Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH2:14]([NH:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([OH:21])=[O:5])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)c1cccc(NCc2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cccc(NCc2ccccc2)c1

Procedure:
A solution of 3-benzylamino-benzoic acid tert-butyl ester (1 g, 3 mmol) in trifluoroacetic acid/dichloromethane (1:5 v/v) (100 ml) was stirred for 16 hrs. The reaction was concentrated to dryness in vacuo to afford the title compound as a white solid. HPLC retention time 2.59 min. Mass spectrum (ES+) m/z 227.8 (M+).
Reaction SMILES: [CH3:1][C:2]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:28])[CH2:3][N:4]1[CH2:8][CH2:7][C@@H:6]([NH:9][C:10]2[N:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21]C3CCCCO3)=[O:19])=[N:14][CH:15]=2)[CH2:5]1.[ClH:35].CC(C)=O>CCO>[ClH:35].[ClH:35].[OH:21][NH:20][C:18](=[O:19])/[CH:17]=[CH:16]/[C:13]1[CH:12]=[N:11][C:10]([NH:9][C@@H:6]2[CH2:7][CH2:8][N:4]([CH2:3][C:2]([CH3:1])([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH3:28])[CH2:5]2)=[CH:15][N:14]=1
Reactant: CC(C)(CN1CC[C@@H](Nc2cnc(/C=C/C(=O)NOC3CCCCO3)cn2)C1)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Product: CC(C)(CN1CC[C@@H](Nc2cnc(/C=C/C(=O)NO)cn2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2E)-3-[5-({(3R)-1-[2-methyl-2-phenylpropyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (130 mg) in EtOH (0.7 mL) was added 2N—HCl solution in EtOH (0.7 mL) and the reaction mixture was stirred for 2 hours at ambient temperature. Acetone was added to the mixture and filtered. The filtrate was evaporated and dried to give (2E)-N-hydroxy-3-[5-[{(3R)-1-(2-methyl-2-phenylpropyl)-3-pyrrolidinyl}amino]-2-pyrazinyl]acrylamide dihydrochloride (108 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:24]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][NH2:42])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH:24]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:9](=[O:11])[CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCNC(c1ccccc1)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(C=Cc1cccnc1)NCCCCNC(c1ccccc1)c1ccccc1

Procedure:
Batch size: 1.9 g (12.6 mmol) 3-(3-pyridyl)-acrylic acid, 2.5 g (15.1 mmol) CDI and 3.7 g (14.5 mmol) 4-(benzhydryl-amino)-butylamine in 60 ml abs. THF.
Reaction SMILES: C([C:4]1[C:9](=[O:10])[C:8]([CH3:11])=[C:7]([CH3:12])[C:6](=[O:13])[C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)C.[BH4-].[Na+].Cl.I([O-])(=O)(=O)=O.[Na+].O1CCC[CH2:31]1.O>CO.O.C(OCC)(=O)C>[CH2:15]([NH:14][C:5]1[C:6](=[O:13])[C:7]([CH3:12])=[C:8]([CH3:11])[C:9](=[O:10])[CH:4]=1)[C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:31]=1
Reactant: C1CCOC1
Reactant: CC(=O)C1=C(Nc2ccccc2)C(=O)C(C)=C(C)C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC1=C(C)C(=O)C(NCc2ccccc2)=CC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54 %

