Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:12]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][N:13]1[C:12]2[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:11]=2[N:10]=[C:9]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[O:8][CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1cccc(Cl)c1
Reactant: BrCC1CCCC1
Product: Fc1cc2nc(-c3ccc(Cl)cc3OCC3CCCC3)n(Cc3cccc(Cl)c3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, from 5-chloro-2-[1-(3-chloro-benzyl)-5,6-difluoro-1H-benzoimidazol-2-yl]-phenol (Example 53, intermediate a) and bromomethyl-cyclopentane (CAS Reg. No. 3814-30-0). Colorless powder (29%). MS (Turbo Spray): m/z=487.1 (M+H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:15][CH3:16])[NH:12]2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4].[C:18](=O)([O-])[O-].[K+].[K+].BrC[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Cl:31]>CN(C=O)C.O>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:15][CH3:16])[N:12]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([Cl:31])[CH3:18])=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: ClCCCCCCBr
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC(C)Cl)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 115.2 %

Procedure:
To a solution of 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifuoroacetate salt (3 g, 8.54 mmol) in DMF (30 ml) was added potassium carbonate (2.95 g, 21.35 mmol) and the mixture stirred at 60° C. for 1 hour under an atmosphere of nitrogen. The mixture was then cooled to room temperature and 1-bromo-6-chlorohexane (1.27 ml, 8.54 mmol) was added and the reaction heated to 50° C. and stirred overnight under an atmosphere of nitrogen. The reaction mixture was diluted with water (ca. 50 ml) and extracted with ethyl acetate (2×70 ml). The combined organic extracts were dried (MgSO4), filtered and the filtrate concentrated to give an orange oil (ca. 3.5 g). This material was dissolved in dichloromethane and purified on a Flashmaster II (70 g aminopropyl cartridge) using a 0-100% ethyl acetate in cyclohexane gradient over 60 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow oil which solidified to a pale yellow solid (1.2 g). LCMS (System D): tRET=3.59 min; MH+=356, 358
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[CH:3]=1.[NH2:20][C:21]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C@H:34]([NH:38]C(OC(C)(C)C)=O)[C:35]([OH:37])=[O:36])=[CH:29][CH:28]=2)[CH:24]=[C:23](Cl)[N:22]=1.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[NH2:38][C@@H:34]([CH2:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH:24]=[C:23]([O:13][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[N:14]3[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]3)[C:9]([F:12])([F:11])[F:10])[N:22]=[C:21]([NH2:20])[N:26]=2)=[CH:28][CH:29]=1)[C:35]([OH:37])=[O:36]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(Cl)nc(N)n2)cc1)C(=O)O
Reactant: Cc1ccn(-c2cc(Cl)ccc2C(O)C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(-c3ccc(C[C@H](N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
1-[4-Chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoro-ethanol (0.120 g, 0.41 mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (0.176 g, 0.45 mmol), 1,4-dioxane (4 ml), and Cs2CO3 (0.533 g, 1.64 mmol) were combined in a 20 ml sealed tube, and the mixture was heated at 100° C. for 12 hours. The mixture was concentrated. To the residue, 10% methanol in DCM (50 ml) was added and the mixture was filtered. The filtrate was concentrated to give a crude product, which was taken in THF/3N HCl (30 ml/15 ml) and the resulting mixture was stirred at 40-45° C. for 12 hours. LCMS indicated the completion of reaction with desired product. The mixture was concentrated to give a crude product, which was dissolved in MeOH and H2O (1:1) and purified by preparative HPLC using MeOH/H2O/TFA as solvent system to give (S)-2-amino-3-[4-(2-amino-6-{1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoro-ethoxy}-pyrimidine-4-yl)-phenyl]-propionic acid as a TFA salt. LCMS: M+1=547. 1H-NMR (400 MHz, CD3OD): δ (ppm) 2.30 (s, 3H), 3.10-3.30 (m, 2H), 4.20 (t, 1H), 6.32 (d, 1H), 6.74 (s, 1H), 7.0 (q, 1H), 7.38 (d, 2H), 7.50 (m, 2H), 7.72 (m, 1H), 7.90 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].CO.C(N(CC)CC)C.Br.[NH2:25][C@@H:26]([CH3:30])[C:27]([NH2:29])=[O:28]>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:25]([C@@H:26]([CH3:30])[C:27]([NH2:29])=[O:28])[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: C[C@H](N)C(N)=O
Agent: Br
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H](C(N)=O)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 50 °C

