Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:14][OH:15])[NH:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].C(N(C(C)C)CC)(C)C.[C:26](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:14][OH:15])[N:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:11])[CH3:12])([CH3:8])[CH3:9])[C:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H](CO)NO[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CO)N(O[Si](C)(C)C(C)(C)C)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To t-butyldimethylsilyloxyserine methyl ester (27.5 g; 0.118 mol) dissolved in CH2Cl2 (125 ml) and diisopropylethylamine (25 ml; 0.14 mol) and cooled to 0° C. is added tritylchloride (33. g; 0.118 mol) portionwise over 2 minutes. The reaction is stirred for 4 hours at 25° C., diluted with CH2Cl2 and washed with H2O 3x. The organic phase is dried (MgSO4) and concentrated to dryness to give N-trityl-t-butyldimethylsilyloxy serine methyl ester as a tan solid which is used directly next Step C.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH2:1]([C:5]1[N:6]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Br:13])=[CH:15][CH:16]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(Br)cc1
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(Br)cc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
In 200 ml of N,N-dimethylacetamide (DMAC) were dissolved 31.0 g (0.166 mol) of 2-n-butyl-4-chloro-5-formylimidazole and 41.5 g (0.166 mol) of p-bromobenzyl bromide. After this solution was cooled to -10° C., 23.7 g (0.168 mol) of potassium carbonate particles which had a specific surface area of 1.5 m2 /g and in which the content of particles each having a diameter of 74 μm or smaller was 30% by weight were added to the solution over 10 minutes while holding the solution at -10 to -5° C. The resultant mixture was stirred at -10° C. for 2 hours, subsequently heated to room temperature, and then stirred for 2 hours to complete the reaction (which was conducted in an air atmosphere). Thereafter, the reaction mixture was filtered and the filtrate was cooled to 0° C. Thereto was added 320 ml of 15° C. water. The crystals thus precipitated were taken out by filtration to obtain 55.8 g of 2-n-butyl-4-chloro-1-(4-bromobenzyl)-5-formylimidazole having a purity of 99.8% (yield, 98.0%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[C:17]([CH:20]=1)[CH:18]=[O:19].[H-].[Na+]>CN(C=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([O:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[C:17]([CH:18]=[O:19])[CH:20]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: O=C(O)Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1Oc1cccc(CC(=O)O)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
3-Hydroxyphenylacetic acid (1.34 g, 8.8 mmol) and 5-bromo-2-fluorobenzaldehyde (1.78 g, 8.8 mmol) were combined in DMF (30 mL) at room temperature. Sodium hydride (60% in mineral oil; 0.72 g, 18.0 mmol) was added, and the reaction was stirred at 70° C. for 2 hours. Aqueous work-up yielded the title compound.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[OH:27].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:26][C:22]1[C:21]([OH:27])=[C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc(F)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(F)c1O
Yield: 50.2 %

Procedure:
The product is prepared according to the procedure described in example 5, using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 357 mg of 2-amino-6-fluorophenol, and 600 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 4 ml of pyridine and 4 ml of N,N-dimethylformamide. 335 mg of N-(3-fluoro-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[P:7]([OH:10])([OH:9])[OH:8].[ClH:11]>>[ClH:11].[CH3:2][N:1]([O:8][P:7]([CH2:3][C:4]([OH:6])=[O:5])([OH:10])=[O:9])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CNCC(=O)O
Reactant: OP(O)O
Agent: Cl
Product: CN(CC(=O)O)OP(=O)(O)CC(=O)O

Procedure:
In a like manner to Example 1, a solution of sarcosine (8.9 parts by weight), orthophosphorous acid (8.2 parts by weight) in 100 parts by weight of 18% hydrochloric acid is reacted to give, on evaporation, 25.8 parts by weight of 2-(N-methyl-N-carboxymethylamino)phosphonoacetic acid hydrochloride as a pale yellow amorphous solid having a 31P-nmr signal at 13.3 ppm downfield from H3PO4 in water (JP-CH =18H3).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[C:3]1[CH:13]=[CH:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>C(O)C.[Ni]>[OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[C:3]1[CH2:13][CH2:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCC(=O)C=CC1=C(CCC(=O)O)C(=O)CC1O
Agent: [Ni]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCCC(=O)CCC1=C(CCC(=O)O)C(=O)CC1O

