Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C2C(=CC=1)NC(C(N[C@@H]1CC3C(=CC=CC=3)NC1=O)=O)=C2.[C:25]([CH2:29][N:30]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@@H:33]([NH:41][C:42]([C:44]2[NH:45][C:46]3[C:51]([CH:52]=2)=[CH:50][C:49]([Cl:53])=[CH:48][CH:47]=3)=[O:43])[C:31]1=[O:32])([O:27][CH3:28])=[O:26].C(OC(N[C@@H]1CC2C(=CC=CC=2)NC1=O)=O)(C)(C)C>>[C:25]([CH2:29][N:30]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@H:33]([NH:41][C:42]([C:44]2[NH:45][C:46]3[C:51]([CH:52]=2)=[CH:50][C:49]([Cl:53])=[CH:48][CH:47]=3)=[O:43])[C:31]1=[O:32])([O:27][CH3:28])=[O:26]
Reactant: COC(=O)CN1C(=O)[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Agent: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2NC1=O
Agent: O=C(N[C@@H]1Cc2ccccc2NC1=O)c1cc2cc(Cl)ccc2[nH]1
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21

Procedure:
The title compound was prepared from (S)-3-t-butyloxycarbonylamino-3,4-dihydrocarbostyril (prepared in Example 5) by the procedures described for the preparation of (R)-1-carbomethoxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril (Example 7) from (R)-3-t-butyloxycarbonylamino-3,4-dihydrocarbostyril. HPLC/MS [M+H]+, 412.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]([C:8]1[C:13]([B:14]2[O:18]C(C)(C)C(C)(C)[O:15]2)=[CH:12][C:11]([O:23][CH3:24])=[CH:10][C:9]=1[CH3:25])=O.[BH4-].[Na+].C(OB(O)O)C1C=CC=CC=1>CO>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH:6]1[O:18][B:14]([OH:15])[C:13]2[CH:12]=[C:11]([O:23][CH3:24])[CH:10]=[C:9]([CH3:25])[C:8]1=2
Reactant: COC(=O)CCC(=O)c1c(C)cc(OC)cc1B1OC(C)(C)C(C)(C)O1
Agent: OB(O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCC1OB(O)c2cc(OC)cc(C)c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a solution of 4-[4-methoxy-2-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-4-oxo-butyric acid methyl ester (0.33 g, 0.87 mmol) in MeOH (3 mL) was added NaBH4 (0.073 g, 1.92 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes, quenched with 6 N HCl and extracted with EtOAc. The organic extracts were dried and concentrated in vacuo. The residue was dissolved in CH3CN and treated with polymer-bounded benzyl boric acid (2 equiv) for 2 hours. The mixture was filtered, concentrated and purified by silica gel flash column chromatography to give 3-(1-hydroxy-6-methoxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-propionic acid methyl ester (0.160 g, 69%). 1H NMR (400 MHz, MeOD-d4) δ 6.98 (s, 1H), 6.80 (s, 1H), 5.25 (m, 1H), 3.80 (s, 3H), 3.60 (s, 3H), 2.50-2.30 (m, 6H), 1.77 (m, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:19]4[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=4[O:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>>[F:24][C:22]1[CH:21]=[CH:20][C:19]2[CH:15]([NH:14][C:11]3[O:12][CH2:13][C:8]4[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:31][CH2:30][CH2:29][O:28][CH3:27])[CH:26]=[CH:25][C:9]=4[N:10]=3)[CH2:16][O:17][C:18]=2[CH:23]=1
Reactant: COCCN
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(NC1COc3cc(F)ccc31)=N2
Product: COCCNCC(=O)Nc1ccc2c(c1)COC(NC1COc3cc(F)ccc31)=N2
Yield: 68.9 %

