Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.[BH-](OC(C)=O)(OC(C)=O)[O:36][C:37](C)=[O:38].[Na+]>C(Cl)(Cl)Cl.CO>[CH:37]([OH:38])=[O:36].[CH:37]([OH:38])=[O:36].[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=5)[CH:13]=[CH:12][C:11]4=[O:22])[CH2:6][CH2:7]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=CO
Product: O=c1ccc2c(F)cc(F)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
1-[2-(4-Amino-1-piperidinyl)ethyl]-5,7-difluoro-2(1H)-quinolinone (150 mg; 0.49 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (80 mg; 0.49 mmol) were dissolved in a 5:1 mixture of chloroform and MeOH (5 ml: 1 ml) and stirred at rt for 1 h. This was then treated with NaBH(OAc)3 (310 mg; 1.47 mmol) and stirred for a further 2 h under the same conditions. The solvents were then removed from the reaction and the crude residues purified by column chromatography on silica gel using a 0-20% 2M NH3:MeOH/DCM gradient. Fractions containing the desired product were concentrated to afford the free base of the title compound (200 mg; 89%) however this was shown to be impure so was further purified by MDAP to afford the title compound (30 mg; 14%) directly as the diformate salt.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O-:14])=O)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.O>CN(C)C=O>[O:18]1[CH2:19][CH2:20][N:15]([C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[NH:1][C:2](=[O:3])[CH2:4][CH2:5]3)=[O:14])[CH2:16][CH2:17]1
Reactant: O=C1CCc2cc(C(=O)[O-])ccc2N1
Reactant: C1COCCN1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(C(=O)N3CCOCC3)ccc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.0 Gram of succenimide 3,4-dihydrocarbostyril-6-carboxylate and 0.37 g of morpholine were dissolved in 2 ml of dimethylformamide and stirred at room temperature for 3 hours. Then water was added to the reaction mixture and extracted with chloroform, the chloroform layer was washed with water and a saturated sodium chloride aqueous solution in this order. After drying the chloroform layer with anhydrous sodium sulfate, then chloroform was removed by distillation under a reduced pressure, then acetone was added to the thus obtained residue to crystallize the product. 150 Milligrams of 6-morpholinocarbonyl-3,4-dihydrocarbostyril was obtained. Colorless granular crystals. Melting point: 206°-207° C. (from ethanol).
Reaction SMILES: [N:1]([CH:4]([C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)[CH2:5][CH3:6])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>C1COCC1.O>[N:8]1[CH:9]=[CH:10][N:11]=[CH:12][C:7]=1[CH:4]([NH2:1])[CH2:5][CH3:6]
Reactant: CCC(N=[N+]=[N-])c1cnccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCC(N)c1cnccn1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
The 2-(1-azidopropyl)pyrazine (56 mg) was dissolved in the THF (5 ml) and water (1 ml) and the PS-PPh3 (225 mg) added. The reaction mixture was heated to 50° C. and left to stir for approx. 20 hours. The mixture was filtered under vacuum and rinsed with DCM (a precipitate formed and re-dissolved with MeOH) then MeOH. The filtrate was evaporated to yield the title compound as a yellow oil which was used without further purification. [M+H]+ 138.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[OH:10])[CH:5]=O.Cl.[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([BH3-])#N.[Na+].[C:26](O)(=[O:28])C>N1C=CC=CC=1>[CH2:13]([O:20][N:21]([CH2:5][C:4]1[CH:3]=[C:2]([Cl:1])[C:9]([OH:10])=[C:8]([Cl:11])[CH:7]=1)[CH:26]=[O:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)O
Reactant: O=Cc1cc(Cl)c(O)c(Cl)c1
Reactant: NOCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccncc1
Product: O=CN(Cc1cc(Cl)c(O)c(Cl)c1)OCc1ccccc1

Procedure:
