Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[NH:5][C:6]([CH2:13][CH3:14])=[C:7]([C:9]([F:12])([F:11])[F:10])[N:8]=1>S(=O)(=O)(O)O>[CH2:13]([C:6]1[NH:5][C:4]([CH:3]=[O:2])=[N:8][C:7]=1[C:9]([F:11])([F:12])[F:10])[CH3:14]
Reactant: CCc1[nH]c(C(OC)OC)nc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: CCc1[nH]c(C=O)nc1C(F)(F)F
Yield: 29.1 %

Procedure:
The same operation as in Example (33b) was performed using 2-(dimethoxymethyl)-5-ethyl-4-(trifluoromethyl)-1H-imidazole obtained in Example (39c) (about 4.09 mmol) and 2 N sulfuric acid (30 mL), to obtain 228.3 mg of the title compound as a white solid (29%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([O:14][C:15]([C:17]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:20]([CH:28]=O)[NH:19][C:18]=1[CH3:30])=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C:17]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:20]([CH:28]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:19][C:18]=1[CH3:30])=[O:16])[CH3:13]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1-c1ccccc1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1-c1ccccc1
Yield: 59.6 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (60 mg, 0.29 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (75 mg) to give 78 mg (60%) of the title compound as an orange solid.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]#[N:16])[CH2:10][CH2:9]2)C=CC=CC=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>O1CCCC1>[C:15]([CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:10]1)#[N:16]
Reactant: N#CCC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(CC#N)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 81.4 %

Procedure:
To a solution of 25 parts of 1-(phenylmethyl)-4-piperidineacetonitrile in 178 parts of tetrahydrofuran were added dropwise 37.97 parts of ethyl chloroformate at room temperature. The reaction mixture was stirred for 15 hours at room temperature and was then evaporated. The residue was taken up in 90 parts of ethyl acetate and the whole was washed successively with HCl 3N, NaHCO3 and NaCl (sat.). The solvent was evaporated and the residue was distilled (100°-110° C./6.7 Pa), yielding 18.7 parts (81.4%) of ethyl 4-(cyanomethyl)-1-piperidinecarboxylate (interm. 24).
Reaction SMILES: [CH2:1]([O:3][C:4](/[CH:6]=[C:7]1\[CH2:8][N:9]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:11][CH:12]\1[OH:13])=[O:5])[CH3:2].[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].N1C=CN=C1>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Si:33]([O:13][CH:12]1[CH2:11][CH2:10][N:9]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:8]/[C:7]/1=[CH:6]\[C:4]([O:3][CH2:1][CH3:2])=[O:5])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CCOC(=O)/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of (E)-3-[(ethoxycarbonyl)methylidene]-1-(triphenylmethyl)piperidin-4-ol (14.97 g) in N,N-dimethylformamide (130 ml) were added successively t-butyldimethylsilyl chloride (6.86 g), 1H-imidazole (3.34 g) and 4-dimethylaminopyridine (0.43 g) under ice-cooling, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:19) as the eluent to afford the title compound (16.38 g, yield: 86%) as a colourless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[N:10]=[C:9]2[CH3:20])=[CH:6][CH:5]=[CH:4][N:3]=1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>CN(C)C=O>[Cl:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[N:10]=[C:9]2[CH:20]=[CH:23][N:24]([CH3:26])[CH3:25])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1nc2ccc(F)cc2c(=O)n1-c1cccnc1Cl
Solvent: CN(C)C=O
Product: CN(C)C=Cc1nc2ccc(F)cc2c(=O)n1-c1cccnc1Cl
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A mixture of 3-(2-chloro-pyridin-3-yl)-6-fluoro-2-methyl-3,4-dihydro-quinazolin-4-one (3.5 g, 12.0 mmol) and dimethylformamide dimethyl acetal (3.2 mL, 24 mmol) in dimethylformamide (12 mL) was refluxed for 24 hours. The reaction was cooled to ambient temperature and concentrated at reduced pressure to afford an orange solid. The solid was triturated with ethanol and the yellow crystalline solid was collected and dried to give 3.61 g (87%) of 3-(2-chloro-pyridin-3-yl)-6-fluoro-2-(2-dimethylamino-vinyl)-3,4-dihydro-quinazolin-4-one, which had: mp 197-200° C.; H 1H NMR δ 8.46 (dd, J=1.5, 5 Hz, 1H), 7.85 (d, J=12.2 Hz, 1H), 7.70 (dd, J=3, 8.5 Hz, 1H), 7.68-7.65 (m, 1H), 7.45-7.38 (m, 2H), 7.31 (dt, J=3, 8.5 Hz, 1H), 3.87 (d, J=12.2 Hz, 1H), 2.80 (br s, 6H). Analysis calculated for C17H14ClFN4O: C, 59.22; H, 4.09; N, 16.25. Found: C, 59.14; H, 3.96; N, 16.25.
