Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[C:17]1([NH2:24])[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1>C(O)(C)C>[CH3:16][N:12]1[CH:13]=[CH:14][N:15]=[C:11]1[C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[NH:23][C:20]2[CH:21]=[CH:22][C:17]([NH2:24])=[CH:18][CH:19]=2)[CH:8]=1
Reactant: Nc1ccc(N)cc1
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Solvent: CC(C)O
Product: Cn1ccnc1-c1cc2nccc(Nc3ccc(N)cc3)c2s1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
A mixture of 214 (500 mg, 2.0 mmol, scheme 46) and benzene-1,4-diamine (500 mg, 4.62 mmol) in iso-PrOH (15 mL) was refluxed overnight, cooled to room temperature and filtered. The solid was collected, washed with iso-PrOH/H2O mixture, to afford the title compound 301 (300 mg, 44% yield) as a yellowish solid. MS (m/z): 322.1 (M+H) (found).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[O:31][CH:32]=[CH:33][CH:34]=1)(=[O:29])=[O:28].[OH-].[NH4+:36]>>[NH2:36][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[N:9][C:8]=2[C:7]2[C:2]([Cl:1])=[C:3]([NH:26][S:27]([C:30]3[O:31][CH:32]=[CH:33][CH:34]=3)(=[O:28])=[O:29])[CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1ccco1
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccco3)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 21 using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide (0.100 g, 0.186 mmol) and ammonium hydroxide (1.21 mL, 9.29 mmol) heated to 120° C. for 20 min in a microwave reactor the title compound was obtained as a white solid (54 mg, 0.104 mmol, 56.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.47 (s, 1H), 7.90 (d, J=5.5 Hz, 2H), 7.43 (d, J=3.8 Hz, 2H), 7.30 (d, J=3.3 Hz, 1H), 7.03 (d, J=3.3 Hz, 1H), 6.43-6.62 (m, 3H), 5.47 (d, J=5.3 Hz, 1H), 3.71 (t, J=4.7 Hz, 4H), 3.45 (t, J=4.7 Hz, 4H). MS (ESI): 519.00 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[CH2:21]([O:28][C:29]1[N:34]=[C:33]2[CH:35]=[CH:36][N:37]([C:38]([C:40]3[CH:45]=[C:44](Cl)[N:43]=[CH:42][N:41]=3)=[O:39])[C:32]2=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:21]([O:28][C:29]1[N:34]=[C:33]2[CH:35]=[CH:36][N:37]([C:38]([C:40]3[N:41]=[CH:42][N:43]=[C:44]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:45]=3)=[O:39])[C:32]2=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: O=C(c1cc(Cl)ncn1)n1ccc2nc(OCc3ccccc3)ccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)n4ccc5nc(OCc6ccccc6)ccc54)ncn3)CC1)C(=O)N2
Reaction time: 0.5 h

Procedure:
0.11 g (0.40 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.14 g (0.38 mmol) (5-benzyloxy-pyrrolo[3,2-b]pyridin-1-yl)-(6-chloro-pyrimidin-4-yl)-methanone and 0.10 mL (0.58 mmol) DIPEA in 5 mL DMF were stirred overnight at RT. The reaction mixture was diluted with water and stirred for 30 min. The precipitate formed was suction filtered, washed with water and MeOH and dried.
Reaction SMILES: C1C=CC(O[C:8](OC2C=CC=CC=2)=[N:9][C:10]#[N:11])=CC=1.[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.[Cl:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)=[CH:33][CH:34]=[N:35]2)=[CH:30][CH:29]=1>C(O)(C)C>[Cl:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32]([N:38]3[CH2:43][CH2:42][N:41]([C:8](=[N:9][C:10]#[N:11])[NH:24][C:23]4[CH:25]=[CH:26][C:20]([F:19])=[CH:21][CH:22]=4)[CH2:40][CH2:39]3)=[CH:33][CH:34]=[N:35]2)=[CH:30][CH:29]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: Nc1ccc(F)cc1
Solvent: CC(C)O
Product: N#CN=C(Nc1ccc(F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
Diphenyl cyanocarbonimidate (0.24 g, 1.0 mmol) and 4-fluoroaniline (104 4μL, 1.1 mmol) are stirred in isopropanol (10 mL) for 15 h. The reaction mixture is concentrated, and the residue dissolved in EtOAc. Washing with sat NaHCO3, drying (MgSO4) and removing the solvent delivers 0.34 g of N-cyano-N′-(4-fluorophenyl)-O-phenylisourea as a colorless solid. It is dissolved in pyridine (15 mL) and 7-chloro-4-(piperazin-1-yl)quinoline (0.25 g, 1.0 mmol) is added. The reaction mixture is heated at reflux for 4 h and afterwards concentrated. Column chromatography of the residue with hexane-EtOAc gives the title product as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:13]2[CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:26]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]2[CH:13]1[CH2:12][N:11]([CH3:26])[CH2:10]2)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C2CNCC21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CC2C(C1)N(C(=O)OC(C)(C)C)CCN2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
Added to a solution of 29 mg of the thus obtained 2,5-bis-tert-butoxycarbonyl-2,5,8-triazabicyclo[4,3,0]-nonane in acetonitrile (0.7 ml) were 0.038 ml (0.51 mmol) of a 37% aqueous solution of formaldehyde and 9.4 mg (0.15 mmol) of sodium cyanoborohydride. After the mixture was stirred for 1 hour and 20 minutes at room temperature, acetic acid was added until the reaction mixture reached pH 4, and the resultant mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, and the resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 29 mg (yield: 96%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([F:25])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.CN(C)CCCN=C=NCC.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40].Cl>ClCCl.O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:16]([C:17]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:18])=[C:15]([F:25])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.2 %

