Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10](O)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]([C:20](=O)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8]1)[CH3:2].[BrH:30].O>>[BrH:30].[BrH:30].[CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH:11]=[C:10]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:9]2[CH2:8]1)[CH3:2]
Reactant: CCN(CC)CCCN1CCC(O)(c2ccccc2)C(C(=O)c2ccccc2)C1
Agent: Br
Solvent: O
Product: CCN(CC)CCCN1CC=C2C(=C(c3ccccc3)c3ccccc32)C1
Temperature: 25 °C

Procedure:
A mixture of 20.0 parts of 1-(3-diethylaminopropyl)-3-benzoyl-4-hydroxy-4-phenylpiperidine and 100 parts by volume of 48 percent hydrobromic acid is refluxed for 2.5 hours. After cooling to room temperature, the solvent is removed under reduced pressure and acetone repeatedly added and removed under reduced pressure. The resulting yellow solid is recrystallized from 50:50 methanol-ether and dried at 90°C. for 5 hours to afford 2,3-dihydro-2-(3-diethylaminopropyl)-9-phenyl-1H-indeno[2,1-c]pyridine dihydrobromide containing 11/2 moles of water of hydration per mole. This compound melts at 136°-138°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C([Mg]Cl)(C)C.C([Li])CCC.N1(C=O)CC[O:33][CH2:32]C1>C1COCC1>[Si:10]([O:9][CH2:8][CH2:7][O:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:19]=[CH:18][CH:17]=1)[CH:32]=[O:33])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCCOCc1cccc(Br)c1
Reactant: O=CN1CCOCC1
Agent: CC(C)[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCOCc1cccc(C=O)c1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
(2-(3-Bromobenzyloxy)ethoxy)(tert-butyl)dimethylsilane [Aromatic Intermediate 25, step b] (2.3 g) was dissolved in THF (15 mL) and the solution cooled to −10° C. Isopropylmagnesium chloride (2M in THF, 1.2 mL) was added, followed by butyllithium (2.1M in hexanes, 2.4 mL). The mixture was stirred for 10 min before being added to a solution of morpholine-4-carbaldehyde (1.4 mL) in THF (15 mL). The mixture was stirred for 1 hour, then poured onto ammonium chloride solution (30 mL) and extracted into ether (2×30 mL). The combined ether extracts were washed with water and dried over sodium sulphate. The solvent was evaporated in vacuo to give the titled compound as a colourless oil. Yield 1.8 g.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12](I)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].C(B(CC)[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)C.C(=O)([O-])[O-].[K+].[K+]>O.C(COC)OC.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>[C:1]([C:3]1[CH:18]=[CH:17][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: CCB(CC)c1cccnc1
Reactant: N#Cc1ccc2c(c1)ncn2-c1cccc(I)c1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccc2c(c1)ncn2-c1cccc(-c2cccnc2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of (31) (4 g, 11.6 mmol), diethyl 3-pyridylborane (2.04 g, 13.9 mmol), potassium carbonate (4.8 g, 34.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in a mixture of water (20 ml) and dimethoxyethane is stirred at 80° C. in a nitrogen atmosphere overnight. After cooling the resulting suspension is poured into water and the crude product is filtered off, washed with water and dried. Purification is achieved by column-chromatography on silica gel using a mixture of ethyl acetete and methanol (9:1) as the eluent. Yield 2.46 g (72%) of the title compound. Mp.191-193° C.
Reaction SMILES: Cl.[CH2:2]1[C:6]2([CH2:10][CH2:9][NH:8][CH2:7]2)[CH2:5][CH2:4][O:3]1.C(N(CC)CC)C.[CH3:18][C:19]1[CH:26]=[C:25]([O:27][CH:28]2[CH2:31][N:30]([C:32]([C:34]3[O:35][C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[N:37][N:38]=3)=[O:33])[CH2:29]2)[CH:24]=[CH:23][C:20]=1[CH:21]=O.[Na].C([O-])(O)=O.[Na+]>ClCCl>[CH2:2]1[C:6]2([CH2:10][CH2:9][N:8]([CH2:21][C:20]3[CH:23]=[CH:24][C:25]([O:27][CH:28]4[CH2:31][N:30]([C:32]([C:34]5[O:35][C:36]([C:39]6[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=6)=[N:37][N:38]=5)=[O:33])[CH2:29]4)=[CH:26][C:19]=3[CH3:18])[CH2:7]2)[CH2:5][CH2:4][O:3]1
Reactant: C1CC2(CCOC2)CN1
Reactant: Cc1cc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)ccc1C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)ccc1CN1CCC2(CCOC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
2-Oxa-7-azaspiro[4.4]nonane HCl salt (0.07 g, 0.43 mmol) was dissolved in dichloromethane (2 ml). Triethylamine (0.064 ml, 0.47 mmol) was added, followed by 2-methyl-4-(1-(5-phenyl-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)benzaldehyde (0.13 g, 0.36 mmol) and sodium triacetoxyhydroborate (0.152 g, 0.72 mmol). The resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with dichloromethane (10 ml) and then shaken with NaHCO3 (sat. 3 ml). The two phases were separated by the use of a phase separator. Evaporation of the organic phase afforded crude material, which was purified by preparative reverse-phase HPLC at pH 10 to give 85 mg (50%) of the desired product as a solid.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH:20](=[O:22])[CH3:21]>C1COCC1.CCOCC>[C:1]1([C:7]#[C:8][CH:20]([OH:22])[CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)C#Cc1ccccc1
Reaction time: 1 h
Yield: 46.5 %

