Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[S:15][C:14]([NH:16][C:17](=[O:40])[CH:18]([C:28]3[CH:33]=[CH:32][C:31]([S:34]([CH:37]4[CH2:39][CH2:38]4)(=[O:36])=[O:35])=[CH:30][CH:29]=3)[O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])=[N:13][CH:12]=2)=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[CH:37]1([S:34]([C:31]2[CH:30]=[CH:29][C:28]([CH:18]([O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[C:17]([NH:16][C:14]3[S:15][C:11]([O:10][C:7]4[CH:6]=[CH:5][C:4]([C:3]([OH:41])=[O:2])=[CH:9][CH:8]=4)=[CH:12][N:13]=3)=[O:40])=[CH:33][CH:32]=2)(=[O:35])=[O:36])[CH2:38][CH2:39]1
Reactant: COC(=O)c1ccc(Oc2cnc(NC(=O)C(Oc3ccc(F)cc3F)c3ccc(S(=O)(=O)C4CC4)cc3)s2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(Oc2cnc(NC(=O)C(Oc3ccc(F)cc3F)c3ccc(S(=O)(=O)C4CC4)cc3)s2)cc1
Reaction time: 2.5 h
Yield: 85.6 %

Procedure:
4-{2-[2-(4-Cyclopropanesulfonyl-phenyl)-2-(2,4-difluoro-phenoxy)-acetylamino]thiazol-5-yloxy}-benzoic acid methyl ester (1.4 g, 2.33 mmol, obtained in example A74) was taken in THF: MeOH (1:1, 20 mL), to it was added aqueous solution of LiOH (0.34 g, 7.94 mmol in 10 mL water) and stirred for 1-4 h. After completion of the reaction, organic solvent was removed under reduced pressure. The aqueous layer was washed with diisopropyl ether then acidified with 1 N HCl to pH 2. The solid formed was filtered, washed with water, followed by washing with diisopropyl ether & dried under vacuum to get the title compound (1.17 g, 86%).
Reaction SMILES: Cl[Sn]Cl.O.[F:5][C:6]1[CH:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][C:25]=3[NH:26][S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[CH:17][CH:16]=2)[CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1.C([O-])(O)=O.[Na+]>CCO>[NH2:12][C:10]1[CH:11]=[C:6]([F:5])[CH:7]=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[S:22][CH:23]=[CH:24][C:25]=3[NH:26][S:27]([CH:30]([CH3:31])[CH3:32])(=[O:28])=[O:29])=[CH:19][CH:20]=2)[CH:9]=1
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2cc(F)cc([N+](=O)[O-])c2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2cc(N)cc(F)c2)cc1

Procedure:
Add SnCl2.2 H2O (8.5 mmol) to a solution of propane-2-sulfonic acid [2-(3′-fluoro-5′-nitro-biphenyl-4-yl)-thiophen-3-yl]-amide (1.2 mmol) in EtOH (40 mL). Heat the reaction at 70° C. for 30 min and then at room temperature overnight. Add a saturated solution of NaHCO3 (pH=11-12) and extract with EtOAc (2×50 mL). Dry over NaSO4, filter and evaporate to dryness to provide the title compound. MS (ES−): 389 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1/[CH:12]=[C:13](/[C:16](=O)[CH3:17])\[C:14]#[N:15].[NH2:19][C:20]([CH:24]([F:26])[F:25])=[CH:21][C:22]#[N:23]>>[F:25][CH:24]([F:26])[C:20]1[NH:19][C:16]([CH3:17])=[C:13]([C:14]#[N:15])[CH:12]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=2[F:1])[NH:8][N:7]=[C:6]3[CH3:11])[C:21]=1[C:22]#[N:23]
Reactant: CC(=O)/C(C#N)=C/c1cc2c(C)n[nH]c2cc1F
Reactant: N#CC=C(N)C(F)F
Product: CC1=C(C#N)C(c2cc3c(C)n[nH]c3cc2F)C(C#N)=C(C(F)F)N1

