Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH:24]([CH3:26])[CH3:25])[C:19]([C:27]([N:29]2[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[CH2:31][CH2:30]2)=[O:28])=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:36]=[S:32]1(=[O:35])[CH2:33][CH2:34][N:29]([C:27]([C:19]2[N:20]([CH:24]([CH3:25])[CH3:26])[C:21]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:23][CH:22]=3)=[O:28])[CH2:30][CH2:31]1
Reactant: CC(C)n1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(OC3CCNCC3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a cold (0° C.) mixture of 4-[2-(1,1-dioxo-1λ6-thiomorpholine-4-carbonyl)-1-isopropyl-1H-indol-5-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (410 mg, 1.0 eq.) in dichloromethane (8 mL) was added dropwise trifluoroacetic acid (920 mg, 10 eq.). The mixture was stirred overnight at room temperature then concentrated in vacuo. The residue was partitioned between a potassium carbonate aqueous solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and dried in vacuo. The residue was then purified on silica eluting with dichloromethane/methanol/ammoniac 95:5:0.25 v:v:v. to yield 296 mg (86%) of the desired product as off-white oil. MS (m/e): 420.4 (MH+, 100%).
Reaction SMILES: [F-:1].[K+].C(=O)=O.[C:6]([O:10][C:11]([C:14]([C:17](F)=[O:18])([F:16])[F:15])([F:13])[F:12])([F:9])([F:8])[F:7].[C:20](=[C:23]([C:25]([F:28])([F:27])[F:26])[F:24])([F:22])[F:21]>COCCOCCOC>[F:13][C:11]([F:12])([O:10][C:6]([F:7])([F:8])[F:9])[C:14]([F:15])([F:16])[C:17](=[O:18])[C:23]([F:24])([C:25]([F:28])([F:27])[F:26])[C:20]([F:1])([F:22])[F:21]
Reactant: O=C(F)C(F)(F)C(F)(F)OC(F)(F)F
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: [F-]
Agent: O=C=O
Agent: [K+]
Solvent: COCCOCCOC
Product: O=C(C(F)(F)C(F)(F)OC(F)(F)F)C(F)(C(F)(F)F)C(F)(F)F
Reaction time: 1 h
Yield: 130.9 %

Procedure:
Into a clean dry 600 mL Parr reactor were added 11.6 g (0.20 mol) of anhydrous potassium fluoride and 113.5 g of anhydrous diglyme. The contents of the reactor were stirred and cooled with dry ice, then 230 g (0.96 mol) of CF3OCF2CF2COF (approximately 97 percent purity) was added to the sealed reactor using isolated vacuum. With the reactor at 80° C. and pressure of 80 psig (4900 torr), 154 g (1.03 mol) of CF2═CFCF3 was gradually added over a 3½ hour time period. Following a one hour reaction hold time, the product was recovered from the reaction mixture by distillation and phase split prior to fractionation to give 100 g of 1,1,2,2,4,5,5,5-octafluoro-1-trifluoromethoxy-4-trifluoromethylpentan-3-one, having a boiling point of 77° C. and a purity of 99.8% as determined by gas chromatography. The structure was confirmed by gas chromatography and mass spectroscopy.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.S=[C:17]1[CH2:21][S:20][C:19](=[O:22])[NH:18]1>C(O)C>[O:22]=[C:19]1[N:18]=[C:17]([NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:21][S:20]1
Reactant: CCOC(=O)CN
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.5 %

Procedure:
To a solution of ethyl glycinate hydrochloride (5.00 g) and triethylamine (4.99 mL) in ethanol (60 mL) was added 4-thioxo-1,3-thiazolidin-2-one (3.98 g), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.84 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Sn](CCCC)(CCCC)CCCC)[N:3]=1.I[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]3[O:35][C:34]([NH:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=4)=[N:33][N:32]=3)[CH:29]=2)[N:24]([S:46]([C:49]2[CH:55]=[CH:54][C:52]([CH3:53])=[CH:51][CH:50]=2)(=[O:48])=[O:47])[CH:23]=1.CN(C=O)C>C(Cl)Cl.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]4[O:35][C:34]([NH:36][CH2:37][C:38]5[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=5)=[N:33][N:32]=4)[CH:29]=3)[N:24]([S:46]([C:49]3[CH:50]=[CH:51][C:52]([CH3:53])=[CH:54][CH:55]=3)(=[O:48])=[O:47])[CH:23]=2)[CH:5]=[N:6][CH:7]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(Cl)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Temperature: 100 °C
Yield: 49.1 %

