Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][CH2:9][C:10]([N:12]1[CH2:21][CH:20]([O:22][CH3:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)=[O:11])(OC(C)(C)C)=O>Cl.CCOC(C)=O>[NH2:8][CH2:9][C:10]([N:12]1[CH2:21][CH:20]([O:22][CH3:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)=[O:11]
Reactant: COC1CN(C(=O)CNC(=O)OC(C)(C)C)Cc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COC1CN(C(=O)CN)Cc2ccccc21
Yield: 80.3 %

Procedure:
A solution of N-(N′-Boc-glycyl)-4-methoxy-1,2,3,4-tetrahydroisoquinoline (4.97 g, 16 mmol) in 30 mL of 3 N HCl and 30 mL of EtOAc was heated to reflux for 0.5 hour. The resulting solution was basified to pH 9 and extracted with EtOAc. The aqueous layer was then extracted with 10% iPrOH—CH2Cl2. Drying over MgSO4 of the iPrOH—CH2Cl2 solution and removal of the solvent gave 2.83 g (89%) of N-glycyl-4-methoxy-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([OH:9])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.Cl.[Cl:43][C:44]1[C:45]([NH:72][C:73](=[O:93])[C:74]2[CH:79]=[CH:78][C:77]([N:80]3[CH2:85][CH2:84][N:83]([C:86](=[O:91])[C:87]([CH3:90])([CH3:89])[CH3:88])[CH2:82][C@H:81]3[CH3:92])=[N:76][CH:75]=2)=[CH:46][C:47]([O:67][C:68]([F:71])([F:70])[F:69])=[C:48]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[N:57]=[C:58]([C@@H:61]4[CH2:65][C@H:64]([CH3:66])[CH2:63][NH:62]4)[NH:59][CH:60]=3)=[CH:52][CH:51]=2)[CH:49]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@@H:6]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([N:62]1[CH2:63][C@@H:64]([CH3:66])[CH2:65][C@H:61]1[C:58]1[NH:59][CH:60]=[C:56]([C:53]2[CH:54]=[CH:55][C:50]([C:48]3[CH:49]=[C:44]([Cl:43])[C:45]([NH:72][C:73]([C:74]4[CH:75]=[N:76][C:77]([N:80]5[CH2:85][CH2:84][N:83]([C:86](=[O:91])[C:87]([CH3:90])([CH3:89])[CH3:88])[CH2:82][C@H:81]5[CH3:92])=[CH:78][CH:79]=4)=[O:93])=[CH:46][C:47]=3[O:67][C:68]([F:70])([F:71])[F:69])=[CH:51][CH:52]=2)[N:57]=1)=[O:9]
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Reactant: C[C@@H]1CN[C@H](c2nc(-c3ccc(-c4cc(Cl)c(NC(=O)c5ccc(N6CCN(C(=O)C(C)(C)C)C[C@H]6C)nc5)cc4OC(F)(F)F)cc3)c[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)C(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
To a solution of (S)-methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (9.4 mg, 0.046 mmol; Preparation 29) in DMA (5 mL) was added HATU (45.3 mg, 0.12 mmol). The reaction mixture was stirred at RT for 15 min, and N-{5-chloro-4′-[2-((2S,4S)-4-methyl-pyrrolidin-2-yl)-1H-imidazol-4-yl]-2-trifluoromethoxy-biphenyl-4-yl}-6-[(R)-4-(2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-nicotinamide tri-HCl (30.0 mg, 0.036 mmol; Preparation 31 was added followed by DIPEA (86.4 μL, 0.50 mmol). The reaction mixture was stirred at RT overnight, concentrated by rotary evaporation, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC to provide the di-TFA salt of the title compound (14 mg, 37% yield). (m/z): [M+H]+ calcd for C46H54ClF3N8O7 923.38. found 923.8.