Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([NH2:17])=[O:16])[CH3:2].[O:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[C:4]2[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[S:6][C:5]=2[C:15](=[O:16])[NH:17][C:21]21[CH2:22][CH2:23][O:18][CH2:19][CH2:20]2)[CH3:2]
Reactant: CCNc1cc(-c2ccncc2)sc1C(N)=O
Reactant: O=C1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCN1c2cc(-c3ccncc3)sc2C(=O)NC12CCOCC2
Temperature: 100 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
A mixture of 3-(ethylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.100 g, 0.400 mmol), tetrahydro-4H-pyran-4-one (1.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 3 h at 100° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate/THF (4:1, 100 mL, 50 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 12 g silica gel, dichloromethane to 90:10 dichloromethane/methanol), then triturated with ethyl acetate, and the precipitate was collected by filtration to afford the title compound (0.0715 g, 54%) as a yellow solid:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:21])([CH3:20])[CH2:18][NH2:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3][CH2:2]1.[CH2:27]([N:29]([CH2:32]C)CC)C.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:36].CN.[OH-].[Na+]>ClCCl.C(OCC)(=O)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:20])([CH3:21])[CH2:18][NH:19][C:27]([NH:29][CH3:32])=[O:36])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:2][CH2:3]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)CN)ccc2n1CC1CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)CC
Agent: CN
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNC(=O)NCC(C)(C)S(=O)(=O)c1ccc2c(c1)nc(CC(C)(C)C)n2CC1CC1
Reaction time: 0.5 h
Yield: 16.7 %

Procedure:
To a solution of 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropan-1-amine (Step K of Example 13, 177 mg, 0.469 mmol) and triethylamine (131 μL, 0.938 mmol) in dichloromethane (4 mL) was added p-nitrophenyl chloroformate (104 mg, 0.516 mmol) at room temperature. After stirring for 30 min, methylamine (40% aqueous solution, 3 mL) was added to the mixture and the whole was stirred for 2 h. To the resulting mixture was added ethyl acetate and 2 mol/L sodium hydroxide aqueous solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (ODS, gradient elution with Acetonitrile 10.01% aq. NH3=4:96 to 96:4, by volume; flow rate 40 mL/min) to afford the title compound (34 mg, 17%) as an amorphous.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:12][CH2:13][C:14]#[CH:15])=[N:4][C:5](S(C)=O)=[N:6][C:7]=1[Cl:8].[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[N:17]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Br:1][C:2]1[C:3]([NH:12][CH2:13][C:14]#[CH:15])=[N:4][C:5]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17]2)=[N:6][C:7]=1[Cl:8]
Reactant: C#CCNc1nc(S(C)=O)nc(Cl)c1Br
Reactant: c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: C#CCNc1nc(-n2ncc3ccccc32)nc(Cl)c1Br
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 0.5 g (1.62 mmol) of 5-bromo-6-chloro-2-(methylsulfinyl)-N-(prop-2-ynyl)pyrimidine-4-amine (intermediate 31) in 2 ml of DMSO, 0.19 g (1.62 mmol) indazole and 0.32 g of cesium carbonate were added. The slightly yellow solution was stirred at room temperature for 20 minutes. The reaction mixture was poured onto 10 ml of cold water. The resulting precipitate was filtered, washed with cold water and dried. The desired product was obtained as a white solid 0.31 g (52.8%).
