Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:15][CH2:14][C:13]1([CH3:19])[C:16]([OH:18])=O)=[O:11].C1COCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52][NH2:53])=[CH:50][CH:49]=1>CN(C=O)C>[CH3:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52][NH:53][C:16]([C:13]2([CH3:19])[CH2:14][CH2:15][N:12]2[C:10](=[O:11])[CH2:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[O:18])=[CH:50][CH:49]=1
Reactant: Cc1ccc(CN)cc1
Reactant: CC1(C(=O)O)CCN1C(=O)Cc1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(CNC(=O)C2(C)CCN2C(=O)Cc2ccc(Cl)cc2Cl)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[2-(2,4-dichloro-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid, Intermediate 120 (1 eq.) in either THF or DMF was added TEA (4 eq.) and TBTU (2 eq.). The reaction was stirred at 20° C. for 30 min, then 4-methyl-benzylamine (1.5 eq.) was added. The reaction was stirred at 20° C. for 72 h. The crude was concentrated under reduced pressure then partitioned between water and EtOAc. The organic layer was washed twice with water, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by preparative LCMS to afford 1-[2-(2,4-dichloro-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid 4-methyl-benzylamide.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH2:9][CH:10]1[CH2:16][CH:15]2[N:17]([C:18]3[C:19]4[C:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[C:25]([C:33](=[O:38])[NH:34][CH:35]([CH3:37])[CH3:36])[S:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH:12]([CH2:13][CH2:14]2)[CH2:11]1)(=O)=O.[N-:39]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN1C(=O)CCC1.C(Cl)Cl>[NH2:39][CH2:6][CH2:7][O:8][CH2:9][CH:10]1[CH2:11][C@H:12]2[N:17]([C:18]3[C:19]4[C:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[C:25]([C:33]([NH:34][CH:35]([CH3:37])[CH3:36])=[O:38])[S:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C@H:15]([CH2:14][CH2:13]2)[CH2:16]1
Reactant: CC(C)NC(=O)c1sc2ncnc(N3C4CCC3CC(COCCOS(C)(=O)=O)C4)c2c1-c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CC(C)NC(=O)c1sc2ncnc(N3[C@@H]4CC[C@H]3CC(COCCN)C4)c2c1-c1ccccc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
2-[[8-[6-(isopropylcarbamoyl)-5-phenyl-thieno[2,3-d]pyrimidin-4-yl]-8-azabicyclo[3.2.1]octan-3-yl]methoxy]ethyl methanesulfonate (0.3 g, 0.5 mmol) was dissolved in NMP (2 mL). Sodium azide (0.2 g, 3 mmol) was added and the reaction heated to 150° C. in the microwave for 30 minutes. The reaction mixture was diluted with DCM (20 mL), washed with water (2×20 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was dissolved in THF (5 mL). Triphenylphosphine (0.2 g, 0.8 mmol) was added and the reaction stirred overnight at room temperature. It was heated to reflux for 5 hours. The solvent was removed at reduced pressure. The resulting residue was taken up in DCM, washed with water, dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by flash chromatography, eluting with a gradient of DCM to 90/10/1 DCM/MeOH/NH4OH to afford 4-[(1R,5S)-3-(2-aminoethoxymethyl)-8-azabicyclo[3.2.1]octan-8-yl]-N-isopropyl-5-phenyl-thieno[2,3-d]pyrimidine-6-carboxamide (100 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1.C(Cl)(Cl)Cl>CC(C)=O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)c2ccc(O)cc2o1
Reactant: Fc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: O=c1cc(OCc2ccccc2)c2ccc(OCCc3ccc(F)cc3)cc2o1

Procedure:
A mixture of 4-benzyloxy-7-hydroxycoumarin (5.36; 0.02 mole) anhydrous potassium carbonate (4.0 g) and 1-bromo-2-(4-fluorophenyl) ethane (4.06 g) in acetone (100 ml) was stirred at reflux for 20 hours and the inorganic material filtered off. Evaporation of the filtrate in vacuo gave an oil which rapidly set solid on scratching. Chloroform (200 ml) was added and the mixture filtered to remove unchanged 4-benzyloxy-7-hydroxycoumarin. Reevaporation of the filtrate afforded a white solid, 3.34 g (43%) of m.p. 120°, νmax (mull) 1715, 1675, 1620 cm-1 ; τ(CDCl3); 6.93 (2H, t, J 6.7 Hz); 5.80 (2H, t, J 6.7 Hz); 4.87 (2H, S); 4.38 (1H, ); 3.29-2.49 (6H, m) 2.32 (1H, d, J 10 Hz); (Found C, 73.75 H, 5.14 C24H19FO4 requires; C, 73.84; H, 4.91%).
