Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH2:25][C:24]1=[O:43])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:54]([Si](C)(C)C)O[Si](C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C1COCC1>[Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH:25]([OH:54])[C:24]1=[O:43])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)OO[Si](C)(C)C
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)C(O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
(5R,6S)-1-((S)-1-(Tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (1.100 g, 1.744 mmol; Example 185, Step C) was dissolved in THF (8.72 mL) and sparged with argon for 5 minutes. The mixture was cooled to −78° C. and 1.0 M lithium bis(trimethylsilyl)amide solution in THF (2.093 mL, 2.093 mmol) was added dropwise. After 30 minutes, peroxybis(trimethylsilane) (0.413 mL, 1.918 mmol) was added dropwise. After 1 hour, the cooling bath was removed. After stirring overnight, the mixture was quenched with sat. aq. NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4, and concentrated. The residue was dissolved in EtOH (14 mL) and pyridine p-toluenesulfonate (131 mg, 0.523 mmol) was added. After 1 hour, the mixture was basified with sat. aq. NaHCO3 solution. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (40 g column, eluent: 5 to 50% ethylacetate/hexanes) to afford the title compound.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11](C=O)=[CH:10][N:9]=1.C([Mg]Br)=C.[Cl-].[NH4+].[O:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([C@@H:35]([CH2:34][OH:33])[CH:36]=[CH2:37])=[CH:10][N:9]=1
Reactant: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C=O)cc1Cl
Reactant: C1CCOC1
Agent: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: C=C[C@H](CO)c1cnc(N2CCCC2CO)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-5-formyl-4-(3-chloro-4-methoxybenzylamino)pyrimidine (4.1 g) in tetrahydrofuran (30 ml) is added to a solution of vinyl magnesium bromide in tetrahydrofuran (43.5 ml) at 0° C., and the mixture is stirred at 0° C. for 1 hour. To the mixture is added a saturated aqueous ammonium chloride solution, and the mixture is extracted with ethyl acetate. The extract is washed with water and then brine, and dried over sodium sulfate. Sodium sulfate is removed by filtration, and the filtrate is concentrated in vacuo. The residue is purified by column chromatography (silica gel, 100 g; ethyl acetate→ethyl acetate:methanol=20:1, and then silica gel, 50 g; chloroform:methanol=50:1) to give (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-5-(1-hydroxymethyl-2-propen-1-yl)-4-(3-chloro-4-methoxybenzylamino)pyrimidine (2.70 g) as colorless amorphous. MS(APCI): 405 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].C[O:10][C:11](=O)[C:12]([OH:23])([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.[Na]>C1(C)C=CC=CC=1.C(OCC)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:11](=[O:10])[C:12]([OH:23])([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)C(O)(c1cccs1)c1cccs1
Reactant: CN1CCC[C@H]1CO
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CN1CCC[C@H]1COC(=O)C(O)(c1cccs1)c1cccs1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
To a mixture of molecular sieve 4A, ((S)-1-Methyl-pyrrolidin-2-yl)-methanol (3.71 g, 31.2 mmol) and Hydroxy-di-thiophen-2-yl-acetic acid methyl ester (3.96 g, 15.6 mmol) in toluene (40 ml) is added sodium (65 mg) and the suspension is heated under stirring to 80° C. for 3.5 hours. Additional sodium (65 mg) is then added and the reaction mixture stirred at 80° C. for 16 hours. The reaction mixture is cooled to room temperature, diluted with diethylether (100 ml) and extracted with HCl 1 M (2×100 ml). The combined acidic aqueous layers are washed with diethylether (50 ml) and basified with sodium hydroxide 4 M whilst cooling in ice. The solution is then extracted with ethylacetate and diethylether. The combined organic layers are dried over magnesium sulphate, filtered and evaporated to dryness to give the title product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[C:12]([NH:14][C@H:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12]2[O:17][CH2:16][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:24]=[CH:25][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](CO)c1ccccc1)c1cccc(OCc2ccccc2)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(COc2cccc(C3=N[C@H](c4ccccc4)CO3)c2)cc1
Reaction time: 4 h
Yield: 86 %

