Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([SH:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:12]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:10]2[O:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Sc1nc2cccc(Br)c2o1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1nc2cccc(Br)c2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6 g (26.1 mmol) 7-bromo-benzooxazole-2-thiol, 7.28 g (52.2 mmol) K2CO3, 4.1 g (28.7 mmol) MeI in 80 ml DMF is stirred at room temperature for 1 h. The reaction mixture is then poured on water and extracted 2× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([CH2:14]Br)[CH:12]=[CH:13][C:8]=2[O:7][CH:6]=1.[CH3:17][NH:18][CH3:19]>C1COCC1.C(O)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([CH2:14][N:18]([CH3:19])[CH3:17])[CH:12]=[CH:13][C:8]=2[O:7][CH:6]=1
Reactant: COC(=O)Cc1coc2ccc(CBr)cc12
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)Cc1coc2ccc(CN(C)C)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of (5-bromomethyl-benzofuran-3-yl)-acetic acid methyl ester (198 mg, 0.70 mmol) in THF (4.0 mL) is added a 5.6 M solution of dimethylamine in ethanol (1.0 mL). The resulting reaction mixture is stirred for 2 h at room temperature, filtered through a microfilter (25 μm) and the filtrate concentrated at reduced pressure to afford the title compound as a yellow oil (170 mg, 0.69 mmol, 98%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.56 (s, 1H), 7.45 (s, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.23 (d, J=8.6 Hz, 1H), 3.66 (s, 3H), 3.64 (s, 2H), 3.52 (s, 2H), 2.24 (s, 3H). MS (ES+): 248 (M(C14H17NO3)+H)+.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]([CH3:48])([CH3:47])[C@H:6]([NH:18][C:19]([C@H:21]([CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:35]([F:46])[CH:34]=1)[C@H:22]([O:27][CH2:28][CH3:29])[C:23]([O:25]C)=[O:24])=[O:20])[C:7]([NH:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])=[O:8].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:48][C:5]([CH3:4])([CH3:47])[C@H:6]([NH:18][C:19]([C@H:21]([CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[C:35]([F:46])[CH:34]=1)[C@H:22]([O:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24])=[O:20])[C:7]([NH:9][C@@H:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:11])=[O:8]
Reactant: CCO[C@H](C(=O)OC)[C@@H](CCCc1ccc(Oc2ccccc2)c(F)c1)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCO[C@H](C(=O)O)[C@@H](CCCc1ccc(Oc2ccccc2)c(F)c1)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Yield: 18.1 %