Procedure:
In a 20 mL glass microwave tube, 2-chloro-6-(tributylstannyl)pyrazine (0.807 g, 1.999 mmol), 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (1.00 g, 1.665 mmol), CuI (0.381 g, 1.999 mmol), Pd(PPh3)4 (0.096 g, 0.083 mmol) was purged with argon and treated with DMF (15 mL). The tube was heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 1 h. The crude mixture was then diluted with DCM and washed with water. The organic layer was dried, filtered and concentrated and the residue was purified with flash chromatography to give 5-(3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (0.48 g, 0.818 mmol, 49%) as a light yellow amorphous solid. MS (ESI, pos. ion) m/z: 586.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.44 (1H, s), 9.02 (1H, s), 8.85 (1H, s), 8.71 (1H, s), 8.28-8.36 (1H, m), 8.18 (1H, d, J=8.8 Hz), 8.03 (1H, m, J=8.4 Hz), 7.95 (1H, s), 7.88-7.95 (1H, m), 7.45 (1H, m, J=8.2 Hz), 7.33 (2H, m, J=8.6 Hz), 6.90 (2H, m, J=8.6 Hz), 4.37 (2H, d, J=6.1 Hz), 3.72 (3H, s), 2.33 (3H, s).
Reaction SMILES: [C@H:1]1([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O.[O-:23][Mn](=O)(=O)=O.[K+]>CC(C)=O>[O:23]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@H:1]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:2][CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1CCCc2ccccc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1CC[C@@H](N2C(=O)c3ccccc3C2=O)c2ccccc21
Reaction time: 8 h
Yield: 3.4 %

Procedure:
To a solution of (R)-2-(1,2,3,4-tetrahydronaphthalen-1-yl)isoindoline-1,3-dione (3.9 g) in acetone (60 mL) at 0° C. was added MgSO4.7H2O (11.5 g) and water (20 mL). Then KMnO4 (11.5 g) was added portionwise over the period of 2 h and stirring continued at room temperature overnight. The brown solid was filtered off and the filtrate treated with saturated sodium metabisulfite, filtered, and extracted with CH2Cl2. The combined organic layer was washed with distilled water and saturated brine, dried over MgSO4, and concentrated in vacuo. The resultant was chromatographed on silica gel (EtOAc/hexane, 25/75) to afford 0.14 g of the title compound.
Reaction SMILES: C([C:4]1[CH:5]=[C:6]([N:10]2[C:14](S)=[N:13]N=N2)[CH:7]=[CH:8][CH:9]=1)(O)=O.C(NN[C:20]1[CH:25]=[CH:24][C:23](N)=[CH:22][CH:21]=1)=O.CN(C)C=[O:30]>>[C:14]([NH:10][CH:6]1[CH2:5][CH2:4][CH2:9][CH2:8][CH2:7]1)([NH:13][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:30]
Reactant: Nc1ccc(NNC=O)cc1
Reactant: O=C(O)c1cccc(-n2nnnc2S)c1
Reactant: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
Then, 11.1 g of 1-(3-carboxyphenyl)-5-mercaptotetrazole and 7.6 g of 1-formyl-2-(4-aminophenyl)hydrazine were dissolved in 50 ml of dimethylformamide and a solution of 10.3 g of dicyclocarbodiimide in 5 ml of dimethylformamide was added dropwise to the solution with stirring at 0° C. under a nitrogen atmosphere over a period of 15 minutes. Thereafter, the mixture was stirred for 1 hour and for 2 hours at 25° C. Dicyclohexylurea formed was removed by filtration and the filtrate was added to 1.5 liters of ice water. Crude crystals thus deposited were collected by filtration and dispersed in 100 ml of methanol under heating for 15 minutes. The reaction mixture was cooled to room temperature and filtered to provide 9.6 g of desired Compound 1. The yield was 54% and the melting point was 198°-200° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH2:12][NH2:13].Br[CH2:15][C:16]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:17]=1[C:18](OCC)=[O:19].C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH2:12][N:13]1[CH2:15][C:16]2[C:17](=[CH:23][CH:24]=[CH:25][C:26]=2[N+:27]([O-:29])=[O:28])[C:18]1=[O:19]
Reactant: CCOC(=O)c1cccc([N+](=O)[O-])c1CBr
Reactant: NCCN1CCc2ccccc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1c2cccc([N+](=O)[O-])c2CN1CCN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
To a solution of 2-(3,4-dihydro-1H-isoquinolin-2-yl)ethylamine (36) (0.36 g, 2.0 mmol) in dichloromethane (4 mL) was added the bromide 35 (0.75 g, 2.6 mmol) in dichloromethane (5 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 16 hours before it was poured into saturated NaHCO3 (aq. 50 mL) and extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water (70 mL), brine (70 mL), dried over MgSO4, and concentrated on a rotavap. The residue was chromatographed on silica gel eluting with 3:1 to 1:1 hexanes/EtOAc to give 37 (0.39 g, 57%).
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Br:36])(=[O:19])[CH3:18].O>C1(C)C=CC=CC=1.FC(F)(F)C(O)=O>[C:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[C@H:28]1[C@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Br:36])[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:14]1)(=[O:19])[CH3:18]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CC(=O)Oc1ccc(Cl)cc1/C=C/c1ccccc1Br
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccc(Cl)cc1[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1Br
Temperature: 25 °C