Procedure:
To a mixture of 2-(3-benzyloxybenzamido)-2(R)-phenylethan-1-ol (29 g, 83 mmol) and triphenylphosphine (28.4 g, 108 mmol) in dry tetrahydrofuran (200 ml) was added dropwise a solution of diisopropyl azodicarboxylate (19.6 ml, 108 mmol) in dry tetrahydrofuran (30 ml). The reaction mixture was stirred for 4 hours and volatiles removed by evaporation. The residue was purified by column chromatography on silica gel eluting with ethyl acetate-hexane (=1:9) to afford 2-(3-benzyloxyphenyl)-4,5-dihydro-4(R)-phenyloxazole (23.5 g, 85%) as pale yellow solids.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][CH2:12][C:13]2([C:17]([OH:19])=O)[CH2:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1>O>[Br:6][C:7]1[CH:8]=[C:9]2[C:10](=[CH:20][CH:21]=1)[O:11][CH2:12][C:13]1([CH2:14][CH2:15][CH2:16]1)[C:17]2=[O:19]
Reactant: O=C(O)C1(COc2ccc(Br)cc2)CCC1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1c2cc(Br)ccc2OCC12CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.8 %

Procedure:
To sulfuric acid (5 mL) was added 1-[(4-bromophenoxy)methyl]cyclobutanecarboxylic acid (1.9 g, 6.6 mmol) at 0° C. in an ice bath. After stirring for 1 hour at room temperature, ice was added to the mixture portionwise. The mixture was diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane:EtOAc=100:0-70:30) to give 6-bromo-4H-spiro[chromene-3,1′-cyclobutan]-4-one (649 mg).
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4]([O-:6])=[O:5].Br[CH:12]([CH2:14][CH2:15][CH3:16])[CH3:13].[Br-].[Na+]>C(O)C>[CH3:13][CH:12]([CH2:14][CH2:15][CH3:16])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCCC(C)Br
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Br-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCCC(C)CC(=O)O
Temperature: 25 °C
Yield: 76.1 %

Procedure:
Sodium metal (42.0 g, 1.827 mol) was dissolved in absolute ethanol (500 ml) under argon atmosphere. Ethyl malonate (289.3 g, 1.806 mol) was added at a stretch to the solution with stirring. Further, 2-bromopentane (262.6 g, 1.738 mol) was added dropwise at first slowly and, after sodium bromide was precipitated, in such a rate that ethanol was slowly refluxed. After 3 hour reflux, the mixture was cooled to room temperature, and 50% aqueous potassium hydroxide solution (510 g) was added dropwise slowly. The mixture was again warmed slowly and refluxed for 4 hours. After distilling off ethanol, concentrated hydrochloric acid (500 ml) was added and the mixture was refluxed for one hour. The reaction mixture was cooled to room temperature, and extracted with ether (500 ml×3). The combined ether layers were washed with brine (200 ml×2) and dried over anhydrous sodium sulfate. After distilling off ether, the residue was heated at 180° C. until carbon dioxide was no longer generated. The resulting residue was distilled under reduced pressure to give dl-3-methylhexanoic acid (172 g, 1.323 mol, 76%, b.p.: 112°-113° C./15 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[N:12]([CH2:14][CH2:15][NH:16][C:17](=O)[CH3:18])[CH:11]=[CH:10][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:20]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[N:12]4[CH2:14][CH2:15][N:16]=[C:17]([CH3:18])[C:11]4=[CH:10][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:20]=1
Reactant: CC(=O)NCCn1ccc2c1-c1ccc(Cl)cc1CC2
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: CC1=NCCn2c1cc1c2-c2ccc(Cl)cc2CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
N-[2-(7-Chloro-4,5-dihydro-1H-benzo[g]indol-1-yl)ethyl]acetamide (2.8 g) was treated with 20 ml of phosphorus oxychloride under argon and the mixture was stirred at 100° C. for 30 minutes. The cooled mixture was added to 1500 g of ice-water and treated with 100 ml of 2N sodium hydroxide solution and 150 ml of 28% sodium hydroxide solution. The mixture was extracted once with 300 ml of methylene chloride and twice with 100 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. The residue (2.6 g) was dissolved in a 20-fold amount of hot ethanol and treated while hot with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 3.3 g (88%) of 3-chloro-5,6,10,11-tetrahydro-8-methylbenzo[g]pyrazino[1,2-a]indole fumarate (1:1); m.pt. 195°-196° C. (dec.).
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2C=C[C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.[S:28]1C=CC=C1C=O>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[S:28][CH:17]=[CH:16][CH:15]=2)[O:6][C:7]=1[CH3:8]
Reactant: O=Cc1cccs1
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: CC(=O)/C(C)=N/O
Product: Cc1oc(-c2cccs2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and thiophene-2-carbaldehyde gave 4-iodomethyl-5-methyl-2-thiophen-2-yloxazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([F:10])=[CH:8][N:9]=1)[CH:5]=[O:6].[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:13][CH2:12][CH2:11][O:6]2)[C:7]([F:10])=[CH:8][N:9]=1
Reactant: OCCO
Reactant: O=Cc1cc(Br)ncc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1cnc(Br)cc1C1OCCO1

