Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)([CH3:17])([CH3:16])[CH3:15].[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([S:7][C:1]2[CH:2]=[CH:3][C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][CH:6]=2)=[CH:13][CH:12]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: c1ccc(Sc2ccccc2)cc1
Reactant: CC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(C)(C)c1ccc(Sc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a mixture of 93 g of phenyl sulfide, 92.5 g of t-butyl chloride and 200 mL of CS2 cooled in an ice bath, 133 g of AlCl3 was added over a period of 1 hour. Following complete addition, the mixture was allowed to warm slowly to room temperature and stirred overnight. The mixture was subjected to decomposition with ice, extraction with ether and washing of the ether solution successively with water, 5% NaHCO3, water and saturated NaCl solution and gave after evaporation of dried (MgSO4) extracts, a solid which upon crystallization from methanol gave 145 g (97%) of the sulfide as white crystals, m.p. 83-84; 'H NMR (CDCl3) δ 1.32 (s, 18H, CH3), 7.35 (s, 8H, aryl).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([CH2:31][C:32]([NH:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:9]=[CH:10]3)=[O:33])=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc2c(cnn2CCN2CCCC2)c1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Product: O=C(Cc1ccc(Oc2ccccc2)cc1)Nc1ccc2c(cnn2CCN2CCCC2)c1

Procedure:
1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-ylamine and (4-phenoxy-phenyl)-acetic acid were processed as described in Example 17 to provide the title compound. MS (DCI/NH3) MS m/z 441 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ ppm 1.83 (m, 2 H), 1.99 (m, 2 H), 3.05 (m, 2 H), 3.52 (m, 2 H), 3.65 (s, 2 H), 3.71 (q, J=5.93 Hz, 2 H), 4.74 (t, J=6.24 Hz, 2 H), 6.99 (m, 4 H), 7.13 (m, 1 H), 7.37 (m, 4 H), 7.54 (m, 1 H), 7.69 (m, 1 H), 8.14 (m, 2 H), 9.63 (br s, N H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25]([CH:36]([CH3:38])[CH3:37])=[CH:24][C:10]=1[C:11]([N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:22]=O)[CH:19]=2)[CH2:14]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:25]([CH:36]([CH3:38])[CH3:37])=[CH:24][C:10]=1[C:11]([N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:22][N:43]3[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]3)[CH:19]=2)[CH2:14]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc(C=O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)c1cc(C(=O)N2Cc3ccc(CN4CCN(C)CC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 5 h
Yield: 86.1 %

Procedure:
To a solution of 2-(2,4-bis-benzyloxy-5-isopropyl-benzoyl)-2,3-dihydro-1H-isoindole-5-carbaldehyde (0.316 g, 0.63 mmol) and n-methyl piperazine (63 mg, 0.63 mmol) in CH2Cl2 (10 ml) was added AcOH (38 mgs 0.63 mmol) and NaBH(OAc)3 (0.28 g, 1.33 mmol), then stirred at ambient for 5 hours. The reaction was quenched with water, layers separated and aqueous washed CH2Cl2. The organics were combined, washed with brine, dried (MgSO4), filtered and evaporated to give 0.32 g of (2,4-bis-benzyloxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl]-methanone. MS: [M+H]+ 588.
Reaction SMILES: C[C:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1O)=O.C12CC3CC(CC(C3)C1=[O:25])C2.N1CCCC1.[OH2:31]>C1(C)C=CC=CC=1>[CH3:7][C:6]1[CH:5]=[C:4]([CH3:2])[CH:13]=[C:12]2[C:11]=1[CH2:10][CH2:9][C:8](=[O:25])[O:31]2
Reactant: O
Reactant: CC(=O)c1ccc2ccccc2c1O
Reactant: O=C1C2CC3CC(C2)CC1C3
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2c(c1)OC(=O)CC2