Procedure:
To a stirred solution of 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid (0.52 g, 1.50 mmol) in dichloromethane (40 mL) and tetrahydrofuran (40 mL) were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.43 g, 2.24 mmol), and 4-(dimethylamino)pyridine (0.42 g, 3.43 mmol). The reaction mixture was stirred at ambient temperature for 10 min, methanesulfonamide (0.22 g, 2.28 mmol) was added and stirring continued at ambient temperature for 36 h. 5% aqueous hydrochloric acid (10 mL) were added and then diluted with ethyl acetate (200 mL), washed with water and brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (10% to 30% gradient ethyl acetate in hexanes) afforded the title compound as a colorless solid (0.45 g, 70%): 1H NMR (300 MHz, CDCl3) δ 8.72 (d, J=16.2 Hz, 1H), 7.58 (d, J=9.3 Hz, 1H), 6.56 (d, J=14.7 Hz, 1H), 3.56 (s, 2H), 3.41 (s, 3H), 2.09-2.00 (m, 4H), 1.81-1.58 (m, 12H), 0.99-0.91 (m, 2H), 0.70-0.62 (m, 2H); MS (ES−) m/z: 420.2 (M−1).
Reaction SMILES: [NH2:1][C:2](=[N:14][OH:15])[C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].CCN([CH:22]([CH3:24])[CH3:23])C(C)C.[CH2:25]1[CH2:29]O[CH2:27][CH2:26]1>O>[CH3:27][C:26]1[CH:2]=[C:3]([C:12]2[O:15][N:14]=[C:2]([C:3]3[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=3)[C:8]([O:10][CH3:11])=[O:9])[N:1]=2)[CH:4]=[CH:5][C:25]=1[C:29]1[CH:8]=[CH:7][CH:6]=[CH:24][C:22]=1[CH3:23]
Reactant: COC(=O)c1cc(C(N)=NO)ccc1O
Reactant: CCN(C(C)C)C(C)C
Reactant: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(-c2noc(-c3ccc(-c4ccccc4C)c(C)c3)n2)ccc1O
Temperature: 150 °C