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH:4]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][CH2:2]1.[C:11]1([S:21](Cl)(=[O:23])=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:11]1([S:21]([N:1]2[CH2:10][CH2:9][CH:4]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][CH2:2]2)(=[O:23])=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: COC(=O)C1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)C1CCN(S(=O)(=O)c2cccc3ccccc23)CC1
Reaction time: 8 h
Yield: 73.9 %

Procedure:
Methyl isonipecotate (1.0 g, 6.9 mmol), 1-naphthalenesulfonyl chloride (1.58 g, 6.9 mmol) and DMAP (0.17 g, 1.4 mmol) were dissolved in pyridine (10 mL). After stirring overnight, the reaction mixture was concentrated in vacuo, diluted with water (15 mL) and extracted into methylene chloride (3×10 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting yellow oil was purified by column chromatography on SiO2 eluted with hexanes/ethyl acetate (1:1) to yield 1.7 g (73%)of the title compound as a white foam. 1H NMR (400 MHz, Chloroform-d) δ, ppm: 1.67-1.77 (m, 2 H), 1.93 (dd, J=13.64, 3.79 Hz, 2 H), 2.25-2.34 (m, 1 H), 2.68-2.77 (m, 2 H), 3.63 (s, 3 H), 3.74 (ddd, J=12.51, 3.66, 3.54 Hz, 2 H), 7.56-7.66 (m, 3 H), 7.92 (d, J=9.35 Hz, 1 H), 8.07 (d, J=8.34 Hz, 1 H), 8.21 (d, J=7.33 Hz, 1 H), 8.71 (d, J=8.08 Hz, 1 H); ESI-MS: m/z 334.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[Li]CCCC.CN([CH:20]=[O:21])C.Cl>O1CCCC1.O>[CH:20]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])=[O:21]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)O)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a stirred solution of 3-bromo-4-methylbenzoic acid (2.14 g, 10.00 mmol, 1.00 equiv) in tetrahydrofuran (30 mL) under nitrogen at −78° C. was added n-BuLi (10 mL, 2.5 M in THF, 2.50 equiv) dropwise. After stirring for 1 h below −70° C., DMF (5 mL) was slowly added. The resulting solution was warmed slowly to room temperature and stirred for 1 h. After carefully quenching the reaction by slowly adding 50 mL of water, the pH was adjusted to ˜3-4 using aqueous HCl (6 M). The resulting mixture was extracted with 2×50 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 1.6 g (98%) of the title compound as a yellow solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[C:3]1=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[N:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]1.N(C([O-])=O)=NC([O-])=O>O1CCCC1>[C:53]([O:52][C:50]([N:47]1[CH2:48][CH2:49][N:44]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[O:1][CH:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=3)[C:3]2=[O:17])[CH2:45][CH2:46]1)=[O:51])([CH3:56])([CH3:54])[CH3:55]
Reactant: O=C1C(O)CCN1c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2OC2CCN(c3ccc(C(F)(F)F)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 241 mg (0.983 mmol) 3-hydroxy-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one, 15 mL dry tetrahydrofuran, 645 mg (2.45 mmol) triphenylphosphine, and 328 mg (1.18 mmol) N-(2-hydroxyphenyl)-4-t-butoxycarbonyl-piperazine. A solution of 398 mg (1.97 mmol) disopropyl azodicarboxylate in 10 mL dry tetrahydrofuran was added dropwise over 5 minutes, and the reaction stirred at room temperature overnight. The reaction was quenched with aqueous sodium bicarbonate solution, separated, and the aqueous layer extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated. The residue was chromatographed on silica using hexane/ethyl acetate as eluant to afford 320 mg (64%) of an oil.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Si:7]([O:14][C@H:15]1[C:20](=[CH2:21])[C@H:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:18][C:17](CO)([OH:30])[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>CO.[Cl-].