Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:30])[CH2:16][C:17]2[NH:18][C:19](=[O:29])[CH:20]=[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:22]=2)=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7]>CO>[F:3][C:4]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:30])[CH2:16][C:17]2[NH:18][C:19](=[O:29])[CH:20]=[C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:22]=2)=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.4 %

Procedure:
0.4 ml of 2M sodium hydroxide is added to a solution of 310 mg of methyl 2-fluoro-5-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}-amino)benzoate prepared in Example 57, in 7 ml of methanol. After stirring overnight at ambient temperature, a further 0.4 ml of 2M sodium hydroxide is added and the resulting mixture is brought to reflux for 3 hours. After cooling, the reaction mixture is concentrated under reduced pressure. The evaporation residue is taken up with water. The aqueous phase is extracted with ethyl acetate and then acidified with a 1N aqueous solution of hydrochloric acid (pH=5). The insoluble material is filtered off. The filtrate is concentrated under reduced pressure and then taken up with water and a few drops of a 1N aqueous solution of hydrochloric acid. The precipitate formed is filtered off, rinsed with petroleum ether and concentrated to dryness under reduced pressure. 52 mg of 2-fluoro-5-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}amino)benzoic acid are obtained in the form of a pale pink solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:29])[CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=2[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[N:10][CH2:9][C:8]1=O)[CH2:2][CH3:3].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:31].N1C=CC=CC=1>C(Cl)Cl.O>[CH2:1]([O:4][C:5](=[O:29])[CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=2[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[N:10][CH2:9][C:8]1=[S:31])[CH2:2][CH3:3]
Reactant: CCCOC(=O)CN1C(=O)CN=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCCOC(=O)CN1C(=S)CN=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc21

Procedure:
A mixture of 0.01 mole of 7-nitro-2,3-dihydro-5-(o-chlorophenyl)-2-oxo-1H-1,4-benzodiazepin-1-acetic acid propyl ester, 0.0105 mole of phosphorus pentasulfide and 100 ml. of pyridine is heated under reflux for about 24 hours. The mixture is evaporated and the residue thus obtained is dissolved in methylene chloride-water. The organic layer is separated, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The residue thus obtained is chromatographed on silica gel and eluted to give 7-nitro-2,3-dihydro-5-(o-chlorophenyl)-2-thioxo-1H-1,4-benzodiazepin-1-acetic acid propyl ester.
Reaction SMILES: CI.[C:3](=O)(O)[O-].[Na+].[CH3:8][O:9][C:10]1[CH:26]=[CH:25][C:13]([CH2:14][S:15][C@@H:16]2[CH2:20][NH:19][C@H:18]([C:21](=[O:24])[NH:22][CH3:23])[CH2:17]2)=[CH:12][CH:11]=1.[Cl-].[Na+]>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][S:15][C@@H:16]2[CH2:20][N:19]([CH3:3])[C@H:18]([C:21](=[O:24])[NH:22][CH3:23])[CH2:17]2)=[CH:25][CH:26]=1
Reactant: O=C([O-])O
Reactant: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
244 μl of methyl iodide and 300 mg of sodium bicarbonate were added, whilst ice-cooling, to a solution of 1.00 g of (2S, 4S)-4-(4-methoxybenzylthio)-2-methylcarbamoylpyrrolidine [prepared as described in step (4) above] dissolved in 6 ml of dry dimethylformamide. The mixture was then stirred at 0° to 5° C. for 1 hour and allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel (eluted with a 10:1 by volume mixture of ethyl acetate and methanol), to afford 222 mg of the title compound as colorless crystals, melting at 82°-84° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[CH3:21][C:22]1([CH3:30])[O:26][C@@H:25]([CH2:27][O:28][NH2:29])[CH2:24][O:23]1.CN1CCOCC1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1.O>[CH3:21][C:22]1([CH3:30])[O:26][C@@H:25]([CH2:27][O:28][NH:29][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[C:3]=2[NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])[CH2:24][O:23]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](CONC(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid (39.3 g, 100.0 mmol) in dry tetrahydrofuran (500 mL, 0.2 M), under nitrogen atmosphere, was added (R)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (14.7 g, 100.0 mmol), followed by N-methylmorpholine (27.5 mL, 0.25 mole). The orange-colored solution was cooled with an ice-water bath. Diphenylphosphinic chloride (22.9 mL, 0.12 mole) was added dropwise. Some solid formed. The mixture was warmed to ambient temperature and stirred for 18 hrs. Water was added to quench the reaction and the tetrahydrofuran was evaporated in vacuo. The remaining oil was dissolved in ethyl acetate (500 mL), washed with a mixture of saturated brine and saturated sodium bicarbonate (1:1) two times. The ethyl acetate was removed and the crude oily solid was purified by flash chromatography (silica gel, hexane-acetone/2:1) to give N-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide as an off-white solid after drying in a vacuum oven at 40° C. for 20 hrs: 41.7 g (79.8%), m.p. 124–125° C. The impure fractions were combined and purified by a second column chromatography using the same condition to give a 2nd batch of 6.4 g (12.3%), mp 124–125° C., total yield 48.1 g (92.1%). 1H NMR (d6-DMSO): δ 11.9 (s, br, 1H), 8.7 (s, br, 1H), 7.6 (d, 1H, J=10.99 Hz), 7.4 (m, 2H), 7.2 (m, 1H), 6.7 (m, 1H), 4.2 (m, 1H), 4.0 (t, 1H, J1=8.3 Hz, J2=6.8 Hz), 3.8 (m, 2H), 3.7 (m, 1H), 1.3 (s, 3H), 1.2 (s, 3H); 19F NMR (d6-DMSO): δ−128.0, −133.1, −144.3; MS: 523 (M++1).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:26]1[CH2:36][CH2:35][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27]1.CC(=O)CC>C(OCC)(=O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:26]3[CH2:27][CH2:28][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:35][CH2:36]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2nc(-c3ccc(Cl)cc3)c(CCCOc3ccccc3OC)o2)CC1
Yield: 69.2 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (378 mg), ethyl isonipecotate (1.57 g) and 2-butanone (10 ml) was stirred with heating under reflux for 6 hours. The reaction mixture was diluted with ethyl acetate (100 ml), and the organic layer was washed with a 10% aqueous solution of citric acid (50 ml) and dried over anhydrous magnesium sulfate. After the organic layer was concentrated, the residue was recrystallized from ethyl acetate-hexane to give ethyl N-[4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]-2-oxazolyl]isonipecotate as pale yellow prisms (345 mg, 69%). Melting point 80-81° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[F:11].[BH4-].[Na+].O>CO.Cl[Ni]Cl>[Br:1][C:2]1[C:3]([F:11])=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: O=[N+]([O-])c1cccc(F)c1Br
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1cccc(F)c1Br
Reaction time: 0.08 h
Yield: 63.2 %

Procedure:
To a solution of 2-bromo-1-fluoro-3-nitrobenzene (1.0 g, 5.0 mmol) in CH3OH (50 mL) was added NiCl2 (2.2 g 10 mmol) and NaBH4 (0.50 g 14 mmol) at 0° C. After the addition, the mixture was stirred for 5 min. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL×3). The organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 2-bromo-3-fluoroaniline (600 mg, 70%). NMR (400 MHz, CDCl3) δ 7.07-7.02 (m, 1 H), 6.55-6.49(m, 1 H), 4.22 (br s, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Mg+2].II.C1([C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)O)O.[CH3:25]C(C)=O>>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[NH:6][C:23]([CH3:24])([CH3:25])[CH:22]=[C:21]2[CH3:19]
Reactant: Oc1ccccc1O
Reactant: CC(C)=O
Reactant: Nc1ccc(Br)cc1
Agent: II
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CC1=CC(C)(C)Nc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
4-Bromoaniline (50 g, 0.290 mol), magnesium sulfate (250 g, 2 mol), iodine (2.5 g, 0.01 mol) and catechol (2.24 g, 0.020 mol) were combined in acetone (750 mL) in a sealed-tube reaction flask. The reaction vessel was placed in a pre-equilibrated oil bath set at 125° C. and stirred overnight. The reaction mixture was then cooled to room temperature, filtered over a pad of diatomaceous earth, and concentrated in vacuo. Chromatography on silica gel provided 6-bromo-2,2,4-trimethyl-1,2-dihydroquinoline as tan colored crystals (21 g, 27% yield).
