Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C@H:11]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([F:36])[C:33]=1[CH:34]=O)[C:28]([OH:30])=[O:29].C(O)(=O)C>CO>[C:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][O:16][C@H:11]([CH2:10][N:9]2[C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[N:1]=[C:34]2[C:33]2[C:32]([F:36])=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=2[F:24])[CH2:12]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ccc(NC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)c(N)c1
Reactant: O=Cc1c(F)cc(C(=O)O)cc1F
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc2c(c1)nc(-c1c(F)cc(C(=O)O)cc1F)n2C[C@@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.3 %

Procedure:
A mixture of (R)-tert-butyl 2-((2-amino-4-methylphenylamino)methyl)morpholine-4-carboxylate (600 mg, 1.87 mmol), 3,5-difluoro-4-formylbenzoic acid (347 mg, 1.87 mmol) and acetic acid (0.534 ml, 9.33 mmol) in methanol (15.0 ml) was stirred for 1.5 hr at room temperature. The mixture was then concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography, eluting with mixtures of EtOAc and heptane, to afford (R)-4-(1-((4-(tert-butoxycarbonyl)morpholin-2-yl)methyl)-5-methyl-1H-benzo[d]imidazol-2-yl)-3,5-difluorobenzoic acid (750 mg, 82%) as an oil. The oil was analyzed on analytical HPLC MS using the high pH gradient method (mobile phase: 5-95% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v; B: CH3CN; 2.25 min run; X-Bridge C18; column size: 2.1×30 mm; particle size: 5 μm). MS m/z 488.4 [M+H]+ (ESI), Rt 1.56 min.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:16]=[C:15]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][N:12]3S(C2C=CC=CC=2)(=O)=O)=[N:5][N:4]=1.[CH3:35][S:36]([O-:38])=[O:37].[Na+].[OH-].[Na+].Cl>C(O)C.C(O)(C)C>[NH:21]1[C:22]2[C:18](=[C:17]([C:15]3[CH:14]=[C:13]4[C:9]([CH:10]=[N:11][NH:12]4)=[C:8]([C:6]4[O:7][C:3]([CH2:2][S:36]([CH3:35])(=[O:38])=[O:37])=[N:4][N:5]=4)[CH:16]=3)[CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(-c3cccc4[nH]ccc34)cc21
Reactant: CS(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)O
Product: CS(=O)(=O)Cc1nnc(-c2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)o1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
4-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazole (50 mg, 0.102 mmol) and sodium methanesulfinate (10.42 mg, 0.102 mmol) in ethanol (0.8 ml) were heated under microwave irradiation to 100° C. for 30 mins then 150° C. for 30 min, followed by 150° C. for a further 30 mins. Additional sodium methanesulfinate (10.42 mg, 0.102 mmol) was added and the reaction heated to 150° C. for a further 30 mins. The solvent was removed and the resultant beige solid treated with isopropanol (1 ml) and 2M aqueous sodium hydroxide (1.003 ml, 2.006 mmol) and stirred at 20° C. for 20 h. The mixture was neutralised with 2M aqueous hydrogen chloride, evaporated to dryness and azeotroped with isopropanol (2 ml). The residue was partitioned between dichloromethane (5 ml) and water (5 ml) and shaken vigorously. The aqueous phase was pipetted off, then the heterogeneous solution was treated with methanol (5 ml), absorbed onto Florisil and the solvents removed. The Florisil was placed on top of a silica cartridge (10 g) and eluted with 0-3% methanol/dichloromethane. Appropriate fractions were combined and concentrated to give a beige solid, 16 mg. Further purification by Mass Directed Automated Preparative HPLC afforded the title compound as a white solid (5 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:16])=[C:5]2[C:9](=[CH:10][CH:11]=1)/[C:8](=[CH:12]/[C:13]([OH:15])=[O:14])/[CH2:7][CH2:6]2.[CH2:17](N(CC)CC)C.[Si](C=[N+]=[N-])(C)(C)C>CO>[CH3:1][O:2][C:3]1[C:4]([CH3:16])=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][C:13]([O:15][CH3:17])=[O:14])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1C)CC/C2=C\C(=O)O