[Na+].O>[Si:7]([O:14][C@H:15]1[C:20](=[CH2:21])[C@H:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:18][C:17](=[O:30])[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(O)(CO)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium periodate saturated water (2.2 mL) was added to a solution of the diol 4 (146 mg, 0.36 mmol) in methanol (9 mL) at 0° C. The solution was stirred at 0° C. for 1 h, poured into brine and extracted with ether and benzene. The organic extracts were combined, washed with brine, dried (MgSO4) and evaporated. An oily residue was dissolved in hexane (1 mL) and applied on a silica Sep-Pak cartridge. Pure 4-methylenecyclohexanone derivative 5 (110 mg, 82%) was eluted with hexane/ethyl acetate (95:5) as a colorless oil: 1H NMR (CDCl3) δ 0.050 and 0.069 (6H and 6H, each s, 4×SiCH3), 0.881 (18H, s, 2×Si-t-Bu), 2.45 (2H, ddd, J=14.2, 6.9, 1.4 Hz), 2.64 (2H, ddd, J=14.2, 4.6, 1.4 Hz), 4.69 (2H, dd, J=6.9,4.6 Hz), 5.16 (2H, s); MS m/z (relative intensity) no M+, 355 (M+-Me, 3), 313 (M+-t-Bu, 100), 73 (76).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][C:26]([O:28]C(C)(C)C)=[O:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26]([OH:28])=[O:27])[C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3cn[nH]c3c2)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3cn[nH]c3c2)cc1

Procedure:
prepared by reaction of 4-tert-butyl-N-(1H-indazol-6-yl)-benzenesulfonamide with tert-butyl bromoacetate
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:6])[CH3:5].O=P[O:9][P:10]=[O:11].[OH2:12]>C(O)(=O)C>[C:4]([NH:3][CH2:2][P:10]([OH:11])(=[O:12])[OH:9])(=[O:6])[CH3:5]
Reactant: CC(=O)NCO
Reactant: O
Reactant: O=POP=O
Solvent: CC(=O)O
Product: CC(=O)NCP(=O)(O)O
Temperature: 5 °C
Yield: 154.4 %

Procedure:
20 g (0.225 mol) of N-hydroxymethylacetamide were dissolved in 20 ml of acetic acid and cooled to 5° C. under a nitrogen atmosphere and with stirring. 12.4 g (0.113 mol) of diphosphorus trioxide (P2O3) were then added dropwise at 5° to 10° C. with stirring during the course of 20 minutes. The mixture was then stirred without cooling until room temperature was reached. It was then heated to reflux for 31/2 hours. It was then cooled. 2 g (0.11 mol) of water were then added dropwise with stirring, the temperature rising to 35° C. After cooling, the acetic acid was removed under reduced pressure and with continuous warming to 95° C. The crystalline residue was digested with ethanol. 26 g of crude acetylaminomethanephosphonic acid having a melting point of 171°-175° C. were obtained. After recrystallization from 88% strength aqueous acetic acid, 19 g (55% of theory) of acetylaminomethanephosphonic acid having a melting point of 186° to 90° C. were obtained. The CHNP elemental analysis of a sample gave:
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(Cl)=[O:11].[CH3:14][O:15][C:16]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].CN(C)C>N1C=CC=CC=1>[CH3:14][O:15][C:16]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:10]([N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])=[O:11]
Reactant: COc1ccc(CN)c(OC)c1OC
Reactant: O=C(Cl)Cl
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: CN(C)C
Solvent: c1ccncc1
Product: COc1ccc(CNC(=O)n2cc(F)c(=O)[nH]c2=O)c(OC)c1OC
Temperature: 5 °C
Reaction time: 2 h

Procedure:
5-Fluorouracil, 3.9 g, was dissolved in 80 ml of pyridine, the solution was cooled to 5° C., and 4 g of phosgene was blown into it. After stirring at 20° C. for 2 hr, the solution was cooled to 5° C., 5.8 g of 2, 3, 4-trimethoxybenzylamine and 3 ml of trimethylamine were gradually added to it, and the temperature was raised to 20° C. in 2 hr. After removing precipitate, pyridine was evaporated from the solution. Hydrochloric acid water and dichloromethane were added to the remainder. The solution was shaked, the dichloromethane layer was evaporated, the residue was recrystallized from methanol, and 4.5 g of 1-(2, 3, 4-trimethoxybenzylcarbamoyl)-5-fluorouracil (melting point: 159° C.) was obtained (Compound No. 7). NMR: 2.74 (6H s CH3) 2.98 (3H s CH3) 4.48 (2H d CH2) 6.7-7.1 (2H m C6H2) 8.42 (H d C6 -H) 9.56 (H s NH).
