Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@H:10]([CH2:26][C:27](OC)=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH3:31].CO.[C-]#N.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11](=[O:25])[C@H:10]([CH2:26][C:27]([NH2:31])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Reactant: N
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: NC(=O)C[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A sealed tube was charged with methyl 2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetate (Example 59, Step A) (109 mg, 0.244 mmol), ammonia, 7N solution in methanol (2 ml, 14.00 mmol) and sodium cyanide (1.197 mg, 0.024 mmol). The tube was sealed and heated to 50° C. The pressure reached 35 kilopascals after 1 hour. The reaction was stirred at 50° C. for 18 h. The reaction was cooled to rt and anhydrous ammonia (gas) was bubbled through the solution for ten minutes at room temperature. The reaction mixture was capped and heated to 50° C. for 18 h. The reaction was cooled to rt and anhydrous ammonia (gas) was bubbled through the solution for twenty minutes at room temperature. The reaction mixture was capped and heated to 50° C. for 2 days. The crude reaction was concentrated under reduced pressure and purified by reversed phase preparatory HPLC (column: Gemini-NX C18 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes) to afford the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:13][NH:12][CH2:11]2)[S:6][CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:45]=[C:46]1[NH:55][C:54]2[N:53]=[CH:52][C:51](/[CH:56]=[CH:57]/[C:58](O)=[O:59])=[CH:50][C:49]=2[CH2:48][CH2:47]1>CN(C)C=O>[CH3:2][C:3]1[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:11][N:12]([C:58](=[O:59])[CH:57]=[CH:56][C:51]3[CH:50]=[C:49]4[C:54](=[N:53][CH:52]=3)[NH:55][C:46](=[O:45])[CH2:47][CH2:48]4)[CH2:13]2)[S:6][CH:7]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: Cc1csc(COC2CNC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1csc(COC2CN(C(=O)C=Cc3cnc4c(c3)CCC(=O)N4)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
3-(4-methyl-thiophen-2-ylmethoxy)-azetidine hydrochloride (128.0 mg, 0.6 mmol), EDCI (113.0 mg, 0.6 mmol), HOBt (80.0 mg, 0.6 mmol) and diisopropylethylamine (170 μL, 1.0 mmol) were successively added to a solution of (E)-3-(7-Oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (100.0 mg, 0.4 mmol) in dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred at room temperature overnight and then partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous layer was separated and extracted with ethyl acetate (2×20 ml). The combined organic phases were washed with a saturated solution of sodium chloride (3×20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (99:1 to 95:5) as eluent. The residue was triturated with acetone to give a white solid (40 mg, 27%).
Reaction SMILES: CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Si:44]([O:51][CH2:52][C:53]1([CH2:70][O:71][Si:72]([C:75]([CH3:78])([CH3:77])[CH3:76])([CH3:74])[CH3:73])[CH2:69][C:56]2=[CH:57][C:58]3[C:63]([C:64]([C:65](=[O:67])[CH3:66])=[C:55]2[CH2:54]1)=[CH:62][CH:61]=[CH:60][C:59]=3Cl)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45].CCCCCC.CCOCC.[CH3:90][NH:91][CH3:92]>C1COCC1>[Si:44]([O:51][CH2:52][C:53]1([CH2:70][O:71][Si:72]([C:75]([CH3:78])([CH3:77])[CH3:76])([CH3:74])[CH3:73])[CH2:69][C:56]2=[CH:57][C:58]3[C:63]([C:64]([C:65](=[O:67])[CH3:66])=[C:55]2[CH2:54]1)=[CH:62][CH:61]=[CH:60][C:59]=3[N:91]([CH3:92])[CH3:90])([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]
Reactant: CNC
Reactant: CC(=O)c1c2c(cc3c(Cl)cccc13)CC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)C2
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(=O)c1c2c(cc3c(N(C)C)cccc13)CC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)C2
Yield: 71 %

