Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][CH2:10][OH:11])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH2:12]([C:14]1[O:18][C:17]([CH2:19][CH2:20][NH:21][C:22]([NH:24][C:25]2[S:26][C:27]([C:31]3[CH:36]=[C:35]([CH3:37])[N:34]=[C:33](S(C)=O)[N:32]=3)=[C:28]([CH3:30])[N:29]=2)=[O:23])=[N:16][CH:15]=1)[CH3:13]>>[CH2:12]([C:14]1[O:18][C:17]([CH2:19][CH2:20][NH:21][C:22]([NH:24][C:25]2[S:26][C:27]([C:31]3[CH:36]=[C:35]([CH3:37])[N:34]=[C:33]([O:11][CH2:10][CH2:9][N:3]4[CH2:8][CH2:7][O:6][CH2:5][CH2:4]4)[N:32]=3)=[C:28]([CH3:30])[N:29]=2)=[O:23])=[N:16][CH:15]=1)[CH3:13]
Reactant: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(S(C)=O)n3)s2)o1
Reactant: OCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Product: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(OCCN4CCOCC4)n3)s2)o1
Temperature: 70 °C

Procedure:
Sodium hydride (0.020 mg, 0.50 mmol) is added to a stirred solution of 2-morpholin-4-yl-ethanol (0.084 ml, 0.69 mmol) and 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(2-methanesulfinyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-urea (Example 40) (0.10 g, 0.23 mmol). The reaction is heated at 70° C. for 8 hours then allowed to cool and filtered. The filtrate is evaporated and the residue is dissolved in DCM (50 ml) and washed with water (3×50 ml). The product is extracted into 1M HCl and the aqueous phase is washed with DCM. The aqueous phase is then basified with aq. NaOH and the product is re-extracted into DCM. After drying (MgSO4) the solvent is removed to give the titled compound.
Reaction SMILES: [N+](C1C=CC(C([O:10][C@H:11]2[CH2:14][C@H:13]([N:15]3[C:19]4=[N:20][CH:21]=[N:22][C:23]([NH2:24])=[C:18]4[C:17]([C:25]4[CH:30]=[CH:29][C:28]([O:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[CH:27][CH:26]=4)=[N:16]3)[CH2:12]2)=O)=CC=1)([O-])=O.[OH-].[K+]>CO>[NH2:24][C:23]1[N:22]=[CH:21][N:20]=[C:19]2[N:15]([C@H:13]3[CH2:12][C@H:11]([OH:10])[CH2:14]3)[N:16]=[C:17]([C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:29][CH:30]=3)[C:18]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@H]1C[C@H](O)C1
Yield: 89.6 %

