Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]=[CH:12][NH:13][C:14](=[O:15])[C:5]=3[C:4]=2[CH:3]=1.C1C(=O)N([Br:23])C(=O)C1.[Al].O>CN(C=O)C>[Br:23][C:11]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=3[C:5]=2[C:14](=[O:15])[NH:13][CH:12]=1
Reactant: O=c1[nH]ccc2[nH]c3ccc(F)cc3c12
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]cc(Br)c2[nH]c3ccc(F)cc3c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 8-fluoro-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (46 g, 228 mmol) in DMF (370 mL) was added NBS (44.5 g, 250 mmol) in small portions at 0° C. The reaction mixture was covered with aluminum foil and left to stir at room temperature overnight. The reaction mixture was treated with water (460 mL), left to stir for 3 h, filtered, and washed with water. The cake was dissolved in MeOH and filtered to remove residual solids. The filtrate was treated with charcoal, and warmed to 40° C. for 2 h. The mixture was cooled to room temperature, filtered through a pad of Celite, and concentrated. The residue was treated with isopropanol and heptane, filtered, and washed with MTBE to afford the title compound as the isopropanol solvate. 1H NMR (600 MHz, CD3SOCD3) 3 12.03 (s, 1H); 11.47 (s, 1H); 7.71 (dd, 1H); 7.59 (s, 1H); 7.52 (dd, 1H); 7.17 (dt, 1H). LRMS (APCI) calc'd for (C11H6BrFN2O) [M+H]+, 281.0. found 280.9.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH3:32][CH:33]([SH:35])[CH3:34]>O>[CH:33]([S:35][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)([CH3:34])[CH3:32]
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: CC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Sc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 60 °C
Yield: 77.4 %

Procedure:
To a mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.50 g of potassium carbonate and 2 ml of DMF, a mixture of 0.15 g of 2-propanethiol and 0.5 ml of DMF was added. The reaction mixture was stirred while heating at 60° C. for two hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with 5% aqueous solution of potassium carbonate and a saturated sodium chloride solution, sequentially, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.26 g of 2-(3-isopropylthiopyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 43”).
Reaction SMILES: CO[C:3](=[N:12][N+:13]([O-:15])=[O:14])[NH:4][CH2:5][C:6]1[S:10][C:9]([Cl:11])=[N:8][CH:7]=1.[CH3:16][NH2:17]>O>[Cl:11][C:9]1[S:10][C:6]([CH2:5][NH:4][C:3]([NH:17][CH3:16])=[N:12][N+:13]([O-:15])=[O:14])=[CH:7][N:8]=1
Reactant: CN
Reactant: COC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Solvent: O
Product: CNC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 92.1 %

Procedure:
To a suspension of O-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea (1.00 g, 4.00 mmol) in water (10 ml) was added 40% aqueous solution of methylamine (0.77 g; 9.92 mmol) dropwise. The mixture was stirred at room temperature for 14 hours and the resulting crystals were collected by filtration, washed with water (10 ml), and dried. As a result, 0.92 g (92.0% yield) of 1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitroguanidine was obtained.
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:25][CH:26]([OH:29])[CH2:27][OH:28]>C(#N)C>[F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1.[OH:29][CH:26]([CH2:27][OH:28])[CH2:25][O:17][C:5]1[C:6]2[S:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[C:15]=2[C:2]([F:1])=[CH:3][CH:4]=1
Reactant: OCC(O)CCl
Agent: O=C([O-])[O-]
Agent: O=c1c2ccccc2sc2c(O)ccc(F)c12
Agent: [K+]
Solvent: CC#N
Product: O=c1c2ccccc2sc2c(OCC(O)CO)ccc(F)c12

