Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[CH3:17][N:18]([CH:20]=O)[CH3:19].[C:22](#[N:24])C>C(OCC)(=O)C>[N:24]1[CH:22]=[C:17]([CH2:11][CH2:10][CH2:15][N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[N:18]2[CH:20]=[CH:4][CH:3]=[CH:2][C:19]=12
Reactant: CN(C)C=O
Reactant: CC#N
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2ccccc2n1C1CCN(CCCc2cnc3ccccn23)CC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
240 mg (2.21 mmol) of 1-piperidin-4-yl-1,3-dihydrobenzimidazol-2-one is dissolved in 3.5 ml of acetonitrile and 3.5 ml of DMF at 50° C. and at this temperature a solution of 240 mg (1.00 mmol) of the compound of Example 11.3 in 7.5 ml of ethyl acetate is added dropwise. The mixture is initially stirred for 5 hours at 50° C., then for 72 hours at RT. The solution is evaporated down and the residue is purified by flash chromatography (dichloromethane/ethanol 90:10), yielding 48 mg of product. MS: m/z 376 [(M+H)+]; melting point: 185° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:14][CH3:15].[NH2:16][C:17]1[N:22]=[C:21]([NH2:23])[C:20]([CH2:24]O)=[CH:19][N:18]=1.C(O)(=O)C.[ClH:30]>CC(C)=O>[ClH:30].[ClH:30].[NH2:16][C:17]1[N:22]=[C:21]([NH2:23])[C:20]([CH2:24][C:5]2[C:6]3[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)[C:2]([NH2:1])=[C:3]([O:14][CH3:15])[CH:4]=2)=[CH:19][N:18]=1
Reactant: COc1ccc2ccc(OC)c(N)c2c1
Reactant: Nc1ncc(CO)c(N)n1
Agent: Cl
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: COc1ccc2c(Cc3cnc(N)nc3N)cc(OC)c(N)c2c1
Yield: 78 %

Procedure:
A mixture of 1-amino-2,7-dimethoxynaphthalene (2.03 g, 10.00 mmol) [O. Fischer and W. Kern, J. Prakt. Chem., 94, 34(1916)], 2,4-diamino-5-hydroxymethylpyrimidine (1.40 g, 10.0 mmol), glacial acetic acid (20 mL) and concentrated hydrochloric acid (1.4 mL) was refluxed for 2 hr. The cooled reaction mixture was diluted with acetone and the resulting precipitate was collected and dried giving the title compound as a grey solid (3.40 g, 78%). Recrystallization from aqueous ethanol with concentrated HCl gave an analytical sample, mp >210° dec. Anal. Calcd for C17H19N5O2.2HCl.2H2O: C, 47.01; H, 5.80; N, 16.12; Cl, 16.32. Found: C, 47.19; H, 5.90; N, 16.05; Cl, 16.37.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.C([Li])CCC.[C:14](=[O:16])=[O:15].O>O1CCCC1>[F:8][C:4]1[N:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[C:14]([OH:16])=[O:15]
Reactant: Fc1cccc(F)n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(F)nc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
To 2,6-difluoropyridine (58, 7.10 g, 0.0617 mol) in tetrahydrofuran (150.0 mL) under an atmosphere of nitrogen at −78° C., n-butyllithium (26.0 mL, 2.50 M in hexane) was added slowly. After 30 minutes, dry ice (3.0 g) was added to the reaction. After 1 hour, the reaction was allowed to warm to room temperature, then poured into water and extracted with ethyl acetate. The aqueous layer was acidified with 1 N HCl to pH=4-5 and extracted with ethyl acetate. The organic layer was dried over anyhydrous sodium sulfate, filtered and concentrated to give the crude compound as a light yellow solid (59, 5.6 g, 57.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:13]=[C:12]([Br:14])[C:11]([CH3:15])=[C:10]([N+:16]([O-])=O)[C:9]2=[O:19])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C.Cl.O>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:13]=[C:12]([Br:14])[C:11]([CH3:15])=[C:10]([NH2:16])[C:9]2=[O:19])=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cc(Br)c(C)c([N+](=O)[O-])c2=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Cn2cc(Br)c(C)c(N)c2=O)cc1
Reaction time: 3.5 h
Yield: 61.5 %

Procedure:
To a stirred solution of 1-(4-methoxybenzyl)-5-bromo-4-methyl-3-nitro-2-pyridone (0.23 g 0.65 mmol) in glacial acetic acid (3 mL) was added a solution of stannous chloride dihydrate (1.0 g) in concentrated HCl (2 mL). After 3.5 hours, the reaction mixture was diluted with water, neutralized with NaHCO3, and extracted with methylene chloride. The organic phase was dried, filtered, and evaporated to give 1-(4-methoxybenzyl)-5-bromo-4-methyl-3-amino-2-pyridone (0.13 g, 0.40 mmol, 61%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[N:5][N:4]=[C:3]1[C:17]12[CH2:24][CH2:23][C:20]([C:25]([NH:27][NH2:28])=[O:26])([CH2:21][CH2:22]1)[CH2:19][CH2:18]2.[F:29][C:30]([F:35])([CH3:34])[C:31](O)=O>C(Cl)Cl>[F:29][C:30]([C:34]1[O:26][C:25]([C:20]23[CH2:23][CH2:24][C:17]([C:3]4[N:2]([CH3:1])[C:6]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[C:13]([F:15])([F:14])[F:16])=[N:5][N:4]=4)([CH2:18][CH2:19]2)[CH2:22][CH2:21]3)=[N:27][N:28]=1)([F:35])[CH3:31]
