Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(Cl)CCl.C1C=CC2N(O)N=[N:24]C=2C=1.N>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:24])=[O:13])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: O=C(O)c1cc(Br)cc2cc[nH]c12
Reactant: On1nnc2ccccc21
Agent: N
Solvent: ClCCCl
Solvent: ClCCl
Product: NC(=O)c1cc(Br)cc2cc[nH]c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a solution of 5-bromo-1H-indole-7-carboxylic acid (10.0 g, 42 mmol) in CH2Cl2 (100 mL) at room temperature, EDC (9.66 g, 50.4 mmol), HOBt (6.81 g, 50.4 mmol) and NH3 (2.0 M in MeOH, 84 mL, 168 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The water layer was extracted with ethyl acetate (2×100 mL) and the combined organic phase was dried over MgSO4 and concentrated to give 10 g (98%) of the title compound as a crude product.
Reaction SMILES: CC(C)=CCC1C=C([C:12]2[O:22][C:21]3[CH:20]=[C:19]([OH:23])[CH:18]=[C:17](O)[C:16]=3[C:14](=[O:15])[C:13]=2[OH:25])C=CC=1O.CC1[CH2:41][C@@H:40]2[C:42]3C=CC(O)=CC=3O[C@]3(C4C=CC(O)=CC=4O)[CH:39]2[C@@H:30]([C:31]2[C:32]([OH:68])=[CH:33][C:34](C4OC5C=C(O)C=CC=5C=4)=[CH:35][C:36]=2[O:37]3)C=1.C[OH:70]>>[CH3:41][C:40]([CH3:42])=[CH:39][CH2:30][C:31]1[C:36]([OH:37])=[CH:35][C:34]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([OH:23])=[C:18]([OH:70])[CH:17]=3)=[C:13]([OH:25])[C:12](=[O:22])[C:33]=2[C:32]=1[OH:68]
Reactant: CC1=C[C@@H]2c3c(O)cc(-c4cc5ccc(O)cc5o4)cc3O[C@]3(c4ccc(O)cc4O)Oc4cc(O)ccc4[C@@H](C1)C23
Reactant: CO
Reactant: CC(C)=CCc1cc(-c2oc3cc(O)cc(O)c3c(=O)c2O)ccc1O
Product: CC(C)=CCc1c(O)cc2oc(-c3ccc(O)c(O)c3)c(O)c(=O)c2c1O

Procedure:
Yellow powder; UV (MeOH) λmax (log ε) 261 (4.13), 205 (4.79) nm; 1H NMR (CD3COCD3, 500 MHz) δ 1.66 (3H, s, H-5′), 1.82 (3H, s, H-4′), 3.56 (2H, d, J=6.0 Hz, H-1′), 5.29 (1H, m, H-2′), 6.36 (1H, s, H-8), 7.00 (1H, d, J=8.3 Hz, H-5′), 7.72 (1H, brd, J=7.4 Hz, H-6′), 7.87 (1H, s, H-2′); EIMS m/z 370 (M+, 100), 355 (94), 315 (45), 302 (37), 244 (12), 137 (21).
Reaction SMILES: [Na].[C:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]3[N:27]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[C:26]4[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=4[N:24]=3)[CH2:18][CH2:17][CH2:16]2)=[CH:9][CH:8]=1)([OH:4])=[O:3].Cl.[CH:41](O)([CH3:43])[CH3:42]>>[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:27]2[C:26]3[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=3[N:24]=[C:23]2[N:19]2[CH2:20][CH2:21][CH2:22][N:15]([CH2:14][CH2:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C:2]([O:4][CH:41]([CH3:43])[CH3:42])=[O:3])=[CH:12][CH:11]=3)[CH2:16][CH2:17][CH2:18]2)=[CH:30][CH:31]=1
Reactant: O=C(O)CCc1ccc(CCN2CCCN(c3nc4ccccc4n3Cc3ccc(F)cc3)CCC2)cc1
Reactant: CC(C)O
Agent: Cl
Agent: [Na]
Product: CC(C)OC(=O)CCc1ccc(CCN2CCCN(c3nc4ccccc4n3Cc3ccc(F)cc3)CCC2)cc1

