Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH3:14])([CH3:13])[CH:7]=[C:6]2[CH3:15])[CH3:2].[C:16](Cl)(=[O:18])[CH3:17]>N1C=CC=CC=1>[C:16]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:1][CH3:2])=[CH:12][CH:11]=2)[CH:6]([CH3:15])[CH2:7][C:8]1([CH3:14])[CH3:13])(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: CCc1ccc2c(c1)C(C)=CC(C)(C)N2
Solvent: c1ccncc1
Product: CCc1ccc2c(c1)C(C)CC(C)(C)N2C(C)=O

Procedure:
Acylation of 1,2-dihydro-6-ethyl-2,2,4-trimethylquinoline (800 mg) with acetyl chloride (3.5 ml) and a catalytic amount of N,N-dimethylaminopyridine in pyridine (25 ml) was performed according to the method described in example 37.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Li]C(C)(C)C.[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:25][C:11]1[C:12]2[NH:13][C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[S:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: [Li]C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1cccc2c1Nc1ccccc1S2
Temperature: 25 °C

Procedure:
This compound was prepared according to a procedure by A. R. Katritzky et al., Synthesis, 1988, 215-217. To a solution of phenothiazine (10.0 g, 50.18 mmol) in anhydrous THF (200 mL) and cooled to −78° C. was added a solution of n-BuLi (24.1 mL, 60.2 mmol, 2.5 M in hexanes) dropwise. The mixture was stirred until a yellow precipitate formed, and then allowed to warm to room temperature, until a clear yellow solution resulted. The solution was again cooled to −78° C. and CO2 gas was bubbled through the mixture for 5 min. The resulting solution was allowed to warm to RT and the solvent was evaporated to give a residue. The residue was again dissolved in anhydrous THF (200 mL) and cooled to −78° C., before t-BuLi (50 mL, 85 mmol, 1.7 M in pentane) was added dropwise. The resulting mixture was allowed to warm to −20° C. and was stirred at this temperature for 2 h. The reaction mixture was again cooled to −78° C. and a solution of hexachloroethane (100 mmol) in THF (50 mL) was added dropwise. The mixture was stirred at this temperature for 1 hour then allowed to warm to −20° C. and stirred for 2 h. The reaction mixture was quenched with ice cold 1 N HCL and extracted with EtOAC. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to give a residue. The residue was purified by flash silica gel chromatography to give of an beige solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:25]3[CH:26]=[CH:27][C:28]4[C:32]([CH:33]=3)=[N:31][N:30]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:29]=4)[CH:9]=[C:10]([CH:11]3[CH2:14][N:13](C(OCC4C=CC=CC=4)=O)[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1>Cl>[NH:13]1[CH2:14][CH:11]([C:10]2[N:6]3[C:7]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[C:8]([C:25]3[CH:26]=[CH:27][C:28]4[C:32]([CH:33]=3)=[N:31][N:30]([CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:29]=4)[CH:9]=2)[CH2:12]1
Reactant: Nc1ncnn2c(C3CN(C(=O)OCc4ccccc4)C3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: Cl
Product: Nc1ncnn2c(C3CNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 100 °C
Reaction time: 1 h
Yield: 11.5 %

Procedure:
A mixture of benzyl 3-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]azetidine-1-carboxylate (304 mg, 0.57 mmol) and 6N aqueous HCl (10 mL) were stirred at 100° C. for 1 h. The mixture was concentrated to dryness. The residue was purified by preparative HPLC using a gradient elution from 15% to 50% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 26 mg (11%) of the desired product, which was approximately 70% pure. ES-MS m/z 396.42 [M+H]+, HPLC RT (min) 2.04.
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:28][C:29]([CH2:32][O:33][CH3:34])=[CH:30][N:31]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:35])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[F:37]C1(C2C=CC(C#N)=CC=2)CCNCC1.Cl.N1CCC(C2C=CC(C#N)=CC=2)CC1>>[CH:1]1([C:5]2[C:26]([C:27]3[NH:28][C:29]([CH2:32][O:33][CH3:34])=[CH:30][N:31]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][C:14]([C:17]4[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=4)([F:37])[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:35])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COCc1cnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Agent: Cl
Agent: N#Cc1ccc(C2CCNCC2)cc1
Product: COCc1cnc(-c2cc(C(=O)N3CCC(F)(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for preparation of 4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 246), using 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2 HCl salt) instead of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5). m/z (ES+) 487 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 7.79-7.67 (m, 2H), 7.66 (d, 3H), 7.53-7.39 (m, 2H), 4.99-4.93 (m, 1H), 4.85 (s, 2H), 3.76-3.56 (m, 3H), 3.50 (s, 3H), 2.42 and 2.34 (2 singlets, amide rotamers, ArCH3, 3H), 2.27-1.97 (m, 8H), 1.92-1.81 (m, 2H), 1.35-1.26 (m, 1H).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([Sn](CCCC)(CCCC)[C:17]1[S:18][CH:19]=[CH:20][N:21]=1)CCC.O>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:18]1[CH:19]=[CH:20][N:21]=[C:17]1[C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1ncsc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ncsc1-c1nccs1