Procedure:
Following the procedure described for Example 1, 100 mg (0.411 mmol) (2E)-2-[(6-fluoro-3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 4A) were treated with 3-amino-4,4-difluorobut-2-enenitrile. The crude product was purified by preparative RP-HPLC (aceto-nitrile/water+0.1% TFA gradient, final mixture 90:10 v/v) to yield 50 mg (35% of th.) of the racemic title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].C(OCC)(=O)C.Cl>N1C=CC=CC=1>[C:11]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)(=[O:13])[CH3:12]
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C(=O)O)cn1
Temperature: 140 °C
Reaction time: 24 h
Yield: 25.9 %

Procedure:
A mixture of 6-aminonicotinic acid 5.00 g (36.5 mmol) and acetic anhydride 3.80mL (40.2 mmol) in pyridine 30 mL was stirred at 140° C. for 24 hours. To the reaction mixture was added ethyl acetate and acidified with diluted HCl solution to pH 2. The organic layer was washed with water and brine, dried over MgSO4, filtrated and the solvent was evaporated. The residue was washed with diisopropyl ether to give the title compound 1.70 g as off-white solid. Yield 26%.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32]N)=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:28][CH:27]=1
Reactant: NNc1ccc(F)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccc(F)cc3)n2)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (4-fluoro-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=411.2 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1.C(N(CC)CC)C.[F:35][C:36]([F:42])([F:41])[S:37](Cl)(=[O:39])=[O:38].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][S:37]([C:36]([F:42])([F:41])[F:35])(=[O:39])=[O:38])=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1
Reactant: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(O)cc2)c(C)c1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c(C)c1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To a solution of 4-[2-methyl-4-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-sulfonyl]-phenol (122 mg, 0.318 mmol), prepared by the method described in Example 2, and triethylamine (0.053 mL, 0.38 mmol) in CH2Cl2 (3 mL) was added trifluoromethanesulfonyl chloride (0.037 mL, 0.35 mmol) at 0° C. The reaction mixture was stirred under N2 and slowly warmed to room temperature. The mixture was treated with saturated aqueous NaHCO3, and extracted (3×) with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (67:33 hexanes/EtOAc) to provide trifluoromethanesulfonic acid 4-[2-methyl-4-(2,4,6-trimethylphenylamino)-pyrimidine-5-sulfonyl]-phenyl ester (150 mg, 91%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.79 (s, 1H), 8.15 (br s, 1H), 8.08 (d, J=8.9 Hz, 2H), 7.47 (d, J=8.9 Hz, 2H), 6.92 (s, 2H), 2.42 (s, 3H), 2.31 (s, 3H), 1.98 (s, 6H); ESI MS m/z 516 [(M+H)+, calcd for C21H21F3N3O5S2, 516.1].
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:25])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7].[BH4-].[Na+].O>C(O)C>[CH3:1][O:2][CH2:3][CH:4]([OH:25])[CH2:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)(=[O:7])=[O:8]
Reactant: COCC(=O)CS(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COCC(O)CS(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
A suspension of Example 126A (850 mg, 2.28 mmol) in ethanol (100 mL) at ambient temperature was treated with sodium borohydride (103 mg, 2.74 mmol), stirred for 30 minutes, treated with water, extracted with ethyl acetate, dried (Na2SO4) and concentrated to provide 820 mg (96%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:24]([O-])=O)=[CH:14][CH:13]=2)[C:9](=[O:27])[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]>C(O)C.[Ni]>[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:6][CH:7]=[CH:8][C:9]2=[O:27])=[CH:13][CH:14]=1
Reactant: CCCCc1cccc(=O)n1Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CCO
Product: CCCCc1cccc(=O)n1Cc1ccc(-c2ccccc2N)cc1

Procedure:
A solution of 1 g of 6-butyl-1-(2'-nitrobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxopyridine in 30 ml of ethanol is hydrogenated on 1 g of Raney Ni at 20° until the uptake of H2 has ceased. The mixture is filtered and evaporated to give 1-(2'-aminobiphenyl-4-ylmethyl)-6-butyl-1,2-dihydro-2-oxopyridine.
Reaction SMILES: [C:1]([N:10]([CH2:12][C:13]([NH2:15])=[S:14])[CH3:11])([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:2].N1C=CC=CC=1.[Cl:22][CH2:23][C:24](=O)[CH2:25]Cl>C(O)C>[Cl:22][CH2:23][C:24]1[N:15]=[C:13]([CH2:12][N:10]([C:1]([O:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:2])[CH3:11])[S:14][CH:25]=1
Reactant: CN(CC(N)=S)C(=O)Oc1ccccc1
Reactant: O=C(CCl)CCl
Solvent: c1ccncc1
Solvent: CCO
Product: CN(Cc1nc(CCl)cs1)C(=O)Oc1ccccc1
Yield: 77.1 %

