Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([Cl:20])[C:11]=1[O:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1.[CH2:28]([NH2:34])[CH:29]1[O:33][CH2:32][CH2:31][CH2:30]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:28]([NH:34][C:2]([N:24]1[C:25]([CH3:27])=[CH:26][C:22]([O:21][C:11]2[C:10]([Cl:9])=[CH:15][C:14]([C:16]([F:19])([F:17])[F:18])=[CH:13][C:12]=2[Cl:20])=[N:23]1)=[O:3])[CH:29]1[O:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: NCC1CCCO1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C(=O)NCC1CCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.3 %

Procedure:
Trichloromethyl chloroformate (0.49 g, 2.5 mmol) was added to a chloroform (10 mL) solution of 3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.78 g, 2.5 mmol) at 0° C., and while the mixture was allowed to gradually warm up to a room temperature, it was further stirred at room temperature for 3 hours. Tetrahydrofurfurylamine (0.51 g, 5.0 mmol) and triethylamine (1.01 g, 10 mmol) were added to the reaction mixture, and the mixture was refluxed under heating for 4 hours. After completion of the reaction, the reaction mixture was poured into ice and extracted with chloroform (20 mL×3 times). The organic layer was washed with water and dried over anhydrous magnesium sulfate, the desiccant was removed by filtering, and the solvent was distilled off the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate:hexane=1:7) to give a white solid of N-tetrahydrofurfuryl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.31 g, yield: 28.3%). Melting point: 74˜76° C., 1H-NMR (CDCl3, TMS, ppm): δ1.45˜1.65 (m, 1H), 1.75-2.05 (m, 3H), 2.58 (d, J=0.8 Hz, 3H), 3.32 (dt, J=6.2 and 13.9 Hz, 1H), 3.47 (ddd, J=3.7, 5.6 and 13.9 Hz, 1H), 3.60˜3.85 (m, 2H), 3.95˜4.15 (m, 1H), 5.75 (q, J=0.8 Hz, 1H), 6.85˜7.15 (m, 1H), 7.66 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[OH:16].[H-].[Na+].[CH2:19](I)[CH2:20][CH3:21]>CN(C=O)C.CCCCCC>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[O:16][CH2:19][CH2:20][CH3:21]
Reactant: CCCI
Reactant: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCCOc1c(Br)cc(C(C)(C)C)cc1C(C)(C)C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
A solution of 2-bromo-4,6-di-tert-butyl-phenol (18.58 g, 65 mmol) in DMF (200 mL) was added to a stirred slurry of sodium hydride in anhydrous DMF (500 mL) precooled to −7° C. over 15 min. The resulting reaction mixture was stirred at <0° C. for 0.5 h. n-Propyl iodide was added and stirring of the olive green reaction mixture was continued for 18 h. after removal of the ice bath. The reaction was quenched with de-ionized water (2.5 L), 1 M HCl (250 mL) and 5% LiCl solution (250 mL). The resulting mixture was extracted with ethyl acetate (2×250 mL). Sodium chloride (q.s. to saturation) was added to facilitate the separation. The aqueous layer was extracted with hexane (200 mL). The combined organic layers were washed with 5% LiCl (2×200 mL) dried (MgSO4) and filtered. The solvent was removed under vacuum to give a viscous oil which was a 2:1 ration of product to DMF. The residue was dissolved in hexane (100 mL) and the solution was washed with 5% LiCl solution (3×30 mL). The hexane solution was dried (MgSO4), filtered, and the hexane was removed under vacuum to give a light brown oil which crystallized on standing to give a tan solid (21.23 g, 99%). The product may be purified by sublimation at 150° C. at 0.5 torr to give a light yellow solid. NMR (250 Mz, CDCl3): δ 7.32 (d, 1H, J=2.4 Hz), 7.20 (d, 1H, J=2.4), 3.92 (t, 2H, J=6.8), 1.82 (sex, 2H), 1.00 (t, 3H, J=7.4). MS [EI+] 326, 328 (M+H)+.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:9][C:7](=[O:8])[NH:6][C:4]1=[O:5].[N:10]1[C:17]([Cl:18])=[N:16][C:14](Cl)=[N:13][C:11]=1[Cl:12].C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:12][C:11]1[N:10]=[C:17]([Cl:18])[N:16]=[C:14]([NH:2][N:3]2[CH2:9][C:7](=[O:8])[NH:6][C:4]2=[O:5])[N:13]=1
