Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].C(N(CC)CC)C.[CH3:18][O:19][C:20]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:21]=1[CH2:22][N:23]=[C:24]=[O:25]>C(Cl)(Cl)Cl>[CH3:18][O:19][C:20]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:21]=1[CH2:22][NH:23][C:24]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:10])[CH:7]([CH3:9])[CH3:8])=[O:25]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: COc1ccc(CN=C=O)c(OC)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H](NC(=O)NCc1ccc(OC)cc1OC)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
To a solution of L-valine methyl ester hydrochloride (2.6 g) and triethylamine (1.6 g) in chloroform (30 mL) was added 2,4-dimethoxybenzyl isocyanate (3.0 g), and the mixture was stirred at room temperature overnight. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate) to afford methyl N-[(2,4-dimethoxybenzyl)carbamoyl]-L-valinate (4.2 g).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:4]1.[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CO>[C:12]1([C:5]2[C:6]3[C:11](=[N:10][CH:9]=[CH:8][CH:7]=3)[NH:3][CH:4]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: C1=C(c2c[nH]c3ncccc23)CCCC1
Temperature: 0 °C
Yield: 76.2 %

Procedure:
Methanol (150 mL) was added dropwise to a chilled (0° C.) 1 L flask containing sodium hydride (60% dispersion in mineral oil, 19.3 g, 480 mmol). To the stirred suspension was added 7-azaindole (10.2 g, 86 mmol) in MeOH (100 mL) and cyclohexanone (35 mL, 340 mmol) in MeOH (65 mL). The cloudy solution was refluxed for 24 h, then the solvent was removed under reduced pressure. The oily residue was cooled in an ice bath and 3 N HCl was added with vigorous stirring until the pH=8 (pH paper). The resulting yellow ppt. was collected by filtration, washed with H2O, triturated with tBME/C6H14 (1:1, 50 mL), and dried by toluene azeotrope to give the title compound as a white solid (13.0 g, 76% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.66-1.78 (m, 2H) 1.78-1.91 (m, 2H) 2.20-2.35 (m, 2H) 2.47 (d, J=1.76 Hz, 2H) 6.28 (d, J=3.78 Hz, 1H) 7.10 (dd, J=8.06, 4.78 Hz, 1H) 7.34 (s, 1H) 8.25 (dd, J=8.06, 1.26 Hz, 1H) 8.33 (dd, J=4.66, 1.39 Hz, 1H) 11.8 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ ppm 22.43, 22.98, 25.65, 27.88, 115.52, 117.31, 118.32, 121.57, 122.16, 129.39, 131.07, 141.99, 149.53.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]2[CH2:14][CH2:13][N:12]([C:15](=O)[CH2:16][O:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:32])=O.C(OCC)(=O)C>O1CCCC1.O>[CH:26]1[CH:25]=[CH:24][C:23]([C@@H:8]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:11][CH2:10]2)[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:28][CH:27]=1.[ClH:32].[ClH:1]
Reactant: O=C(O)COCC(=O)N1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cl
Product: O=C(O)COCCN1CCN([C@H](c2ccccc2)c2ccc(Cl)cc2)CC1
Temperature: 60 °C

