Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([O:21]C)=[CH:14][C:13]=2[F:23])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:12]2[C:13]([F:23])=[CH:14][C:15]([OH:21])=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:8])[F:9]
Reactant: COc1cc(F)c(-c2nn(C)c(C(F)(F)F)c2Cl)cc1[N+](=O)[O-]
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1nc(-c2cc([N+](=O)[O-])c(O)cc2F)c(Cl)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
A solution of 1.4 g (4 mmole) 4-chloro-3-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole in 20 mL methylene chloride was chilled to 0° C. Next 5.0 mL of a 1M methylene chloride solution of BBr3 (4.9 mmole) was added slowly over 10 minutes. The solution was allowed to stir overnight at room temperature. The solution was washed two times with water, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was recrystallized from hexane to give 0.7 g (54%) of 4-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-fluoro-2-nitrophenol as a beige solid, mp 89°-90° C.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[C:20]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[C:21]3[CH:27]=[N:26][NH:25][C:22]3=[N:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1.[C:34]([O:38][C:39]([N:41]([CH:54]([CH3:56])[CH3:55])[CH2:42][C@H:43]([C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=1)[C:44](O)=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:53][C:50]1[CH:51]=[CH:52][C:47]([C@H:43]([C:44]([N:31]2[CH2:32][CH2:33][N:28]([C:20]3[C:19]([C:15]4[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=4)=[CH:24][N:23]=[C:22]4[NH:25][N:26]=[CH:27][C:21]=34)[CH2:29][CH2:30]2)=[O:45])[CH2:42][N:41]([CH:54]([CH3:55])[CH3:56])[C:39](=[O:40])[O:38][C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:48][CH:49]=1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: Fc1cccc(-c2cnc3[nH]ncc3c2N2CCNCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(-c3cccc(F)c3)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
DIEA (d 0.742; 0.0790 mL, 0.454 mmol) was added to a solution of 5-(3-fluorophenyl)-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.070 g, 0.113 mmol), (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.0388 g, 0.113 mmol, see Example B) and TBTU (0.0437 g, 0.136 mmol) in DCM (1 mL) and stirred at room temperature for 18 hours. The mixture was directly loaded onto a silica column and purified by chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-(3-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.2 mL) was added. The mixture was stirred at room temperature for 1 hour and then concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-2-(4-chlorophenyl)-1-(4-(5-(3-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one dihydrochloride (0.022 g, 32%). MS APCI (+) m/z 521.4 detected.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH3:19])[CH:5]=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:5]=1
Reactant: CCC=CCCc1cc(C(=O)OC)cc(OC)c1OC
Solvent: CCOC(C)=O
Product: CCCCCCc1cc(C(=O)OC)cc(OC)c1OC
Reaction time: 2.5 h

Procedure:
3-Hexyl-4,5-dimethoxybenzoic acid methyl ester was prepared from 3-hex-3-enyl-4,5-dimethoxybenzoic acid methyl ester by following Method H using EtOAc as a solvent. The reaction was conducted for 2.5 h under hydrogen atmosphere. The product obtained in quantitative yield was used without further purification.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12].[CH3:17][N:18]=[C:19]=[O:20].C(N(CC)CC)C>C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:19]([NH:18][CH3:17])=[O:20])(=[O:13])=[O:12]
Reactant: NS(=O)(=O)c1ccccc1C=CC(F)(F)F
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)NS(=O)(=O)c1ccccc1C=CC(F)(F)F
Yield: 96.2 %

