Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:2]1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:38][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:35])([F:33])[F:34])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCCNC3)cc2)ncc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a suspension of 2-(2-(2-(2-((4-(piperidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (4) (0.021 g, 0.043 mmol) in anhydrous methanol (2 mL) were added a 37% aq. solution of formaldehyde (0.006 g, 0.195 mmol) followed by sodium triacetoxyborohydride (0.046 g, 0.217 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 1 hour, the volatiles were removed in vacuo and the residue was diluted with EtOAc (15 mL) and sat. aq. NaHCO3 (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (15 mL), the combined organic layers were washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (5) (20 mg, 93% yield) as a an off-white solid; 1H NMR (400 MHz, d4-MeOD) δ 8.54 (s, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.30-7.15 (m, 6H), 3.67 (s, 2H), 3.19-3.12 (m, 2H), 3.12-3.02 (m, 2H), 2.96 (d, J=11.1 Hz, 2H), 2.85-2.74 (m, 1H), 2.34 (s, 3H), 2.13-2.03 (m, 2H), 1.96-1.67 (m, 3H), 1.49 (ddd, J=24.8, 12.5, 3.9 Hz, 1H). LCMS Method C: rt 4.86 min; m/z 498.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CN2CCOCC2)cc1

Procedure:
4-Methyoxybenzylchloride (25 g, 0.16 mol), morpholine (14 g, 0.16 mol), and potassium carbonate (22 g, 0.16 mol) were taken up in acetonitrile and Kl (8.7 g, 0.04 mol) added. The reaction mixture was heated at reflux for 18 h, filtered, and the filtrate concentrated and azeotropped with benzene to give 17.5 g (88%) as an oil; IR(film, υ=cm−1) 2956, 2806, 1514, 1246, 1118, 866; 1H NMR (300 MHz, DMSO-d6) δ 2.29 (4H, br. s), 3.35 (2H, s), 3.53 (4H, t, J=4.4 Hz), 3.71 (3H, s), 6.86 (2H, d, J=8.5 Hz), 7.19 (2H, d, J=8.5 Hz); MS(DCl)m/z: 208 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH:13]1[C:17]3[C:18]([O:22][CH3:23])=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH2:14]1)[CH:6]=[CH:5]2.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=1>>[CH3:23][O:22][C:18]1[C:17]2[CH:13]([NH:12][C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([NH:24][C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=5)[CH:3]=4)[N:8]=3)[CH2:14][O:15][C:16]=2[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc2c1C(Nc1ccc3cc(Br)ccc3n1)CO2
Reactant: Cc1cccc(N)n1
Product: COc1cccc2c1C(Nc1ccc3cc(Nc4cccc(C)n4)ccc3n1)CO2

Procedure:
The title compound, yellow foam, MS: m/e=399.2 (M+H+), was prepared in accordance with the general method of example 66 from rac-(6-bromo-quinolin-2-yl)-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-amine (see example 109, step C) and commercially available 2-amino-6-methyl-pyridine.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11](=[O:12])[NH:10][C:9]2[N:8]=[C:7]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)[CH:6]=[CH:5][C:4]=2[C:3]1=[O:19].Cl.[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][N:33]([CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:7]2[N:8]=[C:9]3[C:4]([C:3](=[O:19])[C:2]([CH3:20])([CH3:1])[C:11](=[O:12])[NH:10]3)=[CH:5][CH:6]=2)[CH2:32][CH2:31]1
Reactant: CC1(C)C(=O)Nc2nc(OCCCC=O)ccc2C1=O
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)Nc2nc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 30 %

