Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:15](O)=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].P([O-])([O-])(O)=O.[NH4+:22].[NH4+].S1(CCCC1)(=O)=O>O>[CH:5]1[C:1]([N+:2]([O-:4])=[O:3])=[C:15]([NH2:22])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Reactant: [NH4+]
Agent: O=P([O-])([O-])O
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
Picric acid (10.0 g, 43.8 mmol), diammonium hydrogen phosphate (11.6 g, 87.6 mmol) and dry sulfolane (40 ml) are placed in a glass-lined, stainless steel reactor to form a 1.1M concentration reaction slurry. The reactor is sealed and the reaction slurry is stirred with heating for 2 hr as the temperature increases from 25 to 175° C. (20 psi pressure). The temperature is maintained at 175° C. and stirring is continued for an additional 20 hr. The cooled reaction mixture is mixed with water (400 ml) and the insoluble material is collected, washed with water and dried to produce picramide in 93% yield (Table 2, entry 5).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]([NH2:22])=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23](OC)(OC)OC.Cl>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[N:22]=[CH:23]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc(F)ccc1NC1CCN(Cc2ccccc2)CC1
Reactant: COC(OC)OC
Agent: Cl
Product: Fc1ccc2c(c1)ncn2C1CCN(Cc2ccccc2)CC1

Procedure:
The title compound was prepared from 170 mg of 1-N-(1-benzyl-piperidin-4-yl)-4-fluoro-benzene-1,2-diamine (from Step A), 7 mL of trimethyl orthoformate, and 0.2 mL of concentrated HCl, using a procedure analogous to that described in Example 95, Step B to provide 123 mg of the title compound as a viscous brown oil
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N1CC[C@@H](N)C1)(OC(C)(C)C)=O.Br[C:21]1[CH:22]=[CH:23][C:24]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]3([C:48]4[C:39](=[CH:40][C:41]5[O:46][CH2:45][CH2:44][O:43][C:42]=5[CH:47]=4)[O:38][CH2:37]3)[C:29]2=[O:49])=[N:25][CH:26]=1.BrC1C=CC(CN2C3C(=CC=CC=3)C3(C4C=C(F)C(F)=CC=4OC3)C2=O)=CC=1>>[N:1]1([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][N:28]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]4([C:48]5[C:39](=[CH:40][C:41]6[O:46][CH2:45][CH2:44][O:43][C:42]=6[CH:47]=5)[O:38][CH2:37]4)[C:29]3=[O:49])=[N:25][CH:26]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C1N(Cc2ccc(Br)cn2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: C1COCCN1
Agent: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: O=C1N(Cc2ccc(Br)cc2)c2ccccc2C12COc1cc(F)c(F)cc12
Product: O=C1N(Cc2ccc(N3CCOCC3)cn2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 33.1 and making non-critical variations using morpholine to replace (R)-(+)-1-Boc-3-aminopyrrolidine, and 1′-[(5-bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 1′-(4-bromobenzyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 1′-[(5-morpholin-4-ylpyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (60%) as a pale yellow solid: mp 204-206° C.; 1H NMR (300 MHz, CDCl3) δ8.23 (d, J=2.4 Hz, 1H), 7.23-7.11 (m, 4H), 7.01 (dd, J=7.5, 7.5 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.27 (s, 1H), 5.13 (d, J=15.3 Hz, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.89 (d, J=15.6 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.21-4.11 (m, 4H), 3.87 (t, J=4.8 Hz, 4H), 3.17 (t, J=5.0 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 177.4, 155.3, 146.3, 146.2, 144.6, 142.2, 138.3, 137.3, 132.2, 128.8, 123.7, 123.4, 123.2, 122.0, 121.1, 111.7, 109.7, 99.4, 80.2, 66.6, 64.5, 63.9, 58.1, 48.5, 45.6; MS (ES+) m/z 472.2 (M+1).
Reaction SMILES: I[C:2]1[C:10]2[C:9]([OH:11])=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:7]=[N:6][C:5]=2[N:4]([CH3:18])[N:3]=1.[NH:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu](I)I>[CH3:18][N:4]1[C:5]2[N:6]=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([OH:11])[C:10]=2[C:2]([N:19]2[CH2:26][CH2:25][CH2:24][CH2:20]2)=[N:3]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cn1nc(I)c2c(O)c(-c3ccccc3)nnc21
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nc(N2CCCC2)c2c(O)c(-c3ccccc3)nnc21
Temperature: 110 °C

