Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:46])[NH:4][CH:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4[NH:37][C:38]([CH:41]5[CH2:45][CH2:44][CH2:43][NH:42]5)=[N:39][CH:40]=4)=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:13])[CH2:6][CH2:7][C:8]([F:11])([F:10])[F:9].[CH3:47][O:48][C:49]([NH:51][CH:52]([CH:56]([CH3:58])[CH3:57])[C:53](O)=[O:54])=[O:50].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:46])[NH:4][CH:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:19]1[NH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4[NH:37][C:38]([CH:41]5[CH2:45][CH2:44][CH2:43][N:42]5[C:53](=[O:54])[CH:52]([NH:51][C:49]([O:48][CH3:47])=[O:50])[CH:56]([CH3:58])[CH3:57])=[N:39][CH:40]=4)=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)=[CH:22][N:23]=1)=[O:13])[CH2:6][CH2:7][C:8]([F:9])([F:11])[F:10]
Reactant: COC(=O)NC(C(=O)O)C(C)C
Reactant: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5)[nH]4)cc3)cc2)[nH]1
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: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
To a solution of crude [4,4,4-Trifluoro-1-(2-{5-[4′-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-butyl]-carbamic acid methyl ester (125 mg, 0.20 mmol) in dimethylformamide (0.6 mL) was added a solution of 2-methoxycarbonylamino-3-methyl-butyric acid (38 mg, 0.22 mmol) and HATU (82 mg, 0.22 mmol) in dimethylformamide (0.6 mL). Diisopropylethylamine (70 μL, 0.40 mmol) was then added and the reaction was stirred at room temperature for 16 hours. The solution was concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H) to yield (4,4,4-trifluoro-1-{2-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-butyl)-carbamic acid methyl ester (73 mg, 47%). LCMS-ESI+: calculated for C40H47F3N8O6: 792.85; observed [M+1]+: 794.33. 1H-NMR: 400 MHz, (CD3OD) δ: 7.82-7.70 (m, 4H), 7.68-7.63 (m, 4H), 7.32-7.31 (m, 2H), 5.20-5.16 (m, 2H), 4.56-4.51 (m, 1H), 4.26-4.22 (m, 1H), 4.04-3.96 (m, 1H), 3.91-3.84 (m, 2H), 3.67 (s, 3H), 3.66 (s, 3H), 3.51-3.46 (m, 1H), 2.38-1.96 (m, 12H), 1.90-1.78 (m, 1H), 1.01-0.89 (m, 6H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:11][N:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]1=[O:1]
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc([N+](=O)[O-])ccc1=O
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a solution of 2-hydroxy-5-nitropyridine (600 mg, 4.28 mmol, 1 eq) in DMF (5 mL) was added cesium carbonate (1.67 g, 5.16 mmol, 1.2 eq), followed by methyl iodide (0.4 mL, 6.42 mmol, 1.5 eq). After stirring overnight, the reaction mixture was quenched with water and extracted with ethyl ether (5×20 mL). The ether was dried over Na2SO4 and concentrated under reduced pressure. The crude material was column chromatographed, eluting with 50% EtOAc/hexanes to give 450 mg of compound 50B.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[Na+]>O>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:11]/[C:12](=[O:13])[CH3:14]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)/C=C/c1ccc(F)cc1F
Temperature: 0 °C

Procedure:
To a mixture of 2,4-difluorobenzaldehyde (5.0 ml, 45.7 mmol) and acetone (10.75 ml, 146 mmol) in Water (10 ml), was added 0.25M sodium hydroxide (18.30 ml, 4.57 mmol). The reaction mixture was heated to for 2 h. The mixture was poured into ice water. It was extracted with ethyl acetate (200 ml). The organic layer was dried, filtered, and evaporated to give (E)-4-(2,4-difluorophenyl)but-3-en-2-one as yellow oil. It was used for the next reaction without purification. 1H NMR (CDCl3/400 MHz): δ (ppm) 7.60 (d, 1H), 7.60-7.53 (m, 1H), 6.96-6.86 (m, 2H), 6.73 (d, 1H), 2.39 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:15]=[C:14]([CH3:16])[O:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4].[B-](F)(F)(F)[F:18].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[C:15]([F:18])=[C:14]([CH3:16])[O:13][N:12]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](c2cc(C)on2)CC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: COC(=O)[C@H]1CC[C@H](c2noc(C)c2F)CC1
