Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH2:18]([O:20][C:21](=[O:31])[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:23])[CH3:19].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.C(N(CC)CC)C>[CH2:18]([O:20][C:21](=[O:31])[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:23][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:16][CH:15]=1)[CH3:19]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 4-(4-hydroxyphenyl)benzoic acid (3.0 g) and L-phenylalanine ethyl ester hydrochloride (3.38 g) in DMF (30 ml) were added WSC.HCl (2.7 g), HOBT (1.89 g) and triethylamine (2 ml), and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a 10% aqueous citric acid solution, water, a saturated aqueous sodium hydrogen-carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]([NH2:19])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=2)[CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:20]1[N:24]=[CH:23][N:22]([C:25](N2C=NC=C2)=[S:26])[CH:21]=1>C(Cl)Cl>[N:19]([C:11]1[CH:10]=[C:9]([CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=1)[O:8][CH2:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[C:25]=[S:26].[NH:22]1[CH:21]=[CH:20][N:24]=[CH:23]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(OCCN2C=CCC2)cc(C(F)(F)F)c1
Solvent: ClCCl
Product: FC(F)(F)c1cc(N=C=S)cc(OCCN2CCCC2)c1
Product: c1c[nH]cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A flask was charged with 3-(2-pyrrolin-1-yl-ethoxy)-5-trifluoromethyl-phenylamine (Step C), (560.0 mg, 2 mmol) and CH2Cl2 (10 mL) and placed in an ice bath. To this solution, 1,1-thiocarbonyldiimidazole (463 mg, 2.6 mmol) was added and the reaction was warmed to RT. After 4 h, the solvent was concentrated in vacuo and the residual yellow solid was titrated with acetone to yield the title compound as a 1/1 mixture with imidazole. This mixture was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[F:13][C:14]1[CH:19]=[CH:18][C:17]([Mg]Br)=[CH:16][CH:15]=1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=1)[OH:12]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Br)cc2C1(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 5-bromoindoline-2,3-dione (120 g, 530 mmol, 1.0 eq) in THF (1 L) was added dropwise (4-fluorophenyl)magnesium bromide in THF (0.8 M, 1.6 L, 1280 mmol, 2.4 eq) at 0° C.˜15° C., the mixture was stirred for overnight at room temperature. Then mixture was cooled to 0° C., quenched with H2O (20 mL), concentrated to give crude product, which was dissolved in EtOAc (2 L), washed with 1N HCl.aq (2 L), brine (1 L×2), dried over Na2SO4, the organic phase was concentrated to give crude product. Then the crude product was stirred in PE, filtered to obtained yellow solid, and dried in air to give 136 g (yield 80%) product, which was used to the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δH 10.58 (s, 1H), 7.44-7.46 (dd, 1H, J1=8.4 Hz, 2.0 Hz), 7.28-7.32 (m, 2H), 7.22-7.25 (m, 1H), 7.14-7.18 (t, 2H, J=8.8 Hz), 6.87-6.89 (d, 1H, J=8.4 Hz), 6.84 (s, 1H). MS (ESI) [M+1-18]+ 304, 306.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[F:13])=[O:4].[O:14]1[CH:18]=[CH:17][N:16]=[C:15]1[NH2:19].C1COCC1>C(#N)C>[BrH:1].[NH:19]=[C:15]1[N:16]([CH2:2][C:3]([C:5]2[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=2[F:13])=[O:4])[CH:17]=[CH:18][O:14]1
Reactant: Nc1ncco1
Reactant: O=C(CBr)c1cc(F)c(F)cc1F
Solvent: C1CCOC1
Solvent: CC#N
Product: Br
Product: N=c1occn1CC(=O)c1cc(F)c(F)cc1F
Temperature: 23 °C
Reaction time: 20 h
Yield: 78.9 %

