Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([OH:30])=O)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[OH:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][CH2:35][NH:34][C:28](=[O:30])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([CH2:24][CH:19]3[CH2:20][CH2:21][CH2:22][CH:23]=[C:18]3[C:9]3[O:10][C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH:26]=2)=[CH:38][CH:39]=1
Reactant: NCCc1ccc(O)cc1
Reactant: O=C(O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCCc1ccc(O)cc1)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
To a mixture of (±)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoic acid (300 mg, 0.690 mmol) and tyramine (123 mg, 0.897 mmol) in DMF (5 ml) was added 1-hydroxybenzotriazole (140 mg, 1.04 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (265 mg, 1.38mmol). After stirring the resulting mixture at room temperature for 3 hours, the reaction mixture was diluted with EtOAc (30 ml), washed with 1N-hydrochloric acid, water, saturated sodium hydrogencarbonate solution, water and brine successively, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 3:2 elution) to give (±)-N-[2-(4-hydroxyphenyl)ethyl]-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzamide (358.4 mg, 94%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1-c1ccc(C(C)CNS(C)(=O)=O)cc1
Temperature: 100 °C
Yield: 92.1 %

Procedure:
To a degassed solution of 1.0 g (3.4 mmol) of material from Example 1, 0.8 g (5.1 mmol) of 2-methoxybenzeneboronic acid and 0.7 g (5.1 mmol) of potassium carbonate in 15 mL of dioxane and 5 mL of water was added 0.2 g (0.2 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixture was heated to 100° C. for 16 hours. The reaction mixture was cooled to ambient temperature, diluted with 10 mL of water and extracted three times with ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography on 50 g silica gel (35% ethyl acetate/hexane) afforded 1.0 g (90%) of the title compound as a viscous oil.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH:15][C:16](=[N:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[S:17][CH2:18][CH3:19])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:28]([S:31](Cl)(=[O:33])=[O:32])[CH2:29][CH3:30]>C(Cl)Cl>[CH2:21]([N:20]([S:31]([CH2:28][CH2:29][CH3:30])(=[O:33])=[O:32])[C:16](=[N:15][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:17][CH2:18][CH3:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCS(=O)(=O)Cl
Reactant: CCCCCCCN=C(NCCCCCCC)SCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCN=C(SCC)N(CCCCCCC)S(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.8 g (0.018 mole) of triethylamine was added to 4.5 g (0.015 mole) N,N'-diheptyl-S-ethyl-isothiourea in 50 ml methylene chloride in a stirred round bottom flask. A solution of propanesulfonyl chloride (0.018 mole, 2.6 g) in 8 ml methylene chloride was added dropwise to the above solution at 0° C. The mixture was stirred 1.5 hours at room temperature then at 30°-35° C. for 1.5 hours. The cooled solution was washed twice with 20 ml water, once with 25 ml saturated sodium bicarbonate solution and twice more with 20 ml of water. The organic phase was dried over magnesium sulfate and evaporated invacuo to yield the product as a yellow oil. nD30 1.4805. Yield was 5.2 g (85.4% of theory). The structure was confirmed by IR spectrum. Compound No. 203 in Table I.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]2)=[O:6])[CH2:2]1.CCN(C(C)C)C(C)C.[CH3:30][C:31]1[N:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:30][C:31]1[N:36]=[CH:35][C:34]([C:37]([N:1]2[CH2:4][CH:3]([C:5]([N:7]3[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]3)=[O:6])[CH2:2]2)=[O:38])=[CH:33][CH:32]=1
Reactant: Cc1ccc(C(=O)Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)C2CNC2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CC(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)C2)cn1
Yield: 36.4 %