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C[C@H]1CCc2c1ccc(OC)c2C
Temperature: 25 °C
Reaction time: 24 h
Yield: 771.6 %

Procedure:
To a solution of (2E-)-(5-methoxy-4-methyl-2,3-dihydro-1H-inden-1-ylidene)acetic acid (1.0 g, 4.58 mmol, from Step F) in methanol (10 mL) was added [(S)-(−)-2,2′bis(diphenylphosphino)-1,1′-binaphthyl]ruthenium (II) (36.0 mg, 0.0458 mmol) and triethylamine (64 μL, 0.458 mmol). The resultant mixture was subjected to 3 atm H2 and was shaken at ambient temperature for 24 hr. The reaction mixture was filtered through Celite®, and concentrated in vacuo. The residue was dissolved in THF (5 mL) and methanol (5 mL) and treated with TMSCHN2 (6.51 mL, 13.0 mmol) at ambient temperature. After 1 hr, the reaction mixture was concentrated in vacuo and purified by flash chromatography (3% EtOAc/hexanes) on SiO2 to give 828 mg of the title compound as a colorless liquid: 1H NMR (500 MHz, CDCl3) δ 1.71-1.78 (m, 1H), 2.15 (s, 3H), 2.37-2.46 (m, 2H), 2.73-2.81 (m, 2H), 2.86-2.92 (m, 1H), 3.53-3.59 (m, 1H), 3.73 (s, 3H), 3.82 (s, 3H), 6.69 (d, 1H, J=8.2 Hz), 6.96 (d, 1H, J=8.2 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:17][C:6]2=[CH:7][C:8]3[C:9]([CH3:16])=[CH:10][C:11]([CH3:15])=[N:12][C:13]=3[CH:14]=[C:5]2[CH:4]=[CH:3]1.ClC1C=CC=[C:22]([C:26]([O:28]O)=[O:27])C=1.CO.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:26]([O:28][CH2:15][C:11]1[CH:10]=[C:9]([CH3:16])[C:8]2[CH:7]=[C:6]3[O:17][C:2]([CH3:18])([CH3:1])[CH:3]=[CH:4][C:5]3=[CH:14][C:13]=2[N:12]=1)(=[O:27])[CH3:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C)c2cc3c(cc2n1)C=CC(C)(C)O3
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)OCc1cc(C)c2cc3c(cc2n1)C=CC(C)(C)O3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 2,2,7,9-tetramethyl-2H-pyrano[2,3-g]quinoline (3.0 g, 12.5 mmol) in chloroform (30.0 mL), a solution of m-chloroperbenzoic acid (4.76 g, 27.6 mmol) in chloroform (12 mL)-methanol (3 mL) was added dropwise at room temperature, and the resulting mixture was stirred at room temperature for 30 minutes. Upon the completion of the reaction, sodium thiosulfate aqueous solution was added to the reaction solution, and it was extracted. The resulting organic phase was washed with sodium hydrogencarbonate and then with sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent, acetic anhydride (12 mL) was added to the residue, and the resulting mixture was stirred at 150° C. for 1 hour. Upon the completion of the reaction, acetic anhydride was distilled off, the residue was neutralized with sodium carbonate aqueous solution, extracted with chloroform, and the resulting organic phase was washed with sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by medium pressure column chromatography (hexane/ethyl acetate=2/1) and the aimed product was obtained (yield: 64%).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:13])=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2)[CH:2]=[CH2:3].C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>C1COCC1>[CH2:1]([C:4]1[C:5]([O:13][C:21](=[O:23])[CH3:22])=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)ccc2cn[nH]c12