Procedure:
1 g of product of R-2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl-2-oxoethoxy)acetic acid was dissolved in 10 ml of dry tetrahydrofurane at 0° C. During intensive stirring 0.23 ml of oxalylchloride was added dropwise. After half an hour when the conversion of acid to acid chloride was completed 0.8 ml of dimethylsulphide borane complex (10 M calculated on BH3) was added in three portion. After the reaction was completed, the reaction mixture was poured in water (250 ml) and additionally stirred for half an hour. To the suspension 100 ml of ethyl acetate was added, pH was adjusted to 10 and the phases were separated. To the water phase 100 ml of methylene chloride was added, pH was adjusted with concentrated hydrochloric acid to 4.2 and phases were separated: the organic layer was rinsed with water, dried with sodium sulphate and evaporated to dryness. The oil residue was dissolved in 30 ml of acetone and HCl gas was introduced until pH reached the value of less than 1. The reaction mixture was heated to 60° C. and refluxed for 20 minutes. It was cooled to 30-35° C. and then filtered and the cake was washed with 20 ml of acetone. Then it was dried at 50-55° C. under reduced pressure (−0.08˜−0.1 MPa) for 8 hours. 720 mg of levocetirizine dihydrochloride were obtained.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([C:26]3[CH2:27][CH2:28][O:29][CH2:30][CH:31]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[C:35]([F:43])[CH:34]=1>C(OCC)C>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:41])([F:42])[F:40])=[C:35]([F:43])[CH:34]=3)[OH:25])=[C:11]([C:26]3[CH2:27][CH2:28][O:29][CH2:30][CH:31]=3)[C:10]1=2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)c1nc2c(c(C3=CCOCC3)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: Fc1cc(Br)ccc1C(F)(F)F
Solvent: CCOCC
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@@H](O)c1ccc(C(F)(F)F)c(F)c1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-(3,6-dihydro-2H-pyran-4-yl)-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 4-bromo-2-fluoro-1-(trifluoromethyl)benzene. Diethylether is used instead of toluene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[C:18](O)=[N:19][CH:20]=[N:21][CH:22]=4)=[C:11]3[O:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:18]1[C:17]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:9][O:10][C:11]=23)=[CH:22][N:21]=[CH:20][N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncncc1-c1ccnc2c(-c3ccc(F)cc3)noc12
Product: Fc1ccc(-c2noc3c(-c4cncnc4Cl)ccnc23)cc1
Temperature: 90 °C
Yield: 100.6 %

Procedure:
A suspension of 5-(3-(4-fluorophenyl)isoxazolo[4,5-b]pyridin-7-yl) pyrimidin-4-ol (45 mg, 0.146 mmol) in phosphorus oxychloride (503 μl, 5.40 mmol) was heated at 90° C. for 1 h, then allowed to cool to room temperature. The solvent was evaporated to afford the title compound (48 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH:47]([C:52]1[N:53]=[N:54][C:55]([Cl:58])=[CH:56][CH:57]=1)C(OC)=O.CO.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:58][C:55]1[N:54]=[N:53][C:52]([CH2:47][C:3]2[CH:4]=[C:5]([C@H:8]3[C@H:13]([O:14][CH2:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C@@H:12]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:11]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[O:9]3)[CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:57][CH:56]=1
Reactant: COC(=O)C(c1ccc(Cl)nn1)c1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Clc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To a solution of Methyl 2-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)phenyl)-2-(6-chloropyridazin-3-yl)acetate (compound 23, 9.9 g, 12 mmol) from Step 1 in terahydrofuran (40 mL) was added methanol (56 mL) and lithium hydroxide solution (0.1 M in water, 180 mL, 180 mmol). The reaction mixture was allowed to stir at room temperature overnight. After cooling to 0° C., hydrochloric acid (1.0 M) was added to neutralize the reaction mixture. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was slurried in methanol (100 mL) and the slurry was stirred at ambient temperature for 2 h. The resulting solid was isolated by filtration and dried in vacuo to yield the title compound (7.8 g, 10 mmol, 86%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:16][CH3:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].Cl.Cl[C:32]([O:34][CH3:35])=[O:33]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH2:15][N:16]([C:32]([O:34][CH3:35])=[O:33])[CH3:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)c1c(CNC)c2ccccc2n1Cc1cccc2ccc(F)cc12
Agent: Cl
Product: CCOC(=O)c1c(CN(C)C(=O)OC)c2ccccc2n1Cc1cccc2ccc(F)cc12

