Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]1([S:19]([CH2:22][CH2:23][S:24][C:25]2[N:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=O)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:37]=[C:38]([CH:42]([NH2:44])[CH3:43])[CH:39]=[CH:40][CH:41]=1.C(OCC)(=O)C.CCCCCC>C(Cl)Cl>[C:13]1([S:19]([CH2:22][CH2:23][S:24][C:25]2[N:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([NH:44][CH:42]([C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([C:35]([F:34])([F:45])[F:46])[CH:37]=2)[CH3:43])=[O:29])(=[O:20])=[O:21])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(N)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1cccnc1SCCS(=O)(=O)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(NC(=O)c1cccnc1SCCS(=O)(=O)c1ccccc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
264 mg (1.62 mmol) of CDI were added to a solution of 500 mg (1.55 mmol) of 2-(2-(phenylsulfonyl)ethylthio)nicotinic acid in DCM (12 ml), and the mixture was stirred for 1 h at RT. A solution of 292 mg (1.55 mmol) of 1-(3-(trifluoromethyl)phenyl)ethylamine in DCM (12 ml) was then added, and stirring was continued for a further 16 h at RT. The reaction solution was then washed in each case three times with sat. aq. ammonium chloride solution and saturated aqueous NaCl solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. CC with the residue (ethyl acetate/hexane 1:1) yielded 462 mg (0.93 mmol, 60%) of 2-(2-(phenylsulfonyl)ethylthio)-N-(1-(3-(trifluoromethyl)phenyl)ethyl)nicotinamide. MS: m/z 495.1 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH2:11]1[N:16]2[CH2:17][N:18]3[CH2:20][N:14]([CH2:15]2)[CH2:13][N:12]1[CH2:19]3>C(Cl)(Cl)Cl>[Br-:1].[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][N+:12]12[CH2:13][N:14]3[CH2:20][N:18]([CH2:17][N:16]([CH2:15]3)[CH2:11]1)[CH2:19]2
Reactant: O=C(CBr)c1ccccc1
Reactant: C1N2CN3CN1CN(C2)C3
Solvent: ClC(Cl)Cl
Product: O=C(C[N+]12CN3CN(CN(C3)C1)C2)c1ccccc1
Product: [Br-]
Temperature: 50 °C
Yield: 96.8 %

Procedure:
2-Bromo-1-phenylethanone (2.0 g, 10.05 mmol) was added to a solution of hexamethylenetetramine (1.409 g, 10.05 mmol) in CHCl3 (60 mL), and the resulting mixture was heated at 50° C. for 1 hour. The mixture was cooled to room temperature and the white precipitate was collected by filtration, washed with CHCl3, and dried under vacuo to afford the title compound (3.3 g) as a white solid. LC-MS (ES) m/z=259 [M+H]+.
Reaction SMILES: Br[C:2](Br)=[CH:3][CH2:4][CH2:5][C:6]([F:9])([F:8])[F:7].[Li]CCCC.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].CCCCCC>O1CCCC1>[F:7][C:6]([F:9])([F:8])[CH2:5][CH2:4][C:3]#[C:2][Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: FC(F)(F)CCC=C(Br)Br
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](C#CCCC(F)(F)F)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution the product from Step A (0.935 mg, 3.31 mmol) in 10 mL of tetrahydrofuran was added n-BuLi solution (2.65 mL, 6.63 mmol, 2.5 M hexanes) dropwise. The reaction was stirred at −78° C. for one hour, then allowed to warm to room temperature for one hour. The solution was cooled to 0° C., and tributyltin chloride (0.898 mL, 3.31 mmol) was added. After 10 minutes, the solution was poured into hexane, washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The product was isolated as a brown liquid which was used without further purification.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[C:15]([O:18][CH:19]([CH3:21])[CH3:20])[CH:16]=[N:17][C:10]=2[N:9]([CH3:30])[C:8]1=[O:31])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:31])[N:9]([CH3:30])[C:10]=3[N:17]=[CH:16][C:15]=2[O:18][CH:19]([CH3:20])[CH3:21])=[CH:28][CH:27]=1
Reactant: CC(C)Oc1cnc2c(c1Cc1ccc(F)cc1)c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cnc2c(c1Cc1ccc(F)cc1)c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.6 %