Reactant: NN1CC(=O)NC1=O
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C1CN(Nc2nc(Cl)nc(Cl)n2)C(=O)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 107.2 %

Procedure:
An ice-cold suspension of 1-aminohydantoin hydrochloride (457 mg, 3.0 mmol), cyanuric chloride (500 mg, 2.73 mmol) and sodium bicarbonate (505 mg, 6 mmol) in acetonitrile (5 mL) was stirred under an atmosphere of nitrogen for 2 h and then stirred at room temperature for 20 h. The reaction mixture was evaporated to dryness under reduced pressure and the residue was extracted with ethyl acetate and the ethyl acetate was separated and dried (MgSO4). The crude product (770 mg) gave a single spot on thin layer chromatography [silica; CH2Cl2/MeOH (10:1)] and was used in the next step without further purification. 1H NMR (CD3CN): δ=4.11 (s, 2H); 8.71 (s, 1H); 8.85 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:22])[C:7](=[O:21])[CH2:8][CH2:9][N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35]N(C)[CH2:33][CH2:32]2)=[O:29])=[CH:26][C:25]=1[O:40][CH3:41].O.[C:43]1(C)C=CC(S(O)(=O)=O)=CC=1.CO>CC(O)C>[CH:31]1([NH:30][C:28](=[O:29])[C:27]2[CH:38]=[CH:39][C:24]([NH:23][C:2]3[N:12]=[C:11]4[C:5]([N:6]([CH3:22])[C:7](=[O:21])[CH2:8][CH2:9][N:10]4[CH2:13][CH2:14][N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:4][N:3]=3)=[C:25]([O:40][CH3:41])[CH:26]=2)[CH2:32][CH2:33][CH2:43][CH2:35][CH2:36]1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN1C(=O)CCN(CCN2CCOCC2)c2nc(Cl)ncc21
Solvent: O
Solvent: CO
Solvent: CC(C)O
Product: COc1cc(C(=O)NC2CCCCC2)ccc1Nc1ncc2c(n1)N(CCN1CCOCC1)CCC(=O)N2C
Yield: 35.9 %

Procedure:
10-chloro-6-methyl-2-(2-morpholin-4-ylethyl)-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 160; 95 mg, 0.29 mmol), -amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 86 mg, 0.35 mmol) and p-toluenesulphonic acid monohydrate (110 mg, 0.58 mmol) were heated together in IPA (4 mL) by microwave irradiation at 150° C. for 20 minutes. The reaction mixture was loaded onto an SCX-2 (5 g) column pre-wet with methanol; the column was washed with methanol and the product eluted with 2M NH3/MeOH. Product containing fractions were combined and evaporated. The resultant material was purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (56 mg, 36%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CC1C(C)=CC=CC=1C([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:29]3[CH:30]=[CH:31][CH:32]=[C:33]([CH3:34])[C:28]=3[NH:27][C:26](=[O:35])[CH2:25][C:24]2=[O:36])=[CH:19][CH:18]=1)=O.I[C:43]1C=CC=CC=1C(Cl)=O>>[CH3:34][C:33]1[C:28]2[NH:27][C:26](=[O:35])[CH2:25][C:24](=[O:36])[N:23]([C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:4](=[O:6])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[I:1])=[CH:22][CH:21]=3)[C:29]=2[CH:30]=[CH:31][C:32]=1[CH3:43]
Reactant: O=C(O)c1ccccc1I
Reactant: Cc1cccc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c(C)cccc43)cc2)c1C
Reactant: O=C(Cl)c1ccccc1I
Product: Cc1ccc2c(c1C)NC(=O)CC(=O)N2c1ccc(NC(=O)c2ccccc2I)cc1
Yield: 87 %

Procedure:
