Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH2:2]([N+:5]1[C:14]2[C:13]3[O:15][CH2:16][CH2:17][O:18][C:12]=3[CH:11]=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH:3]=[CH2:4].[OH-:19].[K+].O>O1CCOCC1>[CH2:2]([N:5]1[C:14]2[C:13]3[O:15][CH2:16][CH2:17][O:18][C:12]=3[CH:11]=[CH:10][C:9]=2[CH:8]=[CH:7][C:6]1=[O:19])[CH:3]=[CH2:4]
Reactant: [OH-]
Reactant: C=CC[n+]1cccc2ccc3c(c21)OCCO3
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=CCn1c(=O)ccc2ccc3c(c21)OCCO3
Yield: 64.2 %

Procedure:
10-(2-Propen-1-yl)-2,3-dihydro[1,4]dioxino[2,3-h]quinolin-10-ium iodide (5.91 g; 16.65 mmol), KOH (4.10 g; 73.26 mmol) and K3-[Fe(CN)6] (12.05 g; 36.63 mmol) were stirred in 50% aqueous 1,4-dioxane at RT for 1.5 h. Water (250 ml) was added and the aqueous layer was extracted with 10% MeOH/DCM (150 ml) and the organics were washed with water (250 ml). The organics were dried with MgSO4 and the solvents removed. The crude residues were purified by column chromatography on silica gel using a 0-7% MeOH/DCM gradient to give the desired product (2.6 g; 65%). MS (ES+) m/z 244 (MH+).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)([OH:15])=[O:14]>CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:7]([C:5]1[S:6][C:2]([C:19]2[CH:20]=[CH:21][C:16]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)=[CH:3][CH:4]=1)=[O:12]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: O=C(c1ccc(Br)s1)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-c2ccc(C(=O)C(F)(F)F)s2)cc1

Procedure:
The titled compound was prepared from 1-(5-bromo-2-thienyl)-2,2,2-trifluoroethanone (C2) (1.0 eq) and the corresponding 4-carboxyphenylboronic acid (1.3 eq) in DMF (1.0M) following the general procedure for Suzuki cross-coupling described in example 3 step 1. After completation of the reaction the solution mixture was concentrated under reduced pressure and 1N HCl solution was added. The resulting precipitate formed was washed several times with DCM and used in the next coupling reaction without further purification. 1H NMR (400 MHz, DMSO, 300K) δ 13.14 (1H, broad s), 8.18 (1H, broad s), 8.06-8.00 (4H, m), 7.95 (1H, d, J=4.2 Hz). MS (ES) C13H7F3O3S requires: 300, found: 301 (M+H+).
Reaction SMILES: Cl.[NH2:2]O.[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[CH:13]=O)[CH2:8][CH2:7][CH2:6][CH2:5]1>C(OC(=O)C)(=O)C>[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[C:13]#[N:2])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: NO
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C#N)cc1OC1CCCC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
Hydroxylamine hydrochloride (3.82 g) is added to a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (11.0 g) in acetic anhydride (30 mL) and the suspension heated in an oil bath at 100° C. until refluxing starts. The heating is then removed while the exothermic reaction refluxes gently. Heating at 100° C. is then continued for a further 1 hour. The dark solution is concentrated and the crude product dissolved in cyclohexane (200 mL). The solution is washed with 5% sodium bicarbonate solution (2×50 mL), water (2×50 mL) and brine (50 mL), and dried over magnesium sulfate. Upon evaporation, an amber oil (11.8 g) that is purified by flash chromatography (dichloromethane as eluant on silica column) gives 3-cyclopentyloxy-4-methoxybenzonitrile (8.6 g) as a pale yellow oil. [Elemental analysis: C,71.7; H,6.93; N,6.47%; calculated for C13H15NO2 : C,71.87; H,6.96; N,6.45%⟧
