Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C1(C([N:15]2[CH2:18][CH:17]([CH2:19][N:20]([CH3:22])[CH3:21])[CH2:16]2)C2C=CC=CC=2)C=CC=CC=1>CO.[Pd]>[ClH:1].[ClH:1].[NH:15]1[CH2:18][CH:17]([CH2:19][N:20]([CH3:22])[CH3:21])[CH2:16]1
Reactant: CN(C)CC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)CC1CNC1
Reaction time: 96 h
Yield: 76 %

Procedure:
Hydrogen chloride in methanol was added to a mixture of [1-(1,1-diphenylmethyl)azetidin-3-ylmethyl]dimethylamine (9.9 g, 35 mmol) in methanol (150 mL) until pH=4. Palladium hydroxyde (1.5 g, 20%) was added and the resulting mixture hydrogenated at room temperature at 50 p.s.i. for 4 days. The mixture was filtered through Celite and the filtrate evaporated under reduced pressure to give the title compound (5.0 g, 76%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1>>[F:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:13]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: F[C@H]1CCNC1
Product: Cn1ncc([N+](=O)[O-])c1N1CC[C@H](F)C1
Yield: 83 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and (S)-3-fluoropyrrolidine gave (S)-5-(3-fluoropyrrolidin-1-yl)-1-methyl-4-nitro-1H-pyrazole as a yellow solid (220 g, 83%). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 5.48-5.31 (m, 1H), 3.79 (s, 3H), 3.73-3.57 (m, 2H), 3.49-3.37 (m, 2H), 2.46-2.27 (m, 2H)
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:19][C:20]([F:31])([F:30])[O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]([F:30])([F:31])[O:21][C:22]1[CH:23]=[C:24]([CH2:25][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(OC(F)(F)F)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.7 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (935 mg, 3.85 mM), 3-trifluoromethoxybenzyl bromide (1.0 g, 3.93 mM), and potassium carbonate (531 mg, 3.85 mM) in 20 mL DMF was stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated to afford 1.6 g (100%) of the 9-[(3-trifluoromethoxyphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a foam. 1H NMR (DMSO-d6) δ7.7 (dd, 1H, J=1 and 8 Hz), 7.45 (t, 1H, J=8 Hz), 7.3-7.1 (m, 4H), 7.05 (d, 1H, J=8 Hz), 5.6 (s, 2H), 3.8 (s, 3H), 3.0 (m, 2H), 2.45 (m, 2H), and 2.1 (m, 2H). IR (CDCl3, cm−1) 1729, 1647, 1439, 1259, 1176, and 1116. MS (ES) m/e 418.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3]([CH3:6])(=[O:5])=[O:4].C([Li])CCC.[NH2:13][C:14]1[CH:24]=[C:23]([Cl:25])[C:22]([O:26][CH3:27])=[CH:21][C:15]=1[C:16](OCC)=[O:17]>>[NH2:13][C:14]1[CH:24]=[C:23]([Cl:25])[C:22]([O:26][CH3:27])=[CH:21][C:15]=1[C:16](=[O:17])[CH2:6][S:3](=[O:5])(=[O:4])[N:2]([CH3:7])[CH3:1]
Reactant: CCOC(=O)c1cc(OC)c(Cl)cc1N
Reactant: CN(C)S(C)(=O)=O
Agent: [Li]CCCC
Product: COc1cc(C(=O)CS(=O)(=O)N(C)C)c(N)cc1Cl