Procedure:
3-[3-Hydroxy-5-oxo-2-(3-oxo-oct-1-enyl)cyclopent-1-enyl]propanoic acid (1.0 g.) was dissolved in absolute ethanol (50 ml.) and triethylamine (5 ml.) and hydrogenated over a Raney Nickel W2 catalyst at room temperature for 80 minutes. The catalyst was removed by filtration and the filtrate rotary evaporated to a crystalline solid. The solid was dissolved in chloroform and shaken with 1 M hydrochloric acid and then with brine. After drying over anhydrous sodium sulphate the solvent was removed by rotary evaporation to yield an oil. Chromatography on a silicic acid column (Bio Sil A) with chloroform as eluant was effective in purification of the product, 3-[3-hydroxy-5-oxo-2-(3-oxo-octan-1-yl)cyclopent-1-enyl]propanoic acid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][S:40](=[O:44])(=[O:43])[CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:37]5[CH2:42][CH2:41][S:40](=[O:44])(=[O:43])[CH2:39][CH2:38]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Reactant: O=S1(=O)CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCS(=O)(=O)CC1
Yield: 22.1 %

Procedure:
The title compound was prepared as described in Example 57B by using compound 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea from Example 16C (200 mg, 0.39 mmol), thiomorpholine 1,1-dioxide (158 mg, 1.17 mmol), tetrabutylammonium iodide (144 mg, 0.39 mmol) and N,N′-diisopropylethylamine (139 μL, 0.78 mmol) in N,N′-dimethylformamide (2 mL) to afford 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{6-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethoxy]-7-methoxy-quinazolin-4-yloxy}-phenyl)-urea (52.75 mg, 23%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.00 (s, 1H), 8.56 (s, 1H), 7.61 (d, 2H), 7.40-7.37 (m, 2H), 7.25 (d, 1H), 6.97 (d, 1H), 6.47 (s, 1H), 4.31 (m, 2H), 4.00 (s, 3H), 3.10-3.03 (m, 10H), 1.27 (s, 9H); LC-MS (ESI) m/z 611 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=O)[CH2:10][CH2:9][CH2:8]2)([CH3:3])[CH3:2].[CH3:16][Mg]I>>[CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12]([C:11]([CH3:16])=[CH:10][CH2:9][CH2:8]2)=[CH:13][CH:14]=1)([CH3:3])[CH3:2]
Reactant: C[Mg]I
Reactant: CC(C)Oc1ccc2c(c1)CCCC2=O
Product: CC1=CCCc2cc(OC(C)C)ccc21

Procedure:
Using general procedure A (Exp. 1.1), 6-isopropoxy-3,4-dihydro-2H-naphthalen-1-one was reacted with MeMgI to give 7-isopropoxy-4-methyl-1,2-dihydro-naphthalene as a colorless oil. MS: 203.4 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.Cl.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(CCC(=O)O)cc1

Procedure:
A mixture of 5.0 g. of 4-nitrocinnamic acid and 100 mg. of 10% palladium-on-carbon in 200 ml. of ethanol containing 5 drops of 5.5N ethanolic hydrogen chloride is treated with hydrogen in a Parr apparatus at room temperature for 3 hours. The mixture is then filtered through celite and the filtrate is evaporated, affording 4-aminohydrocinnamic acid.
Reaction SMILES: CO.[BH4-].[Li+].[Cl:5][C:6]1[CH:11]=[C:10]([C:12](OC)=[O:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[NH:26][N:25]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH:24][N:23]=1>O1CCCC1>[Cl:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[NH:26][N:25]([C:27]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH:24][N:23]=1
Reactant: COC(=O)c1ccc(-c2ccccc2C2=NNN(C(c3ccccc3)(c3ccccc3)c3ccccc3)N2)c(Cl)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(-c2ccccc2C2=NNN(C(c3ccccc3)(c3ccccc3)c3ccccc3)N2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
1.27 g of methanol (39.6 mmol) and 1.29 g of lithium borohydride (59.4 mmol) are added to a solution of 22.0 g (39.6 mmol) of the compound from Example XXXIV in 180 ml of tetrahydrofuran, and the mixture is then stirred at room temperature for 30 minutes and under reflux for 1 hour. Addition of a further 0.63 g of methanol (0.20 mmol) and stirring under reflux for 1 hour brings the reaction to completion. The reaction mixture is concentrated; the residue is taken up in 200 ml of methylene chloride and 100 ml of 1N potassium hydrogen sulphate solution are slowly added under a vigorous stream of argon, using an ice-bath. After the phases have been separated, the aqueous phase is extracted with methylene chloride. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated, to give 20.5 g of white crystals [98.19% of theory; melting point 186°-7° C. (decomposition), Rf 0.15 (hexane:ethyl acetate=3:1)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:30]([O:32]CC)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:30]([OH:32])=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.2 %