Procedure:
A mixture of 3-iodo-1-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazin-4-ol (100 mg, 0.28 mmol), copper iodide (11 mg, 0.056 mmol), L-proline (13 mg, 0.11 mmol), K2CO3 (193 mmol, 1.4 mmol) in anhydrous DMF (5.6 mL) was degassed by bubbling nitrogen through for 10 minutes, then heated to 110° C. for 20 h. The mixture was left to cool to room temperature, then partitioned between ethyl acetate and water, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried (MgSO4), filtered and evaporated. The residue (117 mg) was used as such in the next step.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][NH:2]2.[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+].CCOCC>C(COC)OC>[CH2:12]([N:2]1[CH2:3][CH2:4][CH:5]2[CH2:9][CH:1]1[CH2:8][CH2:7][CH2:6]2)[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: C1CC2CCNC(C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COCCOC
Product: C=CCN1CCC2CCCC1C2
Yield: 50.7 %

Procedure:
To a solution (6.5 ml) of 2-azabicyclo[3.3.1]nonane (100 mg, 0.62 mmol) in dimethoxyethane were added allylbromide (105 mg, 0.87 mmol) and potassium carbonate (94 mg, 0.68 mmol) and the mixture was heated at reflux temperature for 3.5 hours. Ether (10 ml) was added to the reaction mixture, followed by filtration and removal of the solvent, and the residue was purified with silica gel column chromatography (chloroform-methanol-triethylamine=100:9:1), to obtain 2-allyl-2-azabicyclo[3.3.1]nonane (52 mg, 51%) as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-])=O.[H][H]>[Ni].CO>[NH2:10][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:2]=1[NH2:1]
Reactant: [H][H]
Reactant: Nc1ccc(C=O)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(CO)cc1N

Procedure:
A mixture of 8.3 parts of 4-amino-3-nitrobenzaldehyde in 200 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 8.5 parts of 3,4-diaminobenzenemethanol as an oily residue.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:10]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[CH:5][CH:4]=1.[CH2:30]([S:33](Cl)(=[O:35])=[O:34])[CH2:31][CH3:32]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[Cl:20])[CH2:13][CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][S:33]([CH2:30][CH2:31][CH3:32])(=[O:35])=[O:34])[CH:12]=2)[CH2:7][CH2:8][CH:9]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27]
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CN)cc2C1Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(NC(=O)OC(C)(C)C)CC2

Procedure:
tert-Butyl [7-(aminomethyl)-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (120 mg, 0.276 mmol, cf. Example 38) was dissolved in dichloromethane (5 mL). 4-Dimethylaminopyridine (35 mg, 0.289 mmol) was added. After stirring at room temperature for 5 min propane-1-sulfonyl chloride (39 mg, 0.031 mmol) was added and stirring was continued over night. The reaction mixture was diluted with dichloromethane and washed successively with 0.5 N hydrochloric acid (2×2 mL) and saturated NaHCO3 (1×2 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The crude product was used for the next step without further purification. Yield: 125 mg (0.231 mmol, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:51]2([C:54]#[N:55])[CH2:53][CH2:52]2)=[C:6]([CH2:8][N:9]([CH3:50])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[C:31]([N:35]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N:30][CH:29]=[CH:28]3)[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:56](Cl)(Cl)=[O:57]>C(#N)C.ClCCl>[C:38]([O:37][C:36]([N:35]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:50])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[C:51]4([C:54]#[N:55])[CH2:52][CH2:53]4)[NH:1][C:56](=[O:57])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[C:15]([CH3:23])=[CH:14][C:13]3=[CH:18][CH:17]=4)=[CH:34][CH:33]=2)[CH:28]=[CH:29][N:30]=1)[C:43](=[O:44])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:42])([CH3:39])([CH3:40])[CH3:41]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(C)Cc2cc(N)ccc2C2(C#N)CC2)ccc1[C@@H](C)CO
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1ccc(C3(C#N)CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 36.8 %

