Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12](I)=[CH:13][N:14]=[C:8]2[CH:7]=1)C.ClC1C=CN2C([C:27]3[CH:28]=[C:29]([NH:33][C:34]([NH:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[O:35])[CH:30]=[CH:31][CH:32]=3)=CN=C2C=1.C([O-])([O-])=O.[K+].[K+].CO>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.O.CCO>[NH2:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:31]3[CH:30]=[C:29]([NH:33][C:34]([NH:36][CH2:37][C:38]([F:39])([F:40])[F:41])=[O:35])[CH:28]=[CH:27][CH:32]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: CCOC(=O)Nc1ccn2c(I)cnc2c1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)ccn23)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Yield: 11.5 %

Procedure:
To a solution of (3-Iodo-imidazo[1,2-a]pyridin-7-yl)carbamic acid ethyl ester (100 mg, 0.30 mmol) in toluene (0.5 ml) was added 1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (described in procedure A4) (126 mg, 0.36 mmol), K2CO3 (250 mg, 1.80 mmol), MeOH (0.5 ml), EtOH (0.5 ml) and water (0.7 ml) [reaction degassed by bubbling N2 through]. Bis(tri-tert-butylphosphine)palladium (0) (1.5 mg, 0.003 mmol) was added and the reaction was heated in a CEM discover microwave synthesizer (300W) at 135° C. for 30 min. The mixture was partitioned between water and EtOAc and the organic fraction was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the product (12 mg). MS: [M+H]+=350.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=3)[N:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)(=O)=O.[C:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([OH:29])=[O:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:27]([C:30]1[CH:35]=[CH:34][C:33]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=4)[N:16]=2)[N:13]=[CH:12][CH:11]=[CH:10]3)=[CH:32][CH:31]=1)([OH:29])=[O:28]
Reactant: N#Cc1cccc(-c2nc(OS(=O)(=O)C(F)(F)F)cc3cccnc23)c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2nc(-c3ccc(C(=O)O)cc3)cc3cccnc23)c1
Reaction time: 2.5 h
Yield: 56.2 %

Procedure:
To a solution of 6-trifluoromethylsulfonyloxy-8-(3-cyanophenyl)-1,7-napthyridine (2.15 g, 5.67 mmol) in DMF (21.5 ml) is added 4-carboxy-phenylboronic acid (1.13 g, 6.81 mmol), bis(dibenzylidenacetone) palladium (131 mg, 0.23 mmol), triphenylphosphine (95 mg, 0.36 mmol) and aqueous K2CO3 (2N, 17 ml). The reaction mixture is stirred at 80° for 2.5 h. The hot solution is filtered through cellit and the crude product is precipitated by carefully adding water (10 ml) and aqueous HCl (2N, 8 ml). The suspension is filtered and the crude product is stirred in hot THF (30 ml). The cold suspension is filtered again to yield the title compound (1.12 g). M+H=352. Melting point >300°. Retention time HPLC=7.58 min (column: LiChroCart 125-4, Supersphere 60 RP-select B, 400; eluent: acetonitrile-water (0.1% TFA)=45:55; 1 ml/min; detection at 254 nm).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([S:4]([NH:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)=[O:9])(=[O:6])=[O:5])[CH3:3]>[Pd].O.C(O)C>[CH3:3][C:2]([CH3:19])([S:4]([NH:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)=[O:9])(=[O:6])=[O:5])[CH3:1]
Reactant: CC(C)(C)S(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(C)(C)S(=O)(=O)NC(=O)c1cccc(N)c1
Yield: 99.1 %

