Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3]1[CH:7]=[CH:6][CH:5](OC)[O:4]1.[CH2:10]([O:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11].O>[Cl-].[Zn+2].[Cl-].C(O)(=O)C>[CH2:10]([O:12][C:13](=[O:20])[CH:14]([C:5]1[O:4][CH:3]=[CH:7][CH:6]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COC1C=CC(OC)O1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
340 g (2.5 mmol) of zinc chloride were added in one portion to a solution of 217 g (1.67 mol) of 2,5-dimethoxy-2,5-dihydrofuran, 1500 ml (10 mol) of malonic acid diethyl ester, 167 ml of Water and 330 ml of glacial acetic acid. The temperature rose to 35°. The dark solution was stirred at room temperature overnight, poured onto ice, extracted three times with diethyl ether, washed in succession with saturated sodium bicarbonate and sodium chloride solutions, and finally dried. After evaporating the excess malonic acid diethyl ester (70°/13 Pa), the remaining oil was distilled over a Vigreux column, to obtain 109.2 g (29%) of 2-furylmalonic acid diethyl ester (purity 94%), boiling point 100°-110°/39 Pa.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:31])[N:6]([CH3:30])[C:7]2[C:12]([C:13]=1[NH2:14])=[CH:11][C:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[N:8]=2)(=[O:3])[CH3:2].[H-].[Na+].[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>C1COCC1>[C:1]([C:4]1[C:5](=[O:31])[N:6]([CH3:30])[C:7]2[C:12]([C:13]=1[NH:14][C:37](=[O:38])[CH2:36][O:35][CH3:34])=[CH:11][C:10]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)=[C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[N:8]=2)(=[O:3])[CH3:2]
Reactant: COCC(=O)Cl
Reactant: CC(=O)c1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(=O)Nc1c(C(C)=O)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of the product from Example 2 (100 mg) in THF (3 mL), under nitrogen, was treated with sodium hydride (60% in mineral oil) (10 mg). The suspension was stirred for 5 min were upon methoxyacetyl chloride (40 uL) was added. The reaction was allowed to warm to room temperature and was stirred 30 min. The reaction mixture was quenched with aqueous NaHCO3 (saturated) and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluted with 0-30% EtOAc in hexane afforded the title compound. HPLC/MS: 543.8 (M+1), 545.8 (M+3); Rt=4.19 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:16][CH:17]=1)=[O:22]
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2[nH]cc(CCNC(=O)c3ccc(-c4ccccc4)cc3)c2c1
Yield: 63.9 %

Procedure:
N-(2-(5-Methoxy-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was obtained following Method C starting from 2-(5-methoxy-1H-indol-3-yl)ethanamine (0.100 g, 0.515 mmol), biphenyl-4-carbonyl chloride (0.120 g; 0.541 mmol), and triethylamine (0.087 mL; 0.616 mmol) in dichloromethane (5 mL). Flash chromatography on silica gel (eluent with 10% ethyl acetate in dichloromethane) furnished 0.122 g (64%) of N-(2-(5-Methoxy-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[O:8][CH:9]=[CH:10][CH:11]=1.[CH3:12][C:13]1([CH:18]=[O:19])[CH2:17][CH2:16][CH2:15][O:14]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:6][C:7]1[O:8][C:9]([CH:18]([C:13]2([CH3:12])[CH2:17][CH2:16][CH2:15][O:14]2)[OH:19])=[CH:10][CH:11]=1
Reactant: CC1(C=O)CCCO1
Reactant: Cc1ccco1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)C2(C)CCCO2)o1
Temperature: -70 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
24 ml (60 mmol, 1.5 eq) of a 2.5 M solution of n-butyllithium in hexane were added dropwise to a solution of 5.0 g (60 mmol, 1.5 eq) of 2-methylfuran in 100 ml of tetrahydrofuran cooled to −70° C. The reaction medium was stirred and allowed to return to ambient temperature for 2 hours. The reaction medium was cooled to −70° C. and then 6.0 g (40 mmol, 1 eq) of 2-methyltetrahydrofuran-2-carbaldehyde at 77% were added. The reaction medium was stirred at ambient temperature for 3 hours. The reaction medium was treated with a saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, washed with a saturated sodium chloride solution, filtered over magnesium sulfate and evaporated. 5.21 g of (5-methylfuran-2-yl)-(2-methyltetrahydrofuran-2-yl)methanol were obtained. Yield=66%. TLC/SiO2: heptane/EtOAc (60/40), developing with KMnO4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13]C(OCC3C=CC=CC=3)=O)[C:9]2=[O:24])=[CH:4][CH:3]=1>C(O)C.C1CCCCC=1.[OH-].[Pd+2].[OH-]>[NH2:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]1=[O:24]
Reactant: O=C(N[C@@H]1CCN(c2ccc(Cl)cc2)C1=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: N[C@@H]1CCN(c2ccc(Cl)cc2)C1=O

