Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5]OC.[CH3:19][C:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[C:22]([CH3:27])[N:21]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[CH3:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[CH3:15])[C:8]([C:4]1[C:3](=[O:18])[C:24]2[C:25](=[C:20]([CH3:19])[N:21]=[C:22]([CH3:27])[CH:23]=2)[NH:26][CH:5]=1)=[O:17]
Reactant: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Reactant: Cc1ccc(N)c(C)n1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: Cc1cc2c(=O)c(C(=O)c3ccc(C)c(C)c3)c[nH]c2c(C)n1
Temperature: 250 °C
Yield: 7.3 %

Procedure:
0.50 g (2.01 mmol) of 2-(3,4-Dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester and 0.25 g (2.01 mmol) of 2,6-Dimethyl-pyridin-3-ylamine were heated at 100° C. for two hours. After cooling to room temperature 30 mL of diphenyl ether was added and heated at 250° C. for two hours. The reaction was allowed to cool to room temperature and hexane was added. The brown precipitate was collected by filtration to yield 45 mg of 3-(3,4-Dimethyl-benzoyl)-6,8-dimethyl-1H-[1,7]naphthyridin-4-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][C:8]=1[OH:9].[CH3:14][CH:15]([CH3:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](O)=[O:23]>CCCCCC>[CH3:14][CH:15]([CH3:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:13][CH2:12][CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:23]
Reactant: COc1cc(CCCO)ccc1O
Reactant: CC(C)CCCCCCC(=O)O
Solvent: CCCCCC
Product: COc1cc(CCCOC(=O)CCCCCCC(C)C)ccc1O
Temperature: 50 °C
Yield: 95.7 %

Procedure:
3-(3-Methoxy-4-hydroxyphenyl)propyl alcohol (833 mg, 4.57 mmol), 8-methylnonanoic acid (753 mg, 4.35 mmol) and Novozyme 435 (51 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr while reducing the pressure by an aspirator. The reaction mixture was allowed to cool to room temperature, n-hexane (25 ml) was added, and Novozyme 435 and the precipitated insoluble material were removed by filtration. N-hexane (50 ml) was added, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2), saturated brine (25 ml), 5% aqueous sodium hydrogen carbonate solution (25 ml×2) and saturated brine (25 ml), and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (n-hexane:ethyl acetate=3:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give 3-(3-methoxy-4-hydroxyphenyl)propyl 8-methylnonanoate (1.40 g, yield 95.4%) as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](=[O:26])[CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:10]=2)[O:5][C:4]([CH3:28])([CH3:27])[CH2:3]1.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>ClCCl.CN(C1C=CN=CC=1)C.O>[CH3:27][C:4]1([CH3:28])[CH2:3][CH:2]([O:1][S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](=[O:26])[CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:10]=2)[O:5]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(CC(=O)c2ccc3c(c2)C(O)CC(C)(C)O3)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COc1cc(CC(=O)c2ccc3c(c2)C(OS(=O)(=O)c2ccc(C)cc2)CC(C)(C)O3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution 1-(4-hydroxy-2,2-dimethyl-chroman-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethanone (3.5 mg, 0.009 mmol) dissolved in anhydrous dichloromethane (1.0 mL) is added TsCl (1.94 mg, 0.011 mmol), DMAP (1.24 mg, 0.011 mmol) and TEA (21.3 μL, 0.015 mmole). The reaction mixture continues stirring at room temperature overnight. The next day, the reaction mixture is diluted with water. The aqueous layer is separated and extracted with ethyl acetate (3×). All combined organic layers are dried over Na2SO4, filtered, and concentrated to yield an oil. The crude material is purified using silica gel chromatography to yield the desired product.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]#[CH:18])[CH:16]=1>C(N(CC)CC)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:10][C:11]1[CH:16]=[C:15]([C:17]#[C:18][C:2]2[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=2)[CH:14]=[N:13][CH:12]=1
Reactant: C#Cc1cncc(Cl)c1
Reactant: Cc1ccc(N)c(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(N)c(C#Cc2cncc(Cl)c2)n1
Yield: 72.5 %