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCc1c(OC(C)=O)ccc2cn[nH]c12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of the product from Step B (6.35 g, 37 mmol) in THF (100 mL) containing triethylamine (7.6 ml, 55 mmol) was stirred for 5 minutes at ambient temperature, cooled to 0° C. (ice bath), and acetyl chloride (2.63 mL, 37 mmol) was added. The mixture was stirred at 0° C. for 2 hours, additional acetyl chloride (0.26 mL, 3.7 mmol) was added, and the mixture stirred for 10 min at which point another portion of acetyl chloride (0.26 ml, 3.7 mmol) was added and stirring continued for 15 min. The reaction was quenched with triethyl amine (1 mL) and saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (100 mL). The extract was dried (MgSO4) and evaporated to an oil (9.27 g) which was purified by chromatography (silica, 10% to 50% EtOAc/hexane) to give a white solid, (3.50 g, 44%): LC/MS (+APCI) m/z 217 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:23][C:24]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)=[O:29])([CH3:26])[CH3:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([N:31]3[CH2:32][CH2:33][CH2:34][N:30]3[C:28]([O:27][C:24]([CH3:26])([CH3:25])[CH3:23])=[O:29])=[O:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CC(C)(C)OC(=O)N1CCCN1
Product: CC(C)(C)OC(=O)N1CCCN1C(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and 1-pyrazolidinecarboxylic acid 1,1-dimethylethyl ester (CAN 57699-91-9) as starting materials; MS (EI) 486.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]1[CH2:23][O:22]1)([CH3:16])([CH3:15])[CH3:14]>CCO.O>[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]([OH:22])[CH2:23][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC[C@@H](O)CNc1ccc2c(c1)NC(=O)CO2
Yield: 40.2 %

Procedure:
A solution of 6-amino-4H-benzo[1,4]oxazin-3-one (commercial; 6.49 g, 39.5 mmol) and (2R)-tert-butyl-dimethyl-(2-oxiranyl-ethoxy)-silane (first eluting compound of step 18.i, 8.0 g, 39.5 mmol) in 9-1 EtOH/H2O (240 mL) was heated at 80° C. for 2 days. The mixture was concentrated under reduced pressure. Residual starting aniline could be removed by addition of Et2O/MeOH followed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by CC (DCM/MeOH/NH4OH 1000:50:4) to afford the title intermediate as a brown oil (5.82 g, 40% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[O:25]1[CH2:29][CH2:28][C@@H:27]([NH2:30])[CH2:26]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][C@@H:27]4[CH2:28][CH2:29][O:25][CH2:26]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: N[C@@H]1CCOC1
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N[C@@H]3CCOC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-tetrahydrofuran-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79-1.94 (m, 1H) 2.03-2.19 (m, 1H) 2.36 (s, 3H) 3.56 (dd, J=9.09, 4.04 Hz, 1H) 3.66 (td, J=8.15, 5.94 Hz, 1H) 3.75-3.88 (m, 2H) 4.42 (dtt, J=8.07, 6.29, 6.29, 4.20, 4.20 Hz, 1H) 7.54-7.63 (m, 1H) 7.66 (s, 1H) 7.71 (br. s., 1H) 8.11 (br. s., 1H) 8.20-8.62 (m, 2H) 8.71 (d, J=6.32 Hz, 1H) 8.80-8.90 (m, 1H) 13.12 (br. s., 1H). MS m/z [M+H]+ 390.2
Reaction SMILES: [CH2:1]([N:7]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8]([C:10]1[C:11](=[O:20])[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Cl)[CH:30]=1.O>CN(C)C=O>[CH2:21]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]([C:10]1[C:11](=[O:20])[N:12]([CH2:35][C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCN(CCCCCC)C(=O)c1cc2ccccc2[nH]c1=O
Reactant: ClCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCN(CCCCCC)C(=O)c1cc2ccccc2n(Cc2cccnc2)c1=O
Temperature: 25 °C
Yield: 37.1 %

Procedure:
To a solution of 1.01 g of N,N-dihexyl-1,2-dihydro-2-oxoquinoline-3-carboxamide in 13 ml of N,N-dimethylformamide was added 136 mg of 60% sodium hydride/oil, followed by stirring at room temperature for an hour. To the reaction solution was added 434 mg of 3-picolyl chloride, followed by stirring at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica gel; Wakogel C200 (manufactured by Wako Pure Chemicals), developing solvent; hexane−ethyl acetate=7:13−1:19) and recrystallized from ethyl acetate to give 0.47 g of N,N-dihexyl-1-(3-picolyl)-1,2-dihydro-2-oxoquinoline-3-carboxamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:16]2[C@H:11]([C@H:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[C:20]([F:35])[CH:19]=3)[CH2:13][S:14][CH2:15]2)[O:10][C:9]1([CH3:37])[CH3:36])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)=[O:40].OO.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:16]2[C@H:11]([C@H:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([O:27][CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:26])=[C:20]([F:35])[CH:19]=3)[CH2:13][S@:14](=[O:40])[CH2:15]2)[O:10][C:9]1([CH3:37])[CH3:36])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1[C@H]2CSC[C@@H](Cc3ccc(NC(=O)OCc4ccccc4)c(F)c3)[C@@H]2OC1(C)C
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H]2C[S@@](=O)C[C@@H](Cc3ccc(NC(=O)OCc4ccccc4)c(F)c3)[C@@H]2OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (3aR*,7S*,7aS*)-7-(4-benzyloxycarbonylamino-3-fluoro-benzyl)-2,2-dimethyl-tetrahydro-1-oxa-5-thia-3-aza-indene-3-carboxylic acid tert-butyl ester (54.1 g, 102 mmol) in THF (500 mL) was added AcOH (200 mL) and H2O2 (27.8 g, 50% in H2O, 408 mmol) at 0-5° C. and the reaction mixture was stirred for 16 h at 25° C. The reaction mixture was slowly added to a cold 25% aq. Na2S2O3 solution, stirred for 3 h at 0-5° C. and extracted with EtOAc. Combined organic layers were washed with water, saturated K2CO3 solution and brine, dried over MgSO4, filtered and evaporated. The crude product was filtered through a short plug of ammonia deactivated silicagel and the title compound was obtained as a 3:2 mixture of the (3aR*,5R*,7S*,7aS*)- and (3aR*,5S*,7S*,7aS*)-diastereoisomer after crystallization from Et2O-hexane: TLC (EtOAc-MeOH 19:1) Rf=0.51; HPLC RtA=2.34 min and 2.38 min; ESIMS [M+H]+=547. Separation of the racemic 3:2 mixture on Chiralpak IC (heptene-EtOH 85:15) and on Chiralpak AD-I (hexane-EtOH-CHCl3 80:10:10) provided the diastereoisomers (3aR,5R,7S,7aS)-7-(4-benzyloxycarbonylamino-3-fluoro-benzyl)-2,2-dimethyl-5-oxo-hexa-hydro-1-oxa-5lambda*4*-thia-3-aza-indene-3-carboxylic acid tert-butyl ester (peak 1 on Chiralpak IC) in >98% ee: [α]D−21.5° (c 1, CHCl3); 1H NMR (600 MHz, DMSO-d6): δ 9.43 (s, 1H), 7.56 (s, 1H), 7.40 (m, 4H), 7.33 (t, 1H), 7.08 (d, 1H), 6.99 (d, 1H), 5.14 (s, 2H), 3.6-3.8 (m, 2H), 3.40 (t, 1H), 2.92 (m, 2H), 2.6-2.8 (m, 3H), 2.37 (t, 1H), 1.55 (s, 3H), 1.50 (s, 3H), 1.41 (s, 9H) and (3aR,5S,7S,7aS)-7-(4-benzyloxycarbonylamino-3-fluoro-benzyl)-2,2-di-methyl-5-oxo-hexahydro-1-oxa-5lambda*4*-thia-3-aza-indene-3-carboxylic acid tert-butyl ester (peak 2 on Chiralpak IC): 1H NMR (600 MHz, DMSO-d6): δ 9.44 (s, 1H), 7.57 (s, 1H), 7.40 (m, 4H), 7.35 (t, 1H), 7.08 (d, 1H), 6.99 (d, 1H), 5.14 (s, 2H), 3.9-4.2 (m, 1H), 3.65 (t, 1H), 2.5-3.5 (m, 6H), 2.25 (m, 1H), 1.51 (s, 6H), 1.42 (s, 9H) followed by the (3aS,5R,7R,7aR)- and (3aS,5S,7R,7aR)-diastereoisomers (peak 3 and peak 4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][CH2:22][CH2:23]OS(C)(=O)=O)=[CH:18][CH:19]=2)[C:14]([CH3:30])([CH3:29])[O:13]1.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32]>O1CCOCC1.CCOC(C)=O>[CH2:31]([N:33]([CH2:34][CH3:35])[CH2:23][CH2:22][CH2:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[C:12](=[C:5]1[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]1=[O:11])[O:13][C:14]2([CH3:29])[CH3:30])[CH3:32]
Reactant: CC1(C)OC(=C2C(=O)Nc3ccc(F)cc32)c2ccc(CCCOS(C)(=O)=O)cc21
Reactant: CCNCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCN(CC)CCCc1ccc2c(c1)C(C)(C)OC2=C1C(=O)Nc2ccc(F)cc21
Yield: 55.2 %