Procedure:
The reactant 1-fluoro-4-hydroxy-thioxanthen-9-one was prepared as described above in Example 1a. To a suspension of 1-fluoro-4-hydroxy-9H-thioxanthen-9-on (92%) (306 g, 1.14 mol) in acetonitrile (3500 mL), potassium carbonate (464 g, 3.36 mol) was added while stirring vigorously. 3-Chloro-1,2-propanediol (371 g, 3.36 mol) was added drop wise over 30 minutes. The reaction mixture was heated to reflux and allowed to stir for 24 hours. The mixture was filtered and the residue was washed with warm acetonitrile (500 mL) (70° C.). The filtrate was evaporated under reduced pressure. The residual solid was treated with a mixture of methyl-tert-butylether (400 mL) and acetone (40 ml) and stirred for about an hour. The crude 4-(2,3-dihydroxy-propoxy)-1-fluoro-thioxanthen-9-one was isolated by filtration and dried. The crude 4-(2,3-dihydroxy-propoxy)-1-fluoro-thioxanthen-9-one was treated twice with 1000 mL water at 60° C., isolated by filtration and dried.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:11](O)[CH:12]=[CH2:13].Cl[Si](C)(C)C>>[CH2:13]([O:6][C:5](=[O:7])[CH2:4][CH2:3][CH:2]([NH2:1])[C:8]([OH:10])=[O:9])[CH:12]=[CH2:11]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: C=CCO
Agent: C[Si](C)(C)Cl
Product: C=CCOC(=O)CCC(N)C(=O)O
Yield: 62 %

Procedure:
L-Glutamic acid (3) was protected in 62% yield as the γ-allyl ester using allyl alcohol and chlorotrimethylsilane to provide 2-amino-pentanedioic acid 5-allyl ester 4 as follows:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:35][O:34][C:32](=[O:33])[NH:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][N:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=23)=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: COC(=O)Cl
Reactant: NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Reaction time: 24 h
Yield: 26.4 %

Procedure:
A Mixture of 4-[2-(3-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridin-3-yl]benzenesulfonamide (0.1 g 0.23 mmol), methyl chloroformate (Aldrich) (0.028 g 0.3 mmol) and potassium carbonate (0.07 g 0.05 mmol) were stirred and heated at reflux under nitrogen in acetone (10 ml) for 18 hr. Additional methyl chloroformate (0.028 g) and potassium carbonate (0.07 g) were added and heating continued for a further 24 hr. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with brine (30 ml), dried (MgSO4) and the solvent removed. The residues were purified by SPE chromatography, elution with cyclohexane:ethyl acetate (3:1) gave the title compound as a white solid (0.03 g 26%). MH− 492
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([C:18]1[CH:31]=[CH:30][C:21]2[O:22][C:23]([CH3:29])([CH3:28])[C@@:24]3([CH3:27])[O:26][C@H:25]3[C:20]=2[CH:19]=1)(=[O:17])=[O:16])(C(C)(C)C)(C)C.[CH3:32][N:33]1[C:38](=[O:39])[CH:37]=[CH:36][C:35]([OH:40])=[N:34]1.N1C=CC=CC=1>O1CCOCC1>[CH3:32][N:33]1[C:38](=[O:39])[CH:37]=[CH:36][C:35]([O:40][C@H:25]2[C@@:24]([OH:26])([CH3:27])[C:23]([CH3:29])([CH3:28])[O:22][C:21]3[CH:30]=[CH:31][C:18]([S:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[OH:8])(=[O:17])=[O:16])=[CH:19][C:20]2=3)=[N:34]1
Reactant: Cn1nc(O)ccc1=O
Reactant: CC1(C)Oc2ccc(S(=O)(=O)c3ccccc3O[Si](C)(C)C(C)(C)C)cc2[C@@H]2O[C@@]21C
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: Cn1nc(O[C@@H]2c3cc(S(=O)(=O)c4ccccc4O)ccc3OC(C)(C)[C@@]2(C)O)ccc1=O

