Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:5]=[CH:4][N:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>C1COCC1>[N:8]1([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Sn:24]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23])[CH:7]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: Brc1cc(-n2cccn2)ccn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(-n2cccn2)ccn1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a round-bottomed flask, 2-bromo-4-(1H-pyrazol-1-yl)pyridine (0.15 g, 0.67 mmol) was dissolved in THF (4.4 mL). The light yellow solution was cooled to 0° C. and isopropylmagnesium chloride lithium chloride complex (1.3 M solution in THF, 0.57 mL, 0.74 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 25 min and at room temperature for 1.5 h. Additional isopropylmagnesium chloride lithium chloride complex (1.3 M solution in THF, 0.29 mL, 0.38 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C. and tributyltin chloride (0.21 mL, 0.77 mmol) was slowly added. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NH4Cl solution and then extracted with 50 mL EtOAc (2×). The combined organic layers were washed with ˜5 mL water and ˜5 mL brine then dried over sodium sulfate, filtered and concentrated to provide 4-pyrazol-1-yl-2-tributylstannanyl-pyridine as a light brown oil which was used without further purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[N:17]=[N:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=2)[CH:9]=[N:8]1.C([O-])([O-])=O.[K+].[K+].[C:28](=S)=[S:29]>C(O)C.O>[CH3:1][Si:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:28]([SH:29])=[N:19][N:18]=3)[N:17]=2)[CH:9]=[N:8]1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccc(NN)nn2)cn1
Reactant: S=C=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(-c2ccc3nnc(S)n3n2)cn1
Temperature: 80 °C

Procedure:
To a solution of {6-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-pyridazin-3-yl}-hydrazine (490 mg, 1.6 mmol) in ethanol (6.5 mL) and water (1.8 mL) was added K2CO3 (359 mg, 2.6 mmol), followed by CS2 (0.212 mL, 3.5 mmol). The mixture was stirred and heated at 80° C. for 3 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated to 50% volume in vacuo and acidified to pH 1 with 1 N aqueous HCl. The resulting precipitate was collected, washed with water, and dried in vacuo to provide title compound as a dark red solid (quantitative yield): 1H NMR (DMSO-d6) δ 0.01 (9H, s), 0.90 (2H, t), 3.63 (2H, t), 5.56 (2H, s), 7.82 (1H, d), 8.24 (1H, d), 8.27 (1H, s), 8.80 (1H, s), 15.23 (1H, bs); MS (m/z) 349 [M+H]+.
Reaction SMILES: N.[Na].[CH3:3][C:4]1[C:14]2[CH2:13][CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:21][CH2:22][CH2:23][NH2:24]>O.C1(C)C=CC=CC=1>[CH3:3][C:4]1[C:14]2[CH2:13][CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[C:9]([CH2:21][CH2:22][CH2:23][N:24]=[CH:3][C:4]3[CH:14]=[CH:8][CH:7]=[CH:6][CH:5]=3)([OH:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: NCCCCl
Reactant: Cc1cccc2c1CCc1ccccc1C2=O
Agent: N
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc2c1CCc1ccccc1C2(O)CCCN=Cc1ccccc1
Temperature: 80 °C

Procedure:
To a 250 ml. 3-neck vessel, equipped with a stirrer, a dropping funnel and an ammonia coolant, are added 75 ml. of liquid ammonia, and it is treated by adding a sodium chip to obtain a stable blue color. A solution containing 22.2 g. of 1-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one in 50 ml. of dry toluene is added dropwise with stirring. Thereafter, 4.6 g. of sodium are added piece by piece over a 30-minute period. The mixture is stirred for an additional 30 minutes and a solution containing 11.4 g. of freshly distilled 1-chloro-3-aminopropane in 40 ml. of dry toluene is added. The ammonia coolant is replaced by a water-cooler and the mixture is stirred overnight. The following morning, the mixture is cautiously decomposed with 50 ml. of water, whereby the 1-methyl-10,11-dihydro-5-(3-aminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene partially crystallizes. Its melting point, after recrystallization from benzene/petroleum ether, is 155°-156° C. The crystals are removed by filtration and together with the separated toluene layer are treated with 13 g. of freshly distilled benzaldehyde. The mixture is heated at 80° C. under reduced pressure, so that the toluene and the residual water distil over. After recrystallization of the residue from ethanol, there is obtained 1-methyl-10,11-dihydro-5-(3-benzylideneaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene as colorless crystals having a melting point of 130°-131° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:18])=[CH2:17])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[Br:1][CH2:17][C:16]([C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1)=[CH2:18]
Reactant: C=C(C)c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: C=C(CBr)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 44.3 %

