Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([C:17]([O:19]C)=[O:18])=[N:12][CH:13]=[CH:14][C:15]=1[Cl:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O>[Si:1]([O:8][CH2:9][C:10]1[C:11]([C:17]([OH:19])=[O:18])=[N:12][CH:13]=[CH:14][C:15]=1[Cl:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)c1nccc(Cl)c1CO[Si](C)(C)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1c(Cl)ccnc1C(=O)O
Temperature: 19 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
A mixture of 160d (25 g, 76 mmol) and sodium hydroxide (6.1 g, 152 mmol) in ethanol (200 mL) and water (200 mL) was stirred at 19° C. for 2 h. See FIG. 5. The mixture was diluted with water (200 mL) and the resulting mixture was extracted with EtOAc (200 mL×2). The organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-chloropicolinic acid 160e (20 g, 87%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH3:15][O:16][NH:17][CH3:18].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:15][O:16][N:17]([CH3:18])[C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)=[O:14]
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Reactant: CNOC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 6-bromo-naphthalene-2-carboxylic acid (0.6 g, 2.4 mmol) and O,N-dimethyl-hydroxylamine (0.28 g, 2.87 mmol) in CH2Cl2 (20 mL), was added EDC (0.55 g, 2.87 mmol), HOBt (0.39 g, 2.87 mmol) and TEA (0.66 mL, 4.8 mmol). The reaction was stirred at RT overnight. The solvent was removed in vacuo and the crude material was purified by silica gel column chromatography with (20-40% EtOAc/hexane) to give the titled compound as a white solid. MS (ESI, pos. ion) m/z: 294.0 (M+1).
Reaction SMILES: B.O1CCCC1.[Br:7][C:8]1[CH:17]=[C:16]2[C:11]([O:12][CH2:13][C:14](=O)[NH:15]2)=[N:10][CH:9]=1>O1CCCC1>[Br:7][C:8]1[CH:17]=[C:16]2[C:11]([O:12][CH2:13][CH2:14][NH:15]2)=[N:10][CH:9]=1
Reactant: O=C1COc2ncc(Br)cc2N1
Agent: B
Solvent: C1CCOC1
Product: Brc1cnc2c(c1)NCCO2
Temperature: 100 °C
Yield: 69.3 %

Procedure:
Borane-tetrahydrofuran complex (1 M in tetrahydrofuran, 32 mL, 32 mmol) was added dropwise at 0° C. to a solution of 7-bromo-1H-4-oxa-1,5-diaza-naphthalen-2-one (1.45 g, 6.33 mmol) in tetrahydrofuran (240 mL). The ice bath was removed and the solution heated at reflux over 3 h, then volatile material was removed by distillation. The residue was taken up in 37% aq. hydrochloric acid solution and the reaction mixture, heated at 100° C. for 75 min, basified to pH 10 with 30% aq. sodium hydroxide solution, and extracted three times with dichloromethane. The combined organic layers were dried (Na2SO4) and evaporated to afford 7-bromo-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene (944 mg, 69%). White solid, MS (ISP)=215.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1.C([Li])CCC.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.O>O1CCCC1.CCCCCC>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][C:5]1[S:4][C:3]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)=[C:2]([CH3:1])[CH:6]=1
Reactant: Cc1ccsc1C1OCCO1
Reactant: BrCCCCBr
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(CCCCBr)sc1C1OCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
A solution of 2-(3-methyl-2-thienyl)-1,3-dioxolane (12.3 g) in dry tetrahydrofuran (150 ml) was treated with a solution of n-butyl lithium in hexane (1.6M, 50 ml) at -60°, under nitrogen. After 1 h, 1,4-dibromobutane (17.3 g) was added and the mixture was stirred at -50° for 3 h and at room temperature for 18 h. Water (75 ml) was added and the mixture extracted with ether. The organic extract was distilled to give the title compound as a light brown oil (15.1 g) b.p. 250°/0.15 mm.
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[O:17][CH:16]=1>[Cu]I>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[O:17][CH:16]=[C:15]([N:3]3[CH2:4][C@:5]4([CH:10]5[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]5)[CH2:6]4)[O:1][C:2]3=[O:13])[CH:19]=2)[CH:21]=1
Reactant: Brc1coc(-c2cccnc2)c1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Agent: [Cu]I
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1coc(-c2cccnc2)c1

