Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][N:5]2[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C@H:4]2[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:39]([C:42]1[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][CH:43]=1)([O-:41])=[O:40].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[N+:39]([C:42]1[CH:43]=[CH:44][C:45]([C:46]([O:1][C@@H:2]2[CH2:19][N:5]3[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:10][C@H:4]3[CH2:3]2)=[O:47])=[CH:49][CH:50]=1)([O-:41])=[O:40]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@H](O)C[C@@H]2C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C[C@@H]2C1
Temperature: -78 °C

Procedure:
tert-Butyl (8R,9aR)-8-hydroxy-5-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate (50 mg, 0.185 mmol, 1.0 equivalent, Part D), triphenylphosphine (60.6 mg, 0.231 mmol, 1.25 equivalents), and 4-nitrobenzoic acid (46.4 mg, 0.277 mmol, 1.5 equivalents) were dissolved in tetrahydrofuran (1.0 mL), and the resulting solution was cooled to −78° C. Diisopropyl azodicarboxylate (0.043 mL, 0.222 mmol, 1.2 equivalents) was dissolved in tetrahydrofuran (0.5 mL), and the resultant solution was added to the reaction mixture. The reaction mixture was removed from the cooling bath and warmed to room temperature for 0.5 hour. After the addition of 1 drop of saturated sodium bicarbonate, the tetrahydrofuran solution was loaded directly onto 2 sequentially linked 4 g silica gel cartridges, eluted with 50-100% ethyl acetate/heptanes over 20 minutes. The titled compound co-eluted with triphenylphosphine oxide and was used without additional purification (225 mg combined material). 1H NMR (400 MHz, CDCl3) δ ppm 8.28 (d, J=8.9 Hz, 2H), 8.15 (d, J=8.9 Hz, 2H), 5.52 (t, J=4.0 Hz, 1H), 4.53-3.94 (m, 4H), 3.73 (dd, J=14.1, 4.2 Hz, 1H), 3.02 (br s, 1H), 2.78-2.59 (m, 3H), 2.55 (dt, J=13.7, 7.0 Hz, 1H), 2.03-1.91 (m, 1H), 1.47 (s, 9H); MS (ESI+) m/z 419.8 (M+H)+.
Reaction SMILES: C([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][C:19]3[CH:20]=[C:21]([C@H:28]4[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@H:31]([OH:36])[C@@H:30]([CH2:37][OH:38])[O:29]4)[CH:22]=[CH:23][C:24]=3[CH:25]([CH3:27])[CH3:26])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>CO.[Pd]>[OH:38][CH2:37][C@@H:30]1[C@@H:31]([OH:36])[C@H:32]([OH:35])[C@@H:33]([OH:34])[C@H:28]([C:21]2[CH:22]=[CH:23][C:24]([CH:25]([CH3:27])[CH3:26])=[C:19]([CH2:18][C:15]3[CH:16]=[C:17]4[C:12]([CH2:11][CH2:10][CH2:9][NH:8]4)=[CH:13][CH:14]=3)[CH:20]=2)[O:29]1
Reactant: CC(C)c1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)N(Cc1ccccc1)CCC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)c1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)NCCC2
Reaction time: 18 h
Yield: 74.8 %

