Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([Br:18])=[CH:12][CH:13]=3)[C:8]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)([OH:19])[C:7]([O:28][CH3:29])([CH3:27])[C:6]=2[CH:5]=1.[NH4+].[OH-].[CH3:32]S(C)=O>>[Br:18][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[C:6](=[CH:5][C:4]([Br:3])=[CH:17][CH:16]=3)[C:7]([O:28][CH3:29])([CH3:27])[C:8]([O:19][CH3:32])([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[C:9]=2[CH:10]=1
Reactant: COC1(C)c2cc(Br)ccc2-c2ccc(Br)cc2C1(O)c1ccc(C)cc1
Reactant: CS(C)=O
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Product: COC1(C)c2cc(Br)ccc2-c2ccc(Br)cc2C1(OC)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.52 g (113 mmol) of NaH as a 60% strength dispersion in mineral oil were placed in a dry apparatus, 40 ml of dry DMSO were added, 36.8 g (75.4 mmol) of 2,7-dibromo-10-methoxy-10-methyl-9-p-tolyl-9,10-dihydrophenanthren-9-ol in 100 ml of dry DMSO were subsequently added dropwise and the mixture was stirred at RT for 30 minutes. 7 ml (113 mmol) of Mel were then added dropwise over a period of 1 hour while cooling in ice and the mixture was stirred at RT for 1 hour. To work up the mixture, it was cooled to 5° C., 150 ml of 15% NH4OH were added dropwise, the precipitate was filtered off with suction, washed twice with water and twice with MeOH. To purify it further, it was recrystallized four times from EtOH/toluene. This left 16.7 g (44%) of colorless crystals having a purity determined by RP-HPLC of 99.90%.
Reaction SMILES: C(OC([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[C:31]([F:32])=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:26]([CH3:33])=[N:27]4)=[CH:15][C:16]=2[C:17]([O:19]CC)=[O:18])[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:39]>O1CCOCC1.O.CCOCC>[ClH:39].[NH2:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[C:31]([F:32])=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:26]([CH3:33])=[N:27]4)=[CH:15][C:16]=2[C:17]([OH:19])=[O:18])[CH2:10][CH2:11]1
Reactant: CCOC(=O)c1cc(-c2c(F)ccc3nc(C)c(NC(C)(C)C)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: Cc1nc2ccc(F)c(-c3cc(C(=O)O)c(C4(N)CC4)[nH]3)c2nc1NC(C)(C)C
Temperature: 110 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
A glass microwave reaction vessel was charged with ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (295b) (230 mg, 0.44 mmol) and LiOH monohydrate (Sigma-Aldrich) (184 mg, 4.38 mmol) in dioxane (1.5 mL) and water (0.75 mL). The reaction mixture was heated at 110° C. for 17 h. After cooling to RT, the reaction mixture was diluted with Et2O and water and the layers were separated. The Et2O layer was discarded. The aq. layer was acidified with 2 M HCl and extracted with EtOAc (3×). The combined EtOAc layers were dried over anhydrous Na2SO4, filtered and concentrated to give a light yellow solid. m/z (ESI, +ve) 498.2 (M+H)+. The light yellow solid was dissolved in 1 mL of dioxane and treated with 4.0 M HCl in 1,4-dioxane (Sigma-Aldrich) (5 mL, 20.00 mmol) at RT. After 24 h, the reaction mixture was concentrated and the orange solid was collected by filtration to give 2-(1-aminocyclopropyl)-5-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (295c) (180 mg, 0.42 mmol, 95% yield). m/z (ESI, +ve) 381.1 (M−NH2)+.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:22][C@H:23]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26]>ClCCl>[NH:22]([C:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9])[C@H:23]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
Phenylacetyl chloride (5.7 ml) was added dropwise to a mixture of TsOH.H-L-Leu-OBzl (14.15 g) and TEA (12 ml) in dichloromethane (300 ml) under ice-bath cooling. After being stirred for 10 minutes at the same temperature, the mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate (300 ml). The solution was washed with 1N HCl (100 ml), water (100 ml), 1M aqueous sodium bicarbonate (100 ml), and brine (100 ml×2), dried over magnesium sulfate and evaporated to give N-phenylacetyl-L-Leu-OBzl (14 g). This product was used in a next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][O:14][CH3:15])[N:12]=1)(C)(C)C.[ClH:17].O1CCOCC1>>[ClH:17].[CH3:15][O:14][CH2:13][C:11]1[N:12]=[C:8]([NH2:7])[S:9][CH:10]=1