Procedure:
A mixture of 1-hydroxy-2-acetonaphthone (10.1 g), (1A), adamantanone (9 g) and pyrrolidine (10 cm3) in toluene (300 cm3) was boiled (10 hours) and water separated. The yellow reaction mixture turned first crimson and then dark brown. Toluene was removed under reduced pressure and the residual enamine crystallised from acetone as discoloured crystals (8 g). The enamine (2) (10 g) was treated with conc. hydrochloric acid (1 cm3) in methanol (200 cm3). The crimson solution was evaporated and the residual dark oil crystallised from acetone, yielding the chromanone (3) (8.4 g) as yellow needles. The chromanone (0.5 g) was reduced by sodium borohydride (0.5 g) in methanol to yield the chromanol (4) (0.32 g) which was heated with anhydrous copper sulphate to give HC7 (formula (5) R=H) (0.28 g) as a discoloured solid which was decolourised with activated charcoal and recrystallised from acetone.
Reaction SMILES: [CH:1]1([C:5]([N:7]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[CH:17]=[CH:16][N:15]=2)C(C2CCC2)=O)=[O:6])[CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+].CN(C)C=O.C(O)C>[Fe].O>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([NH:7][C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:6])[CH:19]=2)=[CH:22][CH:23]=1
Reactant: O=C(C1CCC1)N(C(=O)C1CCC1)c1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1ccc(Oc2ccnc(NC(=O)C3CCC3)c2)cc1
Yield: 25.2 %

Procedure:
N1-Cyclobutanecarbonyl-N1-[4-(4-nitrophenoxy)-2-pyridyl]-1-cyclobutanecarboxamide (720 mg), iron powder (1.4 g), ammonium chloride (2.4 g), dimethylformamide (52 ml), ethanol (2 ml) and water (1 ml) were stirred at 100° C. for 15 minutes. The mixture was filtered with celite, and then water and ethyl acetate were added for extraction. The organic layer was washed 5 times with ammonium chloride water and then dried over magnesium sulfate. The drying agent was filtered off, the solvent was distilled off under reduced pressure, ethyl acetate and hexane were added to the residue and the precipitated solid was filtered out to obtain 130 mg of a solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].C(O)(C(F)(F)F)=O>>[CH:16]1([N:7]2[CH2:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Yield: 75.8 %

Procedure:
2-Chloro-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (Intermediate 3) (0.35 g, 1.14 mmol, 1 eq), 4-amino-3-methoxybenzoic acid (0.57 g, 3.42 mmol, 3 eq) and TFA (0.42 mL, 5.7 mmol, 5 eq) were heated to reflux in TFE (10 mL) for 36 hours. Solvent was evaporated in vacuo and the resulting residue was triturated with EtOAc to give 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (0.38 g, 76%).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[S:38][C:39]([CH3:42])=[N:40][N:41]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[S:38][C:39]([CH3:42])=[N:40][N:41]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Cc1nnc(Br)s1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1nnc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)s1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 2-bromo-5-methyl-[1,3,4]thiadiazole following a procedure analogous to that described in Example 171. Mass spectrum (ESI−): m/z=496 [M+HCOO]−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:18][CH2:17][C:10]3([NH:14]C(=O)N[C:11]3=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.[OH-:19].[Na+].Cl>O1CCOCC1>[NH2:14][C:10]1([C:11]([OH:19])=[O:16])[CH2:17][CH2:18][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: O=C1NC(=O)C2(CC[C@@H](c3ccc(Br)cc3)C2)N1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: NC1(C(=O)O)CC[C@@H](c2ccc(Br)cc2)C1

