Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:18])[C:9](Br)=[C:10]([CH3:16])[C:11]=2[N+:13]([O-])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(Cl)(Cl)Cl.[CH3:23][OH:24]>[Pd]>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:18])[CH:9]=[C:10]([CH3:16])[C:11]=2[NH:13][C:23](=[O:24])[C:7]([CH3:12])([CH3:8])[CH3:6])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)N1CCc2c(C)c(Br)c(C)c([N+](=O)[O-])c21
Agent: [Pd]
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCc2c(C)cc(C)c(NC(=O)C(C)(C)C)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Acetyl-5-bromo-4,6-dimethyl-7-nitroindoline (30 g) was dissolved in a mixture (600 ml) of CHCl3/MeOH=1/1 and 5% Pd-C (5.0 g) was added, which was followed by catalytic hydrogenation at 35° C. The precipitate was collected by filtration together with Pd-C, and dissolved in CHCl3 (300 ml). The mixture was washed with saturated aqueous solution of sodium hydrogencarbonate. The solvent was evaporated under reduced pressure from the filtrate and CHCl3 (300 ml) was added. The mixture was washed with saturated aqueous solution of sodium hydrogencarbonate and combined with the layer of above-mentioned CHCl3. The combined CHCl3 layer was washed with saturated brine and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure and the residue was dissolved in CHCl3 (150 ml). Thereto were successively added at 10° C. pivaloyl chloride (11.7 g) and Et3N (10.8 g). The mixture was stirred at room temperature for 1 hr and CHCl3 (200 ml) was added. The mixture was washed successively with 5% aqueous citric acid and water, and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure and the obtained crude residue was washed with cool Et2O (100 ml) to give 21 g of N-(1-acetyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][N:7]1[C:11]([C:12](=[O:28])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[N:18]([N:20]=[C:21]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[N:22]=3)[CH:19]=2)=[C:10]([C:29](O)=[O:30])[CH:9]=[N:8]1>>[N:23]1([C:21]2[N:22]=[C:17]3[CH:16]=[CH:15][C:14]([NH:13][C:12]([C:11]4[N:7]([CH3:6])[N:8]=[CH:9][C:10]=4[C:29]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:30])=[O:28])=[CH:19][N:18]3[N:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(N3CCCC3)nn2c1
Product: Cn1ncc(C(=O)N2CCCC2)c1C(=O)Nc1ccc2nc(N3CCCC3)nn2c1

Procedure:
Using pyrrolidine and 1-Methyl-5-(2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. White solid (46 mg, 58%). MS: m/z=409 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[Br:15][C:16]1[CH:17]=[C:18]([C:19]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(Br)c3)nc2c1
Temperature: 120 °C
Yield: 87.9 %

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (0.5 g, 2.55 mmol) in N,N-dimethylacetamide (30 mL) was added 3-bromo-benzaldehyde (0.32 mL, 2.80 mmol) followed by NaHSO3 (0.39 g, 3.82 mmol) and p-toluenesulfonic acid monohydrate (0.24 g, 1.27 mmol). The reaction was heated at 120° C. for 20 h. After that time it was cooled to room temperature (rt), concentrated under reduced pressure and diluted with water. The precipitated solids were collected by filtration, washed with water and dried under vacuum. The product was triturated with diethyl ether to give 2-(3-bromo-phenyl)-5,7-dimethoxy-3H-quinazolin-4-one (0.81 g, 88%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.84 (d, J=7.0 Hz, 1H), 7.66 (d, J=7.0 Hz, 1H), 7.38 (t, J=7.0 Hz, 1H), 6.8 (s, 1H), 6.46 (s, 1H), 3.94 (s, 3H), 3.90 (s, 3H).
Reaction SMILES: Cl.[Cl-].[N:3]1[CH:8]=[CH:7][C:6]([N+:9]2[CH:14]=[CH:13]C=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N1CCOCC1)=[O:16]>>[O:16]1[CH2:13][CH2:14][N:9]([C:6]2[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=2)[CH2:10][CH2:11]1
Reactant: c1cc[n+](-c2ccncc2)cc1
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Cl-]
Product: c1cc(N2CCOCC2)ccn1
Yield: 59 %