Temperature: 90 °C

Procedure:
A mixture of trans-4-(5-methyl-isoxazol-3-yl)-cyclohexanecarboxylic acid methyl ester (250 mg, 1.12 mmol) and Selectfluor® (476 mg, 1.34 mmol) in acetonitrile (5.6 ml) was heated at 90° C. for 20 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and water (25 ml). The layers were separated. The aqueous layer was extracted with two 50 ml-portions of ethyl acetate. The combined organic layers were washed with one 25 ml-portion of water/brine (1:1), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification with n-heptane/tert-butyl methyl ether as eluent gave the title compound (35 mg, 13%) as light yellow oil. MS m/e: 241 ([M+H]+)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6]1.[NH:15]1[CH2:20][CH:19]=[C:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O.CC(C)=O>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([C:18]2[CH2:19][CH2:20][N:15]([CH2:2][CH2:3][CH2:4][N:5]3[C:13](=[O:14])[N:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]4=[N:6]3)[CH2:16][CH:17]=2)=[CH:22]1
Reactant: O=c1n(CCCCl)nc2ccccn12
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=c1n(CCCN2CC=C(c3c[nH]c4ccccc34)CC2)nc2ccccn12
Reaction time: 18 h
Yield: 58.9 %

Procedure:
2-(3-Chloro-propyl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one 211 mg (1 mmol) was loaded into a round bottomed flask, followed by 396 mg (2 eq) of 3-(1,2,3,6-Tetrahydro-pyridin-4-yl)-1H-indole, 1.0 gram of potassium iodide, 1.0 gram of potassium carbonate, 100 ml acetone. The mixture was stirred under nitrogen for 18 hours. It was then poured into about 300 ml water and extracted with ethyl acetate (2×200 ml). The combined organic layers were dried over magnesium sulfate and filtered and concentrated. Flash column chromatography using 10%˜100% ethyl acetate/hexane and yielded 220 mg of product (59%). mp: 173.3° C. M+:374.0; (300 MHz, CDCl3): 8.60 (s, 1H, NH), 7.90 (d, 1H), 7.75 (d, 1H), 7.34 (d, 1H), 7.11 (m, 5H), 6.44 (m, 1H), 6.16 (s, 1H), 4.12 (t, CH2), 3.22 (d, CH2), 2.70 (t, CH2) 2.60(m, 4H), 2.17 (t, CH2).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29]>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:26]4[CH2:27][CH2:28][O:24][C:25]4=[O:29])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C1NCCO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3)CC2)c(C)c1
Yield: 74.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (591 mg) described in Preparation Example 77 and oxazolidin-2-one (134 mg), the title compound (396 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH2:39][CH:36]3[CH2:38][CH2:37]3)[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Reactant: BrCC1CC1
Product: COc1ccc(CC2c3c(OC)ccc(OCC4CC4)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with cyclopropyl-methyl bromide
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]([NH:17][OH:18])=[NH:16])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[CH:19]1([C:25]2[CH:33]=[CH:32][C:28]([C:29]([Cl:31])=O)=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[ClH:31].[CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2[N:16]=[C:29]([C:28]3[CH:32]=[CH:33][C:25]([CH:19]4[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]4)=[CH:26][CH:27]=3)[O:18][N:17]=2)[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCC(CCCC(=N)NO)CC1