Procedure:
To a solution of N-bromo succinimide (8.6 g, 48.48 mmol) in chloroform (60 mL) was added 1-fluoro-4-isopropenyl-benzene (6 g, 44.11 mmol) at RT. The reaction mixture was stirred at 60° C. for 15 h. The progress of reaction was monitored by TLC. The reaction mixture was cooled to RT and filtered. The residue was rinsed with DCM (50 mL). The combined filtrate was concentrated under reduced pressure to obtain crude product that was purified by column chromatography using silica (100:200) and pure hexane to yield 4.2 g of 1-(1-bromomethyl-vinyl)-4-fluoro-benzene.
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C@H:12]3[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][C@H:13]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[CH2:23](I)[CH3:24]>>[CH2:23]([N:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C@@H:13]4[CH2:14][NH:15][CH2:16][CH2:17][C@@H:12]4[N:10]([C:9]=23)[CH2:11][CH2:2]1)[CH3:24]
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Reactant: CCI
Product: CCN1CCN2c3c(cccc31)[C@@H]1CNCC[C@@H]12

Procedure:
Utilizing the material from Example 255 Step A, the title compound was prepared in analogous fashion using ethyl iodide as the alkyl halide and following the procedure of Step B–D of Example 255, as a light brown amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 1.15 (t, 3H), 1.70–2.01 (m, 3H), 2.65–2.70 (t, J=9.6 Hz, 3H), 2.70–2.95 (m,2H), 2.95–3.13 (m, 2H), 3.13–3.72 (m, 5H), 3.60–3.95 (m, 1H), 6.39 (d, J=8.0 Hz, 1H), 6.47 (d, J=7.4 Hz, 1H), 6.64 (t, J=7.3 Hz), 1H) ppm. MS (CI): 244 (M+H+).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.Cl>C(Cl)Cl>[N:15]1([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([OH:20])=[CH:22][CH:23]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=Cc1ccc(O)cc1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(CN2CCCC2)cc1
Yield: 98.2 %

Procedure:
NaB(OAc)3H (32 g, 0.15 mol) was added in portions for 15 min to a mixture of pyrrolidine (9.1 mL, 0.11 mol) and 4-hydroxybenzaldehyde (12.2 g, 0.1 mol) in CH2Cl2 (100 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon Ar. The mixture was stirred for 20 h and cooled with an ice bath. Concentrated HCl (20 mL) was added. The organic layer was separated and discarded. The aqueous one was alkalized with K2CO3 to pH 9 (40 mL) and extracted with chloroform (3×100 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (17.4 g, 98%) was obtained as white crystals. LCMS-data: (M+H)+ 178.1 and 179.1 (calculated for C11H15NO 177.0). 1H NMR (400Mz)-data (DMSO-d6, J, Hz): 9.19 (br s, 1H, OH); 7.03-7.11 (t, 1H, ArH, J=7.5 Hz); 6.66-6.73 (m, 1H, ArH); 6.34-6.59 (dd, 1H, ArH, J1=1.7 Hz, J2=6.4 Hz); 3.46 (s, 2H, CH2Ar); 2.37-2.43 (m, 4H, CH2CH2CH2CH2); 1.62-1.73 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:26])[NH:18][C:19]2[S:20][CH:21]=[C:22]([S:24][CH3:25])[N:23]=2)=[CH:13][CH:12]=1)(=[O:9])[CH3:8]>O.CO>[C:7]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:26])[NH:18][C:19]2[S:20][CH:21]=[C:22]([S:24]([CH3:25])=[O:1])[N:23]=2)=[CH:15][CH:16]=1)(=[O:9])[CH3:8]
Reactant: CSc1csc(NC(=O)c2ccc(OC(C)=O)cc2)n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)Nc2nc(S(C)=O)cs2)cc1

Procedure:
Using the Oxone® procedure as described in section 1.5.1.7 for the synthesis of compound (I), a solution of Oxone® (3.68 g, 6.00 mmol) is dissolved in a minimum amount of water (30.0 mL) and is added to a cold solution (0° C.) of 512 (0.63 g, 2.0 mmol) dissolved in a minimum amount of methanol (200 mL). Workup and purification by flash chromatography affords 3 as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([N:12]1[CH2:16][CH2:15][CH2:14]C1)[CH2:6][CH2:5]2.C(N)(=[O:20])C=C>C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3[CH2:14][CH2:15][C:16](=[O:20])[NH:12][C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)CCC(N1CCCC1)=C2
Reactant: C=CC(N)=O
Solvent: CCO
Product: O=C1CCC2=C(CCc3cc(Cl)ccc32)N1

