Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N.C(=O)([O-])[O-].[K+].[K+].[C:19]([NH:22][C:23]1[C:24]([I:38])=[C:25]([C:30]([I:37])=[C:31](N=C=O)[C:32]=1[I:33])[C:26]([NH:28][CH3:29])=[O:27])(=[O:21])C.[CH3:39][N:40]([CH3:43])[CH:41]=[O:42]>>[I:37][C:30]1[C:25]([C:26]([NH:28][CH3:29])=[O:27])=[C:24]([I:38])[C:23]([N:22]=[C:19]=[O:21])=[C:32]([I:33])[C:31]=1[C:41]([N:40]([CH3:43])[CH3:39])=[O:42]
Reactant: CN(C)C=O
Reactant: CNC(=O)c1c(I)c(N=C=O)c(I)c(NC(C)=O)c1I
Agent: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CNC(=O)c1c(I)c(N=C=O)c(I)c(C(=O)N(C)C)c1I
Reaction time: 8 h

Procedure:
To glucosamine (1.97 g., 0.011 mole) and potassium carbonate (4.14 g.; 0.03 mole) in dimethylformamide (49 ml.) was added dropwise (required about 5 minutes) 3-acetamido-2,4,6-triiodo-5-isocyanato-N-methylbenzamide (III; 6.11 g.; 0.01 mole) dissolved in dimethylformamide (20 ml.). After being stirred overnight, the reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in water (64 ml.) and the aqueous solution was adjusted to pH 1 with concentrated hydrochloric acid. The solution was extracted with aqueous 90% phenol (4 × 25 ml.). The combined, phenolic layers were washed with water (4 × 25 ml.), diluted with ether (300 ml.) and extracted with water (4 × 25 ml.). The combined aqueous layers were washed with chloroform-isopropyl alcohol (3:1; 5 × 100 ml., contact time 15 min.), treated with "Darco G-60" (0.25 g.) overnight, and evaporated under reduced pressure at 40° C. (water bath), to give 3-acetamido-5-{3-[2-D-gluco-2-deoxy-3,4,5,6-tetrahydroxy-1-oxohexyl]ureido}-2,4,6-triiodo-N-methylbenzamide (IV) as a faint-yellow foam, 5.08 g. (64.5%), m.p. 186°-251° C. (dec.). The infrared and nuclear magnetic resonance spectra were consistent with the assigned structure. The material was homogeneous by thin-layer chromatography (chloroform-methanol-triethylamine, 65:35:5) and the aqueous solubility was determined to be 18-20% (w/v).
Reaction SMILES: [NH2:1][S:2]([C:5]1[O:9][C:8]([C:10]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:57]([O:59][C:60](=[O:81])[C@H:61]([O:63][C:64]1[CH:69]=[C:68](Cl)[N:67]=[C:66]([S:71][CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([F:79])[C:74]=2[F:80])[N:65]=1)[CH3:62])[CH3:58]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([NH:12][C:10]([C:8]1[O:9][C:5]([S:2]([NH:1][C:68]2[N:67]=[C:66]([S:71][CH2:72][C:73]3[CH:78]=[CH:77][CH:76]=[C:75]([F:79])[C:74]=3[F:80])[N:65]=[C:64]([O:63][C@H:61]([CH3:62])[C:60]([O:59][CH2:57][CH3:58])=[O:81])[CH:69]=2)(=[O:4])=[O:3])=[CH:6][CH:7]=1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)NC(=O)c1ccc(S(N)(=O)=O)o1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)c2ccc(C(=O)NC(C)(C)C)o2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of 5-(aminosulfonyl)-N-(tert-butyl)-2-furamide (0.25 g), tris(dibenzylideneacetone)dipalladium (0) (58 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (30 mg), cesium carbonate (0.65 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (product of Example 11 step i) (0.26 g) in dioxane (1.0 mL). Purification was trituration with Et2O to give the subtitle compound as a white solid. Yield: 0.25 g
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:5]2[CH:12]=[CH:13][C:14]([C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:4]=2[N:3]=1.Cl.[C:25](=O)(O)[O-].[Na+]>CO>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]([O:11][CH3:25])=[O:10])[C:5]2[CH:12]=[CH:13][C:14]([C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:4]=2[N:3]=1
Reactant: Nc1nc2cc(C(=O)c3ccccc3)ccc2n1CCC(=O)O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCn1c(N)nc2cc(C(=O)c3ccccc3)ccc21
Reaction time: 16 h

