Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:6]2=[CH:7][C:8]3[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][C:13]=3[N:5]2[CH2:4][CH2:3]1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28](O)=[O:29])[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([NH:14][C:10]4[CH:11]=[CH:12][C:13]5[N:5]6[CH2:4][CH2:3][C:2]([CH3:15])([CH3:1])[C:6]6=[CH:7][C:8]=5[CH:9]=4)=[O:29])[CH2:26][CH2:27]3)=[CH:24][C:19]=2[O:18][CH2:17]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CC1(C)CCn2c1cc1cc(N)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CCn2c1cc1cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1,1-Dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-amine (40.0 mg, 0.200 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (41.2 mg, 0.200 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.2 μL, 0.600 mmol) and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added to the mixture and the resulting solution was allowed to stir for 5 minutes at room temperature. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(1,1-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]-indol-7-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 388.2, found 389.2 (M+1)+. Retention time of 2.02 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.06-7.02 (m, 2H), 6.96-6.90 (m, 2H), 6.03 (s, 2H), 5.98 (d, J=0.7 Hz, 1H), 4.06 (t, J=6.8 Hz, 2H), 2.35 (t, J=6.8 Hz, 2H), 1.42-1.38 (m, 2H), 1.34 (s, 6H), 1.05-1.01 (m, 2H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2.[OH-].[Na+].[CH2:15]1[CH2:21][S:18](=[O:20])(=[O:19])[O:17][CH2:16]1>O.C1COCC1>[CH:10]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]([CH2:5]3)[CH:3]1[NH:2][CH2:16][CH2:15][CH2:21][S:18]([OH:20])(=[O:19])=[O:17])[CH2:9]2
Reactant: O=S1(=O)CCCO1
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(O)CCCNC1C2CC3CC(C2)CC1C3
Yield: 74 %

Procedure:
The 2-aminoadamantane hydrochloride (2×5 g) was treated with NaOH in water. The aqueous mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate. The solvent was removed under reduced pressure. The resulting white solid was dried 30 minutes at room temperature under vacuum. A solution of 1,3-propane sultone (7.4 g, 60 mmol) in THF was added to a solution of the free amine (7.98 g, 52 mmol) in THF (70 mL, total). The mixture was heated under reflux for 4 h, cooled into an ice bath. The solid was collected by filtration, air-dried for 15 min, and further dried in vacuo (11.2 g). Recrystallization was done with methanol/water (60 mL/35 mL). After cooled in a fridge, the solid was collected by filtration, rinsed with methanol, dried in the vacuum oven at 60° C. overnight. A white crystalline sandy solid (small plates, 10.45 g, 74% yield) was obtained. The 1H and 13C NMR were consistent with the structure of Compound BZ.
Reaction SMILES: [CH3:1][S:2]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38](O)=[O:39])=[CH:32][CH:31]=1)(=[N:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[O:25][CH:26]=[CH:27][C:28]=3[CH3:29])=[O:23])[CH:16]=2)[CH:12]=1)=[O:6])=[O:3].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH:68]1[CH2:73][CH2:72][O:71][CH2:70][CH2:69]1>CN(C=O)C.CCOC(C)=O>[CH3:29][C:28]1[CH:27]=[CH:26][O:25][C:24]=1[C:22]([NH:21][C:17]1[CH:16]=[C:15]([C:14]#[C:13][C:11]2[CH:10]=[N:9][CH:8]=[C:7]([CH:12]=2)[C:5]([N:4]=[S:2]([CH3:1])([C:30]2[CH:31]=[CH:32][C:33]([CH2:36][CH2:37][C:38]([N:68]3[CH2:73][CH2:72][O:71][CH2:70][CH2:69]3)=[O:39])=[CH:34][CH:35]=2)=[O:3])=[O:6])[CH:20]=[CH:19][CH:18]=1)=[O:23]
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)O)cc3)c2)c1
Reactant: C1COCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)N4CCOCC4)cc3)c2)c1
Reaction time: 0.33 h
Yield: 40.9 %

Procedure:
3-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)phenyl]propanoic acid (0.050 g, 0.090 mmol) was dissolved in DMF (1 mL) then treated with BOP (0.051 g, 0.117 mmol) and TEA (0.050 mL, 0.360 mmol) and allowed to stir for 20 min. Morpholine (0.015 mL, 0.180 mmol) was then added and the reaction was allowed to stir for an additional 4 h. The resulting reaction mixture was dissolved in EtOAc (5 mL) and then extracted with brine (2×5 mL). The organic layer was then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude mixture was then purified via column chromatography (silica gel, gradient eluant mixture of MeOH in EtOAc: 0% to 0% MeOH) give the title compound (0.023 g, 41%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].I[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:36][C:37]([CH3:40])([CH3:39])[CH2:38][O:34][C:31]1[CH:32]=[CH:33][C:28]([N:4]2[C:5](=[O:27])[C:6]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]2[CH2:1][CH3:2])=[CH:29][CH:30]=1
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCCc1nc(CC)n(-c2ccc(OCC(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 86.5 %

Procedure:
To a solution of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.4 g) in N,N-dimethylacetamide (10 mL) were added 1-iodo-2,2-dimethylpropane (0.26 g) and cesium carbonate (0.44 g), and the mixture was stirred at 120° C. for 24 hr. The mixture was allowed to cool to room temperature and the insoluble material was filtered off. The filtrate was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound as a pale-yellow solid (0.40 g, 87%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6](N)=[CH:5][CH:4]=1.O.N([O-])=O.[Na+].[CH3:17][CH2:18][O:19][C:20]([S-:22])=[S:21].[K+]>Cl.CO.CCCCCC>[C:20](=[S:21])([O:19][CH2:18][CH3:17])[S:22][C:6]1[CH:7]=[N:8][C:3]([C:2]([F:11])([F:10])[F:1])=[CH:4][CH:5]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CO
Solvent: O
Product: CCOC(=S)Sc1ccc(C(F)(F)F)nc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
After 6-trifluoromethylpyridin-3-ylamine (1.00 g, 6.02 mmol) was dissolved in 1N hydrochloric acid (15 ml) and methanol (3 ml), a water (3 ml) solution of sodium nitrite (506 mg, 7.22 mmol) was added dropwise to the resulting solution at −10° C. The reaction mixture was added dropwise to a water (15 ml) solution of potassium o-ethyl dithiocarbonate (1.93 g, 12.0 mmol) heated to 65° C. At the same temperature, the reaction mixture was stirred for 30 minutes. After the reaction mixture was cooled to room temperature, the product thus obtained was extracted with ethyl acetate. The extract was washed with brine. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=100:1 eluate was concentrated under reduced pressure to give the title compound (895 mg, 3.35 mmol, 56%) as a yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH3:7][CH:8]([CH3:12])[CH:9]([OH:11])[CH3:10].C(N(C(C)C)CC)(C)C.Cl>ClCCl>[CH3:10][CH:9]([O:11][C:1](=[O:5])[CH:2]=[CH:3][CH3:4])[CH:8]([CH3:12])[CH3:7]
Reactant: CC(C)C(C)O
Reactant: C/C=C/C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC=CC(=O)OC(C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
Crotonoyl chloride (21.35 g) in dichloromethane (100 mL) was charged into a 2-L reaction flask and cooled to 0° C. 3-Methyl-butan-2-ol (18 g) was added followed by diisopropylethylamine (31.7 g). The reaction mixture was aged at 0-10° C. for about 30 minutes and poured into dilute hydrochloric acid (33 g in 170 g water). Hexanes were added and the aqueous and organic layers were split. The organic layer was separated and subsequently purified via liquid chromatography to provide but-2-enoic acid 1,2-dimethyl-propyl ester (25.6 g).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@@H:6]([CH3:13])[N:5]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:4]=2[N:3]=1.C(N(CC)CC)C.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:7](=[O:12])[C@@H:6]([CH3:13])[N:5]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[C:4]=2[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: C[C@@H]1C(=O)Nc2cnc(Cl)nc2N1C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1C(=O)N(c2ccccc2)c2cnc(Cl)nc2N1C1CCCCC1
Temperature: 25 °C
Yield: 39 %

Procedure:
To a solution of (7R)-2-chloro-8-cyclohexyl-7-methyl-7,8-dihydropteridin-6(5H)-one (280 mg, 1.0 mmol) in 10 mL of dry dichloromethane was added triethylamine (1.39 mL, 10 mmol), cupric acetate (363 mg, 2.0 mmol), phenylboronic acid (244 mg, 2.0 mmol) and 4 Å molecular sieves (2.0 g). The reaction mixture was allowed to stir at room temperature with air balloon on. The reaction mixture was then filtered over Celite, washed with dichloromethane and the organic layer was washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel flash chromatography, using dichloromethane-methanol mixture (v:v=99:1) as eluent, to give titled compound (yield: 39%). 1HNMR (300 MHz, CDCl3): δ 1.20-1.22 (m, 1H), 1.47-1.49 (m, 6H), 1.72-1.77 (m, 3H), 1.87-1.89 (m, 2H), 2.10-2.13 (m, 1H), 4.44-4.49 (m, 2H), 7.17 (s, 1H), 7.20-7.24 (m, 2H), 7.48-7.56 (m, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Br[CH2:8][CH:9]1[O:14][C:13](=[O:15])[NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CN(C=O)C.O>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][CH:9]2[O:14][C:13](=[O:15])[NH:12][CH2:11][CH2:10]2)[CH:6]=1
Reactant: O=C1NCCC(CBr)O1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCC(Cn2cc(I)cn2)O1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 4-iodo-1H-pyrazole (1 g, 5 mmol), 6-(bromomethyl)-1,3-oxazinan-2-one (1 g, 5 mmol), cesium carbonate (3.2 g, 10 mmol) and potassium iodide (20 mg, 0.1 mmol) in DMF (80 mL) was stirred at 80° C. for 12 hours. After cooling to room temperature, the mixture was diluted with water and extracted with DCM. The organic layer was concentrated under reduced pressure to afford 6-((4-iodo-1H-pyrazol-1-yl)methyl)-1,3-oxazinan-2-one. MS ESI calc'd. for C8H11IN3O2 [M+H]+ 308. found 308.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.[OH-].[Na+].N1C=CN=C1.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>[Ni].C(O)C.C(Cl)Cl>[Si:24]([O:12][CH:9]1[CH2:10][C:11]2[C:2]([NH2:1])=[CH:3][CH:4]=[CH:5][C:6]=2[CH2:7][CH2:8]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1cccc2ccc(O)cc12
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC1CCc2cccc(N)c2C1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
A mixture of 8-amino-2-naphthol (47.55 g, 298.7 mmol), Raney nickel (20.20 g), and 50% aq. NaOH (1.97 g) in ethanol (480 mL) in a sealed reactor was purged three times (3×40 psi H2/vacuum cycles), then the reactor was pressurized with 1300 psi H2 and heated at 85° C. for 7 hours. After this time, the catalyst was filtered off (Celite), and the filtrate was evaporated to afford a dark oil. The oil was dissolved in CH2Cl2 (600 mL) and was treated with imidazole (65.9 g, 969 mmol) and tert-butylchlorodimethylsilane (59.0 g, 392 mmol). The reaction mixture was stirred at room temperature for 18 hours, and washed with water and brine. The organic solution was dried over Na2SO4 and evaporated. The residue was chromatographed on silica gel (9:1 to 4:1 hexane-ethyl acetate, eluant) to afford the title compound as a dark purple oil, 44.22 g (49%). 1H NMR (300 MHz, DMSO-d6) δ 6.76 (m, 1H), 6.40 (m, 1H), 6.27 (d, J=7.5 Hz, 1H), 4.68 (br, 2H), 4.07 (m, 1H), 2.57-2.79 (m, 3H), 2.22 (m, 1H), 1.81 (m, 1H), 1.58 (m, 1H), 0.87 (s, 9H), 0.08 (s, 6H). MS (ESI+) m/z 278 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+]>O1CCCC1>[Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CCl)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(CCl)c1ccccc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 101.2 %

Procedure:
A solution of 2-chloroacetophenone (5 g, 0.032 mol), sodium borohydride (6.1 g, 0.16 mol) in tetrahydrofuran (30 ml) was allowed to stir at 60° C. for 18 hours. The reaction was quenched by water (200 ml) and stirred for another 2 hours. The mixture was extracted with methylene chloride (3×100 ml) and washed with water (3×150 ml). The organic layer was dried over sodium sulfate and filtered. The solvent was removed under vacuum and afforded 5.07 g(100%) of product as a clear oil. MS EI m/e 156 (M+)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:47])[NH:10][C:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]1[C:20](=[O:46])[C:21]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:22]([C:24](=O)[NH:25][CH2:26][C:27](=O)[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[N:23]=[C:12]21)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:57])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:47])[NH:10][C:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]1[C:20](=[O:46])[C:21]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:22]([C:24]3[S:57][C:27]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)=[CH:26][N:25]=3)[N:23]=[C:12]21)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1)Cc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: O=C(NC12CCC(CC1)Cn1c2nc(-c2ncc(Cc3ccc(F)cc3)s2)c(OCc2ccccc2)c1=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
