Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:52])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:51])[CH2:12][CH2:13][C@@:14]3([C:30]([NH:32][CH2:33][CH2:34][CH:35]4[O:40][C:39]([CH3:42])([CH3:41])[O:38][CH:37]([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:36]4)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:54])[CH3:53])(=O)C.C1COCC1.[OH-].[Na+]>CO>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:52])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:51])[CH2:12][CH2:13][C@@:14]3([C:30]([NH:32][CH2:33][CH2:34][CH:35]4[O:40][C:39]([CH3:41])([CH3:42])[O:38][CH:37]([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:36]4)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:54])[CH3:53]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC3CC(CC(=O)OC(C)(C)C)OC(C)(C)O3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC3CC(CC(=O)OC(C)(C)C)OC(C)(C)O3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.8 %

Procedure:
Tert-butyl 2-(6-(2-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamido)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (Example 78, 2.0 g) was taken in MeOH:THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (1.5 g in 4 ml water) was added and contents were stirred for 6 hours at room temperature. Completion of the reaction was monitored by TLC, reaction mixture was evaporated under reduced pressure and the residue was taken in water and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (1.45 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 10H); 1.65-1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 3.29-3.38 (m, 1H); 3.89-3.90 (m, 1H); 4.15-4.18 (m, 2H); 4.56 (s, 1H); 4.71 (s, 1H); MASS: 712 (100%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:28]([NH2:31])([CH3:30])[CH3:29]>C1COCC1>[OH:26][C@@H:25]([CH2:27][NH:31][CH:28]([CH3:30])[CH3:29])[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: CC(C)N
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H]1CO1
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H](O)CNC(C)C
Temperature: 75 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
A mixture of (2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (100 mg, 0.28 mmol), (prepared as described for the starting material in Example 297), and isopropylamine (1.0 ml) in THF (10 ml) was stirred at 75° C. for 18 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by silica gel chromatography using gradient elution with dichloromethane/methanolic ammonia (7M) (100/0 to 90/10) to give (2S)-7-(2-hydroxy-3-(isopropylamino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline (66 mg, 56%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].CC1(C)C(C)(C)OB([C:32]2[S:33][CH:34]=[C:35]([CH3:37])[CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.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>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:32]4[S:33][CH:34]=[C:35]([CH3:37])[CH:36]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Reactant: Cc1csc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1csc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 120 °C
Yield: 36.2 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (100 mg, 0.232 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.7 mL). 4,4,5,5-Tetramethyl-2-(4-methyl-2-thienyl)-1,3,2-dioxaborolane (78 mg, 0.347 mmol), tetrakis(triphenylphosphine)palladium(0) (26.8 mg, 0.023 mmol) and potassium carbonate (96 mg, 0.695 mmol) were added and the mixture heated in a microwave at 120° C. for 15 min. Ethyl acetate (10 mL) was added and the mixture washed with water (2×5 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-30% ethyl acetate in cyclohexane and further triturated with MeOH, to give the title compound (37.7 mg). LCMS (A) m/z: 449 [M+1]+, Rt 1.53 min (acidic).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:26]=[CH:25][C:24]([NH:27]C(=O)C)=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.C(=O)(O)[O-].[Na+]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Yield: 56 %

Procedure:
To a solution of example 63 (0.060 g, 0.152 mmol) in ethanol (1 ml) was added con. HCl (0.5 ml) and refluxed for 2 h. The reaction mixture was cooled, basified with sodium bicarbonate solution, extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as a brown solid (0.030 g, 42%). M.P.: 190-193° C. MS (m/z): 353.18 (M++1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH2:22]([N:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(-c2nc3ccccc3[nH]2)nc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(Cn2c(-c3ccccn3)nc3ccccc32)cc1
Yield: 82.1 %

