Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)=O)[CH3:2].[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([NH:26][C:27](=[O:29])[CH3:28])=[CH:24][CH:23]=1.Cl.N[C:34]1C=CC(NC(=O)C)=C[CH:35]=1.C(O)CCC>O>[CH2:1]([O:3][C:4](=[O:20])[CH:5]=[C:6]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([NH:26][C:27](=[O:29])[CH3:28])=[CH:30][CH:31]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH2:2][CH2:34][CH3:35]
Reactant: CCOC(=O)CC(=O)c1ccc(C2CCCCC2)cc1
Reactant: CC(=O)Nc1ccc(N)cc1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: CCCCOC(=O)C=C(Nc1ccc(NC(C)=O)cc1)c1ccc(C2CCCCC2)cc1
Temperature: 400 °C
Reaction time: 48 h
Yield: 98 %

Procedure:
3-(4-Cyclohexylphenyl)-3-oxo-propionic acid ethyl ester 50.25 g (0.183 moles), 4′-aminoacetanilide 25 g (0.167 moles), 4′-aminoacetanilide hydrochloride salt, 1.55 g (0.008 moles), and 500 mL of dry n-butanol were placed in a 1 liter single neck round bottom flask equipped with a Soxhlet extractor apparatus with condenser, magnetic stirrer and nitrogen inlet. In the Soxhlet thimble (33×118 mm) was placed highly activated 4A sieves (1.7-2.4 mm beads). The sieves were activated immediately before use under high vacuum with heating (400° C. for 30 min). The mixture was then brought to reflux such that the butanol azeotropically removed water, so as to drive the equilibrium reaction, and the water was removed from the butanol by the sieves before being returned to the reaction pot. The reaction was allowed to continue for 48 hrs. The charge of sieves was replaced after the first 24 hrs. Transesterification to the butyl ester along with removal of ethanol occurred concomitantly with enamine formation. After 48 hrs the reaction pot was cooled, placed in a −40° C. freezer and crystals were-allowed to form for 24 hrs. Crystals were collected by vacuum filtration and solids washed with cold ethanol. The product was then dried in a vacuum oven to give 73.8 g (98%) of the desired enamine.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(c2cccnc2O)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3cccnc3O)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(2-hydroxy-pyridin-3-yl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [C:1]([C:3]12[CH2:10][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH2:4]2)#[CH:2].Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C(#N)C.C(OCC)(=O)C.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.[Cu]I>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]#[C:1][C:3]12[CH2:10][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH2:4]2
Reactant: Clc1ccccn1
Reactant: C#CC12CCCC(NC(=O)OC(C)(C)C)(CC1)C2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC12CCCC(C#Cc3ccccn3)(CC1)C2
Temperature: 70 °C
Yield: 76.3 %

Procedure:
To a stirred solution of tert-butyl 5-ethynylbicyclo[3.2.1]octan-1-ylcarbamate (5.8 g, 23.3 mmol) and 2-chloropyridine (3.18 g, 28 mmol) in TEA (30 mL) and acetonitrile (150 mL) under N2 was added Pd(PPh3)4 (266 mg, 0.23 mmol), followed by CuI (266 mg, 1.4 mmol). The reaction mixture was heated at 70° C. for three hours. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate (250 mL), washed with water (150 mL) and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1) to give 5.8 g (76%) of the title compound, tert-butyl 5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-ylcarbamate, as a white solid. ESI-MS m/z: 298 (M-55)+.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:8]3=[N:13][S:14][N:15]=[C:7]3[CH:6]=[CH:5][C:4]=2[N:3]=1.[N+:16]([O-])([O-:18])=[O:17].[K+]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:8]3=[N:13][S:14][N:15]=[C:7]3[C:6]([N+:16]([O-:18])=[O:17])=[CH:5][C:4]=2[N:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1nc2ccc3nsnc3c2nc1O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2nsnc12
Temperature: 0 °C
Reaction time: 24 h
Yield: 71.2 %