Procedure:
A mixture of ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexanecarboxylate (0.37 g, 0.72 mmol) and lithium hydroxide monohydrate (0.174 g, 7.28 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexane carboxylic acid (0.25 g) as a white solid. 1H-NMR (CDCl3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.55 (s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 2.48 (dd, 2H); 1.52-1.81 (m, 6H); 1.33 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:32])[S:14]([C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15]>>[CH3:12][N:13]([CH3:32])[S:14]([C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:30])=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1)(=[O:15])=[O:16]
Reactant: Nc1ccc2cccnc2c1
Reactant: CN(C)S(=O)(=O)c1cccc(-c2ccc(C(=O)O)cc2)c1
Product: CN(C)S(=O)(=O)c1cccc(-c2ccc(C(=O)Nc3ccc4cccnc4c3)cc2)c1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (18 mg, 0.13 mmol) and 3′-dimethylsulfamoyl-1,1′-biphenyl-4-carboxylic acid (D68) (45 mg, 0.15 mmol) as a yellow oil. MS(ES): MH+ 432, M-H+ 430
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([N+:13]([O-:15])=[O:14])=[CH:8][N:7]=1.[N+]([NH:19][C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[CH:22][N:21]=1)([O-])=O.C(O)C>N1C=CC=CC=1>[OH2:14].[CH3:12][C:11]1[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:20]2[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[CH:22][N:21]=2)=[N:7][CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=1.[CH3:12][C:11]1[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:19][C:20]2[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[CH:22][N:21]=2)=[N:7][CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1NCCCN
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1ccc(Cc2cnc(NCCCNc3ncc([N+](=O)[O-])cc3C)[nH]c2=O)cn1
Product: O
Yield: 79.7 %

Procedure:
2-(3-Aminopropylamino)-3-methyl-5-nitropyridine, (1.58 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (1.44 g) were heated together under reflux in pyridine (3 ml) for 22 hr. On cooling, the mixture was treated with ethanol and a mustard coloured solid filtered off (1.88 g,) m.p. 166°-68° C. Recrystallisation from dimethyl formamide/ethanol and finally twice from dimethyl formamide/water gave 2-[3-(3-methyl-5-nitropyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone hemihydrate (1.67 g; 74%) m.p. 110° C. (softens).
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)[C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:10]=3[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:10]=3[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2nc3ccc(OC)cc3n2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2nc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)n(C)c2c1
Reaction time: 8 h

Procedure:
To a mixture of methyl 4-{[cyclohexyl(6-methoxy-1-methyl-1H-benzimidazol-2-yl)methyl]amino}benzoate (625 mg) synthesized above, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (5.00 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (5.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (600 mg, quantitative) as a pale-brown solid.
Reaction SMILES: COC1C=CC([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21](N)=[CH:20][C:19]=4[F:25])=[C:11]3[CH:10]=[N:9]2)=CC=1.CC[N:30]=C=NCCCN(C)C.[F:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47]([C:49]2([C:52]([OH:54])=O)[CH2:51][CH2:50]2)=[O:48])=[CH:42][CH:41]=1>>[F:25][C:19]1[CH:20]=[C:21]([N:46]([C:43]2[CH:42]=[CH:41][C:40]([F:39])=[CH:45][CH:44]=2)[C:47]([C:49]2([C:52]([NH2:30])=[O:54])[CH2:50][CH2:51]2)=[O:48])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH3:7])[N:9]=[CH:10][C:11]=12
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccc(Cn2ncc3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Product: Cn1ncc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc21
Yield: 3 %