Procedure:
To a flask were added 2.0 g 2-(2-pyridyl)benzimidazole, 1.8 g potassium carbonate, 30 ml N,N-dimethylformamide and the mixture was stirred under nitrogen at 10 C. 1.5 g benzyl chloride were added and the mixture allowed to warm to 22 C and stirred for 3 hours. Another 0.3 g benzyl chloride was added and the reaction was stirred at 22 C for another 16 hours. The reaction was quenched with 40 ml water and the product was filtered and washed with water. The product was dissolved in 10 ml ethanol and 15 ml of water were added. After cooling to 5 C, the product was filtered, washed and dried resulting in 2.4 g of off-white solid.
Reaction SMILES: O[C:2]([O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[CH2:24][CH2:23][CH:22]2C)([CH:9]1[O:14][CH2:13][CH2:12][N:11]([CH:15]([CH3:17])[CH3:16])[CH2:10]1)C1C=CC=CC=1.[C:29]1(C)[CH:34]=[CH:33][C:32](S(O)(=O)=O)=[CH:31][CH:30]=1.[C:40]1(C)C(C)=CC=CC=1>>[CH:15]([N:11]1[CH2:12][CH2:13][O:14][CH:9]([CH:2]([O:18][C:19]2[CH:20]=[C:21]3[C:25]([C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:23][CH2:22]3)=[CH:26][CH:27]=2)[CH3:40])[CH2:10]1)([CH3:16])[CH3:17]
Reactant: CC1CCc2ccc(OC(O)(c3ccccc3)C3CN(C(C)C)CCO3)cc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccccc1C
Product: CC(Oc1ccc2c(c1)CC=C2c1ccccc1)C1CN(C(C)C)CCO1
Yield: 62.7 %

Procedure:
In 50 ml. of xylene was dissolved 1.5 g. of 2-(1-hydroxy-3-methyl-1-phenyl-5-indanyloxymethyl)-4-isopropylmorpholine and after adding to the solution 5 mg. of p-toluenesulfonic acid, the mixture was refluxed for 3 hours. Then, xylene was distilled off and the residue formed was adsorbed on a silica gel column prepared from 100 ml. of silica gel in chloroform and eluted with ethyl acetate. After removing the first 10 ml. of the ethyl acetate eluate emerging from the column, 200 ml. of the subsequent ethyl acetate eluate was collected and dried to provide 0.9 g. (yield 62.7%) of 4-isopropyl-2-(1-methyl-3-phenyl-6-indenyloxymethyl)morpholine. The citrate of the product had a melting point of 111°-112.5° C.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11](F)[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[C-:18]#[N:19].[K+].O>CS(C)=O>[C:1]([C:5]1[NH:6][C:7]2[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([C:18]#[N:19])[C:12]=2[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)c1cc2c(F)c([N+](=O)[O-])ccc2[nH]1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)c1cc2c(C#N)c([N+](=O)[O-])ccc2[nH]1
Temperature: 70 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
To a solution of 2-tert-butyl-4-fluoro-5-nitro-1H-indole (4.0 g, 17 mmol) in DMSO (30 mL) was added KCN (3.4 g, 51 mmol). The mixture was stirred at 70° C. for 3 hours, and poured into water (80 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (7% EtOAc in petroleum ether) to afford 2-tert-butyl-5-nitro-1H-indole-4-carbonitrile (2.2 g, 53%). 1H NMR (DMSO, 300 MHz) δ 12.23 (br s, 1H), 8.09 (d, J=9.0 Hz, 1H), 7.75 (d, J=9.0 Hz, 1H), 6.50 (s, 1H), 1.38 (s, 9H). MS (ESI) m/z: 244.2 [M+H+].
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[O:11][C:12]1[CH:13]=[C:14]2[C:20]3([CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH2:19][N:18]([C:33]3[C:34]4[C@H:41]([CH3:42])[CH2:40][CH2:39][C:35]=4[N:36]=[CH:37][N:38]=3)[C:15]2=[CH:16][CH:17]=1)=O)(C)(C)C.[ClH:49]>C(Cl)Cl.O1CCOCC1.CCOCC>[ClH:49].[ClH:49].[ClH:49].[CH3:42][C@H:41]1[C:34]2[C:33]([N:18]3[C:15]4[C:14](=[CH:13][C:12]([O:11][CH:10]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)[CH2:9][NH2:8])=[CH:17][CH:16]=4)[C:20]4([CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)[CH2:19]3)=[N:38][CH:37]=[N:36][C:35]=2[CH2:39][CH2:40]1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(OC(CNC(=O)OC(C)(C)C)c5ccccc5)ccc43)c21
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4cc(OC(CN)c5ccccc5)ccc43)c21
Reaction time: 8 h
Yield: 5 %