Procedure:
A solution of trans 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutyl 4-nitrobenzoate (0.081 g, 0.000164 mol) in methanol (5 mL) was reacted with potassium hydroxide (0.091 g, 0.00164 mol) at reflux for one hour. The solvent was removed in vacuo and the residue was partitioned between water (10 mL) and ethyl acetate (5 mL). The layers were separated and the water layer was extracted aqueous with ethyl acetate (2×5 mL). The combined organics were washed with 1 N aqueous sodium hydroxide (5 mL) and brine (5 mL). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was suspended in water and lyopholyzed to give trans 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclobutanol (0.055 g, 0.000147 mol) as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[CH2:18](I)[CH3:19].[H-].[Na+].O1CCCC1>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([N:12]([CH2:18][CH3:19])[CH2:13][C:14]([F:16])([F:17])[F:15])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1cc(NCC(F)(F)F)ncn1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC#CCOc1cc(N(CC)CC(F)(F)F)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
In 2 ml of N,N-dimethylformamide were dissolved 40 mg of 4-(2-butynyloxy)-6-(2,2,2-trifluoroethylamino)pyrimidine and 31 mg of ethyl iodide, to which 8 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 1 hour. Then, 6 ml of tetrahydrofuran was added, and the mixture was further stirred at room temperature for 4.5 hours. Then, ice water was added to the reaction mixture, from which the tetrahydrofuran was distilled out under reduced pressure. The residue was extracted with tert-butyl methyl ether. The organic layer was washed twice with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel thin layer chromatography to give 37 mg of 4-(2-butynyloxy)-6-(N-ethyl-N-2,2,2-trifluoroethylamino)pyrimidine (the present compound (115)).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[C:12]3[O:14][CH2:15][O:16][C:11]3=[CH:10][C:4]=2[S:5][C:6]=1[C:7](O)=[O:8].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(O)(C)C.[Cl-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]2[CH:13]=[C:12]3[O:14][CH2:15][O:16][C:11]3=[CH:10][C:4]=2[S:5][C:6]=1[CH2:7][OH:8]
Reactant: O=C(O)c1sc2cc3c(cc2c1Cl)OCO3
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: OCc1sc2cc3c(cc2c1Cl)OCO3
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.14 mol of the compound obtained in Step B is added at 5° C. under an inert atmosphere to a solution of 0.15 mol of LiAlH4 in 450 ml of tetrahydrofuran. After 2 hours' reaction at ambient temperature, the reaction mixture is hydrolysed by the addition of 85 ml of isopropanol and 31 ml of saturated sodium chloride solution. After stirring for 12 hours at ambient temperature, the reaction mixture is filtered over Celite. The organic phase is then concentrated under reduced pressure, taken up in dichloromethane and washed with water and then with saturated NaCl solution. After the organic phase has been dried over calcium sulphate, the solution is concentrated under reduced pressure, allowing the expected product to be obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]=[N:6][NH:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:25])[F:24])[CH2:12][CH2:11]1)=[O:9])[CH3:2].C([O-])(=O)C.[Na+].BrBr>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[O:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:25])([F:24])[F:26])[CH2:12][CH2:11]2)=[N:7][N:6]=1)=[O:28])[CH3:2]
Reactant: CCOC(=O)C=NNC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a solution of {[4-(2-trifluoromethylbenzoyl)piperazine-1-carbonyl]-hydrazono}acetic acid ethyl ester (1.32 g, 3.29 mmol) and sodium acetate (1.01 g, 12.31 mmol) in acetic acid (5 mL) was added a solution of bromine (0.480 g, 3 mmol) in acetic acid (2 mL) at 0° C. The mixture was stirred for 1 hour at 0° C. and another hour at room temperature and then refluxed for 30 minutes. The solvents were removed in vacuo. The residue was diluted with water, extracted with dichloromethane. The organic layer was washed with water and then concentrated to yield the crude product. The title compound was obtained as a white solid in 49% yield (0.550 g) after purification by flash column chromatography.
Reaction SMILES: [F:1][C:2]([F:26])([CH:15]([F:25])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)[CH2:3][N:4]1C(=O)C2C(=CC=CC=2)C1=O>C(O)C.O1CCCC1.O.NN>[F:1][C:2]([F:26])([CH:15]([F:25])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)[CH2:3][NH2:4]
Reactant: O=C1c2ccccc2C(=O)N1CC(F)(F)C(F)c1cccc([N+](=O)[O-])c1
Agent: NN
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: NCC(F)(F)C(F)c1cccc([N+](=O)[O-])c1
Reaction time: 18 h
Yield: 65.6 %

Procedure:
To a solution of 2-(2,2,3-trifluoro-3-(3-nitrophenyl)propyl)isoindoline-1,3-dione (C33, 531 mg) in ethanol (4 mL) and tetrahydrofuran (4 mL), hydrazine monohydrate (349 μL) was added at room temperature, and the mixture was stirred at the same temperature for 18 hours. The insoluble matter was removed by filtration, and then the solvent was evaporated under reduced pressure to obtain 2,2,3-trifluoro-3-(3-nitrophenyl)propan-1-amine (C34, 224 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:42][C:43]([F:52])([F:51])[C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47]>CN(C)C=O.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:47][C:46]2[CH:48]=[CH:49][CH:50]=[C:44]([C:43]([F:42])([F:51])[F:52])[CH:45]=2)=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(Br)ccn1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 21 h
Yield: 75.7 %

