Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][O:34][CH2:35][CH2:36][CH2:37]N.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:37][CH2:36][CH2:35][O:34][CH3:33])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Reactant: COCCCN
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCCCNC(=O)Nc1cn(-c2cccc(F)c2)cc1C(=O)N[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Yield: 71 %

Procedure:
Following general method 6, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and 3-methoxy-propylamine afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-60% ethyl acetate in DCM) afforded the title compound as a glass (100 mg, 71%). LCMS (method B): RT=3.67 min, M+H+=518.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:14]=[C:13]([C:27]([O:29]C)=O)[C:9]=3[NH:10][C:11]=2[CH:12]=1)([O-:3])=[O:2].[NH3:31]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:18]=4)[CH:14]=[C:13]([C:27]([NH2:31])=[O:29])[C:9]=3[NH:10][C:11]=2[CH:12]=1)([O-:3])=[O:2]
Reactant: N
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc([N+](=O)[O-])ccc12
Solvent: CO
Product: NC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc([N+](=O)[O-])ccc12
Temperature: 80 °C
Yield: 79 %

Procedure:
A suspension of methyl 7-nitro-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (250 mg, 0.602 mmol) in 7 N NH3 in MeOH (5 mL) in a sealed microwave vial was heated in an oil bath at 80° C. for 16 h. After cooling to RT, the solid was collected by filtration and washed with MeOH to afford 7-nitro-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (200 mg, 0.475 mmol, 79% yield). MS (ESI) m/z 401.1 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.26 (1H, br. s.), 8.62-8.81 (5H, m), 8.54 (1H, d, J=8.85 Hz), 8.03-8.19 (2H, m), 7.75-7.88 (2H, m).
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][N:12]3[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.[CH3:27][C@H:28]1[O:33][C@@H:32]([CH3:34])[CH2:31][NH:30][CH2:29]1>ClCCl>[Cl:17][C:15]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:20])=[C:8]([C:6]2[O:7][C:3]([CH2:2][N:30]3[CH2:29][C@H:28]([CH3:27])[O:33][C@H:32]([CH3:34])[CH2:31]3)=[CH:4][N:5]=2)[CH:16]=1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3ncc(CBr)o3)cc(Cl)cc21
Reactant: C[C@@H]1CNC[C@H](C)O1
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
4-[5-(Bromomethyl)-1,3-oxazol-2-yl]-6-chloro-1-(phenylsulfonyl)-1H-indazole (0.580 g, 1.28 mmol) was dissolved in dichloromethane (5 ml) and (2R,6S)-2,6-dimethylmorpholine (0.317 ml, 2.56 mmol) added. The reaction mixture was stirred at RT for 3 h then the solvent removed under a stream of nitrogen. The resultant yellow solid was dissolved in dichloromethane (5 ml) and washed with water (2×2.5 ml). The layers were separated (hydrophobic frit) and the organic evaporated in vacuo to give the title compound as a pale yellow solid (0.60 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].IC.[CH:12](Cl)(Cl)Cl>C(=O)([O-])[O-].[Ag+2].C(N(CC)CC)C>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([O:9][CH3:12])=[CH:4][CH:3]=1
Reactant: Cc1[nH]c(=O)ccc1Br
Reactant: ClC(Cl)Cl
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CI
Solvent: CCN(CC)CC
Product: COc1ccc(Br)c(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A mixture of 5-bromo-6-methyl-1H-pyridin-2-one (5.5 g, 29 mmol), silver carbonate (10.89 g, 39 mmol), iodomethane (13.6 mL, 217 mmol) and chloroform (115 mL) is stirred overnight in the dark at room temperature. Triethylamine (10 mL) is added and stirring continued for 1.5 hr. The reaction mixture is filtered through a pad of Hi-Flo and the filtrate is washed with water (100 mL), dried, filtered and concentrated. The residue is purified by filtration through a pad of silica gel washing with cyclohexane-20% ethyl acetate. The solvent is concentrated to afford 3-bromo-6-methoxy-2-methylpyridine (3.7 g, 63% yield) as an oil. LC/MS RT 3.76 min; MS m/e=202/204 (M); NMR (CDCl3) 7.6 (1H, d), 6.43 (1H, d), 3.89 (3H, s), 2.57 (3H, s).
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[C:10]([F:16])[CH:9]=1>C1COCC1.[Cl-].[Na+].O>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH2:1])=[C:10]([F:16])[CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc(Cl)cc1F
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(Cl)cc1F
Temperature: 15 °C
Reaction time: 1 h