Procedure:
A solution of tert-butyl 5-(2-(tert-butoxycarbonylamino)-1-phenylethoxy)-1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.235 g, 0.358 mmol) in DCM (4 mL) was treated with 4N HCl in dioxane (1 mL). The reaction was stirred at about room temperature overnight. The solvents were removed and the crude residue was partitioned between DCM and 1N HCl. The aqueous phase was extracted with DCM (×3), and then basified with 1N NaOH. The free base was extracted with DCM. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by reverse phase column chromatography (0-60% ACN/H2O) to give the free base, which was taken up in DCM and acidified with 2N HCl in ether. Removal of the solvents under reduced pressure afforded 2-(1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-5-yloxy)-2-phenylethanamine trihydrochloride (0.008 g, 5%). LCMS (APCI+) m/z 456.2 [M+H]+; Rt=2.49 min.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10](=[O:27])[O:11][CH:12]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH2:2]2.[Br:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[I-].[K+]>C(OCC)(=O)C>[Br-:28].[F:26][C:22]1[CH:21]=[C:20]([CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[O:11][C:10]([NH:9][C@@H:3]2[CH:4]3[CH2:7][CH2:8][N+:1]([CH2:29][CH2:30][O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([CH2:6][CH2:5]3)[CH2:2]2)=[O:27])[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(N[C@H]1CN2CCC1CC2)OC(c1cccc(F)c1)c1cccc(F)c1
Reactant: BrCCOc1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1C[N+]2(CCOc3ccccc3)CCC1CC2)OC(c1cccc(F)c1)c1cccc(F)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
(R)-Bis(3-fluorophenyl)methyl quinuclidin-3-ylcarbamate (50 mg, 0.13 mmol, prepared as in example 1) was added to a solution of (2-bromoethoxy)benzene (27.0 mg, 0.13 mmol) in ethyl acetate (2 ml). The mixture was stirred at room temperature overnight. Then (2-bromoethoxy)benzene (27 mg, 0.13 mmol) was added, and the mixture was heated at 100° C. for 15 minutes under microwave irradiation. A catalytic amount of potassium iodide was added, and the reaction was heated at 120° C. for 1 hour under microwave irradiation. The precipitate was collected by filtration and dried to obtain (R)-3-((bis(3-fluorophenyl)methoxy)carbonylamino)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane bromide (17 mg).
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[NH:24]C(=O)C)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:6][N:5]=1)([CH3:3])[CH3:2].[ClH:28]>>[ClH:28].[NH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[C:16]1[CH:17]=[CH:18][C:13]([S:10]([NH:9][C:7]2[S:8][C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]=2)(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: CC(=O)N[C@@H]1CCC[C@H]1c1ccc(S(=O)(=O)Nc2nnc(C(C)C)s2)cc1
Agent: Cl
Product: CC(C)c1nnc(NS(=O)(=O)c2ccc([C@@H]3CCC[C@H]3N)cc2)s1

