Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:11]C)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=[O:7].[OH-].[Na+:14]>C(#N)C>[C:1]([O-:11])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7].[Na+:14].[Na+:14]
Reactant: COC(=O)CCCCC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: O=C([O-])CCCCC(=O)[O-]

Procedure:
17.4 g. (0.1 mole) of dimethyl adipate were dissolved in 100 mls. of acetonitrile and heated to 70° C. 8.2 g. (0.2 mole) of 97% pure sodium hydroxide were added to the reaction mixture as a fine powder (50 mesh). The reaction mixture was stirred at reflux temperature for 18 hours. The resulting solution was filtered hot and the solids were air dried to yield disodium adipate as the reaction product.
Reaction SMILES: C1([C@@H](N2CC[C@H](OC3CCCCO3)C2)CO)C=CC=CC=1.[C:22]1([C@H:28](O)[CH2:29][N:30]2[CH2:34][CH2:33][C@H:32]([O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[CH2:31]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl:43][C:44]1[CH:53]=[C:52]([NH:54][CH3:55])[CH:51]=[CH:50][C:45]=1[C:46]([O:48][CH3:49])=[O:47]>>[Cl:43][C:44]1[CH:53]=[C:52]([N:54]([C@@H:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:29][N:30]2[CH2:34][CH2:33][C@H:32]([O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[CH2:31]2)[CH3:55])[CH:51]=[CH:50][C:45]=1[C:46]([O:48][CH3:49])=[O:47]
Reactant: CNc1ccc(C(=O)OC)c(Cl)c1
Reactant: O[C@H](CN1CC[C@H](OC2CCCCO2)C1)c1ccccc1
Agent: OC[C@@H](c1ccccc1)N1CC[C@H](OC2CCCCO2)C1
Product: COC(=O)c1ccc(N(C)[C@H](CN2CC[C@H](OC3CCCCO3)C2)c2ccccc2)cc1Cl
Yield: 40 %

Procedure:
This was prepared from 2-(R)-phenyl-2-(3-(S)-tetrahydropyran-2-yloxypyrrolidin-1-yl)ethanol and 1-(S)-phenyl-2-(3-(S)-tetrahydropyran-2-yloxypyrrolidin-1-yl)ethanol and methyl 2-chloro-4-methylaminobenzoate in 40% yield according to a procedure similar to that described in Example 1 (i).
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][C:12]([CH3:16])([OH:15])[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[NH2:8][CH:9]1[CH2:14][CH2:13][C:12]([CH3:16])([OH:15])[CH2:11][CH2:10]1
Reactant: CC1(O)CCC(NCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC1(O)CCC(N)CC1
Yield: 100.7 %

Procedure:
A solution of 4-(benzylamino)-1-methylcyclohexanol (4.9 g, 22.3 mmol) in MeOH (150 mL) was stirred with 7% Pd/C (700 mg) under H2 atmosphere at RT overnight. The resulting mixture was filtered to remove Pd/C and the filtrate was concentrated in vacuo to afford a white solid (2.9 g, quantitative yield) which was used in the next step directly.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([S:20][CH3:21])[N:17]=[C:18](Cl)[C:9]=2[C:8]1=[O:22].[F:32][C:33]1[CH:38]=[CH:37][C:36](OB(O)O)=[CH:35][CH:34]=1>>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([S:20][CH3:21])[N:17]=[C:18]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)[C:9]=2[C:8]1=[O:22]
Reactant: CSc1nc(Cl)c2c(n1)NCCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Reactant: OB(O)Oc1ccc(F)cc1
Product: CSc1nc2c(c(-c3ccc(F)cc3)n1)C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 91.2 %

Procedure:
In a similar manner to Reference Example 10, 6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 7; 2.43 g) was reacted with 4-fluorophenylboric acid (840 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine (2.49 g, 91%).
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([OH:38])(=[O:37])[C@H:31]([CH2:33][C:34]([OH:36])=[O:35])[OH:32]>CO>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([O-:38])(=[O:37])[C@H:31]([CH2:33][C:34]([O-:36])=[O:35])[OH:32]
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CO
Product: O=C([O-])C[C@H](O)C(=O)[O-]
Temperature: 27.5 °C

