Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][OH:14])[CH:11]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OCCc1cc(CCO)cs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCc1cc(CCOS(C)(=O)=O)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 2-(4-(2-hydroxyethyl)thiophen-2-yl)ethyl acetate [Aromatic Intermediate 21, step b] (0.6 g) and triethylamine (0.47 mL) in DCM (30 mL) at 0° C. was treated dropwise over 20 minutes with a solution of methanesulphonyl chloride (0.24 mL) in DCM (3 mL). The mixture was stirred at 20° C. for 1 hour and then washed with water. The organic layer was dried, filtered and the solvent evaporated under reduced pressure to afford the titled compound. Yield 0.80 g.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[N:10]1([C:16](=[O:19])[CH2:17][CH3:18])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C=O)C>[C:16]([N:10]1[CH2:15][CH2:14][N:13]([C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:11]1)(=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)N1CCNCC1
Reactant: O=Cc1cccc(Br)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)N1CCN(c2cccc(C=O)n2)CC1
Temperature: 120 °C
Yield: 30.8 %

Procedure:
To a high-pressure tube was added 6-bromopicolinaldehyde (1, 2.00 g, 10.7 mmol), 1-(piperazin-1-yl)propan-1-one (18, 3.82 g, 26.9 mmol), potassium carbonate (6.69 g, 48.4 mmol) and anhydrous DMF (12 mL). The tube was sealed and the reaction mixture was heated at 120° C. for 17 h. The reaction suspension was poured into water (100 mL) and the mixture was brought to pH 7 using 2 N aq. HCl (20 mL). The solution was extracted with CH2Cl2 (3×100 mL), washed with brine (300 mL), dried over Na2SO4, filtered and concentrated to a brown oil. The product was purified by silica gel chromatography eluting with 0-5% CH3OH in CH2Cl2 to afford the title compound (0.815 g, 31%) as an orange solid: 1H NMR (500 MHz, CDCl3) δ 9.89 (s, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 3.84-3.73 (m, 2H), 3.68-3.59 (m, 2H), 2.40 (q, J=7.5 Hz, 2H), 1.19 (t, J=7.5 Hz, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[CH:5]=[CH:4][CH:3]=1.[CH2:11]([N:15]1[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=[N:16]1)[CH2:12][C:13]#[CH:14]>>[N:16]1[N:15]([CH2:11][CH2:12][C:13]#[C:14][C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[CH:5]=[CH:4][CH:3]=2)[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=12
Reactant: CCNc1cccc(Br)n1
Reactant: C#CCCn1nc2ccccc2n1
Product: CCNc1cccc(C#CCCn2nc3ccccc3n2)n1
Yield: 24 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from (6-bromo-pyridin-2-yl)-ethyl-amine (100 mg, 0.50 mmol) and 2-but-3-ynyl-2H-benzo[d][1,2,3]triazole (0.13 g, 0.75 mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 35 mg (0.12 mmol, 24%) of 6-(4-(2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)-N-ethylpyridin-2-amine as a brown solid (M.P.=73-78° C.).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:21]=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:24][CH2:23]1>C1COCC1>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:22]2([OH:21])[CH2:23][CH2:24][N:25]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH2:26][CH2:27]2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
n-Butyllithium (1.6M in hexane, 42.9 ml, 107.18 mmol) was added dropwise to 1-(benzyloxy)-4-bromobenzene (28.2 g, 107.18 mmol, CAS 6793-92-6) in THF (367 ml) at −78° C. over a period of 15 minutes under nitrogen. The resulting solution was stirred at −78° C. for 1 hour then benzyl 4-oxopiperidine-1-carboxylate (20 g, 85.74 mmol) in THF (122 ml) was added dropwise. The resulting mixture was stirred at −78° C. for 10 minutes, then allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was evaporated to dryness and quenched with saturated ammonium chloride (50 mL), then then extracted with EtOAc (500 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 1 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford crude product. The crude product was further purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to afford benzyl 4-[4-(benzyloxy)phenyl]-4-hydroxypiperidine-1-carboxylate (13.49 g, 30.1%) as a gum.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.Cl[CH2:21][C:22]1[N:23]([CH2:35][CH2:36][CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:24]2[C:33]3[N:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:34]=1>CN(C=O)C.O>[O:7]=[C:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:12])[N:2]1[O:1][CH2:21][C:22]1[N:23]([CH2:35][CH2:36][CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:43])([CH3:42])[CH3:44])[C:24]2[C:33]3[N:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:34]=1
Reactant: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2cnc3cccnc3c21
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCn1c(CON2C(=O)c3ccccc3C2=O)nc2cnc3cccnc3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
N-Hydroxyphthalimide (2.06 g, 12.7 mmol) and triethylamine (2.40 mL, 17.3 mmol) were added to a solution of tert-butyl 3-[2-(chloromethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]propylcarbamate (prepared as described in Parts A-D of Example 92, 11.5 mmol) in DMF (60 mL). The reaction was allowed to stir overnight at room temperature. The resulting orange suspension was diluted with water (40 mL) and the solid was isolated by filtration, washed with water (2×30 mL), and dried in a vacuum oven at 70° C. to afford 4.86 g of tert-butyl 3-(2-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)propylcarbamate as a white solid. The material was used without further purification in the next step.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OC)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[C:20](O)(=[O:22])C>COCCCOCCCO>[CH3:20][O:22][C:4]1[CH:3]=[C:2]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: C1CNCCN1
Reactant: CC(=O)O
Reactant: COc1ccc2nccc(Cl)c2c1
Agent: COCCCOCCCO
Product: COc1cc(N2CCNCC2)c2ccccc2n1
Yield: 66 %

