Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5]2.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[C:26]1[C:30]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)=[C:29]([CH:48]([CH3:50])[CH3:49])[O:28][N:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.O1CCOCC1>[Cl:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[C:20]=1[C:26]1[C:30]([CH2:31][O:32][C:33]2[CH:34]=[CH:35][C:36]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]=[C:7]([CH3:12])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5]4)=[CH:37][CH:38]=2)=[C:29]([CH:48]([CH3:50])[CH3:49])[O:28][N:27]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2nc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2nc1C
Temperature: 60 °C
Yield: 52 %

Procedure:
Palladium(II)acetate (1.2 mg, 5.3 μmol) was added to ethyl 6-bromo-2-methyl-3-quinolinecarboxylate (31.0 mg, 105.5 μmol), 3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-({[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxy}methyl)isoxazole (51.5 mg, 105.5 μmol), triphenylphosphine (2.7 mg, 10.5 μmol), and potassium phosphate (78.3 mg, 369.2 μmol). Then, dioxane (2.1 mL) was added to the mixture, followed by water (10.5 μL), and the reaction mixture was heated open to the atmosphere at 60° C. in an oil bath for 21 hours, then allowed to cool to room temperature. Water was added, followed by ethyl acetate, and the mixture was filtered through Celite®. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 3:7 ethyl acetate:hexanes to give 31.6 mg (52%) of ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-methyl-3-quinolinecarboxylate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.87 (s, 1H), 8.32 (d, J=2 Hz, 1H), 8.11 (dd, J=9, 2 Hz, 1H), 7.99 (d, J=9 Hz, 1H), 7.70 (d, J=9 Hz, 2H), 7.66-7.60 (m, 2H), 7.55 (dd, J=9, 7 Hz, 1H), 6.93 (d, J=9 Hz, 2H), 4.88 (s, 2H), 4.38 (q, J=7 Hz, 2H), 3.48 (septet, J=7 Hz, 1H), 2.85 (s, 3H), 1.38 (t, J=7 Hz, 3H), 1.34 (d, J=7 Hz, 6H). ESI-LCMS m/z 575 (M+H)+.
Reaction SMILES: IC1C=CC(C2C(C(O)=O)=CON=2)=CC=1.ClC1C=CC=CC=1[C@H](O)C.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C@H:33]([O:35][C:36]([NH:38][C:39]1[C:40]([C:44]2[CH:49]=[CH:48][C:47]([CH:50]=[CH:51][CH2:52][CH2:53][C:54]([O:56]C)=[O:55])=[CH:46][CH:45]=2)=[N:41][O:42][CH:43]=1)=[O:37])[CH3:34]>>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C@H:33]([O:35][C:36]([NH:38][C:39]1[C:40]([C:44]2[CH:45]=[CH:46][C:47]([CH:50]=[CH:51][CH2:52][CH2:53][C:54]([OH:56])=[O:55])=[CH:48][CH:49]=2)=[N:41][O:42][CH:43]=1)=[O:37])[CH3:34]
Reactant: COC(=O)CCC=Cc1ccc(-c2nocc2NC(=O)O[C@H](C)c2ccccc2Cl)cc1
Agent: C[C@@H](O)c1ccccc1Cl
Agent: O=C(O)c1conc1-c1ccc(I)cc1
Product: C[C@@H](OC(=O)Nc1conc1-c1ccc(C=CCCC(=O)O)cc1)c1ccccc1Cl

Procedure:
According to methods similar to those of Step 5 and Step 6 of Example 19 using 3-(4-iodophenyl)isoxazole-4-carboxylic acid and (R)-2-chloro-α-methylbenzyl alcohol, methyl 5-(4-{4-[(1R)-1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}phenyl)-4-pentenoate was synthesized, which was reacted in the same manner as in Example 2 to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([CH:16]([OH:23])[CH2:17][CH:18]3[O:22][CH2:21][CH2:20][O:19]3)([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[CH:40]([C:43]1[CH:48]=[C:47]([CH:49]([CH3:51])[CH3:50])[CH:46]=[C:45]([CH:52]([CH3:54])[CH3:53])[C:44]=1[S:55](Cl)(=[O:57])=[O:56])([CH3:42])[CH3:41].C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:42][CH:40]([C:43]1[CH:48]=[C:47]([CH:49]([CH3:50])[CH3:51])[CH:46]=[C:45]([CH:52]([CH3:54])[CH3:53])[C:44]=1[S:55]([O:23][CH:16]([C:13]1([OH:15])[CH2:12][N:11]([C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[C:3]=2[NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[O:10])[CH2:14]1)[CH2:17][CH:18]1[O:22][CH2:21][CH2:20][O:19]1)(=[O:56])=[O:57])[CH3:41]
Reactant: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)(C(O)CC2OCCO2)C1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)OC(CC2OCCO2)C2(O)CN(C(=O)c3ccc(F)c(F)c3Nc3ccc(I)cc3F)C2)c(C(C)C)c1
Temperature: 35 °C
Reaction time: 3.5 h
Yield: 13.8 %