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(C(=O)NN)(CC1)CC2
Reactant: CC(F)(F)C(=O)O
Solvent: ClCCl
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(c3nnc(C(C)(F)F)o3)(CC1)CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]octane-1-carbohydrazide (4-A) (334 mg, 0.850 mmol) and 2,2-difluoropropionic acid (78 mg, 0.708 mmol) was suspended in methylene chloride, and DMC (1.2 g, 7.08 mmol) was added as solid. The mixture was stirred at room temperature under nitrogen for 48 hours before it was diluted with methylene chloride, washed with water, saturated sodium bicarbonate and brine. The crude product was purified by column chromatography to give 4-B as a white solid. MS (ESI+)=468.3 (M+1); 1H NMR (500 MHz, CDCl3): δ 2.15-2.33 (15H, m), 3.52 (3H, s), 7.61 (1H, m), 7.72 (2H, m), 7.85 (1H, m) ppm. Shh-Light II Assay: IC50: 9.3 μM.
Reaction SMILES: [N:1]1[C:6]2[S:7][C:8]([CH:10]=O)=[CH:9][C:5]=2[CH:4]=[N:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:17][NH2:18]>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:17][N:18]=[CH:10][C:8]1[S:7][C:6]2[N:1]=[CH:2][N:3]=[CH:4][C:5]=2[CH:9]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: O=Cc1cc2cncnc2s1
Solvent: ClCCl
Product: COc1ccc(CN=Cc2cc3cncnc3s2)cc1OC
Yield: 100 %

Procedure:
Thieno[2,3-d]pyrimidine-6-carbaldehyde (intermediate 13) (40 mg), 3,4-dimethoxybenzylamine (0.04 ml) and 4 Å molecular sieves (150 mg) were heated at reflux in DCM (5 ml) for 3 hours under an inert atmosphere. The molecular sieves were removed by filtration and the solvent evaporated to afford the title compound as a pale yellow solid (76 mg, 100%);
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]3[C:41]4[C:17](=[C:18]5[C:38](=[CH:39][CH:40]=4)[C:22]4[N:23]=[C:24]([C@@H:26]6[CH2:30][CH2:29][CH2:28][N:27]6[C:31](OC(C)(C)C)=[O:32])[NH:25][C:21]=4[CH:20]=[CH:19]5)[O:16][CH2:15][C:13]=3[CH:14]=2)[O:3]1.Cl.[CH3:44][O:45][C:46]([NH:48][C@@H:49]([CH:53]([CH3:55])[CH3:54])C(O)=O)=[O:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.C(O)C>[CH3:54][CH:53]([CH3:55])[C@H:49]([NH:48][C:46](=[O:47])[O:45][CH3:44])[C:31](=[O:32])[N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[C:24]1[NH:25][C:21]2[CH:20]=[CH:19][C:18]3[C:38](=[CH:39][CH:40]=[C:41]4[C:12]5[CH:11]=[CH:10][C:9]([B:4]6[O:3][C:2]([CH3:42])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]6)=[CH:14][C:13]=5[CH2:15][O:16][C:17]4=3)[C:22]=2[N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2c(ccc3c4c(ccc32)-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2CO4)[nH]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2c(ccc3c4c(ccc32)-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2CO4)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A solution of tert-butyl (2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate (0.98 g, 1.7 mmol), concentrated HCl (2 mL) and ethanol (20 mL) was heated to 60° C. for 2 hours. The reaction was concentrated and redissolved in a minimal amount of methanol. An equal volume of dichloromethane was added and the solution was again concentrated. Dichloromethane was added to the resulting residue and concentrated off two more times. The resulting crude material was dissolved in dimethylformamide (17 mL). To this solution was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (455 mg, 2.6 mmol), HATU (955 mg, 2.5 mmol) and diisopropylethylamine (3 mL, 17 mmol). The reaction was stirred at room temperature for one hour then diluted with ethyl acetate. The organics were washed with water (×2) and brine, dried with magnesium sulfate and concentrated. The resulting residue was purified by flash column chromatography to yield Intermediate methyl [(2S)-3-methyl-1-oxo-1-{(2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl}pyrrolidin-1-yl]butan-2-yl]carbamate (780 mg, 72% yield over 2 steps).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([OH:15])(=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9]>>[Cl:1][S:2]([C:12]1[CH:11]=[CH:10][C:8]([OH:9])=[C:7]([CH:13]=1)[C:6]([OH:15])=[O:14])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccccc1O
