Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 50 °C
Yield: 53.4 %

Procedure:
A solution of 4-bromoaniline (20 g, 116 mmol), 4-(trifluoromethyl)phenylboronic acid (15 g, 79 mmol), potassium carbonate (36.3 g, 263 mmol), and palladium(II) acetate (946 mg, 4.21 mmol) in 1,2-dimethoxyethane (80 mL) and water (80 mL) was stirred at 30° C. overnight. The reaction was then heated to 50° C. for 7 hours. The reaction was filtered through Celite and extracted with ethyl acetate (3×200 mL). The combined organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0.5-1.7% petroleum ether/ethyl acetate) gave 4′-(trifluoromethyl) biphenyl-4-amine (10 g, 40%) as an off white solid. 1H NMR (400 MHz, (CD3)2SO, δ): 7.73-7.82 (m, 4H), 7.55 (dd, 2H), 6.72 (d, 2H), 5.47 (s, 2H). MS (M+1): 238.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:26][C:27]1[CH:28]=[CH:29][C:30]([CH:33](OS(C(F)(F)F)(=O)=O)[C:34]([F:37])([F:36])[F:35])=[N:31][CH:32]=1>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][CH:33]([C:30]3[CH:29]=[CH:28][C:27]([Br:26])=[CH:32][N:31]=3)[C:34]([F:37])([F:36])[F:35])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OC(c1ccc(Br)cn1)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NC(c3ccc(Br)cn3)C(F)(F)F)cc2)COC1(C)C
Reaction time: 0.25 h
Yield: 37.9 %

Procedure:
To a stirred solution of (S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (150 mg, example 6b) in dry THF (0.2 ml) under an argon atmosphere was added sodium hydride (34 mg, 60% dispersion in mineral oil) and stirring was continued for 15 minutes. Trifluoro-methanesulfonic acid 1-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl ester (182 mg) was then added and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed sequentially with water and with saturated brine. The organic phase was separated, dried over sodium sulphate, and concentrated in vacuo. The reside was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-(2-{4-[1-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethylamino]-phenyl}-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (99 mg, 38%) as a yellow oil. MS (ISP): 560.1 ([{81Br}M+H]+), 558.1 ([{79Br}M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[C:8]([N+:20]([O-])=O)[CH:7]=1.[NH4+].[Cl-]>[Fe]>[NH2:20][C:8]1[CH:7]=[C:6]([O:5][CH2:4][C:3]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:2]=2[Cl:1])[CH:11]=[CH:10][C:9]=1[S:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cc(OCc2cc(F)ccc2Cl)ccc1Sc1ccc(O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1cc(OCc2cc(F)ccc2Cl)ccc1Sc1ccc(O)cc1
Yield: 78.3 %

Procedure:
The product from Example 236c (4.2 g, 10.2 mmol) was reacted with Fe and NH4Cl as described in Example 10E to give the title compound (3.0 g, 77%).
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]([CH3:35])[C@@H:21]([NH:28]S(C(C)(C)C)=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>CO>[NH2:28][C@@H:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:20]([CH3:35])[CH2:19][OH:18]
Reactant: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H](NS(=O)C(C)(C)C)c1ccccc1
Agent: Cl
Solvent: CO
Product: C[C@@H](CO)[C@@H](N)c1ccccc1
Temperature: 70 °C
Reaction time: 7 h
Yield: 98.9 %

Procedure:
N-[(1R,2R)-3-{[tert-butyl(diphenyl)silyl]oxy}-2-methyl-1-phenylpropyl]-2-methylpropane-2-sulfinamide (Example 136b, 1.46 g) was stirred in methanol (10 mL) and then Hydrogen chloride (4M in dioxane) (10 mL) added. The reaction was stirred at 70° C. for 7 h and then concentrated in vacuo. The crude product was azeotroped with toluene then triturated in ether for 2 days after which the solvent was concentrated in vacuo to give the subtitle compound (0.47 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].C1(C)C=CC(S(O[CH2:41][CH2:42][CH:43]([C:50]([F:53])([F:52])[F:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])(=O)=O)=CC=1>C1COCC1.CN(C)C=O>[F:51][C:50]([F:52])([F:53])[CH:43]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:42][CH2:41][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=3)=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reactant: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(O)cc3)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OCCC(CCCCCC)C(F)(F)F)cc3)nc2)cc1
Yield: 45.6 %