Procedure:
In the same way as that described in Example 11, Step 2, using 1-(1,1-dimethylethylsulphonylaminocarbonyl)-3-nitrobenzene (0.36 g, 1.26 mmol), 10% palladium on carbon (0.1 g, 28% (w/w)) in water (2 ml) and ethanol (25 ml), the title compound (0.32 g, 99%) was afforded as a colourless solid. mp 150° C. (dec.). 1H NMR (360MHz, D6-DMSO) δ 1.30 (9H, s), 4.99 (2H, brs), 6.56-6.63 (1H, m), 6.97 (1H, t, J=7.7 Hz), 7.13-7.25 (2H, m).
Reaction SMILES: C(O)C.[Cl-].[NH4+].[O:6]=[C:7]1[N:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[CH:18]=[C:19]([Cl:25])[C:20]([N+:22]([O-])=O)=[CH:21][C:9]=2[S:8]1>[Fe].O>[O:6]=[C:7]1[N:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[CH:18]=[C:19]([Cl:25])[C:20]([NH2:22])=[CH:21][C:9]=2[S:8]1
Reactant: CCOC(=O)Cn1c(=O)sc2cc([N+](=O)[O-])c(Cl)cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cn1c(=O)sc2cc(N)c(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.4 %

Procedure:
To a mixture of ethanol (10 liters) and water (1 liter) were added ammonium chloride (25 g) and iron metal (300 g). To the mixture was added ethyl 2-oxo-5-chloro-6-nitro-3-benzothiazolineacetate (434.6 g) under mild reflux. After refluxing with stirring for 4 hours, the resultant mixture was filtered under warm condition. The filter cake was washed with ethanol. The combined filtrate and washings were concentrated under reduced pressure and cooled to ambient temperature to give crystals, which were separated by filtration to give crystalline ethyl 2-oxo-5-chloro-6-amino-3-benzothiazolineacetate (347.8 g).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:16]=[CH:15][C:14](I)=[CH:13][C:10]=1[CH2:11][OH:12].[C:18]([C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:27]=1)[C:25]#[N:26])#[CH:19]>O1CCCC1.[Br-].[Zn+2].[Br-].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>[F:8][C:9]1[CH:16]=[CH:15][C:14]([C:19]#[C:18][C:20]2[CH:21]=[N:22][CH:23]=[C:24]([CH:27]=2)[C:25]#[N:26])=[CH:13][C:10]=1[CH2:11][OH:12]
Reactant: C#Cc1cncc(C#N)c1
Reactant: OCc1cc(I)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cncc(C#Cc2ccc(F)c(CO)c2)c1
Temperature: 60 °C
Yield: 61.6 %

Procedure:
Dissolve zinc (II) bromide (374 mg, 14.3 mmol) in tetrahydrofuran (30 mL) and treat with triethylamine (7.96 mL, 57.1 mmol). After 5 min add 2-fluoro -5-iodobenzyl alcohol, (prepared as described in PREPARATION 33), (3.00 g, 11.9 mmol), 5-ethynylnicotinonitrile, (prepared as described in PREPARATION 4), (1.83 g, 14.3 mmol) and tetrakis(triphenylphosphine)palladium (0) (688 mg, 0.595 mmol) to the reddish solution. Heat to 60° C. for 2 h, cool to room temperature, and filter through diatomaceous earth. Purify by silica gel chromatography, eluting with 75:25 to 60:40 hexanes:ethyl acetate, to give the title compound as a yellow crystalline solid (1.85 g, 62%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([NH2:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21](=[O:28])[CH2:22][C:23](=O)[CH:24](Br)[CH3:25].O1CCOCC1.C1(C)C=CC=CC=1>O>[CH3:19][O:20][C:21](=[O:28])[CH2:22][C:23]1[N:10]=[C:8]([C:7]2[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]([OH:14])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)[O:9][C:24]=1[CH3:25]
Reactant: CC(C)(C)c1cc(C(N)=O)cc(C(C)(C)C)c1O
Reactant: COC(=O)CC(=O)C(C)Br
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)Cc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)oc1C
Yield: 48.5 %