2-Iodobenzoic acid (34 mg, 0.137 mmol) was made into acid chloride in a conventional manner. By using 1-(4-aminophenyl)-6,7-dimethyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (20 mg, 0.068 mmol) obtained in Example 56, and 2-iodobenzoyl chloride mentioned above, the title compound (31 mg, yield 87%) was obtained in the same manner as that of Example 1.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[N:11]=[C:12]([N:19]3[CH2:24][CH2:23][CH:22]([CH2:25][C:26]([OH:28])=O)[CH2:21][CH2:20]3)[C:13]3[S:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[C:5]([F:29])[CH:4]=1.[Cl-].[NH4+:31].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>O.CN(C=O)C.C(N(CC)CC)C>[Cl:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[N:11]=[C:12]([N:19]3[CH2:24][CH2:23][CH:22]([CH2:25][C:26]([NH:31][Cl:1])=[O:28])[CH2:21][CH2:20]3)[C:13]3[S:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[C:5]([F:29])[CH:4]=1
Reactant: Cl
Reactant: [NH4+]
Reactant: O=C(O)CC1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CC1)NCl
Temperature: 25 °C
Reaction time: 120 h
Yield: 115.4 %

Procedure:
A mixture of 500 mg of {1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperidine-4-yl}acetic acid hydrochloride, 316 mg of ammonium chloride, 0.82 ml of triethylamine, 319 mg of HOBt, 452 mg of EDCI and 10 ml of DMF was stirred for 5 days at room temperature. 60 ml of water was added to the reaction mixture and after the precipitate was filtered and washed with water, it was dried at 50° C. under reduced pressure. The obtained solid was dissolved in 10 ml of THF and was added to 2 ml of 4M HCl-dioxane solution. The resultant was concentrated under reduced pressure to give a solid. This solid washed with ether to give 573 mg of 2-{1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperidine-4-yl}acetamido hydrochloride.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:5]1[CH:23]=[CH:22][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:21])[CH2:17][CH2:18][CH:19]=[O:20])=[CH:12][CH:11]=2)=[C:7]([OH:24])[CH:6]=1)[CH3:4].C(O)(=O)C>CO.O>[CH2:3]([C:5]1[CH:23]=[CH:22][C:8]([O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:21])[CH2:17][CH2:18][CH2:19][OH:20])=[CH:14][CH:15]=2)=[C:7]([OH:24])[CH:6]=1)[CH3:4]
Reactant: CCc1ccc(Oc2ccc(C(=O)CCC=O)cc2)c(O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCc1ccc(Oc2ccc(C(=O)CCCO)cc2)c(O)c1
Temperature: -5 °C
Reaction time: 5 h

Procedure:
To a suspension of NaBH4 (0.052 mmol; 2 mg) in dry methanol, under argon at −78° C., (0.5 mL) was added 4-[4-(4-ethyl-2-hydroxyphenoxy)phenyl]-4-oxobutanal (0.040 mmol; 12 mg). The reaction was stirred 5 hours with gradual warming to −5° C., and treated with acetic acid. The mixture was diluted with water and extracted with ethyl acetate. Combined organic layers were dried over Na2SO4 and concentrated in vacuo. The title compound was obtained as a clear oil (7.6 mg; 63%) after purification on preparative TLC (cyclohexane/ethyl acetate: 5/5).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18]Cl.[Na+].[Cl-]>CN(C)C=O>[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][O:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1
Reactant: COCCOCCl
Reactant: Oc1ccc2ncsc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCOc1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1 g of 6-hydroxybenzothiazole in dimethyl-formamide was dropped into a solution of 0.4 g of 60% sodium hydride in 3 ml of dimethylformamide at 0° C. After the mixture was stirred at room temperature for 1 hour, 0.75 ml of (2-methoxyethoxy)methylchloride was added dropwise into the mixture and the mixture was stirred for another 1 hour. NaCl was added to the reaction mixture and the mixture was extracted with ether. The extracts were dried over sodium sulfate and concentrated, and then the residue was purified by column-chromatography (hexane : ethyl acetate=5:1) to give 0.6 g of 6-[(2-methoxyethoxy)-methoxy]benzothiazole. 1 1H-NMR(CDCl3): 3.38(s,3H), 3.58(m,2H), 3.87(m,2H), 7.22(dd,J=8.8,2.4 Hz,1H), 7.66(d,J=2.4 Hz,1H), 8.82(d,J=8.8 Hz,1H), 8.86(s,1H) IR(neat) cm-1 : 2927, 1674, 1475, 1230, 1103, 999 MS(EI) m/z: 239(M+), 89, 59
