]1[CH:46]=[CH:45][C:44]([S:47][CH3:48])=[CH:43][CH:42]=1)=O)[CH3:36]>C1COCC1>[CH2:35]([O:37][C:38](=[O:49])/[C:39](/[C:41]1[CH:46]=[CH:45][C:44]([S:47][CH3:48])=[CH:43][CH:42]=1)=[CH:15]/[CH2:14][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:36]
Reactant: CCOC(=O)C(=O)c1ccc(SC)cc1
Reactant: c1ccc([P+](CCC2CCCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K]
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/CC1CCCCC1)c1ccc(SC)cc1
Reaction time: 1 h

Procedure:
Add potassium-tert.-butoxide (4.3 mL, 1.0 M in THF, 4.3 mmol) to a suspension of (2-cyclohexyl-ethyl)-triphenyl-phosphonium iodide (2.15 g, 4.3 mmol) at room temperature and stir the reaction mixture for 1 h. Dissolve (4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (prepared as described by I. T. Barnish et. al. J. Med. Chem. 1981, 24, 399-404) in THF and add the resulting solution to the reaction mixture. Stir at room temperature over night. Evaporate the solvent and add 15 mL hexane to the remaining solid. Stir at 40° C. for 30 minutes, filter and concentrate the filtrate under vacuum to afford 1.3 g raw material as a yellow oil. Further purify this material via silica gel chromatography, eluting with a gradient from 98:2 to 90:10 hexane:ethyl acetate to afford a colorless oil (379 mg).