Procedure:
5.0 g of 2-(3,3,3-trifluoro-1-propen-1-yl)phenysulfonamide and 1.7 g of methyl isocyanate are suspended in 25 ml of methylene chloride and 3.0 g of triethylamine are added dropwise for 10 minutes, whereupon a clear solution forms. The solution is concentrated, the residue is dissolved in a 5% sodium carbonate solution, and insoluble constituents are removed by filtration. The clear solution is acidified with 10% hydrochloric acid, to give 5.9 g of N-[2-(3,3,3-trifluoro-1-propen-1-yl)phenylsulfonyl]-N'-methylurea as a colorless precipitate with a melting point of 190°-192° C.
Reaction SMILES: N#N.[O:3]=[C:4]([CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.CCN(CC)CC.ClC(OCC(C)C)=O.Cl.[CH3:29][O:30][C:31](=[O:36])[C@H:32]([CH2:34][OH:35])[NH2:33]>C1COCC1>[CH3:29][O:30][C:31](=[O:36])[CH:32]([NH:33][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][C:4](=[O:3])[CH3:12])[CH2:34][OH:35]
Reactant: COC(=O)[C@@H](N)CO
Reactant: CC(=O)CCCCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(CO)NC(=O)CCCCC(C)=O
Temperature: -30 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 6-oxo-heptanoic acid (2.00 g, 13.32 mmol) in THF (82 mL) at −30° C. was treated sequentially with Et3N (3.89 mL, 27.97 mmol) followed by isobutyl chloroformate (1.95 mL, 14.65 mmol). After stirring for 1 h at −30° C., serine methylester hydrochloride (2.32 g, 14.65 mmol was added and the reaction mixture was allowed to warm gradually to rt and stirred for an additional 2 h at rt. The resulting suspension was filtered, the solid washed with THF and the filtrate was concentrated under reduced pressure. Purification of the residue by FC (97:3 EA-MeOH) gave the title compound as a colorless oil. TLC: rf (97:3 EA-MeOH)=0.26. LC-MS-conditions 02: tR=0.56 min [M+H]+=246.44.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:11].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.C(N(C(C)C)CC)(C)C>CC#N>[O:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[NH:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:11]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Clc1nc2ccccc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3ccccc3o2)c1
Temperature: 25 °C

Procedure:
A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone (40 mg, 122 μmol), 2-chlorobenzoxazole (38 mg, 245 μmol) and diisopropylethyl amine (DIPEA; 43 μL, 245 μmol) in CH3CN (2 mL) was heated at reflux overnight. The mixture was cooled to rt and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with satd. NaHCO3, brine, and dried (MgSO4). The solvent was removed and the crude was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 442 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]([NH2:13])[CH3:12]>C(Cl)Cl>[CH2:11]([NH:13][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[F:1])[CH3:12]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CCN
Solvent: ClCCl
Product: CCNC(=O)c1ccccc1F
Yield: 87.8 %

Procedure:
2-Fluorobenzoyl chloride (2 g, 12.6 mmol) and 70% aq ethyl amine (1.78 g, 27.7 mmol) were combined in CH2Cl2 according to General Method E1, and kugelrohr distilled to give 1.85 g of N-ethyl-2-fluorobenzamide as a colorless oil, an 87% yield.
Reaction SMILES: [C:1]1(=[O:13])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][C:3](=[O:12])[NH:2]1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[H-].[Na+]>CN(C=O)C>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:2]1[C:3](=[O:12])[CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:1]1=[O:13]
Reactant: BrCCCCCBr
Reactant: O=C1CCc2ccccc2C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2ccccc2C(=O)N1CCCCCBr
Reaction time: 1.5 h
Yield: 58.9 %

Procedure:
In 20 ml of DMF was dissolved 100 mg of 1,3,4,5-tetrahydro-2-benzazepine-1,3-dione and the solution then ice-cooled. Then, to the resulting solution were added 0.117 ml (1.5 equivalent) of 1,5-dibromopentane and 27.4 mg (1.2 equivalent) of a 60% sodium hydride oil dispersion and the mixture was stirred for 1.5 hour with ice-cooling. Thereafter, the reaction solution was reacted and/or treated and purified in the same manner as in Reference Example 1 to give 109 mg (yield: 58.9%) of the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:24])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)O1>>[OH:21][CH2:20][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[N:7]=3)=[O:24])=[CH:14][CH:15]=1)([CH3:23])[CH3:22]
Reactant: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Product: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(-c4ccncc4)nc3s2)cc1
Yield: 63 %