Procedure:
A solution of KOt-Bu (19.5 g, 174 mmol) in dry THF (300 mL) was cooled with an ice/water bath. Portionwise addition of MePPh3Br (62.2 g, 174 mmol) resulted in a suspension, which was stirred for 5 min at 0° C. and for 1 h at 15° C. Subsequently, the temperature was lowered to 0° C. and a solution of 4-chloro-2-fluorobenzaldehyde (25.1 g, 158 mmol) in dry THF (100 mL) was added dropwise. The temperature was raised to room temperature slowly. The reaction mixture was stirred at room temperature for 20 h. Addition of brine (100 mL) resulted in a clear two phase system and a white solid. The combination of layers was decanted from the solid. The layers were separated, the aqueous layer was combined with the solid residue and Et2O (200 mL). The combination of layers was decanted from the solid. The layers were separated, the combination of organic layers was dried (Na2SO4) and concentrated at a controlled vacuum of 100 mbar. The residual oil was combined with pentane (300 mL) and Na2SO4. The suspension was triturated. Filtration and pentane washing provided a filtrate, which was concentrated at a controlled vacuum of 100 mbar to arrive at 26.76 g (97%, 90% purity) of impure title compound as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:16])([CH3:15])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])=[O:5].CCN(C(C)C)C(C)C.[CH2:26]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)[CH3:27]>C(Cl)Cl>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][NH:6][C:4](=[O:5])[C:3]([CH3:16])([CH3:15])[CH2:2][NH:1][C:35]([NH:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:26][CH3:27])=[CH:29][CH:30]=1)=[O:36]
Reactant: CCc1ccc(N=C=O)cc1
Reactant: CC(C)(CN)C(=O)NCc1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1ccc(NC(=O)NCC(C)(C)C(=O)NCc2ccccc2Cl)cc1
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a solution of 3-amino-N-(2-chlorobenzyl)-2,2-dimethylpropanamide (0.45 mmol) in DCM (5 mL) was added DIEA (157 μL, 0.90 mmol, 2 equiv.) and 4-ethylphenyl isocyanate (97.0 μL, 0.675 mmol, 1.5 equiv.). The reaction mixture was stirred for 30 min. The mixture was concentrated and purified on RP-HPLC using a mixture of acetonitrile and H2O to give N-(2-chlorobenzyl)-3-(3-(4-ethylphenyl)ureido)-2,2-dimethylpropanamide (29.6 mg, 17% for two steps). LRMS (M+H+) m/z 388.1.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[C:14]([NH:18][NH2:19])(=O)[CH2:15][CH3:16]>C(O)CCC>[CH2:15]([C:14]1[N:3]2[N:4]=[C:5]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[CH:6]=[CH:7][C:2]2=[N:19][N:18]=1)[CH3:16]
Reactant: Clc1ccc(-c2cccnc2)nn1
Reactant: CCC(=O)NN
Solvent: CCCCO
Product: CCc1nnc2ccc(-c3cccnc3)nn12