Procedure:
A solution of 5-[2-[4-(2-carboxyethyl)phenyl]ethyl]-1-[1(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane sodium salt (163 mg) in an isopropanol solution saturated with HCl was refluxed for 4 hours. The solvent was removed under reduced pressure, and the residue was dissolved in methylene chloride (20 ml). The solution was washed with a saturated aqueous NaHCO3 solution and brine. The organic layer was dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of methylene chloride, diethyl ether and methanol (1:1:0.25) as eluent to give 1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4-(2-isopropoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctane (123mg) as a colorless oily liquid.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4](C(Cl)=O)=[CH:3][CH:2]=1.C(O)C[O:20]CCO.C(N(CC)CC)C>O1CCCC1>[C:1]1(=[O:20])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: OCCOCCO
Reactant: O=C(Cl)c1cccc2c1-c1ccccc1C2=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1C=CC=C2C1=Cc1ccccc12
Reaction time: 0.5 h

Procedure:
A 10.0 g quantity of 9-fluorenone-4-carbonyl chloride (0.04 mole, obtained from Aldrich Chemicals Co, Milwaukee, Wis. 53201, USA) and 100 ml of tetrahydrofuran (obtained from Aldrich) were added to a 250 ml, 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The solution was stirred for about ½ hour, and then 2.186 g of diethylene glycol (0.02 mole, obtained from Aldrich) in 50 ml of tetrahydrofuran were added, followed by the addition of 4.17 g of triethylamine (0.04 mole, obtained from Aldrich). The solution was refluxed for 6 hours, filtered hot to remove triethylamine hydrochloride salt byproduct, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was recrystallized from ethyl acetate with activated charcoal. The product was dried at 60° C. in a vacuum oven for 6 hours to yield a third dimeric fluorenone derivative, which was a yellow solid (5.0 g, 47% yield). The product had a melting point of 137° C. A 1H-NMR (300 MHz) spectrum in CDCl3 yielded chemical shifts (ppm) of: 3.88–4.00 (t, 4H); 4.56–4.65 (t, 4H); 7.15–7.34 (m, 4H); 7.40–7.49 (td, 2H); 7.61–7.68 (d, 2H); 7.71–7.77 (dd, 2H); 7.85–7.92 (dd, 2H); 8.20–8.27 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[NH2:13].[CH3:14][O:15][CH2:16][C:17](Cl)=[O:18]>N1C=CC=CC=1>[CH3:14][O:15][CH2:16][C:17]([NH:8][C:7]1[CH:6]=[C:5]([C:9]([F:11])([F:12])[F:10])[CH:4]=[C:3]([NH:13][C:17](=[O:18])[CH2:16][O:15][CH3:14])[C:2]=1[Cl:1])=[O:18]
Reactant: Nc1cc(C(F)(F)F)cc(N)c1Cl
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Product: COCC(=O)Nc1cc(C(F)(F)F)cc(NC(=O)COC)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-3,5-diaminobenzotrifluoride (4.2 g) in pyridine (80 ml) is added dropwise methoxyacetyl chloride (4.0 ml) at room temperature. The mixture is stirred at room temperature for 3 hours, and thereafter, pyridine is distilled off under reduced pressure. To the residue is added water, and the resulting solid substance is separated by filtration and washed with water. The resulting crude crystals are recrystallized from ethanol to give the title compound (5.0 g) having the following physical properties.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16](=O)[NH:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=O)[CH2:14][N:13]([C:29](=[O:31])[CH3:30])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])(=O)C.[NH4+:37]>>[CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)[N:37]=2)[CH2:14][N:13]([C:29](=[O:31])[CH3:30])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: [NH4+]
Reactant: COC(=O)NC(C(=O)N1CN(C(C)=O)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CN(C(C)=O)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
(1-{3-Acetyl-5-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-imidazolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (203 mg, 0.397 mmol) was dissolved in m-xylenes (4 mL) and heated at 135° C. Solid ammonium acetate (200 mg, 2.58 mmol) was added and the reaction was stirred at 135° C. After 120 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc w 10% MeOH/hexanes) to yield the product {1-[1′-Acetyl-4-(4-bromo-phenyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (162 mg, 0.329 mmol): LCMS-ESI+: calc'd for C21H26BrN5O4: 492.4 (M+). Found: 492.3/494.3 (M+H+).
Reaction SMILES: Br[C:2]1[N:3]([CH2:24][C:25]#[C:26][CH3:27])[C:4]2[C:9](=[O:10])[N:8]([CH2:11][C:12]3[N:21]=[C:20]([CH3:22])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[N:7]=[CH:6][C:5]=2[N:23]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+].N1CCCC(NC(=O)OC(C)(C)C)C1>CS(C)=O.O>[CH2:24]([N:3]1[C:4]2[C:9](=[O:10])[N:8]([CH2:11][C:12]3[N:21]=[C:20]([CH3:22])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[N:7]=[CH:6][C:5]=2[N:23]=[C:2]1[N:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:29]1)[C:25]#[C:26][CH3:27]
Reactant: CC#CCn1c(Br)nc2cnn(Cc3nc(C)c4ccccc4n3)c(=O)c21
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Agent: CC(C)(C)OC(=O)NC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2cnn(Cc3nc(C)c4ccccc4n3)c(=O)c21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A solution of 240 mg (0.57 mmol) 2-bromo-3-(but-2-ynyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one and 140 mg (0.70 mmol) tert-butyl (R)-piperidin-3-yl-carbamate in 4 ml dimethylsulphoxide was combined with 95 mg (0.90 mmol) sodium carbonate and stirred for 3 h at 80° C. Then another 50 mg tert-butyl piperidin-3-yl-carbamate was added and the mixture was stirred for a further 2 h at 80° C. After cooling to ambient temperature the mixture was combined with 10 ml of water and stirred for 30 minutes. The product thus precipitated was suction filtered, washed with 5 ml of water and dried.
Reaction SMILES: C(O[C@H:9]1[C@H:15]([OH:16])[CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C@@H:10]1[CH:11]=[O:12])C1C=CC=CC=1.[OH2:27].C(=O)([O-])[O-].[Ba+2].BrBr>O1CCOCC1>[CH2:20]([C@H:9]1[C@@H:15]([OH:16])[CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[C@@H:10]1[C:11]([OH:12])=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O
Reactant: O=C[C@@H]1[C@@H](OCc2ccccc2)[C@H](O)CN1C(=O)OCc1ccccc1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1[C@@H](Cc2ccccc2)[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 75 %