Procedure:
To a solution of 4-(6,6-dimethyl-5,7-dioxo-5, 6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.520 g, 1.88 mmol) in DCE (6 mL) was added 1-(2,3-dichloro-phenyl)-piperazine hydrochloride (0.503 g, 1.88 mmol) followed by Et3N (0.53 mL, 3.76 mmol). The mixture was stirred for 20 minutes at room temperature and NaBH(OAc)3 (0.56 g, 2.60 mmol) was added. The reaction was stirred for 2.5 h and quenched with saturated NaHCO3 and water. The mixture was extracted with EtOAc and the organic layer was washed with saturated NaHCO3, water and brine, dried over Na2SO4 and concentrated. Purification by liquid chromatography on silica gel (0–5% MeOH/CH2Cl2) gave a white solid (0.277 g, 0.564 mmol, 30%). MS: APCI: M+1: 491.1 (Exact Mass: 490.15).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[CH:9]=O)=[C:4]([N+:19]([O-])=O)[CH:3]=1.[H][H]>O1CCCC1.[Ni]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[O:6][C:7]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=3[CH2:9][NH:19][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: COc1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c(C=O)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CNc1cc(Cl)ccc1O2
Yield: 48.9 %

Procedure:
5.00 g of 2-(4-chloro-2-nitrophenoxy)-5-methoxybenzaldehyde, prepared as described above in Example 1, in 50 mL of tetrahydrofuran (THF) was shaken in a Parr hydrogenator at 5 psi hydrogen with Raney nickel at 25° C. for 5 hours. The catalyst was filtered from the reaction and the solution evaporated in vacuo. The crude product was purified by column chromatography in the manner described by Still et al., "A Rapid Chromatographic Technique for Preparative Separations with Moderate Resolution," J. Org. Chem, 43, 2923 (1978), through silica gel 60 using hexane:ethyl acetate (2:1) to yield 2.08 g (48.9%) of product as a white solid. Melting Point: 111°-113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[Cl:1])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccc(O)c(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C=O)cc1Cl
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 94.9 %

Procedure:
To 3-chloro-4-hydroxybenzaldehyde (5.00 g, 31.9 mmol) and pyridine (5.0 mL, 61.8 mmol) in dichloromethane (40 mL) at 0° C. was added acetic anhydride (4.0 mL, 42.3 mmol) over a 20-minute period. The mixture was stirred for 1.5 hours more, warmed to 20° C., then worked up (10% hydrochloric acid wash) to afford 4-acetoxy-3-chlorobenzaldehyde as a pale-yellow solid (6.01 g, 92% yield): m.p. 33-35° C.; Rf0.30 (20% ethyl acetate/hexane); 1H NMR spectrum (400 MHz, CDCl3) δ 2.39 (s, 3, CH3), 7.34 (d, J=8.0 Hz, 1, ArH), 7.82 (dd, J=7.6,2 Hz, 1, ArH), 7.98 (d, J=1.6 Hz, 1, ArH), 9.96 ppm (s, 1, CHO).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH2:6][CH2:5]2.[CH2:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([S:14]([CH2:12][CH3:13])(=[O:16])=[O:15])[CH2:6][CH2:5]2
Reactant: CCS(=O)(=O)Cl
Reactant: Fc1cc(Br)cc2c1NCC2
Product: CCS(=O)(=O)N1CCc2cc(Br)cc(F)c21
Yield: 60.2 %

Procedure:
This compound was prepared using the general procedure for sulfonylation of indolines and tetrahydroquinolines described in Example 4 using 5-bromo-7-fluoroindoline (0.21 g, 0.97 mmol) and ethanesulfonyl chloride (0.18 mL, 1.9 mmol) to provide 5-bromo-1-(ethylsulfonyl)-7-fluoroindoline (0.18 g). MS (ES) m/z 307.6; HPLC purity 98.4% at 210-370 nm, 9.0 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1.[F:28]C1C=C(OCC2C=CC3C(=CC=CC=3)N=2)C=CC=1C(N(OC)C)=O>>[F:28][C:11]1[CH:12]=[C:13]([O:16][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:14]=[CH:15][C:10]=1[C:8](=[O:9])[CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1F
Product: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1F