Procedure:
1-(7-Fluoro-naphthalen-1-ylmethyl)-3-methylaminomethyl-1H-indole-2-carboxylic acid ethyl ester; salt with HCl was reacted with methyl chloroformate as described in Example 77.1. to give 1-(7-fluoro-naphthalen-1-ylmethyl)-3-[(methoxycarbonyl-methyl-amino)-methyl]-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give 1-(7-fluoro-naphthalen-1-ylmethyl)-3-[(methoxycarbonyl-methyl-amino)-methyl]-1H-indole-2-carboxylic acid as a white solid. MS: 419.5 ([M−H]−).
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:13]([O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCCCCCCCCCO
Reactant: BrCc1ccccc1
Solvent: ClCCl
Product: OCCCCCCCCCCOCc1ccccc1
Yield: 65 %

Procedure:
To a stirred suspension of decane-1,10-diol (3 g, 17.21 mmol), benzyl bromide (2.25 ml, 18.94 mmol) and Ag2O (5.98 g, 25.82 mmol) in dry DCM (50 ml) were added, the reaction mixture was refluxed overnight, then the Ag2O was filtered off. The crude product was purified by silica gel column (10% EtOAc in Hexane) to afford 10-(benzyloxy)decan-1-ol as a gummy colorless liquid (2.96 g, 65%).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[S:13][C:14]1[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:15]=1[N+:22]([O-:24])=[O:23].[CH3:25][NH2:26]>C1(C)C=CC=CC=1.O1CCOCC1>[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[S:13][C:14]1[S:18][C:17]([C:19]([NH:26][CH3:25])=[O:20])=[CH:16][C:15]=1[N+:22]([O-:24])=[O:23]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2cccc(Cl)c2Cl)s1
Reactant: CN
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1cc([N+](=O)[O-])c(Sc2cccc(Cl)c2Cl)s1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
Thionyl chloride (0.102 g, 0.86 mmol) was added to a suspension of 5-(2,3-dichlorophenylsulfanyl)-4-nitrothiophene-2-carboxylic acid (0.15 g, 0.43 mmol) in toluene (5 mL) and the stirred mixture was heated at 80° C. for 1 hour. TLC analysis showed no acid remaining so the mixture was allowed to cool to ambient temperature and then concentrated in vacuo to give the dark brown viscous oil. The oil was dissolved in 1,4-dioxane (1 mL) and added at 5° C. to stirred 40% aqueous methylamine solution (5 mL). The mixture was stirred for 15 minutes then the resulting solid was collected by filtration, washed with water (3×1 mL) and dried in vacuo at 40° C. overnight to afford the title product as a beige solid (55 mg, 35% yield). 1H NMR (CDCl3) δ: 7.84 (1H, s) 7.70 (2H, m), 7.36 (1H, m), 6.01 (1H, broad s), 2.95 (3H, d, J=4.9 Hz).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][C:39]([NH2:41])=[O:40]>CN(C=O)C.C(OCC)(=O)C.CO>[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[C:17]4[CH:20]=[CH:21][C:22]([CH:24]5[CH2:29][CH2:28][N:27]([CH2:38][C:39]([NH2:41])=[O:40])[CH2:26][CH2:25]5)=[CH:23][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Reactant: NC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCN(CC(N)=O)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.5 %

Procedure:
A mixture of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (120 mg, 0.28 mmol) in DMF (1.5 mL) was treated with potassium carbonate (97 mg, 0.7 mmol) followed by bromo acetamide (43 mg, 0.336 mmol) and stirred at RT for 18 h. The reaction mixture was diluted with ethyl acetate/methanol and washed with water, the organic layer dried (Na2SO4), filtered and concentrated in vacuo. The resultant solid residue was recrystallised from methanol to give 250 as a white solid (51 mg, 41%). 1H NMR δ (ppm)(DMSO-d6): 8.27 (1 H, d, J=8.28 Hz), 7.81 (1 H, s), 7.16 (1 H, s), 7.07 (1 H, s), 7.01 (1 H, dd, J=8.36, 1.78 Hz), 6.87 (1 H, d, J=1.72 Hz), 5.81-5.73 (1 H, m), 4.45-4.41 (4 H, m), 2.89-2.82 (2 H, m), 2.83 (2 H, s), 2.20 (3 H, s), 2.16-2.07 (2 H, m), 1.72-1.66 (4 H, m), 1.40 (6 H, d, J=6.61 Hz). 1 Proton obscured by solvent peak. LCMS: RT=2.97 [M+H]+=450
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[N:24]=[CH:23][NH:22][C:21](=[O:25])[N:20]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.CC1C=CC(S(O[CH2:37][C:38]2[S:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[N:24]=[CH:23][N:22]([CH2:37][C:38]4[S:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=4)[C:21](=[O:25])[N:20]=3)[CH2:17][CH2:18]2)=[CH:9][CH:8]=1
Reactant: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)nc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCc2ccc(C(F)(F)F)s2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)ncn1Cc1ccc(C(F)(F)F)s1
Reaction time: 2 h
Yield: 11.9 %

