Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)[NH2:25].C(=O)([O-])O.[Na+]>C(O)(C)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:39])[F:37])[CH:31]=1
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Cl)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Yield: 85.2 %

Procedure:
A solution of tert-butyl [2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (712 mg) and 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (830 mg) in isopropyl alcohol (7.1 mL) was stirred at 80° C. for 12 hrs. Aqueous sodium hydrogen carbonate was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→ethyl acetate) to give the title compound (1.12 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([NH:29][C@H:30]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]3)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[ClH:44]>C(OCC)(=O)C>[ClH:44].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)=[O:15])[C@H:11]([C:27]([NH:29][C@H:30]3[CH2:34][CH2:33][NH:32][CH2:31]3)=[O:28])[CH2:10]2)=[CH:42][CH:43]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N[C@H]3CCN(C(=O)OC(C)(C)C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N[C@H]3CCNC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1

Procedure:
A mixture of 1.00 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[(3S)-1-(t-butoxycarbonyl)pyrrolidin-3-ylaminocarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in step (i) above] and 10 ml of ethyl acetate was heated to form a solution. 2.5 ml of a 4N solution of hydrogen chloride in ethyl acetate were then added to this solution, and the resulting mixture was heated under reflux for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and then, in order to remove the acid, ethyl acetate was added to the residue and the solvent was again removed by distillation under reduced pressure. The residue was triturated with diethyl ether and washed by decantation to give 630 mg of the title compound, as a powder.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C@@H:6]2[CH2:30][CH2:29][C@@:28]3([CH3:31])[C@@H:8]([CH2:9][CH2:10][C@@H:11]4[C@@H:27]3[CH2:26][CH2:25][C@@:24]3([CH3:32])[C@H:12]4[CH2:13][CH2:14][C@@H:15]3[C@H:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:7]2)[CH2:3]1.C(N(CC)CC)C.[CH2:40]([S:56](Cl)(=[O:58])=[O:57])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>C1C=CC=CC=1>[CH2:40]([S:56]([O:1][CH:2]1[CH2:3][N:4]([C@@H:6]2[CH2:30][CH2:29][C@@:28]3([CH3:31])[C@@H:8]([CH2:9][CH2:10][C@@H:11]4[C@@H:27]3[CH2:26][CH2:25][C@@:24]3([CH3:32])[C@H:12]4[CH2:13][CH2:14][C@@H:15]3[C@H:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:7]2)[CH2:5]1)(=[O:58])=[O:57])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](N5CC(O)C5)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCS(=O)(=O)OC1CN([C@@H]2CC[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]43)C2)C1
Temperature: 25 °C
Reaction time: 480 h

Procedure:
To a stirred suspension of 1.5 g 3α-(3-hydroxy-1-azetidinyl)-5α-cholestane (prepared as described in Example 1 and purified by column chromatography, m.p. 191.5°-195.5° C.) and 0.34 g triethylamine in 33 ml dry benzene, add a solution of 0.78 g 98% hexadecanesulfonyl chloride in 7 ml dry benzene. Stir the resultant cloudy solution at room temperature for 20 days. Concentrate the reaction mixture in vacuo to about one-third the original volume and filter the resultant precipitate. Remove the solvent in vacuo from the filtrate. Dissolve the resultant residue in 80 ml ethyl ether and filter through a column of 45-50 g silica gel eluting with additional ethyl ether as needed to afford the title compound, m.p. 64.5°-68.0° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:15][NH2:16])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=1.[N:17]1[CH:22]=[C:21]([C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[CH:20]=[N:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=1)[CH2:15][NH:16][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([C:21]2[CH:20]=[N:19][CH:18]=[N:17][CH:22]=2)=[CH:31][CH:30]=1
Reactant: O=C(O)c1ccc(-c2cncnc2)cc1
Reactant: Cc1cc(-c2ccc(CN)cc2F)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(CNC(=O)c3ccc(-c4cncnc4)cc3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (3-fluoro-4-(2-methylpyridin-4-yl)phenyl)methanamine 15-3 (10.8 mg, 0.05 mmol), 4-(pyrimidin-5-yl)benzoic acid 15-4 (10.0 mg, 0.05 mmol), and HATU (23 mg, 0.06 mmol) were added N,N-diisopropylethylamine (DIEA, 17 μL, 0.1 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and was subjected directly to reverse phase preparative HPLC to yield N-(3-fluoro-4-(2-methylpyridin-4-yl)benzyl)-4-(pyrimidin-5-yl)benzamide 15 as a white powder. MS m/z 399.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.Br[CH:18]=[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[CH3:20].N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:18]=[C:19](/[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])\[CH3:20])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: CC(=CBr)c1ccccc1F
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CCN(C)CC2)c1ccccc1F
Temperature: 85 °C

