Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COCC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f36) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C(=O)(OCC1C2(O)ON(CC3C2N3)C2C1=C(O)C=C(C=O)C=2)N.NC1C=CC=CC=1.[C:31](=[O:59])([O:33][CH2:34][CH:35]1[C:47]2([OH:49])[O:48][N:42]([CH2:43][CH:44]3[CH:46]2[NH:45]3)[C:41]2[C:36]1=[C:37]([OH:58])[CH:38]=[C:39]([CH:50]=[N:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH:40]=2)[NH2:32]>CO.[Pd]>[C:31](=[O:59])([O:33][CH2:34][CH:35]1[C:47]2([OH:49])[O:48][N:42]([CH2:43][CH:44]3[CH:46]2[NH:45]3)[C:41]2[C:36]1=[C:37]([OH:58])[CH:38]=[C:39]([CH2:50][NH:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[CH:40]=2)[NH2:32]
Reactant: NC(=O)OCC1c2c(O)cc(C=Nc3ccccc3)cc2N2CC3NC3C1(O)O2
Agent: [Pd]
Agent: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Solvent: Nc1ccccc1
Solvent: CO
Product: NC(=O)OCC1c2c(O)cc(CNc3ccccc3)cc2N2CC3NC3C1(O)O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]-tetradeca-2,4,6-trien-8-ylmethyl carbamate (50 mg) was dissolved in methanol (5 ml). Aniline (0.05 ml) was added to this solution and the mixture was allowed to stand at room temperature for 3 hours to give a solution containing 6,9-dihydroxy-4-phenyliminomethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate. 10% Palladium on carbon (100 mg) was added to the solution, and the mixture was stirred for 2 hours at room temperature under hydrogen atmosphere (4.5 atm). The mixture was filtered through cellulose powder and the filter cake was washed with methanol (20 ml). The filtrate and the washings were combined and evaporated in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform, methanol and water (65:25:4, v/v/v) to afford 4-anilinomethyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (25 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:14]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[N-:33]=[N+:34]=[N-:35].[Na+].Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:32][N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]([S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]3[NH:35][N:34]=[N:33][N:2]=3)[CH:4]=2)(=[O:10])=[O:11])[CH:13]=1)[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30]
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C#N)c2)c1)C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(-c3nnn[nH]3)c2)c1)C(=O)OC(C)(C)C
Yield: 16.4 %

Procedure:
A mixture of tert-butyl ({1-[(3-cyanophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate (0.29 g), sodium azide (70 mg), triethylamine hydrochloride (0.19 g) and toluene (10 ml) was heated under reflux for 7 days. After cooling the reaction mixture, ethyl acetate was added to the mixture, and the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=10:1) to give the title compound as an oil (yield 0.052 g, 16%).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[N:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.[CH2:15]([S:18]([NH:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])(=[O:20])=[O:19])[CH2:16][CH3:17].O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]2[C:9]([C:25]([C:24]3[CH:23]=[C:22]([NH:21][S:18]([CH2:15][CH2:16][CH3:17])(=[O:20])=[O:19])[CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:10][NH:11][C:12]2=[N:13][CH:14]=1
Reactant: CCCS(=O)(=O)Nc1cccc(C(=O)Cl)c1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)(=O)Nc1cccc(C(=O)c2c[nH]c3ncc(Br)cc23)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To aluminum trichloride (4.8 g, 36.0 mmol) in methylene chloride (70.0 mL), under an atmosphere of nitrogen, was added 5-bromo-1H-pyrrolo[2,3-b]pyridine (67, 797 mg, 4.04 mmol) dissolved in methylene chloride (5.0 mL). The reaction was stirred at room temperature for 30 minutes, followed by addition of 3-(propane-1-sulfonylamino)-benzoyl chloride (77, 1.10 g, 4.20 mmol) dissolved in methylene dichloride (4.0 mL). The reaction was stirred at room temperature for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give a white solid (P-1116, 300.0 mg). MS(ESI) [M−H+]−=420.1, 422.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]([Cl:9])=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=2)[C:6]([C:18]([O:20][CH3:21])=[O:19])=[CH:5]1.Cl.[CH2:23]=O.N>CO.O>[Cl:9][C:8]1[N:4]2[CH2:3][CH2:2][NH:1][CH2:23][C:5]2=[C:6]([C:18]([O:20][CH3:21])=[O:19])[C:7]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1
Reactant: COC(=O)c1cn(CCN)c(Cl)c1-c1cccc(C#N)c1
Reactant: C=O
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Product: COC(=O)c1c(-c2cccc(C#N)c2)c(Cl)n2c1CNCC2
Temperature: 90 °C
Reaction time: 4 h
Yield: 224.9 %

Procedure:
To a solution of 8.41 g (27.7 mmol) of methyl 1-(2-aminoethyl)-5-chloro-4-(3-cyanophenyl)-1H-pyrrole-3-carboxylate in 20 ml of methanol are added 84 ml (340 mmol) of aqueous 4N hydrochloric acid solution. The formation of a white precipitate is rapidly observed and the medium then becomes clear, while the mixture is heated to 90° C. and 0.92 g (10 mmol) of paraformaldehyde is added. Heating is continued at 90° C. for 4 hours. After cooling, the reaction medium is poured into 200 ml of water and the solution is basified by adding aqueous ammonia. The product is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give an orange-coloured oil, which is chromatographed on a column of 80 g of silica gel, eluting with a mixture of 2% methanol in dichloromethane, to give 7.1 g of methyl 6-chloro-7-(3-cyanophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylate in the form of a yellow oil.