Reactant: O=C(Cl)c1ccc(C2CCCCC2)cc1
Product: CCC(CC)N1CCC(CCCc2noc(-c3ccc(C4CCCCC4)cc3)n2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 3, starting from 4-(1-(1-ethylpropyl)piperidin-4-yl)-N-hydroxybutyramidine and 4-cyclohexylbenzoyl chloride.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:9]=[C:10](Cl)[C:11]2[CH:16]=[CH:15][S:14][C:12]=2[N:13]=1>>[Cl:7][C:8]1[N:9]=[C:10]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:11]2[CH:16]=[CH:15][S:14][C:12]=2[N:13]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2ccsc2n1
Product: Clc1nc(N2CCOCC2)c2ccsc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
Morpholine (85.1, 0.977 mol, 2.2 equiv.) was added to a solution of 2,4-dichlorothieno[2,3-d]pyrimidine 17 (91 g, 0.444 mol, 1.0 equiv.). The reaction mixture was stirred at ambient temperature for 1 h and the resulting slurry was filtered, rinsed with water (500 ml). The cake was dried in vacuum oven at 55° C. for 24 hours to give 442-chlorothieno[2,3-d]pyrimidin-4-yl)morpholine 18 as an off-white solid (100.3 g, 88% yield). 1H NMR (400 MHz, DMSO-d6) δ 3.736 (t, J=4.8 Hz, 4H), δ 3.897 (t, J=5.2 Hz, 4H), δ 7.658 (d, J=6.4 Hz, 1H), δ 7.682 (t, J=6.4 Hz, 4H δ). LCMS (ESI pos) m/e 257 (M+1).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[N:32]4[N:33]=[C:34]([C:36]([O:38][CH:39]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[O:37])[N:35]=[C:31]4[N:30]=[C:29]([CH3:52])[CH:28]=2)[C@H:20]([NH:53][C:54](=[O:83])/[C:55](/[C:58]2[N:59]=[C:60]([NH:63][C:64]([C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)[C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[S:61][CH:62]=2)=[N:56]\[OH:57])[C:19]3=[O:84])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:91][CH2:92][C:93]([O:95][C:96]1[C:104]([O:105][C:106](=[O:109])[CH2:107][Cl:108])=[CH:103][C:99]([C:100](Cl)=[O:101])=[C:98]([CH3:110])[CH:97]=1)=[O:94]>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[N:32]4[N:33]=[C:34]([C:36]([O:38][CH:39]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)=[O:37])[N:35]=[C:31]4[N:30]=[C:29]([CH3:52])[CH:28]=2)[C@H:20]([NH:53][C:54](=[O:83])/[C:55](/[C:58]2[N:59]=[C:60]([NH:63][C:64]([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)([C:77]4[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=4)[C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[S:61][CH:62]=2)=[N:56]\[O:57][C:100](=[O:101])[C:99]2[CH:103]=[C:104]([O:105][C:106](=[O:109])[CH2:107][Cl:108])[C:96]([O:95][C:93](=[O:94])[CH2:92][Cl:91])=[CH:97][C:98]=2[CH3:110])[C:19]3=[O:84])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(OC(=O)CCl)c(OC(=O)CCl)cc1C(=O)Cl
Reactant: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)n2nc(C(=O)OC(c3ccccc3)c3ccccc3)nc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(=O)c4cc(OC(=O)CCl)c(OC(=O)CCl)cc4C)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)n2nc(C(=O)OC(c3ccccc3)c3ccccc3)nc2n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of (6R, 7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-hydroxyimino)acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester (1.0 g) in dry dichloromethane (24 ml) was added potassium carbonate (0.17 g) at once, followed by dropwise addition of a solution of 4,5-bis(chloroacetoxy)-2-methylbenzoyl chloride (0.43) dry dichloromethane (16 ml) over a period of ten minutes, and the mixture was stirred at 0° C. for three hours. After filtering off the insoluble matters, the filtrate was washed twice with water, once with brine, and dried over anhydrous magnesium sulfate. The dried solution was concentrated under reduced pressure, and the residue was crystallized with ether, giving 1.13 g of the objective compound as pale yellow crystals.