Procedure:
A mixture of 4-chloro-6-methoxyquinoline (0.97 g, 5 mmol), piperazine (4.3 g, 50 mmol) and glacial acetic acid (0.3 ml) was heated under reflux with stirring in dipropyleneglycolmonomethylether for 48 hours. The mixture was filtered, the filtrate was evaporated to dryness under reduced pressure and the raw product was purified by column chromatography on a silica column using ethyl acetate and methanol with the addition of 0.1% NH3 to yield 0.85 g of a brown solid (3.3 mmol, 66%). MS (ES) m/z=243.8 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](OCC1C2C=CC=CC=2C2C1=CC=CC=2)=[O:13])[CH:2]([CH3:4])[CH3:3].[C:44]([NH:47][C:48]1[CH:53]=[CH:52][C:51]([S:54]([NH:57][C@H:58](C(O)=O)[CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)(=[O:56])=[O:55])=[CH:50][CH:49]=1)(=[O:46])[CH3:45]>>[CH3:3][CH:2]([CH2:1][N:5]([S:32]([C:35]1[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=1)(=[O:33])=[O:34])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@@H:58]([NH:57][S:54]([C:51]1[CH:50]=[CH:49][C:48]([NH:47][C:44]([CH3:45])=[O:46])=[CH:53][CH:52]=1)(=[O:56])=[O:55])[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)=[O:13])[CH3:4]
Reactant: CC(C)CN([C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
The title compound was prepared from solid phase bound Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine (step A) as described in general procedure Bb using Nα-(4-acetamidobenzenesulfonyl)-L-phenylalanine (400 mg, 1.2 mmol) which was prepared in step A of example 3. The final product was purified by preparative HPLC to yield 55 mg (60%) of the desired material.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][NH:12][CH3:13].CN[C:16](C1N(C)C2C(C=1)=CC=CC=2)=[O:17]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:17][CH3:16])[CH:9]=2)[CH:4]=[C:3]1[CH2:11][NH:12][CH3:13]
Reactant: CNCc1cc2ccccc2n1C
Reactant: CNC(=O)c1cc2ccccc2n1C
Product: CNCc1cc2ccc(OC)cc2n1C
Yield: 76 %