Procedure:
The title compound was prepared by a method analog to that described in Preparation 3 from (S)-spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 3-bromo-5-(3-pyridyl)-furan with 3 equivalents of copper (I) iodide. The title compound (119 mg) was obtained as a pale yellow solid, m/z 342 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:7]=1[CH3:8].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([SH:35])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35][CH2:2][C:3]2[N:4]=[CH:5][NH:6][C:7]=2[CH3:8])=[CH:31][CH:30]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1[nH]cnc1CSc1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to example 42 using 4-chloromethyl-5-methyl-1-trityl-1H-imidazole (CAS106147-85-7) for the alkylation of 4-chlorobenzenethiol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:18]3[N:17]=[C:16]([C:19]4[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][C:20]=4[Br:26])[NH:15][C:14]=3[C:13]3[C:8](=[CH:9][C:10]([Br:27])=[CH:11][CH:12]=3)[C:6]=2[CH:7]=1.[H-].[Na+].[CH3:30][Si:31]([CH2:34][CH2:35][O:36][CH2:37]Cl)([CH3:33])[CH3:32].O>C1COCC1>[Br:27][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[N:15]=[C:16]([C:19]4[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][C:20]=4[Br:26])[N:17]([CH2:37][O:36][CH2:35][CH2:34][Si:31]([CH3:33])([CH3:32])[CH3:30])[C:18]=3[C:5]3[C:6](=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[C:8]=2[CH:9]=1
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1c1[nH]c(-c3c(Br)cccc3Br)nc21
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1c(-c2c(Br)cccc2Br)nc2c3ccc(Br)cc3c3cc(Br)ccc3c21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
To a suspension of 6,9-dibromo-2-(2,6-dibromophenyl)-1H-phenanthro[9,10-d]imidazole from Step 1 (61.8 g, 0.1 mol) in THF (980 mL) at 0° C., was added sodium hydride (60% dispersion in mineral oil, 10 g, 0.25 mol). The suspension was stirred at 0° C. for 15 minutes, followed by addition of SEMCl (45 mL, 0.25 mol). The mixture was warmed to room temperature and stirred for 3 h, after which it was poured into water. The aqueous phase was extracted with ethyl acetate, the organic layer washed once with brine, dried over Na2SO4, filtered and concentrated. The crude material was swished in hexanes/diethyl ether for 4 h, then filtered to obtain 6,9-dibromo-2-(2,6-dibromophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-phenanthro[9,10-d]imidazole as a beige powder (71.5 g, 95%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22].C([N+](CCCC)(CCCC)CCCC)CCC>CC(C)CC(=O)C>[Cl:3][C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:19][CH2:20][CH2:21][Cl:22])[C:6]=2[CH:5]=1
Reactant: ClCCCBr
Reactant: Clc1ccc2c(c1)Nc1ccccc1S2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Product: ClCCCN1c2ccccc2Sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
40 ml of a sodium hydroxide solution (50% by weight) are added to a solution of 2.34 g (10 mmol) of 2-chlorophenothiazine, 4.73 g (30 mmol) of 1-bromo-3-chloropropane and 0.34 g (1 mmol) of tetrabutylammonium hydrogenosulfate in 40 ml of 4-methylpentan-2-one. The mixture is stirred at ambient temperature for 48 hours. After customary treatment of the organic phase, drying over sodium sulfate, evaporation of the solvent and purification by chromatography on silica gel, 2.17 g of pure product are obtained (eluant: petroleum ether).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:20]=2)[CH:4]=1.C(NC1N=C(C2C=CC=CN=2)C=C(C2C=NC=C(Br)C=2)C=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:1]([NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:20]=2)[CH:4]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CNc1cc(-c2cncc(-c3cnn(C4CCNCC4)c3)c2)cc(-c2ccccn2)n1
Reactant: Brc1cncc(-c2cc(NCc3ccccc3)nc(-c3ccccn3)c2)c1
Product: c1ccc(CNc2cc(-c3cncc(-c4cnn(C5CCNCC5)c4)c3)cc(-c3ccccn3)n2)cc1