Reaction SMILES: C(O[C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])C1C=CC=CC=1.ClC1C=CC(N)=C(F)C=1>CC(O)C>[ClH:19].[CH3:21][O:20][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:9]=1)[N:16]=[CH:15][N:14]=[CH:13]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: Nc1ccc(Cl)cc1F
Solvent: CC(C)O
Product: COc1ccc2ncncc2c1
Product: Cl
Yield: 143.7 %

Procedure:
A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline (1.2 g, 4 mmol), (prepared as described for the starting material in Example 1), and 4-chloro-2-fluoroaniline (444 μl, 4 mmol) in 2-propanol (40 ml) was refluxed for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with 2-propanol then ether and dried under vacuum to give 7-benzyloxy-44-chloro-2-fluoroanilino)6-methoxyquinazoline hydrochloride (1.13 g. 64%).
Reaction SMILES: Cl[C:2]1[CH:9]2[CH2:10][N:5]([CH2:6][CH2:7][CH2:8]2)[CH2:4][C:3]=1[C:11]1[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:13][S:14][N:15]=1.C([OH:23])C.C(N(CC)CC)C.[CH:31]([OH:33])=[O:32]>[Pd]>[C:17]([OH:16])(=[O:23])[C:31]([OH:33])=[O:32].[CH2:17]([O:16][C:12]1[C:11]([C:3]2[CH2:4][N:5]3[CH2:10][CH:9]([CH:2]=2)[CH2:8][CH2:7][CH2:6]3)=[N:15][S:14][N:13]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOc1nsnc1C1=C(Cl)C2CCCN(C1)C2
Reactant: CCO
Reactant: O=CO
Agent: [Pd]
Solvent: CCN(CC)CC
Product: CCCCOc1nsnc1C1=CC2CCCN(C1)C2
Product: O=C(O)C(=O)O
Temperature: 80 °C

Procedure:
To a solution of 4-chloro-3-(3-butoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo-[3.3.1]non-3-ene (0.63 g, 2.0 mmol) in abs. ethanol (20 ml), triethyl amine (3 ml) and formic acid (1 ml) were added. The reaction mixture was heated to 80° C. under nitrogen. At this temperature palladium on carbon (0.5 g, 5%) was added in one portion. After 15 min. another portion of palladium on carbon (0.25 g, 5%) was added. The last addition of palladium on carbon was repeated twice. After cooling, the reaction mixture was filtered and evaporated. The residue was dissolved in water basified with potassium carbonate and extracted with ether (3×75 ml). The ether extracts were dried and evaporated. The crude compound was purified by column chromatography (eluent: CH2Cl2 /MeOH (9:1)), yielding 80 mg of free base. The title compound was crystallized with oxalic acid from acetone/ether in 80 mg yield. (Compound 95). M.p. 150-151° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH:16]([NH2:19])([CH3:18])[CH3:17]>C(O)CCC>[CH:16]([NH:19][C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1)([CH3:18])[CH3:17]
Reactant: Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1
Reactant: CC(C)N
Solvent: CCCCO
Product: CC(C)Nc1cc(C(F)(F)F)cc2nc(N)nn12
Temperature: 120 °C
Yield: 61.1 %

Procedure:
A suspension of 5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A7), 183.00 mg; 0.77 mmol; 1.00 eq.) and isopropylamine (664.58 μl; 7.74 mmol; 10.00 eq.) in n-butanol (1.50 mL) was heated at 120° C. for 1 h30 under MW irradiation. The reaction mixture was then concentrated under vacuum till dryness. The solid obtained was triturated in water/MTBE and filtered. The solid which precipitated in mother liquor was finally filtered, washed with water and dried under vacuum at 40° C. to give the title compound as an off-white solid (122 mg, 61%). HPLC, Rt: 2.64 min. (purity 86.5%). LC/MS, M+(ESI): 259.9, M−(ESI): 257.9.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:22])[C:4]1[C:5]([CH3:21])=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7]2.C(N(CC)CC)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[O:40][CH:41]([CH3:43])[CH3:42])[C:34](Cl)=[O:35]>ClCCl>[Cl:30][C:31]1[CH:32]=[C:33]([C:34]([O:1][NH:2][C:3](=[NH:22])[C:4]2[C:5]([CH3:21])=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][N:9]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:8][CH2:7]3)=[O:35])[CH:37]=[CH:38][C:39]=1[O:40][CH:41]([CH3:43])[CH3:42]
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1Cl
Reactant: Cc1c(C(=N)NO)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(=N)NOC(=O)c2ccc(OC(C)C)c(Cl)c2)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
To a solution of 1,1-dimethylethyl 6-[(hydroxyamino)(imino)methyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 17; 435 mg; 1.42 mmol) in dichloromethane (10 ml) was added triethylamine (0.30 ml; 2.14 mmol) followed by 3-chloro-4-[(1-methylethyl)oxy]benzoyl chloride (Preparation 8; 365 mg; 1.57 mmol) in dichloromethane (5 ml). After 30 min, the reaction was concentrated, and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with a gradient of 10-50% ethyl acetate in cyclohexane gave the title compound as a white foam (413 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.Cl.[CH3:14][O:15][C:16]([C:18]1([NH2:27])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17]>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:14][O:15][C:16]([C:18]1([NH:27][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([Br:1])[CH:3]=2)[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17]
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Reactant: COc1ccc(C(=O)O)cc1Br
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(Br)c2)Cc2ccccc2C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
3-Bromo-4-methoxybenzoic acid (22.8 g, 98.8 mmol) was dissolved in thionyl chloride (42 ml) and stirred at 60° C. for 30 min. The volatiles were evaporated in vacuo and the residue was stripped with dioxane. The obtained acid chloride was dissolved in DCM (50 ml). 2-Amino-indane-2-carboxylic acid methyl ester hydrochloride (15.0 g, 65.9 mmol) was suspended in DCM (100 ml), EDIA (10.2 g, 79.1 mmol) was added, the mixture was cooled in an ice bath, and the solution of the acid chloride was slowly added. The mixture was stirred overnight at room temperature and evaporated to dryness. The residue was purified by silica gel chromatography (DCM/methanol gradient) and subsequent crystallization from EA to give 21.8 g of the title compound.
