Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C:7](=[O:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1.[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C@:7]2([OH:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C@H:2]2[CH3:1])=[CH:14][CH:13]=1
Reactant: C[C@@H]1NC(C)(C)COC1=O
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H]1NC(C)(C)CO[C@@]1(O)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 28.8 %

Procedure:
A solution of 15 (166 mg, 1.16 mmol) in dry THF (1.2 mL, 1M) under an N2 atmosphere was cooled to −78° C. and treated with 4-fluorophenylmagnesium bromide (1.3 equiv., 1.5 mmol, 1.9 mL, 0.8 M solution in THF). The reaction mixture was stirred at −78° C. for 3 h. A saturated aqueous solution of NH4Cl was added to the reaction vessel, and the mixture was allowed to warm to room temperature. EtOAc (5 mL) was added to the reaction vessel and the organic layer was separated. The aqueous phase was extracted with EtOAc (three times). The combined organic extracts were washed (water, brine), dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel using CH2Cl2 to CH2Cl2-MeOH (90:10) as the eluent to afford 80 mg of 4h as a white solid: [α]22D +31.2° (c 0.5, CHCl3); 1H NMR (CDCl3) δ 7.60-7.55 (m, 2H), δ 7.08-7.00 (m, 2H), 3.83 (d, 1H, J=11.3 Hz), 3.40 (d, 1H, J=11.3 Hz), 3.17 (q, 1H, J=6.4 Hz), 1.38 (s, 3H), 1.08 (s, 3H), 0.78 (d, 3H, J=6.4 Hz); 13C NMR (CDCl3) δ 128.0, 127.9, 114.87, 114.58, 103.2, 98.4, 96.8, 69.5, 53.5, 27.3, 22.8, 16.4; LCMS (ESI) m/z 240.0 [(M+H)+, M=C13C18FNO2].
Reaction SMILES: [CH2:1]([C:13]1[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[NH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1C=CC=CC=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.Cl>O>[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34]([N:20]([C:18]([C:15]2[NH:16][CH:17]=[C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:14]=2)=[O:19])[NH2:21])(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: CCCCCCCCCCCCc1c[nH]c(C(=O)NN)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1c[nH]c(C(=O)N(N)S(=O)(=O)c2ccc(C)cc2)c1
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
Into a mixture of 3.29 g (11 mmol) of 4-dodecylpyrrole-2-carboxylic acid hydrazide obtained in Synthesis Example 9 and 35 ml of pyridine, was added little by little 2.23 g (12 mmol) of p-toluenesulfonyl chloride under stirring and cooling with ice. The reaction was carried out for 1.5 hours at room temperature, and the reaction mixture was added to an iced water containing 70 ml of 6N hydrochloric acid. The crystals precipitated by stirring were collected by filtration, washed with water and recrystallized from a mixed solvent of ethanol/water (10/1) to obtain 4.55 g of 4-dodecylpyrrole-2-carboxylic acid p-toluenesulfonylhydrazide as white crystals. The yield was 91% and the melting point was 134.5° to 135.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([NH2:22])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([NH:22][C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)cc1C
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(N)c3O2)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Nc4ccc(C)c(C)c4)c3O2)cc1
Yield: 40.1 %