Procedure:
A solution of 3-(2-amino-5-benzoylbenzimidazol-1-yl)-propionic acid (6.1 g.) in methanol (30 ml.) was treated with a saturated solution (30 ml.) of hydrogen chloride in methanol. The mixture was left at room temperature for 16 hours and then evaporated. The residue was dissolved in water. The solution obtained was adjusted to pH 8.5 with aqueous sodium bicarbonate solution and then extracted with ethyl acetate (3×50 ml.). The extracts were dried (MgSO4) and evaporated to give methyl 3-(2-amino-5-benzoylbenzimidazol-1-yl)propionate as an oil. This oil was dissolved in methanol (60 ml.) and the solution heated at reflux for 5 hours. The solid which precipitated was collected and washed successively with methanol, acetone and then ether to give 8-benzoyl-3,4-dihydropyrimido[1,2-a]-benzimidazol-2(1H)-one (3.4 g.), m.p. 323°-330° C., microanalysis, C17H13N3O2 requires: C, 70.1; H, 4.5; N, 14.4% found: C, 69.9; H, 4.4; N, 14.0%.
Reaction SMILES: [C:1]([C:6]1[CH:16]=[CH:15][C:9]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]>CCO.[Rh]>[CH2:4]([O:3][C:1]([C:6]1[CH:16]=[CH:15][C:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)=[O:2])[CH3:5]
Reactant: CCOC(=O)c1ccc(C=CC(=O)O)cc1
Agent: [Rh]
Solvent: CCO
Product: CCOC(=O)c1ccc(CCC(=O)O)cc1
Yield: 45.1 %

Procedure:
A solution of 4-carbethoxycinnamic acid (4.9 g) in EtOH (120 ml) was hydrogenated over 5% Rh/C (485 mg) at atmospheric pressure for 21 hr. The solution was filtered and stripped. The residue was crystallized from cyclohexane to afford 2.23 g (46%) of the title compound as white crystals; mp 108.5°-110.5°.
Reaction SMILES: [P:1]([O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[N:23]=[C:22]([C:24]2[C:25]([O:30][C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:38]4[C:47]5[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=5)[C:41]([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)=[N:40][N:39]=4)=[CH:33][CH:32]=3)=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][N:19]=1)([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].[ClH:54]>O1CCOCC1>[ClH:54].[ClH:54].[P:1]([OH:8])([OH:3])([O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[N:23]=[C:22]([C:24]2[C:25]([O:30][C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:38]4[C:47]5[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=5)[C:41]([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)=[N:40][N:39]=4)=[CH:33][CH:32]=3)=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][N:19]=1)=[O:2]
Reactant: CC(C)(C)OP(=O)(OCCCNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)n1)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: O=P(O)(O)OCCCNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of di-tert-butyl 3-(4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylamino)propyl phosphate (95 mg, 0.13 mmol) in 1,4-dioxane (3.7 ml, 0.04 M) under nitrogen was added 4M HCl in Dioxane (0.23 mL, 0.91 mmol). Reaction stirred at RT for 18 hrs. The mixture appeared heterogeneous, and the solids were filtered, washed with dioxane and ether, and dried under reduced pressure to afford 3-(4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylamino)propyl dihydrogen phosphate dihydrochloride as a yellow solid. Mass of the title compound was obtained as the free base: MS m/z=622 [M+H]+. Calc'd for C32H30C12N7O5P: 621.6.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[N:5][CH:4]=1)#[N:2].[CH3:21][O:22][CH:23]([CH3:26])[CH2:24][NH2:25]>>[C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([NH:25][CH2:24][CH:23]([O:22][CH3:21])[CH3:26])=[O:18])=[CH:13][CH:14]=2)[CH:6]=[N:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)n2)cc1
Reactant: COC(C)CN
Product: COC(C)CNC(=O)C(C)(C)c1ccc(-c2cncc(C#N)n2)cc1
Yield: 70 %

