Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([N:9]1[CH2:32][CH:31]([CH2:33][OH:34])[O:30][C:11]2([CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH3:29])[CH:20]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:10]1)C1C=CC=CC=1.[H-].[Na+].I[CH2:38][CH3:39].C([O-])=O.[NH4+]>CN(C=O)C.CCOC(C)=O.CO.[Pd]>[CH2:38]([O:34][CH2:33][CH:31]1[O:30][C:11]2([CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH3:29])[CH:20]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:10][NH:9][CH2:32]1)[CH3:39]
Reactant: CCI
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(CO)O3)ccc1OC(C)C
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOCC1CNCC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 71.1 %

Procedure:
To [8-benzyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone hydrochloride salt (43 mg, 0.09 mmol) in DMF (0.5 mL) was added sodium hydride (11 mg, 0.30 mmol) and the reaction mixture was stirred for 20 minutes. Iodoethane (30 μL, 0.38 mmol) was added and the reaction mixture was stirred for 3 hours, then diluted with EtOAc, filtered, concentrated in vacuo. The residue was purified by silica gel column chromatography using 10-100 EtOAc/hexanes eluent to give the ether intermediate as pale yellow oil. The oil was dissolved in methanol (0.6 mL), and Pd (5 mg, 0.004 mmol) and ammonium formate (27 mg, 0.44 mmol) were added and the reaction mixture was heated at 75° C. for 40 minutes. The reaction mixture was filtered, concentrated in vacuo, diluted with ethyl acetate, washed with 1:1 3M NaOH/sat. aq. NaHCO3, dried over MgSO4, filtered and concentrated in vacuo to give [10-(ethoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (25 mg, 74%) as a pale yellow oil. ESI-MS m/z calc. 390.5. found 391.3 (M+1)+; Retention time: 1.17 minutes (3 min run).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([C:45]2[CH:46]=[C:47]3[C:52](=[C:53]([CH:55]([N:57]([C:59]4[CH:64]=[C:63]([F:65])[CH:62]=[C:61]([F:66])[CH:60]=4)[CH3:58])[CH3:56])[CH:54]=2)[O:51][C:50]([N:67]2[CH2:72][CH2:71][O:70][CH2:69][CH2:68]2)=[CH:49][C:48]3=[O:73])=[O:44])[CH2:39][CH2:38]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[F:66][C:61]1[CH:60]=[C:59]([N:57]([CH3:58])[CH:55]([C:53]2[CH:54]=[C:45]([C:43]([N:40]3[CH2:39][CH2:38][CH:37]([OH:36])[CH2:42][CH2:41]3)=[O:44])[CH:46]=[C:47]3[C:52]=2[O:51][C:50]([N:67]2[CH2:72][CH2:71][O:70][CH2:69][CH2:68]2)=[CH:49][C:48]3=[O:73])[CH3:56])[CH:64]=[C:63]([F:65])[CH:62]=1
Reactant: CC(c1cc(C(=O)N2CCC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC2)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(c1cc(C(=O)N2CCC(O)CC2)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Reaction time: 2 h

Procedure:
Tetrabutylammonium fluoride (1N in THF) (7.83 mL, 7.83 mmol) was added dropwise to a stirred solution of 6-(4-(tert-butyldiphenylsilyloxy)piperidine-1-carbonyl)-8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-2-morpholino-4H-chromen-4-one (3 g, 3.92 mmol, enantiomer 2 in Example 7.0a, [α]D20°: −102°) dissolved in THF (20 mL) at RT under nitrogen and stirred for 2 hrs. The mixture was evaporated to dryness, diluted with DCM, washed with water. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (80 g) eluting with 3 to 7% MeOH in DCM. The solvent was evaporated to dryness to give a foam which was triturated in ether (2-5 mL). The resulting white solid was collected by filtration and dried to give 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-6-(4-hydroxypiperidine-1-carbonyl)-2-morpholino-4H-chromen-4-one enantiomer 2 (1.7 g, 82%) as a white solid. Mass Spectrum: M+H+ 528. [α]D20°: +7° in MeCN.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)[C:12](Cl)=[O:13]>ClC(Cl)C>[C:1]1([CH2:7][C:8]([N:10]=[C:12]=[O:13])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)Cc1ccccc1
Solvent: CC(Cl)Cl
Product: O=C=NC(=O)Cc1ccccc1
Reaction time: 0.08 h

