Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C@:25]([OH:29])([C:27]#[CH:28])[CH3:26])[N:21]=1>N1CCCCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:29][C@:25]([C:22]1[N:21]=[C:20]([CH3:19])[O:24][N:23]=1)([CH3:26])[C:27]#[C:28][C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Reactant: NC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(c2)-n2nc(C(N)=O)cc2CCO3)no1
Temperature: 60 °C
Yield: 49.9 %

Procedure:
A mixture of 9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide (100 mg, 0.28 mmol), (R)-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-but-3-yn-2-ol (70 mg, 0.46 mmol), and copper(I) iodide (10 mg, 0.05 mmol) in piperidine (1.5 ml) was sonicated under a stream of argon for 15 minutes. After the addition of tetrakis(triphenylphosphine)palladium (0) (40 mg, 0.035 mmol) the mixture was heated at 60° C. for 3 hours before the being concentrated. The residue was taken up in ethyl acetate (100 ml) and pre-absorbed onto a small amount of silica. Purification by FCC (silica, 0-10% methanol in dichloromethane) gave a solid residue, which was re-crystallised from heptane/dichloromethane (˜10 ml, 2/1). Filtration and drying of the crystalline material under high vacuum provided 53 mg (40%) of the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.83 (3H, s), 2.61 (3H, s), 3.17 (2H, t, J=5.80 Hz), 4.49 (2H, t, 0.1=5.80 Hz), 6.71 (1H, s), 6.74 (1H, s), 7.22 (1H, d, J=8.39 Hz), 7.35 (1H, s), 7.38 (1H, dd, J=8.32, 2.06 Hz), 7.81 (1H, s), 8.03 (1H, d, J=1.98 Hz); M+1=380.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2)([O-:3])=[O:2].[N+:17]([O-])([O-:19])=[O:18].[K+]>OS(O)(=O)=O>[N+:17]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[C:13]([Cl:14])[CH:12]=[C:11]2[C:6]=1[NH:7][C:8](=[O:16])[C:9](=[O:15])[NH:10]2)([O-:19])=[O:18]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])c([N+](=O)[O-])c2[nH]c1=O
Temperature: 4 °C
Reaction time: 48 h
Yield: 70.5 %

Procedure:
To a solution of 6-nitro-7-chloro-1,4-dihydro-2,3-quinoxalinedione (120 mg, 0.50 mmol) in concentrated H2SO4 (1.0 mL) was added KNO3 (61 mg, 0.60 mmol, Baker). The mixture was stirred at 4° C. for 2 days, then ice (2 g) was added. The precipitate was collected by filtration and the solid was dissolved in 1N NaOH (5 mL) and filtered. The filtrate was acidified to pH=2 with 4N HCl (~1.2 mL) to give a yellow precipitate, which was collected by filtration and was washed with water (2×1 mL), then was dried at 50° C. for 4 h, affording crude title compound (101 mg, 70%) as a yellow 1.5 powder. The crude compound (100 mg) was dissolved into acetone (2 mL) and the insoluble material was removed by centrifugation. Water (1 mL) was added to the clear solution of acetone and the resultant solution was allowed to stand at 4° C. overnight to give purer compound. Recrystallization from acetone/water again gave pure title compound (55 mg). Mp: 298°-300° C. (dec.); IR (KBr, cm-1): 3434, 3295, 3111, 2920, 1716, 1571. 1H NMR (DMSO-d6): δ12.560 (s, 1H), 12.421 (s, 1H), 7.442 (s, 1H). HRMS; calcd for C8H3ClN4O6 (M+) m/z: 285.9740, found: 285.9741.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:22][CH:21]=2)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:27][CH2:28][N:29]([CH2:2][C:3]4[CH:12]=[CH:11][C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[N:4]=4)[CH2:30][CH2:31]3)[CH2:22][CH:21]=2)=[CH:16][CH:15]=1
Reactant: Fc1ccc(C2=CCC(N3CCNCC3)CC2)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(C2=CCC(N3CCN(Cc4ccc5ccccc5n4)CC3)CC2)cc1
Yield: 53 %

