Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[CH3:14][CH:15](O)[CH:16]=[CH2:17].COC(OC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:14]([CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[CH:15]=[CH:16][CH3:17]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC=CCC1CCc2cc(OC)ccc2C1=O
Reaction time: 50 h
Yield: 57 %

Procedure:
3,4-dihydro-6-methoxy-1(2H)-naphthalenone (198 g) was dissolved in 2000 ml of toluene under argon and treated in succession with 193 ml of 3-buten-2-ol, 206 ml of 2,2-dimethoxypropane and 1.9 g of p-toluenesulphonic acid. The reaction mixture was boiled at reflux for 20 hours, treated with a further 175 ml of 3-buten-2-ol and 180 ml of 2,2-dimethoxypropane and boiled for a further 50 hours. After cooling the solution was washed with 500 ml of saturated sodium hydrogen carbonate solution, the aqueous phase was extracted once with 600 ml of ethyl acetate, the organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 269 g of brown oil, was chromatographed on 3000 g of silica gel with hexane/diethyl ether (5:1) as the eluent. There were obtained 147 g (57%) of 2-(2-butenyl)-3,4-dihydro-6-methoxy-1(2H)-naphthalenone which was processed without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].Cl[C:7]1[NH:11][C:10]2[CH:12]=[C:13]([NH:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:39])([F:38])[F:37])=[O:29])[CH:14]=[C:15]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[CH3:26])=[O:17])[C:9]=2[N:8]=1>>[Cl:25][C:21]1[C:20]([CH3:26])=[C:19]([NH:18][C:16]([C:15]2[C:9]3[N:8]=[C:7]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[NH:11][C:10]=3[CH:12]=[C:13]([NH:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:37])([F:38])[F:39])=[O:29])[CH:14]=2)=[O:17])[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(Cl)nc12
Reactant: COCCN
Product: COCCNc1nc2c(C(=O)Nc3cccc(Cl)c3C)cc(NC(=O)c3ccccc3C(F)(F)F)cc2[nH]1

Procedure:
2-Methoxyethylamine (2 mL) was added to 2-chloro-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (40 mg, Example 135). The mixture was stirred at 150° C. in a sealed pressure-proof stainless steel container for 17 hours. The reaction mixture was washed with brine and concentrated under reduced pressure. The residue was purified on column chromatography to obtain N-(3-chloro-2-methylphenyl)-2-[(2-methoxyethyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (35 mg) as white powder. This was dissolved in MeOH (1 mL), 2N hydrogen chloride/EtOH solution (1 Eq) was added, and it was stirred and concentrated. The residue was triturated in diethyl ether, and the precipitate was collected by filtration and dried to obtain the titled compound (28 mg) as white powder.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8][CH:7]=1)=[O:4].[C:18]([OH:21])(=[O:20])C>[Pt]=O>[F:17][C:2]([F:1])([F:16])[C:3]([NH:5][CH:6]1[CH:15]2[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:9][N:8]([C:18]([O:21][C:10]([CH3:15])([CH3:11])[CH3:9])=[O:20])[CH2:7]1)=[O:4]
Reactant: O=C(Nc1cncc2ccccc12)C(F)(F)F
Reactant: CC(=O)O
Agent: O=[Pt]
Product: CC(C)(C)OC(=O)N1CC2CCCCC2C(NC(=O)C(F)(F)F)C1
Temperature: 2.5 °C
Reaction time: 15 h

