Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]1[C:14]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[C:29]([C:33]([O:35]CC)=[O:34])=[CH:28][CH:27]=[CH:26]4)=[CH:19][CH:18]=2)=[C:13]([CH:38]([CH3:40])[CH3:39])[O:12][N:11]=1.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][C:10]1[C:14]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[C:29]([C:33]([OH:35])=[O:34])=[CH:28][CH:27]=[CH:26]4)=[CH:21][CH:22]=2)=[C:13]([CH:38]([CH3:40])[CH3:39])[O:12][N:11]=1
Reactant: CCOC(=O)c1cccc2cc(-c3ccc(OCc4c(Cc5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1onc(Cc2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(=O)O)cccc3c2)cc1
Temperature: 100 °C
Yield: 102.5 %

Procedure:
A solution of ethyl 6-[4-({[3-[(2,6-dichlorophenyl)methyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylate (0.116 g, 0.20 mmol) in tetrahydrofuran (2 mL) was placed in a microwave reaction tube. Ethanol (1 mL) was added followed by 1 N sodium hydroxide (0.312 mL, 0.31 mmol). The tube was sealed and heated in a microwave reactor to 100° C. for 500 seconds. Additional sodium hydroxide solution (0.2 mL, 0.2 mmol) was added and the solution was heated in a microwave reactor to 100° C. for another 500 seconds. The solution was neutralized with 1 N hydrochloric acid and concentrated. The residue was slurried in hexanes. The solid was slurried in water and the mixture was decanted and the solid dried to yield the title compound as a white solid (0.112 g, 100% as 0.15EtOAc). 1H NMR (DMSO-d6) 13.14 (s, 1H), 8.91 (d, J=9 Hz, 1H), 8.26 (s, 1H), 8.20 (d, J=8 Hz, 1H), 8.10 (d, J=7 Hz, 1H), 7.96 (dd, J=2, 9 Hz, 1H), 7.80 (d, J=9 Hz, 2H), 7.58 (m, 1H), 7.46 (d, J=8 Hz, 2H), 7.31 (t, J=8 Hz, 1H), 7.16 (d, J=9 Hz, 2H), 5.08 (s, 2H), 4.29 (s, 2H), 3.36 (septet, J=7 Hz, overlapping H2O 1H), 1.22 (d, J=7 Hz, 6H). HRMS C31H25NO4Cl2 m/z 546.1239 (M+H)+Cal; 546.1226 (M+H)+Obs.
Reaction SMILES: Cl[C:2]([N:4]1[C:8]([S:9][CH3:10])=[CH:7][C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5]1)=[O:3].[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16].O>C1C=CC=CC=1>[CH2:15]([N:17]([CH2:18][CH3:19])[C:2]([N:4]1[C:8]([S:9][CH3:10])=[CH:7][C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5]1)=[O:3])[CH3:16]
Reactant: CCNCC
Reactant: CSc1cc(C(C)(C)C)nn1C(=O)Cl
Solvent: O
Solvent: c1ccccc1
Product: CCN(CC)C(=O)n1nc(C(C)(C)C)cc1SC

Procedure:
To a stirred solution of 1-chlorocarbonyl-3-tert-butyl-5-(methylthio)pyrazole (23 g) in benzene (200 ml) at room temperature was added dropwise diethylamine (16 g, 23 ml). A white precipitate formed rapidly. The reaction mixture was refluxed (at 80°) for two hours, allowed to cool, and water (100 ml) added. The organic layer was washed once again with water, separated, dried and evaporated to give 1-(diethylcarbamoyl)-3-t-butyl-5-(methylthio)pyrazole. Recrystallisation from petrol gave the pure compound (16.5 g, 59% yield), of melting point 55°-6°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.CN.C[CH2:20][N:21](CC)CC>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][C:13]([NH:21][CH3:20])=[CH:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)nc1
Reactant: CCN(CC)CC
Agent: CN
Solvent: CCO
Product: CNc1ccc(C(=O)c2ccc(Cl)cc2)cn1
Temperature: 80 °C
Yield: 54.4 %