Procedure:
Was prepared from 150 mg trans-N-{2-[4-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-phenyl]-cyclopentyl}-acetamide by heating it in 10 ml of 2n HCl at 100° C. for 13 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
Part A: To a cooled (ice bath) solution of 2,4-dichlorobenzoyl chloride (5 mL, 35.66 mmol) in 50 mL CH2Cl2 was added phenol (3.13 mL, 35.66 mmol), followed by triethylamine (4.97 mL, 35.66 mmol). The resulting reaction mixture was stirred at room temperature for 5 h. The mixture was then partitioned between CH2Cl2 and water. The organic layer was dried (Na2SO4), filtered, and evaporated in vacuo to yield 9.5 g of phenyl 2,4-dichlorobenzoate. MS (NH3—CI) 284 (M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:5]([O:14][CH3:15])=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:32][C:33]#[N:34]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:5]([O:14][CH3:15])=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:32][C:33]#[N:34])[CH2:12][CH2:13]2)[CH:7]=1
Reactant: COc1c(N2CCNCC2)cc(Br)cc1C(C)(C)C
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(N2CCN(CC#N)CC2)cc(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
1-[5-bromo-3-(tert-butyl)-2-methoxyphenyl]piperazine (550 mg), potassium carbonate (302 mg), dimethylformamide (7 ml) and bromoacetonitrile (0.12 ml) were combined and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, the insoluble portion was filtered off, and the concentrated residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (480 mg) as colorless crystals (78%).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])[CH:8]=1)([O-])=O.[C:14]([O:18][C:19]([NH:21][CH:22]([CH2:26][CH2:27][CH3:28])[C:23](O)=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19](=[O:20])[NH:21][CH:22]([C:23](=[O:24])[NH:1][C:4]1[N:5]=[CH:6][N:7]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])[CH:8]=1)[CH2:26][CH2:27][CH3:28])([CH3:15])([CH3:16])[CH3:17]
Reactant: CCCC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(=O)CCn1cnc([N+](=O)[O-])c1
Product: CCCC(NC(=O)OC(C)(C)C)C(=O)Nc1cn(CCC(C)=O)cn1

Procedure:
4-(4-nitro-1H-imidazol-1-yl)butan-2-one was reduced and coupled with 2-[(tert-butoxycarbonyl)amino]pentanoic acid to afford the title compound; MS 353 m/z (M+1).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH:10]2[CH:11]=[CH:12][CH:5]1[CH:6]1[CH:9]2[N:8]=[N:7]1.[CH3:13]I>C(#N)C>[CH3:13][O:3][CH:4]1[CH:10]2[CH:11]=[CH:12][CH:5]1[CH:6]1[CH:9]2[N:8]=[N:7]1
Reactant: OC1C2C=CC1C1N=NC21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: COC1C2C=CC1C1N=NC21
Reaction time: 12 h