Procedure:
A solution of 36I (0.371 g, 0.495 mmol) in acetonitrile (5 mL) and dichloromethane (5 mL) was cooled to 0° C. To this solution, was added phosgene (20% in toluene, 0.257 mL, 0.520 mmol). The mixture was stirred at 0° C. for 15 min, then bubbled with Ar for 25 min to remove excess phosgene and HCl. The resulting solution was added dropwise over 5 h via a syringe pump into a solution of TEA (0.690 mL, 4.95 mmol) in dichloromethane (200 mL). The solution was stirred for an additional 30 min and then concentrated. The crude product was purified by flash chromatography (1-15% MeOH/dichloromethane) to give di-Boc protected intermediate (0.326 g, 85%) as a diastereomeric mixture. The diastereomers were separated by a prep chiral HPLC (CHIRALCEL® OD 10 um 4.6×250 mm) to yield 36J (0.141 g, 0.182 mmol, 73.5% yield) as a yellowish solid. MS (ESI) m/z: 775.3 [M+1]+. 1H NMR: (400 MHz, CD3OD) δ ppm 8.05 (1H, d, J=5.81 Hz), 7.68 (1H, dd, J=7.83, 1.77 Hz), 7.61 (1H, d, J=9.09 Hz), 7.52 (1H, d, J=5.81 Hz), 7.46 (1H, d, J=8.08 Hz), 7.27 (1H, dd, J=9.22, 2.15 Hz), 7.18-7.24 (2H, m), 6.88 (1H, d, J=2.02 Hz), 6.71 (1H, dd, J=8.08, 2.27 Hz), 6.11 (1H, d, J=2.02 Hz), 5.73 (1H, s), 5.67 (1H, d, J=16.93 Hz), 4.65 (1H, t, J=10.99 Hz), 4.14 (1H, d, J=16.93 Hz), 3.96 (1H, dd, J=10.86, 4.29 Hz), 3.40 (3H, s), 2.31 (3H, s), 1.27 (25H, s).
Reaction SMILES: Cl.CN1[CH2:8][CH2:7][CH:6]([C:9]([C:11]2[C:16]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)=O)CC1.F.[B].C1N[C:33](=O)[NH:32][C:30](=O)[C:29]=1C(F)(F)F>>[Cl:25][C:21]1[CH:22]=[CH:23][C:24]2[C:9](=[C:6]3[CH2:7][CH2:8][CH2:29][CH2:30][N:32]3[CH3:33])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:16]3[CH2:17][CH2:18][C:19]=2[CH:20]=1
Reactant: O=c1[nH]cc(C(F)(F)F)c(=O)[nH]1
Reactant: CN1CCC(C(=O)c2ncccc2CCc2cccc(Cl)c2)CC1
Agent: Cl
Agent: F
Agent: [B]
Product: CN1CCCCC1=C1c2ccc(Cl)cc2CCc2cccnc21

Procedure:
To a solution of a product of Step D above (59 g, 0.15 mole) in 120 mL (120 g, 6.0 mole) of hydrofluoric acid at -35° C. is added boron trifluoridine (44.3 g, 0.66 mole) over 1 hour. Completeness of the reaction is determined by thin-layer chromatography. The reaction is quenched using ice, water and potassium hydroxide to a final pH of 10. The product is extracted into toulene and the toluene solution is washed with water and brine. The toluene solution is concentrated to a residue, which is dissolved in hot hexane. Insolubles are removed by filtration and the filtrate is concentrated to an off-white powder. Yield: 45.7 g (HPLC purity 96%), 92% of theory.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>CC#N.CN(C=O)C>[C:13]([O:17][C:18](=[O:19])[NH:20][CH2:21][CH2:22][CH2:23][NH:24][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(NCCCNC(=O)OC(C)(C)C)n1
Temperature: 40 °C
Yield: 96.5 %

Procedure:
A mixture of 2-chloro-6-methoxy-3-nitropyridine (5.9 g; commercial), N-(tert-butoxycarbonyl)-1,3-propanediamine (4.48 g; commercial) and K2CO3 (3.55 g) in MeCN (90 mL) and DMF (25 mL) was heated at 40° C. for 30 min. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was taken up in EA, sequentially washed with water and brine and evaporated under reduced pressure, affording 8.1 g (96% yield) of a crude yellow solid which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH3:20])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([O:22][CH3:23])[CH2:10][CH2:11][C:12](=[O:21])[CH2:13]4.[N:24]#CBr.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:20]([N:19]1[CH2:18][CH2:17][C@@:14]23[C:15]4[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[CH2:7][C@@H:8]1[C@:9]2([O:22][CH3:23])[CH2:10][CH2:11][C:12](=[O:21])[CH2:13]3)#[N:24]
Reactant: N#CBr
Reactant: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@]1(OC)CCC(=O)C3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc2c(c1)[C@]13CCN(C#N)[C@H](C2)[C@]1(OC)CCC(=O)C3

Procedure:
A solution of 3,14-dimethoxy-17-methylmorphinan-6-one (0.490 g, 1.55 mmol) in methylene chloride (25 ml) was treated with cyanogen bromide (0.977 g, 9.3 mmol) and anhydrous potassium carbonate (1.285 g, 9.3 mmol). The mixture was refluxed for 22 hours, filtered through Celite and the filtrate washed with water (3×50 ml). The organic solution was separated, dried over MgSO4, filtered and concentrated under reduced pressure to give 0.463 g (92% theory) of the desired product as a yellow solid (m.p. 172°-176°). Recrystallization from ethanol gave 0.427 g (85% theory) of the product as a white solid, m.p. 176°-177° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:18][CH2:17]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:28].[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:18][CH2:17]2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1