Procedure:
To a solution of 0,4 g (1,8 mmol) 7,8-dihydroxy-1,2,5-thiadiazolo(3,4-f)quinoxaline in 20 ml concentrated sulfuric acid was added at 0° C. 0,19 g (1,9 mmol) potassium nitrate. Stirring was continued at 0° C. for 30 min. and at 25° C. for 24 h. The reaction mixture was poured into 100ml ice-water to give 0,34 g (71%) 7,8-dihydroxy-4-nitro-1,2,5-thiadiazolo(3,4-f)quinoxaline as a precipitate, m.p.>300° C. NMR (DMSO-d6) 12,3 (1H, broad s), 11.6 (1H, broad s), 8.43 (1H,s).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH2:12]([Zn]CC)[CH3:13].O.Cl>O1CCOCC1>[CH2:12]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])[CH3:13]
Reactant: CC[Zn]CC
Reactant: COC(=O)c1ccncc1Br
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCc1cnccc1C(=O)OC
Temperature: 70 °C
Yield: 21.2 %

Procedure:
Methyl 3-bromopyridine-4-carboxylate (5 g, 23.1 mmol) was dissolved in anhydrous dioxane (150 mL). A solution of diethyl zinc (18.9 mL, 20.8 mmol, 1.1 M in toluene) was added dropwise and then was added catalyst ((1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (254 mg, 347 μmol). The mixture was heated at 70° C. for 3.5 hours and then water followed with 1 N HCl was added. The mixture was extracted 3 times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in DCM and purified on silica gel using 0-20% hexane/ethyl acetate to afford methyl 3-ethylpyridine-4-carboxylate (730 mg, 19% yield).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16](OC)=[O:17])[N:10]=[CH:9]2)#[N:2].CO.[BH4-].[Na+]>C(Cl)Cl>[F:24][C:22]1[CH:21]=[CH:20][C:4]([O:5][C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH2:15][CH2:16][OH:17])[N:10]=[CH:9]3)=[C:3]([CH:23]=1)[C:1]#[N:2]
Reactant: COC(=O)Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cc(F)ccc1Oc1ccc2c(cnn2CCO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
A flask was charged with methyl 2-(5-(2-cyano-4-fluorophenoxy)-1H-indazol-1-yl)acetate (100.0 g, 307.4 mmol) and MeOH (620 mL, 0.5M) and purged with nitrogen, Sodium borohydride (40.00 g, 1057 mmol) was added portionwise to the reaction mixture over 2.5 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. To the residue were added 1000 mL of saturated aqueous NH4Cl solution and 1000 mL of EtOAc. The mixture was stirred for 1 hour at ambient temperature. The layers were separated and the aqueous layer was extracted with EtOAc. The combined extracts were washed with saturated NH4Cl and brine, dried over MgSO4, filtered through a Celite pad, and concentrated under reduced pressure to provide 91.1 g of the crude product. The crude solid was dissolved in CH2Cl2 (1500 mL). Hexanes (2500 mL) were added to the solution with stirring. The light brown solid which crashed out of solution was filtered, washed with 1:2 CH2Cl2:hexanes and dried under high vacuum to provide 84.8 g (92.8%) of the title product. 1H NMR (400 MHz, CdCl3) δ 7.98 (s, 1H), 7.50 (d, J=8.98 Hz, 1H), 7.39-7.35 (m, 2H), 7.21-7.15 (m, 2H), 6.80 (dd, J=4.29 Hz. 9.37 Hz, 1H), 4.49 (t, J=5.00 Hz, 2H), 4.19-4.10 (m, 2H), 2.90 (br s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.[C-:32]#[N:33].[Na+]>CN1CCCC1=O>[CH3:21][C:5]1[CH:4]=[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:2]([C:32]#[N:33])=[N:7][C:6]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C#N)nc1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 150 °C
Yield: 29.4 %