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:20]=[CH:19][C:14]([O:15][CH2:16][C:17]#[N:18])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:3]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[N-:32]=[N+:33]=[N-:34].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:20]=[CH:19][C:14]([O:15][CH2:16][C:17]4[NH:34][N:33]=[N:32][N:18]=4)=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:3]1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCCCCc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(OCC#N)cc3)cc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(OCc4nnn[nH]4)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(1-methyl-3-pentyl-2-phenyl-1H-indol-5-yl)-phenoxy]-acetonitrile (0.152 g, 0.372 mmol) was reacted with NaN3 (0.121 g, 1.860 mmol) and NH4Cl (0.099 g, 1.860 mmol) in DMF (5 ml) to give the product (0.117 g, 0.259 mmol, 70%) as a white solid, dec. 181-185° C. 1H NMR (DMSO-d6) δ 0.76 (t, J=7.0 Hz, 3H), 1.13-1.22 (m, 4H), 1.51-1.57 (m, 2H), 2.66 (t, J=7.5 Hz, 2H), 3.56 (s, 3H), 5.53 (s, 2H), 7.15 (d, J=8.7 Hz, 2H), 7.42-7.45 (m, 3H), 7.48 (t, J=8.6 Hz, 2H), 7.54 (t, J=7.2 Hz, 2H), 7.65 (d, J=8.7 Hz, 2H), 7.74 (d, J=1.2 Hz, 1H), 16.80 (broad s, 1H); IR (solid) 3030, 2930, 2860, 1605, 1520, 1480, 1370 and 1240 cm−1; [ESI(−)], m/z 450 (M−H)−; Anal. Calcd. for C28H29N5O: C, 74.48; H, 6.47; N, 15.51 Found: C, 74.49; H, 6.26; N, 15.30.
Reaction SMILES: I.[NH2:2][C:3](=[N:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[O:12][C:13]([CH2:16][N:17]=[C:18]([NH2:21])SC)=[CH:14][CH:15]=2)[N:10]=1)[NH2:4].[N:22]#[C:23][NH2:24].C(N(CC)CC)C>CN(C)C=O>[NH2:2][C:3](=[N:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[O:12][C:13]([CH2:16][NH:17][C:18]([NH2:21])=[N:24][C:23]#[N:22])=[CH:14][CH:15]=2)[N:10]=1)[NH2:4]
Reactant: N#CN
Reactant: CSC(N)=NCc1ccc(-c2csc(N=C(N)N)n2)o1
Agent: I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CN=C(N)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Yield: 24.5 %

Procedure:
A solution of 2-(diaminomethyleneamino)-4-[5-(2-methyl-3-isothioureido)methylfuran-2-yl]thiazole hydriodide (1.0 g), cyanamide (120 mg) and triethylamine (1.2 g) in N,N-dimethylformamide (20 ml) was heated at 100° C. for 3 hours. The solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (20:1, V/V). Recrystallization from 20% methanol afforded 2-(diaminomethyleneamino)-4-[5-(2-cyanoguanidino)methylfuran-2-yl]thiazole (170 mg).