Procedure:
According to the procedure of Preparation 1 (c), except substituting N,1-dimethyl-6-methoxy-1H-indole-2-carboxamide for N,1-dimethyl-1H-indole-2-carboxamide, the title compound (76%) was prepared as a light gray solid: MS (ES) m/e 205.2 (M+H)+, 409.4 (2M+H)+.
Reaction SMILES: CN(C)[CH:3]=[O:4].[OH:6][C:7]1[CH:29]=[CH:28][C:10]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[C:30](=O)([O-])[O-].[K+].[K+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:4][CH2:3][CH2:30][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)[CH2:17][CH2:18]2)=[CH:28][CH:29]=1
Reactant: Oc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: OCCOc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Temperature: 80 °C
Reaction time: 28 h
Yield: 69 %

Procedure:
N,N-Dimethylformamide (2.5 ml) was added to 1-[1-(4-hydroxyphenethyl)piperidin-4-yl]indoline (0.1 g), potassium carbonate (0.081 g) and 1-bromo-2-di(t-butyl)dimethylsilyloxyethane (0.20 g) and the resultant mixture was heated and stirred at 80° C. for 28 hr. After allowing to cool, it was extracted with ethyl acetate (200 ml), washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give a colorless oil. Then this product was dissolved in tetrahydrofuran (1.3 ml) anda 2.0 Msolution (0.88 ml) of tetrabutylammonium fluoride in tetrahydrofuran was added thereto followed by stirring the mixture at room temperature for 1 hr. The resultant mixture was extracted with ethyl acetate (200 ml), washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (0.124 g) as a colorless oil (yield: 69.0%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[CH3:25][S:26]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](O)=[O:33])(=[O:28])=[O:27]>>[ClH:16].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=2[NH:29][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:11][C:12]=1[F:17]
Reactant: CS(=O)(=O)Nc1ccccc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Product: CS(=O)(=O)Nc1ccccc1C(=O)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1
Product: Cl

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and 2-[(methylsulfonyl)amino]benzoic acid, and by a method similar to that of Example 39, the title compound was obtained.
Reaction SMILES: N#N.[CH3:3][O:4][C:5](=[O:24])[CH2:6][CH2:7][CH2:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21].S(OC)(O[CH3:29])(=O)=O.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:3][O:4][C:5](=[O:24])[CH2:6][CH2:7][CH2:8][C:9](=[O:23])[N:10]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21])[CH3:29]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)CCCC(=O)Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CCCC(=O)N(C)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 22.5 h

Procedure:
To a 100 mL round bottom 3-neck flask equipped with stir bar, thermocouple, and N2 sweep were charged 16.67 g (53.6 mmol) of 4-(2,4-dinitro-phenylcarbamoyl)-butyric acid methyl ester and 50 mL (5 volumes vs. dinitroaniline) of acetonitrile at room temperature. To this clear yellow stirred solution was then added 6.09 mL (8.10 g, 64.2 mmol, 1.2 equiv) of dimethyl sulfate and 14.80 g (107 mmol, 2.0 equiv) of K2CO3. The mixture turned dark reddish orange with the addition and exhibited an exotherm of less than 5° C. The reaction was monitored periodically by HPLC Method A and was complete after 22.5 hours at room temperature.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].Br[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C>[CH2:25]([O:24][C:22]([C:21]1[C:10]2[C:11](=[O:13])[CH2:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][C:9]=2[O:14][CH:20]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)C(=O)CBr
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1coc2c1C(=O)CC(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-phenylcyclohexane-1,3-dione (0.94 g) in ethanol (15 ml) was added sodium ethoxide (0.37 g), and the mixture was stirred, under argon atmosphere, at room temperature for 15 minutes. To the mixture was added ethyl bromopyruvate (0.83 ml), and the mixture was stirred, under argon atmosphere, at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added xylene (15 ml), and the mixture was stirred, under argon atmosphere, at 150° C. for 4 hours. The reaction solution was cooled, and to the mixture was added ice-water. The mixture was extracted with ethyl acetate. The upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate/hexane to give 3-ethoxycarbonyl-6-phenyl-4,5,6,7-tetrahydrobenzofuran-4-one (1.04 g).
Reaction SMILES: Br.[CH3:2][CH:3]([CH3:15])[CH2:4][C@H:5]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:6]([OH:8])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:49][C:50]1[CH:55]=[CH:54][C:53]([CH:56]([C:63]2[CH:68]=[CH:67][C:66]([F:69])=[CH:65][CH:64]=2)[N:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)=[CH:52][CH:51]=1>CN(C=O)C.C(OCC)C>[F:69][C:66]1[CH:65]=[CH:64][C:63]([CH:56]([C:53]2[CH:54]=[CH:55][C:50]([F:49])=[CH:51][CH:52]=2)[N:57]2[CH2:58][CH2:59][N:60]([C:6](=[O:8])[C@@H:5]([N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:4][CH:3]([CH3:2])[CH3:15])[CH2:61][CH2:62]2)=[CH:68][CH:67]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CC(C)C[C@@H](C(=O)O)N1CCCCC1
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.8 %

