Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:25][O:26][CH3:27])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[CH:31][CH:30]=1>>[CH:1]1([CH:7]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[CH:33][CH:34]=2)[C:9]2[C:10]([CH2:25][O:26][CH3:27])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: COCc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 38.4 %

Procedure:
Using cyclohexyl{3-(methoxymethyl)-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}methanol (0.75 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.55 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.43 g, 39%) was obtained as a colorless solid.
Reaction SMILES: CN(C)C=O.[O:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[C:17]([NH2:25])=[N:16]2)[CH2:8][CH2:7]1.Br.Br[CH2:28][CH2:29][CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[O:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[C:17]([NH:25][CH2:28][CH2:29][CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[N:16]2)[CH2:8][CH2:7]1
Reactant: Nc1nn(CCCN2CCOCC2)c2ccc(Cl)cc12
Reactant: CCN(CC)CCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)CCCNc1nn(CCCN2CCOCC2)c2ccc(Cl)cc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 59.1 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 9.63 g of the 1-(3-morpholinopropyl)-3-amino-5-chloroindazole, 8.98 g of 3-bromopropyldiethylamine hydrobromide and 7.89 g of anhydrous potassium carbonate, and the mixture was stirred for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. The pH of the layer was adjusted to at least 11 with potassium carbonate, and the alkali layer was extracted three times with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography (alumina: 200 g) using chloroform as the developing solvent to give 7.87 g of 1-(3-morpholinopropyl)-3-(3-diethylaminopropylamino)-5-chloroindazole having the following analytical values in a yield of 59%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[I:12](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>C(O)(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([I:12])[CH:5]=1
Reactant: O=I(=O)Cl
Reactant: COC(=O)c1ccc(N)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(N)c(I)c1
Temperature: 55 °C

Procedure:
To a solution of 4-amino-benzoic acid methyl ester (1 g) in 10 mL of acetic acid and 10 mL of CH2Cl2 was added benzyltrimethylammonium dichloroiodate (2.763 g) at ambient temperature. The reaction mixture was heated at 55° C. for 1.5 h. The reaction mixture was concentrated to give the crude 4-amino-3-iodo-benzoic acid methyl ester: MS (m/z) 278.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:16]2[N:17]([CH3:32])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20](Cl)[N:19]=3)([O:14][CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:33]([C:36]1[NH:37][C:38]2[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=1)([CH3:35])[CH3:34].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:16]2[N:17]([CH3:32])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20]([N:37]2[C:38]4[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=4[N:40]=[C:36]2[CH:33]([CH3:35])[CH3:34])[N:19]=3)([O:14][CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2ccccc2[nH]1
Reactant: COC1(c2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CCCN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC1(c2nc3c(N4CCOCC4)nc(-n4c(C(C)C)nc5ccccc54)nc3n2C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 110 °C
Yield: 65.1 %

