Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[F:28][C:29]([F:35])([F:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C:29]([F:35])([F:34])[F:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)CC(F)(F)F
Agent: Cl
Product: O=C(CC(F)(F)F)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (49 mg, 70%), MS (ISP) m/z=441.4 [(M+H)+], mp 216.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) 3,3,3-trifluoropropanoic acid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:18])[CH2:4][CH2:3]1.Cl[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][N:28]=2)[N:25]=1>>[F:31][C:29]([F:30])([F:32])[C:26]1[N:24]2[N:25]=[C:20]([N:2]3[CH2:7][CH2:6][CH:5]([N:8]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[CH2:11][CH2:10][C:9]4=[O:18])[CH2:4][CH2:3]3)[CH:21]=[CH:22][C:23]2=[N:28][N:27]=1
Reactant: O=C1CCc2ccccc2N1C1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Agent: Cl
Product: O=C1CCc2ccccc2N1C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
A mixture of 1-piperidin-4-yl-3,4-dihydroquinolin-2-one hydrochloride and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 4. The crude product was purified by hplc using a Phenomenex Luna C18 100A column (10μ silica, 21 mm diameter, 150 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 1-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]-3,4-dihydroquinolin-2-one.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCCCc1nc(C)n(-c2ccc(Cl)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 4-chlorophenylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.68 g, 52%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[CH:5]([CH:6]([OH:11])[CH2:7][CH2:8][CH:9]=2)[C:4]([CH3:13])([CH3:12])[CH:3]1[CH3:14].[CH2:16]([O:18][CH2:19]Cl)[CH3:17]>C([N-]C(C)C)(C)C.[Li+]>[CH3:1][C:2]1([CH3:15])[CH:10]2[CH:5]([CH:6]([O:11][CH2:19][O:18][CH2:16][CH3:17])[CH2:7][CH2:8][CH2:9]2)[C:4]([CH3:13])([CH3:12])[CH:3]1[CH3:14]
Reactant: CC1C(C)(C)C2=CCCC(O)C2C1(C)C
Reactant: CCOCCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCOCOC1CCCC2C1C(C)(C)C(C)C2(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A reaction flask was charged with 100 mL of lithium diisopropyl amide (LDA, available from Aldrich Chemical Company) (2M in heptane/THF) and cooled to 0° C. 1,1,2,3,3-Pentamethyl-tetrahydro-4-indanol, as described in U.S. Pat. No. 3,636,165, 40 g (0.19 mole) was added in portions to the LDA solution. The reaction was aged 30 minutes then 18.5 g (0.2 mole) of ethoxy methyl chloride was added to the reaction mass at 0° C. The mass was allowed to exotherm to 25° C. The reaction was quenched with 100 g of 10% aqueous sodium carbonate. The mass was transferred to a separatory funnel and water washed. The organic layer was distilled. The procedure afforded a 60% yield (30 g) of 1,1,2,3,3-pentamethyl-hexahydro-4-(ethoxymethoxy)-1H-indene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(C)(C)C)=[C:4]([C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH:3]=1.[OH-].[Na+]>OS(O)(=O)=O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:16]
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C(=O)c1cccnc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Cl)cc1C(=O)c1cccnc1
Temperature: 95 °C
Yield: 77.5 %

