Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([O:9][C:10](=[O:59])[C@H:11]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[CH:50][CH:49]=1)[NH:12][C:13]([C:15]1([CH2:20][C@H:21]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:22][NH:23][C:24](=[O:39])[C@H:25]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[NH2:26])[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])([CH3:8])([CH3:7])[CH3:6].[CH:60](=O)[CH3:61].Cl>C(O)C>[C:5]([O:9][C:10](=[O:59])[C@H:11]([CH2:47][C:48]1[CH:49]=[CH:50][C:51]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[CH:52][CH:53]=1)[NH:12][C:13]([C:15]1([CH2:20][C@H:21]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:22][NH:23][C:24](=[O:39])[C@H:25]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[NH:26][CH2:60][CH3:61])[CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:14])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)NC[C@H](CC1(C(=O)N[C@@H](Cc2ccc(OC(C)(C)C)cc2)C(=O)OC(C)(C)C)CCCC1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCN[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)NC[C@H](CC1(C(=O)N[C@@H](Cc2ccc(OC(C)(C)C)cc2)C(=O)OC(C)(C)C)CCCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.4 %

Procedure:
Sodium cyanoborohydride (45 mg) was added in one portion to a stirred, ice cold solution of N-{1-[2-(S)-t-butyloxycarbonyl-3(N6 -t-butyloxycarbonyl-(S)-lysylamino)propyl]-1-cyclopentanecarbonyl}O-t-butyl-(S)-tyrosine-t-butyl ester (507 mg) and acetaldehyde (31 mg) in aqueous ethanol (80%, 10 ml) and the pH adjusted to 5 with 1N hydrochloric acid. The resulting solution was allowed to warm to room temperature and stirred for 1.5 hours. The reaction mixture was evaporated to dryness and the residue partitioned between water and ethyl acetate. The phases were separated and the organic phase washed with a little aqueous sodium bicarbonate, dried (MgSO4), filtered and evaporated. The residue was chromatographed over silica gel, eluting with mixtures of hexane and ethyl acetate containing 1% diethylamine to yield the title compound as an oil (370 mg, 64%) Rf 0.55 (silica; CH2Cl2, CH3OH, NH4OH; 90:10:1).
Reaction SMILES: [OH-].[Na+].O.C[O:5][C:6](=[O:42])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:38][CH3:39])([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:25]([CH3:37])[CH:24]=3)[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:40])=[CH:10][C:9]=1[Cl:41].Cl>CO>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][C:6]([OH:42])=[O:5])=[C:9]([Cl:41])[CH:10]=2)=[C:15]([CH3:40])[CH:16]=1)([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:34])([CH3:35])[CH3:33])=[C:25]([CH3:37])[CH:24]=1)[CH2:38][CH3:39])[CH3:22]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(Cl)c2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)O)c(Cl)c2)c(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 9.8 %

Procedure:
A mixed solution of a 6 N sodium hydroxide aqueous solution (0.009 mL) with water (0.027 mL) was added to a solution of (4′-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-3-chloro-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 61-(2); 2.3 mg, 0.042 mmol) in methanol (0.08 mL) at room temperature, and the mixture was stirred at room temperature for six hours. The mixture was acidified with dilute hydrochloric acid aqueous solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (2.2 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH:10]([F:12])[F:11])[C:3]=1[C@H:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([C:24]3[CH:25]=[N:26][N:27]([CH:30]4[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]4)[C:28]=3[CH3:29])[CH:22]=2)[NH:17][CH:16]=1)[CH3:14].C[O:38][C:39]([C@H:41]1[NH:45][CH2:44][CH2:43][CH2:42]1)=[O:40].Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCCl.C(N(CC)CC)C.O.[OH-].[Li+].CO>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH:10]([F:11])[F:12])[C:3]=1[C@H:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([C:24]3[CH:25]=[N:26][N:27]([C@H:30]4[CH2:31][CH2:32][C@H:33]([N:45]5[CH2:44][CH2:43][CH2:42][C@H:41]5[C:39]([OH:40])=[O:38])[CH2:34][CH2:35]4)[C:28]=3[CH3:29])[CH:22]=2)[NH:17][CH:16]=1)[CH3:14]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: Cc1c(-c2cnc3[nH]cc([C@H](C)c4c(OC(F)F)ccc(F)c4Cl)c3c2)cnn1C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: Cc1c(-c2cnc3[nH]cc([C@H](C)c4c(OC(F)F)ccc(F)c4Cl)c3c2)cnn1[C@H]1CC[C@H](N2CCC[C@H]2C(=O)O)CC1