Procedure:
To a solution of N-[(3R)-1-(4-chlorophenyl)-2-oxopyrrolidin-3-yl](phenylmethoxy)carboxamide (0.2 g, 0.58 mmol) in ethanol (10 ml) and cyclohexene (4 ml) was added palladium hydroxide (40 mg). The reaction was refluxed vigorously overnight. Palladium was removed by filtration and the filtrate was concentrated to yield (3R)-3-amino-1-(4-chlorophenyl)pyrrolidin-2-one.
Reaction SMILES: CS(O[CH2:6][C:7]1[O:8][CH:9]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[C:30]3[C:25](=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][CH:22]=2)[C:11](=[O:13])[CH:12]=1)(=O)=O.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>ClCCl>[F:34][C:31]([F:33])([F:32])[C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[N:24]=[CH:23][CH:22]=[C:21]2[O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:10]1[C:11](=[O:13])[CH:12]=[C:7]([CH2:6][N:39]2[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]2)[O:8][CH:9]=1
Reactant: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ccnc3c(C(F)(F)F)cccc23)co1
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(Cc2cc(=O)c(OCCCCCOc3ccnc4c(C(F)(F)F)cccc34)co2)CC1
Temperature: 45 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
Methanesulfonic acid 4-oxo-5-[5-(8-trifluoromethyl-quinolin-4-yloxy)-pentyloxy]-4H-pyran-2-ylmethyl ester 19 (94 mg, 0.187 mmol) was dissolved in dichloromethane (5 mL). 1-Methyl-piperazine (52 μL, 0.47 mmol) was added via syringe. The mixture was stirred at 45° C. for 1 h. CH2Cl2 (75 ml) was added and the solution washed with NaHCO3 10% (3×50 mL) and brine (3×50 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=9:1. 5-(5-(8-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-((4-methylpiperazin-1-yl)methyl)-4H-pyran-4-one EHT 5847 was obtained (13.6 mg, 15% yield) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([NH2:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.C(N(CC)CC)C.Cl>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:1][O:2][C:3](=[O:13])[CH:4]([NH:12][C:17]1[CH:16]=[C:15]([F:14])[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:18]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCCCCC(N)C(=O)OC
Reactant: OB(O)c1cc(F)cc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCCCCC(Nc1cc(F)cc(C(F)(F)F)c1)C(=O)OC
Reaction time: 0.08 h
Yield: 206.9 %

Procedure:
Reaction performed in parallel in 8×50 mL reaction flasks. Copper (II) acetate (270 mg, 1.48 mmol., 1.1 eq.) and 4 Å molecular sieves (700 mg) were charged in 50 mL round bottom flask. Dichloromethane (10 mL, previously saturated with air) was added a single portion. 2-amino-non-8-enoic acid methyl ester (250 mg, 1.35 mmol., 1.0 eq.) was added and the reaction mixture was stirred for a further 5 min by when the initial light blue solution had turned dark blue. 3-fluoro-5-trifluoromethylbenzene boronic acid (560 mg, 2.70 mmol., 2 eq.) was added followed by triethylamine (218 mg, 2.70 mmol., 2 eq.). The reaction mixture was stirred over night under an air atmosphere. The 8 reaction mixtures were combined together and 1M hydrochloric acid (150 mL) was added. The mixture was stirred for a further 5 min until the aqueous layer turned pale blue and the organic layer turned pale yellow. The organic layer was collected, dried over sodium sulfate and the solvent removed under vacuum. The residue was purified by flash column chromatography, using a dichloromethane:heptanes gradient (from neat heptane to 50% dichloromethane in heptanes). After combining the relevant fractions and solvent removal, 970 mg (26%) of the title compound was isolated as a yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 6.66 (d, J=8.54 Hz, 1 H), 6.61 (s, 1 H), 6.42 (d, J=10.83 Hz, 1 H), 5.72-5.87 (m, J=6.71, 6.71, 10.26, 17.05 Hz, 1 H), 5.00 (dd, J=1.83, 17.09 Hz, 1 H), 4.95 (dt, J=0.95, 10.15 Hz, 1 H), 4.48 (d, J=8.54 Hz, 1 H), 4.05 (dt, J=6.45, 8.32 Hz, 1 H), 3.76 (s, 3H), 2.05 (q, J=6.92 Hz, 2 H), 1.82-1.93 (m, 1 H), 1.71-1.82 (m, 1 H), 1.30-1.45 (m, 6 H). LC-MS: purity 94% (UV), tR 2.63 min, m/z [M+H]+ 348.00.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][NH2:16])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>O1CCCC1>[Cl:24][CH2:25][C:26]([NH:16][CH2:15][C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:27]
Reactant: CC1(CN)OCCc2c1[nH]c1ccccc21
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(CNC(=O)CCl)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.5 %

