Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Na].[C:10]([CH2:12][N:13]=[CH:14]OC)#[N:11]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[N:11]=[CH:14][NH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COC=NCC#N
Agent: [Na]
Solvent: CO
Product: Brc1ccc(Oc2c[nH]cn2)cc1

Procedure:
To a mixture of liquid 4-bromophenol (25 g, mp 64-68° C.) at 100-110° C. and its sodium salt [Prepared from 3.5 g (20 mmol) 4-bromo-phenol and sodium metal (0.46 g, 20 mmol) in anhydrous methanol. The resultant solution was concentrated and the residual solvent removed under vacuum overnight], neat methyl N-(cyano-methyl)methanimidate (2 mL, 20 mmol; Hosmane, R. S. et al, J. Org. Chem., p. 1212, 1984) was added dropwise over a period of 10 minutes under a slow stream of dry argon. The resultant mixture was stirred at 100° C. for 2 h, and the reaction product partitioned between methylene chloride (250 mL) and aqueous sodium hydroxide (1M, 250 mL). The aqueous layer was separated and extracted with methylene chloride (3×50 mL). The organic extracts were combined, washed with brine (50 mL), dried over anhydrous potassium carbonate, filtered and concentrated. The residue was subjected to column chromatography on silica gel eluting with a mixture of 7:3 v/v chloroform and acetone. Collection and concentration of appropriate fractions provided the titled compound as white powder.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([C:21]#[C:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][CH:16]=2)[C:11]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([CH2:21][CH2:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][CH:16]=2)[C:11]=1[C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2ccc(C#CC3CCCC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O
Solvent: CC#N
Solvent: O
Product: Cc1cc2ccc(CCC3CCCC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(2-cyclopentylethyl)-3-methylnaphthalen-2-yl)acetic acid (90) was prepared using the procedure of Example 87 from 2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(cyclopentylethynyl)-3-methylnaphthalen-2-yl)acetic acid. 1H-NMR: 400 MHz, (CD3OD) δ: 7.69 (d, J=9 Hz, 1H), 7.63 (s, 1H), 7.56 (m, 3H), 7.29 (m, 2H), 6.99 (s, 1H), 5.18 (s, 1H), 2.60 (m, 2H), 2.58 (s, 3H), 1.71 (m, 3H), 1.52 (m, 6H), 1.07 (m, 2H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 5.0 min run): tR (min)=4.54.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]([F:13])([F:12])[F:11])=[C:6]([NH2:8])[CH:7]=1.[N:14]#[C:15][NH2:16].Cl>CCO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]([F:11])([F:12])[F:13])=[C:6]([NH:8][C:15]([NH2:16])=[NH:14])[CH:7]=1
Reactant: N#CN
Reactant: Nc1cc(Br)ccc1OC(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCO
Product: N=C(N)Nc1cc(Br)ccc1OC(F)(F)F
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a suspension of 5-bromo-2-trifluoromethoxy-phenylamine (5.0 g, 19.5 mmol) in EtOH (15 mL), cyanamide (1.64 g, 39 mmol) dissolved in 5 mL of EtOH and 1 mL H2O, and HCl 37% (3.25 mL) diluted in 10 mL EtOH were added drop wise into the mixture under stirring. The mixture was refluxed for 72 h. The mixture was cooled down to room temperature, concentrated then diluted with water; NaOH 1N was added to basic pH and extracted several times with ethyl acetate, dried over sodium sulfate and concentrated to afford 5.2 g of the title compound (89% yield).
Reaction SMILES: CON(C)[C:4](=[O:13])[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:7]1([CH2:6][CH2:5][CH:4]=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CON(C)C(=O)CCN1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=CCCN1CCCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
The above amide (1 equiv) is dissolved in dry THF and the solution is cooled to −78° C. Solid LAH (0.5 equiv) is carefully added. The reaction mixture is then immersed in an ice-bath at 0° C. and stirred 30 min. The reaction is quenched by the addition of EtOAc followed by water. The mixture is diluted with Et2O and the layers are separated. The organic is washed with brine, dried over Na2SO4, decanted and concentrated to yield 3-(piperid-1-yl)-propanal which is used immediately in the next step.
Reaction SMILES: Br[C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[OH-].[NH4+:18]>O.S([O-])([O-])(=O)=O.[Cu+2]>[NH2:18][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: O=C(O)c1nc(-c2ccccc2)ncc1Br
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [OH-]
Solvent: O
Product: Nc1cnc(-c2ccccc2)nc1C(=O)O
Temperature: 80 °C