Procedure:
To a solution of 3-(5-(4-fluorobenzyl)-6-isopropoxy-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (89 mg, 0.21 mmol) in THF (3 mL) and water (3 mL) was added LiOH.H2O (17.4 mg, 0.42 mmol). The reaction was stirred at RT for 15 min then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-fluorobenzyl)-3-(3-hydroxypropyl)-6-isopropoxy-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 36% yield) as a white solid. 1H NMR (CDCl3) δ: 8.33 (s, 1H), 7.22 (dd, J=8.6, 5.5 Hz, 2H), 6.95-6.84 (m, 2H), 4.73 (s, 2H), 4.64 (dt, J=12.1, 6.0 Hz, 1H), 4.27-4.15 (m, 2H), 3.69 (s, 3H), 3.52 (dd, J=11.6, 6.1 Hz, 2H), 3.19 (t, J=6.9 Hz, 1H), 1.96-1.84 (m, 2H), 1.35 (d, J=6.0 Hz, 6H). LCMS: MH+ 402 and TR=2.728 min.
Reaction SMILES: C(N(C(C)C)[CH:4]([CH3:6])[CH3:5])C.Br[CH2:11][CH2:12][CH3:13].[NH2:14][CH2:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]4[CH2:35][CH2:36][C@H:26]4[C:25]=23)[N:17]=1>CN(C)C=O>[CH2:11]([N:14]([CH2:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]4[CH2:35][CH2:36][C@H:26]4[C:25]=23)[N:17]=1)[CH2:5][CH2:4][CH3:6])[CH2:12][CH3:13]
Reactant: CCCBr
Reactant: NCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)no1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)no1
Reaction time: 12 h
Yield: 55 %

Procedure:
1.74 ml of N-ethyldiisopropylamine and 0.55 ml (6 mmol) of 1-bromopropane were added to a solution of 0.500 g (1.52 mmol) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-I 1,11a-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one in 15 ml of dimethylformamide and the mixture was stirred at 70° for 12 hours. The dimethylformamide was evaporated and the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase was extracted twice with methylene chloride and the organic phases were dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl acetate/methanol 20:1) yielded 0.350 g (55%) of (S)-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colourless foam, Rf=0.44 (silica gel, ethyl acetate/methanol 20:1).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([F:15])[C:12]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]2=[O:28])=[CH:11][C:3]=1[O:4][C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1.S(Cl)([Cl:31])=O>>[Cl:1][C:2]1[CH:14]=[C:13]([F:15])[C:12]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[N:18]([CH3:27])[C:17]2=[O:28])=[CH:11][C:3]=1[O:4][C:5]1([C:8]([Cl:31])=[O:10])[CH2:6][CH2:7]1
Reactant: O=S(Cl)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC3(C(=O)O)CC3)c(Cl)cc2F)c1=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC3(C(=O)Cl)CC3)c(Cl)cc2F)c1=O

Procedure:
1.2 g of 1-[2-chloro-4-fluoro-5-{3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl}phenoxy]cyclopropanecarboxylic acid was dissolved in 12 ml of thionyl chloride and the solution was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 1-[2-chloro-4-fluoro-5-{3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl}phenoxy]cyclopropanecarboxylic acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](=O)[C:17](O)=[O:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([N:9]=[C:16]([C:12]3[S:11][CH:15]=[CH:14][CH:13]=3)[C:17](=[O:18])[NH:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: O=C(O)C(=O)c1cccs1
Product: COc1ccc2nc(-c3cccs3)c(=O)[nH]c2c1

Procedure:
The quinoxalin-2-one of the present example is prepared with 4-Methoxy-benzene-1,2-diamine and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 7-Methoxy-3-thiophen-2-yl-1H-quinoxalin-2-one.
Reaction SMILES: [CH2:1]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[C:9]2[CH:31]=[CH:32][CH:33]=[CH:34][C:8]=2[N:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].FC(F)(F)C(O)=O>>[CH2:1]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]([OH:26])=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[C:9]2[CH:31]=[CH:32][CH:33]=[CH:34][C:8]=2[N:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-pentyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f3) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH2:12])[C:8]([NH2:11])=[CH:9][CH:10]=1)(=[O:4])=[O:3].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](=O)[C:19](O)=[O:20]>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:11][C:19](=[O:20])[C:18]([C:14]1[S:13][CH:17]=[CH:16][CH:15]=1)=[N:12]2)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(N)c(N)c1
Reactant: O=C(O)C(=O)c1cccs1
Product: CS(=O)(=O)c1ccc2[nH]c(=O)c(-c3cccs3)nc2c1

