Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg+].[Br-].C(OCC)C.[NH:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15].[NH4+].[Cl-]>C1COCC1.C(Cl)Cl>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:10]2[NH:9][CH:13]=[CH:12][CH:11]=2)=[O:22])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1cc[nH]c1
Agent: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc[nH]1
Reaction time: 1 h

Procedure:
CH3MgBr (3M) in diethylether (30 mL, 90 mmol) was added by dropwise to the solution of pyrrole (6.95 mL, 100 mmol) in THF (150 mL) at −78° C. and continued for 1 h at r.t. 4-nitrobenzoyl chloride (13 g, 70 mmol) in THF (200 mL) was added by dropwise to the solution and stirring was continued for 3 hours at r.t. The mixture was poured into saturated aqueous NH4Cl, and the precipitate dissolved in DCM and added to the aqueous solution. The organic layer was washed with water, dried over MgSO4 and concentrated under vacuum to give an oily product. Compound 1 was isolated by chromatography on silica gel flash column eluting with EtOAc/Hex to furnish a yellow solid (12.4 g, 81%). 1H-NMR (CDCl3) δ 10.01 (bs, 1H, NH), 8.34 (d, J=8.4, 2H), 8.03 (d, J=8.7, 2H), 7.24 (bs, 1H), 6.86 (bs, 1H), 6.38 (bs, 1H); 13C-NMR (CDCl3) δ 182.51, 149.61, 143.62, 130.57, 129.74, 126.67, 123.55, 120.37, 111.69. ESI-MS m/z (M+H) calc'd: 217.0 found 216.9.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)([O-:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:13]1[CH:14]=[CH:15][N:16]=[C:12]1[N+:9]([O-:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: ClCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1nccn1Cc1ccccc1
Temperature: 25 °C
Yield: 50.4 %

Procedure:
Benzyl chloride (1.8 mL, 15.4 mmol, 1.2 equiv) was added to a solution of 2-nitroimidazole (1.45 g, 12.8 mmol) and triethylamine (3.6 mL, 25.7 mmol, 2 equiv) in DCM (40 mL). The reaction mixture was stirred at reflux for 72 h, allowed to cool to rt, diluted with DCM, washed with H2O and brine, dried (sodium sulfate), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc, 7:3) to afford 1.31 g of the title compound as a white solid: ES-MS: 204.0 [M+H]+; tR=3.72 min (System 1); TLC: Rf=0.22 (Hex/EtOAc, 7:3).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1.C([Li])CCC.CN([CH:23]=[O:24])C.O>C1COCC1.CCCCCC>[CH:10]1([CH2:9][O:8][C:5]2[CH:4]=[CH:3][C:2]([CH:23]=[O:24])=[CH:7][N:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Brc1ccc(OCC2CCCC2)nc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=Cc1ccc(OCC2CCCC2)nc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of Intermediate 28 (895 mg) in anhydrous THF (10 ml) was added dropwise with a 1.6 M solution of n-butyllithium in hexane (2.70 ml, Ald) over 5 minutes with cooling at −78° C. under argon gas atmosphere, and stirred for 20 minutes. This reaction mixture was added with dehydrated DMF (330 μl, WAKO) over 3 minutes, stirred for 30 minutes, then warmed to room temperature, and further stirred for 1 hour. The reaction mixture was added with water (10 ml), and extracted with ethyl acetate (30 ml×3). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=10:1) to obtain the title compound (Intermediate 29, 1.04 g).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:41][CH:42]([F:44])[F:43])(=O)=O>C(#N)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:41][CH:42]([F:44])[F:43])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1
Reactant: Fc1cccnc1[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Fc1cccnc1[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CN(CC(F)F)C3)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of trans-8-chloro-1-[4-(3-fluoro-pyridin-2-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50.0 mg, 0.126 mmol), cesium carbonate (81.9 mg, 0.251 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (53.8 mg, 0.251 mmol) in acetonitrile (0.6 ml) was stirred at room temperature for 20 h. The reaction mixture was partitioned between a water-brine mixture (1:1) (2 ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with two 5-ml portions of ethyl acetate. The combined organic layers were concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (24 mg, 37%) as off-white solid. MS m/e: 462 ([M+H]+)
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([OH:12])[CH2:6][C:5]1([CH3:14])[CH3:13].[C:15](OC(=O)C)(=[O:17])[CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:15]([O:1][CH2:2][CH2:3][N:4]1[C:5]([CH3:14])([CH3:13])[CH2:6][CH:7]([OH:12])[CH2:8][C:9]1([CH3:10])[CH3:11])(=[O:17])[CH3:16]
Reactant: CC1(C)CC(O)CC(C)(C)N1CCO
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCCN1C(C)(C)CC(O)CC1(C)C
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Into a 250 ml flask equipped with a magnetic stirbar, thermometer, addition funnel and nitrogen atmosphere was placed 1-(2-hydroxyethyl)-2,2,6,6-tetramethyl-4-piperidinol (10.0 g, 0.499 mole) and 75 ml of methylene chloride. The resulting slurry was cooled to -20° C. and the addition funnel was charged with acetic anhydride (5.1 g, 0.496 mole) and 15 ml of methylene chloride. The anhydride was added dropwise to the diol slurry with no apparent reaction. The mixture was warmed to 15° C. at which temperature the solids began to dissolve. The mixture was stirred at ambient temperature for 2 hours. The mixture was poured into 80 ml of 10% sodium carbonate (aqueous) and stirred for 15 minutes at ambient temperature. The mixture was transferred to a separatory funnel and extracted with 100 ml of methyl t-butyl ether. The ether solution was dried with anhydrous magnesium sulfate and the solvent removed using aspirator and high vacuum systems. The product was a white solid melting at 56°-58° C. This material was used without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH:21]=[C:22]1[S:26][C:25](SC)=[N:24][C:23]1=[O:29])=[CH:10][CH:9]=2)(=[O:4])=[O:3].[NH3:30]>CO>[NH2:30][C:25]1[S:26]/[C:22](=[CH:21]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[C:14]3[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)/[C:23](=[O:29])[N:24]=1
Reactant: N
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncc(S(C)(=O)=O)c(-c4ccccc4)c3c2)S1
Solvent: CO
Product: CS(=O)(=O)c1cnc2ccc(/C=C3\SC(N)=NC3=O)cc2c1-c1ccccc1