Procedure:
To a suspension of 8.75 g (0.0314 mole) of 5-bromo-2-phenyl-pyrimidine-4-carboxylic acid in 69 mL of concentrated ammonium hydroxide was added 0.39 g of copper (II) sulfate in 1.6 mL water. The mixture was sealed and heated to 80° C. for 6 days. After cooling to room temperature, and filtration, the solid was taken in 100 ml boiling water, filtered, cooled and acidified with acetic acid. Filtration and drying yielded 4.40 g of 5-amino-2-phenyl-pyrimidine-4-carboxylic acid as a tan solid, mp. 199-202° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:12](OC)=[O:13])=[CH:3]1.[BH4-].[Na+]>CO>[OH:13][CH2:12][C:4]1[O:5][C:6]2[C:11]([C:2](=[O:1])[CH:3]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COC(=O)c1cc(=O)c2ccccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=c1cc(CO)oc2ccccc12

Procedure:
500 mg of methyl 4-oxo-4H-chromene-2-carboxylate were dissolved in 25 ml of anhydrous methanol at room temperature, and NaBH4 was thereafter added to the solution slowly, until the starting material was no longer detected by TLC (about 300 mg). The solvent was then evaporated and a mixture of 1.1 gram of NaH2PO4.2H2O in 30 ml of water was added to the resulting residue. The pH of the mixture was maintained between 5 and 9, so as to prevent decomposition of chromone. The aqueous solution was washed with chloroform (3×50 ml) and the combined organic extracts were dried over Na2SO4. The solvent was evaporated to give 2-(hydroxymethyl)-4H-chromen-4-one which was used without future purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10](C(=O)C)[C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15]([CH2:19][C:20]1[NH:21][CH:22]=[CH:23][N:24]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15]([CH2:19][C:20]1[NH:24][CH:23]=[CH:22][N:21]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c3c(Cc4ncc[nH]4)cccc3n(C(C)=O)c2cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cc2c(cn1)[nH]c1cccc(Cc3ncc[nH]3)c12

Procedure:
A suspension of 0.11 g of 9-acetyl-5-(1-imidazolylmethyl)-beta-carboline-3-carboxylic acid ethyl ester in 5 ml of ethanol is mixed with 10 mg of K2CO3 and refluxed for two hours. After filtering, the solution is concentrated in a vacuum, the residue is mixed with water, suctioned off and recrystallized from water. Yield 70 mg (71%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[I:11]([O-])(=O)=O.[K+].II.C(OCC)C>C(O)(=O)C.O>[I:11][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=1[OH:10]
Reactant: [O-][I+2]([O-])[O-]
Reactant: CC(C)c1cccc(O)c1
Agent: II
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)c1ccc(I)c(O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 286.2 %

Procedure:
To a solution of 3-isopropylphenol (25.0 g, 0.184 mol) in acetic acid (200 mL), a suspension of potassium iodate (7.88 g, 0.0368 mol) in water (75 mL) and iodine (18.7 g, 0.0736 mol) were added. This reaction mixture was stirred at room temperature for 20 hours. After addition of diethyl ether (400 mL) and water (300 mL), the organic layer was separated. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogen carbonate and brine, and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to give 2-iodo-5-isopropylphenol (27.6 g, 57%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C@@:4]1([C:20]([F:23])([F:22])[F:21])[CH2:19][N:7]2[C:8](=[O:18])[CH:9]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:11]=[C:6]2[NH:5]1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:3][C@@:4]1([C:20]([F:23])([F:21])[F:22])[CH2:19][N:7]2[C:8](=[O:18])[CH:9]=[C:10]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[N:11]=[C:6]2[N:5]1[C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:31]
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1C(=O)c1ccccc1