Procedure:
A mixture of 3,5-di-tert-butyl-4-hydroxybenzamide (16.0 g, 64.3 mmol), 4-bromo-3-oxopentanoic acid methyl ester (18.6 g, 64.26 mmol), dioxane (60mL), and toluene (600 mL) was refluxed for 5 days with continuous water removal (Dean Stark trap). Then, the volatiles were removed in vacuo and the residue was purified by flash chromatography on silica gel (eluting solvent: hexane/EtOAc 3/1) to give a brown viscous oil (11.2 g). Crystallization of the brown oil from ethyl ether (after cooling to 0° C.) gave a white solid (9.2 g, 40% yield), m.p. 121°-123° C.
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1([S:24][CH:25]([C:29](O)=[O:30])[C:26](O)=[O:27])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[OH:30][C:29]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:26](=[O:27])[C:25]=1[S:24][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C(Sc1cccc2ccccc12)C(=O)O
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Product: O=c1oc(-c2ccccc2)cc(O)c1Sc1cccc2ccccc12

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(1-naphthyl)thio]propanedioic acid (1.61 g, 5.07 mmol). m.p. 242-243° C.; 1H NMR (400 MHz, DMSO-d6) δ 6.83 (s, 1H), 7.19 (d, 1H), 7.39 (t, 1H), 7.64-7.42 (m, 5H), 7.69 (d, 1H), 7.83 (m, 2H), 7.94 (d, 1H), 8.28 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:11])[NH:4][CH:5]=[CH:6][C:7]=1[C:8](Cl)=[O:9].[C:12]1([C@@H:18]2[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[OH:1][C:2]1[C:3](=[O:11])[NH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:24][C@H:21]1[CH2:20][CH2:19][C@@H:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:23][CH2:22]1)=[O:9]
Reactant: N[C@H]1CC[C@@H](c2ccccc2)CC1
Reactant: O=C(Cl)c1cc[nH]c(=O)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@@H](c2ccccc2)CC1)c1cc[nH]c(=O)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-hydroxy-2-oxo-1,2-dihydropyridine-4-carbonyl chloride (Intermediate 17) (38.1 mg, 0.219 mmol) and cis-4-phenylcyclohexanamine (Intermediate 14) (50 mg, 0.29 mmol) in DCM (1 mL) was added Et3N (0.061 mL, 0.44 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was partitioned between H2O and DCM. The DCM layer was dried over Na2SO4 and filtered through a silica gel plug. The solvent was removed under reduced pressure to give Example 36A which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]2[CH2:19][CH:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9]1.[BH4-].[Na+]>CO.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([C:15]2[CH2:19][CH:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9]1
Reactant: CC(=O)NCC1CC(c2ccc(-n3ccc(C=O)c3)c(F)c2)=NO1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)NCC1CC(c2ccc(-n3ccc(CO)c3)c(F)c2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
(-)-5-Acetamidomethyl-3-(3-fluoro-4-(3-formyl-pyrrol-1-yl)phenyl)isoxazoline (Example 15) (658 mg) is suspended/dissolved in 20 ml methanol under nitrogen. The mixture is treated with sodium borohydride (76 mg) and the reaction is stirred 1 hour at room temperature. The reaction is diluted with 1×10 ml 2N sodium hydroxide and the volatiles are removed in vacuo. The residue is diluted with 20 ml water and the white solid is collected and dried to give 609 mg of the title compound as an off white solid, mp 162-164° C., [α]25D -72° (c 0.54, methanol).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[C:8]([O:13][CH2:14][CH2:15][O:16][C:17](ON1C(=O)CCC1=O)=[O:18])(=[O:12])[CH2:9][CH2:10][CH3:11]>>[C:8]([O:13][CH2:14][CH2:15][O:16][C:17]([NH:1][C@H:2]([CH2:3][OH:4])[C:5]([OH:7])=[O:6])=[O:18])(=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: CCCC(=O)OCCOC(=O)ON1C(=O)CCC1=O
Reactant: N[C@H](CO)C(=O)O
Product: CCCC(=O)OCCOC(=O)N[C@H](CO)C(=O)O
Yield: 48.4 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, D-serine (252 mg, 2.4 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl butanoate (546 mg, 2.0 mmol) were reacted to provide 255 mg (40% yield) the title compound (30) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=6.80 (m, 1H), 6.09 (t, 1H), 5.81 (br s, 1H), 4.41 (m, 1H), 4.07 (m, 1H), 3.92 (m, 1H), 2.31 (m, 2H), 1.65 (m, 2H), 1.50 (d, 3H), 0.99 (m, 3H). MS (ESI) m/z 286.07 (M+Na)+; 262.06 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:17][OH:18])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=2)=[N:4][O:5][N:6]=1.C1N=CN([C:24](N2C=NC=C2)=[O:25])C=1>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=3)[C:24](=[O:25])[O:18][N:17]=2)=[N:4][O:5][N:6]=1
Reactant: Nc1nonc1C(=NO)Nc1ccc(F)c(Br)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 84.6 %