Procedure:
To a cooled solution of (N-carbophenoxy-N-methylamino)thioacetamide (1.0 g; 4.46 mmoles) and dry pyridine (0.36 ml, 4.46 mmoles) in 6 ml of absolute ethanol was added a solution of 1,3-dichloropropanone (0.57 g; 4.49 mmoles) in 3 ml of absolute ethanol. The mixture was heated at reflux temperature for 1.5 hours, then evaporated under reduced pressure and the oil residue partitioned between ether and water. The aqueous layer was extracted with ether and the combined ether phase was washed with water, saturated aqueous sodium chloride solution and dried. Filtration and evaporation yielded 1.02 g of the title compound as a viscous oil; TLC [silica/CH2Cl2 :CH3CN (85:15)] gave Rf=0.82. The NMR spectrum (60 MHz) in CDCl3 gave the following resonances δ: 7.16 (m, 6H); 4.77 (broad s, 2H); 4.60 (s, 2H); 3.07 (broad s, 3H).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[C:10]([OH:12])=O)[CH:2]=[C:3]([CH3:5])[CH3:4].[NH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][CH3:30]>>[CH2:29]([N:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[CH2:23][NH:22][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[C:7]([O:6][CH2:1][CH:2]=[C:3]([CH3:4])[CH3:5])[CH:8]=1)[CH3:30]
Reactant: CC(C)=CCOc1ccc(C(=O)O)cc1OCC=C(C)C
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1ccc(OCC=C(C)C)c(OCC=C(C)C)c1
Yield: 55 %

Procedure:
In a manner identical to Example 15, 3,4-diprenyloxybenzoic acid(1.45 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.09 g(55%) of the aimed compound. m.p. 80.0-81.5° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[S:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:26])=[O:25]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Yield: 94.7 %

Procedure:
To a solution of 25 g (0.15 mol) of L-Proline methyl ester hydrochloride in 500 mL of CH2Cl2 was added 70 mL (0.5. mol) of triethylamine with stirring to give copious white precipitate. The mixture was filtered and the filtrate cooled to 0° C. (ice bath) with stirring. To the cooled solution was added a solution of 20 mL (0.15 mol) of benzenesulfonyl chloride in 50 mL of CH2Cl2 dropwise over fifteen minutes. The addition funnel was rinsed with an additional 25 mL of CH2Cl2, and the cloudy, colorless mixture was allowed to warm to room temperature with stirring overnight. The solution was washed 2× with 400 mL of 1N HCl, 2× with 400 mL of 1N NaOH, 1× with brine, then dried (MgSO4), filtered, and concentrated to a pale yellow solid. This material was recrystallized three times from ethyl acetate/hexanes to give 38.2 g (0.142 mol, 95%) of N-(benzenesulfonyl)-Proline methyl ester (MW=269) as broad white needles (TLC vs. 2:1 hexanes/ethyl acetate, Rf=0.35). M/z=270.2 (M+H+). N-(benzenesulfonyl)-Proline: To a solution of 38.2 g (0.142 mol) of the above methyl ester in 500 mL methanol was added 140 mL (0.28 mol) of freshly-prepared 2M aqueous LiOH with stirring to give a colorless solution. This was stirred overnight, after which HPLC showed no starting material. The solution was reduced by 50% in vacuo and partitioned between 1N HCl and CH2Cl2 (200 mL each). The phases were separated and the aqueous layer was washed again with CH2Cl2. The organic phases were combined, dried (MgSO4), and concentrated to a white solid. This was recrystallized twice from ethyl acetate/hexanes to give 34.7 g (0.136 mol, 96%) of the title compound as fine white needles. M/z=256.2 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=1>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=3)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: COc1cccc(N)c1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: COc1cccc(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)c1