Procedure:
A solution of 2,2,2-trifluoro-N-isoquinolin-4-ylacetamide (1.57 g) and platinum oxide (150 mg) in acetic acid (25 ml) was subjected to hydrogenation (5 atm) at 60° C. for 8 hr. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The residue was neutralized with saturated aqueous sodium hydrogen carbonate, and evaporated under reduced pressure. The residue was extracted with THF (30 ml×2), and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. THF (25 ml) and diisopropylethylamine (1 g) were added to the residue, and the mixture was cooled to 0 to 5° C. Di-tert-butyl dicarbonate (1.42 g) was added and the mixture was stirred at room temperature for 15 hr. The solvent was evaporated under reduced pressure, and ethyl acetate (50 ml) was added to the residue. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with hexane-ethyl acetate (9:1-7:3) was concentrated under reduced pressure to give the object compound (1.8 g) as an oil.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:31]=[CH:30][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.[SiH4].C([Si]([O:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH:59]2[CH2:61][O:60]2)=[CH:53][CH:52]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][NH:20][C:18]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:61][C@H:59]([OH:60])[CH2:58][O:57][C:54]4[CH:55]=[CH:56][C:51]([OH:50])=[CH:52][CH:53]=4)=[CH:31][CH:30]=3)[CH2:17][CH2:16]2)=[O:19])=[CH:28][CH:27]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCCc3ccc(F)cc3)CC2)cc1
Agent: [SiH4]
Solvent: O=CO
Product: O=C(NCCc1ccc(F)cc1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 18.8 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(4-fluorophenethyl)-1-piperidinecarboxamide formate (0.875 g, 2.03 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane silane (0.740 g, 1.86 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.275 g, 0.35 mmol).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([CH3:31])[C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:32]([O:36][CH3:37])(=[O:35])[C:33]#[CH:34].O>CC(N(C)C)=O>[CH3:37][O:36][C:32]([C:33]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[C:6]([C:7](=[O:8])[NH:9][C:10]3[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]=3[O:25][CH3:26])[CH:27]=[C:28]([CH3:31])[C:29]=2[CH3:30])[CH:34]=1)=[O:35]
Reactant: C#CC(=O)OC
Reactant: COc1c(NC(=O)c2cc(C)c(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cn(-c2cc(C(=O)Nc3cc(C(C)(C)C)cc(NS(C)(=O)=O)c3OC)cc(C)c2C)nn1
Temperature: 25 °C
Yield: 42.7 %

Procedure:
A mixture of 0.112 g (0.252 mmol) of 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4,5-dimethyl-benzamide and 0.069 mL (0.756 mmol) of methyl propiolate was stirred in 0.5 mL of DMA at 110° C. overnight. The vial was cooled to room temperature, and the contents were poured into stirring water. The precipitate was collected and chromatographed (10–60% EtOAc in hexanes). Fractions containing predominantly the major product were collected and further purified by precipitating from dichloromethane with hexanes to provide 57 mg of a white powder. The filtrate was combined with the mixed fractions from the first chromatography, and the resulting mixture was chromatographed again to provide 22 mg of the title compound as a pale yellow solid for a total yield of 79 mg (0.149 mmol; 59%), mp: 199° C. ESI MS (m/z 528, 100, M−H).
Reaction SMILES: [C:1]([N:5]1[CH2:9][CH2:8][O:7][P:6]1Cl)([CH3:4])([CH3:3])[CH3:2].[OH:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[N:15]([O:20][CH:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]([CH3:30])([CH3:29])[CH2:13]1.C(N(CC)CC)C.CCCCCC>O1CCCC1>[C:1]([N:5]1[CH2:9][CH2:8][O:7][P:6]1[O:11][CH:12]1[CH2:17][C:16]([CH3:18])([CH3:19])[N:15]([O:20][CH:21]([CH3:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:14]([CH3:29])([CH3:30])[CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1CCOP1Cl
Reactant: CC(ON1C(C)(C)CC(O)CC1(C)C)c1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC(ON1C(C)(C)CC(OP2OCCN2C(C)(C)C)CC1(C)C)c1ccccc1
Reaction time: 3 h
Yield: 40.8 %