Reaction SMILES: OCC[C:4]1[C:5]([N+:15]([O-:17])=[O:16])=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1.[N+](C1C=CC=[C:23]2[C:24](OC(=O)C=12)=[O:25])([O-])=O.C(CN)O.OCCN1C(=O)C2=C(N=[N+]=[N-])C=CC=C2C1=O>C1(C)C=CC=CC=1.CN(C)C=O>[OH:25][CH2:24][CH2:23][N:10]1[C:11](=[O:12])[C:6]2=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=[CH:14][CH:13]=[C:7]2[C:8]1=[O:9]
Reactant: O=C1NC(=O)c2c1ccc(CCO)c2[N+](=O)[O-]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Agent: [N-]=[N+]=Nc1cccc2c1C(=O)N(CCO)C2=O
Solvent: Cc1ccccc1
Solvent: NCCO
Solvent: CN(C)C=O
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1CCO
Yield: 76 %

Procedure:
N-(β-Hydroxyethyl-3-nitrophthalimide, used in the above example, can be prepared as follows: a mixture of 19.3 g (0.1 mol) of 3-nitrophthalic anhydride, 6.7 g (0.1 mol) of ethanolamine, 50 ml of N,N-dimethylformamide (DMF) and 30 ml of toluene is boiled, the water formed in the course of the reaction being removed azeotropically. The reaction mixture is then evaporated to dryness. The residue is dissolved in 200 ml of methylene chloride and the solution is extracted by shaking with 100 ml of saturated sodium chloride solution. The methylene chloride solution is then dried with anhydrous sodium sulphate and evaporated. 18 g (76% of theory) of N-(β-hydroxyethyl)-3-nitrophthalimide are obtained as an oily residue, which crystallises in a short time; melting point 93° C. IR spectrum (CH2Cl2): 1790 cm-1 and 1730 cm-1 (CO--N--CO); 1550 cm-1 and 1370 cm-1 (CO2).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:14]=[C:15]([NH2:18])[NH:16][N:17]=1.C(N(CC)CC)C.[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[O:34]1CCOCC1>O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:14]=[C:15]([NH:18][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:16][N:17]=1
Reactant: C1COCCO1
Reactant: Cc1onc(-c2ccccc2)c1-c1cc(N)[nH]n1
Reactant: ClCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1-c1cc(NC(=O)c2ccccc2)[nH]n1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
3-(5-Methyl-3-phenyl-isoxazol-4-yl)-3-oxo-propionitrile (0.391 g, 1.73 mmol) in Ethanol (3 mL) was treated with hydrazine (0.168 mL, 3.46 mmol) and heated to reflux. Evaporation in vacuum gave 5-(5-Methyl-3-phenyl-isoxazol-4-yl)-2H-pyrazol-3-ylamine used without purification. To the resulting amine (0.039 g, 0.16 mmol) in dioxane was added triethyl amine followed by benzyl chloride (0.019 mL, 0.16 mmol). The reaction was stirred at 10° C. for 1 hr and 2 hr at ambient temperature. The solution was diluted with water extracted with ethyl acetate, washed with saturated NaHCO3, Brine, dried over MgSO4 and concentrated in vacuum. HPLC purification afforded 1.4 mg of title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:18])[N:8]3[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17].C(N(CC)CC)C.[F:26][C:27]([F:35])([F:34])[C:28]([F:33])([F:32])[C:29](O)=[O:30]>C(#N)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:18])[N:8]3[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:29](=[O:30])[C:28]([F:33])([F:32])[C:27]([F:35])([F:34])[F:26]
Reactant: Cc1nc2cccc3n(CCCCN)c(=O)c1n23
Reactant: O=C(O)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc2cccc3n(CCCCNC(=O)C(F)(F)C(F)(F)F)c(=O)c1n23
Temperature: 25 °C

Procedure:
To a solution of 2.44 g (10.0 mmol) of 3-methyl-1-[4-(amino)butan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one and 1.81 ml (13.0 mmol) of triethylamine in 100 ml of acetonitrile was added, while stirring at room temperature, 2.31 g (12.0 mmol) of ethyl ester of pentafluoropropionic acid. The mixture was stirred for 14 hours at the same temperature. The solvent was distilled off. To the residue was added methylene chloride. The mixture was washed with water, which was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent:ethyl acetate), and recrystallized from ethyl acetate--hexane to afford 1.53 g (39.1%, a colorless crystals) of the desired compound.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:8][C:6]1[CH:7]=[C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
