Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH:12]=2)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1>>[F:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]([C:19]3[CH:20]=[CH:21][C:22]4[C:23]5[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29][C:24]=5[N:25]([CH3:28])[C:26]=4[CH:27]=3)[C:13](=[O:17])[CH:12]=2)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=c1cc(OCc2ncc(F)cc2F)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ncc(F)cc5F)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)CC2
Yield: 31.2 %

Procedure:
4((3,5-Difluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (100 mg, 0.418 mmol) and tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (206 mg, 0.544 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (70 mg, 30%) as a brown oil; ESI MS m/z 537 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH:6](C)[CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3][CH:4]=[O:5].Br[CH:14]=[CH:15][CH:16](C)C>>[CH3:1][C:2]1[CH:3]([C:4](=[O:5])/[CH:14]=[CH:15]\[CH3:16])[C:9]([CH3:10])([CH3:11])[CH2:8][CH2:7][CH:6]=1
Reactant: CC(C)=CCC(C)C(C)=CC=O
Reactant: CC(C)C=CBr
Product: C/C=C\C(=O)C1C(C)=CCCC1(C)C

Procedure:
2,6,6-Trimethyl-1-tetrolyl-2-cyclohexene obtained according to the description of paragraph (c) herebelow was hydrogenated according to the method described in Example 18, paragraph (a). Thus, cis-2,6,6-trimethyl-1-crotonoyl-2-cyclohexene was obtained in 85-00% yield. The spectral characteristics were as follows: NMR spectrum (CCl4): 0.85 (3 H, s); 0.96 (3 H, s), 1.62 (3 H, s broad), 2.12 (3 H, d, J=5.5 cps), 1.0-2.3 (4 H, complex band), 2.95 (1 H, s broad), 5.49 (1 H, s broad), 6.25 (2 H, complex band) ppm (δ).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH2:30][C@H:31]5[CH2:33][O:32]5)[CH2:22][CH2:21]4)[C:14]3=[O:34])[CH:7]=2)[CH2:3][CH2:2]1.[CH2:36]([NH2:38])[CH3:37]>>[CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH2:30][C@H:31]([OH:32])[CH2:33][NH:38][CH2:36][CH3:37])[CH2:22][CH2:21]4)[C:14]3=[O:34])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OC[C@H]3CO3)CC2)c1=O
Reactant: CCN
Product: CCNC[C@@H](O)COc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)ccc3C)c2=O)CC1

Procedure:
The title compound was prepared using a similar method to that described for Example 299b from (R)-N-cyclopropyl-4-methyl-3-(3-(1-(2-(oxiran-2-ylmethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)benzamide (Example 299a) and ethylamine.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[S:12]1[C:16]([C:17]([NH:19][NH2:20])=[O:18])=[CH:15][C:14]2[CH:21]=[CH:22][CH:23]=[CH:24][C:13]1=2>>[CH2:2]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[N:20]/[NH:19][C:17]([C:16]2[S:12][C:13]3[CH:24]=[CH:23][CH:22]=[CH:21][C:14]=3[CH:15]=2)=[O:18])/[C:2]1=[O:3])[CH2:4][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: NNC(=O)c1cc2ccccc2s1
Product: CCCCCCN1C(=O)/C(=N\NC(=O)c2cc3ccccc3s2)c2ccccc21
Yield: 82 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 3 and Benzo[b]thiophene-2-carboxylic hydrazide according to the synthetic method E. The resulting solid was washed with ethanol. Yield: 82%. 1H NMR (DMSO-d6): δ 0.86 (t, J=6.9 Hz, 3H), 1.26-1.36 (m, 6H), 1.64-1.66 (m, 2H), 3.79 (t, J=7.2 Hz, 2H), 7.19-7.27 (m, 2H), 7.48-7.59 (m, 3H), 7.75 (d, J=7.5 Hz, 1H), 8.13 (d, J=7.5 Hz, 2H), 8.31 (br s, 1H), 13.65 (br s, 1H). 13C NMR (DMSO-d6): δ 14.33 (CH3), 22.44 (CH2), 26.40 (CH2), 27.41 (CH2), 31.34 (CH2), 39.81 (CH2), 110.71 (CH), 115.52 (C), 119.55 (C), 121.52 (CH), 123.35 (CH), 123.69 (CH), 125.75 (CH), 126.51 (CH), 127.83 (CH), 132.38 (CH), 143.64 (C═N), 161.60 (C═O). HRMS (ES+) calcd for C23H24N3O2S(M+H+), m/e, 406.1596; found, 406.1584.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]2[O:20][CH2:21][CH2:22][CH3:23])=[C:4]([F:24])[CH:3]=1.[CH2:25](Br)[C:26]#[CH:27].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH2:27][C:26]#[CH:25])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]=[C:10]2[O:20][CH2:21][CH2:22][CH3:23])=[C:4]([F:24])[CH:3]=1
Reactant: CCCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCOc1cc(-n2c(OCCC)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-propoxy-4-trifluoromethyl-6(1H)-pyrimidinone and propargyl bromide with sodium carbonate in acetone there is obtained 1-[4-chloro-2-fluoro-5-(2-propynyloxy) -phenyl]-2-propoxy-4-trifluoromethyl-6(1H)-pyrimidinone, 1H-NMR (CDCl3, 400 MHz): 7.34 ppm (d,1H), 6.98 ppm (d,1H), 6.60 ppm (s,1H), 4.76 ppm (m,2H), 4.39 ppm (m,2H), 2.56 ppm (t,1H), 1.67 ppm (m,2H), 0.85 ppm (t,3H);
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[O:19][C:13]4=[C:14]([NH2:18])[N:15]=[CH:16][CH:17]=[C:12]4[CH:11]=3)[C:5]=12.C1C(=O)N([I:27])C(=O)C1>CN(C=O)C>[CH:1]1[N:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[O:19][C:13]4=[C:14]([NH2:18])[N:15]=[CH:16][C:17]([I:27])=[C:12]4[CH:11]=3)[C:5]=12
Reactant: Nc1nccc2cc(-c3cccn4cncc34)oc12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Nc1ncc(I)c2cc(-c3cccn4cncc34)oc12
Reaction time: 1 h
Yield: 9.5 %