Procedure:
To a solution of 5-nitro-isochromen-1-one (1.5 g, 0.0078 mol) in methanol (20 mL, 0.4 mol) was added triethylamine (2 mL, 0.02 mol) and (S)-2-aminopropanamide hydrobromide (1.6 g, 0.0094 mol) and the resulting mixture was heated at 50° C. overnight. The reaction mixture was cooled to room temperature wherein the product precipitated out. The precipitate was filtered and dried to yield the pure product as a yellow solid. MS m/z=262.2 (M+H).
Reaction SMILES: [Sn](C)(C)(C)[CH3:2].Br[C:7]1[C:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)=[N:9][S:10][C:11]=1[NH:12][C:13]([C@@H:15]1[CH2:17][C@H:16]1[CH3:18])=[O:14]>CN(C=O)C.CCOC(C)=O.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:8]2[C:7]([CH3:2])=[C:11]([NH:12][C:13]([C@@H:15]3[CH2:17][C@H:16]3[CH3:18])=[O:14])[S:10][N:9]=2)=[CH:20][CH:21]=1)[CH3:27]
Reactant: C[Sn](C)(C)C
Reactant: CCOc1ccc(-c2nsc(NC(=O)[C@@H]3C[C@H]3C)c2Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nsc(NC(=O)[C@@H]3C[C@H]3C)c2C)cc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
Add PdCl2(PPh3)2 (0.07 g, 0.09 mmol) and Sn(CH3)4 (0.34 mL, 0.44 g, 2.48 mmol) to (R,R)—N-[4-bromo-3-(4-ethoxyphenyl)isothiazol-5-yl]-2-methylcyclopropane-carboxamide (0.24 g, 0.62 mmol) in DMF (1 mL) and stir the reaction mixture at 130° C. in a sealed tube overnight. Dilute with EtOAc (100 mL) and brine (100 mL). Collect the organic phase, dry (MgSO4), and evaporate. Filter over silica gel and wash with EtOAc. Evaporate and crystallize from EtOAc/hexane to afford (R,R)—N-[3-(4-ethoxyphenyl)-4-methylisothiazol-5-yl]-2-methylcyclopropanecarboxamide. Yield: 81.7%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:36][CH:37]([CH3:46])[C:38]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39]>ClCCl.O.C(N(CC)CC)C>[C:38]([N:40]1[CH2:45][CH2:44][N:43]([C:8]([C:7]2[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=2)[C:3]([O:2][CH3:1])=[O:4])=[O:10])[CH2:42][CH2:41]1)(=[O:39])[CH:37]([CH3:46])[CH3:36]
Reactant: CC(C)C(=O)N1CCNCC1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)N2CCN(C(=O)C(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To a solution of 3-(methoxycarbonyl)benzoic acid (0.9 g, 5 mmol) in dichloromethane (20 mL), 1-hydroxybenzotriazole (0.75 g, 5.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.06 g, 5.5 mmol) and triethyl amine (2 mL) was added. The mixture was stirred at room temperature for 30 min, then 2-methyl-1-(piperazin-1-yl)propan-1-one (1.0 g, 5 mmol) was added and the mixture was stirred at room temperature for 16 h. The resulting mixture was added water (50 mL) and extracted with dichloromethane (100 mL×3). The organic phase was washed with sodium bicarbonate and brine and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 20:1 to 2:1) to give 1.25 g of methyl 3-(4-isobutyrylpiperazine-1-carbonyl)benzoate as an oil. Yield 94%. 1H-NMR (400 MHz, CDCl3) 1.14-1.15 (d, J=6.4 Hz, 6H), 2.81 (brs, 1H), 3.44-3.80 (m, 8H), 3.94 (s, 3H), 7.52-7.55 (t, J=7.6 Hz, 1H), 7.62-7.64 (d, J=8.0 Hz, 1H), 8.08-8.14 (m, 2H); LC-MS (ESI) m/z: 319 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:10][N:20]=[N+:21]=[N-:22])[CH2:16][CH:17]([CH3:19])[CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Yield: 73.3 %