Procedure:
Follows general procedure (pag. 13): [RuPhos Palladacyle] (0.0013 g, 0.0018 mmol), LHMDS (0.15 mL of a 1.0 M solution in THF, 0.15 mmol), 5c (0.040 g, 0.075 mmol) in THF (0.3 mL), dimethylamine (0.056 mL of a 2.0 M solution in THF, 0.11 mmol). The title compound was isolated (n-hexane/Et2O 8:2, 0.029 g, 71% yield) as a yellow oil.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.ClCCl.N1C=CC=CC=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:51]([CH:52]([OH:64])[C:53]3[CH:58]=[CH:57][C:56]([O:59][C:60]([F:63])([F:62])[F:61])=[CH:55][CH:54]=3)=[C:50]([CH:65]([CH3:67])[CH3:66])[CH:49]=[C:48]3[C:40]=2[C:41](=[O:68])[CH2:42][C:43]2([O:47]3)[CH2:46][CH2:45][CH2:44]2)=[CH:35][CH:34]=1>C(OCC)(=O)C.[OH-].[Na+]>[F:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[C:51]([C:52](=[O:64])[C:53]3[CH:58]=[CH:57][C:56]([O:59][C:60]([F:62])([F:63])[F:61])=[CH:55][CH:54]=3)=[C:50]([CH:65]([CH3:66])[CH3:67])[CH:49]=[C:48]3[C:40]=2[C:41](=[O:68])[CH2:42][C:43]2([O:47]3)[CH2:46][CH2:45][CH2:44]2)=[CH:37][CH:38]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(OC(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(=O)c1ccc(OC(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Temperature: 0 °C
Reaction time: 6 h

Procedure:
68 mg (0.16 mmol) of 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-one are dissolved in 0.6 ml of abs. dichloromethane and cooled to −30° C. 9 μl (0.11 mmol) of pyridine are added, followed by the dropwise addition of 55 mg (0.11 mmol) of 5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethoxy)phenyl]methyl}-7-isopropylspiro-[chromen-2,1′-cyclobutan]-4(3H)-one (Example 58A), dissolved in 0.4 ml of abs. dichloromethane. The mixture is slowly warmed to 0° C. and stirred at this temperature for 6 h. The mixture is diluted with ethyl acetate, 5 ml of 1 N aqueous sodium hydroxide solution are added and the mixture is then extracted twice with ethyl acetate. The combined organic phases are washed once with 1 N hydrochloric acid and twice with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product is dried under high vacuum and then reacted without further purification. This gives 54 mg (98% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH2:23])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH:23][CH2:29][C:28]2[CH:31]=[CH:32][C:33]([Cl:34])=[C:26]([Cl:25])[CH:27]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2NCc2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.7 %

Procedure:
A mixture of tert-butyl[3-(2-amino-5-chlorophenoxy)benzyl]carbamate (3.49 g, 10 mmols), 3,4-dichlorobenzyl chloride (2.1 ml, 15 mmols), potassium carbonate (1.38 g. 10 mmols) and N,N-dimethylformamide (30 ml) was stirred at room temperature for 12 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with brine, then dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography to give an oil of tert-butyl[3-[5-chloro-2-(3,4-dichlorobenzylamino)phenoxy]benzyl]carbamate (3.03 g, 59.8%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([NH:9][C:10]1[C:19]3[C:14](=[CH:15][CH:16]=[C:17](Br)[CH:18]=3)[NH:13][C:12](=[O:21])[C:11]=1[C:22]1[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=1)[CH2:2]2.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>COCCOC>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([NH:9][C:10]1[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:36]4[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=4)[CH:18]=3)[NH:13][C:12](=[O:21])[C:11]=1[C:22]1[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=1)[CH2:2]2
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=c1[nH]c2ccc(Br)cc2c(N[C@@H]2CN3CCC2CC3)c1-c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1ccc(-c2ccc3[nH]c(=O)c(-c4nc5ccccc5[nH]4)c(N[C@@H]4CN5CCC4CC5)c3c2)cc1
Temperature: 90 °C