Procedure:
Similar procedure as described in example 41c was used, starting from 5-(3-methanesulfonyl-4-phenyl-quinolin-6-ylmethylene)-2-methylsulfanyl-thiazol-4-one (example 61k), and ammonia in methanol to give 2-amino-5-[1-(3-methanesulfonyl-4-phenyl-quinolin-6-yl)-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 410 (MH+).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:24][CH3:25])[C:22](Br)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:24][CH3:25])[C:22]([N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c3c(cccc3c1Br)C(=O)N(OCc1ccccc1)C2=O
Reactant: CN1CCNCC1
Product: COc1cc2c3c(cccc3c1N1CCN(C)CC1)C(=O)N(OCc1ccccc1)C2=O

Procedure:
2-Benzyloxy-6-bromo-5-methoxy-benzo[de]isoquinoline-1,3-dione (0.5 g, from Example Z) was reacted with N-methylpiperazine (30 mL) following the procedure of Example 18 to give 0.5 g of 2-benzyloxy-5-methoxy-6-(4-methyl-piperazin-1-yl)-benzo[de]isoquinoline-1,3-dione. Hydrogenation of 2-benzyloxy-5-methoxy-6-(4-methyl-piperazin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.3 g) at 40 psi in the presence of Pd/C (10%) in DMA (20 mL) afforded 0.2 g of the title compound as the free base. A solution of acetyl chloride (0.03 mL) in ethanol (1 mL) was added to a solution of 2-hydroxy-5-methoxy-6-(4-methyl-piperazin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.12 g, 0.4 mmol) in ethanol (5 mL). The solution was stirred for 30 minutes, and the precipitate was filtered, washed with ether, and dried to give 0.13 g of the title compound as the HCl salt, mp 296-300° C.;
Reaction SMILES: [CH3:1][C:2]1([C:5](=[O:7])[CH3:6])[CH2:4][CH2:3]1.Br[Mg][C:10]#[CH:11]>O1CCCC1>[CH3:1][C:2]1([C:5]([OH:7])([C:10]#[CH:11])[CH3:6])[CH2:4][CH2:3]1
Reactant: CC(=O)C1(C)CC1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(C)(O)C1(C)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure A. In a 100-mL 3-necked round-bottom flask, a solution of 1-(1-methylcyclopropyl)ethan-1-one (2 g, 20.38 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) was added into a solution of bromo(ethynyl)magnesium (0.5 M in THF, 53 mL, 1.30 equiv) in tetrahydrofuran (5 mL). The resulting solution was stirred for 8 h at 0° C. in an ice/salt bath. The reaction was then quenched by the addition of 50 mL of sat. aq. NH4Cl. The resulting solution was extracted with 3×150 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×150 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 120 mg (5%) of 2-(1-methylcyclopropyl)but-3-yn-2-ol as colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:10](=[O:27])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([N:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:10](=[O:27])[N:9]1[CH2:29][CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCBr
Reactant: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(Cc3ccccc3)c2=O)cn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2cnn(Cc3c(C)noc3C)c2)c(=O)n1Cc1ccccc1
Temperature: 25 °C
Yield: 37.6 %