Procedure:
To a solution of ethyl 5-bromo-1,3-thiazole-4-carboxylate in toluene were added 2-(tributylstannyl)-1,3-thiazole and PdCl2(PPh3)2, followed by heating under reflux for 6 hours. Water was added thereto and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane: EtOAc) to obtain ethyl 2,5′-bi-1,3-thiazole-4′-carboxylate as a yellow solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([N:15]1[C:20]2[N:21]=[C:22]([CH:37]([CH3:39])[CH3:38])[C:23]([C:32](OCC)=[O:33])=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:19]=2[C:18](=[O:40])[NH:17][C:16]1=[O:41])[CH2:12][CH2:13][CH3:14].[H-].C([Al+]CCCC)CCC.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:11]([N:15]1[C:20]2[N:21]=[C:22]([CH:37]([CH3:38])[CH3:39])[C:23]([CH2:32][OH:33])=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:19]=2[C:18](=[O:40])[NH:17][C:16]1=[O:41])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCn1c(=O)[nH]c(=O)c2c(-c3ccc(F)cc3)c(C(=O)OCC)c(C(C)C)nc21
Agent: CC(C)C[Al+]CC(C)C
Agent: CCCC[Al+]CCCC
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCn1c(=O)[nH]c(=O)c2c(-c3ccc(F)cc3)c(CO)c(C(C)C)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
135 ml of a 1 molar solution of diisobutylaluminum hydride in toluene are slowly added under argon to a suspension of 19.2 g (45 mmol) of the compound from Example 3 in 400 ml of toluene at -75° C., which leads to a clear solution. After 1 hour, a further 30 ml of dibutylaluminum hydride solution are added at the same temperature, the mixture is stirred for a further hour and then allowed to warm to room temperature, 400 ml of water and 200 ml of ethyl acetate being added cautiously from -30° C. The mixture is filtered off with suction through kieselguhr and subsequently washed with ethyl acetate. After phase separation, the aqueous phase is extracted with ethyl acetate, and the combined organic phases are washed with sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed in a column (φ 6 cm) on 500 g of 230-400 mesh silica gel using petroleum ether/ethyl acetate (2:1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][CH:37]=1)[C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[C:13]([CH:19]=1)[O:14][CH2:15][C:16]([OH:18])=[O:17])=[O:8])([OH:3])=[O:2].[BH4-].[Na+]>O1CCOCC1.O>[C:1]([C:4]1[CH:5]=[C:6]([CH:7]([C:9]2[CH:10]=[CH:11][C:12]([O:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]/[C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)=[C:13]([CH:19]=2)[O:14][CH2:15][C:16]([OH:18])=[O:17])[OH:8])[CH:35]=[CH:36][CH:37]=1)([OH:3])=[O:2]
Reactant: COc1ccc(/C=C/CCCCOc2ccc(C(=O)c3cccc(C(=O)O)c3)cc2OCC(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(/C=C/CCCCOc2ccc(C(O)c3cccc(C(=O)O)c3)cc2OCC(=O)O)cc1
Yield: 89.6 %

