Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]([F:40])([F:39])[CH2:28][O:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1>CCCCCCC.CCOC(C)=O>[CH3:25][N:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:35]1[C:30]([O:29][CH2:28][C:27]([F:39])([F:26])[F:40])=[N:31][CH:32]=[CH:33][CH:34]=1)[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Reactant: OB(O)c1cccnc1OCC(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1cccnc1OCC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 98, intermediate a) and 2-(2,2,2-trifluoroethoxy)pyridin-3-ylboronic acid (Combi-Blocks Inc.) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Colorless solid (58%). MS (ESI): m/z=524.103 [M+H]+.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][C@H:36]([C:40]([N:42]([CH:57]2[CH2:65][C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[CH2:58]2)[CH2:43][C:44]([NH:46][CH:47]([CH:54]([CH3:56])[CH3:55])[C:48](=[O:53])[C:49]([F:52])([F:51])[F:50])=[O:45])=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:34])=[CH:29][CH:28]=1)(O)=[O:25]>>[CH2:12]([O:19][C:20]([CH2:21][NH:22][C:24]([C:27]1[CH:28]=[CH:29][C:30]([C:33]([NH:35][C@H:36]([C:40]([N:42]([CH:57]2[CH2:58][C:59]3[C:64](=[CH:63][CH:62]=[CH:61][CH:60]=3)[CH2:65]2)[CH2:43][C:44]([NH:46][CH:47]([CH:54]([CH3:56])[CH3:55])[C:48](=[O:53])[C:49]([F:51])([F:52])[F:50])=[O:45])=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:34])=[CH:31][CH:32]=1)=[O:25])=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)C(NC(=O)CN(C(=O)[C@@H](NC(=O)c1ccc(C(=O)O)cc1)C(C)C)C1Cc2ccccc2C1)C(=O)C(F)(F)F
Reactant: NCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)C(NC(=O)CN(C(=O)[C@@H](NC(=O)c1ccc(C(=O)NCC(=O)OCc2ccccc2)cc1)C(C)C)C1Cc2ccccc2C1)C(=O)C(F)(F)F
Yield: 97.1 %

Procedure:
3(RS)-[[4-[(Benzyloxycarbonyl)methylaminocarbonyl]phenylcarbonyl]-L-valyl-N-(2-indanyl)glycyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (250 mg) was prepared from glycine benzyl ester p-toluenesulfonate (118 mg) and 3(RS)-[(4-carboxyphenylcarbonyl)-L-valyl-N-(2-indanyl)glycyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (206 mg) by a similar method to that of Example 1.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)[N:17]=1)[CH:10]=[C:9]2[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.Br[CH2:39][CH2:40][CH2:41][OH:42].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13]([CH:12]=[C:11]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=4)[N:17]=3)[CH:10]=[C:9]2[N:32]2[CH2:33][CH2:34][N:35]([CH2:39][CH2:40][CH2:41][OH:42])[CH2:36][CH2:37]2)=[CH:14][CH:15]=1
Reactant: OCCCBr
Reactant: COc1cccc(CNc2nccc(-c3cc(N4CCNCC4)c4cc(OC)ccc4c3)n2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cccc(CNc2nccc(-c3cc(N4CCN(CCCO)CC4)c4cc(OC)ccc4c3)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
A mixture of 4-(6-methoxy-4-(piperazin-1-yl)naphthalen-2-yl)-N-(3-methoxybenzyl)pyrimidin-2-amine tris hydrochloride salt (1.0 g, 1.78 mmol), 3-bromopropan-1-ol (250 mg, 1.80 mmol), potassium carbonate (1.23 g, 8.91 mmol) and acetonitrile (20 ml) was stirred for 16 hours at room temperature. The mixture was diluted with water (100 ml) and extracted with dichloromethane (3×50 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (24 g) using a gradient of ethyl acetate-hexanes to afford 3-(4-(7-methoxy-3-(2-((3-methoxybenzyl)amino)pyrimidin-4-yl)naphthalen-1-yl)piperazin-1-yl)propan-1-ol 193 as a yellow solid (600 mg, 66%). 400 M Hz 1H NMR (DMSO-d6) δ: 8.35 (d, J=5.2 Hz, 1H), 8.29 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.80 (bm, 2H), 7.42 (s, 1H), 7.23 (m, 3H), 6.99 (bm, 2H), 6.78 (dd, J=2.4 and 8.4 Hz, 1H), 4.55 (m, 3H), 3.91 (s, 3H), 3.71 (s, 3H), 3.50 (m, 3H), 3.06 (bm, 6H), 2.73 (bm, 3H), 1.67 (m, 2H); LCMS[M+H]: 514.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16]C1C=CC(C(O)=O)=C(I)C=1.FC1C=CC(I)=C(C=1)C(O)=O>>[F:16][C:3]1[CH:2]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[CH:4]=1