A solution of 3,5-dichloro-4-hydroxybenzaldehyde (2.00 g, 10.5 mmol) and O-benzylhydroxylamine hydrochloride (1.84 g, 11.55 mmol) in 5 ml of pyridine was stirred for 2 h. All volatiles were removed in vacuo and the resulting imine intermediate was treated with sodium cyanoborohydride (1.98 g, 31.5 mmol) in 10 ml of glacial acetic acid for 4 h. The reaction mixture was quenched with water and neutralized with sodium bicarbonate powder, extracted with ethyl acetate and dried (sodium sulfate). Removal of all volatiles in vacuo afforded the crude 4-(Benzyloxyamino-methyl)-2,6-dichlorophenol (4.02 g) as a light yellow oil (M+1=298). This was converted to the title compound using the method described in example 1c (2.01 g, 59%) as a thick colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.38 (m, 3H), 7.28 (m, 2H), 7.19 (s, 2H), 5.97 (s, 1H), 4.78 (s, 2H), 4.55 (s, 2H). M+1=326.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])=[CH:15][C:14]=1[O:26][CH2:27][CH:28]1[CH2:30][CH2:29]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:33]=[N+:34]([O-:57])[CH:35]=[C:36]([Cl:56])[C:37]=1[CH2:38][C@@H:39]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH:48]([F:50])[F:49])=[C:43]([O:51][CH2:52][CH:53]2[CH2:55][CH2:54]2)[CH:42]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][CH2:20][C:21]([O:23][C@H:39]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH:48]([F:49])[F:50])=[C:43]([O:51][CH2:52][CH:53]3[CH2:54][CH2:55]3)[CH:42]=2)[CH2:38][C:37]2[C:36]([Cl:56])=[CH:35][N+:34]([O-:57])=[CH:33][C:32]=2[Cl:31])=[O:22])=[O:18])=[CH:15][C:14]=1[O:26][CH2:27][CH:28]1[CH2:29][CH2:30]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)OCC(=O)O)cc1OCC1CC1)S(C)(=O)=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(c1ccc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 78 %

Procedure:
2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)-benzoyloxy)acetic acid (1.7 g, 3.83 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (1.611 g, 3.83 mmol), EDC (2.205 g, 11.50 mmol), and DMAP (0.702 g, 5.75 mmol) were dissolved in DCM (60 ml); the mixture was stirred at RT for 2 days. Then it was concentrated to about half volume, diluted with EtOAc (about 200 ml) and washed with HCl 1N and NaHCO3 sat. sol. The organic layer was dried over Na2SO4, and the solvent was evaporated to dryness. The crude (3.35 g) was purified by flash chromatography on silica gel (eluent: Et20/EtOAc 2/1); (S)-4-(2-(2-(4-(N-(tert-butoxycarbonyl)methyl-sulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide was obtained as a white amorphous solid (2.52 g, 2.98 mmol, 78% yield, MS/ESI+ 846.0 [MH]+).
Reaction SMILES: CNCCNC.[C:7]1([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1>[Cu].C1(C)C(C)=CC=CC=1>[CH:17]1[CH:16]=[CH:15][C:14]([N:13]([C:24]2[CH:25]=[CH:26][C:21]([Br:20])=[CH:22][CH:23]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:19][CH:18]=1
Reactant: Brc1ccc(I)cc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Cu]
Agent: CNCCNC
Solvent: Cc1ccccc1C
Product: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
N,N′-dimethylethylenediamine 1.76 g was added to diphenylamine 16.9 g, 4-bromoiodobenzene 28.2 g sodium t-butoxide 14.4 g, copper powder 3.81 g and a xylene 100 ml solution, and the mixture was heated and refluxed for 24 hours under argon atmosphere. After cooled down to room temperature, the mixture was filtered to remove an insoluble matter, and the filtrate was concentrated. The residue was refined by silica gel chromatography to obtain 22.7 g of white crystal of 4-bromotriphenylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:7](=[O:17])[CH2:6][CH2:5]2.I.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](SC)=[NH:25]>C(O)C.CCOCC>[CH3:16][N:14]([CH3:15])[CH2:13][CH2:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[NH:25])=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:17]
Reactant: CN(C)CCN1C(=O)CCc2cc(N)ccc21
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCOCC
Solvent: CCO
Product: CN(C)CCN1C(=O)CCc2cc(NC(=N)c3cccs3)ccc21
Reaction time: 18 h

Procedure:
A solution of 6-amino-1-(2-(dimethylamino)ethyl)-3,4-dihydroquinolin-2(1H)-one (0.045 g, 0.182 mmol) in dry ethanol (5 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.103 g, 0.361 mmol) at room temperature and the resulting mixture was stirred over night (18 h). The reaction was diluted with ether (45 mL) and the precipitate collected by vacuum filtration. The precipitate was washed from the filter with methanol and the solvent was evaporated. The residue was diluted with 1N sodium hydroxide solution (5 mL) and product was extracted into ethyl acetate (3×10 mL). The combined ethyl acetate layer was washed with brine and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography (2M ammonia in methanol:dichloromethane, 1:19). Product was dried under high vacuum. Yield: 40 mg of yellow oil 4 (58%) 1H NMR (CDCl3) δ 7.44 (dd, J=1, 5.4 Hz, 1H), 7.41 (d, J=3.3 Hz, 1H), 7.09 (t, J=4.2 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.88 (dd, J=2.1, 8.4 Hz, 1H), 6.83 (d, J=2.1 Hz, 1H), 4.87 (br s, 2H), 3.98 (t, J=7.2 Hz, 2H), 2.87 (t, J=7.2 Hz, 2H), 2.63 (t, J=7.2 Hz, 2H), 2.37 (t, J=7.2 Hz, 2H), 2.25 (s, 6H), 1.89-1.79 (m, 2H). MS (ESI): 357.2 (M+1). ESI-HRMS calculated for C19H25N4SO (MH+): 357.1743, Observed: 357.1752.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N:28]5[CH2:33][CH2:32][CH:31]([N:34]6[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]6)[CH2:30][CH2:29]5)[CH:23]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(C2CCN(c3cccc(Br)c3)CC2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(C2CCN(c3cccc(Nc4nc5c(-c6ccc(S(C)(=O)=O)cc6)cccn5n4)c3)CC2)CC1

Procedure:
1-[1-(3-Bromo-phenyl)-piperidin-4-yl]-4-methyl-piperazine was prepared from 3-bromophenylboronic acid (0.50 g, 2.5 mmol) and 1-methyl-4-piperidin-4-yl-piperazine (0.23 g, 1.2 mmol) in a manner analogous to Step 49a. The reaction product was isolated as a brown viscous oil (0.069 mg, 16%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.08 (t, J=8.0 Hz, 1H), 7.03 (s, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 3.72 (d, J=11.7 Hz, 2H), 2.78-2.33 (m, 11H), 2.30 (s, 3H), 1.93 (d, J=12.9 Hz, 2H), 1.69-1.57 (m, 2H). MS=338, 340 (MH)+. 58b) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyri din-2-yl]-{3-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (55.0 mg, 0.191 mmol) and 1-[1-(3-bromo-phenyl)-piperidin-4-yl]-4-methyl-piperazine (69.0 mg, 0.204 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.035 g, 34%). MP=237-239° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.5 Hz, 1H), 8.25 (d, J=6.9 Hz, 2H), 8.08 (d, J=7.7 Hz, 2H), 7.65 (d, J=7.1 Hz, 1H), 7.31 (s, 1H), 7.24-7.18 (m, 1H), 7.04-6.95 (m, 2H), 6.82 (s, 1H), 6.60 (d, J=7.9 Hz, 1H), 3.81 (d, J=11.4 Hz, 2H), 3.10 (s, 3H), 2.77 (t, J=12.2 Hz, 2H), 2.72-2.33 (m, 9H), 2.30 (s, 3H), 1.96 (d, J=11.2 Hz, 2H), 1.75-1.63 (m, 2H). MS=546 (MH)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH2:10][C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].[NH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([F:54])[C:28]=1[CH2:29][CH2:30][C@H:31]1[O:36][CH2:35][C@H:34]([CH2:37][O:38][C:39]([NH:41][CH2:42][C:43]([F:46])([F:45])[F:44])=[O:40])[N:33]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:32]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH2:10][C:11]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[C:27]([F:54])[C:28]=2[CH2:29][CH2:30][C@H:31]2[O:36][CH2:35][C@@H:34]([CH2:37][O:38][C:39](=[O:40])[NH:41][CH2:42][C:43]([F:46])([F:44])[F:45])[N:33]([C:47]([O:49][C:50]([CH3:51])([CH3:53])[CH3:52])=[O:48])[CH2:32]2)=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc([C@@H](CC(=O)O)c2ccc(F)c(F)c2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cncc2F)OC[C@@H]1COC(=O)NCC(F)(F)F
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)C[C@H](c2ccc(C#N)cc2)c2ccc(F)c(F)c2)OC[C@H]1COC(=O)NCC(F)(F)F
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