Procedure:
To a suspension of 2-phenylacetamide (68 mg, 0.5 mmol) in dichloroethane (2 mL) was added oxalyl chloride (0.175 mL, 2.0 mmol). The suspension dissolved quickly and a new suspension formed. LC/MS analysis of the reaction mixture after 5 min indicated none of the desired product had formed. The mixture was warmed to 80° C., LC/MS after 30 min indicated a small amount of product. The reaction was heated at 70° C. for 2 days and became mostly clear. LC/MS analysis indicated mostly product. The mixture was shaken and heated at 80° C. for another 4 h. Almost all of the yellow solid on the walls of the reaction vessel had dissolved. The mixture was concentrated in vacuo. The residue dissolved in dichloroethane (1.5 mL), concentrated, and redissolved in dichloroethane (2 mL). The resulting 0.25 M solution was used without further purification.
Reaction SMILES: C1(CO[C:9]([N:11]2[CH2:16][CH2:15][N:14]3[C:17](=[O:22])[O:18][C:19]([CH3:21])([CH3:20])[CH:13]3[CH2:12]2)=[O:10])C=CC=CC=1.[F:23][C:24]1[CH:33]=[CH:32][C:27]([CH2:28][N:29]=C=O)=[CH:26][CH:25]=1>C(O)C.[C].[Pd]>[F:23][C:24]1[CH:33]=[CH:32][C:27]([CH2:28][NH:29][C:9]([N:11]2[CH2:16][CH2:15][N:14]3[C:17](=[O:22])[O:18][C:19]([CH3:20])([CH3:21])[CH:13]3[CH2:12]2)=[O:10])=[CH:26][CH:25]=1
Reactant: CC1(C)OC(=O)N2CCN(C(=O)OCc3ccccc3)CC21
Reactant: O=C=NCc1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OC(=O)N2CCN(C(=O)NCc3ccc(F)cc3)CC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
(Phenylmethyl)tetrahydro-3-oxo-1,1-dimethyl-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate (0.12 g, 0.39 mmol) was dissolved in ethanol (10 mL). 10% Palladium carbon (12 mg) was added thereto, and the mixture was stirred under hydrogen atmosphere at room temperature overnight. The reaction solution was filtered through Celite, the Celite was washed with ethanol, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). 4-Fluorobenzyl isocyanate (0.20 mL, 1.6 mmol) was added thereto, and the mixture was stirred at 50° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:9) to obtain the title compound (0.11 g, yield 86%).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37]S(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:22])([O:14][C:15]4[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=4)[C:4]([OH:23])=[O:3])=[CH:12][CH:11]=3)[N:34]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(C)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Product: Cc1cccc(OC(C)(Cc2ccc(OCCc3nc(C4CCCCC4)oc3C)cc2)C(=O)O)c1

