Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:14][C:13]2[C:8](=[N:9][C:10]([Cl:15])=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])C.[OH-].[Na+].C(O)(=O)C>C(O)C.ClCCl>[Cl:15][C:10]1[N:9]=[C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:14][C:13]2=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cc2nc(Cl)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1cc2nc(Cl)ccc2[nH]1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester (Preparation 5, 151 mg, 0.67 mmol) in ethanol (10 mL) was added sodium hydroxide (0.35 mL, 2M) and the stirred solution was heated at 70° C. for 2 h. The reaction mixture was then allowed to cool to rt and left to stand for 16 h. The pH was adjusted to 4 by addition of glacial acetic acid, the solvents removed in vacuo to give a white solid, which was suspended in dichloromethane and filtered through a sinter, washing with additional dichloromethane. The filter cake was washed with ethyl acetate (3×30 mL) and dried to give the title compound as a white solid. δH (CD3OD): 6.97 (1H, s), 7.17 (1H, d, 8.35 Hz), 7.83 (1H, d, 8.35 Hz); m/z (ES+)=197 [M+H]+; RT=2.82 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][NH:5][C:6](=[O:25])[C@H:7]([CH3:24])[NH:8][C:9](=[O:23])[CH2:10][NH:11][C:12](=[O:22])[CH2:13][NH:14]C(OC(C)(C)C)=O>FC(F)(F)C(O)=O>[NH2:14][CH2:13][C:12]([NH:11][CH2:10][C:9]([NH:8][C@H:7]([C:6]([NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:26])=[O:25])[CH3:24])=[O:23])=[O:22]
Reactant: COC(=O)CNC(=O)[C@H](C)NC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CNC(=O)[C@H](C)NC(=O)CNC(=O)CN

Procedure:
A solution of Boc-Gly-Gly-Ala-Gly-OMe (2.0 g, 5.35 mmole, described in Example 4) in trifluoroacetic acid (25 ml) is stirred at 0° C for 1 hr. The solvent is evaporated, the residue triturated with ether, the solid collected and dried to give the tetrapeptide of formula H-Gly-Gly-Ala-Gly-OMe isolated as the trifluoroacetic acid addition salt.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].CN.C[CH2:35][N:36]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]([NH:36][CH3:35])=[O:26])[CH2:22][CH2:23]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:30][CH:31]=1)([CH3:3])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC(C(=O)O)CC3)n3nccc3n2)cc1
Agent: CN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CNC(=O)C1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)CC1
Yield: 54.5 %

Procedure:
A solution of 1-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-4-carboxylic acid (Compound 244, 80 mg, 0.189 mmol), methylamine (33 μL, 0.378 mmol), EDCI (72 mg, 0.378 mmol), and HOBT (13 mg, 0.094 mmol) in DMF (4 mL) were stirred for 12 hours at room temperature. The reaction was complete as determined by LCMS analysis. The reaction mixture was then partitioned between ethyl acetate and water and the separated organic layer was dried over Mg2SO4, filtered, and concentrated under reduced pressure. Purification by preparatory HPLC, 30-50% (MeCN/H2O gradient+0.01% TFA) provided the titled compound as a yellow oil (45 mg, 55%). 1HNMR (DMSO-d6) δ: 10.90 (s, 1H), 8.09 (d, J=2.3 Hz, 1H), 8.00 (d, J=8.8 Hz, 2H), 7.80-7.87 (m, 1H), 7.60 (d, 2H), 7.41 (s, 1H), 6.35 (d, J=2.3 Hz, 1H), 4.46 (d, J=12.1 Hz, 2H), 3.10 (td, J=12.3, 2.8 Hz, 2H), 2.59 (d, J=4.5 Hz, 3H), 1.71-1.90 (m, 4H), 1.44 (s, 6H). ESI-MS: m/z 437.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:22])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([NH:22][C:4]1[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:35]
Reactant: Cc1cnc(N2CCC(CCN3CCCCC3)CC2)c(N)c1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnc(N2CCC(CCN3CCCCC3)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a solution of 0.075 g (0.25 mmol) of 5′-methyl-4-(2-piperidin-1-yl-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine in methylene chloride (5 mL) is added 0.050 mL (0.30 mmol) of triethylamine followed by 0.044 g (0.25 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred overnight at room temperature then purified by preparative reverse phase HPLC to give 0.033 g (30%) of the title compound (3) as a white solid. [M+H]+=441.3.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][O:32][CH2:33][CH3:34])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][N:20]3C(=O)C4C(=CC=CC=4)C3=O)[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.NN>>[NH2:20][O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:31][O:32][CH2:33][CH3:34]
Reactant: CCOCc1nc2c(N)nc3c(c2n1CCCCON1C(=O)c2ccccc2C1=O)CCCC3
Agent: NN
Product: CCOCc1nc2c(N)nc3c(c2n1CCCCON)CCCC3