Procedure:
Under Argon atmosphere, Intermediate 3 (147.08 mg; 0.65 mmol) was stirred in anhydrous DCM (5 mL). Oxalyl chloride (57.75 μL; 0.68 mmol) was added followed by DMF (0.50 μL; 0.01 mmol). The reaction mixture was stirred 3 hours at RT. Solvents were evaporated to give 2,2′-dimethylbiphenyl-4-carbonyl chloride as a yellow oil. The latter was dissolved in anhydrous THF (3 mL), Intermediate 46 (136.62 mg; 0.65 mmol) and DIEA (221.08 μL; 1.30 mmol) were added under argon. The mixture was heated in the microwave at 150° C. for 15 min. The reaction mixture was diluted in water and extracted with EtOAc, the organic phase was then washed with NH4Cl, NaHCO3 and NaCl sat. solution. The organic layer was then dried over magnesium sulfate, filtered and concentrated, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound. LC/MS (Method A): 398.9 (M−H)−, 400.8 (M+H)+. HPLC (Method A) Rt 6.37 min (Purity: 98.8%).
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:26])[C:7]1[CH:12]=[C:11]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)[CH:10]=[C:9]([N:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]2=[O:25])[CH:8]=1>O.C1COCC1>[CH3:24][C:21]1[CH:22]=[CH:23][N:18]([C:9]2[CH:8]=[C:7]([CH:12]=[C:11]([N:13]3[CH:17]=[N:16][N:15]=[N:14]3)[CH:10]=2)[C:6]([OH:26])=[O:5])[C:19](=[O:25])[CH:20]=1
Reactant: COC(=O)c1cc(-n2cnnn2)cc(-n2ccc(C)cc2=O)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccn(-c2cc(C(=O)O)cc(-n3cnnn3)c2)c(=O)c1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A solution of LiOH.H2O (95 mg, 2.25 mmol) in H2O (7 mL) was added dropwise to a suspension of 3-(4-methyl-2-oxo-2H-pyridin-1-yl)5-tetrazol-1-yl-benzoic acid methyl ester (500 mg, 1.61 mmol) in THF (4 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred until the reaction solution turned into clear. Solvent was removed under vacuum and the aqueous solution was acidified by addition of 10% HCl to pH=2. The resulting precipitate was collected and dried to afford 3-(4-methyl-2-oxo-2H-pyridin-1-yl)-5-tetrazol-1-yl-benzoic acid as yellow solid (453 mg, 95%). MS (M+H)=298.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[NH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@@H:22]2[O:28][C@H:27]([CH3:29])[C@@H:25]([OH:26])[C@H:23]2[OH:24])=[C:15]([S:30][NH2:31])[N:14]=1>C(O)C>[NH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@@H:22]2[O:28][C@H:27]([CH3:29])[C@@H:25]([OH:26])[C@H:23]2[OH:24])=[C:15]([S:30]([NH2:31])=[O:6])[N:14]=1
Reactant: C[C@H]1O[C@@H](n2cnc3c(SN)nc(N)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Product: C[C@H]1O[C@@H](n2cnc3c(S(N)=O)nc(N)nc32)[C@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 44.5 %

Procedure:
A solution of m-chloroperoxybenzoic acid (0.10 g, 0.5 mmol) in ethanol (10 mL) was added dropwise to an ice-cooled stirred solution of 41 (0.15 g, 0.5 mmol) in ethanol (25 mL), during 15 min. The reaction mixture was allowed to stand at 0° C. overnight and then evaporated to dryness under reduced pressure. The residue was triturated with a mixture of ethanol (2 mL) and ethyl ether (30 mL). The precipitated crystalline product was collected by filtration and dried at 80° C. for 3 h to yield 70 mg (45%) of the title compound, mp >100° C. (dec.). IR (KBr): 1050 (vs, s, S=O), 3100-3600 (NH2, OH)cm-1 :UV: λmax (pH 1) 330 nm (ε 3,600): λmax (pH 7) 324 nm (4,400): λmax (pH 11) 321 nm 4,300): 1H NMR (DMSO-d6): δ 1.30 (d, 3, CH3), 5.80 (d, 1, J 5.25 Hz, C1'H), 6.51 (s, 2, SONH2, exchanged with D2O), 6.98 (s, 2, NH2, exchanged with D2O), 8.40 (s, 1, C8H), and other sugar protons. Anal. Calcd. for C10H14N6O4S (314.32): C, 38.21; H, 4 49; N, 26.74; S, 10.20. Found: C, 37.98; H, 4.41; N, 26.51; S, 9.91.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.Cl.[CH3:20][NH:21][O:22][CH3:23].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:23][O:22][N:21]([CH3:20])[C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]2)=[CH:17][CH:16]=1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (10.05 g), N,O-dimethylhydroxylamine hydrochloride (4.35 g), WSC (9.32 g), HOBt (6.57 g), and TEA (6.21 ml) in DMF (80 ml) was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) and crystallized from hexane to give the title compound (7.60 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[N:25]4[CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=[C:24]4[C:23](Cl)=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:35]1[CH2:40][CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH2:37][CH2:36]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[N:25]4[CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=[C:24]4[C:23]([C:38]4[CH2:39][CH2:40][O:35][CH2:36][CH:37]=4)=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cn2c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)cnc(Cl)c2n1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Product: CCOC(=O)c1cn2c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)cnc(C3=CCOCC3)c2n1
Yield: 44 %