Procedure:
A round bottom flask was charged with 2-bromo-1-(2,4,5-trifluorophenyl)ethanone (50.0 g, 198 mmol; Example #N.1), oxazole-2-amine (11.1 g, 132 mmol; GL Synthesis), THF (200 mL), and ACN (330 mL). The resulting mixture was stirred at about 23° C. for about 20 h. The suspension was cooled to about −10° C. for about 15 min and the solid was collected by vacuum filtration, washed with additional ACN (150 mL), and dried under vacuum to give 2-(2-iminooxazol-3(2H)-yl)-1-(2,4,5-trifluorophenyl)ethanone hydrobromide (35.1 g, 79%) as a white solid. A portion of this material (20.0 g, 59.3 mmol) was suspended in toluene (140 mL) and the suspension was cooled to about 0° C. To the flask was added a 1.0 M solution of TiCl4 in toluene (154 mL) over about 30 min. The mixture was stirred at about 0° C. for about 30 min and was then heated to about 100° C. for about 3 h. The mixture was cooled to ambient temperature, the toluene was decanted off, and ice was added with stirring to the remaining residue. The mixture was adjusted to about pH 8 with the addition of solid Na2CO3, followed by the addition of EtOAc. The mixture was stirred for about 1 h and then passed through a pad of Celite®. The layers were separated and the organic solution was dried over MgSO4, filtered, and concentrated to dryness under reduced pressure to give the title compound as a white solid (11.7 g, 83%): LC/MS (Table 1, Method d) Rt=2.11 min; MS m/z 239.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[OH:41][C:42]1[C:51]([C:52](O)=[O:53])=[C:50]([CH3:55])[C:49]2[C:44](=[CH:45][C:46]([C:56]([F:59])([F:58])[F:57])=[CH:47][CH:48]=2)[N:43]=1>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:52]([C:51]1[C:42]([OH:41])=[N:43][C:44]2[C:49]([C:50]=1[CH3:55])=[CH:48][CH:47]=[C:46]([C:56]([F:58])([F:59])[F:57])[CH:45]=2)=[O:53]
Reactant: NCc1cccc(F)c1
Reactant: Cc1c(C(=O)O)c(O)nc2cc(C(F)(F)F)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)NCc2cccc(F)c2)c(O)nc2cc(C(F)(F)F)ccc12
Temperature: 50 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
508 mg (4.1 mmol) 3-fluorobenzylamine, 1.4 g (3.7 mmol) HATU and 1.5 ml (10.7 mmol) NEt3 were added consecutively to a solution of 1.0 g (3.7 mmol) 2-hydroxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid (synthesis see Example 4 Section a)) in THF (28 ml) and the solution was then stirred for 16 h at 50° C. The solution was subsequently diluted with EtOAc (30 ml). The resultant precipitate was filtered off and suspended in a EtOAc/MeOH/DCM mixture. Concentration in a vacuum was subsequently carried out. 1.0 g (2.6 mmol, 71%) N-(3-fluorobenzyl)-2-hydroxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid amide was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C:16](=[O:25])[C:17]([Br:24])=[CH:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2].[CH3:26][Al](C)C.O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C:16](=[O:25])[C@H:17]([Br:24])[C@@H:18]1[CH3:26])[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: C[Al](C)C
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)C(Br)=C[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)[C@H](Br)[C@H](C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
14.3 mg (0.1 mmol) of CuBr is added at room temperature to 818 mg (2 mmol) of 17β-acetoxy-2-bromo-5α-androst-1-en-3-one (produced according to J. Org. Chem. 1982, 47, 5090; from 17β-acetoxy-2-brom-5α-androst-1-en-3-one) in 4 ml of ethyl acetate. 1.9 ml (2.2 mmol) of a 10% solution of trimethyl aluminum in toluene is instilled at room temperature. It is stirred at room temperature for 45 minutes. For hydrolysis, 0.18 ml of water is added, the solid is suctioned off and washed again with ethyl acetate. The solution is concentrated by evaporation and the residue is chromatographed on silica gel with hexane/ethyl acetate as eluent. After concentration by evaporation of the chromatography fractions, 600 mg of 17β-acetoxy-2α-bromo-1α-methyl-5α-androstan-3-one is obtained.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH3:18])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=O.[CH:19]([N:22]=[C:23]=[O:24])([CH3:21])[CH3:20].C(N(CC)CC)C.FC(F)(F)C(O)=O>CC(C)=O>[CH:12]1([C:9]2[CH:10]=[CH:11][C:6]([C:4]3[N:22]([CH:19]([CH3:21])[CH3:20])[C:23](=[O:24])[NH:2][C:3]=3[CH3:18])=[CH:7][CH:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(C)N=C=O
Reactant: CC(N)C(=O)c1ccc(C2CCCCC2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(=O)n(C(C)C)c1-c1ccc(C2CCCCC2)cc1
Reaction time: 1 h