Procedure:
A mixture of 1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indole-1-methanamine(15 g, described in Example 11), triethylamine(7 g), chloroacetyl chloride (7.9 g) and tetrahydrofuran (300 ml) is stirred at 0° C. for 5 minutes and at 25° C. for 18 hours, filtered and evaporated. The residue is crystallized from chloroform-diethyl ether to obtain the title compound (13.7 g); mp 186°-187° C.; nmr (CDCl3) δ3.41(d), 3.61(d), 3.89(m), 4.09(s), 6.75-7.50(m) and 8.0(t).
Reaction SMILES: [N:1]1[C:10]2[N:9]3[CH2:11][CH2:12][O:13][CH2:14][CH:8]3[CH2:7][NH:6][C:5]=2[CH:4]=[N:3][C:2]=1[C:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[N:17](C(OC(C)(C)C)=O)[CH:16]=1.C(Cl)Cl.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>>[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37].[CH3:25][O:24][C:20]1[CH:19]=[C:18]2[C:23]([C:15]([C:2]3[N:3]=[CH:4][C:5]4[NH:6][CH2:7][CH:8]5[CH2:14][O:13][CH2:12][CH2:11][N:9]5[C:10]=4[N:1]=3)=[CH:16][NH:17]2)=[CH:22][CH:21]=1
Reactant: COc1ccc2c(-c3ncc4c(n3)N3CCOCC3CN4)cn(C(=O)OC(C)(C)C)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(-c3ncc4c(n3)N3CCOCC3CN4)c[nH]c2c1
Yield: 35 %

Procedure:
A solution of tert-Butyl 3-(5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)-6-methoxy-1H-indole-1-carboxylate (97 mg, 0.222 mmol) and CH2Cl2/TFA (1:1, 3 mL) was stirred at room temperature for 30 minutes. The reaction mixture was subsequently concentrated in vacuo and the crude product was purified by LC/MS using a gradient of 20-30% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The pure fractions were combined and lyophilized to give a TFA salt of the title compound as a pale yellow solid (26 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ 2.92-3.03 (m, 1H), 3.33-3.35 (m, 3H), 3.55-3.68 (m, 1H), 3.80 (s, 3H), 3.82-3.88 (m, 1H), 3.94-4.18 (m, 2H), 4.70-4.81 (m, 1H), 6.33-6.46 (br s, 1H), 6.82-6.93 (m, 1H), 6.97-7.08 (m, 1H), 7.36-7.50 (m, 1H), 8.07-8.22 (m, 2H), 11.77-11.94 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C18H19N5O2S, 338.15. found 338.4.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[NH:12][CH:13]=[C:14]([C:16](=O)[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][N:19](C)C)[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:30]N>C(O)C>[CH2:1]([NH:8][C:9]([C:11]1[NH:12][CH:13]=[C:14]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][NH:19][N:30]=2)[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CN(C)C=C(C(=O)c1c[nH]c(C(=O)NCc2ccccc2)c1)c1ccccc1
Solvent: CCO
Solvent: O
Product: O=C(NCc1ccccc1)c1cc(-c2n[nH]cc2-c2ccccc2)c[nH]1
Reaction time: 12 h

Procedure:
To a solution of compound 3 (1 equivalent) in ethanol, at ambient temperature, was added hydrazine hydrate (3 equivalents) and the resulting mixture heated at reflux. After 12 hours, the solvent was evaporated and the crude product purified by preparatory HPLC (reverse phase; 10→90% MeCN in water; 15 minutes) to afford the desired compound II-5. LC/MS (M+1) 343.3, (M−1) 341.2.
Reaction SMILES: CO[C:3]1([O:14]C)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[CH:5]=[CH:4]1.[C:16]1([S:22]([N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([S:22]([N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[C:26]2[C:3]2([OH:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:13])[CH:5]=[CH:4]2)(=[O:24])=[O:23])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC1(OC)C=CC(=O)c2ccccc21
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Product: O=C1C=CC(O)(c2cc3ccccc3n2S(=O)(=O)c2ccccc2)c2ccccc21
Yield: 20 %