Reactant: O=C(O)c1ccc(F)cc1I
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: O=C(O)c1cc(F)ccc1I
Product: O=C(O)c1ccc(F)cc1-n1nccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 1, substituting for 4-fluoro-2-iodo-benzoic acid for 5-fluoro-2-iodo-benzoic acid in Step A. 1H NMR (400 MHz, CD3OD): 7.93 (s, 2H), 7.88 (dd, J=8.7, 5.9 Hz, 1H), 7.56 (dd, J=9.2, 2.5 Hz, 1H), 7.38-7.30 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]2)[C:8]2[N:13]=[N:12][N:11](CC3C=CC(OC)=CC=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C.[C:36](O)([C:38]([F:41])([F:40])[F:39])=[O:37]>>[C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C@H:25]([O:28][C:36](=[O:37])[C:38]([F:41])([F:40])[F:39])[CH2:24]2)[C:8]2[N:13]=[N:12][NH:11][C:9]=2[N:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccc(Cn2nnc3c(N4CC[C@H](O)C4)nc(C(C)(C)C)nc32)cc1
Reactant: O=C(O)C(F)(F)F
Agent: CC[SiH](CC)CC
Product: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Temperature: 70 °C

Procedure:
A mixture of (S)-1-[5-tert-Butyl-3-(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol and triethylsilane in TFA was heated to 70° C. for 22 h and evaporated to dryness. The residue was used without further purification in the consecutive step.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.Cl.[NH2:22][OH:23].[OH-].[Na+]>CCO.O>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[N:22][OH:23])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(OCc2ccccc2C(F)(F)F)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccc(OCc2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
4-(2-Trifluoromethyl-benzyloxy)-benzaldehyde (which may be prepared as described in Panetta, J. A. et al. U.S. Pat. No. 6,251,928 Column 25; 28.8 g, 102.7 mmol) was combined with 9:1 EtOH/H2O (210 mL) and hydroxylamine hydrochloride (11 g, 158 mmol) was added. A solution of 3.15 M NaOH in 9:1 EtOH/H2O (70 mL, 221 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h and then heated at 50° C. for 1 h. The mixture was partitioned between EtOAc and H2O, and the organic layer was dried, filtered, and evaporated to give 4-(2-trifluoromethyl-benzyloxy)-benzaldehyde oxime (14 g, 46%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:22][O:21][C:20]3[CH:23]=[C:24]4[C:28](=[CH:29][C:19]1=3)[CH2:27][CH2:26][O:25]4)[C:5](=[O:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2CCCCC.[N:57]1[CH:62]=[C:61](B(O)O)[CH:60]=[N:59][CH:58]=1.CN(C)C1N=CC(B(O)O)=CC=1>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:6]1[C:7]2[C:3](=[C:2]([C:61]3[CH:62]=[N:57][CH:58]=[N:59][CH:60]=3)[CH:10]=[CH:9][CH:8]=2)[C:4]2([CH2:22][O:21][C:20]3[CH:23]=[C:24]4[C:28](=[CH:29][C:19]2=3)[CH2:27][CH2:26][O:25]4)[C:5]1=[O:18]
Reactant: OB(O)c1cncnc1
Reactant: O=C1N(Cc2ccccn2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Agent: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: CN(C)c1ccc(B(O)O)cn1
