Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:21]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:31])[C:29]#[CH:30])=[CH:23][CH:22]=1>[Cu]I>[C:21]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:31])[C:29]#[C:30][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: Ic1ccc(CCN2CCCC2)cc1
Reactant: C#CC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(C#Cc1ccc(CCN2CCCC2)cc1)Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
25 mL of THF are degassed and combined with 0.25 g (0.83 mmol) of 1-[2-(4-iodophenyl)ethyl]pyrrolidine, 0.81 g (2.49 mmol) of cesium carbonate, 16 mg (0.083 mmol) of copper (I) iodide and 38 mg (0.033 mmol) of tetrakistriphenylphosphine palladium. Then the mixture is again degassed, and 184 mg (0.83 mmol) of propynoic acid-biphenyl-4-ylamide are added. The reaction mixture is stirred for 3 hours at ambient temperature, poured onto water and extracted with ethyl acetate. The organic phase is extracted three times with water and dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (dichloromethane/methanol/ammonia=10:1:0.1)). Yield: 90 mg (27.5% of theory); melting point: 180-189° C.; C27H26N2O (M=394.52); calc.: molecular ion peak (M+H)+: 395; found: molecular ion peak (M+H)+: 395.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10](N)[CH2:11][NH2:12]>>[NH2:12][CH2:11][CH2:10][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: NCCN
Product: N#Cc1ccc(CCN)cc1

Procedure:
4-Fluorobenzonitrile is reacted with an excess of ethylenediamine in an aprotic solvent to give 4-(2-aminoethyl)benzonitrile which is then mono-alkylated with ethyl bromoacetate in a polar solvent such as ethanol or acetonitrile in the presence of an inorganic base or a tertiary amine. Acylation with chloroacetyl chloride followed by cyclization and hydrolysis give the acid (1).
Reaction SMILES: Br.[Br:2][C:3]1[C:8](=[O:9])[N:7]2[C:10]3([NH:37][C:38](=[O:39])[C:6]2=[C:5]([Cl:40])[CH:4]=1)[CH2:16][N:15](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:14][CH2:13][N:12](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:11]3>C(O)(=O)C.O1CCOCC1>[Br:2][C:3]1[C:8](=[O:9])[N:7]2[C:10]3([NH:37][C:38](=[O:39])[C:6]2=[C:5]([Cl:40])[CH:4]=1)[CH2:11][NH:12][CH2:13][CH2:14][NH:15][CH2:16]3
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CC3(C2)NC(=O)c2c(Cl)cc(Br)c(=O)n23)cc1
Agent: Br
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C1NC2(CNCCNC2)n2c1c(Cl)cc(Br)c2=O
Temperature: 100 °C

Procedure:
To a stirred solution of hydrogenbromide (1.43 g, 15.24 mmol) in acetic acid in 1,4-dioxane (30 mL), 6-bromo-8-chloro-1′,4′-ditosyl-2H-spiro[imidazo[1,5-a]pyridine-3,6′-[1,4]diazepane]-1,5-dione (1 g, 1.52 mmol) was added at room temperature. The vial was sealed and heated the reaction mass to 100° C. for 16 h. After completion, solvent was removed under reduced pressure and crude was triturated with dichloromethane to afford 6-bromo-8-chloro-2H-spiro[imidazo[1,5-a]pyridine-3,6′-[1,4]diazepane]-1,5-dione (4) as brown solid. Yield: 0.5 g, 94%; MS (ESI) m/z 362.28 [M+1]+.
Reaction SMILES: Cl.[NH:2]([C:4]([C:6]1([NH:9][C:10]([C:12]2([NH:15][C:16]([C:18]3[N:22]4[C@@:23]([CH2:36][C:37]5[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=5)([CH3:35])[C:24](=[O:34])[N:25]([C:26]5[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=5)[C:21]4=[N:20][CH:19]=3)=[O:17])[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7]1)=O)[NH2:3].Cl.C(O[C:49]([CH:51]1[CH2:53][CH2:52]1)=[NH:50])C.CCN(CC)CC>CN(C=O)C>[CH:51]1([C:49]2[NH:50][C:4]([C:6]3([NH:9][C:10]([C:12]4([NH:15][C:16]([C:18]5[N:22]6[C@@:23]([CH2:36][C:37]7[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[CH:41][CH:42]=7)([CH3:35])[C:24](=[O:34])[N:25]([C:26]7[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=7)[C:21]6=[N:20][CH:19]=5)=[O:17])[CH2:13][CH2:14]4)=[O:11])[CH2:7][CH2:8]3)=[N:2][N:3]=2)[CH2:53][CH2:52]1
Reactant: CCOC(=N)C1CC1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(C(=O)NN)CC4)CC3)n21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5nnc(C6CC6)[nH]5)CC4)CC3)n21
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 27.3 %