Procedure:
A solution of (7R)-7-(4-bromophenyl)-1,3-diazaspiro[4.4]nonane-2,4-dione (I-2B, 6.80 g, 22 mmol) in dioxane (20 mL) and NaOH (2N aq) (120 mL, 240 mmol) was heated in an oil bath set to 95° C. The resulting clear, pale yellow solution was left to stir over the weekend. The solution was cooled in an ice bath and neutralized to approximately pH 7 with 6 N HCl resulting in the formation of a precipitate. The solids were collected and left to air dry overnight. The white solid was slurried in hot ethanol (˜100 mL) and re-collected by filtration and the solid was air-dried then placed under high vacuum. (5.8 g, 20.41 mmol). HPLC retention time=0.64 min (Condition G); LC/MS M+1=284/286. 1H NMR (500 MHz, methanol-d4) δ 7.52-7.38 (m, 2H), 7.31-7.17 (m, 2H), 3.55-3.40 (m, 1H), 2.68 (dd, J=13.3, 6.7 Hz, 1H from single diastereomer), 2.58-2.39 (m, 1H), 2.26-2.15 (m, 1H), 2.10-1.98 (m, 1H), 1.98-1.81 (m, 1H), 1.70 (dd, J=13.2, 11.8 Hz, 1H from single diastereomer).
Reaction SMILES: N[C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:3]1.[CH3:33]C(O)=O.C=O.[BH3-][C:40]#[N:41].[Na+]>CO>[C:10]([O:9][C:7]([N:5]1[CH2:6][C@H:2]([N:41]([CH3:40])[CH3:33])[CH2:3][C@H:4]1[CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN(C)[C@@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
To a stirred solution of trans-4-amino-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy) methylpyrrolidine (400 mg, 0.88 mmol), AcOH (120 ml, 2.0 mmol), and 37% HCHO aq (500 ml) in MeOH (10 ml) was added NaBH3CN (111 mg, 1.76 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hr. After concentrated in vacuo, water was added and extracted with CH2Cl2. The extract was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH—CH2Cl2 (3:97, v/v) as eluent to give trans-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy)methyl-4-dimethylaminopyrrolidine (330 mg, 78%) as a pale yellow oil. 1H-NMR (CDCl3) δ 1.06 (s, 9H), 1.33 and 1.45 (each s, total 9H), 1.80–2.25 (m, 2H), 2.23 (br s, 6H), 2.95–4.05 (m, 6H), 7.36–7.39 (m, 6H), 7.63–7.65 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=O)[C:5](=O)[NH:6]2.[C:13]1([NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]>C(O)(=O)C>[Br:1][C:2]1[C:3]2[C:4]3[C:5]([NH:19][C:14]4[C:13]([N:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1Nc2cccc(Br)c2C1=O
Reactant: Nc1ccccc1N
Solvent: CC(=O)O
Product: Brc1cccc2nc3[nH]c4ccccc4nc-3c12
Reaction time: 16 h

Procedure:
A solution of 3.40 g (15.0 mmol) of 4-bromoisatin and 1.63 g (1 eq.) of 1,2-phenylenediamine in 50 ml of acetic acid was refluxed for 2 hours. The reaction solution was allowed to stand at room temperature for 16 hours, and the resulting precipitate was collected by filtration to give 10-bromoindolo[2,3-b]quinoxaline.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:34]=[N:33][C:12]2[O:13][C:14]([CH3:32])([CH3:31])[C:15](=[O:30])[N:16]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=1.CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.[C:53](=O)([O-])[O-:54].[Cs+].[Cs+]>[Cu](I)I.O.CO>[CH3:53][O:54][C:9]1[CH:34]=[N:33][C:12]2[O:13][C:14]([CH3:32])([CH3:31])[C:15](=[O:30])[N:16]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)Oc3ncc(Br)cc32)CC1
Reactant: O=C([O-])[O-]
Agent: I[Cu]I
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: COc1cnc2c(c1)N(C1CCN(C(=O)OC(C)(C)C)CC1)C(=O)C(C)(C)O2
Temperature: 80 °C
Reaction time: 21 h
Yield: 24.9 %