Procedure:
Following the procedure for the preparation of 2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone but substituting 2-Fluoro-n-methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide provided the title compound. MS: (M+H m/z=373.0).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([C:15]3[N:16]=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[S:18][CH:19]=3)=[C:10]([CH3:24])[CH:9]=2)=[CH:5][CH:4]=1.[Br:27]Br.O>C(O)(=O)C>[Br:27][C:19]1[S:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[N:16][C:15]=1[C:11]1[C:10]([CH3:24])=[CH:9][C:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:26][CH:25]=2)=[CH:13][C:12]=1[CH3:14]
Reactant: BrBr
Reactant: COc1ccc(Oc2cc(C)c(-c3csc(NC(C)=O)n3)c(C)c2)cc1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Oc2cc(C)c(-c3nc(NC(C)=O)sc3Br)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To a solution of N-{4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-yl}acetamide (2-2, 465 mg, 1.3 mmol) in acetic acid (10.2 mL) was added bromine (0.060 mL, 1.3 mmol) dropwisely. The reaction was stirred at room temperature for 4.0 h. The solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give N-{5-bromo-4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-yl}acetamide (2-3, 547 mg) as white solids, which was used directly for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:20]([NH2:21])=[CH:19][C:5]2[O:6][C:7]([CH3:18])([CH3:17])[C@@H:8]([OH:16])[C@H:9]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:4]=2[CH:3]=1.Cl.[C:23](Cl)([Cl:25])=[O:24]>C1(C)C=CC=CC=1>[ClH:25].[OH:16][C@@H:8]1[C:7]([CH3:17])([CH3:18])[O:6][C:5]2=[CH:19][C:20]3[NH:21][C:23](=[O:24])[NH:1][C:2]=3[CH:3]=[C:4]2[C@H:9]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC1(C)Oc2cc(N)c(N)cc2[C@@H](N2CCCCC2)[C@@H]1O
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: CC1(C)Oc2cc3[nH]c(=O)[nH]c3cc2[C@@H](N2CCCCC2)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 6,7-diamino-3,4-dihydro-2,2-dimethyl-trans-4-piperidino-2H-benzo[b]pyran-3-ol (0.12 g) in 5N-hydrochloric acid (10 ml) was treated with a 12.5% solution of phosgene in toluene (20 ml) and the mixture was stirred at room temperature for 45 minutes. A vigorous stream of nitrogen was then passed through the mixture for 10 minutes, and the solution was evaporated to dryness in vacuo. The residue was recrystallised from ethanol-ether to give the hygroscopic 3,6,7,8-tetrahydro-trans-7-hydroxy-6,6-dimethyl-8-piperidino-pyrano[2,3-f]benzimidazole-2 (1H)-one hydrochloride (1) (0.067 g) mp 177°-180° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2([C:39]([F:42])([F:41])[F:40])[O:28][N:27]=[C:26]([C:29]3[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[C:31]([CH3:38])[CH:30]=3)[CH2:25]2)[CH:20]=[C:21]([Cl:23])[CH:22]=1>ClCCl>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([C:26]3[CH2:25][C:24]([C:19]4[CH:20]=[C:21]([Cl:23])[CH:22]=[C:17]([Cl:16])[CH:18]=4)([C:39]([F:42])([F:41])[F:40])[O:28][N:27]=3)=[CH:30][C:31]=2[CH3:38])=[N:3][CH:4]=1)#[N:9]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Reactant: N#Cc1ccc(N)nc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ccc(C#N)cn1
Reaction time: 1 h
Yield: 71.2 %

Procedure:
In a solution of 0.39 g of 2-amino-5-cyanopyridine and 0.71 g of pyridine in 20 mL of dichloromethane, a solution of 1.31 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 in 20 mL of dichloromethane was added dropwise. After the completion of the addition dropwise, it was continued to stir at the same temperature further for 1 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, precipitated insoluble material was removed through silica gel column, and the solvent was distilled off under reduced pressure. The residual solid was washed with diisopropyl ether to obtain 1.11 g of the aimed product as colorless resinous substance.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:18]2[CH:17]=[C:16]3[C:8]([C:9]4[CH:10]=[C:11]5[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][C:19]([CH3:26])([CH3:25])[C:12]5=[CH:13][C:14]=4[CH2:15]3)=[CH:7][C:6]=2[C:5]([CH3:28])([CH3:27])[CH2:4][CH2:3]1.[Li]CCCC.[CH3:35][C:36]([CH3:42])=[C:37]1[CH:41]=[CH:40][CH:39]=[CH:38]1>C1COCC1>[CH:37]1([C:36]([CH:20]2[CH2:21][C:22]([CH3:24])([CH3:23])[C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][C:12]=3[C:19]2([CH3:26])[CH3:25])[CH2:15][C:16]2[CH:17]=[C:18]3[C:2]([CH3:29])([CH3:1])[CH2:3][CH2:4][C:5]([CH3:28])([CH3:27])[C:6]3=[CH:7][C:8]4=2)([CH3:42])[CH3:35])[CH:41]=[CH:40][CH:39]=[CH:38]1
Reactant: CC(C)=C1C=CC=C1
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CCC2(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CC(C(C)(C)C1C=CC=C1)C2(C)C
Temperature: 2 °C
Yield: 68.1 %