Procedure:
To a suspension of 4-bromo-pyridine-2-carboxylic acid (1.00 g, 5.00 mmol) in dimethylformamide (5 mL) was added 1-methylmorpholine (1.1 mL, 10 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (HATU) (2.37 g, 6.23 mmol). The mixture became an orange solution after 10 minutes. 3-Trifluoromethylaniline (0.5 mL, 5.5 mmol) was added and the solution was stirred at room temperature for 21 hours. The dimethylformamide was evaporated in vacuo and the residue was triturated with water. The resulting solid was filtered and washed twice with water and then vacuum dried at 40° C. to give a crude residue. Chromatography on silica gel (40 g), sample applied in dichloromethane and eluted with hexanes:ethyl acetate (1:1) gave the title compound (1.306 g, 76%).
Reaction SMILES: C([O:3][C:4](=[O:44])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[C:11]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:44])=[O:3])=[CH:10][C:11]=3[CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)c(CCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1CCc1ccccc1
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-phenethylphenoxy}-2-methylpropionic acid ethyl ester (0.57 mmol) in ethanol (10 mL) was treated with 2.5 N aqueous NaOH (1.1 mL), and heated at 55° C. for 2 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with ethyl acetate (40 mL) and water (20 mL) and acidified to ph=1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-phenethylphenoxy}-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) δ8.03 (d, J=8.3 Hz, 2H), 7.67-7.62 (m, 4H), 7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.3 Hz, 1H), 7.26-7.21 (m, 3H), 7.15 (t, J=7.3 Hz, 1H), 7.08 (d, J=6.8 Hz, 2H), 6.76 (d, J=1.5 Hz, 2H), 6.64 (s, 1H), 4.24 (t, J=6.4 Hz, 2H), 3.00 (t, J=6.4 Hz, 2H), 2.87-2.79 (m, 4H), 2.35 (s, 3H), 1.43 (s, 6H), MS (ES) m/e 562 (M+1).
Reaction SMILES: FC1(F)CCN(C(C2NC3C(C=2)=CC(O[CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=CC=3)=O)CC1.[CH2:30]([O:32][C:33]([C:35]1[NH:36][C:37]2[C:42]([CH:43]=1)=[CH:41][C:40]([OH:44])=[C:39]([Br:45])[CH:38]=2)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([C:35]1[NH:36][C:37]2[C:42]([CH:43]=1)=[CH:41][C:40]([O:44][CH:20]1[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]1)=[C:39]([Br:45])[CH:38]=2)=[O:34])[CH3:31]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: CCOC(=O)c1cc2cc(O)c(Br)cc2[nH]1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)c(Br)cc2[nH]1

Procedure:
In analogy to the procedure described for the synthesis of intermediate 1, step 2, the title compound was synthesized from 6-bromo-5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (example 41, step 3). The title compound was obtained in 56% yield as light yellow solid. MS (m/e): 409.0 (MH+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2/[CH:14]=[N:15]/[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:4][CH:3]=1.[C:20]1([CH2:26][CH2:27][CH2:28][Mg]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1/C=N/S(C)(=O)=O
Reactant: Br[Mg]CCCc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(CCCc1ccccc1)NS(C)(=O)=O

Procedure:
Prepared according to the procedure described in Example 114, Step 3, using N-[1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-meth-(E)-ylidene]-methanesulfonamide and 3-(phenyl)propylmagnesium bromide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[F:17][C:18]([F:35])([F:34])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]([C:31](Cl)=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>>[CH2:15]([O:14][C:12]([C:3]1[CH:4]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:31]([C:26]1[C:25]([C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:17])([F:34])[F:35])=[CH:20][CH:21]=2)=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:32])=[O:13])[CH3:16]
Reactant: CCOC(=O)c1cc(CC(=O)O)ccc1N
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1cc(CC(=O)O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 58.6 %

Procedure:
The 4-amino-3-ethoxycarbonylphenylacetic acid (1.51 g) obtained in Example 9-4d) and 4′-trifluoromethylbiphenyl-2-carboxylic acid chloride (1.99 g) were subjected to reactions similar to those in Example 7a) with the proviso that sodium bicarbonate was used as a base, thereby the title compound (1.87 g) was given as a pale yellow amorphous powder.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[C:12]([NH:14][CH3:15])[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>O1CCCC1>[C:23]([N:11]1[C:12]([NH:14][CH3:15])=[N:13][C:9]([S:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:10]1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: CNc1nc(SCc2ccccc2)n[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNc1nc(SCc2ccccc2)nn1C(C)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-Benzylthio-5-methylamino-1,2,4-triazole (11.2 g) was dissolved in tetrahydrofuran (70 ml) and triethylamine (5.7 g) was added. Acetyl chloride (4 ml) in tetrahydrofuran (20 ml) was added, and the mixture was stirred at room temperature for 5 hours. The triethylamine hydrochloride was filtered off, and the filtrate was concentrated to give 13.4 g of the desired crude product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[OH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:3][C:4]2=[O:18])=[CH:11][CH:12]=1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Reactant: BrCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccncc2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 400 mg (1.63 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 20 mL DMF is added 0.45 g (1.79 mmol) 4-bromomethyl-pyridine and 0.68 g (4.89 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, diluted with 60 mL of EtOAc and is washed twice with water. The organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Waters symmetry C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][CH:7]([C:12](=[O:14])[CH3:13])[C:8]([O:10][CH3:11])=[O:9])=[O:4]>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:5][CH2:6][C@@H:7]([C@H:12]([OH:14])[CH3:13])[C:8]([O:10][CH3:11])=[O:9])=[O:4]
Reactant: COC(=O)C(CNC(=O)CCl)C(C)=O
Solvent: ClCCl
Product: COC(=O)[C@@H](CNC(=O)CCl)[C@@H](C)O
Yield: 79.6 %