Procedure:
Prepared in a similar manner to Example 20 from 2-(4-(6-Cyanopyrazin-2-yl)phenyl)-2-methylpropanoic acid (example 20a) and 2-methoxypropan-1-amine. Yield 70%. 1H NMR (400 MHz, dMSO): δ 0.93-0.94 (d, 3H), 1.48-1.49 (d, 6H), 2.99-3.11 (m, 2H), 3.17 (s, 3H), 3.29-3.30 (m, 1H), 7.41-7.42 (m, 1H), 7.49-7.51 (d, 2H), 8.11-8.14 (d, 2H), 9.15 (s, 1H), 9.55 (s, 1H); MS+H (339).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[Br:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([Br:22])[CH:24]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2cccc(Br)c2)c1C(=O)OC
Yield: 106.3 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.3 g, 6.2 mmol) in acetone (30 mL) and potassium carbonate (2.5 g, 18.4 mmol) was added 3-bromobenzyl bromide (1.6 g, 6.4 mmol) and refluxed overnight. The solvent was evaporated and the residue was partitioned between water (100 mL) and ethyl acetate (150 mL) and washed with water (2×100 mL). The combined organic phases was dried, concentrated and purified by flash column chromatography (EtOAc/Hexane) to give 3-(3-bromo-benzyloxy)-phthalic acid dimethyl ester (2.5 g, 109% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=2[Cl:21])([CH3:11])[C:9]#[N:10])=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].S1C=CC=C1.[H][H]>CO.[Pt]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:22]([F:25])([F:23])[F:24])[CH:4]=2)([CH3:11])[C:9]#[N:10])=[C:13]([Cl:21])[CH:14]=1
Reactant: CC(C#N)(c1ccc(Cl)c(C(F)(F)F)c1)c1ccc([N+](=O)[O-])cc1Cl
Reactant: [H][H]
Agent: [Pt]
Solvent: c1ccsc1
Solvent: CO
Product: CC(C#N)(c1ccc(Cl)c(C(F)(F)F)c1)c1ccc(N)cc1Cl

Procedure:
A mixture of 31.1 parts of 4-chloro-α-(2-chloro-4-nitrophenyl)-α-methyl-3-(trifluoromethyl)benzeneacetonitrile, 2 parts of a solution of thiophene in methanol 4% and 480 parts of methanol was hydrogenated in the Parr apparatus at 50° C. with 3 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off, washed with tetrahydrofuran and the filtrate was evaporated in vacuo. The residue was crystallized from 160 parts of 2-propanol. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 23.7 parts (82.4%) of (4-amino-2-chloro-α-[4-chloro-3-(trifluoromethyl)phenyl]-α-methylbenzeneacetonitrile; mp. 180.4° C. (intermediate 26).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:9][C@H:5]2[O:6][CH2:7][CH2:8][C@@:4]2([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH2:3]1.[CH3:28][O:29][C@H:30]1[C:35](=O)[CH2:34][CH2:33][O:32][CH2:31]1>>[CH3:28][O:29][C@H:30]1[C@@H:35]([NH:1][C@@H:2]2[CH2:9][C@H:5]3[O:6][CH2:7][CH2:8][C@@:4]3([C:10]([N:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:19])[CH2:16][CH2:17]3)=[O:11])[CH2:3]2)[CH2:34][CH2:33][O:32][CH2:31]1
Reactant: CO[C@@H]1COCCC1=O
Reactant: N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)C1
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)C1

Procedure:
The product of Step H was prepared from the reaction of the product of Step G and (R)-3-methoxydihydro-2H-pyran-4(3H)-one (Intermediate 1) following the procedure described in Example 1, Step H. Calculated for C26H37N3O6: 488.3 (M+1). found: 488.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1.[Na+].[I-].C(O)C(N)(CO)CO>CN(C=O)C>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:10]=[CH:9]3)=[CH:4][CH:3]=2)=[CH:26][CH:27]=1)#[N:32]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Oc1ccc(-n2ccc3ccccc32)cc1
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: N#Cc1ccc(COc2ccc(-n3ccc4ccccc43)cc2)cc1
Yield: 77.1 %