Procedure:
With complete analogy to Examples 5 and 6, the reaction of 4-pyridylpyridinium chloride hydrochloride with N-formylmorpholine produced, in a 59% yield, 4-morpholinopyridine, m.p. 93-95° C. (from ligroin).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]2[N:10]([CH2:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][C:18]([C:24](=O)[CH3:25])=[CH:17]4)[N:11]=[N:12][C:7]2=[N:6][CH:5]=1)(=O)[CH3:2].[NH2:27][O:28][CH2:29][CH2:30][OH:31]>CO.C(O)(=O)C>[OH:31][CH2:30][CH2:29][O:28]/[N:27]=[C:24](/[C:18]1[CH:19]=[N:20][C:21]2[C:16]([CH:17]=1)=[CH:15][C:14]([CH2:13][N:10]1[C:8]3=[N:9][C:4](/[C:1](=[N:27]/[O:28][CH2:29][CH2:30][OH:31])/[CH3:2])=[CH:5][N:6]=[C:7]3[N:12]=[N:11]1)=[CH:23][CH:22]=2)\[CH3:25]
Reactant: CC(=O)c1cnc2ccc(Cn3nnc4ncc(C(C)=O)nc43)cc2c1
Reactant: NOCCO
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\OCCO)c1cnc2ccc(Cn3nnc4ncc(/C(C)=N/OCCO)nc43)cc2c1
Yield: 16.2 %

Procedure:
A solution of 1-(6-((6-acetyl-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinolin-3-yl)ethanone (74 mg, 0.213 mmol) and 2-aminooxy-ethanol (35 mg, 0.45 mmol) in 5 mL of methanol and 0.1 mL of acetic acid was stirred at 40° C. overnight. The solvent was removed under reduced pressure and the residue was diluted with DCM and methanol. The precipitate was collected, washed with DCM, dried to afford the title compound (16 mg, 15%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.31 (s, 1H), 9.23 (d, 1H), 8.52 (d, 1H), 8.03 (d, 1H), 7.98 (s, 1H), 7.86 (dd, 1H), 6.22 (s, 2H), 4.76 (d, 2H), 4.31 (t, 2H), 4.22 (t, 2H), 3.72-3.69 (m, 4H), 2.32 (s, 3H), 2.29 (s, 3H). LCMS (method E): [MH]+=465, tR=4.85 min.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:15][C:16]1[C:17]([CH2:22]Br)=[CH:18][CH:19]=[CH:20][CH:21]=1>O1CCCC1>[C:1]([C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:22][C:17]2[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15]1)([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)OCC)Cc2ccccc2C1
Temperature: 5 °C
Yield: 73.5 %