Procedure:
(3S,4S)-6-(2-tert-Butyldimethylsilyloxyphenyl)sulphonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo[b]pyran (0.5 g) (see Preparation 16) and 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridazin (0.41 g) (see J.Org.Chem., 1971, 36, 3372) were suspended in dry 1,4-dioxane (8 ml), pyridine (0.085 g) was added and the mixture was heated under reflux (a calcium chloride drying tube was attached to the flask) for 20 hours. The solvent was removed under reduced pressure, the residue was stirred with dichloromethane (30 ml) and filtered. The filtrate was evaporated and the residue was chromatographed on silica using 1:1 hexane:ethyl acetate as the eluent to yield a mixture of the required product and the epoxide starting material. This mixture was redissolved in dry 1,4-dioxane (7 ml), 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridazin (0.2 g) and pyridine (0.08 g) were added and the reaction was heated under reflux for a further 18 hours. The solvent was removed under reduced pressure and the residue was dissolved in 5% methanol/dichloromethane and filtered. The filtrate was evaporated and the residue was chromatographed on silica using 2.5:97.5 methanol:dichloromethane as the eluent to yield (3S,4R)-3,4-dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridazin-6-yl)oxy-3-hydroxy-6-(2-hydroxyphenyl)-sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran (0.17 g) as a yellow foam. Found: C,54.19; H,4.85; N,5.21. C23H24N2O7S, 0.625 CH2Cl2 requires C,54.06; H,4.73; N,5.34%.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[S:8][CH:6]1[OH:7])(=[O:3])[CH3:2].[CH2:25]([C:27]1[CH:41]=[CH:40][C:30]([CH2:31][C:32]2[C:38](O)=[CH:37][CH:36]=[CH:35][C:33]=2[OH:34])=[CH:29][CH:28]=1)[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[S:8][C@H:6]1[O:7][C:38]1[CH:37]=[CH:36][CH:35]=[C:33]([OH:34])[C:32]=1[CH2:31][C:30]1[CH:29]=[CH:28][C:27]([CH2:25][CH3:26])=[CH:41][CH:40]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1SC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCc1ccc(Cc2c(O)cccc2O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCc1ccc(Cc2c(O)cccc2O[C@@H]2S[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 16.6 %

Procedure:
2,3,4,6-Tetra-O-acetyl-5-thio-D-glucopyranose (1.29 g, 3.54 mmol), 2-(4-ethylbenzyl)resorcinol (2.42 g, 10.6 mmol), triphenylphosphine (1.86 g, 7.09 mmol) and toluene (13 mL) were mixed, and to the resulting mixture, diisopropyl azodicarboxylate (40% in toluene, 3.58 g) was then slowly added dropwise in ice. After stirring at room temperature for 24 hours, the reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=65:35-50:50) to give a crude product of 3-hydroxy-2-(4-ethylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranoside (338 mg). To a mixture of this crude product (338 mg) and pyridine (2 mL), acetic anhydride (0.5 mL) was added at room temperature. After stirring at room temperature for 20 hours, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate =2:1) to give the titled compound (134 mg, 6%) as a light-yellow gum.
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:28]=[CH:27][C:11]([CH2:12][O:13][C:14](=[O:26])[CH:15]([N:17]2[C@H:20]([S:21][C:22](=[O:24])[CH3:23])[CH2:19][C:18]2=[O:25])O)=[CH:10][CH:9]=1)([O-:7])=[O:6]>O1CCOCC1>[N+:5]([C:8]1[CH:28]=[CH:27][C:11]([CH2:12][O:13][C:14](=[O:26])[CH:15]([N:17]2[C@H:20]([S:21][C:22](=[O:24])[CH3:23])[CH2:19][C:18]2=[O:25])[Cl:3])=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)S[C@@H]1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1COCCO1
Product: CC(=O)S[C@@H]1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2.86 g (~24 mmol) of thionyl chloride in 20 ml of dioxan is added dropwise to a suspension, stirred at room temperature, of 12 g of poly-Hunig base in a solution of 2.83 g (7.59 mmol) of 2-[(4R)-4-acetylthio-2-oxoazetidin-1-yl]-2-hydroxyacetic acid p-nitrobenzyl ester in 100 ml of dioxan. The mixture is stirred for 1.5 hours at room temperature and filtered off from the poly-Hunig base, which is subsequently washed with dioxan. The filtrate is concentrated in vacuo. The 2-[(4R)-4-acetylthio-2-oxoazetidin-1-yl]-2-chloroacetic acid p-nitrobenzyl ester obtained is used in the next stage in crude form.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])=[CH:4][CH:3]=1.[CH:12]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:12][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=3)[CH2:16][CH2:15]2)=[CH:6][CH:7]=1
Reactant: N[C@@H]1C[C@H]1c1ccc(I)cc1
Reactant: COC(=O)c1ccc(CN2CCC(C=O)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccc(I)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.5 %