Procedure:
Treatment of (±)-(7-amino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) with 4-bromo-1,2-dimethylbenzene (0.558 g, 3.0 mmol), generally according to the procedure described for Intermediate 202 provided 0.51 g (38%) (±)-{7-[(3,4-dimethylphenyl)amino]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a yellow solid. mp 88-90° C.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:13](=[O:26])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=[O:23].Cl.[OH-].[Na+]>C1COCC1>[CH:1]1([NH:4][C:13](=[O:26])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:3][CH2:2]1
Reactant: COC(=O)CCCCCCCCC(=O)Cl
Reactant: NC1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCC(=O)NC1CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
All reactions reported in this invention were carried in oven-dried three-necked, round-bottomed flasks equipped with a Teflon-coated magnetic stirring bar. The reaction flask was purged with nitrogen, and during the entire operation, the reaction was under nitrogen. To a stirred solution of cyclopropanamine (0.615 g, 10.78 mmol) in 25 mL of dried THF, triethylamine (1.20 g, 11.90 mmol) was added in one portion. After the reaction had been cooled to about 0° C., methyl 10-chloro-10-oxodecanoate (2.53 g, 10.78 mmol) in 5 mL of THF was added dropwise via an addition funnel. After the addition, the reaction was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was subjected to roto-vap distillation to remove the majority of solvent, and the residue was poured with stirring into a mixture of ice-water containing 10 mL of HCl aqueous 2N solution (20 mmol) leading to the immediate precipitation of a white solid. Stirring was continued for an additional 30 min, and then the precipitation was filtered off with suction through a sintered glass funnel. The collected solid was washed with two 50-mL portions of water. The NMR analysis of a dried sample of the material confirmed the structure of the desired ester. The GC retention time of the ester is 12.79 min. The ester was saponified with 20 mL of NaOH aqueous 2N solution (40 mmol) at room temperature overnight. Ice was added to the reaction and acidification with a 30 mL of HCl aqueous 2N solution (60 mmol) led to the immediate precipitation of a white solid. Stirring was continued for an additional 30 min, and then the precipitation was filtered off with suction through a sintered glass funnel. The collected solid was successively washed with three 50-mL portions of water, and two 25-mL portions of hexane. The collected solid was dried in vacuo for two days at ambient temperature to afford 1.81 g (70%) of 10-(cyclopropylamino)-10-oxodecanoic acid as a white solid. HPLC: Rt: 3.52 min. 1H NMR (400 MHz DMSO-d6) δ: 0.25 (m, 2H), 0.48 (m, 2H), 1.14 (m, 9H), 1.37 (m, 4H), 1.89 (m, 2H), 2.09 (m, 2H), 7.70 (br. s, 1H), 1.850 (s, 1H). 13C NMR (100 MHz DMSO-d6) δ: 5.60(C2 & C3), 22.0(C8), 24.46(C13), 25.18(C1), 28.63(C9, C10, C11 & C12), 33.64(C14), 35.0(C7), 173.2(C5), 174.45(C15). LC/MS m/z: 242 [(M+1)+].
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[S:13][CH:12]=[C:11]([CH3:14])[C:9]=2[N:10]=1>CCO>[Cl:4][C:5]1[N:6]=[C:7]([NH:2][NH2:3])[C:8]2[S:13][CH:12]=[C:11]([CH3:14])[C:9]=2[N:10]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1csc2c(NN)nc(Cl)nc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
Hydrazine monohydrate (2.21 mL; 45.6 mmol; 2.0 equiv) was added to a suspension of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine (5 g; 22.8 mmol; 1.0 equiv) in 40 mL of EtOH. The reaction was stirred at ambient temperature for 2 days. The solid was filtered, washed with H2O and dried to give 2-chloro-4-hydrazino-7-methylthieno[3,2-d]pyrimidine as an off-white solid (4.4 g; 90% yield); MS (ES) 214.97 (M+H), 212.99 (M−H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:8]([C:11]1[NH:15][N:14]=[C:13]([CH3:16])[CH:12]=1)([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.CCOC(C)=O>[CH:8]([C:11]1[CH:12]=[C:13]([CH3:16])[N:14]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:15]=1)([CH3:10])[CH3:9]
Reactant: Cc1cc(C(C)C)[nH]n1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(C(C)C)cc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 34 %

Procedure:
Ethyl bromoacetate (1.00 mL, 9.03 mmol) was added to 5-isopropyl-3-methyl-1H-pyrazole (1.07 g, 8.60 mmol) and potassium carbonate (3.57 g, 25.9 mol) in DMF (10 mL). The mixture was stirred at room temperature for 17 hours then EtOAc (20 mL) and aqueous HCl (20 mL, 1 M) were added. The organic phase was dried over magnesium sulphate then evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:EtOAc 4:1) to afford the title compound as a yellow oil in 34% yield, 607 mg.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[NH2:10].[CH2:11]([S:13][C:14](SCC)=[C:15]1[C:20](=O)[O:19]C(C)(C)[O:17][C:16]1=[O:24])C>C(O)C>[CH3:11][S:13][C:14]1[N:10]=[C:2]2[N:3]([C:20](=[O:19])[C:15]=1[C:16]([OH:24])=[O:17])[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=1[S:1]2
Reactant: CCSC(SCC)=C1C(=O)OC(C)(C)OC1=O
Reactant: Nc1nc2c(s1)CCCC2
Solvent: CCO
Product: CSc1nc2sc3c(n2c(=O)c1C(=O)O)CCCC3
Temperature: 87.5 °C
Yield: 46.8 %

Procedure:
The suspension of 4,5,6,7-tetrahydro-benzothiazol-2-yl-amine (8 gm, 0.0519 mol) and 5-(bis-ethylsulfanyl-methylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (14.2 gm, 0.0572 mol) in ethanol (60 ml) was heated at 85-90° C. for 10 hours. Reaction mixture was cooled to room temperature and filtered. The solid, thus obtained, was washed with ethanol (20 ml) followed by with diethyl ether (50 ml) and suck dried to give 7.2 gm of title compound as a solid.
Reaction SMILES: [CH2:1]([P:3]([OH:11])([CH2:5][CH:6]([CH3:10])[C:7]([OH:9])=[O:8])=[O:4])[CH3:2].[CH2:12](O)[CH2:13][CH2:14][CH2:15][OH:16]>C1(C)C=CC=CC=1>[CH2:1]([P:3]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])([CH2:5][CH:6]([CH3:10])[C:7]([O:9][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[O:8])=[O:4])[CH3:2]
Reactant: CCP(=O)(O)CC(C)C(=O)O
Reactant: OCCCCO
Solvent: Cc1ccccc1
Product: CCP(=O)(CC(C)C(=O)OCCCCO)OCCCCO
Yield: 91.9 %