Procedure:
The method described in Part F of Example 169 can be used to treat 2-{4-[4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]-1H-isoindole-1,3(2H)-dione with anhydrous hydrazine to provide 1-[4-(aminooxy)butyl]-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][OH:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:18]([C:27]([F:30])([F:29])[F:28])=[N:19][N:20]([CH2:23][C:24](O)=[O:25])[C:21]=1[CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[Cl:16][C:17]1[C:18]([C:27]([F:29])([F:28])[F:30])=[N:19][N:20]([CH2:23][C:24]([N:11]2[CH2:12][CH2:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([CH2:14][OH:15])[CH2:9][CH2:10]2)=[O:25])[C:21]=1[CH3:22]
Reactant: OCC1(c2ccc(Cl)cc2)CCNCC1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(CO)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 25 mL flask was taken 500 mg of [4-(4-chloro-phenyl)-piperidin-4-yl]-methanol (2.44 mmol, 1.0 equiv), 591 mg of (4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (2.44 mmol, 1.00 equiv), 1.29 g BOP (2.92 mmol, 1.2 equiv), 1.36 mL TEA (9.75 mmol, 4.00 equiv) and 15 mL NMP. A stir bar was placed in the flask and the mixture stirred overnight at room temperature under N2. The crude product was purified by reversed phase HPLC (acetonitrile—H2O with 0.1% TFA as the eluent) to yield 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-4-hydroxymethyl-piperidin-1-yl]-ethanone. MS (ES) M+H expected=450.0, found=450.3
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([CH3:34])=[C:11]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]=2[C:16]2[CH:21]=[CH:20][C:19](Cl)=[CH:18][CH:17]=2)[N:7]=1)(=[O:3])[CH3:2].C(O[C@@H](C1C(C2CCCCC=2)=C2C(=CC=1C)[N+]([O-])=C(C)C=C2)C(OCC)=O)(C)(C)C.ClC1C=CC(C2C=C(C)C=C3C=2C=CC(C)=[N+]3[O-])=CC=1>>[C:1]([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([CH3:34])=[C:11]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]=2[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=2)[N:7]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(COC(C)=O)ccc2c1-c1ccc(Cl)cc1
Agent: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(ccc(C)[n+]2[O-])c1C1=CCCCC1
Agent: Cc1cc(-c2ccc(Cl)cc2)c2ccc(C)[n+]([O-])c2c1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(COC(C)=O)ccc2c1C1=CCCCC1

Procedure:
(S)-Ethyl 2-(2-(acetoxymethyl)-5-cyclohexenyl-7-methylquinolin-6-yl)-2-tert-butoxyacetate was prepared following the procedure used to prepare compound (S)-ethyl 2-(2-(acetoxymethyl)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetate of Example 16, except that (S)-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-cyclohexenyl-2,7-dimethylquinoline 1-oxide was used instead of 2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-2,7-dimethylquinoline 1-oxide. LCMS-ESI+ (m/z): 454.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH2:5][NH:6][CH:7]([CH3:10])[CH2:8][OH:9].O1[CH2:17][CH:16]1[CH2:18][N:19]1C(=O)C2C(=CC=CC=2)C1=O.S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH2:5][N:6]1[C@H:7]([CH3:10])[CH2:8][O:9][C@H:16]([CH2:18][NH2:19])[CH2:17]1
Reactant: CC(CO)NCc1ccc(Cl)c(Cl)c1
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Agent: O=S(=O)(O)O
Solvent: O
Product: C[C@@H]1CO[C@H](CN)CN1Cc1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 42 h
Yield: 72.3 %