Procedure:
To a solution of trans-2-(4-iodophenyl)cyclopropanamine (420 mg, 1.621 mmol) in methanol (7 mL) were added methyl 4-((4-formylpiperidin-1-yl)methyl)benzoate (466 mg, 1.783 mmol), sodium cyanoborohydride (204 mg, 3.24 mmol), and acetic acid (0.028 mL, 0.486 mmol), and the mixture was stirred at room temperature for 18 h. The mixture was then quenched with saturated NaHCO3 aqueous solution (2 ml) and concentrated. The residue was treated with water (4 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 10% MeOH/EtOAc) to give 241 mg of product as pale yellow solid. MS: (M+H)+=505.3 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.97-1.16 (m, 2H), 1.19-1.38 (m, 2H), 1.46-1.63 (m, 1H), 1.71-1.92 (m, 3H), 2.00-2.10 (m, 2H), 2.29 (ddd, J=7.45, 4.42, 3.28 Hz, 1H), 2.56-2.65 (m, 2H), 2.86-2.98 (m, 2H), 3.56-3.66 (m, 2H), 3.89-3.98 (m, 3H), 6.80-6.92 (m, 2H), 7.43-7.62 (m, 4H), 7.94-8.05 (m, 2H).
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:23])[C@@H:8]([NH:15]C(OC(C)(C)C)=O)[CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)Cl>[CH:1]1([O:6][C:7](=[O:23])[C@@H:8]([NH2:15])[CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)OC1CCCC1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](C(=O)OC1CCCC1)C1CCCCC1
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
(S)-tert-butoxycarbonylamino-cyclohexyl-acetic acid cyclopentyl ester (1.17 g, 3.60 mmol) was dissolved in a TFA/DCM mixture (1:1, 10 ml) at 0° C. The solution was stirred for 90 minutes, the solvent removed in vacuo. The residue was azetroped with a DCM/heptane mixture (2×) to give a gum. The gum was redissolved in DCM (10 ml) and washed with saturated aqueous NaHCO3 solution (3×10 ml), dried (MgSO4) and filtered. The solvent of the filtrate was removed in vacuo to give the product as an oil (0.780 g, 78% yield). 1H NMR (300 MHz, CDCl3), δ: 1.00-1.40 (10H, m, CH×10), 1.50-2.00 (8H, m, CH×8), 3.25 (1H, d, CH, J=7.2 Hz), 5.20 (1H, m, CH).
Reaction SMILES: [C:1]([NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([Cl:25])=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:26].[Na+].OO>CO.CS(C)=O>[C:1]([NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([Cl:25])=[C:15]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:16]([C:17]([NH2:18])=[O:26])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)N1CCn2c(Cl)c(-c3ccccc3)c(C#N)c2C1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)(C)NC(=O)N1CCn2c(Cl)c(-c3ccccc3)c(C(N)=O)c2C1

Procedure:
To a solution at 65° C. of 40.0 g (112 mmol) of N-tert-butyl-6-chloro-8-cyano-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide in 400 ml of methanol and dimethyl sulfoxide (3:2) are added 10.1 ml (118 mmol) of aqueous 35% sodium hydroxide solution and then 19.8 ml (21.8 mmol) of 35-volumes aqueous hydrogen peroxide solution in 4 fractions every 15 minutes. After reaction for 30 minutes at 65° C., the mixture is cooled, partially concentrated under reduced pressure and taken up in dichloromethane. The organic phase is washed with water and is then dried over sodium sulfate, and the solvent is evaporated off under reduced pressure to give a yellow solid, which is crystallized from acetonitrile and then recrystallized from acetonitrile, to give 25.2 g of N2-(tert-butyl)-6-chloro-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a white powder after filtering off and drying.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[C:4](Cl)[CH:3]=1.[C:14]1([C@H:20]([NH:22][C:23]([NH2:25])=[O:24])[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[C:4]([NH:25][C:23]([NH:22][C@@H:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:21])=[O:24])[CH:3]=1
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Reactant: COCc1nc(Cl)cc(Cl)c1C#N
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCc1nc(NC(=O)N[C@H](C)c2ccccc2)cc(Cl)c1C#N
Temperature: 50 °C