Procedure:
To a stirred solution of the 3-acetyl-2-anilino-5,6-dimethyl-1,4-benzoquinone (700 mg, 2.6 mmol) in tetrahydrofuran-water (5:4, 12.5 mL) was added sodium borohydride (197 mg, 5.2 mmol) at room temperature. The mixture was stirred at room temperature for 10 minutes. 1N hydrochloric acid (1 mL) and ethyl acetate (50 mL) were added and the mixture was stirred for 10 minutes. The organic layer was washed with sodium bicarbonate solution and brine. The solution was dried over magnesium sulfate and concentrated in vacuo to give pale red oil. This product was dissolved in methanol (7 mL). To the solution was added sodium periodate in water at room temperature. The mixture was stirred for 5 minutes then extracted with ethyl acetate (50 mL) and washed with brine (10 mL×4). The solution was dried over magnesium sulfate and concentrated in vacuo to give a dark red oil. This was subjected to a silica gel column eluted with ethyl acetate hexane (1:3.5). The desired red color fraction was crystallized from hexane-diisopropyl ether to give red powder of the title compound (380 mg, 54% yield). Mp 101.2°-101.6° C.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]([C:12]1[CH2:19][N:18]2[N:14]([C:15](=[O:28])[CH:16]([NH:20]C(OC(C)(C)C)=O)[CH2:17]2)[C:13]=1[C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>C(O)(=O)C>[ClH:1].[CH2:2]([O:9][C:10]([C:12]1[CH2:19][N:18]2[N:14]([C:15](=[O:28])[CH:16]([NH2:20])[CH2:17]2)[C:13]=1[C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CCOC(=O)C1=C(C(=O)OCc2ccccc2)CN2CC(NC(=O)OC(C)(C)C)C(=O)N12
Agent: Cl
Solvent: CC(=O)O
Product: C=CCOC(=O)C1=C(C(=O)OCc2ccccc2)CN2CC(N)C(=O)N12
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Under a nitrogen atmosphere, allyl 3-(benzyloxycarbonyl)-7-(R,S)-(t-butoxycarbonylamino)-8-oxo-1,5-diazabicyclo[3.3.0]octa-2-ene-2-carboxylate hydrochloride (370 mg, 0.81 mmol) was combined with a 3N hydrochloric acid solution in glacial acetic acid (15 ml) and the solution was stirred at room temperature for 25 minutes. The acid was removed in vacuo and the remaining volatiles on the resultant residue were removed by azeotropic distillation with methylene chloride (2×) to give the title salt.
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C@@H:7]([CH:8]=[CH:9][C:10]4[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=43)[C@@H:6]1[CH2:5][CH2:4][C:3]2=O.NN.[OH-].[K+].Cl>C(O)COCCO.O>[CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C@@H:7]([CH:8]=[CH:9][C:10]4[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=43)[C@@H:6]1[CH2:5][CH2:4][CH2:3]2
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C=C[C@H]3[C@@H]1CCC2=O
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Solvent: OCCOCCO
Product: C[C@@]12CCC[C@H]1[C@@H]1C=Cc3cc(O)ccc3[C@H]1CC2

Procedure:
Estra-1,3,5(10),6-tetraen-3-ol-17-one (91.1 mg, 0.339 mmol), hydrazine (54 μL, 1.7 mmol), and potassium hydroxide (0.06 g) in 1.8 mL of diethylene glycol were heated in a 200° C. bath under argon for 2 h. After cooling to RT 10 mL of water were added and the solution was acidified to pH≈2 with 1N HCl. The resulting suspension was extracted three times with 10 mL of ether and the combined organic extracts were washed with 10 mL of brine, dried over magnesium sulfate, filtered through Celite, and concentrated under reduced pressure. The crude solid was purified by preparative TLC (25% ethyl acetate/hexane on silica gel) to give product homogeneous to TLC (5.9 mg, 23 μmol, 7%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][CH:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=5)[N:24]=[CH:23][CH:22]=4)[O:13][C:12]3=[O:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Br[CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47].[Na+].[I-]>C1COCC1>[CH3:49][O:48][C:46](=[O:47])[CH2:45][CH2:44][N:18]([CH2:17][CH2:16][CH:14]1[O:13][C:12](=[O:33])[N:11]([C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH2:15]1)[CH2:19][CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=2)[N:24]=[CH:23][CH:22]=1
Reactant: COc1ccc2nccc(CCNCCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)c2n1
Reactant: COC(=O)CCBr
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CCN(CCc1ccnc2ccc(OC)nc12)CCC1CN(c2ccc3c(c2)OCCO3)C(=O)O1
Temperature: 80 °C
Yield: 42.4 %

Procedure:
A solution of the compound of Example 72 (0.2 g, 0.44 mmol) in THF (3 mL) was treated with DIPEA (0.147 mL, 2 eq.), methyl 3-bromopropionate (0.074 g, 1 eq.) and NaI (0.067 g, 1 eq.). The mixture was heated at 80° C. for 2 h, partitioned between EA and water. The org. phase was dried over MgSO4 and concentrated. The residue was purified by FC (EA) to give the title compound as a yellowish oil (0.1 g, 42% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH:14]([CH3:24])[CH2:15][NH:16]C(=O)OC(C)(C)C)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>>[NH2:16][CH2:15][CH:14]([CH3:24])[CH2:13][NH:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)(=[O:11])=[O:10]
Reactant: CC(CNC(=O)OC(C)(C)C)CNS(=O)(=O)c1ccc(C#N)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(CN)CNS(=O)(=O)c1ccc(C#N)cc1
Yield: 65.6 %