Procedure:
To an N,N-dimethylformamide solution (1 mL) of 4-[4-(4-fluorophenyl)piperazin-1-yl]-1,3,5-triazin-2(1H)-one (50.0 mg, 0.18 mmol) synthesized in Reference Synthesis Example 3, [5-(trifluoromethyl)thiophen-2-yl]methyl 4-methylbenzenesulfonate (121 mg, 0.36 mmol) synthesized in Reference Synthesis Example 51 and potassium carbonate (99 mg, 0.72 mmol) were added and the resultant mixture was stirred at 80° C. for 2 hours. To the reaction solution, [5-(trifluoromethyl)thiophen-2-yl]methyl 4-methylbenzenesulfonate (500 mg, 0.48 mmol) was added and the resultant reaction solution was stirred further for 2 hours. After the completion of the reaction, water was added to the reaction solution and extraction with ethyl acetate from the resultant reaction solution was performed three times. The organic layer was washed with brine, was dried over anhydrous magnesium sulfate, and was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain the title compound (9.4 mg, yield: 12%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:35])[C:5]([CH3:34])=[C:6]([CH2:12][C:13]2[C:14]([O:30]C(=O)C)=[C:15]([CH:27]=[CH:28][CH:29]=2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:35])[C:5]([CH3:34])=[C:6]([CH2:12][C:13]2[C:14]([OH:30])=[C:15]([CH:27]=[CH:28][CH:29]=2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(Cl)cc3Cl)c2OC(C)=O)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(Cl)cc3Cl)c2O)=C(C)C1=O
Yield: 50.7 %

Procedure:
N-[3-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-2,4-dichloroaniline (0.075 g, 0.145 mmol) was dissolved in methanol (2 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (1.5 ml), the solution was stirred at room temperature for 2 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.035 g, 0.0735 mmol, 51%).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:19](/B(O)O)=[CH:20]\[CH2:21][CH2:22][CH2:23][CH3:24].[ClH:28]>CCOCC>[ClH:28].[CH2:15]([N:14]([CH2:17][CH3:18])[CH2:13][CH2:12][NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2](/[CH:19]=[CH:20]/[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:3][N:4]=2)[N:7]=1)[CH3:16]
Reactant: CCCC/C=C/B(O)O
Reactant: CCN(CC)CCNc1ccc2ncc(Br)n2n1
Agent: Cl
Solvent: CCOCC
Product: CCCC/C=C/c1cnc2ccc(NCCN(CC)CC)nn12
Yield: 59 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2. The free-base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (74 mg, 59%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 7.74 (d, J=9.6 Hz, 1H), 7.62 (s, 1H), 6.85 (d, J=9.6 Hz, 1H), 6.71-6.62 (m, 2H), 3.83 (t, J=6.3 Hz, 2H), 3.51 (t, J=6.4 Hz, 2H), 3.34 (q, J=7.0 Hz, 4H), 2.32-2.39 (m, 2H), 1.54-1.48 (m, 2H), 1.46-1.40 (m, 2H), 1.38-1.34 (t, J=7.3 Hz, 6H), 0.96 (t , J=7.3 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 155.7, 136.6, 135.3, 129.5, 125.7, 125.1, 115.8, 115.4, 51.0, 37.6, 34.4, 32.7, 23.4, 14.3, 9.2 (one signal overlapping with solvent); HPLC tR=9.3 min (Luna), 96.7%; ES-MS: (M+H)=316 m/z.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][CH:10]=[CH:11][C:12]3[NH:13][C:14]4[CH2:15][N:16](C(OCC5C=CC=CC=5)=O)[CH2:17][C:5]([C:6]=4[C:7]=32)=[N:4][NH:3]1.[H][H]>CO.[Pd]>[CH2:17]1[NH:16][CH2:15][C:14]2[NH:13][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:2](=[O:1])[NH:3][N:4]=[C:5]1[C:6]=2[C:7]=34
Reactant: O=C1NN=C2CN(C(=O)OCc3ccccc3)Cc3[nH]c4cccc1c4c32
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1NN=C2CNCc3[nH]c4cccc1c4c32

