Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:19]=[CH:18][C:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:8][CH:7]=2)=[CH:2]1.C(OC([N:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O)=O)(C)(C)C.[H-].[Na+].C([O-])(O)=O.[Na+].[ClH:51]>CN(C=O)C.O1CCOCC1.C1COCC1>[ClH:51].[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:32][C@H:28]4[CH2:29][CH2:30][CH2:31][NH:27]4)=[CH:13][CH:12]=3)=[CH:18][CH:19]=2)=[CH:2]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(Cc2ccc(-c3ccsc3)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: c1cc(-c2ccc(Cc3ccc(OC[C@H]4CCCN4)cc3)cc2)cs1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(4-Thiophen-3-yl-benzyl)-phenol (9 g, 33.8 mmol, 1 eq.) and (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (12.6 g, 35.5 mmol, 1.05 eq.) in DMF (80 ml) was added sodium hydride (60% in mineral oil, 1.62 g, 40 mmol, 1.2 eq.) at 0° C. in one portion. The mixture was stirred at 85° C. overnight. Since (R)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester was consumed with about 15% of 4-(4-thiophen-3-yl-benzyl)-phenol remaining (by TLC and 1H NMR analysis), 1.23 g of additional of (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.46 mmol, 0.1 eq.) was added and the mixture was stirred for overnight. After cooling to room temperature, the mixture was poured into NaHCO3 aq. (500 ml). The mixture was extracted with EtOAc (150 ml×3). The combined EtOAc layers were washed with water (50 ml×3), dried over anhydrous MgSO4. Evaporation of solvent under reduced pressure gave the crude product as oil (15 g), of which 1H NMR indicated existence of 13% of starting 4-(4-Thiophen-3-yl-benzyl)-phenol. Then the crude product thus obtained was treated with 4N HCl in dioxane (40 ml) overnight to form a solid, which was suspended in THF (3.5 L) and stirred at room temperature overnight. The solid was filtered off and washed with ether. After drying on a vacuum line at 65° C. overnight, 7 g of desired product was obtained as off-white solid. The mother liquid (THF) was evaporated under reduced pressure to 500 ml and the suspension was collected by filtration and washed with ether to give 2.5 g of product; m.p. 187.6˜188.3° C.; LC-MS: 99% purity; HPLC: 99% purity; ee: 99%, determined by chiral HPLC; Elemental analysis (C22H25ClNOS): Calculated (%): C, 68.29; H, 6.51; N, 3.62; S, 8.29. Found (%): C, 67.97; H, 6.36; N, 3.49; S, 8.36. 1H NMR (400 MHz, DMSO-d6) δ 1.70 (m, 1H), 1.90 (m 2H), 2.1 (m, 1H), 3.2 (m, 2H), 3.86 (m, 1H), 3.89 (S, 2H), 4.08 (dd, J=8.0 J2=10.4 Hz, 1H), 4.20 (dd, J1=3.6 Hz, J2=10.8 Hz, 1H), 6.92 (d, J=8.8 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.51 (dd, J=1.6, 4.8 Hz, 1H), 7.62 (m, 3H), 7.79 (d, J=1.6, 3.2 Hz, 1H).
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1.CS(O)(=O)=O.C([CH:22]([CH2:26][CH2:27][CH2:28][C@H:29]1[C@@H:37]2[C@@H:32]([NH:33][C:34]([NH:36]2)=[O:35])[CH2:31][S:30]1)[C:23](=[O:25])[OH:24])C1C=CC=CC=1.C(O)(=O)C>O>[OH:25][C:23]([CH2:22][CH2:26][CH2:27][CH2:28][C@H:29]1[C@@H:37]2[C@@H:32]([NH:33][C:34]([NH:36]2)=[O:35])[CH2:31][S:30]1)=[O:24]
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCC(Cc2ccccc2)C(=O)O)N1
Agent: CS(=O)(=O)O
Solvent: Cc1cc(C)cc(C)c1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 80 °C
Reaction time: 4 h

Procedure:
35.34 g of the compound obtained in Example 5, 121 ml of mesitylene and 116.1 g of methanesulfonic acid were heated at an inner temperature of 130° C. By setting a reaction starting time when the mixture reached to 125° C., the mixture was stirred at 128° C. to 133° C. for 4 hours, disappearance of monobenzylbiotin was confirmed by high performance liquid chromatography. The reaction mixture was cooled to 80° C., 30 ml of acetic acid was added thereto, and methanesulfonic acid layer was added dropwise to 710 ml of purified water. The mesitylene layer was separated, ice-cooled for 1 hour, and then, crude crystal was collected by filtration, and washed with 200 ml of water, and then, with methanol until black color of the washed solution disappeared. The crystal was dried at 50° C. by blowing air overnight to give 15.89 g of crude (+)-biotin.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([S:25]([CH3:28])(=[O:27])=[O:26])=[C:21]([CH2:23][NH2:24])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Br:16][C:17]1[CH:18]=[CH:19][C:20]([S:25]([CH3:28])(=[O:27])=[O:26])=[C:21]([CH:22]=1)[CH2:23][N:24]1[CH:10]=[C:11]([Cl:12])[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1]1=[NH:2]
Reactant: CS(=O)(=O)c1ccc(Br)cc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Br)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 47.7 %