Procedure:
To a cooled (0° C.) solution of 2-(imidazo[1,5-a]pyridin-8-yl)furo[2,3-c]pyridin-7-amine (82.0 mg, 0.328 mmol) in DMF (4 mL) was added NIS (74.0 mg, 0.329 mmol) in portions. After stirring from 0° C. to RT over 1 h, the mixture was adsorbed onto silica gel. Purification by ISCO chromatography (50 to 100% ethyl acetate:heptane and then 15% methanol:dichloromethane), followed by mass-directed purification afforded 11.7 mg (10%) of the title compound as a yellow solid. 1H NMR (400 MHz, MeOH-d4): δ 9.37 (s, 1H), 8.65 (br s, 1H), 8.62 (d, J=7.07 Hz, 1H), 8.02 (d, J=7.07 Hz, 1H), 7.98 (s, 1H), 7.64 (s, 1H), 7.23 (t, J=7.10 Hz, 1H); MS (ESI): 376.93 [M+H]+; HPLC tR=2.76 min (ZQ3: polar—5 min).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([O:11][C:12]([N:14]1[CH2:18][C@H:17]([CH:19]=[CH2:20])[C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:4]([O:11][C:12]([N:14]1[CH2:18][C@H:17]([CH:19]2[CH2:3][CH2:20]2)[C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]1)=[O:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C=[N+]=[N-]
Reactant: C=C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An excessive amount of a solution of diazomethane in diethyl ether (30 mL) was added to (3S,4S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-vinylpyrrolidine (270 mg, 779 μmol). Under cooling with ice, palladium acetate (10 mg) was added thereto, followed by stirring at room temperature for 2 hours. After completion of reaction, insoluble matter was removed through filtration. The filtrate was concentrated under reduced pressure, and the obtained residue was purified though silica gel column chromatography (ethyl acetate:n-hexane=1:9 to 1:4), to thereby yield the title compound as a colorless oily substance (269 mg, 96%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[N:6]=1)=O.[BH4-].[Na+]>C(O)C.CO>[C:12]([O:11][C:7]1[N:6]=[C:5]([CH2:3][OH:2])[CH:10]=[CH:9][CH:8]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)c1cccc(OC(C)(C)C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)Oc1cccc(CO)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2.32 g (11.1 mmol) of the ester from step C in 25 ml of ethanol is reduced by portion wise addition of 2.09 g (55.4 mmol) of sodium borohydride. HPLC analysis after stirring at r.t. for 12 hours shows complete reaction. The mixture is diluted with methanol and extracted with ethyl acetate/water to yield a yellow oil.
Reaction SMILES: C(NC(NC1[N:8]=[C:9]2[CH:14]=[C:13]([C:15]3[CH:16]=[N:17][C:18](OC)=[N:19][CH:20]=3)[CH:12]=[CH:11][N:10]2C=1)=O)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N:35]1[CH:40]=CC=C[CH:36]=1>C(OCC)(=O)C>[NH2:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[N:19][C:18]([N:35]([CH3:40])[CH3:36])=[N:17][CH:16]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CCNC(=O)Nc1cn2ccc(-c3cnc(OC)nc3)cc2n1
Reactant: c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Product: CN(C)c1ncc(-c2ccnc(N)c2)cn1
Temperature: 80 °C
Yield: 79 %