Procedure:
A solution of 3-O-benzyl-N-benzyloxycarbonyl-2,5-dideoxy-2,5-imino-D-lyxose (15) (900 mg, 2.54 mmol), in a 1:1 mixture of water and 1,4-dioxan (15 ml) containing barium carbonate (1.46 g, 7.62 mmol), was cooled to 0° C. and treated with bromine (298 μl, 5.33 mmol). After stirring for 24 hours excess bromine was destroyed by the dropwise addition of 10% sodium thiosulphate solution and the suspension acidified with 2M HCl (20 ml). The product was extracted into dichloromethane (4×50 ml), dried, filtered and evaporated. Purification by flash chromatography (ethyl acetate-hexane (1:1 to ethyl acetate) afforded (2S,3R,4R)-3-benzyl-N-benzyloxycarbonyl-4-hydroxyproline (738 mg, 75%) as a clear oil, [α]20D -3.7° (c, 0.88 in chloroform); νmax (film) 3400 (OH), 2950, 1680 (2×CO), 1425, 1360 and 1195 cm-1 ; 1H NMR δ 3.62-3.78 (2H, 2×dd, H-5); 4.21, 4.26 (2H, s, and bs, H-3, H-2); 4.49-4.69 (3H, m, CH2Ph); 5.06-5.18 (2H, 2×dd, CH2 -Z); 5.6 (2H, bs, 2×OH); 7.27-7.38 (10H, m, 2×H-Ph). m/z: 91 (100%), 310 (45%), 372 (M+H+, 30%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:35])([C:29]2[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=2)[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[C:13]3[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:5][CH:4]=1.[NH:36]1[CH:40]=[CH:39][N:38]=[CH:37]1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[Cl:28][C:24]1[CH:23]=[C:22]([C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:9]([OH:35])([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][N:36]5[CH:40]=[CH:39][N:38]=[CH:37]5)=[CH:4][CH:5]=4)[C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[CH:11]=3)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: c1c[nH]cn1
Reactant: Cn1cncc1C(O)(c1ccc(CCl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cn1cncc1C(O)(c1ccc(Cn2ccnc2)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Yield: 13.4 %