Product: O=C(O)c1cc(S(=O)(=O)Cl)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3.26 mol chlorosulfonic acid at 0° C. was added 652 mmol salicylic acid in small portions and the mixture was then allowed to stir at RT for 1 h, then at 50° C. for 1 h, and finally at 70° C. for 1 h. The mixture was then added dropwise to 1000 ml ice-water with stirring and stirring continued for an additional 30 min. The ensuing white crystals were collected by filtration, washed three times with water, and then dried in vacuo at 45° C. for 16 h to yield the title compound. MS (m/e): 236.8 ([{37Cl}M−H]−, 33%), 235.0 ([{37Cl}M−H]−, 100%)
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[C:10]1([C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][C:22](B(O)O)=[CH:23]3)=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[CH3:8][C:7]1[C:2]([C:22]2[CH:21]=[CH:20][C:19]3[C:24](=[CH:25][C:16]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:17][CH:18]=3)[CH:23]=2)=[N:3][CH:4]=[C:5]([CH3:9])[N:6]=1
Reactant: OB(O)c1ccc2ccc(-c3ccccc3)cc2c1
Reactant: Cc1cnc(Cl)c(C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cnc(-c2ccc3ccc(-c4ccccc4)cc3c2)c(C)n1
Yield: 65 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were placed 0.62 g of 2-chloro-3,5-dimethylpyrazine, 1.07 g of 7-phenylnaphthalene-2-boronic acid, 0.46 g of sodium carbonate, 0.020 g of bis(triphenylphosphine)palladium(II) dichloride (abbreviation: Pd(PPh3)2Cl2), 10 mL of water, and 10 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was irradiated with microwaves (2.45 GHz, 100 W) for 15 minutes, so that heating was performed. Then, the reaction container was cooled to 50° C. or less. Water was added to the reaction solution, and the organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and dried with magnesium sulfate. The solution which had been dried was filtered. The solvent of this solution was distilled, and the obtained residue was purified by silica gel column chromatography with a developing solvent of dichloromethane, whereby Hdm7p2npr, which is the pyrazine derivative to be produced, was found to be obtained (as a white powder in 65% yield). Note that the microwave irradiation was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). The synthesis scheme of Step 4 is illustrated in the following (d-5).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=O)[CH:12]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[C:25]([O:39][CH3:40])=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:30]([C:28]1[CH:27]=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:25]([O:39][CH3:40])=[C:24]([NH:23][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][C:21]([CH3:22])=[C:13]([N:11]3[CH:12]=[C:8]([C:5]4[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[N:10]3)[CH:14]=2)[CH:29]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccc(Cl)nc2)nn1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4ccc(Cl)nc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[4-(6-Chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzoic acid (470 mg; 1.49 mmol), N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide (WO 02/083628) (488 mg; 1.79 mmol), and 0.87 mL (5.0 mmol) of DIPEA were combined in 15 mL DMF. Then 1.14 g (2.99 mmol) of HATU and 403 mg (2.99 mmol) of HOBt were added and the dark brown solution was stirred overnight at room temperature. The mixture was then partitioned between EtOAc and water. The layers were separated and the organic portion was washed with water (2×50 mL), brine (50 mL), dried (MgSO4), filtered, and concentrated. Chromatography provided 375 mg (0.66 mmol; 44%) of the title compound with 95% purity. ESI MS m/z 569 [C27H29ClN6O4S+H]+.