Procedure:
Prepared according to the procedure for Example 2, Step A, substituting 3-fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)benzenamine (22 mg, 0.085 mmol; obtained from Example 3, Step C) for 4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine. In addition, the amount of EDCI (94 mg, 0.51 mmol) and ((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (117 mg, 0.51 mmol) were both increased. The crude was purified by preparative TLC eluting with EtOAc. The product was obtained as a white solid (1.4 mg, 3%). LRMS (ESI+): 97% purity, 220 nm, m/z 464 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 10.0 (br s, 1H), 8.35 (d, J=5 Hz, 1H), 8.10 (s, 1H), 7.78 (m, 1H), 7.76 (s, 1H), 7.45 (m, 2H), 7.23 (m, 1H), 7.07 (m, 2H), 6.41 (d, J=5 Hz, 1H), 4.14 (s, 3H), 1.81 (m, 2H), 1.62 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11]([OH:20])=[CH:10][N:9]=1.Br[CH2:22][CH2:23][O:24][CH3:25]>O>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11]([O:20][CH2:22][CH2:23][O:24][CH3:25])=[CH:10][N:9]=1
Reactant: COCCBr
Reactant: COc1ccc2c(Cl)ncc(O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCCOc1cnc(Cl)c2ccc(OC)cc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
Potassium carbonate (659 mg, 4.77 mmol) was added to a solution of 1-chloro-6-methoxyisoquinolin-4-ol (500 mg, 2.385 mmol) and 1-bromo-2-methoxyethane (663 mg, 4.77 mmol) and stirred for 3 hrs at 50° C. After 3 hrs, the reaction was diluted with water and extracted with EtOAc. The organic layer was washed with water (2×) followed by brine. The organic layer was collected, dried over MgSO4, filtered and evaporated to give the crude product 1-chloro-6-methoxy-4-(2-methoxyethoxy)isoquinoline (560 mg, 88% yield) as an orange solid. Crude material used as is in next step. MS: MS m/z 268.15(M++1).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][C:5]([CH3:15])=[CH:4][C:3]=1[CH2:16][NH:17][C:18]1[C:19]([CH3:26])=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[CH3:24].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][C:5]([CH3:15])=[CH:4][C:3]=1[CH2:16][NH:17][C:18]1[C:19]([CH3:26])=[C:20]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:25][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]
Reactant: Cc1cc(CNc2c(C)ccc(O)c2C)c(F)c(-c2cccc(F)c2)c1
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(CNc2c(C)ccc(OCC(=O)OC(C)C)c2C)c(F)c(-c2cccc(F)c2)c1
Reaction time: 1 h
Yield: 74.4 %

Procedure:
To a solution of 3-[[2-fluoro-3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]-2,4-dimethyl-phenol (114 mg, 0.32 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (158 mg, 0.48 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 30 min the isopropyl bromoacetate (70 mg, 0.39 mmol, 1.2 eq) was added. The reaction mixture was stirred a further 1 h then poured into water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 30:1 to 20:1) to give the title compound as colorless oil (108 mg, 76%).
Reaction SMILES: [CH2:1]([C:8]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].Cl>ClCCl>[CH2:31]([O:30][C:28]([N:10]1[CH2:9][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:11]1)=[O:29])[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: COc1cccc(C2(Cc3ccccc3)CNC2)c1
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CCOC(=O)N1CC(Cc2ccccc2)(c2cccc(OC)c2)C1
Temperature: 25 °C

Procedure:
To a stirred and cooled solution of 3-benzyl-3-(3-methoxyphenyl)azetidine (0.45 g, 1.776 mmol) under argon in dichloromethane containing diisopropylamine (0.465 ml, 2.66 mmol) was added dropwise ethyl chloroformate (0.26 ml, 2.7 mmol). The reaction was stirred over night while it was allowed to warm up to room temperature. Hydrochloric acid (1N) was added and the mixture diluted with dichloromethane. The organic layer was separated and the aqueous layer extracted twice with dichloromethane. The combined organic layers were washed subsequently with water, sodium bicarbonate and brine, dried over sodium bicarbonate, filtered and the solvent evaporated to obtain desired product. m=546 mg (61%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](SC)[N:10]=1)[CH3:2].O[O:19][S:20]([O-:22])=O.[K+].[CH3:24]O>O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([S:20]([CH3:24])(=[O:22])=[O:19])[N:10]=1)[CH3:2]
Reactant: CCOC(=O)CCCCc1ccnc(SC)n1
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Solvent: O
Product: CCOC(=O)CCCCc1ccnc(S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 26-3 (2.0 g, 8.0 mmol) in MeOH (100 mL) was added a solution of Oxone® (14.5 g, 24 mmol) in H2O (100 mL). The resulting solution was stirred at ambient temperature for 20 h, then the MeOH was removed at reduced pressure and the aqueous phase diluted with sat. NaHCO3 (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were dried, filtered and concentrated to afford 26-4 as a colorless oil.