Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:14]2[CH:13]=[C:12]([NH:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)[CH:11]=[CH:10][C:9]=2[C:8]([CH3:28])([CH3:27])[CH2:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:35](Br)[CH:36]=[CH2:37].CC(N(C)C)=O>CCOCC>[C:1]([C:5]1[C:14]2[CH:13]=[C:12]([N:15]([CH2:37][CH:36]=[CH2:35])[C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=3)[CH:11]=[CH:10][C:9]=2[C:8]([CH3:27])([CH3:28])[CH2:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C(C)(C)C)=CCC3(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: C=CCN(c1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C(C)(C)C)=CCC2(C)C
Temperature: 75 °C

Procedure:
A mixture of ethyl 4-(8-t-butyl-5,5-dimethyl-5,6-dihydronaphthalen-2-ylamino)-benzoate (Compound 84, 170 mg, 0.45 mmol), K2CO3 (900 mg), allyl bromide (1 mL) and dimethylacetamide (5 mL) was heated to 75° C. in a sealed tube for 7 days. The mixture was diluted with ether (70 mL), washed with brine, dried and the solvent was removed. Silica gel flash chromatography gave the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:19](=O)[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]=3[CH3:29])=[C:11]([C:15]([O:17]C)=O)[NH:12]2)=[CH:8][CH:7]=1.O.[NH2:32][NH2:33]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]=4[CH3:29])=[N:33][NH:32][C:15](=[O:17])[C:11]=3[NH:12][C:13]=2[CH:14]=1
Reactant: COCCOc1ccc2c(C(=O)c3cccc([N+](=O)[O-])c3C)c(C(=O)OC)[nH]c2c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COCCOc1ccc2c(c1)[nH]c1c(=O)[nH]nc(-c3cccc([N+](=O)[O-])c3C)c12
Temperature: 25 °C
Yield: 50.5 %

Procedure:
A yellow, homogeneous solution of methyl 6-(2-methoxyethoxy)-3-(2-methyl-3-nitrobenzoyl)-1H-indole-2-carboxylate (1.546 g, 3.75 mmol) and hydrazine hydrate (0.982 mL, 13.13 mmol) in ethanol (55.1 mL) under nitrogen was refluxed overnight. The reaction was cooled to room temperature and concentrated in vacuo. It was dissolved in EtOAc (150 mL) and washed with water (40 mL) and brine (40 mL), dried over MgSO4, and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 120 g column eluting with 0-100% EtOAc/hexanes. Appropriate fractions were collected and concentrated in vacuo to give the desired product (0.7461 g, 1.892 mmol, 50.4% yield) as a light yellow solid.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:25](O)=[O:26]>>[CH:25]([C:6]1[CH:5]=[CH:4][C:3]([O:8][CH3:9])=[C:2]([CH:7]=1)[C:1]([O:11][CH3:12])=[O:10])=[O:26]
Reactant: COC(=O)c1ccccc1OC
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COC(=O)c1cc(C=O)ccc1OC

Procedure:
16.6 g of methyl o-anisate was dissolved in 100 ml of trifluoroacetic acid. Thereto was added 14.0 g of hexamethylenetetramine with ice-cooling. The mixture was refluxed for 2 hours. The solvent was removed by distillation under reduced pressure. The residue was poured into 120 ml of water. The mixture was neutralized with sodium hydrogencarbonate and then extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: n-hexane/ethyl acetate=2/1) to obtain 16.1 g of methyl 5-formyl-2-methoxybenzoate. It was recrystallized from diisopropyl ether to obtain 14.0 g of colorless crystals having a melting point of 85°-86° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].C(N(CC)CC)C.[C:14](Cl)(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1(C)C=CC=CC=1>[C:14]([N:2]([CH3:1])[C:3]([NH:5][CH3:6])=[O:4])(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CNC(=O)NC
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)N(C)C(=O)NC
Reaction time: 8 h

Procedure:
To a solution of 1,3-dimethylurea in toluene with an appropriate base (e.g., triethylamine) is added an equimolar amount of lauroyl chloride. This is stirred overnight, filtered and concentrated to give the above product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:39])C=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19]([CH3:20])=[O:39])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CSCc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
200 mg (0.49 mmol) of the compound from Example 279 were introduced into 20 ml of dichloromethane at 0° C., 120 mg (0.49 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 134 mg (65% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[N:13][NH:12][C:11](=[O:15])[CH:10]=2)=[CH:5][CH:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1>>[CH3:28][N:25]1[C:26]2[CH:27]=[C:19]([N:12]3[C:11](=[O:15])[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][CH:5]=4)[CH:14]=[N:13]3)[CH:20]=[CH:21][C:22]=2[C:23]2[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cn[nH]1
Product: Cn1c2c(c3ccc(-n4ncc(-c5ccc(C(F)(F)F)cc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 30.2 %