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]1[CH2:16][O:15][CH2:14][C@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:12]([OH:24])[C@H:11]([CH3:25])[O:10][C:9]1=[O:26])([CH3:4])([CH3:3])[CH3:2].[C:28](Cl)(=[O:32])[CH:29]([CH3:31])[CH3:30].O>N1C=CC=CC=1>[C:28]([O:24][C@@H:12]1[C@@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][O:15][CH2:16][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:27])[C:9](=[O:26])[O:10][C@H:11]1[CH3:25])(=[O:32])[CH:29]([CH3:31])[CH3:30]
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1O
Reactant: CC(C)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)C(=O)O[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.7 %

Procedure:
To a solution of tert-butyl-(3S,7S,8R,9S)-7-benzyl-8-hydroxy-9-methyl-2-oxo-1,5-dioxonan-3-ylcarbamate (72 mg, 0.19 mmol) in pyridine (1 mL) at 0° C. was added isobutyryl chloride (80 μL, 0.76 mmol) and the solution was stirred at 0° C. for 2 h. The crude reaction mixture was warmed to room temperature, water (1 mL) was added, and the solution was stirred for 30 min. The reaction mixture was extracted with Et2O (3×) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, 20% EtOAc/hexanes, TLC Rf=0.5) to furnish (3S,6S,7R,8S)-8-benzyl-3-(tert-butoxycarbonylamino)-6-methyl-4-oxo-1,5-dioxonan-7-yl isobutyrate as a white foam (45 mg, 53%): 1H NMR (400 MHz, CDCl3) δ 7.31-7.11 (m, 5H), 5.14 (d, J=8.0 Hz, 1H), 5.03 (m, 1H), 4.94 (t, J=9.2 Hz, 1H), 4.66 (d, J=7.7 Hz, 1H), 3.89 (dd, J=11.7, 7.2 Hz, 1H), 3.56 (d, J=10.7 Hz, 1H), 3.46 (m, 1H), 3.35 (dd, J=11.4, 6.8 Hz, 1H), 2.71 (dd, J=13.9, 3.6 Hz, 1H), 2.58 (dt, J=13.9, 7.0 Hz, 1H), 2.25 (t, J=12.6 Hz, 1H), 2.04 (s, 1H), 1.43 (s, 9H), 1.32 (d, J=6.2 Hz, 3H), 1.21 (dd, J=7.0, 0.9 Hz, 6H); ESIMS m/z 471.9 ([M+Na]1).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][C:14]([CH:17]([O:23][CH2:24][CH2:25][C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)[C:18]3[S:19][CH:20]=[CH:21][N:22]=3)=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:4][CH:3]=1.Cl.[C:35]([O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH2:44][S:45][CH3:46])[NH2:42])([CH3:38])([CH3:37])[CH3:36].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][C:14]([CH:17]([O:23][CH2:24][CH2:25][C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)[C:18]3[S:19][CH:20]=[CH:21][N:22]=3)=[CH:13][C:9]=2[C:10]([NH:42][C@@H:41]([CH2:43][CH2:44][S:45][CH3:46])[C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:47])=[O:11])=[CH:32][CH:33]=1
Reactant: CSCC[C@H](N)C(=O)OC(C)(C)C
Reactant: Cn1cncc1CCOC(c1ccc(CCc2ccc(F)cc2)c(C(=O)O)c1)c1nccs1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSCC[C@H](NC(=O)c1cc(C(OCCc2cncn2C)c2nccs2)ccc1CCc1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(4-fluorophenethyl)-5-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoic acid (0.47 g, 1.06 mmol) (from Example 63), DMAP (0.62 g, 5.05 mmol), L-methionine tert-butyl ester HCl (0.62 g, 3.02 mmol), EDC (0.39 g, 2.02 mmol) and HOBT (0.137 g, 1.01 mmol) in DMF (25 ml) was stirred at ambient temperature under a nitrogen atmosphere for 16 hours. The reaction was evaporated to dryness and washed with aqueous citric acid (1M, 10 ml) and extracted with dichloromethane (20 