Procedure:
To a solution of 0.038 g (0.18 mmol) 1-(4-hydroxyphenyl)-1H-indole in 1.2 ml DMF was added 0.05 g (0.38 mmol) K2CO3 and the slurry was mixed for 30 min. 59 mg (0.3 mmol) α-bromo-p-tolunitrile and 0.01 g (66 μmol) NaI was added and the slurry was mixed at 60° C. for 4 hr. The solution was allowed to cool and an additional 2 ml DMF was added, followed by 0.10 g PS-Trisamine scavenger reagent (Argonaut Technologies, San Carlos, Calif.). The slurry was mixed at 60° C. for a further 3 hr and allowed to cool. The reaction was filtered and the solution was concentrated to afford 0.045 g 1-{4-[(4-cyanobenzyl)oxy]phenyl}-1H-indole as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH2:14]([S:17][C:18]([CH3:22])([CH3:21])[CH:19]=O)[C:15]#[CH:16].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[SH:13][C:10]([CH3:11])([CH3:12])[CH2:9][NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:19][C:18]([S:17][CH2:14][C:15]#[CH:16])([CH3:22])[CH3:21]
Reactant: C#CCSC(C)(C)C=O
Reactant: CC(C)(S)CNc1ccccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C#CCSC(C)(C)CNc1ccccc1NCC(C)(C)S
Temperature: 21 °C
Reaction time: 17 h
Yield: 74.8 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (5.59 g, 2.85×10-2 mol) and 2-(2-propynylthio)-2-methylpropanal 6.07 g, 4.28×10-2 mol, 150 M %) were mixed, then 125 ml methanol and 5.27 ml (5.7×10-2 mol, 200 M %) acetic acid were added and solids were allowed to dissolve. Sodium cyanoborohydride (5.39 g, 8.56×10-2 mol, 300 M %) was added to the reaction solution in three equal portions. The reaction was stirred at 21° C. for 17 hr, then quenched with 100 ml 0.5M HCl, stirred for 15 min, and then extracted with 2×150 ml ether. The ether layers were combined, washed with 60 ml saturated NaCl solution and dried over Na2SO4. The solvent was removed on the rotary evaporator and the residue was purified by filtration through flash silica in a 600 ml sintered glass funnel 3/4 full of silica, eluting with 500 ml portions of 2 × hexane and 2× 90% hexane/ether to produce 6.88 g (75% yield) 2-(2-mercapto-2-methyl-propylamino)-1-[2-(2-propynylthio)-2methylpropylamino]-benzene.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([N+:13]([O-])=O)=[CH:5][N:4]=1)#[N:2].[H][H]>[Ni]>[C:1]([C:3]1[C:8]([C:9]([F:12])([F:10])[F:11])=[CH:7][C:6]([NH2:13])=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ncc([N+](=O)[O-])cc1C(F)(F)F
Reactant: [H][H]
Agent: [Ni]
Product: N#Cc1ncc(N)cc1C(F)(F)F

Procedure:
Alternatively, 2-cyano-3-(trifluoromethyl)-5-nitropyridine A10 can be reacted with hydrogen over Raney-Ni to obtain 2-cyano-3-(trifluoromethyl)-5-aminopyridine, A11.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.[CH2:19]([C:26]1[O:30][N:29]=[C:28]([NH2:31])[CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.P(Cl)(Cl)(Cl)=O.O>N1C=CC=CC=1>[CH2:19]([C:26]1[O:30][N:29]=[C:28]([NH:31][C:16]([C:13]2[CH:12]=[CH:11][C:10]3[CH:9]=[C:8]4[C:2](=[O:1])[NH:3][CH2:4][CH2:5][CH2:6][N:7]4[C:15]=3[CH:14]=2)=[O:18])[CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cc(Cc2ccccc2)on1
Reactant: O=C(O)c1ccc2cc3n(c2c1)CCCNC3=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1cc(Cc2ccccc2)on1)c1ccc2cc3n(c2c1)CCCNC3=O
Temperature: 0 °C
Yield: 53 %

Procedure:
A 0.5-2 mL microwave reactor vial is charged with a mixture of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (Intermediate J, 100 mg, 0.41 mmol) and 5-benzyl-3-aminoisoxazole (107 mg, 0.61 mmol) in pyridine (500 μL) and the vial is sealed with a Teflon lined septa cap. The mixture is cooled to 0° C. and phosphorous oxychloride (40 μL, 0.43 mmol) is added. The mixture is allowed to warm to room temperature and is then irradiated in a microwave reactor at 150° C. for 60 min. The mixture is poured into water and the resulting solid is collected by filtration and is purified via preparative HPLC using a gradient elution from 10-75% acetonitrile/water with 0.1% TFA to obtain the title compound (87 mg, 53%). LCMS: 401.20 (M+H+). (System V1)
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[F:14][C:15]1[CH:16]=[C:17]([CH:22]2[NH:27][C:26]([O:28][CH3:29])=[N:25][C:24]([CH3:30])=[C:23]2[C:31]([O:33][CH3:34])=[O:32])[CH:18]=[CH:19][C:20]=1[F:21]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:14][C:15]1[CH:16]=[C:17]([CH:22]2[N:27]([C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[C:26]([O:28][CH3:29])=[N:25][C:24]([CH3:30])=[C:23]2[C:31]([O:33][CH3:34])=[O:32])[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: COC(=O)C1=C(C)N=C(OC)NC1c1ccc(F)c(F)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1=C(C)N=C(OC)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
4-Nitrophenyl chloroformate (1.82 g, 9.04 mmol) was added to a solution of 6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methylpyrimidine (2.82 g, 9.46 mmol) and 4-dimethylaminopyridine (1.16 g, 9.52 mmol) in CH2Cl2 (50 mL), at 0-5° C. and the mixture was then allowed to warm to room temperature. After 12 h, the solvent was evaporated and the residue was purified by flash chromatography (EtOAc/hexane, 1/9 to 3/20), giving the desired product as white crystals (3.72, 85%): mp 172-174° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[F:13][C:14]1[C:19](B(O)O)=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])O.[Na+].O1CCOCC1>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:13][C:14]1[C:19]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:11][CH3:12])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: OB(O)c1cccnc1F
Reactant: COc1cc([N+](=O)[O-])ccc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])ccc1-c1cccnc1F