Procedure:
The titled compound (yield=63%, white solid) was prepared using a procedure analogous to that described in connection with 10 (Example 10) except 2F (Example 2) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (s, 6H) 3.49 (s, 2H) 7.59 (d, J=8.59 Hz, 2H) 8.10-8.12 (d, J=8.59 Hz, 2H) 8.31-8.36 (m, 1H) 8.37-8.44 (m, 3H) 8.85 (d, J=5.31 Hz, 2H) 13.15 (s, 1H); ESI-MS: m/z 405.0 (M+H)+.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH:13]1[CH2:15][CH2:14]1)[C:7]2=[O:12].N([O-])=O.[Na+].CS(C)=O.[IH:24].C([O-])([O-])=O.[Na+].[Na+]>>[CH:13]1([N:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[I:24])[C:7]2=[O:12])[CH2:15][CH2:14]1
Reactant: I
Reactant: Nc1cccc2c(=O)n(C3CC3)ccc12
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=c1c2cccc(I)c2ccn1C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Amino-2-cyclopropylisoquinolin-1(2H)-one (2.0 g, 0.0095 mol) was added to a solution of sodium nitrite (3 g, 0.04 mol) in dimethyl sulfoxide (100 mL, 2 mol) at room temperature. Aqueous hydrogen iodide (10 mL, 0.08 mol) in dimethyl sulfoxide (100 mL, 2 mol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with saturated aq. Na2CO3 and extracted with methylene chloride (3×200 mL). The combined methylene chloride extracts were washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was chromatographed on 120 g of silica gel column (0-25% EtOAc/Hexane) to give the desired product as a yellow solid. MS m/z (M+H) 312.2.
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)(=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>ClCCl>[C:1]1([CH:7]2[O:12][CH2:11][CH2:10][N:9]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCC(=O)Cl
Reactant: c1ccc(C2CNCCO2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)N1CCOC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.3 %

Procedure:
A solution of 2-phenylmorpholine (326 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and pentanoyl chloride (301 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing 1-(2-phenylmorpholin-4-yl)pentan-1-one are collected and the solvent is removed in vacuo to give 412 mg of colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:23][S:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[C:10]1[S:14][C:13]([NH:15]C(=O)OC(C)(C)C)=[N:12][CH:11]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][C:13]1[S:14][C:10]([C@H:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[NH:23][S@@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])=[CH:11][N:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc([C@H](NS(=O)C(C)(C)C)c2ccc(F)cc2Cl)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[S@@](=O)N[C@H](c1cnc(N)s1)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
To a solution of (R)-tert-Butyl 5-((2-chloro-4-fluorophenyl)(1,1-dimethylethylsulfinamido)methyl)thiazol-2-ylcarbamate (1.6 g, 3.5 mmol) in CH2Cl2 (6 mL) was added TFA (6 mL). The reaction was stirred at room temperature for 2 h. The TFA and CH2Cl2 were removed under vacuum. The crude product was re-dissolved in CH2Cl2, washed with aqueous NaHCO3 solution, dried over MgSO4 and concentrated. The crude product was recrystallized from EtOAc to provide (R)-N-((S)-(2-aminothiazol-5-yl)(2-chloro-4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide as colorless solid (672 mg, 53%). 1H NMR (400 MHz, CDCl3) δ 7.56 (dd, J=8.7, 5.9 Hz, 1H), 7.16 (dd, J=8.4, 2.6 Hz, 1H), 7.06 (td, J=8.2, 2.6 Hz, 1H), 6.89 (d, J=0.8 Hz, 1H), 6.07 (d, J=4.6 Hz, 1H), 5.22 (d, J=2.9 Hz, 2H), 4.06 (d, J=4.6 Hz, 1H), 1.28 (s, 9H); HPLC ret. time 2.28 min, 10-99% CH3CN, 5 min run; ESI-MS 362.3 m/z (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[N:3]=1.[NH3:15]>O1CCOCC1>[NH2:15][C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([NH:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[N:5]=1
Reactant: COCCCNc1nc(Cl)cc(Cl)n1
Reactant: N
Solvent: C1COCCO1
Product: COCCCNc1nc(N)cc(Cl)n1
Temperature: 0 °C
Yield: 61.6 %