Product: O=C1N(Cc2ccccn2)c2cccc(-c3cncnc3)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bromo-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and pyrimidin-5-ylboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (16%) as a colorless solid: mp>200° C.; 1H NMR (300 MHz, CDCl3) δ 9.09 (s, 1H), 8.59 (d, 1H), 8.14 (s, 2H), 7.74 (t, 1H), 7.67 (d, 1H), 7.63 (d, 1H), 7.52 (d, 1H), 7.47-7.42 (m, 1H), 7.37 (d, 1H), 7.30 (d, 1H), 7.09 (d, 1H), 6.82 (d, 1H), 6.62 (s, 1H), 6.07 (s, 1H), 5.18 (ABq, 2H), 4.62 (ABq, 2H), 4.62-4.48 (m, 2H), 3.02 (t, 2H); MS (ES+) m/z 449.5 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:63]1[CH2:68][CH2:67][S:66](=[O:69])[CH2:65][CH2:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:63]1[CH2:68][CH2:67][S:66](=[O:69])[CH2:65][CH2:64]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: O=S1CCNCC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCS(=O)CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and thiomorpholine-1-oxide in DMSO at ambient temperature.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][CH:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([CH:25]=O)[CH:11]=2.Cl.[CH3:31][O:32][NH2:33]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][CH:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([CH:25]=[N:33][O:32][CH3:31])[CH:11]=2
Reactant: CON
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(C=O)ccc3n2Cc2cccc(F)c2)C1
Agent: Cl
Solvent: c1ccncc1
Product: CON=Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CCC(NC(=O)C(C)C)C1
Yield: 33.7 %

Procedure:
Add N-[9-(3-fluoro-benzyl)-6-formyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (Example 197) (crude, 506 mg, 1.29 mmol) to a suspension of methoxyamine hydrochloride salt (140 mg, 1.48 mmol) and pyridine (10 mL). Stir the reaction at ambient temperature for 12 h. Remove the pyridine under vacuum and dissolve the resultant residue in ethyl acetate (100 mL). Wash with saturated aqueous copper sulfate (2×50 mL) and water (2×50 mL). Separate the organic layer and dry over magnesium sulfate, filter, and concentrate under vacuum to give a greasy yellow solid. The solid was purified with column chromatography (silica gel; 10% to 50% ethyl acetate in hexanes) to give 183 mg (34%) of the title compound as a white solid. mp: 180-182° C.; ESI MS m/z 422 [C25H28FN3O2+H]+; 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.79 (s, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.26-7.17 (m, 2H), 6.93 (t, J=7.1 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.62 (d, J=9.1 Hz, 1H), 5.49 (br d, J=7.0 Hz, 1H), 5.24 (s, 2H), 4.40 (br s, 1H), 3.97 (s, 3H), 3.15 (dd, J=15.8, 4.7 Hz, 1H), 2.71-2.61 (m, 3H), 2.28 (septet, J=6.8 Hz, 1H), 2.07-2.00 (m, 2H), 1.14 (d, J=6.7 Hz, 3H), 1.12 (d, J=6.7 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:21])[N:4]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[NH:22]([C:2]1[C:3](=[O:21])[N:4]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: O=C1C(Cl)=C(c2ccccc2)C(=O)N1Cc1cccnc1
Solvent: CN(C)C=O
Product: O=C1C(Nc2ccccc2)=C(c2ccccc2)C(=O)N1Cc1cccnc1
Temperature: 150 °C
Yield: 42.8 %

Procedure:
To a solution of 3-chloro-4-phenyl-1-(pyridin-3-ylmethyl)-1H-pyrrole-2,5-dione (0.25 mmol, 75 mg) in DMF (0.5 mL) was added aniline (0.55 mmol, 51 mg). The mixture was heated in a microwave reactor at 150° C. for five min. After cooling, the reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 38 mg (43%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 8.72 (bs, 1H), 8.54 (d, br, 1H), 7.79-7.75 (m, 1H), 7.47 (bs, 1H), 7.29-7.23 (m, 1H), 7.17-7.06 (m, 3H), 7.04-6.93 (m, 5H), 6.66-6.60 (m, 2H), 4.79 (s, 2H).