Procedure:
2-Amino-4'-cyclohexylpropiophenone hydrochloride (477 mg, 1.78 mmol) was suspended in acetone (30 ml) under ice-cooling, and isopropyl isocyanate (198 mg, 2.33 mmol) was added thereto. Triethylamine (533 mg, 5.28 mmol) was added, and the mixture was stirred for one hour under ice-cooling. After addition of trifluoroacetic acid (2 ml), the mixture was stirred for 2 days at room temperature. The solvent was removed by evaporation in vacuo, and the residue was extracted with dichloromethane. The extract was washed successively with water and saturated aqueous sodium chloride, and dried over magnesium sulfate. Evaporation of the solvent provided a crude product, which was purified by column chromatography (chloroform/ ethanol=50/1 (v/v)) and recrystalization (ethanol-chloroform) to give the title compound. Yield: 351 mg (66%), m.p. 274° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1>CC(C)=O>[C:11]1([CH3:21])[CH:12]=[CH:13][C:14]([S:17]([O-:20])(=[O:18])=[O:19])=[CH:15][CH:16]=1.[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH3+:8])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: [NH3+]c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.38 g (0.01 mole) p-nitroaniline in 10 mL of acetone was added a solution of p-toluenesulfonic acid (2.375 g, 0.0125 mole) in 10 mL of acetone at room temperature. After stirring for 1 hour at room temperature, the reaction mixture was cooled to 5° C. and the product was isolated by filtration. The yield was 2.49 g (80% of theory) of a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([Cl:28])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:27]=[C:26]([Cl:28])[S:25][C:15]=3[N:16]=2)[CH:20]=1
Reactant: Clc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3cccnc3)nc3sc(Cl)cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3-nitrobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:22](O)(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[C:22]([O:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCC(O)CC(=O)OC(C)(C)C
Product: CCCCCCCCCCCC(=O)OC(CCCCCCCCCCC)CC(=O)OC(C)(C)C
Yield: 89.2 %

Procedure:
tert-Butyl 3-hydroxytetradecanoate (314 mg) was acylated by the acid chloride derived from dodecanoic acid (1 g) according to similar manner to that of Preparation 1-(2) to afford tert-butyl 3-dodecanoyloxytetradecanoate (450 mg).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][CH:30]1[CH2:32][CH2:31]1>>[CH:30]1([CH2:29][N:22]2[CH2:21][C@@H:20]([CH3:25])[N:16]3[C:17]4[CH:18]=[CH:19][C:11]([O:10][CH:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)=[CH:12][C:13]=4[CH:14]=[C:15]3[C:23]2=[O:24])[CH2:32][CH2:31]1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(CC3CC3)C2=O)CC1
Yield: 47 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and 1-(bromomethyl)cyclopropane, to give the desired product as a light yellow oil (47%).
Reaction SMILES: [NH2:1][C@@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:3]1=[O:24].[C:25]([C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH2:34][C:33]1([C:41](=[O:42])[NH:40][C:39](=[O:43])[NH:38]1)[CH2:32][CH2:31]2)(O)=[O:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:43]=[C:39]1[NH:38][C:33]2([CH2:32][CH2:31][C:30]3[C:35](=[CH:36][CH:37]=[C:28]([C:25]([NH:1][C@@H:2]4[N:8]=[C:7]([C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=5)[C:6]5[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=5[N:4]([CH2:19][C:20]([F:21])([F:23])[F:22])[C:3]4=[O:24])=[O:26])[CH:29]=3)[CH2:34]2)[C:41](=[O:42])[NH:40]1
Reactant: O=C1NC(=O)C2(CCc3cc(C(=O)O)ccc3C2)N1
Reactant: N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C1NC(=O)C2(CCc3cc(C(=O)N[C@@H]4N=C(c5ccccc5)c5ccccc5N(CC(F)(F)F)C4=O)ccc3C2)N1