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:17][CH2:18][C@@H:19]([C:21]1[CH:22]=[CH:23][C:24]([OH:32])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=1)[OH:20]>>[OH:20][C@H:19]([C:21]1[CH:22]=[CH:23][C:24]([OH:32])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=1)[CH2:18][NH:17][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: NC(=O)c1ccc(N2CCC(=O)CC2)cc1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(C(N)=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 4-(4-oxo-piperidin-1-yl)-benzamide (which was obtained in Example 147) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as a white solid; mp>75° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.2–1.40 (m, 2 H), 1.70–1.90 (m, 2 H), 2.55–2.95 (m, 5 H), 2.97 (s, 3 H), 3.70–3.85 (m, 2 H), 4.48 (dd, J=8.0, 4.3 Hz, 1 H), 6.81 (d, J=8.2 Hz, 1 H), 6.91 (d, J=9.0 Hz, 2 H), 6.99 (dd, J=8.2, 2.0 Hz, 1 H), 7.17 (d, J=2.0 Hz, 1 H), 7.67 (br s, 2 H), 7.72 (d, J=9.0 Hz, 2 H); MS (ES) m/z: 448.9 (MH+); HRMS Calcd. for C21H29N4O5S (MH+): 449.1853. Found: 449.1853.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[NH:7][C:6]=2[N:18]=1.[H-].[Na+].[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29]Cl)[CH2:24][CH2:23]1>CN(C)C=O>[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[N:10]([CH3:13])[C:11](=[O:12])[C:5]3[C:4]([CH3:19])=[CH:3][C:2]([CH3:1])=[N:18][C:6]2=3)[CH2:24][CH2:23]1
Reactant: ClCCN1CCOCC1
Reactant: Cc1cc(C)c2c(n1)Nc1ccccc1N(C)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(n1)N(CCN1CCOCC1)c1ccccc1N(C)C2=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture consisting of 5.06 gm of 6,11-dihydro-2, 4,6-trimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 1.1 gm of 50% sodium hydride in mineral oil and 60 ml of dimethyl formamide was stirred at 80° C. for 1 hour. Then, 4.5 gm of 2-morpholino-ethyl chloride were added, and the mixture was stirred at 120° C. for 3.5 hours more. The precipitate formed thereby was suction-filtered off, the solvent was removed from the filtrate in vacuo, and the oily residue was purified on a silica gel column. The product was recrystallized from petroleum ether (b.p. 100°-140° C.), yielding 64% of theory of the compound named in the heading, which had a melting point of 133°-135° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)[N:17]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].O=[C:28](N1C=CN=C1)[N:29]1C=CN=[CH:30]1.CNC>ClCCl.O>[CH3:28][N:29]([CH3:30])[C:22]([C:21]1[CH:25]=[CH:26][C:18]([N:16]2[CH:15]=[C:12]3[C:11]([CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:3])([CH3:1])[CH3:4])=[O:7])[CH2:14][CH2:13]3)=[N:17]2)=[CH:19][CH:20]=1)=[O:24]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(C(=O)O)cc3)nc2CC1
Agent: CNC
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)c1ccc(-n2cc3c(n2)CCN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-[6-{[(1,1-dimethylethyl)oxy]carbonyl}-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]benzoic acid (may be prepared as described in Description 23) (185 mg, 0.52 mmol) in dichloromethane (10 ml) was added 1,1′-(oxomethanediyl)bis-1H-imidazole (168 mg, 1.04 mmol) and the reaction stirred at room temperature, under argon, overnight. Dimethylamine (93 mg, 2.07 mmol) was added and stirring continued, under argon, at room temperature for 4 hours. The resulting crude mixture was diluted with water, and extracted with dichloromethane (×2). The combined organic fractions were washed with water (×1), dried over magnesium sulphate and solvent evaporated in vacuo to afford the title compound (D41). MS (ES+) m/e 385 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5]P(=O)(OCC)OCC.C[O-].[Na+].C1OCCOCCOCCOCCOCCOC1.[CH:38](=O)[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)/[CH:5]=[CH:38]/[C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1