Procedure:
A mixture of compound B (23.4 g, 93.22 mmol), methylamine (88 mL, 932 mmol, 33% solution in ethanol) and Et3N (37.51 mL, 280 mmol) in EtOH (100 mL) was heated in a sealed tube at 80° C. for 3 h. EtOH was removed under reduced pressure and the residue was dissolved in DCM (150 mL), washed with water and brine. The organic layer was dried (Na2SO4), filtered and evaporated. The crude product was purified by triturating with diethyl ether to obtain 12.5 g (55%) of compound C as off-white solid.
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[S:3]Cl.C(N(CC)CC)C.C1([N:17]2[C:21](=[O:22])[CH2:20][NH:19][C:18]2=[O:23])CC1>N1CC(=O)NC1=O>[Cl:1][C:2]([Cl:6])([Cl:5])[S:3][N:19]1[CH2:20][C:21](=[O:22])[N:17]([S:3][C:2]([Cl:6])([Cl:5])[Cl:1])[C:18]1=[O:23]
Reactant: ClSC(Cl)(Cl)Cl
Reactant: O=C1CNC(=O)N1C1CC1
Agent: O=C1CNC(=O)N1
Solvent: CCN(CC)CC
Product: O=C1CN(SC(Cl)(Cl)Cl)C(=O)N1SC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.9 %

Procedure:
At about 25° C., 37.2 g (0.2 mole) of trichloromethylsulfenyl chloride and subsequently 20.2 g (0.2 mole) of triethylamine are dripped, while stirring thoroughly, into a suspension of 14.0 g (0.1 mole) of 3-cyclopropylhydantoin in 150 ml of anhydrous hydantoin. After stirring for 12 hours at room temperature, the precipitated triethylamine hydrochloride is filtered off and the reaction mixture is worked up as in Example 1. There is obtained 23.5 g (59% of theory) of 1,3-bis-(trichloromethylthio)-hydantoin; m.p. 140°-142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]([F:13])[C:3]=1[C:4]([O:6]C)=[O:5].[Li+].[I-]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]([F:13])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(F)cc(I)cc1Cl
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(O)c1c(F)cc(I)cc1Cl
Temperature: 115 °C
Yield: 111.8 %

Procedure:
To a solution of methyl 2-chloro-6-fluoro-4-iodo-benzoate (4.48 g, 14.2 mmol) in pyridine (28 mL) was added LiI (4.0 g, 29.9 mmol). The reaction mixture was heated at 115° C. for 4 hours. The solvent was removed under vacuum. The resultant solid was dissolved in water, and extracted with EtOAc. The aqueous layer was acidified with 1 N HCl to pH=4, extracted with EtOAc (3×30 mL). The combined organic phases were washed with 10% citric acid (2×30 mL), brine, dried (Na2SO4), filtered and concentrated to give the title compound (4.77 g, quantitative yield) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ 7.73 (s, 1H), 7.62 (dd, J=8.4, 1.1 Hz, 1H). LCMS (ESI) m/z 300.8 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:19]3[N:18]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:22][CH:21]=4)[C:17](=O)[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([O:36][CH3:37])[CH:15]=4)[C:10]=3[CH2:9][CH2:8][C:7]=2[CH:38]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:19]3[N:18]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:22][CH:21]=4)[CH2:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([O:36][CH3:37])[CH:15]=4)[C:10]=3[CH2:9][CH2:8][C:7]=2[CH:38]=1
Reactant: COc1ccc2c(c1)CCc1c-2n(-c2ccc(OCCN3CCCCC3)cc2)c(=O)c2cc(OC)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CN(c1ccc(OCCN3CCCCC3)cc1)C1=C2CCc2cc(OC)ccc21
Reaction time: 2 h
Yield: 72.4 %