Procedure:
To a solution of (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid [1-(1-hydrazinocarbonyl-cyclopropylcarbamoyl)-cyclopropyl]-amide hydrochloride (0.080 g, 0.12 mmol) and cyclopropanecarboximidic acid ethyl ester hydrochloride (0.018 g, 0.12 mmol) in DMF (1 mL) was added Et3N (0.051 mL, 0.37 mmol). The reaction was heated in a microwave at 140° C. for 45 min and then at 180° C. for 1.5 h. The mixture was cooled to room temperature and purified via reverse-phase HPLC to give (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid {1-[1-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)-cyclopropylcarbamoyl]-cyclopropyl}-amide (0.022 g, 28%) as a white solid, m/z 670.8 [M+1]+.
Reaction SMILES: [CH:1]1([C@H:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[O:5][CH2:6][C@H:7]([OH:24])[CH2:8][NH:9][C:10]([CH3:23])([CH3:22])[CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:38]1(=[O:44])[O:43][C:41](=[O:42])[CH:40]=[CH:39]1>C(Cl)(Cl)Cl>[CH:1]1([C@H:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[O:5][CH2:6][C@H:7]([O:24][C:38](=[O:44])/[CH:39]=[CH:40]\[C:41]([OH:43])=[O:42])[CH2:8][NH:9][C:10]([CH3:23])([CH3:22])[CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH2:2][CH2:3]1
Reactant: O=C1C=CC(=O)O1
Reactant: Cc1ccccc1[C@H](OC[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1)C1CC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1[C@H](OC[C@@H](CNC(C)(C)Cc1ccc2ccccc2c1)OC(=O)/C=C\C(=O)O)C1CC1
Reaction time: 4 h
Yield: 90.7 %

Procedure:
(2R)-1-[(1R)-(Cyclopropyl)-(2-methylphenyl)methoxy]-3-[[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino]propan-2-ol (1.25g) was dissolved in chloroform (10 ml) and, under ice-cooling, pyridine (0.485 ml) and maleic anhydride (294 mg) were added and the mixture was stirred for 4 hr. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the obtained residue. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (1.40 g).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[N:21]1[CH:26]=[C:25]([NH:27][C:28](=O)[O:29]C2C=CC([N+]([O-])=O)=CC=2)[CH:24]=[N:23][CH:22]=1>CC#N>[N:21]1[CH:26]=[C:25]([NH:27][C:28]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:29])[CH:24]=[N:23][CH:22]=1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: O=C(Nc1cncnc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: O=C(Nc1cncnc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1