Reactant: COCc1csc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Product: COCc1csc(N)n1

Procedure:
Carbamate IV (Example 5) (254 mg, 1.04 mmol) was stirred with HCl/dioxane (4 M, 15 mL) for 24 hours, the mixture was allowed to warm from 0° C. to ambient temperature over this period. Volatiles were removed under reduced pressure and the residue was azeotroped several times with toluene. 1H NMR (300 MHz, CD3OD) δ 3.37 (s, 3H), 4.34 (s, 2H), 6.82 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[N:6][C:7]=1Br.C(N)C1C=CC=CC=1.O.C[C:35]([N:37](C)[CH3:38])=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[N:6][C:7]=1[N:37]([CH3:38])[CH3:35]
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: CC(=O)N(C)C
Solvent: O
Solvent: NCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)n1nc(-c2nc(N(C)C)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 122.5 °C

Procedure:
A mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (100 mg) and benzylamine (0.085 ml) in DMA (0.2 ml) was heated at 120-125° C. for 50 hours. After addition of water (4 ml), an aqueous layer was removed by decantation to give a residue. The residue was dissolved in CHCl3, dried over MgSO4, concentrated under reduced pressure and purified by preparative TLC on silica gel (CHCl3 only). A less polar zone was gave 6-[5-amino-6-(dimethylamino)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone as a solid (18 mg) and a more polar zone was gave 6-[5-amino-6-(benzylamino)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone as a solid (67 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([CH:7]=1)[O:8][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: Oc1cc(Br)cc(F)c1F
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Fc1cc(Br)cc(OC2CCCCO2)c1F
Yield: 64.6 %

Procedure:
A solution of 5-bromo-2,3-difluorophenol (2.75 g, 13.16 mmol), 3,4-dihydro-2H-pyran (2.39 mL, 26.3 mmol) and PPTS (0.165 g, 0.658 mmol) in DCM (10 mL) was stirred for 1 h at rt. At this time, analytical HPLC showed that the reaction was complete. The reaction was concentrated in vacuo. The crude oily product was chromatographed [SiO2; continuous gradient of EtOAc/hexane (0% to 20% over 15 min)] to give the title compound (2.5 g, 8.5 mmol, 65% yield) as a clear oil. 1H NMR (CDCl3) δ: 7.17 (dt, J=6.4, 2.2 Hz, 1H), 6.99 (ddd, J=8.8, 6.2, 2.4 Hz, 1H), 5.45 (t, J=3.0 Hz, 1H), 3.88 (td, J=11.0, 3.0 Hz, 1H), 3.72-3.62 (m, 1H), 2.11-1.82 (m, 3H), 1.80-1.59 (m, 3H); 19F NMR (CDCl3) δ: −135.00, −158.84.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.Br[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=2)[CH:25]=1
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cccnc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (400 mg) and 3-bromopyridine (226 mg) were dissolved in DMF (4 ml), and K2CO3 (536 mg) and a 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex were added, followed by stirring at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain tert-butyl 3′,6′-dihydro-3,4′-bipyridine-1′(2′H)-carboxylate (249 mg).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:21]([O:28][C@@H:29]([CH2:36][CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[C@H:30]([CH3:35])/[CH:31]=[CH:32]/[CH2:33][OH:34])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.[O-]S([O-])(=O)=O.[Cu+2]>[Si:21]([O:28][C@@H:29]([CH2:36][CH2:37][O:38][Si:39]([C:42]([CH3:43])([CH3:45])[CH3:44])([CH3:40])[CH3:41])[C@H:30]([CH3:35])/[CH:31]=[CH:32]/[CH2:33][O:34][C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:23])[CH3:22]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@H](/C=C/CO)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: [Cu+2]
