Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[CH:12](OCC)=[O:13].O>C(OCC)C>[OH:13]/[CH:12]=[CH:9]/[C:8](=[O:10])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC=O
Reactant: CC(=O)Cc1ccccc1
Agent: [Na]
Solvent: O
Solvent: CCOCC
Product: O=C(/C=C/O)Cc1ccccc1
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of 1-phenylpropan-2-one (1.78 g, 13 mmol) in anhydrous diethyl ether (50 ml) containing sodium cut in small pieces (299 mg, 13 mmol), ethyl formate (1.4 g, 20 mmol) was added slowly with stirring and ice-cooling. After standing overnight at rt, water was added, and the ether layer was washed with water. The organic phase was dried, concentrated, and purified by flash column chromatography (PE/EtOAc=10:1) to give the title compound (1.2 g, 57%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([Mg]Cl)(C)C.[Li]CCCC.[CH3:35][S:36]SC>C1COCC1>[CH3:18][C:15]1[CH:14]=[C:13]([C:6]2[C:7](=[O:12])[NH:8][C:9]3[C:4]([C:5]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:3][C:2]([S:36][CH3:35])=[CH:11][CH:10]=3)[O:17][N:16]=1
Reactant: Cc1cc(-c2c(-c3ccccc3)c3cc(Br)ccc3[nH]c2=O)on1
Reactant: CSSC
Agent: CC(C)[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc2[nH]c(=O)c(-c3cc(C)no3)c(-c3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A flask was charged with 6-bromo-3-(3-methyl-isoxazol-5-yl)-4-phenyl-1H-quinolin-2-one (30 mg, 0.079 mmol)(example 39), 1 mL of THF and cooled to 0° C. A 2M solution of i-PrMgCl in THF (0.39 mL, 0.077 mmol) was added and the reaction stirred for 5 minutes at 0° C. and then cooled to −78° C. and a 2M solution of n-BuLi in hexanes (0.06 mL, 0.12 mmol) was added. After stirring for 15 minutes dimethyldisulfide (15 mg, 0.16 mmol) was added and the reaction allowed to attain RT and stirred for 30 minutes. The reaction was diluted with EtAc (10 mL) and washed with brine (2×10 mL). The organic layer was concentrated and the title product (14 mg, 50%) eluted from a 5 g SPE with 50% EtOAc/hexanes. 1H NMR (400 MHz, CD3OD) δ 7.54 (dd, 1H), 7.48 (m, 3H), 7.48 (d, 1H), 7.24 (m, 2H), 7.06 (d, 1H), 6.36 (s, 1H), 2.34 (s,3H), 2.24 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C20H16N2O2S 348.1, found 349.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:37]([CH3:39])[CH3:38])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34](O)=O)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.[C:46]([C:50]1[CH:51]=[C:52]([NH2:57])[C:53]([NH2:56])=[CH:54][CH:55]=1)([CH3:49])([CH3:48])[CH3:47].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:46]([C:50]1[CH:55]=[CH:54][C:53]2[NH:56][C:34]([CH2:33][CH2:32][CH:30]3[CH2:31][CH:28]([N:27]([CH2:26][C@@H:18]4[C@H:19]5[O:23][C:22]([CH3:24])([CH3:25])[O:21][C@H:20]5[C@H:16]([N:13]5[C:9]6[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]7[CH:40]=[CH:41][C:42]([O:44][CH3:45])=[CH:43][C:3]=7[O:2][CH3:1])[C:8]=6[CH:15]=[CH:14]5)[CH2:17]4)[CH:37]([CH3:38])[CH3:39])[CH2:29]3)=[N:57][C:52]=2[CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanoic acid (490 mg, 0.79 mmol) and 4-tert-butylbenzene-1,2-diamine (155 mg, 0.946 mmol) in N,N-Dimethylformamide (8.1 ml) was treated with N,N-Diisopropylethylamine (0.453 ml, 2.60 mmol) dropwise followed by N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (449 mg, 1.18 mmol) in one portion. The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated under high vacuum and the residue was partitioned between 50 ml EtOAc and 50 ml 1/1 H2O/sat NaHCO3. The aqueous phase was extracted with 30 ml EtOAc and the combined organic phase was washed with 30 ml portions of H2O and brine. The organic phase was dried over Na2SO4, filtered and concentrated to give a glass/stiff foam. The crude material was purified by flash chromatography (SiO2, eluting with 4% 7N N NH3 in CH3OH/CH2Cl2) to give the desired intermediate as a mixture of amide regioisomers (400 mg). A solution of intermediate (0.40 g) in Acetic acid (15 ml) was heated at 65° C. for 2.5 h, the reaction mixture was cooled and placed under high vacuum to remove the acetic acid. The residue was taken up in 60 ml CH2Cl2 and washed with 40 ml portions of sat NaHCO3 and 2% Na2CO3 solution. The organic phase was dried over Na2SO4, filtered and concentrated to yield a glass/stiff foam. The material was placed on high vacuum and used directly in the next step (380 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].C1C(=O)N([Br:19])C(=O)C1>CN(C=O)C>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Br:19])=[C:4]([CH:3]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)cc1N
Solvent: CN(C)C=O
Product: Cc1cc(Br)c(C(=O)O)cc1N