Procedure:
A solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.30 mmol, example 30 (step 1)) and 4-nitrophenyl pyrimidin-5-ylcarbamate (93.8 mg, 0.36 mmol) in MeCN (3 mL) was heated to 70° C. overnight, and then was subjected to microwave irradiation at 120° C. for 15 min. The mixture was filtered and the filtrate was purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the title compound in solution of H2O (0.1% TFA) and MeCN (0.1% TFA). The solvent was partially removed and saturated NaHCO3 (10 mL) was added. The mixture was extracted with EtOAc (2×5 mL). The combined organic extracts were dried over MgSO4, concentrated, and dried in vacuo to give the title compound as a light yellow solid. MS (ESI, positive ion) m/z: 399 (M+H).
Reaction SMILES: Cl[Sn]Cl.[F:4][C:5]1[C:10]([F:11])=[C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=2)[C:8]([F:23])=[C:7]([F:24])[N:6]=1>CCO>[F:4][C:5]1[C:10]([F:11])=[C:9]([C:12]#[C:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[NH2:20])[C:8]([F:23])=[C:7]([F:24])[N:6]=1
Reactant: O=[N+]([O-])c1cccc(C#Cc2c(F)c(F)nc(F)c2F)c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cccc(C#Cc2c(F)c(F)nc(F)c2F)c1
Yield: 33 %

Procedure:
SnCl2 (3.94 g, 20.8 mmol) was added to the solution of 2,3,5,6-tetrafluoro-4-((3-nitrophenyl)ethynyl) pyridine, (12b) (1.23 g, 4.15 mmol) in EtOH (100 mL). The reaction mixture was refluxed for 1.5 hours. After basification till pH>9 with NaOH (1.0 N solution), the product was extracted with dichloromethane. Solvent was evaporated and 0.73 g (66%) of the product aniline was purified by recrystallization with benzene. The residue was purified by column chromatography on silica gel using EtOAc:Hexane=1:5 as the eluent to yield the product (0.37 g, 33%): 1H-NMR (300 MHz, CDCl3) δ 7.21 (dd, J=7.2, 7.2 Hz, 1H), 7.03 (d, J=7.5 Hz, 1H), 6.93 (s, 1H), 6.79 (dd, J=7.4, 1.5 Hz, 1H), 3.80 (s, 2H); 13C-NMR (150 MHz, CDCl3) δ 146.7, 143.6 (dm, J=241.8 Hz), 142.0 (dm, J=262.4 Hz), 129.8, 122.8, 121.4, 118.2, 117.7 (m), 117.6, 107.4 (t, J=3.8 Hz), 72.9 (t, J=4.3 Hz); HRMS (ESI+): calcd for C13H7F4N2 [M+H]+ 267.05454, found 267.05405; m.p. 172-173° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:28]([OH:29])=[CH:27][CH:26]=[C:25]([F:30])[C:5]=1[CH2:6][O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C@H:11]1[CH2:23][CH3:24])=[O:9].[CH3:31]I.[ClH:33]>CN(C=O)C>[ClH:33].[F:3][C:4]1[C:28]([O:29][CH3:31])=[CH:27][CH:26]=[C:25]([F:30])[C:5]=1[CH2:6][O:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]1[CH2:23][CH3:24])=[O:9]
Reactant: CI
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)ccc(O)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H]1CNCCN1C(=O)OCc1c(F)ccc(OC)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A mixture of 5.03 mg (0.126 mmol) NaH (60% suspension in mineral oil) and 33.6 mg (0.084 mmol) (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(2,6-difluoro-3-hydroxy-benzyl) ester in 1 ml DMF was stirred for 30 min at room temperature under argon. 13.1 mg (0.092 mmol) methyliodide was added and the mixture was stirred 30 min at room temperature. After addition of 0.06 ml HCl (37%) the mixture was purified with preparative HPLC eluting with an acetonitrile/water gradient. The fractions containing the desired intermediate were combined and evaporated to dryness. The residue was taken up in 1 ml dioxane and 0.125 ml HCl (37%) and stirred for 30 min at 60° C. Evaporation of the mixture yielded 22 mg (75%) of the title compound. MS (ISP): 315 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1)[CH3:12]
Reactant: CCOC(=O)Cc1ccsc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccsc1-c1cccs1
Yield: 137.5 %