Procedure:
A solution of the compound obtained in Step 1 (273 mg, 0.77 mmol) in TFA (1 mL, 12.98 mmol) was stirred at room temperature for min, and the mixture was concentrated under reduced pressure. To the residue were added ethyl acetate and 1N aqueous sodium hydroxide solution, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure to give N-(3-amino-2-methylpropyl)-4-cyanobenzenesulfonamide (128 mg, 0.505 mmol, 65.4%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH2:10]([C:12]([CH3:18])([CH2:16][CH3:17])[CH2:13][CH:14]=O)[CH3:11]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:11]/[CH2:10][C:12]([CH2:16][CH3:17])([CH3:18])[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(C)(CC)CC=O
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CCC(C)(CC)C/C=N/CC(=O)OC(C)(C)C
Yield: 100.9 %

Procedure:
Step E In a manner similar to the method described in Example 1a, glycine tert-butyl ester (1.0 g, 7.8 mmol) was reacted with 3-ethyl-3-methyl-pentanal (1 g, 7.8 mmol) in CH2Cl2 at room temperature for 5 h to give [3-ethyl-3-methyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.9 g, 100%).
Reaction SMILES: [Cl-].[Li+].C(OP([CH:11]([CH2:17][CH2:18][CH:19]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)CC)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.[CH2:51]([O:58][C:59]([N:61]1[C@@H:65]([CH2:66][CH:67]([CH3:69])[CH3:68])[C@H:64]([CH:70]=O)[O:63][C:62]1([CH3:73])[CH3:72])=[O:60])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.Cl>O1CCCC1>[CH2:51]([O:58][C:59]([N:61]1[C@@H:65]([CH2:66][CH:67]([CH3:68])[CH3:69])[C@H:64]([CH:70]=[C:11]([CH2:17][CH2:18][CH2:19][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:63][C:62]1([CH3:72])[CH3:73])=[O:60])[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CC(C)C[C@H]1[C@H](C=O)OC(C)(C)N1C(=O)OCc1ccccc1
Reactant: CCOC(=O)C(CCC(CC)OC1CCCCO1)P(=O)(OCC)OCC
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)CCCOC1CCCCO1
Temperature: 0 °C
Yield: 84.3 %

Procedure:
63.4 mg of lithium chloride was suspended in 5 ml of dry tetrahydrofuran under an argon gas stream. A solution prepared by dissolving 546 mg of ethyl 2-diethylphosphono-5-(2-tetrahydropyranyloxy)heptanoate in 0.6 ml of dry tetrahydrofuran, was added thereto under stirring. The mixture was stirred for five minutes at room temperature, and then 1.4 ml of a 20% dry tetrahydrofuran solution of diazabicycloundecene was added. The mixture was stirred for 10 minutes at room temperature. Then, a solution prepared by dissolving 396 mg of (4S,5R)-3-benzyloxycarbonyl-2,2-dimethyl-5-formyl-4-isobutyloxazolidine in 1.0 ml of dry tetrahydrofuran, was added thereto, and the mixture was stirred overnight at room temperature. The mixture was cooled to 0° C. and then neutralized with 1N hydrochloric acid. Insolubles were filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in 20 ml of ethyl acetate and washed with water. The aqueous layer was further extracted twice with 15 ml of ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (8 g of Kieselgel 60) by using a mixture of hexane/ethyl acetate (10/1) to obtain 556 mg of ethyl 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidine- 5-yl]-2-[3-(2-tetrahydropyranyloxy)propyl]-2-propenoate (E/Z (60/40)) as a colorless oily substance.
Reaction SMILES: Br[CH2:2][C:3]([O:5]C)=[O:4].C(=O)([O-])[O-].[K+].[K+].[Br:13][C:14]1([N+:37]([O-:39])=[O:38])[CH:19]=[C:18]([C:20]2[C:32]3[C:31]([CH3:33])=[C:30]([CH3:34])[S:29][C:28]=3[C:27]([Br:35])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:17]=[CH:16][CH:15]1[OH:36].O>CN(C=O)C>[Br:13][C:14]1([N+:37]([O-:39])=[O:38])[CH:19]=[C:18]([C:20]2[C:32]3[C:31]([CH3:33])=[C:30]([CH3:34])[S:29][C:28]=3[C:27]([Br:35])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:17]=[CH:16][CH:15]1[O:36][CH2:2][C:3]([OH:5])=[O:4]
Reactant: Cc1sc2c(Br)c3ccccc3c(C3=CC(Br)([N+](=O)[O-])C(O)C=C3)c2c1C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1sc2c(Br)c3ccccc3c(C3=CC(Br)([N+](=O)[O-])C(OCC(=O)O)C=C3)c2c1C
Reaction time: 15 h
Yield: 68.1 %