Procedure:
In a 30 ml-round-bottomed flask, a solution of 0.188 g (0.50 mM) of 2-(4-hydroxyphenyl)-5-(4-octyloxyphenyl)pyrimidine in dry THF and 2 ml of dry N,N-dimethylformamide were placed and sufficiently stirred. To the mixture, 40 mg of 60%-sodium hydride was added and 0.183 g (0.50 mM) of (-)-3-trifluoromethylnonyl p-toluene sulfonate was further added dropwise, followed by stirring for 6 hours at 130° C. After the reaction, distilled water was added to the reaction mixture and extracted with ether, followed by drying with anhydrous sodium sulfate and purification by thin-layer chromatography (developing solvent: hexane/ethyl acetate =3/1 (first) and 4/1 (second)) to obtain 0.13 g (0.23 mM) of 2-{4-(3-trifluoromethylnonyloxy)phenyl}-5-(4-octyloxyphenyl)pyrimidine (Yield: 46.0%). ##STR86##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][N:22]=1>C(Cl)Cl.CO>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([NH2:20])=[N:22][CH:23]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cn1
Yield: 69 %

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 2-aminopyridine-5-boronic acid pinacol ester with the reaction time of 15 h. Chromatography (methylene chloride/methanol 97:3) gave 69% of the title compound as a light yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=1[OH:29])[CH:24]=O)([CH3:20])([CH3:19])[CH3:18]>CO>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH:24]([S:11][C:9]2[CH:8]=[C:7]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=2)[C:23]2[CH:22]=[C:21]([C:17]([CH3:18])([CH3:20])[CH3:19])[C:28]([OH:29])=[C:27]([C:30]([CH3:31])([CH3:32])[CH3:33])[CH:26]=2)[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CO
Product: CC(C)(C)c1cc(SC(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Yield: 86.6 %

Procedure:
The procedure of Example 1 is repeated using 23.84 grams of 2,6-di-tert-butyl-4-mercaptophenol, 11.72 grams of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 150 ml of methyl alcohol. Trituration with methyl alcohol gives 30 grams (87% yield) of white crystals, mp 175°-177° C.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1)C.Cl.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27]N)=[CH:23][CH:22]=1.C(N(CC)CC)C>C(O)C>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:6]([C:7]3[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=3)=[N:5][CH:4]=[N:2]2)=[CH:23][CH:22]=1
Reactant: CN(C)C=NC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-n2ncnc2-c2ccc(S(C)(=O)=O)cc2)cc1
Yield: 7.7 %

Procedure:
A mixture of N-(dimethylamino-methylene)-4-(methyl-sulfonyl)-benzamide (4 g, 15.7 mol), 4-methoxy-phenylhydrazine hydrochloride (2.75 g, 15.7 mmol), triethylamine (2.2 ml, 15.7 mmol) in ethanol (20 ml) was heated to reflux for 25 h. After cooling, the reaction mixture was concentrated to dryness, then diluted with ethyl acetate. The organic phase was washed with water and saturated brine and dried over sodium sulfate. The residue was chromatographed on silica gel using a 70/30 mixture of toluene/dioxane as the eluent, then recrystallized from ethanol to give a light orange solid (0.4 g, 15%).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([C:34]3[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:31]=[CH:32][CH:33]=2)O1>>[Si:13]([O:12][CH2:11][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:32]3[CH:31]=[C:30]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:29]=[CH:28][CH:33]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OCc1ccn2c(Br)cnc2n1
Product: CC(C)(C)[Si](C)(C)OCc1ccn2c(-c3cccc(-c4ccccc4C#N)c3)cnc2n1