Reactant: CCOP(=O)(Cc1cccc(Br)c1)OCC
Reactant: O=Cc1cccnc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccc(/C=C/c2cccnc2)c1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To diethyl 3-bromobenzylphosphonate (Kennedy, G. Perboni, A. D. Tetrahedron Lett. 1996, 37, 7611-7614; 1.91 g, 6.22 mmol) in dimethylformamide (20 mL) was added sodium methanolate (0.672 g, 12.44 mmol) followed by 18-crown-6 (0.658 g, 2.488 mmol) and nicotinaldehyde (0.666 g, 6.22 mmol). The reaction mixture was heated to 120° C. for 2 h at which time the heating bath was turned off and the reaction mixture was allowed to reach ambient temperature over 18 h. The mixture was poured into water and extracted with 3×75 mL ethyl acetate. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to 1.7 g amber liquid which was loaded onto a 90 g silica gel cartridge and eluted with 5 to 60% ethyl acetate/hexanes over 1300 mL. The major spot (Rf=0.45; 50% ethyl acetate/hexanes; UV) was collected and concentrated to 939 mg as a colorless oil. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.72 (1H, d, J=1.83 Hz), 8.50 (1H, dd, J=4.73, 1.68 Hz), 7.81 (1H, dt, J=8.01, 1.95 Hz), 7.67 (1H, t, J=1.68 Hz), 7.37-7.46 (2H, m), 7.29 (1H, dd, J=7.93, 4.88 Hz), 7.20-7.25 (1H, m), 7.07 (2H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[NH:10])[CH:3]=1.[C:21]1(OB(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][NH:11][C:9]([NH:8][C:4]1[CH:3]=[C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[CH:6][N:5]=1)=[NH:10]
Reactant: COc1ccccc1CNC(=N)Nc1cc(Br)ccn1
Reactant: OB(O)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccccc1CNC(=N)Nc1cc(-c2ccccc2)ccn1
Temperature: 110 °C
Yield: 35 %

Procedure:
The preparation was carried out analogously to Example 56, using 0.150 g (0.447 mmol) N-(4-bromopyridin-2-yl)-N′-(2-methoxybenzyl)guanidine, 0.081 g (0.651 mmol) phenylboric acid, 0.142 g (1.343 mmol) sodium carbonate, and 0.036 g (0.031 mmol) tetrakis-(triphenylphosphine)palladium(0). The mixture was likewise heated in a reaction block for 17.5 hr at 110° C. under a nitrogen atmosphere. After appropriate workup and purification via preparative HPLC, 52 mg pure N-(2-methoxybenzyl)-N′-(4-phenylpyridin-2-yl)guanidine was obtained in the form of the acetate salt (base/acetate in a ratio of 1:1.2).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11](O)=[O:12])[C:4]=2[CH:3]=1.[CH:20]([C:23]1[CH:29]=[C:28]([S:30][C:31]#[N:32])[CH:27]=[C:26]([CH:33]([CH3:35])[CH3:34])[C:24]=1[NH2:25])([CH3:22])[CH3:21]>>[CH:20]([C:23]1[CH:29]=[C:28]([S:30][C:31]#[N:32])[CH:27]=[C:26]([CH:33]([CH3:35])[CH3:34])[C:24]=1[NH:25][C:11]([CH:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[CH2:7][O:6][C:5]2[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][C:4]1=2)=[O:12])([CH3:22])[CH3:21]
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Reactant: CC(C)c1cc(SC#N)cc(C(C)C)c1N
Product: Cc1ccc2c(c1)C(C(=O)Nc1c(C(C)C)cc(SC#N)cc1C(C)C)c1ccccc1CO2
Yield: 78.6 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.12 g of Compound A and 1.24 g of 2,6-diisopropyl-4-thiocyanatoaniline in place of aniline to obtain 1.63 g of Compound 31.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:26])=[C:4]([C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:19])[C:5]([I:17])=[C:6]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[C:7]=1[I:8].[C:27](Cl)(Cl)=[O:28].C1(C)C=CC=CC=1>O1CCOCC1>[N:11]1([C:9]([C:6]2[C:5]([I:17])=[C:4]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[C:3]([I:26])=[C:2]([N:1]=[C:27]=[O:28])[C:7]=2[I:8])=[O:10])[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: Nc1c(I)c(C(=O)N2CCOCC2)c(I)c(C(=O)N2CCOCC2)c1I
