Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O>[F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(I)cc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 36 %

Procedure:
(+)-[2-Fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (1.00 g, 2.6 mmol, prepared in example 1a), 4-carboxybenzene boronic acid (627 mg, 3.8 mmol), potassium carbonate (520 mg, 3.8 mmol), tetrakis(triphenyl phosphine)palladium(0) (206 mg, 0.2 mmol) and dioxane/water (112 mL, 3:1) were mixed together in a 250 mL single neck flask and stirred at 80° C. for 4 hours. The reaction was cooled to room temperature and poured into 1N HCl and the desired product was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to yield 1.43 g as a dark oil. This material was purified via silica gel chromatography employing the chromatotron and using a 4000 micron rotor while eluting with a solvent of methylene chloride/methanol 9:1 to yield the title compound (355 mg, 36%) as a tan solid. Ion spray M.S. 378.3 (M*−1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([OH:11])=[C:4]([F:12])[CH:3]=1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([F:12])[C:5]=1[OH:11]
Reactant: O=[N+]([O-])c1cc(Br)cc(F)c1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(Br)cc(F)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A mixture of 4-bromo-2-fluoro 6-nitrophenol(1 g, 4.2 mmol) and tin (II) chloride (4.78 g, 21.2 mmol) in ethanol(50 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(710 mg, 82%). 1H NMR (CD3OD): δ 6.51-6.40 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:32][C:33]=1[CH3:34])[CH2:6][O:7][C:8]1[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:32][C:33]=1[CH3:34])[CH2:6][O:7][C:8]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:9]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 60 °C
Reaction time: 5 h
Yield: 92.5 %

Procedure:
A mixture of ethyl 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-4-carboxylate (3.00 g), 1N aqueous sodium hydroxide solution (10 mL), tetrahydrofuran (30 mL) and ethanol (30 mL) was stirred at 60° C. for 5 hrs. 1N Hydrochloric acid (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained colorless crystals were collected by filtration to give 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-4-carboxylic acid (2.63 g, yield 92%). The crystals were recrystallized from acetone-hexane. melting point: 209-210° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2.[H-].[Na+].[CH3:14]I>CN(C)C=O>[OH:1][CH2:2][C:3]1[N:4]([CH3:14])[C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2
Reactant: CI
Reactant: OCc1nc2ncccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CO)nc2ncccc21

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that 45 g of 2-hydroxymethyl-1H-imidazo[4,5-b]pyridine, 13.17 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 20.7 ml of methyl iodide and 1.43 liter of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 1:1 by volume as the eluent, to give 3.24 g of the title compound, melting at 130-132° C.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH3:60][N:61]1[CH:66]2[CH2:67][CH2:68][CH:62]1[CH2:63][CH:64]([NH2:69])[CH2:65]2>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:69][CH:64]5[CH2:65][CH:66]6[N:61]([CH3:60])[CH:62]([CH2:68][CH2:67]6)[CH2:63]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN1C2CCC1CC(N)C2
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CC3CCC(C2)N3C)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 8-methyl-8-azabicyclo[3.2.1]octan-3-amine dihydrochloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.45 (m, 4 H) 1.37-1.85 (m, 12 H) 1.99 (s, 2 H) 2.29 (br. s., 2 H) 3.31 (s, 3 H) 3.93 (s, 3 H) 3.97-4.22 (m, 3 H) 4.45 (m, 1 H) 7.47 (d, J=8.0 Hz, 1 H) 7.49 (s, 1 H) 7.90 (s, 1 H) 8.15 (d, 1 H) 8.20 (s, 1 H) 8.25 (d, J=8.34 Hz, 1 H). [M+H] calculated for C30H39F2N7O3, 584; found 584.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:9])[C:4](=[O:19])O1.[CH2:21]=[N:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CO>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][NH:10][C:8]([C:7]2[CH2:21][N:22]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:4](=[O:19])[C:5]=2[OH:6])=[O:9])=[CH:17][CH:16]=1
Reactant: C=NCCN1CCOCC1
Reactant: CC1(C)OC(=O)C(=CC(=O)NCc2ccc(F)cc2)O1
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Temperature: 25 °C
Yield: 32 %