Procedure:
To a suspension of (S)-4-methyl-2-piperidin-1-yl-pentanoic acid monohydrobromide (0.28 g, 1.0 mmol, Example 22, Step A) and N,N-diisopropylethylamine (0.52 mL, 3.0 mmol) in dry DMF (6 mL) was added solid O-benzotriazol-1-yl -N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.39 g, 0.99 mmol) under nitrogen atmosphere at 0° C. The resulting reaction mixture, which became a clear solution after addition of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate, was stirred at that temperature for 20 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.29 g, 1.0 mmol) was then added. After additional 3 hours stirring while the reaction mixture was allowed to slowly warm up to ambient temperature, reaction mixture was mixed with 100 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×100 mL), brine (2×100 mL), and dried over MgSO4. The solution was concentrated in vacuo affording an amber oil. The crude product was further purified by flash chromatography (20:80:1 EtOAc:hexane:MeOH) to provide 0.37 g (79%) of the pure titled compound as a white foam. APCI-MS m/z 470.3 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1>[N+:8]([C:7]1[CH:6]=[CH:5][C:4]([C:11](=[O:13])[CH3:12])=[CH:3][C:2]=1[O:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:10])=[O:9]
Reactant: Oc1ccccc1
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CC(=O)c1ccc([N+](=O)[O-])c(Oc2ccccc2)c1
Yield: 44 %

Procedure:
A mixture of 3'-chloro-4'-nitroacetophenone (3.0 g), phenol (2.5 g), and potassium carbonate (4.0 g) in xylene (70 ml) was refluxed for 8 hours. The insoluble was filtered off and the filtrate was concentrated under reduced pressure. The oily residue (2.7 g) was subjected to column chromatography on silica gel (70 g) eluting with toluene. The fractions containing the desired compound were combined and concentrated under reduced pressure to give crystals of 4'-nitro-3'-phenoxyacetophenone (1.7 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=O)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][NH:24][CH3:25].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:24]([CH2:23][CH2:22][N:21]([CH3:26])[CH3:20])[CH3:25])[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1cc(C=O)cc(Cl)c1F
Reactant: CNCCN(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)CCN(C)Cc1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1