Reaction SMILES: C=C[C@@H]1[C@@H]2C[C@H]([C@@H:11]([OH:22])[C:12]3C=CN=C4C=CC=CC=34)N(CC2)C1.N1C=CC=CC=1.[CH3:29][NH:30][C:31]([C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:43]([C:45]3[N:46]=[CH:47][N:48]([S:50]([C:53]4[CH:59]=[CH:58][C:56]([CH3:57])=[CH:55][CH:54]=4)(=[O:52])=[O:51])[CH:49]=3)=[O:44])[CH:39]=2)[CH:34]=1)=[O:32].C(O)(=O)[CH2:61][C:62](CC(O)=O)(C(O)=O)[OH:63]>C(OCC)(=O)C>[OH:44][C@@:43]([C:38]1[CH:37]=[CH:36][C:35]2[C:40](=[CH:41][CH:42]=[C:33]([C:31]([NH:30][CH3:29])=[O:32])[CH:34]=2)[CH:39]=1)([C:45]1[N:46]=[CH:47][N:48]([S:50]([C:53]2[CH:54]=[CH:55][C:56]([CH3:57])=[CH:58][CH:59]=2)(=[O:51])=[O:52])[CH:49]=1)[CH2:61][C:62]([O:22][CH2:11][CH3:12])=[O:63]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(S(=O)(=O)c4ccc(C)cc4)cn3)ccc2c1
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccccc12
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C[C@](O)(c1ccc2cc(C(=O)NC)ccc2c1)c1cn(S(=O)(=O)c2ccc(C)cc2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
The Reformatsky reagent was obtained according to the method described in Example 14. The obtained Reformatsky reagent (27.1 mL, corresponding to 2.5 eq.) was cooled to 0° C., cinchonine (2.1 g, 7.2 mmol) and pyridine (1.9 mL, 23.0 mmol) was added thereto, and the mixture was stirred at the same temperature for 30 min. The reaction mixture was cooled to −25° C., N-methyl-6-[(1-tosyl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (2.5 g, 5.76 mmol) was added thereto, and the mixture was stirred at the same temperature for 1 hr. To the obtained reaction mixture was added the Reformatsky reagent (10.9 mL, corresponding to 1.0 eq.) at −25° C., and the mixture was stirred for 1 hr. The Reformatsky reagent (5.4 mL, corresponding to 0.5 eq.) was added again −25° C., and the mixture was stirred for 1 hr. To the obtained reaction mixture were added ethyl acetate (35 mL) and 20 w/v % aqueous citric acid solution (35 mL) at 10° C. or below. The separated organic layer was washed with 10% sodium chloride-containing 20 w/v % aqueous citric acid solution (35 mL) at 5° C. (twice), 5 w/v % aqueous sodium bicarbonate (35 mL) (three times), and water (35 mL). The separated organic layer was concentrated under reduced pressure to give ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-tosyl-1H-imidazol-4-yl)propanoate (2.92 g, 5.6 mmol). yield: 97%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[O:7][CH2:6]2.[OH-:15].[Na+].[O-][Mn](=O)(=O)=O.[K+].[OH2:23]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([OH:23])=[O:15])[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([OH:7])=[O:14]
Reactant: [OH-]
Reactant: O
Reactant: COc1cc2c(cc1OC)C(=O)OC2
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: COc1cc(C(=O)O)c(C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a mixture of 5,6-dimethoxy-3H-isobenzofuran-1-one (4.5 g) and 7% aqueous NaOH (47 ml) was added KMnO4 (4.0 g) diluted in water (125 ml). The mixture was stirred at room temperature for 4 days. Insoluble material was removed by filtration. The filtrate was cooled with ice-water bath and acidified with concentrated HCl. The acidic solution was extracted three times with ethyl acetate (300 ml). The combined organic layers were dried over anhydrous Na2SO4 and evaporated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[C:6]([C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7].OC1C=C(C=CC=1)C(C1C2C=CC=CC=2OC=1C1C=CC=CC=1)=O.[CH2:50]([N:52]([CH2:57][CH3:58])[CH2:53][CH2:54]CCl)[CH3:51]>>[CH2:50]([N:52]([CH2:57][CH3:58])[CH2:53][CH2:54][CH2:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[C:6]([C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:7])[CH3:51]
Reactant: COc1cccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)c1
Reactant: CCN(CC)CCCCl
Agent: O=C(c1cccc(O)c1)c1c(-c2ccccc2)oc2ccccc12
Product: CCN(CC)CCCOc1cccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)c1

Procedure:
Demethylation of 3-(3-methoxybenzoyl)-2-phenylbenzofuran followed by reaction of 3-(3-hydroxybenzoyl)-2-phenylbenzofuran with 3-diethylaminopropyl chloride as described in Example 1 gives the title compound.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:29])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([C:25](=[O:27])[CH3:26])[C@@H:9]([CH3:28])[CH2:8]1)[CH3:3].[CH3:30][NH2:31].C1COCC1.[BH4-].[Na+]>CO>[CH3:3][CH:2]([O:4][C:5](=[O:29])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][NH:31][CH3:30])=[CH:21][CH:22]=3)[CH:15]=2)[N:10]([C:25](=[O:27])[CH3:26])[C@@H:9]([CH3:28])[CH2:8]1)[CH3:1]