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a cooled solution (5° C.) of 3-amino-4-methylbenzoic acid (3.02 g, 20 mmol) in DMF (20 mL) was added NBS (3.38 g, 19 mmol) in small portions at such a rate that the reaction mixture temperature was kept below 15° C. After being stirred for one hour, the reaction mixture was poured onto ice water (100 mL) with stirring. The solid formed was collected by filtration, and the filter cake was washed with ice water (3×100 mL) and then dried at 60° C. under high vacuum to give 5-amino-2-bromo-4-methylbenzoic acid (3.55 g, yield 77.5%) as a pink solid. MS: m/z=230.0 (M+1, ESI+).
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:24])=[CH:5][C:6]([CH3:23])=[C:7]([CH:22]=1)[C:8]([N:10]1[CH2:13][CH:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH2:11]1)=[O:9])=O.[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[N:36]=[CH:35][C:34]([NH2:37])=[C:33]([NH2:38])[CH:32]=2)[CH2:27][CH2:26]1.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:23][C:6]1[CH:5]=[C:4]([CH3:24])[C:3]([C:1]2[NH:37][C:34]3[CH:35]=[N:36][C:31]([N:28]4[CH2:29][CH2:30][O:25][CH2:26][CH2:27]4)=[CH:32][C:33]=3[N:38]=2)=[CH:22][C:7]=1[C:8]([N:10]1[CH2:11][CH:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH2:13]1)=[O:9]
Reactant: Cc1cc(C)c(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1C=O
Reactant: Nc1cnc(N2CCOCC2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c(-c2nc3cc(N4CCOCC4)ncc3[nH]2)cc1C(=O)N1CC(c2ccc(C#N)cc2)C1
Temperature: 70 °C
Reaction time: 72 h
Yield: 38.2 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-(1-(5-formyl-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile (compound 151.4, 159 mg, 0.50 mmol) in ethanol (16 mL). 6-Morpholinopyridine-3,4-diamine (compound 151.2, 194 mg, 1.00 mmol) and NH4OAc (308 mg, 4.00 mmol) were added to the reaction. The reaction mixture was stirred for 3 days at 70° C. under air. The pH of the solution was adjusted to 8-9 with sodium bicarbonate (sat.). The reaction mixture was extracted with 1×100 mL of ethyl acetate. The organic layer was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-010(Waters)): Column, SunFire Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, WATER WITH 0.05% TFA and CH3CN (20.0% CH3CN up to 36.0% in 10 min, up to 100.0% in 1 min, down to 20.0% in 2 min); Detector, UV 254 and 220 nm. This resulted in 94.1 mg (38%) of the title compound as a brown solid. m/z (ES+) 493 (M+H)+.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[CH3:12]/[C:13](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:14]\[CH2:15]O>ClCCl>[CH3:12]/[C:13](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:14]\[CH2:15][Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)=CCC/C(C)=C/CO
Solvent: CSC
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a stirred solution of 4.75 g (35.6 mmol) of N-chlorosuccinimide in 180 mL of dichloromethane at -35° C. (internal thermometer) under argon was added 3.3 mL (45.4 mmol) of dimethyl sulfide over 10 minutes. The mixture was allowed to warm to 0° C. for 15 minutes then cooled again to -35° C. A solution of 5.0 g (32.4 mmol) of (E)-3,7-dimethyl-2,6octadien-1-ol (geraniol) in 25 mL of dichloromethane was added dropwise over 10 minutes. After addition, the reaction was allowed to warm gradually to 0° C. over 2 hours. After 1 hour at 0° C., the reaction was quenched with ice-cold water, diluted with 500 mL of hexane, and the organic layer was separated. The hexane extract was washed with water, brine, dried over MgSO4 and evaporated to provide 5.21 g (93%) of title compound in the form of a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]([CH2:23][CH3:24])[C:12]3[C:17]([C:18]=2[C:19]#[N:20])=[CH:16][CH:15]=[C:14]([O:21][CH3:22])[CH:13]=3)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1>[C:19]([C:18]1[C:17]2[C:12](=[CH:13][C:14]([O:21][CH3:22])=[CH:15][CH:16]=2)[N:11]([CH2:23][CH3:24])[C:10]=1[C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:32](=[O:34])[CH3:33])=[CH:3][CH:4]=1)#[N:20]
Reactant: CCn1c(C#Cc2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCn1c(C#Cc2ccc(NC(C)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (95 mg, 0.29 mmol), prepared as described in Example 1H, is dissolved in THF (1.4 mL). Triethylamine (84 μL, 0.6 mmol) is added, followed by dropwise addition of acetyl chloride (44 μL, 0.5 mmol). This is stirred at room temperature for 1 h. The reaction mixture is partitioned between H2O and EtOAc. The organic layer is dried and concentrated. Purification by silica chromatography (9/1, CH2Cl2/EtOAc) yields N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-acetamide (103 mg, 96%) as a yellow solid.