Procedure:
A mixture of 2-bromo-5-fluoroisonicotinaldehyde (495 mg, 2.43 mmol), ethylene glycol (0.27 mL, 4.85 mmol) and p-toluenesulfonic acid monohydrate (508 mg, 2.67 mmol) in toluene (13.5 mL) was refluxed for 4 hours. The mixture was concentrated and taken up in CH2Cl2, washed with 1 M NaOH, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (cyclohexane/EtOAc) to give INT 44.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH2:14][OH:15])=[CH:4][CH:3]=1.[C:16](=[O:19])([O-])[O-:17].[Na+].[Na+].ClCCl>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:16]([O:17][C:5]([CH3:8])([CH3:6])[CH3:4])=[O:19])[CH2:10][C@H:9]2[CH2:14][OH:15])=[CH:4][CH:3]=1
Reactant: OC[C@@H]1CNCC[C@H]1c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@H](CO)C1
Reaction time: 0.5 h
Yield: 184.7 %

Procedure:
To a mixture of [(3S,4R)-4-(4-fluorophenyl)piperidine-3-yl]methanol (3.0 g, 14 mmol), sodium carbonate (6.1 g, 57 mmol), dichloromethane (40 mL) and water (40 mL) was added di-tert-butyl Bicarbonate (3.8 g, 17 mmol) under ice cooling, followed by stirring at the same temperature for 30 minutes. The reaction mixture was added to a mixed solution of dichloromethane and water, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:1) to give the title compound (4.0 g, 90% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][CH:20]=O)[C:11](=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[C:28]2[CH:29]=[CH:30][C:31]([CH2:33][N:34]([CH:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:32][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCl>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][CH2:20][N:45]2[CH2:46][CH2:47][CH:42]([N:34]([CH2:33][C:31]3[CH:30]=[CH:29][C:28]4[O:23][CH2:24][CH2:25][O:26][C:27]=4[CH:32]=3)[C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:43][CH2:44]2)[C:11](=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCn1c(=O)cc(OCc2ccccc2)c2ccccc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(OCc3ccccc3)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To 30 mL of a dichloromethane solution containing 1.20 g of (4-benzyloxy-2-oxoquinolin-1(2H)-yl)acetaldehyde, 40 mL of a dichloromethane solution containing 1.71 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 0.25 g of acetic acid were added, and stirred at room temperature for 90 min. To the reaction mixture, 1.37 g of sodium triacetoxyborohydride was added, and stirred at the same temperature for 2.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:1], to give 2.10 g of tert-butyl (1-(2-(4-benzyloxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate as a white solid.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:43]([O:47][CH2:48][CH3:49])(=[O:46])[CH:44]=[CH2:45]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:8][C:2]=1/[CH:45]=[CH:44]/[C:43]([O:47][CH2:48][CH3:49])=[O:46]
Reactant: C=CC(=O)OCC
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc(OC(F)(F)F)ccc1N
Temperature: 120 °C