Procedure:
Dissolve diethyl malonate (7.6 mL, 50 mmol) in anhydrous tetrahydrofuran (500 mL) and place under an argon atmosphere. Cool to 5° C., add sodium hydride (1.2 g, 50 mmol) and stir briefly until homogeneous. Add α,α'-dibromo-o-xylene (13.2 g, 50 mmol) and stir an additional 15 minutes. Add additional sodium hydride 1.2 g, 50 mmol) and stir for 16 hours while warming to room temperature. Filter, evaporate the solvent in vacuo and purify by silica gel chromatography (1:1 methylene chloride/hexane) to give 2,2-dicarboethoxyindan (9.64 g, 74%).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:14][C:15]([F:24])([F:23])[C:16]1[CH:21]=[CH:20][C:19]([O:13][CH:10]2[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)=[CH:18][CH:17]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 1-Boc-3-pyrrolidinol (1 g, 5.34 mmol; available from Sigma-Aldrich #706620) and 4-(Trifluoromethyl)phenol (0.86 g, 5.34 mmol) in dry tetrahydrofuran (10 ml), Triphenylphosphine (1.54 g, 5.87 mmol) and diisopropyl azodicarboxylate (1.15 ml, 5.87 mmol) were added. The reaction mixture was stirred at room temperature for 2 days. Solvents were evaporated in vacuo and the residue was loaded on SPE-Si (25 g) cartridge and purified eluting with a mixture petroleum ether/ethylacetate (from 100/0 to 80/20). Collected fractions gave, after evaporation, the title compound (D34) (1.8 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl-].[N+:7]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[CH2:13][NH3+:14])([O-:9])=[O:8].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([NH:14][CH2:13][C:12]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(C[NH3+])cc1[N+](=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CNS(C)(=O)=O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9.4 ml (0.244 mol) of methanesulfonyl chloride are metered over 30 minutes with ice-cooling to a solution of 30.1 g (0.122 mol) of 3-nitro-4-methoxycarbonyl-benzylammonium chloride and 34 ml (0.244 mol) of triethylamine in 300 ml of dichloromethane, and stirring of the mixture is continued for one hour. For work-up, the reaction mixture is treated with ice water, the phases are separated, and the aqueous phase is reextracted twice more with dichloromethane. After drying (Na2SO4), filtration and concentration, 31.3 g (89%) of methyl 4-methanesulfonylaminomethyl-2-nitrobenzoate remain as a syrupy oil.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:13]([OH:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Cl)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.67 ml benzylbromide are added dropwise to 1.73 g 3-hydroxy-4-chloro-benzoic acid and 3.04 g potassium carbonate in 10 ml N,N-dimethylformamide, and the reaction mixture is stirred overnight at ambient temperature. Then the reaction mixture is mixed with water and extracted with ethyl acetate. The combined organic phases are dried on magnesium sulphate and evaporated down. The flask residue is taken up in 5 ml of methanol, combined with 3 ml of 10 M aqueous potassium hydroxide solution and stirred for 4 h at 50° C. gerührt. The reddish solution is diluted with water and acidified with 3 N aqueous hydrochloric acid. The precipitate formed is suction filtered, washed with water and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].N1CC[C@@H:23]([OH:26])[CH2:22]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:19][CH2:22][C@@H:23]([OH:26])[CH2:20]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: O[C@@H]1CCNC1
Reactant: COc1cc(N2CCC(N(C)C)CC2)ccc1[N+](=O)[O-]
Product: COc1cc(N2CCC(N3CC[C@@H](O)C3)CC2)ccc1[N+](=O)[O-]

Procedure:
(R)-1-[1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-yl]-pyrrolidin-3-ol was prepared in an analogous fashion to [1-(3-Methoxy-4-nitro-phenyl)-piperidine-4-yl]dimethyl-amine of Example 475a replacing Dimethylamine with (R)-Pyrrolidin-3-ol. The crude material was purified via trituration with Et2O to yield a yellow solid, MP 137-139° C. (248 mg, 64%). LC/MS (E/I+) 322.16 (M+H).
Reaction SMILES: [Na].Cl[C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[CH:32][CH:33]=1)[N:8]=[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3[N:26]=[C:25]([NH2:27])[C:24]4[C:19](=[CH:20][C:21]([O:30][CH3:31])=[C:22]([O:28][CH3:29])[CH:23]=4)[N:18]=3)[CH2:13][CH2:12]1)[N:10]=2.O.[CH2:35]([OH:37])[CH3:36]>>[CH2:35]([O:37][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[CH:32][CH:33]=1)[N:8]=[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3[N:26]=[C:25]([NH2:27])[C:24]4[C:19](=[CH:20][C:21]([O:30][CH3:31])=[C:22]([O:28][CH3:29])[CH:23]=4)[N:18]=3)[CH2:13][CH2:12]1)[N:10]=2)[CH3:36]
Reactant: COc1cc2nc(N3CCN(c4nc5ccc(Cl)ccc-5n4)CC3)nc(N)c2cc1OC
Reactant: CCO
Agent: [Na]
Solvent: O
Product: CCOc1ccc2nc(N3CCN(c4nc(N)c5cc(OC)c(OC)cc5n4)CC3)nc-2cc1
Reaction time: 2 h