Procedure:
Under the conditions of example 5A, 100 mg of 5-(3-carboxybenzoyl)-2-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-phenoxy acetic acid is reacted with 31 mg of sodium borohydride in 5 ml of dioxane and 0.5 ml of water and worked up (>pH 3-4). 90 mg of the title compound is obtained as colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:12][OH:13])[CH:3]=1.N1C=CN=C1.[CH3:19][CH:20]([Si:22](Cl)([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH3:21]>CN(C=O)C.CN(C1C=CN=CC=1)C.[Cl-].[NH4+]>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:12][O:13][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:21])[CH3:19])[CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCc1cc(Br)c2ccccc2c1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)[Si](OCc1cc(Br)c2ccccc2c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
To a solution of the (4-bromonaphthalen-2-yl)methanol in DMF (100 mL) was added imidazole (7.6 g, 112 mmol), DMAP (0.68 g, 5.6 mmol), and TIPSCl (18 mL, 84 mmol). The resulting solution was stirred at room temperature for 12 h, diluted with a saturated ammonium chloride and extracted with EtOAc. The organic layer was washed with water then brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (3-10% EtOAc/hexanes) to yield the title compound (19.6 g, 82%) as colorless oil.
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[Cl:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=O)=[CH:14][CH:13]=1)=[O:11].Cl.[CH3:24][O:25][C:26](=[O:30])[CH:27]([CH3:29])[NH2:28].C(=O)(O)[O-].[Na+]>O1CCCC1.C(#N)C.CN(C)C=O.C(N(CC)CC)C>[CH3:24][O:25][C:26](=[O:30])[C@H:27]([CH3:29])[NH:28][C:20](=[O:22])[CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:10](=[O:11])[CH2:9][Cl:8])=[CH:17][CH:16]=1
Reactant: O=C(O)CCc1ccc(C(=O)CCl)cc1
Reactant: COC(=O)C(C)N
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)NC(=O)CCc1ccc(C(=O)CCl)cc1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
A solution of pivaloyl chloride (4.41ml.) in tetrahydrofuran (30ml.) was added to a stirred solution, cooled to -15° C., of 3-[4-(chloroacetyl)phenyl]propionic acid (9.7g.) and triethylamine (5.5ml.) in tetrahydrofuran (30ml.) and acetonitrile (40ml.). The resultant mixture was stirred for one hour at -15° C. A suspension of DL-alanine methyl ester hydrochloride (5.0g.) in dimethylformamide (30ml.) containing triethylamine (5.5ml.) was then added over 15 minutes. The mixture was stirred at -15° C. for 1 hour and then for 16 hours at room temperature. Saturated sodium bicarbonate solution (30ml.) was added and the solution was stirred for 30 minutes and then evaporated in vacuo. The residue was mixed with water (150ml.) and was extracted with chloroform (2 × 100ml.). The extracts were washed successively with 10% hydrochloric acid (200ml.), water (200ml.), saturated sodium bicarbonate solution (200ml.) and water (200ml.), dried (MgSO 4) and evaporated. The residue was recrystallised from toluene/petrol to give N-{3-[4-(chloroacetyl)phenyl]propionyl} alanine methyl ester, m.p. 122°-124° C.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[CH:33][C:32]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[C:37]([C:34]1[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[C:36]([CH:35]=1)[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)(=[O:39])[CH3:38]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: COc1ccc(C(C)=O)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(C(C)=O)cc1O[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.1 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-methoxy-5-acetylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (1.60 mg, 22.2% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.52 (d, 2H, J=2.4 Hz), 7.3–7.2 (m, 5H), 7.20 (m, 3H), 6.97 (apparent d, 1H, J=6.7 Hz), 6.69 (apparent d, 1H, J=8.0 Hz), 5.47 (apparent dd, 1H, J=4.3, 7.8 Hz), 3.95 (s, 3H), 3.38 (m, 2H), 2.93 (m, 2H), 2.61 (s, 1H), 2.53 (apparent sept, partially hidden, 1H, J=7.6 Hz), 2.50 (s, 3H), 2.30–2.10 (m, 6H), 1.82 (m, 2H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 529.6 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:6]=[CH:7][CH:8]=1.Cl[P:23]([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25]>C1(C)C=CC=CC=1>[CH:24]([P:23]([CH:27]([CH3:29])[CH3:28])[C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[N:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:16]2[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:26])[CH3:25]
Reactant: CC(C)P(Cl)C(C)C
Reactant: COc1cccc(-n2c3ccccc3c3ccccc32)c1
Solvent: Cc1ccccc1
Product: COc1cccc(-n2c3ccccc3c3ccccc32)c1P(C(C)C)C(C)C
Yield: 70.2 %