Procedure:
The mesylate from example 88 (32.6 g, 110 mmol) was treated with sodium azide (21.45 g, 330 mmol) in DMF at 80° C. for 24 hrs. The solvent was evaporated, the residue was taken up in DCM, filtered and washed with saturated NaHCO3 (aq). The solution was dried with Na2SO4 and concentrated to a brown oil which was purified by flash chromatography using a gradient of ethyl acetate and hexane to afford the title compound as a white solid (19.55 g, 73%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:27])[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20](=O)[CH2:19]1>[Zn].Cl[Ti](Cl)(Cl)Cl.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[CH2:23][C:18]([CH3:27])([CH3:17])[CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: O=C(c1ccc(O)cc1)c1ccc(F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(F)cc2)CC(C)(C)C1
Yield: 80.5 %

Procedure:
The coupling procedure described for 1 (example 1, step 1) was employed. A mixture of (4-fluorophenyl)(4-hydroxyphenyl)methanone (4.32 g, 20 mmol), 3,3,5,5-tetramethylcyclohexanone (9.26 g, 60 mmol), Zn (13 g, 200 mmol), TiCl4 (10.9 mL, 100 mmol), and THF (400 mL) was refluxed for 2.5 h. Standard work-up followed by purification afforded 5.450 g (80%) of the title product 9 as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.15-7.11 (m, 2H), 7.04 (d, J=8.7 Hz, 2H), 7.00-6.94 (m, 1H), 6.76 (d, J=8.7 Hz, 2H), 4.68 (br s, 1H), 2.0 (s, 2H), 1.96 (s, 2H), 1.31 (s, 2H), 0.95 (s, 6H), 0.94 (s, 6H). LCMS (APCI): m/z 429 (M+H)+.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[CH:35][C:36](OC)=[C:37]([OH:39])[CH:38]=1.[CH2:42]1COCC1>>[OH:39][C:37]1[CH:38]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]4[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]5[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])=[CH:18][CH:19]=4)=[O:13])[CH:10]=3)[NH:5][C:4]2=[O:31])[CH:34]=[CH:35][C:36]=1[CH3:42]
Reactant: COc1ccc(N)cc1O
Reactant: C1CCOC1
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)cc1
Product: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CNc2ccc(C)c(O)c2)C(=O)N3)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (as prepared in Example 7, 70 mg, 0.168 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methoxyphenol (22.8 mg, 0.184 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 62% (56 mg, 0.104 mmol) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:18]([CH3:19])=[CH:17][C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1.[Li]CCCC.[C:33](C#N)(=[O:37])[O:34][CH2:35][CH3:36]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:18]([CH3:19])=[CH:17][C:16]2[C:12](=[C:13]([C:33]([O:34][CH2:35][CH3:36])=[O:37])[N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=2)[CH:11]=1
Reactant: CCOC(=O)C#N
Reactant: COc1ccc(-c2cc3cn(COCC[Si](C)(C)C)nc3cc2C)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c2cc(-c3ccc(OC)cc3F)c(C)cc2nn1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 58.1 %

Procedure:
To a solution of 5-(2-fluoro-4-methoxyphenyl)-6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (650 mg, 1.68 mmol) in THF (10 mL) at −78° C. was added n-BuLi (2.5M in hexanes, 0.74 mL, 1.85 mmol) dropwise via syringe. The reaction was stirred at −78° C. for 10 minutes, warmed to room temperature for 5 minutes, and cooled back to −78° C. A solution of ethyl cyanocarbonate (188 mg, 1.90 mmol) in THF (1 mL) was added via syringe. The cooling bath was removed and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched with aqueous NH4Cl solution and diluted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc/heptane) to provide the title compound (448 mg, 58% yield). MS (ES+) 459.3 (M+H)+. 1H NMR (500 MHz, CDCl3) δ 7.87 (s, 1H), 7.69 (s, 1H), 7.22 (t, J=8.54 Hz, 1H), 6.81 (dd, J=8.42, 2.32 Hz, 1H), 6.75 (dd, J=11.34, 2.32 Hz, 1H), 6.20 (s, 2H), 4.49 (q, J=7.07 Hz, 2H), 3.89 (s, 3H), 3.66-3.72 (m, 2H), 2.29 (s, 3H), 1.44 (t, J=7.07 Hz, 3H), 0.93-1.00 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][O:20][C:21]2[C:22]([CH2:27][C:28]#[N:29])=N[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1.O1CCCC1.[OH-:37].[Na+].Cl.[OH2:40]>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:25][C:24]([OH:40])=[O:37])=[N:29][CH:28]=[CH:27][CH:22]=2)=[CH:30][CH:31]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2cccnc2CC#N)cc1
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2cccnc2CC(=O)O)cc1
Yield: 47 %