Procedure:
In a similar manner to tht described in Example 12(a), N,N-dimethylmethanesulphonamide was reacted with n-butyl lithium and the product reacted with ethyl 2-amino-4-chloro-5-methoxybenzoate to give the novel compound 1-(2-amino-4-chloro-5-methoxyphenyl)-2-(N,N-dimethylsulphamoyl)ethanone, m.p. 59°-62°.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([N:15]1[CH2:20][CH:19]3[CH2:21][CH:16]1[CH2:17][N:18]3C(OC(C)(C)C)=O)(=[O:14])=[O:13])=[CH:7]2>CCOC(C)=O>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([N:15]1[CH2:20][CH:19]3[CH2:21][CH:16]1[CH2:17][NH:18]3)(=[O:13])=[O:14])=[CH:7]2
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2S(=O)(=O)c1ccc2c(Cl)cccc2c1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc2c(Cl)cccc2c1)N1CC2CC1CN2
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
2-(5-chloro-2-naphthylsulfonyl)-5-tertiary butoxy carbonyl-2,5-diazabicyclo[2.2.1] heptane (0.50 g, 2 mmol) was dissolved in about 5 ml. EtOAc. HCl gas was bubbled through the solution, resulting in an immediate change of color from orange to yellow. HCl was bubbled in for 15 minutes more and a precipitate started forming at this time. After 30 minutes, the ice bath was removed. The reaction was complete at 2 hours. The precipitate was filtered and triturated with Et2O to give 0.37 g of an off-white powder, mp: 225°-2270° C.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:25])[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:13]3[N:14]=[C:15]([N:18]4[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]4)[S:16][CH:17]=3)[CH:6]=[CH:5][C:4]1=2.[Si]([O:33][CH2:34][CH:35]=O)(C(C)(C)C)(C)C.Cl>O1CCOCC1>[CH3:2][C:3]1([CH3:25])[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:13]3[N:14]=[C:15]([N:18]4[CH2:23][CH2:22][CH:21]([NH:24][CH2:35][CH2:34][OH:33])[CH2:20][CH2:19]4)[S:16][CH:17]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCCc2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)CCCc2cc(-c3csc(N4CCC(NCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out as described starting from 60 mg (0.16 mmol) of 1-[4-(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrochloride and 34 μl (0.16 mmol) of (tert-butyldimethylsilanyloxy)acetaldehyde. The protecting group is cleaved off using a 4N HCl solution in dioxane. The purification is carried out by means of preparative HPLC. The product is in the form of the formate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:16][CH2:17][CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:16][CH2:17][CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1
Reactant: CCCC(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCC(C(=O)OCC)c1ccc(N)cc1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
5.3 g of ethyl 2-(4-nitrophenyl)pentanoate are dissolved in 55 ml of tetrahydrofuran, 1 g of 5% Pd/C (52.3% of water) is added, and the mixture is stirred at 23° C. under a hydrogen atmosphere for 1 h. After aeration, the solid material is filtered off, and the filtrate is evaporated to dryness in vacuo. Yield: 4.7 g (99%) of ethyl 2-(4-aminophenyl)pentanoate (oil); LC-MS retention time: 1.40 min (“nonpolar” gradient).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[C:9]([SH:11])[CH:8]=[N:7]1)[CH3:2].Cl[CH2:14][C:15](=[O:17])[CH3:16]>>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[C:9]([S:11][CH2:14][C:15](=[O:17])[CH3:16])[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1cc(S)cn1
Reactant: CC(=O)CCl
Product: CCOC(=O)Cn1cc(SCC(C)=O)cn1

Procedure:
Prepared according to the procedure described in Example 1, Step 3, using the following starting materials: (4-mercapto-pyrazol-1-yl)-acetic acid ethyl ester and chloroacetone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[C:39](OC(=O)C)(=[O:41])[CH3:40]>>[C:39]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cn2)c(=O)n(-c2ccccc2)n1C
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)nc2)ccn1
Temperature: 30 °C
Reaction time: 12 h
Yield: 60.1 %

Procedure:
To a solution of N-(5-((2-aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (300 mg, 0.72 mmol) in acetic anhydride (4 mL) was added Et3N (400 mg, 4 mmol), the reaction mixture was stirred at 30° C. for 12 hours and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=40/1) to give the title compound as a light yellow solid (197 mg, 60.1%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][CH:37]([F:44])[C:38](N(OC)C)=[O:39].C1COCC1>CC(OC)(C)C>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:38](=[O:39])[CH:37]([F:44])[F:36])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)C(F)F
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@@H](C)O1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)C(F)F)c(F)c2F)C[C@@H](C)O1