Procedure:
14.2 mg of sodium hydride are added to a solution of 150 mg of (2S)-2-methyl-7-morpholin-4-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]-pyrimidin-5-one (Example 1j), in 3 ml of tetrahydrofuran. After stirring for 25 minutes at a temperature in the region of 20° C., 0.092 ml of benzoyl chloride is added. The reaction medium is stirred for 1 hour at ambient temperature before the addition of 1.5 ml of a saturated solution of sodium bicarbonate and ethyl acetate. The organic phase is successively separated, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered, and then concentrated under reduced pressure. After purification by silica column chromatography (eluent: dichloromethane/methanol: 98/02), 49 mg of (2S)-2-methyl-7-(morpholin-4-yl)-1-(phenylcarbonyl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)one are obtained in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9]/[CH:10]=[C:11](\[C:18]([O:20][CH3:21])=[O:19])/[CH:12]=[CH:13]/[C:14](OC)=[O:15].C[O-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:18]([O:20][CH3:21])=[O:19])=[CH:10]1
Reactant: COC(=O)/C=C/C(=C/Nc1c(Cl)cccc1Cl)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(=O)n(-c2c(Cl)cccc2Cl)c1
Temperature: 25 °C
Yield: 65.2 %

Procedure:
To a solution of dimethyl (2E,4Z)-4-{[(2,6-dichlorophenyl)amino]methylene}-2-pentenedioate (7.3 g) in MeOH (73 mL) was added 28% sodium methoxide in MeOH (4.3 mL). The mixture was refluxed for 8 hr under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and poured into 1 M HCl (140 ml) at 0° C. The resulting mixture was extracted with EtOAc (70 mL×2). The combined extracts were washed with saturated aqueous NaHCO3 (100 mL) and brine, dried over MgSO4 and filtered. The filtrate was evaporated in vacuo, and the residue was triturated with a mixture of EtOAc and hexane (1:3) to provide methyl 1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxylate (4.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CO.C(O)(=O)C>C(OCC)(=O)C.[Pt](=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([CH:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN1CC=C(c2ncc(-c3ccc(Cl)cc3)cn2)CC1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN1CCC(c2ncc(-c3ccc(Cl)cc3)cn2)CC1
Reaction time: 18 h
Yield: 44.8 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 5-(4-chlorophenyl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine (0.31 g) in a mixture of ethyl acetate (20 ml), methanol (3 ml) and acetic acid (1 ml) and the mixture was hydrogenated at atmospheric pressure for 18 h. The mixture was then filtered through celite, washing with 10% methanol/ethyl acetate, and evaporated under reduced pressure. The residue was treated with 2 M sodium hydroxide (15 ml) and extracted with diethyl ether (2×25 ml), and the organic extracts were washed with water (2×10 ml), saturated brine (20 ml), dried (Na2SO4) and evaporated under reduced pressure and the residue purified by silica gel column chromatography with 10% methanol/dichloromethane with 0.5% concentrated aqueous ammonia as eluent, to yield the title compound as a white solid (0.14 g, 45%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:22][C:21]3[NH:20][C:19]4[C:14](=[CH:15][C:16]([Cl:23])=[CH:17][CH:18]=4)[C:13](=[O:24])[C:12]=3[C:11](=O)[CH2:10]2)=[CH:5][CH:4]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([NH2:35])[CH2:31][CH2:30]1>C(O)C>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([N:35]=[C:11]2[C:12]3[C:13](=[O:24])[C:14]4[C:19](=[CH:18][CH:17]=[C:16]([Cl:23])[CH:15]=4)[NH:20][C:21]=3[CH2:22][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:26])([F:1])[F:27])=[CH:8][CH:7]=3)[CH2:10]2)[CH2:31][CH2:30]1
Reactant: CN1CCN(N)CC1
Reactant: O=C1CC(c2ccc(C(F)(F)F)cc2)Cc2[nH]c3ccc(Cl)cc3c(=O)c21
Solvent: CCO
Product: CN1CCN(N=C2CC(c3ccc(C(F)(F)F)cc3)Cc3[nH]c4ccc(Cl)cc4c(=O)c32)CC1

Procedure:
39.15 g (0.1 mole) of 3-(4-trifluoromethylphenyl)-7-chloro-3,4-dihydroacridine-1,9(2H,10H)-dione are suspended in 500 ml of ethanol, 11.5 g (0.1 mole) of N-methyl-N'-aminopiperazine are added and the reaction mixture is heated to reflux for 90 minutes. A clear solution is formed during this. After cooling down, the ethanol is distilled out in a rotary evaporator and the solid residue is recrystallized from toluene/cyclohexane (1:1). 44 g (=90% of theory) of the title compound are thus obtained in the form of pale yellow crystals of melting point 246° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:20][N:21]=[C:22]=[O:23]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]([NH:12][C:22]([NH:21][CH3:20])=[O:23])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)NC(=O)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Yield: 21.3 %