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccncc1
Product: C[C@H](/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 99.5 %

Procedure:
Trityl chloride (4.1 g, 14.7 mmol) and DMAP (1.8 g, 14.7 mmol) were added to a solution of alcohol 11 (2.75 g, 7.1 mmol) in pyridine (71 mL). The mixture was heated to reflux for 18 h, cooled to ambient temperature and added to a solution of sat'd CuSO4 (200 mL). The mixture was extracted with Et2O (2×20 mL) and the combined organic extracts were washed sat'd CuSO4 (2×20 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (EtOAc/hexane 1:19) provided 12 (4.46 g, quantitative) as a pale yellow oil: IR (CHCl3) 2954, 2856, 1471, 1448, 1254, 1095, 835, 773, 705 cm−1; 1H NMR (300 MHz, CDCl3) ε7.56 (m, 6H), 7.32 (m, 9H), 5.79 (dd, J=15.6, 6.7 Hz, 1H), 5.65 (dd, J=15.7, 5.0 Hz, 1H), 3.85 (m, 1H), 3.74 (m, 1H), 3.66 (d, J=4.9 Hz, 1H), 2.43 (m, 1H), 1.70 (q, J=6.5 Hz, 2H), 1.21 (d, J=6.9 Hz, 3H), 0.99 (s, 9H), 0.97 (s, 9H), 0.154 (s, 3H), 0.150 (s, 3H), 0.13 (s, 3H), 0.12 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 144.4, 134.2, 128.7, 127.7, 126.9, 126.8, 86.8, 72.6, 65.1, 60.2, 42.1, 36.6, 26.0, 18.3, 18.1, 15.3, −4.4, −5.3; LRMS (EST) 653.3 [M+Na]+, 422.4, 243.2; HRMS (ESI) calcd for C39H58O3Si2Na 653.3822 [M+Na]+, found 653.3851; [α]20D−1.9 (c 0.42, CHCl3).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20].[F:23][C:24]1[C:25]([C:31](Cl)=[O:32])=[N:26][CH:27]=[C:28]([F:30])[CH:29]=1.[Cl-].[NH4+]>C1COCC1.O>[F:23][C:24]1[C:25]([C:31](=[O:32])[CH:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[F:11])[C:19]([O:21][CH3:22])=[O:20])=[N:26][CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: COC(=O)Cc1ccccc1F
Reactant: O=C(Cl)c1ncc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C(=O)c1ncc(F)cc1F)c1ccccc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
21.4 ml (21.4 mmol) of lithium hexamethyldisilazide (1.0 M in THF) were initially charged in THF (30 ml) under argon and a solution of 3.00 g (17.8 mmol) of methyl 2-fluorophenylacetate in THF (15 ml) was added dropwise at −78° C. The reaction mixture was stirred at −78° C. for 1 h, and then a solution of 3.80 g (21.4 mmol) of the compound from Example 12A in THF (15 ml) was added dropwise. The solution was stirred at −78° C. for 1 h, then brought to RT, and saturated aqueous ammonium chloride solution was added in portions. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated. The residue was stirred with MTBE, the solids were filtered off and the filtrate was concentrated. Silica gel chromatography (eluent: 30:1, 20:1 cyclohexane-ethyl acetate) of the residue gave 3.66 g (87% purity, 57% of theory) of the title compound. The crude product was converted without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH3:22]/[C:23](/[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:24]\[CH2:25]O>C(#N)C>[Br:20][CH2:25]/[CH:24]=[C:23](\[CH3:22])/[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: BrBr
Reactant: CCCCCCCCC/C(C)=C/CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCCCCCCCC/C(C)=C/CBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
An acetonitrile solution (100 ml) of triphenylphosphine (18.6 g, 70.9 mmols) was stirred at 0° C. Bromine (11.4 g, 3.7 ml, 71.3 mmols) was slowly blended into the solution. To the mixture, an acetonitrile (30 ml) solution of (E)-3-methyl-2-dodecen-1-ol (3′) was added dropwise, followed by stirring for 2 hours at 0° C. The solvent was removed under vacuum, and the residue was dissolved in dichloromethane. The solution was washed with saturated sodium bicarbonate and a saturated aqueous solution of sodium chloride, then dried over sodium sulfate, and concentrated. Pentane was added to the residue, and a solid formed was removed by filtration. The filtrate was concentrated in a vacuum to obtain 17.9 g (97%) of (E)-1-bromo-3-methyl-2-dodecene (4′).