Procedure:
A mixture of (±)-6-[[4-(chloromethyl)phenyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (described in Example B14) (0.00039 mol), 1-H-imidazole (0.00079 mol) and K2CO3 (0.0016 mol) in CH3CN (2 ml) was stirred and refluxed for 4 hours, poured out into H2O and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.2 g) was purified twice by column chromatography over kromasil (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.5 then CH3OH/H2O 60/40; 10 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.028 g (13%) of (±)-4-(3-chlorophenyl)-6-[hydroxy[4-(1H-imidazol-1-ylmethyl)phenyl](1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone, as a white foam, MS (ESI) m/z:536, 538 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH3:15][N:16]1[C:21](=[O:22])[N:20]([CH3:23])[C:19](=[O:24])[C:18]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:17]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([N:28]1[CH2:27][CH2:26][N:25]([C:18]2[C:19](=[O:24])[N:20]([CH3:23])[C:21](=[O:22])[N:16]([CH3:15])[N:17]=2)[CH2:30][CH2:29]1)=[O:8].[F:12][C:11]([F:14])([F:13])[C:5]1[CH:4]=[CH:3][C:2]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:6]=1[C:7]([N:28]1[CH2:27][CH2:26][N:25]([C:18]2[C:19](=[O:24])[N:20]([CH3:23])[C:21](=[O:22])[N:16]([CH3:15])[N:17]=2)[CH2:30][CH2:29]1)=[O:8]
Reactant: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Reactant: Cn1nc(N2CCNCC2)c(=O)n(C)c1=O
Product: Cn1nc(N2CCN(C(=O)c3cc(C(F)(F)F)ccc3C(F)(F)F)CC2)c(=O)n(C)c1=O
Product: Cn1nc(N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)c(=O)n(C)c1=O
Yield: 86 %

Procedure:
The compound 42 (solid) is prepared from 5-fluoro-2-trifluoromethyl-benzoyl chloride and from the intermediate 12a according to the synthesis method 2 under the operating conditions described for Example 40 (yield: 86%).
Reaction SMILES: [C:1]([Si:5]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:6][CH2:7][C:8]([CH3:15])([CH3:14])[C:9](=O)[CH2:10][C:11]#[N:12])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:29]([O:36][C:37]1[CH:38]=[C:39]([NH:43][NH2:44])[CH:40]=[CH:41][CH:42]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C>C(O)C.CCOC(C)=O>[CH2:29]([O:36][C:37]1[CH:38]=[C:39]([N:43]2[C:11]([NH2:12])=[CH:10][C:9]([C:8]([CH3:15])([CH3:14])[CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:44]2)[CH:40]=[CH:41][CH:42]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)CC#N
Reactant: NNc1cccc(OCc2ccccc2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(N)n(-c2cccc(OCc3ccccc3)c2)n1
Yield: 107 %

Procedure:
A solution of Intermediate 153b (1.00 g, 2.63 mmol) in ethanol (IMS grade, 20 mL) was treated with 3-benzyloxyphenylhydrazine hydrochloride (0.66 mL, 2.63 mmol) then DIPEA (0.46 mL, 2.63 mmol) and the mixture was heated to reflux for 114 h. The cooled reaction mixture was diluted with EtOAc and a saturated aqueous sodium bicarbonate solution and the mixture was filtered and the phases separated. The aqueous layer was extracted with EtOAc (×2) and the combined organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo to give an orange oil (1.62 g). The gum was purified by FCC, using 0-20% EtOAc in cyclohexane, to give the title compound as a yellow oil (1.21 g, 80%). LCMS (Method 3): Rt 5.40 min, m/z 576.5 [MH+].
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)=S)[CH3:2].[N:16]#[C:17][NH2:18].[Pb]>>[C:17]([NH:18][C:4]([NH:3][CH2:1][CH3:2])=[N:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)#[N:16]
Reactant: CCNC(=S)NCCNCc1nccs1
Reactant: N#CN
Agent: [Pb]
Product: CCNC(=NCCNCc1nccs1)NC#N