Procedure:
701 g (3 mol) of 1-(6-chloro-3,4-dihydro-2-naphthyl)pyrrolidine and 640 g (19 mol) of acrylamide in 7 ml of ethanol were boiled under reflux for 3 days with the addition of 70 g of Amberlite IR200. The separated solid was filtered off. Extractive crystallization with dioxan gave 8-chloro-1,4,5,6-tetrahydrobenzo[f]-quinolin-3(2H)-one of melting point 228°-230° C.
Reaction SMILES: [O:1]=[C:2]1[NH:15][C:5]2=[N:6][CH:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:9]=[C:4]2[CH2:3]1.[C:16]([O:19][CH:20](OCC)OCC)(=O)[CH3:17].C(OCC)C>C(O)(=O)C>[CH2:16]([O:19]/[CH:20]=[C:3]1\[C:2](=[O:1])[NH:15][C:5]2[C:4]\1=[CH:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][N:6]=2)[CH3:17]
Reactant: CCOC(=O)c1cnc2c(c1)CC(=O)N2
Reactant: CCOC(OCC)OC(C)=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCO/C=C1\C(=O)Nc2ncc(C(=O)OCC)cc21
Temperature: 110 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
Ethyl 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.040 g, 0.19 mmol) and diethoxymethyl acetate (0.16 mL, 0.97 mmol) were combined and dissolved in acetic acid (1 mL). The reaction was warmed to 110° C. and stirred at this temperature for 1 h. The reaction was cooled to room temperature, and diethyl ether was added to precipitate the title compound as a beige solid that was collected by filtration (35 mg, 69% yield). 1H NMR 400 MHz (DMSO-d6): δ 11.30 (s, 1H); 8.58 (s, 1H); 8.05 (s, 1H); 7.93 (s, 1H); 4.44 (m, 2H); 4.28 (m, 2H); 1.35 (m, 3H); 1.28 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([C@H:28]2[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]2)[C:13](=[O:27])[NH:14][C:15]2[S:16][C:17]([S:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])=[CH:18][N:19]=2)[CH:5]=[CH:6][C:7]=1OC.OCCC1C=C(F)C=C([Cl:45])C=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[Cl:45][C:6]1[CH:5]=[C:4]([CH2:10][CH2:11][N:12]([C@H:28]2[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]2)[C:13](=[O:27])[NH:14][C:15]2[S:16][C:17]([S:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])=[CH:18][N:19]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: OCCc1cc(F)cc(Cl)c1
Reactant: COc1ccc(CCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1F
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCc2cc(F)cc(Cl)c2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-{2-[3-[2-(3-fluoro-4-methoxy-phenyl)-ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 1-(2-hydroxy-ethyl)-3-chloro-5-fluoro-benzene and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [N:1]([O-])=O.[Na+].[F:5][C:6]1[CH:7]=[C:8]([NH2:13])[C:9]([NH2:12])=[CH:10][CH:11]=1>O.C(O)(=O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]2[NH:12][N:1]=[N:13][C:8]=2[CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(F)cc1N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccc2[nH]nnc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of sodium nitrite (284 mg, 4.12 mmol) in water (1 mL) was added to a solution of 4-fluoro-benzene-1,2-diamine (520 mg, 4.12 mmol) in acetic acid (0.50 mL) and water (2.50 mL) at 0° C. The reaction mixture was stirred for few minutes at 50° C. and 1 hour at 0° C. The precipitate was filtered, washed with cold water and dried to yield 5-fluoro-1H-benzo[d][1,2,3]triazole (565 mg, 3.50 mmol, 85%).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([O:14]CC)=[O:13])[C:8]=2[C:17]([F:20])([F:19])[F:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>CO.O>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[C:8]=2[C:17]([F:19])([F:20])[F:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1noc(-c2ccccc2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 202.2 %

