Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C@H:13]([OH:16])CO)[C@@H:10]([OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+].[BH4-].[Na+]>C(O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][OH:16])[C@@H:10]([OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H]([C@H](O)CO)[C@@H](O)C1
Agent: [BH4-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H](CO)[C@@H](O)C1
Temperature: 0 °C
Yield: 92.1 %

Procedure:
N-tert-Butoxycarbonyl-(3R,4S)-3-hydroxy-4-[(1S)-1,2-dihydroxyethyl]pyrrolidine (3.4 g, 13.7 mmol) in ethanol (50 mL) was added dropwise to a stirred solution of sodium periodate (3.4 g, 16 mmol) in water (25 mL) while maintaining the reaction temperature at 0° C. The reaction was left an additional 20 min after which time sodium borohydride (2.0 g, excess) was added portionwise while again ensuring the reaction temperature was maintained at 0° C. On complete addition the solid was filtered, washed with ethanol (50 mL) and concentrated in vacuo to afford a syrup. Chromatography afforded 1 (2.74 g, 92%) as a syrup.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@:19]([CH3:25])([CH:22]([CH3:24])[CH3:23])[CH2:20][OH:21]>>[OH:21][CH2:20][C@@:19]([NH:18][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:25])[CH:22]([CH3:24])[CH3:23]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)[C@@](C)(N)CO
Product: CC(C)[C@](C)(CO)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 15, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g; 100 mg, 0.42 mmol) and (2R)-2-amino-2,3-dimethyl-1-butanol (CAN 155158-75-1, 107.06 mg, 0.64 mmol) as starting materials, and isolated (20 mg, 14.04%) as off white sticky solid, LC-MS (UV peak area, ESI) 100%, 334.4 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:10]([CH3:30])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:31]([NH2:35])(=[O:34])[CH:32]=[CH2:33].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:30][C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2](/[CH:33]=[CH:32]/[C:31]([NH2:35])=[O:34])[CH:7]=[CH:6][CH:5]=2)[N:16]2[C:11]=1[CH:12]=[N:13][C:14]([NH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[N:15]2
Reactant: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Br)c4)n3n2)cc(OC)c1OC
Reactant: C=CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(/C=C/C(N)=O)c4)n3n2)cc(OC)c1OC
Temperature: 25 °C
Yield: 8.3 %

Procedure:
To a mixture of 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (0.054 g, 0.12 mmol), acrylamide (0.025 g, 0.35 mmol), palladium (II) acetate (2.7 mg, 0.012 mmol) and tris(o-tolyl)phosphine (7.3 mg, 0.024 mmol) in acetonitrile (1 mL) was added triethylamine (0.050 mL, 0.35 mmol). The solution was heated to reflux for 30 minutes. After cooling to room temperature, the solution was filtered, and silica gel (1 g) was added, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexanes (50:50) to ethyl acetate:hexanes (100:0) to ethyl acetate:methanol (99:1) using a RediSep silica gel cartridge (4 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give (2E)-3-(3-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]-imidazo[5,1-f][1,2,4]triazin-7-yl}phenyl)prop-2-enamide (0.0046 g) as a yellow solid. 1H NMR (CD3OD): δ9.05 (s, 1H), 8.49 (s, 1H), 8.37 (d, J=7.3 Hz, 1H), 7.67-7.51 (m, 4H), 7.05 (s, 2H), 6.68 (d, J=15.9 Hz, 1H) 3.74 (s, 3H), 3.72 (s, 6H), 2.60 (s, 3H). MS m/z 461 (M+1).
Reaction SMILES: C(O[C:4](=[O:12])[CH2:5][C:6](=O)[C:7]([F:10])([F:9])[F:8])C.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][NH2:22]>C(O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[C:4]([OH:12])=[CH:5][C:6]([C:7]([F:8])([F:9])[F:10])=[N:22]1
Reactant: NNc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: Oc1cc(C(F)(F)F)nn1-c1ccccc1Cl