Procedure:
A mixture of Intermediate 4 (0.470 g) and 2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (0.410 g) was heated at 80° C. under nitrogen for 5 h. The mixture was treated with concentrated sulphuric acid (0.6 ml) then stirred at 150° C. for 42 h. The mixture was treated with water (50 ml) then washed with ethyl acetate (2×50 ml). The dark aqueous phase was basified to ˜pH 11 using 5M aqueous sodium hydroxide then extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with water and brine, dried (Na2SO4) and concentrated under vacuum to give the title compound as a brown oil (0.42 g).
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[CH:12]=[C:11]([F:15])[CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:16]#[N:17])=[CH:4][N:3]=1.CCO.[NH4+:21].[OH-:22]>O>[NH2:21][C:2]1[C:14]2[C:13]3[CH:12]=[C:11]([F:15])[CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:16]([NH2:17])=[O:22])=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: [OH-]
Reactant: N#Cc1cnc(Cl)c2c1[nH]c1ccc(F)cc12
Solvent: CCO
Solvent: O
Product: NC(=O)c1cnc(N)c2c1[nH]c1ccc(F)cc12
Temperature: 150 °C

Procedure:
A mixture of 1-chloro-8-fluoro-5H-pyrido[4,3-b]indole-4-carbonitrile in a 1:1 (v/v) mixture of EtOH and conc. NH4OH (0.13 M) was heated in a microwave reactor at 150° C. for 1 h in a sealed tube. After cooling to room temperature, the suspension was diluted with H2O and filtered. The crude material was placed in a flask cooled to 0° C. before conc. H2SO4 (excess) was added dropwise under vigorous stirring. The final mixture was warmed to room temperature and, after 4 h, poured carefully into a diluted aqueous solution of NH4OH cooled to 0° C. The precipitate was collected by filtration and was purified by flash chromatography (20-50% ethanol in CH2Cl2) to provide the title compound as an off-white solid.
Reaction SMILES: [OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][CH:17]([OH:21])[CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:30])[CH2:3]1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1>[OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][CH:17]([O:21][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([O:30][C:2](=[O:1])[C:27]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:26]=2)[CH2:3]1
Reactant: CC(C)C(O)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)C(CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(=O)c5ccccc5)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C)OC(=O)c1ccccc1
Reaction time: 24 h

Procedure:
250 mg of 1α,3β,24-trihydroxycholesta-5,7-diene prepared in the same way as in Example 14, (D-1) was mixed with 210 mg of benzoyl chloride and 5 ml. of pyridine, and the mixture was allowed to stand at 23° C. for one day. The resulting reaction mixture was treated in the same way as in Example 21 to afford 1α-hydroxy-3β,24-dibenzoyloxycholesta-5,7-diene.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:26])[CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].Cl>O.O1CCOCC1>[CH2:19]([O:18][C:16]([NH:15][CH2:14][C:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]([OH:27])=[O:4])=[O:26])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccccc1NC(=O)CNC(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(CNC(=O)OCc1ccccc1)Nc1ccccc1C(=O)O
Reaction time: 8 h