Procedure:
Methyl bromoacetate (0.150 mL, 1.58 mmol) was added to a stirred suspension of potassium carbonate (0.223 g, 1.61 mmol), 2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol (0.400 g, 0.789 mmol) in DMF (2.8 mL). After 15 h, the reaction mixture was added to water and extracted with ethyl acetate. Silica gel was added to the ethyl acetate and the solvent was removed. The adsorbate was flashed (9:1 petroleum ether: ethyl actetate) to provide the title compound as a yellow solid (0.305 g, 67%). This solid (0.050 g, 0.086 mmol) was dissolved in 1:1 THF:methanol (2 mL) and treated with aqueous potassium hydroxide (1.0 N, 0.30 mL, 0.30 mmol). After 25 min the reaction mixture was diluted with water, acidified with 10% aqeous HCl and extracted with ether. The ether phase was dried (sodium sulfate), concentrated and recrystallized from petroleum ether:ether to provide the title compound as a white solid (0.025 g, 51%): mp 228-229° C.: NMR (DMSO-d6); δ8.23 (d, J=9 Hz, 1H), 8.14 (d, J=2 Hz, 1H), 8.04 (d, J=2 Hz, 1H), 7.69 (ddd, J=8, 7, 1, 1H), 7.54 (ddd, J=8, 7, 1 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 4.87 (d, J=6 Hz, 1H), 4.82 (d, J=6 Hz, 1H), 2.46 (s, 3H), 1.62 (s, 3H); MS (+FAB): 2 bromine isotope pattern 563 (40%), 565 (100%), 567 (50%); Anal. Calc. for C22H15Br2NO5S: C, 46.75, H, 2.68; N, 2.48. Found: C, 45.18; H, 2.66; N, 2.38.
Reaction SMILES: O[C:2]([C:19]1[C:20](=[O:56])[NH:21][C:22](=[O:55])[N:23]([CH:54]=1)[C@@H:24]1[O:53][C@H:43]([CH2:44][O:45][Si](C(C)(C)C)(C)C)[C@@H:34]([O:35][Si](C(C)(C)C)(C)C)[C@H:25]1[O:26][Si](C(C)(C)C)(C)C)([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:19]2[C:20](=[O:56])[NH:21][C:22](=[O:55])[N:23]([CH:54]=2)[C@@H:24]2[O:53][C@H:43]([CH2:44][OH:45])[C@@H:34]([OH:35])[C@H:25]2[OH:26])[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[CH:4][CH:5]=1
Reactant: COc1ccc(C(O)(c2ccc(OC)cc2)c2cn([C@@H]3O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c(=O)[nH]c2=O)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(c2ccc(OC)cc2)c2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c(=O)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
The product of step (i) (3.8 g) was dissolved in dichloromethane (75 ml) and triethylsilane (0.8 ml) and was treated with trifluoroacetic acid(3.59 ml). After stirring for 1 hour at room temperature, the volatiles were removed under reduced pressure and any remaining traces removed by azeotroping four times with toluene. The residue was treated with 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (15 ml). After stirring for 36 hours, the solvent was removed under reduced pressure and the residue was purified by silica-gel chromatography eluting with 2% methanol in ethyl acetate to afford 5-(1,1-bis(4-methoxyphenyl)methyl)uridine as a white solid (1.4 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[C:15]([SH:19])[N:14]=[C:13]([O:20][CH3:21])[C:12]=2[C:22]#[N:23])=[CH:7][CH:6]=1.Cl[CH2:25][C:26]1[N:27]=[C:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[S:29][CH:30]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C.CO>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([C:28]2[S:29][CH:30]=[C:26]([CH2:25][S:19][C:15]3[C:16]([C:17]#[N:18])=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=4)[C:12]([C:22]#[N:23])=[C:13]([O:20][CH3:21])[N:14]=3)[N:27]=2)=[CH:36][CH:35]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: COc1nc(S)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Reaction time: 0.03 h