5-Fluoro-2-nitrotoluene (1 mL, 8.20 mmol, commercially available from Aldrich), Boc-piperazine (1.68 g, 9.02 mmol, commercially available from Aldrich), anhydrous potassium carbonate (2.27 g, 16.40 mmol) and DMF (25 mL) were combined and heated to 50° C. for 24 hours. Upon allowing the reaction mixture to cool to room temperature, water was added to the reaction mixture and the resulting precipitate was filtered as product, washed with ether and dried under reduced pressure to give 2.21 g tert-butyl 4-(3-methyl-4-nitrophenyl)piperazine-1-carboxylate. 1H-NMR (400 MHz, CDCl3), δ 7.96 (d, 1H), 6.90 (s, 1H), 6.85 (s, 1H), 3.35 (m, 4H), 3.19 (m, 4H), 2.55 (s, 3H), 1.42 (s, 9H). MS (EI): 322 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:10]=[C:11]([N+:14]([O-])=O)[NH:12][CH:13]=2)[CH2:4][CH2:3]1.CO.C1COCC1.CO.[S:26]1[CH:30]=[C:29]([C:31]2[C:40]3[N:39]=[CH:38][CH:37]=[N:36][C:35]=3[C:34]([C:41](O)=[O:42])=[CH:33][CH:32]=2)[C:28]2[CH:44]=[CH:45][CH:46]=[CH:47][C:27]1=2>[Ni].C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:10]=[C:11]([NH:14][C:41]([C:34]3[C:35]4[N:36]=[CH:37][CH:38]=[N:39][C:40]=4[C:31]([C:29]4[C:28]5[CH:44]=[CH:45][CH:46]=[CH:47][C:27]=5[S:26][CH:30]=4)=[CH:32][CH:33]=3)=[O:42])[NH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2c[nH]c([N+](=O)[O-])n2)CC1
Reactant: O=C(O)c1ccc(-c2csc3ccccc23)c2nccnc12
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2c[nH]c(NC(=O)c3ccc(-c4csc5ccccc45)c4nccnc34)n2)CC1
Temperature: 65 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but stirring the reaction mixture for 20 h at 65° C., using 1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1) instead of 2-nitroimidazole in Step 14.3, Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2, and 8-benzo[b]thiophen-3-yl-quinoxaline-5-carboxylic acid (Example 59) in Step 14.1. Title compound: ESI-MS: 484.0 [M+H]+; tR=3.36 min (System 1); TLC: Rf=0.10 (DCM/MeOH, 9:1).
Reaction SMILES: Br[C:2]1[C:3]([N:8]2[CH2:11][CH:10]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:74]([O:78][Na])(C)(C)C>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]>[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[CH:10]1[CH2:11][N:8]([C:3]2[C:2]([N:22]3[CH2:27][CH2:26][CH:25]([CH2:74][OH:78])[CH2:24][CH2:23]3)=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:9]1
Reactant: Brc1cccnc1N1CC(c2ccc3ccccc3n2)C1
Reactant: CC(C)(C)O[Na]
Reactant: C1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: OCC1CCN(c2cccnc2N2CC(c3ccc4ccccc4n3)C2)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a solution of 2-[1-(3-bromo-pyridin-2-yl)-azetidin-3-yl]-quinoline (150 mg, 0.51 mmol), piperidine (43.35 mg, 0.51 mmol), BINAP (31.1 mg, 0.05 mmol), t-BuONa (196 mg, 2 mmol) in dioxane (15 mL) was added Pd2(dba)3 (45.75 mg, 0.05 mmol) then the reaction mixture was stirred at 90° C. under a N2 atmosphere overnight. The reaction mixture was filtered through CELITE™ and washed with EtOAc (50 mL). The filtrate was concentrated and the crude product was purified by silica gel column to give [2′-(3-quinolin-2-yl-azetidin-1-yl)-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl]-methanol (60 mg, 0.17 mmol, yield 34%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:10]/[S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])/[CH3:9])[CH:5]=[CH:4][N:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([C@@H:8]([NH:10][S:11]([C:13]([CH3:14])([CH3:16])[CH3:15])=[O:12])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: C/C(=N\S(=O)C(C)(C)C)c1ccnc(Br)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](NS(=O)C(C)(C)C)c1ccnc(Br)c1
Reaction time: 2.5 h

Procedure:
To a chilled (−78° C.) solution of 2-methyl-propane-2-sulfinic acid [1-(2-bromopyridin-4-yl)-eth-(E)-ylidene]-amide (9.3 g, 31 mmol) in THF (280 mL) is added a 1 M solution of L-Selectride in THF (61.3 mL, 61.3 mmol) dropwise. After 2.5 hours, the chilled mixture is quenched with saturated aqueous NH4Cl (100 mL). The layers are separated and the aqueous layer is extracted with EtOAc (2×400 mL). The combined organic layers are washed with brine, and concentrated. The residue is purified by silica gel chromatography eluting with a gradient of 50-90% EtOAc in hexanes to afford 2-methyl-propane-2-sulfinic acid [(S)-1-(2-bromopyridin-4-yl)-ethyl]-amide as an oil which contained 5% of the opposite diastereomer.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH:10]([CH3:15])[C:9](=[O:16])[C:8]=2[CH:17]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH:10]([CH3:15])[C:9](=[O:16])[C:8]=2[CH:17]=1
Reactant: CC1C(=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Agent: [Pd]
Solvent: CO
Product: CC1C(=O)c2cc(N)ccc2OC1(C)C
Reaction time: 5 h
Yield: 102.3 %

Procedure:
A mixture of of 6-nitro-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one (23.5 g, 0.1 mol) and 10% palladium on carbon (2 g) in methanol was stirred under an atmosphere of hydrogen at 40°-50° C. for five hours at atmospheric pressure. The solution was then filtered, and the solvent removed from the filtrate under reduced pressure to give 21 g of 6-amino-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one as an oil. B. To a mixture of water (293 ml) and concentrated hydrochloric acid (25.7 ml) at 0° C. was added a solution of 6-amino-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one (20.5 g, 0.1 mol) in ethanol (140 ml). A solution of sodium nitrite (7.6 g, 0.11 mol) in water (90 ml) was then added, such that the temperature did not rise above 0° C. After fifteen minutes at 0° C., the reaction mixture was poured into a solution containing potassium cyanide (58.6 g, 0.90 mol) and cuprous cyanide (80.61 g, 0.90 mol) in water at 90° C., whilst maintaining the temperature of the reaction above 70° C. The resulting mixture was heated at 90° C. for one hour and then cooled to 20° C., extracted with ethyl acetate and the extract washed with water. The organic layer was separated and the solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with dichloromethane/acetone (99/1) to give 16.58 g of 6-cyano-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one, 1H NMR (CDCl3): δ1.2 (d, 3H), 1.30 (s, 3H), 1.5 (s, 3H), 2.8 (q, 1H), 7.0 (d, 1H), 7.70 (d, 1H), 8.1 (s, 1H).
Reaction SMILES: C(O)(=O)C.C(N)CC.C([O-])(=O)C.C([NH3+])CC.[Cl:17][C:18]1[CH:19]=[C:20]([C:25]2[O:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[CH:21]=[CH:22][C:23]=1[Cl:24].[N+:32]([CH3:35])([O-:34])=[O:33]>CO>[Cl:17][C:18]1[CH:19]=[C:20]([C:25]2[O:31][C:28](/[CH:29]=[CH:35]/[N+:32]([O-:34])=[O:33])=[CH:27][CH:26]=2)[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: O=Cc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: CCC[NH3+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCCN
Product: O=[N+]([O-])/C=C/c1ccc(-c2ccc(Cl)c(Cl)c2)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A stirred solution of acetic acid (1.4 ml, 1.46 g, 24.3 mmol) in methanol (3.5 ml) under nitrogen atmosphere at 0° C. was treated dropwise with n-propylamine (2.0 ml, 1.42 g, 24.0 mmol). The resulting n-propylammonium acetate solution was stirred at 0° C. for 5 min, then added dropwise to a stirred solution of 5-(3,4-dichlorophenyl)furfural (10.04 g, 41.6 mmol) in nitromethane (6.8 ml, 7.61 g, 124.7 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 30 min. Then the cooling bath was removed, and stirring was continued at RT. From time to time, 10 ml of THF was added five times. After stirring overnight THF was evaporated and water was added. A solid was filtrated, washed with water and heptane to afford 11.46 g of 2-(3,4-dichlorophenyl)-5-((E)-2-nitrovinyl)furan. 1H NMR (400 MHz, DMSO-d6): 7.38 (1H, d), 7.43 (1H, d), 7.76 (1H, d), 7.95 (1H, dd), 8.03 (1H, d), 8.19 (1H, d), 8.31 (1H, d)