Procedure:
540 g (3.0 mol) of 3-(ethylhydroxyphosphinyl)-2-methylpropionic acid (produced as in Example 17) are at 80° C. dissolved in 400 ml of toluene and admixed with 594 g (6.6 mol) of 1,4-butanediol and esterified at about 100° C. in a distillation apparatus equipped with water trap during 4 h. On completion of the esterification the toluene is removed in vacuo to leave 894 g (92% of theory) of 4-hydroxybutyl 3-(ethyl-4-hydroxybutoxyphosphinyl)-2-methylpropionate as colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH3:16])[C:8]([OH:10])=O)[CH3:2].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:6]=[C:7]([C:8]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:10])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH3:16])[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)O)ccc1OCC
Reactant: C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1cc(C(=O)N2CCCCC2)ccc1OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of 4-ethoxy isopthalic acid 3-ethyl ester (600 mg, 2.5 mmol) in 10 mL of acetonitrile was added piperidine (429 mg, 5.0 mmol). The resulting mixture was cooled to 0° C. To this solution was added HBTU (1.4 g, 3.78 mmol, in 5 mL of acetonitrile) followed by N,N-diisopropylethylamine (2.2 mL, 12.6 mmol). The reaction was allowed to stir overnight at room temperature. The reaction mixture was concentrated in vacuo. The residue was diluted with 10% potassium carbonate and extracted with methylene chloride. The organic extract was concentrated and purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave 632 mg (2.07 mmol, 82%) of pure 2-ethoxy-5-(piperidine-1-carbonyl)-benzoic acid ethyl ester. LC-MS: 306.3 [(M+H)+].
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH2:13].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[S:22]([NH:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[F:3])(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To NaH (60% dispersion in mineral oil) (0.734, 18.3 mmol) in THF (100 mL) at 0° C. was added dropwise a solution of 2-fluoro-4-nitrobenzenamine (2.20 g, 14.1 mmol) in THF (25 mL). The solution turned deep red in color and was stirred at 0° C. for 1 hour. A solution of 2,3-dichlorobenzene-1-sulfonyl chloride (3.80 g, 15.5 mmol) in THF (25 mL) was then added dropwise, at which point the reaction turned orange/yellow in color. The mixture was allowed to warm to room temperature and then was stirred for and additional 30 minutes. The reaction was quenched by addition of NH4Cl (aq., sat.), and then concentrated. The mixture was partitioned between water and ethyl acetate. The organics were dried with MgSO4, filtered, and concentrated to afford 2,3-dichloro-N-(2-fluoro-4-nitrophenyl)benzenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([O:25]CC)=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:28][CH2:29][CH3:30])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:28][CH2:29][CH3:30])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCO[C@@H]1CN(c2ncc(C(=O)O)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 83.2 %

Procedure:
The same operation as in Example (91d) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-1,3-thiazole-5-carboxylate obtained in Example (125b) (0.27 g, 0.59 mmol), 2 N lithium hydroxide (5 mL, 10 mmol), methanol (5 mL) and THF (5 mL), to obtain 0.21 g of the title compound as a colorless solid (83%).
Reaction SMILES: Cl[C:2]1[S:6][C:5]([CH2:7][NH:8][C:9]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][NH:18][CH3:19])[N:16]=2)=[O:10])=[CH:4][CH:3]=1.[F:20]C1SC(NC)=CC=1>>[F:20][C:2]1[S:6][C:5]([CH2:7][NH:8][C:9]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][NH:18][CH3:19])[N:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CNc1ccc(F)s1
Reactant: CNCc1csc(NC(=O)NCc2ccc(Cl)s2)n1
Product: CNCc1csc(NC(=O)NCc2ccc(F)s2)n1

Procedure:
It was prepared following the same method of the preparation of Intermediate 29, starting from (5-fluoro-thiophen-2-yl)-methylamine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:26][NH:27][O:28][CH3:29]>CN(C=O)C>[CH3:29][O:28][N:27]([CH3:26])[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)=[O:12]
Reactant: CNOC
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1n[nH]c2ccccc12
Temperature: 62.5 °C
Yield: 78.9 %