Procedure:
In a 200 ml three-necked flask purged with nitrogen, 3.11 g (8.04 mmol, 1 eq) of 1,1,4,4,7,7,10,10-octamethyl-1,2,3,4,7,8,9,10-octahydrodibenzo(b,h)-fluorene was placed at room temperature. Then, 40 ml of dehydrated THF was added, and the mixture was stirred by a magnetic stirrer to give a solution. The solution was cooled to 2° C. with an ice bath (light yellow solution). To the solution, 5.2 ml (8.48 mmol, 1.05 eq) of n-BuLi (hexane solution) was dropwise added over a period of 10 minutes, and 10 ml of dehydrated THF was further added. The ice bath was removed, and the mixture was stirred at room temperature for 22 hours (dark red slurry). After the slurry was cooled to 0° C. with an ice bath, a solution of 1.05 ml (8.54 mmol, 1.06 eq) of 6,6-dimethylfulvene in 10 ml of dehydrated THF was dropwise added over a period of 15 minutes (dark red solution). The ice bath was removed, and the solution was stirred at room temperature for 23 hours. The resulting dark red brown solution was poured into 100 ml of a diluted hydrochloric acid solution to perform quenching. After the organic phase was washed with 100 ml of a saturated saline solution, the soluble component was extracted from the aqueous layer with 50 ml of diethyl ether. The soluble component and the dispensed organic phase were together dried over MgSO4, then the MgSO4 was filtered off, and from the filtrate the solvent was vacuum distilled off by a rotary evaporator to obtain a yellowish orange solid. The solid was purified by silica gel column chromatography (developing solvent: hexane) to obtain a white powder (2.70 g, yield: 68%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:3][CH:4]=1)[CH3:15]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 14 h
Yield: 87.4 %

Procedure:
A mixture of (R)-ethyl 4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (1.5 g, 3.88 mmol), phenylboronic acid (0.710 g, 5.82 mmol), Pd(Ph3P)4 (0.449 g, 0.388 mmol) and aqueous Na2CO3 (3.88 mL, 7.77 mmol) in toluene (25 mL) is allowed to stir at 95° C. under nitrogen for 14 hours. The reaction mixture is cooled to room temperature and quenched with brine. The mixture is extracted twice with ethylacetate, and the combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 50:50) to give (R)-ethyl-4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (1.30 g); HPLC retention time=1.61 minutes (condition B); MS (ES+)=328.0 (m-tBu+2); 284.1 (m-Boc+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.1 Hz, 3 H) 2.48 (A of ABX, Jab=16.1 Hz, Jax=5.9 Hz, 1 H) 2.53 (B of ABX, Jab=16.0 Hz, Jbx=5.3 Hz, 1 H) 2.83-3.00 (m, 2 H) 4.14-4.19 (m, 3 H) 5.06 (br s) 7.26-7.27 (m, 2 H) 7.31-7.35 (m, 2 H) 7.43 (t, J=7.6 Hz, 2H) 7.52-7.58 (m, 4 H).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([NH2:23])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:6][CH:5]=1)[CH3:2].C([NH:33][CH2:34][C:35](O)=[O:36])(OC(C)(C)C)=O.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:24]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2([NH:23][C:35](=[O:36])[CH2:34][NH2:33])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:8][CH:9]=1)[CH3:25]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCN(CC)c1ccc(NC(=O)C2(N)CCc3ccccc3C2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(NC(=O)C2(NC(=O)CN)CCc3ccccc3C2)cc1
Reaction time: 8 h
Yield: 59.1 %