Procedure:
Reacting N-(2-thiazolylmethyl)ethylenediamine with ethyl isothiocyanate by the procedure of Example 3(b) and then chromatographing gives N-ethyl-N'-[2-(2-thiazolylmethylamino)ethyl]thiourea. Reacting this thiourea with lead cyanamide by the procedure of Example 3(b) gives N-cyano-N'-ethyl-N"-[2-(2-thiazolylmethylamino)ethyl]-guanidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](=[O:11])[NH:9][C@@H:8]([CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[H-].[Na+].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C1C[O:29]CC1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10](=[O:11])[N:9]([CH2:22][C:21]3[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=3)[C@@H:8]([CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[Cl:1][C:2]1[CH:3]=[C:4]2[C:10](=[O:11])[N:9]([CH2:22][C:21]3[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=3)[C:8]([OH:29])([CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: C1CCOC1
Reactant: CC(C)[C@@H]1NC(=O)c2cc(Cl)cnc21
Agent: [H-]
Agent: [Na+]
Product: CC(C)C1(O)c2ncc(Cl)cc2C(=O)N1Cc1ccc(Cl)cc1
Product: CC(C)[C@H]1c2ncc(Cl)cc2C(=O)N1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 29 %
Yield: 29 %

Procedure:
To a degassed solution of (S)-3-chloro-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (42.2 mg, 200 μmol) in THF (2 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 9.6 mg, 240 μmol). The mixture was stirred at 0° C. for 30 min, at which point 4-chlorobenzyl bromide (49.3 mg, 240 μmol) was added. The mixture was allowed to warm to rt and was stirred for 15 h. The mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with EtOAc (10 mL). The organic phase was washed with brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 5% EtOAc in hexanes, gradient to 50%) to afford (S)-3-chloro-6-(4-chlorobenzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (19.6 mg, 29%) and 3-chloro-6-(4-chlorobenzyl)-7-hydroxy-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (20.1 mg, 29%). LCMS: tR=1.09 min in in 1 min chromatography, MS (ESI) m/z 335.3 [M+H]+. 1H NMR (CD3OD, 400 MHz): δ 8.74 (d, J=2.0 Hz, 1H), 8.17 (d, J=2.4 Hz, 1H), 7.37-7.32 (m, 4H), 5.16 (d, J=15.6 Hz, 1H), 4.47 (d, J=15.2 Hz, 1H), 4.40 (d, J=3.2 Hz, 1H), 2.56-2.48 (m, 1H), 1.27 (d, J=7.2 Hz, 3H), 0.48 (d, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[F:9][C:10]1[CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][C:15]=1F>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:1][C:15]1[CH:14]=[CH:13][C:12]([N+:17]([O-:19])=[O:18])=[CH:11][C:10]=1[F:9]
Reactant: OCc1ccccn1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Product: O=[N+]([O-])c1ccc(OCc2ccccn2)c(F)c1
Yield: 57.7 %

Procedure:
An analogous reaction to that described in example 42b, but starting with 2-(hydroxymethyl)pyridine (3.50 g, 36 mmol) and 3,4-difluoronitrobenzene (5.00 g, 31.4 mmol), yielded 2-((2-pyridyl)methoxy)-5-nitrofluorobenzene (4.50 g, 58% yield) as a yellow solid. d) An analogous reaction to that described in example 42c, but starting with 2-((2-pyridyl)methoxy)-5-nitrofluorobenzene (4.5 g, 18.1 mmol), yielded 3-fluoro-4-((2-pyridyl)methoxy)aniline (1.86 g, 47% yield) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[C:29]([NH2:34])([CH2:32][CH3:33])([CH3:31])[CH3:30]>C(Cl)(Cl)Cl>[C:29]([NH:34][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])([CH2:32][CH3:33])([CH3:31])[CH3:30]
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: CCC(C)(C)N
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(C)(C)NC(=O)c1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 54 %