Procedure:
Sunitinib (10 g) was suspended in methanol (1540 mL) under stirring and L-malic acid (3.36 g) was added to it at a temperature 25-30° C. The reaction mass was stirred to get a clear solution. It was filtered and methanol was distilled off under vacuum below 40° C. Acetonitrile (50 mL) was charged and the solvent was distilled off. It was cooled to 25-30° C. 380 mL of acetonitrile was added to the mass and it was mentained at 45-50° C. under stirring for a period of 15 minutes. The reaction mass was cooled to 30-35° C. The solid obtained was filtered and washed with acetonitrile (10 mL). The resultant compound was suck dried and dried under vacuum over a period of 4-5 hrs at 50° C. to obtain sunitinib L-malate. (12.0 g; yield 90%)
Reaction SMILES: [P:1]([CH2:5][NH:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])([OH:4])([OH:3])=[O:2].[OH-].[Na+].[CH3:15][CH:16]1[CH2:21][C:20](=[O:22])[O:19][C:17]1=[O:18]>O>[C:8]([CH2:7][N:6]([CH2:5][P:1]([OH:4])([OH:3])=[O:2])[C:20](=[O:22])[CH2:21][CH:16]([CH3:15])[C:17]([OH:19])=[O:18])([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC1CC(=O)OC1=O
Reactant: CCOC(=O)CNCP(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)CN(CP(=O)(O)O)C(=O)CC(C)C(=O)O

Procedure:
A suitable reaction vessel is charged with 3.94 grams (0.02 mole) of ethyl N-phosphonomethylglycinate in 15 ml. of water. While cooling below about 15° C. in an icebath, 50% aqueous sodium hydroxide is added to obtain a pH of about 8. There is then added 2.51 grams (0.022 mole) of methylsuccinic anhydride with stirring and continued cooling. Two further 1.0 gram portions of anhydride are added to complete the reaction, the pH being maintained with additional alkali. The reaction mixture is diluted with water and passed through a column of ion exchange resin in the acid form. The first seven 20 ml. cuts are combined in 20 ml. of water, and a further 1.2 gram portion of anhydride is added. The resultant reaction mixture is passed through the column, and the first four 20 ml. cuts are combined and dried. The product is cooled in dry ice to yield N-carbethoxymethyl-N-(phosphonomethyl)-2-methylsuccinamic acid (in the monohydrate form) as a clear glass-gum. Elemental analysis gives 4.01% nitrogen and 9.13% phosphorus as against calculated values of 4.25% and 9.40% for C10H18NO8P.H2O. ##STR18##
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[C:16]([CH3:27])([CH3:26])[CH2:17][C:18]([OH:25])([C:21]([F:24])([F:23])[F:22])[CH2:19][OH:20].C(Cl)(=O)C(Cl)=O.CS(C)=O>C(OCC)C.C(N(CC)CC)C>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[C:16]([CH3:27])([CH3:26])[CH2:17][C:18]([OH:25])([C:21]([F:23])([F:24])[F:22])[CH:19]=[O:20]
Reactant: COc1cc(C)ccc1C(C)(C)CC(O)(CO)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOCC
Product: COc1cc(C)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Yield: 84.6 %

Procedure:
Analogously to Example 7, 4.84 g of 4-(2-methoxy-4-methylphenyl)-4-methyl-2-oxopentanoic acid ethyl ester is reacted with 7 ml of trifluoromethyltrimethylsilane and 3 ml of tetrabutylammonium fluoride solution (1 M in THF) in 56 ml THF to form 4.14 g of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoic acid ethyl ester. The product is reduced with 856 mg of lithium aluminum hydride in 170 ml of diethyl ether to 3.58 g of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanol. The oxidation of the diol is carried out analogously to Example 7 under Swern conditions with 1.1 ml of oxalyl chloride, 2.1 ml of DMSO and 8.0 ml of triethylamine to 3.01 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[F:19][C:20]1[C:25]([F:26])=[C:24]([F:27])[CH:23]=[CH:22][C:21]=1[S:28](Cl)(=[O:30])=[O:29].N12CCN(CC1)CC2>C(#N)C>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1)[S:28]([C:21]1[CH:22]=[CH:23][C:24]([F:27])=[C:25]([F:26])[C:20]=1[F:19])(=[O:30])=[O:29]
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1F
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(F)c(F)c2F)c(OC)c1
Yield: 30.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidine-4-amine (400 mg, 1.63 mmol) prepared in Example 14a, 2,3,4-trifluorobenzenesulfonyl chloride (752 mg, 3.26 mmol), 1,4-diazabicyclo[2.2.2]octane (366 mg, 3.26 mmol) and acetonitrile (8.0 mL), to yield the title compound (221 mg, 31%) as a colorless amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[CH:10]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].OS(O)(=O)=O>N1CCCCC1.N1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1/[CH:10]=[CH:13]/[C:14]([OH:16])=[O:15]
Reactant: O=C(O)CC(=O)O
Reactant: Cn1cc([N+](=O)[O-])cc1C=O
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cn1cc([N+](=O)[O-])cc1/C=C/C(=O)O
Yield: 90.2 %