Procedure:
Prepared from the above described rac-2-chloro-N- [2-(6-fluoro-2,3-dihydro-benzofuran-3-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (50 mg, 0.133 mmol, HPLC 1.056 min) and 2-methoxyethylamine (230 ul, 2.66 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white solid (38 mg, 70%, HPLC 0.466 min 100%), MS (ISP) m/e=415.3 [(M+H)+].
Reaction SMILES: C([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:40])[C@@H:15]([NH:25][C:26](=[O:39])/[C:27](/[CH3:38])=[CH:28]/[C:29](=[O:37])[N:30]([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:41][CH2:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:9]1)=[O:7])(C)(C)C.[ClH:49].C(OCC)C>FC(F)(F)C(O)=O.ClCCl>[ClH:49].[CH:43]1([CH2:42][O:41][C@@H:10]2[O:11][CH2:12][C@H:13]([C@@H:14]([OH:40])[C@@H:15]([NH:25][C:26](=[O:39])/[C:27](/[CH3:38])=[CH:28]/[C:29](=[O:37])[N:30]([CH2:31][CH2:32][CH3:33])[CH2:34][CH2:35][CH3:36])[CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[N:8]([C:6]([OH:7])=[O:5])[CH2:9]2)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: CCCN(CCC)C(=O)/C=C(\C)C(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCC2CCCCC2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CCCN(CCC)C(=O)/C=C(\C)C(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCC2CCCCC2)CN1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
Dissolve (2R,5R)-2-cyclohexylmethoxy-5-[(1S,2S)-3-(3,5-difluorophenyl)-2-((E)-3-dipropylcarbamoyl-2-methylacryloylamino)-1-hydroxypropyl]-morpholine-4-carboxylic acid tert-butyl ester (0.051 g, 0.075 mmol) in trifluoroacetic acid (1.5 mL) and stir at room temperature for 15 minutes. Dilute with dichloromethane (15 mL), concentrate, dissolve in ethyl acetate (30 mL), wash with 1:1 saturated aqueous sodium chloride:saturated aqueous sodium bicarbonate (30 mL), dry (sodium sulfate) and concentrate. Dissolve the residue in ethyl acetate and add 1 M hydrogen chloride in diethyl ether (0.20 mL, 0.20 mmol) and concentrate to give the title compound (0.045 g, 97.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[C:23]([NH:33][CH3:34])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([CH3:32])=[CH:27][CH:26]=2>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:21][C:22]1[C:23]([NH:33][CH3:34])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([CH3:32])=[CH:27][CH:26]=2
Reactant: CNc1nc2ccc(C)cc2cc1CCl
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CNc1nc2ccc(C)cc2cc1Cc1c(O)nc(C)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (40 mg, 182 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 2 N aq. KOH solution (0.17 mL, 0.34 mmol) at RT followed by 3-(chloromethyl)-N,6-dimethylquinolin-2-amine hydrochloride MDE 32062 (39 mg, 152 μmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before to be extracted with EtOAc (50 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). Both organic phases were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6 to 90:10) gave 12 mg of 6,7-dimethoxy-1-methyl-4-((6-methyl-2-(methylamino)quinolin-3-yl)methyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (1.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-1-methyl-4-((6-methyl-2-(methylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 33 as a brown solid (14 mg, 19% yield).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11](Cl)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.S([O-])([O-])=O.[Na+:19].[Na+]>O>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([O-:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[Na+:19]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S([O-])c1cccc2cnccc12
Yield: 24.9 %

Procedure:
After a mixture of 5-isoquinolinesulfonyl chloride 1.58 g (7.0 mmol), sodium sulfite 880 mg (7.0 mmol) and water 10 ml was heated and refluxed for 1 hour, the reaction mixture was concentrated under reduced pressure. Ethanol was added to the resulting residue to filter off insoluble materials, and the filtrate was concentrated under reduced pressure to give sodium 5-isoquinolinesulfinate 375 mg (25.0%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[C:9]([C:20]([O:22][CH3:23])=[O:21])=[N:10][C:11]([O:18]C)=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Si](Cl)(C)(C)C>C(#N)C>[CH3:7][C:4]1[N:3]([C:8]2[C:9]([C:20]([O:22][CH3:23])=[O:21])=[N:10][C:11]([OH:18])=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: COC(=O)c1nc(OC)c(C(F)(F)F)cc1-n1c(C)ccc1C
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Product: COC(=O)c1nc(O)c(C(F)(F)F)cc1-n1c(C)ccc1C