Procedure:
A mixture containing 8.16 g (0.04 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 6.2 ml (0.044 mol) of triethylamine in 240 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 4 ml (0.042 mol) of ethyl chloroformate in 20 ml of chloroform is dropped to the above mixture at a temperature between -12° C. and -17° C. during 15 minutes. After stirring for 5 minutes, 3.84 g (0.044 mol) of tert.-pentylamine dissolved in 40 ml of chloroform are dropped to the above solution at the same temperature during 15 minutes. The reaction mixture is stirred for 1 hour at about -10° C. and then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 50 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 50 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated. The residue slowly becomes crystalline to give 5.9 g (54%) of the named compound, m.p. 87°-89° C. after recrystallization from ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].Cl.[OH-:11].[Na+].[CH3:13]S(C)=O>[Cu](Cl)Cl>[NH2:4][C:3]1[C:2]([CH3:1])=[CH:8][C:7]([CH:13]=[O:11])=[C:6]([CH3:9])[CH:5]=1
Reactant: Cc1ccc(C)c(N)c1
Reactant: [OH-]
Reactant: CS(C)=O
Agent: Cl[Cu]Cl
Agent: Cl
Agent: [Na+]
Product: Cc1cc(C=O)c(C)cc1N
Temperature: 90 °C
Yield: 22.8 %

Procedure:
6.06 g (50.0 mmol) of 2,5-dimethylaniline are initially charged in 1000 ml of DMSO, 13.55 g (100.0 mmol) of copper(II) chloride are added and concentrated hydrochloric acid is then added slowly. The reaction mixture is heated at 90° C. for 3 h and then added to ice-water. After addition of aqueous sodium hydroxide solution, the mixture is filtered and extracted repeatedly with ethyl acetate, and the combined organic phases are dried over Na2SO4 and freed from solvent under reduced pressure. The crude product is purified by column chromatography. (2.27 g, purity 75.0%, yield 22.8%, log P (pH 2.3)=1.34).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8][C:7]1=[O:15].CC1(C)CC(=O)NC(=O)C1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N:26]1([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:11](=[O:12])[CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8][C:7]2=[O:15])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: C1CNCCN1
Reactant: CC1(C)CC(=O)N(CCCCBr)C(=O)C1
Agent: CC1(C)CC(=O)NC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)CC(=O)N(CCCCN2CCNCC2)C(=O)C1
Yield: 85 %

Procedure:
A mixture of N-(4-bromobutyl)-3,3-dimethylglutarimide (20.0 g; 0.07 mole [prepared from 3,3-dimethylglutarimide using the method of Example 2]); piperazine (31.0 g; 0.36 mole); K2CO3 (29.8 g; 0.22 mole); and KI (0.1 g) was refluxed in 250 mL acetonitrile for 18 hr. The mixture was filtered, concentrated and the unreacted piperazine removed by vacuum sublimation. The residual material was distilled to yield 17.2 g (85%) product, b.p. 170°-178° C. at 0.01 mm.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[N+:9]([O-:11])=[O:10].Cl.[CH3:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]1[NH2:20].[CH:21](N(CC)C(C)C)(C)C>CC(O)C>[CH3:21][N:20]([C@H:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]1[CH3:13])[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Reactant: C[C@@H]1CCCC[C@@H]1N
Agent: Cl
Solvent: CC(C)O
Product: C[C@@H]1CCCC[C@@H]1N(C)c1ccnc(N)c1[N+](=O)[O-]

Procedure:
In a microwave reaction vessel 4-chloro-3-nitro-2-pyridinamine (70 mg) and (1S,2R)-2-methylcyclohexanamine hydrochloride (66 mg) were suspended in 2-propanol (0.35 mL). To the mixture was added N,N-diisopropylethylamine (0.21 mL). The vessel was sealed and reacted in the microwave reactor at 130° C. for 1hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give N4-methyl-N4-[(1S,2R)-2-methylcyclohexyl]-3-nitro-2,4-pyridinediamine (75 mg) as a yellow amorphous.