Procedure:
1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol (148 mg, 0.262 mmol), was dissolved in dichloromethane (10 mL) and treated with 4-(dimethylamino)pyridine (38 mg, 0.31 mmol), triethylamine (0.036 mL, 0.262 mmol) and 2,4,6-triisopropylbenzenesulfonyl chloride (303 mg, 1.0 mmol) at 35° C. for 15 h. 2,4,6-Triisopropylbenzenesulfonyl chloride (100 mg, 0.33 mmol) was added and the mixture was stirred at 35° C. for 3.5 h. The mixture was adsorbed on to silica and purified by column chromatography (silica gel, 40-50% ethyl acetate in hexanes and then 100% ethyl acetate) to give 1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-2-(1,3-dioxolan-2-yl)ethyl 2,4,6-tris(1-methylethyl)benzenesulfonate (30 mg, 0.0361 mmol, 14% yield): MS (EI) for C36H42F3IN2O7S: 831 (MH+).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[CH2:10][NH:11][C:12]2[C:16]([C:17](OCC)=O)=[CH:15][NH:14][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].CO>C1COCC1.C1(C)C=CC=CC=1.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[CH2:10][NH:11][C:12]2[C:16]([CH3:17])=[CH:15][NH:14][N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1c[nH]nc1NCc1ccc(OC)c(OC2CCCC2)c1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2n[nH]cc2C)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
A stirred solution of ethyl 3-(3-cyclopentyloxy-4-methoxybenzylamino-pyrazole-4-carboxylate) (from EXAMPLE 12) (5.4 g, 0.015 mol) in THF (50 mL) at 0° was treated with sodium bis (2-methoxyethoxy)aluminum hydride (0.03 mole), 9 mL of 3.4 M solution in toluene. After 3 hours, another 9 mL portion of the sodium bis(2-methoxy-ethoxy)aluminum hydride solution (0.03 mol) was added. The reaction was stirred overnight at room temperature and methanol (20 mL) was added. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate extracts were washed with water and evaporated under reduced pressure. The residue crystallized upon trituration with hexanes. Pure title compound (1.7 g, 38%), mp 76-77°, was obtained after two crystallizations from methyl t-butylether.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([OH:37])(=[S:36])[CH3:35].[C:38]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]([CH2:66][C:67]2[CH:72]=[CH:71][C:70]([O:73][CH2:74][CH2:75]O)=[CH:69][CH:68]=2)[C:49]([NH:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH:60]3[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)=[CH:54][CH:53]=2)=[O:50])=[CH:44][CH:43]=1)([CH3:41])([CH3:40])[CH3:39]>C1COCC1>[C:38]([C:42]1[CH:43]=[CH:44][C:45]([CH:48]([C:49](=[O:50])[NH:51][C:52]2[CH:53]=[CH:54][C:55]([O:58][CH2:59][CH:60]3[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)=[CH:56][CH:57]=2)[CH2:66][C:67]2[CH:72]=[CH:71][C:70]([O:73][CH2:74][CH2:75][S:36][C:34](=[O:37])[CH3:35])=[CH:69][CH:68]=2)=[CH:46][CH:47]=1)([CH3:39])([CH3:40])[CH3:41]
Reactant: CC(O)=S
Reactant: CC(C)(C)c1ccc(C(Cc2ccc(OCCO)cc2)C(=O)Nc2ccc(OCC3CCCCC3)cc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SCCOc1ccc(CC(C(=O)Nc2ccc(OCC3CCCCC3)cc2)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a solution of triphenylphosphine (125 mg, 0.48 mmol) in anhydrous THF (5 mL) at 0° C. was added diisopropylazodicarboxylate (94 uL, 0.48 mmol). After stirring for 30 min. a solution consisting of thioacetic acid (34 uL, 0.48 mmol) and 2-(4-tert-Butylphenyl)-N-(4-cyclohexylmethoxyphenyl)-3-[4-(2-hydroxyethoxy)-phenyl]-propionamide (126 mg, 0.23 mmol) was added. The resulting solution was allowed to warm to rt overnight. The mixture was partitioned between ethyl acetate and H2O and the organic portion concentrated under vacuum. Purification of the crude by preparative TLC (SiO2, 2 mm) using hexane/ethyl acetate (4:1) as eluant afforded Thioacetic acid S-(2-{4-[2-(4-tert-Butylphenyl)-2-(4-cyclohexylmethoxyphenyl carbamoyl)-ethyl]-phenoxy}-ethyl)ester (102 mg, 73%). TLC: Rf=0.38 hexane/ethyl acetate (4:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22]=O)[C:8]([F:11])=[CH:9][CH:10]=1.[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:27]([NH2:34])[C@H:26]1[OH:35]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:13]=2[CH2:22][NH:34][C@@H:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25][C@@H:26]2[OH:35])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CN[C@@H]2c3ccccc3C[C@@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 25, Step 4, using the following starting materials: (6-fluoro-2′-formyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and (1R,2S)-(+)-cis-1-amino-2-indanol.
Reaction SMILES: [OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH:13][CH2:14][CH2:15][C:16]1[S:20][CH:19]=[C:18]([CH2:21][CH2:22][N:23]2[CH2:43][CH2:42][C:26]3([O:31][CH2:30][CH2:29][N:28]([C:32]([C:34]4[N:35]=[C:36]([CH:39]([CH3:41])[CH3:40])[S:37][CH:38]=4)=[O:33])[CH2:27]3)[CH2:25][CH2:24]2)[CH:17]=1.[C:44]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])(=[O:47])[CH:45]=[CH2:46].C(#N)C>C1(C)C=CC=CC=1>[CH:39]([C:36]1[S:37][CH:38]=[C:34]([C:32]([N:28]2[CH2:27][C:26]3([CH2:42][CH2:43][N:23]([CH2:22][CH2:21][C:18]4[CH:17]=[C:16]([CH2:15][CH2:14][O:13][CH2:46][CH2:45][C:44]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[S:20][CH:19]=4)[CH2:24][CH2:25]3)[O:31][CH2:30][CH2:29]2)=[O:33])[N:35]=1)([CH3:40])[CH3:41]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4csc(CCO)c4)CC3)C2)cs1
Reactant: C=CC(=O)OC(C)(C)C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4csc(CCOCCC(=O)OC(C)(C)C)c4)CC3)C2)cs1
Reaction time: 18 h