Procedure:
Alternatively, a solution of 1 (0.20 g, 1.30 mmol), malonic acid (0.68 g, 6.5 mmol) and piperidine (2 drops) in pyridine (2 mL) was stirred at room temperature at for 20 h and at 100° C. for 4 h, then 30% aqueous H2SO4 (10 mL) was added. The precipitate that formed was removed by filtration and washed with water to give (E)-1-methyl-4-nitro-2-pyrroleacrylic acid (2) as fine yellow needles (0.23 g, 92%). 1H NMR [(CD3)2SO] δ12.35 (br s, 1 H, CO2H), 8.13 (d, J=1.9 Hz, 1 H, H-5), 7.44 (d, J=15.9 Hz, 1 H, H-β), 7.41 (d, J=1.9 Hz, 1 H, H-3), 6.46 (d, J=15.9 Hz, 1 H, H-α), 3.79 (s, 3 H, NCH3). 13C NMR δ167.4 (CO2H), 135.3, 129.9 (C-2, 4), 130.6, 127.0, 118.6, 105.8 (C-3, 5, α, β), 34.8 (NCH3). Anal. Calculated for C8H8N2O4: C, 49.0; H, 4.1; N, 14.3. Found: C, 49.0; H, 4.0; N, 14.1%.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].[N+:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15])([O-:10])=[O:9]>ClCCCl.C(N(CC)CC)C>[N+:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([O:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])=[O:15])([O-:10])=[O:9]
Reactant: C[Si](C)(C)CCO
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 5 °C
Reaction time: 12 h
Yield: 81.4 %

Procedure:
H--2-Trimethylsilylethyl 3-nitrobenzoate may be prepared as follows: a solution of 41.8 g of 2- trimethylsilylethanol in 200 cm3 of 1,2-dichloroethane and 51 cm3 of triethylamine is added to a solution of 66.0 g of 3-nitrobenzoyl chloride in 1000 cm3 of 1,2-dichloroethane cooled to 5° C. The reaction mixture is stirred for 12 hours at a temperature in the vicinity of 25° C., then the insoluble product is separated by filtration and washed with 2 times 50 cm3 of 1,2-dichloroethane. The filtrate is concentrated to dryness under reduced pressure at 40° C. The oily residue obtained is purified by chromatography on silica [eluent: ethyl acetate/cyclohexane (30/70 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. 76.9 g of 2-trimethylsilylethyl 3-nitrobenzoate are thus obtained in the form of an oil used as it is in subsequent syntheses.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][CH2:7]2)[N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:4][N:3]1[CH2:29][C:30]1[CH:31]=[C:32]([CH:40]=[CH:41][CH:42]=1)[C:33]([O:35]C(C)(C)C)=[O:34].Cl>O1CCOCC1.C([SiH](CC)CC)C>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][C:15](=[O:22])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11]2)[N:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:4][N:3]1[CH2:29][C:30]1[CH:31]=[C:32]([CH:40]=[CH:41][CH:42]=1)[C:33]([OH:35])=[O:34]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCC(=O)c4ccccc4)CC3)C2=O)c1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCC(=O)c4ccccc4)CC3)C2=O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To tert-butyl 3-((4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.1 g, 0.18 mmol) was added 4M solution of HCl in dioxane (2 mL) and triethylsilane (0.1 mL). After stirring at room temperature for 4 hours, the reaction mixture was concentrated in vacuo and isolated by reverse phase HPLC to obtain the title compound as an acetate salt (0.044 g, 43%); 1H NMR (DMSO-d6): δ 1.58 (d, 2H, J=13.6 Hz), 1.84 (t, 2H, J=6.8 Hz), 2.42-2.53 (m, 4H), 2.74-2.78 (m, 4H), 3.05 (t, 2H, J=7.2 Hz), 4.58 (d, 4H, J=13.2 Hz), 6.70-6.75 (m, 3H), 7.12 (t, 2H, J=7.2 Hz), 7.48-7.54 (m, 3H), 7.63 (t, 2H, J=7.6 Hz), 7.85 (d, 2H, J=2 Hz), 7.98 (dd, 2H, J=8 and 1.6 Hz); MS for C31H33N3O4 m/z 512.07 (M+H)+.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1.[S:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1>C(Cl)Cl>[O:8]=[C:7]1[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3][CH:2]1[C:14]1[S:13][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccsc1
Reactant: O=C1Nc2ccccc2SC1Cl
Solvent: ClCCl
Product: O=C1Nc2ccccc2SC1c1cccs1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 70.3 %