Procedure:
A solution of the product of Example 12 (350 mg, 0.69 mmol) in THF (25 mL) was treated with lithium aluminum hydride (129 mg, 3.4 mmol) inducing a moderate exotherm. The mixture was allowed to return to room temperature and stirred for 2 h, then briefly warmed to reflux, cooled, and quenched with ethyl acetate (50 mL) followed by saturated ammonium chloride (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL), and the combined organic layers were dried (sodium sulfate), concentrated; and purified via radial chromatography (silica gel, 1:1 hexane:ethyl acetate, 5% methanol, under an ammonia atmosphere) to provide 248 mg (64%) of the title compound as a yellow foam: 1H NMR (300 MHz, CDCl3) δ7.28 (d, J=8.5 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.79 (m, 3H), 6.72 (d, J=2.6 Hz, 1H), 6.65 (d, 9.0 Hz, 2H), 6.58 (d, J=2.6 Hz, 1H), 6.52 (dd, J=8.6, 2.6 Hz, 1H), 4.65 (s, 2H), 3.94 (t, J=6.1 Hz, 2H), 3.74 (s, 3H), 3.74 (s, 3H), 2.96 (dd, J=8.3, 5.6, 2H), 2.81 (dd, J=8.3, 5.9 Hz, 2H), 2.66 (t, J=6.1 Hz, 2H), 2.43 (m, 4H), 1.5-1.6 (m, 4H), 1.3-1.5 (m, 2H); 13C NMR (75 MHz, CDCl3) δ158.5, 158.3, 153.3, 141.7, 138.4, 134.6, 132.3, 126.6, 126.2, 125.3, 122.9, 121.7, 120.5, 114.9, 113.4, 112.3, 111.2, 111.0, 65.8, 57.8, 55.6, 55.2, 55.1, 54.8, 29.0, 25.7, 24.0, 22.2; IR (CHCl3) 1610, 1506 cm-1 ; MS (FD) m/e 496 (M+); Anal. calc'd. for C32H36N2O3 : C, 77.37; H, 7.32; N, 5.64. Found: C, 77.25; H, 7.12; N, 5.75.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C1C=CC=CC=1.[C:45]([C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][CH:48]=1)#[CH:46]>C1C=CC=CC=1.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>[C:47]1([C:45]#[C:46][C:2]2[CH:3]=[C:4]3[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]3=[CH:11][CH:12]=2)[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][CH:48]=1
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: C#Cc1cccc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C1OC(=O)c2cc(C#Cc3cccc4ccccc34)ccc21
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To a solution of 4-bromophthalic anhydride (4.54 g, 20.0 mmol), triphenylphosphine (520 mg, 2.0 mmol), cuprous iodide (190 mg, 1.0 mmol), bis(triphenylphosphine)palladium dichloride (280 mg, 0.4 mmol) in 2:1 triethylamine/benzene (75 mL) was added 1-ethynylnaphthalene (4.94 g, 32.5 mmol) in benzene (25 mL) by cannula transfer and the mixture was heated at reflux for 2 h. The cooled solution was filtered and the precipitate was added to water (150 mL), filtered and washed with water (3×5 mL). The crude yellow solid was recrystallized from toluene, filtered and washed with hexanes (3×5 mL). The product was then added to 0.15 M NaHCO3(aq), stirred vigorously for 1 h and filtered. The yellow solid was dried at reduced pressure to constant weight to yield 4-(1-naphthylethynyl)phthalic anhydride (2.16 g, 36.2%). mp 220-222° C.; 1H NMR (CDCl3, 300 MHz) δ7.48-7.68 (m, 3H), 7.82 (d, J=7.2 Hz, 1H), δ7.92 (t, J=8.1 Hz, 2H), δ7.99 (d, J=7.8 Hz, 1H), δ8.07 (d, J=8.0 Hz, 1H), δ8.20 (s, 1H), δ8.35 (d, J8.1 Hz, 1H); 13 C NMR (CDCl3, 300 MHz) δ92.0, 94.6, 119.3, 125.5, 125.8, 125.9, 127.0, 127.6, 128.4, 128.8, 129.7, 130.6, 131.7, 131.9, 132.2, 133.3, 133.4, 138.7, 162.3, 162.3. Anal. Calcd for C20H10O3: C, 80.53;H, 3.38. Found: C, 80.37;H, 3.36.
Reaction SMILES: [Si]([O:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1)[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12]1)(C(C)(C)C)(C)C.C(=O)(O)[O-].[Na+].Cl.[NH2:37][OH:38]>CC(O)C.C(OCC)(=O)C>[OH:8][C@H:9]([C:23]1[CH:24]=[CH:25][C:26](/[C:29](=[N:37]/[OH:38])/[NH2:30])=[CH:27][CH:28]=1)[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12]1
Reactant: NO
Reactant: CCOC(=O)C[C@H]1CCCN(C[C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(C#N)cc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H]1CCCN(C[C@H](O)c2ccc(/C(N)=N/O)cc2)C1
Temperature: 75 °C
Yield: 120.6 %