Procedure:
1-benzyl-4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,2,4-triazolidine-3,5-dione (100 mg, 0.27 mmol), bromoethane (149 mg, 1.36 mmol), and cesium carbonate (355 mg, 1.1 mmol) in DMF (5 mL) were heated at 80° C. for 15 hours. The reaction was cooled to room temperature, diluted with brine (50 mL) and extracted with ethyl acetate (2×, 50 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated on the rotovap. The residue was purified by HPLC (5 to 95% acetonitrile in H2O:25 minute gradient) to afford 1-benzyl-4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2-ethyl-1,2,4-triazolidine-3,5-dione (40 mg, 37%) as an oil. 1H NMR (DMSO-d6, 400 MHz): δ0.97 (t, J=7.2 Hz, 3H), 2.13 (s, 3H), 2.39 (s, 3H), 3.58 (q, J=6.8 Hz, 2H), 4.80 (s, 2H), 5.18 (s, 2H), 7.28-7.36 (m, 5H), 7.77 (s, 1H), 8.19 (s, 1H). MS M+H calculated 395.18. found 395.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.04 μM.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH:18]([NH:21][CH2:22][CH2:23][NH2:24])([CH3:20])[CH3:19]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:24][CH2:23][CH2:22][NH:21][CH:18]([CH3:20])[CH3:19])[N:3]=1
Reactant: CC(C)NCCN
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: CC(C)NCCNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and N-isopropylethylenediamine in DME. ES-MS m/e (%): 287 (M+H+, 100), 228 ([M+H-iPrNH2]+, 40).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=3)[C:10]([CH2:20][C:21]([OH:23])=[O:22])=[CH:9][C:8]2=[O:24])=[CH:4][CH:3]=1.Cl>[Fe].C(O)(=O)C>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:7]([CH2:6][C:5]1[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:8](=[O:24])[CH:9]=[C:10]2[CH2:20][C:21]([OH:23])=[O:22]
Reactant: O=C(O)Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccc([N+](=O)[O-])cc12
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Product: Nc1ccc2c(c1)c(CC(=O)O)cc(=O)n2Cc1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 1.17 h
Yield: 52 %

Procedure:
Iron powder (18 g.) was added over 40 minutes to a stirred solution of 1-(4-chlorobenzyl)-1,2-dihydro-6-nitro-2-oxoquinol-4-ylacetic acid (13 g.) in 50% v/v aqueous acetic acid (200 ml.) at 90° C. When the addition was completed, the mixture was stirred a further 70 minutes at 90° C. and then poured into an ice-water mixture (700 ml.). The mixture was adjusted to pH 1 with hydrochloric acid, and then filtered. The filtrate was adjusted to pH 6 with ammonium hydroxide solution, and the resulting mixture filtered. The solid residue (13 g.) was dissolved as far as possible in 2 N-sodium hydroxide solution, and the mixture was filtered. The filtrate was adjusted to pH 6 with glacial acetic acid, and the precipitated solid was filtered off, stirred with hot water (85° C., 200 ml.) and filtered while hot to give 6-amino-1-(4-chlorobenzyl)-1,2-dihydro-2-oxoquinol-4-ylacetic acid, m.p. 196°-9° C., (decomposition) in 52% yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:5]=[C:4]([Cl:17])[N:3]=1.[C@@H:18]1([NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[NH2:24]>C(#N)C>[Cl:17][C:4]1[N:3]=[C:2]([NH:24][C@@H:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C@H:18]2[NH2:25])[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:5]=1
Reactant: Clc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1
Reactant: N[C@@H]1CCCC[C@H]1N
Solvent: CC#N
Product: N[C@@H]1CCCC[C@H]1Nc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1