Procedure:
A solution of rac-2-(3,4-dichloro-phenyl)-2-(tetrahydro-pyran-4-yloxy)-acetamide (278 mg, 0.91 mmol) in toluene (10 mL) was treated with methyl isocyanate (0.08 mL, 1.37 mmol). The resulting solution was heated at reflux for 24 h and then the cooled reaction was concentrated in vacuo. The resulting oil was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 20/80 hexanes/ethyl acetate) to afford [1[(3,4-dichloro-phenyl)-(tetrahydro-pyran-4-yloxy)-acetyl]-3-methyl-urea (70 mg, 21% yield) as a colorless oil: EI-HRMS m/e calcd for C15H18N2Cl2O4 (M+) 360.0643, found 360.0865.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.Cl.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][NH:31][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][N:31]([C:8](=[O:10])[CH2:7][CH:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:17][CH2:18]1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(O)CC1CCOCC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCOCC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from tetrahydro-2H-pyran-4-ylacetic acid (Combi-Blocks, Cat. #AM-1005) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=451.1.
Reaction SMILES: NC1C=CC2N=CN(C(C3C=CC=CC=3)CC(OCC)=O)C=2C=1.N1C2C(=CC=CC=2)C(CCC(O)=O)=C1.[NH:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]([CH2:47][CH2:48][C:49]([NH:51][C:52]2[CH:53]=[CH:54][C:55]3[N:59]=[CH:58][N:57]([CH:60]([C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)[CH2:61][C:62]([O:64]CC)=[O:63])[C:56]=3[CH:73]=2)=[O:50])=[CH:39]1.[OH-].[Na+]>>[NH:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]([CH2:47][CH2:48][C:49]([NH:51][C:52]2[CH:53]=[CH:54][C:55]3[N:59]=[CH:58][N:57]([CH:60]([C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)[CH2:61][C:62]([OH:64])=[O:63])[C:56]=3[CH:73]=2)=[O:50])=[CH:39]1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)CCc3c[nH]c4ccccc34)cc21
Agent: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(N)cc21
Agent: O=C(O)CCc1c[nH]c2ccccc12
Agent: [Na+]
Product: O=C(O)CC(c1ccccc1)n1cnc2ccc(NC(=O)CCc3c[nH]c4ccccc34)cc21

Procedure:
Using a similar procedure to that described in Preparation 21, the title compound (25 mg) was prepared from ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate and 3-indolepropionic acid. Hydrolysis of the intermediate ethyl 3-(6-{[3-(1H-indol-3-yl)propanoyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropanoate in this case was carried out using an aqueous solution of sodium hydroxide (2N), followed by RP-HPLC purification of the concentrated residue. [LCMS (Method A, Mobile Phase I) RT=4.29 min, MH+ 453].
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=N1.C(OC([NH:35][CH:36]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][CH:42]=1)[C:37]([OH:39])=O)=O)(C)(C)C.N1CCCC1.C(N1CCOCC1)C.[C:62]([OH:68])([C:64]([F:67])([F:66])[F:65])=[O:63]>CN(C=O)C.C(Cl)Cl>[F:65][C:64]([F:67])([F:66])[C:62]([OH:68])=[O:63].[NH2:35][CH:36]([CH2:40][C:41]1[CH:42]=[CH:43][C:44]([C:47]#[N:48])=[CH:45][CH:46]=1)[C:37]([N:10]1[CH2:11][CH2:16][CH2:15][CH2:14]1)=[O:39]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(C#N)cc1)C(=O)O
Agent: CCN1CCOCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCNC1
Solvent: ClCCl
Product: N#Cc1ccc(CC(N)C(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.5 g of BOP are added to a mixture of 4.06 g of 2-(tert-butoxycarbonylamino)-3-(4-cyanophenyl)propionic acid and 1.15 ml of pyrrolidine in 20 ml of DMF, and the mixture is stirred for 2 hours at RT, while keeping the pH at 7 by adding N-ethylmorpholine. The reaction mixture is concentrated under vacuum and the residue is chromatographed on silica gel, eluting with a chloroform/MeOH mixture (95/5; v/v). The product obtained is taken up in 20 ml of TFA in 20 ml of DCM, and the reaction mixture is stirred for 30 minutes at RT and concentrated under vacuum. The residue is taken up in ether and the precipitate formed is filtered off by suction. 3.95 g of the expected product are obtained after drying.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].[BH4-].[Na+].S([O-])([O-])(=O)=O.[NH4+].[NH4+].C(OCC)(=O)C>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH:15]([OH:17])[CH3:16]
Reactant: CC(=O)c1cc(-c2cccc(F)c2)ccc1N
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(O)c1cc(-c2cccc(F)c2)ccc1N
Reaction time: 4 h
Yield: 66.5 %