Procedure:
The title compound was prepared from 4,4-dimethoxy-4H-naphthalen-1-one and 1-benzenesulfonyl-1H-indole, according to Method E, described above. Yield 20%; mp 175-177° C.; 1H NMR (CDCl3) δ 8.19-8.23 (dd, J=7 Hz, 1H), 8.02-8.05 (dd, J=9 Hz, 1H), 7.80-7.92 (m, 4H), 7.68-7.73 (t, J=7 Hz, 1H), 7.55-7.64 (m, 2H), 7.42-7.48 (t, J=7 Hz, 2H), 7.25-7.32 (m, 3H), 7.14-7.20 (m, 1H), 6.37 (d, J=11 Hz, 1H); 13C NMR (CDCl3) δ 189.7, 153.9, 149.7, 148.9, 143.7, 143.2, 139.0, 137.9, 135.7, 134.2, 133.7, 133.6, 132.4, 131.6, 131.3, 130.8, 129.4, 126.7, 120.5, 74.9; MS (AP+) m/z 416.07 (M++1), 398.06.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1)[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)(=[O:32])=[O:31])=[CH:28][CH:29]=1)=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: CCC(=O)C(Cc1ccc(S(=O)(=O)N2CCOCC2)cc1)C(=O)OC
Reactant: COC(=O)COc1ccc(F)c(N)c1
Solvent: O
Solvent: C1COCCO1
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.22 g), 2-[4-(morpholine-4-sulfonyl)benzyl]-3-oxopentanoic acid methyl ester (0.41 g), polyphosphoric acid (1 g) and dioxane (20 mL) was heated at 130° C. for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate, dichloromethane and methanol (1:4:0 to 1:1:0 to 0:9:1 by volume) to afford title compound, 0.14 g.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[O:10].[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:8]([O:13][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])(=[O:12])[C:9]([CH3:11])=[O:10]
Reactant: CC(=O)C(=O)O
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOC(=O)C(C)=O
Temperature: 25 °C
Yield: 60.1 %

Procedure:
A toluene solution (1 L) containing pyruvic acid (220 g, 2.5 mol), stearyl alcohol (675 g, 2.5 mol) and p-toluenesulfonic acid monohydrate (1.2 g) was heated and refluxed for 16 hours under nitrogen flow. The reaction led to generation of water in the system. However, the water was removed using Dean-Stark trap. The resultant reaction solution was cooled down to room temperature, followed by removal of toluene using an evaporator under a reduced pressure. The residual was then purified using reduced pressure distillation (1 mmHg, 110 to 120° C.) to give stearyl pyruvate (512 g, yield: 80%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)([N:13]1C=CN=C1)=O>C(Cl)Cl>[C:1]1([CH2:7][C:8]([NH2:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1ccccc1
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1
Reaction time: 0.67 h

Procedure:
Using the method of Example 6, a solution of 2.81 g of phenylacetic acid in 200 ml of methylene chloride is treated at 0° C. with 3.35 g of carbonyldiimidazole. The mixture is stirred for 40 minutes. Then 2.86 g (0.0159 mole) of the (±)-amine from Example 1, Part C, above is added. The mixture is stirred for 24 hr and partitioned with saturated aqueous sodium bicarbonate. The organic phase is dried and concentrated to yield the titled (±)-benzeneacetamide product free base which is dissolved in a minimum volume of methanol and treated with one equivalent of maleic acid which has been dissolved in a minimum volume of methanol, and the mixture is diluted with diethyl ether to give the titled maleate salt.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=2[C:12]([OH:14])=O.[CH3:15][C:16]1[N:17]=[CH:18][N:19]([C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])[C:20]=1[CH3:21].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:15][C:16]1[N:17]=[CH:18][N:19]([C:22]2[CH:23]=[C:24]([NH:25][C:12]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[NH:3][C:2]([CH3:1])=[C:10]4[CH3:11])=[O:14])[CH:26]=[CH:27][CH:28]=2)[C:20]=1[CH3:21]
Reactant: Cc1ncn(-c2cccc(N)c2)c1C
Reactant: Cc1[nH]c2c(C(=O)O)cccc2c1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ncn(-c2cccc(NC(=O)c3cccc4c(C)c(C)[nH]c34)c2)c1C
Reaction time: 12 h
Yield: 42.8 %