Procedure:
5-(4-(Trifluoromethyl)phenyl)pyridazin-3(2H)-one (100 mg, 0.41 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (151 mg, 0.41 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (65 mg, 30%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.20 (s, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H), 7.59 (d, J=1.6 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.31 (d, J=6.9 Hz, 1H), 7.26-7.24 (m, 1H), 4.62 (s, 2H), 3.89-3.80 (br m, 2H), 3.66 (s, 3H), 2.84 (br m, 2H), 1.51 (s, 9H).
Reaction SMILES: O.[CH2:2]([NH2:6])[CH2:3][CH2:4][CH3:5].[C:7](OC)(=[O:10])[C:8]#[CH:9].[Na+].[Cl-]>C(O)(=O)C>[CH2:2]([NH:6][C:7](=[O:10])[C:8]#[CH:9])[CH2:3][CH2:4][CH3:5]
Reactant: C#CC(=O)OC
Reactant: CCCCN
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C#CC(=O)NCCCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 30 mL of water and 7.3 g (100 mmol) n-Butylamine is added dropwise 8.4 g (100 mmol) methyl propiolate at 0° C. for 30 minutes. The mixture was stirred for 2 h at 0° C., then acetic acid (2 mL) was added. The mixture was stirred for another 10 minutes and saturated with NaCl, followed by extraction with ethyl acetate (3×20 mL). The combined organic phase was washed with saturated aqueous solution of NaHCO3 (20 mL), dried over Na2SO4, and removed by rotary evaporation to give product (12.0 g, yield 96%, purity 96% by GC).
Reaction SMILES: C(OC([N:8]1[CH2:24][CH2:23][N:11]2[CH2:12][C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])=O)(C)(C)C.[ClH:25]>>[ClH:25].[ClH:25].[F:21][C:19]([F:20])([F:22])[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH2:12][N:11]1[CH2:23][CH2:24][NH:8][CH2:9][C@H:10]12
Reactant: CC(C)(C)OC(=O)N1CCN2Cc3c(cccc3C(F)(F)F)[C@@H]2C1
Agent: Cl
Product: FC(F)(F)c1cccc2c1CN1CCNC[C@@H]21
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindole (37 mg, 0.11 mmmol) was added concentrated aqueous hydrogen chloride (1 mL). After 15 min, the solution was concentrated, diluted with water, and lyopholized to give (R)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindole bis hydrochloric acid salt (33 mg, 99%) as an off white solid. MS (ESI) 243.3 (M−HCl2).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:5]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CSc1ccc(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CSc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1C(F)(F)F
Reaction time: 24 h

Procedure:
4-Methylsulfanyl-3-trifluoromethyl-phenylamine (828 mg; 4.00 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (876 mg; 4.40 mmol) and sodium triacetoxyborohydride (2.52 g; 12.00 mmol) are suspended in dichloromethane (18 mL) and the resulting mixture is stirred for 1 day. The suspension is then diluted with dichloromethane (50 mL) and is washed with water (30 mL) and aq. sat. ammonium chloride (3×30 mL). The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure to deliver the desired product in the presence of remaining traces of solvent (1.8 g; 4.6 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15](/[CH:16]=[C:17]3/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/3)=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.CN(C=O)C.Cl.[NH2:33][OH:34]>C1COCC1>[OH:34][N:33]=[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:10][O:11][C:12]1[CH:25]=[CH:24][C:15](/[CH:16]=[C:17]2/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/2)=[CH:14][CH:13]=1
Reactant: NO
Reactant: COc1cccc(C(=O)COc2ccc(/C=C3\SC(=O)NC3=O)cc2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cccc(C(COc2ccc(/C=C3\SC(=O)NC3=O)cc2)=NO)c1
Reaction time: 8 h