Procedure:
2.095 g (6.399 mmol) of 4-[4-(2-hydroxyethoxy)phenyl]-2-methoxy-6-sulphanylpyridine-3,5-dicarbonitrile together with 1.875 g (7.679 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 1.613 g (19.197 mmol) of sodium bicarbonate in 50 ml of DMF are stirred at room temperature overnight. Water and methanol are added, and the reaction mixture is placed in an ultrasonic bath for 2 minutes. A white solid precipitates out and is filtered off, washed with methanol and dried under high vacuum. The mother liquor is concentrated to half of the original volume and placed in the fridge for 30 minutes. The precipitated solid is filtered off, washed with methanol and dried under high vacuum. The two precipitated solids are combined, giving a total of 2.98 g (85% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[S:14])[C:11]#[N:12])=[CH:5][CH:4]=1.I[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].CCN(C(C)C)C(C)C>C(#N)C>[C:11]([C:10]1[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:14][C:13]=1[N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)#[N:12]
Reactant: COc1ccc(C=C(C#N)C(=S)N2CCOCC2)cc1
Reactant: CCOC(=O)CI
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C1SC(N2CCOCC2)=C(C#N)C1c1ccc(OC)cc1
Reaction time: 0.17 h
Yield: 63 %

Procedure:
A mixture of 3-(4-methoxyphenyl)-2-(morpholin-4-ylcarbonothioyl)acrylonitrile (from step 1), ethyl iodoacetate (0.25 mL, 2.1 mmol) and DIPEA (0.5 mL, 2.9 mmol) was dissolved in ACN (2 mL) and subjected to MWI at 150° C. for 10 min. The mixture was allowed to cool and was concentrated. The residue was diluted with 5% sodium bisulfite solution and extracted with EtOAc. The organic solutions were combined, washed with sat NaHCO3 and brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give ethyl 4-cyano-3-(4-methoxyphenyl)-5-morpholin-4-yl-2,3-dihydrothiophene-2-carboxylate (0.168 g, 63% over two steps). LCMS: (AA) ES+ 375, ES− 373.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:32])[CH:9]([NH:24]C(=O)OC(C)(C)C)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])[CH:12]=2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[NH2:24][CH:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:22])([F:23])[CH:19]([F:20])[F:21])[CH:12]=1)[CH:8]([C:5]1[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=1)[OH:32]
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)nc1
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
To a solution of 1,1-dimethylethyl(1RS,2SR)-2-(6-fluoropyridin-3-yl)-2-hydroxy-1-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethylcarbamate (1.0 g, 2.16 mmol) was added trifluoroacetic acid (10 ml), and the mixture was stirred at room temperature for 10 min. The reaction solution was concentrated under reduced pressure and 1N aqueous sodium hydroxide solution (10 ml) was added. The mixture was extracted with ethyl acetate (20 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS,2SR)-2-amino-1-(6-fluoropyridin-3-yl)-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol (750 mg, 96%).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C@H:15]2[C@H:10]([CH2:11][CH2:12][C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([OH:18])[CH2:14]2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:13]2([OH:18])[CH2:12][CH2:11][C@H:10]3[C@H:15]([CH2:16][CH2:17][NH:8][CH2:9]3)[CH2:14]2)=[CH:24][CH:23]=1
Reactant: OC1(c2ccc(F)cc2)CC[C@@H]2CN(Cc3ccccc3)CC[C@@H]2C1
Agent: O=C[O-]
Agent: [NH4+]
Product: OC1(c2ccc(F)cc2)CC[C@@H]2CNCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Part A: Nitrogen gas was bubbled through methanol (25 mL). The following reagents were added in order: 10% palladium on carbon (0.5 g), the product of Example 8 (0.5 g, 1.5 mmol) and ammonium formate (1.0 g). The reaction mixture was heated to reflux temperature and stirred for 30 min. The reaction mixture was cooled to ambient temperature and filtered through Celite. The filter pad was washed with methanol and chloroform. The combined filtrates were concentrated in vacuo. The residue was treated with a 1N NaOH solution and extracted three times with ethylacetate. The combined organic layers were dried over magnesium sulfate and filtered. Solvent was removed in vacuo to give cis-6-(4'-fluorophenyl)-6-hydroxydecahydroisoquinoline: NMR (CDCl3, 300 MHz): 7.45 (dd, 2H, J=8, 6), 7.0 (t, 2H, J=8), 3.15-1.4 (m, 16H); HRMS: Calcd: 249. 1529 Found: 249.1531.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.[N:40]1([C:47](=O)[CH2:48]Cl)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[N:40]1([CH2:47][CH2:48][O:39][C:38]2[CH:37]=[CH:36][C:4]([CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]3[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=3[CH:16]3[CH2:17][CH2:18][C:23]4[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:24]=4[CH2:25]3)=[CH:3][C:2]=2[F:1])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: O=C(CCl)N1CCCCCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCCCC3)c(F)c2)C(C)C)c1
Yield: 16 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 1-azepan-1-yl-2-chloroethanone (17 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.2 mg) was obtained.