Procedure:
This compound is prepared analogously to Methyl-[5″-(1-piperidin-4-yl-1H-pyrazol-4-yl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (Example 2.183) by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1; step1) with Benzyl-(5″-bromo-[2,2′;4′,3″]terpyridin-6′-yl)-amine (Example 1.25).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([C:13]2[CH:21]=[CH:20][C:19]3[N:18]([CH3:22])[C:17]4[CH2:23][CH:24]5[NH:28][CH:27]([C:16]=4[C:15]=3[C:14]=2C(OC(C)(C)C)=O)[CH2:26][CH2:25]5)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[ClH:36]>C(OCC)C>[ClH:36].[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[C:17]2[CH2:23][CH:24]4[NH:28][CH:27]([C:16]3=2)[CH2:26][CH2:25]4)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cccc([N+](=O)[O-])c4)ccc31)C1CCC(C2)N1
Agent: Cl
Solvent: CCOCC
Product: Cn1c2c(c3cc(S(=O)(=O)c4cccc(N)c4)ccc31)C1CCC(C2)N1

Procedure:
The product of step A was subjected to Boc-deprotection with 2 M HCl in diethyl ether following the procedure of Example 28, step B. The crude material was purified by flash column chromatography (SiO2, 96:4 dichloromethane/methanol). The free base was treated with 1.25 M HCl in methanol (1.5 mL). The solution was concentrated in vacuo and the residue lyophilized to give 2-(3-aminophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (14 mg, 91%, AUC HPLC >99%) as an off-white solid: mp 220-222° C.; 1H NMR (CD3OD, 300 MHz) δ 8.27 (d, J=1.5 Hz, 1H), 7.72 (dd, J=8.7, 1.5 Hz, 1H), 7.54-7.60 (m, 3H), 7.41-7.46 (m, 1H), 7.18 (dd, J=7.8, 1.5 Hz 1H), 5.30 (d, J=4.2 Hz, 1H), 4.50 (br s, 1H), 3.72 (s, 3H), 3.52 (dd, J=18.0, 6.0 Hz, 1H), 3.07 (d, J=17.4 Hz, 1H), 2.25-2.50 (m, 3H), 1.97-2.00 (m, 1H); ESI MS m/z 368 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C:10](=[O:11])[CH:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][S:7]1)=[O:5])[CH3:2].[BH4-].[Na+].CC(C)=O.C(O)(=O)C>CCO>[CH2:1]([O:3][C:4]([C@H:6]1[CH:10]([OH:11])[CH:9]([NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:8][S:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1SCC(NC(=O)OC(C)(C)C)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H]1SCC(NC(=O)OC(C)(C)C)C1O
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
The oxo-ester (13) (9.16 g, 31.7 mmole) in EtOH 90 mL was reduced with NaBH4 (844 mg, 22 mmole) added portion wise at −30° C. After 30 min at −30° C., acetone 8.7 mL followed with acetic acid 1.1 mL were added. The crude mixture was concentrated at 40° C. under 100 mbar, extracted with EtOAc and brine to pH 7. The solvent was removed under 0.1 mbar, crude 9.20 g (yield 99%) of (R)-ethyl-4-[(tert-butoxycarbonyl)amino]tetrahydro-3-hydroxy-2-thiophenecarboxylate.
Reaction SMILES: [BH4-].[Li+].C[Si](Cl)(C)C.[NH2:8][C@@H:9]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10](O)=[O:11]>O1CCCC1>[NH2:8][C@@H:9]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][OH:11]
Reactant: CC(C)(C)C[C@H](N)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)C[C@H](N)CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.2 %