Procedure:
Benzyltrimethylammonium hydroxide (40% in water, 0.27 mL) was added in one portion to a stirred solution of (9-(2-(5-(2-hydroxyethyl)thiophen-3-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone [Example 78, step b] (0.92 g) and tert-butyl acrylate (0.38 g) in toluene (1 mL). The resultant mixture was stirred vigorously at 20° C. for 4 hours. Acetonitrile (1 mL) was added and the mixture was stirred for 18 hours and then purified without work up. The crude product was purified by flash silica chromatography, using 6% methanol in ethyl acetate with 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 0.84 g.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].N1C=CC=CC=1.[CH3:13][C:14]([CH2:18][CH2:19][CH:20]=[C:21]([CH3:33])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[CH:15][CH2:16]Br>O1CCOCC1>[CH3:13][C:14]([CH2:18][CH2:19][CH:20]=[C:21]([CH3:33])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[CH:15][CH2:16][NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCBr
Reactant: CN(C)CCN
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCNCCN(C)C
Temperature: 0 °C
Yield: 33.4 %

Procedure:
4.4 g of N,N-dimethylethylenediamine was dissolved in 40 ml of dioxane. 5 ml of pyridine was added to the solution. 17.6 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl bromide was added thereto and the mixture was heated under reflux for 2 h and poured in ice-water. After extraction with n-hexane followed by washing with water and concentration, the resulting reaction mixture was treated by alumina column chromatography to obtain 6 g (33%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([CH3:41])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][NH:17][CH2:16][C@H:15]2[CH2:37][NH:38][CH:39]=O)=[CH:10][CH:9]=1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([O:3][C@H:4]([CH3:41])[CH2:5][O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][NH:17][CH2:16][C@H:15]2[CH2:37][NH:38][CH3:39])=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CNC=O)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CNC)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
A solution of 1 mmol of N-{(3S,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-3-ylmethyl}-formamide (example 7) 8 ml of THF is mixed with 2 mmol of LiAlH4 (1M in THF) and stirred at RT for 13 h (conversion checked by HPLC or TLC), then the reaction mixture is heated to 40° C. for 2 h. The reaction mixture is poured on saturated aqueous NaHCO3 solution and extracted with TBME (3×). The combined organic phases are washed with H2O and brine and evaporated in vacuo. The title compound is obtained from the residue by flash chromatography (SiO2 60F) and identified based on the Rf value.
Reaction SMILES: [F:1][C:2]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1.Cl.N([O-])=O.[Na+].NC(N)=O.[Na+].[I-:27]>O>[F:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:3]([O:4][C:5]2[CH:11]=[CH:10][C:8]([I:27])=[CH:7][CH:6]=2)[C:2]=1[F:1]
Reactant: [I-]
Reactant: Nc1ccc(Oc2cccc(F)c2F)cc1
Agent: Cl
Agent: NC(N)=O
Agent: O=N[O-]
Solvent: O
Product: Fc1cccc(Oc2ccc(I)cc2)c1F
Temperature: 0 °C
Yield: 79.1 %