Procedure:
A mixture of (3R)-3-amino-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepine (Shi et al. Tetrahedron 1999, 55, 909) (507 mg, 1.52 mmol), (±)-6′-carboxy-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione (described in Intermediate 1) (396 mg, 1.52 mmol), EDC (438 mg, 2.28 mmol), HOBT (308 mg, 2.01 mmol), and N,N-diisopropylethylamine (0.795 mL, 4.56 mmol) was stirred in DMF (5 mL) at ambient temperature for 18 h. The crude mixture was partitioned between saturated aqueous NaHCO3 (25 mL) and CH2Cl2 (25 mL), and the aqueous phase was extracted further with CH2Cl2 (2×25 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 95:5 to provide the title compound as an off-white solid. MS: m/z=576 (M+1). HRMS: m/z=576.1840; calculated m/z=576.1853 for C30H24F3N5 O4.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[C:5]([NH2:8])=[N:6][N:7]=1.C(N(CC)CC)C.S(O[CH2:37][CH2:38][O:39][CH2:40][CH2:41]OS(C1C=CC(C)=CC=1)(=O)=O)(C1C=CC(C)=CC=1)(=O)=O.C(OCC)(=O)C>CN(C=O)C>[F:18][C:13]1[CH:12]=[C:11]([NH:10][N:9]=[C:4]2[C:3]([CH2:2][N:1]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[N:7][N:6]=[C:5]2[NH2:8])[CH:16]=[CH:15][C:14]=1[F:17]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: NCC1=NN=C(N)C1=NNc1ccc(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC1=NN=C(CN2CCOCC2)C1=NNc1ccc(F)c(F)c1
Temperature: 87 °C
Yield: 14.3 %

Procedure:
The mixture of 5-aminomethyl-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (125 mg, 0.5 mmole) and triethylamine (152 mg, 1.5 mmole) in 5 mL of dry DMF was heated to 87° C. To this solution was added slowly di(2-tosyloxyethyl)ether (311 mg, 0.75 mmole) in 1 mL of DMF. The reaction mixture was heated at 87° C. for 1.5 hours, and then worked up by the addition of saline and ethyl acetate. The crude material was purified by preparative TLC (CH2Cl2:CH3OH=16:1) to yield 23 mg of the title compound as a yellow powder. MS (m/z, ES+): 323 (M+1, 100%); 1H NMR (ppm, 300 MHz, CDCl3) δ 7.52 (m, 2H), 7.24 (m, 1H), 6.25 (br s, 2H), 3.95 (s, 2H), 3.74 (m, 4H), 2.64 (m, 4H).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21](OC)=[O:22])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:27][OH:28].[OH-].[Na+].C1COCC1>CO>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([NH:27][OH:28])=[O:22])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: COC(=O)c1ccc(CN2c3ccccc3C=Cc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NO)c1ccc(CN2c3ccccc3C=Cc3ccccc32)cc1
Yield: 26 %

Procedure:
Title compound 350 (147 mg, 0.43 mmol), hydroxylamine (50% in water, 6 mL) and sodium hydroxide (138 mg, 3.40 mmol) were stirred in methanol (3 mL) and THF (3 mL) at room temperature overnight. The organic solvent was evaporated and the precipitate was filtered off and washed with a little bit of cold methanol to afford title compound 351 (39 mg, 26%) as a yellow solid. 1H NMR (DMSO-d6) δ (ppm): 11.06 (s, 1H), 8.96 (s, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.21 (td, J=1.6 and 7.2 Hz, 2H), 7.18-7.13 (m, 2H), 7.10 (dd, J=1.6 and 7.6 Hz, 2H), 6.6 (td, J=1.2 and 7.2 Hz, 2H), 6.85 (s, 2H), 5.00 (s, 2H). LRMS: 342.1 (calc). 343.2 (found).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6]N=[C:4]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)[N:3]=1.[Br:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([CH:32]=1)[CH:30]=O.S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[CH2:43](O)C>O>[Br:24][C:25]1[CH:32]=[C:29]([C:30]2[NH:1][C:2]3=[N:3][C:4]([N:11]4[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]5[CH2:20][CH2:21][CH2:22][CH2:23]5)=[O:18])[CH2:12]4)=[CH:43][CH:6]=[C:7]3[N:8]=2)[CH:28]=[N:27][CH:26]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: CCO
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ncc1[N+](=O)[O-]
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4cncc(Br)c4)[nH]c3n2)C1)N1CCCC1
Temperature: 120 °C
Yield: 60 %

Procedure:
To a solution of (R)-(1-(4-amino-5-nitropyrimidin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (0.5 g, 1.5 mmol) in a mixture of ethanol and water were added 5-bromonicotinaldehyde (0.35 g, 1.6 mmol) and sodium dithionate (1.1 g, 5.9 mmol). The reaction mixture was heated to 120° C. for 16 h. The reaction mixture was concentrated and partitioned between water and ethyl acetate. The organics were concentrated under reduced pressure and the resulting crude was purified via preparative TLC to afford (R)-(1-(2-(5-bromopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (400 mg, 60%).
Reaction SMILES: O[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.P(Cl)(Cl)([Cl:13])=O>>[ClH:13].[Cl:13][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Oc1nc2ccccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cl
Product: Clc1nc2ccccc2[nH]1