To a solution of benzyl(3-(benzyloxy)-2-((3-(4-fluorophenyl)-2-oxopropyl)carbamoyl)-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl)carbamate, Intermediate 7 (120 mg, 0.188 mmol) in toluene was added Lawesson's Reagent (76 mg, 0.188 mmol) and stirred for 15 min at room temperature, 30 min at 60° C. and 2 h at 100° C. The resulting clear yellow mixture was then cooled, concentrated and purified by preparative HPLC to provide the title compound (60 mg, 0.094 mmol, 50.2% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.79 (1H, s), 7.47-7.52 (2H, m), 7.29-7.39 (8H, m), 7.17 (2H, dd, J=8.28, 5.27 Hz), 6.94-7.07 (3H, m), 5.38 (2H, s), 5.09 (2H, s), 4.09-4.19 (4H, m), 2.69-2.84 (2H, m), 2.49 (1H, br. s.), 1.94-2.04 (4H, m), 1.65-1.76 (2H, m). LCMS (M+H)=637.27.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[CH3:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]2[CH:20]=[C:21]([C:25]#[CH:26])[CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1.CON(C)[C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[C:33]1([C:32](=[O:39])[C:26]#[C:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH2:17][C:16]3[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:28][CH:27]=3)[CH:20]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: C#Cc1cccc(OCc2ccc(OC)cc2)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: COc1ccc(COc2cccc(C#CC(=O)c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Place lithium hexamethyldisilazane (2 mL of a 1M solution in tetrahydrofuran, 2 mmol) and tetrahydrofuran (8 mL) under an argon atmosphere and cool to 0° C. Add a solution of 3-(4methoxybenzyloxy)phenylacetylene (0.48 g, 2 mmol) in tetrahydrofuran and stir the brown solution for 45 minutes at 0° C. Add N-methoxy-N-methylbenzamide (0.4 g, 2.4 mmol), remove the cooling bath andstir at room temperature for 1 hour. Partition the mixture between ethyl ether and water, separate the organic phase and dry (MgSO4). Filter and evaporate the solvent in vacuo to yield an oil. Filter through silica gel and elute with 10% ethyl acetate/hexane to yield a crude solid. Recrystallize (hexane, ethyl ether) to yield 0.26 g (lst crop) and 0.15 g (2nd crop) of the title compound; mp 79°-80 C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:11]C(=O)[O:9][C:8](=O)[C:7]=2[CH:14]=1.[NH2:15][NH2:16]>O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:11])=[C:7]([CH:14]=1)[C:8]([NH:15][NH2:16])=[O:9]
Reactant: CSc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: NN
Solvent: O
Product: CSc1ccc(N)c(C(=O)NN)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-methylthio-2H-3,1-benzoxazine-2,4-(1H)-dione (25.11 g; 0.72 mole) is added to a cold solution of 54.4% hydrazine (75 ml) in water (75 ml). After stirring at room temperature overnight, the while solid is filtered, washed with cold water and dried. Yield 21.3 g; mp 124°-127°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[OH:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.C([BH3-])#N.[Na+].Cl>C(O)(=O)C.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:32][C:31]4[CH:34]=[CH:35][C:28]([OH:27])=[CH:29][CH:30]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccc(O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (15 mg, 0.045 mmol), in 10-20% acetic acid in anhydrous methanol (0.20 mL)was added p-hydroxybenzaldehyde (16 mg, 0.14 mmol) and a freshly prepared solution of sodium cyanoborohydride (4.0 mg, 0.060 †mmol) in anhydrous methanol (0.24 mL). The mixture was shaken at room temperature for 14-18 h and then loaded onto an ion exchange resin (SCX, Varian). Elution with methanol (4 column volumes) followed by 2 N ammonia in methanol (2 column volumes) and concentration of the appropriate fractions provided the crude product. After drying the sample under vacuum for 12-20 h, the residue was dissolved in methanol and treated with hydrochloric acid (1-2 eq). The mixture was then concentrated in vacuo to give the title compound as the hydrochloride salt.