Procedure:
Following general procedure II, 1-{6-chloro-4-[trans-4-(pyrrolidin-1-ylmethyl)-cyclohexylamino]-1,5-naphthyridin-3-yl}ethanone (67 mg, 0.17 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (58 mg, 0.21 mmol) followed by formation of the dihydrochloride salt to afford the desired product (36 mg, 36%) as an off-white solid: 1H NMR (300 MHz, CD3OD) δ 9.15 (s, 1H), 8.47 (d, J=9.0 Hz, 1H), 8.34 (d, J=9.0 Hz, 1H), 8.12 (s, 2H), 5.75-5.67 (m, 1H), 3.72-3.65 (m, 2H), 3.17-3.06 (m, 4H), 2.76 (s, 3H), 2.48-2.40 (m, 2H), 2.20-1.99 (m, 6H), 1.73-1.61, (m, 2H), 1.47-1.36 (m, 2H); ESI MS m/z 513 [M+H]+; HPLC 95.7% (AUC), tR=10.21 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([NH:20][C@H:21]2[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]2)=[N:15]3)=O)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C(=O)([O-])[O-].[Na+].[Na+].O>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([NH:20][C@H:21]2[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]2)=[N:15]3)=[N:31][OH:32])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C(c1ccc(F)cc1)c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Yield: 32.9 %

Procedure:
A stirred suspension of (4-fluoro-phenyl)-[2-((R)-indan-1-ylamino)-quinolin-5-yl]-methanone (example 83) (100 mg, 0.26 mmol), hydroxylamine hydrochloride (55 mg, 0.79 mmol) and sodium carbonate (83 mg, 0.78 mmol) in EtOH (2 ml) was heated under reflux conditions for 18 hours, the reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/ethyl acetate) and crystallization (diethyl ether/heptane) to yield the title compound as off-white solid (34 mg, 33%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[C:9]([O:13][C:14](=[O:17])[CH:15]=[CH2:16])([CH3:12])([CH3:11])[CH3:10]>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:9]([O:13][C:14](=[O:17])[CH2:15][CH2:16][S:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: Nc1ccc(S)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCSc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-aminothiophenol (2.36 g) in tetrahydrofuran (THF; 20 ml), 2-propenoic acid t-butyl ester (3.51 ml) and 1.0M tetrabutylammonium fluoride in THF solution (340 μl) were added. The mixture solution was stirred for 30 minutes at room temperature to give the title compound. The compound was used for next reaction as such.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[P:5]([CH2:10][CH:11]([F:17])[C:12](OCC)=[O:13])([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[NH4+:21]>C(O)C>[NH2:21][C:12](=[O:13])[CH:11]([F:17])[CH2:10][P:5]([CH:4]([O:18][CH2:19][CH3:20])[O:3][CH2:1][CH3:2])(=[O:6])[O:7][CH2:8][CH3:9]
Reactant: [NH4+]
Reactant: CCOC(=O)C(F)CP(=O)(OCC)C(OCC)OCC
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(F)C(N)=O)OCC
Reaction time: 16 h
Yield: 27 %