Reaction SMILES: CC1(C)S[C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][C:14]3[CH:15]=CC=C[CH:19]=3)=O)[C:8](=[O:9])N2[C@H]1C([O-])=O.[K+].C[C@@H]1[O:30][C@@H:29]([O:31][C@H]2[C@H](O)[C@@H](O)[C@H](NC(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H:28](O[C@@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2NC)[C@@]1(O)C=O.N[C@H](C(O)=O)CCC(=[O:71])N.C(=O)=O>CS(C)=O>[CH3:15][C:14]([C@@H:13]1[C@H:5]([CH2:28][C:29]([OH:31])=[O:30])[C@@H:7]([C:8]([OH:9])=[O:71])[NH:10][CH2:11]1)=[CH2:19]
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CS(C)=O
Product: C=C(C)[C@H]1CN[C@H](C(=O)O)[C@H]1CC(=O)O
Reaction time: 60 h

Procedure:
Cortical neurons were prepared from embryonic day 18 Sprague-Dawley rats. After the cortices had been removed from the brain, isolated cells were plated onto Poly d-Lysine (PDL) (P0899, Sigma)-coated 48 well plates (150687, NUNC) at a density of 2×105 cell per well using Neurobasal Medium (NB) (21103-049, Gibco) with B27 supplement (17504-044, Gibco), penicillin/streptomycin (15140, Gibco) and 1 mM L-glutamine (25030, Gibco). The cell culture was incubated at 37° C. in a humidified atmosphere of 5% CO2 in air. Medium was changed to growth medium (Neurobasal Medium with penicillin/streptomycin and B27 supplement) after 3 hours. Half medium was changed with growth medium every 2-3 days to maintain the cells until day 10 in vitro (DIV 10). Serial dilutions of samples were prepared in growth medium and DMSO was used as vehicle control. For pre-treating assay, half of the medium was removed from wells, and equal amount of diluted samples were replaced. Cells were then incubated for 2 hours at 37° C. in a humidified atmosphere of 5% CO2 in air. Culture was subsequently rinsed with Locke's solution (5 mM potassium chloride, 128 mM sodium chloride, 2.7 mM calcium chloride, 1 mM di-sodium hydrogen orthophosphate, 5 mM HEPES and 10 mM Glucose in Milli-Q water), then incubated with Locke's solution in the presence of glycine (10 μM) for 15 minutes before N-Methyl-D-Aspartic Acid (NMDA) (M-3262, Sigma) treatment. Kainate dissolved in Locke's plus glycine solution was then substituted and incubated for 20 minutes at 37° C. For co-treated kainate assay, serial dilutions of samples were prepared in Locke's solution plus glycine and kainate solution and incubated for 20 minutes at 37° C., 5% CO2. Afterwards, cells were incubated in growth medium for 18-24 hours and detected with Cytotoxicity Detection Kit (1644793, Roche).
Reaction SMILES: [CH3:1][C:2]1[C:9]([F:10])=[C:8]([F:11])[C:5]([C:6]#[N:7])=[C:4]([F:12])[C:3]=1[F:13].[C:14]([OH:17])(=[O:16])[CH3:15].[H][H]>[Pd].O>[C:14]([O-:17])(=[O:16])[CH3:15].[CH3:1][C:2]1[C:3]([F:13])=[C:4]([F:12])[C:5]([CH2:6][NH3+:7])=[C:8]([F:11])[C:9]=1[F:10]
Reactant: [H][H]
Reactant: Cc1c(F)c(F)c(C#N)c(F)c1F
Reactant: CC(=O)O
Agent: [Pd]
Solvent: O
Product: CC(=O)[O-]
Product: Cc1c(F)c(F)c(C[NH3+])c(F)c1F
Reaction time: 2 h
Yield: 73.8 %

Procedure:
A mixture of 30.0 g 4-methyl-2,3,5,6-tetrafluorobenzonitrile (0.1556 mol), 0.3 g wetting agent (Nopco 8050), 1.40 g palladium on carbon Johnson Matthey type 58 catalyst, 150 g glacial acetic acid and 217 g water was stirred under 5 barg hydrogen pressure. The reaction temperature was allowed to increase from an initial 5° C. to 30° C. over 3 hours, the reaction then being continued for a further 2 hours at which time no further hydrogen was seen to be taken up. The catalyst was removed by filtration and the solid residue washed with dichloromethane. A sample of the aqueous filtrates were evaporated to dryness and further dried under vacuum at 40° C. to give the product 4-methyl-2,3,5,6-tetrafluorobenzylammonium acetate as a white solid, melting point 113-114° C. NMR (200 MHz, D2O); d 1.90 (3H, s), 2.17 (2H, m), 2.24 (3H, t, J=2.2 Hz). This solid was than used as a technical standard to estimate the strength of the remaining solution. The solution was estimated to be 3.84% 4-methyl-2,3,5,6-tetrafluorobenzylamine. This gave an overall yield. based on 583.1 g of filtrates isolated yield of 73.8%. A sample of the free amine was isolated by basification of the reaction mass. NMR (200 MHz, D2O): d 2.08 (2H, m), 2.17 (3H, t, J=2.2 hz), 3.86 (2H, s)