Procedure:
A mixture of 2-chloromethylquinoline (4.7 mmole), and 1-[4-(4-fluorophenyl)-3-cyclohexen-1-yl]piperazine (4.7 mmole) and excess powdered K2CO3 was heated at reflux for 18 hr. The insolubles were removed by filtration, the solution concentrated in vacuo, and the residue crystallized from hexane to give the product (53%, mp: 111-114° C.). Calc'd for C26H28FN3: C, 77.78%; H, 7.03%; N, 10.47%. Found: C, 77.61; H, 6.91%; N, 10.72%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)=[C:4]([Cl:15])[C:3]=1[O:16]CC1C=CC=CC=1>CCO.[Pd]>[NH2:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)=[C:4]([Cl:15])[C:3]=1[OH:16]
Reactant: Nc1c(OCc2ccccc2)c(Cl)c2c(c1C(=O)O)CCCC2
Agent: [Pd]
Solvent: CCO
Product: Nc1c(O)c(Cl)c2c(c1C(=O)O)CCCC2
Reaction time: 2 h
Yield: 86.9 %

Procedure:
7-Amino-6-benzyloxy-8-carboxy-5-chlorotetralin (33 mg, 0.10 mmol) was dissolved in EtOH (3 mL) and 5% Pd/C (4 mg) was added. Hydrogenation at room temperature and atmospheric pressure for 2 h, filtration, evaporation and vacuum-drying gave the title compound (21 mg). Mp: 147° C. (dec); 1H NMR (DMSO-d6): δ 7.9 (br, NH, OH), 2.66 (t, J=6.0 Hz, 2H), 2.54 (t, J=6.7 Hz, 2H), 1.70-1.64 (m, 2H), 1.63-1.57 (m, 2H); 13C NMR (DMSO-d6): δ 169.73, 138.12, 136.45, 128.13, 123.32, 121.36, 115.15, 27.86, 26.91, 22.45, 22.25; MS (EI, 70 eV): m/z (rel.int.) 243/241 (M+, 21/65), 225/223 (35/100), 197/195 (61/100).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[Cl:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: O=C(O)c1cc2cc(Cl)ccc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, 5-chloro-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 334.0 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]3[N:14]=[C:15]([NH2:17])[N:16]=[C:9]23)=[CH:4][CH:3]=1.[CH3:18][C:19]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)[S:21][N:20]=1.[BH4-].[Na+].C(O)C>ClC(Cl)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]3[N:14]=[C:15]([NH:17][CH:27]4[CH2:26][CH2:25][N:24]([C:22]5[S:21][N:20]=[C:19]([CH3:18])[N:23]=5)[CH2:29][CH2:28]4)[N:16]=[C:9]23)=[CH:4][CH:3]=1
Reactant: Nc1nc2n(n1)CCCC2c1ccc(F)cc1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(Cl)Cl
Product: Cc1nsc(N2CCC(Nc3nc4n(n3)CCCC4c3ccc(F)cc3)CC2)n1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (60 mg, 0.258 mmol) and 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (76 mg, 0.387 mmol) in dry dichloroethane (3 mL) was added tetraisopropyl-orthotitanate (236 μL, 0.775 mmol) under an argon atmosphere and heated to 85° C. for 12 hours. The reaction mixture was cooled to room temperature, sodium borohydride (20 mg, 0.517 mmol) and ethanol (1.5 mL) were added and stirred at room temperature for 3 hour and at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature and evaporated. An aqueous solution of Na2CO3 (2M) was added to the residue. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using dichloromethane/methanol (with 10% ammonia) as eluent. The title compound was obtained as a white solid (28.8 mg, 27%).
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([N:10]1C(=O)C2C(=CC=CC=2)C1=O)[C@@H:5]([CH3:9])[CH2:6][CH:7]=[CH2:8]>Cl.C(O)(=O)C>[NH2:10][C@H:4]([C@@H:5]([CH3:9])[CH2:6][CH:7]=[CH2:8])[C:3]([OH:21])=[O:2]
Reactant: C=CC[C@H](C)[C@H](C(=O)OC)N1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CC(=O)O
Product: C=CC[C@H](C)[C@@H](N)C(=O)O
Temperature: 25 °C
Yield: 50 %