Procedure:
A well stirred suspension of 0.30 g (0.66 mmol) of [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) and 0.098 g (2.0 mmol) of sodium cyanide in 5.0 ml of 1-methyl-pyrrolidin-2-one was heated for 16 hours at 150° C. After cooling down to RT, the reaction mixture was poured into crashed ice/NaCl-solution (sat. in H2O) and extracted three times with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 4:1) to give 0.086 g (29%) of 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carbonitrile as light yellow solid. MS: 443.4 (MH+); and 0.045 g (15%) of 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid amide as light yellow solid. MS: 461.4 (MH+).
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1>C(OCC)C>[Br:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([CH3:1])([OH:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)Cc1cccc(Br)c1
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC(C)(O)Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
Methylmagnesium bromide (3M solution in diethyl ether, 51.6 mL, 155 mmol) was slowly added to a solution of 1-(3-bromo-phenyl)propan-2-one (15.0 g, 70 mmol) in dry diethyl ether (200 mL) at 0° C. and the mixture was stirred for 3 hours. The reaction mixture was then re-cooled to 0° C. and slowly quenched with saturated aqueous ammonium chloride solution. The organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residual yellow oil was then purified by column chromatography on silica gel eluting with dichloromethane:pentane:methanol, 90:5:5, to afford a pale yellow oil in 83% yield, 13.26 g. 1H NMR (400 MHz, CDCl3) δ: 1.22 (6H, s), 1.42 (1H, bs), 2.74 (2H, s), 7.15 (2H, m), 7.40 (2H, m)
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:28]#[N:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>COCCO>[C:28]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[C:21]([CH3:27])=[CH:22][CH:23]=[CH:24][C:25]=3[CH3:26])=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:7])[N:9]=1)#[N:29]
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3c(C)cccc3C)cc2c1O
Reactant: NCCCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: Cc1cccc(C)c1Oc1ccc2c(C#N)nc(C(=O)NCCCCC(=O)O)c(O)c2c1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
A mixture of 1-cyano-6-(2,6-dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (80 mg, 0.20 mmol), 5-aminovaleric acid (480 mg, 4.10 mmol) and NaOMe (166 mg, 3.07 mmol) in 2-methoxyethanol (10 mL) was refluxed for 2 h. After the mixture was cooled to r.t., solvent was evaporated. The residue was partitioned between EtOAc (50 mL) and water (50 mL). 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-60% EtOAc/hexanes+2% AcOH) to give 67 mg of the title compound as a pale pink solid. MS: (+) m/z 434.18 (M+1).
Reaction SMILES: [CH2:1]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:36])[CH2:18][CH2:19][C:20]2[CH:35]=[CH:34][C:23]([O:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][N:26]=3)=[CH:22][CH:21]=2)[CH2:13][CH2:12]1)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[Cl:37][C:38]1[CH:39]=[C:40]([CH:42]=[CH:43][C:44]=1[Cl:45])[NH2:41]>C1COCC1>[CH2:1]([N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:36])[CH2:18][CH2:19][C:20]2[CH:35]=[CH:34][C:23]([O:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([NH:41][C:40]4[CH:42]=[CH:43][C:44]([Cl:45])=[C:38]([Cl:37])[CH:39]=4)=[O:31])=[CH:27][N:26]=3)=[CH:22][CH:21]=2)[CH2:15][CH2:16]1)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(Oc2ccc(CCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1ccc(Oc2ccc(CCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}nicotinic acid (1.23 g, 2.5 mmol) in THF (35 mL) was added N,N′-carbonyldiimidazole (540 mg, 3.3 mmol), and the resulting solution was stirred for 30 minutes at room temperature. The resulting reaction solution was concentrated under reduced pressure, and to the residue was added 3,4-dichloroaniline (4.07 g, 25 mmol). The resulting solution was stirred for 3 days at room temperature. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and the resulting product was recrystallized from diethyl ether, to thereby yield 510 mg of the title compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH2:28])=[N:25][C:26]=3[F:27])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:38]=O)[C:33]([O:36][CH3:37])=[N:34][CH:35]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:28][CH2:38][C:32]4[C:33]([O:36][CH3:37])=[N:34][CH:35]=[C:30]([F:29])[CH:31]=4)=[N:25][C:26]=3[F:27])=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ncc(F)cc1C=O
Reactant: Nc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Br)cc23)c(F)n1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ncc(F)cc1CNc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Br)cc23)c(F)n1
Temperature: 80 °C
Yield: 82.5 %