Procedure:
To a mixture of 2-bromo-4-(trifluoromethoxy)aniline (1.00 mmol), triethylamine (1.5 mmol) and P(o-tol)3 (0.40 mmol) in DMF (0.5 M) in a glass pressure tube under nitrogen gas were added ethyl acrylate (1.0 mmol) and palladium acetate (0.20 mmol). The tube was sealed and heated to 120° C. for 18 h. The resulting solution was concentrated under vacuum and purified by column chromatography. Retention time (min)=2.467, method [1], MS (ESI) 276.1 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=1.BrB(Br)Br>>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:18]=[CH:19][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:21][CH:22]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(NS(C)(=O)=O)cc1
Agent: BrB(Br)Br
Product: CS(=O)(=O)Nc1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 9.8 %

Procedure:
Following General Procedure F, N-[4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl]methanesulfonamide (40 mg, 0.10 mmol) was reacted with tribromoborane (3.0 mL) to afford the desired product (3.8 mg, 10%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 7.61 (d, J=5.4 Hz, 1H), 7.44-7.43 (m, 2H), 7.39 (d, J=5.4 Hz, 1H), 7.29-7.27 (m, 2H), 7.16 (d, J=8.4 Hz, 1H), 6.12 (d, J=5.0 Hz, 1H), 3.09 (s, 3); ESI MS m/z 387 [C18H14N2O4S2+H]+; HPLC >99%, tR=9.69 min.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]#[C:13][C:14]1[C:15]([O:51][CH2:52][CH2:53][CH2:54][S:55]([OH:58])(=[O:57])=[O:56])=[C:16]([C:21]([O:43][CH2:44][CH2:45][CH2:46][S:47]([OH:50])(=[O:49])=[O:48])=[C:22]([C:32]#[C:33][CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:23]=1[O:24][CH2:25][CH2:26][CH2:27][S:28]([OH:31])(=[O:30])=[O:29])[C:17]([O:19]C)=[O:18])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O>[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]#[C:13][C:14]1[C:15]([O:51][CH2:52][CH2:53][CH2:54][S:55]([OH:58])(=[O:57])=[O:56])=[C:16]([C:21]([O:43][CH2:44][CH2:45][CH2:46][S:47]([OH:50])(=[O:49])=[O:48])=[C:22]([C:32]#[C:33][CH2:34][NH:35][C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[C:23]=1[O:24][CH2:25][CH2:26][CH2:27][S:28]([OH:31])(=[O:29])=[O:30])[C:17]([OH:19])=[O:18])=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: COC(=O)c1c(OCCCS(=O)(=O)O)c(C#CCNC(=O)OC(C)(C)C)c(OCCCS(=O)(=O)O)c(C#CCNC(=O)OC(C)(C)C)c1OCCCS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)NCC#Cc1c(OCCCS(=O)(=O)O)c(C#CCNC(=O)OC(C)(C)C)c(OCCCS(=O)(=O)O)c(C(=O)O)c1OCCCS(=O)(=O)O
Temperature: 55 °C
Yield: 91 %

Procedure:
Aq. KOH solution (1 M, 793 μl, 0.793 mmol, 5.00 eq) was added to a solution of 8d (184 mg, 0.159 mmol, 1.00 eq) in water (1.00 ml) and the mixture was heated to 55° C. for 15 h. The product was purified by reverse phase HPLC (Waters Xterra C18 RP 30×100 column, 0-27% AcN in 0.1 M TEAB, Akta Purifier) to give 8f (122 mg, 67% yield). LCMS: Calculated Mass 842.2, Observed Mass 841.1 (M−).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:19])=[O:18]
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccccc1OCc1ccccc1
Yield: 96.9 %