Procedure:
10 g (0.042 mole) of 4,6-dichloro-2-(3-methoxypropylamino)-pyrimidine are dissolved in 100 ml of dioxane and 60 ml of aqueous ammonia solution are added. After the reaction mixture has been heated to the boil for four hours, it is mixed with 1 liter of ice water and extracted with methylene chloride. The extract is dried over sodium sulphate and concentrated, and the residue which remains is boiled up with white spirit, filtered off and dried. 5.6 g (61.6% of theory) of the desired pyrimidine, melting point 141° C., are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[C:14]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:20]([C:28]4[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=4)[O:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:7]=1>ClCCl.C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[C:14]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:20]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:7]=1
Reactant: COC(=O)COc1cccc(Nc2ncnc3oc(-c4ccc(Br)cc4)c(-c4ccccc4)c23)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)COc1cccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccccc4)c23)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dissolve 200 mg (0.377 mmol) of 3-{[6-(4-bromophenyl)-5-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenoxyacetic acid methyl ester in 5 ml of dichloromethane and 2 ml of THF and, under argon, add 40 mg of 10% palladium on activated carbon. Stir the mixture under a hydrogen atmosphere of 3 bar gauge at RT for 3 h, before filtering off the catalyst. Wash the catalyst residue with dichloromethane and methanol, concentrate the combined filtrates under reduced pressure and chromatograph the residue on silica gel (eluent: dichloromethane/ethyl acetate 10:1). 79.1 mg (45.5% of theory) of the target compound are obtained as a colourless solid.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([OH:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:26]([N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27]>CN(C)C=O>[N:28]1([C:26]([O:17][C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[O:27])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(Cl)N1CCCCC1
Reactant: Oc1cc(-c2ccccc2)c2ccccc2n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Oc1cc(-c2ccccc2)c2ccccc2n1)N1CCCCC1
Yield: 13.7 %

Procedure:
The procedure is as in Example 33, but starting with 4-phenyl-2-quinolinol (2.47 g), triethylamine (2.33 cc) and 1-(chlorocarbonyl)piperidine (2.47 g) in dimethylformamide (30 cc). The residue obtained is purified by chromatography on silica gel using a cyclohexane/ethyl acetate (80:20 by volume) eluant. 4-Phenyl-2-quinolyl 1-piperidinecarboxylate (0.51 g), m.p. 85° C., is thereby isolated.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]([CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:6]([CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([N:17]2[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]2[CH3:23])[N:11]=1)[CH2:7]O)[CH:2]=[CH2:3].CS(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:4][C@H:5]1[CH2:24][N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:7][C@H:6]1[CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([N:17]2[C:18]([CH3:23])=[CH:19][CH:20]=[C:21]2[CH3:22])[N:11]=1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H](CNCc1ccccc1)[C@@H](CO)Cc1cc(C)cc(-n2c(C)ccc2C)n1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCO[C@H]1CN(Cc2ccccc2)C[C@H]1Cc1cc(C)cc(-n2c(C)ccc2C)n1
Reaction time: 0.03 h
Yield: 100 %