Procedure:
Phenylacetylene (5.5 mL; 50 mmol) was dissolved in THF (40 mL) and cooled to -78°. A 1.35M solution of n-butyllithium in hexane (37 mL; 50 mmol; 1.0 equiv.) was added dropwise and the resulting mixture was stirred at -78° for 1 h. Acetaldehyde (2.8 mL; 50 mmol; 1.0 equiv.) was added and the reaction mixture was allowed to warm overnight to room temperature. The mixture was diluted with ether (50 mL) and washed with water (3×25 mL). The organic solution was dried (MgSO4) and concentrated, and the crude product was distilled in vacuo, affording 3.4 g (47%) of 1f, bp 94° C./approximately 2 mm Hg. 1H nmr (300 MHz, CDCl3): 7.444-7.261 (5H, m); 4.762 (1H, q, J=5 96 Hz); 1.972 (1H, s); 1.557 (3H, d, J=6.58 Hz). IR (neat film, cm-1): 3400 (s); 1600 (w). FDMS (m/e): 146 (M+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@H:13]([NH2:15])[CH3:14])[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].C([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:44]3[C:39](=[CH:40][C:41]([C:45](O)=[O:46])=[CH:42][CH:43]=3)[C:38]([CH3:48])=[C:37]2[CH3:49])=[CH:31][CH:30]=1)=[O:22])(C)(C)C>>[F:2][C:3]1[CH:4]=[C:5]([C@H:13]([NH:15][C:45]([C:41]2[CH:40]=[C:39]3[C:44](=[CH:43][CH:42]=2)[N:36]([CH2:35][C:32]2[CH:31]=[CH:30][C:29]([C:24]4[C:23]([C:21]([OH:22])=[O:20])=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:34][CH:33]=2)[C:37]([CH3:49])=[C:38]3[CH3:48])=[O:46])[CH3:14])[CH:6]=[CH:7][C:8]=1[C:9]([F:11])([F:12])[F:10]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)c(F)c1
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](C)c3ccc(C(F)(F)F)c(F)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-1-(3-fluoro-4-(trifluoromethyl)phenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 589 [M+H]+.
Reaction SMILES: [CH2:1]([S:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]([OH:26])=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[C:9]2[CH:27]=[CH:28][CH:29]=[CH:30][C:8]=2[N:7]=1)[CH2:2][CH3:3].[OH:31]O>C(O)(=O)C>[CH2:1]([S:4]([CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]([OH:26])=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[C:9]2[CH:27]=[CH:28][CH:29]=[CH:30][C:8]=2[N:7]=1)=[O:31])[CH2:2][CH3:3]
Reactant: CCCSCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: OO
Solvent: CC(=O)O
Product: CCCS(=O)Cc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 63 from 4'-[(2-n-propylthiomethyl-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid and hydrogen peroxide in glacial acetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[NH:30]1[C:38]2[C:33](=[CH:34][C:35](B(O)O)=[CH:36][CH:37]=2)[CH:32]=[CH:31]1>>[NH:30]1[C:38]2[C:33](=[CH:34][C:35]([O:1][C:2]3[CH:3]=[C:4]([C:8]4[C:17]5[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=5)[N:11]=[CH:10][C:9]=4[C:22]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:23])[CH:5]=[CH:6][CH:7]=3)=[CH:36][CH:37]=2)[CH:32]=[CH:31]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(Oc2ccc3[nH]ccc3c2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxy-phenyl)-8-trifluoromethylquinolin-3-yl]-phenyl methanone and 5-Indolylboronic acid, following the procedure of Example 519: MS m/z 509; MS m/z 507.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][N:16]([S:33]([CH2:36][CH2:37][CH3:38])(=[O:35])=[O:34])[C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][N:16]([S:33]([CH2:36][CH2:37][CH3:38])(=[O:34])=[O:35])[C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCCS(=O)(=O)N(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCS(=O)(=O)N(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 0.17 h