Procedure:
Following the same procedure as described in Example 1, (2-bromo-6-methyl-pyridin-3-yl)amine (150 mg, 0.80 mmol) reacted with (PPh3)2PdCl2 (28 mg, 40 μmol), Cul (8 mg, 40 μmol) and 3-chloro-5-ethynyl-pyridine (165 mg, 1.20 mmol) in triethylamine (5 ml). The crude residue was purified by flash chromatography (hexane/ethyl acetate 7:3) to yield 141 mg (0.58 mmol, 72%) of (2-(5-chloro-pyridin-3-ylethynyl)-6-methyl-pyridin-3-yl)amine as a yellow solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:40]3[O:41][C:42]4[CH:48]=[CH:47][C:46]([CH2:49][CH3:50])=[CH:45][C:43]=4[N:44]=3)=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:33]3[CH:38]=[CH:37][C:36]([NH:39][C:40]4[O:41][C:42]5[CH:48]=[CH:47][C:46]([CH2:49][CH3:50])=[CH:45][C:43]=5[N:44]=4)=[CH:35][CH:34]=3)[C:10]=12
Reactant: CCc1ccc2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Reactant: CN1CCN(C2CCC(n3nc(I)c4c(N)ncnc43)CC2)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: O
Solvent: COCCOC
Product: CCc1ccc2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 80 °C

Procedure:
A mixture of 3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.06 g, 0.00014 mol), N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-ethyl-1,3-benzoxazol-2-amine (0.062 g, 0.00017 mol), tetrakis(triphenylphosphine)palladium (0.011 g, 0.00001 mol) and sodium carbonate (0.037, 0.00035 mol) in ethylene glycol dimethyl ether (3 mL) and water (1 mL) was heated at 80° C. for 16 hours. The mixture was allowed to cool to ambient temperature, and the solvent was removed under the reduced pressure. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure, and the residue was purified by flash column chromatography on silica using 2% aqueous ammonium hydroxide solution/5%-25% methanol/dichloromethane as a mobile phase. The solvent was removed under reduced pressure to give cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-ethyl-1,3-benzoxazol-2-amine (0.065 g, 0.00012 mol). 1H NMR (DMSO-d6, 400 MHz) δ 11.25 (s, 1H), 8.65 (s, 1H), 8.37 (d, 2H), 8.09 (d, 2H), 7.84 (d, 1H), 7.76 (s, 1H), 7.42 (d, 1H), 5.22 (br, 1H), 3.13 (q, 2H), 2.52 (br, 7H), 2.69 (br, 4H), 2.64 (s, 3H), 2.49 (br, 2H), 2.11 (br, 2H), 2.01 (br, 2H), 1.63 (t, 3H). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-95% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 10.3 min. MS: MH+ 552
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])=[O:5])[CH3:2].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C.ClCCl>[C:18]([O:17][C:13]([CH2:14][CH2:15][C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCOC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CCOC(=O)C1(CCC(=O)OC(C)(C)C)CCCCC1=O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 2-ethoxycarbonylcyclohexanone (5.0 g, 0.029 mol) and tert-butyl acrylate (4.83 g, 0.037 mol) in tert-butanol (30 ml) was added, in one portion, potassium carbonate (4.0 g, 0.029 mol). The suspension was stirred at room temperature for 22 hours, diluted with dichloromethane (100 ml) and distilled water (100 ml) and the layers separated. The aqueous layer was extracted with dichloromethane (2×100 ml) and the combined dichloromethane extracts dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica by eluting with hexane/ethyl acetate (4:1) to give, after combination and evaporation of appropriate fractions, the title compound as a colorless oil, (7.99 g, 92.3%; 98.92% by GC normalization) (MH+ 299.03, 8.53%). Rf. 0.15 (silica, hexane/ethyl acetate 4:1). 1H-NMR (300 MHz, CDCl3):=1.20 (t, 3H), 1.37 (s, 9H), 1.52-2.46 (m, 12H), 4.08-4.21 (m, 2H) ppm. 13C-NMR (62 MHz, CDCl3):=13.97, 22.38, 27.36, 27.91, 29.52, 30.49, 36.06, 40.85, 59.87, 61.19, 80.10, 171.61, 172.22, 207.39 ppm. Analysis %: Found: C, 64.19; H, 8.80; C16H26O5 requires: C, 64.41; H, 8.78.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:18])[CH3:17])[N:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[Cl:8][C:6]1[CH:7]=[C:2]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=[C:4]([N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:18])[CH3:17])[N:5]=1
Reactant: C1CCNC1
Reactant: CC1(C)CCCC(C)(C)N1c1nc(Cl)cc(Cl)n1
Product: CC1(C)CCCC(C)(C)N1c1nc(Cl)cc(N2CCCC2)n1
Yield: 75.08 %