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)CC)C.C([OH:41])C>>[CH2:1]([N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][N:16]([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][C:26]3=[O:41])[CH2:15][CH2:14]2)[N:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClC1CCCCC1
Reactant: O=C1N(Cc2ccccc2)CN(c2ccccc2)C12CCNCC2
Reactant: CCO
Solvent: CCN(CC)CC
Product: O=C1CCCCC1N1CCC2(CC1)C(=O)N(Cc1ccccc1)CN2c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 0.30 g (0.93 mmol) 3-benzyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, 0.14 g (1.0 mmol) 2-chlorocyclohexane, and 0.2 ml (1.4 mmol) triethylamine in ethanol was refluxed overnight. The reaction mixture was cooled to ambient temperature, concentrated and then quenched with saturated NaHCO3 and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated. Purification of the crude product over a silica gel plug (10:1) with n-heptane/AcOEt as eluent provided 0.14 g rac-3-benzyl-8-(2-oxo-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one as a light yellow oil; MS (ISP): 418.4 MH+.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.Br[C:31]1[N:32]=[C:33]([CH3:48])[C:34]([NH:38][CH:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:41][CH2:40]2)=[N:35][C:36]=1[CH3:37].[CH3:49][C:50]1[CH:55]=[C:54]([O:56][CH3:57])[CH:53]=[CH:52][C:51]=1B(O)O>>[CH:39]1([NH:38][C:34]2[C:33]([CH3:48])=[N:32][C:31]([C:51]3[CH:52]=[CH:53][C:54]([O:56][CH3:57])=[CH:55][C:50]=3[CH3:49])=[C:36]([CH3:37])[N:35]=2)[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][CH2:40]1
Reactant: Cc1nc(NC2CCc3ccccc32)c(C)nc1Br
Reactant: COc1ccc(B(O)O)c(C)c1
Agent: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: COc1ccc(-c2nc(C)c(NC3CCc4ccccc43)nc2C)c(C)c1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-N-(2,3-dihydro-1H-inden-1-yl)-3,6-dimethylpyrazin-2-amine and 2-methyl-4-methoxy phenyl boronic acid, and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.92, 2.17, 2.26, 2.39, 2.80, 2.98, 3.07, 3.85, 4.54, 5.82, 6.84, 7.15, 7.30, 7.41; MS (ESI+) for C23H25N3O1 m/z 360.4 (M+H)+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49](B2OC(C)(C)C(C)(C)O2)[C:48]([CH3:61])=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd]Cl.C1(C)C=CC=CC=1.C(O)C.O>[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[C:48]([CH3:61])=[N:47]1
Reactant: COc1cccc(Cn2nc(C)c(B3OC(C)(C)C(C)(C)O3)c2C)c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1cccc(Cn2nc(C)c(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(-c5ccc(N6CCN(C(=O)OC(C)(C)C)CC6)cc5)cc34)c2C)c1
Yield: 17.9 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (250 mg, 0.3 mmol) was coupled with 1-(3-methoxybenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 53) (131 mg, 0.4 mmol) in sodium carbonate (123 mg, 1 mmol), PdCl2 (dppf) (140 mg, 0.18 mmol), Toluene/ethanol/water (2/2/1 ml) to give 40 mg (14% yield) of titled compound. MS: m/z=747.3 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:18]3[C:19]4[C:24]([N:25]=[C:26]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[C:17]3=[N:16][CH:15]=2)=[CH:23][C:22]([C:32]([F:35])([F:34])[F:33])=[CH:21][CH:20]=4)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:9][CH:10]=[C:11]([C:14]2[N:18]3[C:19]4[C:24]([N:25]=[C:26]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[C:17]3=[N:16][CH:15]=2)=[CH:23][C:22]([C:32]([F:34])([F:33])[F:35])=[CH:21][CH:20]=4)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4n23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(C3=CCNCC3)cnc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-[4-(3-hydroxy-propylamino)-7-trifluoromethyl-imidazo[1,2-a]quinoxalin-1-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.10 