Procedure:
To a solution (2S,3R,4R,5S,6R)-2-[3-(1-benzyl-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (1.0 g, 1.0 mmol) in methanol (20 mL) was added 10% dry palladium on charcoal (200 mg) and conc. HCl (0.2 mL), and the mixture was stirred under hydrogen balloon pressure for 18 h. The reaction mixture was filtered through a celite bed which was washed with methanol and the filtrate was concentrated. The resulting residue was purified by preparative HPLC to furnish (2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol (320 mg).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[C:18]([NH:32][CH2:33][CH2:34][CH2:35]O)=[N:19][C:20]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)=[N:21][CH:22]=1.O.C(OCC)(=O)C>C(Cl)Cl.COCCN(S(F)(F)F)CCOC>[N:32]1([C:18]2[C:17]([C:16]#[C:15][CH2:14][CH2:13][CH2:12][N:3]3[C:4](=[O:11])[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:2]3=[O:1])=[CH:22][N:21]=[C:20]([NH:23][C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=3)[N:19]=2)[CH2:33][CH2:34][CH2:35]1
Reactant: N#Cc1ccc(Nc2ncc(C#CCCCN3C(=O)c4ccccc4C3=O)c(NCCCO)n2)cc1
Agent: COCCN(CCOC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Nc2ncc(C#CCCCN3C(=O)c4ccccc4C3=O)c(N3CCC3)n2)cc1
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a suspension of 4-((5-(5-(1,3-dioxoisoindolin-2-yl)-1-pentyn-1-yl)-4-((3-hydroxypropyl)amino)pyrimidin-2-yl)amino)benzonitrile (J15, 51 mg) in methylene chloride (1 mL), bis(2-methoxyethyl)aminosulfur trifluoride (188 μL) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, water and ethyl acetate were added. The solid matter was taken by filtration, washed successively with water and ethyl acetate, and then dried under reduced pressure to obtain 4-((4-(azetidin-1-yl)-5-(5-(1,3-dioxoisoindolin-2-yl)-1-pentyn-1-yl)pyrimidin-2-yl)amino)benzonitrile (J16, 48 mg) as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([N+:12]([O-])=O)=[C:4]([F:15])[CH:3]=1.O>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([NH2:12])=[C:4]([F:15])[CH:3]=1
Reactant: C#CCOc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: C#CCOc1cc(N)c(F)cc1Cl
Temperature: 90 °C
Yield: 72.6 %

Procedure:
A suspension of electrolytic iron powder (3.5 g) in a 5% aqueous acetic acid solution was heated to 90° C., and a solution of 4-chloro-2-fluoro-5-(2-propynyloxy)nitrobenzene (5.7 g) in acetic acid (40 ml) was dropwise added thereto at the same temperature. The resultant mixture was stirred for at 90°-105° C. for 1 hour and allowed to cool to room temperature. Water (200 ml) was added thereto. Insoluble materials were filtered off, and the filtrate was neutralized, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated. The residue was washed with petroleum ether and carbon tetrachloride to give 3.6 g of 4-chloro-2-fluoro-5-(2-propynyloxy)aniline. M.P. 61.0°-61.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31].N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:22]=[C:21]([CH:23]=[C:29]2[S:25][C:26](=[O:31])[NH:27][C:28]2=[O:30])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(C=O)cc3Cl)c2n1
Reactant: O=C1CSC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(C=C4SC(=O)NC4=O)cc3Cl)c2n1
Yield: 73.3 %

Procedure:
A suspension of methyl 3-(2-chloro-4-formylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (200 mg, 0.582 mmol), thiazolidine-2,4-dione (82 mg, 0.698 mmol) and piperidine (25 mg, 0.291 mmol) in ethanol (4 ml) was refluxed under heating overnight. The reaction mixture was cooled, and the precipitated crystals were filtrated to give the objective compound (189 mg) as pale-yellow crystals.
Reaction SMILES: CC(C)=[O:3].[CH2:5]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[C:10]([F:16])[C:9]=1[F:17])[CH3:6]>[O-2].[Cr+3].[O-2].[O-2].[Cr+3].O>[CH2:5]([O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]([OH:3])=[O:13])=[C:10]([F:16])[C:9]=1[F:17])[CH3:6]
Reactant: CC(C)=O
Reactant: CCOc1ccc(CO)c(F)c1F
Agent: [Cr+3]
Agent: [O-2]
Solvent: O
Product: CCOc1ccc(C(=O)O)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetone solution (140 mL) containing 4-ethoxy-2,3-difluorobenzyl alcohol (2.1 g) was dropped into a 1.5 M sulfuring acid solution (70 mL) containing chromium (III) oxide (4.23 g), at 0° C. over one hour. The reaction mixture was stirred at room temperature for 24 hours, and added with water to thereby terminate the reaction. The organic layer was extracted three times with ethyl acetate, the organic layers were combined, and the combined organic layer was extracted twice with a 1 M aqueous sodium hydroxide solution. The organic layer was then neutralized with a 2 M hydrochloric acid, extracted three times with ethyl acetate, the organic layers were combined, and the combined organic layer was washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was vaporized off under reduced pressure, to thereby obtain 4-ethoxy-2,3-difluorobenzoic acid (7) (yield=1.8 g, yield ratio=80%) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:8][C:9]1[C:17]2[C:12](=[C:13]([Br:18])[CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:41]([NH:51][C@H:52]([C:56](O)=[O:57])[CH:53]([CH3:55])[CH3:54])([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C.O>[CH2:44]([O:43][C:41]([NH:51][C@@H:52]([CH:53]([CH3:55])[CH3:54])[C:56]([NH:2][CH:3]([CH2:8][C:9]1[C:17]2[C:12](=[C:13]([Br:18])[CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5])=[O:57])=[O:42])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)C(N)Cc1c[nH]c2c(Br)cccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1c[nH]c2c(Br)cccc12)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.8 %