Procedure:
To a stirred suspension of lithium borohydride (0.75 g, 34.4 mmol, 2.0 equiv.) in tetrahydrofuran (60 mL) was added trimethylsilyl chloride (7.48 g, 68.85 mmol, 4.0 equiv.) slowly over a period of 5 minutes at 0° C. under argon. To the reaction mixture was added (S)-2-amino-4,4-dimethyl-pentanoic acid (available from Chem-Impex International, Inc., Wood Dale, Ill., USA; 2.50 g, 17.2 mmol, 1.0 equiv.) in portions over a span of 10 minutes at the same temperature and the reaction was allowed to stir for 24 hours at room temperature. The reaction mixture was quenched with the slow addition of methanol (50 mL) at 0° C., and volatiles were removed by vacuum distillation. The obtained residue was treated with an aqueous solution of 20% potassium hydroxide (w/v; 10 mL) and extracted with dichloromethane (3×20 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (S)-2-amino-4,4-dimethyl-pentan-1-ol (1.9 g, 84%).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH2:12][N:13]2[C:17]([CH3:18])=[C:16]([I:19])[CH:15]=[N:14]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]=[CH2:3].C12BC(CCC1)CCC2.[O:29]1CCCC1.[OH-].[Na+].OO>O1CCCC1>[I:19][C:16]1[CH:15]=[N:14][N:13]([CH2:12][C:5]2([O:4][CH2:1][CH2:2][CH2:3][OH:29])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[C:17]=1[CH3:18]
Reactant: C=CCOC1(Cn2ncc(I)c2C)CCCCCC1
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Product: Cc1c(I)cnn1CC1(OCCCO)CCCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of EXAMPLE 155A (1.7 g) in tetrahydrofuran (20 mL) was added a 0.5 M 9-borabicyclo[3.3.1]nonane-tetrahydrofuran solution (50 mL, 0.5 M) at 0° C. After the reaction mixture was stirred for 24 hours at room temperature, a 0.5 M NaOH aqueous solution (30 mL) and 30% H2O2 aqueous solution (5.5 mL) were added. After the reaction mixture was stirred for 16 hours, the reaction was then quenched by adding water (15 mL). The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous NaCl solution. After the organic layer was dried over Na2SO4, and filtered, the solvent was evaporated under reduced pressure. The crude product was purified on a silica gel column, eluting with 10-50% ethyl acetate in hexanes, to provide the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([C:6]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])=[CH:7][CH:8]=O)[CH3:5]>C(Cl)(Cl)Cl.CO>[CH2:4]([C:6]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])=[CH:7][CH:8]=[N:2][OH:3])[CH3:5]
Reactant: NO
Reactant: CCC(=CC=O)C(C)[N+](=O)[O-]
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCC(=CC=NO)C(C)[N+](=O)[O-]
Yield: 73 %

Procedure:
Hydroxylamine hydrochloride (100 mg) was added to a solution of 3-ethyl-4-nitro-2-pentenal (100 mg) in chloroform (3 ml) and methanol (2 ml) with stirring. The resulting mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was diluted with water and extracted with ethyl acetate (50 ml×2). The combined extracts were washed successively with water, 5% sodium bicarbonate and brine, and then dried over magnesium sulfate. Removal of the solvent gave an oil which was purified by a preparative thin layer chromatography (5% methanol-chloroform) to give 3-ethyl-4-nitro-2-pentenal oxime (80 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: COc1cccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)c1

Procedure:
The title compound was prepared from the product of Example 65A and 3-methoxyphenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 336.0 (M+H)+, retention time 1.32 minutes.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]3[N:32]4[CH2:33][CH2:34][CH2:35][N:36]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:37][C:31]4=[N:30][C:25]=3[CH:26]=[N:27]2)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[NH4+:43].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]3[N:32]4[CH2:33][CH2:34][CH2:35][N:36]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:37][C:31]4=[N:30][C:25]=3[C:26]([NH2:43])=[N:27]2)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)N1CCCn2c(nc3cnc4cc(OCc5ccccc5)ccc4c32)C1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)N1CCCn2c(nc3c(N)nc4cc(OCc5ccccc5)ccc4c32)C1
Reaction time: 0.17 h