Procedure:
1H-indazole-3-carboxylic acid (VIII) (100 g, 617 mmol) in DMF was treated with carbonyldiimidazole (110 g, 678 mmol) at r.t. until the evolution of gas ceased (ca. 15 minutes). The reaction was heated to 60-65° C. for two hours and then allowed to cool to r.t. N,O-Dimethylhydroxylamine-HCl (66.2 g, 678 mmol) was added as a solid and the mixture was heated to 65° C. for 3 hours. The reaction was concentrated to a paste and taken up in DCM, and washed subsequently with water and 2N HCl. The product could be seen coming out of solution. The solid was filtered and rinsed separately with EtOAc. The EtOAc and DCM layers were separately washed with sodium bicarbonate followed by brine, dried over MgSO4 and concentrated under reduced pressure. The resulting solids were combined, triturated with 1:1 mixture of DCM-ether, filtered, and dried to produce N-methoxy-N-methyl-1H-indazole-3-carboxamide (IX) as a white solid (100 g, 487 mmol, 79% yield). 1H NMR (DMSO-d6) δ ppm 3.46 (s, 3H), 3.69-3.85 (m, 3H), 7.13-7.31 (m, 1H), 7.41 (t, J=7.25 Hz, 1H), 7.56-7.65 (m, 1H), 7.93-8.08 (m, 1H); ESIMS found for C10H11N3O2 m/z 206 (M+H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:35][C:36]1[CH:41]=[C:40]([C:19]([C:11]2[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:8])=[O:9])[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]([CH3:23])[CH3:22])[CH:39]=[CH:38][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)C=C(c1cccc(Cl)c1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Yield: 95.4 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 130, 3.0 g, 6.0 mmol), 3-chloro-phenylboronic acid (2.35 g, 15 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.42 g, 0.6 mmol) in dioxane (30 mL) and an aqueous sodium carbonate solution (2N, 15 mL) was heated in a microwave at 100° C. for 2 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with a saturated sodium bicarbonate solution (2×50 mL). The organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (30 g, 5% ethyl acetate/petroleum ether) afforded 2-(1-(3-chloro-phenyl)-3-methyl-but-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.5 g, 95.4%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ ppm 8.51 (dd, 1H, J1=4.8 Hz, J2=1.8 Hz), 7.89 (dd, 1H, J1=7.8 Hz, J2=1.8 Hz), 7.68 (dd, 2H, J1=8.7 Hz, J2=1.5 Hz), 7.44 (m, 1H), 7.28-7.06 (m, 5H), 6.53 (s, 1H), 6.13 (d, 1H, J=10.2 Hz), 2.65 (m, 1H), 1.15-1.08 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)=[CH:22][CH:21]=1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: OB(O)c1ccc(F)cc1
Product: Fc1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cc1

Procedure:
The title compound was prepared from the product of Example 65A and 4-fluorophenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 324.0 (M+H)+, retention time 1.31 minutes.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:8]=3[CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[O:10][CH2:11][C:5]2=[N:4][N:3]1[CH3:24].C(Cl)(Cl)Cl.C(Cl)(=O)OCC>C(N(CC)CC)C>[O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:8]=3[CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[O:10][CH2:11][C:5]2=[N:4][N:3]1[CH2:24][CH2:5][N:6]([CH3:7])[CH3:2]
Reactant: Cn1nc2n(c1=O)-c1ccc(Cl)cc1C(c1ccccc1Cl)OC2
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C)CCn1nc2n(c1=O)-c1ccc(Cl)cc1C(c1ccccc1Cl)OC2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Compound 33 is mixed with chloroform (20 ml), triethylamine (0.708 g), and ethyl chlorocarbonate (0.76 g), and the mixture is stirred at room temperature for 20 minutes, then refluxed under heating for 3.5 hours, and washed with water. The chloroform layer is dried and concentrated to give crystalline Compound 34 (2.15 g), which is recrystallized from ethanol.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]1([CH2:54][NH2:55])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:55][CH2:54][CH:47]4[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: NCC1CCCCCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCC2CCCCCC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with N-cycloheptylmethyl-amine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C44H58Cl2N5O3 [(M+H)+] 774.391 1, observed 774.3909.
Reaction SMILES: N1CCC[CH2:2]1.[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:15]=2)[CH:12]=1>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[C:14]([N:16]3[CH2:17][CH2:2][CH:20]([O:19][CH3:18])[CH2:21]3)[N:15]=2)[CH:12]=1
Reactant: C1CCNC1
Reactant: Brc1ccc2nc(N3CCOCC3)nn2c1
Product: COC1CCN(c2nc3ccc(Br)cn3n2)C1

Procedure:
Using pyrrolidine, this compound was prepared following the same method as for the synthesis of 6-bromo-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridine Brown solid (2.5 g, 47%). MS: m/z=298 (M+H+).