Procedure:
A mixture of 2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-acetamide (77 mg, 0.275 mmol) and a 0.2 mmol solution of methylene-(2-morpholin-4-yl-ethyl)-amine in methanol (1.5 mL, 0. mmol) was heated at 70° C. for 1 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC using methanol/water (0.1% TFA) as the eluent. The fractions containing the product were combined and concentrated to give the title compound as a pale yellow powder (42 mg, 32% yield). 1H NMR (500 MHz, DMSO) δ: 11.92 (1H, br s), 9.48 (1H, br s), 7.95 (1H, t, J=4.9 Hz), 7.34–7.31 (2H, m), 7.17–7.13 (2H, m), 4.42 (2H, d, J=4.9 Hz), 4.04 (2H, s), 4.01–3.95 (2H, m), 3.80–3.77 (2H, m), 3.66–3.39 (6H, m), 3.15–3.06 (2H, m). HRMS calcd for C18H21FN3O4 (M+H): 362.1516. found: 362.1505.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[CH:12][N+:13]([O-:15])=[O:14])[CH2:9][N+:8]([O-:16])=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1.[N:25]([O-])=[O:26].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]([N+:13]([O-:15])=[O:14])=[N:25][OH:26])[CH2:9][N+:8]([O-:16])=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1
Reactant: O=N[O-]
Reactant: O=[N+]([O-])C=C1C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc2N1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])C(=NO)C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=[N+]([O-])C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-Chloro-5-(2-fluorophenyl)-1,3-dihydro-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide* 7 g (0.02 mole), was dissolved by heating in 250 ml of glacial acetic acid. The solution was cooled with tap water and when the temperature reached 70° C. the addition of 1.9 g (0.0275 mole) of sodium nitrite was started. The sodium nitrite was added over a period of 10 min while cooling was continued. Following the addition, the mixture was stirred for 11/2 hr at room temperature, diluted with water and extracted with methylene chloride. The extracts were washed with water, dried over sodium sulfate and evaporated. Crystallization of the residue from ethyl acetate yielded yellow crystals.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[C:13]=3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[C:30]([O:34][C:35](=[O:56])[N:36]([C:48]1[CH:53]=[CH:52][C:51]([CH:54]=[O:55])=[CH:50][N:49]=1)[CH2:37][C:38]1[CH:39]=[N:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=1)([CH3:33])([CH3:32])[CH3:31].Cl>O1CCCC1>[C:30]([O:34][C:35](=[O:56])[N:36]([C:48]1[CH:53]=[CH:52][C:51]([CH:54]([C:12]2[C:13]3[C:18]([CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[N:17][CH:16]=[N:15][C:14]=3[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:11]=2)[OH:55])=[CH:50][N:49]=1)[CH2:37][C:38]1[CH:39]=[N:40][C:41]([C:44]([F:47])([F:45])[F:46])=[CH:42][CH:43]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)nc1)c1ccc(C=O)cn1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2c(C3CCCC3)ncnc21
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)nc1)c1ccc(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncnc(C4CCCC4)c23)cn1
Temperature: 0 °C

Procedure:
To 7-benzenesulfonyl-4-cyclopentyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (50, 0.119 g, 0.262 mmol) in 1.8 mL of tetrahydrofuran at −20° C. under nitrogen, isopropylmagnesium chloride (0.144 mL, 2.0 M in tetrahydrofuran, 0.289 mmol) was added and the reaction stirred and allowed to warm to 0° C. over 1 hour. The reaction was cooled to −15° C. and (5-formyl-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (51, 0.120 g, 0.315 mmol) in 0.53 mL of tetrahydrofuran was added. The reaction was poured into 0.1 N aqueous hydrochloric acid and extracted with ethyl acetate.
Reaction SMILES: C(OCC)C.[Cl:6][SiH:7]([Cl:9])[Cl:8].[Cl:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]Cl>C(N(CC)CC)C>[Cl:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][Si:7]([Cl:9])([Cl:8])[Cl:6]
Reactant: ClC/C=C\CCl
Reactant: Cl[SiH](Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: ClC/C=C\C[Si](Cl)(Cl)Cl
Reaction time: 8 h
Yield: 54 %