Procedure:
Lithium hydroxide (55 mg, 1.32 mmol) in water (0.8 mL), was added to a solution of the benzoate (1) (300 mg, 0.88 mmol) in dioxane (4 mL). After stirring overnight, the reaction mixture was concentrated at 40° C. to give a viscous oil, which was treated with 10% aqueous hydrochloric acid (31 mL), with the resulting emulsion formed being extracted with ethyl acetate (4×). The organic phases were combined, dried (MgSO4) and concentrated to give the title benzoic acid (2) quantitatively as a white solid:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=O)=[N:6][CH:7]=1.[NH2:12][C:13]1[CH:18]=[C:17]([C:19]([C:21]2[C:25]3[CH:26]=[N:27][CH:28]=[CH:29][C:24]=3[N:23]([CH:30]([CH3:32])[CH3:31])[CH:22]=2)=[O:20])[CH:16]=[CH:15][N:14]=1.CCCP(=O)=O.C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:12][C:13]2[CH:18]=[C:17]([C:19]([C:21]3[C:25]4[CH:26]=[N:27][CH:28]=[CH:29][C:24]=4[N:23]([CH:30]([CH3:32])[CH3:31])[CH:22]=3)=[O:20])[CH:16]=[CH:15][N:14]=2)=[O:11])=[N:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cn1
Reactant: CC(C)n1cc(C(=O)c2ccnc(N)c2)c2cnccc21
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)n1cc(C(=O)c2ccnc(NC(=O)Cc3ccc(Br)cn3)c2)c2cnccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-bromopyridin-2-yl)acetic acid (Preparation 83, 92 mg, 0.427 mmol) and (2-aminopyridin-4-yl)(1-isopropyl-1H-pyrrolo[3,2-c]pyridin-3-yl)methanone (Preparation 20, 120 mg, 0.427 mmol) in THF (3 mL) was added propylphosphonic anhydride (786 uL, 1.281 mmol) and triethylamine (151 uL, 1.99 mmol) and the reaction was stirred at room temperature for 18 hours. The reaction was diluted with EtOAc, washed with saturated aqueous NaHCO3 solution, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified using preparative TLC eluting with 5% MeOH in DCM to afford the title compound.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[H-].[Na+].[CH2:12]([C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1)[CH2:13][CH2:14][CH3:15].O>C1COCC1.C(OCC)(=O)C>[CH2:12]([C:16]1[N:17]=[N:18][C:19]([O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[CH:20][C:21]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:26][CH:27]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: OC1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nnc(OC2CN3CCC2CC3)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1-aza-bicyclo[2.2.2]octan-3-ol (0.44 mmol, 0.055 g) in THF (1 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (0.58 mmol, 0.023 g) and continued stirring for 15 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 0.29 mmol, 0.1 g) in THF (1 mL). After completion of addition, the reaction mixture was warmed to 50° C. for 1 h. LCMS showed the reaction was about 50% complete, so the temperature was raised to 68° C. and the reaction was stirred over night. The reaction was poured into a mixture of water (3 mL) and ethyl acetate (5 mL). The mixture was shaken and separated. The ethyl acetate layer was washed with brine (2 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 4 g SiO2 cartridge using 4-6% (2N NH3 in MeOH) in DCM to provide 3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-1-azabicyclo[2.2.2]octane. The amine was treated with 2N HCl in diethyl ether (2 mL) and DCM (2 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.05 g). LCMS: m/z 437 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.92 (1H, s), 7.51-7.49 (2H, m), 7.10-7.17 (2H, m), 5.49-5.56 (1H, m), 4.41-4.50 (1H, m), 3.99-3.93 (1H, m), 3.61 (1H, d), 3.35-3.51 (4H, m), 3.14-3.21 (2H, m), 2.64-2.71 (1H, m), 2.41-2.34 (1H, m), 1.94-2.25 (5H, m), 1.77-1.87 (2H, m), 1.25-1.65 (10H, m), 0.82 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:14]CN(CC)CC.ClC(OC)=O>C(Cl)Cl.CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:14])=[O:8]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: COC(=O)Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
To a solution of 10 g (49.6 mmol) of 5-chloro-2-nitrobenzoic acid and 9 mL (64.5 mmol) Et3N in 300 ml CH2Cl2 at 0° C. was added 4.6 mL (59.5 mmol) methyl chloroformate. The cold bath was removed and after 10 minutes, 0.200 mL methanol was added. Bubbles Of CO2 could be seen rising from the solution. After 2 hours, the mixture was diluted with Et2O, was washed with 5% HC1, was washed with saturated NaHCO3 solution, was washed with brine, was dried over MgSO4 and decolorized with charcoal, then was stripped of solvent in vacuo to give the product. Rf 0.35 in 15% EtOAc/hexane, visualized by UV; 1H--NMR (400 MHz, CDCl3): δ7.92 (d, J=8.6 Hz, 1H), 7.69 (d, J=2.3 Hz, 1H), 7.59 (dd, J1 =2.2 Hz, J2 =8.8 Hz, 1H), 3.94 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4]>[Pt].CCO>[Br:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([NH2:10])[C:3]=1[NH2:4]
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1Br
Agent: [Pt]
Solvent: CCO
Product: Nc1ccc(F)c(Br)c1N
Reaction time: 22 h