Procedure:
A mixture of 3-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester (3.0 g, 6.42 mmol), 2-isopropylbenzimidazole (1.24 g, 7.71 mmol), tris(dibenzylideneacetone)dipalladium (150 mg, 0.16 mmol), XPhos (306 mg, 0.64 mmol) and Cs2CO3 (3.14 g, 9.64 mmol) in dioxane (50 mL) was purged with argon then heated at 110° C. for 16 h. The reaction mixture was partitioned between EtOAc and H2O, the organic phase washed with brine then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 30-70%) affording 3-[2-(2-Isopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-methoxypiperidine-1-carboxylic acid tert-butyl ester (2.47 g, 65%). LCMS (method A): RT 3.52 min, [M+H]+ 591.5
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:6]=2[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:27]([NH:34][C@H:35]([CH2:40][OH:41])[CH2:36][CH:37]([CH3:39])[CH3:38])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:17]1([CH2:16][N:7]2[C:6]3[CH:20]=[C:2]([O:41][CH2:40][C@@H:35]([NH:34][C:27](=[O:28])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:36][CH:37]([CH3:39])[CH3:38])[CH:3]=[CH:4][C:5]=3[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8]2=[O:15])[CH2:19][CH2:18]1
Reactant: O=c1c2cnccc2c2ccc(Cl)cc2n1CC1CC1
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(CC3CC3)c2c1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution 8-chloro-6-(cyclopropylmethyl)benzo[c][2,7]naphthyridin-5(6H)-one (100 mg, 0.351 mmol) in anhydrous toluene (5 mL) at room temperature was added cesium carbonate (172 mg, 0.527 mmol) and Boc-L-leucinol (229 mg, 1.054 mmol) and the mixture was degassed with nitrogen for 5 min. The mixture was then treated with di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (48.5 mg, 0.211 mmol) followed by palladium(II)acetate (23.65 mg, 0.105 mmol) and degassed for another 10 min. The reaction mixture was sealed and heated at 80° C. After overnight stirring the reaction mixture was cooled to room temperature and filtered through diatomaceous earth (Celite®). The bed was washed with ethyl acetate (15 mL) and the filtrate was concentrated under reduced pressure to afford crude compound which was purified by preparative HPLC (ethyl acetate in petroleum ether) to afford (S)-tert-butyl (1-((6-(cyclopropylmethyl)-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (80 mg, 0.172 mmol, 49% yield) as a brown gummy solid. LC/MS (ESI) m/e 466.3 [(M+H)+, calcd C27H36N3O4466.3]; LC/MS retention time (method A): tR=2.199 min.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=3[C:23]([O:25][CH3:26])=[O:24])[C:12]2=[O:31])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[CH2:32]=[O:33].C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[OH:1][C:2]1[C:3]([C:11]2([CH2:32][OH:33])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=3[C:23]([O:25][CH3:26])=[O:24])[C:12]2=[O:31])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: C=O
Reactant: COC(=O)c1ccccc1CN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1CN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A solution of methyl 2-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate (17.1 g, 40.0 mmol) and paraformaldehyde (10.3 g, 330 mmol) in THF (500 mL) was degassed by bubbling through argon for 2 hours. To this solution was added lithium diisopropylamide solution (45.1 mL, 2 M solution, 90.0 mmol) slowly at −78° C. The mixture was stirred at ambient temperature overnight and quenched with saturated ammonium chloride solution. The mixture was concentrated in vacuo to remove THF followed by the addition of ethyl acetate (500 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was recrystallized from ethyl acetate/hexanes to give the title compound (13.7 g, 75%): 1H NMR (300 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.95 (dd, 1H), 7.53-7.33 (m, 3H), 7.08-6.82 (m, 4H), 6.53 (d, 1H), 6.25 (s, 1H), 5.93-5.86 (m, 2H), 5.31-5.07 (m, 3H), 4.26-4.17 (m, 1H), 4.00-3.92 (m, 1H), 3.88 (s, 3H); MS (ES+) m/z 448.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[NH:16][C:15]([CH:17]3[CH2:20][O:19][CH2:18]3)=[N:14][C:13]=2[CH3:21])=[CH:7][C:3]=1[C:4]([OH:6])=O.CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.Cl.[F:40][C:41]1([C:45]2[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=2)[CH2:44][NH:43][CH2:42]1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[NH:16][C:15]([CH:17]3[CH2:20][O:19][CH2:18]3)=[N:14][C:13]=2[CH3:21])=[CH:7][C:3]=1[C:4]([N:43]1[CH2:42][C:41]([C:45]2[CH:46]=[CH:47][C:48]([C:49]#[N:50])=[CH:51][CH:52]=2)([F:40])[CH2:44]1)=[O:6]
Reactant: Cc1cc(C)c(-c2[nH]c(C3COC3)nc2C)cc1C(=O)O
Reactant: N#Cc1ccc(C2(F)CNC2)cc1
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: Cc1cc(C)c(-c2[nH]c(C3COC3)nc2C)cc1C(=O)N1CC(F)(c2ccc(C#N)cc2)C1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5, except 2,4-dimethyl-5-(4-methyl-2-(oxetan-3-yl)-1H-imidazol-5-yl)benzoic acid (compound 180.4) was used in place of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 445 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 11.80 (br, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.0 Hz, 2H), 7.24 (s, 1H), 7.18 (d, J=7.2 Hz, 2H), 4.87-4.75 (m, 4H), 4.60-4.36 (m, 4H), 4.31-4.21 (m, 1H), 2.35 (s, CH3, 3H), 2.90 and 2.20 (2 singlets, CH3, 3H), 2.13 and 2.02 (2 singlets, CH3, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]#[N:22])[C:11]=3[N:10]=[C:9]2[C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[N:36][CH:35]=[CH:34][N:33]=3)=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.Cl.C(=O)([O-])[O-].[NH4+:43].[NH4+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]([NH2:43])=[NH:22])[C:11]=3[N:10]=[C:9]2[C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[N:36][CH:35]=[CH:34][N:33]=3)=[CH:28][CH:27]=2)=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: N#Cc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5cnccn5)cc4)nc32)c1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: N=C(N)c1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5cnccn5)cc4)nc32)c1