Procedure:
The quinoxalin-2-one of the present example is prepared with 4-Methanesulfonyl-benzene-1,2-diamine and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 6-Methanesulfonyl-3-thiophen-2-yl-1H-quinoxalin-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([OH:15])[CH2:11][CH2:10]1)=[O:5].[C:28](OC(=O)C)(=[O:30])[CH3:29].[OH-].[NH4+]>O>[C:28]([NH:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([OH:15])[CH2:11][CH2:10]1)=[O:5])(=[O:30])[CH3:29]
Reactant: Nc1cc(F)ccc1C(=O)NCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cc(F)ccc1C(=O)NCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 80 °C

Procedure:
A mixture of 5.8 parts of 2-amino-N-{2-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]ethyl}-4-fluorobenzamide, 5.5 parts of acetic acid anhydride and 55 parts of water is stirred and heated for 30 minutes in a water-bath at about 80° C. The reaction mixture is cooled and alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The aqueous phase is separated and extracted with trichloromethane. The combined organic phases are washed three times with water, dired, filtered and evaporated. The oily residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 4.5 parts of 2-(acetylamino)-N-{2-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]ethyl}-4-fluorobenzamide; mp. 175.1° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[F:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:21]=[C:20]([CH:19]=[CH:18][CH:17]=1)[O:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: Oc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(F)c1
Yield: 86 %

Procedure:
The title compound (D42) (D021/047/1) (252.3 mg) was prepared according to the experimental procedure described in Description 40 starting from (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (D41) (200 mg, 0.993 mmol) and 3-Fluorophenol (0.089 ml, 0.993 mmol).
Reaction SMILES: [CH3:1][S:2]([C:4]([S:19][CH3:20])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)=O.N1C=CC=CC=1.S(Cl)([Cl:29])=O>C(Cl)Cl>[CH3:1][S:2][C:4]([S:19][CH3:20])=[C:5]([Cl:29])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1
Reactant: CSC(=Cc1cccc(Oc2ccccc2)c1)S(C)=O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSC(SC)=C(Cl)c1cccc(Oc2ccccc2)c1
Yield: 70.4 %

Procedure:
1-Methylsulfinyl-1-methylthio-2-(m-phenoxyphenyl)ethylene (4.56 g) was dissolved in 40 ml of methylene chloride, and 2 ml of pyridine was added. With stirring under ice cooling, 10 ml of a methylene chloride solution of 2.15 g of thionyl chloride was added dropwise over the course of 5 minutes. The mixture was further stirred for 1 hour under ice cooling, and methylene chloride was added in an amount sufficient to adjust the total amount of the mixture to 80 ml. The mixture was then washed three times with 20 ml of water. The product was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a Florisil column using hexane/benzene as an eluant to afford 3.403 g of 1,1-bis(methylthio)-2-chloro-2-(m-phenoxyphenyl)ethylene as an oil in a yield of 70%. Samples for analysis were obtained by short-path distillation of this product [160°-180° C. (bath temperature)/0.01 mmHg].
Reaction SMILES: C1(CNC(C2NC=C(C(C3[C:16]([C:21]4[CH:26]=[CH:25][C:24](F)=CC=4)=[N:17]OC=3C)=O)C=2)=O)CC1.[F:28][C:29]1[CH:30]=[C:31]([C:37]2[C:41]([C:42]([C:44]3[CH:45]=[C:46]([C:49](=[O:54])C(Cl)(Cl)Cl)[NH:47][CH:48]=3)=[O:43])=[C:40]([CH3:55])[O:39][N:38]=2)[CH:32]=[C:33]([F:36])[C:34]=1[F:35].C1(N)CCCC1>>[CH:16]1([NH:17][C:49]([C:46]2[NH:47][CH:48]=[C:44]([C:42]([C:41]3[C:37]([C:31]4[CH:30]=[C:29]([F:28])[C:34]([F:35])=[C:33]([F:36])[CH:32]=4)=[N:38][O:39][C:40]=3[CH3:55])=[O:43])[CH:45]=2)=[O:54])[CH2:21][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1onc(-c2cc(F)c(F)c(F)c2)c1C(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1c[nH]c(C(=O)NCC2CC2)c1
Agent: NC1CCCC1
Product: Cc1onc(-c2cc(F)c(F)c(F)c2)c1C(=O)c1c[nH]c(C(=O)NC2CCCC2)c1