Procedure:
A mixture of 4-amino-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (65.7 g, 208 mmol), N,N-carbonyldiimidazole (Sigma-Aldrich) (50.6 g, 312 mmol, 1.5 equiv.), and ethyl acetate (750 mL) was heated to 60° C. and stirred for 20 min. LCMS indicated reaction completed. The reaction was cooled to room temperature, washed with 1 N hydrochloric acid (2×750 mL), dried over sodium sulfate, and concentrated. The crude product was triturated with a mixture of dichloromethane, ethyl acetate, and diethyl ether to give the desired product (60.2 g, 85%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.05 (m, 1H), 7.69 (m, 1H), 7.57 (t, 1H, J=8.7 Hz), 6.58 (s, 2H); C10H5BrFN5O3 (MW 342.08), LCMS (EI) m/e 342/344 (M++H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH:21]1(B(O)O)[CH2:23][CH2:22]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O>[C:17]([Si:14]([CH3:16])([CH3:15])[O:13][CH2:12][CH2:11][O:10][C:5]1[CH:4]=[CH:3][C:2]([CH:21]2[CH2:23][CH2:22]2)=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:20])([CH3:19])[CH3:18]
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)cc1C=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(C2CC2)cc1C=O
Temperature: 100 °C
Yield: 71.8 %

Procedure:
To a solution of 5-bromo-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-benzaldehyde (5 g, 13.9 mmol) prepared in example 130a in toluene (75 mL) and water (7.5 mL) was added cyclopropylboronic acid (1.7 g, 19.8 mmol) (Aldrich) and potassium phosphate (14.6 g, 68.9 mmol). After the reaction mixture was degassed for 5 min, dichloro-bis-(tricyclohexyl-phosphine) (1.03 g, 1.39 mmol) (Strem) was added and the reaction mixture was heated at 100° C. under nitrogen for 4 h. The reaction mixture was cooled to room temperature and diluted with water, extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was purified with chromatography to give 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-cyclopropyl-benzaldehyde as yellow oil (Yield: 3.2 g, 76.2%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[N:23]1[CH:24]=[CH:25][C:20]([C:19]2[O:26][C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:17])([C:13]([F:14])([F:16])[F:15])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=3[N:18]=2)=[CH:21][CH:22]=1
Reactant: O=C(Nc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1O)c1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: FC(F)(F)C(F)(c1ccc2oc(-c3ccncc3)nc2c1)C(F)(F)F
Reaction time: 2.3 h