Procedure:
A vial was charged with the hydrochloride salt of 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-yl)-6-bromoquinolin-2(1H)-one (1.0 equivalent) and 4-methoxyphenyl boronic acid (1.3 equivalents). To this solution was added DME and 2 M aqueous Na2CO3 (10%). The mixture was degassed by bubbling argon through the solution for 5 minutes. Pd(dppf)2Cl2.CH2Cl2 (0.2 equivalents) was then added to the degassed solution. The mixture was heated at 90° C. for 16 hours, and the top organic layer was separated and filtered. The solvent was removed, and the residue was purified by reverse phase HPLC affording the desired product. MS m/z 492.6 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=1
Reactant: Cc1n[nH]c(=O)c(-c2ncc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2ncc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
0.66 g of 5-(4-chlorophenyl)-4-(3,5-dichloro-2-pyridyl)-6-methyl-2H-pyridazin-3-one and 6 g of phosphorus oxychloride were mixed. The mixture was stirred for 2 hours on an oil bath of 110° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.67 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.47 g of 3-chloro-5-(4-chlorophenyl)-4-(3,5-dichloro-2-pyridyl)-6-methylpyridazine (hereinafter, described as compound (11) of the present invention.).
Reaction SMILES: C(OCC1CSC2N(C(=O)C2NC(=O)CC2N=C(C3C=CC=CC=3O)SC=2)C=1C(O)=O)(=O)C.C1(C([O:47][C:48]([C:50]2[N:51]3[CH:54]([S:55][CH2:56][C:57]=2[Cl:58])[CH:53]([NH:59][C:60](=[O:74])[CH2:61][C:62]2[N:63]=[C:64]([C:67]4[C:72]([OH:73])=[CH:71][CH:70]=[CH:69][N:68]=4)[S:65][CH:66]=2)[C:52]3=[O:75])=[O:49])C2C=CC=CC=2)C=CC=CC=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O>C(Cl)CCl>[Cl:58][C:57]1[CH2:56][S:55][CH:54]2[N:51]([C:52](=[O:75])[CH:53]2[NH:59][C:60](=[O:74])[CH2:61][C:62]2[N:63]=[C:64]([C:67]3[C:72]([OH:73])=[CH:71][CH:70]=[CH:69][N:68]=3)[S:65][CH:66]=2)[C:50]=1[C:48]([OH:49])=[O:47]
Reactant: O=C(Cc1csc(-c2ncccc2O)n1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Cl)CSC12
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ccccc4O)n3)C2SC1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1csc(-c2ncccc2O)n1)NC1C(=O)N2C(C(=O)O)=C(Cl)CSC12
Yield: 90.2 %

Procedure:
The procedure used for the preparation of 9a was repeated with 8j (186 mg, 0.301 mmol), Et3SiH (0.480 mL, 3.01 mmol), and trifluoroacetic acid (0.927 mL, 12.0 mmol) in dry ClCH2CH2Cl (6 mL) at 0° C. under nitrogen to give 9j (123 mg, 90%) a s a brownish solid after crystallization from THF/CH2Cl2 /hexane. mp 175° C. (dec); IR (KBr) 3600-2700 (br), 3277, 1780, 1730, 1663 cm-1 ; 1H NMR (DMSO-d6) δ3.63 (1H, d, J=18.0 Hz), 3.78 (2H, s, CH2), 3.98 (1H, d, J=18.0 Hz), 5.15 (1H, d, J=4.8 Hz), 5.69 (1H, dd, J=8.1 and 4.8 Hz), 7.37 (1H, dd, J=8.4 and 4.3 Hz), 7.44 (1H, dd, J=8.4 and 1.1 Hz), 7.58 (1H, s), 8.14 (1H, dd, J=4.3 and 1.1 Hz), 9.23 (1H, d, J=8.1 Hz, NH), 11.62 (1H, s, OH), 13.80 (1H, br s, CO2H); FDMS m/z 453 (M+ +1, 35Cl), 455 (M+ +1, 37Cl); HRMS m/z Calcd for C17H1435ClN4O5S2 (M+ +1): 453.0094, Found: 453.0090.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([N:16]1[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])[CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C(#N)C>[C:9]([N:16]1[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][C:23]2[CH:28]=[C:27]([Br:1])[C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])[CH2:17]1)([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10]
Reactant: COc1ccc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)c(OC)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1cc(OC)c(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1Br
Reaction time: 66 h