Procedure:
To a mixture of 2-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-pyridyl]acetonitrile (0.55 g), tetrahydrofuran (1 mL) and ethanol (4 mL) was added a 2N aqueous sodium hydroxide solution (4 mL) and the mixture was stirred with heating under reflux for 12 hrs. 1N Hydrochloric acid (8 mL) and water were added to the reaction mixture, and the precipitated solid was collected by filtration and dried with air to give crystals (0.35 g, 47%) of 2-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-pyridyl]acetic acid. Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 115-116° C. (dec.)
Reaction SMILES: [CH2:1]([N:5]([CH3:24])[C:6]([C:8]1[CH:9]=[C:10]([C:21](O)=[O:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:13]=1)=[O:7])[CH:2]([CH3:4])[CH3:3].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[N:48]1[CH:49]=[CH:50][N:51]2[CH:56]=[CH:55][C:54]([CH2:57][NH2:58])=[CH:53][C:52]=12.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[N:48]1[CH:49]=[CH:50][N:51]2[CH:56]=[CH:55][C:54]([CH2:57][NH:58][C:21]([C:10]3[CH:11]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=4)[CH:13]=[C:8]([C:6]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH3:24])=[O:7])[CH:9]=3)=[O:22])=[CH:53][C:52]=12
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N(C)CC(C)C)c2)cc1
Reactant: NCc1ccn2ccnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)NCc3ccn4ccnc4c3)cc(C(=O)N(C)CC(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(isobutyl(methyl)carbamoyl)-4′-methylbiphenyl-3-carboxylic acid (15 mg, 0.046 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (18 mg, 0.092 mmol), 1-hydroxybenzotriazole hydrate (7.0 mg, 0.046 mmol), and CH2Cl2 (2 mL) were added imidazo[1,2-a]pyridin-7-ylmethanamine (10 mg, 0.069 mmol) and N,N-diisopropylethylamine (12 μL, 0.069 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 40-70% MeCN/water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C@H:11]2[CH2:13][O:12]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:14].[OH2:15].[C:16]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:15][CH2:13][C@@H:11]([C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:14])[O:5][CH2:4]2)[O:12][CH3:16]
Reactant: O
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CO[C@@H](CO)c1ccc2c(c1C)COC2=O
Temperature: 80 °C

Procedure:
To a solution of (S)-4-methyl-5-(oxiran-2-yl)isobenzofuran-1(3H)-one (2.00 g, 10.5 mmol) in MeOH (20 mL) was added p-toluenesulfonic acid monohydrate (0.100 g, 0.526 mmol). After heating at 80° C. for 48 h, the reaction mixture was cooled to RT and then concentrated. The crude product was purified by column chromatography eluting with 0-45% EtOAc/Hexane. LC-MS (IE, m/z): 223.2 (M+1)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.[NH2:20][CH2:21][CH2:22][OH:23]>>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:20][CH2:21][CH2:22][OH:23])=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Reactant: NCCO
Product: OCCNc1nc2nc(SCc3ccccc3)nc(Cl)c2s1