Procedure:
To a mixture of ethyl 2-((R)-1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-cyanophenyl)ethyl)piperidin-3-yl)acetate (940 mg, 2.183 mmol) and sodium bicarbonate (733 mg, 8.73 mmol) in 2-propanol (50 mL) was added hydroxylamine hydrochloride (303 mg, 4.37 mmol). The reaction mixture was heated at 75° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated NaCl. The organic layer was dried MgSO4, filtered, and concentrated to yield 920 mg of ethyl 2-((S)-1-((R)-2-hydroxy-2-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidin-3-yl)acetate. (M+H)=464; HPLC RT=1.57 minutes. 1H NMR (400 MHz, CDCl3) δ ppm 9.48 (1H, s), 7.55 (2H, d), 7.24 (2H, d), 5.68 (1H, s), 4.74 (1H, m), 4.00 (2H, q), 2.73 (1H, m), 2.65 (1H, m), 2.38 (1H, dd), 2.20 (1H, dd), 2.13 (2H, t), 2.00 (1H, m), 1.80 (3H, m), 1.58 (1H, m), 1.48 (1H, m), 1.38 (1H, m), 1.13 (3H, t), 1.0 (1H, m), 0.85 (9H, s), 0.00 (3H, s), −0.15 (3H, s).
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([OH:10])=O)=[O:4].Cl.CN.[CH3:40][N:41]1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:23]=3[C:33]([F:36])([F:34])[F:35])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([NH:41][CH3:40])=[O:10])=[O:4]
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CN1CCOCC1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 34.1 %

Procedure:
(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Example 22, 22 mg, 0.044 mmol), methanamine-HCl (4.43 mg, 0.066 mmol), 4-methylmorpholine (17.72 mg, 0.175 mmol), and HATU (21.65 mg, 0.057 mmol) were added to DMF (1 mL). This was stirred for 1 h and then purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.6 min) to provide (R/S)-3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)-N-methylpropanamide (9 mg, 0.015 mmol, 35.2% yield): LCMS=516.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.36 Hz), 7.53-7.77 (7 H, m), 5.11 (1 H, s), 3.50 (2 H, td, J=6.71, 2.64 Hz), 2.69 (3 H, s), 2.40 (2 H, t, J=6.71 Hz); HPLC peak RT=8.3 min (Method A).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([N:15]([CH3:35])[CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:24][CH2:23]4)[C:12]([C:36]([F:39])([F:38])[F:37])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[Li+].[OH-].O.[CH2:43]1COC[CH2:44]1>CO>[CH2:43]([CH:29]([C@H:25]1[C:26]2[C:22](=[CH:21][C:20]([O:19][CH2:18][CH2:17][CH2:16][N:15]([C:13]3[C:12]([C:36]([F:37])([F:38])[F:39])=[CH:11][CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=4)[N:14]=3)[CH3:35])=[CH:28][CH:27]=2)[CH2:23][CH2:24]1)[C:30]([OH:32])=[O:31])[CH3:44]
Reactant: C1CCOC1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(-c4ccc(CC)cc4)ccc3C(F)(F)F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1ccc(-c2ccc(C(F)(F)F)c(N(C)CCCOc3ccc4c(c3)CC[C@H]4C(CC)C(=O)O)n2)cc1