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=C=Nc1c(I)c(C(=O)N2CCOCC2)c(I)c(C(=O)N2CCOCC2)c1I
Temperature: 50 °C

Procedure:
To a solution of [3-Amino-2,4,6-triiodo-5-(morpholine-4-carbonyl)-phenyl]-morpholin-4-yl-methanone (8 g, 11.4 mmol) in 1,4-dioxane (40 mL) was added ˜11 equivalents of 20% phosgene solution in toluene (60 mL, 120 mmol) at ambient temperature, the solution was heated at 50° C. for 15 hours. The reaction was allowed to cool to ambient temperature and then concentrated at reduced pressure to yield an off white, semi-crystalline solid. Dioxane (30 mL×2) was added and removed slowly at reduced pressure to give a light brown, semi-crystalline solid which was placed on a vacuum line to remove any residual solvent. The material was used without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:3][C:2]([F:17])([F:18])[F:1])[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:6][C:7]=1[C:13]([F:16])([F:14])[F:15])#[N:10]
Reactant: N#Cc1ccc(NCC(F)(F)F)cc1C(F)(F)F
Reactant: COC(=O)CBr
Product: COC(=O)CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized in a manner similar to step B of example 1 using 4-[(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and methyl bromoacetate: 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=8.8 Hz, 1H), 7.01 (d, J=2.4 Hz, 1H), 6.88 (dd, J=8.8, 2.6 Hz, 1H), 4.24 (s, 2H), 4.06 (q, J=8.5 Hz, 2H), 3.81 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][N:9]1[C:15](=[O:16])[CH2:14][CH:13]2[C:17](=[O:18])[CH:10]1[CH:11]=[CH:12]2.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O>[N:19]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][N:9]1[C:15](=[O:16])[CH2:14][CH:13]2[C:17](=[O:18])[CH:10]1[CH:11]=[CH:12]2)=[N+:20]=[N-:21]
Reactant: O=C1C2C=CC1N(OCCCCCCBr)C(=O)C2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCON1C(=O)CC2C=CC1C2=O
Temperature: 65 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a stirring solution of 3b (100 mg, 0.302 mmol) in DMF (10 mL) was added sodium azide (98 mg, 1.51 mmol). The solution was allowed to stir at 65° C. overnight. After cooling to room temperature, the solution was diluted with water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic phase was dried over Na2SO4. The drying agent was removed by filtration and the solvent was removed under reduced pressure to afford 3c as a clear oil (73 mg, 83%). The oil was taken on without further purification immediately, as 3c was found to be unstable. 1H-NMR (CDCl3, 300 MHz): δ 6.70 (dd, J=5.8, 1.0 Hz, 1H), 6.49 (dd, J=6.0, 1.7 Hz, 1H), 5.47 (d, J=1.1 Hz, 1H), 4.50 (d, J=1.6 Hz, 1H), 3.92 (ABX2, JAX=JBX=6.7 Hz, JAB=9.2 Hz, 2H), 3.27 (t, J=7.0 Hz, 2H), 1.71-1.56 (m, 4H), 1.48 (s, 3H), 1.48-1.39 (m, 4H), 1.04 (s, 3H). 13C-NMR (CDCl3, 75 MHz): δ 175.4, 135.3, 134.6, 90.6, 87.1, 75.3, 51.2, 48.8, 28.5, 27.9, 26.7, 26.3, 25.3, 19.6. HRESI-MS calcd for C14H22N4O3 [M+H]+ 295.1765. found 295.1758.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:4]=1[C:5](O)=O.[OH-:23].[NH4+]>>[CH3:1][O:2][C:3]1([OH:23])[C:4]2[C:8](=[CH:12][C:13]3[C:18]([CH:5]=2)=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH:9]=[CH:10][CH2:11]1
Reactant: COc1cccc(Cc2cccc(C(F)(F)F)c2)c1C(=O)O
Reactant: [OH-]
Agent: [NH4+]
Product: COC1(O)CC=Cc2cc3cc(C(F)(F)F)ccc3cc21