Procedure:
The coupling of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8) and 3-methoxyphenylamine according to procedure A followed by deprotection yielded the title compound as an off white solid. MS (ESI): m/z=385.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:14])[N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:26][C@@H:27]1[CH2:31][CH2:30][O:29][CH2:28]1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:14][C:4]1[N:3]=[C:2]([NH:26][C@@H:27]2[CH2:31][CH2:30][O:29][CH2:28]2)[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=1
Reactant: N[C@@H]1CCOC1
Reactant: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc2cc(Cl)nc(N[C@@H]3CCOC3)c2c1=O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (75 mg, 0.33 mmol), (R)-3-aminotetrahydrofuran toluene-4-sulfonate (101 mg, 0.39 mmol), Hunig's base (0.23 mL, 1.32 mmol) and dioxane (4 mL) was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature and worked-up. The residue was purified using slilica gel flash column chromatography (eluent: 0-10% methanol in dichloromethane) to afford (R)-7-chloro-3-methyl-5-(tetrahydrofuran-3-ylamino)pyrido[4,3-d]pyrimidin-4(3H)-one as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[NH2:20][C:21]1[CH:25]=[C:24]([CH:26]2[CH2:28][CH2:27]2)[NH:23][N:22]=1>C1COCC1>[CH:26]1([C:24]2[CH:25]=[C:21]([NH:20][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=[C:4]([CH2:12][O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:3]=3)[NH:22][N:23]=2)[CH2:28][CH2:27]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: Clc1nc(COc2ccccc2)nc2ccccc12
Solvent: C1CCOC1
Product: c1ccc(OCc2nc(Nc3cc(C4CC4)n[nH]3)c3ccccc3n2)cc1
Temperature: 65 °C

Procedure:
To a solution of the above 4-chloro-2-phenoxymethylquinazoline (0.5 g, 1.85 mmol) in THF (30 mL) is added 3-amino-5-cyclopropylpyrazole (0.47 g, 3.69 mmol) and the reaction mixture is heated at 65° C. for 24 hours. Solvent is evaporated and ethanol is added. A white solid forms and is collected by filtration and dried under vacuum to give (5-cyclopropyl-2H-pyrazol-3-yl)-(2-phenoxymethyl-quinazolin-4-yl)-amine.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]CCl)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:29][CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClCCc1ccc(OCc2ccccc2)cc1
Reactant: O=C1NCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C1c2ccccc2CN1Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 166 %

Procedure:
2,3-dihydro-isoindol-1-one (100 mg, 0.751 mmol) was dissolved in anhydrous acetonitrile and cesium carbonate (730 mg, 0.225 mmol) and 1-benzyloxy-4-chloroethylbenzene (349 mg, 0.150 mmol) were added to the solution and stirred at room temperature for 12 hours. The reaction was partitioned between ethyl acetate and water and the organic was washed with brine, dried over anhydrous sodium sulphate and concentrated. The compound was purified by column chromatography (20% ethyl acetate/hexanes) to yield a yellow solid (82 mg, 33%). 1H NMR (300 MHz, CDCl3): δ 7.91 (d, 1H), 7.37-7.53 (m, 9H), 7.25-7.28 (m, 1H), 6.95 (d, 2H), 5.06 (d, 2H), 4.77 (d, 2H), 4.27 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].Cl[CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26].Cl>CN(C=O)C.C1COCC1>[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: COCCOCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOCOc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87 %