Procedure:
Into a 250 mL flask was weighed 5.01 g of 4,4,4-trifluoro-3-oxo-butyric acid ethyl ester, 4.88 g of 2-chlorophenylhydrazine hydrochloride, and 100 mL of ethanol. The resulting solution was heated at 90-950C for 18 h then was concentrated in vacuo to remove ethanol. The residue was washed into a separatory funnel with ethyl acetate and 1 M HCl. The ethyl acetate was separated, washed with brine, was dried, and concentrated in vacuo. The residue was partially purified by silica gel flash chromatography (Jones Flashmaster, 70 g Silica gel, gradient elution from 100% hexanes to 20% ethyl acetate over 30 minutes). Appropriate fractions were combined and concentrated and product was precipitated by addition of excess hexanes. The solid precipitate was collected by filtration and was dried under high vacuum to afford the intermediate 2-(2-Chlorophenyl)-5-trifluoromethyl-2H-pyrazol-3-ol as a tan powder, yield: 3.73 g (52%). 1H NMR (DMSO-d6): δ 12.25 (br s, 1H), 7.72 (d, J=8 Hz, 1H), 7.5-7.65 (m, 3H), 5.94 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([N:23]2[CH2:37][C:26]3=[C:27]4[N:32]([N:33]=[C:25]3[CH2:24]2)[C:31]([CH3:34])=[C:30]([Cl:35])[C:29]([CH3:36])=[N:28]4)=[O:22])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:35][C:30]1[C:29]([CH3:36])=[N:28][C:27]2[N:32]([N:33]=[C:25]3[CH2:24][N:23]([C:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][O:13][C@H:10]4[CH2:11][CH2:12][NH:8][CH2:9]4)=[O:22])[CH2:37][C:26]3=2)[C:31]=1[CH3:34]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1CO[C@H]1CCN(C(=O)OC(C)(C)C)C1)C3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1CO[C@H]1CCNC1)C3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.6 %

Procedure:
A mixture of (S)-3-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-benzyloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester (60 mg; 0.11 mmol; 1 eq.) and TFA (2 mL) in DCM (2 mL) was stirred at room temperature for 15 minutes then concentrated in vacuo. The residue was taken up in water, the pH made basic with 5M NaOH and extracted with DCM (2×). The combined organic layer was dried over magnesium sulfate and concentrated in to afford the title compound (49 mg, quantitative) as an off-white solid. 1H NMR (CDCl3) δ 7.46-7.33 (m, 4H), 5.02-4.95 (m, 2H), 4.68-4.46 (m, 4H), 4.21 (m, 1H), 3.26-2.97 (m, 1H), 2.92-2.82 (m, 3H), 2.70-2.58 (m, 3H), 1.96-1.59 (m, 2H). HPLC (max plot) 100%, Rt 2.56 min. UPLC/MS: (MS+) 426.2 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:10][C:9](=[O:11])[CH2:8][CH:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2.[Li+].[CH3:14]C([N-]C(C)C)C.CI>C1COCC1>[CH3:1][C:2]1([CH3:12])[CH2:10][C:9](=[O:11])[CH:8]([CH3:14])[CH:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2
Reactant: CC1(C)CC(=O)CC2CCCN21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1C(=O)CC(C)(C)N2CCCC12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
Hexahydro-5,5-dimethylindolizin-7(1H)-one (racemic) (1.41 g, 8.43 mmol) was dissolved in dry THF (50 ml); the flask was flushed with nitrogen and cooled to −78° C. LDA (5.9 ml, 11.8 mmol) was added via syringe and stirred for 30 minutes. Subsequently, neat methyl iodide (1.30 ml, 21.1 mmol) was added via syringe. The clear, pale yellow solution was stirred overnight and allowed to warm to room temperature. The reaction was then quenched with a saturated NH4Cl solution and extracted with ethyl acetate (3×40 ml). The organic phases were passed through a plug of MgSO4 and solvents were evaporated in vacuo. The crude product (849 mg) was obtained in form of a yellow-brown oil and used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6].[C:12](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[F:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(F)cc(F)c1O
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1c(F)cc(F)cc1C=O
Yield: 66 %