Procedure:
A solution of sodium (0.53 g) in ethanol (22 ml) was added over a period of 1 hr to a suspension of 2-[4-(6-chloro-2-cycloheptimidazolyl)-1-piperazinyl]-6,7-dimethoxy-4-quinazolinamine (2.6 g, described in Example 2). The resulting mixture was stirred at 20°-25° C. for 2 hr, refluxed for 1 hr, cooled and poured into water at 0° to 5° C. The precipitate was collected, washed with water, dried and chromatographed through silica gel using methanoldichloromethane (1:9). The eluates were evaporated to give the title compound (1.18 g): mp>250° C.; ir (nujol) 3430, 3300 and 3170 cm-1 ; uv max (MeOH) 214 (ε=27685), 253 (ε=70380), 275 (ε=38560), 370 (ε=38560) and 390 nm (ε=21950); nmr (DMSO-d6) δ 1.4 (t, 3H), 3.9 (m, 14H), 6.75 (s, 1H), 7.17 (s, 2H), 7.4 (s, 1H), and 7.5-8 (m, 4H); and Anal. Calcd for C24H27N7O3 : C, 62.46% H, 5.90% N, 21.24% and Found: C, 62.13% H, 6.01% N, 20.95%.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[CH3:19][S:20]([NH:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:22])=[O:21]>>[F:14][C:11]1[CH:12]=[CH:13][C:8]2[CH2:7][CH2:6][C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[C:3](=[CH:2][C:26]3[CH:25]=[C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])[CH:29]=[CH:28][CH:27]=3)[C:9]=2[CH:10]=1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: Fc1ccc2c(c1)C(=CBr)c1ccccc1CC2
Product: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3ccc(F)cc32)c1

Procedure:
Following the procedures essentially as described in Example 219, below, and using 5-bromomethylene-3-fluoro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (200 mg, 0.660 mmol) and 3-methanesulfonylaminophenylboronic acid (156 mg, 0.726 mmol), affords 212 mg (82%) of a mixture of geometric isomers of the title compound as a yellow solid. MS (ES) 411 (M+NH4), 392 (M−H); HPLC shows 98% purity.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:28]2[C:22]([C:23](Cl)([N:25]=[CH:26][N:27]=2)[NH2:24])=[N:21][CH2:20]1)(=[O:3])[CH3:2].N[C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1.C(N(CC)CC)C>C(O)C>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:28]2[N:27]=[CH:26][N:25]=[C:23]([NH:24][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=3)[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2]
Reactant: Nc1cccc(O)c1
Reactant: CC(=O)OC[C@H]1O[C@@H](N2CN=C3C2=NC=NC3(N)Cl)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Nc4cccc(O)c4)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Yield: 24.8 %

Procedure:
To a solution of O2′,O3′,O5′-tri-acetyl-6-chloroadenosine (5.4 g) in absolute ethanol (30 mL) were added 3-aminophenol (4.28 g) and dry triethylamine (3.96 g), and the mixture was refluxed 8 h at 60° C. The solution was allowed to cool and was concentrated in vacuo and the residue was chromatographed (ethyl acetate:petroleumether=2:1) to give O2′,O3′,O5′-tri-acetyl-N6-(3-hydroxylphenyl)adenosine as a white solid (1.51 g).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9](=[O:21])[CH2:10][C:11](=[O:20])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:25]([C:10]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:11](=[O:20])[CH:12]=[CH:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:9](=[O:21])[CH:8]=[CH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: O=C(C=Cc1ccccc1)CC(=O)C=Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1)C(Cc1ccccc1)(Cc1ccccc1)C(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 121.7 %