Procedure:
A mixture of 2-hydroxybenzimidazole (200 g) and phosphorus oxychloride (1100 ml) was heated at reflux temperature for 1 hr and HCl gas was bubbled into the mixture for 3.5 hr. The excess phosphorus oxychloride was removed on a rotary evaporator. The residual oil was poured into ice water (2 L) and a solid impurity was removed by filtration. The filtrate was basified to pH 8 with concentrated ammonium hydroxide. The solid product was collected and dried at 60° C. in vacuo for 18 hrs. The product was recrystallized from acetone to obtain 70 g of the title compound.
Reaction SMILES: N1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:14])C2C=CN=CC=2)[CH2:2]1.NC1C=C[C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18]C=1>>[N:6]([C:3]1[CH:2]=[CH:18][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:5][CH:4]=1)=[C:7]=[O:14]
Reactant: O=C(N[C@@H]1CCNC1)c1ccncc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(N=C=O)cc1

Procedure:
This compound is prepared analogously to Intermediate R by replacing 3-aminobenzenesulphonamide with 4-aminobenzenesulphonamide.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[C:14]3[C@@H:15]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][C@@H:16]4[NH:17][C:18]=3[CH:19]=[CH:20][CH:21]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:27]1(O)CCCC1>>[CH:1]1([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[C:14]3[C:15]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][C:16]=4[NH:17][C:18]=3[CH:19]=[CH:20][CH:21]=2)[CH2:27][CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OC1CCCC1
Reactant: c1ccc(-c2cccc3c2[C@@H]2CCNCC[C@@H]2N3)c(OC2CCCC2)c1
Product: c1ccc(-c2cccc3[nH]c4c(c23)CCNCC4)c(OC2CCCCC2)c1

Procedure:
Following the procedure for the preparation of (5aS*,10bS*)-10-[2-(cyclopentyloxy)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole and substituting cyclohexanol for cyclopentanol while making non-critical variations the title compound was obtained as 278 mg (32%) of a white foam: 1H NMR (400 MHz, CDCl3) δ 7.84 (br s, 1 H), 7.35-7.26 (m, 3 H), 7.15-7.11 (m, 1 H), 7.04-7.01 (m, 2 H), 6.95 (d, J=7.2 Hz, 1 H), 4.08-4.06 (m, 1 H), 3.09-3.07 (m, 2 H), 2.97-2.96 (m, 2 H), 2.85-2.83 (m, 2 H), 2.47-2.37 (m, 2 H), 1.90 (m, 2 H) 1.71 (m, 2 H), 1.51 (m, 2 H), 1.41 (m, 2 H), 1.15 (m, 3 H); HRMS (FAB) calcd for C24H28N2O+H1: 361.2280 found 361.2270.
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16](N)=O.O>O1CCCC1.ClCCl>[C:2]1([C:1]2[N:8]=[C:16]([C:15]3[CH:14]=[CH:22][N:21]=[CH:20][CH:19]=3)[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cnccc1C(N)=O
Reactant: NC(=NO)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: c1ccc(-c2noc(-c3ccncc3)n2)cc1
Temperature: 50 °C
Yield: 25.2 %

Procedure:
To a mixture of benzamide oxime (12.8 g, 94 mmol) and 4 Å sieves (80 g) in tetrahydrofuran (250 ml) under a nitrogen atmosphere was carefully added sodium hydride (55% dispersed in oil, 4.3 g, 98 mmol) portionwise. When addition was complete the reaction was heated at 50° C. for 1 hour. Methyl isonicotinamide (5.6 ml, 47 mmol) in tetrahydrofuran (50 ml) was added, and the reaction stirred at reflux for 2 hours. The reaction was cooled to room temperature and water (200 ml) and dichloromethane (300 ml) added. The mixture was filtered through a pad of Celite and the two phases separated. The aqueous phase was extracted with a further portion of dichloromethane (250 ml). The combined organic phases were washed with saturated brine (200 ml), dried (MgSO4) and evaporated in vacuo. The residue was triturated with ethyl acetate to yield the title compound as a white solid (2.64 g, 25%). δH (CDCl3) 7.50-7.56 (3H, m, ArH), 8.05-8.07 (2H, m, ArH), 8.16-8.19 (2H, m, ArH), 8.89 (2H, dd, J 4.4, 1.6 Hz, pyridyl 2-H, 6-H).