Procedure:
1 part of NaH was added, a little at a time, to 5 parts of 9-hydroxy-3,4-diazatricyclo[4,2,1,02,5 ]nona-3,7-diene and 100 parts of acetonitrile at 20° C., while stirring. Thereafter, 20 parts of methyl iodide were added and stirring was continued for 12 hours at 20° C. The reaction mixture was evaporated down in a rotary evaporator at from 20° to 50° C. and under 20 mbar, and the residue was extracted with 200 parts of petroleum ether. The petroleum ether phase was evaporated down to give 5 parts (90 mole %) of 9-methoxy-3,4-diazatricyclo[4,2,1,02,5 ]-nona-3,7-diene as an oil. 1H-NMR (δ in ppm): 6.2 (bs, 2H), 4.1 (bs, 2H), 3.1-3.3 (m, 6H).
Reaction SMILES: O=[C:2]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].[CH2:21]([SH:24])[CH2:22][SH:23].O>ClCCl>[CH2:14]([C:2]1([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[S:24][CH2:21][CH2:22][S:23]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: SCCS
Reactant: CCCCCCCC(=O)CCCCCCCC(=O)OC
Solvent: O
Solvent: ClCCl
Product: CCCCCCCC1(CCCCCCCC(=O)OC)SCCS1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Under a nitrogen atmosphere, methyl 9-oxo-hexadecanoate (No. 4984860; 2.39 g, 8.40 mmol) was dissolved in dichloromethane (47 mL), and the solution was cooled to 0° C. While maintaining the temperature at 0° C., 1,2-ethanedithiol (840 μL, 10.1 mmol), and borontrifluoride-ethylether complex (1.24 mL, 10.1 mmol) were sequentially added, and the mixture was stirred at 0° C. for 5 minutes and at room temperature for 2 hours. Water was added to the reaction solution to stop the reaction, and the solution was extracted with dichloromethane. The organic layer was sequentially washed with a saturated sodium bicarbonate aqueous solution and a saturated brine, and dried over anhydrous sodium sulfate. After the organic layer was filtered and the solvent was distilled off, the resulting residue was purified with SP1 (SiO2 cartridge, 5.0% ethyl acetate/n-hexane, Rf=0.5) to obtain methyl 8-(2-heptyl-[1,3]dithiolan-2-yl)-octanoate (No. 5553355; 2.57 g, 85% yield).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([CH2:14][C:15]2[CH:16]=[C:17]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])=[C:5]([CH3:28])[N:4]=1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33](CO)[CH2:32][CH2:31]1>O1CCOCC1>[NH2:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([CH2:14][C:15]2[CH:16]=[C:17]([CH2:23][C:24]([O:26][CH2:27][CH:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[O:25])[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])=[C:5]([CH3:28])[N:4]=1
Reactant: CN1CCC(CO)CC1
Reactant: CCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)OC)ccc1OC
Agent: Cl
Solvent: C1COCCO1
Product: CCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)OCC2CCN(C)CC2)ccc1OC
Temperature: 80 °C

Procedure:
4M HCl in dioxane (1.5 mL) was added to a mixture of the product from step (v) (300 mg) and (1-methylpiperidin-4-yl)methanol (520 mg). The suspension was heated at 80° C. for 24 h and the solvent evaporated under reduced pressure. The residue was purified by RPHPLC to give the title compound as a gum, 10 mg.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[S:22][C:23]([CH3:26])=[CH:24][N:25]=1>>[CH3:26][C:23]1[S:22][C:21]([NH:20][C:4]([C:6]2[C:11]([NH:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])=[N:25][CH:24]=1
Reactant: Cc1cnc(N)s1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cccnc1
Product: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ncc(C)s2)n1

Procedure:
The title compound, was prepared from 6-Methyl-3-(pyridin-3-ylamino)-pyridine-2-carboxylic acid ethyl ester and 2-Amino-5-methylthiazole in accordance with the general method of example 78, step 2 to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=326.1 (M+H+).
Reaction SMILES: [CH3:1][CH:2]1[O:6][C:5]2[CH:7]=[C:8]([N+:15]([O-:17])=[O:16])[C:9]([NH:11]C(C)=O)=[CH:10][C:4]=2[O:3]1.C[O-].[Na+].C(O)(=O)C>CO>[CH3:1][CH:2]1[O:6][C:5]2[CH:7]=[C:8]([N+:15]([O-:17])=[O:16])[C:9]([NH2:11])=[CH:10][C:4]=2[O:3]1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OC(C)O2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1Oc2cc(N)c([N+](=O)[O-])cc2O1
Yield: 89.8 %

Procedure:
39.6 g of 2-methyl-5-acetamino-6-nitro-1,3-benzodioxole were boiled at reflux for 1 hour in 4 l of methanol with 4 g of sodium methoxide. After adding 5 ml of glacial acetic acid, the solution was evaporated in vacuo. The last traces of glacial acetic acid were removed by evaporation with toluene. The residue was dissolved in methylene chloride and filtered through a small amount of silicon dioxide. The evaporated filtrate was crystallized from isopropanol. There were obtained 29.3 g (90.1% of theory) of 2-methyl-5-amino-6-nitro-1,3-benzodioxole of melting point 139° C.