Procedure:
To a suspension of 2,3-dimethyl-1H-indole-7-carboxylic acid (95 mg) and 3-(4,5-dimethylimidazol-1-yl)aniline (94 mg) in dichloromethane (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (135 mg) and 4-dimethylaminopyridine (31 mg), and the mixture was stirred for 12 hours. The mixture was diluted with dichloromethane and washed with water and brine. The mixture was dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with dichloromethane, and the insoluble material was collected by filtration and dried to give N-[3-(4,5-dimethyl-imidazol-1-yl)-phenyl]-2,3-dimethyl-1H-indole-7-carboxamide (77 mg, 43.0%).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[CH2:8](OC(OCC)OCC)[CH3:9]>C(O)C>[CH2:8]([O:6][C:5](=[O:7])[C@@H:2]([CH2:3][SH:4])[NH2:1])[CH3:9]
Reactant: N[C@H](CS)C(=O)O
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: CCOC(=O)[C@H](N)CS
Temperature: 70 °C
Yield: 109.6 %

Procedure:
To a suspension of D-cysteine 1.5 hydrate hydrochloride (Q-1, Scheme Q where RQ-1 and RQ-1 are equal to hydrogen, RQ-3 is hydrogen and stereochemistry is (S)) (5 g, 27.1 mmol) in absolute ethyl alcohol (50 mL) was added triethylorthoformate (13.5 mL, 81.2 mmol) at ambient temperature. A stream of anhydrous HCl gas was bubbled through the solution for 30 min. The stream of anhydrous HCl gas was maintained as the mixture heated to 70° C. for 2 h. The reaction mixture was concentrated in vacuo and the resulting residue triturated with diethyl ether to afford D-cysteine ethyl ester (4.43 g) as a white solid which was used without further purification. Physical data as follows: 1H NMR (300 MHz, D2O) 4.36 (1H), 4.27 (2H), 3.12 (2H), 1.25 (3H); MS (ESI+) for C5H11NO2S m/z 150.0 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([CH3:23])([CH3:22])[C:15](OC(C)(C)C)=[O:16])=[CH:10][CH:9]=1.CCOC(C)=O>C1COCC1>[F:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([CH3:23])([CH3:22])[CH2:15][OH:16])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)c1ccc(F)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(CO)c1ccc(F)nc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
Lithium aluminum hydride (1.0M in THF) (Aldrich, St. Louis, Mo.; 12.98 mL, 12.98 mmol) was added to a solution of tert-butyl 2-(6-fluoropyridin-3-yl)-2-methylpropanoate (2.07 g, 8.65 mmol) in THF (34 mL) at 0° C. (gas evolution), and the resulting solution was stirred at 0° C. for 5 min. EtOAc (15 mL) was then added at 0° C. to quench excess lithium aluminum hydride, followed by 10% aqueous Na/K tartrate (150 mL). The resulting mixture was stirred at 25° C. for 10 min and then partitioned between EtOAc (200 mL) and water (50 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (150 mL). The combined organic extracts were washed with brine (150 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to provide 2-(6-fluoropyridin-3-yl)-2-methylpropan-1-ol (1.46 g, 8.63 mmol, 100% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.22 (br. s., 1H), 7.78-7.84 (m, 1H), 6.89 (dd, J=8.6, 3.1 Hz, 1H), 3.63 (s, 2H), 1.36 (s, 6H). 19F NMR (377 MHz, CDCl3) δ −72.21 (br. s., 1 F). m/z (ESI, +ve) 170.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:11])=[C:5]([O:40][CH3:41])[CH:4]=1)#[N:2].[OH:42]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:11])=[C:5]([O:40][CH3:41])[CH:4]=1)(=[O:42])[NH2:2]
Reactant: OO
Reactant: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cc(F)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(C(N)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cc(F)cc(Cl)c1
Temperature: 10 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
To the solution of rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-Spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide (0.14 g, 0.2 mmol) prepared in Example 114 in DMSO (1 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.4 g, 3.5 mmol), then aqueous solution (1N) of NaOH (1.2 mL, 1.2 mmol) was added dropwise. The reaction mixture was stirred at 10° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-2-methoxy-phenyl)-amide as a white solid (Yield 0.13 g, 87%)