Procedure:
To a solution of ethyl [2-methyl-4-({(propylsulfonyl)[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}methyl)phenoxy]acetate (20 mg, 0.036 mmol) in MeOH (1 mL) and THF (1 mL) at room temperature was added 2M NaOH (0.5 mL, 1 mmol). The resultant mixture was stirred for 2 h. The solvents were removed in vacuo and the residue was partitioned between CH2Cl2 (2×10 mL) and 2M HCl (10 mL). The organic solution was passed though a hydrophobic frit and the solvent was removed in vacuo. Purification by autoprep. HPLC conducted on a Supelco ABZ+ column (5 μm, 10 cm×21.2 mm ID), eluting at a flow rate of 8 mL/min with a gradient of 50–95% B over 20 mins and held at 95% B for 10 mins. Where solvent A=0.1% HCO2H in H2O and solvent B=0.05% HCO2H in MeCN. The title compound was afforded as a yellow oil (10.7 mg).
Reaction SMILES: [SH:1][C:2]1[NH:10][C:9]2[C:4](=[N:5][CH:6]=[N:7][C:8]=2[NH2:11])[N:3]=1.Br[C:13]1[C:21]([Br:22])=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:22][C:21]1[C:13]([S:1][C:2]2[NH:3][C:4]3[C:9]([N:10]=2)=[C:8]([NH2:11])[N:7]=[CH:6][N:5]=3)=[CH:14][C:15]2[O:19][CH2:18][O:17][C:16]=2[CH:20]=1
Reactant: Brc1cc2c(cc1Br)OCO2
Reactant: Nc1ncnc2nc(S)[nH]c12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Nc1ncnc2[nH]c(Sc3cc4c(cc3Br)OCO4)nc12
Temperature: 100 °C
Yield: 31.9 %

Procedure:
To 250 mL flask was charged with 8-mercaptoadenine (2.00 g, 11.98 mmol), 5,6-dibromo-benzo-[1,3]dioxole (6.70 g, 24.0 mmol), Pd2 dba3 (0.548 g, 0.599 mmol), Xantphos (0.693 g, 1.20 mmol), K2CO3 (3.31 g, 23.95 mmol), and dry dioxane (25 mL). The resulting mixture was heated at 100° C. for 16 h under nitrogen. After cooling, the reaction mixture was filtered and washed with a 2/2/0.5 mixture of CH2Cl2, EtOAc, and MeOH. The combined filtrates were concentrated in vacuo. The dark brown residue was purified by chromatography on SiO2 (CH2Cl2/EtOAc/MeOH, 2/2/0/5) and subsequent recrystallization from MeOH provided the title compound (1.4 g, 32%). 1H NMR (DMSO-d6) δ 8.08 (s, 1H), 7.38 (s, 1H), 7.23 (s, 1H), 6.12 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15]C)=[C:6]([C:8]2[C:9](N)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.N([O-])=O.[Na+]>C1COCC1.[H+].[B-](F)(F)(F)F.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:15][C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[C:6]=2[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1cccnc1N
Agent: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccc2oc3ncccc3c2c1
Temperature: -5 °C
Reaction time: 1 h
Yield: 35.5 %