The product from step 1 (50 mg, 0.16 mmol) and the product from step 4 of Example 89 (78 mg, 0.16 mmol) were dissolved in pyridine (1 mL) and the stirred solution was cooled to −10° C. in an ice/acetone bath. To the cold solution was added POCl3 dropwise (0.02 mL, 0.18 mmol). The mixture was stirred at −10° C. for 30 min. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution (1 mL) and the mixture was allowed to warm to ambient temperature. The mixture was diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The combined dichloromethane phases were dried (Na2SO4), filtered, and the filtrate solvents were removed in vacuo. The residue was purified on a 12 g silica gel column using a gradient elution of 0-100% EtOAc:hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H-Boc)+=650.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[CH3:3].[OH:5]N1C(=O)C2=CC=CC=C2C1=O>C(#N)C1C=CC=CC=1>[C:2]([OH:5])([CH3:4])([CH3:3])[CH3:1].[CH3:1][C:2]([CH3:4])=[O:5]
Reactant: CC(C)C
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: N#Cc1ccccc1
Product: CC(C)(C)O
Product: CC(C)=O
Yield: 81 %
Yield: 14 %

Procedure:
To benzonitrile was added 5 mmol of isobutane, 0.5 mmol of N-hydroxyphthalimide (NHPI) and 0.0125 mmol of cobalt acetate Co(OAc)2, and the resultant mixture was stirred under an air atmosphere at a pressure of 10 atm and at a temperature of 100° C. for 8 hours. The products in the reaction mixture were analyzed by gas chromatography, and, as a result, t-butanol (yield 81%) and acetone (yield 14%) were formed.
Reaction SMILES: C(O[C@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[BrH:28].C(OCC)(=O)C.CCCCCC>ClCCl>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][C@@H:5]1[Br:28])(=[O:10])[CH3:9]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Br
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C

Procedure:
1,2,3,4,6-penta-O-acetyl-α-D-glucopyranose (1.0 g, 2.60 mmol) was dissolved in 20 mL of dichloromethane and 1.90 mL of hydrobromic acid (33% in acetic acid) at 0° C., and the reaction was stirred while warming to room temperature. TLC (40% ethyl acetate-hexane) after 18 h showed complete consumption of the starting material and formation of a higher running spot. The reaction was slowly diluted with saturated sodium bicarbonate (25 mL), extracted into dichloromethane (2×100 mL), dried over sodium sulfate, filtered and concentrated to afford 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide which was used without purification.
Reaction SMILES: O=C1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]=[N:6][C:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[CH:4][C:3]1=2.C[Mg]Cl.[CH3:25]CCCCC.C([O:34][CH2:35][CH3:36])(=O)C>O1CCCC1>[CH3:25][C:35]1([OH:34])[CH2:36][CH:10]([CH3:11])[CH2:9][C:8]2[N:7]=[N:6][C:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[CH:13]=3)=[CH:4][C:3]1=2
Reactant: O=C1CCCc2nnc(-c3cccc(C(F)(F)F)c3)cc21
Reactant: CCCCCC
Reactant: CCOC(C)=O
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: CC1Cc2nnc(-c3cccc(C(F)(F)F)c3)cc2C(C)(O)C1
Temperature: -20 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
5-Oxo-3-(3-trifluoromethylphenyl)-7,8-dihydro-6H-cinnoline (200 mg, 0.65 mmol) obtained in Example 66 was dissolved in tetrahydrofuran (1 mL) and cooled to −20° C., followed by adding a tetrahydrofuran solution (0.26 mL, 0.78 mmol) of 3N methylmagnesium chloride to the reaction liquid and reacting for 3 hours while elevating temperature. To the reaction liquid was added distilled water (1 mL) to quench, followed by adding ethyl acetate (5 mL) and a 1N aqueous solution of sodium hydrogen sulfate (5 mL) for extraction, washing an organic layer with a saturated saline solution (3 ml), drying with sodium sulfate anhydride and purification of residue obtained by concentration using silica gel column chromatography (hexane/ethyl acetate=2/1 to 1/1) to obtain an objective compound (74.1 mg, 35%) as pale yellow crystal.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[C:17]([F:22])[CH:18]=[CH:19][CH:20]=5)[NH:15][CH2:14][C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C.[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1>[C:41]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[N:12]2[CH:11]=[N:10][C:9]([C:6]3[N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[O:8][N:7]=3)=[C:13]2[CH2:14]1)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: Fc1cccc2c1NCc1c(-c3noc(C4CC4)n3)ncn1-2