Procedure:
A mixture of 4,6-dichloro-2-(methoxymethyl)nicotinonitrile (75.7 mg, 0.349 mmol), (R)-1-(1-phenylethyl)urea (77 mg, 0.469 mmol) and Xantphos G2 (39 mg, 0.044 mmol) in THF (2 ml) was sealed, sparged with argon, charged with triethylamine (0.17 ml, 1.220 mmol) and heated to 50° C. for 17 hr. The mixture was cooled and filtered through celite, eluted with EtOAc before it was concentrated in vacuo and purified via flash chromatography (25-100% Et2O/hexane) to provide (R)-1-(4-chloro-5-cyano-6-(methoxymethyl)pyridin-2-yl)-3-(1-phenylethyl)urea. MS ESI calc'd for C17H18ClN4O2 [M+H]+ 345. found 345.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:23]([O:25]C)=[O:24].[I-].[Li+].Cl>N1C=CC=CC=1.O>[O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:21])[CH3:19])[CH:13]=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:23]([OH:25])=[O:24]
Reactant: COC(=O)c1cnc2c3ccc(NC(=O)C(C)(C)C)cc3ncn2c1=O
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccc2c(c1)ncn1c(=O)c(C(=O)O)cnc21
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
A mixture of methyl 4-oxo-9-pivalamido-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (6.5 g) and anhydrous lithium iodide (16.25 g) in dry pyridine (65 ml) was stirred at 100° C. for 1 hour and 30 minutes and at 120° C. for additional 30 minutes. The reaction mixture was concentrated under reduced pressure to give an oily residue, which was dissolved in water. The resulting solution was adjusted to pH 1 with conc. hydrochloric acid to give yellow crystals, which were separated by filtration, washed with water, and dried. The crude crystals were dissolved in a mixture of chloroform and methanol under heating. The solution was filtered to remove insoluble materials. The solution was concentrated under reduced pressure until crystallization began and cooled. The resulting crystals were collected by filtration and dried. There was obtained 4-oxo-9-pivalamido-4H-pyrimido[1,2-C]quinazoline-3-carboxylic acid (2.9 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1[C:14]2[C:15]3[N:16]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[CH:27]=3)[CH2:17][C:18](=[O:20])[NH:19][C:13]=2[CH:12]=[CH:11][CH:10]=1.O>CN(C)C=O>[Br:1][C:27]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:16]2[C:15]=1[C:14]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[NH:19][C:18](=[O:20])[CH2:17]2
Reactant: O=C1Cn2c(cc3ccccc32)-c2ccccc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Cn2c(c(Br)c3ccccc32)-c2ccccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A solution of 2.36 g N-bromosuccinimide in 50 ml dimethylformamide was added dropwise to a solution of 3.0 g indolo[1,2-d][1,4]benzodiazepin-6(7H)-one in 50 ml dimethylformamide, during which the reaction mixture was cooled with cold water. The resulting solution was stirred at room temperature for two hours and then poured into 800 ml water. The precipitate was collected, washed with water and dried under vacuum (P2O5) to give 3.7 g solid;
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)=[O:15])=[CH:6][C:5]=1[CH2:27][OH:28].O.Cl>C1COCC1>[CH:3]([C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)=[O:15])=[CH:6][C:5]=1[CH2:27][OH:28])=[O:2]
Reactant: COC(OC)c1nc2c(cc1CO)CCCN2C(=O)Nc1ccc(C(F)(F)F)cn1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1nc2c(cc1CO)CCCN2C(=O)Nc1ccc(C(F)(F)F)cn1
Reaction time: 0.25 h

Procedure:
A solution of 7-(dimethoxymethyl)-6-(hydroxymethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 14, 18 mg, 0.042 mmol) in THF (0.8 ml) was treated with water (0.6 ml) and conc. HCl (0.2 ml) and stirred for 15 min. The reaction mixture was quenched by addition of sat. aq. NaHCO3 (gas evolution), extracted with DCM (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was triturated with EtOAc/heptanes 10:1, filtered and dried under vacuum to give the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[NH:10][CH:9]=1)=[O:7])[CH3:4].[CH3:18]I.O>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[N:10]([CH3:18])[CH:9]=1)=[O:7])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)c1c[nH]c2ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2ccc(Br)cc12
Reaction time: 0.5 h

Procedure:
Sodium hydride (537 mg) was added to a solution of 5-bromo-1H-indole-3-carboxylic acid ethyl ester (3.00 g) in N,N-dimethylformamide (22 ml) at room temperature, and stirred at the same temperature for 0.5 hour. Methyl iodide (2.1 ml) was added and the mixture was stirred at the same temperature for two hours. After completion of the reaction, water was added and the precipitated solid was collected by filtration. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 5-bromo-1-methyl-1H-indole-3-carboxylic acid ethyl ester (3.10 g) as a white solid.