Procedure:
Methyl 3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methoxy-5-(trifluoromethyl)picolinate (100 mg, 0.305 mmol) in acetonitrile (3.05 ml) was treated with KI (202 mg, 1.218 mmol) and TMS-Chloride (0.156 ml, 1.221 mmol) and heated at reflux for 6 hours. The solvent removed was in vacuo and the crude product was dissolved in EtOAc (20 ml) and washed with water (2×10 ml) and brine (10 ml), dried over a phase separator and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with iso-hexane: EtOAc (gradient of 0 to 30% EtOAc) afforded the title compound as an yellow powder. LC-MS Rt=1.11 mins [M+H]+ 315.4 (Method 2minLC_v003).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C.C(Cl)Cl.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[CH2:9]1.[C:25]([OH:27])([C:24]([F:29])([F:28])[F:23])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCCC(N2CCOCC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CNCC(N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Morpholin-4-yl-piperidine-1-carboxylic acid tert-butyl ester (2.70 g, 9.99 mmol) was dissolved in Methylene chloride (50.0 mL, 7.80E2 mmol) and the reaction mixture was treated with Trifluoroacetic Acid (6.0 mL, 78 mmol). The reaction was allowed to stir overnight at room temperature. The solvent was then removed en vacuo to afford the -Piperidin-3-yl-morpholine as a TFA salt. (M+H)=171.06. The crude product contained TFA which was neutralized in the next step. Crude NMR showed evidence of product formation. 1H NMR (400 MHz, DMSO, d6) δ 8.99 (m, 1H), 3.68 (m, 2H), 3.48 (m, 2H), 3.28 (m, 5H), 3.10 (m, 2H), 2.81 (m, 2H), 1.97 (m, 2H), 1.66 (m, 2H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[F:33][C:34]([F:42])([F:41])[CH2:35]CS([O-])(=O)=O>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH2:35][C:34]([F:42])([F:41])[F:33])[C:16]([C:21]([N:23]2[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:27][CH2:28]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Reactant: O=S(=O)([O-])CCC(F)(F)F
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(C)(=O)=O)CC2)n3CC(F)(F)F)CC1
Yield: 54 %

Procedure:
The title compound was synthesized in analogy to example 3, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone (example 1) and 2,2,2-trifluoroethyl-methanesulfonate to afford the desired product as a colorless foam (54%). MS (ISP): 544.3 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:10])[C@@H:3]([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)[OH:4].N[C@@H](C)[C@H:13](C1SC=CN=1)[OH:14].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:10][C@H:2]1[C@@H:3]([C:5]2[S:6][CH:7]=[CH:8][N:9]=2)[O:4][C:13](=[O:14])[NH:1]1
Reactant: C[C@H](N)[C@@H](O)c1nccs1
Reactant: C[C@H](N)[C@H](O)c1nccs1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: C[C@@H]1NC(=O)O[C@@H]1c1nccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13 %

Procedure:
To a mixture of (1S,2S)-2-amino-1-thiazol-2-yl-propan-1-ol and (1R,2S)-2-amino-1-thiazol-2-yl-propan-1-ol (2.9 g, 12.5 mmol) in CH2Cl2 (40 mL) was added under argon NEt3 (10.5 mL, 75 mmol) at 0° C. Then, triphosgene (1.86 g, 6.27 mmol) dissolved in 40 mL of CH2Cl2 was added slowly, and the temperature was allowed to warm from 0° C. to room temperature. The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was then quenched by addition of aqueous NaHCO3. The organic layers were separated, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography using EtOAc in heptane from 0% to 100% in order to give the desired product (330 mg, 13%). LC-MS: [M+H] 185.0; Rt 0.48 min; (LCMS method 1). 1H NMR (400 MHz, CHCl3-d): 7.79 (d, 1H), 7.34 (d, 1H), 5.91 (d, 1H), 5.71 (br s, 1H), 4.48-4.38 (m, 1H), 0.89 (d, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=2[OH:18])=[CH:5][CH:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[CH2:27]([O:18][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:8]=1[CH2:7][C:6]1[CH:19]=[CH:20][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)[C:12]([O:14][CH3:15])=[O:13])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CCc1ccc(Cc2ccc(C(=O)OC)cc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(Cc2ccc(C(=O)OC)cc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution methyl 4-(4-ethylbenzyl)-3-hydroxybenzoate (1.28 g) in N,N-dimethylformamide (14 mL) were added potassium carbonate (0.98 g) and benzyl bromide (0.62 mL), and the mixture was stirred at room temperature for 19 hours. The reaction mixture was poured into water, and the mixture was extracted twice with diethyl ether. The combined organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give methyl 3-benzyloxy-4-(4-ethylbenzyl)benzoate (1.6 g).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[C:5]2=[N:13][NH:14][C:15](=[O:16])[N:4]2[CH:3]=1.[C:17]([O:21][C:22](=[O:36])[NH:23][CH2:24]/[CH:25]=[CH:26]/B1OC(C)(C)C(C)(C)O1)([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>[C:17]([O:21][C:22](=[O:36])[NH:23][CH2:24]/[CH:25]=[CH:26]/[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[C:5]2=[N:13][NH:14][C:15](=[O:16])[N:4]2[CH:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: O=c1[nH]nc2c3cc(Cl)ccc3c(Br)cn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC/C=C/c1cn2c(=O)[nH]nc2c2cc(Cl)ccc12
Temperature: 100 °C
Reaction time: 18 h