Procedure:
Title compound (1-2) (5.0 g) was obtained as a colorless powder by the same procedure as in the second step of Example 1, except that the reaction was conducted by use of the toluene solution of the crude product of N-(3-methoxyphenyl) carbazole (4-1) in an amount equivalent to 18.3 mmol, that chlorodiisopropylphosphine was used instead of Cy2PCl, and further that the product was isolated and purified by crystallization from toluene/methanol. Two Steps Overall Isolated Yield: 70.2%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13]O.C1C=CC(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:29]([CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1ccccc1-c1cnccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1ccccc1-c1cnccn1
Temperature: 25 °C

Procedure:
To a stirred solution of (2-pyrazin-2-ylphenyl)methanol (1.14 g, 6.13 mmol) in anhydrous THF (12.5 mL) at 0° C. was added DPPA (1.59 ml, 7.36 mmol) and DBU (1.01 mL, 6.75 mL). The resulting cloudy yellow mixture was allowed to warm to room temperature, and after 3.5 h was warmed to 80° C. for 3 h. The mixture was then cooled to room temperature and the THF was removed in vacuo. The residue was partitioned between EtOAc and H2O. The layers were separated and the aqueous layer was further extracted with EtOAc. The combined organic extracts were washed successively with a 10% aqueous solution of citric acid, saturated aqueous NaHCO3 and brine. The organic solution was dried (anhydrous Na2SO4), filtered and concentrated to a yellow-brown oil. Silica gel chromatography (40% EtOAc-hexanes) afforded the title compound as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.82 (d, J=1.6 Hz, 1 H), 8.67 (dd, J=1.6, 2.4 Hz, 1 H), 8.59 (d, J=2.4 Hz, 1 H), 7.55–7.48 (m, 4 H), 4.60 (s, 2 H). LCMS (M+H): 212.1.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]([N:14]2[CH2:18][C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C@@H:16]([C@@H:27]([O:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][N:31]=3)[CH3:28])[CH2:15]2)=[O:13])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([C:12]([N:14]2[CH2:18][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[CH:16]([CH:27]([O:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][N:31]=3)[CH3:28])[CH2:15]2)=[O:13])[CH2:11]1
Reactant: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CN(C(=O)C2CN(C(=O)OC(C)(C)C)C2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)C2CNC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a stirred solution of 3-[(3R,4S)-3-[(S)-1-(5-cyano-pyridin-2-yloxy)-ethyl]-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester (0.14 g, 0.25 mmol) in 4 mL of CH2Cl2 was added 1 mL of TFA. After one hour at RT, the reaction was quenched by addition of aq. NaOH 1M (until ph=10) and the product was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated under vacuo to yield 0.106 g (92%) of the title compound as a white foam. ES-MS m/e: 445.1 (M+H+).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][CH:14]=3)[CH:12]=2)=[O:5])[CH2:3][CH2:2]1.[O:24]=[S:25]1(=[O:39])[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(CCCN=C=N)C>CN(C=O)C.O>[O:39]=[S:25]1(=[O:24])[CH2:26][CH2:27][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:11]4[CH:12]=[C:7]([NH:6][C:4]([CH:1]5[CH2:2][CH2:3]5)=[O:5])[CH:8]=[CH:9][C:10]=4[O:22][CH3:23])=[CH:18][CH:17]=3)=[O:20])=[CH:34][CH:33]=2)[CH2:29][CH2:30]1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Reactant: COc1ccc(NC(=O)C2CC2)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc(NC(=O)C2CC2)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Reaction time: 18 h