Reaction SMILES: [C:1](#N)[CH3:2].S(O)(=O)(=O)C.[C:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]2[N:24]([CH3:25])[C:23]3[CH:26]=[CH:27][C:28]([C:30]([N:32]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[O:31])=[CH:29][C:22]=3[N:21]=2)=[CH:14][CH:13]=1)(=[NH:11])[NH2:10].[C:46](=[O:49])([O-])[O-:47].[K+].[K+].O>C(OCC)(=O)C>[CH3:9][CH2:12][CH2:13][CH2:14][CH2:1][CH2:2][O:47][C:46](/[N:11]=[C:9](\[NH2:10])/[C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH2:19][C:20]2[N:24]([CH3:25])[C:23]3[CH:26]=[CH:27][C:28]([C:30]([N:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[O:31])=[CH:29][C:22]=3[N:21]=2)=[CH:16][CH:17]=1)=[O:49]
Reactant: CC#N
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: O=C([O-])[O-]
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
n-hexanol (30.8 g) was added to a solution of N, N-carbonyldiimidazole (61.15 g) and dichloromethane (360 ml) at 15-25° C. and stirred for 3 hours. The organic layer was washed with water followed by sodium chloride solution. Distilled off the solvent from the organic layer completely under reduced pressure to get amide compound. Acetonitrile (157.5 ml) was added to the obtained amide compound. This was added to a mixture of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-11 (90 g), potassium carbonate (62.5 g), acetonitrile (378 ml) and water (252 ml) at 25-35° C. The reaction mixture was heated to 40-50° C. and stirred for 8 hours. After completion of the reaction, both the organic and aqueous layers were separated; the organic layer was cooled to −5 to +5° C. and stirred for 2 hours. Filtered the precipitated solid washed with acetonitrile and water. The obtained compound was dissolved in a mixture of acetone (270 ml) and acetonitrile (270 ml) at 45-50° C. Cooled the reaction mixture to 25-30° C. and water (360 ml) was added to it. Filtered the obtained solid and dissolved in the mixture of dichloromethane and sodium chloride solution at 35-40° C. Both the organic and aqueous layers were separated; the organic layer was distilled under reduced pressure and then co-distilled with ethyl acetate. The obtained crude compound was dissolved in ethyl acetate (540 ml) by heating it to 70-80° C. and stirred for 30 minutes. Filtered the reaction mixture, the filtrate was cooled to 35-45° C. and ethanol (8 ml) was added to the reaction mixture. The reaction mixture was again cooled to 25-35° C. and stirred for 3 hours. Filtered the precipitated solid and then dried to get pure title compound.
Reaction SMILES: [O:1]1[CH2:6][C:5](=[O:7])[NH:4][C:3]2[CH:8]=[N:9][CH:10]=[CH:11][C:2]1=2.[H-].[Na+].[Br:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([Br:26])[C:23]=1[O:24][CH3:25])[C:18](Cl)=[O:19]>O>[Br:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([Br:26])[C:23]=1[O:24][CH3:25])[C:18]([N:4]1[C:5](=[O:7])[CH2:6][O:1][C:2]2[CH:11]=[CH:10][N:9]=[CH:8][C:3]1=2)=[O:19]
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Reactant: O=C1COc2ccncc2N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1c(Br)cc(C(=O)N2C(=O)COc3ccncc32)cc1Br

Procedure:
By the same method as in Example 56, 4H-pyrido[4,3-b][1,4]oxazin-3-one (200 mg, 1.33 mmol), sodium hydride (56 mg, 1.40 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (437 mg, 1.33 mmol) were reacted, and then water was added thereto and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of ethyl acetate:methanol=9:1. The fractions containing the product were collected and evaporated to obtain the target compound 57, i.e., 4-(3,5-dibromo-4-methoxy-benzoyl)-4H-pyrido[4,3-b][1,4]oxazin-3-one, as white solid (125 mg, 21%).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccnc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC=C(c2cccnc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(3-pyridyl)-2-naphthalenyl)ethynyl]benzoate (Compound 11) 45.0 mg (0.110 mmol) in 3 ml of EtOH and 2 ml of THF was added 48.0 mg (1.20 mmol, 1.20 ml) of NaOH (1.0M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ 8.60 (1H, d, J=4.6 Hz), 8.55 (1H, s), 7.90 (2H, d, J=8.3 Hz), 7.76 (1H, d, J=7.5 Hz), 7.60 (2H, d, J=8.3 Hz), 7.51-7.46 (3H, m), 6.94 (1H, s), 6.14 (1H, t, J=4.5 Hz), 2.37 (2H, d, J=4.5 Hz), 1.31 (6H, s).