Procedure:
To 5-(1-benzenesulfonyl-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-ylamine (167, 0.342 g, 0.741 mmol) in 10 mL of acetonitrile, 5-fluoro-2-methoxy-pyridine-3-carbaldehyde (37, 0.118 g, 0.763 mmol), triethylsilane (0.529 mL, 3.71 mmol) and trifluoroacetic acid (0.286 mL, 3.71 mmol) were added. The reaction was heated at 80° C. for 4 hours, then concentrated under vacuum and combined with aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as an off-white solid (168, 367 mg). MS (ESI) [M−H+]−=599.6 and 601.6.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[CH:31]1([NH:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]#[CH:42])=[CH:37][N:36]=2)[CH2:33][CH2:32]1>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:42]=[C:41]([C:38]4[CH:37]=[N:36][C:35]([NH:34][CH:31]5[CH2:33][CH2:32]5)=[CH:40][CH:39]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: C#Cc1ccc(NC2CC2)nc1
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4ccc(NC5CC5)nc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 26 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and cyclopropyl-(5-ethynyl-pyridin-2-yl)-amine in the same manner as Example 15. ESI MS m/z 590 [C30H35N7O4S+H]+.
Reaction SMILES: O1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3[CH:34]=[C:33]([C:35](=[O:48])[NH:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=4)[CH:32]=[CH:31][N:30]=3)[CH:8]=2)[CH2:3][CH2:2]1.C1[CH:53]2CCC[CH:52]2[CH2:51]N1>>[CH2:3]1[CH:2]2[CH2:51][CH2:52][CH2:53][CH:6]2[CH2:5][N:4]1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=2)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]2[CH:34]=[C:33]([C:35](=[O:48])[NH:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:46])[F:47])[CH:39]=3)[CH:32]=[CH:31][N:30]=2)[CH:8]=1
Reactant: C1CC2CNCC2C1
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CC4CCCC4C3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of 3-((3-((4-morpholino-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)-carbamoyl)benzyl)thio)propanoic acid 14, using octahydrocyclopenta[c]pyrrole in place of morpholine. 1H-NMR (300 MHz, DMSO-d6+D2O, ppm): δ 9.54 (s, 1H), 8.92 (d, J=3 Hz, 1H), 8.25 (s, 1H), 8.11 (d, J=9 Hz, 1H), 7.73 (m, 2H), 7.58 (m, 2H), 7.49 (m, 2H), 7.45 (m, 2H), 7.02 (s, 1H), 6.80 (d, J=9 Hz, 1H), 4.60 (s, 2H), 3.84 (s, 2H), 3.05 (d, J=6 Hz, 2H), 2.77 (m, 2H), 2.56 (m, 3H), 1.80 (m, 2H), 1.52 (m, 3H). MS (ES, m/z): 703 [M+H]+.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:4]=2[N:3]=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:25])[C:18]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:22]3[CH2:23][CH2:24][N:19]([C:18]4[C:17]([Cl:25])=[CH:16][N:15]=[CH:14][C:13]=4[Cl:12])[CH2:20][CH2:21]3)[NH:3][C:4]=2[CH:10]=1
Reactant: Clc1cncc(Cl)c1N1CCNCC1
Reactant: Clc1ccc2[nH]c(Cl)nc2c1
Product: Clc1ccc2nc(N3CCN(c4c(Cl)cncc4Cl)CC3)[nH]c2c1