ml). The extracts were washed with saturated brine, dried and filtered. Purification by flash column chromatography eluting with dichloromethanel methanol (95:5, 9:1 and 85:15) gave a gum. This was dissolved in ethyl acetate and treated with 1M ethereal HCl (10 ml). The resulting solid precipitate was isolated by centrifuging, further washing with diethyl ether and drying under high vacuum to give tert-butyl (2S)-2- (2-(4-fluorophenethyl)-5-[1-(thiazol-2-yl)-2-(1 -methylimidazol-5-yl)ethoxymethyl]benzoylamino}-4-methylsulfanylbutyrate as a white solid, (0.366 g, 55%).
Reaction SMILES: [N+]([O-])(O)=O.[CH3:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:9][CH:8]=1.OO.[OH2:26].[OH-:27].[Na+]>C(O)(=O)C>[CH3:5][S:6]([C:7]1[CH:8]=[CH:9][C:10]([CH:13]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:11][CH:12]=1)(=[O:27])=[O:26]
Reactant: CCCCC(Cn1ccnc1)c1ccc(SC)cc1
Reactant: [OH-]
Reactant: O
Agent: OO
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCCCC(Cn1ccnc1)c1ccc(S(C)(=O)=O)cc1
Reaction time: 1 h

Procedure:
To 7.0g (0.021 mole) of 1-[β-(p-methylthiophenyl)hexyl]imidazole nitric acid salt in 75 ml of glacial acetic acid is added dropwise at less than 10°, 8.0g (0.083 mole) of 35% hydrogen peroxide. When the addition is complete, the reaction is stirred for one hour heated on a steambath for a second hour and then poured into iced water. The solution is made basic to litmus with sodium hydroxide and the product is extracted out with ether.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C([O-])(O)=O.[Na+].[Cl:25]CCl>C(COC)OC.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>[Cl:25][C:4]1[N:5]=[C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])[CH:7]=[CH:2][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: COc1ccccc1B(O)O
Reactant: ClCCl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1-c1ccnc(Cl)n1
Temperature: 25 °C
Yield: 73 %

Procedure:
4,6-Dichloro-pyrimidine (6 g, 0.04 mol) (Ranganathan, Subramania et al., Proceedings—Indian Academy of Sciences, Chemical Sciences (1994), 106(5), 1051-70. Maggiali, C. et al., Farmaco, Edizione Scientifica (1988), 43(3), 277-91. Gershon, Herman et al., J. of Med. Chem. (1963), 6, 87-9) and (2-methoxy-phenyl)-boronic acid (4.37 g, 0.029 mol) were dissolved in dimethoxyethane (120 mL) and water (18 mL). To this solution were added NaHCO3 (6.72 g, 0.08 mol), PdCl2(PPh3)2 (0.84 g) and allowed to reflux for 7 hrs (TLC control). Then the mixture was cooled down to room temperature and the solvents removed under reduced pressure. The obtained crude solid was dissolved in dichloromethane (100 mL), washed with water (1×100 mL), the organic layer was separated, dried over K2CO3, filtered and the solvent removed under reduced pressure. The obtained solid was further purified by flash-chromatography (eluent dichloromethane) to afford a crude product that was crystallized from hexane to yield 2-chloro-4-(2-methoxy-phenyl)-pyrimidine (4.7 g, 73%).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:49]1[CH:53]=[C:52]([C:54]2[CH:55]=[C:56]([NH2:60])[CH:57]=[CH:58][CH:59]=2)[CH:51]=[N:50]1>CN(C=O)C>[NH:49]1[CH:53]=[C:52]([C:54]2[CH:55]=[C:56]([NH:60][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:57]=[CH:58][CH:59]=2)[CH:51]=[N:50]1
Reactant: Nc1cccc(-c2cn[nH]c2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn[nH]c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 8.9 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-pyrazol-4-yl)-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.002 g of product in 11% yield: LCMS (ESI) m/z 348 (MH+).