Procedure:
A stirring suspension of (5Z)-5-{4-[2-(3-methoxyphenyl)-2-oxoethoxy]benzylidene}-1,3-thiazolidine-2,4-dione (1.42 g, 3.84 mmol; Supplier=Kalexsyn; Lot=1003-TTP-149) in THF (15 ml) was heated with a heat gun—no solution. Added DMF (5 ml) and heated—no solution. Added another 5 ml DMF and heated until all solids dissolved. The hydroxylamine hydrochloride was added portionwise. Added HONH2.HCl (100 mg) and allowed to sit at RT overnight. HPLC showed a ratio of ca. 2:1 SM:pdt. Added 100 mg HONH2.HCl. After 4 hours there was little change in HPLC. Added 100 mg HONH2.HCl and left to stir over the weekend. The reaction was complete. The reaction mixture was partitioned between EtOAc (30 ml) and 1M KHSO4 (30 ml). The aqueous phase was extracted with EtOAc (30 ml). The combined organic phases were washed with saturated NaHCO3 (30 ml), brine (30 ml), dried (Na2SO4), filtered and evaporated in vacuo to give 1.34 g yellow solid. 1H-NMR (DMSO-d6): δ 12.53(brs, 1H), 12.02(brs, 1H), 7.73(s, 1H), 7.54(d, J=8.9 Hz, 2H), 7.30(t, J=7.9 Hz, 1H), 7.20(m, 2H), 7.10(d, J=8.9 Hz, 2H), 6.95(dd, J=8.1, 2.5 Hz, 1H), 5.31(s, 2H), 3.74(s, 3H). HPLC: 3.690 min., 10 area %, and 3.788 min., 89 area % @ 210 nm; 3.690 min., 6 area %, and 3.789 min., 94 area % @ 254 nm. MS (ESI−) for C19H16N2O5S m/z 383.3 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7]Cl)[N:6]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:6]=1
Reactant: C1CCNC1
Reactant: ClCc1csc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1nc(CN2CCCC2)cs1
Yield: 62.6 %

Procedure:
2-Chloro-4-chloromethyl-thiazole (610 mg, 3.6 mmol), pyrrolidine (0.4 mL, 4.8 mmol), and potassium carbonate (1.05 g, 7.6 mmol) were stirred in DMF (6 mL) for 5 hours. After completion, the reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was thrice extracted with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-5% [8:1 EtOH:NH4OH(aq)]/DCM). This resulted in 457 mg (63% yield) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:39]C(=O)OC(C)(C)C)[C@@H:9]([OH:38])[CH2:10][C@H:11]([NH:25][C:26](=[O:37])[C@@H:27]([NH:32][C:33]([O:35][CH3:36])=[O:34])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:39][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([OH:38])[CH2:10][C@H:11]([NH:25][C:26]([C@@H:27]([NH:32][C:33](=[O:34])[O:35][CH3:36])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:37])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.3 %

Procedure:
A solution of the product of Example 1G (1.55 g, 2.45 mmol) in dichloromethane (12.5 mL) was treated with trifluoroacetic acid (12.5 mL), stirred at 25° C. for 1 hour and concentrated. The concentrate was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase extract was washed with brine, dried over MgSO4, filtered and concentrated to give the title compound (1.4 g) which was used without further purification.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[C:2]=[S:3].Cl.[CH:15]([NH2:17])=[NH:16].[OH-].[Na+]>C1COCC1>[NH2:17][CH:15]=[N:16][C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[S:3]
Reactant: N=CN
Reactant: COc1ccc(N=C=S)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(NC(=S)N=CN)cc1OC
Reaction time: 3 h

Procedure:
A mixture of 10 g (51.2 mmol) 4-isothiocyanato-1,2-dimethoxybenzene in 51 ml THF at 0° C. was treated with 5.1 g (63.3 mmol) formamidine hydrochloride and 63.3 ml 1N NaOH and allowed to stirr for 3 h after which the mixture was concentrated. 500 ml ethyl acetate and 100 ml water was added and the precipitate was filtered off and dried to yield the intermediate 1-[1-Amino-methylidene]-3-(3,4-dimethoxy-phenyl)-thiourea (MH+ 240.2) which was used without further purification. The thiourea was taken up in 50 ml THF and treated with 8.55 g (51.2 mmol) ethyl bromoacetate and 14.2 ml NEt3 and stirred at room temperature for 16 h and at 50° C. for 8 h. The mixture was concentrated and extracted with CHCl3. The organic layer was washed with aqueous Na2CO3 (1M) and saturated NaCl solution, dried with MgSO4 and evaporated. The residue was purified with reversed phase preparative HPLC to yield 4.04 g (26%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[C:20](CN(C(OC(C)(C)C)=O)C)[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]([O:39][C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[C:47]1[NH:48][C:49]([C:52]2[CH:57]=[CH:56][C:55](B3OC(C)(C)C(C)(C)O3)=[C:54](C(OC)=O)[CH:53]=2)=[CH:50][N:51]=1)=[O:41])([CH3:38])([CH3:37])[CH3:36].C(=O)(O)[O-].[Na+]>O.CCOC(C)=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>[C:35]([O:39][C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[C:47]1[NH:48][C:49]([C:52]2[CH:57]=[CH:56][C:55]([C:21]3[CH:20]=[CH:19][C:18]([C:15]4[NH:14][C:13]([CH:9]5[CH2:10][CH2:11][CH2:12][N:8]5[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[N:17][CH:16]=4)=[CH:23][CH:22]=3)=[CH:54][CH:53]=2)=[CH:50][N:51]=1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: CN(Cc1cc(-c2cnc(C3CCCN3C(=O)OC(C)(C)C)[nH]2)ccc1Br)C(=O)OC(C)(C)C
Reactant: COC(=O)c1cc(-c2cnc(C3CCCN3C(=O)OC(C)(C)C)[nH]2)ccc1B1OC(C)(C)C(C)(C)O1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Temperature: 80 °C
Yield: 52.5 %