Procedure:
As for Example 2, a mixture of 3-chloro-6-(3-pyridyl)pyridazine (2.0 g.) and propionic acid hydrazide in 60 ml. of n-butyl alcohol is refluxed for 48 hours to give the product of the Example.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[C:43]([NH2:47])[CH:44]=[N:45][CH:46]=2)[CH2:37][CH2:36]1.Cl[C:49]1[C:58]2[C:53](=[CH:54][C:55]([F:60])=[CH:56][C:57]=2[F:59])[N:52]=[C:51]([C:61]2[CH:66]=[C:65]([CH3:67])[CH:64]=[CH:63][N:62]=2)[C:50]=1[CH3:68].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:59][C:57]1[CH:56]=[C:55]([F:60])[CH:54]=[C:53]2[C:58]=1[C:49]([NH:47][C:43]1[CH:44]=[N:45][CH:46]=[C:41]([N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)[CH:42]=1)=[C:50]([CH3:68])[C:51]([C:61]1[CH:66]=[C:65]([CH3:67])[CH:64]=[CH:63][N:62]=1)=[N:52]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)c1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.023 g, 0.047 mmol), 5-morpholinopyridin-3-amine (0.064 g, 0.35 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (0.09 g, 0.30 mmol) Pd2dba3 (0.011 g, 0.012 mmol) and sodium tert-butoxide (0.071 g, 0.74 mmol) in toluene (2.7 mL) at 120° C. for 10 days. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product 5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)-N-(5-morpholinopyridin-3-yl)-quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (1H, d, J=4.9 Hz), 7.95 (1H, d, J=2.2 Hz), 7.81 (1H, d, J=2.2 Hz), 7.65-7.62 (2H, m), 7.20 (1H, m), 6.98-7.07 (2H, m), 6.62 (2H, app t, J=4.5 Hz), 3.86 (4H, t, J=1.9 Hz), 3.20 (4H, t, J=1.9 Hz), 2.48 (3H, s), 2.15 (3H, s). Mass Spectrum (ESI) m/e=448.1 (M+1).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=1[C:17]([F:20])([F:19])[F:18].[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>ClCCl>[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:12][C:11]=1[C:17]([F:18])([F:19])[F:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(N)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)C(C)(C)C)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Triethylamine (6.24 ml, 44.8 mmol) was added to a solution of 4-methoxy-3-(trifluoromethyl)aniline (4.29 g, 22.4 mmol) in dichloromethane (45.0 ml), and the resulting mixture was ice-cooled, followed by adding dropwise thereto pivaloyl chloride (2.84 g, 23.5 mmol) at 0 to 5° C. The resulting mixture was warmed up to room temperature and stirred for 1 hour while maintaining the temperature. The mixture was partitioned by the use of a 5%-aqueous sodium hydrogencarbonate solution and ethyl acetate, and the organic layer was washed with a 5% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain N-[4-methoxy-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide (6.16 g, 100%).
Reaction SMILES: [IH:1].[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C(O)C>C(OCC)C>[IH:1].[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8]([NH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=1)=[NH:11]
Reactant: NCc1ccc(F)cc1
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Agent: I
Solvent: CCOCC
Solvent: CCO
Product: N=C(NCc1ccc(F)cc1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 5.85 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydroiodide (U.S. Pat. No. 3,657,337) and 3.75 g. of p-fluorobenzylamine in 25 ml. of absolute ethanol is heated under reflux for 24 hours and then evaporated under reduced pressure, giving a mixture of gum and crystals. This mixture is dissolved in 50 ml. of absolute ethanol and diluted with 175 ml. of diethyl ether. The colorless plates which form are removed by filtration and discarded. The filtrate is diluted with petroleum ether (b.p. 30°-60° C), causing colorless needles to separate. These needles are removed by filtration and recrystallized from a mixture of ethanol-diethyl ether-petroleum ether (b.p. 30°-60° C), giving the desired product as colorless crystals, m.p. 162.5°-164° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([C:23]3[C:24]([CH3:41])=[N:25][C:26]([CH:29]4[CH2:33][CH2:32][N:31](CC5C=CC=CC=5)[CH2:30]4)=[CH:27][CH:28]=3)[CH2:19][CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:42])[O:4][N:3]=1.ClC(OC(Cl)C)=O.CO>C(#N)C>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH2:19][CH:20]([CH3:21])[CH3:22])[C:23]3[C:24]([CH3:41])=[N:25][C:26]([CH:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[CH:27][CH:28]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:42])[O:4][N:3]=1
Reactant: Cc1nc(C2CCN(Cc3ccccc3)C2)ccc1N(CC(C)C)S(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC#N
Solvent: CO
Product: Cc1nc(C2CCNC2)ccc1N(CC(C)C)S(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1

Procedure:
To a solution of 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}-N-{2-methyl-6-[1-(phenylmethyl)-3-pyrrolidinyl]-3-pyridinyl}-N-(2-methylpropyl)benzenesulfonamide (114 mg, 0.194 mmol) in acetonitrile (3 mL) was added 1-chloroethyl chloroformate (0.027 mL, 0.252 mmol) and the reaction mixture was heated at reflux under nitrogen for 2 hours. To this was added methanol (3 mL) and the reaction mixture was refluxed under nitrogen for 1 hour. The solvent was removed in vacuo. The sample was then purified by mass directed autoprep (formic acid buffered) to give the required product as formic acid salt (33 mg). LCMS (2 min, formic) Rt 0.86 min, m/z (ES+) 499 (M+H).
Reaction SMILES: [C:1]1([C:7]2N=N[NH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](Cl)([Cl:14])=[S:13]>C(COC)OC>[Cl:14][C:12]1[S:13][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:11][N:10]=1
Reactant: c1ccc(-c2nn[nH]n2)cc1
Reactant: S=C(Cl)Cl
Solvent: COCCOC
Product: Clc1nnc(-c2ccccc2)s1
Yield: 41.2 %