Procedure:
3-(5-Chloro-2-methoxyphenyl)pyridin-2-amine (5.00 g, 21 mmol) was dissolved in the mixture of THF (409 mL), HBF4 (50% aqueous solution, 36 mL) and 15 mL of water. The solution was cooled to −5° C., and sodium nitrite (1.70 g in 20 mL of water) was added dropwise. Reaction was kept 1 hour at −5° C., then was allowed to warm up to room temperature and stirred overnight at room temperature. Then pH of the reaction mixture was adjusted to 10, and it was extracted with ethyl acetate (4×25 mL). Organic fractions were combined, dried over sodium sulfate and evaporated. The residue was subjected to column chromatography on silica gel, eluent hexane/ethyl acetate 9/1 mixture. Chromatography product contained 3-(5-chloro-2-methoxyphenyl)-2-fluoropyridine, pure 6-chlorobenzofuro[2,3-b]pyridine (1.52 g, colorless long needles) was obtained by crystallization from hexane/ethyl acetate.
Reaction SMILES: [C:1]1([CH2:7][S:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:20])=O>C1C=CC=CC=1>[C:1]1([CH2:7][S:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([Cl:20])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccccc1SCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1ccccc1SCc1ccccc1
Yield: 94.1 %

Procedure:
A suspension of 100 g of 2-[(phenylmethyl)thio]benzoic acid and 97.6 g of thionyl chloride in 800 ml of benzene was refluxed for about three hours then evaporated to dryness under vacuum. The residue was triturated with hexane to yield 101.2 g of 2-[(phenylmethyl)thio]benzoyl chloride, m.p. 113° to 116° C.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:6](Br)[CH:5]=1)(=[O:3])[CH3:2].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CC(O)(C)C.O.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:6]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:18]([F:29])([F:28])[F:17])[CH:24]=2)[CH:5]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)COc1ccc(C(C)=O)cc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)COc1ccc(C(C)=O)cc1-c1cccc(C(F)(F)F)c1
Yield: 73.8 %

Procedure:
Methyl 2-(4-acetyl-2-bromophenoxy)acetate (16) (710 mg, 2.5 mmol, 1 eq), 3-(trifluoromethyl)phenylboronic acid (709 mg, 3.75 mmol, 1.5 eq, Aldrich, Milwaukee, Wis., USA) and tetrakis(triphenylphosphine) palladium (100 mg, 0.086 mmol, 0.03 eq) were dissolved in t-BuOH (1 mL) and K2CO3 (1 mL of a 4 M solution in H2O) and heated in a microwave at 120° C. for 20 min. The resultant reaction mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The obtained residue was purified via silica gel chromatography (20% EtOAc/hexane) to give 650 mg (74%) of methyl 2-(4-acetyl-2-(3-trifluoromethylphenyl)phenoxy)acetate (17) as white solid. 1HNMR (CDCl3, 400 MHz): δ 8.43 (s, 2H), 7.90 (m, 2H), 7.60 (m, 2H), 6.89 (d, 1H), 4.72 (s, 2H), 3.79 (s, 3H), 2.59 (s, 3H). MS (ES-API): M+1=353.1. HPLC (Method B) tR=3.28 min.
Reaction SMILES: C(OC(=O)C)(=O)C.C1(=O)OC(=O)CC1.C1(=O)OC(=O)C=C1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:28]([N:30](CC)[CH2:31]C)C>C(Cl)(Cl)Cl.C(Cl)Cl.O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:28][N:30]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=1)[CH3:31]
Reactant: CCN(CC)CC
Reactant: c1ccncc1
Agent: O=C1C=CC(=O)O1
Agent: O=C1CCC(=O)O1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccccn1

Procedure:
For the production of compound (1) wherein R5 is RB, for example, as shown by the following formulas, compound (1-1) obtained in Step 3A is reacted with acid anhydride such as acetic anhydride, succinic anhydride, maleic anhydride and the like or acyl halide in chloroform, methylene chloride, tetrahydrofuran, toluene, ethyl acetate and the like or a mixed solvent thereof, in the presence of a base such as pyridine, triethylamine, dimethylaminopyridine and the like, whereby compound (1-8) can be obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH2:28])[CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[C:40](O)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[N:43][CH:42]=1>>[NH2:28][C:23]1[CH:22]=[C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([CH:2]([NH:1][C:40](=[O:47])[C:41]2[CH:46]=[CH:45][CH:44]=[N:43][CH:42]=2)[CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[O:4])(=[O:19])=[O:20])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: O=C(O)c1cccnc1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(F)c(N)c1
Product: CC(C)CN(C(CO)CCCCNC(=O)C(Cc1ccc2ccccc2c1)NC(=O)c1cccnc1)S(=O)(=O)c1ccc(F)c(N)c1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(3-amino4-fluoro-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (example 81) as described in general procedure E using nicotinic acid. The final product was obtained in 35% yield.
Reaction SMILES: [CH2:1]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([C:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:18][N:17]=3)[CH:13]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(O)COCCO.O.NN.[OH-].[K+]>C(OCC)(=O)C.O>[CH2:1]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:18][N:17]=3)[CH:13]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCC(=O)c1ccc(-c2ccc3c(c2)CC(CCCCCC)C3)nc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: OCCOCCO
Product: CCCCCCCCCCc1ccc(-c2ccc3c(c2)CC(CCCCCC)C3)nc1
Reaction time: 1 h
Yield: 37.2 %