Procedure:
N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-2,2-dimethyl-propionamide (0.65 g) was suspended in 5 mL of 70% H2SO4 and heated at 95° C. in oil bath overnight. After cooling to room temperature the solution was added drop wise with stirring to 20 mL of 40% NaOH solution placed in an ice-water bath. The fine yellow precipitate formed was collected by vacuum filtration, washed well with water and dried under vacuum to give 370 mg of product. 1H NMR (CDCl3) δ 8.84 (dd, J=2.4 Hz, 0.8 Hz, 1H) 8.77 (dd, J=4.8 Hz, 2.0 Hz, 1H) 7.93 (dt, J=8.4 Hz, 2.0 Hz, 1H) 7.43 (m, 1H) 7.35 (d, J=2.0 Hz, 1H) 7.25 (d, J=0.8 Hz, 1H) 6.71 (d, J=8.8 Hz, 1H) 6.21 (s, 2H) MS (ES) m/z=233.0 (MH)+
Reaction SMILES: [Li].C1C2C(=CC=CC=2)C=CC=1.[NH2:12][C@@H:13]1[CH2:19][CH2:18][C@@H:17]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@@:14]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:15][C@H:16]2S(C1C=CC=CC=1)(=O)=O>O1CCCC1>[NH2:12][C@@H:13]1[CH2:19][CH2:18][C@@H:17]2[N:20]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@@:14]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:15][CH2:16]2
Reactant: N[C@@H]1CC[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccccc1)N2Cc1ccccc1
Agent: [Li]
Solvent: C1CCOC1
Solvent: c1ccc2ccccc2c1
Product: N[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
Lithium (175 mg, 25 mmol) was added to a solution of naphthalene (3.2 g, 25 mmol) in tetrahydrofuran (25 mL), and the mixture sonicated for 2 hours. The green solution formed was then slowly added to a solution of (1R*,2R*,5S*,6R*)-2-amino-8-benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octane (Description 8; 2.0 g, 4.6 mmol) in tetrahydrofuran (50 mL), already cooled to −78° C. The mixture was stirred at −78° C. for 1 hour, then quenched with aqueous saturated ammonium chloride solution (50mL). After warming to ambient temperature, the mixture was extracted with ethyl acetate (2×100 mL) and the extracts dried (MgSO4). Concentration in vacuo yielded a solid, which was purified by silica chromatography to give the title compound as a gum (900 mg, 3.1 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[CH:15][CH:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Br
Product: O=[N+]([O-])c1ccncc1NCc1ccc(F)cc1
Yield: 35.8 %

Procedure:
In accordance with the same procedures as in Preparation 2, except for using 3-bromo-4-nitropyridin-N-oxide prepared in Step 2 of Preparation 1 and 4-fluorobenzylamine, the titled compound was obtained as a yellow solid. (Yield: 35.8%)
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[CH3:55][NH:56][C:57]([CH3:105])([C:59]([NH:61][C@H:62]([C:66]([N:68]([C@@H:70]([C@@H:101]([CH3:104])[CH2:102][CH3:103])[C@H:71]([O:99][CH3:100])[CH2:72][C:73]([N:75]1[CH2:79][CH2:78][CH2:77][C@H:76]1[C@H:80]([O:97][CH3:98])[C@@H:81]([CH3:96])[C:82]([NH:84][C@H:85]([C:93]([OH:95])=[O:94])[CH2:86][C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1)=[O:83])=[O:74])[CH3:69])=[O:67])[CH:63]([CH3:65])[CH3:64])=[O:60])[CH3:58]>ClCCl.CS(C)=O.CN(C=O)C>[O:7]=[C:4]1[CH:5]=[CH:6][C:2](=[O:1])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([N:56]([CH3:55])[C:57]([CH3:105])([C:59]([NH:61][C@H:62]([C:66]([N:68]([C@@H:70]([C@@H:101]([CH3:104])[CH2:102][CH3:103])[C@H:71]([O:99][CH3:100])[CH2:72][C:73]([N:75]1[CH2:79][CH2:78][CH2:77][C@H:76]1[C@H:80]([O:97][CH3:98])[C@@H:81]([CH3:96])[C:82]([NH:84][C@H:85]([C:93]([OH:95])=[O:94])[CH2:86][C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1)=[O:83])=[O:74])[CH3:69])=[O:67])[CH:63]([CH3:64])[CH3:65])=[O:60])[CH3:58])=[O:14]
Reactant: O=C(O)CCCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)CCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 3.3 %