Procedure:
To a mixture of 2-amino-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (4-diethylamino-phenyl)-amide (100 mg, 0.3 mmol) from Example 8 and N-Boc-glycine (52 mg, 0.3 mmol) in DMF (1.0 mL) was added Et3N (61 mg, 0.6 mmol) and TBTU (96 mg, 0.3 mmol). The mixture was stirred overnight and the precipitates were collected by filtration(130 mg) and dissolved in dichloromethane (10 mL) and TFA (5.0 mL). The mixture was concentrated under reduced pressure and ethyl acetate (20 mL) were added and the resulting solution was washed with 1N NaOH. The organic phase was dried over MgSO4 and then concentrated under reduced pressure to give 2-(2-amino-acetylamino)-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (4-diethylamino-phenyl)-amide (70 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[CH2:9][CH:10]=[O:11])=[C:4]([O:14][CH3:15])[CH:3]=1.C[Si](C)(C)[C:18]([F:21])([F:20])[F:19].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[F:19][C:18]([F:21])([F:20])[CH:10]([OH:11])[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[O:14][CH3:15])([CH3:12])[CH3:13]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1cc(F)ccc1C(C)(C)CC=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)ccc1C(C)(C)CC(O)C(F)(F)F
Reaction time: 0.5 h

Procedure:
To 1.89 g (8.99 mmol) of 3-(4-fluoro-2-methoxyphenyl)-3-methylbutyraldehyde was added 25 mL (12.5 mmol) of a 0.5 M solution of trimethyl(trifluoromethyl)silane in tetrahydrofuran and 2 mL (2 mmol) of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran was added over a 2 minute period. The mixture stirred for 30 minutes and then an additional 8 mL (8 mmol) of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran was added. The mixture was then diluted with water and extracted with three 25 mL portions of EtOAc. The combined organic layers were washed with three 20 mL portions of 1 N aqueous HCl, three 20 mL portions of brine, and three 20 mL portions of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated to afford 2.78 g of 1,1,1-trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol as an oil. The oil was dried under high vacuum to a constant weight of 2.36 g (93%) and was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].[CH3:19]O.S(=O)(=O)(O)O>O>[Cl:1][C:2]1[C:3]([S:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([O:7][CH3:19])=[O:6]
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1Sc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(Cl)c(Cl)c1Sc1ccccc1

Procedure:
A mixture of 3,4-dichloro-2-phenylsulphenylbenzoic acid (25.0 g), methanol and concentrated sulphuric acid (5 ml) was heated at reflux for 22 hours. Water was added and the mixture concentrated. The residue was taken up in ethyl acetate, washed with aqueous sodium bicarbonate, dried over anhydrous magnesium sulphate and filtered. The solvent was evaporated and the oil purified by chromatography on silica, using a mixture of cyclohexane, ether and toluene to give methyl 3,4-dichloro-2-phenylsulphenylbenzoate (13.8 g) as a clear oil, 1H NMR (CDCl3) 3.7 (3H,s), 7.1 (SH,m), 7.4(2H, m).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=[CH:15][C:14]=1[N+:27]([O-:29])=[O:28]>CS(C)=O>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[C:14]([N+:27]([O-:29])=[O:28])[CH:15]=1
Reactant: COc1ccccc1-c1ccc(F)c([N+](=O)[O-])c1
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc(-c2ccccc2OC)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Dimethyl malonate (14 mL) was added dropwise to 2.9 g of sodium hydride suspended in 50 mL of dimethylsulfoxide. The mixture was stirred at 100° C. for 15 minutes and cooled to room temperature. Crude 4-fluoro-2′-methoxy-3-nitrobiphenyl in 60 mL of dimethylsulfoxide was added and the mixture stirred at 100° C. for 2 hours. The reaction mixture was cooled, quenched with 300 mL of saturated ammonium chloride solution and extracted twice with ethyl acetate. The extracts were combined, washed with saturated ammonium chloride, water, and brine, dried over anhydrous sodium sulfate and concentrated to give crude dimethyl 2′-methoxy-3-nitrobiphenyl-4-malonate as a yellow oil.