Procedure:
0.50 g (1.15 mM) of 2-hexyl-5-(5-decanoylpyridine-2-yl) indan, 3.5 ml of diethylene glycol, 0.18 ml (2.96 mM) of 80%-hydrazine hydrate (density: 1.03), and 0.23 g (3.48 mM) of 85%-KOH were mixed and heat-stirred for 1 hour at 144°-216° C. After the reaction, the reaction mixture was poured into water, followed by addition of ethyl acetate and saturated common salt aqueous solution and stirring at room temperature to obtain an insoluble matter through filtration under reduced pressure. The insoluble matter was dissolved in toluene and dried with anhydrous sodium sulfate. The filtrate was subjected to extraction with ethyl acetate and washed with saturated common salt aqueous solution, followed by drying with anhydrous sodium sulfate. Each of the sodium sulfate was removed by filtration and each of the filtrate (toluene solution and ethyl acetate solution) was evaporated into a residue. The thus-prepared two-species of residues were mixed and purified by silica gel column chromatography (eluent: toluene), followed by concentration. To the concentrated matter, methanol was added, followed by cooling in a refrigerator. After the cooling, the resultant insoluble matter was recovered by filtration to obtain 0.18 g of 2-hexyl-5-(5-decylpyridine-2-yl)indan (Yield: 37.2%). ##STR306##
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:31][C:32](=[O:43])[C@H:33](O)[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C@@H:33]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:32]([OH:43])=[O:31])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Reactant: COC(=O)[C@H](O)CCc1ccccc1
Product: O=C(O)[C@H](CCc1ccccc1)Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-ol, and (R)-(−)-2-hydroxy-4-phenylbutyric acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a white solid, mp 152-154° C.; MS m/e 537 (M−H)+;
Reaction SMILES: [OH-].[K+].[CH2:3]1[O:11][C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=2)[O:4]1.C(O)[CH2:19][OH:20]>>[N+:12]([C:8]1[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:5]([OH:4])=[C:10]([O:11][CH2:3][CH2:19][OH:20])[CH:9]=1)([O-:14])=[O:13]
Reactant: OCCO
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(O)c(OCCO)cc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
0.2 mol (13.2g) of potassium hydroxide pellets (85%) is added to 100 ml of ethylene glycol which has been heated beforehand to 50° C. 0.1 mol (21.2g) of 4,5-methylenedioxy-1,2-dinitrobenzene is added in a single portion to this solution. The heating is maintained for 2 hours.
Reaction SMILES: [S:1]([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)([O:4][CH2:5][C@H:6]([OH:17])[C@H:7]([CH3:16])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])=[O:2].C(N(CC)CC)C.[Si:32](OS(C(F)(F)F)(=O)=O)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>C(Cl)Cl>[S:1]([C:18]1[CH:19]=[CH:20][C:21]([CH3:22])=[CH:23][CH:24]=1)([O:4][CH2:5][C@H:6]([O:17][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C@H:7]([CH3:16])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:2])=[O:3]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)[C@H](C)CCc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)CCc2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
A solution of tosylate 18 (100 g, 0.29 mol) and triethylamine (81.0 mL, 0.58 mol) in CH2Cl2 (1200 mL) was treated with neat TBS-OTf (99 mL, 0.43 mol) dropwise with continued stirring for another 20 min. The reaction was washed twice with brine, dried over MgSO4 and concentrated to dryness. The oil was dissolved in a minimal amount of hexanes and filtered over a silica pad, eluting with hexanes:EtOAc (9:1) to yield the title compound as a slightly amber oil, 134 g.