Procedure:
3-Bromo-7-(tert-butyldimethylsilanyloxymethyl)imidazo[1,2-a]pyrimidine (1.37 g, 4.00 mmol) was coupled with 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3′-[7-(tert-butyldimethylsilanyloxymethyl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2-carbonitrile as a yellow solid. This solid was suspended in methanol (25 ml) and treated with conc. hydrochloric acid (1 ml) and left to stir at ambient temperature for 5 min. The solution was loaded onto a cartridge of strong cation-exchange resin, eluting with methanol then with 10% conc. ammonia in methanol. The basic fractions were concentrated in vacuo and the residue purified further by chromatography on silica gel. Elution with dichloromethane (containing 1% conc. ammonia) on a gradient of methanol (2-5%) afforded 3′-(7-hydroxymethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile (587 mg, 45%) as a yellow powder: δH (400 MHz, CDCl3) 1.90 (1H, s), 4.88 (2H, s), 6.91 (1H, d, J 7), 7.51 (1H, td, J 8 and 1), 7.57-7.73 (5H, m), 7.77 (1H, dd, J 1 and 1), 7.82 (1H, dd, J 8 and 1), 7.89 (1H, s), 8.94 (1H, d, J 7); m/z (ES+) 327 (M++H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]([I:28])[C:22]=4[N:21]=[N:20]3)[CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])C.O[Li].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCO.O>[I:28][C:27]1[C:22]2[N:21]=[N:20][N:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH:12][CH:9]4[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]4)[N:18]=3)[C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)C1CCC(Nc2nccc(-n3nnc4c(I)cccc43)n2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]O
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCC(Nc2nccc(-n3nnc4c(I)cccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a mixture of 4-[4-(4-iodobenzotriazol-1-yl)-pyrimidin-2-ylamino]-cyclohexane-carboxylic acid ethyl ester (2.56 g) in THF (20 mL), EtOH (20 mL) and H2O (15 mL) was added LiOH.H2O (0.65 g), and the resulting mixture stirred at RT overnight. The reaction mixture was then acidified with citric acid (2.99 g) in H2O (10 mL), and the solvent removed in vacuo. The resulting light orange solid was stirred in H2O for 30 min, filtered, washed with H2O, and dried to obtain 4-[4-(4-iodobenzotriazol-1-yl)-pyrimidin-2-ylamino]-cyclohexanecarboxylic acid (2.1 g, 87%) as a light orange powder. Mp=252-254° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]3[CH2:16][C:15](=O)[NH:14][CH2:13][C:12]4[CH:18]=[CH:19][CH:20]=[CH:21][C:11]3=4)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]4[CH:18]=[CH:19][CH:20]=[CH:21][C:11]3=4)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1CC(c2ccc3[nH]ccc3c2)c2ccccc2CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)CNCCC2c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-water bath cooled suspension of 5-(1H-indol-5-yl)-1,2,4,5-tetrahydro-benzo[c]azepin-3-one (0.50 g, 1.8 mmol) in tetrahydrofuran (75 mL) was added lithium aluminum hydride (0.27 g, 7.2 mmol) as a slurry in tetrahydrofuran (5 mL). The mixture was heated to reflux for 100 minutes, then cooled in an ice-water bath and quenched with water (0.6 mL), 15% aqueous KOH (0.6 mL), and also crushed sodium sulfate decahydrate (14 g). The mixture was stirred mixture at room temperature for 30 minutes, then filtered and washed with ethyl acetate. The organic layer was concentrated to a yellow oil that was purified by flash chromatography (ammonium hydroxide/methanol/dichloromethane) to afford pure 5-(1H-indol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a colorless foam (0.20 g, MS (M+H)=263), as well as some product (0.23 g) contaminated with an uncharacterized tetrahydrofuran-aluminum complex as a colorless foam. The contaminated product was dissolved in 1:1 ethyl acetate:diethyl ether (5 mL), and 1.0 M HCl in diethyl ether (0.9 mL) was added dropwise, under a blanket of dry nitrogen gas. The white solid precipitate was collected by filtration and washed with ice-cold diethyl ether and tetrahydrofuran. The solid was suspended in ethanol and evaporated to dryness under reduced pressure, and that process was repeated to afford pure 5-(1H-indol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine hydrochloride as an off-white powder (0.16 g).
Reaction SMILES: O.[OH-].[Li+].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[O:10][C:11]([CH3:43])=[C:12]([CH2:14][O:15][C:16]2[CH:42]=[CH:41][C:19]([CH2:20][O:21]/[N:22]=[C:23](/[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[CH:18][CH:17]=2)[N:13]=1.O.Cl>O1CCCC1.C(O)C>[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[O:10][C:11]([CH3:43])=[C:12]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][O:21]/[N:22]=[C:23](/[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:41][CH:42]=2)[N:13]=1
Reactant: CCOC(=O)CCCCCC/C(=N\OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CO/N=C(\CCCCCCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
Lithium hydroxide monohydrate (143 mg) was added to a solution of ethyl E-8-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-8-phenyloctanoate (618 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4 ml) and stirred at room temperature for 4 hours. 1N hydrochloric acid (3.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-8-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-8-phenyloctanoic acid (523 mg, yield 90%) as colorless crystals. m.p. 75-77° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:42]=[C:43]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[CH2:44][NH:45][C:46]([C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:50][CH:49]=1)=[O:47]>CN(C=O)C.O>[F:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:11]([F:10])[C:12]=1[C:13]([N:63]1[CH2:62][CH2:61][N:60]([C:43](=[O:42])[CH2:44][NH:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:50][CH:49]=2)=[O:47])[CH2:65][CH2:64]1)=[O:15]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2c(F)cccc2F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 39.6 %