Procedure:
Into a 250-mL 4-necked round-bottom flask, was placed 4-(2,3-difluorophenoxy)-aniline (8.84 g, 39.96 mmol, 1.00 equiv), hydrogen chloride (10.14 g, 100.01 mmol, 2.50 equiv), and water (20 mL). A solution of NaNO2 (3.04 g, 44.06 mmol, 1.10 equiv) in water (10 mL) was added dropwise with stirring in portions at 0° C. The mixture was stirred at 0° C. for half an hour. To this was added urea (1 g, 16.65 mmol). The mixture was stirred at 0° C. for 20 min and poured into the solution of NaI (18 g, 120.00 mmol, 3.00 equiv) in water (20 mL) at room temperature. The resulting solution was stirred at room temperature for 1 h and then extracted with ethyl acetate. The organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 10.5 g (79%) of 1,2-difluoro-3-(4-iodophenoxy)benzene as brown oil.
Reaction SMILES: Br[C:2]([C:7]1[C:8]([C:31](Br)([C:34]#[N:35])[C:32]#[N:33])=[C:9]2[C:28](=[CH:29][CH:30]=1)[C:27]1[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=1)C1C(=CC=CC=1)[C:15]1[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=1)([C:5]#[N:6])[C:3]#[N:4].C([Sn](CCCC)(CCCC)[C:42]1[S:43][CH:44]=[CH:45][CH:46]=1)CCC>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>[S:43]1[CH:44]=[CH:45][CH:46]=[C:42]1[C:7]1([CH:2]([C:3]#[N:4])[C:5]#[N:6])[CH:30]=[CH:29][C:28]2[C:27]3[C:22](=[C:23]([C:44]4[S:43][CH:42]=[CH:46][CH:45]=4)[CH:24]=[CH:25][CH:26]=3)[C:8]3[C:7](=[CH:30][CH:29]=[CH:28][CH:9]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]1[CH:31]([C:32]#[N:33])[C:34]#[N:35]
Reactant: N#CC(Br)(C#N)c1ccc2c(c1C(Br)(C#N)C#N)-c1ccccc1-c1ccccc1-c1ccccc1-2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: N#CC(C#N)C1C2=C(C=CC1(c1cccs1)C(C#N)C#N)c1cccc(-c3cccs3)c1-c1ccccc1-c1ccccc12
Temperature: 25 °C
Yield: 203.6 %

Procedure:
Dibromotetraphenylenedimalononitrile 10 (180 mg, 0.187 mmol), 2-tributylstannylthiophene (168 mg, 0.449 mmol), and Pd(PPh3)4 (15 mg) in anhydrous toluene (8.0 mL) were heated overnight at 110° C. under nitrogen. The reaction mixture was cooled to room temperature and concentrated to dryness. The crude product was purified by column chromatography on silica gel (CHCl3/hexanes (7:3)) to give 2,8-dithien-2-yl-tetraphenylenedimalononitrile (10B) as a yellow solid (0.114 g, 70% yield). 1H NMR (CDCl3): δ 0.88-1.66 (m, 46H), 2.10 (t, 4H), 7.13 (t, 2H) 7.35 (d, 2H, J=4.5 Hz), 7.44 (d, 2H, J=3.5 Hz), 7.51 (s, 2H), 7.75 (d, 2H, J=8.0 Hz), 8.69 (s, 2H), 8.78 (s, 2H) ppm; m.p: 280-281° C.; MS(MALDI-TOF) m/z (M+): 870.8; and Elemental Analysis: C, 79.80; H, 7.74.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([NH:20][CH2:21][C:22]([OH:24])=[O:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].Br[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30].[K]>O1CCCC1.CCCCCC.O>[C:16]([O:15][C:13]([NH:20][CH:21]([CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:22]([OH:24])=[O:23])=[O:14])([CH3:18])([CH3:19])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)CCCBr
Agent: [K]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: O
Product: CC(C)CCCC(NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 1 h
Yield: 50 %