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([NH:15][CH:16]1[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:26][C:27]([O:29]C)=[O:28])[C:17]1=[O:31])=[O:14])=[CH:7]2>O.C1COCC1>[C:27]([CH2:26][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:25][CH:16]([NH:15][C:13]([C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][C:4]([Cl:3])=[CH:12][CH:11]=3)=[O:14])[C:17]1=[O:31])([OH:29])=[O:28]
Reactant: COC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Reaction time: 3 h
Yield: 115.3 %

Procedure:
LiOH (91.5 g, 2.18 mmol) in H2O (2 mL) was added to a stirring solution of 5-chloro-N-[1-(methoxycarbonylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-1H-indole-2-carboxamide (Example 1; 557 mg, 1.09 mmol) in THF (11 mL) and the reaction was stirred for 3 h. The reaction was quenched by addition of 1M aqueous HCl (40 mL) and EtOAc (60 mL) and the organic layer was dried (MgSO4), filtered and evaporated. The resultant white foam was triturated with hot Et2O (20 mL) cooled, filtered, dried and collected by filtration to afford the title compound (500 mg, 92%) as a white solid.
Reaction SMILES: [Na+].[OH:2]C1C=CC(S([O-])(=O)=O)=CC=1[N+]([O-])=O.[CH:16]1([N:22]=[C:23]=[N:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C1(=O)N(NCCCCCC(O)=O)C(=O)C=C1>CN(C)C=O>[C:23]([NH:22][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)([NH:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:2]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)[O-])ccc1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)CCCCCNN1C(=O)C=CC1=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
One molar equivalent (2.24 g) of 4-hydroxy-3-nitrobenzene sulfonic acid sodium salt (HNSA) was mixed together with one molar equivalent (2.06 g) of dicyclohexylcarbodiimide and one molar equivalent (2.10 g) of N-maleimido-6-aminocaproic acid in 25 ml of dimethylformamide (DMF) at room temperature overnight. A white precipitate of dicyclohexylurea was formed. The precipitate was filtered and 300 ml diethyl ether was added to the mother liquor. After about 10 minutes to 4 hours a gummy solid precipitated from the mother liquor. This solid was found to contain 58% of active HNSA ester and 42% of free HNSA.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].CCN(CC)CC.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[C:19]=2[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[N:12]=1
Reactant: COCCc1nc2c(N)nc3c(c2n1CCOCCN)CCCC3
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1nc2c(N)nc3c(c2n1CCOCCNS(C)(=O)=O)CCCC3
Temperature: 0 °C
Yield: 31.5 %

Procedure:
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.00 mmol) was dissolved in 30 mL of anhydrous CH2Cl2 and cooled to 0° C. under N2. To the stirred solution were added Et3N (0.84 mL, 6.00 mmol) and methanesulfonyl chloride (232 μL, 3.00 mmol) and the reaction was allowed to warm to room temperature overnight. The reaction mixture was then quenched by addition of saturated NaHCO3 solution (30 mL). The organic layer was separated and washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The solid was triturated with Et2O and a few drops of MeOH. The resulting white powder was isolated by filtration and further purified by column chromatography (SiO2, 3% MeOH/CHCl3 saturated with aqueous NH4OH) to give 389 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)methanesulfonamide as a white powder. m.p. 151.0-153.0° C.;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][C:25](O)=[O:26].C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][C:25]([N:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:9][CH2:10]1)=[O:26]
Reactant: COc1ccc(CC(=O)O)c(OC)c1