Temperature: 50 °C

Procedure:
To a mixture of 4-[4-(3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methyl-1H-pyrazol-1-yl]cyclohexanone (20.0 mg, 0.0387 mmol), H-L-PRO-OME HCl (64.08 mg, 0.3869 mmol), sodium triacetoxyborohydride (32.80 mg, 0.1548 mmol) and 1,2-dichloroethane (5 mL, 70 mmol) was added triethylamine (39.15 mg, 0.3869 mmol), and the reaction was heated to 50° C. overnight. The material was partitioned between DCM and water, and the organic layer was concentrated in vacuo. Lithium hydroxide monohydrate (8.118 mg, 0.1934 mmol) and MeOH (3 mL, 60 mmol) were added, and the mixture was heated to 50° C. for 3 h. The solution was concentrated in vacuo, and the crude product was redissolved in minimal DMF. The solution was purified via HPLC, and the fractions containing the separate cis and trans products were concentrated in vacuo to afford the title compound as white solid. 1H NMR (400 MHz, CD3OD): δ=1.74-1.83 (m, 2H), 1.84 (d, J=7.3 Hz, 3H), 1.91 (ddd, J=17.1, 6.6, 3.8 Hz, 1H), 1.97-2.14 (m, 5H), 2.18-2.27 (m, 5H), 2.27-2.45 (m, 2H), 3.21-3.29 (m, 1H), 3.33-3.42 (m, 1H), 3.67-3.79 (m, 1H), 4.08 (dd, J=9.7, 4.2 Hz, 1H), 4.22-4.32 (m, 1H), 5.11 (q, J=7.2 Hz, 1H), 6.44 (br. s., 1H), 7.12 (dd, J=8.5, 4.2 Hz, 1H), 7.19 (t, J=8.6 Hz, 1H), 7.37 (d, J=1.8 Hz, 1H), 7.40 (d, J=1.0 Hz, 1H), 7.49 (s, 1H), 8.13 (br. s., 1H). MS (ES+): m/z=616.22/618.20 (100/50) [MH+]. HPLC: tR=1.06 min (polar—2 min, UPLC-ACQUITY).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:16][C:17](=[O:19])[CH3:18])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-])=O.[Cl-].[NH4+]>C1COCC1.O.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:16][C:17](=[O:19])[CH3:18])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1
Reactant: CC(=O)Nc1cc(-c2ccccc2)cc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cc(N)cc(-c2ccccc2)c1
Temperature: 45 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of N-(5-nitrobiphenyl-3-yl)acetamide (1.2 g, 4.68 mmol) in THF (10 ml) were added a solution of ammonium chloride (2 g, 37.4 mmol, 8 eq.) in water (2 ml) and zinc (2.36 g, 37.4 mmol, 8 eq.). The mixture was stirred at 45° C. for 2 h and filtered. The filtrate was diluted with water and extracted as in Example 1(d). The solvent was distilled off to afford the product in 94% yield (1 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[C:14]1([CH3:23])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:12][C:3]1[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:10]=[CH:11][C:2]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH3:23]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Br)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)O)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
A suspension of methyl 4-bromo-3-methoxybenzoate (Combi-blocks CA-4192; 2.5 g; 10.2 mmol; 1 eq.), o-tolylboronic acid (Aldrich 393606; 1.53 g; 11.2 mmol; 1.1 eq.), potassium carbonate (7.05 g; 51 mmol; 5 eq.) and Pd(PPh3)4 (1.18 g; 1.02 mmol; 0.1 eq.) in toluene (12.5 mL) and water (12.5 mL) was refluxed for 2 hours. The reaction mixture was cooled down to room temperature and filtered through a pad of CELITE which was further washed with toluene (200 mL). The filtrate was concentrated in vacuo and the residue taken up in Ethyl acetate (500 mL). The organic layer was washed with sat. aq. NaHCO3 (150 mL), water (150 mL) and brine (150 mL) then dried over magnesium sulfate and concentrated in vacuo. The residue (2.5 g; 9.75 mmol; 1 eq.) was taken up in EtOH (75 mL), sodium hydroxide (5M; 5.85 mL; 29.3 mmol; 3 eq.) was added and the reaction mixture was stirred at 60° C. for two hours. After concentration in vacuo, the residue was taken up in water (400 mL) and the aqueous phase was washed with Ethyl acetate then acidified to pH 2 with cone. HCl. The solution was concentrated to ca. 80 mL and the precipitate filtered off and dried to afford the title compound (1.95 g, 79%) as a beige solid.