Procedure:
3,5-Difluoro-2-hydroxybenzaldehyde in the form of a crude product (corresponding to 0.35 mol) was dissolved in 800 ml of acetonitrile. 110 g (0.8 mol) of potassium carbonate and 61 ml (0.96 mol) of methyl iodide were added thereto, and the mixture was heated under reflux for 5 hr. After cooling the mixture, insolubles were removed by filtration, and the mother liquor was concentrated. 1.3 l of ether was added to the concentrate, and the mixture was washed twice with 500 ml of water. Then, the mixture was washed with a saturated saline solution, and the ether layer was dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo to prepare 39.6 g (yield: 66%) of the intended product (in two states).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH:14](O)[CH3:15]>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH:14]([Cl:3])[CH3:15]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(C)O)c(Cl)c1
Solvent: ClCCl
Product: COc1ccc(C(C)Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.9 ml) was added to a solution of 1-(2-chloro-4-methoxy-phenyl)-ethanol (2 g) in DCM (5 ml) at 0° C. The mixture was allowed to warm to room temperature and then stirred for 1 h. The mixture was concentrated to an oil and filtered over SiO2 (1 g) to give the title compound (2 g) as a light brown oil. 1H NMR (300 MHz, CDCl3) δ 7.5 (1H, d), 6.8-6.9 (2H, m), 5.5 (1H, q), 3.8 (3H, s), 1.8 (3H, d).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-])=[CH:5][CH:4]=1)#[N:2].P(Cl)(Cl)([Cl:12])=O>>[Cl:12][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][N:6]=1)[C:1]#[N:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cc[n+]([O-])cc1
Product: N#Cc1ccnc(Cl)c1
Temperature: 110 °C

Procedure:
4-cyanopyridine-N-oxide (10.0 g) was added to phosphorus oxychloride (85 mL) and heated to 110° C. for 2.5 h. The mixture was cooled to room temperature and the excess phosphorus oxychloride removed under reduced pressure. The residue was dissolved in water and made basic with concentrated ammonia. The product was extracted into methylene chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using methylene chloride as eluent to give 7.19 g of the title compound: 1H NMR (CDCl3) δ 7.48, 7.6, 8.6.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]1=2.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:6]2[CH:7]=[C:8]3[C:3](=[CH:4][CH:5]=2)[C:2](=[O:1])[CH2:11][CH2:10][CH2:9]3)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Product: COc1cccc(-c2ccc3c(c2)CCCC3=O)c1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 3-methoxyphenyl boronic acid according to the coupling procedure as described in example 6. MS (ESI) m/z 253.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][N:26]1[C:30](=[O:31])[C:29]([CH3:33])([CH3:32])[NH:28][C:27]1=[O:34]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[C:29]([CH3:33])([CH3:32])[C:30](=[O:31])[N:26]([CH3:25])[C:27]4=[O:34])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CN1C(=O)NC(C)(C)C1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4(C)C)cc3F)CC2)c(C)c1
Yield: 16.5 %