Procedure:
A solution of 9.8 grams (54 mmol) of 3-tert-butyl-2-chloro-1,3,2-oxazaphospholidine in 40 ml of tetrahydrofuran is added dropwise over 30 minutes to a solution of 15.0 grams (54 mmol) of 4-hydroxy-1-alpha-methylbenzyloxy-2,2,6,6-tetramethylpiperidine, prepared in Example 2A, 6.0 grams (159 mmol) of triethylamine and 80 ml of tetrahydrofuran. The reaction temperature increases from 20° C. to 32° C. during the addition. The reaction mixture is stirred for three hours after the addition is complete. Triethylamine hydrochloride is removed by filtration, and the filtrate is concentrated under reduced pressure to yield an oil. Trituration of the crude product with hexane affords 9.3 grams (41% yield) of the title compound as a white solid melting at 110-113° C.
Reaction SMILES: N(N=[N+]=[N-])[C@H:2](C(N[C@H](C(N=[N+]=[N-])=O)CCCNC(N)=O)=O)C(C)C.N(N=[N+]=[N-])[C@H](C(N[C@H](C(N=[N+]=[N-])=O)CCCCN)=O)CC1C=CC=CC=1.[O:51]=[C:52]1[O:58][C@H:57]([C@H:59]([CH2:61]O)[OH:60])[C:55](O)=[C:53]1O>CN(C=O)C>[CH3:61][CH:59]([OH:60])[CH2:57][O:58][C:52]([C:53]([CH3:55])=[CH2:2])=[O:51]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: CC(C)[C@H](NN=[N+]=[N-])C(=O)N[C@@H](CCCNC(N)=O)C(=O)N=[N+]=[N-]
Agent: [N-]=[N+]=NN[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCCN)C(=O)N=[N+]=[N-]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCC(C)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The copolymer alkyne-P(HPMA-DTX-Gem)-alkyne and N3-Val-Cit-N3 or N3-Phe-Lys-N3 will be dissolved in degassed solution of L-ascorbic acid (0.5×) in DMF. Under nitrogen atmosphere, CuBr (0.5×) solution in DMF will be added. The reaction mixture will be kept stirring for 48 h at room temperature. The polymer will be precipitated into acetone and purified by dialysis against 10 mM EDTA solution, then in water to remove copper salts, and then freeze-dried.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]([Cl:24])[C:15]=1[N+:25]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Sn](Cl)(Cl)(Cl)Cl.N>C(O)C>[NH2:25][C:15]1[C:16]([Cl:24])=[N:17][C:18]2[C:23]([C:14]=1[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: N
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCCNc1c(N)c(Cl)nc2ccccc12
Yield: 25.9 %

Procedure:
0.5 g (1.27 mmol) of 4-[4-(tert-Butoxycarbonylamino)butylamino]-2-chloro-3-nitroquinoline was dissolved in 13 ml of ethanol. 1.0 g (4.43 mmol) of tin chloride [II] dihydrate was added thereto and the mixture was refluxed under heating for one hour. The reaction mixture was poured into 2N aqueous ammonia. The resulting solution was extracted twice with chloroform, washed (brine), and dried (Na2SO4). The solvent was distilled off under reduce pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1 (v/v)) to collect the product. After the solvent was distilled off, the resulting product was triturated with diethyl ether to obtain 0.12 g (0.329 mmol) of 3-amino-4-[4-(tert-butoxycarbonylamino)butylamino]-2-chloroquinoline shown below as orange crystals. ##STR42## Its spectroscopic data are as follows: IR (KBr) cm- : 3270, 1680, 1540, 760. 1H-NMR (CDCl3) δ (ppm) : 1.44 (9H, s), 1.64 (4H, m), 3.17 (2H, q, J=6.0 Hz), 3.27 (2H, t, J=6.6 Hz), 3.89 (1H, H, br), 4.15 (2H, br), 4.59 (1H, br), 7.47 (2H, m), 7.77 (1H, d, J=7.6 Hz), 7.89 (1H, d, J=7.2 Hz).
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@:12]3([O:40][C@@H:13]3[C@@H:14](Cl)[C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[C@@H:17]3[CH2:38][C@@H:18]3[C@@H:19]2[O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)C.CC(C)=O.C(OC(C)C)(C)C>C(O)(=O)C.[Zn]>[C:1]([O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@:12]([OH:40])([CH:13]=[CH:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[C@@H:17]3[CH2:38][C@@H:18]3[C@@H:19]2[O:29][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@H]3[C@@H]([C@H](Cl)[C@H]4O[C@]45C[C@@H](OC(=O)c4ccccc4)CC[C@]35C)[C@@H]1[C@@H]1C[C@@H]1[C@@H]2OC(=O)c1ccccc1
Agent: [Zn]
Solvent: CC(C)OC(C)C
Solvent: CC(C)=O
Solvent: CC(C)O
Product: C[C@]12CC[C@H]3[C@@H](C=C[C@]4(O)C[C@@H](OC(=O)c5ccccc5)CC[C@]34C)[C@@H]1[C@@H]1C[C@@H]1[C@@H]2OC(=O)c1ccccc1
Yield: 69.4 %