Reactant: Cc1ccccc1N1CCNCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)N2CCN(c3ccccc3C)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(2-methylphenyl)piperazine (.087 g, 0.41 mmol) and 2,4-dimethoxyphenylacetic acid (0.096 g, 0.49 mmol) were dissolved in 20 DMF (5 ml) and treated with EDC (0.091 g, 0.47 mmol) and HBT (0.071 g, 0.52 mmol). Triethylamine was added to the stirred mixture to bring the pH (moistened E. Merck colorpHast indicator) to ca. 9. The mixture was stirred at ambient temperature for 18 hours, then concentrated in vacuo. The residue was taken up in ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and the filtrate was concentrated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 1.5% methanol in methylene chloride. The combined product fractions were evaporated to dryness in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH2:16]([C:23]1[CH:31]=[C:30]([Br:32])[CH:29]=[CH:28][C:24]=1[C:25](O)=[O:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.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>>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:30]([Br:32])=[CH:31][C:23]=2[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1ccc(Br)cc1Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2ccc(Br)cc2Cc2ccccc2)Cc2ccccc2C1
Yield: 86.2 %

Procedure:
2-Amino-indane-2-carboxylic acid ethyl ester (2) (250 mg, 1.2 mmol), 2-benzyl-4-bromo-benzoic acid (239) (354 mg, 1.2 mmol) and HATU (555 mg, 1.46 mmol) are taken in a vial, evacuated and refilled with nitrogen. Anhydrous DMF (2 mL) is added and stirring is initiated. After few min, DIPEA (0.302 mL, 1.82 mmol) is added and stirred at RT overnight. Analysis by tlc of the reaction mixture (silica, 50% EtOAc/heptanes) indicates complete consumption of the starting amine. Water (10 mL) is added, extracted with EtOAc (3×5 mL), dried over Na2SO4, concentrated and the crude product is chromatographed on a 25 g silica gel column using 20-50% EtOAc in heptane as a gradient to afford 2-(2-benzyl-4-bromo-benzoylamino)-indan-2-carboxylic acid ethyl ester (495 mg, 86%).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl>C(O)CCC>[ClH:1].[NH2:2][CH2:3][C:4]1([CH2:10][C:11]([O:13][CH2:3][CH2:4][CH2:5][CH3:6])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NCC1(CC(=O)O)CCCCC1
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)CC1(CN)CCCCC1

Procedure:
A solution of 1-aminomethyl-1-cyclohexane-acetic acid hydrochloride in n-butanol is saturated with hydrogen chloride at 0° C. The reaction mixture is then heated to 110° C for two hours while hydrogen chloride is passed through. The solution thus obtained is then evaporated at 60° C and the residue stirred up with hexane is filtered and dried. n-Butyl 1-aminomethyl-1-cyclohexane acetate hydrochloride is obtained in form of a white powder having a melting point of 106° - 109° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][NH:8][C:9]1[C:13]([C:14]2[N:18]([CH2:19][C:20]3[O:21][CH:22]=[C:23]([Br:25])[CH:24]=3)[C:17](=[O:26])[O:16][N:15]=2)=[N:12][O:11][N:10]=1)(=O)=O.[N-:27]=[N+:28]=[N-:29].[Na+].O>CN(C)C=O>[N:27]([CH2:6][CH2:7][NH:8][C:9]1[C:13]([C:14]2[N:18]([CH2:19][C:20]3[O:21][CH:22]=[C:23]([Br:25])[CH:24]=3)[C:17](=[O:26])[O:16][N:15]=2)=[N:12][O:11][N:10]=1)=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCNc1nonc1-c1noc(=O)n1Cc1cc(Br)co1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCNc1nonc1-c1noc(=O)n1Cc1cc(Br)co1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
2-[(4-{4-[(4-Bromo-2-furyl)methyl]-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl}-1,2,5-oxadiazol-3-yl)amino]ethyl methanesulfonate (9.1 g, 20 mmol, containing also some of the corresponding bromo-compound) was dissolved in dimethylformamide (90 mL). Sodium azide (1.97 g, 30.3 mmol) was added in one portion and after 5 minutes, the temperature was brought to 65° C. The reaction stirred for 2 hours and was allowed to cool back to room temperature. Water (200 mL) was added to quench the reaction. The product was extracted with ethyl acetate (3×100 mL) and the combined organic layers were washed with brine (2×150 mL) and water (150 mL). After drying over sodium sulfate, the solvent was removed in vacuo to give the desired product (7.7 g, 96%). LCMS calculated for C11H9BrN8NaO4 (M+Na)+: m/z=418.7, 421.0. 1H NMR (400 MHz, DMSO-d6): δ 7.88 (s, 1H), 6.71 (t, J=5.7 Hz, 1H), 6.68 (s, 1H), 5.08 (s, 2H), 3.54 (t, J=5.7 Hz, 2H), 3.47 (q, J=5.7 Hz, 2H).