Procedure:
To a stirred solution of tert-butyl 4-(azetidin-3-ylcarbonyl)-1,4-diazepane-1-carboxylate (1.02 g, 3.6 mmol) and DIPEA (1.41 g, 10.8 mmol) in DCM (20 mL) was added a solution of 6-methylpyridine-3-carbonyl chloride (420 mg, 4.32 mmol) in DCM (5 mL) at 0° C. After 3 hours the reaction was diluted with DCM (10 mL), washed with saturated aqueous NaHCO3 (10 mL), brine (5 mL), dried (MgSO4), filtered and concentrated at reduced pressure. Purification by silica FCC (eluting with 100:0:0 to 95:4.5:0.5 gradient of DCM/MeOH/NH3) gave the title compound (527 mg, 36%) as an orange-brown oil.
Reaction SMILES: Br.C(O[NH:7][CH:8]([CH3:20])[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[NH2:19])(C)(C)C.C(N(CC)CC)C.[CH3:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C(Cl)Cl>[NH2:7][CH:8]([CH3:20])[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[NH:19][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([CH3:28])=[CH:30][CH:31]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(Cn1c(N)nc2ccccc21)NOC(C)(C)C
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2nc3ccccc3n2CC(C)N)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(2-tert-butoxyaminopropyl)-2-aminobenzimidazole hydrobromide (1.00 g, 2.70 mmol) and triethylamine (1.9 mL, 3.79 mmol) in CH2Cl2 (50 mL) was added 4-methylbenzoyl chloride (0.46 g, 29.73 mmol) at 0° C. This mixture was stirred at 0° C. for 1 h and at room temperature overnight. The volatiles were evaporated and the residue was purified by flash chromatography using ethyl acetate-hexane (1:1). The fractions collected were concentrated in vacuo and the residue was dissolved in trifluoroacetic acid (5 ml) and stirred overnight. The trifluoroacetic acid was evaporated and the residue was dissolved in ethyl acetate and washed with a saturated solution of bicarbonate. Ethyl acetate was evaporated and the residue was purified by flash chromatography using CH2Cl2-MeOH (9.5: 0.5). The oil recovered after evaporation of solvent was transformed to the hydrochloride salt. MS 308 (M+1). 1HNMR (DMSO): δ 1.3(d, 3H), 2.37 (s, CH3), 3.80 (m, 1H), 4.45 (m, 2H), 7.26 (m, 4H), 7.55 and 7.62 (2d, 2H), 8.15 (d, 2H), 11.61 (bs, NH).
Reaction SMILES: [C:1]1([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15]C1C=CC(C(=O)C)=CC=1>CCOC(C)=O>[CH3:14][O:15][C:4]1[CH:3]=[CH:2][C:1]([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH3:10])=[CH:6][CH:5]=1
Reactant: CCC(=O)CC(=O)c1ccccc1
Reactant: COc1ccc(C(C)=O)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)CC(C)=O)cc1

Procedure:
The title compound was prepared (as described above for Intermediate 16) from 3.0 g of 4′-methoxyacetophenone and 3.95 mL of EtOAc. Purification by recrystallization from toluene/hexane afforded the title compound: 1H NMR (400 MHz, CDCl3, enol form) δ7.70 (d, 2H, J=8.20), 7.34 (d, 2H, J=8.20), 6.17 (s, 1H), 3.87 (s, 3H), 2.17 (s, 3H); low resolution MS (ES)m/e 193.1 (MH+)
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:12]([Si:15]([Cl:18])([Cl:17])[Cl:16])(Cl)Cl>>[C:1]1([C:12]([Si:15]([Cl:18])([Cl:17])[Cl:16])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(Cl)(Cl)[Si](Cl)(Cl)Cl
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 18.9 %