Procedure:
Using (4-bromo-2-fluorophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (157 mg) described in Preparation Example 114 and 3,5,5-trimethylimidazolidine-2,4-dione (63 mg) described in Preparation Example 218 and by the reaction and treatment in the same manner as in Example 536, the title compound (30 mg) was obtained.
Reaction SMILES: [CH2:1]1[O:25][C:24]2[CH:23]=[CH:22][C:5](/[CH:6]=[CH:7]/[CH2:8][C:9]3[S:10][CH:11]=[CH:12][C:13]=3[S:14](N3C=CC=C3)(=[O:16])=[O:15])=[CH:4][C:3]=2[O:2]1.[OH-].[K+].S(Cl)([Cl:31])(=O)=O>C(O)(C)C>[Cl:31][S:14]([C:13]1[CH:12]=[CH:11][S:10][C:9]=1[CH2:8]/[CH:7]=[CH:6]/[C:5]1[CH:22]=[CH:23][C:24]2[O:25][CH2:1][O:2][C:3]=2[CH:4]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=S(=O)(c1ccsc1C/C=C/c1ccc2c(c1)OCO2)n1cccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=S(=O)(Cl)c1ccsc1C/C=C/c1ccc2c(c1)OCO2

Procedure:
3-chlorosulfonyl-2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene was prepared in the same manner as described in Example 64E from N-{2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene-3-sulfonyl}pyrrole by basic hydrolysis (using isopropanol and potassium hydroxide) to the corresponding potassium sulfonate (100%) followed by conversion of the salt to the corresponding sulfonyl chloride in a 31% overall yield.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([S:16][CH3:17])[N:12]([CH3:18])[C:11]2=[O:19])=[CH2:5])C.O.C1C(=O)N([Br:28])C(=O)C1>C1COCC1>[Br:28][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([S:16][CH3:17])[N:12]([CH3:18])[C:11]2=[O:19])=[O:5]
Reactant: C=C(OCC)c1cccc2c(=O)n(C)c(SC)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: CSc1nc2c(C(=O)CBr)cccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Et3N (0.094 mL, 0.674 mmol) and TBSOTf (0.131 mL, 0.570 mmol) were sequentially added to a yellow solution of 8-acetyl-3-methyl-2-(methylthio)quinazolin-4(3H)-one (128.7 mg, 0.518 mmol) in DCM (2.7 mL) at 0° C., and the resulting light-yellow solution was stirred at 0° C. for 30 min. The mixture was partitioned between DCM (50 mL) and saturated aq. NaHCO3 (20 mL). The organic layer was separated, and the aq. layer was extracted with DCM (30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide crude 8-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3-methyl-2-(methylthio)quinazolin-4(3H)-one as a peach-colored solid. This material was combined with 8-(1-ethoxyvinyl)-3-methyl-2-(methylthio)quinazolin-4(3H)-one (35.5 mg, 0.128 mmol), and the resulting mixture was taken up in THF (2.70 mL). Water (0.149 mL, 8.29 mmol) and NBS (115 mg, 0.648 mmol) were sequentially added at 25° C., and the resulting solution was stirred at 25° C. for 30 min. The mixture was partitioned between Et2O (50 mL) and water (30 mL). The organic layer was separated, sequentially washed with saturated aq. NaHCO3 (20 mL), water (20 mL), and brine (20 mL), then dried over Na2SO4, filtered, and concentrated in vacuo to provide crude 8-(2-bromoacetyl)-3-methyl-2-(methylthio)quinazolin-4(3H)-one as an off-white solid. NH4OAc (200 mg, 2.59 mmol) and piperidine-2,4-dione (88 mg, 0.777 mmol) were added to this solid, and the resulting mixture was taken up in EtOH (2.70 mL) and heated under argon in a sealed flask at 40° C. for 16 h. The reaction suspension was vacuum filtered, and the collected solid was washed with MeOH (20 mL) and dried in vacuo. The residue was triturated with DMSO (2.0 mL), and the resulting suspension was vacuum filtered. The collected solid was sequentially washed with MeOH (5 mL) and DCM (5 mL) and dried in vacuo to provide 3-methyl-2-(methylthio)-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinazolin-4(3H)-one (57.1 mg, 0.168 mmol, 26% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.67 (1H, br. s.), 8.05 (1H, dd, J=7.6, 1.2 Hz), 7.95 (1H, dd, J=7.8, 1.0 Hz), 7.44 (1H, t, J=7.8 Hz), 7.03 (1H, d, J=2.3 Hz), 6.96 (1H, br. s.), 3.56 (3H, s), 3.41 (2H, td, J=6.8, 2.2 Hz), 2.85 (2H, t, J=6.9 Hz), 2.74 (3H, s). m/z (ESI, +ve) 341.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([O:8][CH2:19][CH3:20])=[O:7])=[CH:4][N:3]=1
Reactant: Nc1ncc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cnc(N)c([N+](=O)[O-])c1
Yield: 73 %