Procedure:
1,7-Diphenyl-1,6-heptadiene-3,5-dione (3b, 0.25 g, 0.9 mmol) was stirred in dichloromethane (4 ml) for 5 min at room temperature. A solution of sodium hydroxide (80.0 mg, 2.0 mmol), tetrabutylammonium chloride (0.29 g, 1.0 mmol) and water (2 ml) was added and the mixture stirred for 10 min at room temperature. Benzyl bromide (10, 0.22 ml, 1.8 mmol) was added and the mixture stirred for 1 hr at 40° C. The resulting mixture was cooled to room temperature, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was chromatographed on silica gel with ethyl acetate/hexane to give a solid. The solid was recrystallized from methanol to give 0.25 g (61%) of a white solid: mp 182-183° C. [expected mp 181° C.]; 1H NMR: δ 3.39 (s, 4H), 6.70 (d, 2H, J=15.5 Hz), 7.09-7.44 (m, 20H), 7.73 (d, 2H, J=15.5 Hz); 13C NMR: δ 37.7, 70.3, 123.1, 126.7, 128.1, 128.6, 128.8, 130.3, 130.7, 134.2, 136.3, 142.7, 196.8.
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].[CH3:47][NH:48][C@H:49]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH3:50]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:48]([CH3:47])[C@H:49]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[CH3:50])=[O:43])[CH2:38][CH2:39]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)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN[C@@H](C)c1ccccc1
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
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C)[C@@H](C)c2ccccc2)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 coupled with N-methyl-N-((S)-1-phenyl-ethyl)amine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C45H54Cl2N5O3 [(M+H)+] 782.3598, observed 782.3596.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH3:14].[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27](O)=O)=[CH:25][C:24]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>O1CCCC1>[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27]3[O:12][C:11](=[O:13])[C:10]4[C:2](=[C:3]([CH3:14])[CH:4]=[C:5]5[CH:6]=[N:7][NH:8][C:9]5=4)[N:1]=3)=[CH:25][C:24]([O:30][CH2:31][C:32]([F:35])([F:33])[F:34])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1cc(OCC(F)(F)F)nn1-c1ncccc1Cl
Reactant: Cc1cc2cn[nH]c2c(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(OCC(F)(F)F)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 500 mg (2.61 mmol) of 6-amino-5-methyl-1H-indazole-7-carboxylic acid in 20 mL of anhydrous tetrahydrofuran is added 790 mg (2.61 mmol) of 2-(3-chloro-pyridin-2-yl)-5-(2,2,2-trifluoro-ethoxy)-2H-pyrazole-3-carboxylic acid followed by 945 μL (11.7 mmol) of pyridine. The mixture is stirred at ambient temperature during 30 minutes. Then the suspension is cooled to 0° C. and 708 μL (9.1 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at 50° C. for 16 hours. Then the solvent is evaporated and the residue is triturated with a minimum of cold water. The precipitate, which is formed is filtrated and washed with cold water. The pale yellowish product obtained (1.0 g) is engaged in the next step: LC/MS:477/479 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:19]3[CH:18]([CH2:20][C:21]([O:23][CH2:24]C)=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3[C:8]2=[C:9]([F:26])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=1.C[C@H](NC)[C@H](O)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19]3[CH:18]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3[C:8]2=[C:9]([F:26])[CH:10]=[CH:11][CH:12]=3)=[CH:27][CH:28]=1
Reactant: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(F)cccc21
Agent: CN[C@@H](C)[C@H](O)c1ccccc1
Product: COC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(F)cccc21

Procedure:
Following the method of Example 18, but using the ethyl ester from Example 15 in Step I and using 1(-)ephedrine in Step II, there is obtained the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C:12]([CH:16]1[CH2:20][CH2:19][C:18](=O)[CH2:17]1)([CH3:15])([CH3:14])[CH3:13].N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:18]1([CH2:19][CH2:20][CH:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:17]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CC(C)(C)C1CCC(=O)C1
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)C1CCC2(CC(=O)c3cc(Br)ccc3O2)C1
Yield: 88.5 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (573 mg, 2.68 mmol), 3-tert-butylcyclopentanone (750 g, 5.36 mol) and pyrrolidine (362 mg, 5.092 mol) in methanol was refluxed overnight. The reaction mixture was removed in vacuo. The residue was diluted with an equal volume of H2O and then added HCl until pH=1. The mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-3′-tert-butylspiro[chroman-2,1′-cyclopentan]-4-one (0.8 g, 89%). 1H NMR (CDCl3): 0.77 (s, 9H), 1.34 (m, 1H), 1.48 (m, 2H), 1.63 (m, 2H), 1.81 (m, 2H), 2.09 (m, 2H), 2.72 (m, 2H), 6.73 (t, 1H), 7.47 (d, 1H), 7.89 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[O:20]=[C:21]1[C:26]2[CH:27]=[C:28]([C:30](O)=[O:31])[O:29][C:25]=2[CH2:24][CH2:23][CH2:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:30]([C:28]1[O:29][C:25]2[CH2:24][CH2:23][CH2:22][C:21](=[O:20])[C:26]=2[CH:27]=1)=[O:31]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1cc2c(o1)CCCC2=O
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1cc2c(o1)CCCC2=O

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-oxo-4,5,6,7-tetrahydro-benzofuran-2-carboxylic acid. MS: 422.4 (M+H).