Procedure:
The reaction of 4,6-dichloro-2-(2,2,6,6-tetramethyl-1-piperidinyl) pyrimidine with pyrrolidine as described in Example 7 gives the title compound in a yield of 75.08%, m.p.:130°-135° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[Br-:7].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:42])[CH2:16][N+:17]23[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]2)[C@@H:19]([O:25][C:26](=[O:41])[C@@H:27]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:18]3)=[CH:11][CH:10]=1>C(Cl)Cl>[Br-:7].[CH2:3]([O:2][C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:42])[CH2:16][N+:17]23[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24]2)[C@@H:19]([O:25][C:26](=[O:41])[C@@H:27]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:18]3)=[CH:11][CH:10]=1)=[O:5])[CH3:4]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(C(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)[C@H](Nc2ccccc2)c2ccccc2)C3)cc1
Agent: [Br-]
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc(C(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)[C@H](Nc2ccccc2)c2ccccc2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
Ethyl carbonochloridate (10.5 μl, 0.11 mmol) was added to a solution of (R)-1-(2-(4-aminophenyl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (diastereomer 1 of I74) (60 mg, 0.11 mmol) in TEA (15.2 μl, 0.11 mmol) and DCM (2 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the product was purified by preparative HPLC (eluents: CH3CN/H2O) to obtain (R)-1-(2-(4-(ethoxycarbonylamino)phenyl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (14 mg, 20.6% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=O)[CH3:10].[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]([CH:32]1[C:41]2[N:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH2:35][CH2:34][CH2:33]1)[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH3:10])=[CH:26][CH:25]=1)[CH:32]1[C:41]2[N:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH2:35][CH2:34][CH2:33]1
Reactant: COc1ccccc1C(C)=O
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccccc1C(C)NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.2 %

Procedure:
Using General Procedure B: To a stirred solution of 1-(2-methoxy-phenyl)-ethanone (69 uL, 0.50 mmol), N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (200 mg, 0.50 mmol) and AcOH (0.10 mL, 1.4 mmol) in THF (5 mL) was added NaBH(OAc)3 and the mixture was stirred at room temperature for 48 hours. Purification of the crude light yellow foam (267 mg) by column chromatography on silica gel (100:1:1—CH2Cl2:MeOH:NH4OH) followed by radial chromatography on silica gel (100:1:1—CH2Cl2:MeOH:NH4OH) afforded the desired product (83 mg, 27%) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38][NH2:39]>CN(C=O)C>[Cl:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38][NH:39][C:8]([C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH2:6]1)=[O:10]
Reactant: NCc1ccccc1Cl
Reactant: COC(=O)C1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)C1(C(=O)NCc2ccccc2Cl)CC1
Reaction time: 2 h
Yield: 35.2 %

Procedure:
To a solution of 1-(methoxycarbonyl)cyclopropanecarboxylic acid (500 mg, 3.5 mmol) in DMF (5 mL) were added HATU (1.98 g, 5.2 mmol, 1.5 equiv.) and 2-chlorobenzylamine (622 μL, 5.2 mmol, 1.5 equiv.). The reaction mixture was stirred for 2 h. The reaction mixture was purified twice on RP-HPLC using a mixture of acetonitrile and H2O to give methyl 1-(2-chlorobenzylcarbamoyl)cyclopropanecarboxylate (330 mg, 34%). LRMS (M+H+) m/z 268.0.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:32])[C@H:7]([CH3:31])[CH2:8][C@@H:9]1[O:13]C(C)(C)[N:11](C(OC(C)(C)C)=O)[C@H:10]1[CH2:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26]([OH:28])=O)[CH2:2][CH2:3][CH3:4].[CH3:33][O:34][CH2:35][CH2:36][CH:37]1[CH2:42][NH:41][C:40]2[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=2[O:38]1>>[CH2:1]([NH:5][C:6](=[O:32])[C@H:7]([CH3:31])[CH2:8][C@H:9]([OH:13])[C@@H:10]([NH2:11])[CH2:23][C:24]([CH3:29])([CH3:30])[CH2:25][C:26]([N:41]1[C:40]2[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=2[O:38][CH:37]([CH2:36][CH2:35][O:34][CH3:33])[CH2:42]1)=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H](C)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CC(=O)O
Reactant: COCCC1CNc2ccccc2O1
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC(C)(C)CC(=O)N1CC(CCOC)Oc2ccccc21