Reaction SMILES: [I-].[CH3:2][N+:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]3=2)[C:5]([CH3:17])([CH3:16])[C:4]=1[CH3:18].[OH-].[Na+].[CH3:21][O:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29]([OH:35])=[C:30]2[N:33]=O)=[CH:25][CH:24]=1>CCCCCC>[CH3:21][O:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29]3[O:35][C:4]4([C:5]([CH3:17])([CH3:16])[C:6]5[C:11](=[C:10]6[CH:12]=[CH:13][CH:14]=[CH:15][C:9]6=[CH:8][CH:7]=5)[N:3]4[CH3:2])[CH:18]=[N:33][C:30]=32)=[CH:25][CH:24]=1
Reactant: CC1=[N+](C)c2c(ccc3ccccc23)C1(C)C
Reactant: COc1ccc2ccc(O)c(N=O)c2c1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Product: COc1ccc2ccc3c(c2c1)N=CC1(O3)N(C)c2c(ccc3ccccc23)C1(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 1.05 grams (3.0 mmole) of 1,2,3,3-tetramethyl-3H-benz[g] indolium iodide in 15 milliliters (ml) of hexane at 25° C. was added 10 ml (50 mmole) of 20% sodium hydroxide. The two phase mixture was stirred vigorously under nitrogen for about 30 minutes. The organic layer was separated, transferred to a reaction flask equipped with a reflux condenser and diluted with 15 ml of absolute ethanol. To this solution was added 0.61 grams (3.0 mmole) of 7-methoxy-1-nitroso-2-naphthol and the resulting reaction mixture refluxed under nitrogen for about 6 hours. The reaction mixture was cooled, the volume reduced under vacuum and 0.29 grams (0.71 mmole) of the product, 9'-methoxy-1,3,3-trimethylspiro [benz[g] indoline-2,3'-[3H] naphth [2,1-b][1,4] oxazine] was obtained as yellow-orange crystals. A solution of the crystals dissolved in ethanol or toluene was colorless. The solution turned blue when irradiated with ultraviolet light.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:19]C(=O)OCC3C=CC=CC=3)[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1>[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(NCC1Cc2cccc(-c3ccc(F)cc3F)c2O1)OCc1ccccc1
Agent: [Pd]
Product: NCC1Cc2cccc(-c3ccc(F)cc3F)c2O1
Yield: 66.2 %

Procedure:
Treatment of (−)-benzyl {[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (0.612 g, 1.55 mmol) with palladium on carbon (0.061 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.268 g (66%) of (−)-1-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]D25=−4.66 (c 10.0 in dimethylsulfoxide); mp 222-224° C.; Anal. calcd. for C15H13F2NOHCl: C, 60.51; H, 4.74; N, 4.7. Found: C, 60.34; H, 4.58; N, 4.48.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[CH2:15]([O:22][CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:24][NH2:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:25][CH2:24][CH:23]([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCC(OCc1ccccc1)c1ccccc1
Solvent: CO
Product: N#CNC(=NCC(OCc1ccccc1)c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.20 g, 1.1 mmol) was dissolved in methanol (5 ml), and 2-benzyloxy-2-phenylethylamine (0.26 g, 1.1 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 20 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure to give N-cyano-N'-(2-benzyloxy-2-phenylethyl)-3-pyridinecarboximidamide (0.24 g, 0.7 mmol, yield: 64%) as colorless syrup. Next, to this syrup was added a 5% hydrogen chloride in methanol (2 ml). The solution was crystallized from methanol-diethyl ether to give N-cyano-N'-(2-benzyloxy-2-phenylethyl)-3-pyridinecarboximidamide hydrochloride as colorless powder.