Procedure:
N-bromosuccinimide (29 mg, 0.16 mmol) was added to a solution of N-Boc-(R)-2-(2,4-dimethoxy-benzyl)-morpholine (54 mg, 0.16 mmol) in acetonitrile (6.0 mL). The mixture was shaken for 66 h, concentrated and the residue partitioned between ethyl acetate and water. The organic phase was separated, dried and concentrated to give N-Boc-(R)-2-(5-bromo-2,4-dimethoxy-benzyl)-morpholine which was immediately deprotected using hydrogen chloride (4M in dioxane) in methanol affording example 57 as a brown oil (55 mg, 100%).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.C([O:15][C:16](=O)[CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[CH2:25][CH2:24][CH2:23][NH:22][C:21]=2[N:20]=1)C>C1COCC1>[CH3:4][O:3][P:2]([CH2:1][C:16](=[O:15])[CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[CH2:25][CH2:24][CH2:23][NH:22][C:21]=2[N:20]=1)(=[O:7])[O:5][CH3:6]
Reactant: CCOC(=O)CCc1ccc2c(n1)NCCC2
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CCc1ccc2c(n1)NCCC2)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of dimethyl methylphosphonate (1.9 mL, 17.08 mmol) in THF (20 mL) at −78° C. was added nBuLi (10.94 mL, 17.5 mmol). After 30 minutes, 4-9 (1 g , 4.27 mmol) in THF (5 mL) was added. After 1 hour, the reaction was quenched with saturated NH4Cl (10 mL) and warmed to ambient temperature. The mixture was diluted with ethyl acetate, washed with sat. NaHCO3, brine, and dried over MgSO4. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70/25/5 CHCl3/EtOAc/MeOH) to give 4-10 as a yellow oil.
Reaction SMILES: [ClH:1].Cl.OC1([C:10]2(O)[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[O:16]C(F)(F)F)CCCCC1.Cl.Cl.OC1(C([C:48]2[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([O:55][C:56]([F:59])([F:58])[F:57])[CH:49]=2)CN2CCNCC2)CCCCC1>>[ClH:1].[ClH:1].[OH:16][C:11]1([CH:21]([C:48]2[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([O:55][C:56]([F:57])([F:59])[F:58])[CH:49]=2)[CH2:22][N:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]2)[CH2:10][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Oc1ccc(C(CN2CCNCC2)C2(O)CCCCC2)cc1OC(F)(F)F
Reactant: CN1CCN(CCC2(OC(F)(F)F)C=CC=CC2(O)C2(O)CCCCC2)CC1
Agent: Cl
Product: CN1CCN(CC(c2ccc(O)c(OC(F)(F)F)c2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 24, 4-[1-(1-hydroxycyclohexyl)-2-(4-methylpiperazin-1-ylethyl]-2-(trifluoromethoxy)phenol dihydrochloride was prepared from 4-[1-(1-hydroxycyclohexyl)-2-piperazin-1-ylethyl]-2-(trifluoromethoxy)phenol dihydrochloride (see Example 400). MS (ESI) m/z 403; HRMS: calcd for C20H29F3N2O3+H+, 403.22030. found (ESI, [M+H]+), 403.2201.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[CH2:16][NH3+:17].[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([CH:28]=[CH2:29])[CH:20]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:17][CH2:16][C:7]2[C:6]3[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([O:3][CH3:2])[CH:5]=3)[N:10]=[CH:9][CH:8]=2)=[O:24])=[C:21]([CH:28]=[CH2:29])[CH:20]=1
Reactant: COc1cc2nccc(C[NH3+])c2cc1OC
Reactant: C=Cc1cc(Cl)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1cc(Cl)ccc1C(=O)NCc1ccnc2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(6,7-Dimethoxyquinolin-4-yl)methanaminium chloride (0.80 g, 2.8 mmol), 4-chloro-2-vinylbenzoic acid (0.46 g, 2.5 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.58 g, 3.0 mmol) and 1-hydroxybenzotriazole hydrate (0.41 g, 3.0 mmol) were combined in methylene chloride (30 ml), then triethylamine (1.4 ml, 10.0 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified by silica gel chromatography (ethyl acetate) to give 4-chloro-N-((6,7-dimethoxyquinolin-4-yl)methyl)-2-vinylbenzamide. MS (ESI, pos. ion) m/z: 383 (M+1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13]>>[CH2:10]([NH:14][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCN
Reactant: N#Cc1ccccc1F
Product: CCCCNc1ccccc1C#N

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and butylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[C:6]([O:8]C)=[O:7].[C:15]1([CH2:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[C:4]([C:22](=[O:23])[CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)c1cc(OC)cc(OC)c1
Product: COc1cc(OC)c(C(=O)Cc2ccccc2)c(C(=O)O)c1