Procedure:
In a 1-L three-neck round-bottom flask equipped with an efficient reflux condenser, a tru-bore mechanical stirrer equipped with a Teflon paddle and a pressure-equalizing addition funnel was placed cuprous chloride (0.65 g, 6.5 mmol), triethylamine (73.9 g, 0.73 mol) and diethyl ether (500 mL). Trichlorosilane (98.2 g, 0.73 mol), 1,4-dichloro-cis-2-butene (80.6 g, 0.65 mol) and diethyl ether (60 mL) were placed in the addition funnel. This solution was added to the vigorously stirred greenish suspension of cuprous chloride and triethylamine over a period of 4 h. The reaction mixture was stirred overnight. The triethylammonium hydrochloride salts were removed by filtration under argon. These were washed several times with pentane. The solvents were removed from the combined filtrate by distillation through a 15 cm vacuum-jacketed Vigreux column at atmosphere pressure. The residue was transferred to a 250-mL round-bottom flask. The product was purified by fractional distillation under reduced pressure. A fraction with b.p. 72°-73° C./2.8 mmHg, 78.2 g, 54% yield was isolated. It had the following spectral properties.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[O:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]2)=[CH:15][CH:14]=1)#[CH:12]>C(N(CC)C(C)C)(C)C.[Cu]I>[F:10][C:7]1[CH:8]=[CH:9][C:4]([N:1]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]4)=[CH:17][CH:18]=3)[N:3]=[N:2]2)=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=Nc1ccc(F)cc1
Reactant: C#Cc1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-c3cn(-c4ccc(F)cc4)nn3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.4 %

Procedure:
1-Azido-4-fluorobenzene (24 mg, 0.174 mmol) was dissolved in N,N-diisopropylethylamine (0.75 ml), then (S)-tert-butyl 2-(4-ethynylphenyl)morpholine-4-carboxylate (50 mg, 0.175 mmol) was added followed by copper(I) iodide (33 mg, 0.174 mmol). The mixture was stirred at room temperature for 3 h. The green mixture was concentrated on the rotavap, silica gel (0.5 g) was added and after short grinding the mixture was put on a silica gel column for purification. Flash chromatography (5 g silica gel, 30% ethyl acetate in heptane) yielded a white solid (21 mg, 28%). MS (ISP): 369.1 ([M-tBu+H]+), 425.2 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1>C(#N)C>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:50])=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(Cl)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 41.1 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0295 g, 0.0639 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0530 mL, 0.383 mmol) and 4-chlorobenzenesulfonyl chloride (0.0400 g, 0.192 mmol) to obtain 4-(4-chlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0167 g, yield 41%).
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:7]
Reactant: COc1ccc(S)cc1
Reactant: CCCCCC(Br)C(=O)OCC
Product: CCCCCC(Sc1ccc(OC)cc1)C(=O)OCC
Yield: 108.8 %

Procedure:
2-(4-Methoxy-phenylsulfanyl)-heptanoic acid ethyl ester (13.8 g, 98%) was prepared according to the general method as outlined in example 1 starting from ethyl 2-bromoheptanoate (11 g, 47 mmol) and 4-methoxythiophenol (6 g, 42.8 mmol), as a yellow oil; MS: 297.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.OS(O)(=O)=O.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:18])[CH3:17])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cn1
Temperature: 130 °C
Yield: 98 %

Procedure:
To a hot solution of 2-amino-5-nitropyridine (1.4 g, 10 mmol) in acetic anhydride (5 mL) at 100° C. was added conc. H2SO4 (0.1 mL). The resulting mixture was heated at 130° C. for 2 h, cooled and partitioned between EtOAc (200 mL) and water (100 mL). The layers were separated and the aqueous layer was washed once with EtOAc (100 mL). The combined organic layers were washed with water (100 mL), saturated aqueous NaHCO3 (100 mL) and then brine (50 mL); dried over anhydrous MgSO4 and concentrated under reduced pressure to afford N-(5-nitropyridin-2-yl)acetamide (1.8 g, 98%), which was used without further purification. 1H-NMR (CDCl3): δ 9.14 (1H, d), 8.50 (1H, dd), 8.40 (1H, d), 8.23 (1H, br s), 2.29 (3H, s).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH:21]1[C:33]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][C:22]=1[OH:34].[OH-].[Na+]>>[CH:21]1[C:33]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][C:22]=1[O:34][CH2:16][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1
Reactant: Oc1ccc2c(c1)Cc1ccccc1-2
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3c(c2)Cc2ccccc2-3)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 9H-Fluoren-2-ol under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C26H26O5 [M+Na]+: 441.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:16]=1[CH:17]=[O:18])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH:36]1([Mg]Br)[CH2:39][CH2:38][CH2:37]1.Cl>O1CCCC1>[F:33][C:30]([F:31])([F:32])[C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:29]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:16]=1[CH:17]([CH:36]1[CH2:39][CH2:38][CH2:37]1)[OH:18])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Br[Mg]C1CCC1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C=O)n1
Agent: Cl
Solvent: C1CCOC1
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCC2)n1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 25 %