Procedure:
10 g (43.8 mmol) of 4′-hydroxybiphenyl-4-carboxylic acid methyl ester, 100 ml of THF and 150 ml of DMF are introduced in order and under a nitrogen stream into a 500 ml three-necked flask. 1.93 g (48.2 mmol) of NaH at 60% in oil are added in small portions and the mixture is stirred at room temperature for 15 hours. 5.75 ml of 1-chloromethoxy-2-methoxyethane are added dropwise, and the mixture is stirred at room temperature for 30 minutes. The reaction medium is poured over a 1N HCl solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulphate. After filtration and evaporation 12 g of 4′-(2-methoxyethoxymethoxy)biphenyl-4-carboxylic acid methyl ester are obtained in the form of a beige powder after filtration and evaporation (yield=87%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][CH:17]=O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8].O.[NH2:20][NH2:21]>CO>[NH2:20][N:21]1[C:7]([OH:8])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:15]=2)[N:16]=[CH:17]1
Reactant: O=CNc1ccc(Br)cc1C(=O)c1ccccn1
Reactant: NN
Solvent: CO
Solvent: O
Product: NN1C=Nc2ccc(Br)cc2C1(O)c1ccccn1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of 11.2 g. of the 2-(5-bromo-2-formamidobenzoyl)pyridine prepared in the experiment (a) in 50 ml. of methanol is added 10 ml. of hydrazine hydrate (100 %). The resulting mixture is heated at 60° C for several minutes and thereafter left to stand at room temperature for 5 hours. The resulting precipitate is collected by filtration and washed with methanol and ether and dried to give 3-amino-6-bromo-4-hydroxy-4-(2-pyridyl)-3,4-dihydroquinazoline as colorless granules melting at 185° to 187° C. (decomposition).
Reaction SMILES: [CH2:1]([C:3](Cl)=[O:4])[CH3:2].C(Cl)Cl.[N:9]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:26]=4[CH3:32])[C:23]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH:13]=[CH:12][N:11]=[CH:10]1>N1C=CC=CC=1>[N:9]1([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([NH:31][C:3](=[O:4])[CH2:1][CH3:2])=[CH:27][C:26]=4[CH3:32])[C:23]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: Cc1cc(N)ccc1-n1c(CCC(=O)O)ccc1-c1ccc(-n2ccnc2)cc1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)Nc1ccc(-n2c(CCC(=O)O)ccc2-c2ccc(-n3ccnc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of pyridine (1 mL) and C2H5COCl/DCM (v/v=1/100, 4.2 mL) was added a solution of 20B (see scheme 20) (150 mg, 0.389 mmol) in pyridine (1 mL) at 0° C. The mixture was stirred at room temperature overnight. The solvents were removed under reduced pressure and the resulting solid was acidified with 10% hydrochloric acid to pH=5.0. The resulting precipitate was isolated by centrifuge, rinsed with water, dried under reduced pressure to afford the crude product as a brown powder, After purification by prep-HPLC, 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(2-methyl-4-propionamidophenyl)-1H-pyrrol-2-yl)propanoic acid (32 mg, 19%) was obtained as a brown oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]1([CH3:35])[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([NH:19][C:20]([C:22]3[S:26][C:25]([NH:27]C(=O)OC(C)(C)C)=[N:24][CH:23]=3)=[O:21])[S:17][CH:18]=2)=[CH:10][CH:9]=1>C(Cl)(Cl)Cl>[NH2:27][C:25]1[S:26][C:22]([C:20]([NH:19][C:16]2[S:17][CH:18]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([CH3:35])=[CH:9][CH:10]=3)[N:15]=2)=[O:21])=[CH:23][N:24]=1
Reactant: Cc1ccc(-c2csc(NC(=O)c3cnc(NC(=O)OC(C)(C)C)s3)n2)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2csc(NC(=O)c3cnc(N)s3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
TFA (0.100 mL) was added to a solution of tert-butyl 5-(4-p-tolylthiazol-2-ylcarbamoyl)thiazol-2-ylcarbamate (80 mg, 0.19 mmol) in CHCl3 (1 mL). The resulting solution was stirred at RT overnight. Then the solvents were evaporated and the crude product was dissolved in H2O. After neutralization with NaHCO3 saturated aqueous solution, it was extracted with AcOEt, dried and concentrated. Purification by column chromatography (100% AcOEt) yielded 2-amino-N-(4-p-tolylthiazol-2-yl)thiazole-5-carboxamide (40 mg, 67%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][C@@H:10]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:21]([O-])=O.[CH:24]1([C:27]2[N:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25]1>>[CH:24]1([C:27]2[N:32]=[C:31]([C:33]3[NH:1][C:2]4=[N:7][C:6]([N:8]5[CH2:13][CH2:12][O:11][C@@H:10]([C:14]([N:16]6[CH2:20][CH2:19][CH2:18][CH2:17]6)=[O:15])[CH2:9]5)=[CH:5][CH:4]=[C:3]4[N:21]=3)[CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25]1
Reactant: Nc1nc(N2CCO[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Reactant: O=Cc1cccc(C2CC2)n1
Product: O=C([C@H]1CN(c2ccc3nc(-c4cccc(C5CC5)n4)[nH]c3n2)CCO1)N1CCCC1

Procedure:
The title compound was prepared by a method analogous to the one used for Example 112, but using Intermediate 31 and 6-cyclopropylpicolinaldehyde. MS (ES+) (M+H) 418.9; LCMS retention time 2.411 (Method G).