Procedure:
A stirred mixture of 74.4 g (0.50 mole) of 5-phenyl-2H-tetrazole and 74.0 g (0.65 mole) of thiophosgene in 550 ml of dimethoxyethane was allowed to reflux overnight. The reaction mixture was cooled and filtered. The filtrate was taken to dryness at reduced pressure and the resulting residue leached with two 220-ml portions of hexane. Upon cooling and concentration of the combined hexane portions 40.5 g of the desired product was obtained: mp 82°-84° (lit. 86°-88°).
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[CH2:27][C:26]3[C:21](=[C:22]([NH:28][C:29]([CH:31]4[CH2:33][CH2:32]4)=[O:30])[CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:34])[CH2:15][C:16]([OH:18])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:48][OH:49].O>O1CCCC1>[F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[C:20](=[O:34])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][C:22]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:27]2)[CH2:15][C:16](=[O:18])[NH:48][OH:49])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: O=C(O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Reactant: NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
To a solution of 3-(3,4-bis-difluoromethoxy-phenyl)-3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid (400 mg, 0.81 mmol) in tetrahydrofurane was added carbonyldiimidazole (200 mg, 1.21 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added hydroxylamine (120 mg, 1.6 mmol). The resulted mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile:water=45:55) to give cyclopropanecarboxylic acid {2-[1-(3,4-bis-difluoromethoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (230 mg, 46%): mp, 191–193° C.; 1HNMR (CDCl3): δ 0.88–0.93 (m, 2H, cyclopropyl ring CH2), 1.09–1.12 (m, 2H, cyclopropyl ring CH2), 1.64–1.67 (m, 1H, cyclopropyl ring CH), 2.84–2.92 (m, 1H, CHHCO), 3.38–3.48 (m, 1H, CHHCO), 4.18 (d, J=18 Hz, 1H, CHHN), 4.36 (d, J=18 Hz, 1H, CHHN), 5.47–5.49 (m, 1H, CHN), 6.52 (t, JH-F=75 Hz, 1H, OCF2H), 6.54 (t, JH-F=75 Hz, 1H, OCF2H), 6.99 (d, J=8 Hz, 1H, Ar), 7.25–7.31 (m, 3H, Ar), 7.45 (t, J=8 Hz, 1H, Ar), 8.43 (d, J=8 Hz, 1H, Ar), 9.20 (broad, 1H, NHOH), 10.35 (s, 1H, NHCO); 13C NMR (DMSO):30.82, 35.26, 38.47, 46.17, 47.50, 51.68, 112.50, 116.83, 117.01, 117.39, 117.66, 117.99, 120.56, 120.97, 121.73, 125.73, 133.41, 137.47, 138.38, 142.76, 146.83, 166.12, 168.68, 172.21, 179.98. Anal. Calcd. for C23H21F4N3O6: C, 54.02; H, 4.14; N, 8.22. Found: C, 53.89; H, 3.96; N, 8.22.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:29]=[CH:28][C:15]3[CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH2:20][C:14]=3[CH:13]=2)=[C:7]([O:30][CH3:31])[CH:6]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][NH:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:29]=[CH:28][C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[C:7]([O:30][CH3:31])[CH:6]=1
Reactant: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCNCC3)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.9 %

Procedure:
1,1-Dimethylethyl 7-{[4-[(methylamino)carbonyl]-2-(methyloxy)phenyl]oxy}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (E264, Step 5) (100 mg, 0.23 mmol) was dissolved in dry dichloromethane (2 ml), treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue dissolved in methanol and applied to a SCX column eluting with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The basic fractions were combined and concentrated in vacuo to afford the title compound (78 mg); MS (ES+) m/e 327 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:29](=O)(O)[O-].[Na+]>CO.Cl>[OH:25][C@@H:23]1[CH2:22][CH2:21][C@@:20]2([CH3:26])[CH:19]([CH2:18][C@@H:17]([OH:27])[C@@H:16]3[C@@H:15]2[CH2:14][CH2:13][C@@:12]2([CH3:28])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]([O:7][CH3:29])=[O:6])[CH2:24]1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 80 °C