Procedure:
2.00 g (7.17 mmol) of 2-iodo-5-nitroanisole, 2.02 g (14.3 mmol) of (2-fluoropyridin-3-yl)boronic acid (A. Bouillon, J.-C. Lancelot, V. Collot, P. R. Bovy, S. Rault, Tetrahedron 2002, 58, 3323-3328.), 1.81 g (21.5 mmol) of sodium hydrogen carbonate and 117 mg (0.14 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride are heated to 100° C. in a degassed mixture of 40 ml of dioxane and 10 ml of water for 1 h. After cooling, the mixture is diluted with water and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate, clarified over activated carbon and concentrated. Purification is effected by chromatography on silica gel (eluent: dichloromethane) to obtain 1.55 g (87% of theory) of the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[F:5][C:6]([F:11])([F:10])[C:7](=O)[CH3:8]>ClCCl>[CH3:8][C:7]1([C:6]([F:11])([F:10])[F:5])[NH:1][CH2:2][CH2:3][O:4]1
Reactant: CC(=O)C(F)(F)F
Reactant: NCCO
Solvent: ClCCl
Product: CC1(C(F)(F)F)NCCO1
Temperature: -30 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
A solution of 2-aminoethanol (10.15 g, 10.0 ml, 166 mmol, Eq: 1.00) in dichloromethane (250 ml) was cooled to −30° C. and stirred while 1,1,1-trifluoropropan-2-one (20.1 g, 16.1 ml, 179 mmol, Eq: 1.08), followed by molecular sieves (4 Å, powder <5 micron, activated; 20.0 g, 166 mmol, Eq: 1.00) were added. The mixture was stirred at −30° C. for 3 h and then allowed to warm to room temperature and left stirring for overnight. The mixture was filtered, washed with dichloromethane, and concentrated to obtain 2-methyl-2-(trifluoromethyl)oxazolidine (39) (oil, 15.60 g, 101 mmol, 60.5% yield).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].N1C=CC=CC=1.CN(C1C=CC=CN=1)C>ClCCl>[C:22]1([CH3:23])[CH:24]=[CH:25][C:19]([S:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: CCCCc1ccc(CCCCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1ccc(CCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A solution of 1.1 g of 4-(4-butylphenyl)butanol, 1.05 g of tosyl chloride, 0.48 ml of pyridine and a catalytic amount of dimethylaminopyridine in dichloromethane was allowed to stand at room temperature overnight. The reaction mixture was poured into 50 ml of ice water and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was distilled away. The residue was purified by silica gel column chromatography (ethyl aeetate:hexane=1:6) to give 1.2814 g of 4-(4-butylphenyl)butyl p-toluenesulfonate as a colorless, oily substance.
Reaction SMILES: I[C:2]1[CH:23]=[N:22][C:5]2[NH:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][C:18]([F:21])([F:20])[F:19])[C:4]=2[CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:28])[C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:23]=[N:22][C:5]3[NH:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[O:17][C:18]([F:21])([F:20])[F:19])[C:4]=3[CH:3]=2)=[CH:31][CH:30]=1)[CH3:25]
Reactant: FC(F)(F)Oc1ccccc1CN1CCNc2ncc(I)cc21
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2OC(F)(F)F)CCN3)cc1

Procedure:
7-Iodo-1-[2-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (699 mg) was reacted with (4-ethoxycarbonylphenyl)boronic acid as in General Procedure 4B to give the title compound as a yellow solid. m.p.=153° C., LCMS: m/z=458.00 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.38 (3H, t, J=7.1 Hz), 3.47 (2H, m), 3.64 (2H, m), 4.36 (2H, quartet, J=7.1 Hz), 4.56 (2H, s), 5.22 (1H, bs), 6.73 (1H, s), 7.25 (1H, m), 7.31 (2H, m), 7.37 (1H, d, J=7.3 Hz), 7.42 (2H, d, J=7.8 Hz), 7.75 (1H, s), 8.00 (2H, d, J=8.1 Hz).