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1([C:22](=[O:24])[CH3:23])[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:1]1([C:7]2[S:11][CH:10]=[C:9]([C:12]([N:18]3[CH2:19][CH2:20][CH2:21][N:15]([C:22](=[O:24])[CH3:23])[CH2:16][CH2:17]3)=[O:14])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)N1CCCNCC1
Reactant: O=C(O)c1csc(-c2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCCN(C(=O)c2csc(-c3ccccc3)c2)CC1
Reaction time: 0.5 h
Yield: 17.1 %

Procedure:
5-Phenyl-thiophene-3-carboxylic acid (0.1 g, 0.5 mmol) was dissolved in DMF (3 mL). 1-[1,4]Diazepan-1-yl-ethanone (0.5 mmol), DIPEA (1.5 mmol) and HATU (0.5 mmol) were added and the reaction mixture stirred for 0.5 hours. Ethyl acetate (20 mL) was added and the organic solution was washed with 1 N hydrochloric acid, dried with magnesium sulfate, filtered and the solvent removed by evaporation. The residue was purified by HPLC, eluting with 70%-90% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum and freeze-dried to give the title compound (28 mg). LCMS m/z 329.20 [M+H]+ R.T.=8.20 min (Analytical Method 1). 1H NMR (400 MHz, CHCl3-d): δ 7.6 (m, 2H), 7.55-7.3 (m, 5H), 3.9-3.5 (m, 8H), 2.1 (s, 3H), 2.0-1.3.2 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C.[CH:20]1([CH2:23][CH:24]=O)[CH2:22][CH2:21]1.C([BH3-])#N.[Na+]>C(O)C>[CH2:11]([O:10][C:8]([C@@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][CH2:24][CH2:23][CH:20]1[CH2:22][CH2:21]1)=[O:9])[CH3:12].[CH2:11]([O:10][C:8]([C@@H:4]1[CH2:5][CH2:6][CH2:7][C@H:3]1[NH:2][CH2:24][CH2:23][CH:20]1[CH2:22][CH2:21]1)=[O:9])[CH3:12]
Reactant: O=CCC1CC1
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)[C@@H]1CCC[C@@H]1NCCC1CC1
Product: CCOC(=O)[C@@H]1CCC[C@H]1NCCC1CC1
Reaction time: 12 h
Yield: 90.5 %

Procedure:
To a solution of cis-ethyl 2-amino-1-cyclopentanecarboxylate hydrochloride (250.0 mg, 1.28 mmol) in ethanol (5 mL) was added triethylamine (0.2 mL, 1.42 mmol), cyclopropylacetaldehyde (288.0 mg, 1.92 mmol), and sodium cyanoborohydride (59.2 mg, 0.895 mmol) at 25° C. After stirring for 12 h, the mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The crude material was purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-50% ethyl acetate in hexanes) to afford cis-2-(2-cyclopropylethylamino)-cyclopentanecarboxylic acid ethyl ester as a yellowish oil (42.7 mg, 0.189, 15%) and trans-2-(2-cyclopropylethylamino)-cyclopentanecarboxylic acid ethyl ester as a yellowish oil (130.5 mg, 0.579 mmol, 45%). cis-2-(2-Cyclopropylethylamino)-cyclopentanecarboxylic acid ethyl ester: 1H NMR (400 MHz, CDCl3) δ 0.08-0.12 (2H, m), 0.45-0.49 (2H, m), 0.63-0.72 (1H, m), 1.29 (3H, t, J=7.0 Hz), 1.46-1.52 (2H, m), 1.58-1.77 (2H, m), 1.85-2.10 (4H, m), 2.73-2.87 (2H, m), 3.03 (1H, q, J=6.7 Hz), 3.36 (1H, q, J=7.3 Hz), 4.17 (2H, q, J=7.0 Hz). LC-MS (ESI) calcd for C13H23NO2 225.17, found 226.2 [M+H+]. trans-2-(2-Cyclopropylethylamino)-cyclopentanecarboxylic acid ethyl ester: 1H NMR (400 MHz, CDCl3) δ 0.12-0.16 (2H, m), 0.50-0.55 (2H, m), 0.65-0.72 (1H, m), 1.31 (3H, t, J=7.1 Hz), 1.53-1.59 (2H, m), 1.64-1.84 (2H, m), 1.89-2.13 (4H, m), 2.81-2.87 (1H, m), 2.95-3.01 (1H, m), 3.07 (1H, q, J=7.1 Hz), 3.44 (1H, q, J=7.2 Hz), 4.20 (2H, q, J=7.0 Hz). LC-MS (ESI) calcd for C13H23NO2 225.17, found 226.2 [M+H+].