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH2:32][CH2:33][NH2:34].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:5]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH:34][CH2:33][CH2:32][C:26]1[C:25]2[C:29](=[CH:30][CH:31]=[C:23]([Cl:22])[CH:24]=2)[NH:28][CH:27]=1)=[O:17])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)c1cccc(Cc2ccccc2)c1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cc2ccccc2)c1
Temperature: 65 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
Thionyl chloride (0.113 mL; 1.55 mmol) was added to a mixture of 3-benzylbenzoic acid (0.110 g; 0.518 mmol) in chloroform (10 mL). The reaction mixture was stirred at 65° C. for 18 hours and evaporated to dryness. The resulting residue was dissolved in chloroform (6 mL) and the solution is cooled to 0° C. A solution of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.110 g; 0.466 mmol) and triethylamine (0.363 mL; 2.59 mmol) in chloroform (6 ml) was then added and the mixture was stirred for 30 minutes at room temperature. The volatiles were removed under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluent 1 to 20% ethyl acetate in dichloromethane) to furnish 0.154 g (76%) of 3-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)benzamide as a white solid.
Reaction SMILES: [CH3:1][C:2](=[O:23])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH:13]=[CH:14]2)[CH:9]=[CH:8]3)[CH2:5][CH2:4]1.I.[OH-].[Na+]>C(O)(=O)C>[CH3:1][C:2](=[O:23])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH:13]=[CH:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Treat each of the 1,4,6-pregnatriene-3,20-dione compounds of Example 13A(2) with dry hydrogen iodide in acetic acid in the manner described in Example 9A. After stirring the reaction mixture at room temperature for 15 minutes, pour into ice water, neutralize with sodium hydroxide, separate the resultant precipitate by filtration, and purify each of the precipitates in a manner similar to that described in Example 9A to obtain the 7α-iodo derivative of each of the 1,4-pregnadiene-3,20-dione starting compounds of Example 13A(2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
A dry 10 gallon glass-lined vessel was charged with the alcohol (2) (3.39 kg d.b., 18.1 Mol) and ethyl acetate (50 l) under nitrogen. The solution was cooled to -5° C. and triethylamine (Lancaster B/N 076337, 5.1 l) was added in one portion. Methanesulphonyl chloride (Lancaster B/N 79561, 1.68 l, 21.7 Mol) was added dropwise over 1 h, maintaining the reaction temperature at -5°-2° C. On complete addition, the slurry was aged at -5° C. for 30 min. Water (20 1) was added over 10 min and the phases well mixed The aqueous layer was separated and the organics washed with 1M aqueous hydrochloric acid (10 l), saturated sodium bicarbonate (10 1) and dried (Na2SO4). Solvent evaporation gave the product as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.C(N(CC)CC)C>[Ni].C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:3]=1)[NH2:10]