Procedure:
To a toluene suspension (5.6 ml) of tert-butyl 4-(7-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)piperidine-1-carboxylate (Example 52-1) (1.11 g), copper iodide (24.0 mg), 3,4,7,8-tetramethyl-1,10-phenanthroline (59.6 mg) and cesium carbonate (1.23 g) was added methanol (0.204 ml), followed by stirring at 80° C. for 21 hours. After the reaction solution was brought back to room temperature, water was added, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-(7-methoxy-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)piperidine-1-carboxylate (246 mg).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:27]=[CH:26][C:10]2[O:11][CH2:12][C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=3/[C:15](=[CH:16]/[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])/[C:9]=2[CH:8]=1.C=[O:29].[O:30]1[CH2:34]CCC1>CCCCCC>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17]/[CH:16]=[C:15]1\[C:9]2[CH:8]=[C:7]([C:34]([OH:30])=[O:29])[CH:27]=[CH:26][C:10]=2[O:11][CH2:12][C:13]2[CH:25]=[CH:24][CH:23]=[CH:22][C:14]\1=2
Reactant: CN(C)CC/C=C1/c2ccccc2COc2ccc(Br)cc21
Reactant: C1CCOC1
Reactant: C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CN(C)CC/C=C1/c2ccccc2COc2ccc(C(=O)O)cc21
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyl lithium in hexane (1.6M, 3.5 mL) was added dropwise to a solution of 1.8 g. pure (Z)-3-(2-bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine in 100 mL of dry tetrahydrofuran at -70° C. under a nitrogen atmosphere. After the yellowish-orange solution was stirred at -70° C. for 10 minutes, gaseous carbon dioxide was bubbled through the reaction medium to give a pale yellow solution. The solution was allowed to warm gradually to room temperature and was then concentrated under reduced pressure. The foamy residue was dissolved in water, and the mixture was neutralized with 1N hydrochloric acid and then extracted with chloroform. Concentration of the chloroform and recrystallization of the residue from water gave 0.5 g. pure Z-2-carboxylic acid, m.p. 121°-123° C. pmr (CDCl3) δ: 7.87 (d, J≤1 Hz, 1H, H1), 7.81 (dd, J=7.8, 2.2 Hz, 1H, H3), 7.25-7.28 (m, 4H, aromatic), 6.82 (degenerate d, J=8.8 Hz, 1H, H4), 6.45 (br s, 1H, CO2H), 5.50 (m, 1H, CH=), 5.20 (br, s, 2H, CH2O), 2.92 (m, 4H, NCH2CH2), 2.66 (s, 6H, NMe2).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([OH:8])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].[F:34][C:35]([F:45])([F:44])[C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1>O>[Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[C:5](=[O:8])[N:6]([CH2:40][C:39]2[CH:38]=[CH:37][C:36]([C:35]([F:34])([F:44])[F:45])=[CH:43][CH:42]=2)[N:7]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: Oc1nnc(Cl)c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c(Cl)nn1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask was added 6-chloro-4,5-bis(4-chlorophenyl)pyridazin-3-ol (1.5 gm, 4.26 mmol), DMF (15 ml) and K2CO3 (1.17 gm, 8.52 mmol). The reaction was stirred at rt for 30 min. After this time, 4-trifluoromethylbenzyl bromide (1.2 gm, 5.19 mmol) was added to the reaction and the reaction was stirred at rt for an additional 8 hrs. The reaction mixture was then diluted with water (40 ml). The reaction mixture was poured into a separatory funnel and extracted with EtOAc (2×50 ml). The combined organic layers were washed with water (4×30 ml) and saturated aqueous NaCl (30 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give product 6-chloro-4,5-bis(4-chlorophenyl)-2-(4-(trifluoromethyl)benzyl)pyridazin-3(2H)-one as off white solid (1.5 gm, 65.1% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:38][C:39]1[CH:44]=[N:43][CH:42]=[C:41]2[S:45][C:46]([C:48]3[S:52][C:51]([NH2:53])=[N:50][N:49]=3)=[CH:47][C:40]=12.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:38][C:39]1[CH:44]=[N:43][CH:42]=[C:41]2[S:45][C:46]([C:48]3[S:52][C:51]([NH:53][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=4)=[N:50][N:49]=3)=[CH:47][C:40]=12
Reactant: Nc1nnc(-c2cc3c(Cl)cncc3s2)s1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(C(F)(F)F)c1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(C(F)(F)F)c1)C(=O)Nc1nnc(-c2cc3c(Cl)cncc3s2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-2-((tert-Butoxycarbonyl)amino)-3-(3-(trifluoromethyl)phenyl)propanoic acid (1 g, 3 mmol) purchased from Peptech was mixed with EDC (0.766 g, 4 mmol) and HOBt (0.810 g, 6 mmol) in 5 mL DMF in a round bottom flask. The mixture was stirred at room temperature for 30 minutes. 5-(4-Chlorothieno[2,3-c]pyridin-2-yl)-1,3,4-thiadiazol-2-amine (0.268 g, 1 mmol) was added to the flask followed by addition of DIEA (1.4 mL, 8 mmol). The mixture was heated at 50° C. for one hour. After the DMF was removed under reduced pressure, the remaining residue was mixed with 200 mL EtOAc. The EtOAc solution was washed three times with saturated ammonium chloride aqueous solution, three times with saturated aqueous NaHCO3, and then dried over Na2SO4. After removing the solvent, the product was obtained and used directly in the next step.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[Cl:9][CH2:10]OC>CN(C)C=O>[ClH:9].[S:1]1[C:2]2[CH2:6][CH2:7][NH:8][CH2:10][C:3]=2[CH:4]=[CH:5]1
Reactant: COCCl
Reactant: NCCc1cccs1
Solvent: CN(C)C=O
Product: Cl
Product: c1cc2c(s1)CCNC2
Temperature: 70 °C
Yield: 31.4 %