Reaction SMILES: Br[C:2]1[N:3]([CH:18]([CH3:20])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([O-])(=O)C.[Na+].[CH3:26][O:27][N:28]([CH3:33])[C:29](=[O:32])[CH:30]=[CH2:31]>CN(C=O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]([CH:18]([CH3:20])[CH3:19])[C:2]=2/[CH:31]=[CH:30]/[C:29]([N:28]([O:27][CH3:26])[CH3:33])=[O:32])=[CH:12][CH:13]=1
Reactant: CC(C)n1c(Br)c(-c2ccc(F)cc2)c2ccccc21
Reactant: C=CC(=O)N(C)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Reaction time: 0.75 h

Procedure:
2 g (6.02 mmol) of 2-bromo-3-(4-fluorophenyl)-1-isopropyl-1H-indole and 10 ml of DMF are introduced into a 50 ml three-necked round-bottomed flask, which has been purged with nitrogen and is equipped with a magnetic stirrer, thermometer, reflux condenser, gas inlet tube and nitrogen delivery line, and degassing is carried out for 45 min. by introducing nitrogen. 24 mg (1.0 mol %) of the catalyst K4 from WO-A-99/47474 and 0.539 g (6.59 mmol) of sodium acetate are then added and degassing is carried out for a further 15 min. 1.08 g (8.43 mmol) of N-methoxy-N-methylacrylamide (prepared analogously to a procedure of S. Nahm, Tetrahedron Letters 22, 3815 (1981)) are subsequently added and the suspension is heated at reflux for 1.75 hours. A further 0.5 g (4.34 mmol) of N-methoxy-N-methylacrylamide is added and refluxing is carried out for 1.5 hours. Cooling is then carried out followed by dilution with 50 ml of water and extraction three times with 50 ml of ethyl acetate. The combined organic phases are washed three times with 50 ml of water, dried over magnesium sulfate, filtered and concentrated by evaporation. Purification by means of flash chromatography (hexane/ethyl acetate=2:1) yields a yellow solid that is pure according to NMR. Recrystallisation from 94% ethanol yields slightly yellow crystals having a melting point of from 123 to 124° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:19]2[CH:20]=[C:21]([CH:24]=[C:25]([F:27])[CH:26]=2)[C:22]#[N:23])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]12[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([O-])=O.[Sn].CCOCC>C(O)(=O)C.Cl>[NH2:1][C:4]1[CH:5]=[C:6]([C:19]2[CH:20]=[C:21]([CH:24]=[C:25]([F:27])[CH:26]=2)[C:22]#[N:23])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]12[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: N#Cc1cc(F)cc(-c2cc([N+](=O)[O-])c3c(c2)C2(CCCCC2)C(=O)N3)c1
Agent: Cl
Agent: [Sn]
Solvent: CCOCC
Solvent: CC(=O)O
Product: N#Cc1cc(F)cc(-c2cc(N)c3c(c2)C2(CCCCC2)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a solution of 3-(7′-nitro-1′,2′-dihydro-2′-oxospiro-[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile (1.0 eq, 0.16 g, 0.4 mmol) in glacial acetic acid (4 mL) at room temperature was added a solution of tin II chloride dihydrate (0.25 g, 1.1 mmol) in hydrochloric acid (2 mL). The yellow mixture was boiled for 30 min at which point the yellow color disappeared. After cooling to room temperature, 1 N HCl (10 mL) and ether (20 mL) were added. The layers were separated and the aqueous phase was extracted with ether (2×20 mL). The organic layers were combined, washed sequentially with water (2×20 mL), saturated aqueous NaHCO3 (20 mL), and brine (20 mL). The solution was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 40% EtOAc/hexane) to give the title compound (70 mg, 50%) as an oil which crystallized upon addition of 10% EtOAc/hexanes, mp 241-3° C. 1H NMR (DMSO-d6; 400 MHz) δ 1.50-1.75 (m, 8H), 1.82-1.95(m, 2H), 4.98 (s, 2H), 6.90 (d, 1H, J=Hz), 7.09 (d, 1H, J=1.5 Hz), 7.75 (m, 2H), 7.90 (‘s’, 1H), 9.96 (bs, 1H). MS ((+)-APCI) m/z 336 [(M+H)+]. Anal. Calcd for C20H18FN3O: C, 71.63; H, 5.41; N, 12.18. Found: C, 71.16; H, 5.58; N, 12.18.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:14][O:15]C(Cl)Cl>C(Cl)Cl.C[N+]([O-])=O>[CH:14]([C:4]1[CH:3]=[C:2]([C:6]([O:8][CH3:9])=[O:7])[NH:1][CH:5]=1)=[O:15]