Procedure:
A 500 mL round-bottomed flask containing Pt/C (5%, 6.00 g, 1.54 mmol) and 2-bromo-3-fluoro-6-nitroaniline (600b) (20.85 g, 89 mmol) were treated with EtOH (250 mL) and stirred under an atmosphere of H2 (balloon) for 22 h. LC-MS indicated ca. 35% conversion to the desired material (M+1=204.9/206.9). Another balloon of H2 was added and it was stirred for another 16 h resulting in >90% conversion to the desired product (M+1=204.9/207.1) by LC-MS. The suspension was filtered through a plug of Celite washing with EtOH and concentrated affording crude 3-bromo-4-fluorobenzene-1,2-diamine (18 g, 88 mmol, 99% yield) as a black/purple viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 6.60 (1H, dd, J=8.5, 5.2 Hz), 6.42-6.50 (1H, m). 19F NMR (376 MHz, CDCl3) δ ppm −116.48 (1F, s). m/z (ESI, +ve ion) 204.9/206.9 (M+H)+.
Reaction SMILES: CCO.[OH-].[K+].[F:6][C:7]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:11][C:10]([NH2:25])=[C:9]([NH2:26])[CH:8]=1.[C:27](=S)=[S:28]>C(O)(=O)C.O>[C:16]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:14][C:13]([C:12]2[C:7]([F:6])=[CH:8][C:9]3[NH:26][C:27](=[S:28])[NH:25][C:10]=3[CH:11]=2)=[CH:18][CH:17]=1
Reactant: Nc1cc(F)c(-c2ccc(-c3ccccc3)cc2)cc1N
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Fc1cc2[nH]c(=S)[nH]c2cc1-c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of EtOH (20 mL), H2O (4 mL) and KOH (593 mg, 11 mmol) was added 4 (2.46 g, 8.8 mmol). CS2 (0.65 mL, 11 mmol) was then added and the suspension was heated to reflux for 2 h. The reaction mixture was cooled to 25° C., then 40 mL of H2O and 0.8 mL of acetic acid were added resulting in a tan precipitate. The precipitate was collected by vacuum filtation resulting in title compound 5, which required no further purification.
Reaction SMILES: C([NH:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[O:14])=[CH:9][CH:8]=1)([CH3:6])[CH3:5])=O.O.Cl>C(O)(=O)C>[NH2:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])=[O:14])=[CH:9][CH:8]=1)([CH3:5])[CH3:6]
Reactant: CC(C)(NC=O)c1ccc(C(=O)C(=O)c2ccccc2)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(N)c1ccc(C(=O)C(=O)c2ccccc2)cc1

Procedure:
4(2-formamidoprop-2-yl)-benzil, prepared as described in Step 6 (6.17 g) was dissolved in 100 ml of glacial acetic acid, 84 ml of water and 6 ml of concentrated HCl. The mixture was stirred at reflux for 3 hours and then the solvent removed under vacuum at 60 C. The residue was converted to the free based form, extracted with organic solvent, washed with water, dried and concentrated to provide the title compound as an oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH:15]=[CH2:16].[Cl-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:13]([C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:3][CH2:2][CH:1]=[CH2:6])[C:8]#[N:9])[CH2:14][CH2:15][CH3:16]
Reactant: C=CCCBr
Reactant: N#CCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCC(C#N)(CCCC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-phenylacetonitrile (1 mL) in DMF (1.0 mL) at 0° C. was added sodium hydride (95% oil dispersion, 547 mg) and the resulting suspension was stirred at 0° C. for 10 min. 4-Bromobut-1-ene (2.2 mL) was added, and the reaction mixture was stirred at room temperature for 2 h. Saturated sodium chloride was added followed by ethyl acetate, the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated in vacuo. The residue was purified by silica gel flash chromatography eluting with 10% ethyl acetate/90% hexanes to give the title compound as an oil (773 mg). 1H NMR (400 MHz, CDCl3) δ 1.8-2.3 (8H, m), 4.95 (4H, m), 5.73 (2H, m), and 7.31 (5H, m).
Reaction SMILES: [CH:1](=[C:8]1[C:20]2[N:19]3[CH:21]=[CH:22][N:23]=[C:18]3[C:17](=[O:24])[NH:16][C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H][H]>[Pd].CO>[CH2:1]([CH:8]1[C:20]2[N:19]3[CH:21]=[CH:22][N:23]=[C:18]3[C:17](=[O:24])[NH:16][C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c2c3ccccc3c(=Cc3ccccc3)c2n2ccnc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1[nH]c2c(n3ccnc13)C(Cc1ccccc1)c1ccccc1-2
Yield: 37.3 %

Procedure:
A mixture of 0.4 g of 10-benzylidene-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 90 ml of dimethylformamide and 10 ml of methanol is hydrogenated at a temperature in the region of 20° C. at a pressure of 1.9 bar of hydrogen for 3 hours in the presence of 10% palladium on charcoal. The catalyst is then filtered off under inert atmosphere and the solvents are evaporated off. The brown solid obtained (0.37 g) is purified by chromatography on a column of silica (35 g) with a mixture of dichloromethane and methanol (90/10 by volume). After trituration with 5 ml of dichloromethane, filtration and drying at 100° C., 0.15 g of 10-benzyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is obtained, in the form of a beige solid melting above 260° C. (Analysis % calculated C: 76.66, H: 4.82, N: 13.41, O: 5.11, % found C: 76.3, H: 4.6, N: 13.4).