Procedure:
According to the procedure described for the synthesis of 4-(5-methyl-3-(4-fluorophenyl)-isoxazole-4-carbonyl)-1H-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (example 229, step 2), the title compound has been synthesized from 4-[3-(3,4,5-trifluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-2-trichloroacetyl-1H-pyrrole (intermediate 18) and cyclopentylamine (commercially available) in 49.6 yield. (m/e): 418.3 (MH+; 100%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7]CCCCC(O)=O.Br[CH2:16][CH2:17][C:18]([OH:20])=[O:19]>>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: O=C(O)CCBr
Reactant: Cn1ccnc1SCCCCC(=O)O
Product: Cn1ccnc1SCCC(=O)O

Procedure:
3-(1-methyl-1H-imidazol-2-ylthio)propanoic acid 28a was prepared as described for 5-(1-methyl-1H-imidazol-2-ylthio)pentanoic acid (Tweit, et al. (1973) J. Med. Chem. 16:1161), except that 3-bromopropanoic acid was used as the starting material. 1H NMR (400 MHz, CDCl3): 2.62-2.65 (t, 2H, J=6.4 Hz), 3.13-3.16 (t, 2H, J=6.4 Hz), 3.73 (s, 3H), 7.34-7.35 (d, 1H, J=2.1 Hz), 7.38-7.39 (d, 1H, J=2.1 Hz), 11 (br s, 1H). MS (ESI): 187 [M+H]+.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][O:15][C:16]3[C:21]4[S:22][CH:23]=[CH:24][C:20]=4[C:19]([CH:25]=[O:26])=[CH:18][CH:17]=3)[N:12]=2)[CH:7]=1.[CH2:27]([C@H:34]1[CH2:38][O:37][C:36](=[O:39])[N:35]1[C:40](=[O:44])[CH2:41][O:42][CH3:43])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.B(OS(C(F)(F)F)(=O)=O)(CCCC)[CH2:46]CCC>>[CH2:27]([C@H:34]1[CH2:38][O:37][C:36](=[O:39])[N:35]1[C:40](=[O:44])[C@@H:41]([O:42][CH3:43])[C@H:25]([OH:26])[C:19]1[C:20]2[CH:24]=[CH:23][S:22][C:21]=2[C:16]([O:15][CH2:14][CH2:13][C:11]2[N:12]=[C:8]([C:6]3[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=3)[O:9][C:10]=2[CH3:46])=[CH:17][CH:18]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CCCCB(CCCC)OS(=O)(=O)C(F)(F)F
Reactant: Cc1cccc(-c2nc(CCOc3ccc(C=O)c4ccsc34)co2)c1
Product: CO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2sccc12

Procedure:
In analogy to the procedures described in examples 11 a] to 11 c], 7-[2-(5-methyl-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophene-4-carbaldehyde was reacted with (S)-4-benzyl-3-methoxyacetyl-oxazolidin-2-one and nBu2BOTf to yield (S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-propionyl]-oxazolidin-2-one (according to NMR, one of the four isomers is strongly predominating; the configuration was tentatively assigned as 2S, 3R according to Tetrahedron Asymmetry 1999, 1353). Reduction of (S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-propionyl]-oxazolidin-2-one with triethylsilane in trifluoroacetic acid then gave (S)-4-benzyl-3-(2(S)-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-propionyl)-oxazolidin-2-one. The (S)-4-benzyl-3-(2(S)-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-propionyl)-oxazolidin-2-one was subsequently saponified with 1N NaOH in THF to yield (S)-2-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-propionic acid as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:18]=[N:19][CH:20]=2)[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([CH:8]([NH2:10])[CH3:9])[CH:7]=1.Br[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][NH:26]2.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:1][C:2]1[C:3]2[N:4]([CH:18]=[N:19][CH:20]=2)[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([CH:8]([NH:10][C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][NH:26]3)[CH3:9])[CH:7]=1
Reactant: CC(N)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Temperature: 130 °C