Procedure:
At 0° C., 3-[5-(4-chloro-phenyl)-4-oxo-6-(4-pyrazin-2-yl-phenyl)-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzonitrile (prepared as described in example 47, 0.65 g, 1.29 mmol) is added to methanol saturated with hydrogen chloride gas (20 mL) with stirring. The reaction mixture is allowed to reach rt and stirred there for 40 h. The reaction mixture is then concentrated to a dry residue (0.7 g). It is taken in dry methanol (40 mL) and ammonium carbonate (1.15 g, 7.36 mmol) is added. After stirring at rt for 40 h, the reaction mixture is concentrated and the residue obtained is purified by column chromatography to afford 3-[5-(4-chloro-phenyl)-4-oxo-6-(4-pyrazin-2-yl-phenyl)-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzamidine. 1H NMR (DMSO-d6, 400 MHz) δ 9.25 (s, 1H), 8.71 (s, 1H), 8.63 (m, 1H), 8.55 (m, 2H), 8.29 (dd, 1H), 8.16 (s, 1H), 8.07 (m, 1H), 7.90 (m, 1H), 7.67 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.44 (m, 4H); LC-MS calculated for C28H19ClN8O (M+H+) 519.1, found 519.9.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:13]([F:17])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[F:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)[CH2:9][NH:8][CH2:16]2
Reactant: CC(C)(C)OC(=O)N1Cc2cc(F)c(N3CCOCC3)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc2c(cc1N1CCOCC1)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 5-fluoro-6-morpholin-4-yl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. MS (m/e): 223.4 (M+H]+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13]C)[CH:8]=1)=[O:5]>Br.C(O)(=O)C.O>[F:1][C:2]1[CH:18]=[C:17]([C:19]([F:25])([F:24])[C:20]([F:21])([F:23])[F:22])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5]
Reactant: COc1cc(NC(=O)c2ccc(C(F)(F)C(F)(F)F)cc2F)ccn1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)C(F)(F)F)cc1F
Temperature: 100 °C
Reaction time: 4 h
Yield: 71.6 %