Procedure:
The title compound of Example 3 (256.6 g, 770 mmol), TBTU (296.4 g, 1.2 eq) and Cbz-L-valine (212.7 g, 1.1 eq) were dissolved in dimethylformamide (DMF, anhydrous, 2,700 mL) and cooled to 0° C. for 30 min. Diisopropylethylamine (DIEA, 268 mL) was added slowly and the solution was allowed to warm to room temperature. Stirring was continued for 4 hours at which time HPLC indicated completion of reaction. The reaction was diluted with ethyl acetate (11 L) and water (7.5 L). The mixture was stirred for 1 hour and allowed to separate. The organic layer was washed once with water (7.5 L), twice with brine (7.5 L) and twice with saturated NaHCO3 (7.5 L). The material was dried with sodium sulfate and concentrated to brown black solid. The material was taken up in methylene chloride (7.5 L) and combined with 22.2 g of another lot of similar quality material and silica gel (400 g). The solvent was removed to support the crude compound on silica. This material was divided in half and each half was chromatographed on a 6 in×4 ft silica gravity column. Each was eluted with methylene chloride (20 L) followed by 5% acetone in methylene chloride (20 L) followed by 8% acetone in methylene chloride (30 L) to give the title compound (383 g, 89% yield). 1H NMR (CDCl3): consistent with proposed structure.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([O:27]C)=[O:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.Cl.[OH-].[Na+]>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([OH:27])=[O:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:35])([F:34])[F:36])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)O)cc32)cc1
Temperature: 130 °C

Procedure:
A mixture of methyl 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido-[2,3-b][1,5]benzodiazepine-8-carboxylate (90 mg, intermediate 56), water (0.63 mL), conc. HCl (1.25 mL), and glacial acetic acid (2.0 mL) was heated at 130° C. for 2 h. After cooling to rt, 4N aqueous NaOH was added until pH=6. The reaction mixture was extracted with DCM (3×), and the extracts were dried, filtered, and concentrated to provide the title compound. LC/MS: m/e 506.1 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 8.12 (1H, s), 7.79 (1H, dd, J=8.5, 1.6 Hz), 7.49 (1H, d, J=7.5 Hz), 6.99 (3H, m), 6.79 (3H, m), 4.45-4.70 (2H, br), 1.11 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[Br:11]Br>C(Cl)(Cl)(Cl)Cl>[Br:11][C:8]1[C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]=2[O:10][CH:9]=1
Reactant: Clc1nccc2occc12
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1nccc2occ(Br)c12
Temperature: 25 °C
Yield: 96.3 %

Procedure:
A solution of 4-chlorofuro[3,2-c]pyridine (10.60 g, 69 mmol, 1.0 eq) in carbon tetrachloride (135 mL) was cooled to −15° C. and bromine (12.13 g, 80 mmol, 1.2 eq) was added drop-wise over a fifteen minute time period. The mixture was stirred at ambient temperature for eighteen hours. The solvent was removed in vacuo, and the residue was dissolved in methanol (250 mL). A solution of 20% aqueous sodium hydroxide (35 mL) was added and the mixture was stirred 1 hour at ambient temperature. The methanol was removed in vacuo, and the residue was partitioned between water (100 mL) and dichloromethane (50 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (50 mL). The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give the title compound (15.45 g, 96%) as a solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.54 (s, 1H), 8.37 (d, 1H), 7.87 (d, 1H); RP-HPLC (Conditions f) Rt 11.46 min.; MS: MH+ 232, 234.
Reaction SMILES: [CH2:1]([O:15][CH2:16][CH:17]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:46]1(C)C=CC(S(OC)(=O)=O)=CC=1.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.Cl>[OH:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH:17]([CH2:16][O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:18][CH3:46]
Reactant: CCCCCCCCCCCCCCOCC(O)COCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Product: CCCCCCCCCCCCCCOCC(COCCOCCO)OC
Yield: 88.8 %