Procedure:
(2R,3S)-2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-3-methyl-hex-5-enoic acid methyl ester (2.01 g, 7.00 mmol) is dissolved in a 2:1 mixture of 6 N hydrochloric acid and glacial acetic acid (62.5 mL), and the solution is heated at reflux for 4 h. The solution is cooled to room temperature and concentrated under reduced pressure. The product is taken up in water and the solution is filtered. The filtrate is concentrated under reduced pressure and the residue is dissolved in water, then the solution is applied to a column of Amberlite™ IR 120 cation exchange resin (NH4+ form.). The column is washed with water (2.5 L), then eluted with aqueous ammonia solution (2.5 L). The eluate is boiled until no ammonia can be detected, then concentrated under reduced pressure affording the title compound (0.5 g, 3.50 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:19](=O)[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[NH:12]1.[Cl:21]C(OC(Cl)(Cl)Cl)=O>C1(C)C=CC=CC=1.ClCCCl>[Cl:21][C:19]1[N:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[F:1])[N:12]=[C:13]2[C:18]=1[CH2:17][CH2:16][CH2:15][CH2:14]2
Reactant: O=c1c2c([nH]n1-c1cc([N+](=O)[O-])ccc1F)CCCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(F)c(-n2nc3c(c2Cl)CCCC3)c1

Procedure:
To a solution of 2-(2-fluoro-5-nitrophenyl)1,2,4,5,6,7-hexahydro-3H-indazol-3-one (66.87 g) in toluene (125 ml) and 1,2-dichloroethane (175 ml), there was added trichloromethyl chloroformate (71.57 g), and the resultant mixture was allowed to react in an autoclave at a temperature of 120° to 130° C. under a pressure of 25 kg/cm2, for 3 hours. After cooling, the solvent was removed by distillation. The residue was purified by silica gel column chromatography using a mixture of ethyl acetate and n-hexane (1 : 6) as an eluent to give 3-chloro-2-(2-fluoro-5-nitrophenyl)-4,5,6,7-tetrahydro-2H-indazole. m.p., 109.1° C.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][OH:20])[CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2]>[OH:20][CH2:19][CH:10]1[CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:12][NH:8][CH2:9]1
Reactant: OCC1CN(Cc2ccccc2)CC1c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Product: OCC1CNCC1c1ccccc1
Reaction time: 1 h
Yield: 100.5 %

Procedure:
A mixture of 302 mg (1.1 mmol) of 1-benzyl-3-(SR)-hydroxymethyl-4-(SR)-phenylpyrrolidine (from Example 1, Step B) and 154 mg of 20% Pd(OH)2/C was hydrogenated at 40 psi on a Paar apparatus for 1 h. The catalyst was filtered and the filtrate was concentrated in vacuo to afford 196 mg (98%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3): δ2.53-2.57 (m, 2H), 3.06-3.60 (6H), 7.24-7.35 (5H). Mass Spectrum (NH3-CI): m/z 178 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([Li])CCC.[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]([OH:19])[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1
Reactant: Clc1ccc(Br)cc1
Reactant: O=Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.8 %

Procedure:
A solution of 4-bromochlorobenzene (20.0 g, 104 mmol) in 125 mL of dry tetrahydrofuran under nitrogen was cooled to -78° and 70 mL of 1.5M n-butyllithium in hexane was added dropwise over 20 minutes. After stirring another 10 minutes, 12.5 mL (104 mmol) of 3-bromobenzaldehyde was added dropwise and the reaction was stirred for another 10 minutes at -78°. Saturated aqueous ammonium chloride (100 mL) was added and the reaction was warmed to room temperature and extracted with 300 mL of ether. The ethereal layer was extracted with three 75 mL portions of 1M sodium bisulfite, 75 mL of 1M sodium hydroxide, 75 mL of water, and 75 mL of brine. The ether layer was dried over magnesium sulfate and the solvent removed to give 31.2 g of 3-bromo-4'-chlorobenzhydryl alcohol as a pale yellow solid. A portion was recrystallized from hexanes containing 5% ether to give white needles, m.p. 67°-68°. Calc. for C13H10Br C10: C, 52.47; H, 3.39; Br, 26.85; Cl, 11.91. Found: C, 52.25; H, 3.25; Br, 26.72; Cl, 12.09.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH3:14])[CH:8]=2)=[CH:4][CH:3]=1.[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1)[CH3:18]>>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([NH:1][C:26]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([CH2:17][CH3:18])=[CH:20][CH:21]=3)=[O:27])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: COc1cc(Oc2ccc(N)cc2)ccn1
Reactant: CCc1ccc(N=C=O)cc1
Product: CCc1ccc(NC(=O)Nc2ccc(Oc3ccnc(OC)c3)cc2)cc1