Procedure:
To a dried 250 ml three-neck round-bottom flask containing 50 ml of dry THF containing dichlorobis-(triphenylphosphine)palladium (1.20 g) was cannulated 8.5 grams (34 mmol) of ethyl 2-bromothiophene-3-acetate dissolved in 80 ml of dry THF. The mixture was refluxed for 24 hours. The solvent was removed under vacuum, and the residue was dissolved in CH2Cl2 (100 ml). The solution was washed with water (100 ml×3), and dried with MgSO4. The solvent was evaporated and the residue was purified by column chromatography using silica with toluene as eluent. A total of 5.9 grams of ethyl(2,2′-bithiophene)-3-acetate was obtained as a clear oil resulting in a 69% yield. 1H-NMR (CDCl3): 7.33 (dd, 1H), 7.23 (d, 1H), 7.19 (dd, 1H), 7.08 (dd, 1H), 7.05(d, 1H), 4.17 (q, 2H), 3.75 (s, 2H), 1.27 (t, 3H)
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:50][OH:51]>CN(C)C=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)=[O:21])[N:16]=2)[CH2:11][C:12]([NH:50][OH:51])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCC(c3ccncc3)CC2)no1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCC(c3ccncc3)CC2)no1)NO
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 29.4 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-(3-{[4-(4-pyridinyl)-1-piperidinyl]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoic acid (Preparation 32) (311 mg, 0.68 mmol) and N-methylmorpholine (83 μl, 0.75 mmol) in N,N-dimethylformamide (15 ml) was cooled to 0° C., treated dropwise with isobutyl chloroformate (98 μl, 0.75 mmol) and the resulting solution was stirred at 0° C. for 45 minutes. Hydroxylamine hydrochloride (142 mg, 2.05 mmol) was then added followed by further N-methylmorpholine (226 μl, 2.05 mmol) and the mixture was stirred for 18 hours being allowed to warm to room temperature over this time. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (50 ml) and water (50 ml). The layers were separated and the aqueous phase extracted with ethyl acetate (×2). The combined organic phases were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by HPLC to afford a residue that was partitioned between ethyl acetate and water. The organic phase was separated, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was triturated with diethyl ether to yield the title compound as a white solid (94 mg).
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH:18]([F:20])[F:19])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:21][C:22]1[N:27]=[C:26](Cl)[N:25]=[C:24]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[N:23]=1>CC(C)=O>[Si:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH:18]([F:19])[F:20])[N:14]([C:26]3[N:27]=[C:22]([Cl:21])[N:23]=[C:24]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)[N:25]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]c(C(F)F)nc12
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Solvent: CC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1

Procedure:
Reaction of 4-(tert-butyldimethylsilyloxy)-2-(difluoromethyl)-1H-benzimidazole with 2,4-dichloro-6-(4-morpholinyl)-1,3,5-triazine as in Example 2, but using acetone as solvent, followed by chromatography on silica gel eluting with CH2Cl2/hexanes 3:1 gave 4-(tert-butyldimethylsilyloxy)-1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole: mp (hexanes) 143-145° C.; 1H NMR (CDCl3) δ 7.99 (d, J=8.4 Hz, 1H), 7.46 (t, JHF=53.5 Hz, 1H), 7.32 (t, J=8.2 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 3.96 (m, 3.5H), 3.88 (m, 0.5H), 3.81 (m, 3.5H), 3.75 (m, 0.5H), 1.05 (s, 9H), 0.29 (s, 6H); MS (APCI+) 497.9/499.9 MH+. Anal. Calcd. for C21H27ClF2N6O2Si: C, 50.75; H, 5.5; N, 16.9. Found: C, 50.7; H, 5.6; N, 17.0%.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:20])[C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:13][CH2:14][C:15]([O:17]CC)=[O:16].[Cl:21][C:22]1[CH:23]=[C:24]([C:32](O)=O)[CH:25]=[N:26][C:27]=1[O:28][CH:29]([CH3:31])[CH3:30].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([C:32]2[O:1][N:2]=[C:3]([C:4]3[CH:12]=[CH:11][CH:10]=[C:9]4[C:5]=3[CH:6]=[CH:7][N:8]4[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[N:20]=2)[CH:25]=[N:26][C:27]=1[O:28][CH:29]([CH3:30])[CH3:31]
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Reactant: CCOC(=O)CCn1ccc2c(C(=N)NO)cccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Oc1ncc(-c2nc(-c3cccc4c3ccn4CCC(=O)O)no2)cc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 20.6 %