Procedure:
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-2-fluorobenzene (260 mg, 1.2 mmol), L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CD3OD, TFA salt) δ (ppm): 7.56 (dd, 1H), 7.53 (s, 1H), 7.40 (m, 1H), 7.30 (d, 1H), 7.20 (m, 3H), 6.80 (s, 1H), 3.80 (m, 2H), 3.40 (m, 3H), 3.30 (m, 2H), 3.15 (m, 1H), 3.05 (s, 3H), 1.85 (s, 3H).
Reaction SMILES: [CH:1]([Si:5]([CH:9]([CH2:11][CH3:12])[CH3:10])([CH3:8])OC)([CH2:3][CH3:4])[CH3:2].[ClH:13]>>[CH:1]([Si:5]([CH:9]([CH2:11][CH3:12])[CH3:10])([CH3:8])[Cl:13])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)[Si](C)(OC)C(C)CC
Reactant: Cl
Product: CCC(C)[Si](C)(Cl)C(C)CC
Yield: 81 %

Procedure:
The resulting organic layer containing di-sec-butyl methylmethoxysilane was treated with 35% hydrochloric acid in the same manner as in Example 15(d). The organic layer was separated from the aqueous layer and was subjected to a fractional distillation under a reduced pressure to afford 32 g of di-sec-butylmethylchlorosilane as a fraction boiling at 78° C.-81° C./16 mm Hg (yield; 81%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[C:15]1(=[O:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>CCOCC.Cl>[F:9][C:2]([F:1])([F:8])[C:3]([CH:16]1[CH2:17][CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]1=[O:25])=[O:5]
Reactant: CCOC(=O)C(F)(F)F
Reactant: O=C1CCCc2ccccc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: O=C1c2ccccc2CCC1C(=O)C(F)(F)F
Temperature: 25 °C
Yield: 66.1 %

Procedure:
A 250 mL one necked round bottomed flask equipped with a reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with ethyl trifluoroacetate (28.4 g, 0.2 mol) and 75 mL of ether. To this solution was added 48 mL of 25% sodium methoxide in methanol (0.21 mol). A solution of 1-tetralone (29.2 g, 0.2 mol) in 50 mL of ether was added over about 5 minutes. The reaction mixture was stirred at room temperature for 14 hours and was diluted with 100 mL of 3N HCl. The phases were separated and the organic layer was washed with 3N HCl, and with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was taken up in 70 mL of boiling ethanol/water and cooled to room temperature, whereupon crystals of 2-trifluoroacetyl-1-tetralone formed which were isolated by filtration and air dried to give pure compound (32 g, 81%): mp 48-49° C.; 1H NMR CDCl3 δ 2.8 (m, 2H), 2.9 (m, 2H), 7.2 (d, j=3.0 Hz, 1H), 7.36 (m, 1H), 7.50 (m, 1H), 7.98 (m, 1H); 19F NMR CDCl3 δ -72.0. EI GC-MS M+=242.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[CH3:19][CH:20]([CH3:25])[CH2:21][C:22](Cl)=[O:23]>>[CH3:19][CH:20]([CH3:25])[CH2:21][C:22]([NH:12][C:10]1[S:11][C:7]([C:4]2[N:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[C:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:9]=1)=[O:23]
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Reactant: CC(C)CC(=O)Cl
Product: Cc1nc(-c2sc(NC(=O)CC(C)C)nc2-c2ccccc2)no1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and 3-methyl-butyryl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:12][C:11]2[CH2:13][C@@H:14]([O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C@H:15]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[C:10]=2[CH:9]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:12][C:11]2[CH2:13][C@@H:14]([O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C@H:15]([CH2:16][OH:17])[C:10]=2[CH:9]=1
Reactant: COC(=O)CCCCc1cc2c(o1)C[C@@H](OC1CCCCO1)[C@@H]2CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)CCCCc1cc2c(o1)C[C@@H](OC1CCCCO1)[C@@H]2CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
A solution of 900 mg of the furan derivative produced in Example 12 in 120 ml of absolute tetrahydrofuran is combined with 960 mg of tetrabutylammonium fluoride dissolved in 10 ml of tetrahydrofuran, and the mixture is stirred under argon at room temperature for 1 hour. Thereafter the reaction solution is precipitated into ice water, and the aqueous phase is extracted repeatedly with ether. The organic phases are combined, washed with water and then with semisaturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product is chromatographed over 60 g of silica gel in a hexane/20% acetone-hexane gradient, thus obtaining 648 mg of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[N:19]=[CH:18]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:24][N:20]1[C:21]2[C:17](=[CH:16][C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])=[CH:23][CH:22]=2)[CH:18]=[N:19]1
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Cn1ncc2cc(Br)ccc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3c(cnn3C)c2)C1=O
Yield: 32.8 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.5649 mmol) was reacted with 5-bromo-1-methyl-1H-indazole (142 mg, 0.6794 mmol), 1,4-dioxane (15 mL), copper iodide (10 mg, 0.0526 mmol), trans-L2-diamino cyclohexane (19 mg, 0.1666 mmol) and potassium phosphate (36 mg, 1.698 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 57 mg of the product (32.94% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][N:3]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][N:3]=1
Reactant: CCOC(=O)C=Cc1ccc(Cl)nc1
Solvent: CCO
Product: CCOC(=O)CCc1ccc(Cl)nc1
Yield: 79.9 %