Reaction SMILES: COC1C=CC(P(=S)=[S:10])=CC=1.[S:12]1[C:16]2[C:17]([C:21]([NH2:23])=O)=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1>C1(C)C=CC=CC=1>[S:12]1[C:16]2[C:17]([C:21](=[S:10])[NH2:23])=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1
Reactant: NC(=O)c1cccc2nnsc12
Reactant: COc1ccc(P(=S)=S)cc1
Solvent: Cc1ccccc1
Product: NC(=S)c1cccc2nnsc12
Yield: 56.4 %

Procedure:
A suspension of 2.42 g of p-methoxyphenylthiono-phosphine sulfide and 1.79 g of benzo-1,2,3-thiadiazole-7-carboxamide in 95 ml of toluene is refluxed under a nitrogen atmosphere for 6 hours. The mixture is then evaporated in vacuon and the residue is suspended in ethyl acetate and filtered off. The filtrate is recrystallized from ethyl acetate/tetrahydrofuran with added active charcoal. 1.1 g of yellow crystals of melting point 129°-131° C. result.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[Br-].[CH:16]1([Zn+])[CH2:20][CH2:19][CH2:18][CH2:17]1.[C:22]([O-])(O)=O.[Na+]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:16]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:22])=[O:7])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: [Zn+]C1CCCC1
Reactant: O=C([O-])O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2CCCC2)c(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)benzoate (196.7 g, 824 mmol) in THF (100 mL), cyclopentylzinc(II) bromide (1979 mL, 989 mmol) was added dropwise at 7.8° C. The temperature at the end of the addition rose to 22° C. Bis(tri-t-butylphosphine)palladium (21.07 g, 41.2 mmol) was added to the dark brown solution at the same temperature, and the resulting mixture was stirred at 70° C. for 8 h. The mixture was added to saturated aqueous NaHCO3 (100 mL) at 0° C., stirred at the same temperature for 30 min and then at 22° C. for 2 h. The resulting suspension was filtered through Celite® and the filtrate concentrated under vacuum. The solids were washed with EtOAc (3×300 mL), the filtrate was combined with the previous concentrate and the combined organics were washed with H2O (2×600 mL), brine (2×500 mL), dried (Na2SO4), decanted and concentrated under reduced pressure to give the title compound as an orange oil (227 g) without further purification. LCMS m/z=273.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.71-1.60 (m, 2H), 1.83-1.75 (m, 2H), 1.95-1.87 (m, 2H), 2.21-2.11 (m, 2H), 3.46 (quintet, J=8.8 Hz, 1H), 3.97 (s, 3H), 7.58 (d, J=8.4 Hz, 1H), 8.18 (dd, J=8.0 Hz, 1.6 Hz, 1H), 8.31 (d, J=1.6 Hz, 1H).