Procedure:
2-Amino-4-bromopyridine 4 (5.00 g, 28.9 mmol) and p-toluenesulfonyl chloride (6.10 g, 31.8 mmol) were dissolved in dry pyridine (100 mL) and heated at 80° C. for 5 h. The pyridine was removed under reduced pressure to give a solid. The solid was suspended in ethyl acetate, then collected by filtration and washed with ethyl acetate to give the tosylate 5 as a crystalline solid (yield: 7.50 g, 79%); 1H NMR [400 MHz, (CD3)2SO] δ 11.6 (v br s, 1H), 7.99 (br d, J=5.6 Hz, 1H), 7.78 (d, J=8.3 Hz, 2H), 7.37 (d, J=7.0 Hz, 2H), 7.27 (br s, 1H), 7.17 (br d, J=5.2 Hz, 1H), 2.36 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:31][C@H:30]([CH2:32][O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C@@H:21]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:12]3[O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:41]>CO>[CH2:14]([O:13][C@H:12]1[C@H:21]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:30]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:31][C@H:11]1[N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH2:41])[C:3]=2[CH:10]=[CH:9]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Clc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: N
Solvent: CO
Product: Nc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 3 g of 4-chloro-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine, 3 ml of methanol, and 20 ml of liquid ammonia is placed in a stainless steel reactor and heated at 100° C. for 5 hours. The ammonia is allowed to evaporate and the residue, after evaporation of the methanol, is distributed between ethyl acetate and water. The aqueous layer is reextracted with ethyl acetate and the dried (MgSO4) ethyl acetate solution is evaporated in vacuo to provide 2.6 g of 7-(2,3,5tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a crude yellow syrup. Chromatography of this material over silica gel with ethyl acetate provides 2.6 g of pure product as a colorless syrup.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:5]=2[N:6]=1.[C:22]1([CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH2:30]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:29][CH2:30][S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[O:15][CH2:16][C:17]([OH:19])=[O:18])[C:5]=3[N:6]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: ICCC(c1ccccc1)c1ccccc1
Product: O=C(O)COc1cccc2c1CCc1sc(SCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 34 %

Procedure:
Using ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate and 3,3-diphenylpropyl iodide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 34%.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[NH2:24]>CC#N>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[C:21]([Cl:20])[CH:22]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(N2CCOCC2)c(Cl)c1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CCCCN1C(=O)C(Nc2ccc(N3CCOCC3)c(Cl)c2)=C(c2ccccc2)S1(=O)=O
Yield: 0 %

Procedure:
A solution of 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.025 g, 0.083 mmol) and 3-chloro-4-morpholinoaniline (0.039 g, 0.183 mmol) in MeCN (1 ml) was heated in a microwave reactor at 130° C. for 90 mins. The product was purified by preparative HPLC (Kromasil C8, 0.1M NH4OAc/MeCN, gradient). The combined product fractions were evaporated and freeze-dried to give the title compound (0.004 mg, 9%). 1H NMR (400 MHz, CD3CN): δ 7.74 (bs, 1H), 7.29-7.24 (m, 1H), 7.20-7.15 (m, 2H), 7.12-7.08 (m, 2H), 6.80-6.75 (m, 3H), 3.76-3.71 (m, 6H), 2.85-2.81 (m, 4H), 1.85-1.76 (m, 2H), 1.52-1.42 (m, 2H), 1.00 (t, 3H); Mass Spectrum: M+H+ 476.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:38])([F:37])[C:12]1[N:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][CH:24]([O:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1.[CH3:39][NH:40][CH2:41][CH2:42][OH:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:43][CH2:42][CH2:41][N:40]([CH3:39])[C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([O:27][CH:24]2[CH2:23][CH2:22][N:21]([C:18]3[CH:19]=[CH:20][C:15]4[N:16]([C:12]([C:11]([F:37])([F:10])[F:38])=[N:13][N:14]=4)[N:17]=3)[CH2:26][CH2:25]2)=[CH:36][CH:35]=1
Reactant: O=C(O)c1ccc(OC2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: CNCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCO)C(=O)c1ccc(OC2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.1 %