Procedure:
2-(Benzyloxy)phenol (3.00 g, 14.98 mmol) was dissolved in dry DCM (70 mL) under nitrogen atmosphere and cooled on an ice-water bath. Methanesulfonyl chloride (2.06 g, 17.98 mmol) was added during stirring followed by TEA (2.27 g, 22.47 mmol). The reaction mixture was stirred at rt for 2 h and then washed with aqueous saturated NaHCO3, dried (MgSO4), filtered and evaporated affording the title compound (4.04 g, 96.9%). 1H NMR (500 MHz, CDCl3): δ 3.09 (s, 3H), 5.15 (s, 2H), 7.02 (dt, 1H), 7.09 (dd, 1H), 7.27 (dt, 1H), 7.34-7.48 (m, 6H); 13C NMR (125 MHz, CDCl3): δ 38.72, 71.37, 114.67, 121.79, 125.06, 127.95, 128.50, 128.68, 129.00, 136.20, 138.96, 150.91.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH:16]([CH3:18])[CH3:17])[CH:14]=O)=[O:11])([CH3:8])([CH3:7])[CH3:6].Cl.[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:24]>CO.C(O)(=O)C>[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:24][CH2:14][C@@H:13]([NH:12][C:10]([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
Sodium cyanoborohydride (2.0 g, 0.03 mole) was added portionwise (one hour) to a solution of the known compound 2(S)-t-butoxycarbonylamino-3-methylbutyraldehyde (5.8 g, 0.029 mole) and phenylalanine methyl ester hydrochloride (6.1 g, 0.028 mole) in methanol (150 ml) and acetic acid (1.5 ml). The clear reaction mixture was stirred at room temperature under argon for 2 hours and concentrated in vacuo. The residue was cooled in an ice bath, neutralized with saturated NaHCO3 and extracted (3×) with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated to give a pale yellow residue, which was purified by column chromatography on silica gel using 20% ethyl acetate-hexane. The title compound (8.4 g) was obtained as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Pt]>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][CH:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:11][CH:10]1[OH:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1Cc2ccccc2CC1O
Agent: [Pt]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CC2CCCCC2CC1O
Yield: 85.2 %

Procedure:
A solution of 3-tert-butoxycarbonylamino-1,2,3,4-tetrahydro-2-naphthalenol (1.05 g) in acetic acid (100 ml) was hydrogenated over platinum oxyde (121 mg) under pressure (5.5.6 bars) at room temperature for 3 days. The catalyst was filtered and the solvent was evaporated under vacuum. The residue was purified by chromatography on silica gel [140 g, elution with ethyl acetate:cyclohexane, 2:8 (0.7 1) and 5:7 (1 1)] to afford the title compound as an oil (915 mg).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.[CH:9]([C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[C:13]=1[NH2:14])([CH3:11])[CH3:10].C(O)=O>CO>[CH:9]([C:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:19]([CH3:21])[CH3:20])[C:2]=1[NH:14][C:13]1/[C:15](=[N:14]/[C:13]2[C:12]([CH:9]([CH3:11])[CH3:10])=[CH:18][CH:17]=[CH:16][C:15]=2[CH:19]([CH3:21])[CH3:20])/[CH2:16][CH2:17][CH2:18][CH:12]=1)([CH3:10])[CH3:11]
Reactant: O=C1CCCCC1=O
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: O=CO
Solvent: CO
Product: CC(C)c1cccc(C(C)C)c1/N=C1\CCCC=C1Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 51.8 %

Procedure:
Synthesis based on literature procedure (Gates, D. P.; Svejda, S. A. Onate, E.; Killian, C. M.; Johnson, L. K.; White, P. S.; Brookhart M. Macromolecules, 2000; 33:2320-2334.). Cyclohexane-1,2-dione (2.062 g, 18.39 mmol) and 2,6-diisopropylaniline (6.52 g, 36.78 mmol) are dissolved in 70 mL of methanol. To this solution is added 1 mL of formic acid and the mixture is stirred for 3 days at room temperature. Precipitated white crystalline solid is collected on the frit, washed with methanol (2×15 mL) and dried under reduced pressure to give 4.1 g (51.8% yield) of title compound of Preparation 1.