Procedure:
Ethyl 3-{4-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}propanoate (D57) (150 mg) in DMF (2.5 ml) was added to a solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (D61) (118 mg), HOBT (81 mg) and EDCI (114 mg) which had been stirring at RT for 10 minutes in DMF (2.5 ml). The resultant mixture was stirred at RT for 2 hours then heated at 80° C. for three days. The reaction mixture was evaporated to dryness and extracted from H2O (25 ml) with EtOAc (2×25 ml). The combined organics were evaporated and the residue stirred in EtOH/2 M aq. NaOH (1:1 mixture, 20 ml) at 50° C. for 2 hours. The EtOH was evaporated and the precipitate removed by filtration. This was acidified then purified by MDAP to give the title compound (48 mg) as an off white solid. δH (d6-DMSO, 400 MHz): 1.40 (6H, d), 2.80 (2H, t), 4.50 (2H, t), 5.46 (1H, septet), 7.08 (1H, d), 7.36 (1H, apparent t), 7.60 (1H, d), 7.82 (1H, d), 7.95 (1H, d), 8.60 (1H, d), 8.97 (1H, d). MS (ES−): C21H1935ClN4O4 requires 426; found 425 (M−H+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([N:18]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:19]([C:23]1([OH:29])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[C:20]([OH:22])=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[C:38]1[C:43]([F:44])=[C:42]([F:45])[CH:41]=[CH:40][C:39]=1[N+:46]([O-:48])=[O:47].OS([O-])(=O)=O.[K+]>C1COCC1.O>[CH2:30]([N:18]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:19]([C:23]1([O:29][C:38]2[C:43]([F:44])=[C:42]([F:45])[CH:41]=[CH:40][C:39]=2[N+:46]([O-:48])=[O:47])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[C:20]([OH:22])=[O:21])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)C(N(Cc1ccccc1)Cc1ccccc1)C1(O)CCOCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(N(Cc1ccccc1)Cc1ccccc1)C1(Oc2c([N+](=O)[O-])ccc(F)c2F)CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31.8 %

Procedure:
Potassium bis(trimethylsilyl) amide, 1 M solution in THF (4.22 mL, 4.22 mmol, Eq: 3.00), was added to a solution of 2-(dibenzylamino)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-acetic acid (0.5 g, 1.41 mmol, Eq: 1.00) in THF (10 mL) at RT and the mixture stirred for 15 min. The mixture was cooled to 0° C., 2,3,4-trifluoronitrobenzene (1.25 g, 0.83 mL, 7 mmol, Eq: 5.00) was added and the mixture stirred at 0° C. for 45 min. The mixture was diluted with H2O at 0° C. and was warmed to RT. The pH was adjusted to ˜2-3 with sat KHSO4, the mixture extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, concentrated and the residue purified by flash chromatography to afford 2-(dibenzylamino)-2-(4-(5,6-difluoro-2-nitrophenoxy)tetrahydro-2H-pyran-4-yl)-acetic acid (0.23 g, 32% yield). MS m/z 513.0 (MH+)
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:30])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[CH:22][C:21]=1[Cl:29])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:31]1CCCC1.C(O)(C)(C)C.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:30])[CH:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[CH:22][C:21]=1[Cl:29])[CH2:16][CH:17]=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: C=CC[C@@H](Cc1c(Cl)cc(OC)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cc(Cl)c(CC(CC=O)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c(Cl)c1
Yield: 49 %