Procedure:
N-benzyl-N-methoxymethyl-N-(trimethylsilylmethyl)amine (5.0 g, 21.06 mmol) was added dropwise with a syringe over 30 minutes to a suspension of (E)-2-(2-bromostyryl)-4-chlorophenyl acetate (Example 1; 7.0 g, 19.9 mmol) in toluene (25 ml) containing trifluoroacetic acid (3 drops) while stirring at room temperature. After additional stirring for one hour water (10 ml) was added. The toluene layer was separated. The aqueous layer was extracted with toluene (25 ml). The combined organic layers were dried with Na2SO4 and evaporated under vacuum to give the crude cycloadduct as a clear and colorless oil, 10.76 g (>100%) in quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl:42][C:43]1[CH:44]=[C:45]([CH2:49][C:50](O)=[O:51])[CH:46]=[CH:47][CH:48]=1.CO>C1COCC1>[Cl:42][C:43]1[CH:44]=[C:45]([CH2:49][C:50]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[N:18]=4)=[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][N:10]4[N:9]=3)[CH:3]=2)=[O:51])[CH:46]=[CH:47][CH:48]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Cc1cccc(Cl)c1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.9 %

Procedure:
To a solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-phenyl-2-pyrimidine (30 mg, 0.08 mmol) (see Example 3, Step H) in THF (3 mL) was added CDI (14 mg, 0.09 mmol). The resultant mixture was stirred at rt for 1 hour. To the mixture was added (3-chlorophenyl)acetic acid (15 mg, 0.09 mmol) and then stirred at rt for 15 h. Methanol (2 mL) was added and the mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (hexanes/EtOAc) to give the title compound (25 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6): δ 3.68 (s, 2H), 6.53 (d, 1H, J=5.3 Hz), 6.92 (m, 1H), 6.92 (m, 1H), 7.12 (m, 1H), 7.21-7.50 (m, 9H), 7.68-7.76 (m, 3H), 7.89 (m, 1H), 8.26 (d, 1H, J=5.3 Hz), 8.47 (m, 1H), 8.83 (d, 1H, J=6.8 Hz), 9.56 (s, 1H), 10.35 (s, 1H). ES-LC/MS m/z=531 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:6]2[N:7]([CH3:10])[CH:8]=[N:9][C:5]=2[CH:4]=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21].COCCO.[ClH:33]>C(O)(C)C>[ClH:33].[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:6]2[N:7]([CH3:10])[C:8]([N:25]3[CH2:26][CH2:27][N:22]([C:20]([C:16]4[O:15][CH:19]=[CH:18][CH:17]=4)=[O:21])[CH2:23][CH2:24]3)=[N:9][C:5]=2[CH:4]=1
Reactant: O=C(c1ccco1)N1CCNCC1
Reactant: COc1cc2ncn(C)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Solvent: COCCO
Product: COc1cc2nc(N3CCN(C(=O)c4ccco4)CC3)n(C)c2cc1OC