Procedure:
A solution of 6-amino-5-nitronicotinic acid (10 g) and concentrated sulfuric acid (20 ml) in ethanol (250 ml) was heated under reflux for 18 hr. The reaction mixture was concentrated, diluted with water and adjusted with sodium hydrogencarbonate to pH 8. The precipitated crystals were collected by filtration and washed with water to give the title compound (8.5 g, yield 73%) as yellow crystals. purity 84%. M+H: 212.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[C:6]([CH:9]=1)[C:7]#[N:8].Cl.[F:12][C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.CCN(C(C)C)C(C)C>CC#N>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:15]2[CH2:16][CH2:17][C@H:13]([F:12])[CH2:14]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)cnc1Cl
Reactant: F[C@H]1CCNC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Br)cnc1N1CC[C@H](F)C1

Procedure:
5-Bromo-2-chloro-nicotinonitrile (6) (5.0 g, 23.0 mmol) was dissolved in MeCN (100 mL). (S)-3-Fluoropyrrolidine hydrochloride (5.7 g, 53.0 mmol) and DIPEA (12.0 mL, 68.9 mmol) were added and the mixture was stirred at reflux for 1 hour. The solvent was evaporated in vacuo and the residue partitioned between EtOAc (100 mL) and H2O (50 mL). The layers were separated and the organic phase washed with saturated brine solution (50 mL), then dried (MgSO4), filtered and the solvent evaporated in vacuo. The title compound was obtained as an off-white solid (6.2 g, 100%); LCMS, Rt=2.91 min (MeOH-FA method), m/z 270, 272 (MH+).
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[N:11]([CH2:12][C@H:13](O)[C:14]2[C:15]([CH3:24])=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[O:18][CH2:17]3)[CH2:10][CH2:9][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:7]1)(=[O:3])[CH3:2].S(Cl)([Cl:35])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([S:4][CH2:5][C@H:6]1[N:11]([CH2:12][CH:13]([Cl:35])[C:14]2[C:15]([CH3:24])=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[O:18][CH2:17]3)[CH2:10][CH2:9][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:7]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C[C@H](O)c1ccc2c(c1C)COC2=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC(Cl)c1ccc2c(c1C)COC2=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a cooled with an ice bath solution of (S)-tert-butyl 3-(acetylthiomethyl)-4-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazine-1-carboxylate (573 mg, 1.233 mmol) in anhydrous toluene (12.3 mL) was added thionyl chloride (0.268 mL, 3.70 mmol). Then, anhydrous pyridine (0.399 mL, 4.93 mmol) was added dropwise. The reaction mixture was kept at 0° C. for 20 min, then warmed to room temperature and stirred for 3 hours. TLC showed the consumption of the starting material. The reaction was concentrated under reduced pressure and dried on high vacuum overnight. Used directly in the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[C:3]([C:5]1[CH:37]=[CH:36][C:8]([O:9][C:10]2[C:24]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32]([CH3:35])(=[O:34])=[O:33])=[CH:23][C:13]3[NH:14][C:15]([C:17]4C=C[CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=1)=[O:4].[S:39]1C=CN=C1C=O>>[CH3:1][N:2]([CH3:38])[C:3]([C:5]1[CH:37]=[CH:36][C:8]([O:9][C:10]2[C:24]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32]([CH3:35])(=[O:34])=[O:33])=[CH:23][C:13]3[NH:14][C:15]([C:17]4[S:39][CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: O=Cc1nccs1
Reactant: CN(C)C(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2Oc2ccccc2S(C)(=O)=O)cc1
Product: CN(C)C(=O)c1ccc(Oc2cc3nc(-c4nccs4)[nH]c3cc2Oc2ccccc2S(C)(=O)=O)cc1