Procedure:
A suspension of 0.84 g (1 eq) or Te powder and 0.6 g (2 eq) of NaEH4 in 32 ml of ethanol was heated under nitrogen until it became a homogeneous purple solution. To the above hot solution was added ethyl β-(2-chloropyridin-5-yl)acrylate (1.38 g, 6.5 mmol) and the mixture was refluxed for 4 h. The crude product was purified by flash chromatography (silica gel; hexane/ethyl acetate, 3:1) to afford 1.11 g (84,6%) of ethyl 3-(2-chloropyridin-5-yl)propionate.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[Na+].[CH:11]1([CH2:14]Cl)[CH2:13][CH2:12]1.[I-].[K+]>O.C(O)(C)C>[CH:11]1([CH2:14][O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: ClCC1CC1
Reactant: Oc1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Oc1ccc(OCC2CC2)cc1

Procedure:
A mixture of 11.0 g of hydroquinone, 80 ml of isopropanol, 4.1 g of sodium hydroxide in 4.5 ml water, 9.9 g of cyclopropylmethyl chloride and 0.5 g of potassium iodide is stirred under reflux for 12 hours. The solvent is evaporated and the residue is extracted with ether. The ether extract is washed successively with water, sodium bicarbonate solution, dilute sodium bisulfite solution, water and sodium chloride solution and dried. The crude product obtained after evaporation of solvent is purified by preparative chromatography on silica gel, using first toluene and then toluene-ethyl acetate (90:5 to 85:15) as eluent to yield p-(cyclopropylmethoxy)-phenol, m.p. 49°-52°.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]([CH2:22][CH3:23])[CH:20]=O)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:9][C:10]1[C:11](=[O:12])[C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:19]([CH2:22][CH3:23])[CH:20]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C=O)c1ccccc1C(=O)COC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cc(OC(=O)c2ccccc2)c(=O)c2ccccc21
Reaction time: 15 h

Procedure:
A mixture of 2-[2-(N-ethylformamido)phenyl]-2- C oxoethyl benzoate (21.2 g), potassium carbonate (11.82 g) and dry dimethylformamide (330 ml) was stirred at 60° for 15 hours. The reaction mixture was filtered and the residue washed with dimethylformamide (150 ml). The combined filtrate and washings were evaporated under reduced pressure at 60° and the residue triturated with water (200 ml) and then with acetone (2×30 ml) to give the novel compound 1-ethyl-4-oxo-1,4-dihydroquinol-3-yl benzoate, m.p. 190°-192°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:9]=1)[CH2:5][OH:6].CCN(C(C)C)C(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[S:25]([O:6][CH2:5][C:4]1[CH:7]=[C:8]([O:10][C:11]([F:12])([F:13])[F:14])[CH:9]=[C:2]([Cl:1])[CH:3]=1)(=[O:27])(=[O:26])[CH3:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc(Cl)cc(OC(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(Cl)cc(OC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
To a solution of 3-chloro-5-trifluoromethoxybenzyl alcohol (6.1 g, 26.9 mmol; see Example 6(v) above) in CH2Cl2 (250 mL) at 0° C. under a nitrogen atmosphere was added DIPEA (4.2 g, 32.3 mmol) and methanesulfonyl chloride (3.4 g, 29.6 mmol). The solution was stirred at 0° C. for 1.5 hours and quenched with H2O. The organics were separated and then washed with H2O (1×), 1N HCl (1×), H2O (1×) and aqueous NaHCO3 (1×) and then dried (Na2SO4), filtered and concentrated to afford the sub-title compound (8.2 g, 99%) as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3][CH2:2]1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>>[CH:34]1([C:37]([N:1]2[CH2:2][CH2:3][CH:4]([CH2:7][NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[C:28]6[O:27][CH2:26][O:25][C:24]=6[CH:23]=[CH:22][C:21]=5[O:29][CH2:30][CH:31]5[CH2:32][CH2:33]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:5][CH2:6]2)=[O:38])[CH2:36][CH2:35]1
Reactant: O=C(Cl)C1CC1
Reactant: O=C(NCC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: O=C(NCC1CCN(C(=O)C2CC2)CC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-4-ylmethyl)-amide (example A144) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14](Br)=[C:13](Br)[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1cccc(F)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCOC(=O)c1ncc2c(ccn2Cc2cccc(F)c2)c1O