Procedure:
To a stirring solution of 5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)pentanoic acid (12 mg, 0.061 mM) in 0.4 mL of dichloromethane, and 0.1 mL of DMF, HATU (23.2 mg, 0.061 mM) was added followed by Hunig's base (0.033 mL, 0.188 mM). The reaction was allowed to stir for 5 minutes before #115 (39 mg, 0.047 mM) was added as a solution in 0.4 mL of dichloromethane, and 0.1 mL of DMF. The reaction was allowed to stir at room temperature for 3 hours and 15 minutes before being quenched through the addition of water containing a small amount of TFA. Reaction was then reduced down. Crude material was dissolved with DMSO and purified by reverse phase chromatography (Method J). The appropriate fractions were concentrated then (Genevac). Material was then further purified by reverse phase chromatography (Method K) with the appropriate fractions being concentrated (Genevac). Material was then transferred to a small vial using dichloromethane and methanol before being reduced down (Genevac) to afford mv#115 (1.4 mg, 3.3%) oil/solid mix. HPLC (Protocol A at 45° C.): m/z 897.5 [M+H+], retention time=9.149 minutes (purity >97%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([N:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=3[C:14](I)=[CH:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:23]1([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][C:33](B4OC(C)(C)C(C)(C)C4)=[CH:34][CH:35]=3)[N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>CN(C=O)C.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.O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([N:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=3[C:14]([C:33]3[CH:32]=[C:31]4[C:36]([CH:37]=[CH:38][C:29]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[N:30]4)=[CH:35][CH:34]=3)=[CH:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@@H](n2cc(I)c3c(N)ncnc32)CC1
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@@H](n2cc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)ncnc32)CC1
Temperature: 80 °C

Procedure:
A solution of cis-4-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclohexanecarboxylic acid ethyl ester (16.2 mg 0.0391 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline (15.6 mg, 1.2 eq.), Pd(PPh3)4 (2.7 mg, 0.06 eq.) and Na2CO3 (10.4 mg, 2.5 eq.) in DMF (2.5 mL)/H2O (0.5 mL) was flushed with N2 for 30 min at rt and heated at 80° C. for 16 h under nitrogen. After that time, the reaction mixture was treated with H2O and extracted with EtOAc (3×10 mL). The combined extracts were washed with H2O (2×5 mL) and brine (5 mL), and dried over MgSO4. The drying agent was filtered off, the filtrate was concentrated in vacuo, and the crude yellow oil was purified by HPLC to obtain the title compound as yellow oil. 1H NMR (CDCl3, 400MHz): δ=1.29-1.36 (t, 3H, J=7.2 Hz), 1.74-2.09 (m, 6H), 2.34-2.41 (m, 2H), 2.75 (m, 1H), 4.19-4.25 (q, 2H, J=7.2 Hz), 4.77-4.85 (m, 1H), 5.22 (brs, 2H), 7.22 (s, 1H), 7.46-7.57 (m, 3H), 7.68-7.70 (dd, 1H, J=1.6 & 8.0 Hz), 7.89-7.93 (m, 2H), 8.18-8.20 (dd, 2H, J=0.8 & 8.0 Hz), 8.25-8.27 (m, 2H), 8.37 (s, 1H). MS (ES+): 492.1 [MH+]. HPLC: tR=3.1 min (polar—5 min).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]([O:6]C)=O.S(Cl)(Cl)(=O)=O.[CH3:13][O:14][C:15]1[C:21]([CH3:22])=[CH:20][C:18]([NH2:19])=[C:17]([CH3:23])[CH:16]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.C(N(CC)CC)C>ClCCl.O>[CH3:22][C:21]1[C:15]([O:14][CH3:13])=[CH:16][C:17]([CH3:23])=[C:18]2[C:20]=1[CH:3]([S:2][CH3:1])[C:4](=[O:6])[NH:19]2
Reactant: COC(=O)CSC
Reactant: COc1cc(C)c(N)cc1C
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: CCN(CC)CC
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Product: COc1cc(C)c2c(c1C)C(SC)C(=O)N2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.1 %

Procedure:
To a solution of methyl (methylthio)acetate (14.8 ml, 115 mmol) in dichloromethane (400 ml) was added sulfuryl chloride (9.64 ml, 120 mmol) at −78° C. and stirred for 15 minutes. To the mixture was added dropwise a solution of 4-methoxy-2,5-dimethylaniline (15.1 g, 100 mmol) and proton sponge (22.5 g, 105 mmol) in dichloromethane (100 ml) over 1 hour and the mixture was stirred at the same temperature for 1 hour. Then, triethylamine (15.3 ml, 110 mmol) was added, and the mixture was allowed to warm to room temperature slowly. After stirring at room temperature for 1 hour, water was added and the precipitated crystals were collected by filtration and washed with dichloromethane and water to obtain 18.3 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[O:12])[C:6](=[O:9])[C:7]=1[Br:8].[CH3:21][CH:22]1[CH:30]([OH:31])[CH2:29][CH:25]2[C:26]([CH3:28])([CH3:27])[CH:23]1[CH2:24]2.[H-].[Na+].O>O1CCOCC1>[Br:8][C:7]1[C:6](=[O:9])[N:5]([CH2:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[O:12])[N:4]=[CH:3][C:2]=1[O:31][C@@H:30]1[CH2:29][C@@H:25]2[CH2:24][C@@H:23]([C:26]2([CH3:28])[CH3:27])[C@H:22]1[CH3:21]
Reactant: CC1C(O)CC2CC1C2(C)C
Reactant: O=C(Cn1ncc(Br)c(Br)c1=O)NCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Oc1cnn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Temperature: 100 °C
Reaction time: 120 h
Yield: 2.9 %