Procedure:
The title compound was prepared from 3-(4-hydroxyphenyl)-2-methyl-2-m-tolyloxy-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester using the procedure of Example 60.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:18](=[O:20])[CH3:19])[CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:21]>C(Cl)Cl.C(OCC)C>[ClH:21].[CH:15]1([N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:18](=[O:20])[CH3:19])[CH2:17][CH2:16]1
Reactant: CC(=O)N(C1CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)N(C1CCNCC1)C1CC1
Temperature: 30 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(acetyl-cyclopropyl-amino)-piperidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.8 mmol) in DCM (9 mL) was added 2 M HCl in diethyl ether (4.5 mL). The reaction mixture was stirred (30° C., 16 h). The mixture was concentrated to an orange solid and used without additional purification. MS (ESI): mass calcd. for C10H18N2O, 182.14; m/z found, 183.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 4.07-3.95 (m, 1H), 3.48-3.40 (m, 2H), 3.11-2.98 (m, 2H), 2.77 (s, 1H), 2.49-2.36 (m, 2H), 2.22 (s, 3H), 1.97-1.89 (m, 2H), 1.00-0.94 (m, 2H), 0.90-0.82 (m, 2H).
Reaction SMILES: [Mg].Br[C:3]1([CH3:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH:3]1([CH2:9][C:11]2[CH2:19][C:18]3[C:13]([CH:12]=2)=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: BrC1=Cc2ccccc2C1
Reactant: CC1(Br)CCCCC1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: C1=C(CC2CCCCC2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of freshly ground magnesium turnings (0.40 g, 16 mmol) in 100 mL of ether was added about 20 percent of a 100 ml ether solution containing 2.5 g (14 mmol) of bromo-methyl-cyclohexane. The reaction was heated to reflux and the remaining bromo-methyl-cyclohexane solution added over one hour. After 1 hour, an additional 150 mg of freshly ground Mg was added and after 5 hours, the mixture was cooled to room temperature. The Grignard solution was added over one hour to a mixture of 2.45 g (13 mmol) of 2-bromo-indene, 100 mg of NiCl2(dppp) (0.15 mmol) and 100 mL of ether. The system was gently heated to reflux overnight and then cooled and quenched by adding 150 mL of 1.0 M aqueous hydrochloric acid. The product was isolated and purified (hexanes/silica) as for 2-benzyl-indene.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:7]=1[CH:18]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][C:26]=1[CH3:35])[CH2:19][CH2:20]C(OC)=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CC(O)=O.Cl>C1(C)C=CC=CC=1>[CH3:35][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:25]=1[CH:18]1[C:7]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9][N:10]([CH3:11])[C:6]=2[CH2:5][C:4](=[O:3])[CH2:20][CH2:19]1)[C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)Cc1c(C(CCC(=O)OC)c2ccc(C(=O)OC)cc2C)c(-c2ccccn2)nn1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(C(=O)O)ccc1C1CCC(=O)Cc2c1c(-c1ccccn1)nn2C
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
A flask fitted with a Dean-Stark apparatus containing dry molecular sieves was charged with a solution of methyl 4-(1-(5-(2-ethoxy-2-oxoethyl)-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-methoxy-4-oxobutyl)-3-methylbenzoate (0.590 g, 1.20 mmol) in toluene (120 mL). The mixture was heated to reflux for about 16 h. The Dean-Stark apparatus was removed and the mixture was cooled to about 0° C. 1 M lithium bis(trimethylsilyl)amide in toluene (1.20 mL, 1.20 mmol) was added in dropwise manner. The mixture was allowed to slowly warm to rt in the cold bath. After about 2 h, 1 M lithium bis(trimethylsilyl)amide in toluene (0.60 mL, 0.60 mmol) was added dropwise. After about 4 h, 1 M lithium bis(trimethylsilyl)amide in toluene (0.30 mL, 0.30 mmol) was added dropwise and the reaction was stirred at rt for about 16 h. The mixture was cooled to about 0° C. then HOAc (10 mL) was added. The mixture was partitioned between EtOAc (100 mL) and brine (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in 1,4-dioxane (4 mL) and 6 N aqueous HCl (8.0 mL, 48.0 mmol). The mixture was heated at about 100° C. for about 16 h then cooled to rt and concentrated in vacuo to remove the dioxane. The mixture was neutralized with saturated NaHCO3 then adjusted to pH 5 with HOAc. The mixture was extracted with EtOAc (2×100 mL). The combined organic solutions were dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, O-5% MeOH/DCM) to give 3-methyl-4-(1-methyl-7-oxo-3-(pyridin-2-yl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)benzoic acid (0.277 g, 58%): LC-MS (Table 1, Method g) Rt=1.66 min, m/z 376 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 12.57 (s, 1H), 8.32-8.25 (m, 1H), 7.72-7.57 (m, 3H), 7.43-7.39 (m, 1H), 7.07-7.03 (m, 1H), 6.68 (d, J=8.0 Hz, 1H), 5.32-5.27 (m, 1H), 4.23 (d, J=15.6 Hz, 1H), 3.97 (d, J=15.6 Hz, 1H), 3.89 (s, 3H), 2.64-2.55 (m, 4H), 2.40-2.27 (m, 2H), 2.18-2.05 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:41])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[CH:13][CH:12]=1.Cl>>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([O:41][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(O)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(F)cc3)CC2)c1
Agent: Cl
Product: COc1ccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(F)cc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using 4-methoxyphenol and N-(3-{1-[6-(4-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.11 (s, 1H), 7.65-6.84 (m, 12H), 5.21-5.10 (m, 1H), 3.66-3.56 (m, br, 2H), 3.02-2.82 (br, 2H), 2.82-2.56 (m, br, 4H), 2.54 (s, 3H), 2.53-2.32 (m, br, 2H), 2.02-1.70 (m, br, 6H), 1.64-1.48 (m, br, 1H), 1.48-1.34 (br, 3H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 547.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:11](=[O:29])[C:12]([N:14]3[CH2:19][CH2:18][C:17](=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:21]#[N:22])[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:10][C:3]=12.C([Sn](CCCC)(CCCC)[C:35]1[S:36][CH:37]=[CH:38][N:39]=1)CCC.O1CCOCC1>CO.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>[O:29]=[C:11]([C:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([C:35]3[S:36][CH:37]=[CH:38][N:39]=3)=[C:3]2[NH:10][CH:9]=1)[C:12]([N:14]1[CH2:19][CH2:18][C:17](=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21]#[N:22])[CH2:16][CH2:15]1)=[O:13]
Reactant: N#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(Cl)ccnc23)CC1)c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: N#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(-c4nccs4)ccnc23)CC1)c1ccccc1
Yield: 16.2 %