Procedure:
A mixture of 5′-(cyclopropanecarbonyl-amino)-2′-methoxy-biphenyl-4-carboxylic acid (50 mg), 4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenylamine (38 mg), N-methylmorpholine (0.03 ml), 1-hydroxybenzotriazole (21 mg) and 1-ethyl-3-(3-(dimethylaminopropyl)carbodiimide hydrochloride (30 mg) in dry DMF (1 ml) was stirred at 20 C for 18 h. The mixture was then added to water and the resulting colourless precipitate collected by filtration and dried (38 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1noc2cc(F)ccc12
Agent: O=S(=O)(O)O
Product: Cc1noc2cc(F)c([N+](=O)[O-])cc12
Reaction time: 1 h

Procedure:
A mixture of 6-fluoro-3-methyl-1,2-benzisoxazole (23.5 g, 0.156 mol) in concentrated sulfuric acid is cooled with an ice-bath, treated dropwise with 90% nitric acid (8.50 mL) while maintaining the reaction mixture temperature below 15° C., stirred for one hour at ice-bath temperature, treated with additional 90% nitric acid (5.80 mL), warmed to and stirred at room temperature overnight, and poured onto ice. The resultant aqueous mixture is filtered to obtain a solid. The solid is air-dried and dissolved in methylene chloride. The resultant organic solution is dried over anhydrous magnesium sulfate, diluted with hexanes, and filtered to give the title product as a purple solid which is identified by 1H NMR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH3:20])[CH:13]=2)[C:6]=1[CH2:7][C:8]([OH:10])=[O:9].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:20])[CH:13]=2)[C:6]=1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: COc1ccc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.6 %

Procedure:
4-Chloro-1-(4-methoxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid (1.1 g) was suspended in 20 ml of dichloromethane and 4 ml of a dichloromethane solution containing 1 g of boron tribromide was added dropwise under stirring at room temperature. A precipitate separated out immediately after dissolution of the starting material. The mixture was allowed to stand for 6 hours. The supernatant was discarded and the precipitate was stirred with 50 ml each of ethyl acetate and water. The ethyl acetate layer was washed with water and evaporated to dryness under reduced pressure. The residue was washed with a small amount of acetone and recrystallized from aqueous alcohl to give 0.8 g of 4-chloro-1-(4-hydroxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid as colorless scales, m.p. 193°-195° C. (decompn.).
Reaction SMILES: C(O[C:6](=[O:31])[NH:7][C@H:8]([C:10](=[O:30])[NH:11][C@H:12]([B:17]1[O:25][C@H:24]2[C@:19]([CH3:29])([C@H:20]3[CH2:26][C@@H:22]([CH2:23]2)[C:21]3([CH3:28])[CH3:27])[O:18]1)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:9])(C)(C)C.[CH:32]([C:35]1[CH:36]=[C:37]([NH:41][C@@H:42]([CH2:46][C:47]2[CH:52]=[C:51]([O:53][CH3:54])[C:50]([O:55][CH3:56])=[C:49]([O:57][CH3:58])[CH:48]=2)C(O)=O)[CH:38]=[CH:39][CH:40]=1)([CH3:34])[CH3:33]>>[CH:32]([C:35]1[CH:36]=[C:37]([NH:41][C@@H:42]([CH2:46][C:47]2[CH:48]=[C:49]([O:57][CH3:58])[C:50]([O:55][CH3:56])=[C:51]([O:53][CH3:54])[CH:52]=2)[C:6]([NH:7][C@H:8]([C:10](=[O:30])[NH:11][C@H:12]([B:17]2[O:25][C@H:24]3[C@:19]([CH3:29])([C@H:20]4[CH2:26][C@@H:22]([CH2:23]3)[C:21]4([CH3:27])[CH3:28])[O:18]2)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:9])=[O:31])[CH:38]=[CH:39][CH:40]=1)([CH3:34])[CH3:33]
Reactant: COc1cc(C[C@H](Nc2cccc(C(C)C)c2)C(=O)O)cc(OC)c1OC
Reactant: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Product: COc1cc(C[C@H](Nc2cccc(C(C)C)c2)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)cc(OC)c1OC

Procedure:
The title compound is prepared as described in example 1 but using {(S)-1-[(R)-3-Methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester and (S)-2-(3-Isopropyl-phenylamino)-3-(3,4,5-trimethoxyphenyl)-propionic acid.