Procedure:
was prepared according to Scheme C2 (step C) from (3-chloro-2-fluoro-5-formyl-benzyl)-carbamic acid tert-butyl ester (200 mg, 0.59 mmol), N,N,N′-trimethyl-ethylendiamine (71 mg, 0.70 mmol), acetic acid (0.06 mL, 1.0 mmol) and sodium triacetoxyborohydride (368 mg, 1.7 mmol) in THF (8 mL). MS (LC-MS): 374.0 [M]+; tR (HPLC conditions c): 3.53 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].Br[CH2:15][CH2:16][CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+].CCCCCC.CCOC(C)=O>CC#N>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:2]([O:1][CH2:15][CH2:16][CH2:17][OH:18])[CH:3]=1
Reactant: OCCCBr
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC)c(OCCCO)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3-hydroxy-4-methoxybenzoate (4.94 g, 26.6 mmol), 3-bromo-1-propanol (2.86 mL, 31.9 mmol) and anhydrous K2CO3 (5.51 g, 39.9 mmol) in MeCN (50 mL) is refluxed with stirring overnight, and after cooling is poured into ice/water. The aqueous layer is extracted with AcOEt, and the combined organics are washed with brine, dried (Na2SO4) and concentrated. Purification by flash chromatography on silica gel (hexane/AcOEt 1:2) gives a solid residue which is stirred in a 9:1 mixture of hexane/AcOEt over 30 min. Filtration of the suspension and drying in vacuo gives the title compound as white solid. TLC, Rf (hexane/AcOEt 1:1)=0.09. MS: 241.2 [M+H]+. tR (HPLC, Nucleosil C18HD column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 2.86 min. 1H-NMR (CDCl3): δ 2.13 (m, 2H), 2.59 (m, 1H), 3.92 (s, 3H), 3.93 (s, 3H), 4.29 (m, 2H), 6.92 (m, 1H), 7.60 (s, 1H), 7.73 (m, 1H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][C:11]([OH:17])=[CH:12][CH:13]=3)[O:8][CH:7]=2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([C:36]([F:39])([F:38])[F:37])[CH:24]=[C:25]([C:27]2OC=[C:30]([CH2:32][CH2:33][CH2:34]I)[N:31]=2)[CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O.[OH2:50]>>[F:20][C:21]1[CH:26]=[C:25]([C:27]2[O:50][C:32]([CH2:33][CH2:34][O:17][C:11]3[CH:10]=[C:9]4[C:14]([C:15](=[O:16])[C:6]([C:5]5[CH:18]=[CH:19][C:2]([OH:1])=[CH:3][CH:4]=5)=[CH:7][O:8]4)=[CH:13][CH:12]=3)=[CH:30][N:31]=2)[CH:24]=[C:23]([C:36]([F:38])([F:39])[F:37])[CH:22]=1
Reactant: O
Reactant: Fc1cc(-c2nc(CCCI)co2)cc(C(F)(F)F)c1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=c1c(-c2ccc(O)cc2)coc2cc(OCCc3cnc(-c4cc(F)cc(C(F)(F)F)c4)o3)ccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
4′,7-Dihydroxyisoflavone (31.3 mg, 0.123 mmol), 2-[5-fluoro-3-(trifluoromethyl)phenyl]-4-(3-iodopropyl)-1,3-oxazole (48.9 mg, 0.123 mmol, 1.0 equiv.) and cesium carbonate (40.0 mg, 0.123 mmol, 1.0 equiv) were placed in a 25 mL flask. To the flask was added dimethylsulfoxide (3 mL) at room temperature to dissolve the starting materials, and the reaction mixture stirred room temperature for 15 hours. To the mixture were added water (30 mL) and the whole was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (30 mL) and dried with sodium sulfate to give a crude mixture as colorless oil (64.2 mg). The crude mixture was purified by column-chromatography (SiO2=80 g, hexane/EtOAc=2:1 to 1:1) to give 7-(2-{2-[3-fluoro-5-(trifluoromethyl)phenyl](1,3-oxazol-5-yl)}ethoxy)-3-(4-hydroxyphenyl)chromen-4-one (49.1 mg, 0.0934 mmol, 76%) as colorless crystals. Similarly prepared was 7-(3-{2-[3-fluoro-5-(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}propoxy)-3-(4-hydroxyphenyl)chromen-4-one.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:33]=[CH:32][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:31])([F:30])[F:29])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH:60]2[CH2:62][O:61]2)=[CH:54][CH:53]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[F:30][C:28]([F:31])([F:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:62][C@H:60]([OH:61])[CH2:59][O:58][C:55]3[CH:56]=[CH:57][C:52]([OH:51])=[CH:53][CH:54]=3)=[CH:33][CH:32]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3ccccc3C(F)(F)F)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: O=CO
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccccc1C(F)(F)F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 22.4 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-[2-(trifluoromethyl)benzyl]-1-piperidinecarboxamide formate (0.50 g, 1.07 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.433 g, 1.07 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.211 g, 0.24 mmol).