Procedure:
To a mixture of 0.79 g of N-[2-hydroxy-5-(heptafluoroisopropyl)phenyl]isonicotinamide, 8 ml of tetrahydrofuran and 0.60 g of triphenylphosphine, 0.99 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred for 2.3 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-(pyridin-4-yl)-5-(heptafluoroisopropyl)benzoxazole (hereinafter, referred to as “active compound 67”).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[CH3:14][CH:15]([CH:17]=O)[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[N:6]=[CH:14][CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12]
Reactant: CC(C)C=O
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Product: CC(C)C=Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,6-Diisopropylaniline (9.4 mL, 50 mmol, Aldrich) was mixed with isobutyric aldehyde (9.1 mL, 100 mmol, Aldrich), p-toluenesulfonic acid (0.48 g, 2.5 mmol, Aldrich), chloroform (50 mL) and MgSO4 (12 g, 100 mmol). The mixture was stirred for 2 h at RT. Assay by 1H-NMR (crude reaction mixture) showed the presence of product and starting material (8/1 ratio). The reaction mixture was filtered, the precipitate washed with chloroform (50 mL), and 5 Å molecular sieves were added. After stirring for 20 h at RT the solution was filtered, the molecular sieves were washed with chloroform (2×50 mL), the solvent was evaporated, and the residue distilled at reduced pressure. After a few drops of forerun (67–76° C./27 Pa) product was collected at 76–77° C./27 Pa as a colorless oil, 8.66 g (74.8%). 1H NMR (CDCl3) 7.60 (d, 1H; J=4.8 Hz); 7.20–7.05 (m, 3H); 3.00 (septet, 2H; J=6.8 Hz); 2.78 (d of septets, 1H; J=4.8; 6.7 Hz); 1.33 (d, 6H; J=6.7 Hz); 1.23 (d, 12H; J=6.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.FC(F)(F)C(O)=[O:12].OO>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:12]
Reactant: O=C(O)C(F)(F)F
Reactant: Clc1cccc(Cl)n1
Agent: OO
Solvent: O
Product: [O-][n+]1c(Cl)cccc1Cl

Procedure:
24 g of 2,6-dichloropyridine, 200 ml of trifluoroacetic acid and 28 ml of 33% hydrogen peroxide are heated to 100° C. for 4 hours. The mixture is cooled, 600 ml of water are then added and the resulting mixture is concentrated under vacuum to a volume of 50-100 ml. It is alkalinized with sodium hydrogen carbonate and then extracted with DCM, and the organic phase is separated after settling has taken place and dried over sodium sulphate. It is filtered and concentrated under vacuum, and the residue is recrystallized from AcOEt to obtain 18.8 g of 2,6-dichloropyridine N-oxide; m.p.=138°-140° C.
Reaction SMILES: C([O:8][C:9]1[C:16](O)=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[OH:8][C:9]1[C:16]([O:37][CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12]
Reactant: O=Cc1cccc(O)c1OCc1ccccc1
Reactant: OCCc1ccccn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1cccc(OCCc2ccccn2)c1O
Reaction time: 12 h
Yield: 91.7 %

Procedure:
2-benzyloxy-3-hydroxy-benzaldehyde 16 (0.30 g, 1.3 mmol), triphenylphosphine (0.41 g, 1.6 mmol) and 2-(2-hydroxyethyl)pyridine (0.18 ml, 1.6 mmol) were stirred in THF (15 ml), followed by the addition of DEAD (0.25 ml, 1.6 mmol). After stirring for 12 h, the reaction mixture is partitioned between ethyl acetate (200 ml) and saturated aqueous sodium hydrogen carbonate (200 ml). The organic layer is separated, dried (MgSO4), filtered and concentrated to give a brown oil. The brown oil is purified by flash chromatography (50% ethyl acetate/hexanes) to afford 0.29 g (66%) of 2-hydroxy-3-(2-pyridin-2-ylethoxy)benzaldehyde 17 as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-])=O.[H][H]>[Pt]=O.C(O)(=O)C>[NH:12]1[C:13]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[NH2:1])[CH2:9][CH2:10][CH2:11]1
Reactant: O=[N+]([O-])c1cccc2cccnc12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: Nc1cccc2c1NCCC2
Yield: 71.4 %