Procedure:
In a 100 ml-volume stainless steel autoclave whose atmosphere had been displaced with nitrogen was added a solution of 2.21 g (10 mmole) of methyl 2-(N-chloroacetylamino)methyl-3-oxobutanoate and 180 mg (0.1 mmol) of Ru2Cl4 ((+)-T-BINAP)2NEt3 in 20 ml of methylene chloride, and a reaction was conducted at 50° C. under a hydrogen pressure of 100 kg/cm2 for 20 hours. The reaction mixture was concentrated under reduced pressure of 20 mmHg and purified by silica gel chromatography using a 8/2 (by volume) mixture of hexane and isopropanol as an eluent to obtain 1.78 g (yield: 80%) of methyl (2S, 3R)-2-(N-chloroacetylamino)methyl-3-hydroxybutanoate having an optical purity of 95 %ee as determined in the same manner as in Example 2.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].C(N(CC)CC)C.[C:18]([NH:20][C:21](=[N:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH2:39][CH2:40][CH2:41][N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])=[C:32]([O:47][CH3:48])[CH:31]=1)OC1C=CC=CC=1)#[N:19].FC(F)(F)C(O)=O.C(N(CC)CC)C>CC(N(C)C)=O>[CH2:45]([N:42]([CH2:43][CH3:44])[CH2:41][CH2:40][CH2:39][O:38][C:33]1[C:32]([O:47][CH3:48])=[CH:31][C:30]([NH:29][C:21]2[N:20]=[C:18]([NH2:19])[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[F:2])[N:10]=2)=[CH:35][C:34]=1[O:36][CH3:37])[CH3:46]
Reactant: CCN(CC)CCCOc1c(OC)cc(N=C(NC#N)Oc2ccccc2)cc1OC
Reactant: NNc1ccccc1F
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCN(CC)CCCOc1c(OC)cc(Nc2nc(N)n(-c3ccccc3F)n2)cc1OC
Temperature: 120 °C
Reaction time: 20 h
Yield: 4 %