Procedure:
Analogously to Example 2, 13.5 g of 3β,17β-dibenzoyloxy-7α-chloro-5,6β-epoxy-15β,16β-methylene-5β-androstane is reacted in 130 ml of acetic acid and 130 ml of propan-2-ol with 49.5 g of zinc dust and worked up. Chromatography on silica gel yields 8.8 g of 3β,17β-dibenzoyloxy-15β,16β-methylene-5β-androst-6-en-5-ol, mp 223°-225° C. (acetone-diisopropyl ether).
Reaction SMILES: C1C2(CC(=O)NC(=O)C2)CCC1.[H][H].[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]#[C:29][CH2:30][N:31]2[C:40](=[O:41])[CH2:39][C:34]3([CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:33][C:32]2=[O:42])[CH2:23][CH2:22]1>O1CCCC1.[Pd]>[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][N:31]2[C:40](=[O:41])[CH2:39][C:34]3([CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:33][C:32]2=[O:42])[CH2:23][CH2:22]1
Reactant: O=C1CC2(CCCC2)CC(=O)N1CC#CCN1CCN(c2ncccn2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C1CC2(CCCC2)CC(=O)N1
Solvent: C1CCOC1
Product: O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2ncccn2)CC1
Reaction time: 0 h
Yield: 98.7 %

Procedure:
A solution of 100 g (0.26 mole) of 8-[4-[4-pyrimidine-2-yl)-piperazine-1-yl]-but-2-inyl]-8-aza-spiro[4.5]decane-7,9-dione in 50 ml of tetrahydrofurane is added to a suspension of 1 g of a palladium/carbon catalyst (palladium content about 5% by weight) and 50 ml of tetrahydrofurane under vigorous stirring under the introduction of hydrogen under a pressure of 2 bar at such a rate that the hydrogen uptake of the unsaturated 8-[4-[4-(pyrimidine-2-yl)-piperazine-1-yl]-but-2-inyl]-8-aza-spiro[4.5]decane-7,9-dione added is substantially identical with the calculated hydrogen consumption. This means practically that when the addition of the starting material is stopped, the decrease of the hydrogen pressure in the apparatus ceases within 5-10 seconds. The addition of the starting material takes 1-4 hours, depending on the intensity of stirring. The reaction temperature is adjusted to 15°-30° C. during the complete period of addition. At the end of hydrogenation the catalyst is filtered off. The catalyst can be directly used in the next hydrogenating operations without any further treatment. The filtrate is evaporated, the residue is suspended in isopropanol and filtered. Thus in the form of white crystals 99.7 g of 8-[4-[4-(pyrimidine-2-yl)-piperazine-1-yl]-butyl]-8-aza-spiro[4.5]decane-7,9-dione are obtained, yield 98.7%. Melting point: 105°-106° C. (according to prior art 90°-98° C.). Content (on the base): 99.8-100.1%. According to HPLC analysis the product contains only 0.1% of contaminations.
Reaction SMILES: C(O)(=O)C.C([O:8][C:9]1[C:10]([CH2:19]O)=[CH:11][C:12]2[O:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:18]=1)(=O)C.[C:21]([C:24]1[CH:30]=[CH:29][C:27]([S-:28])=[CH:26][CH:25]=1)(=[O:23])[CH3:22].[K+].[OH-].[Na+].Cl>CN(C)C=O>[OH:8][C:9]1[C:10]([CH2:19][S:28][C:27]2[CH:29]=[CH:30][C:24]([C:21](=[O:23])[CH3:22])=[CH:25][CH:26]=2)=[CH:11][C:12]2[O:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:18]=1
Reactant: CC(=O)c1ccc([S-])cc1
Reactant: CC(=O)Oc1cc2c(cc1CO)OCCC2
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(SCc2cc3c(cc2O)CCCO3)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 14.5 %