Procedure:
Starting from 230 mg of 3-[N-tert-butoxycarbonyl-4(S)-(3-carboxy-2,2-dimethylpropyl)-2,2-dimethyl-1,3-oxazolidin-5(S)-yl]-2(R)-methyl-propionic acid (N-butyl)amide and 193 mg of 2(R,S)-methoxyethyl-3,4-dihydro-2H-1,4-benzoxazine, the title compound is obtained via (4O,5N-isopropylidene)-5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(R),7,7-trimethyl-8-[2(R,S)-methoxyethyl-3,4-dihydro-2H-1,4-benzoxazin-4-ylcarbonyl]-octanoic acid (N-butyl)amide (analogously to Example 1a); Rf (A)=0.19; Rt (VI)=36.6/36.9 min) and 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(R),7,7-trimethyl-8-[2(R,S)-methoxyethyl-3,4-dihydro-2H-1,4-benzoxazin-4-ylcarbonyl]-octanoic acid (N-butyl)amide (Rf (X)=0.36; Rt (VI)=30.6 min; FAB-MS: (M+H)+ =592) in a manner analogous to that described in Example 1) as a diastereomer mixture:Rf (V)=0.32; Rt (VI)=23.7/24.1 min; FAB-MS: (M+H)+ =492.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([C:18]1([NH2:40])[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]2[CH:31]=[C:32]([N+:35]([O-:37])=[O:36])[CH:33]=[CH:34][C:21]=2[N:20]([CH3:38])[C:19]1=[O:39])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([C:18]2([NH2:40])[N:24]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:22]3[CH:31]=[C:32]([N+:35]([O-:37])=[O:36])[CH:33]=[CH:34][C:21]=3[N:20]([CH3:38])[C:19]2=[O:39])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](N)C(=O)C1(N)N=C(c2ccccc2)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)N=C(c2ccccc2)c2cc([N+](=O)[O-])ccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-H), the title compound was prepared as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][N:25]=[C:26]([CH:29](C(OCC)=O)[C:30]([O:32]CC)=[O:31])[CH:27]=4)[N:22]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][O:41]4)[N:21]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][N:25]=[C:26]([CH2:29][C:30]([OH:32])=[O:31])[CH:27]=4)[N:22]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][O:41]4)[N:21]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(C(=O)OCC)c1cc2c(-c3cccc(N4CCN(C(=O)OC(C)(C)C)CC4)n3)nn(C3CCCCO3)c2cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(CC(=O)O)cc34)n2)CC1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
A mixture of diethyl 2-(3-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)malonate (117 mg (0.188 mmol) and 0.5 ml of 1 M aqueous solution of LiOH in 6 ml of methanol/THF mixture (2:1) was heated at 60° C. for 1 hour. The mixture was acidified with 1 N aqueous HCl to pH<1 and stirred for 20 min. The mixture was concentrated, the residue partitioned between ethyl acetate and water. The pH of the mixture was adjusted to 4 by careful addition of saturated aqueous sodium bicarbonate. The organic extracts were washed with brine, dried over MgSO4 and concentrated to afford 2-(3-(6-(4-(tertButoxycarbonyl)piperazin-1-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)acetic acid (68 mg, 32% over two steps. ESI MS m/z 523.4 (M+1).
Reaction SMILES: [H-].[K+].[OH:3][C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.[O:14]1[CH2:18]C[CH2:16][CH2:15]1>CN(C)C=O>[CH3:18][O:14][CH2:15][CH2:16][O:3][C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: C1CCOC1
Reactant: Oc1cnc2ccccc2c1
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.75 g of a potassium hydride suspension (20% in oil) is added to a solution of 0.5 g of 3-hydroxyquinoline in 10 ml of tetrahydrofuran, while cooling with ice, and the mixture is stirred for 1 h. 1.25 ml of 2-bromomethyl methyl ether, dissolved in 10 ml of dimethylformamide, are then added and the mixture is allowed to warm to room temperature and is finally stirred at 60° C. for 1 h. After customary working up, the 3-(Methoxyethoxy)quinoline thus obtained is purified by means of FC over 80 g of silica gel (mobile phase B): Rf (97:3:0.5 mixture of methylene chloride, methanol and concentrated ammonia)=0.31. 1.0 g of the quinoline derivative mentioned in 10 ml of ethanol is hydrogenated in the presence of 0.1 g of palladium-on-charocal (10% of Pd) at 50° C. for 4 h. FC over 50 g of silica gel with a 100:1 mixture of methylene chloride and methanol as the eluting agent gives 3(R,S)-methoxyethoxy-1,2,3,4-tetrahydroquinoline: Rf (97:3:0.5 mixture of methylene chloride, methanol and concentrated ammonia)=0.49; MS: M+ =207.
Reaction SMILES: [NH2:1][C:2](=[N:15][OH:16])[C:3]1[CH:12]=[CH:11][C:6](C(OC)=O)=[CH:5][C:4]=1OC.[OH:17][CH2:18][CH2:19][N:20]([CH2:22]C1C=C(C=CC=1)C#N)[CH3:21]>>[OH:16][NH:15][C:2](=[NH:1])[C:3]1[CH:4]=[CH:5][CH:6]=[C:11]([CH2:21][N:20]([CH2:19][CH2:18][OH:17])[CH3:22])[CH:12]=1
Reactant: COC(=O)c1ccc(C(N)=NO)c(OC)c1
Reactant: CN(CCO)Cc1cccc(C#N)c1
Product: CN(CCO)Cc1cccc(C(=N)NO)c1
Yield: 99 %