g; 2.30 mmol; 1 eq) in anhydrous dichloromethane (12 mL) is slowly added trifluoroacetic acid (1.77 mL; 23.0 mmol; 10 eq). The solution is allowed to stir for 6 hours at room temperature until completion of the reaction. The reaction mixture is concentrated and the residual traces of trifluoroacetic acid are removed by co-distillation with toluene (2×10 mL). The red gum is taken up in water (73 mL) and the resulting aqueous solution is washed with ethyl acetate (375 mL) before adjusting the pH to 8 by addition of sodium bicarbonate in powder. This basic aqueous layer is then extracted with ethyl acetate (5×100 mL). The organic extracts are combined, dried over sodium sulfate and concentrated in vacuum. The resulting crude residue is then passed through a silica gel column (ethyl acetate/methanol 8:2 then ethyl acetate/methanol/triethylamine 8:2:0.3) to afford the title compound still contaminated with minor impurities. The powder is then washed with ether to afford the title compound as an off-white solid (170 mg; 0.44 mmol; 19%)
Reaction SMILES: N1C(C)=CC(C)=CC=1C.Cl[C:11]([O:13][CH3:14])=[O:12].[CH3:15][S:16][C:17](=[NH:39])[C:18](=[N:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=1)[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=1[F:29].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:14][O:13][C:11](=[O:12])[N:39]=[C:17]([S:16][CH3:15])[C:18](=[N:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=1)[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=1[F:29]
Reactant: COC(=O)Cl
Reactant: COc1cc(OC)c(F)c(C(=Nc2ccc(C#N)cc2)C(=N)SC)c1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(OC)c1F
Temperature: 85 °C
Reaction time: 20 h

Procedure:
After adding 2.97 ml of 2,4,6-collidine and 1.74 ml of methyl chloroformate to a solution of 2.01 g of 2-(4-cyanophenylimino)-2-(2-fluoro-3,5-dimethoxyphenyl)thioacetimidic acid methyl ester in 80 ml of toluene, the mixture was stirred at 85° C. for 20 hours under a nitrogen atmosphere. After cooling the reaction mixture, 400 ml of ethyl acetate and 200 ml of a 2% aqueous sulfuric acid solution were added and the organic layer was washed with 300 ml of water and 300 ml of saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate (3:2)) to give the title compound (1.89 g) as a light yellow solid.
Reaction SMILES: C[Li].Br[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[N:13][N:14]=2)=[CH:6][CH:5]=1.C([Li])CCC.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C>O1CCCC1.O.C(O)(=O)C>[O:11]1[CH:12]=[N:13][N:14]=[C:10]1[C:7]1[CH:8]=[CH:9][C:4]([B:24]([OH:25])[OH:23])=[CH:5][CH:6]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc(-c2nnco2)cc1
Agent: [Li]C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: OB(O)c1ccc(-c2nnco2)cc1
Temperature: -65 °C
Yield: 82 %

Procedure:
A solution of methyllithium (8% w/w in diethoxymethane) (65 ml) was added to a suspension of 2-(4-bromophenyl)-1,3,4-oxadiazole (40 g) in tetrahydrofuran (THF) (415 ml) at −65° C. After an hour a solution of n-butyllithium (2.5M in hexanes) (78 ml) was then added at −65° C. After an hour, triisopropylborate (90 ml)) was then added maintaining the reaction mixture at −65° C. The reaction mixture was held at −65° C. for an hour and then warmed to −20° C. and drowned out into a mixture of acetic acid (28 ml) in water (222 ml). The resultant solid was isolated, washed with THF and water, and dried to yield the title compound (28.96 g@ 95.1% w/w, 82%); 400 MHz NMR Spectrum: (DMSOd6) 8.00 (s, 4H), 8.31 (s, 2H), 9.35 (s, 1H); Mass Spectrum MH+ 191.0628 (calc. using 11-B) Found 191.0633.