Reactant: COC(=O)c1ccc[nH]1
Reactant: COC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: COC(=O)c1cc(C=O)c[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
To a solution of 2 (4.50 g, 36.0 mmol) in CH2Cl2:CH3NO2 (1:1, 40 mL) at −40° C., was added AlCl3 (12.48 g, 93.6 mmol) followed by α,α-dichloromethyl methyl ether (4.15 mL, 46.8 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was slowly poured onto ice (10.00 g) and allowed to warm to room temperature. The aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated to give 3 as a dark brown solid (3.40 g, 62%). 1H NMR (400 MHz, CDCl3) δ 10.32 (bs, 1H), 9.83 (s, 1H), 7.59 (d, J=1.6 Hz, 1H), 7.30 (s, 1H), and 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 186.07, 161.71, 129.15, 127.71, 124.99, 114.56, and 52.34.
Reaction SMILES: [F:1][C:2]1[C:11]([O:12][CH:13]([F:15])[F:14])=[C:10]2[C:5]([C:6]([OH:21])=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](I)[CH3:29]>CN(C)C=O>[CH2:28]([N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[C:11]=2[O:12][CH:13]([F:14])[F:15])[C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8]1)[CH3:29]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2c(OC(F)F)c(F)ccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2c(OC(F)F)c(F)ccc2c1=O
Temperature: 100 °C
Reaction time: 14 h
Yield: 33.4 %

Procedure:
In 96 ml of N,N-dimethylformamide was dissolved 3.0 g (0.01 mole) of ethyl 7-fluoro-8-difluoromethoxy-4-hydroxyquinoline-3-carboxylate obtained as described above, and 6.9 g (0.05 mole) of potassium carbonate and 12.5 g (0.08 mole) of ethyl iodide were added thereto. The mixture was stirred at 100° C. for 14 hours. After completion of the reaction, the solvent was removed under reduced pressure, and water was added to the residue. Crystals precipitated were collected by filtration and applied to silica gel column chromatography (the eluent used was a mixture of chloroform:methanol=95:5) to obtain 1.1 g of ethyl 1-ethyl-7-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:10]1[CH2:20][C:18](=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1>C1COCC1.CCOCC>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:18][CH2:20][CH:10]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(Br)c1
Reactant: O=C1CCCc2ccccc21
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cccc(C2=CCCc3ccccc32)c1
Reaction time: 8 h

Procedure:
A solution of the Grignard reagent derived from 50 g (0.27 mol) of 3-bromoanisole in 200 ml of dry THF was treated with a solution of alpha-tetralone in 100 ml of THF added over 1 hour while maintaining the internal temperature at 15°-25° C. After stirring overnight, the mixture was diluted with 500 ml of ether and quenched with 200 ml of 20% aqueous ammonium chloride. The aqueous layer was extracted with 200 ml of ether. The combined organic layers were dried over MgSO4 and evaporated to 66.5 g of the oily alcohol. This was dissolved in 450 ml of dry toluene containing 0.020 g of p-toluenesulfonic acid and refluxed overnight in a Dean-Stark apparatus. After cooling, the mixture was washed with 100 ml of 5% sodium bicarbonate, with 100 ml of water, and then with 100 ml of brine. The mixture was dried over MgSO4 and evaporated. The residue was distilled under reduced pressure to give the title compound, b.p. (0.5 mm) 158°-162° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.[C:19](C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.CI>C(Cl)Cl.C(S([O-])(=O)=O)(F)(F)F.[Ag+]>[CH3:19][O:1][CH2:2][C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)n1
Reactant: COC(=O)[C@@H]1C[C@H](CO)CN1C(=O)OC(C)(C)C
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CI
Product: COC[C@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