Procedure:
A mixture of Example 61a (3.4 g) in acetonitrile (30 mL) and trans-cyclohexane-1,2-diamine was heated at 170° C. for 40 minutes in a Biotage microwave reactor. The reaction mixture was extracted with ethyl acetate (2×), washed with brine and sodium bicarbonate. The combined organic layers were treated with 1M HCl. The aqueous layer was treated with NaOH (1M) and the material crashed out of the solution to give 0.797 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH2:18][CH2:19][OH:20])=[O:15])[C:5]2=[O:21].[CH2:22]([NH:24][C:25](=[O:45])[NH:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[C:29]([C:36]2[S:37][CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[N:40]=2)[CH:28]=1)[CH3:23].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:12]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([C:30]3[CH:31]=[N:32][C:27]([NH:26][C:25](=[O:45])[NH:24][CH2:22][CH3:23])=[CH:28][C:29]=3[C:36]3[S:37][CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[N:40]=3)=[CH:11][N:10]=2)[C:5](=[O:21])[C:6]([C:14]([O:16][CH2:17][CH2:18][CH2:19][OH:20])=[O:15])=[CH:7]1)[CH3:13]
Reactant: CCn1cc(C(=O)OCCCO)c(=O)c2cc(Br)cnc21
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCCCO)cn3CC)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41.8 %

Procedure:
3-Hydroxypropyl 6-bromo-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 24, 400 mg, 1.46 mmol) was dissolved in dimethylformamide (35 mL) and the solution was purged with argon. Tetrakis (triphenylphosphine) palladium (167 mg, 0.14 mM) followed by 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 9, 775 mg, 1.75 mmol) was added and the mixture was stirred for 20 min at room temperature. Sodium carbonate solution (678 mg, 5.84 mmol) (dissolved in minimum amount of water) was added and the reaction mixture was heated to 90° C. for 3 h. The reaction mixture was passed through celite and the celite was washed with dimethylformamide. The dimethylformamide layer was poured into water (100 mL) and a precipitate formed. The precipitate was filtered and dried then purified by flash column chromatography over silica gel (100-200 mesh) using methanol (5%) in chloroform as eluent to afford 360 mg (65%) 3-hydroxypropyl 1-ethyl-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate as white solid.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])O.[CH3:13][NH2:14]>>[CH3:13][NH:14][C@@H:11]1[O:12][C@H:3]([CH2:2][OH:1])[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@H:9]1[OH:10]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CN
Product: CN[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A one necked round bottom flask equipped with a stir bar was charged with glucose (40.0 g, 0.22 mole) and 2.0M methylamine (116.5 ml, 0.23 mole). The mixture was stirred overnight at room temperature (20°-21° C.). A sample was taken and analyzed by gas chromatography after acetylation.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].O.S(=O)(=O)(O)O.[I:26](O)(=O)=O>C(O)(=O)C.II>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([I:26])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: [O-][I+2]([O-])O
Reactant: CCOC(=O)c1ncc2[nH]c3ccccc3c2c1C
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ncc2[nH]c3ccc(I)cc3c2c1C
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 289.2 %