Procedure:
Starting materials (2R,6R)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 43) and 2,2-difluoro-N-methoxy-N-methylacetamide (MTBE was used as solvent instead of THF).
Reaction SMILES: [F-].[K+].[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1Cl)([O-:5])=[O:4].[SH:16][CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[S:16][CH2:17][CH2:18][OH:19])([O-:5])=[O:4]
Reactant: OCCS
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(SCCO)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
217 parts of potassium fluoride are introduced into a solution of 500 parts of 2,4-dinitro-1-chlorobenzene in 590 parts of N,N-dimethylformamide (DMF) and the reaction mixture is stirred for 5 hours at room temperature. 350 parts of 2-mercaptoethanol are then added dropwise, whereupon the internal temperature rises to from 60 to 65° C., and stirring is then carried out for about 15 hours at that temperature. Then, any starting materials still present are made to react by adding 34 parts of potassium carbonate. Finally, the mixture is left to cool to room temperature, salts are filtered off and the filtrate is concentrated. The oily crude product is discharged onto water, whereupon a yellow crystalline precipitate separates out. After filtering off under suction, washing and drying, 2-[2,4-dinitrophenylsulfanyl]ethanol is obtained in an almost quantitative yield and high purity.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH:15][C:16]([C:18]2[C:19]3[CH:26]=[N:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:20]=3[CH:21]=[N:22][CH:23]=2)=[O:17])[CH2:12][CH:13]=[O:14])[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].CC(=CC)C.Cl([O-])=[O:40].[Na+].O.P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[F:33][C:30]1[CH:29]=[CH:28][C:27]([N:24]2[C:20]3[CH:21]=[N:22][CH:23]=[C:18]([C:16]([NH:15][C@H:11]([C:9]4[CH:8]=[CH:7][N:6]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:10]=4)[CH2:12][C:13]([OH:40])=[O:14])=[O:17])[C:19]=3[CH:26]=[N:25]2)=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)c1cc([C@H](CC=O)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CS(=O)(=O)c1cc([C@H](CC(=O)O)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reaction time: 8 h

Procedure:
To a room temperature solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid[(S)-1-(2-methanesulfonyl-pyridin-4-yl)-3-oxo-propyl]-amide (0.10 g, 0.21 mmol) and 2-methyl-2-butene (147 μL, 1.39 mmol) in t-butanol (1 mL) was added a solution of 80% sodium chlorite (31 mg, 0.28 mmol) and sodium dihydrogen phosphate monohydrate (38 mg, 0.28 mmol) in water (400 μL) (addition was exothermic). The mixture stirred overnight and was then concentrated in vacuo, acidified with 1 N aqueous HCl (pH=2), diluted with brine (25 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford (S)-3-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-3-(2-methanesulfonyl-pyridin-4-yl)-propionic acid which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH:6]([CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)=[O:4].BrCC(Cl)=O.[CH3:42][NH:43][CH3:44]>O1CCCC1>[CH3:42][N:43]([CH3:44])[CH2:2][C:3]([NH:5][CH:6]([CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)=[O:4]
Reactant: O=C(CBr)NC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(c1ccccc1)c1ccccc1
Reactant: CNC
Agent: O=C(Cl)CBr
Solvent: C1CCOC1
Product: CN(C)CC(=O)NC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(c1ccccc1)c1ccccc1

Procedure:
A solution of 2-(2-bromoacetamido)-1-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-3,3-diphenylpropane (0.36 g, prepared by an analogous procedure to that described in Example 60, from bromoacetyl chloride) in tetrahydrofuran (20 ml) and dimethylamine (1 ml) was stirred at 0° C. for 1 hour, The solution was poured onto ethyl acetate and the solution washed with water, saturated brine and dried (MgSO4). After removal of the solvent in vacuo the residue was chromatographed on silica gel, followed by oxalate salt formation to give the title compound, m/e (CI+)=539 (M+H), (CI-)=537 (M-H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:13]=[CH:12][N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:10]=2)[N:5]=[C:4]([CH2:22][CH:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)[N:3]=1>C(O)=O>[CH3:1][C:2]1[N:3]=[C:4]([CH2:22][CH:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]2)[N:5]=[C:6]([NH:8][C:9]2[CH:13]=[CH:12][N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[N:10]=2)[CH:7]=1
Reactant: Cc1cc(Nc2ccn(COCC[Si](C)(C)C)n2)nc(CC2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: O=CO
Product: Cc1cc(Nc2ccn(COCC[Si](C)(C)C)n2)nc(CC2CCNCC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
21.2 mg of tert-butyl 4-((4-methyl-6-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methyl)piperidine-1-carboxylate was dissolved in 1 ml of formic acid at room temperature, followed by stirring the reaction mixture at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, basified with saturated aqueous sodium bicarbonate solution, and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O)([O-:11])=[O:10]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[N:8]=[CH:15]/[C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(/C=N/c2ccc(Cl)cc2)c1
Yield: 101.7 %