Procedure:
To a solution of 6-acetoxy-7-hydroxymethyl-3,4-dihydrobenzopyran acetate (1.00 g, 3.78 mmol) in dry dimethylformamide (5 mL) was added a solution of potassium p-acetylthiophenoxide (720 mg, 3.8 mmol) in dimethylformamide (5 mL). The mixture was heated at 50° C. for 2.25 hours, then poured into ice water (75 mL). Sodium hydroxide (10% aqueous, 20 mL) was added, then mixture allowed to stir for 30 minutes, then acidified with 2N hydrochloric acid and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with 7% NaHCO3, and brine (2x), dried (Na2SO4) and concentrated. The crude product was purified by preparative HPLC (30% ethyl acetate hexane as eluant and recrystallized from ethyl acetate hexane to afford 6-hydroxy-7-(4-acetylphenyl)thiomethyl-3, 4-dihydrobenzopyran as a white solid (172 mg), m.p. 192°-193° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[N:8]=[CH:7][C:6]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[Br:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br>CN(C)C=O>[Br:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[C:11]([C:9]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:4][CH:5]=2)=[O:10])=[CH:12]1
Reactant: BrCc1cccc(Br)c1
Reactant: O=C(c1ccc(C(F)(F)F)nc1)c1c[nH]c2ccccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(C(F)(F)F)nc1)c1cn(Cc2cccc(Br)c2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 71 mg (0.22 mmol) of 3-(6-trifluoromethyl-pyridine-3-carbonyl)-1H-quinolin-4-one, 11 mg (0.27 mmol) of 60% sodium hydride, 67 mg (0.27 mmol) of 3-bromobenzyl bromide and 1 mL of N,N-dimethylformamide. Yield: 85 mg of a white solid: LC-MSD, m/z for C23H14BrF3N2O2 [M+H]+=487.0, 489.0; HPLC retention time: 2.7 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH2:14]([OH:17])[CH:15]=[CH2:16].O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:16][CH2:15][CH2:14][OH:17])=[CH:4][CH:3]=1
Reactant: C=CCO
Reactant: Fc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: OCCCc1ccc(F)cc1
Temperature: 50 °C

Procedure:
To a mixture of 1-fluoro-4-iodobenzene (300 g, 1.35 mol), benzyltriethylammonium chloride (300 g, 1.35 mol), NaHCO3 (283 g, 3.4 mol) and allyl alcohol (138 mL, 2.0 mol) in DMF (300 mL) was added palladium acetate (3.0 g, 13.5 mmol). The mixture was heated at 50° C. for 5 h with stirring. Water (1 L) and Et2O (1 L) were added at rt. After filtration through Celite, the filtrate was extracted with Et2O. The extracts were washed with H2O and brine, then dried and concentrated to yield the product: 1H NMR (CDCl3) δ 9.81 (1H, s), 7.16 (2H, m), 6.97 (2H, m), 2.93 (2H, t, J=7.5 Hz), 2.77 (2H, t, J=7.5 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([C@H:15]1[CH2:20][CH2:19][C@@H:18]([C:21](OC)=[O:22])[CH2:17][CH2:16]1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:26]>>[CH2:8]([N:7]([C@H:15]1[CH2:20][CH2:19][C@@H:18]([C:21](=[O:22])[NH2:26])[CH2:17][CH2:16]1)[C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)[C@H]1CC[C@@H](N(Cc2ccccc2)C(=O)OC(C)(C)C)CC1
Reactant: N
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H]1CC[C@@H](C(N)=O)CC1
Temperature: 100 °C