Procedure:
The entitled compound was obtained in the same method as in Example 1 (step 4) or in accordance with the method or by combining it with an ordinary method but using 4-(4-dimethylcarbamoyl-phenoxy)-5-(2-methanesulfonyl-phenoxy)-benzene-1,2-diamine obtained in Example 20 and thiazol-2-carboxaldehyde.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:23])[CH2:9][C@H:10]([OH:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:24][CH:25]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:26](O)=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]1([O:7][C:8](=[O:23])[CH2:9][C@H:10]([O:22][C:26](=[O:27])[CH:25]([Br:24])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)Oc1ccccc1
Reactant: CCCCCCC(Br)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)Oc1ccccc1)OC(=O)C(Br)CCCCCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.5 %

Procedure:
A mixture of 1.02 g phenyl-(R)-3-hydroxytetradecanoate (3.19 mmol), 22 mL dichloromethane, 0.74 g 2-bromooctanoic acid (3.19 mmol), 0.66 g N,N'-dicyclohexylcarbodiimide (3.20 mmol) and 0.39 g 4-dimethylaminopyridine (3.19 mmol) was stirred at room temperature for 1.5 hours. The solution was then concentrated to dryness on a rotary evaporator (ca. 26 mm Hg, 30° C.). 25 mL hexanes was added to the white powdery residue and the resultant mixture was stirred at room temperature for 5 minutes. The slurry was filtered through a coarse sintered glass funnel and the solids were washed with 2×20 mL hexanes. The combined filtrates were placed in a separatory funnel and washed with 2×50 mL 1M HCL, 2×50 mL 10% saturated sodium bicarbonate and 2×50 mL city water. The organic layer was dryed over magnesium sulfate, then gravity filtered through paper, and concentrated on a rotary evaporator (ca. 10 mm Hg, 30° C.). The residue was chromatographed on a 2' by 1" column slurry packed with silica gel (80 g) in hexanes. Product was eluted with 50/50 hexanes and dichloromethane. The chromatography was monitored by TLC (silica gel, 50/50 hexanes: dichloromethane, phosphomolybidic acid visualization). Fractions containing only product were pooled and concentrated on a rotary evaporator (ca. 100 mm Hg, 30° C.). A cloudy oil (0.98 g, 58% yield) was obtained.
Reaction SMILES: C1(N=[C:8]([OH:24])[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]([OH:13])=[S:12])C=CC=CC=1.[OH-:25].[Na+].Cl>>[C:18]1([C:17]2[CH:16]=[CH:15][CH:14]=[C:10]([C:11]([OH:13])=[S:12])[C:9]=2[C:8]([OH:24])=[O:25])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: [OH-]
Reactant: OC(=S)c1cccc(-c2ccccc2)c1C(O)=Nc1ccccc1
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1c(C(O)=S)cccc1-c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
99.4 g (0.3 mol) of 3-phenylthiophthalic acid N-phenylimide are suspended in 1,326 ml of a 20% sodium hydroxide solution and the suspension is heated at 100° C. for 30 minutes, with stirring. After cooling, the alkaline suspension is acidified with 672 ml of 37% hydrochloric acid, with stirring. After one hour, the fine suspension is filtered with suction and the material on the suction filter is suspended, while still wet, in 882 ml of 37% hydrochloric acid and the resulting suspension is refluxed for one hour. The reaction mixture is cooled, the resulting fine suspension is filtered with suction and the product is dried at 80° C./13,000 Pa. 69.4 g (85% of theory) of 3-phenylthiophthalic acid are obtained.