Procedure:
To a solution of 12.7 g (0.1 M) 2-(2-thienyl)ethylamine in 20 ml dimethylformamide heated at 55° C. are added, over 10 minutes, 8.05 g (0.1 M) chloromethylmethylether diluted in 10 ml dimethylformamide. After addition of the chloromethylmethylether, the medium is maintained at 70° C. for 2 hours, and is then cooled to room temperature. The desired product precipitates out and is rinsed with acetone, to give 5.5 g 4,5,6,7-tetrahydro-thieno[3,2-c]-pyridine hydrochloride (M.p=225° C.; Yield: 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=S)[CH2:10][N:9]=1.[NH3:23].CO>O1CCCC1>[NH2:23][C:11]1[CH2:10][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: N
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCC(=S)N2
Solvent: CO
Solvent: C1CCOC1
Product: NC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2Cl)=NC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 14 g of 5-(2-chlorophenyl)-7-nitro-3H-1,4-benzodiazepine-2(1H)-thione (J. B. Hester, A. D. Rudzik & B. V. Kamdar, J. Med. Chem., 1971, 14, 1078-1081) in 700 ml of tetrahydrofuran were added firstly 260 ml of 25% aqueous ammonia solution and then 50 ml of methanol. The solution was stirred at room temperature for 20 h. and then concentrated to about 25 ml in a vacuum. The crystalline precipitate was filtered off and recrystallized from dioxan. There were obtained 13.2 g of 2-amino-5-(2-chlorophenyl)-7-nitro-3H-1,4-benzodiazepine of m.p. 222-224° C.
Reaction SMILES: [O:1]=[C:2]1[C@H:18]2[N:6]([C@H:7]([CH2:19][CH2:20][CH2:21][NH:22]C(=O)OCC3C=CC=CC=3)[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[CH2:17]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:5](=[O:33])[C@@H:4]2[CH2:34][CH2:35][CH2:36][N:3]12>CO.[Pd]>[NH2:22][CH2:21][CH2:20][CH2:19][C@@H:7]1[C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH2:17][C@H:18]2[C:2](=[O:1])[N:3]4[CH2:36][CH2:35][CH2:34][C@H:4]4[C:5](=[O:33])[N:6]12)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: O=C(NCCC[C@@H]1c2[nH]c3ccccc3c2C[C@H]2C(=O)N3CCC[C@H]3C(=O)N12)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCCC[C@@H]1c2[nH]c3ccccc3c2C[C@H]2C(=O)N3CCC[C@H]3C(=O)N12
Yield: 95 %

Procedure:
The solution of benzyl 3-[(5aS,12R,14aS)-5,14-dioxo-2,3,5a,6,11,12,14,14a-octahydro-1H,5H-pyrrolo[1″,2″:4′,5′]pyrazino[2′,1′:6,1]pyrido[3,4-b]indol-12-yl]propylcarbamate (0.1 mmol) in methanol (2.0 ml) was stirred under hydrogen (1.5 atm) in the presence of 5% Palladium on carbon for 1 hour. The solid was removed by filtration, and the solution was evaporated to afford (5aS,12R,14aS)-12-(3-aminopropyl)-1,2,3,5a,6,11,12,14a-octahydro-5H,14H-pyrrolo[1″,2″:4′,5′]pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-5,14-dione (95%). The (5aS,12S,14aS)-12-(3-aminopropyl)-1,2,3,5a,6,11,12,14a-octahydro-5H,14H-pyrrolo[1″,2″:4′,5′]pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-5,14-dione was prepared in a similar manner, but using 3-[(5aS,12S,14aS)-5,14-dioxo-2,3,5a,6,11,12,14,14a-octahydro-1H,5H-pyrrolo[1″,2″:4′,5′]pyrazino[2′,1′:6,1]pyrido[3,4-b]indol-12-yl]propylcarbamate as starting material. ESIMS (MH+): 29a, 353.2; 29b, 353.2.