Procedure:
Compound 90g (1.08 g, 2.10 mmol) was subjected to Suzuki coupling with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane using the method described in Example 87, Step D to obtain compound 90h as a yellow solid (520 mg, 44% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H34N6O5: 535.3 (M+H). found: 535.6.
Reaction SMILES: NN.[CH2:3]([O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[C:32]([C:37]([N:39]2[CH2:43][C:42](=[CH2:44])[CH2:41][C@H:40]2[CH2:45][OH:46])=[O:38])=[CH:31][C:30]=1[N+:47]([O-])=O)[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:15]([N:17]2[CH2:21][C:20](=[CH2:22])[CH2:19][CH:18]2[CH2:23][OH:24])=[O:16])=[CH:9][C:8]=1[N+:25]([O-])=O.C(Cl)(Cl)Cl.CO>CO.[Ni]>[CH2:5]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:15]([N:17]2[CH2:21][C@@H:20]([CH3:22])[CH2:19][C@H:18]2[CH2:23][OH:24])=[O:16])=[CH:9][C:8]=1[NH2:25])[CH2:4][CH2:3][O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[C:32]([C:37]([N:39]2[CH2:43][CH:42]([CH3:44])[CH2:41][CH:40]2[CH2:45][OH:46])=[O:38])=[CH:31][C:30]=1[NH2:47]
Reactant: C=C1CC(CO)N(C(=O)c2cc([N+](=O)[O-])c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)C[C@H]4CO)cc3[N+](=O)[O-])cc2OC)C1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc(OCCCOc2cc(OC)c(C(=O)N3C[C@@H](C)C[C@H]3CO)cc2N)c(N)cc1C(=O)N1CC(C)CC1CO
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of hydrazine (23 mg, 23 μL, 0.72 mmol) in MeOH (5 mL) was added dropwise to a solution of the diol 76 (95 mg, 0.145 mmol) and Raney Ni (20 mg) in MeOH (15 mL) heated at reflux. After 1 hour at reflux TLC (90% CHCl3/MeOH) revealed some amine formation. The reaction mixture was treated with further Raney Ni (20 mg) and hydrazine (23 mg, 23 μL, 0.72 mmol) in MeOH (5 mL) and was heated at reflux for an additional 30 minutes at which point TLC revealed complete reaction. The reaction mixture was then treated with enough Raney Ni to decompose any remaining hydrazine and heated at reflux for a further 1.5 hours. Following cooling to room temperature the mixture was filtered through a sinter and the resulting filtrate evaporated in vacuo. The resulting residue was then treated with CH2Cl3 (30 mL), dried (MgSO4), filtered and evaporated in vacuo to provide the bis-amine (77) as a yellow oil (54 mg, 63%): 1H NMR (270 MHz, CDCl3) (diastereoisomers) δ 6.73 (S, 2Harom) 6.32 (s, 2Harom), 4.60-4.30 (m, 2H, NCHCH2OH) 4.19 (t, 4H, J=5.87 Hz, OCH2CH2CH2O), 3.78-3.50 (m, 14H, NCHCH2OH, NCH2CHCH3 and OCH3), 2.40-1.55 (m, 8H, NCH2CHCH3); OCH2CH2CH2O and NCH2CHCH2CH2), 1.00-0.95 (m, 6H, NCH2CHCH3); MS (EI), m/z (relative intensity) 600 (M+., 16), 459 (46), 345 (16), 206 (13), 186 (17), 180 (31), 166 (37), 149 (6), 142 (76), 100 (6), 98 (13), 97 (29), 84 (81), 69 (7), 55 (100).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[CH:11][C:10]([CH2:25]Cl)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[CH:11][C:10]([CH2:25][N:27]2[CH2:33][CH2:32][CH2:31][N:30]([CH2:25][C:10]3[CH:11]=[C:12]([C:13]4[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=4)[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:9]=3)[CH2:29][CH2:28]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCNC1
Reactant: COc1cc(-c2cc(CCl)nn2Cc2ccccc2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)n(Cc5ccccc5)n4)CC3)nn2Cc2ccccc2)cc(OC)c1OC