Procedure:
In the same apparatus and procedures as EXAMPLE 2 above, 22.88 ml (256 mmol) of benzene and 0.80 g (6.0 mmol) of aluminum chloride were alkylated with 9.04 g (17.2 mmol) of (trichloromethyl)trichlorosilane under dry nitrogen atmospheric pressure for 1 hr at 50° C. The aluminum chloride catalyst was quenched with POCl3 and then stirred for another 1 hour to complete the deactivation. Freshly distilled hexane(50 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic soultion. After hexane and benzene were distilled, recrystallization from chloroform yielded 1.23 g of (triphenylmethyl)trichlorosilane (mp; 195-7: E, yield; 19%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11](I)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:15]([C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1)#[CH:16].C(N(CC)CC)C>C1COCC1.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11]([C:16]#[C:15][C:17]3[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:29][CH:30]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(OCCN2CCCC2)cc1
Reactant: Clc1ccc(-c2cnc(I)cn2)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1ccc(-c2cnc(C#Cc3ccc(OCCN4CCCC4)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an N2 atmosphere 19 mg (0.1 mmol) CuI, 82 mg (0.1 mmol) [1,1′-bis-(diphenylphosphine)-ferrocene]-palladium(II)-chloride are added to a solution of 316 mg (1.0 mmol) 2-(4-chloro-phenyl)-5-iodo-pyrazine and 215 mg (1.0 mmol) 1-[2-(4-ethynyl-phenoxy)-ethyl]-pyrrolidine in 50 mL THF and 0.4 mL (3 mmol) triethylamine and the reaction mixture is stirred overnight at RT. To complete the reaction another 100 mg (0.32 mmol) 2-(4-chloro-phenyl)-5-iodo-pyrazine are added and the mixture is again stirred overnight. It is evaporated down i. vac., the residue is combined with 10% Na2CO3 solution, extracted exhaustively with DCM, the combined organic phases are washed three times with water and dried over MgSO4. This is filtered through activated charcoal, evaporated down i.vac. and the residue is purified by chromatography (silica gel, gradient: EtOAc to EtOAc/MeOH/NH3 9:9:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:14])[C:5]2[C:10]([C:11](=[O:13])[CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H][H]>O1CCCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][C:3](=[O:2])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[O:14][C:11](=[O:13])[CH3:10]
Reactant: COC1=CC(=O)c2ccccc2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(OC(C)=O)c2ccccc2c1OC(C)=O
Reaction time: 1 h

Procedure:
A solution of 2-methoxy-1,4-naphthoquinone (20.0 g) in tetrahydrofuran (150 mL) was hydrogenated at atmospheric pressure over Pd-C (10%, 0.5 g) until the calculated amount of hydrogen was absorbed, approximately 4 hours. While still under a blanket of hydrogen, a solution of acetic anhydride (20 mL) and pyridine (18 mL) in tetrahydrofuran (50 mL) was added to the mixture. After stirring for 1 hour the catalyst was filtered off and the solvent removed from the filtrate under reduced pressure. The residue was dissolved in ether (100 mL) and was washed with 1M hydrochloric acid (3×50 mL) and with brine (2×50 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated. Recrystallization from ether afforded 2-methoxy-1,4-diacetyloxynaphthalene, m.p. 135°-136° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][Cl:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH2:14]>C(O)(=O)C>[Cl:13][CH2:12][C:11]1[C:2](=[O:14])[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: ClCc1cc2ccccc2nc1Cl
Reactant: O
Solvent: CC(=O)O
Product: O=c1[nH]c2ccccc2cc1CCl

Procedure:
2.8 Grams of 2-chloro-3-chloromethylquinoline was dissolved in 30 ml of acetic acid and the solution was refluxed for 2 hours. The reaction mixture was poured into water and the crystals precipitated were collected by filtration, and were recrystallized from methanol to obtain 2.1 g of 3-chloromethylcarbostyril in the form of colorless needle-like crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:15])=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:4]([CH3:15])=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(OC)cc(OC)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC)c(C)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
Solid methyl 3,5-dimethoxy-2-methylbenzoate (5.83 g J. C. S. Perkin I, 1973, 2853.) was dissolved in methanol (80 ml). A solution of aqueous sodium hydroxide (10%, 80 ml) was added and the solution stirred at room temperature for 1 hour. The reaction was then concentrated under reduced pressure to approximately half of the original volume before adding aqueous hydrochloric acid (200 ml). The white precipitate that formed was extracted with ethyl acetate (2×250 ml). The combined extracts were dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to give the sub-title compound as a colourless solid (5.41 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25]CC(=O)N(C)C)[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:21][N:22]([CH3:25])[CH3:23])[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)CCN1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CCN1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Yield: 185.5 %