Procedure:
Prepared in analogy to that of Example 6(a) from 2,3-dibromo-1-(3-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, ammonium formate and Pd/C. The title compound, ESI MS (m/z): 315 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH:25]4[CH2:27][CH2:26]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:28]([N:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36])(=[O:30])[CH3:29]>>[C:28]([N:31]1[CH2:35][CH2:34][N:33]([C:2]2[CH:3]=[CH:4][C:5]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[C:23]([CH3:24])=[CH:22][C:21]([CH:25]5[CH2:27][CH2:26]5)=[CH:20][N:19]=4)[CH2:14][CH2:13]3)=[O:11])=[C:6]([CH:9]=2)[C:7]#[N:8])[C:32]1=[O:36])(=[O:30])[CH3:29]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2C#N)CC1
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C)CC3)c(C#N)c2)C1=O
Yield: 41.9 %

Procedure:
Using 5-bromo-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (1.06 g) described in Preparation Example 189 and 1-acetylimidazolidin-2-one (384 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (494 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1.I[CH2:19][CH2:20][CH3:21]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:17][CH2:19][CH2:20][CH3:21])[C:6]([CH3:15])([CH3:16])[CH2:7][CH:8]=[C:9]2[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)C1=CCC(C)(C)c2cc(O)c(Br)cc21
Reactant: CCCI
Product: CCCOc1cc2c(cc1Br)C(C(C)C)=CCC2(C)C
Yield: 70 %

Procedure:
Following General Procedure O, 3-bromo-5-isopropyl-8,8-dimethyl-7,8-dihydronaphthalen-2-ol (Compound 97, 0.36 g, 1.2 mmol) was reacted with 1-iodopropane to afford 0.29 g (70%) of the title compound as a clear oil.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[C:9]([CH2:15][N+:16]([O-:18])=[O:17])=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1.Cl[CH2:20][NH:21][C:22](=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30].Cl>CN(C)C=O>[Cl:7][C:8]1[C:9]([CH:15]([N+:16]([O-:18])=[O:17])[CH2:20][NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:30])([F:32])[F:31])=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1
Reactant: O=C(NCCl)c1ccccc1C(F)(F)F
Reactant: O=[N+]([O-])Cc1ncc(Cl)cc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCC(c1ncc(Cl)cc1Cl)[N+](=O)[O-])c1ccccc1C(F)(F)F
Temperature: 0 °C
Yield: 70.3 %

Procedure:
To 6.57 g of potassium tert-butoxide in 100 ml of N,N-dimethylformamide, 10.10 g of 3,5-dichloro-2-(nitromethyl)pyridine was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at the same temperature for another 30 minutes. Then, to the reaction mixture, 11.59 g of N-chloromethyl-2-(trifluoromethyl)benzamide in 50 ml of N,N-dimethylformamide was added dropwise with stirring under cooing with ice, and after the addition, the mixture was stirred at room temperature for another 2 hours. After completion of the reaction, the reaction mixture was carefully poured into 100 ml of ice-water, acidified with 10% aqueous hydrochloric acid and extracted with ethyl acetate (100 ml×2). The resulting organic layers were combined, washed with water (100 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 14.00 g of the desired product as a pale yellow resinous substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:44]([O:48][CH2:49][CH:50](O)[CH3:51])([CH3:47])([CH3:46])[CH3:45]>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:50]([CH3:51])[CH2:49][O:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[C:6]([Cl:11])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: CC(O)COC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(C)COC(C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.5 g of 3-chloro-4-hydroxybenzoic acid methyl ester in 20 ml of THF, 1.8 ml of 1-tert-butoxy-2-propanol, 3.16 g of triphenylphosphine, and 1.9 ml of diethylazodicarboxylate were added, and the mixture was stirred, at room temperature for 1 hour. After evaporation of the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent: hexane-EtOAc=100:1˜5:1) to obtain 2.3 g of 4-(1-tert-butoxy-2-propoxy)-3-chlorobenzoic acid methyl ester.