Procedure:
To a solution of 2-chloro-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (9.38 g) and thiophene (7.91 g) in methylene chloride (250 ml) is added in portions stannic chloride (12.2 g) at 0° to 5° C. After stirring at the same temperature for 45 minutes, the mixture is poured into ice water, and the organic layer is separated. The aqueous layer is extracted with ethyl acetate, and the ethyl acetate layer is combined with the above organic layer and distilled to remove the solvent. The resulting solid material is recrystallized from ethanol to give 3-oxo-2-(2-thienyl)-3,4-dihydro-2H-1,4-benzothiazine (8.17 g) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([NH:17][C@H:18]([C:29]([OH:31])=[O:30])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+]([O-])=O)=[CH:22][CH:21]=3)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.O.O.Cl[Sn]Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:15]([NH:17][C@H:18]([C:29]([OH:31])=[O:30])[CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(C(=O)N[C@@H](Cc3ccc([N+](=O)[O-])cc3)C(=O)O)CCCCC2)cc1
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2(C(=O)N[C@@H](Cc3ccccc3)C(=O)O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL scintillation vial was added Wang resin linked N-[[1-(4-methoxyphenyl)cyclohexyl]carbonyl]-4-nitro-L-phenylalanine (241 mg, 0.14 mmol) prepared in Example 140 and 2 mL of a solution of 2M SnCl2.2H2O in DMF. The reaction mixture was shaken overnight at room temperature. The resulting resin was collected by filtration and was washed with DMF, isopropyl alcohol, dichloromethane, and ether to yield 243 mg (0.14 mmol) of 4-amino-N-[[(1-(4-methoxyphenyl)cyclohexyl]carbonyl]-L-phenylalanine on Wang resin.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[O:14][N:13]=1.C(N(CC)CC)C>C(Cl)Cl.[Cl-].[Na+].O>[CH3:11][C:12]1[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH:20]=[O:21])[O:14][N:13]=1
Reactant: Cc1cc(CCCCO)on1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1cc(CCCC=O)on1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 48.6 %

Procedure:
To a solution of oxalyl chloride (0.40 mL of a 2M solution in methylene chloride in 2 mL dry methylene chloride) at -78° C. was added a solution of methyl sulfoxide (126 mg in 1 mL methylene chloride) and the mixture stirred at low temperature for 3 minutes. A solution of 4-(3-methylisoxazol-5-yl)-butan-1-ol (100 mg in 1 mL methylene chloride) was added and the reaction allowed to proceed for 15 minutes after which time 0.67 mL triethylamine were added and the mixture allowed to warm to room temperature. After 30 minutes brine was added and the mixture extracted with methylene chloride. The organic portion was dried over sodium sulfate and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (ethyl acetate:hexane, 1:1) gave the title compound (48 mg).
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9](Cl)=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=[CH:17][C:18]=1[CH2:19][NH:20][CH:21]1[CH2:23][CH2:22]1.C(N(CC)CC)C>O1CCCC1>[Cl:12][C:13]1[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=[CH:17][C:18]=1[CH2:19][N:20]([CH:21]1[CH2:22][CH2:23]1)[C:9]([C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[F:1])=[O:10]
Reactant: Cc1nn(C)c(F)c1C(=O)Cl
Reactant: Clc1cc(-c2ccccc2)ccc1CNC1CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nn(C)c(F)c1C(=O)N(Cc1ccc(-c2ccccc2)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
At ambient temperature, a solution of 226 mg (1.28 mmol) of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride in 1 ml of tetrahydrofurane is added dropwise to a solution of 300 mg (1.164 mmol) of N-[(3-chlorobiphenyl-4-yl)methyl]cyclopropanamine and 0.18 ml of triethylamine in 5 ml tetrahydrofurane. The reaction mixture is stirred for 15 hrs at room temperature. The solvent is removed under vacuum and 10 ml of water are then added to the residue. The watery layer is extracted twice with ethyl acetate (2×50 ml) and the combined organic layers are successively washed by a 1M solution of HCl, a saturated solution of potassium carbonate and brine and filtered over a ChemElut cartridge to yield after concentration 350 mg (72% yield) of N-[(3-chlorobiphenyl-4-yl)methyl]-N-cyclopropyl-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide as a yellow oil (M+H=398).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH:22]=O)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:24][C:25]1[CH:26]=[C:27]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:28]=[CH:29][C:30]=1[CH3:31].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH2:22][N:35]3[CH2:36][CH2:37][N:32]([C:27]4[CH:28]=[CH:29][C:30]([CH3:31])=[C:25]([CH3:24])[CH:26]=4)[CH2:33][CH2:34]3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccc(C)c(C)c4)CC3)nn2-c2ccccc2)cc1