Procedure:
Prepared by the method of Example 231, using the product of Example 219 and 2-aminoethanol.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([CH3:16])[N:6]=1)([CH3:3])[CH3:2].[Cl:17][C:18]1[C:23]([C:24](O)=[O:25])=[C:22]([F:27])[C:21]([CH2:28][NH:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:20][CH:19]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:17][C:18]1[C:23]([C:24]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[N:8]=[C:7]([CH3:16])[N:6]=[C:5]3[NH:4][CH:1]([CH3:3])[CH3:2])=[O:25])=[C:22]([F:27])[C:21]([CH2:28][NH:29][C:30](=[O:35])[C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:20][CH:19]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Cc1nc(NC(C)C)c2cccc(N)c2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(NC(C)C)c2cccc(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)c2n1
Yield: 33.8 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-isopropyl-2-methylquinazoline-4,8-diamine (Intermediate-50, 30 mg, 0.14 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 60 mg, 0.20 mmol), oxalyl chloride (38 mg, 0.30 mmol), DMF (1 drop) and DIPEA (77 mg, 0.60 mmol) in CH2Cl2 (2 mL) to afford 23 mg of the title product. 1H NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 8.65 (d, J=7.6 Hz, 1H), 8.12-8.01 (t, J=8.4 Hz, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.43 (d, J=7.7 Hz, 1H), 7.41-7.35 (m, 3H), 4.57-4.52 (m, 1H), 4.30 (d, J=5.6 Hz, 2H), 2.44 (s, 3H), 1.25 (s, 3H), 1.24 (s, 3H), 1.13 (s, 9H); MS (m/z): 486.27 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:16])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[H-].[Na+].Cl[CH2:20][C:21]1[S:22][CH:23]=[CH:24][CH:25]=1>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([O:16][CH2:20][C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reactant: ClCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cl
Product: Clc1ccc(C(Cn2ccnc2)OCc2cccs2)c(Cl)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
A solution of 1-(2,4-dichloro-phenyl)-2-(1-imidazolyl) ethanol (1.5 g, 5.8mmole) dissolved in dry tetrahydrofuran (10 ml) was added to a stirred suspension of sodium hydride (0.39 g, as 80% dispersion in oil, 16 mmole) in dry tetrahydrofuran (10 ml) and warmed to 70° C for 90 minutes. The mixture was cooled in ice and a solution of 2-chloromethyl-thiophene (1.16 g, 8.8 mmole) in dry tetrahydrofuran was added. The mixture was heated at 70° for 3 hours and allowed to stir at room temperature overnight. The solvent was removed under vacuum and the residue stirred with dry ether (200 ml). The ether solution was filtered through celite and saturated with hydrogen chloride gas to precipitate an oil which was solidified by trituration with ether and ethylacetate. The solid product was collected and recrystallized from a mixture of acetone and di-isopropyl ether to give 1-[2,4-dichloro-β-(2-thienylmethoxy)phenethyl]imidazole hydrochloride as fine white crystals (0.63 g, 31%) m.p. 153°-154° C. (Found: C, 49.2; H, 3.8; N, 7.3. C16H14Cl2N2OS.HCl requires C, 49.3; H, 3.9; N, 7.2%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17]1([CH:23]([CH2:27][CH3:28])[C:24](O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(=O)(O)[O-].[Na+]>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:24](=[O:25])[CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:27][CH3:28])=[CH:15][CH:16]=1
Reactant: CCC(C(=O)O)c1ccccc1
Reactant: ClCCCCCCCCOc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCC(C(=O)c1ccc(OCCCCCCCCCl)cc1)c1ccccc1
Reaction time: 16 h
Yield: 80.7 %

Procedure:
8-Chlorooctoxybenzene (9.1 g, 38 mmol) was added to a stirred solution of 2-phenylbutyric acid (7.48 g, 46 mmol) in trifluoroacetic anhydride (7.5 ml, 52 mmol) and stirring continued for 16 h. The mixture was poured into saturated sodium bicarbonate solution (100 ml), neutralised by addition of sodium bicarbonate, and extracted with ether (2×100 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residues were column-chromatographed (silica; eluant 5-10% dichloromethane in petrol) to give the title compound as a colourless oil (11.86 g, 81%). NMR (CDCl3) δ=0.87 (3H,t,J=7.3 Hz), 1.26-1.50 (8H, m), 1.69-1.90 (5H,m), 2.08-2.26 (1H,m), 3.51 (2H,t,J=6.6 Hz), 3.94 (2H,t,J=6.6 Hz), 4.38 (1H,t,J=7.3 Hz), 6.83 (2H,d,J=8.8 Hz), 7.15-7.20 (1H,m), 7.20-7.28 (4H,m), 7.93 (2H,d,J=8.8 Hz). IR (liq, cm-1) 2933, 2858, 1673, 1600, 1574, 1510 MS(Chemical Ionisation)m/e=387 (M+ +1, 10%)
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH2:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1NC.C[CH2:29][N:30](C(C)C)C(C)C>>[CH:21]1([CH2:29][NH:30][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:20]1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNC1CCCCC1
Product: O=C1N=C(NCC2CCCCC2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-cyclohexyl-methylamine and DIEA to give 2-(cyclohexylmethyl-amino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 352 (MH+).