Reaction time: 0.5 h

Procedure:
2-Methoxy-6-(3'-trifluoromethylbenzyl)benzoic acid (3.1 g.) is added in small portions with stirring to polyphosphoric acid (60 ml.) at 90°-95°C., the reaction mixture is stirred for 30 minutes at this temperature and then allowed to cool. Excess 8N ammonium hydroxide solution is added and the solution is stirred for 15 minutes and then extracted with ether. The ether layer is washed with water and with brine, and evaporated to give 1-methoxy-6-trifluoromethylanthrol, m.p. 102°-110°C., which is used without further purification.
Reaction SMILES: [F:1][C:2]([C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[N:6]O)([F:4])[F:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OC(C)C)(C)C>[F:15][C:14]([F:16])([F:17])[C:10]1[CH:9]=[C:8]([CH:5]([NH2:6])[C:2]([F:1])([F:3])[F:4])[CH:13]=[CH:12][CH:11]=1
Reactant: ON=C(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)OC(C)C
Product: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Reaction time: 3 h

Procedure:
2.5 g (3-trifluoromethyl phenyl) trifluoromethyl Ketoxime are suspended in 40 ml isopropyl ether and to this suspension 4 g lithium aluminium hydride are added. The mixture is heated to reflex for 3 hours then cooled. The excess of reagent is destroyed by cautious addition of an aqueous solution of tartaric acid. The mixture is made basic by adding sodium hydroxide and the ethereous phase is separated. The aqueous phase is further extracted with isopropyl ether; the organic solutions are united, washed with water, dried an evaporated off under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:12]Br)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=O.Cl.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]2[C:3]=1[CH2:12][N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:5]2=[O:7]
Reactant: COC(=O)c1cccc(Br)c1CBr
Reactant: COC(=O)CCCCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCCCCN1Cc2c(Br)cccc2C1=O
Reaction time: 20 h
Yield: 99 %

Procedure:
The procedure of the step 2 in Example 1 was repeated except that methyl 3-bromo-2-(bromomethyl)benzoate instead of methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate, methyl 6-aminohexanoate hydrochloride instead of methyl 4-(aminomethyl)benzoate hydrochloride, triethylamine (2.4 equiv.), and THF as a solvent were used and the reaction was conducted for 20 hrs, to obtain the title compound (99%).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl:9][C:10]1[CH:11]=[C:12]2[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18]([O:28][C@H:29]3[C@H:33]4[O:34][CH2:35][C@@H:36]([OH:37])[C@H:32]4[O:31][CH2:30]3)=[N:17][C:13]2=[N:14][C:15]=1I.CC1(C)C(C)(C)OB([C:46]2[CH:51]=[CH:50][C:49]([CH:52]3[CH2:56][CH2:55][N:54]([CH2:57][C:58]([F:61])([F:60])[F:59])[CH2:53]3)=[CH:48][CH:47]=2)O1>O1CCOCC1.C(Cl)Cl>[Cl:9][C:10]1[CH:11]=[C:12]2[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18]([O:28][C@H:29]3[C@H:33]4[O:34][CH2:35][C@@H:36]([OH:37])[C@H:32]4[O:31][CH2:30]3)=[N:17][C:13]2=[N:14][C:15]=1[C:46]1[CH:47]=[CH:48][C:49]([CH:52]2[CH2:56][CH2:55][N:54]([CH2:57][C:58]([F:60])([F:59])[F:61])[CH2:53]2)=[CH:50][CH:51]=1
Reactant: CC1(C)OB(c2ccc(C3CCN(CC(F)(F)F)C3)cc2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(I)c(Cl)cc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(C4CCN(CC(F)(F)F)C4)cc3)c(Cl)cc21