Procedure:
105 mg (82%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (75 mg, 0.245 mmol), 1-(3,4-dimethylphenyl)piperazine (47 mg, 0.245 mmol), DIPEA (0.064 mL, 0.368 mmol) and NaBH(OAc)3 (156 mg, 0.735 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:60])[NH:7][C@H:8]1[CH2:12][C@@H:11]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][C:16]([C:37](=[O:57])[NH:38][CH2:39][CH2:40][NH:41][C:42]([NH:44][CH:45]2CCN(C4C=CC=CN=4)C[CH2:46]2)=[O:43])=[N:17][C:18]=3[NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:10]([OH:58])[C@@H:9]1[OH:59])([CH3:4])([CH3:3])[CH3:2].[N:61]1([C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][N:76]=2)[CH2:66][CH2:65][CH:64]([NH:67][C:68]([N:70]2[CH:74]=[CH:73]N=[CH:71]2)=[O:69])[CH2:63][CH2:62]1.N1(C2C=CC=CN=2)CCC(NC(N2CCC(NC(N3C=CN=C3)=O)CC2)=O)CC1>>[C:1]([O:5][C:6](=[O:60])[NH:7][C@H:8]1[CH2:12][C@@H:11]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][C:16]([C:37](=[O:57])[NH:38][CH2:39][CH2:40][NH:41][C:42]([NH:44][CH:45]2[CH2:46][CH2:71][N:70]([C:68](=[O:69])[NH:67][CH:64]4[CH2:63][CH2:62][N:61]([C:75]5[CH:80]=[CH:79][CH:78]=[CH:77][N:76]=5)[CH2:66][CH2:65]4)[CH2:74][CH2:73]2)=[O:43])=[N:17][C:18]=3[NH:22][CH2:23][CH:24]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:10]([OH:58])[C@@H:9]1[OH:59])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(NC1CCN(c2ccccn2)CC1)n1ccnc1
Agent: O=C(NC1CCN(c2ccccn2)CC1)N1CCC(NC(=O)n2ccnc2)CC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(C(=O)NC5CCN(c6ccccn6)CC5)CC4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to [(1S,2R,3S,4R)-4-(6-(2,2-diphenyl-ethylamino)-2-{2-[3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-ureido]-ethylcarbamoyl}-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-carbamic acid tert-butyl ester (Example 12) by replacing imidazole-1-carboxylic acid (3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amide (Intermediate C) with 4-[(imidazole-1-carbonyl)-amino]-piperidine-1-carboxylic acid (3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amide (Intermediate H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:33][CH2:34][CH3:35])=[C:9]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:38][S:39]([CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:41])=[O:40]>>[ClH:22].[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:33][CH2:34][CH3:35])=[C:9]([C:11]2[N:12]([C:30]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:49][CH2:48]3)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)[CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1ccc(C(C)(C)C)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1ccc(C(C)(C)C)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
[(4S,5R)-2-(5-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(5-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12d) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 685.3 [(M+H)+]
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:16]I.O>CN(C)C=O>[CH3:13][O:12][N:10]([CH3:11])[C:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([O:1][CH3:16])[CH2:3][CH2:4]1)=[O:9]
Reactant: CON(C)C(=O)[C@H]1CC[C@H](O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)[C@H]1CC[C@H](OC)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
trans-4-Hydroxy-N-methoxy-N-methylcyclohexanecarboxamide (536 mg, 2.86 mmol) in N,N-dimethylformamide (5 mL) was mixed with sodium hydride (55 wt % dispersion in mineral oil, 150 mg, 3.44 mmol) and methyl iodide (214 μL, 3.44 mmol) under cooling with ice and stirred for 3 hours while the temperature was gradually raised to room temperature. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2→1/1 (v/v)) to give the title compound as a colorless oil (556 mg, yield 97%).