Procedure:
To a solution of ethyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-2-fluoropropanoate (16.0 g, 51.1 mmol) in ethanol (22 mL) was added concentrated ammonium hydroxyde (14.8 N, 3.5 mL, 51.1 mmol). The solution was stirred for 16 h and evaporated. The residue was purified by chromatography on a wet-packed silica gel column (7×37 cm) eluting with 96.5:3.5 methylene chloride/methanol. The appropriate fractions were combined and evaporated to give 3.43 g (27%) of ethyl (3-amino-2-fluoro-3-oxopropyl)(diethoxymethyl)phosphinate as a clear oil. Data: 1H NMR (300 MHz, CDCl3) δ 6.43 (s, 1H), 5.70 (s, 1H), 5.21–5.49 (dm, 1H), 4.7 (dd, 1H),4.18–4.31 (m, 2H), 3.65–3.91 (m, 4H), 2.21–2.81 (m, 2H), 1.30–1.40 (m, 3H), 1.20–1.28 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][OH:11]>ClCCl.[O-2].[Mn+2]>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: COc1ccc(CO)c(N)c1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(C=O)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
A mixture of (2-amino-4-methoxyphenyl)methanol (20 g, 131.0 mmol) and manganese oxide (68 g, 786.0 mmol) in dichloromethane (300 mL) was stirred at RT overnight. LCMS showed the reaction was completed. The solid was filtered off, and the filtrate was concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=6:1) to give the title compound (7 g, 35%) as a yellow solid. MS (ES+) C8H9NO2 requires: 151. found: 152 [M+H]+. Synthesis of 2-amino-5-bromo-4-methoxybenzaldehyde
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28]CC2C=CC=CC=2)[CH2:11][CH2:10]1.C(O)C>[Pd].C(OCC)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[CH2:13][CH2:14]1
Reactant: Fc1cccc([C@H]2CC[C@H](C=CCCCCCCCCCCCOCc3ccccc3)CC2)c1F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCCCCCCCCCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
First, 10.9 g of 2,3-difluoro-1-[trans-4-{13-benzyloxy-1-tridecenyl}cyclohexyl]benzene, 1 g of 10% Pd-C, 50 ml of ethanol, and 50 ml of ethyl acetate were placed in a 500 ml autoclave. The mixture was stirred at room temperature for 5 days under a hydrogen pressure of 8 kg/cm2. A catalyst was filtered away and a filtrate was concentrated. Thereafter, the residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=4/1) and recrystallized from acetone to obtain 5.7 g of 2,3-difluoro-1-[trans-4-(13-hydroxytridecyl)cyclohexyl]benzene (Y: 64%). The compound thus obtained had a purity of 97.2% by GC and 99.8% by HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][CH:9]2[C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.[NH2:37][C:38]1[NH:39][C:40]2[CH:46]=[C:45]([C:47]#[N:48])[CH:44]=[CH:43][C:41]=2[N:42]=1>CN(C=O)C>[C:47]([C:45]1[CH:44]=[CH:43][C:41]2[N:42]=[C:38]([NH:37][C:11]([CH:9]3[CH2:10][CH:8]3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[O:13])[NH:39][C:40]=2[CH:46]=1)#[N:48]
Reactant: N#Cc1ccc2nc(N)[nH]c2c1
Reactant: O=C(O)C1CC1c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc(NC(=O)C3CC3c3cccc(F)c3)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(3-Fluoro-phenyl)-cyclopropanecarboxylic acid 2 (90 mg, 0.50 mmol) was dissolved in 10 ml DMF. 115 mg (0.6 mmol) 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and 81 mg (0.6 mmol) 1-Hydroxybenzotriazole (HOBT) were added. The mixture was stirred for 30 min at room temperature (RT). Then 97 mg (0.5 mmol) 2-Amino-3H-benzoimidazole-5-carbonitril hydrochloride 1 were added to the mixture, which was stirred for 16 h at RT. After removing the solvent in vacuo, 20 ml water were added, whereupon the mixture was extracted 3 times with 50 ml acetic acid ethylester. The organic phases were combined, dried with sodium sulfate, and evaporated to dryness. The residue was separated via preparative HPLC. The resulting clean fractions were concentrated and lyophilized. 91 mg (57%) of a colorless, amorphous solid 3 were obtained.
Reaction SMILES: [CH2:1]([N:3]([Si](C)(C)C)[CH2:4][CH3:5])[CH3:2].[F:10][C:11]([F:17])([F:16])[S:12]([O-:15])(=[O:14])=[O:13].[CH3:18][NH+:19]1[CH2:23][CH2:22][N:21]([CH3:24])[CH:20]1Cl>C(Cl)(Cl)Cl>[F:10][C:11]([F:17])([F:16])[S:12]([O-:15])(=[O:14])=[O:13].[CH3:18][NH+:19]1[CH2:23][CH2:22][N:21]([CH3:24])[CH:20]1[N:3]([CH2:4][CH3:5])[CH2:1][CH3:2]
Reactant: CCN(CC)[Si](C)(C)C
Reactant: CN1CC[NH+](C)C1Cl
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCN(CC)C1N(C)CC[NH+]1C
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
0.62 g (4.27 mmol) of N,N-diethyltrimethylsilylamine are added over the course of a few minutes at room temperature with stirring to 1.0 g (3.54 mmol) of 1,3-dimethyl-2-chloroimidazolidinium trifluoromethanesulfonate in 15 ml of chloroform. The reaction mixture is stirred for 30 minutes at room temperature and for 30 minutes at 40-50° C. The volatile constituents are distilled off, and the residue obtained is dried at 50° C. under reduced pressure (7.0 Pa), giving 1.11 g of 1,3-dimethyl-2-diethylaminoimidazolidinium trifluoromethanesulfonate as an oil, corresponding to a yield of 98.2%.