Procedure:
To 2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)-N-(pyridin-4-ylmethyl)acetamide (50 mg, 0.124 mmol) and (1R,2R,3R,5S)-(−)-isopinocampheol (50 mg, 0.324 mmol) in 1,4-dioxane (2 mL), sodium hydride (15 mg, 0.313 mmol) was added at 0° C., and stirred at 100° C. for 5 days. After completion of the reaction, the reaction mixture was mixed with water and extracted with chloroform and ethyl acetate. The combined organic layer was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product (1.7 mg, 3% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[N:10]([CH3:35])[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH2:33][CH3:34])[N:12]=2.[C:37](O)(=[O:41])[C@@H:38]([CH3:40])[OH:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:33]([C:25]1[N:24]([C:13]2[N:12]=[C:11]3[C:16]([N:17]=[C:9]([CH2:8][N:3]4[CH2:4][CH2:5][N:6]([C:37](=[O:41])[C@H:38]([OH:39])[CH3:40])[CH2:7][C:2]4([CH3:1])[CH3:36])[N:10]3[CH3:35])=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:14]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH3:34]
Reactant: C[C@@H](O)C(=O)O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCNCC3(C)C)n(C)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)[C@@H](C)O)CC3(C)C)n(C)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.9 %

Procedure:
A mixture of 8-(2,2-dimethylpiperazin-1-ylmethyl)-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.20 mmol), D-Lactic acid (20 mg, 0.22 mmol), HATU (85 mg, 0.22 mmol) and DIPEA (40 μL, 0.23 mmol) in DCM (2 mL) was allowed to stir at r.t. for 16 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 2%) affording 722 as a white solid (37 mg, 33%). LCMS (method I): RT 2.90 min, [M+H]+ 562.2. 1H NMR (CDCl3, 400 MHz): δ 8.04-7.99 (1 H, m), 7.77-7.76 (1 H, m), 7.35-7.25 (2 H, m), 4.47-4.45 (1 H, m), 4.34 (4 H, brd s), 4.02-3.98 (1 H, m), 3.91 (3 H, s), 3.86 (4 H, t, J=4.67 Hz), 3.82-3.68 (2 H, m), 3.50-3.49 (1 H, m), 3.40-3.31 (3 H, m), 3.27-3.16 (1 H, m), 2.57-2.55 (2 H, m), 1.45 (3 H, t, J=7.47 Hz), 1.39-1.28 (4 H, m), 1.27-1.15 (5 H, m)
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([N:7]=[N:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:16])=[CH:13][C:14]=2[NH2:15])=[CH:5][CH:6]=1.Cl.[Cl:18][S:19]([OH:22])(=O)=[O:20].C1C=CC(N=NC2C=CC(N)=CC=2N)=CC=1.Cl.S(Cl)(O)(=O)=O.[CH2:45]([NH2:63])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]>>[CH:1]1[CH:6]=[CH:5][C:4]([N:7]=[N:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:16])=[CH:13][C:14]=2[NH2:15])=[CH:3][CH:2]=1.[ClH:18].[CH2:45]([NH:63][SH:19](=[O:22])=[O:20])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=S(=O)(O)Cl
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)c1
Product: CCCCCCCCCCCCCCCCCCN[SH](=O)=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A mixture of 4 g of chrysoidine and 20 g of chlorosulfonic acid was stirred at a temperature lower than 20° C. for 2 hours and poured in ice water to salt out chrysoidine sulfochloride. Then 5 g of chrysoidine sulfochloride were reacted with 20 g of stearyl amine molten at 70° C. The reaction product was extracted with benzene and benzene was evaporated yield the intended chrysoidine-N-stearylsulfonamide. A liquid developer was prepared by dispersing 0.1 g of the resulting product in 1 liter of Shellsol 71 (product of Shell Petroleum Co.), which is an isoparaffin hydrocarbon, by effecting ultrasonic vibration for 2 minutes. This liquid developer was excellent in dispersibility and gave a yellow visible negative image of good fixing property.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](=[O:34])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26]CC3C=CC=CC=3)=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H-].[Na+].[C:37](OC)(=[O:42])[CH2:38][C:39]([CH3:41])=[O:40].C([Li])CCC>C1COCC1>[OH:40][C:39]1[CH2:41][C:17]([CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)[O:34][C:37](=[O:42])[CH:38]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(CCc1ccc(OCc2ccccc2)cc1)CCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(CCc2ccc(O)cc2)(CCc2ccc(O)cc2)O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The title compound was prepared as described in General Method 6 using 11.2 g (25 mmol) of 1,5-bis (4-benzyloxy-phenyl)-pentan-3-one (prepared in Example H), 1.0 g (25 mmol) of 60% NaH dispersion in mineral oil, 2.88 g (25 mmol) of methyl acetoacetate, 15.6 mL (1.6M, 25 mmol) of n-butyllithium and 300 mL of THF. The reaction mixture was stirred for 12 hours at room temperature, quenched with aqueous NH4Cl, and worked up in the usual manner.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([O:10][CH3:11])=[C:8]2[CH:12]=[CH:13][O:14][C:7]2=[CH:6][C:5]=1[OH:15])=[O:3].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=1>>[C:2]([C:4]1[C:5]([O:15][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:15][C:5]3[C:4]([C:2](=[O:3])[CH3:1])=[C:9]([O:10][CH3:11])[C:8]4[CH:12]=[CH:13][O:14][C:7]=4[CH:6]=3)=[CH:20][CH:19]=2)=[CH:6][C:7]2[O:14][CH:13]=[CH:12][C:8]=2[C:9]=1[O:10][CH3:11])(=[O:3])[CH3:1]
Reactant: COc1c(C(C)=O)c(O)cc2occc12
Reactant: BrCc1ccc(CBr)cc1
Product: COc1c(C(C)=O)c(OCc2ccc(COc3cc4occc4c(OC)c3C(C)=O)cc2)cc2occc12
Yield: 8 %