Procedure:
This compound is synthesized by reacting methyl 3,5-dimethoxybenzoate with phenylacetyl chloride via the Friedel-Crafts reaction, followed by saponification of the ester obtained, according to the method described in 2.1. It is used in crude form in the following reaction.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].Cl>CN(C)C(=O)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:30][CH:31]=1)(=[O:24])=[O:25]
Reactant: COc1ccccc1S(=O)(=O)c1ccc(N)cc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: COc1ccccc1S(=O)(=O)c1ccc(NC(=O)C(C)(O)C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.42 g, 9.0 mmol) in N,N-dimethylacetamide (13 mL) was added thionyl chloride (1.13 g, 9.5 mmol) and the mixture stirred at -15° to -5° C. for 1 hour. 4-(2-Methoxyphenyl)sulfonyl-benzeneamine (1.58 g, 6.0 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into 250 mL of 0.5N HCl. The clear supernatient was decanted from the resulting gum. The gum was crystallized from methylene chloride/hexane to yield the title propanamide which contained about 10 mole % of methylene chloride by NMR analysis. The methylene chloride was not removed by heating at 140° C./0.1 mm for 40 hours. The yield of white solid was 1.70 g (69%), mp 209°-211° C. 1H-NMR (300 MHz, d6-DMSO): 1.55 (s, 3H, CH3) 3.72 (s, 3H, OCH3) 5.73 (s, CH2Cl) 7.11-7.17 (m, 2H, aromatic) 7.53 (s, 1H, OH) 7.60-7.63 (m, 1H, aromatic) 7.80-7.83 (m, 2H, aromatic) 0.92-7.97 (m, 3H, aromatic) 10.36 (s, 1H, NH). MS (CI, CH4): 294 (M+1). Analysis for C17H16F3NO5S.0.1 CH2Cl2 : Calculated: C, 49.87; H, 3.96; N, 3.40. Found: C, 49.71; H, 3.96; N, 3.35.
Reaction SMILES: CC1N=CN(C2C=C(NC(=O)OC(C)(C)C)C=C(C(F)(F)F)C=2)C=1.[CH3:25][C:26]1[N:27]([C:31]2[CH:32]=[C:33]([NH:41]C(=O)OC(C)(C)C)[CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=2)[CH:28]=[CH:29][N:30]=1>>[CH3:25][C:26]1[N:27]([C:31]2[CH:36]=[C:35]([C:37]([F:40])([F:38])[F:39])[CH:34]=[C:33]([NH2:41])[CH:32]=2)[CH:28]=[CH:29][N:30]=1
Reactant: Cc1nccn1-c1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Agent: Cc1cn(-c2cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c2)cn1
Product: Cc1nccn1-c1cc(N)cc(C(F)(F)F)c1

Procedure:
Utilising the procedure described in Example 91d, but employing [3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 92c) in lieu of [3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester, afforded the title compound as a colourless crystalline solid, m.p. 127-131° C.
Reaction SMILES: [C:1]([C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([O:21][CH3:22])=[CH:18]2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C1COCC1>[Pd].ClCCl>[CH2:1]([C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([O:21][CH3:22])=[CH:18]2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc2ccc(OC)cc2c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCCCCCc1ccc2ccc(OC)cc2c1
Yield: 95.7 %

Procedure:
1-Decyne (1.2 g, 6.5 mmol), PdCl2(PPh3)2 (0.12 g, 0.16 mmol), CuI (13 mg, 0.065 mmol), and triethylamine (14 ml, 9.8 mmol) were added to a THF (20 ml) solution of 7-methoxy-2-naphthyltrifluoromethane sulfonate (1.0 g, 3.3 mmol). The solution was mixed at room temperature for 4 hours, and diluted with water (30 ml). The solution was made acidic with diluted hydrochloric acid (2 M), and extracted with dichloromethane (30 ml×3). The extracted solution was washed with water (100 ml×3), and dried with MgSO4. The solution was condensed, and subjected to column chromatography (silica gel, developed with dichloromethane) to obtain 7-decyn-1-yl-2-methoxynaphthalene as a light yellow oil product. The obtained 7-decyn-1-yl-2-methoxynaphthalene (2.8 mmol) and a THF (13 ml) of 10% Pd/C (0.16 g) were placed in a 50 ml round-bottomed flask. Under a hydrogen atmosphere, the solution was stirred until the reaction was completed (approximately 12 hours) while the reaction was tracked using TLC. When the reaction was completed, a catalyst was filtered out, and the filtrate was condensed. The condensed solution was refined by column chromatography (silica gel, developed with dichloromethane) to obtain 7-decyl-2-methoxynaphthalene (compound (3)-12) (0.80 g, 82%).