Procedure:
Lithium hydroxide hydrate (116 mg, 2.83 mmol) was added to a solution of methyl (2S,3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-2-ethoxy-6-(3-fluoro-4-phenoxyphenyl)hexanoate (368 mg, 0.566 mmol) in methanol:water=10:1 (5 mL) and the mixture was stirred at room temperature for 2 h. The solution was neutralised with 5% aqueous citric acid and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and 5% aqueous citric acid (20 mL), washed with saturated aqueous sodium chloride (20 mL), dried MgSO4), and concentrated under reduced pressure. Purification by flash chromatography (eluting with dichloromethane:methanol=20:1 to 10:1) gave the title compound (62 mg, 18%) as a colourless glass, and some mixed fractions. These were combined and repurified by flash chromatography (eluting with ethyl acetate:hexane:acetic acid=33:66:1 to 50:50:1) to give the title compound (37 mg, 11%), as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:18]([OH:20])=O)=[N:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH3:16])[C:8](=[O:17])[C:7]=12.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[F:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49][NH2:50])=[CH:47][CH:46]=1>CN(C=O)C>[F:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49][NH:50][C:18]([C:4]2[C:3]([O:2][CH3:1])=[C:7]3[C:8](=[O:17])[N:9]([CH3:16])[C:10]4[C:15]([N:6]3[N:5]=2)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[O:20])=[CH:47][CH:46]=1
Reactant: COc1c(C(=O)O)nn2c1c(=O)n(C)c1ccccc12
Reactant: NCc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(=O)NCc2ccc(F)cc2)nn2c1c(=O)n(C)c1ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-methoxy-5-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-2-carboxylic acid (75 mg, 0.27 mmol) in DMF were added HOBT (46 mg, 0.3 mmol), EDC (76 mg, 0.4 mmol), DIEA (0.05 mL, 0.29 mmol), and 4-fluorobenzylamine (50 mg, 0.4 mmol). The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and aqueous sodium bicarbonate. The EtOAc layer was dried (MgSO4), filtered and the solvent was removed under reduced pressure. The residue was triturated in MeOH to give the product as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 8.91 (t, J=5.9 Hz, 1H), 8.26 (d, J=8.0 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.39-7.44 (m, 3H), 7.17 (t, J=8.9 Hz, 2H), 4.49 (d, J=6.1 Hz, 2H), 4.02 (s, 3H), 3.61 (s, 3H); ES MS (M+1)=381.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[N:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:14][CH:15]=2)[CH2:4]1.C(N(C(C)C)CC)(C)C.Cl[C:33]1[N:38]=[CH:37][N:36]=[CH:35][CH:34]=1>CN(C=O)C>[N:36]1[CH:35]=[CH:34][CH:33]=[N:38][C:37]=1[N:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[N:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:14][CH:15]=2)[CH2:4]1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCNC2)cn1
Reactant: Clc1ccncn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCN(c3ncccn3)C2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
To a solution of ethyl (2E)-3-{5-[(3R)-3-piperidinylamino]-2-pyrazinyl}acrylate dihydrochloride (300 mg, 0.86 mmol) in DMF (6 mL) were added diisopropylethylamine (366 mg, 2.84 mmol) and 6-chloropyrimidine (128 mg, 1.11 mmol) at ambient temperature and the mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-MeOH=95-5/hexane-EtOAc=¼) to give ethyl (2E)-3-(5-{[(3R)-1-(2-pyrimidinyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate (141 mg, 46%) as an amorphous powder.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4](Cl)([O:6][CH2:7][CH:8]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:5]>C(Cl)Cl.O>[OH:3][NH:2][C:4](=[O:5])[O:6][CH2:7][CH:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: NO
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(NO)OCC1c2ccccc2-c2ccccc21
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 72.5 %

Procedure:
hydroxylamine hydrochloride (6.0 g, 86 mmol) in CH2Cl2 (250 mL) and water (100 mL) at 0° C. After 10 mins, solid FmocCl (21 g, 81 mmol) is added portionwise with vigorous stirring. After 1 h a white precipitate forms and more CH2Cl2 (100 mL) is added. The solution is allowed to warm to 20° C. and left to stir for 3 d. The white solid that remains is filtered away, re-dissolved in ethyl acetate (300 mL), washed with brine and dried over MgSO4 to yield (9H-fluoren-9-yl)methyl hydroxycarbamate (Mellor, S. L.; McGuire, C.; Chan, W. C.; Tet. Lett., 1997, 38, 3311-3314) as a white solid (15 g, 68%). Furthermore, the mother-liquor is concentrated and purified by column chromatography (silica gel, ethyl acetate/CH2Cl2 1:1 to 1:0) to yield the title compound (by-product) as a white solid (0.55 g, 1%).
Reaction SMILES: [N+:1]([C:4]1[C:5](O)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].N1C2C(=CC=CC=2)C=CC=1.P(Cl)(Cl)([Cl:27])=O.[OH-].[Na+]>>[Cl:27][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc2ncccc2c1
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
3-nitro-5-(trifluoromethyl)pyridin-2-ol (6.80 g, 32.7 mmol) and quinoline (2.72 g, 21.06 mmol) were combined in a 200 mL round-bottom flask with an oversized magnetic stir bar. The assembly was cooled with an RT water bath. Phosphorus oxychloride (4.07 ml, 43.7 mmol) was cautiously added with vigorous stirring. After 5 mm, the resulting gel would no longer stir. The apparatus was equipped with a reflux condenser and was transferred to a 120° C. oil bath. The gel quickly melted and stirring resumed with gentle refluxing. After 3 h, the mixture was cooled to RT and added portion wise to ice water with vigorous stirring. Sodium hydroxide was added to adjust the alkalinity to pH 8-9 and the mixture was extracted with EtOAc (2×100 mL) and CH2Cl2 (2×100 mL). The combined organics were dried (MgSO4), concentrated in vacuo and chromatographed (EtOAc/CH2Cl2) provided 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (6.65 g, 90% yield) as a yellow liquid. 1H NMR (400 MHz, DMSO-d6): δ 9.21 (m, 1 H), 9.09 (m, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15](=[O:23])[CH2:14][CH2:13]1)[NH:6][C:5]2=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[N:52]12[CH2:62][CH2:61][CH2:60][N:59]=C1CCCCC2.NCC1(NC)[CH2:68][O:67][CH2:66]1>CN(C)C=O.O>[NH2:52][CH2:62][C:61]1([CH2:60][NH:59][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=3)[N:8]=[C:7]([N:12]3[CH2:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[S:15](=[O:23])[CH2:14][CH2:13]3)[N:6]=2)[CH2:68][O:67][CH2:66]1
Reactant: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)[nH]c(=O)c2c1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CNC1(CN)COC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(NCC3(CN)COC3)c2c1
Reaction time: 0.17 h
Yield: 69.7 %