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(Br)cc1N
Yield: 104.7 %

Procedure:
A solution of 4-bromo-2-nitro-anisole (7.7 g, 33.1 mmol), triethylamine (4.6 ml, 33.1 mmol) and Raney Nickel catalyst (4 g) was vigorously stirred in ethanol (300 ml) under an atmosphere of hydrogen for 1 h at 20° C. After this time the theoretical amount of hydrogen had been absorbed (2.5 1), so the catalyst was filtered off and the solvent evaporated to afford the title compound as a light yellow solid (7 g, 104% yield), MS: m/e=201 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.B(Cl)(Cl)Cl.[CH2:18]1[CH2:29][O:28][C:27]2[C:20](=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH:22]=[O:23])[O:19]1.C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH:22]([C:21]2[CH:24]=[CH:25][CH:26]=[C:27]3[O:28][CH2:29][CH2:18][O:19][C:20]=23)[OH:23])[CH:3]=1
Reactant: O=Cc1cccc2c1OCCO2
Reactant: CC(C)(C)CNc1ccc(Cl)cc1
Agent: ClB(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)(C)CNc1ccc(Cl)cc1C(O)c1cccc2c1OCCO2
Reaction time: 3.5 h
Yield: 88.5 %

Procedure:
A solution of (4-chloro-phenyl)-(neopentyl)-amine (2.24 g, 11.3 mmol) in benzene (6 mL) was added to a solution of boron trichloride (1.0 M in xylenes; 12.5 mL, 12.5 mmol) in benzene (13 mL) at 0° C. under a nitrogen atmosphere. Once the addition was complete, the resulting mixture was heated at reflux for 3 hours, under a steady stream of nitrogen exiting into an aqueous 5N sodium hydroxide trap, and then recooled to 0° C. A solution of 2,3-ethylenedioxybenzaldehyde (1.86 g, 11.3 mmol), triethylamine (2.29 g, 22.7 mmol, 3.2 mL) and benzene (6 mL) was then added and the resulting mixture stirred 3.5 hours before quenching with aqueous 1N hydrochloric acid. After 1 hour, ethyl acetate was added and the resulting mixture was shaken vigorously. The aqueous layer was alkalized with aqueous 5N sodium hydroxide and the layers separated. The aqueous layer was extracted with ethyl acetate (2×). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography (4:1 hexanes/ethyl acetate) to produce 3.62 g (88%) of the title compound as an off-white foam.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.CN(C)C=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH2:47]([NH:49][C:50]([NH:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[N:60]=[C:61]([N:69]3[CH2:74][CH2:73][O:72][CH2:71][CH2:70]3)[C:62]3[CH2:68][CH2:67][NH:66][CH2:65][C:63]=3[N:64]=2)=[CH:55][CH:54]=1)=[O:51])[CH3:48]>>[CH2:47]([NH:49][C:50]([NH:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[N:60]=[C:61]([N:69]3[CH2:70][CH2:71][O:72][CH2:73][CH2:74]3)[C:62]3[CH2:68][CH2:67][N:66]([C:8]([C:3]4[C:2]([CH3:1])=[N:7][CH:6]=[CH:5][N:4]=4)=[O:10])[CH2:65][C:63]=3[N:64]=2)=[CH:57][CH:58]=1)=[O:51])[CH3:48]
Reactant: Cc1nccnc1C(=O)O
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)c2nccnc2C)C3)cc1
Reaction time: 8 h

Procedure:
3-Methylpyrazine-2-carboxylic acid (0.0501 g, 0.000363 mol) in dry N,N-Dimethylformamide (1.80 mL, 0.0232 mol) was added 1-Hydroxybenzotriazole (0.0580 g, 0.000429 mol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0765 g, 0.000399 mol) then followed by N,N-Diisopropylethylamine (0.1150 mL, 0.0006602 mol) and then 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.1021 g, 0.0002670 mol). The reaction mixture was stirred overnight. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.73-8.60 (m, 2H), 8.55 (s, 1H), 8.17 (dd, J=43.9, 8.8, 2H), 7.47 (dd, J=25.7, 8.8, 2H), 6.22-6.10 (m, 1H), 4.79 (s, 1H), 4.37 (s, 1H), 3.90 (t, J=5.3, 1H), 3.78-3.66 (m, 4H), 3.56-3.37 (m, 6H), 3.21-3.03 (m, 2H), 2.81 (s, 1H), 2.68 (s, 1H), 2.53 (s, 2H), 1.06 (q, J=7.3, 3H). LC/MS-m/z+503.2 (M+H)+
Reaction SMILES: C(OC([NH:11][CH:12]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:13][CH2:14][C:15]([NH:17][C@@H:18]([C:24]([O:26][CH3:27])=[O:25])[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:16])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][CH:12]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:13][CH2:14][C:15]([NH:17][C@@H:18]([C:24]([O:26][CH3:27])=[O:25])[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:16]
Reactant: COC(=O)C[C@@H](NC(=O)CCC(NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)C[C@@H](NC(=O)CCC(N)C(=O)OC(C)(C)C)C(=O)OC
Reaction time: 8 h
Yield: 104.7 %

Procedure:
To a solution of 1.92 g (4.0 mmol) of dimethyl N-[4-(benzyloxycarbonylamino)-4-tert.-butoxycarbonylbutanoyl]-D-aspartate in 15 mL of anhydrous methanol was added 0.43 g of 10% Pd/C and the mixture was then stirred under an atmosphere of hydrogen overnight. The catalyst was removed by filtration through a Celite® pad and the filtrate concentrated in vacuo to yield 1.45 g of dimethyl N-(4-amino-4-tert.-butoxycarbonylbutanoyl)-D-aspartate as a thick clear oil. Mass Spectrum (FD+): M+1=347; IR (CHCl3, cm-1)=840, 1048, 1155, 1371, 1396, 1440, 1511, 1602, 1672, 1739, 2980, 3428, 3691; 1H NMR (30 MHz, CDCl3) δ1.51 (s, 9H), 1.66 (s, 2H), 2.07 (m, 2H), 2.46 (m, 2H), 2.85 (t, J=6.0 Hz, 2H), 3.68 (s, 3H), 3.72 (s, 3H), 3.76 (t, J=6.4 Hz, 1H), 4.78 (t, J=5.7 Hz, 1H), 7.15 (d J=8.0 Hz, 1H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=O.C(O)(=O)C>[Zn].O>[CH3:12][C:9]1[CH:10]=[CH:11][C:3]([CH3:2])=[C:4]2[C:8]=1[CH2:7][CH2:6][CH2:5]2
Reactant: Cc1ccc(C)c2c1CCC2=O
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(C)c2c1CCC2
Reaction time: 12 h
Yield: 81.1 %

Procedure:
Zinc amalgam (prepared by mixing zinc dust (25.0 g), mercuric chloride (2.5 g), concentrated hydrochloric acid (3 ml) and water (50 ml) together for 5 minutes, then decanting the aqueous solution) was added to a mixture of 4,7-dimethylindan-1-one (25.0 g, 156 mmole), acetic acid (50 ml), water (50 ml) and concentrated hydrochloric acid (100 ml). The mixture was refluxed with vigorous stirring for 12 hours, then cooled, poured into water and extracted with diethyl ether. The ether extract was washed successively with water, dilute aqueous sodium bicarbonate solution and water. Then dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography over silica gel (eluant hexane) gave 4,7-dimethylindane (18.5 g, 81.4%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:17])[CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C1OC2C(C3C4OCOC=4C=CC=3P(C3C=CC=CC=3)C3C=CC=CC=3)=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2O1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([OH:17])[CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C)C(=O)Cc1ccccc1F