Procedure:
6-bromo-9-chloro[1,2,4]triazolo[3,4-a]isoquinolin-3(2H)-one (3-9) (60 mg, 0.201 mmol, 1.0 equiv.) and tert-butyl[(2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]carbamate (3-3) (228 mg, 0.804 mmol, 4.0 equiv.) were dissolved in anhydrous 1,4-dioxane (0.6 ml) and 2 M K2CO3 aqueous solution (0.2 mL). The reaction mixture was heated to 100° C. LCMS at 18 hours showed complete conversion. Purification with reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA) afforded the title product 3-10. LRMS m/z (M+H) 375.1 found, 375.1 required.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([OH:10])=O)[N:3]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[NH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]([C:8]([NH:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccncc1
Reactant: O=C(O)c1cccc(Br)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccncc1)c1cccc(Br)n1
Reaction time: 2 h
Yield: 72.5 %

Procedure:
2-Bromopyridine-6-carboxylic acid (5.00 g, 24.8 mmol) was dissolved in DCM (100 mL) and DMF (1 mL), and oxalyl chloride (7.54 g, 59.4 mmol) was added dropwise over 5 min. The reaction mixture was stirred for 2 h and the solvents were removed in vacuo. The reaction mixture was azeotroped twice with DCM and dissolved in DCM (100 mL). DIPEA (12.8 g, 99.0 mmol) and 4-aminopyridine (4.66 g, 49.5 mmol) were added dropwise and the reaction mixture was stirred for 2 h, washed with sat aq NaHCO3 (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was recrystallised from MeOH to give the title compound (5.00 g, 73%) as an off white solid. LCMS (ES+): 278.2 [MH]+.
Reaction SMILES: C1CCCC([O:7][C:8]2[CH:17]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[C:15]([Cl:22])=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])C=1.CCN([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)CC>C(OC(=O)C)C.CCCCCC>[CH2:30]([C:17]1[C:16]([NH:18][C:19](=[O:21])[CH3:20])=[C:15]([Cl:22])[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]=1[OH:7])[CH2:29][CH:28]=[CH:33][CH2:32][CH3:31]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC1C=CCCC1
Reactant: CCN(CC)c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCC=CCCc1c(O)c(C(=O)OC)cc(Cl)c1NC(C)=O
Temperature: 220 °C

Procedure:
A mixture of 0.6 g of methyl 2-(cyclohexen-3-yloxy)-4-acetylamino-5-chlorobenzoate and 0.5 ml diethylaniline is placed under house vaccum and heated to 220° C. for 2 hours. This reaction mixture is then diluted with 40% ethylacetate/hexane and purified by dry column chromatography using the same solvent system as eluent. Three fractions are separated: 1. diethylaniline; 2. starting benzoate compound and 3. methyl 3-(3-hexenyl)-4-acetylamino-5-chlorosalicylate. The latter is used directly in the next step.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][CH2:19][C:20]3[S:24][C:23]([C:25](=[NH:27])[NH2:26])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[OH-].[Na+]>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][CH2:19][C:20]3[S:24][C:23]([C:25](=[NH:26])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)s1)n2C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CCc2ccc(C(=N)N)s2)nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc21

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution.
Reaction SMILES: [NH2:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:3]([NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([CH2:43][C:44](Cl)=[O:45])=[CH:35]1>ClCCl.C(OCC)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11]([NH:10][CH:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:2]([NH:1][C:44](=[O:45])[CH2:43][C:36]2[C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[NH:34][CH:35]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:12])=[CH:15][CH:16]=1
Reactant: NC(c1ccccc1)C(NC(=O)Nc1ccc(Cl)cc1)c1ccccc1
Reactant: O=C(Cl)Cc1c[nH]c2ccccc12
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(Cc1c[nH]c2ccccc12)NC(c1ccccc1)C(NC(=O)Nc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.4 %