Procedure:
To a solution of 6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one (10 g, 29.5 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (16.9 g, 38.3 mmol) in N,N-dimethylformamide (140 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (6.7 g, 44.2 mmol) at room temperature. After being stirred for 10 minutes, (3-aminomethyl-oxetan-3-yl)-methylamine (5.1 g, 44.2 mmol) was added. The mixture was stirred for 4 hours at room temperature and diluted with water (150 mL). The separated aqueous layer was extracted with ethyl acetate (100 mL×6). The organic layers were combined and washed with brine, dried over sodium sulfate, and then concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10% methanol in dichloromethane) to afford 9.0 g of the impure product (purity was 90%). The impure product was purified by preparative HPLC to afford 6.0 g of the desired product as a white solid. MS obsd. (ESI+) [(M+H)+] 438, 1H NMR (400 MHz, CD3OD) δ ppm 8.02 (s, 1 H), 7.82-7.79 (m, 2 H), 7.64 (d, J=1.6 Hz, 1 H), 7.60-7.57 (m, 3 H), 5.44 (d, 1 H), 5.13 (brs, 1 H), 4.77 (brs, 1 H), 4.66-4.59 (m, 4 H), 4.51 (brs, 1 H), 4.24 (s, 2 H), 3.55 (brs, 2 H), 3.44 (s, 2 H), 2.44 (s, 3 H).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:30][Si](C)(C)C.CCOCC>CC(CC)=O>[ClH:30].[CH3:29][N:2]([CH3:1])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2cccc(F)c2)CCC(CC(=O)NCCCc2ccccc2)CC1
Solvent: CCC(C)=O
Solvent: CCOCC
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The less polar diastereoisomer of 2-[4-dimethylamino-4-(3-fluorophenyl)cyclohexyl]-N-(3-phenylpropyl)-acetamide (64.3 mg, 0.16 mmol) was dissolved in ethyl methyl ketone (10 ml), and chlorotrimethylsilane (0.03 ml, 0.24 mmol) was added. After 2 h ether (10 ml) was added to the reaction mixture and the mixture was stirred at RT for 30 min. The hydrochloride was isolated as a colourless, hygroscopic solid in a yield of 78% (54 mg) (Example 53).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[CH3:31][N:32](C=O)C>[C-]#N.[Zn+2].[C-]#N.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:29][C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([C:31]#[N:32])=[N:7][CH:6]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@@H]1CCCC[C@H]1O
Reactant: CN(C)C=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(Cc2cc3c(=O)n([C@@H]4CCCC[C@H]4O)cnc3c3ccccc23)cn1
Temperature: 25 °C

Procedure:
To a solution of rac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one (0.050 g, 0.12 mmol) and zinc cyanide (0.042 g, 0.36 mmol) in 2 mL of DMF under an atmosphere of nitrogen was added bis(tri-tert-butylphosphine)palladium(0) (10 mol %). The mixture was irradiated in a microwave reactor at 160° C. for 1 h, cooled to rt, filtered, and purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 411.0 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 9.04-9.02 (m, 1H), 8.70 (s, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 7.84-7.80 (m, 1H), 7.76-7.64 (m, 2H), 7.57-7.52 (m, 2H), 4.67 (br s, 1H), 4.55 (s, 2H), 4.02 (br s, 1H), 2.30-2.22 (m, 1H), 2.10-2.03 (m, 1H), 2.00-1.83 (m, 3H), 1.59-1.21 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1)([CH3:12])([CH3:11])[CH3:10].N1C=CC=CC=1>ClCCl>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:19]([C@H:16]2[CH2:17][CH2:18][C@H:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:14][CH2:15]2)=[O:20])=[CH:3][CH:4]=1
Reactant: CC(C)(C)[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: Nc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](C(=O)Nc2ccc(O)cc2)CC1
Reaction time: 8 h