Reaction SMILES: [S:1]1[C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=[CH:2]1.Cl[CH:17]([O:19]C)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH:17]([C:2]1[S:1][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1)=[O:19]
Reactant: COC(Cl)Cl
Reactant: O=C1Nc2ccccc2Oc2sccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=Cc1cc2c(s1)Oc1ccccc1NC2=O
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
Thieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.9 g) was suspended in methylene chloride (20 ml) and dichloromethylmethyl ether (4.0 g) was added. To this reaction system was added aluminum chloride (4.6 g) under ice-cooling and the mixture was stirred for 15 minutes. The reaction mixture was poured into ice water-chloroform and the mixture was stirred at room temperature for 20 minutes. The aqueous layer was extracted 5 times with chloroform and the combined organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the residue. The precipitated crystals were collected by filtration to give 2-formylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.2 g).
Reaction SMILES: [N:1]1([C:10]2[N:15]=[C:14]([NH:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:13]([N+:23]([O-])=O)=[C:12]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[O-]S(S([O-])=O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+].CO>C1COCC1.O.C(OCC)(=O)C>[N:1]1([C:10]2[N:15]=[C:14]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[C:13]([NH2:23])=[C:12]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1c(NC2CCOCC2)nc(-n2cnc3ccccc32)nc1-c1ccccc1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1c(NC2CCOCC2)nc(-n2cnc3ccccc32)nc1-c1ccccc1
Temperature: 25 °C
Yield: 70.6 %

Procedure:
To 48 mg (0.11 mmol) of 2-(1H-benzo[d]imidazol-1-yl)-5-nitro-6-phenyl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine in 10 mL THF was added a solution of 300 mg Na2S2O4 and 100 mg NaHCO3 in 30 mL of water, followed by 2 mL of methanol. The reaction mixture was stirred at room temperature (HPLC monitoring). Upon completion of the reaction, the mixture was diluted with 70 mL of ethyl acetate, the layers were separated, and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with brine, dried (anhydrous MgSO4), and the solvent removed in vacuo to give 30 mg (68% yield) of desired product, which was used in the next step without further purification. MS (EI) m/z 387.4 (MH)+.
Reaction SMILES: [CH:1]([N:3]([CH3:5])[NH2:4])=[O:2].[F:6][C:7]1[C:24]([F:25])=[C:23]([F:26])[C:22]([F:27])=[CH:21][C:8]=1[C:9]([C:11](=[CH:17]OCC)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10].O>C(O)C>[F:6][C:7]1[C:24]([F:25])=[C:23]([F:26])[C:22]([F:27])=[CH:21][C:8]=1[C:9]([C:11](=[CH:17][NH:4][N:3]([CH:1]=[O:2])[CH3:5])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Reactant: CN(N)C=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=CNN(C)C=O)C(=O)c1cc(F)c(F)c(F)c1F
Yield: 69 %

Procedure:
3.8 g of 1-formyl-1-methylhydrazine are added dropwise to a solution of 16 g of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-ethoxy-acrylate in 60 ml of ethanol, while cooling with ice and stirring. The mixture is stirred at room temperature for 1 hour, 60 ml of water are added, the mixture is cooled with ice and the precipitate is filtered off with suction and washed with water/ethanol (1:1). 12 g of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-(2-formyl-2-methylhydrazino)-acrylate of melting point 92° C. are obtained.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]([C:12]1[C:13]2[N:14]([N:20]=[C:21]([C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[CH:22]=2)[C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[CH2:10][CH3:11].O>CS(C)=O>[CH3:19][O:18][C:15]1[N:14]2[N:20]=[C:21]([C:23]([F:29])([F:28])[C:24]([F:25])([F:26])[F:27])[CH:22]=[C:13]2[C:12]([C:9](=[O:8])[CH2:10][CH3:11])=[CH:17][CH:16]=1
Reactant: CCC(O)c1ccc(OC)n2nc(C(F)(F)C(F)(F)F)cc12
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=O)c1ccc(OC)n2nc(C(F)(F)C(F)(F)F)cc12
Temperature: 25 °C
Yield: 82.8 %

Procedure:
Triethylamine (6.08 mL) was added to a solution of the compound of Example 355 (1.41 g) in dimethylsulfoxide (30 mL). While the solution was stirred at room temperature, sulfur trioxide-pyridine complex (3.46 g) was added and the mixture was stirred at room temperature for 30 min. Water (150 mL) was then added and the resulting crystals were collected by filtration. The crystals were dissolved in ethyl acetate and the solution was dried over anhydrous sodium sulfate. Purification by amino-silica gel column chromatography (ethyl acetate) afforded the title compound as a colorless powder (1.16 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([CH3:12])[C:3]=1[CH3:13].[C:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)([OH:16])=[O:15].[F-].[Cs+]>O.O1CCOCC1.C(O)C>[OH:9][CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:2]([C:20]2[CH:21]=[CH:22][C:17]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=2)=[C:3]([CH3:13])[C:4]=1[CH3:12]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1c(Br)ccc(OCCO)c1C
Agent: [Cs+]
Agent: [F-]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(OCCO)ccc(-c2ccc(C(=O)O)cc2)c1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of 2-(4-bromo-2,3-dimethylphenoxy)ethanol (0.531 g), 4-carboxyphenylboronic acid (0.360 g), tetrakis-(triphenylphosphine)palladium(0) (0.125 g), cesium fluoride (1.645 g), water (2 mL), ethanol (2 mL) and 1,4-dioxane (8 mL) was stirred at 80° C. for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to afford 4′-(2-hydroxyethoxy)-2′,3′-dimethylbiphenyl-4-carboxylic acid (0.62 g) as a crude product. A mixture of the crude 4′-(2-hydroxyethoxy)-2′,3′-dimethylbiphenyl-4-carboxylic acid, benzyl bromide (0.445 g), and potassium carbonate (0.450 g) in N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to afford the title compound (0.033 g).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].Br[C:33]1[N:34]=[CH:35][NH:36][CH:37]=1>>[NH:36]1[CH:37]=[C:33]([C:9]2[C:10]3[O:14][CH2:13][CH:12]([C:15]4[CH:20]=[CH:19][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:17][CH:16]=4)[C:11]=3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[C:8]=2[CH3:29])[N:34]=[CH:35]1
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Reactant: Brc1c[nH]cn1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1c[nH]cn1)OCC2c1ccc(C(C)C)cc1
Yield: 48 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 4-bromoimidazole, the title compound was obtained in the same manner as in Example 107. Yield: 48%. Melting point: 277-279° C. (ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:13]CC1C2SC3C(=CC=CC=3)C(=O)C=2C(NCCN(CC)CC)=CC=1.O.[OH-].[Na+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:13])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCN(CC)CCNc1ccc(CN)c2sc3ccccc3c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3,4-dichlorobenzenesulfonyl chloride (1.84 g, 7.5 mmol) in 35 mL of dry pyridine was added 2.5 g (7 mmol) of 4-(aminomethyl)-1-[[2-(diethylamino)ethyl]amino]-thioxanthen-9-one (prepared by the method described in Example 4) under nitrogen and the reaction mixture was stirred at room temperature for 15 min. and then was allowed to stand for approximately 72 hours. The reaction mixture was poured into 75 mL of water containing 0.75 g of NaOH, and extracted into chloroform. The organic layer was washed with water (2x) and brine, and dried over sodium sulfate. Chloroform was removed in vacuo, the residue was recrystallized from ethanol to afford 1.24 g of N-[[1-[[2-(diethylamino)]ethyl]amino]-9-oxothioxanthen-4-yl]methyl]-3,4-dichlorobenzenesulfonamide, m.p. 95° C. (dec.). The free base was dissolved in methanol and treated with methanesulfonic acid in methanol to afford the methanesulfonate·1/2 hydrate, m.p. 55° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([C:22](OC)=[O:23])[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][CH2:10]1.C([NH2:28])=O.C[O-].[Na+].CN(C)C=O>[Cl-].[NH4+]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([C:22]([NH2:28])=[O:23])[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: NC=O
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 120 °C
Reaction time: 20 h
Yield: 83 %

Procedure:
A mixture of methyl 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (Example 81; 350 mg, 0.930 mmol), formamide (3.0 mL), and sodium methoxide (28% solution in methanol, 1.0 mL), and N,N-dimethylformamide (3.0 mL) was stirred at 120° C. for 20 hr. The mixture was diluted with aqueous saturated ammonium chloride, and the precipitate was collected by filtration, washed with water, washed with diisopropyl ether to give the title compound as a colorless powder (280 mg, 0.775 mmol, 83%).