Procedure:
To a solution of ethyl 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylate (3.6 g, 12 6 mmol) in methanol (100 mL) and water (20 mL) at room temperature was added lithium hydroxide, monohydrate (0.583 g, 13.9 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The methanol was removed under reduce pressure, and the residue was diluted with water (˜100 mL). Ethyl ether (200 mL) was added, and the pH of the aqueous layer was adjusted to <1 with a 1N aqueous solution of hydrochloric acid. The mixture was transferred to a separatory funnel, and after agitation, the layers were separated. The organic layer was washed with brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated to afford 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylic acid (3.12 g, 12.13 mmol, 96% yield) as a white, crystalline solid. The compound had an HPLC retention time=2.58 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS:(M+Na)=279.95. 1H NMR (400 MHz, CDCl3) δ ppm 7.53-7.64 (m, 3H), and 7.70 (d, J=7.5 Hz, 2H).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[C:5]=2[N:6]=1.[Br-].[C:24]1([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[O:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:5]=3[N:6]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)CCOc1cccc2c1CCc1sc(S)nc1-2
Reactant: c1ccc(Cc2ccccc2)cc1
Agent: [Br-]
Product: O=C(O)CCOc1cccc2c1CCc1sc(SC(c3ccccc3)c3ccccc3)nc1-2
Yield: 35 %

Procedure:
Using ethyl 3-[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]propionate and diphenylmethane bromide, the procedure of Example 21 was otherwise repeated to synthesize the title compound. Yield 35%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].IC.[C:16]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:5]=[CH:4][C:3]=1[O:13][CH3:16]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(OC(F)(F)F)cc1Br
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(OC(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
A mixture of 608 mg (2.4 mmol) of 2-bromo-4-trifluoromethoxyphenol, 0.35 mL (5.6 mmol) of iodomethane and 775 mg (5.6 mmol) of K2CO3 in 2 mL of DMF was stirred at rt for 2.5 h. The reaction mixture was partitioned between 100 mL of hexanes and 100 mL of H2O and the layers were separated. The organic layer was washed with 2×100 mL of H2O, dried over MgSO4 and concentrated in vacuo. Flash chromatography on 25 g of silica gel using hexanes as the eluant afforded 579 mg (89%) of the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ 3.91 (s, 3H), 6.88 (d, J=9.2, 1H), 7.15-7.18 (m, 1H), 7.45 (app d, J=3.2, 1H).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.[C:33]([CH:38]([CH:40]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[OH:41])[OH:39])([O:35][CH2:36][CH3:37])=[O:34]>CCOCC>[CH:18]1([CH2:17][CH2:16][NH:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:41][CH:40]([CH:38]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[OH:39])[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:14])=[CH:8][CH:7]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(Cl)Cc1ccc(N(CCC2CCCCC2)C(=O)C(F)(F)F)cc1
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)C(O)C(OC(=O)Cc1ccc(NCCC2CCCCC2)cc1)C(=O)OCC

Procedure:
A mixture of 4-[N-trifluoroacetyl-(2-cyclohexylethylamino)]phenylacetyl chloride and 1.2 g. triethylamine in 100 ml. warm ether is treated with 2.5 g. diethyl tartrate and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields diethyl O-[4-(2-cyclohexylethylamino)phenylacetyl]-tartrate as a white, crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:21]([C:22](OC(C)(C)C)=[O:23])[CH2:20][CH:19]([CH2:29][Cl:30])[C:12]2=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:33][N:34]([CH3:49])[CH2:35][CH2:36][O:37][C:38]1[CH:48]=[CH:47][C:41](/[CH:42]=[CH:43]/C(O)=O)=[CH:40][CH:39]=1.CCN=C=NCCCN(C)C>CC(N(C)C)=O.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:21]([C:22](=[O:23])/[CH:43]=[CH:42]/[C:41]3[CH:47]=[CH:48][C:38]([O:37][CH2:36][CH2:35][N:34]([CH3:49])[CH3:33])=[CH:39][CH:40]=3)[CH2:20][CH:19]([CH2:29][Cl:30])[C:12]2=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCOc1ccc(/C=C/C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(OCc1ccccc1)c1ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: CN(C)CCOc1ccc(/C=C/C(=O)N2CC(CCl)c3c2cc(OCc2ccccc2)c2ncccc32)cc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 70.7 %