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[N:13]=[C:12](Cl)[N:11]=1)[CH3:8])(=O)=O.C(=O)([O-])[O-:19].[K+].[K+]>O1CCOCC1.O>[Cl:16][C:14]1[CH:15]=[C:10]2[NH:9][C@@H:7]([CH3:8])[CH2:6][N:11]2[C:12](=[O:19])[N:13]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@@H](COS(C)(=O)=O)Nc1cc(Cl)nc(Cl)n1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1Cn2c(cc(Cl)nc2=O)N1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-((2,6-dichloropyrimidin-4-yl)amino)propyl methanesulfonate (1.86 g, 6.20 mmol) and potassium carbonate (2.57 g, 18.6 mmol) in 1,4-dioxane (100 mL) and water (20 mL). The reaction mixture was stirred at 100° C. for 2 h, then concentrated to remove solvent, diluted with water (20 mL), stirred at room temperature for 10 min and filtered. The filter cake was recrystallized with DCM (30 mL) to give the title product.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(=O)([O-])[O-].[K+].[K+].[C:17](Cl)(=O)[C:18]1[C:19]([O:24][CH3:25])=[CH:20][CH:21]=[CH:22][CH:23]=1>CCOCC>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[NH:10][C:1](=[O:9])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1
Reactant: NC(=O)c1ccccc1N
Reactant: COc1ccccc1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
In a 2 L three-necked round-bottomed flask equipped with an overhead stirrer and reflux condenser, anthranilamide (20.0 g, 147 mmol) and potassium carbonate (28.4 g, 206 mmol) were suspended in 1 L dry ether and heated to reflux. o-Anisoyl chloride (32.5 g, 191 mmol) was added slowly to the refluxing mixture. After 3 hours at reflux, the reaction mixture was allowed to cool to room temperature, the ether was removed under reduced pressure, and the resulting residue was filtered and washed with water. The resulting solid was then suspended in 600 mL of 5% aq. NaOH solution and boiled for one hour. The reaction was allowed to cool to room temperature, and it was neutralized with acetic acid, upon which 2-(2-methoxyphenyl)quinazolin-4(3H)-one was precipitated. The product was collected by filtration, washed with water, and dried overnight in vacuo to yield 27 g (73%) of pure 2-(2-methoxyphenyl)quinazolin-4(3H)-one. LC/MS: m/z 253.0 (M+H)+ at 3.22 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (DMSO) 63.86 (s, 3H), δ 7.09 (t, 1H), δ 7.18 (d, 1H), δ 7.53 (m, 2H), δ 7.70 (m, 2H), δ 7.80 (m, 1H), δ 8.14 (d, 1H), δ 12.11 (s, 1H) ppm; 13C NMR (DMSO) δ 55.75, δ 111.86, δ 120.89, δ 120.97, δ 122.74, δ 125.75, δ 126.45, δ 127.26, δ 130.41, δ 132.13, δ 134.32, δ 148.97, δ 152.48, δ157.12, δ 161.35.