Procedure:
The title compound is prepared from 4-(4-amino-phenoxy)-2-methoxy-pyridine (Stage 92.1; 91 mg, 0.42 mmol) and 4-ethyl-phenyl-isocyanate (124 μl, 0.84 mmol) analogously to Example 89: m.p.: 196° C.; Anal.: CHN.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C:23]([C:27]1[CH:31]=[C:30]([NH2:32])[O:29][N:28]=1)([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:16](=[O:18])[CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=2)[O:29][N:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)c1cc(N)on1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1cc(NC(=O)Cc2ccc(OCc3ccccc3)cc2)on1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
(4-Benzyloxy-phenyl)-acetic acid (50 mg, 0.2 mmol, 1 eq) was stirred with 1 mL of thionyl chloride at 80° C. for approximately three hours. The completion of the reaction was checked by TLC. Excess thionyl chloride was removed in vacuo, the residue was dissolved in dichloromethane and added to a mixture of 3-tert-butyl-isoxazol-5-ylamine (28 mg, 0.2 mmol, 1 eq) and DIEA (35 μL, 0.2 mmol, 1 eq). The reaction was stirred overnight at 45° C. The solvent was removed and the product purified by HPLC. Yield: 42 mg (57%), LC/MS [MH+] 365.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Br>C(#N)C>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:21][CH2:22]4)=[O:19])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1nc2cccc(-c3ccc(O)cc3)n2n1)C1CC1
Reactant: COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(COc2ccc(-c3cccc4nc(NC(=O)C5CC5)nn34)cc2)c1

Procedure:
To a solution of cyclopropanecarboxylic acid [5-(4-hydroxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (WW-022) (0.05 g, 0.17 mmol) in acetonitrile (3 mL), potassium carbonate (0.047 g, 0.34 mmol) was added and the mixture was refluxed for 30 min. 3-Methoxybenzylbromide (0.047 mL, 0.34 mmol) was then added and the solution was refluxed overnight. The mixture was filtered and purified by preparatory HPLC. LCMS method: 1, RT: 5.16 min; MI: 415 [M+1]. NMR 1H (DMSO): 0.79-0.83 (m, 4H), 2.06 (brs, 1H), 3.76 (s, 3H), 5.08 (s, 2H), 6.88 (dd, 1H), 77.03-7.08 (m, 2H), 7.16 (d, 2H), 7.24 (dd, 1H), 7.31 (t, 1H), 7.60-7.67 (m, 2H), 8.00 (dd, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8](=[O:10])[NH:9][C:5]=2[CH:4]=1.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>CN(C)C=O>[N:13]1([CH2:2][C:3]2[CH:12]=[CH:11][C:6]3[NH:7][C:8](=[O:10])[NH:9][C:5]=3[CH:4]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=c1[nH]c2ccc(CCl)cc2[nH]1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccc(Cn3ccnc3)cc2[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
A mixture of 6.35 parts of 5-(chloromethyl)-1,3-dihydro-2H-benzimidazol-2-one, 11.9 parts of 1H-imidazole and 135 parts of N,N-dimethylformamide was stirred overnight at 80° C. The whole was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (80:20 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. After standing over weekend at room temperature, the residue was solidified. The product was pulverized and stirred in acetonitrile. The product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (87:13 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was dried in a dry-pistol at 130° C., yielding 0.75 parts (10%) of 1,3-dihydro-5-(1H-imidazol-1-ylmethyl)-2H-benzimidazol-2-one; mp. 254.5° C. (compound 24).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C@H:8]([C@@H:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:9][N:10]=[N+]=[N-].CO>C1COCC1>[CH3:7][C@H:8]([C@@H:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:18])[CH3:19])[CH2:9][NH2:10]
Reactant: CC(C)=CCC[C@H](C)[C@@H](C)CN=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)=CCC[C@H](C)[C@@H](C)CN
Reaction time: 0.25 h