Procedure:
3.50 g. 2-chloro. 5,6-dimethoxy-1-methyl benzimidazole [(J. Org. Chem. USSR 1 1466), (1965)] 7.00 g N-(2-furoyl) piperazine, and 25 ml 2-methoxyethanol were reacted as described in Example I. The product was converted to its hydrochloride by dissolving in isopropyl alcohol and acidifying with a solution of HCl gas in isopropyl alcohol. Yield: 3.99 g product, mp 212°-215° C decomp.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=1)[C:8]([OH:10])=[O:9])=[O:4].CN(C1C=CC=CN=1)C.[C:28](O)([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl>C(Cl)Cl>[CH3:18][S:15]([O:14][C:12]1[CH:13]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[C:7]([CH:11]=1)[C:8]([O:10][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:9])(=[O:17])=[O:16]
Reactant: CC(C)(C)O
Reactant: COC(=O)c1cc(OS(C)(=O)=O)cc(C(=O)O)c1
Agent: CN(C)c1ccccn1
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)c1cc(OS(C)(=O)=O)cc(C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 3-(methoxycarbonyl)-5-[(methylsulfonyl)oxy]benzoic acid (0.74 g, 2.7 mmol) in DCM (25 mL) was added dimethylaminopyridine (0.165 g, 1.35 mmol) and tert-butanol (0.226 g, 3.05 mmol). The reaction mixture was cooled to 0° C. To the reaction was added EDC (0.569 g, 2.97 mmol). The reaction stirred at 0° C. for 2 h and then warmed to room temp over 16 h. The reaction mixture was washed with 1N HCl, H2O, dried with MgSO4, filtered, concentrated and purified by flash chromatography (25 g silica, 10-30% EtOAc/hexanes) to give 0.74 g (83%) of tert-butyl methyl 5-[(methylsulfonyl)oxy]isophthalate. 1H NMR (400 MHz, CDCl3) δ 8.58 (m, 1H), 8.09 (m, 1H), 8.05 (m, 1H), 3.96 (s, 3H), 3.23 (s, 3H) 1.61 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl.CCOCC>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([N:17]2[CH2:18][CH2:19][N:14]([CH:10]3[CH:11]([OH:13])[CH2:12][NH:8][CH2:9]3)[CH2:15][CH2:16]2)=[O:28])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C(N2CCN(C(=O)c3ccc(Cl)cc3)CC2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)N1CCN(C2CNCC2O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
3-[4-(4-Chloro-benzoyl)-piperazin-1-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in CH2Cl2. 4M HCl/dioxane (150 mL) was added. The mixture was stirred at RT for 4 h. White precipitate was formed. The mixture was diluted with ether, filtered. The white solid was washed with ether and dried to give desired product (99% yield). 1H-NMR (300 MHz, DMSO, HCl salt): δ 3.0-4.0 (m, 12H), 4.85 (m, 2H), 7.25 (d, 2H), 7.54 (d, 2H) Retention Time (LC method: formic acid polar): 1.01 min MS (M+H+): 310
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[H-].[Na+].Cl[C:29]1[N:30]([CH2:37][C@:38]2([CH3:41])[CH2:40][O:39]2)[CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[N:33]=1>CN(C=O)C>[CH3:40][C@@:38]1([CH2:41][O:21][C:18]2[CH:19]=[CH:20][C:15]([N:12]3[CH2:11][CH2:10][CH:9]([O:8][C:7]4[CH:22]=[CH:23][C:4]([O:3][C:2]([F:1])([F:24])[F:25])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)=[CH:16][CH:17]=2)[O:39][C:29]2=[N:33][C:32]([N+:34]([O-:36])=[O:35])=[CH:31][N:30]2[CH2:37]1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: Oc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COc2ccc(N3CCC(Oc4ccc(OC(F)(F)F)cc4)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 54.6 %