Reaction SMILES: C(N[C:9](=[O:36])[CH:10]([N:17]1[C:21]2[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:20]=2[N:19]=[C:18]1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[CH3:35])[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)C1C=CC=CC=1.C(OC(=O)C)(=[O:39])C.C(O)(=O)C.N([O-])=O.[Na+]>>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:18]2[N:17]([CH:10]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[C:9]([OH:39])=[O:36])[C:21]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:20]=3[N:19]=2)=[C:29]([CH3:35])[CH:30]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1C(C(=O)NCc1ccccc1)C1CCCCC1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1C(C(=O)O)C1CCCCC1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
N-benzyl-2-[2-(4-chloro-2-methyl-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetamide (3.8 g, 6.508 mmol) were dissolved in 49.3 ml (521.9 mmol) acetic acid anhydride and 24.7 ml (431.5 mmol) acetic acid. The dark brown solution was cooled to 0-5° C. and 2.245 g (32.54 mmol) sodium nitrite were added in four portions within 10 min. After 30 min. the reaction mixture was allowed to warm to room temperature. The reaction mixture was then evaporated, taken up with toluene and evaporated again. The residue was extracted twice ethyl acetate, saturated aqueous sodium bicarbonate solution, water and brine. The organic layers were separated, dried over magnesium sulfate, filtered and evaporated. The crude intermediate was then dissolved in a mixture of tetrahydrofuran and water. To the dark brown solution slowly a solution of lithiumhydroxide monohydrate in 30% aqueous hydrogen peroxide was added dropwise over 20 min (gas evolution, exothermic). The mixture was stirred until all starting material had disappeared. The reaction mixture was then evaporated and the pH of the residue was adjusted to 4 with acetic acid. Ethyl acetate was added, the phases separated and the aqueous layer extracted another time with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate and evaporated. The residue was taken up in toluene, stirred at 0-5° C. for 15′, the solid was filtered off, washed with cold toluene and dried in vacuum to give the desired compound as a beige solid (54%). MS (ESI): 418.87 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16]([NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:17])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16]([NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:17]
Reactant: O=C(NCC1CCNCC1)Nc1cc(-c2cccs2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2cccs2)cc1NC(=O)NCC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To a solution of 1-(2-nitro-5-(thiophen-2-yl)phenyl)-3-(piperidin-4-ylmethyl)urea (0.10 g, 0.28 mmol, 1.0 equiv.) in methanol was added Pd/C (0.03 g, 0.03 mmol, 0.10 equiv.). The reaction mixture was stirred at room temperature under H2 balloon pressure for 1 h. The reaction was filtered through celite and concentrated under reduced pressure. The crude solid was washed with ether to obtain of pure 1-(2-amino-5-(thiophen-2-yl)phenyl)-3-(piperidin-4-ylmethyl)urea (0.06 g, 65% yield). ESI+ MS: m/z 331 ([M]+); 1H NMR (500 MHz, d6-DMSO): δ 7.64 (d, J=12.0 Hz, 2H), 7.33 (d, J=5.5 Hz, 1H), 7.17 (d, J=3.0 Hz, 1H), 7.10-7.09 (m, 1H), 7.03 (t, J=5.0 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 6.34 (m, 1H), 4.90-4.89 (bs, 2H), 3.16 (d, J=12.5 Hz, 2H), 2.99 (t, J=6.0 Hz, 3H), 2.65 (t, J=12.5 Hz, 2H), 1.71 (d, J=13.0 Hz, 1H), 1.62-1.60 (m, 2H), 1.20-1.13 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:20])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[C:8]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]([NH:5][CH2:4][CH2:3][CH2:2][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)=[O:20])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCC(=O)Nc1ccc(C2CCNCC2)cc1
Reactant: O=C(NCCCBr)C(c1ccccc1)c1ccccc1
Product: CCCC(=O)Nc1ccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