Procedure:
CDCA (1.00 g, 2.50 mmol) was dissolved in methanol (43 mL), refluxed at 80° C., and then 12 drops of conc. hydrochloric acid (HCl) was added to this solution. The reaction mixture was heated at reflux for 2.5 h, cooled to room temperature, neutralized with a saturated solution of sodium bicarbonate, and the solvent was removed. 15 mL of water was added to the mixture, and the crude product was extracted with EtOAc (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated, and the crude product was chromatographed (SiO2, gradient, hexane/EtOAc 1:2 to EtOAc only) to give 1.08 g (2.64 mmol, >100%, less dry) of 25 as a white solid. Rf 0.40 (EtOAc); 1H NMR (400 MHz, CDCl3) 3.80 (m, 1H, H-3/H-7), 3.63 (s, 3H, CO2CH3), 3.40 (m, 1H, H-3/H-7), 2.35-0.93 (m, 28H), 0.89 (d, 3H, J=6.5 Hz, CH3), 0.87 (s, 3H, CH3), 0.62 (s, 3H, CH3); MS (ESI) Calcd for C25H42O4Na (M+Na+): 429.3. Found: 429.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:20]3[CH:21]=[C:22]([CH:37]=[CH:38][CH:39]=3)[CH2:23][NH:24][C:25](=[O:36])[C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[N:9][N:10](COCC[Si](C)(C)C)[CH:11]=2)=[CH:3][CH:2]=1>Cl.O1CCOCC1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:20]3[CH:21]=[C:22]([CH:37]=[CH:38][CH:39]=3)[CH2:23][NH:24][C:25](=[O:36])[C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:28][CH:27]=3)=[N:9][NH:10][CH:11]=2)=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c(-c2cccc(CNC(=O)c3ccc(C(F)(F)F)cc3)c2)n1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCc1cccc(-c2n[nH]cc2-c2ccncc2)c1)c1ccc(C(F)(F)F)cc1
Yield: 31.6 %

Procedure:
N-{3-[4-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-benzyl}-4-trifluoromethyl-benzamide (0.10 g, 0.19 mmol) was stirred in HCl 4M in dioxane at room temperature for 4 h. The solvent was evaporated under vacuum and the crude product was purified by reverse phase HPLC yielding N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-4-trifluoromethyl-benzamide (0.025 g, 0.06 mmol, 31%) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([OH:15])=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.[ClH:17].[Cl:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[OH-].[K+]>C1(C)C=CC=CC=1.O>[ClH:18].[ClH:17].[N:22]1([CH2:21][CH2:20][CH2:19][O:1][C:2]2[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][C:8]([O:15][CH2:19][CH2:20][CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:9][CH:10]=4)[C:5](=[O:16])[C:4]=3[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C1c2cc(O)ccc2-c2ccc(O)cc21
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2cc(OCCCN3CCCCC3)ccc2-c2ccc(OCCCN3CCCCC3)cc21
Reaction time: 20 h

Procedure:
A mixture of 63.6 g (0.30 mole) of 2,7-dihydroxy-fluoren-9-one, 188 g (0.95 mole) of 1-(3-chloropropyl) piperidine hydrochloride, 132 g (2.0 mole) of 85% potassium hydroxide in 900 ml of toluene and 300 ml of water is refluxed with vigorous stirring for 20 hours. The layers are separated upon cooling and the organic layer is washed 3 times with water, once with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The mixture is filtered and the solvent removed in vacuo. The residue is taken up in isopropyl alcohol and acidified to Congo Red with ethereal hydrogen chloride. The solid which precipitates is filtered, recrystallized from a mixture of 3 parts isopropyl alcohol to 1 part methanol, and the 2,7-bis(3-piperidinopropoxy)fluoren-9-one dihydrochloride so prepared is dried at 100° C. for 24 hours under vacuum, m.p. 279.5°-80.5° C., λmaxH2O 270, and E1cm1% 1370.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([C:8]1([C:11]2([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:13][O:12]2)[CH2:10][CH2:9]1)#[N:7]>C(#N)C>[C:6]([C:8]1([C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)([OH:12])[CH2:13][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:9][CH2:10]1)#[N:7]
Reactant: N#CC1(C2(c3ccc(F)cc3)CO2)CC1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: N#CC1(C(O)(Cn2ccnc2)c2ccc(F)cc2)CC1
Yield: 40.5 %

Procedure:
4 g (59 mmol) of imidazole and 2.1 g (10 mmol) of 2-(1-cyanocyclopropyl)-2-(4-fluorophenyl)oxirane (IV-2, Example 33) in 20 ml of abs. acetonitrile are heated under reflux for 8 h under a nitrogen atmosphere. After evaporation of the solvent in vacuo, the residue is taken up in ethyl acetate. The mixture is washed with water and dried over Na2SO4, and the solvent is evaporated in vacuo. Chromatographic purification on silica gel (eluent: dichloromethane containing 2% ethanol) gives 1.1 g (39% of theory) of 1-(1-cyanocyclopropyl)-1-(4-fluorophenyl)-2 -(imidazol-1-yl)ethanol having a melting point of 173° C. (dec.), 1H--NMR (CDCl3):