Procedure:
4-[4-(4-Trifluoromethoxyphenoxy)piperidin-1-yl]phenol (17.4 g, 49.0 mmol) was dissolved in DMF (150 ml). To the solution, sodium hydride (2.15 g, 53.8 mmol) was added at room temperature, and the solution was stirred for 20 minutes at 80° C. To the solution, (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (14.9 g, 68.6 mmol) was added with cooling on ice-bath, and the solution was stirred for further 20 minutes at 80° C. To the reaction mixture, ice-water was added, and the mixture was stirred vigorously. The precipitates were filtered off, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=10/1) and then crystallized from methylene chloride/ethyl acetate to afford (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (14.3 g, yield 55%) as a light yellow powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[N:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[ClH:31]>ClCCl.O1CCOCC1>[ClH:31].[N+:21]([C:18]1[N:17]=[CH:16][C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:20][CH:19]=1)([O-:23])=[O:22].[ClH:31]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc([N+](=O)[O-])nc2)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(NC2CCNCC2)cn1
Reaction time: 0.5 h

Procedure:
4-(6-nitro-pyridin-3-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (200 mg; 0.62 mmol, prepared in accordance with Example 93) is dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) is added under stirring. After 30 minutes, the reaction mixture is concentrated under reduced pressure and the residue obtained is co-evaporated with dichloromethane (2×10 mL). The product is then diluted in dioxane (3 mL) and a 4N solution of hydrochloric acid in dioxane (3 mL) is added. The precipitate formed is filtered and dried under high vacuum at 40° C. to afford the desired product as hydrochloride (159 mg; 0.61 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.CO[C:36]1[CH:37]=[C:38]([NH2:46])[CH:39]=[C:40](OC)[C:41]=1OC>>[CH2:2]1[C:40]2[C:41](=[CH:36][CH:37]=[C:38]([NH:46][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:39]=2)[CH2:5][CH2:4][NH:3]1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared by a procedure similar to Example 27, Step D using N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and [3,4,5-tris(methyloxy)phenyl]amine: MS (APCI): 609 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20](O)=[O:21])=[N:18][CH:19]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:20](=[O:21])[C:17]3[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][N:18]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
TEA (0.61 mL, 4.35 mmol) was added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.87 mmol, Example 1, Step H), 5-chloropicolinic acid (160 mg, 1.04 mmol) and BOP-Cl (332 mg, 1.30 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 1 hour, and then a LiOH solution (2 N, 3 mL) was added. The mixture was stirred for 30 minutes, and water (10 mL) was added. The solid formed was collected by filtration, washed with DCM (10 mL) and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-chloropicolinamide (240 mg, 73% yield) as a solid.
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8][CH2:9][O:10]CC(O)=O)[CH:6]=[CH:5][N:4]=[CH:3]1.C[Si](C)(C)N1C=CN=C1.C[Si]([O:28]C(=O)C(Cl)C)(C)C>>[N:2]1([CH2:7][CH2:8][C:9]([OH:10])=[O:28])[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: CC(Cl)C(=O)O[Si](C)(C)C
Reactant: O=C(O)COCCCn1ccnc1
Agent: C[Si](C)(C)n1ccnc1
Agent: Cl
Product: O=C(O)CCn1ccnc1

Procedure:
The 6-(imidazol-1-yl)-3-oxa-hexanoic acid-hydrochloride used as the starting material is prepared in the following manner: 1-trimethylsilylimidazole (b.p.20 : 117°-120° C.) is reacted with chloropropionic acid-trimethylsilyl ester (b.p.1013 : 172°-175° C.) with simultaneous saponification of the esters to form 3-(imidazol-1-yl)-propionic acid (m.p.: 148°-150° C.). Reaction with trimethylchlorosilane in ethanol leads to the corresponding ethyl ester-hydrochloride from which the free 3-(imidazol-1-yl)-propionic acid-ethyl ester (oil) was obtained with 2N sodium hydroxide solution. The 1-(imidazol-1-yl)-3-propanol (oil) obtained after reduction with lithium aluminium hydride is allowed to react with ethyl bromoacetate in dimethyl formamide in the presence of sodium hydride to form 6-(imidazol-1-yl)-3-oxa-hexanoic acid ethyl ester (oil) which is subsequently saponified with 3N hydrochloric acid to form the desired acid.