Procedure:
The title compound was obtained following procedure and work up described for Intermediate 47 step 2 but starting from 3-{[(2-Hydroxy-ethyl)-methyl-amino]-methyl}-benzonitrile obtained in step 1 (4.9 g, 26.28 mmol) to give the title compound as white gummy solid (5.7 g, 99%). 1H NMR (DMSO-d6, 400 MHz) δ 9.58 (s, 1H), 7.60 (s, 1H), 7.51-7.54 (m, 1H), 7.28-7.31 (m, 2H), 5.76-7.83 (s, 2H), 4.38 (bs, 1H), 3.48-3.51 (m, 4H), 2.40-2.43 (m, 2H), 2.13 (m, 3H). LC/MS (Method A): 224.1 (M+H)+. HPLC (Method B): Rt 0.7 min, (Purity 91.1%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Br[CH2:24][C:25]#[C:26][CH3:27]>>[CH2:13]([O:12][C:10](=[O:11])[CH:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:24][C:25]#[C:26][CH3:27])=[CH:3][CH:4]=1)[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[CH3:14]
Reactant: CC#CCBr
Reactant: CCOC(=O)C(Sc1ccc(O)cc1)c1ccc(OC)cc1
Product: CC#CCOc1ccc(SC(C(=O)OCC)c2ccc(OC)cc2)cc1
Yield: 96 %

Procedure:
Ethyl{[4-(2-butynyloxy)phenyl]sulfanyl}(4-methoxyphenyl)acetate was prepared according to the general method as outlined in example 1 (step 1), starting from ethyl [(4-hydroxyphenyl)sulfanyl](4-methoxyphenyl)acetate (15.82 g, 49.7 mmol) and 4-bromo-2-butyne (4.79 ml, 54.7 mmol); 17.66 g yellow oil. Yield 96%; MS(EI): 370.1 (M+H)+
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[O:23]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:31]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.28 mmol) in acetonitrile (20 ml) were added 3-phenoxybenzoic acid (274 mg, 1.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (368 mg, 1.92 mmol) and 1-hydroxy-1H-benzotriazole (196 mg, 1.28 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (400 mg, 61%).