Procedure:
To a solution of 4-aminophenol (3.08 g, 28.2 mmol) in dichloromethane (50 ml) were added cis/trans-4-tert-butyl-cyclohexanecarbonyl chloride (11.43 g, 56.4 mmol) and pyridine (4.56 ml, 56.4 mmol), while cooling the reaction mixture in an ice bath. After the addition was completed, the cooling bath was removed and stirring was continued overnight at room temperature. The solvent was removed by evaporation and the residue was dissolved in THF (300 ml). 6N NaOH (aq, 33 ml) was added and the mixture was stirred at room temperature overnight. The organic phase was removed by evaporation. Water (200 ml) was added and the solid material was collected by filtration, washed with water, dried in vacuo at 40° C. and dissolved in methanol (100 ml). A solution of KOH (2.4 g) in methanol (50 ml) was added. After stirring for 2 h at room temperature water (200 ml) was added and the organic phase was removed by evaporation. The aqueous phase was acidified with 1 N HCl and extracted with ethyl acetate (3×300 ml). The combined organic phases were washed with saturated sodium bicarbonate, dried, filtered and evaporated, yielding a pink oil, which was dried in vacuo at 40° C. The solid material was crystallised from ethyl acetate/heptane yielding the title compound (2.03 g, 26%, pink crystals). From the first aqueous extract a second portion of product was isolated by extraction with ethyl acetate (3×250 ml). The combined organic phases were washed with water (400 ml), saturated sodium bicarbonate (2×400 ml), dried, filtered and evaporated, yielding a pink thick oil. Crystallisation from ethyl acetate/heptane yielded a further amount of title compound (2.75 g, 35%).
Reaction SMILES: Cl[C:2]1(C#N)[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH:4]=[CH:5]2.[OH-:12].[K+]>CS(C)=O.O>[CH:3]12[CH2:9][CH2:8][CH:6]([CH:5]=[CH:4]1)[CH2:7][C:2]2=[O:12]
Reactant: N#CC1(Cl)CC2C=CC1CC2
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1CC2C=CC1CC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 50 %

Procedure:
To a stirred solution of 5-chloro-5-cyanobicyclo[2,2,2]oct-2-ene (65 g, 0.39 mol) (representing several runs of the foregoing procedure) in dimethyl sulfoxide (500 mL) was added potassium hydroxide (87.4 g, 1.56 mol) and water (30 mL). The resulting mixture was stirred at room temperature for 15 h, diluted with water (1000 mL) and extracted with ether (4×500 mL). The combined ether extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel, eluting with mixtures of diethyl ether (1% to 5%) in petroleum ether, to give bicyclo[2,2,2]oct-5-en-2-one (23.8 g. 50% yield) as a white solid, 1H NMR (300 MHz, CDCl3) δ 1.53˜1.84 (m, 4H), 2.01˜2.02 (m, 2H), 2.96˜2.99 (m, 1H), 3.11˜3.13 (m, 1H), 6.15˜6.21 (m, 1H), 6.43˜6.48 (m, 1H); GCMS (m/z): 122.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][S:5][C:6]1[C:7]2[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:8]=2[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]1([O:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH3:1][N:2]([CH2:3][CH2:4][S:5][C:6]1[C:7]2[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:8]=2[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[CH:12]=1)[C:37]([O:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:38]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CSc1ccc2c(c1)C(SCCN(C)C)=Cc1ccccc1O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CSc1ccc2c(c1)C(SCCN(C)C(=O)Oc1ccccc1)=Cc1ccccc1O2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirring solution of 11.3 g of 11-[β-(dimethylamino)ethylthio]-2-(methylthio)dibenz[b,f]oxepin, free base of Example 21, and 10.0 g of potassium carbonate in 50 ml of methylene chloride is added dropwise a solution of 5.7 g of phenylchloroformate in 50 ml of methylene chloride. After total addition the reaction mixture is stirred at ambient temperature for 24 hours and then evaporated to dryness. The residue is triturated with ether and the ethereal solution is sequentially washed successively with a 10% sodium hydroxide solution and water, dried and filtered and the filtrate evaporated to dryness leaving a yellow oil. The oil is chromatographed through a silica gel column with a methylene chloride eluant to obtain the purified orange oil of 11-[β-(N-methyl-N-phenoxycarbonylamino)ethylthio]-2-(methylthio)-dibenz[b,f]oxepin.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][OH:9])[CH:2]=1.[C:10]1([CH3:21])[CH:15]=[CH:14][C:13]([S:16]([O:19]C)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[C:10]1([CH3:21])[CH:11]=[CH:12][C:13]([S:16]([O-:19])(=[O:17])=[O:18])=[CH:14][CH:15]=1.[OH:9][CH2:8][CH2:7][C:3]1[CH:2]=[N+:1]([CH3:10])[CH:6]=[CH:5][CH:4]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: OCCc1cccnc1
Product: C[n+]1cccc(CCO)c1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 200.1 %