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Tripotassium phosphate 2.0 M aqueous solution (0.6 ml, 1.200 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (25.2 mg, 0.031 mmol) were added to a stirred solution of (3R,3aR,6R,6aR)-6-[6-chloro-5-iodo-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (147.1 mg, 0.266 mmol) and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(2,2,2-trifluoroethyl)pyrrolidine (94.6 mg, 0.266 mmol) in dioxane (2.1 ml). The reaction mixture was degassed (3×) and placed under nitrogen before being heated to 80° C. After 18 hours, the reaction mixture was cooled to room temperature before being partitioned between EtOAc (50 ml) and water (50 ml). The aqueous layer was separated and extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×30 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a yellow residue. The residue was dissolved in DCM, loaded onto a 5 g silica solid load cartridge, and purified using an ISCO Rf and a 12 g silica column (CV=16.8 ml) by eluting as follows: 100% Hex (5 CV), 0-70% EtOAc/Hex gradient (50 CV), 70% EtOAc/Hex (35 CV) at 30 ml/min. The product fractions were combined and evaporated under reduced pressure to give the desired product as a yellow residue. LC-MS: calculated for C30H38ClF3N4O5Si 654.23 observed m/e: 655.32 (M+H)+ (Rt 1.37/2 min)
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([OH:53])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2].[CH3:57][O:58][CH:59]([O:62][CH3:63])[CH2:60]Br>[Ag]=O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH2:60][CH:59]([O:62][CH3:63])[O:58][CH3:57])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(O)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: COC(CBr)OC
Agent: O=[Ag]
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OCC(OC)OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 70 °C

Procedure:
A suspension of 17-ethyl-1-hydroxy-12-[2'-(4"-azido-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (25 mg, Example 42) and silver oxide (25 mg) in 2 ml of bromoacetaldehyde dimethyl acetal is heated at 70° C. for 4 days. The solids are removed by filtration, washed with ethyl acetate, and concentrated in vacuo. The resulting oil is purified by preparative tlc on silica gel to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1.Cl.[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH2:19])[CH3:15].C(N(CC)CC)C>C(O)C>[CH3:12][C:4]1[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[N:7]=[C:2]([NH:19][CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:20])[N:3]=1
Reactant: CCOC(=O)CN
Reactant: Cc1nc(Cl)nc(C)c1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CNc1nc(C)c([N+](=O)[O-])c(C)n1
Yield: 87.7 %

Procedure:
A solution of Compound 2 (69 mg), glycine ethyl ester hydrochloride (102 mg) and triethylamine (103 μL) in ethanol was stirred for 3 hours under reflux. After the reaction was completed, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to give 82 mg (86% yield) of the desired product as a pale yellow amorphous.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14](Cl)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O-:24].[Na+].CO>>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:24][CH3:23])[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Cc1cc2c(cc(Cl)c3nnc(C)n32)n1Cc1ccccc1
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cc(C)n2Cc2ccccc2)n2c(C)nnc12
Temperature: 150 °C

Procedure:
A suspension of 6-benzyl-4-chloro-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (10.0 mg, 0.0322 mmol, from Example 228, Step 7) in 25 wt % solution of NaOMe in MeOH (1.3 mL, 5.6 mmol, Aldrich) was heated at 150° C. in the microwave for 3 hours. The reaction was purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (0.7 mg, 7%).