Procedure:
A solution of 1-(4-amino-3′-fluoro[1,1′-biphenyl]-3-yl)ethanone (3 g, 13 mmol) in anhydrous methanol (60 mL) was treated at rt under nitrogen with sodium borohydride in a portion wise manner. After addition, the reaction mixture was stirred for 4 hours, treated with a saturated aqueous ammonium sulfate solution (50 mL) and ethyl acetate (100 mL). The organic layer was separated, dried (MgSO4) and evaporated. The residue was purified on a silica gel column chromatography (hexane:ethyl acetate/3:1) to yield 1-(4-amino-3′-fluoro[1,1′-biphenyl]-3-yl)ethanol as a white solid (2 g, 67%): mp 136-137° C.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][N:28]=[CH:27]2>ClCCCl>[CH:2]([NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][N:28]=[CH:27]2)([CH3:4])[CH3:1]
Reactant: CC(C)=O
Reactant: Nc1ccc2[nH]ncc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.1 %

Procedure:
Acetone (25 μl, 0.340 mmol), sodium triacetoxyborohydride (83 mg, 0.392 mmol) and acetic acid (18 μl, 0.314 mmol) were added in that order to a solution of 5-amino-1H-indazole (40 mg, 0.300 mmol) in 1,2-dichloroethane (1 ml), and the resulting mixture was stirred at room temperature for 20 hours. The reaction was terminated by the use of a saturated aqueous sodium hydrogencarbonate solution (4 ml), followed by extraction with ethyl acetate. The solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: chloroform/methanol=100/2) to obtain N-isopropyl-1H-indazol-5-amine (40 mg, 76%).
Reaction SMILES: [Si]([O:18][C:19]1[CH:55]=[CH:54][C:22]([O:23][CH2:24][C@@H:25]([OH:53])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[C:40]4=[N:41][CH:42]=[CH:43][CH:44]=[C:39]4[N:38]=[C:37]3[C:45]3[CH:50]=[CH:49][C:48]([CH2:51][CH3:52])=[CH:47][CH:46]=3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:51]([C:48]1[CH:47]=[CH:46][C:45]([C:37]2[N:36]([C:33]3[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:53])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:55][CH:54]=4)=[CH:31][CH:32]=3)[C:40]3=[N:41][CH:42]=[CH:43][CH:44]=[C:39]3[N:38]=2)=[CH:50][CH:49]=1)[CH3:52]
Reactant: CCc1ccc(-c2nc3cccnc3n2-c2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCc1ccc(-c2nc3cccnc3n2-c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)cc1
Yield: 83.9 %

Procedure:
(2S)-1-(4-{[tert-butyl(diphenyl)silyl]oxy}phenoxy)-3-({4-[2-(4-ethylphenyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenethyl}amino)-2-propanol (0.13 g, 0.174 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.074 g, 0.146 mmol).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])[NH:2]1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CN(C)C=O>[CH3:14][N:15](/[CH:17]=[C:4]1/[C:3](=[O:11])[NH:2][CH2:1][C:10]2[C:5]/1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:16]
Reactant: COC(OC)N(C)C
Reactant: O=C1Cc2ccccc2CN1
Solvent: CN(C)C=O
Product: CN(C)/C=C1/C(=O)NCc2ccccc21
Temperature: 100 °C
Yield: 21.3 %

Procedure:
A N,N-dimethylformamide (1 mL) solution containing 1,4-dihydro-3(2H)-isoquinolinone (300 mg, 2.04 mmol) and N,N-dimethylformamide dimethylacetal (0.65 mL, 4.89 mmol) is heated at 100° C. for 2.5 hours. After removing the solvents, the residue is washed with ether, water and ether to give 88 mg of the product as a pink solid. The filtrate is evaporated to dryness, and the residue is treated with ether, water and ether to give 105 mg of a second crop of the product with a total yield of 47% (193 mg); MS (ESI) m/z 203.2 (M+1). Ref: Chemistry of Heterocyclic compd. 370-374 (1981).