Procedure:
A solution of methanesulfonic acid 3-[1-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene)-3,3-dimethyl-1,3-dihydro-isobenzofuran-5-yl]-propyl ester (170 mg, 0.39 mmol) and diethylamine (0.30 ml, 2.92 mmol) in dioxane (1.6 ml) was heated at 75° C. in a pressure tube for 36 hours. The mixture was evaporated, dissolved in EtOAc, and the EtOAc washed with H2O and brine. The aqueous layer was also extracted with CHCl3. The organic layers were combined, dried over anhydrous Na2SO4, and then evaporated to a yellow film. The sample was passed through a plug of silica gel eluting with 10% methanol in CHCl3 to give a yellow-orange solid. The solid was dissolved in EtOAc, washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, and evaporated to a yellow solid. The solid was chromatographed eluting with CHCl3/MeOH to give the title compound as a yellow solid (88 mg, 54%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH:13]([CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:20]1)[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.CO.[BH4-].[Na+]>O>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]([OH:16])[CH:13]([CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:21][CH2:20]1)[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCC(CCC1CCN(Cc3ccccc3)CC1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1c2c(nc3ccccc13)CCC(CCC1CCN(Cc3ccccc3)CC1)C2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
0.41 gm of 9-amino-2-(2-(1-benzylpiperidin-4-yl)ethyl)-1,2,3,4-tetrahydroacridin-1-one was dissolved into 10 ml of methanol. To the solution was added 0.15 gm of sodium borohydride, and the mixture was stirred for 2 hours at room temperature. After the addition of 30 ml of water, the reaction mixture was extracted with chloroform. The extract was washed with saturated brine, dried, and evaporated under reduced pressure. 0.28 gm of 9-amino-2-(2-(1-benzylpiperidin-4-yl)ethyl)-1,2,3,4-tetrahydroacridin-1-ol (Compound (I) with R1 =R3 =H, R2 =--NH2, A=>CH(CH2)n --, Y=>CHOH, m=2 and n=2) was obtained by recrystallizing the residue from ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:12]([S:18]([OH:21])(=O)=[O:19])[CH2:13][C:14]([O:16][CH3:17])=[O:15].[N:22]1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.[OH-].N>C(Cl)Cl>[NH2:22][S:18]([CH:12]([C:3]1[CH:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]=1[Br:1])[CH2:13][C:14]([O:16][CH3:17])=[O:15])(=[O:21])=[O:19]
Reactant: COC(=O)CC(c1ccc(C(=O)OC)cc1Br)S(=O)(=O)O
Reactant: c1ccncc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: N
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)CC(c1ccc(C(=O)OC)cc1Br)S(N)(=O)=O
Reaction time: 8 h
Yield: 62.7 %

Procedure:
1-[2-bromo-4-(methoxycarbonyl)phenyl]-3-methoxy-3-oxopropane-1-sulfonic acid—pyridine (1:1) (0.220 g, 0.478 mmol) was dissolved in methylene chloride (2 mL) at room temperature, and phosphorus pentachloride (0.199 g, 0.956 mmol) were added. The mixture was stirred overnight. The reaction solution was cannulated into a 2 mL ammonia hydroxide solution at 0° C. dropwise. After stirring for 1 h, the organic layer was isolated, aqueous layer was extracted with methylene chloride twice. The combined organic solutions were dried over sodium sulfate, filtered, concentrated. The residue was purified by preparative LCMS to afford product as slight yellow solid (114 mg, 63%). 1H NMR (400 MHz, CD3OD): δ 8.24 (d, J=1.5 Hz, 1H), 7.99 (dd, J=8.2, 1.5 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 5.39 (dd, J=10.1, 4.9 Hz, 1H), 3.91 (s, 3H), 3.58 (s, 3H), 3.43 (dd, J=16.6, 4.9 Hz, 1H), 3.18 (dd, J=16.6, 10.1 Hz, 1H). LCMS found for C12H14BrNO6SNa (M+Na)+: m/z=401, 403.