Procedure:
A mixture of Compound 20 (34 mg, 0.1 mmol) and palladium (10%) on carbon (10 mg) in 10 mL of methanol was stirred at RT under a balloon of hydrogen for 5 h. The mixture was then filtered through a pad of celite. The catalyst cake was washed with methanol. The filtrate was concentrated. The resulting residue was purified by HPLC to give the target product as formic acid salt (white solid) (13 mg, 50%). 1H NMR (DMSO-d6) δ 11.7 (s, 1H), 9.86 (s, 1H), 7.40-7.45 (m, 2H), 7.09 (t, 1H, J=8.0 Hz), 3.94 (s, 2H), 3.41 (s, 2H). MS (ESI) m/e [M+1]+ 227.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH2:33])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:14]=2[CH:32]=1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH:33][S:42]([C:39]2[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=2)(=[O:44])=[O:43])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:14]=2[CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccc(OC)cc1
Product: COC(=O)CCCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(Cl)cc1)nc(-c1ccccc1)n2-c1ccc(OC)cc1

Procedure:
6-[(5-Amino-1-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:24][PH:25]([O-])([O-:29])[O:26][CH2:27][CH3:28].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C@H:8]([NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[C:5]1[CH:6]=[CH:7][C:2]([P:25]([CH3:24])(=[O:29])[O:26][CH2:27][CH3:28])=[CH:3][CH:4]=1
Reactant: CC(C)(C)[S@@](=O)N[C@H](c1ccc(Br)cc1)c1ccc(F)cc1F
Reactant: CCO[PH](C)([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc([C@@H](N[S@](=O)C(C)(C)C)c2ccc(F)cc2F)cc1
Reaction time: 8 h
Yield: 81 %

Procedure:
To (R)—N—((R)-(4-bromophenyl)(2,4-difluorophenyl)methyl)-2-methylpropane-2-sulfinamide, 20-c, (1 g, 2.5 mmol), ethyl methylphosphite (0.54 g, 5 mmol) and Et3N (0.63 g, 6.25 mmol) in THF (10 ml) was added PdCl2(dppf) (183 mg). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into ethyl acetate and washed with brine. The organic layer was concentrated under vacuum and the residue was purified over silica gel to give compound, 20-d, (dichloromethane:methanol=50/1) to provide the product (866 mg, 81%).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[CH2:9]([C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:2].[CH2:9]([C:11]1[CH:12]=[C:13]([N:14]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:15]=[CH:16][CH:17]=1)[CH3:10]
Reactant: CCc1cccc(N)c1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCc1cccc(N2CCNCC2)c1
Reaction time: 16 h
Yield: 70.5 %

Procedure:
A solution of 73.3 g (0.411 mol) of bis(2-chloroethyl)amine hydrochloride and 49.7 g (0.411 mol) of 3-ethylaniline in 500 mL of absolute ethanol was heated at reflux for 16 h under a nitrogen atmosphere. The mixture was cooled and 85.2 g (0.617 mol) of anhydrous potassium carbonate was added and heating was continued for 16 h. The hot mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was triturated with ethyl acetate to yield 65.7 g (71%) of solid. A portion of this crude product was recrystallized from 2-propanol to yield a white crystalline solid, mp 194°-195° C.