Procedure:
A mixture of Example 101 (30 mg, 0.074 mmol), 2-tributylstannanyl thiazole (111 mg, 0.30 mmol), Pd(PPh3)4 (172 mg, 0.149 mmol) and dioxane (1 mL) in a sealed tube was heated at 120° C. for 15 h. The reaction mixture was diluted with MeOH, filtered through Celite and concentrated. The residue was purified by preparative HPLC to yield title compound (5.6 mg, 0.012 mmol, 19%) as an orange solid.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:26][C:27]1[S:28][C:29](CCl)=[CH:30][CH:31]=1.Cl>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:29]1[S:28][C:27]([Cl:26])=[CH:31][CH:30]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Product: Clc1ccc(CSc2c(Cl)ccc3c2CCNCC3)s1

Procedure:
Use a method similar to the Example 387, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2-chloro-5-(chloromethyl)thiophene to give, after hydrochloride formation by the General Procedure 2-2, the title compound as a brown solid. MS (APCI+) m/z: 344 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12](Cl)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5]2.[OH-].[Na+].C([OH:22])C.C(Cl)Cl>Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([OH:22])[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5]2
Reactant: CCO
Reactant: COC(=O)C(Cl)c1ccc2cc(C)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)C(O)c1ccc2cc(C)ccc2c1

Procedure:
a mixture of 25 g. of methyl 6-methyl-2-naphthyl-α-chloroacetate, 10 g. of sodium hydroxide, and 200 ml. of ethanol is refluxed for two hours. The cooled mixture is acidified by the addition of IN hydrochloric acid. The resulting product, methyl 6-methyl-2-naphthyl-α-hydroxyacetate, is isolated by extractions with methylene chloride. The product is oxidized by means of the oxidation procedure described in Example 6 to give methyl 6-methyl-2-naphthyl-α-oxoacetate. The latter product is refluxed with 31 g. of difluoromethylene triphenyl phosphorane (prepared by allowing sodium chlorodifluoroacetate to react with triphenyl phosphine in diethyl ether) in 150 ml. of benzene. The resulting mixture is distilled under vacuum. The distillate is evaporated to yield methyl 2-naphthyl-α,α-difluoromethyleneacetate.
Reaction SMILES: C(C1CC2C(=CC(F)=C(OC)C=2C)C1=O)CCC.C(C(CCC)=O)=C.N12CCCN=C1CCCCC2.[CH2:37]([C:41]1([CH2:55][CH2:56][C:57](=[O:61])[CH2:58][CH2:59][CH3:60])[CH2:49][C:48]2[C:43](=[CH:44][C:45]([F:53])=[C:46]([O:51][CH3:52])[C:47]=2[CH3:50])[C:42]1=O)[CH2:38][CH2:39][CH3:40].Cl>O1CCCC1.C(O)(=O)C>[CH2:37]([C:41]12[CH2:55][CH2:56][C:57](=[O:61])[C:58]([CH2:59][CH3:60])=[C:42]1[C:43]1[C:48](=[C:47]([CH3:50])[C:46]([O:51][CH3:52])=[C:45]([F:53])[CH:44]=1)[CH2:49]2)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCC1(CCC(=O)CCC)Cc2c(cc(F)c(OC)c2C)C1=O
Agent: C=CC(=O)CCC
Agent: CCCCC1Cc2c(cc(F)c(OC)c2C)C1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC12CCC(=O)C(CC)=C1c1cc(F)c(OC)c(C)c1C2
Temperature: 50 °C
Reaction time: 64 h