Reaction SMILES: [CH2:1]([Si:3]([CH2:8][CH3:9])([CH2:6][CH3:7])[C:4]#[CH:5])[CH3:2].[Li]CCCC.[F:15][CH2:16][C:17](=[O:19])[CH3:18]>C1COCC1>[F:15][CH2:16][C:17]([CH3:18])([OH:19])[C:5]#[C:4][Si:3]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:1][CH3:2]
Reactant: CC(=O)CF
Reactant: C#C[Si](CC)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[Si](C#CC(C)(O)CF)(CC)CC
Temperature: -78 °C

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure B. A stirred solution of triethyl(ethynyl)silane (1.05 eq, 5.4 mL) in THF. at −78° C. was treated with n-BuLi (2.5 mol/L in hexanes, 1.1 eq) dropwise. The reaction was stirred for 15 minutes before addition of 1-fluoropropan-2-one (2.1 mL) then stirred for another hour at −78° C. whereupon it was slowly warmed to room temperature. The reaction was quenched with a saturated ammonium chloride solution then extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated to give a clear oil. This crude intermediate was purified by ISCO with ELSD option (0-100% Heptane: Ethyl acetate over 25 minutes) to afford 1-fluoro-2-methyl-4-triethylsilyl-but-3-yn-2-ol. 1H NMR (400 MHz, MeOD) δ 4.81 (s, 1H), 4.36-4.27 (m, 1H), 4.24-4.14 (m, 1H), 1.45 (d, J=1.8 Hz, 3H), 1.06-0.97 (m, 9H), 0.65-0.55 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][OH:8].N1C=CC=CC=1.[Br:18]Br>ClCCl>[Br:18][C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:6][CH2:7][OH:8]
Reactant: COc1cccc(CCO)c1
Reactant: BrBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Br)c(CCO)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.2 %

Procedure:
To a stirred mixture of 3-methoxyphenethyl alcohol (1.18 g, 7.8 mmol) and pyridine (0.75 ml, 9.3 mmol) in dry dichloromethane (10 ml) was added bromine (0.47 ml, 18.0 mmol) dropwise under nitrogen at 0° C. The orange solution was stirred at room temperature for 4 hours (hr). The reaction mixture was quenched by the addition of 10% sodium bisulfite aqueous solution., and extracted with dichloromethane. The organic extracts were washed with brine, dried over magnesium sulfate, and concentrated to give crude products, which were purified by silica-gel column chromatography eluted with gradient of hexane and ethyl acetate (10:1, 8:1, 5:1) to give the title compound as a colorless oil (1.5 g, 83.2%). 1H-NMR (CDCl3): 7.43 (d, J=8.8 Hz, 1H), 6.83 (d, J=3.3 Hz, 1H), 6.67 (dd, J=8,8, 3.3 Hz, 1H), 3.91-3.81 (m, 2H), 3.78 (s, 3H), 2.99 (t, J=6.6 Hz, 2H).