To a solution of (2S,4S)-1-tert-butyl 2-methyl 4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (2.57 g, 9.9 mmol) in CH2Cl2 (50 mL) was added AgOTf (4.07 g, 15.8 mmol) and 2,6-di-tert-butylpyridine (4.4 mL, 19.8 mmol). The reaction mixture was cooled to 0° C. (external temperature, ice bath) and MeI (0.98 mL, 15.8 mmol) was slowly added. The resulting slurry was stirred at 0° C. for 1.5 h and at room temperature for 1.5 h. The slurry was diluted with CH2Cl2 and filtered through celite. The filtrate was concentrated to dryness, dissolved in Et2O, and washed with HCl (1N) and brine. The aqueous layers were backextracted with Et2O and the combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by silica gel chromatography (10% to 75% to 100% EtOAc/Hexanes) to provide (2S,4S)-1-tert-butyl 2-methyl 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (2.11 g, 78%). 1H-NMR: 400 MHz, (CDCl3) δ: (mixture of rotomers, major reported) 4.20 (t, 1H), 3.71 (s, 3H), 3.67 (m, 1H), 3.34 (m, 2H), 3.30 (s, 3H), 3.16 (t, 1H), 2.43 (m, 2H), 1.74 (m, 1H), 1.38 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([N:10]=[C:11]=[S:12])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1.C1(C)C=CC=CC=1>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:11]([NH:10][C:8](=[O:9])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[S:12])=[C:30]([CH3:35])[CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: Cc1cccc(C(=O)N=C=S)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
Commercially available 3-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (32 mg, yield 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C=O)C.CCOC(C)=O>[CH2:22]([O:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH:21]=[CH2:20]
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1cc(OC)ccc1C(=O)OC
Reaction time: 2 h

Procedure:
To a solution of methyl 4-methoxysalicylate (2.0 g, 11 mmol) in DMF (20 mL) at room temperature was added Cs2CO3 (1.3 eq, 4.7 g) and allyl bromide (1.3 eq, 1.23 mL). After 2 hr, reaction mixture was diluted with EtOAc and washed with water (3×), brine (1×). The organic layer was dried over Na2SO4 and concentrated to provide the product as a pale yellow oil. Product was used without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].C1(C)C=CC=CC=1.[CH2:20](O)[CH2:21][OH:22]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:7]1([C:5]2([CH2:4][CH2:3][CH2:2][Cl:1])[O:22][CH2:21][CH2:20][O:6]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCCO
Reactant: O=C(CCCCl)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: ClCCCC1(c2ccccc2)OCCO1
Reaction time: 3 h
Yield: 121.2 %

Procedure:
A mixture of 36.5 g (0.2 mole) of γ-chlorobutyrophenone, 14 g of ethylene glycol (0.25 mole), 125 ml of toluene, and 0.1 g of p-toluenesulfonic acid is refluxed under a Dean-Stark trap for 1 hr. An additional 4 g of ethylene glycol is added and reflux continued for 3 hrs more. After cooling, the reaction mixture is washed with 5% sodium bicarbonate solution, dried with anhydrous magnesium sulfate, and concentrated. Upon standing at -10° C. overnight, the mixture partially crystallizes. The crystalline product is filtered and washed with petroleum ether to afford 17.7 g of 2-phenyl-2-(3'-chloropropyl)dioxolane, m.p. 56°-58°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][Zn+]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[F:21])[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccccc1C[Zn+]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Agent: [Cl-]
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cc3ccccc3F)cc21

Procedure:
Starting with 6-chloro-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester, the title compound was prepared by using similar methods to those described in Preparation 117 using 2-fluorobenzylzinc chloride instead of benzylzinc chloride. 1H NMR (Me-d3-OD): 8.15 (1H, s), 7.64-7.20 (3H, m), 7.20-7.03 (2H, m), 4.12 (2H, s), 3.74 (2H, s), 1.50 (9H, s), 1.37 (6H, s). MS: [M+H]+=357.