Procedure:
mCPBA (2.96 g of 77% purity, 13.2 mmol) was added to a solution of 3-(benzyloxy)-9-(methylsulfonyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline (4.648 g, 11 mmol) in chloroform (20 mL), and the reaction was stirred for 10 minutes. Additional mCPBA (1.5 g) was added and the reaction was monitored for disappearance of the starting substrate by thin-layer chromatography (TLC). Ammonium hydroxide (20 mL) was then added and the reaction was stirred for five minutes before the rapid addition of p-toluenesulfonyl chloride (2.31 g, 12.1 mmol). The reaction was stirred overnight at ambient temperature. The organic layer was separated, washed with ammonium hydroxide, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 2 N ammonia in methanol/chloroform in a 43-minute gradient from 1:99 to 25:75) and recrystallization from isopropanol and dried in a vacuum oven at 65° C. to afford 1.1 g of 3-(benzyloxy)-9-(methylsulfonyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine as brown crystals, mp 235-236° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[C:31]([O:30][C:28]([NH:27][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: COC(=O)c1cccnc1-c1cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2C(=O)O)c1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-methoxycarbonylpyridin-2-yl)phenyl)guanidine (282 mg) in methanol (3 ml) was added an aqueous sodium hydroxide solution (1N, 1.2 ml), and the mixture was stirred for 2 hours. The pH of the reaction mixture was adjusted to 5 with 1N hydrochloric acid. The mixture was diluted with water and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether, filtered and dried to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-carboxypyridin-2-yl)phenyl)guanidine (0.23 g).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([C:24]([O:26]C)=[O:25])=[CH:19][N:18]=1)[C:5]([NH:7][CH3:8])=[O:6].[OH-].[Na+]>CO>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([C:24]([OH:26])=[O:25])=[CH:19][N:18]=1)[C:5]([NH:7][CH3:8])=[O:6]
Reactant: CNC(=O)C(=NOC)c1ccccc1COc1ncc(C(=O)OC)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNC(=O)C(=NOC)c1ccccc1COc1ncc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
α-(Methoxyimino)-N-methyl-2-[[[3-chloro-5-(methoxycarbonyl)-2-pyridinyl]oxy]methyl]-benzeneacetamide (15.8 g, 40.4 mmol), prepared utilizing the general procedure described in Example 37, was dissolved in warm methanol (600 mL) to which was added 0.1 N NaOH (600 mL). The solution was stirred at room temperature overnight, then concentrated in vacuo to remove excess methanol. The remainder was extracted with Et2O (200 mL). The aqueous layer was acidified slightly (pH 5-6) resulting in a white precipitate. After 30 minutes of stirring at room temperature, the solid was collected, washed with water and dried in a vacuum oven to give α-(methoxyimino)-N-methyl-2-[[[3-chloro-5-(carboxy)-2-pyridinyl]oxy]methyl]-benzeneacetamide (14.9 g). M.P. 189-195° C.
Reaction SMILES: [Na].[CH2:2]([OH:5])[CH2:3][OH:4].[CH3:6][N:7]([CH3:12])[C:8](=[O:11])[CH2:9]Cl>C(O)CO>[CH3:6][N:7]([CH3:12])[C:8](=[O:11])[CH2:9][O:4][CH2:3][CH2:2][OH:5]
Reactant: OCCO
Reactant: CN(C)C(=O)CCl
Agent: [Na]
Product: CN(C)C(=O)COCCO
Temperature: 50 °C
Reaction time: 1 h

Procedure:
40 ml of ethylene glycol and 8.4 g (0.1 mole) ethylene glycol monosodium salt are weighed into a 100 ml round bottom flask. The reaction mixture is heated to 50° C. with stirring and at this temperature, 12.2 g (0.1 mole) of chloroacetic acid N,N-dimethylamide are added dropwise in 1 hour. The reaction mixture is kept at the same temperature for further 1 hour and subsequently submitted to fractionated distillation. The first fraction (boiling temperature approx. 80° C., 260 Pa) comprises the solvent ethylene glycol. The boiling temperature of the product fraction is 130-135° C. (13 Pa). The purity of the product is higher than 98% as determined by gas chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30]1([CH3:39])[C:31]([C:36](Cl)=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=1>ClCCl>[CH:17]1([N:8]([C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:1][C:36](=[O:37])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH3:39])=[CH:3][CH:4]=2)[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1ccc(N(C(=O)c2ccc(N)cc2)C2CCCC2)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(N(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
To a solution of N-(4-aminobenzoyl)-N-cyclopentyl-p-anisidine (870 mg) and pyridine (443 mg) in dichloromethane (20 ml) was added o-toluoyl chloride (868 mg) at 0° C. Then the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was concentrated and diluted with ethyl acetate and the solution was washed with water, IN-hydrochloric acid and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (SiO2 20 g, ethyl acetate:n-hexane=1:2). The eluent was concentrated and triturated with diethyl ether to give N-cyclopentyl-N-[4-(2-methylbenzoylamino)benzoyl]-p-anisidine (750 mg).