Procedure:
DIPEA (179.7 mg, 0.24 mL, 1.39 mmol) was added to a stirred solution of 2,6-difluoro-benzoic acid (48.8 mg, 0.30 mmol) in DMF (3 mL). HOBT (45.9 mg, 0.34 mmol) and EDCI (148.1 mg, 0.77 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (120 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 60% EtOAc in Hexane as eluent) to afford 55 mg (38.4% yield) of biphenyl-4-carboxylic acid {2-[4-(2,6-difluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 99.12%. 1H NMR (DMSO-d6): δ 8.7-8.6 (t, 1H), 8.0-7.94 (d, 2H), 7.82-7.7 (q, 4H), 7.62-7.54 (m, 1H), 7.54-7.38 (m, 3H), 7.3-7.2 (t, 2H), 4.2 (dd, 2H), 3.8-3.4 (m, 8H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:7]([C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[C:11]2[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=2)=[O:9])[C@@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][N:27]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(-c2nccn2C)c(C(=O)O)c1
Product: Cc1ccc(-c2nccn2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(1-methyl-1H-imidazol-2-yl)benzoic acid and N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 472 [M+1]+.
Reaction SMILES: C(O[C:6]([N:8]([C:11]1[CH:38]=[CH:37][C:14]([CH2:15][N:16]2[C:20]3=[N:21][C:22]([C:25](=[O:35])[NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(=[O:29])=[O:28])=[CH:23][CH:24]=[C:19]3[N:18]=[C:17]2[CH3:36])=[C:13]([Cl:39])[CH:12]=1)CC)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:39][C:13]1[CH:12]=[C:11]([NH:8][CH3:6])[CH:38]=[CH:37][C:14]=1[CH2:15][N:16]1[C:20]2=[N:21][C:22]([C:25](=[O:35])[NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(=[O:29])=[O:28])=[CH:23][CH:24]=[C:19]2[N:18]=[C:17]1[CH3:36]
Reactant: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(N(CC)C(=O)OC(C)(C)C)cc3Cl)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(NC)cc3Cl)c2n1
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of 3-(4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (1.91 g) in dichloromethane (19 ml) was added trifluoroacetic acid (14.5 ml) under ice-cooling, and the mixture was stirred for 1 hr. The solvent was evaporated and methanol (19 ml) was added to the residue for re-dissolution. Water (9.5 ml) was added and 1N aqueous sodium hydroxide solution was added dropwise under ice-cooling to adjust to about pH 4. The resulting precipitate was collected by filtration and dried under reduced pressure to give 3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (1.53 g) as a white powder.
Reaction SMILES: [C:1]([CH:3]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1)C(OC(C)(C)C)=O)#[N:2]>Cl.CCO>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:3][C:1]#[N:2])=[N:12][CH:13]=1)([O-:19])=[O:18]
Reactant: CC(C)(C)OC(=O)C(C#N)c1ccc([N+](=O)[O-])cn1
Agent: Cl
Solvent: CCO
Product: N#CCc1ccc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
The crude product tert-butyl 2-cyano-2-(5-nitropyridin-2-yl)acetate (I-1b, 12 g, 47 mmol) was dissolved in 100 mL of HCl/EtOH (v/v 1:5) and stirred at 80° C. for 4 h. Then the mixture was concentrated, diluted with H2O, and extracted with EtOAc (4×40 mL). The combined extracts were concentrated, and the residue was purified by chromatography on silica gel (PE:EtOAc=3:1) to afford 2-(5-nitropyridin-2-yl)acetonitrile (I-1c) as a solid (7.7 g, 42.0% yield).
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:2].O.[CH2:13]1[CH2:17]OC[CH2:14]1>C(OCC)C.[Ti]>[CH2:14]=[CH:13][CH2:17][C@@H:1]([OH:2])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC=O
Reactant: C1CCOC1
Agent: [Ti]
Solvent: O
Solvent: CCOCC
Product: C=CC[C@@H](O)CCCCCCCCC
Temperature: -74 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A solution of 1.25 mmol of the titanium compound of Example 2b in 60 ml of diethyl ether is cooled to -74° C. and 0.19 ml (0.1 mmol) of freshly distilled capraldehyde is added. The slightly yellow, clear solution is stirred for a further 2 hours at -74° C. and 5 ml of a 5N H2O/THF solution are added and the mixture is warmed to RT, stirred for a further hour at this temperature, filtered with suction and evaporated on a rotary evaporator. The crude product (1.13 g of clear, colourless oil) is flash-chromatographed (60 g of silica gel, 35 cm long, cross-section 2 cm, 5 ml/fraction, 0.4 bar, 10:1 toluene/ethanol) and is then distilled in a bulb tube (b.p.: ≈120-130 at 0.104 mbar). 0.141 g of product is obtained. Yield: 71%, ee: 95%.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][O:27]2)=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C1=COCCC1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC2CCCCO2)cc1

Procedure:
A mixture of 7 g. (19.4 m moles) 4-(hexadecylamino)-benzoic acid, 2 g. (23.8 m moles) dihydropyran and 100 mg. anhydrous p-toluenesulfonic acid in 50 ml. toluene is stirred at room temperature for 20 hours. The solution is washed with saturated sodium bicarbonate, dried, and condensed. The residue is crystallized from methylcyclohexane to white crystals.