Procedure:
tert-Butyl-cis-4-(methoxycarbonyl)cyclohexylbenzylcarbamate (0.25 g, 0.72 mmol) was dissolved in methanolic ammonia (15 ml) in a pressure bomb and heated at 100° C. for three days. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford 200 mg of tert-butyl benzyl-cis-4-carbamoylcyclohexylcarbamate as crude compound. The crude compound (LC-MS shows 30% amide) was directly taken for next step.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:12][C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(=S)=S>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:23]1[CH:24]=[CH:25][C:20]([C:13]([CH3:12])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:21][CH:22]=1)=[O:6]
Reactant: CCOC(=O)C(C)(C)c1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To 700 ml of carbon disulfide containing 36.5 g (0.254 mole) of 4-chlorobutyryl chloride is added 74.5 g (0.56 mole) of aluminum chloride with stirring in an ice bath (about -10° C.). Stirring is continued for about 15 minutes at about 25° C. then the mixture is recooled to 5° C. and 48.4 g (0.294 mole) of ethyl α,α-dimethylphenylacetate in 100 ml of carbon disulfide is added. The reaction mixture is stirred on an ice bath for 31/2 hours then stirred for 151/2 hours at 25° C. then poured into HCl-ice water and extracted with chloroform. The extract is washed with dilute sodium carbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate, and evaporated giving as a solid ethyl 4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetate.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8](S(C)(=O)=O)[C:7]1=[O:17])[CH2:4][CH3:5])[CH3:2].Cl.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([CH3:30])[CH:29]=1)[NH:26][CH2:25][CH2:24]2>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([CH3:30])[CH:29]=1)[N:26]([C:8]1[C:7](=[O:17])[N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:11]=[C:10]([CH3:12])[N:9]=1)[CH2:25][CH2:24]2
Reactant: COc1cc(C)c2c(c1)CCN2
Reactant: CCC(CC)n1cc(C)nc(S(C)(=O)=O)c1=O
Agent: Cl
Product: CCC(CC)n1cc(C)nc(N2CCc3cc(OC)cc(C)c32)c1=O

Procedure:
Example 481 was prepared in a similar fashion as described for Example 413 using XXXIII and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 138–140° C.; 1H NMR (300 MHz, CDCl3): δ 6.68 (d, J=2.2 Hz, 1 H), 6.56 (d, J=2.2 Hz, 1 H), 6.44 (s, 1 H), 4.90–4.79 (brs, 1 H), 4.34 (t, J=7.9 Hz, 2 H), 3.78 (s, 3 H), 3.05 (t, J=7.9 Hz, 2 H), 2.11 (s, 3 H), 2.00 (s, 3 H), 1.82–1.71 (m, 2 H), 1.67–1.60 (m, 2 H), 0.87 (t, J=7.4 Hz, 6 H); HRMS (ESI) calcd for C20H28N3O2 (M+H)+: 342.2182; found m/z 342.2196.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20](O)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]([CH3:32])[CH3:31])=[N:28][CH:29]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20]([NH:23][C:24]1[CH:29]=[N:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)ccc(F)c21
Reactant: CC(C)c1ccc(N)cn1
Product: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)ccc(F)c32)cn1
Yield: 88.6 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 11 using 5-benzyloxy-8-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (2.30 g) and 5-amino-2-isopropylpyridine (1.04 g) as starting materials, 5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (2.83 g) was obtained. melting point: 184.0° C.