Procedure:
18.6 g (30 millimole) of 1-O-tetradecyl-3-O-[2-(2-trityloxyethoxy)ethyl]glycerol, 6.1 g (33 millimole) of methyl p-toluenesulfonate, 8 g (100 millimole) of 50% sodium hydroxide, 192 mg (0.6 millimole) of cetyltrimethylammonium chloride and 20 ml of 2N hydrochloric acid were treated by following a procedure similar to that of Working Example 5, to give 10.4 g (89%) of the above-captioned compound.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][NH:10]C(=O)OC(C)(C)C)[CH2:5][CH2:4]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:10][CH2:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([C:1]#[N:2])[CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C#N)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#C[C@H]1CC[C@H](CN)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (trans-4-cyanocyclohexyl)methylcarbamate (500 mg) in dichloromethane (10 mL) was slowly added trifluoroacetic acid (2 mL) at 0° C. The reaction mixture was warmed to room temperature, stirred for 1 hour and concentrated to provide the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[N:7][CH:8]=1.[O:17]=[C:18]([CH2:24][CH2:25][CH3:26])[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(N(C(C)C)CC)(C)C.O.[Br-].[Li+]>O.O1CCCC1>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[C:6]1[N:7]=[CH:8][C:3]([CH2:2][CH:19]([C:18](=[O:17])[CH2:24][CH2:25][CH3:26])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:5]=1)#[N:12]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cn1
Reactant: CCCC(=O)CC(=O)OC
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)nc1)C(=O)OC
Yield: 91.5 %

Procedure:
Process 1: Under argon atmosphere, tetrahydrofuran (20 mL) mixture containing 2-[5-(bromomethyl)pyridin-2-yl]benzonitrile (1.1 g, 3.9 mmol), methyl 3-oxohexanoate (0.68 g, 4.7 mmol), diisopropylethylamine (1.0 g, 7.8 mmol), and lithium bromide monohydrate (0.49 g, 4.7 mmol) was refluxed under heating for 18 hours. The reaction mixture was added water and extracted three times with chloroform. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residues were subjected to silica gel column chromatography (SNAP100HP manufactured by Biotage) (hexane/ethyl acetate; 5/1→1/1) to give methyl 2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-3-oxohexanoate (1.2 g, 91%) as yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][CH2:12][C:13]([CH3:16])([SH:15])[CH3:14].C([O-])([O-])=O.[K+].[K+].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl>[CH3:14][C:13]([SH:15])([CH3:16])[CH2:12][NH:11][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(S)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CC(C)(S)CNCc1ccc(O)cc1
Yield: 97.5 %

Procedure:
To a hot solution of 4-hydroxybenzaldehyde (8.90 g, 72.8 mmol) in CHCl3 (250 mL) were added 1-amino-2-methyl-2-propanethiol hydrochloride (10.32 g, 72.8 mmol), K2CO3 (20.2 g, 146 mmol), and MgSO4 (5 g). The mixture was stirred and refluxed under nitrogen atmosphere for 3 hours. After cooling, the mixture was filtered to remove inorganic solid, and the filter cake was washed through with MeOH (2×100 mL). Evaporation of the filtrate afforded the product 5a as a white solid (15 g, 98%). mp 85-87° C.; 1H NMR (CDCl3, 300 MHz) δ 7.38 (d, J=8.5 Hz, 2H), 6.76 (d, J=8.5 Hz, 2H), 5.74 (s, 1H), 3.25 (d, J=12.1 Hz, 1H), 3.01 (d, J=12.1 Hz, 1H), 1.59 (s, 3H), 1.58 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH3:18][Sn](C)(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH3:18])[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)c2ccc(C)cc2sc1=O
Temperature: 122.5 °C
Yield: 68.3 %