Reaction SMILES: [Br-].[F:2][C:3]([Zn+])([F:5])[F:4].I[C:8]1[N:9]=[C:10]([NH2:26])[C:11]2[N:12]=[CH:13][N:14]([C:24]=2[N:25]=1)[C@@H:15]1[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:16]1[OH:17]>CN(C=O)C.CN(P(N(C)C)(N(C)C)=O)C.[Cu](Br)Br>[F:2][C:3]([F:5])([F:4])[C:8]1[N:9]=[C:10]([NH2:26])[C:11]2[N:12]=[CH:13][N:14]([C:24]=2[N:25]=1)[C@@H:15]1[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:16]1[OH:17]
Reactant: FC(F)(F)[Zn+]
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Br[Cu]Br
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Nc1nc(C(F)(F)F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of trifluoromethylzinc bromide (1.308 g, 6.10 mmol) in DMF (25 mL) and HMPA (10 mL) was added to copper bromide (0.438 g, 3.05 mmol) and the resulting mixture was stirred for 30 min. 2-Iodoadenosine (0.800 g, 2.03 mmol) was added and the solution was warmed at 70° C. for 4 h. The solvents were evaporated and the residue was purified on silica gel with 10% methanol/chloroform to give 2-trifluoromethyladenosine in 63% yield. 2-Trifluoromethyladenosine was converted to IV by using in sequence the following procedures: Procedure A (58% yield), Procedure B (84% yield), Procedure C (51% yield), Procedure D (73% yield), Procedure E (75% yield), and Procedure F (53% yield): mp 173°-175° C.; 13NMR (Me2SO-d6) δ25.7, 31.8, 62.8, 82.1, 84.5, 119.8, 141.1, 148.3, 156.2; 1H NMR (Me2SO-d6) δ2.10 (m, 2 H), 2.40 (m, 2H), 3.51 (m, 2H), 4.13 (m, 1H), 4.88 (m, 1H), 6.25 (m, 1H), 7.85 (br.s, 2H), 8.54 (s, 1H); UV (H2O) λmax 259.5 nm (λ11300); FAB HRMS obsd (M+ +H) 304.0996, calcd for C11H12F3N5O2 304.1021.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][C:9](=[O:17])[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:19]#[N:20].CN1CCCC1=O.N>S([O-])([O-])(=O)=O.[Cu+2].O>[C:19]([C:2]1[C:7]2[CH2:8][C:9](=[O:17])[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:20]
Reactant: O=C1Cc2c(Cl)cccc2Sc2ccccc21
Reactant: N#C[Cu]C#N
Agent: [Cu+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cccc2c1CC(=O)c1ccccc1S2
Temperature: 200 °C
Reaction time: 8 h

Procedure:
The mixture of 2.6 g of 9-chloro-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin, 2.0 g. of copper cyanide, 0.1 g of anhydrous copper sulfate and 50 ml of N-methyl pyrrolidone was heated with stirring at 200° C. overnight in a flask equipped with a tube packed with silica gel. After cooling, to the reaction mixture were added 100 ml of conc. aqueous ammonia and 200 ml of water, and the resulting mixture was extracted with benzene. The extract was washed with water, diluted hydrochloric acid and then water, which was dried over potassium sulfate and the solvent was evaporated therefrom. The residue thus obtained was chromatographed on 200 g of silica gel, and eluted with chloroform/methanol (50/1). 0.6 g of the starting material was recovered from a first eluate. Recrystallization of the residue of a second eluate from benzene gave 0.7 g of 9-cyano-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin as pale yellow prismatic crystals having a melting point of 165°-167° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.[Li]CCCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.CO>C1COCC1>[CH3:9][N:8]([CH3:10])[C:5]1[N:6]=[CH:7][C:2]([B:16]([OH:21])[OH:17])=[CH:3][CH:4]=1
Reactant: CN(C)c1ccc(Br)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1ccc(B(O)O)cn1
Temperature: -72 °C
Reaction time: 1 h

Procedure:
A solution of 5-bromo-N,N-dimethylpyridin-2-amine (500 mg, 2.5 mmol) in THF (10 mL) was treated with n-BuLi (1.2 mL, 3 mmol) at −72° C. for 2 hours. Triisopropyl borate (705 mg, 3.75 mmol) was then added dropwise. After the completion of the addition, the mixture was stirred at −72° C. for an additional 1 hour and slowly warmed up and stirred at the ambient temperature overnight. MeOH was carefully added, and the volatiles were removed under reduced pressure to give the title compound. MS (m/z): 167 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:16]([N:10]1[C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14][C:5]=3[C:6]=2[CH2:7][CH2:8][CH2:9]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Clc1ccc2c(c1)CCC1=C2CCCN1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)N1CCCC2=C1CCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.00 g (0.032 mol) of 8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline were dissolved in 50 ml of pyridine and 6.75 g (0.048 mol) of benzoyl chloride were added dropwise thereto at 0°. After stirring at room temperature overnight the mixture was extracted with water and chloroform, dried with magnesium sulphate and the solvent was distilled off in vacuo. Chromatography (silica gel, chloroform-hexane, 1:1) and crystallization (chloroform-hexane) gave 4-benzoyl-8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]-quinoline as white crystals of melting point 194°-196°.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)[NH2:7])(=[O:3])[CH3:2].Cl[C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[NH:17][CH:18]=[N:19]2.Cl.[OH-].[K+]>O>[C:1]([C:4]1[CH:5]=[C:6]([NH:7][C:15]2[N:23]=[CH:22][N:21]=[C:20]3[C:16]=2[NH:17][CH:18]=[N:19]3)[CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(N)cc(C(C)=O)c1
Reactant: Clc1ncnc2nc[nH]c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1cc(Nc2ncnc3nc[nH]c23)cc(C(C)=O)c1
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
Compound No. 16: A suspension of 3,5-diacetylaniline (0.531 g) in water (10 mL) was treated with 6-chloropurine (0.464 g) and concentrated HCl (0.25 mL) and heated at reflux for 30 min. After cooling the mixture was treated with 6 mL of aqueous 1N KOH. The mixture was stirred for 10 min and the solid was filtered out, washed with water, and dried, to give 0.80 g of 6-[(3,5-diacetylphenyl)amino]purine, mp dec 340°-350° C.