Procedure:
1-[8-Chloro-5-(3-fluorophenyl)imidazo[1,5-a]pyridine-6-yl]ethanamine (23 mg, 79 μmol), 6-bromo-9H-purine (32 mg, 0.16 mmol, Aldrich 104981) and N,N-diisopropylethylamine (69 μL, 0.40 mmol) were stirred in ethanol (1.0 mL) and heated to 130° C. for 30 minutes in a microwave. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product as a racemic mixture (10 mg, 30%). LCMS calculated for C20H16ClFN7 (M+H)+: m/z=408.1. found: 408.0. 1H NMR (300 MHz, DMSO-d6): δ 8.09 (m, 3H), 8.65 (m, 3H), 7.42 (m, 4H), 5.02 (br s, 1H), 3.30 (m, 1H), 1.42 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:4][N:3]=1.[F-:17].[Cs+]>CS(C)=O>[F:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:4][N:3]=1
Reactant: COCCOc1cnc(Cl)c2ccccc12
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COCCOc1cnc(F)c2ccccc12
Temperature: 140 °C

Procedure:
To a solution of 1-chloro-4-(2-methoxyethoxy)isoquinoline (368 mg, 1.548 mmol) in DMSO (7 mL) was added CsF (470 mg, 3.10 mmol) and heated to 140° C. for 2 hrs. LC/MS showed the desired product. The reaction was diluted with Ethylacteate and washed with water, and brine. The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum to give the crude product which was purified by silica gel chromatography using a gradient of 5-25% EtOAc/Hexanes. The product fractions were collected and the solvent removed under vacuum to give it the desired product 1-fluoro-4-(2-methoxyethoxy)isoquinoline (241 mg, 70.4% yield) as a white solid. MS: MS m/z 222.15 (M++1).
Reaction SMILES: Cl[C:2]1[C:3]([F:15])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[NH:7][CH:8]1[CH2:10][CH2:9]1.[C:16]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:18])[CH3:17].C(N(CC)CC)C>O>[C:16]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:11]=[C:6]([NH:7][CH:8]3[CH2:10][CH2:9]3)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=2[F:15])[CH2:21][CH2:20]1)(=[O:18])[CH3:17]
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1NC1CC1
Reactant: CC(=O)N1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2cc(NC3CC3)c([N+](=O)[O-])cc2F)CC1
Reaction time: 12 h
Yield: 93.3 %

Procedure:
5-Chloro-N-cyclopropyl-4-fluoro-2-nitroaniline (3.5 g, 15.2 mmol) is heated with N-acetylpiperazine (3.89 g, 30.4 mmol) and triethylamine (2.3 g 22.8 mmol) while stirring vigorously and held at 60° for 12 hours. The mass obtained is dissolved in water (200 ml) and extracted with ethyl acetate. The organic phase is washed with 10 percent sodium chloride solution and then dried over magnesium sulfate. After distillation of the solvent the residue is recrystallized from ethanol. There are obtained 4.57 g (93%) of 1-acetyl-4-[5-(cyclopropylamino)-2-fluoro-4-nitrophenyl]piperazine with a m.p. of 142°-143°.
Reaction SMILES: C([Li])CCC.[CH:6]#[C:7][CH2:8][CH2:9][CH3:10].[Cl:11][CH2:12][CH2:13][CH:14]=[O:15].[Cl-].[NH4+]>CCCCCC>[Cl:11][CH2:12][CH2:13][CH:14]([OH:15])[C:6]#[C:7][CH2:8][CH2:9][CH3:10]
Reactant: C#CCCC
Reactant: O=CCCCl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: CCCC#CC(O)CCCl

Procedure:
To 68 ml. of 1.6M butyllithium in hexane at -50° C. is added dropwise, with stirring, 7.4 g. of 1-pentyne. The resulting white sludge is diluted with 20 ml. of hexane, brought to 10° C. and treated with 11 g. of freshly prepared β-chloropropionaldehyde (Org. Syn., Coll. Vol. I, p. 166) at such a rate that the temperature is maintained at 10°-15° C. The solution is allowed to stir at ambient temperature for 18 hours then treated with saturated ammonium chloride solution. The organic phase is separated, washed with dilute hydrochloric solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation gives 5.1 g. of product b.p. 65°-66° C. at 0.3 nm.; λmax. 2.95 (--OH) and 4.55 μ (--C≡C--); vapor phase chromatography shows one peak.