Procedure:
DIPEA (0.087 mL, 0.5 mmol) was added to 4-[[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]oxy]benzoic acid (100 mg, 0.25 mmol), 2-(methylamino)ethanol (20.28 mg, 0.27 mmol) and HATU (114 mg, 0.3 mmol) in DMF (2 mL). The resulting solution was stirred at room temperature for 24 hours. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(2-hydroxyethyl)-N-methyl-4-[[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]oxy]benzamide (64 mg, 55%).
Reaction SMILES: Br[C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH2:11][OH:12].[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH2:11][OH:12]
Reactant: OCc1c(C(F)(F)F)nsc1Br
Reactant: Cc1ccc(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(-c2snc(C(F)(F)F)c2CO)c(C)c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [5-bromo-3-(trifluoromethyl)-1,2-thiazol-4-yl]methanol (100 mg, 0.38 mmol, 1.00 equiv), dioxane (3 mL), (2,4-dimethylphenyl)boronic acid (113 mg, 0.75 mmol, 1.97 equiv), Pd(PPh3)4 (44 mg, 0.04 mmol, 0.10 equiv), K3PO4 (402 mg, 1.89 mmol, 4.96 equiv). The resulting solution was stirred for 3 h at 90° C. in an oil bath. The solvent was removed and the residue was applied onto a TLC plate with ethyl acetate/petroleum ether (1:3). This resulted in 100 mg (crude) of [5-(2,4-dimethylphenyl)-3-(trifluoromethyl)-1,2-thiazol-4-yl]methanol as yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[N+:31]([O-])=O)[CH2:20][CH2:19]3)=[O:17])=[CH:10][CH:9]=2)[CH2:4]1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>[Pd].C(O)(=O)C>[CH3:1][N:2]([CH3:34])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[NH:31][C:35](=[O:37])[CH3:36])[CH2:20][CH2:19]3)=[O:17])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)C1CCN(c2ccc(CNC(=O)C3CCN(c4ccc(Cl)cc4[N+](=O)[O-])CC3)cc2)C1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(Cl)ccc1N1CCC(C(=O)NCc2ccc(N3CCC(N(C)C)C3)cc2)CC1
Reaction time: 1 h

Procedure:
Palladium on carbon (10%; 10 mg) was added to a solution of 1-(4-chloro-2-nitro-phenyl)piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]methylamide (50 mg) in glacial acetic acid (5 ml). The solution was stirred under a hydrogen atmosphere (1 bar), and acetic anhydride (14 μl) was added. After one hour, further acetic anhydride (6 μl) were added and the mixture was stirred for 15 minutes. The suspension was filtered and the filtrate was concentrated. The residue was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (7N in methanol)). This resulted in the product with the molecular weight of 498.07 (C27H36CIN5O2); MS (ESI): 498 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C([O:18][CH:19](O)[CH:20]([F:22])[F:21])C>>[F:21][CH:20]([F:22])[CH:19]([C:3]1[N:4]([CH3:9])[CH:5]=[CH:6][C:7](=[O:8])[C:2]=1[OH:1])[OH:18]
Reactant: CCOC(O)C(F)F
Reactant: Cn1ccc(=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1ccc(=O)c(O)c1C(O)C(F)F
Temperature: 50 °C
Yield: 25 %

Procedure:
A sealed suspension of 3-hydroxy-1-methypyridin-4(1H)-one (1.00 g, 8.0 mmol) and potassium carbonate (0.11 g, 0.8 mmol) in 2.4 mL of difluoroacetaldehyde ethyl hemiacetal was heated to 50° C. for 18 h. The volatile components were evaporated under reduced pressure. The residue was dissolved in 3 mL of de-ionized water then cooled in an ice-water bath, and the pH was adjusted to 5-6 with a 1N HCl solution. The precipitate was collected by suction filtration and dried. Thus, the title compound Apo7078 was obtained (410 mg) as a white solid. Yield=25%; 1H NMR (400 MHz, CD3OD) δ (ppm): 7.62 (d, J=7.1 Hz, 1H), 6.41 (d, J=7.1 Hz, 1H), 6.30 (dt, 3J=55.8 Hz, 2J=5.1 Hz, 1H), 5.45 (dt, 2J=5.1 Hz, 3J=11.4 Hz, 1H), 3.96 (s, 3H); MS m/z 206 [M+1], 188 (100%).
Reaction SMILES: [OH-].[Na+].CO.FC(F)(F)C(CCCCCC)CCO[C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=1>O>[C:15]([OH:17])(=[O:16])[C:14]1[CH:20]=[CH:21][CH:11]=[CH:12][CH:13]=1
Reactant: CCCCCCC(CCOc1ccc(C(=O)OCC)cc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccccc1
Temperature: 50 °C
Yield: 77.2 %