Procedure:
To a mixture of 4-chloro-phenylamine (12.8 g 100 mmol) and 3-nitro-benzaldehyde (15.1 g, 100 mmol) was added 100 mL of toluene. The resulting solution was heated to reflux with a dean-stark trap for 3 h. The toluene was removed and the residue was collect to afford (4-chloro-phenyl)-[1-(3-nitro-phenyl)-meth-(E)-ylidene]-amine as yellow solid (26.5 g, yield: 95%). (4-Chloro-phenyl)-[1-(3-nitro-phenyl)-meth-(E)-ylidene]-amine (10.0 g, 36.5 mmol), isobutene (31 ml, 365.4 mmol, 10 g), boron trifluoride etherate (1.98 ml, 7.31 mmol) and acetonitrile (40 ml) were added into a autoclave and was stirred at room temperature for 72 h. Brine was added and the organic layer was separated, dried and concentrated to afford 6-chloro-4,4-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline as yellow solid (8.7 g, yield: 73%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:35]3[CH2:34][CH2:33][N:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[F:25])[CH2:37][CH2:36]3)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: COC(=O)c1cc(F)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)cc2c1NC(c1cccc(N3CCN(c4ccccc4F)CC3)c1)CC2(C)C
Temperature: 120 °C
Yield: 61 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (392 mg, 1.0 mmol), 1-(2-fluorophenyl)-piperazine (216 mg, 1.2 mmol), palladium (II) acetate (11.2 mg, 0.05 mmol), xantphos (34.7 mg, 0.06 mmol) and cesium carbonate (652 mg, 2 mmol) in toluene (5 mL) was heated for 3 h at 120° C. After colling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (50% ethyl acetate/hexanes) to afford 6-fluoro-2-{3-[4-(2-fluoro-phenyl)-piperazin-1-yl]-phenyl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.3 g, 60%) as a white solid: MS (ESI) M+1=492.1.
Reaction SMILES: O[N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[C:3]1(=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:7])[NH:2]1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1NC(=O)c2ccccc21

Procedure:
contacting the product of (iv) with N-hydroxyphthalimide, triphenylphosphine and diethylazodicarboxylate to obtain a stereoisomer of 2-(1-(t-Boc-amino)methyl)-2-(2-nitro-1H-imidazol-1-yl)ethoxy)1H-isoindole-1,3(2H)-dione;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[I-].[Na+].C(N(C(C)C)[CH:18]([CH3:20])[CH3:19])C.C(Br)C=C>CC(C)=O>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8])[CH:18]=[CH2:19]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CCN(C(C)C)C(C)C
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C=CCBr
Product: C=CCOc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 25 g (150 mmol) 5-hydroxy-2-nitro-benzaldehyde and 44.8 g (299 mmol) sodium iodide in 400 ml acetone are added 51.2 ml (299 mmol) N-ethyldiisopropylamine and 25.3 ml (299 mmol) allyl bromide. After stirring for 18 h at r.t. the reaction mixture is filtered and the solvent is evaporated. Extraction of the residue with 1 M aqueous hydrochloric acid/dichloromethane followed by chromatography (hexane/ethyl acetate) yields 5-allyloxy-2-nitro-benzaldehyde.
Reaction SMILES: C([O:8][C:9]1[C:10]([F:27])=[C:11]([C:16]2[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=2[F:26])[C:12]([F:15])=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[F:27][C:10]1[C:9]([OH:8])=[CH:14][CH:13]=[C:12]([F:15])[C:11]=1[C:16]1[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=1[F:26]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)ccc(OCc3ccccc3)c2F)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(F)c(-c2c(F)ccc(O)c2F)n1
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of methyl 6-(3-(benzyloxy)-2,6-difluorophenyl)-5-fluoropicolinate (1.0 equiv.) in methanol (0.1 M) was added 10% Pd/C (0.1 equiv.) in ethyl acetate. The reaction was placed under an atmosphere of hydrogen and stirred for 2 hours. Upon completion, the solution was filtered over a pad of Celite, the pad was washed with methanol, the filtrate was concentrated in vacuo to give methyl 6-(2,6-difluoro-3-hydroxyphenyl)-5-fluoropicolinate as a grey oil in 86% yield. LC/MS=284.0 (M+H), Rt=0.90 min.
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B1OC(C)(C)C(C)(C)O1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:20]1[CH:21]=[CH:22][C:17]([C:16]2[O:15][N:14]=[C:13]([CH3:24])[C:12]=2[NH:11][C:10]([O:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])=[O:25])=[CH:18][CH:19]=1)[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Reactant: CCOC(=O)Cc1ccccc1B1OC(C)(C)C(C)(C)O1
Product: CCOC(=O)Cc1ccccc1-c1ccc(-c2onc(C)c2NC(=O)O[C@H](C)c2ccccc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester and [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide {4′-[3-Methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-2-yl}-acetic ac id ethyl ester, which was hydrolyzed to the acid as described in Example 34, Step 2.