Procedure:
A suspension of 14 (0.20 g, 0.47 mmol) in cooled (0° C.) dioxane (5 mL) was saturated with HCl, allowed to warm to r.t. over 1 h and evaporated. (E)-4-[2-(Dimethylamino)ethoxy]cinnamic acid hydrochloride (0.13 g, 0.47 mmol) [Atwell et al., J. Med. Chem., 1999, 42, 3400], EDCI (0.27 g, 1.42 mmol) and DMA (3 mL) were added to the remaining yellow solid, and the red mixture was stirred at r.t. for 30 h. The mixture was partitioned between CH2Cl2 and 5% NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (×3). The CH2Cl2 extracts were dried (brine, Na2SO4). Flash chromatography (Alumina, EtOAc/MeOH; 49:1, then 24:1) gave 2-(4-{(1E)-3-[5-(benzyloxy)-1-(chloromethyl)-1,2-dihydro-3H-pyrrolo[3,2-f]quinolin-3-yl]-3-oxo-1-propenyl}phenoxy)-N,N-dimethylethanamine (17c) (0.18 g, 70%) as a yellow solid: mp 172–175° C.; 1H NMR [(CD3)2SO]δ 8.76 (dd, J=4.1, 1.4, 1 H), 8.47 (bs, 1 H), 8.35 (dd, J=8.5, 1.4, 1 H), 7.76 (d, J=8.7, 2 H), 7.67 (d, J=15.3, 1 H), 7.58 (d, J=7.3, 2 H), 7.54 (dd, J=8.5, 4.1, 1 H), 7.44 (t, J=7.2, 2 H), 7.37 (t, J=7.2, 1 H), 7.08 (d, J=15.3, 1 H), 7.02 (d, J=8.7, 2 H), 5.31 (s, 2 H), 4.55 (dd, J=10.7, 9.5, 1 H), 4.44 (dd, J=10.9, 2.5, 1 H), 4.30 (m, 1 H), 4.11 (t, J=5.8, 2 H), 3.99 (dd, J=11.0, 3.0, 1 H), 3.91 (dd, J=11.2, 7.2, 1 H), 2.64 (t, J=5.7, 2 H), 2.23 (s, 6 H); 13C NMR [(CD3)2SO]δ 164.1, 160.1, 154.6, 147.1, 142.6, 142.2, 137.2, 136.7, 131.1, 130.1, 128.3, 127.83, 127 78, 127.3, 125.1, 122.3, 116.9, 115.7, 114.7, 101.6, 70.0, 65.9, 57.5, 52.9, 47.8, 45.4, 40.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[C:16]1(B(O)O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.CCN(CC)CC>C(Cl)Cl>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([O:14][C:18]2[CH:17]=[CH:16][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH:13]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:5]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Oc2ccc3ccccc3c2)cc(C(=O)OC)c1
Yield: 76 %

Procedure:
A solution of 5-hydroxyisophthalic acid dimethylester (208 mg, 1 mmol) and 2 naphthaleneboronic acid (172 mg, 1 mmol), Cu (OAc)2 (61 mg, 0.5 mmol), Et3N (0.16 ml, 1.2 mmol) in 10 ml methylenechloride was refluxed for overnight. The reaction mixture was purified by silica gel column eluted by 15% Teac in hexane to afford the product (76% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.Cl.CO>O>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1C(=Cc2ccc(Cl)cc2)CCc2cc(O)ccc21
Temperature: 25 °C
Yield: 43.9 %

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and 4-chlorobenzaldehyde 1.03 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for 1.5 hours and cooled to room temperature, and water 250 ml was added. The precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 0.77 g.
Reaction SMILES: [OH:1][C:2]([CH3:34])([CH3:33])[CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.OO.C([O-])([O-])=[O:38].[K+].[K+]>CS(C)=O>[OH:1][C:2]([CH3:33])([CH3:34])[CH2:3][C@@:4]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:26]=[CH:25][C:22]([C:23]([NH2:24])=[O:38])=[CH:21][N:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(-c2ccc(C#N)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H](c1ccc(-c2ccc(C(N)=O)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
To a solution of 6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinonitrile (120 mg, 0.26 mmol) in DMSO (8 mL) were added H2O2 (0.5 mL, 30%) and K2CO3 (35 mg, 0.26 mmol), and the mixture was stirred at rt for 3 h. The reaction was quenched with H2O (10 mL) and the mixture was extracted with EtOAc (4×20 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative HPLC to give 6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinamide (55.46 mg, 45%). LC-MS Method 2 tR=1.12 min, m/z=474, 416. 1H NMR (CDCl3): 1.03 (s, 3H), 1.09 (s, 3H), 1.46 (d, 3H), 2.13-2.26 (m, 5H), 2.30 (m, 1H), 2.44 (s, 1H), 2.79 (d, 1H), 5.61 (m, 1H), 6.15-6.38 (s, 1H), 6.97 (d, 2H), 7.13-7.29 (m, 5H), 7.60 (d, 2H), 7.70 (d, 2H), 8.15 (d, 1H), 9.05 (s, 1H).