Procedure:
2-fluoro-N-(2-methoxy-4-pyridyl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide (200 mg, 0.55 mmol) in HBr in acetic acid (1.3 mL of 33% w/v, 5.49 mmol) was stirred at 100° C. for 2 hours, at this time 1 ml of HBr in acetic acid (33% w/v) was added and the mixture was stirred at 100° C. for 4 hours, then cooled to room temperature. The reaction mixture was diluted with water and a precipitate formed. The precipitate was filtered off, washed with water (2×), cold methyl-tert-butyl ether and dried under vacuum to give 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide (138 mg, 72%) as a light grey solid. ESI-MS m/z calc. 350.05. found 351.3 (M+1)+; Retention time: 1.3 minutes (3 minutes run).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][O:4][C:5]([N:7]1[CH2:13][C@H:12]([NH:14]C(OC(C)(C)C)=O)[C:11](=[O:22])[N:10](CC(F)(F)F)[C:9]2[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:8]1=2)=[O:6].[ClH:36]>O1CCOCC1>[ClH:36].[F:34][C:2]([F:1])([F:35])[CH2:3][O:4][C:5]([N:7]1[CH2:13][C@H:12]([NH2:14])[C:11](=[O:22])[NH:10][C:9]2[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:8]1=2)=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCC(F)(F)F)c2cc(F)c(F)cc2N(CC(F)(F)F)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CN(C(=O)OCC(F)(F)F)c2cc(F)c(F)cc2NC1=O
Temperature: 50 °C

Procedure:
A solution of 120 mg of (S)-3-tert-butoxycarbonylamino-7,8-difluoro-4-oxo-5-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-benzo[b][1,4]diazepine-1-carboxylic acid 2,2,2-trifluoro-ethyl ester in 4 ml of dioxane was treated with 0.27 ml of hydrochlorid acid (37%). The reaction mixture was warmed to 50° C. for 3 hours. For the working-up, the mixture was evaporated under reduced pressure. The oily residue was evaporated three times with 25 ml of toluene to yield thereby quantitatively the title compound as a light yellow solid which was engaged in the next step without further purification; MS (m/e): 340 (M+H)+.
Reaction SMILES: [CH2:1]1[C@H:9]([OH:10])[C@H:8]2[N:3]([CH2:4][C@H:5]([OH:13])[C@@H:6]([OH:12])[C@@H:7]2[OH:11])[CH2:2]1.[C:14](Cl)(=[O:18])[CH2:15][CH2:16][CH3:17].O.C(Cl)Cl>N1C=CC=CC=1.C(Cl)(Cl)Cl.CO>[C:14]([O:13][CH:5]1[CH:6]([OH:12])[CH:7]([OH:11])[CH:8]2[N:3]([CH2:2][CH2:1][CH:9]2[OH:10])[CH2:4]1)(=[O:18])[CH2:15][CH2:16][CH3:17]
Reactant: O[C@H]1[C@H](O)[C@@H](O)CN2CC[C@H](O)[C@H]12
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCC(=O)OC1CN2CCC(O)C2C(O)C1O
Temperature: 0 °C
Reaction time: 72 h

Procedure:
To a stirred suspension of 1.5 g of castanospermine in 15 ml of pyridine cooled at 0° C. in an ice-bath was added dropwise 1.0 g of butyryl chloride. The mixture was stirred at room temperature for 3 days and added to a 1:1 mixture of water:methylene chloride (400 ml). After partitioning, the aqueous phase was concentrated in vacuo to provide an oily residue which was fractionated by radial thin layer chromatography (silica gel, 2 mm thickness plate, 2:8 methanol:chloroform) to provide 68 mg of [1S(1α, 6β, 7α, 8β, 8αβ)]-octahydro-1,6,7,8-indolizinetetrol 6-butanoate, homogeneous by thin layer chromatography (silica gel, 2:8 methanol:chloroform, Rf=0.5). Recrystallization of the product from 5:95 isopropanol:hexane gave a colorless solid melting at 113°-114° C. NMR (CDCl3) δ 3.5-3.8 (2t, 2H, C7 -H and C8 -H), 4.4 (m, 1H, C1 -H), 4.95 (m, 1H, C6 -H). MS (CI-CH4) 260 (MH+), 242 (MH+ -H2O), 172 (MH+ -C3H7CO2H).
Reaction SMILES: BrC1C=CC=CC=1C(Cl)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([F:33])[CH:27]=1.[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42]>C1(C)C=CC=CC=1.C(O)C>[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42].[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([NH:43][C:44]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([O:25][C:16]2[C:15]3[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=3)[N:19]=[CH:18][CH:17]=2)=[CH:27][C:28]=1[F:33])=[S:45])=[O:42]
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1ccccc1Br
Agent: O=C(N=C=S)c1ccccc1Br
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Br)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
2-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (73 mg, yield 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][NH:8][C:7](=O)[C:6]=2[CH:14]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[CH:14]=1
Reactant: O=C1CNC(=O)c2cc(Cl)ccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)CNCCN2
Temperature: 63 °C
Reaction time: 19 h