Example 149 was prepared from N-(3-bromopropyl)-2,2-diphenylacetamide and N-[4-(4-piperidinyl)phenyl]butanamide according to the procedures described in Scheme 14: ESMS m/e: 498.3 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].I[CH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CN(C)C=O.O1CCCC1>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Reactant: ICC1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CC1CCOCC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of Example 244A (10 g, 3.1 mmol) in 4:1 N,N-dimethylformamide/tetrahydrofuran (20 mL) were added potassium tert-butoxide (Aldrich, 0.42 g, 3.7 mmol) and 4-(iodomethyl)tetrahydro-2H-pyran (Maybridge, 0.97 g, 4.3 mmol). The reaction mixture was stirred at 80° C. for 16 hours, cooled to room temperature, quenched with saturated aqueous NaHCO3 (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 1.21-1.51 (m, 4H), 1.32 (s, 9H), 2.06-2.35 (m, 1H), 3.20-3.30 (m, 2H), 3.79 (s, 3H), 3.80-3.91 (m, J=9.3, 2.2, 2.0 Hz, 2H), 4.06 (d, J=7.1 Hz, 2H), 7.11 (d, J=8.8 Hz, 1H), 7.30 (s, 1H), 7.45 (dd, J=8.8, 3.1 Hz, 1H), 7.64 (d, J=2.7 Hz, 1H); MS (ESI+) m/z 423 (M+H)+; Anal. Calculated for C21H27ClN2O3S: C, 59.63; H, 6.43; N, 6.62 Found: C, 59.66; H, 6.36; N, 6.56.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C:15]1[C:20]([C:21]2[O:22][C:23]([C:26]3[S:27][CH:28]=[CH:29][C:30]=3[CH3:31])=[N:24][N:25]=2)=[N:19][C:18](Br)=[CH:17][N:16]=1)C(OC(C)(C)C)=O)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:42]2[CH:47]=[CH:46][C:45]([S:48]([CH:51]3[CH2:56][CH2:55][CH2:54][N:53]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:52]3)(=[O:50])=[O:49])=[CH:44][CH:43]=2)O1.O.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[C:1]([O:5][C:6]([NH:7][C:15]1[N:16]=[CH:17][C:18]([C:42]2[CH:47]=[CH:46][C:45]([S:48]([CH:51]3[CH2:56][CH2:55][CH2:54][N:53]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:52]3)(=[O:50])=[O:49])=[CH:44][CH:43]=2)=[N:19][C:20]=1[C:21]1[O:22][C:23]([C:26]2[S:27][CH:28]=[CH:29][C:30]=2[CH3:31])=[N:24][N:25]=1)=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(S(=O)(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1
Reactant: Cc1ccsc1-c1nnc(-c2nc(Br)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1ccsc1-c1nnc(-c2nc(-c3ccc(S(=O)(=O)C4CCCN(C(=O)OC(C)(C)C)C4)cc3)cnc2NC(=O)OC(C)(C)C)o1
Temperature: 65 °C
Yield: 106.2 %

Procedure:
tert-butyl-N-[5-bromo-3-[5-(3-methyl-2-thienyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (750 mg, 1.393 mmol) and tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylpiperidine-1-carboxylate (691.5 mg, 1.532 mmol) were suspended in MeCN (7.500 mL)/water (7.500 mL) and Na2CO3 (1.393 mL of 2 M, 2.786 mmol) was added. The reaction mixture was degassed with 3× nitrogen/vacuum cycles. Pd(tBu3P)2 (71.19 mg, 0.1393 mmol) was added and the reaction mixture again degassed 3 times then heated to 65° C. (Dry Syn Temp) for 1.5 hours. The reaction mixture was cooled to ambient temperature and diluted with ethylacetate/water. The aqueous layer was extracted with ethylacetate (×1) and the combined organic extracts washed with brine (×2), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 80 g column, eluting with 0 to 30% ethyl acetate/petroleum Ether, (loaded in DCM) to give the sub-title product as a yellow solid (1.01 g, 93% Yield). H NMR (400.0 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.59 (d, 2H), 8.16 (d, 2H), 7.96 (d, 1H), 7.24 (d, 1H), 4.14-3.92 (m, 1H), 3.77 (br d, 1H), 3.44 (br s, 1H), 3.02-2.91 (m, 1H), 2.79 (br t, 1H), 2.67 (s, 3H), 2.05 (br s, 1H), 1.76-1.58 (m, 2H) and 1.35-1.22 (m, 28H) ppm; LC/MS m/z 627 [M−100−56]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=O)[CH3:13])=[CH:7][C:6]=1[CH3:15])([O:3][CH3:4])=[O:2].[OH:16][CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[CH2:18][NH2:19]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:19][CH2:18][CH:17]([OH:16])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=2)[CH3:13])=[CH:7][C:6]=1[CH3:15])([O:3][CH3:4])=[O:2]