Procedure:
A solution of 2-fluoro-phenylhydrazine hydrochloride (0.15 g, 0.91 mmol) and triethylamine (0.13 mL, 0.91 mmol) in dimethylacetaimde (1 mL) was stirred 0.5 h at room temperature. N-cyano-N′-(4-(3-diethylamino-propoxy)-3,5-dimethoxy-phenyl)-O-phenylisourea (0.30 g as a mixture with triethylamine-trifluoroacetic acid salt, 0.45 mmol) in dimethylacetamide (1 mL) was added and the reaction was stirred at 120° C. for 20 h. The precipitate was removed and the filtrate was washed with ether. The remaining aqueous phase was evaporated and was purified by semi-preparative HPLC to provide the title compound (0.01 g, 4% yield) as a yellow lyophilate.
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]([S:8]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:10])=[O:9])([CH3:7])[CH3:6])C.O.[OH-].[Li+]>O1CCOCC1.O.O>[CH:11]1([S:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:16])=[O:3])(=[O:10])=[O:9])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)C1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C(=O)O)S(=O)(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
To a solution of 5.4 g (21.7 mmol) of 2-cyclopentanesulfonyl-2-methyl-propionic acid ethyl ester in THF/water (4/1, 60 mL) are added 2.3 g (56.6 mmol) of lithium hydroxide monohydrate. The reaction is stirred at room temperature for 18 h. The reaction is further diluted with water (20 mL) and then washed with DCM (2×15 mL). The basic aqueous layer is cooled in an ice bath and then acidified with 2M aqueous HCl solution to pH 2. The acidic aqueous layer is extracted with 2-propanol/chloroform (1/4, 100 mL). The combined organic extracts are washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate under reduced pressure affords 4.34 g of 2-cyclopentanesulfonyl-2-methyl-propionic acid. Yield: 92%, ES-MS: m/z 221 [M+H]
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:22]([NH2:26])[CH:23]([CH3:25])[CH3:24]>C1COCC1.CN(C=O)C>[CH2:22]([NH:26][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=1)[CH:23]([CH3:25])[CH3:24]
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: CC(C)CN
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)CNC(=O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Oxalyl chloride (132 μL, 1.5 mmol) was added over a 10 minute period to a mixture of 3-phenylbenzoic acid (200 mg, 1 mmol) dissolved in a mixture THF/DMF (3.5 mL/58 μL). After the addition, the reaction was stirred at room temperature for 2.5 hours. Isobutylamine (247 μL, 2.5 mmol) was then added into half of the acid chloride solution at 0° C. The reaction was then stirred at room temperature for 18 hours. The reaction was concentrated and water was added to the residue. The aqueous phase was extracted 3 times with CH2Cl2. The combined organic layers were washed with 2N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. Diethyl ether was added to the residue and a white solid precipitated. It was collected by filtration and rinsed with a small amount of diethyl ether. The white solid was then dried under vacuum (102 mg, 71%). NMR 1H (ppm, CDCl3): 7.97 (t, J4=1.71 Hz, 1H), 7.70 (dd, J3=7.65 Hz, J4=1.77 Hz, 2H), 7.62-7.58 (m, 2H), 7.51-7.34 (m, 4H), 6.18 (br. s., 1H), 3.33-3.29 (m, 2H), 1.91 (n, J3=6.71 Hz, 1H), 0.98 (d, J3=6.68 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:10]2=[C:11]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:12]=[C:13]([C:15]3[NH:19][N:18]=[N:17][N:16]=3)[CH:14]=[C:9]2[C:8]([CH3:30])=[C:7]1[CH3:31].[C:35](=O)([O-])[O-].[K+].[K+].CN(C)C=O.IC>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:10]2=[C:11]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:12]=[C:13]([C:15]3[N:19]([CH3:35])[N:18]=[N:17][N:16]=3)[CH:14]=[C:9]2[C:8]([CH3:30])=[C:7]1[CH3:31]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(C)n(Cc2cccc(Cl)c2)c2c(N3CCc4ccccc4C3)nc(-c3nnn[nH]3)cc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cc1c(C)n(Cc2cccc(Cl)c2)c2c(N3CCc4ccccc4C3)nc(-c3nnnn3C)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
2-[1-(3-Chlorobenzyl)-2,3-dimethyl-5-(1H-tetrazol-5-yl)-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline (50 mg, 0.11 mmol) prepared in Example 852 and potassium carbonate (22.1 mg, 0.16 mmol) were dripped into anhydrous N,N-dimethylformamide (1 ml). Iodomethane (10 t, 0.16 mmol) was added to the reaction mixture, which was then stirred overnight at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v) to give 18 mg of the titled compound as a white solid (Yield: 34%).
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([Cl:18])=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[C:22]([C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH2:30][NH:29][CH2:28][CH2:27]2)#[N:23]>>[ClH:18].[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([N:29]3[CH2:28][CH2:27][C:26]4[C:31](=[CH:32][CH:33]=[C:24]([C:22]#[N:23])[CH:25]=4)[CH2:30]3)=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Cl)c1ccc(OCCCN2CCCCC2)cc1
Reactant: N#Cc1ccc2c(c1)CCNC2
Agent: Cl
Product: N#Cc1ccc2c(c1)CCN(C(=O)c1ccc(OCCCN3CCCCC3)cc1)C2

Procedure:
The title compound was prepared from 4-(3-piperidin-1-ylpropoxy)benzoyl chloride hydrochloride (D3) (0.20 g) and 6-cyano-1,2,3,4-tetrahydroisoquinoline hydrochloride (WO98/50363) (0.15 g) using the procedure described for Example 1 and isolated as a white solid (0.13 g). MS electrospray (+ion) 404 (MH+). 1H NMR δ (DMSO-d6): 10.20 (1H, s), 7.69 (1H, s), 7.65 (1H, d, J=7.5 Hz), 7.45 (3H, m), 7.02 (2H, d, J=8.6 Hz), 4.76 (1H, s), 4.11 (1H, t, J=5.9), 3.68 (2H, m), 3.44 (2H, m), 3.17 (2H, m), 2.90 (4H, m), 2.19 (2H, m), 1.78-1.37 (6H, m).