Procedure:
To a solution of [S-(R*,R*)] and [R-(R*,R*)]-N-(2-amino-1,2-diphenylethyl)-N'-(4-chlorophenyl)urea (0.1 g, 0.27 mmol) in dichloromethane (5 mL) is added triethyl amine (0.03 g, 0.27 mmol) followed by indole-3-acetic acid chloride (0.05 g, 0.27 mmol). The mixture is stirred 1.5 hours at room temperature before diluting with diethyl ether and washing with aqueous 2M HCl, aqueous 1M NaOH, saturated aqueous NaCl, and drying (MgSO4). Filtration and concentration gives an oil which is purified by flash chromatography (SiO2, EtOAc/hexane eluent) to provide 0.05 g (33%) of desired product, mp 224°-227° C. IR (KBr): 3360, 1549, 1492, 1226, 698 cm-1 ; NMR (DMSO-d6): 3.56 (s, 2H), 5.07 (m, 2H), 6.78-7.45 (m, 20H), 8.65 (m, 2H), 10.81 (s, 1H). Analysis calculated for C31H27ClN4O2.0.5H2O: C, 69.98; H, 5.30; N, 10.53. Found: C, 69.65; H, 5.41; N, 10.56.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][NH:3][C:2]1=[O:11].[OH:12][CH:13]([CH:16]1[O:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1)[CH2:14]Br.C(N(CC)CC)C.[ClH:33]>CO.C(OCC)C.O.CN(C)C=O>[ClH:33].[O:21]1[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]1[CH:13]([OH:12])[CH2:14][N:8]1[CH2:7][CH2:6][C:5]2([O:1][C:2](=[O:11])[NH:3][CH2:4]2)[CH2:10][CH2:9]1
Reactant: O=C1NCC2(CCNCC2)O1
Reactant: OC(CBr)C1COc2ccccc2O1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C1NCC2(CCN(CC(O)C3COc4ccccc4O3)CC2)O1
Reaction time: 0.17 h

Procedure:
A mixture of 1.7 g 1-oxa-3,8-diazaspiro[4.5]decan-2-one, 2 g 2-(1-hydroxy-2-bromoethyl)-1,4-benzodioxane [J. Med. Chem., 13, 169 (1970)], 3 ml triethylamine and 5 ml N,N-dimethylformamide is heated at 90° for 18 hours. The mixture is poured into 100 ml water and the resulting mixture stirred for 10 minutes. The stirring is stopped and the aqueous layer decanted. The crude product is filtered through 20 g silica gel with 10% methanol-methylene chloride. Evaporation of the filtrate gives a residue which is taken up in 10 ml methanol. To this solution is added 10 ml of a 3% solution of hydrochloric acid in methanol. Addition of 200 ml of diethyl ether affords a precipitate which is collected by filtration, yielding 1.1 g (mixed erythro and threo) 8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one hydrochloride, mp 235°-247° (d).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[CH:16]=[CH:15][C:14]=1[S:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[Cl:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][O:19][C:17]1[CH:16]=[CH:15][C:14]([S:28][C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)=[C:13]([NH:12][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:18]=1
Reactant: Nc1cc(OCc2cccc(Cl)c2)ccc1Sc1ccc(O)cc1
Reactant: Clc1ccnc2ncccc12
Product: Oc1ccc(Sc2ccc(OCc3cccc(Cl)c3)cc2Nc2ccnc3ncccc23)cc1

Procedure:
The product from Example 16c (50 mg, 0.30 mmol) was reacted with the product from Example 144a (107 mg, 0.30 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (109 mg, 60%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3 H) 5.16 (s, 2 H) 6.25 (d, J=6.98 Hz, 1 H) 6.66 (d, J=8.83 Hz, 2 H) 7.07-7.25 (m, J=8.46 Hz, 5 H) 7.38-7.53 (m, 3 H) 7.80 (d, J=8.45 Hz, 1 H) 8.40 (d, J=6.99 Hz, 1 H) 8.99 (d, J=8.83 HZ, 1 H) 9.79 (s,1 H) 11.02 (br s,1H) 14.38 (br s,1 H); MS (ESI+) m/z 500 (M+H−TFA)+; (ESI−) m/z 498 (M−H−TFA)−.