Procedure:
To a solution of 20 (70 mg, 0.16 mmol) in CH2Cl2 (2.0 mL) at room temperature was added MsCl (15 μL, 0.19 mmol). After 2 min, triethylamine (34 μL, 0.24 mmol) was added dropwise as a solution in CH2Cl2 (340 μL). The reaction was allowed to stir for another 2 min and concentrated by rotary evaporation. The crude material was purified by flash column chromatography (EtOAc:hexanes, 2:1-4:1) to give 2 (66 mg, 0.16 mmol, 100%) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 2.12 (s, 6H), 2.38 (s, 3H), 2.38-2.43 (m, 1H), 2.53-2.56 (dd, J=3.0, 10.0 Hz, 1H), 2.77-2.80 (dd, J=7.5, 8.0 Hz, 1H), 2.80-2.91 (m, 2H), 3.08-3.13 (m, 2H), 3.79-3.83 (dd, J=5.5, 13.0 Hz, 1H), 3.97-3.99 (br s, 2H), 5.14-5.16 (dd, J=1.0, 10.0 Hz, 1H), 5.23-5.26 (dd, J=1.0, 17.0 Hz, 1H), 5.80-5.89 (m, 1H), 5.89 (s, 2H), 6.84 (s, 1H), 7.00 (s, 1H), 7.20-7.40 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 13.5, 21.2, 36.2, 42.5, 58.4, 60.2, 61.0, 70.9, 79.1, 98.9, 106.8, 116.7, 120.1, 123.4, 127.1, 128.5, 128.7, 128.9, 135.2, 149.4, 151.8, 161.3; LCQ-MS (M+H+) calcd for C27H34N3O 416. found 416; LC-TOF-MS (M+H+) calcd for C27H34N3O 416.27019. found 416.26956.
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([CH2:15][NH:16][C:17]([NH2:19])=[S:18])=[CH:13][CH:14]=2)[N:9]=1)[NH2:3].Cl[CH2:21][C:22](=O)[CH3:23]>C(O)C>[NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([CH2:15][NH:16][C:17]3[S:18][CH:21]=[C:22]([CH3:23])[N:19]=3)=[CH:13][CH:14]=2)[N:9]=1)[NH2:3]
Reactant: NC(=S)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Reactant: CC(=O)CCl
Solvent: CCO
Product: Cc1csc(NCc2ccc(-c3csc(N=C(N)N)n3)o2)n1
Yield: 83.6 %

Procedure:
A suspension of 2-(diaminomethyleneamino)-4-(5-thioureidomethylfuran-2-yl)thiazole (0.70 g) and chloroacetone (0.22 g) in ethanol (15 ml) was refluxed for 4 hours with stirring. The solvent was evaporated in vacuo and the residue was recrystallized from a mixture of methanol and diisopropyl ether to afford 2-(diaminomethyleneamino)-4-[5-(4-methylthiazol-2-yl)aminomethylfuran-2-yl]thiazole (0.66 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[SH:26][CH:27](O)[CH3:28].B(F)(F)F>O1CCCC1>[S:26]1[C:2]2([CH2:3][CH2:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]4=[O:24])=[CH:10][C:9]=3[F:25])[CH2:6][CH2:7]2)[O:1][CH2:28][CH2:27]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: CC(O)S
Agent: FB(F)F
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCS4)c(F)c2)C(=O)O1
Yield: 85 %

Procedure:
The mixture of (S)—N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (2.86 mmol), mercaptoethanol (3.15 mmol) and BF3 etherate (5.14 mmol) in 10 ml tetrahydrofuran was heated under reflux for 6 hours. The solvent was evaporated and the residue was extracted with ethyl acetate water mixture the organic layer was concentrated and the crude residue was purified on a silica gel column to afford the titled compound in 85% yield.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:30]([C:29]4[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=4[O:27][CH3:26])=[O:31])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: COc1ccccc1C(=O)O
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4OC)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP3 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2-methoxybenzoic acid as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:13])([CH:11]=[CH2:12])[CH:9]=[CH2:10])=[CH:4][CH:3]=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.O>[CH2:14]([N:21]1[CH2:12][CH2:11][P:8](=[O:13])([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CP(=O)(C=C)c1ccc(F)cc1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=P1(c2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Temperature: 90 °C
Yield: 81.6 %

Procedure:
(4-Fluorophenyl) divinyl phosphine oxide (1.50 g, 7.65 mmol) and benzylamine (1.05 mL, 9.57 mmol) were dissolved in a mixture of 100 mL of THF and 100 mL of deionized water. The reaction mixture was heated at 90° C. overnight. The reaction mixture was concentrated by rotary evaporation and the product was extracted into dichloromethane and washed with saturated brine. The organic phase was dried with sodium sulfate, filtered, and concentrated by rotary evaporation to yield 2.52 g of crude product. Impurities were removed by passing a solution of the crude product in ethyl acetate through a plug of silica. The product was then eluted from the silica with 10% methanol in ethyl acetate. The solvents were removed by rotary evaporation to yield 1.89 g (6.24 mmol, 82%) of 1-benzyl-4-(4-fluorophenyl)-[1,4]azaphosphinane 4-oxide as a colorless oil. ESMS (m/z): (M+1)+ found, 304.