Procedure:
Following the procedure described in Example 308 and starting with ethyl ((1S)-5-{3-[[6-(4-ethylphenyl)-3-trifluoromethyl)-2-pyridinyl](methyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 319, 10 mg, 0.018 mmol), LiOH (0.1 mg, 0.004 mmol) in THF (1 mL), MeOH (1 mL), and water (0.5 mL), the title compound was obtained (0.0024 g, 51%). 1H NMR (400 MHz, CD2Cl2) δ 7.98 (d, 2H), 7.85 (d, 1H), 7.35-7.25 (m, 3H), 7.01 (d, 1H), 6.72 (d, 1H), 6.65 (dd, 1H), 4.02 (t, 2H), 3.83 (t, 2H), 3.47 (qt, 1H), 3.08 (s, 3H), 2.90-2.68 (m, 5H), 2.42-2.30 (m, 2H), 2.15 (qt, 2H), 1.78-1.68 (m, 1H), 1.33 (m, 3H); LC-MS: RT=4.50 min, (M+H)+ 513.2.
Reaction SMILES: Br[CH:2](Br)[CH3:3].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[Cl:13][C:14]1[C:15]([F:32])=[C:16]([F:31])[CH:17]=[C:18]2[C:23]=1[N:22]=[C:21]([SH:24])[C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:19]2[OH:30]>CN(C)C=O>[Cl:13][C:14]1[C:15]([F:32])=[C:16]([F:31])[CH:17]=[C:18]2[C:23]=1[N:22]1[CH:2]([CH3:3])[S:24][C:21]1=[C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:19]2=[O:30]
Reactant: CC(Br)Br
Reactant: CCOC(=O)c1c(S)nc2c(Cl)c(F)c(F)cc2c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2n(c3c(Cl)c(F)c(F)cc3c1=O)C(C)S2

Procedure:
To a suspension of 13.7 g of 1,1-dibromoethane, 5.7 g of potassium iodide and 9.5 g of potassium carbonate in 60 ml of N,N-dimethylformamide, a solution of 11.1 g of ethyl 8-chloro-6,7-difluoro-4-hydroxy-2-mercaptoquinoline-3-carboxylate in 240 ml of N,N-dimethylformamide was added dropwise at from 110° C. to 115° C. during 2 hours with stirring. After stirring for 30 minutes at the same temperature, the reaction mixture was concentrated in vacuo and water was added to the residue. The precipitate was collected by filtration and chromatographed on silica gel using chloroform. The eluent was recrystallized from a mixture of chloroform and diethyl ether to give colorless needles, m.p. 191°-194° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][CH2:20][CH2:21][C:22]#[CH:23].[Na+].[I-].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:23][CH2:22][CH2:21][C:20]#[CH:19])=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: C#CCCCCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: C#CCCCOc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
To a solution of 0.95 g (4.0 mmol) 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 0.42 ml (4.0 mmol) 5-chloro-pent-1-yne in 20 ml acetonitrile were added 0.60 g (4.0 mmol) NaI and 1.56 g (4.80 mmol) Cs2CO3. The mixture was stirred at 50° C. for 3 days and every day 0.42 ml (4.0 mmol) 5-chloro-pent-1-yne and 1.56 g (4.80 mmol) Cs2CO3 were added (two times). After 2 further days stirring at ambient temperature and filtration, the solvent was evaporated. The residue was redissolved in dichloromethane, dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (SiO2, n-heptane/EtOAc 2.5 to 5%) yielded 1.11 g of the title compound as colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:5][C:6]1[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Cl-].[Li+].C([C:27]1[C:32](O)=[C:31](C(C)(C)C)[CH:30]=[C:29](C)[CH:28]=1)(C)(C)C.N>O1CCOCC1>[CH3:20][O:19][C:15]1[CH:14]=[C:4]([CH2:5][C:6]2[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[N:10][CH:11]=2)[CH:3]=[C:2]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:16]=1[O:17][CH3:18]
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(Br)c1OC
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: N
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1cc(Cc2cnc(N)nc2N)cc(-c2ccccc2)c1OC
Yield: 46 %