Procedure:
To a mixture of 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) (150 mg, 0.48 mmol) in DMF was added tetramethyltin (254 mg, 1.43 mmol) and PdCl2(PPh3)2 (17 mg, 0.024 mmol). The resulting mixture was purged with nitrogen gas for 20 seconds and heated in a 120-125° C. oil bath for 1 h. The reaction mixture was diluted with water (15 mL) and the suspended black solid was filtered off. The clear filtrate was acidified to pH 4 using 1 N HCl and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was triturated with MeOH (1 mL) and the solid collected to provide 4-hydroxy-7-methyl-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (82 mg). 1H NMR (200 MHz, CDCl3): δ (ppm)=15.20 (s, 1H), 8.23 (d, J=8.5 Hz, 1H), 7.17 (m, 2H), 4.00 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:21]=[C:20]2[CH:22]=[C:4]([C:5]3[CH:28]=[C:9]([C:10](=[O:27])[NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][CH2:14][NH:15][C:16](=[O:23])[CH2:17][CH2:18][S:19]2)[C:8]([CH3:29])=[CH:7][C:6]=3[CH3:30])[N:3]=1.O[N:32]1[C:36]2C=CC=CC=2N=N1.CN.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:36][NH:32][C:24]([C@H:12]1[NH:11][C:10](=[O:27])[C:9]2=[CH:28][C:5](=[C:6]([CH3:30])[CH:7]=[C:8]2[CH3:29])[C:4]2=[CH:22][C:20](=[N:21][C:2]([NH2:1])=[N:3]2)[S:19][CH2:18][CH2:17][C:16](=[O:23])[NH:15][CH2:14][CH2:13]1)=[O:26]
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(C)c2cc1C(=O)N[C@H](C(=O)O)CCNC(=O)CCSc1cc-2nc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)[C@@H]1CCNC(=O)CCSc2cc(nc(N)n2)-c2cc(c(C)cc2C)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
(S)-4-Amino-18,20-dimethyl-10,16-dioxo-7-thia-3,5,11,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaene-14-carboxylic acid (25 mg, 0.058 mmol) obtained in Example 2-13 and 1-hydroxybenzotriazole (24 mg, 0.175 mmol) were dissolved in N,N-dimethylformamide (580 μl). Methylamine (2.0 M tetrahydrofuran solution, 88 μl, 0.175 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (34 mg, 0.175 mmol), and diisopropylethylamine (0.073 ml, 0.42 mmol) were added to the solution. The resulting mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, and sequentially washed with a saturated aqueous sodium bicarbonate solution, water (three times), and a saturated aqueous sodium chloride solution. The washed organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by preparative thin layer silica gel chromatography (developing solvent: dichloromethane:methanol=10:1) to yield (S)-4-amino-18,20-dimethyl-10,16-dioxo-7-thia-3,5,11,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaene-14-carboxylic acid methylamide (Compound 65) (7 mg) was obtained as a white solid material.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:28][N:27]([C:34]3[CH:39]=[C:38]([N+:40]([O-])=O)[CH:37]=[CH:36][C:35]=3[C:43]([F:46])([F:45])[F:44])[C:26]2=[O:47])=[C:20]([F:48])[CH:19]=1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[H][H]>[Pt]=O.C(O)C>[NH2:40][C:38]1[CH:37]=[CH:36][C:35]([C:43]([F:44])([F:45])[F:46])=[C:34]([N:27]2[C:26](=[O:47])[N:25]([CH2:24][C:21]3[CH:22]=[CH:23][C:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:9](=[O:10])(=[O:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:19][C:20]=3[F:48])[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:28]2)[CH:39]=1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Yield: 66.6 %

Procedure:
A mixture of 185 mg (0.267 mmol) of 4-[[2'-[N-(t-butoxycarbonyl)sulfamoyl]-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-2-[5-nitro-2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step C), 25 mg of platinum oxide, 2 mL of ethyl acetate, and 10 mL of ethanol was shaken with hydrogen at approximately 3 atm for 2 hours. The mixture was centrifuged, and the supernatant was concentrated. Flash chromatography of the residue on silica gel (gradient elution with 1-5% MeOH in CH2Cl2) yielded 118 mg (67%) of the title compound as a white foam, homogeneous by TLC (95:5 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 664 (M+1)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6](Cl)=[O:7].[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1>CCOCC>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: OCc1ccccc1
Reactant: O=C(Cl)C1CCCO1
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)C1CCCO1
Reaction time: 0.67 h

Procedure:
Tetrahydrofuroyl chloride (15.0 g, 112 mmol) was added dropwise to a cold solution of benzyl alcohol (10.9 g, 101 mmol) and pyridine (20.0 g, 253 mmol) in Et2O (200 mL). The solution was stirred at 0° for 40 minutes, then filtered to remove the side product pyridine hydrochloride. The filtrate was washed with 0.1M HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL), and then dried over MgSO4. Filtration and evaporation of the solvent gave a yellow oil, which was distilled. Benzyl tetrahydrofuroate was obtained as a colorless oil (21.1 g), b.p. 118° to 120° at 0.5 mm Hg.