Procedure:
6.3 mL (6.3 mmol) of 1M lithium aluminum hydride in THF was added dropwise to a solution of 2(R),3(S),7-trimethyl-1-azido-6-octene in 10 mL of THF at 0° C. The reaction mixture was heated to reflux 18 hrs. After cooling in ice bath, ~1 mL of methanol was added dropwise cautiously. After the effervescence stopped, the reaction mixture was concentrated to 30% of the volume and 1N solution of potassium sodium tartrate was added. After stirring 15 mins, the reaction mixture was extracted with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous magnesium sulfate and the solvent was removed to give 399 mg of the desired amine as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:3]=12.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1>CN1CCCC1=O.O>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:8](=[O:10])[C:7]3[C:2]([C:3]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=4[NH:5][CH:6]=3)=[N:30]2)=[CH:25][CH:24]=1
Reactant: COc1ccc(NN)cc1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CCCCCCCC2
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(-n2nc3c4c([nH]cc-3c2=O)CCCCCCCC4)cc1

Procedure:
A mixture of 2.00 g of ethyl 4-chloro-5,6,7,8,9,10,11,12-octahydrocyclodeca[b]pyridine-3-carboxylate and 1.12 g of 4-methoxyphenylhydrazine are stirred for eight hours in 20 ml of N-methylpyrrolidinone at 105°. The solution is then diluted with 50 ml of water and twice extracted with ether. The combined ether fractions are extracted twice with 20 ml of 1 N NaOH and the combined alkaline fractions are back-extracted with ether. The alkaline aqueous solution is then treated with an aqueous solution of 2.14 g of ammonium chloride, stirred until a solid forms; the precipitate is filtered off and dried to give 2-(4-methoxyphenyl)-2,3,6,7,8,9,10,11,12,13-decahydrocyclodeca[b]pyrazolo[3,4-d]pyridin-3(5H)-one, m.p. 143°-150°, the compound of example 5/ g.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([Cl:17])[CH:10]=[CH:11][CH:12]=3)[C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl.Cl.C(O)(=O)C>CCOCC>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([Cl:17])[CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C1c2cccc(Cl)c2Cc2cccc(Cl)c21

Procedure:
1,5-dichloroanthraquinone (1) was reduced with SnCl2 in boiling HCl and acetic acid with ether cleavage to give the corresponding 1,5 dichloro-9(10H)-anthracenone (II). To a solution of 1,5-dichloro-9(10H)anthracenone (1 mmol) and 0. 1 mL of pyridine in dry CH2Cl2 (20 mL) was added dropwise a solution of an appropriate acyl chloride (3 mmol) in dry CH2Cl2 (10 mL) under N2. The reaction mixture was stirred at room temperature or refluxed for several hours. The solvent was removed and the residue purified by recrystallization and chromatography. This procedure was used to synthesize each of the compounds in Table 1.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]#[N:9].[NH:16]1[CH2:21][CH2:20][C:19](=[N:22][OH:23])[CH2:18][CH2:17]1>C(O)C>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([N:16]1[CH2:21][CH2:20][C:19](=[N:22][OH:23])[CH2:18][CH2:17]1)=[NH:9]
Reactant: ON=C1CCNCC1
Reactant: N#CNc1ccccc1-c1ccccc1
Solvent: CCO
Product: N=C(Nc1ccccc1-c1ccccc1)N1CCC(=NO)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-biphenylylcyanamide (3.9 g), 4-piperidone oxime (4.5 g) and ethanol (50 ml) was stirred at ambient temperature for 6 hours and then at 50°-60° C. for 5 hours to give a brown solid which was purified by chromatography on an aluminia column eluted successively with hexane, 1:4, 2:3, 3:2 and 4:1 mixtures of dichloromethane and hexane and the 99:1 mixture of dichloromethane and methanol to yield a solid which was recrystallised from ethyl acetate to give N-(2-biphenylyl)-4-hydroxyiminopiperidine-1-carboxamidine (m.p. 175°-176° C.).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@@H:15]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:16][CH2:17][C@@H:10]2[CH2:9]1)(OC(C)(C)C)=O.[ClH:27]>C(Cl)(Cl)Cl.C(OCC)C>[ClH:27].[ClH:27].[F:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][C@@H:15]2[CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]3[CH2:17][CH2:16]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@@H](COc3ccc(F)cc3)CC[C@@H]2C1
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Fc1ccc(OC[C@H]2CC[C@@H]3CNCCN3C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.44 g (1.2 mmol) of (7S,9aR)-2-BOC-7-(4-fluorophenoxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine in 25 mL of chloroform was treated with excess HCl(g) in ethyl ether and stirred at ambient temperature for 2 h. The solvent was evaporated to give 0.40 g of title compound as the dihydrochloride salt which was used for subsequent reactions without purification.