Procedure:
1-Benzyl-3-chloromethyl-5-(3,4,5-trimethoxy-phenyl)pyrazole (559 mg) and homopiperazine (68 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:12])[CH2:7][C:8]([CH2:10]C)=[O:9])[CH3:4].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[C:24]1(C)C=CC=CC=1>>[C:8]([C:7]([CH3:24])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]([O:5][CH2:3][CH3:4])=[O:12])(=[O:9])[CH3:10]
Reactant: CCOC(=O)CC(=O)CC
Reactant: CCOC(=O)CCCCCBr
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CCCCCC(C)(C(C)=O)C(=O)OCC
Reaction time: 0.5 h
Yield: 46 %

Procedure:
In a 1 L three necked flask equipped with a mechanical stirrer and reflux condenser was placed dry toluene (300 ml). The system was flushed with argon and sodium hydride (Aldrich, 60% dispersion in mineral oil) (7.2 g, 0.18 mmol) was added. Ethyl-γ-methylacetoacetate (Aldrich, 21 g, 0.15 mole) was added with stirring over a 30 minutes. The resulting solution was heated under reflux for 2 hrs and cooled slightly. (Note: Reaction mixture becomes a thick paste and mechanical stirrer is essential). Ethyl 6-bromohexanoate (Aldrich, 33.5 g, 0.15 mol) was added (all at once) and the suspension was heated under reflux for 12 hrs, cooled, filtered and the solvent evaporated under pressure. The residue was distilled under vacuum to yield 20 g (46%) of colorless liquid, b.p. 110-115° C. (0.1 mm). IR (neat): σcm−1=1735 (s) and 1713 (s). 1H NMR in CDCl3 δ, 4.1-4.2 (m, 4H, (O—CH2)2); 2.1 (t, J=8.4 Hz, 2H, CH2COO—); 2.15 (s, 3H, CH3CO); 1.5-2.0 (m, 4H, (CH2)2); 1.2-1.4 (m, 13H, 2 CH2 and three —CH3).
Reaction SMILES: [CH3:1][N:2]([C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[C@H:3]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[CH3:4].[CH3:20]N(C)C=O.[S:25]([O:30]C)([O:28][CH3:29])(=[O:27])=[O:26]>C(OCC)(=O)C>[CH3:29][O:28][S:25]([O-:30])(=[O:27])=[O:26].[OH:11][C:7]1[CH:6]=[C:5]([C@@H:3]([N+:2]([CH3:20])([CH3:1])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:4])[CH:10]=[CH:9][CH:8]=1
Reactant: COS(=O)(=O)OC
Reactant: CN(C)C=O
Reactant: C[C@@H](c1ccccc1)N(C)[C@@H](C)c1cccc(O)c1
Solvent: CCOC(C)=O
Product: COS(=O)(=O)[O-]
Product: C[C@@H](c1ccccc1)[N+](C)(C)[C@@H](C)c1cccc(O)c1
Temperature: 60 °C
Yield: 85 %

Procedure:
Mix 5.1 g (0.02 mol) of 3-[(S)-1-(methyl-[(S)-1-phenylethyl]amino)ethyl]phenol (formula V) with 10 ml N,N-dimethylformamide and 12.6 g (0.1 mol) of dimethyl sulfate at room temperature, and heat the mixture to 60° C. for 10 hours. Let it cool to room temperature, and add 100 ml of ethyl acetate. A light yellow solid is produced. Filter and dry it to receive 7.0 g light yellow solid with a yield of 85%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].N[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.N1C=CN=C1>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[N:6]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:5]2=[O:15]
Reactant: Nc1cccnc1
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Agent: c1c[nH]cn1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Nc1cc2c(cc1[N+](=O)[O-])C(=O)N(c1cccnc1)C2=O
Temperature: 190 °C
Yield: 62.2 %

Procedure:
5-Amino-6-nitroisoindoline-1,3-dione (3.00 g, 14.48 mmol), 3-aminopyridine (5.45 g, 57.92 mmol) and imidazole (3.94 g, 57.92 mmol) were suspended in diphenyl ether (50 mL). The mixture was stirred and heated to 190° C. for 3 days under argon. Then, the solid was filtered, washed with hexanes and purified by column chromatography (silica-gel, CH2Cl2/Acetone=7/3 v/v) to give a yellow solid product, 2.56 g, 62.2% yield. MS: 282.8 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 8.65 (d, 1H, J=2.0 Hz), 8.62 (dd, 1H, J=5.0 Hz, J2=1.0 Hz), 8.46 (S, 2H), 8.42 (s, 1H), 7.89 (m, 1H), 7.60-7.58 (m, 1H), 7.55 (s, 1H).