Agent: c1ccc(P(c2ccccc2)c2ccc3c(c2-c2c(P(c4ccccc4)c4ccccc4)ccc4c2OCO4)OCO3)cc1
Product: CCOC(=O)C(C)C(O)Cc1ccccc1F

Procedure:
The thus obtained compound (5) is asymmetrically hydrogenated using ((R)—SEGPHOS™)-Ru complex to obtain optically active ethyl 4-(2-fluorophenyl)-3-hydroxy-2-methylbutyrate (6) as a mixture of diastereomers.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.Br[C:27]1[CH:28]=[C:29]2[C:35]([CH:36]([C:38]3[CH:39]=[C:40]4[C:45](=[CH:46][CH:47]=3)[N:44]=[CH:43][CH:42]=[CH:41]4)[CH3:37])=[N:34][O:33][C:30]2=[N:31][CH:32]=1.C([Sn](CCCC)(CCCC)[C:53]1[N:54]=[CH:55][S:56][CH:57]=1)CCC>CN(C=O)C>[S:56]1[CH:57]=[C:53]([C:27]2[CH:28]=[C:29]3[C:35]([CH:36]([C:38]4[CH:39]=[C:40]5[C:45](=[CH:46][CH:47]=4)[N:44]=[CH:43][CH:42]=[CH:41]5)[CH3:37])=[N:34][O:33][C:30]3=[N:31][CH:32]=2)[N:54]=[CH:55]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: CC(c1ccc2ncccc2c1)c1noc2ncc(Br)cc12
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CN(C)C=O
Product: CC(c1ccc2ncccc2c1)c1noc2ncc(-c3cscn3)cc12
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a pressure vessel was added 2-(dicyclohexylphosphino)biphenyl (12 mg, 0.42 mmol), 6-(1-(5-bromoisoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline (0.10 g, 0.28 mmol), and 4-(tributylstannyl)thiazole (0.16 g, 0.42 mmol) in anhydrous DMF (3 mL). The vial was flushed with argon, sealed and stirred at 90° C. for two hours. The mixture was concentrated and purified by MPLC (eluted with a gradient of 0 to 10% methanol in dichloromethane) to afford the product as an off-white solid. MS m/z=359.0 [M+1]+ Calc'd for C20H14N4OS: 358.4.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=2)[CH:7]=[C:6]([O:17][C:18]2[CH:23]=[CH:22][C:21]([P:24]([O:30][CH:31]([CH3:33])[CH3:32])([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])=[CH:20][CH:19]=2)[CH:5]=1.O1CCOCC1.[OH-].[Na+]>O>[CH:27]([O:26][P:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([S:10][C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[CH:7]=2)[C:3]([OH:34])=[O:2])=[CH:19][CH:20]=1)([O:30][CH:31]([CH3:33])[CH3:32])=[O:25])([CH3:28])[CH3:29]
Reactant: COC(=O)c1cc(Oc2ccc(P(=O)(OC(C)C)OC(C)C)cc2)cc(Sc2nccn2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)OP(=O)(OC(C)C)c1ccc(Oc2cc(Sc3nccn3C)cc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
A mixture of 3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzoic acid methyl ester (292 mg, 0.58 mmol), 3 mL of dioxane, 3 mL of water and 1.2 mL of 1 M aqueous NaOH was stirred for 2 h at rt, diluted with water, washed with EtOAc, the aqueous layer pH lowered to 4 with 1 M NaHSO4, the aqueous layer extracted with 4:1 CH2Cl2/MeOH. The organic extract dried (MgSO4) and evaporated to provide 234 mg (82%) of the title compound: 1H NMR (500 MHz, DMSO-d6): δ 1.18 (d, 6H, J=6 Hz), 1.28 (d, 6H, J=6 Hz), 3.64 (s, 3H), 4.55 (m, 2H), 7.03 (t, 1H, J=2 Hz), 7.13 (s, 1H). 7.15 (dd, 2H, J=8, 3 Hz), 7.31 (dd, 1H, J=2, 1 Hz), 7.35 (t, 1H, J=1 Hz), 7.50 (s, 1H), 7.72 (dd, 2H, J=12, 8 Hz); LCMS (m/z): 491.9 [C23H27N2O6PS+H]+.