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:7]=2[C:6]=1[CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][N:24]2[C:32]3[CH2:31][CH2:30][N:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:28][C:27]=3[C:26]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)=[N:25]2)[CH2:17][CH2:16]1)=[O:4].[OH-].[K+].Cl>C1COCC1.O>[F:14][C:11]1[CH:12]=[CH:13][C:7]2[C:6]([CH:15]3[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH2:23][N:24]4[C:32]5[CH2:31][CH2:30][N:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:28][C:27]=5[C:26]([C:37]5[CH:42]=[CH:41][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:39][CH:38]=5)=[N:25]4)[CH2:19][CH2:20]3)=[C:5]([C:3]([OH:4])=[O:2])[S:9][C:8]=2[CH:10]=1
Reactant: COC(=O)c1sc2cc(F)ccc2c1C1CCN(CCCn2nc(-c3ccc(C(F)(F)F)cc3)c3c2CCN(S(C)(=O)=O)C3)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCC(c3c(C(=O)O)sc4cc(F)ccc34)CC2)C1
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a stirred solution of 635 mg (0.94 mmol) of 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carboxylic acid methyl ester in 10 mL of THF was treated a solution of 53 mg (0.94 mmol) of KOH in 0.5 mL of water. This was stirred overnight, after the hydrolysis was deemed complete 1 mL of 1 N HCl solution was added. This was then extracted with EtOAc (3×30 mL). The combined organic layers were then washed with brine, dried over Na2SO4, and concentrated to yield 622 mg (100%) of a white solid. MS (electrospray): exact mass calculated for C31H32F4N4O4S2: 664.18; m/z found, 665.2 [M+H]+. 1H NMR (DMSO-d6, 400 MHz): 8.12 (dd, J=8.81, 5.28 Hz, 1H), 7.83 and 7.76 (A and B of AB quartet, J=8.41 Hz, 4H), 7.17 (br t, J=8.61 Hz, 1H), 4.47 (s, 2H), 4.29 (br s, 1H), 4.16 (t, J=7.04 Hz, 2H), 3.53 (t, J=5.67 Hz, 2H), 3.28 (br m, 4H), 3.00 (s, 3H), 2.96 (m, 2H), 2.73 (br s, 2H), 2.52 (br m, 2H), 2.13 (br m, 2H), 1.76 (br m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([NH:29]C(=O)C)([CH2:11][C:12]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]2[C:13]=1[N:14]=[C:15]([O:27]C)[C:16]([O:25]C)=[N:17]2)C(OCC)=O)C>Cl>[NH2:29][CH:5]([CH2:11][C:12]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]2[C:13]=1[NH:14][C:15](=[O:27])[C:16](=[O:25])[NH:17]2)[C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)C(Cc1cc([N+](=O)[O-])cc2nc(OC)c(OC)nc12)(NC(C)=O)C(=O)OCC
Agent: Cl
Product: NC(Cc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12)C(=O)O

Procedure:
A suspension of 0.29 g (0.62 mmol) of 2-acetylamino-2-(2,3-dimethoxy-7-nitro-quinoxalin-5-ylmethyl)-malonic acid diethyl ester in 6 ml of 6N hydrochloric acid is heated at reflux for 24 hours and then concentrated to dryness under reduced pressure. After boiling the residue up with water, centrifugation and drying, the title compound is obtained in the form of a yellow powder.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26](=[O:35])[C:27]([C:30](=[O:34])[CH:31](Br)[CH3:32])([CH3:29])[OH:28]>C(#N)C>[CH3:24][O:25][C:26](=[O:35])[C:27]([C:30](=[O:34])[CH:31]([O:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[CH:12][CH:13]=1)[CH3:32])([CH3:29])[OH:28]
Reactant: Oc1ccc(Oc2nc3ccccc3s2)cc1
Reactant: COC(=O)C(C)(O)C(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)(O)C(=O)C(C)Oc1ccc(Oc2nc3ccccc3s2)cc1
Yield: 84.8 %

Procedure:
48.6 g of 4-(2-benzthiazolyloxy)-phenol, 33.1 g of potassium carbonate and 50.2 g of 2-bromopropionyl-lactic acid methyl ester in 250 cc of acetonitrile are refluxed for 8 hours. After cooling the salt precipitate is filtered off and the acetonitrile is distilled off. The residue is fraction-distilled, yielding 68 g (82.5% of theory) of 2-[4-(2-benzthiazolyloxy)-phenoxy]-propionyl-lactic acid methyl ester, b.p. 218° to 220° C./0.01 mbar. ##STR11##