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][C:32]([NH2:39])([CH3:38])[C:33]1[O:37][CH:36]=[CH:35][CH:34]=1>>[CH3:31][C:32]([NH:39][C:22]([C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@:18]1([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]1)=[CH:6][CH2:7]3)=[O:30])([CH3:38])[C:33]1[O:37][CH:36]=[CH:35][CH:34]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: CC(C)(N)c1ccco1
Product: CC(C)(NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C)c1ccco1
Yield: 71 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and α,α-dimethylfurfurylamine (prepared as described in Preparation 11c) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 71%.
Reaction SMILES: ClCCl.[Br:4][C:5]1[C:6]2[C:11]([C:12]3[CH2:17][N:16]([C@H:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]4[OH:24])[C:15](=[O:25])[C:13]=3[CH:14]=1)=[N:10][CH2:9][CH2:8][CH:7]=2.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])(=O)=O>O>[Br:4][C:5]1[CH:14]=[C:13]2[C:15](=[O:25])[N:16]([C@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[O:24][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:17][C:12]2=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: O=C1c2cc(Br)c3c(c2CN1[C@H]1CCCC[C@@H]1O)=NCCC=3
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCCC[C@@H]1N1Cc2c(cc(Br)c3cccnc23)C1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a 15 mL dichloromethane solution of 5-bromo-8-[(1S,2S)-2-hydroxycyclohexyl]-3,9-dihydro-7H-pyrrolo[3,4-h]quinolin-7-one (2.00 g, 5.54 mmol) at 0° C. was added 2,6 lutidine (1.29 mL, 11.1 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (1.91 mL, 8.30 mmol). The mixture was warmed to ambient temperature, and after 15 hr, diluted with water and extracted 2× with ethyl acetate. The combined organic extracts were washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The resultant white crystals were collected via filtration and washed with hexanes to provide 5-bromo-8-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-8,9-dihydro-7H-pyrrolo[3,4-h]quinolin-7-one that gave a proton NMR spectra consistent with theory.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH:25]([O:28][CH3:29])[O:26][CH3:27])[CH:17]=1.O>CC(N(C)C)=O>[CH3:29][O:28][CH:25]([O:26][CH3:27])[C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[N+:22]([O-:24])=[O:23])[O:8][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1
Reactant: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(OC)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h

Procedure:
3-Amino-phenol (0.050 mol) was dissolved in DMA (100 ml). K2CO3 (0.050 mol) was added. 4-Chloro-2-dimethoxymethyl-1-nitro-benzene (0.050 mol) was added and the reaction mixture was stirred overnight at 100° C., then for 2 hours at 120° C. The reaction mixture was poured out into water and this mixture was extracted with diisopropyl ether. The separated organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2:CH3OH 100:0 (to remove starting material) up to 70:30). The desired fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [C:1]([CH:5]([CH:21]1[CH2:24][C:23](=[O:25])[CH2:22]1)[C:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[O:7][SiH3:8])([CH3:4])([CH3:3])[CH3:2].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[C:1]([CH:5]([C@@H:21]1[CH2:22][C@H:23]([OH:25])[CH2:24]1)[C:6]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[O:7][SiH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(C1CC(=O)C1)C(O[SiH3])(c1ccccc1)c1ccccc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)C([C@H]1C[C@@H](O)C1)C(O[SiH3])(c1ccccc1)c1ccccc1
Temperature: -78 °C

Procedure:
In a 50 mL flask with 3-(tert-butyl-diphenyl-siloxyethyl)cyclobutanone (0.48 g, 1.36 mmol) inside, dry THF 10 mL was added under argon to give a light yellow solution. This was cooled to −78° C., after a while, L-selectride (1.0 M in THF, 1.6 mL, 1.63 mmol) was added drop by drop and this was allowed to warm up to room temperature, after which the reaction was quenched with saturated NaHCO3. Then cool the mixture to 0° C., add 30% H2O2 drop by drop, followed by the addition of H2O and EtOAc. The organic phase was separated, washed with H2O twice and brine once, dried over MgSO4 and solvent evaporation gave the crude product, which was purified by silica gel flash chromatography (Hexane: EtOAc=9:1) to give a colorless oil (0.3 g, 61.8%). 1H NMR (CDCl3, 300 MHz): δ 1.04 (s, 9H), 1.40-2.10 (m, 5H), 2.38-2.47 (m, 2H), 3.58-3.62 (t, J=6.3, 2H), 4.04-4.14 (m, 1H), 7.34-7.45 (m, 6H), 7.64-7.67 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[CH2:22][NH:23][C:24]([NH:26][C:27]1[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=1)=[O:25].[ClH:34].O1CCOCC1>CO>[ClH:1].[ClH:34].[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)=[CH:4][C:3]=1[CH2:22][NH:23][C:24]([NH:26][C:27]1[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=1)=[O:25]
Reactant: Cc1ccc(NC(=O)NCc2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2Cl)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(NC(=O)NCc2cc(CN3CCNCC3)ccc2Cl)cn1
Reaction time: 16 h

Procedure:
The tert tert-butyl 4-(4-chloro-3-((3-(6-methylpyridin-3-yl)ureido)methyl)benzyl)piperazine-1-carboxylate from above (954 mg, 2.01 mmol) was dissolved in 40 mL of methanol and treated with 10 mL of 4N HCl in dioxane (40.2 mmol) with stirring for 16 h. The solvents were removed to afford 1.13 g of 1-(2-chloro-5-(piperazin-1-ylmethyl)benzyl)-3-(6-methylpyridin-3-yl)urea trihydrochloride salt as a white solid.
Reaction SMILES: CN1C[CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[O:18]1[CH2:20][CH:19]1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.[CH3:27][N:28](C=O)[CH3:29]>>[CH3:27][N:28]1[CH2:29][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[CH:11]=3)[N:6]([CH2:20][CH:19]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[OH:18])[C:5]=2[CH2:14]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CN(C)C=O
Reactant: c1cncc(C2CO2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2cccnc2)CN(C)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 5 mmol) in 10 mL DMF, was added sodium hydride (600 mg, 15 mmol) portionwise under nitrogen at 0° C. and stirred for 10 min. 3-Oxiranyl-pyridine (908 mg, 15.0 mmol) was added dropwise under nitrogen and the reaction mixture stirred at RT for 12 h. After the complete conversion of starting material (TLC and LCMS), the reaction mixture was poured in ice-cold water and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (5×50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude mixture was purified by reverse phase chromatography to obtain 290 mg of 2-(2,6-dimethyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-1-pyridin-3-yl-ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.62 (s, 1H), 8.57 (d, 1H), 7.67 (d, 1H), 7.3 (m, 2H), 7.19 (d, 1H), 7.01 (d, 1H), 5.09 (t, 1H), 4.13 (m, 2H), 3.70 (d, 1H), 3.36 (d, 1H), 2.79 (m, 3H), 2.703 (m, 1H), 2.5 (s, 3H), 2.45 (s, 3H). Separation by chiral HPLC provided enantiomers 43a and 43b.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:24]([OH:26])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1O)([O-:29])=[O:28].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1.CCOC(C)=O.C(O)(C)C>[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:25][C:24](=[O:26])[C@@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])([O-:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)Oc1ccccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A solution Nα -Boc-Nδ -Cbz-(R)-ornithine (25.0 g; 68.2 mmol) and o-nitrophenol (19.0 g; 136.4 mmol) in pyridine (250 mL) was cooled to 0° C. Dicyclohexylcarbodiimide (13.4 g; 64.8 mmol) was added at 0° C. The solution was stirred at 0° C. for several hours, warmed to room temperature and stirred overnight. The resulting heterogeneous solution was diluted with EtOAc and filtered. The filtrate was concentrated under reduced pressure to afford a thick oil. The oil was dissolved in a minimal amount of warm isopropanol and stirred. The resultant precipitate was collected via vacuum filtration and washed with isopropanol, then diethyl ether. Concentration of the isopropanol/ether filtrate and crystallization from isopropanol provided a second crop. The combined product was dissolved in EtOAc at room temperature and filtered. Concentration of the EtOAc gave the sub-title compound as a solid.