Procedure:
5.08 g of 4-methyl-β-carboline-3-carboxylic acid ethyl ester is dissolved in 40 ml of glacial acetic acid and combined with 0.96 ml of water, 0.24 ml of concentrated sulfuric acid, 688 mg of iodic acid, and 1.768 mg of iodine. The mixture is heated to 80° C. for 3 hours. After cooling, the mixture is suctioned off from undissolved material, and the filtrate is evaporated. The residue is taken up in ethanol/water. The thus-formed crystals are suctioned off, taken up in 500 ml of ethyl acetate, and extracted by stirring with 200 ml of 1N sodium hydroxide solution for 15 minutes. The organic phase is separated, concentrated by evaporation, the residue is extracted by stirring in ethyl acetate, and vacuum-filtered, thus obtaining 4.3 g of 6-iodo-4-methyl-β-carboline-3-carboxylic acid ethyl ester, mp 250°-255° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH:20]3[C:25]4[CH:26]=[CH:27][C:28]([C:30]#[N:31])=[CH:29][C:24]=4[CH2:23][CH2:22][O:21]3)[C@H:14]([CH3:32])[CH2:13]1)=[CH:7][CH:6]=[CH:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH:20]3[C:25]4[CH:26]=[CH:27][C:28]([CH2:30][NH2:31])=[CH:29][C:24]=4[CH2:23][CH2:22][O:21]3)[C@H:14]([CH3:32])[CH2:13]1)=[CH:7][CH:6]=[CH:5]2
Reactant: C[C@@H]1CN(c2cccc3cc(F)ccc23)CCN1CCC1OCCc2cc(C#N)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2cccc3cc(F)ccc23)CCN1CCC1OCCc2cc(CN)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-2-methyl-piperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carbonitrile (0.50 g, 1.2 mmol) in dry THF (4 mL) was added lithium aluminium hydride (1M solution in THF) (1.4 mL, 1.4 mmol) and the mixture stirred overnight at room temperature. The reaction was quenched by cautious addition of 2M sodium hydroxide, then extracted into chloroform. The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by preparative LC-MS to yield the title compound as a yellow oil. M+H=480.
Reaction SMILES: C([O:4][C:5]1[C:18]2[CH:17]([CH3:19])[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[O:10][C:9]=2[CH:8]=[C:7]([CH:20]([CH3:28])[CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:28][CH:20]([C:7]1[CH:6]=[C:5]([OH:4])[C:18]2[CH:17]([CH3:19])[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[O:10][C:9]=2[CH:8]=1)[CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCC(C)C(C)c1cc(OC(C)=O)c2c(c1)OC1=C(CCCC1)C2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC1=C(CCCC1)C2C

Procedure:
1-Acetoxy-3-(1,2-dimethylheptyl)-5,6,7,8-tetrahydro-9-methylxanthene is refluxed with potassium carbonate in 100 ml. of 15% aqueous methanol for 15 minutes. The reaction mixture is diluted with cold water and extracted with hexane. The organic phase is washed with water, dried (Na2SO4) and concentrated in vacuo to give a residue which, upon distillation, gives 3-(1,2-dimethylheptyl)-5,6,7,8,-tetrahydro-1-hydroxy-9-methylxanthene.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Cl:19])[CH:13]=1)=[O:4].[CH3:20][S:21]([NH:24][C:25]1[CH:40]=[CH:39][C:28]2[NH:29][C:30]([CH2:35][C:36](O)=[O:37])=[N:31][S:32](=[O:34])(=[O:33])[C:27]=2[CH:26]=1)(=[O:23])=[O:22].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[N:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Cl:19])[CH:13]=1)[C:36](=[O:37])[CH2:35][C:30]1[NH:29][C:28]2[CH:39]=[CH:40][C:25]([NH:24][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:26][C:27]=2[S:32](=[O:33])(=[O:34])[N:31]=1)=[O:4]
Reactant: COC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)c(Cl)c1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H]1CCC[C@@H]1N(Cc1ccc(F)c(Cl)c1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1

Procedure:
(1R,2S)-2-(3-Chloro-4-fluoro-benzylamino)-cyclopentanecarboxylic acid methyl ester (0.12 g, 0.42 mmol) was dissolved in anhydrous N,N-dimethylformamide (4.2 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.154 g, 0.46 mmol) was added followed by N-methylmorpholine (0.101 mL, 0.92 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.088 g, 0.46 mmol) was added portionwise and the mixture was stirred at 25° C. for 15 h. The reaction mixture was quenched by pouring into 1.0 M aqueous hydrochloric acid solution (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was concentrated in vacuo to afford the crude product, (1R,2S)-2-{(3-chloro-4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid methyl ester, which was used directly in the next step without further purification. LC-MS (ESI) calcd for C24H26ClFN4O7S2 600.09, found 601.1 [M+H+].