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)O1.I[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:20][CH:19]=1.C(Cl)Cl.CO>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:13][C:12]1[CH:11]=[CH:10][C:9]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)CCCc1ccc(I)cc1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)CCCc1ccc(-c2ccc(N)cc2)cc1
Temperature: 110 °C
Yield: 82.5 %

Procedure:
Solid 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (158 mg, 0.723 mmol) and Pd(PPh3)4 (38 mg, 0.033 mmol) were added to a solution of methyl 4-(4-iodophenyl)butanoate (200 mg, 0.657 mmol) in dimethoxyethane/2M Na2CO3 (3 mL, 2:1) at rt. The resulting mixture was degassed with argon gas then heated at 110° C. using microwave for 30 min. The reaction mixture was diluted with EtOAc (10 mL) then washed with H2O (10 mL), brine (10 mL), dried over Na2SO4, and concentrated to give crude (294 mg) as brown oil. Chromatography (9:1, CH2Cl2/MeOH) afforded the title compound (146 mg, 82%) as a light yellow solid. ES/MS calcd. for C17H20NO2+ 270.2. Found m/z=270.2 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])[CH:6]=1)(=O)[CH3:2].[H-].[Na+].Br[CH2:36]C#C.O>CN(C)C=O.C(OCC)(=O)C>[F:23][C:11]1[CH:12]=[C:13]([CH3:22])[C:14]([S:16][CH2:17][C:18]([F:19])([F:20])[F:21])=[CH:15][C:10]=1[N:9]1[C:5]([NH:4][CH2:1][C:2]#[CH:36])=[CH:6][C:7]([O:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:29])([F:30])[F:28])=[N:8]1
Reactant: CC(=O)Nc1cc(OCC(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CCNc1cc(OCC(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
2.0 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole was dissolved in 15 mL of dimethylformamide, and under cooling with ice, the solution was dropwise added to a suspension having 0.23 g of sodium hydride suspended in 10 mL of dimethylformamide, and after completion of the dropwise addition, stirring was carried out at room temperature for 30minutes. The reaction solution was cooled with ice again, and 0.72 g of 1-bromo-2-propyne was added, followed by stirring at room temperature for 1 hour. Then, the reaction mixture was poured into water, extraction with ethyl acetate was carried out, and after washing with water, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was dissolved in 20 mL of ethanol, and 20 mL of a 35 mass % hydrochloric acid aqueous solution was added, followed by stirring under reflux with heating for 2 hours. The reaction mixture was poured into water, extraction with ethyl acetate was carried out, and after washing with water, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 1.4 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)-5-(2-propynylamino)pyrazole.
Reaction SMILES: [Cl:1][CH:2]=[CH:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].C(N(CC)CC)C.[Cl:17][C:18]([Cl:23])([Cl:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:1][CH:2]=[CH:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[C:19](=[O:20])[C:18]([Cl:23])([Cl:22])[Cl:17]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: COCCNCC=CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(CC=CCl)C(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.7 %

Procedure:
N-(3-chloro)allyl-N-methoxyethylamine (2.25 g, 0.015 mol) and 1.52 g (0.015 mol) triethylamine were stirred in 70 ml dichloromethane. The reaction was kept at approximately 5° C. with an ice-water bath. Trichloroacetyl chloride (2.73 g, 0.015 mol) in 10 ml dichloromethane was added dropwise to the cooled solution. Upon completion of the addition, the mixture was stirred at room temperature for 6 hours. The reaction mixture was then washed twice with saturated brine and dried with sodium sulfate. Rotary evaporation yielded 4.1 g of the above-named product.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:4]2[C:5]([N:7]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[C:8](=[O:9])[C:3]=12)=[O:6].Cl[C:23](=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C.[C:36](O)(=O)[CH2:37][C:38]([CH2:43][C:44](O)=[O:45])(C(O)=O)O>CC(C)=O>[C:23]([O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][N:7]2[C:8](=[O:9])[C:3]3[C:4](=[CH:19][CH:20]=[CH:21][C:2]=3[NH:1][C:44](=[O:45])[CH2:43][CH2:38][CH2:37][CH3:36])[C:5]2=[O:6])=[CH:13][CH:14]=1)(=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCC(=O)Cl
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Nc1cccc2c1C(=O)N(CCc1ccc(O)cc1)C2=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCC(=O)Nc1cccc2c1C(=O)N(CCc1ccc(OC(=O)CCCC)cc1)C2=O
Temperature: 25 °C
Yield: 56.2 %

Procedure:
3-Amino-N-[2-(4-hydroxyphenyl)ethyl]phthalimide (110 mg, 0.390 mol, 1 eq) was dissolved in acetone (30 ml), and to this solution were added 1-chloro-1-pentanone (70.5 mg, 0.585 mmol, 1.5 eq) and triethylamine (0.081 ml, 0.585 mol, 1.5 eq) in this order. The mire was refluxed under heating for 30 minutes. This reaction mixture was cooled to room temperature. Ice water (10 ml) and citric acid (10 ml) were added, and the mixture was extracted twice with ethyl acetate (20 ml). The organic layers were combined, washed with saturated brine (30 ml) and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=5/1) to give 4-[2-(1,3-dioxo4-pentanoylamino-1,3-dihydroisoindol-2-yl)ethyl]phenyl pentanoate (80.2 mg, 56.2%) as colorless crystals.