Procedure:
To a stirred suspension of the amide from Step A (82 mg, 0.195 mmol) in 3 mL tetrahydrofuran was added lithium aluminum hydride (1.0M in tetrahydrofuran, 0.39 mL, 0.39 mmol) dropwise. After refluxing for 3 hours, the reaction was quenched with few drops of saturated Na2SO4, and then solvent was removed in vacuo. Purification by silica gel chromatography afforded the title compound (71 mg, 89%). NMR 1.8(m, 2H), 2.4(s, 6H0, 2.4(m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:12]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:17]=[CH:16][C:15]([CH:18]([C:20](C(Br)C2C=CC(C3C=CC=CC=3)=CC=2)=O)Br)=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[C:12]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:13]=[CH:14][C:15]([C:18]2[N:1]=[C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[CH:4][N:3]3[CH:20]=2)=[CH:16][CH:17]=1
Reactant: Nc1nccc2ccccc12
Reactant: O=C(C(Br)c1ccc(-c2ccccc2)cc1)C(Br)c1ccc(-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: c1ccc(-c2ccc(-c3cn4ccc5ccccc5c4n3)cc2)cc1
Temperature: 100 °C

Procedure:
A solution of 4.32 g. (0.03 mole) of 1-amino-isoquinoline and 8.25 g. (0.03 mole) of [(1,1'-biphenyl)-4-yl]-bromomethyl-ketone in 100 ml. of chloroform was heated on a boiling water bath for about 10 minutes until a precipitate separated. The solvent was distilled off at atmospheric pressure and the residue was heated under vacuum for 30 minutes at 100° C. It was subsequently taken up with 50 ml of water and the resulting solution was made alkaline by means of 70 ml. of aqueous 10% sodium hydroxide. After extracting with 500 ml. of methylene chloride and evaporating the solvent, a residue was obtained which was re-crystallized from ethylene glycol monomethylether. Yield 3.0 g. M.p. 221°-22° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[F:18][C:17]([F:19])([F:20])[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:6]2[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]2)=[CH:11][CH:12]=1)([OH:25])[C:21]([F:22])([F:24])[F:23]
Reactant: C[C@@H]1CNCCN1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1
Yield: 30.1 %

Procedure:
(R)-2-Methylpiperazine (37.9 mmol, 3.8 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (37.9 mmol, 12.79 g) and potassium carbonate (76 mmol, 10.49 g) were stirred at room temperature in acetonitrile (50 mL) overnight. The reaction mixture was diluted with ethyl acetate and filtered through dicalite. The filtrate was concentrated under vacuum. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 85/15/1.5 dichloromethane/methanol/ammonia) to afford the title compound (4.06 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][OH:12])([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][OH:12]
Reactant: O=[N+]([O-])c1cnccc1CCO
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cnccc1CCO
Yield: 79.1 %

Procedure:
A solution of 2-(3-nitropyridin-4-yl)ethanol (24) (WO 2006136562) (2.00 g, 11.89 mmol) in MeOH (150 mL) was passed through a Thales H-cube (2.0 mL·min−1, 30° C., 30 bar, Pd/C Cat-Cart, 55 mm, controlled mode). Analysis by LC-MS showed a significant amount of starting material was still present and the solution was passed through the H-cube twice more (2.0 mL·min−1, full hydrogen mode, RT, and 2.0 mL·min−1, full hydrogen mode, 40° C.). Evaporation of the volatiles gave the title compound (25) as a purple oil (1.30 g, 81%): m/z 139 (M+H)+ (ES+).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1>[O:11]=[C:10]1[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[NH:6][C:5]2[CH:16]=[CH:17][C:2]([NH:1][C:25](=[O:27])[CH3:26])=[CH:3][C:4]1=2
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
A solution of 2-amino-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one (Example 6, 200 mg, 0.89 mmol) and triethylamine in tetrahydrofuran (10 mL) was cooled to 0° C. (ice-water bath). To this was added acetic anhydride (90.6 mg, 0.89 mmol) dropwise over a period of 10 minutes. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated at reduced pressure and the residue was chromatographed on silica gel (80% ethyl acetate/20% hexanes then 100% ethyl acetate and finally 2% methanol/ethyl acetate) to give a yellow solid (120 mg, 50.4%). H1 NMR (DMSO d6) δ: 9.82 (s, 1H), 9.80 (s, 1H), 7.82-7.81 (d, 1H, J=4.0), 7.68 (s, 1H), 7.58-7.55 (m, 11H), 6.95-6.86 (m, 5H), 1.97 (s, 3H).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]([CH2:11][C:12](OC)=[O:13])=O)=[CH:7][CH:6]=1>C(O)C>[Cl:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]2[NH:3][N:2]=[C:12]([OH:13])[CH:11]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)CC(=O)c1ccc(Cl)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Oc1cc(-c2ccc(Cl)cc2)[nH]n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.2 %