Reaction SMILES: Cl.[CH:2]([C@@:4]([C:12]([O:14][CH3:15])=[O:13])([CH2:6][CH2:7][C:8](OC)=[O:9])[NH2:5])=[CH2:3].C(=O)([O-])[O-].[Na+].[Na+]>COCCO>[CH3:15][O:14][C:12]([C:4]1([CH:2]=[CH2:3])[NH:5][C:8](=[O:9])[CH2:7][CH2:6]1)=[O:13]
Reactant: C=C[C@](N)(CCC(=O)OC)C(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCO
Product: C=CC1(C(=O)OC)CCC(=O)N1

Procedure:
Dimethyl 2-vinylglutamate hydrochloride (570 mg, 2 mM), is treated with saturated aqueous sodium carbonate (20 ml) and the resulting mixture extracted with dichloromethane. The organic phase is dried and concentrated to afford the free base which is dissolved in 2-methoxyethanol (20 ml) and heated under reflux for 2 hours. The solvent is then removed in vacuo to afford 5-methoxycarbonyl-5-vinyl-2-pyrrolidone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH:18]C(=O)OCC3C=CC=CC=3)[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.I[Si](C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(NCC1Cc2cccc(-c3ccccc3Cl)c2O1)OCc1ccccc1
Agent: C[Si](C)(C)I
Product: NCC1Cc2cccc(-c3ccccc3Cl)c2O1
Yield: 85.8 %

Procedure:
Treatment of (−)-benzyl {[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (0.480 g, 1.22 mmol) with iodotrimethylsilane (0.975 g, 4.87 mmol) generally according to the procedure described for Example 129 afforded 0.272 g (75%) of (+)-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]D25=+9.90 (c 10.0 in dimethylsulfoxide); mp 186-188° C.; Anal. calcd. for C15H14ClNOHCl: C, 60.83; H, 5.1; N, 4.73. Found C, 60.53; H, 5.39; N, 4.62.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH2:14][CH2:15][CH2:16][Cl:17]>CO>[Cl:17][CH2:16][CH2:15][CH2:14][S:12][C:9]1[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1ccc(SCCCCl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 g of potassium hydroxide is dissolved in 40 ml of methanol and mixed with 2.3 g of 4-nitrothiophenol. The suspension is stirred for one hour at room temperature and mixed drop by drop with 1.48 ml of 1-bromo-3-chloropropane. After 4 hours of stirring at room temperature, another 0.15 ml of 1-bromo-3-chloropropane is added in drops. The mixture is stirred for 65 hours at room temperature, concentrated by evaporation in a vacuum and taken up in ethyl acetate. It is extracted with water and saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. After purification by flash chromatography, 2.54 g of 1-(3-chloro-propylsulfanyl)-4-nitro-benzene is obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]#[CH:8])[CH2:4][CH3:5])[CH3:2].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH2:1]([N:3]([CH2:6][C:7]#[C:8][C:11]1[C:10]([F:9])=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:20]/[C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26])/[C:14](=[O:19])[NH:15]2)[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCN(CC)CC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CC#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, N,N-diethyl propargylamine (38 mg, 0.34 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P)4Pd (16 mg) and CuI (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 18 h to give (Z)-4-(3-(N,N-diethylamino)-1-propynyl]-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 20 mg, 42%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]([CH2:28][C:29]([O:31]C)=[O:30])[CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.C1COCC1.CO.O[Li].O>O.Cl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:15][CH2:16][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]([CH2:28][C:29]([OH:31])=[O:30])[CH2:20]3)[CH2:18][CH2:19]1)=[O:13])[CH2:8]2
Reactant: COC(=O)CC1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 2-(1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate isomer A (2.0 mg, 5 μmol) in water (0.25 mL), THF (0.25 mL) and methanol (0.5 mL) was added LiOH.H2O (10 mg, 0.23 mmol). The mixture was stirred overnight at rt. The mixture was diluted with 5% aq HCl (10 mL) and extracted with EtOAc (2×40 mL). The combined organic extracts were dried over Na2SO4 and concentrated to leave crude 2-(1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid isomer A (3 mg, quant) as an oil. 1H NMR (CDCl3) δ=2.49 (m, 1H), 2.63 (m, 1H), 3.00 (m, 1H), 3.1 (1H), 3.65 (1H), 3.92 (1H), 4.02 (2H); LC-MS (3 min) tR=1.90 min, m/z=423.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:8][N:9]=1)(=O)C.Cl>C(O)(=O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2ccc([N+](=O)[O-])cc2)s1
Agent: Cl
Solvent: CC(=O)O
Product: Nc1ncc(Sc2ccc([N+](=O)[O-])cc2)s1
Yield: 75.8 %

Procedure:
A mixture of 2-acetylamino-5-(4-nitrophenylthio)thiazole (4.0 g) in a mixture of acetic acid (30 ml) and aqueous 6N hydrochloric acid (9 ml) was refluxed for 3 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8.5 using aqueous sodium bicarbonate. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-amino-5-(4-nitrophenylthio)thiazole (2.6 g, yield: 76.5%). mp: 162°-164° C.