Procedure:
A mixed solution of 8-nitroquinoline (25.0 g), platinum oxide (600 mg) and glacial acetic acid (300 ml) was stirred at room temperature for 4 hours under the atmosphere of hydrogen at 5 atm. The reaction mixture was filtered through Celite, and the solvent was evaporated under reduced pressure. Then, the solution was extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography to give the title compound as a reddish brown oil (15.2 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=2[N:5]=[C:4]1[CH3:15])[CH3:2].C1C(=O)N([Br:23])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=2[N:5]=[C:4]1[CH2:15][Br:23])[CH3:2]
Reactant: CCn1c(C)nc2c([N+](=O)[O-])cccc21
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCn1c(CBr)nc2c([N+](=O)[O-])cccc21
Temperature: 90 °C
Yield: 54.3 %

Procedure:
To a solution of 0.216 g (1.05 mmol) 1-ethyl-2-methyl-4-nitrobenzimidazole, 50 mL carbon tetrachloride and 0.375 g (2.11 mmol) NBS, was added 50 mg of AIBN. The reaction mixture was heated to 90° C. for five hours and the solution was cooled to room temperature. The solution was concentrated under reduced pressure and the resulting oil was chromatographed on silica to yield 0.16 g (0.57 mmol, 54%) of a light yellow oil.
Reaction SMILES: FC(F)(F)C([O-])=O.[NH2:8][C@H:9]([C@@H:17]([OH:29])[C@H:18]([OH:28])[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:30]([C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([C:42](=[O:50])[N:43]([CH2:47][CH2:48][CH3:49])[CH2:44][CH2:45][CH3:46])[CH:41]=1)[C:36](O)=[O:37])(=[O:32])[NH2:31].CCN(C(C)C)C(C)C>>[CH2:10]([C@H:9]([NH:8][C:36]([C:35]1[CH:34]=[C:33]([C:30]([NH2:31])=[O:32])[CH:41]=[C:40]([C:42]([N:43]([CH2:47][CH2:48][CH3:49])[CH2:44][CH2:45][CH3:46])=[O:50])[CH:39]=1)=[O:37])[C@@H:17]([OH:29])[C@H:18]([OH:28])[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(C(=O)O)c1
Reactant: N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)CCCc1ccccc1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)[C@H](O)CCCc2ccccc2)c1

Procedure:
The trifluoroacetate salt of (2S,3R,4R)-2-amino-1,7-diphenyl-heptane-3,4-diol (0.1 mmol) was reacted with 3-carbamoyl-5-dipropylcarbamoyl-benzoic acid as described in method A (addition of an extra equivalent of DIEA to neutralize the amine salt) to give N1-[(1S,2R,3R)-1-benzyl-2,3-dihydroxy-6-phenylhexyl]-N3 ,N3-dipropylbenzene-1,3,5-tricarboxamide. MS (ESI+) for C34H43N3O5 m/z 574 (M+H)+.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11][C:12]#N)[C:8]([S:14][CH3:15])=[CH:7][C:5]=2[N:6]=1.[OH-:16].[Na+].[BH4-].[Na+].IC>C(O)C.O>[CH3:2][S:3][C:4]1[CH:10]=[C:9]([S:11][CH3:12])[C:8]([S:14][CH3:15])=[CH:7][C:5]=1[NH2:6].[CH2:10]([OH:16])[CH3:4]
Reactant: [OH-]
Reactant: CSc1cc2nc(N)sc2cc1SC#N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CCO
Product: CSc1cc(SC)c(SC)cc1N
Temperature: 25 °C

Procedure:
2,4,5-Trimethylthioaniline was prepared by combining 2-amino-5-methylthio-6-thiocyanatobenzothiazole (220 g, 0.87 mol) with 1.2 L of water, 1.0 L of 50% sodium hydroxide solution, and sodium borohydride (40 g, 1.06 mol) in a 5 L, 3-necked flask. The mixture was stirred with a mechanical stirrer and refluxed under a nitrogen atmosphere for 15 hr. The mixture was cooled to room temperature and ethanol (800 mL) was added followed by addition of iodomethane (300 g, 2.11 mole). The solution was collected and dried. The product was recrystallized from ethanol (66 g, 33% yield).