Procedure:
7-chloro-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (15.05 g, 71.4 mmol) was stirred in THF (120 mL). Lithium aluminum hydride (1M solution in THF, 214.5 mL, 214.4 mmol) was added gradually. When the addition was completed, the reaction mixture was heated to 63° C. and held for 19 hours. After 19 hours, the reaction was cooled to room temperature, and then to 0° C. The reaction mixture was quenched with water, 15% NaOH and another portion of water. After letting the reaction mixture stir for one hour, the precipitate was filtered off and washed with ethyl acetate. THF was removed, and the contents of the reaction flask were transferred to a separatory funnel with ethyl acetate and water. The contents in the separatory funnel were then extracted with ethyl acetate (3×). The combined organic extracts were washed with brine (2×), then dried with magnesium sulfate, filtered and concentrated to give the crude desired product. Further purification by recrystallization (methylene chloride) yielded orange crystals.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]([NH:19][CH:20](NC=O)NC=O)=O.CN(C)C=O>O>[C:1]1([C:7]2[C:8](=[O:16])[C:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:20][NH:19][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Reactant: O=CNC(NC=O)NC=O
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(-c2ccccc2)c[nH]cc1-c1ccccc1

Procedure:
A 1.4 g. portion of 1,3-diphenyl-2-propanone was mixed with 1.0 g. of tris(formylamino)methane in 20 ml. of dimethylformamide. The reaction mixture was stirred at reflux temperature for 3 hours. The mixture was then cooled to approximately room temperature, and poured into water. The precipitated solids were separated by filtration, and the solids were suspended in chloroform. The chloroform was then filtered, and the solids remaining were washed first with water, and then with chloroform. The yield was about 100 mg. of 3,5-diphenyl-4(1H)-pyridone, m.p. greater than 335° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C@H:13]1[CH2:18][NH:17][C@H:16]([CH3:19])[CH2:15][N:14]1[C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23].C(N(CC)CC)C>CCOC(C)=O>[CH3:12][C@H:13]1[CH2:18][N:17]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C@H:16]([CH3:19])[CH2:15][N:14]1[C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:23])[F:24]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1S(=O)(=O)c1ccc(F)cc1
Yield: 56 %

Procedure:
A solution of 4-fluorobenzene sulphonyl chloride (234 mg, 1.2 mmol) in EtOAc (10 ml) was added to a stirred mixture of (R)-[(2S,5R)-2-methyl-5-methyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperazine] (J. Med. Chem., 1999, 42, 2741-2746) (254 mg, 1.0 mmol) and triethylamine (0.17 ml, 1.2 mmol) in EtOAc (15 ml). The resultant mixture was stirred at ambient temperature for 2 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was recrystallized from EtOAc/hexane to give the title compound as a solid (230 mg, 0.56 mmol). Mp: 174-175° C.; NMR: 0.95 (d, 3H), 1.25 (d, 3H), 1.75 (s, 3H), 3.25 (dd, 1H), 3.35 (d, 1H), 3.5 (dd, 1H), 4.15 (m, 2H), 4.3 (s, 1H), 4.75 (s, 1H), 7.2 (d, 2H), 7.8 (d, 2H); m/z 411.