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CC(C)=O)cc1C
Product: COC(=O)c1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1C

Procedure:
The title compound was prepared as in Example 1b from 1-(4-carbomethoxy-3-methylphenyl)propan-2-one (2.0 g) and 2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine (2.0 g), the compound crystallised from hexane m.p. 88°-92° as a 41:59 mixture of diastereoisomers. τ(CDCl3) 8.9 (3H,d,J=6 Hz), 7.4 (3H,s), 6.8-7.8 (5H,m,=2H, replaceable by D2O), 6.1 (3H,s), 5.3 (1H,m), 2.9 (2H,m), 2.3-2.6 (4H,m), 2.1 (1H,dd,J=8 Hz, J=2 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=1[C:17]([F:20])([F:19])[F:18])(=[O:9])=[O:8].[N+:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)([O-:23])=[O:22]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N+:21]([O-:23])=[O:22])=[CH:12][C:11]=1[C:17]([F:20])([F:19])[F:18])(=[O:9])=[O:8]
Reactant: O=S(=O)(NCCCCO)c1ccc(Br)cc1C(F)(F)F
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Product: O=[N+]([O-])c1ccccc1-c1ccc(S(=O)(=O)NCCCCO)c(C(F)(F)F)c1

Procedure:
Using a method analogous to that described in Example 40, 4-bromo-2-trifluoromethylphenyl-sulfonic acid-(4-hydroxybutyl)-amide and 2-nitrophenyl boronic acid were reacted to give the title compound as a thick oil. δC (DMSO, 62.9 MHz): 26.1, 29.5, 42.8, 60.2, 128.2, 124.9, 120.7, 128.7, 130.2, 132.6, 133.1, 133.5, 139.3, 139.8, 141.8 and 147.9.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.Br[C:14]1[CH:15]=[C:16]([CH:29]=[CH:30][N:31]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[CH:21]=1)=[O:18]>>[CH:26]([C:22]1[CH:21]=[C:20]([NH:19][C:17](=[O:18])[C:16]2[CH:15]=[CH:14][N:31]=[C:30]([N:11]3[CH2:10][CH2:9][C:7]4[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[CH2:12]3)[CH:29]=2)[CH:25]=[CH:24][CH:23]=1)([CH3:28])[CH3:27]
Reactant: CSc1ncc2c(n1)CCNC2
Reactant: CC(C)c1cccc(NC(=O)c2ccnc(Br)c2)c1
Product: CSc1ncc2c(n1)CCN(c1cc(C(=O)Nc3cccc(C(C)C)c3)ccn1)C2

Procedure:
In a manner similar to that described for Example 138, 2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine and 2-bromo-N-(3-isopropyl-phenyl)-isonicotinamide were converted to the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](OS(C)(=O)=O)=[CH:7][N:6]=1)=[O:4].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(OS(C)(=O)=O)cn1
Reactant: C1CCNCC1
Product: COC(=O)c1cnc(N2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1 g (4.3 mmol) 5-methanesulfonyloxy-pyrazine-2-carboxylic acid methyl ester and 0.733 (8.6 mmol) piperidine was shaken at room temperature for 4 h. Subsequent purification on silica eluting with a gradient formed from DCM and methanol yielded after evaporation of the product fractions 0.625 g (66%) of the title compound as light yellow crystals. m/z (ES+): 222.0 (M+H).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][CH:23]=[N:24][C:25]=3[CH2:29][CH2:30][O:31][CH3:32])[O:11]1)(C(C)(C)C)(C)C.F>C1COCC1.N1C=CC=CC=1.N1C=CC=CC=1>[CH3:32][O:31][CH2:30][CH2:29][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[C:26]=1[N:27]=[CH:28][N:20]2[C@H:12]1[C@@H:13]2[O:17][C:16]([CH3:18])([CH3:19])[O:15][C@@H:14]2[C@@H:10]([CH2:9][OH:8])[O:11]1
Reactant: COCCc1ncnc2c1ncn2[C@@H]1O[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2OC(C)(C)O[C@H]21
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCCc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@H]2OC(C)(C)O[C@H]21
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a solution of 9-[(3aR,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-6-(2-methoxyethyl)-9H-purine (70 mg, 0.15 mmol) in THF/pyridine (1.5 mL, 1:1) was added hydrofluoric acid in pyridine (15 drops). The reaction was stirred overnight, quenched with saturated aq NaHCO3, extracted with EtOAc, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 50% DCM/EtOAc to furnish 37 mg (70%) of the title compound.