Reactant: CC(=O)N1c2ccc(-c3ccc(C=O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Reaction time: 1 h

Procedure:
1-Methylethyl[(2S,4R)-1-acetyl-6-(4-formylphenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 36) (100 mg, 0.254 mmol) was dissolved in methanol (3 mL) and 2M methylamine in THF (0.254 mL, 0.507 mmol) was added. The yellow solution was stirred under nitrogen at room temperature for 135 minutes at which point sodium borohydride (15.35 mg, 0.406 mmol) was added. The reaction was stirred for 1 h then left sitting overnight. The reaction was quenched with sat. aqueous sodium bicarbonate solution (1 mL) and EtOAc (8 mL) was added. A white solid was filtered off (bond elut reservoir) and found to be the desired product (34 mg). The filtrate was partitioned and the organic layer dried. Concentration of the organic layer gave 67 mg of a colourless residue which was applied to a silica 12+S Biotage column and purified eluting with a gradient of 1-5% methanolic ammonia in DCM. Concentration of the product containing fractions gave another batch of the desired product (52 mg).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1.[O:37]1[CH:41]=[CH:40][C:39]([NH2:42])=[N:38]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>Cl.CCOC(C)=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:42][C:39]4[CH:40]=[CH:41][O:37][N:38]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: COc1cc(Br)c(C)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(Br)c(C)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 0.33 h
Yield: 90.8 %

Procedure:
A solution of perfluorophenyl 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (3.508 g, 4.87 mmol), isoxazol-3-amine (0.540 ml, 7.31 mmol) and THF (48.7 ml) was cooled in an ice-bath for 15 min, then lithium bis(trimethylsilyl)amide (1M in THF) (12.18 ml, 12.18 mmol) was added dropwise. After 20 min, additional portions of 3-aminoisoxazole (0.1 mL) and LHMDS solution (2 mL) were added. After 5 min, the mixture was diluted with 1N aq. HCl and EtOAc. The layers were separated, and the organic layer was washed with 1N aq. HCl. The aq. layers were combined and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was concentrated from DCM, and then taken up in DCM. The resulting suspension was sonicated and filtered. The collected solid was washed with DCM (2×), dried under a stream of N2 (g), then dried under vacuum to give 1-(4-bromo-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (2.169 g, 4.42 mmol, 91% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) □=11.66 (br. s., 1 H), 8.72 (d, J=1.8 Hz, 1 H), 8.35 (d, J=2.2 Hz, 1 H), 8.21 (d, J=9.6 Hz, 1 H), 7.83 (dd, J=2.2, 8.9 Hz, 1 H), 7.52 (s, 1 H), 7.34 (d, J=0.4 Hz, 1 H), 6.78 (d, J=9.6 Hz, 2 H), 6.43 (d, J=1.9 Hz, 1 H), 3.67 (s, 3 H); 2.31 (s, 3 H). m/z (ESI) 489.9 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:15]2[C@:6]34[CH2:18][CH2:17][N:16]([CH3:19])[C@@H:14]2[CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([O:20][C@H:5]3[C:4](=[O:21])[CH2:3]1)[C:7]4=2.[C:22]([O-:25])([O-])=O.[K+].[K+].[N:28]#CBr>C(Cl)(Cl)Cl>[C:19]([N:16]1[CH2:17][CH2:18][C@:6]23[C:7]4[C:8]5[O:20][C@H:5]2[C:4](=[O:21])[CH2:3][C@H:2]([CH3:1])[C@H:15]3[C@H:14]1[CH2:13][C:12]=4[CH:11]=[CH:10][C:9]=5[O:25][CH3:22])#[N:28]
Reactant: N#CBr
Reactant: O=C([O-])[O-]
Reactant: C[C@H]1CC(=O)[C@@H]2Oc3cccc4c3[C@@]23CCN(C)[C@H](C4)[C@H]13
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COc1ccc2c3c1O[C@H]1C(=O)C[C@H](C)[C@H]4[C@@H](C2)N(C#N)CC[C@@]341
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a suspension of Compound 7A (9.39 g, 30 mmole; prepared in Example 7A) and powdered anhydrous K2CO3 (6.00 g, 47 mmole) in 60 ml of chloroform was added a solution of cyanogen bromide in chloroform (1.2 eq, 1.0 g/20 ml) dropwise. Stirring was continued for 30 min at about 20° C. after which the mixture was refluxed for 2 hr. After cooling the mixture, the insoluble material therein was removed by filtration. The filtrate was evaporated to a syrup which crystallized upon azeotropic distillation with ethanol. The crystals were boiled with 40 ml of ethanol and collected after storage at 5° C. overnight to give 7.93 g (82% yield) of product, mp 237°-241°.