Procedure:
The procedures of Reference Example 10 were repeated using 1.00 g of 3-pyridinethanol and 1.51 g of methyl p-toluenesulfonate to give 2.51 g of the desired compound.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][CH2:11][N:12]1[C:20]2[CH:19]=[CH:18][C:17]([NH:21][CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)=[C:16]3[C:32](=[O:39])[C:33]4[CH:34]=[CH:35][N:36]=[CH:37][C:38]=4[C:14]([C:15]=23)=[N:13]1)=O)(C)(C)C>C(O)C>[ClH:1].[ClH:1].[ClH:1].[NH2:9][CH2:10][CH2:11][N:12]1[C:20]2[CH:19]=[CH:18][C:17]([NH:21][CH2:22][CH2:23][NH2:24])=[C:16]3[C:32](=[O:39])[C:33]4[CH:34]=[CH:35][N:36]=[CH:37][C:38]=4[C:14]([C:15]=23)=[N:13]1
Reactant: CC(C)(C)OC(=O)NCCNc1ccc2c3c(nn2CCNC(=O)OC(C)(C)C)-c2cnccc2C(=O)c13
Agent: Cl
Solvent: CCO
Product: NCCNc1ccc2c3c(nn2CCN)-c2cnccc2C(=O)c13
Temperature: 40 °C

Procedure:
Under a nitrogen atmosphere an ethanolic solution of anhydrous HCl (5N; 0.40 mL) is dropped into a stirred suspension of 2-[2-(N-tert-butoxycarbonylamino)ethyl]-5-[[2-(N-tert-butoxycarbonylamino)ethyl]amino]isoquino[8,7,6-cd]indazole-6(2H)-one of Example 10 (0.104 g) in absolute ethanol (2.1 mL). Initial dissolution of the starting material followed by precipitation of a dark-red solid is observed during the addition of ethanolic HCl. This solid is redissolved with absolute ethanol and the solution is heated to 40° C. for 2 h, 30'. The gradual formation of a red-amaranth precipitate is observed during the heating. After cooling to room temperature diethyl ether (10 mL) is added and the precipitate is collected by suction filtration under a nitrogen blanket, to give 2-[2-(amino)ethyl]-5-[[2-(amino)ethyl]amino]isoquino[8,7,6-cd]indazole-6(2H)-one trihydrochloride (0.070 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([O-])=O.O.NN>C1COCC1.C(O)C.[Ni]>[N:8]1([CH2:7][C:6]2[CH:5]=[C:4]([NH2:1])[CH:16]=[CH:15][CH:14]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1cccc(CN2CCOCC2)c1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 117.3 %

Procedure:
To a solution of 4-(3-nitrobenzyl)morpholine (2.0 g; 9.0 mmol) in THF/ethanol mixture (1:1) (50 mL) was added a catalytical amount of Raney-Nickel and hydrazine hydrate (36.0 mmol) and the mixture was stirred at ambient temperature for 15 minutes, then filtered through a Celite-pad and the filtrate was evaporated to provide pure 3-(morpholin-4-yl)methylphenylamine (2.03 g, 98%), which was used in further reactions without purification.