Procedure:
The 2,5-dichloro-1H-benzoimidazole (0.37 g, 1.98 mmol, Example 20b) and 1-(3,5-dichloropyridin-4-yl)piperazine (0.46 g, 1.98 mmol, Maybridge) reacted under the conditions of Example 3c to give the title compound as a white solid. M.p. 258-260° C. MS (ESI, pos. ion) m/z: 382 (M+1).
Reaction SMILES: [NH2-].[Na+].[F:3][C:4]([F:20])([F:19])[C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH:6]=1.N.Cl[CH2:23][CH:24]1[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1>C1(C)C(C)=CC=CC=1.CN(P(N(C)C)(N(C)C)=O)C>[F:20][C:4]([F:3])([F:19])[C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:23][CH:24]3[CH:29]4[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]4)[CH2:25]3)[C:7]=2[CH:6]=1
Reactant: ClCC1CN2CCC1CC2
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1S2
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: FC(F)(F)c1ccc2c(c1)N(CC1CN3CCC1CC3)c1ccccc1S2
Reaction time: 18 h

Procedure:
0.9 ml of a 65% suspension of sodium amide in xylene and then 25 ml of hexamethylphosphotriamide were added to a suspension of 5.3 g of 2-trifluoromethyl-phenothiazine in 25 ml of xylene. The mixture was agitated and heated to reflux. When the evolution of ammonia ceased (2 hours), 16.3 ml of a 9.8% solution of 3-chloromethyl-quinuclidine in xylene were added to the reaction mixture over a period of 30 minutes and refluxing was continued for 18 hours. After cooling, the xylene was evaporated off under reduced pressure and the residual solution was poured into 250 ml of distilled water. The precipitate obtained was separated on Clarcel filter medium, washed with 50 ml of distilled water, and then suspended in 100 ml of ethyl acetate. The insoluble portion was filtered off and the filtrate was washed with 30 ml of distilled water, and then extracted three times with a total of 150 ml of N.aqueous acetic acid. The combined acid extracts were rendered alkaline on an ice bath with 25 ml of ION aqueous sodium carbonate and the oil which separated was extracted twice with a total of 200 ml of ethyl acetate. The combined organic extracts were dried over magnesium sulphate and evaporated. The residue was recrystallised in acetonitrile; 2-trifluoromethyl-10-(3-quinuclidinyl-methyl)-phenothiazine, m.p. 150° C, was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]=1[O:4]C(OC)=O.[OH-].[Na+]>O>[Br:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]=1[OH:4]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1cc(O)c(Br)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Then, 125 g (0.43 mol) of methyl 2-bromo-4-fluoro-5-nitrophenoxyformate was suspended in 200 ml of water, to which 19 g, 0.47 mol) of sodium hydroxide was added, and the mixture was stirred at 50° to 60° C. for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and washed with chloroform. The aqueous layer was acidified with aqueous hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated, which afforded 104 g (0.43 mol) of 2-bromo-4-fluoro-5-nitrophenol.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH2:12][C:13]#[CH:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:16][C:17]([NH2:19])=[S:18].O>C(O)C>[NH2:19][C:17]1[S:18][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][C:13]#[CH:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:16]=1
Reactant: C#CCON=C(C(=O)CCl)C(=O)OCC
Reactant: NC(N)=S
Solvent: O
Solvent: CCO
Product: C#CCON=C(C(=O)OCC)c1csc(N)n1
Yield: 53.5 %

Procedure:
Ethyl 4-chloro-3-oxo-2-propargyloxyiminobutyrate (syn isomer, 61 g.), thiourea (20 g.), sodium acetate 3-hydrate (35.8 g.), water (150 ml.) and ethanol (180 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetate (syn isomer, 35.6 g.).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19]([N:14]1[CH2:15][CH2:16][C:8]2[C:9](=[N:10][C:11]3[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=3[C:7]=2[CH3:17])[CH2:12][CH2:13]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: Cc1c2c(nc3c(Cl)cccc13)CCNCC2
Product: CCOC(=O)N1CCc2nc3c(Cl)cccc3c(C)c2CC1
Yield: 70 %

Procedure:
7-Chloro-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester was prepared from 7-chloro-1,2,4,5-tetrahydro-11methyl-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 63.