Reaction SMILES: ClN1C(=O)CCC1=O.[CH:9](=[N:11][OH:12])[CH3:10].[C:13]([C:15]1[CH:20]=[C:19]([O:21][C:22]2[CH:23]=[CH:24][C:25]([NH:29][C:30](=[O:32])[CH3:31])=[N:26][C:27]=2[CH3:28])[CH:18]=[CH:17][N:16]=1)#[CH:14].O>CN(C=O)C>[CH3:28][C:27]1[N:26]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:24]=[CH:23][C:22]=1[O:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([C:13]2[O:12][N:11]=[C:9]([CH3:10])[CH:14]=2)[CH:20]=1
Reactant: C#Cc1cc(Oc2ccc(NC(C)=O)nc2C)ccn1
Reactant: CC=NO
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(Oc2ccnc(-c3cc(C)no3)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A solution of N-chlorosuccinimide (0.153 g, 1.145 mmol) in DMF (1 mL) was treated with acetaldoxime (0.068 g, 1.145 mmol), stirred at RT for 30 min, then added to a solution of N-(5-((2-ethynylpyridin-4-yl)oxy)-6-methylpyridin-2-yl)acetamide (0.102 g, 0.382 mmol) and TEA (0.5 mL) in DMF (1 mL) and heated at 60° C. for 1 h. The mixture was cooled to RT, treated with H2O, extracted with EtOAc (2×) and the combined organics were washed with H2O, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)acetamide (110 mg, 89%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1 H), 8.55 (d, J=5.7 Hz, 1 H), 8.03 (d, J=8.8 Hz, 1 H), 7.64 (d, J=8.8 Hz, 1 H), 7.35 (d, J=2.5 Hz, 1 H), 6.96 (m, 2 H), 2.28 (s, 3 H), 2.25 (s, 3 H), 2.08 (s, 3 H); MS (ESI) m/z: 325.1 (M+H+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:14]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:38][C:39]#[N:40])[CH:21]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.CCOCC>[CH2:7]([C:14]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][N:20]([CH:21]([C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH2:38][CH2:39][NH2:40])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(C(c2ccc(OC)cc2)N(CC#N)CCCOc2ccc(Cl)cc2Cc2ccccc2)cc1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(c2ccc(OC)cc2)N(CCN)CCCOc2ccc(Cl)cc2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.9 %

Procedure:
LiAlH4 (6.88 mL, 1N in THF) is added dropwise to a stirred solution of {[3-(2-benzyl-4-chloro-phenoxy)-propyl]-[bis-(4-methoxy-phenyl)-methyl]-amino}-acetonitrile (2.48 g, 4.58 mmol) in anhydrous THF (30 mL) at ambient temperature under nitrogen. The resultant mixture is allowed to stir at ambient temperature for 20 hours. The mixture is cooled to 0° C. before it is treated dropwise with CH3OH (5 mL), then followed by the addition of Et2O (30 mL) and saturated Rochelle's salt solution (80 mL). The two-layered mixture is allowed to stir vigorously at ambient temperature under nitrogen for 1 hour. Another 60 mL Et2O is added to the mixture. The organic layer is separated, dried over MgSO4, filtered and concentrated. The crude product is chromatographed on silica (gradient 0-4% 2N NH3/CH3OH in CH2Cl2) to give 1.92 g (3.52 mmol, 77% yield) of the title compound as oil. ESIMS: m/z 545 [(M+H)+, 35Cl]; 547 [(M+H)+, 37Cl].