Procedure:
To a solution of 2-{[(3,5-bis-trifluoromethyl-benzyl)(2-methyl-2H-tetrazol-5-yl)amino]-methyl}-4-trifluoromethyl-benzaldehyde (1.5 g; 2.9 mmol) in tetrahydrofuran (14 mL) at −10° C. was added dropwise cyclobutylmagnesium bromide (9 mL; 5.4 mmol; 0.6M solution in tetrahydrofuran). The reaction was stirred at −10° C. for 1.5 hours. To quench the reaction, at 0° C. was added aqueous 2N hydrochloric acid. Reaction extracted with ethyl acetate. The organic was washed with aqueous 2N hydrochloric acid, water and brine. It was dried sodium sulfate and concentrated under reduced pressure. The residue was purified by 40 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 15-70% ethyl acetate in heptane) to give 420 mg (25% yield) as a gum. MS (ES−): Calc; 567.4, Found: 612.6 (M+HCO2). 1H NMR (400 MHz, CDCl3) δ ppm 7.78 (s, 1H), 7.66 (s, 2H), 7.52 (d, J=8.30 Hz, 1H), 7.49 (d, J=8.30 Hz, 1H), 7.35 (s, 1H), 4.86 (q, J=15.77 Hz, 2H), 4.86 (s, 1H), 4.77 (q, J=15.77, 16.18 Hz, 2H), 4.20 (s, 3H), 2.68 (m, 1H), 2.05-1.96 (m, 2H), 1.93-1.76 (m, 3H), 1.70 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11]>O.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[OH:9]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(F)cc1Cl
Solvent: CCOCC
Solvent: O
Product: O=[N+]([O-])c1cc(F)cc(Cl)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-Chloro-4-fluorophenol (25 g, 0.171 mol) in H2O (100 mL) and Et2O (300 mL) at 0° C. was added dropwise concentrated nitric acid (25 mL). After the addition was complete the reaction was warmed to rt and stirred for 3 hr. The layers were separated and the organic phase washed with 1:1 brine:H2O, brine, dried over MgSO4, filtered and concentrated in vacuo to a slurry. The slurry was diluted with hexane and the yellow solid collected and dried to provide 23.6 g of compound 711. ##STR90##
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[N+](C1C=C(S(O[CH2:23][C@@H:24]2[CH2:26][O:25]2)(=O)=O)C=CC=1)([O-])=O.[F-].[K+]>C1COCC1>[O:25]1[CH2:26][C@H:24]1[CH2:23][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: c1ccc2c(c1)CNC2
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)CN(C[C@@H]1CO1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
To a solution of isoindoline (500 mg, 4.20 mmol) and (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (1.27 g, 5.04 mmol) in THF (100 mL) was added KF (580 mg, 10 mmol) at 0° C. The reaction mixture was warmed to 25° C., stirred for 16 h, filtered and concentrated. The crude product was used in the next step without further purification. (600 mg, yield 68%) MS (ESI+) e/z: 176.1 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([C:15]=2[NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)[C:13]#[N:14])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[NH2:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>COCCOC.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>[NH2:32][C:33]1[CH:34]=[C:35]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([C:8]3[CH:9]=[N:10][CH:11]=[C:12]([C:15]=3[NH:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[CH:20]4)[C:13]#[N:14])[CH:5]=2)[CH:36]=[CH:37][CH:38]=1
Reactant: N#Cc1cncc(-c2cccc(Br)c2)c1Nc1ccc2[nH]ccc2c1
Reactant: Nc1cccc(B(O)O)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: [Na+]
Solvent: COCCOC
Product: N#Cc1cncc(-c2cccc(-c3cccc(N)c3)c2)c1Nc1ccc2[nH]ccc2c1
Temperature: 25 °C

Procedure:
A mixture of 5-(3-bromophenyl)-4-(1H-indol-5-ylamino)nicotinonitrile 113 (39 mg, 0.1 mmol), (Ph3P)4Pd (2.3 mg, 0.002 mmol) and 2M aq. Na2CO3 (0.1 mL) in DME (2 mL) was degassed by bubbling nitrogen for 5 min., then 3-aminophenylboronic acid (17 mg, 0.11 mmol) was added and the mixture was heated at reflux for 12 h. After cooling to r.t., the mixture was filtered and the filtrate was purified by preparative HPLC to give 5-(3′-aminobiphenyl-3-yl)-4-(1H-indol-5-ylamino)nicotinonitrile 117. MS: 402 (M+H), HPLC retention time: 1.72 min.(a).