Procedure:
A solution of 2-butyl-6-fluoro-5-methoxy-4-methyl-1-indanone (118 mg, 0.47 mmol) in anhydrous tetrahydrofuran (0.47 mL) was treated with propyl vinyl ketone (0.065 mL, 0.56 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.0143 mL, 0.094 mmol). The mixture was stirred and heated in an oil bath at 50° C. for 6 hours and then at room temperature for 64 hours. The solvent was evaporated under vacuum to give a residue consisting mainly of 2-butyl-6-fluoro-5-methoxy-4-methyl-2-(3-oxohexyl)-1-indanone. This material was dissolved in acetic acid (2 mL), treated with aqueous 6N HCl (1.5 mL), and stirred while heating in an 80° C. oil bath for 6 hours. After cooling, the mixture was partitioned between EtOAc (25 mL) and saturated aqueous K2CO3 (25 mL). The organic phase was washed with brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum to an oil (138 mg). The crude product was purified by preparative layer chromatography on two 0.1×20×20 cm silica gel GF plates, developing with CH2Cl2. The product bands were eluted with EtOAc and the eluent evaporated under vacuum to afford 9a-butyl-4-ethyl-6-fluoro-7-methoxy-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (93 mg) as an oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:12]=2)=[O:9])=[CH:6][CH:5]=1.[NH:26]1[CH2:30][CH2:29][N:28]=[C:27]1N1C(C)=CC(C)=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:27]3[NH:28][CH2:29][CH2:30][N:26]=3)=[CH:25][CH:24]=2)=[CH:12][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Cc1cc(C)n(C2=NCCN2)n1
Reactant: NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CNC2=NCCN2)cc1

Procedure:
100 mg of the crude HCl salt of 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was reacted with 80 mg of 1-(4,5-dihydro-1H-imidazol-2-yl)-3,5-dimethyl-1H-pyrazole and 110 μL of DIPEA in 1 mL of DMF in the microwave at 150° C. for 5 minutes. The crude product was concentrated to dryness and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4,5-dihydro-1H-imidazol-2-ylamino)methyl)benzamide. MS (Q1) 406 (M)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.Cl.[OH-].[NH4+].[CH:16](O)=O>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:8]=[CH:7][C:6]2[NH:9][CH:16]=[N:10][C:5]=2[CH:4]=1
Reactant: O=CO
Reactant: Nc1ccc(C(F)(F)F)cc1N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: FC(F)(F)c1ccc2[nH]cnc2c1

Procedure:
A mixture of 4-(trifluoromethyl)-1,2-phenylenediamine (3.0 g), formic acid (1.3 mL), and hydrochloric acid (4 M, 17 mL) was heated to reflux for 45 minutes. The mixture was allowed to cool to room temperature and neutralized with concentrated ammonium hydroxide. The aqueous layer was decanted off to give 5-trifluoromethyl-1H-benzimidazole (2.56 g) as a black solid. ESI-MS (m/z) 187 [M+H]+.
Reaction SMILES: COC1C=CC(C(Cl)=O)=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([N:44]=[C:45]=[S:46])=[O:43])=[CH:38][CH:37]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:34][O:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]([N:44]=[C:45]=[S:46])=[O:43])=[CH:40][CH:41]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:45]([NH:44][C:42](=[O:43])[C:39]2[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=2)=[S:46])=[CH:29][CH:28]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: COc1ccc(C(=O)Cl)cc1
Agent: COc1ccc(C(=O)N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
4-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (67 mg, yield 81%).
Reaction SMILES: [C:1]([N:18]=[C:19]=[S:20])(=[O:17])[O:2][CH2:3][CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.[NH2:21][C@:22]1([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[C@H:27]([CH2:28][OH:29])[CH2:26][CH2:25][O:24][CH2:23]1>ClCCl>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[C@@:22]1([NH:21][C:19]([NH:18][C:1](=[O:17])[O:2][CH2:3][CH:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[C:11]3[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=3)=[S:20])[C@H:27]([CH2:28][OH:29])[CH2:26][CH2:25][O:24][CH2:23]1
Reactant: N[C@@]1(c2ccc(F)cc2F)COCC[C@H]1CO
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)COCC[C@H]1CO)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
9H-Fluoren-9-ylmethyl carbonisothiocyanatidate (Fmoc-isothiocyanate) (827 mg, 2.94 mmol) was added to a solution of [(3S,4R)-3-amino-3-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]methanol (C11) (650 mg, 2.67 mmol) in dichloromethane (10 mL), and the reaction mixture was allowed to stir for 4 hours at room temperature. Removal of solvent in vacuo provided a paste, which was purified via silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) to afford the product. Yield: 1.17 g, 2.23 mmol, 84%. LCMS m/z 525.2 (M+1).