Reaction SMILES: CCCCCCC=CCCC.[C:12]1([CH2:18][SH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>CN(C=O)C.CCCCC>[CH2:29]([Sn:24]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:25][CH2:26][CH2:27][CH3:28])[S:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: SCc1ccccc1
Agent: CCCC=CCCCCCC
Solvent: CCCCC
Solvent: CN(C)C=O
Product: CCCC[Sn](CCCC)(CCCC)SCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
]undec-7-ene (DBU) is added dropwise at 20° C., under argon, to a solution of benzenemethanethiol (11.72 ml; 100.0 mmol) in anhydrous DMF (20.0 ml). After 0.5 hour at 20° C., the reaction mixture is cooled to 0° C. and tributyltin chloride is added dropwise. The mixture is allowed to warm to room temperature and stirring is continued for 5 hours. The reaction mixture is taken up in pentane (400 ml), washed with water (3×300 ml) and brine (100 ml), washed with sodium sulphate, filtered and then concentrated under reduced pressure. 39.0 g of tributyl[(phenylmethyl)thio]stannane are obtained in the form of a colourless oil, which is used without further purification in the following step.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[N:8]1.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[F:31][C:17]([F:16])([F:30])[C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=[N:8]3)[CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: ClCCCCCn1nnc2ccccc21
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: FC(F)(F)c1cccc(N2CCN(CCCCCn3nnc4ccccc43)CC2)c1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
1-(5-chloropentyl)-1H-benzotriazole (8.0 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-trifluoro methylphenylpiperazine (6.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 7.7 g compound (I-42) with a yield of 61.5%. ESI-MS [M+H]+: m/z 417.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH3:12][CH:13]([CH3:18])[CH2:14][C:15](=O)[CH3:16]>[Pt].OS(O)(=O)=O.CO>[CH3:16][CH:15]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH2:14][CH:13]([CH3:18])[CH3:12]
Reactant: CC(=O)CC(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [Pt]
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC(C)CC(C)Nc1ccc(F)cc1F
Reaction time: 3 h
Yield: 81.3 %

Procedure:
159.1 g of 2,4-difluoronitrobenzene and 150 g of 4-methylpentan-2-one are mixed in 1.2 1 of methanol with 3 g of concentrated H2SO4 and 5 g of 5% Pt/C, and the mixture is catalytically hydrogenated for 3 hours at 30°-35° under a constant 5 bar of H2. The progress of the hydrogenation is monitored by thin-layer chromatography on silica gel using the mixture petroleum ether/dioxane 4:1 as the mobile phase. When the reaction is complete, the catalyst is filtered off and the solvent is removed by distillation on a rotary evaporator. A brown oil remains which, after removal of some resinous by-product, is rectified in vacuo. The fraction of boiling point 120°-125° at 14 mbar is collected. 173.4 g of N-(1,3-dimethylbutyl)-2,4-difluoroaniline are obtained as a colourless oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH:11]1[S:15][C:14](=[O:16])[NH:13][C:12]1=[O:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27]Br)=[CH:21][CH:20]=1.FC1C=C(C#CCBr)C=C(F)C=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1([CH2:27][C:26]#[C:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[S:15][C:14](=[O:16])[NH:13][C:12]1=[O:17]
Reactant: O=C1NC(=O)C(Sc2nc3ccccc3o2)S1
Reactant: Clc1ccc(C#CCBr)cc1
Agent: Fc1cc(F)cc(C#CCBr)c1
Product: O=C1NC(=O)C(CC#Cc2ccc(Cl)cc2)(Sc2nc3ccccc3o2)S1

Procedure:
Prepared from 5-(benzoxazol-2-ylsulfanyl)-thiazolidine-2,4-dione, (III), Example 89 and [3-(4-chlorophenyl)-prop-2-ynyl]-bromide of formula (IX), Example mp 137°-139° C.; Anal. Calc. for C19H11ClN2O3S2 : C, 55.80; H, 2.67; N, 6.75; Found: C, 54.92; H, 2.76; N, 6.82.