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1)N1Cc2c(-c3noc(C4CC4)n3)ncn2-c2cccc(F)c21
Reaction time: 5 h

Procedure:
To 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-6-fluoro-4,5-dihydroimidazo[1,5-a]quinoxaline (XXXIII, EXAMPLE 103, 0.438 g), diisopropylethylamine (0.26 ml), and dimethylamino-pyridine (0.018 g) in THF (20 ml) is added benzoyl chloride (0.19 ml). After stirring for 5 hr, additional benzoyl chloride (0.20 ml) is added. The reaction is stirred at 20°-25° for 2 hr, then stored over the weekend in the freezer. It is then stirred again at 20°-25° for 24 hr, after which the THF solvent is removed under reduced pressure and replaced with dichloromethane. After stirring for a final 7 hr, the reaction is partitioned between dichloromethane and aqueous sodium bicarbonate. The phases are separated and the organic phase is filtered through sodium sulfate, concentrated, and the crude product chromatographed on silica gel (300 ml) eluting with ethyl acetate/dichloromethane (20/80). The appropriate fractions are pooled and concentrated to give the product which is recrystallized from dichloromethane and hexane to give the title compound, mp 234.5°-235.5°; MS m/z at 401; IR (mineral oil) 1660, 1502, 1366, 786 and 1247 cm-1 ; NMR (CDCl3) 1.21, 2.20, 5.32, 6.98, 7.3-7.5 and 8.19 δ.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:20][C:21](N2C=CN=C2)=[O:22])[S:5][C:6]=1[C:7]1[N:8]=[C:9]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[S:10][CH:11]=1.C(O)(=O)C.[CH3:32][N:33]([CH3:38])[C:34](=[O:37])[CH2:35][NH2:36].C(N(CC)CC)C>CN(C=O)C>[CH3:32][N:33]([CH3:38])[C:34](=[O:37])[CH2:35][NH:36][C:21]([NH:20][C:4]1[S:5][C:6]([C:7]2[N:8]=[C:9]([C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[O:13])[S:10][CH:11]=2)=[C:2]([CH3:1])[N:3]=1)=[O:22]
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1csc(C(=O)N2CCOCC2)n1
Reactant: CN(C)C(=O)CN
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)NCC(=O)N(C)C)sc1-c1csc(C(=O)N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To N-[4′-methyl-2-(morpholin-4-ylcarbonyl)-4,5′-bi-1,3-thiazol-2′-yl]-1H-imidazole-1-carboxamide, prepared as in Step 3 of Example 36, described above (75 mg; 0.19 mmol; 1 eq.) is added DMF (3 ml), glycine dimethylamide acetate (Chem-Impex) (30.1 mg; 0.19 mmol; 1 eq.) and triethylamine (57 μl; 0.41 mmol; 2.20 eq.). The mixture is stirred 3 hours at rt. Solvents are evaporated and the crude product is crystallized in MeOH, affording Compound (46) as a light yellow solid (49 mg; 60%). 1H NMR (DMSO-d6, 300 MHz) δ 2.44 (s, 3H), 2.86 (s, 3H), 2.94 (s, 3H), 3.68 (m, 6H), 4.01 (m, 2H), 4.33 (m, 2H), 6.83 (m, 1H), 7.91 (s, 1H), 10.70 (br s, 1H). M− (ESI): 437.15; M+ (ESI): 439.09. HPLC (method A), Rt: 2.30 min (purity: 99%).
Reaction SMILES: CS(C)=O.[CH2:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[O:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][N:18]=[C:17]([CH2:23][OH:24])[CH:16]=1.C(N(CC)CC)C>O>[CH2:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:6]1[O:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][N:18]=[C:17]([CH:23]=[O:24])[CH:16]=1
Reactant: COc1cnc(CO)cc1OC1Cc2ccccc2C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1cnc(C=O)cc1OC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 72.4 %

Procedure:
To a dimethyl sulfoxide solution (20 ml) of 4-(2-indanyloxy)-5-methoxy-2-pyridinemethanol (5h) (2.71 g, 10 mmol) and triethylamine (3.03 g, 30 mmol) was added sulfur trioxide-pyridine complex (4.77 g, 30 mmol), and the mixture was stirred at room temperature for 7 hours. The reaction mixture was poured into cold water to cause precipitation of crude crystals. The crude crystals were collected by filtration, dried, and purified by silica gel column chromatography, to thereby obtain the title compound (1.95 g, yield 72%).