Procedure:
The compound was prepared from visnaginone and α,α′-dibromo-p-xylene according to the General Procedure. Purification by flash chromatography eluting with ethyl acetate/cyclohexane (1:9 to 2:8) afforded the product (20 mg, 8%) as a white solid:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[N:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:24])=[C:4]([NH:11][C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[N:3]=1
Reactant: COc1cc(Nc2nc(Cl)nc3nc[nH]c23)cc(OC)c1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc(Cl)nc3c2ncn3C)cc(OC)c1OC

Procedure:
168 mg (0.5 mmol) of 2-chloro-6-(3,4,5-trimethoxy-phenyl-amino)-purine, 103 mg (0.75 mmol) of potassium carbonate and 0.156 ml (2.5 mmol) of methyl iodide are stirred in 3 ml of dimethylformamide at room temperature for 5 h. 30 ml of ethyl acetate are added to the slightly cloudy reaction solution and the mixture is extracted with water. The organic phase is dried over sodium sulfate. After removal of the solvent, the residue is recrystallized from ethyl acetate and diethyl ether. 2-Chloro-6-(3,4,5-trimethoxy-phenyl-amino)-9-methyl-9H-purine is obtained; FAB-MS: (M+H)+=350; Rf=0.6 (CH2Cl2:methanol=9:1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].CS[C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17]>>[N+:16]([NH:15][C:14]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[NH:19])([O-:18])=[O:17]
Reactant: NCCNCc1ncccn1
Reactant: CSC(=N)N[N+](=O)[O-]
Product: N=C(NCCNCc1ncccn1)N[N+](=O)[O-]

Procedure:
Reaction of N-(2-pyrimidylmethyl)ethylenediamine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(2-pyrimidylmethylamino)-ethyl]guanidine. Similarly, from the same starting material, according to the procedure of Example 2(iii), there is produced N-methyl-N'-nitro-N"-[2-(2-pyrimidylmethylamino)ethyl]guanidine.