Reaction SMILES: [Mg].[CH3:2][N:3]([CH3:14])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:22](=[O:25])[CH2:23][CH3:24])[CH:19]=[CH:20][CH:21]=1>O1CCCC1>[CH2:23]([C:22]([OH:25])([C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=1)[C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][N:3]([CH3:14])[CH3:2])=[CH:8][CH:9]=1)[CH3:24]
Reactant: CCC(=O)c1cccc(Cl)c1
Reactant: CN(C)CCOc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(OCCN(C)C)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a Grignard reactant prepared from 2.2 g. of magnesium turnings and 23.4 g. of 4-[2-(dimethylamino)-ethoxy]-bromobenzene in 100 ml. of dry tetrahydrofurane a solution of 10 g. of m-chloro-propiophenone in 30 ml. of tetrahydrofurane is added dropwise, at 20° C. The reaction mixture is stirred at room temperature for another two hours, cooled, and filtered onto a 20% aqueous ammonium chloride solution. Tetrahydrofurane is distilled off in vacuo. The residue is extracted with ether, the ethereal phase is washed with water, dried over anhydrous magnesium sulfate, filtered, and ether is distilled off. Crystallization of the residue from a mixture of n-hexane and ethyl acetate yields 14.2 g. of the named compound, melting at 108° to 109° C.
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Mg].II.CON(C)[C:17](=[O:21])[CH2:18][CH2:19][CH3:20]>O1CCCC1>[S:7]1[CH:8]=[CH:9][C:10]2[C:2]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[CH:3][CH:4]=[CH:5][C:6]1=2
Reactant: CCCC(=O)N(C)OC
Reactant: Brc1cccc2sccc12
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC(=O)c1cccc2sccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Approximately 5 ml of a solution of 4-bromobenzo[b]thiophene (2.87 g; prepared in a manner similar to that described in Example 9 Method A) in tetrahydrofuran (30 ml) was added under nitrogen to magnesium turnings (0.45 g). Two crystals of iodine were added and heat was applied to initiate the reaction. The remainder of the 4-bromobenzo[b]thiophene solution was added at reflux temperature over 20 minutes, then the mixture was heated under reflux for a further 15 minutes. A solution of N-methoxy-N,3-dimethylpropionamide (2.12 g) in tetrahydrofuran (15 ml) was added, the mixture was heated under reflux for 30 minutes, then it was cooled to ambient temperature and quenched by the addition of 2M hydrochloric acid (30 ml). The mixture was stirred at ambient temperature for 1.5 hours, then the product was extracted into ethyl acetate (150 ml). The combined extracts were washed with water (2×100 ml) and saturated aqueous sodium chloride solution (200 ml), dried (MgSO4), and the solvents were removed in vacuo. The residue was purified by Biotage flash chromatography over silica using a 97:3 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(benzo[b]thiophen-4-yl)-3-methylpropan-1-one (1.7 g) as a colourless oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=1[OH:24])[CH2:12][CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Ni]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13][OH:14])=[C:16]([OH:24])[CH:17]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N(CCO)c1ccc([N+](=O)[O-])cc1O
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1ccc(N(CCO)C(=O)OCc2ccccc2)c(O)c1
Reaction time: 1 h

Procedure:
0.24 mole (80 g) of 2-[N-benzyloxycarbonyl-N-(β-hydroxyethyl)amino]-5-nitrophenol in 630 ml of ethyl acetate is subjected to a hydrogen pressure of 9×105 pascals (9 bars) in an autoclave in the presence of 15 g of Raney nickel (water content 50%). After one hour at 85° C., the reaction medium is filtered while hot in order to remove the catalyst. On evaporation of the solvent under vacuum, the expected product crystallizes. After draining and drying, the product obtained is recrystallized from 96° strength alcohol It melts at 142° C.