Procedure:
72 mg of sodium hydroxide was dissolved in 0.5 ml of water, followed by addition of 0.5 ml of methanol and 205 mg of ethyl p-(3-trifluoromethylnonyloxy)benzoate and 4 hours of stirring at 50° C. After the reaction, water was added, methanol was removed by distillation under a reduced pressure, and 2N-hydrochloric acid was added, followed by extration with diethyl ether. The ether solution was dried with sodium sulfate, and the solvent was distilled off to obtain 146 mg of optically active p-3-trifluoromethylnonyloxy)benzoic acid (yield: 77.2%).
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([CH2:10][CH:11]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])[CH2:9][CH2:8][CH2:7][CH2:6]1.[OH-].[NH4+]>C(Cl)Cl>[CH:5]1([CH2:10][CH:11]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COc1cccc(C(CC2CCCC2)C(=O)Nc2nccs2)c1
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
A 1.0M solution of boron tribromide in methylene chloride (3.53 mL, 3.53 mmol) at 25° C. was treated with a solution of 3-cyclopentyl-2-(3-methoxy-phenyl)-N-thiazol-2-yl-propionamide (prepared as in Example 110, 0.11 g, 0.35 mmol) in methylene chloride (3.5 mL). This solution was stirred at 25° C. for 1 h. At this time, the reaction was cooled to 0° C. and treated with a dilute aqueous ammonium hydroxide solution. This mixture was stirred at 0° C. for 15 min. At this time, the aqueous layer was separated from the organic layer. The aqueous layer was extracted with chloroform (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-hydroxy-phenyl)-N-thiazol-2-yl-propionamide (50 mg, 44.7%) as a white solid: mp 177-179° C.; EI-HRMS m/e calcd for C17H20N2O2S (M+) 316.1245 found 316.1244.
Reaction SMILES: [CH3:1][CH:2]([CH3:43])[C@H:3]([NH:38][C:39](=[O:42])[O:40][CH3:41])[C:4](=[O:37])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[NH:31][C:30]([C@@H:32]5[CH2:36][CH2:35][CH2:34][NH:33]5)=[N:29][CH:28]=4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1.CCN(C(C)C)C(C)C.[CH3:53][CH:54]([CH3:66])[C@H:55]([NH:59][C:60]1[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=1)[C:56](O)=[O:57].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][CH:2]([CH3:43])[C@H:3]([NH:38][C:39](=[O:42])[O:40][CH3:41])[C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4[NH:31][C:30]([C@@H:32]5[CH2:36][CH2:35][CH2:34][N:33]5[C:56](=[O:57])[C@H:55]([CH:54]([CH3:53])[CH3:66])[NH:59][C:60]5[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=5)=[N:29][CH:28]=4)=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1)=[O:37]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5)[nH]4)cc3)cc2)[nH]1)C(C)C
Reactant: CC(C)[C@H](Nc1cccnc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)[C@@H](Nc5cccnc5)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.4 %

Procedure:
To a solution of methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (cj-13) (0.060 g, 0.103 mmol) in DMF (2 mL) was added iPr2NEt (0.18 mL, 1.02 mmol), (S)-3-methyl-2-(pyridin-3-ylamino)butanoic acid (Cap-88) (0.040 g, 0.206 mmol) and HATU (0.078 g, 0.205 mmol). The reaction mixture was stirred for 1.5 h at room temperature and then it was directly purified by prep HPLC (Luna 5u C18/MeCN—H2O—NH4OAc). The resulting solid was repurified by flash chromatography (SiO2/0-10% MeOH—CH2Cl2) and the obtained product was lyophilized from CH3CN—H2O to give the title compound (0.044 g, 56%) as a solid.