Procedure:
Hydrazine monohydrate (0.80 g, 20 mmol) was added to a solution of methyl 4-chlorobenzoylacetate (3.19 g, 15.0 mmol) in ethanol (40 ml) at 0° C., and the mixture was stirred at room temperature for 2 days. After completion of the reaction, a precipitated solid was filtered and washed with diethyl ether, to give a white solid of 5-(4-chlorophenyl)-3-hydroxypyrazole (2.02 g, yield: 55.1%). mp: 240-241° C.; 1H-NMR (DMSO-d6, DMSO, ppm): δ 5.92 (s, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.70 (d, J=8.5 Hz, 2H), 9.30-10.60 (br s, 1H), 11.60-12.70 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[CH3:13])=[CH:5][CH:4]=1.[N+:16]([O-])([O-:18])=[O:17].[K+]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[CH3:13])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: COc1ccc2[nH]c(=O)c(=O)n(C)c2c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1cc2c(cc1[N+](=O)[O-])[nH]c(=O)c(=O)n2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of 0.5 g (2.4 mmol) 7-methoxy-1-methylquinoxaline-2,3(1H,4H)-dione in 20 ml concentrated sulfuric acid was added at 0° C. 0.25 g (2.48 mmol) potassium nitrate. Stirring was continued at 0° C. for 30 min, and then at 25° C. for 90 min. The reaction mixture was poured into 100 ml ice-water to give 0.51 g (84% of 7-methoxy-1-methyl-6-nitroquinoxaline-2,3(1H,4H)-dione as a precipitate. M.p. 343° C. NMR (DMSO-d6): 11.9 (1H, broad s), 7.67 (1H, s), 7.0 (1H, s), 3.97 (3H, s), 3.53 (3H, s).
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.C(OCC)(=O)C>CS(C)=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][N:8]([N:6]1[CH:5]=[N:4][N:3]=[CH:7]1)[C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(CCCCBr)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 240 mg, 6.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMSO (25 mL) at r.t. The mixture was stirred for 1 hour at this temperature and 1,4-dibromobutane (5 mL, ca 42 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (100 mL) was added. The mixture was transferred into a separation funnel and extracted with water (twice 100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure (water bath temperature <30° C.). The resulting orange oil was mixed with diethyl ether (100 mL) and filtered through a layer of silica (ca. 5 cm). The silica was washed with more diethyl ether (ca. 100 mL) to remove the excess of 1,4-dibromobutane; the crude product was washed from the silica with acetone (120 mL). The acetone solution was concentrated under reduced pressure and the residue was purified by column-chromatography (eluent: ethyl acetate) to give the title compound as a white solid. Yield: 984 mg (61%). 1H-NMR (400 MHz, d6-DMSO) δ=1.53-1.60 (m, 2H), 1.87-1.94 (m, 2H), 3.56 (t, J=6.6 Hz, 2H), 3.87 (t, J=7.4 Hz, 2H), 6.64 (d, J=9.0 Hz, 2H), 7.73 (d, J=9.0 Hz, 2H), 8.99 (s, 2H). LRMS (FAB+): 320.0 (100, [M+H]+).