Procedure:
Treat a mixture of (R)-4-benzyl-3-[(S)-2-(4-methoxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one (6.65 g, 14.87 mmol), tetrahydrofuran (140 mL) and water (45 mL) with 2.5% osmium tetroxide in t-butanol (378 mL, 1.487 mmol). Add sodium periodate (9.55 g, 44.63 mmol) and stir the reaction 4 hr at room temperature. Quench the reaction with water and extract with ethyl acetate. Wash the organic phase with aqueous 1N sodium thiosulfate then brine. Dry the organic layer over magnesium sulfate, filter, and concentrate under vacuum. Purify the crude material by silica gel chromatography using hexanes:ethyl acetate to elute the pure product. Concentrate the fractions containing product under vacuum to afford 3.35 g (49%) of desired product. MS (m/z): 451 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:6]#[N:7].CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:31])C(=O)C1.CCCCCCC>ClCCCl>[Br:31][CH2:11][C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C#N)ccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Solvent: CCCCCCC
Product: COc1cc(C#N)ccc1CBr
Temperature: 82 °C
Reaction time: 0.5 h

Procedure:
14.7 g (0.1 mol) of 3-methoxy-4-methylbenzonitrile were dissolved in 210 ml of 1,2-dichloroethane, bromination was carried out at 82° C. in the presence of catalytic amounts of AIBN with 19.1 g (0.11 mol) of NBS in portions over the course of 1 h and, after the addition was complete, the mixture was stirred at 82° C. for a further 30 min. Addition of n-heptane was followed by removal of precipitated succinimide, and the solvent was stripped off. The product contained, besides small amounts of precursor, also traces of the corresponding benzal bromide. 1H-NMR (DMSO-d6; δ in ppm): 7.60 (dd, 1H); 7.50 (d, 1H); 7.40 (dd, 1H); 4.68 (s, 2H); 3.96 (s, 3H)
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:25]=[CH:24][C:15]([CH:16]=[C:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])=[CH:14][CH:13]=1)[C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[H][H]>O1CCOCC1.[Pd]>[CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])=[CH:24][CH:25]=1)[C:3]1[N:4]=[CH:5][CH:6]=[CH:7][N:8]=1
Reactant: [H][H]
Reactant: CN(CCOc1ccc(C=C2SC(=O)NC2=O)cc1)c1ncccn1
Agent: [Pd]
Solvent: C1COCCO1
Product: CN(CCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ncccn1

Procedure:
5-(4-[2-(N-Methyl-N-(2-pyrimidinyl)amino) ethoxy]benzylidene)-2,4-thiazolidinedione (2.4 g) in dry 1,4-dioxan (150 ml) was reduced under hydrogen in the presence of 10% palladium on charcoal (3 g) until hydrogen uptake ceased. The solution was filtered through diatomaceous earth, the filter pad was washed exhaustively with dioxan and the combined filtrates were evaporated to dryness under vacuum. The title compound (mp 150°-51° C.) was obtained after crystallisation from methanol.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:36]=[CH:35][C:6]([C:7]([N:9]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:34])[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:8])=[CH:5][CH:4]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]([CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])[C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([CH2:2][NH:1][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:36][CH:35]=3)[CH2:21][CH2:22]2)=[O:34])=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(CN)cc1
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(CNS(C)(=O)=O)cc1
Yield: 57.3 %

Procedure:
Using 4-aminomethyl-N-{2-[4-(4-fluorobenzoyl)piperidino]-ethyl}-N-(2-methoxyphenyl)benzamide (60 mg, 0.123 mmol) and methanesulfonyl chloride (11 μl, 0.142 mmol), the procedure of Inventive Example 94 was repeated to obtain 40 mg (57.5%) of the title compound in a colorless amorphous form.