Procedure:
A solution of diisopropylamine (13.2 ml; 0.094 mol) in 130 ml tetrahydrofurane (THF) was cooled down to about −40° C. n-Butyllithium (37 ml of a 2.5 M solution in hexane; 0.094 mol) was added dropwise. The temperature was left to return to about 0° C. At this temperature, Boc-glycine (5 g; 0.028 mol) in solution in 30 ml THF was introduced into the mixture. After ten minutes at this temperature, 1-bromo-4-methylpentane (7.9 ml; 0.056 mol) in solution in 20 ml THF was quickly added. The temperature was then left to return to about 23° C. and the mixture agitated for about one hour at this temperature. After hydrolysis with 100 ml water and acidification with 150 ml of a saturated potassium hydrogenosulfate solution, the obtained mixture was extracted with 2 times 50 ml ethyl acetate. The organic phase was washed with 100 ml water followed by 100 ml of a saturated sodium chloride solution. After drying on magnesium sulfate and evaporation of the solvent, the residue obtained was purified on a silica column (eluent: ethyl acetate-heptane/6-4) to produce a white-colored powder with a yield of 50%. MH+=260.3.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16]I.[Na+].[Cl-]>CN(C=O)C.O>[Cl:13][CH2:14][CH2:15][CH2:16][O:9][C:5]1[CH:4]=[C:3]([N:2]([CH3:10])[CH3:1])[CH:8]=[CH:7][CH:6]=1
Reactant: ClCCCI
Reactant: CN(C)c1cccc(O)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1cccc(OCCCCl)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 103.6 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-(dimethylamino)phenol (3.50 g, 25.51 mmol) in DMF (30 mL) was slowly added over 10 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.80 g of an 80% dispersion in mineral oil, 26.79 mmol) in DMF (40 mL). The mixture was allowed to warm to ambient temperature and further stirred for 1.25 h. The resulting brown mixture was cooled to 0-5C. To this slurry was added drop-wise over 5 min, 1-chloro-3-iodopropane (6.26 g, 30.62 mmol). The resulting reddish brown mixture was stirred at ambient temperature for 4.25 h. Cold water (35 mL) was carefully added, followed by saturated NaCl solution (35 mL). The resulting mixture was extracted with ether (4×50 mL). The combined dull-yellow ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation producing a light-brown oil (5.65 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.[C:13]([O:17][C:18](=[O:30])[NH:19][C:20]1[CH:25]=[C:24]([C:26]([NH:28][NH2:29])=[O:27])[CH:23]=[CH:22][N:21]=1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:30])[NH:19][C:20]1[CH:25]=[C:24]([C:26]([NH:28][NH:29][C:10](=[O:12])[CH2:9][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[O:27])[CH:23]=[CH:22][N:21]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C(O)CCc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)NN)ccn1
Product: CC(C)(C)OC(=O)Nc1cc(C(=O)NNC(=O)CCc2cccc(F)c2)ccn1
Yield: 60 %

Procedure:
In the same manner as in Reference Example 1 and using 3-(3-fluorophenyl)propionic acid instead of benzothiazole-6-carboxylic acid and tert-butyl[4-(hydrazinocarbonyl)-2-pyridyl]carbamate instead of tert-butyl carbazate, the title compound (yield 60%) was obtained as colorless crystals.
Reaction SMILES: [CH:1]1([S:6]([C:9]2[N:14]=[CH:13][C:12]([C:15](=[N+]=[N-])[C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:22][CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(Cl)Cl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH:1]1([S:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCOCC1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(S(=O)(=O)C2CCCC2)nc1
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CCCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
Methyl 2-(6-cyclopentylsulfonyl-3-pyridyl)-2-diazo-acetate (0.25 g, 0.80 mmol) was dissolved in DCM (5 mL) under argon atmosphere. To this solution, 4-hydroxy tetrahydropyran (0.11 mL, 1.21 mmol) was added followed by rhodium (II) acetate dimer (9 mg, 0.021 mmol). Mixture was stirred at 25° C. for 60 min. Reaction mixture was diluted with DCM (10 mL), organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product (280 mg).