Procedure:
To the solution of 2-(5-{4-bromo-3-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (142 mg, 0.27 mmol) and 2-{5-[3-Methoxycarbonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (125 mg, 0.25 mmol) in 1,2-dimethoxyether (2.3 ml) and water (0.7 ml) was added sodium bicarbonate (63 mg, 0.75 mmol), followed by Pd(PPh3)4 (12 mg) and PdCl2(dppf)CH2Cl2 (12 mg). The mixture was heated at 80° C. for 20 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 4,4′-bis-[2-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-biphenyl-2-[(tert-butoxycarbonyl-methyl-amino)-2′-carboxylic acid dimethyl ester (82 mg). m/z: 826 (M+H)+, 413.6 (M+2H)+/2.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][OH:7])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:18]1([NH:21][C:22]([C:24]2[S:37][C:27]3=[N:28][C:29](S(C)=O)=[C:30]([Cl:33])[C:31]([CH3:32])=[C:26]3[C:25]=2[NH2:38])=[O:23])[CH2:20][CH2:19]1>C1COCC1>[CH:18]1([NH:21][C:22]([C:24]2[S:37][C:27]3=[N:28][C:29]([O:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[C:30]([Cl:33])[C:31]([CH3:32])=[C:26]3[C:25]=2[NH2:38])=[O:23])[CH2:20][CH2:19]1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Reactant: CC(=O)NCCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)NCCOc1nc2sc(C(=O)NC3CC3)c(N)c2c(C)c1Cl
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
To a solution of N-acetylethanolamine (1.120 g, 10.86 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes) (3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 80° C. in a sealed tube for 1.5 hours, cooled to room temperature, and then quenched by the addition of water (15 ml). Ice is added to the reaction mixture and, while stirring, a yellow precipitate is formed. This solid is collected by filtration and placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.199 g, 52%). Mass (m/z): 383.2 (M++1), 381.1 (M+−1).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH2:23]([S:30]([CH2:33][CH2:34]Cl)(=[O:32])=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:34][CH2:33][S:30]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:31])=[O:32])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=S(=O)(CCCl)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCS(=O)(=O)Cc2ccccc2)CC1
Yield: 88.6 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.50 g) as a starting compound, 2-benzylsulfonylethyl chloride (1.21 g) and potassium carbonate (1.54 g) were reacted and treated in the same manner as in Example 199 to give 1.72 g of 4-amino-5-chloro-2-methoxy-N-((1-(2-benzylsulfonylethyl)piperidin-4-yl)methyl)-benzamide,
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>C1C=CC=CC=1.C(O)C.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>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: Cc1cc(Br)ccc1C#N
Reactant: COc1ccc(B(O)O)cc1
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: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: COc1ccc(-c2ccc(C#N)c(C)c2)cc1
Temperature: 75 °C
Yield: 102.7 %

Procedure:
4-Bromo-2-methylbenzonitrile (4.9 g, 25.0 mmol), Pd(PPh3)4 (578 mg) in benzene (50 mL) and 2.0 M aqueous solution of Na2CO3 (25 mL, 50.0 mmol) was treated with 4-methoxyphenylboronic acid (4.56 g, 30.0 mmol) in ethanol (20 mL) and heated at 75° C. for 17 hours. The mixture was allowed to cool to room temperature and the phases were separated. The aqueous phase was extracted with diethyl ether (3×40 mL). The original benzene layer and the diethyl ether extracts were combined, filtered over celite, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography over silica using a mixture of hexane/CH2Cl2 (3:1) to provide the title compound as a white powder (5.73 g, 85% yield). 1HNMR (300 MHz, CDCl3) δ2.35 (3H), 3.70 (s, 3H), 6.80-7.50 (m, 7H); MS (DCI) m/z 224 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:15])=O.CN(C)C=O>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([Cl:15])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ccc(C(=O)Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-fluoro-4-methyl-benzoic acid (Aldrich, 3.08 g, 20 mmol) in diethyl ether (30 mL), oxalyl chloride (2.85 mL, 30 mmol) was added slowly followed by a drop of N,N-dimethylformamide. The mixture was stirred at room temperature overnight and the solvent was removed under reduced pressure to give 3-fluoro-4-methyl-benzoyl chloride that was used directly for the next step.