Procedure:
138 mg of 5-(3-bromo-4,5-dimethoxy-benzyl)-pyrimidine-2,4-diamine, 98 mg of trimethyl-phenyl-stannate (Example 1a), 51 mg of lithium chloride, 25 mg of tetrakis-triphenylphosphinepalladium and a crystal of 2,6-di-t-butyl-p-cresol in 10 ml of dioxan are held at reflux under argon for 4 hrs. The yellowish reaction mixture is poured into about 10% aqueous ammonia and extracted three times with methylene chloride. The organic phase is dried over magnesium sulphate and chromatographed on silica gel with methylene chloride/methanol 9:1. 62 mg (46%) of 5-(5,6-dimethoxy-biphenyl-3-ylmethyl)-pyrimidine-2,4-diamine are isolated as a yellowish solid. Mass spectrum: peaks: inter alia at m/e: 336 (M+, 100%), 321 (28%), 305 (54%), 123 (36%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:30])=[C:4]([NH:10][C@H:11]([C@H:27]([OH:29])[CH3:28])[C:12]([NH:14][NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][C:32]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])[CH3:33].N1C=CN=C1>CN(C=O)C>[Si:35]([O:29][C@@H:27]([CH3:28])[C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:30])[C:12]([NH:14][NH:15][C:16](=[O:26])[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:13])([C:32]([CH3:34])([CH3:33])[CH3:31])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H](C)O)ccc(C#N)c1Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc([N+](=O)[O-])cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
N′-((2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-nitrobenzo-hydrazide (2.0 g, 4.63 mmol) was added to DMF (100 mL), followed by addition of TBDMS-Cl (1.74 g, 11.6 mmol) and imidazole (1.58 g, 23.2 mmol) at 0° C. The solution was allowed to stir at 0° C. for 30 minutes and then at room temperature for overnight. The reaction was quenched with the addition of 200 mL brine and extract with EtOAc. Purification by flash column chromatography [EtOAc-hexanes (1:1) as eluent] afforded the title compound as a white solid (780 mg, 82%). 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.88 (br s, 2H), 8.35 (d, J=6.7 Hz, 2H), 8.16 (d, J=6.7 Hz, 2H), 7.53 (d, J=7.5 Hz, 1H), 6.69 (d, J=7.5 Hz, 1H), 5.56 (d, J=6.6 Hz, 1H), 4.46-4.36 (m, 1H), 4.18-4.10 (m, 1H), 3.26 (s, 3H), 1.37 (d, J=7.4 Hz, 3H), 0.94 (s, 9H), 0.14 (s, 3H), 0.11 (s, 3H).
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8]2>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:13]1[CH:12]=[C:11]2[C:7](=[CH:6][C:5]=1[O:4][CH3:3])[CH2:8][CH2:9][CH2:10]2
Reactant: II
Reactant: COc1ccc2c(c1)CCC2
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COc1cc2c(cc1I)CCC2

Procedure:
A mixture of silver sulfate (2.10 g; 6.75 mmol) and iodine (1.71 g; 6.75 mmol) in methanol (20 mL) was treated dropwise over 10 min with a solution of 5-methoxyindane (1 g; 6.75 mmol) in methanol (5 mL). The resultant suspension was stirred at room temperature for 3 h. The reaction was filtered and concentrated in vacuo, slurried with EtOAc (20 mL), and filtered again. The filtrate was concentrated and the residue was purified by flash silica gel chromatography (0-15% EtOAc/hexanes gradient) to afford 5-iodo-6-methoxyindane as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.63 (s, 1H), 6.78 (s, 1H), 3.87 (s, 3H), 2.91-2.85 (m, 4H), 2.15-2.06 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[S:12](=[O:22])(=[O:21])[N:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:14](=[O:15])[C:4]1=2)[CH3:2].C[O-].[Na+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[S:12](=[O:22])(=[O:21])[NH:13][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:14]([OH:15])[C:4]1=2)[CH3:2]
Reactant: CCn1c2c(c3ccccc31)S(=O)(=O)N(CC(=O)OC)C2=O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CCn1c2c(c3ccccc31)S(=O)(=O)NC(C(=O)OC)=C2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
19.3 gm (60 millimols) of methyl 4-ethyl-3,4-dihydro-3-oxo-2H-isothiazolo[4,5-b]indole-2-acetate-1,1-dioxide and a suspension of 9.7 gm (180 millimols) of sodium methylate in 150 ml of toluene were admixed, while vigorously stirring, with 30 ml of dry tert. butanol, and the mixture was stirred for 30 minutes at room temperature and then for 90 minutes at 60° C. Subsequently, the reaction mixture was cooled on an ice bath and admixed with 120 ml of ice water. The organic phase was extracted with water, and the aqueous phase was extracted with ether. The combined aqueous phases were then acidified with hydrochloric acid to pH 3. The precipitate formed thereby was washed with water, methanol and ether, and after recrystallization from ethylene chloride yielded 8.3 gm (43% of theory) of methyl 5-ethyl-2,5-dihydro-4-hydroxy-1,2-thiazino-[5,6-b]indole-3-carboxylate 1.1-dioxide; M.p.: 216° C. (decomposition).