Procedure:
(Step 5) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.95 g), 1-[5-bromo-2-(methylsulfonyl)phenyl]methanamine hydrochloride obtained in Step 4 (3.0 g) and potassium carbonate (3.45 g) were stirred in ethanol (30 ml) at 80° C. for 16 hr. The reaction mixture was treated with 1N sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=4:1). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (3 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized to give the title compound (0.9 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:29])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:10]=2)[CH:8]=1.[OH:30][CH2:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[F:29][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:31]([C:32]2[CH:40]=[CH:39][CH:38]=[C:34]([CH2:35][OH:36])[CH:33]=2)=[O:30])=[CH:8][C:7]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:21]2)[CH:10]=1
Reactant: O=C(O)c1cccc(CO)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CN)ccc3F)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CO)c4)ccc3F)c2)CC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 91.4 %

Procedure:
To a solution of 1,1-dimethylethyl 4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-1-piperazinecarboxylate (100 mg, 0.25 mmol) in DCM (2.5 mL) was added 3-(hydroxymethyl)benzoic acid (38 mg, 0.25 mmol), HBTU (0.104 g, 0.275 mmol), and Et3N (0.0351 mL, 0.25 mmol). The mixture was stirred at room temperature for 21 h. The reaction was quenched with H2O. The organic layer was separated, directly load onto silica gel cartridge and purified by CombiFlash chromatograph to afford the title compound 0.122 g (91%). LC-MS m/z 534 (M+H)+.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][C:7]1[NH:12][C:11](=[S:13])[NH:10][C:9](=[O:14])[CH:8]=1.Cl[CH2:16][C:17]([NH2:19])=[O:18].C(O)C>O>[OH:14][C:9]1[CH:8]=[C:7]([CH3:6])[N:12]=[C:11]([S:13][CH2:16][C:17]([NH2:19])=[O:18])[N:10]=1
Reactant: Cc1cc(=O)[nH]c(=S)[nH]1
Reactant: NC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(O)nc(SCC(N)=O)n1

Procedure:
To a solution of 16.8 g. (0.2 mole) of sodium bicarbonate in 300 ml of water was added 22.8 g.(0.2 mole) of 6-methyl-2-thiouracil. The mixture was heated on a steam bath for 10 minutes. To this mixture was then added 18.6 g.(0.2 mole) of 2-chloroacetamide followed by 100 ml of absolute ethanol. The mixture was heated on a steam bath for 2 hours. The solution was cooled in an ice bath and the precipitate which formed was collected and recrystallized from a mixture of N,N-dimethylformamide and ethanol to afford 8 g. of product, m.p. 238°-240° d.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COCOC.C(Cl)[CH2:15][Cl:16]>[Ti](Cl)(Cl)(Cl)Cl>[CH3:8][S:7][C:1]1[CH:6]=[CH:5][C:4]([CH2:15][Cl:16])=[CH:3][CH:2]=1
Reactant: CSc1ccccc1
Reactant: ClCCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COCOC
Product: CSc1ccc(CCl)cc1
Temperature: -5 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
A solution of 24.8 g. (0.20 mole) of thioanisole in 180 ml. of ethylene dichloride was cooled to -5°C in an ice-methanol bath. 48 Ml. (83.6 g., 0.44 mole) of titanium tetrachloride was added dropwise over 15 minutes while maintaining the temperature at 0°-5°C. Another 10 ml. of ethylene dichloride was employed to wash forward the last quantities of titanium tetrachloride. The solution was cooled to -5°C again and 16.8 g. (0.22 mole) of methylal was added over 15 minutes while holding the temperature at 0-5°C. The reaction was stirred for 24 hours at 0-5°C and was quenched in 250 g. of ice. The organic layer was separated and the aqueous layer was extracted with 2 × 100 ml. of ethylene dichloride. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo at 50°-60°C to give 31.6 g. of crude product. Quantitative vpc analysis showed the product to contain a 64% yield of p-methylthiobenzyl chloride and a 5% yield of the ortho isomer.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:11](=[O:14])([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[C:2]1([C:1]2[S:8][C:2]([CH2:3][CH2:4][CH:11]=[O:14])=[CH:1][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: O=CCCc1cnc(-c2ccccc2)s1

Procedure:
A solution of ethyl formyl β chloracetate in 240 ml of benzene was added to a suspension of 78 g of thiobenzamide in 200 ml of benzene and the mixture was refluxed for 3 hours 30 minutes while eliminating the water formed. The reaction medium was cooled and 320 ml of a 20% solution of potassium carbonate and 220 ml of water were added slowly. Extraction was carried out with ether, followed by washing, drying and distillation under reduced pressure to obtain 75.5 g of the desired product.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:8][O:9][CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][N:8]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1conc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1conc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of 3-(4-chloro-phenyl)-isoxazole-4-carboxylic acid ethyl ester (57.0 g, 226.5 mmol) in ethanol (234 mL) was added aqueous sodium hydroxide (2 N, 175 mL, 351 mmol) and the resulting mixture stirred overnight at room temperature. The mixture was then acidified with HCl solution (4 N, 92.6 mL) to pH 2-3. The precipitate was then filtered off and dissolved in THF (762 mL) and then washed with saturated sodium chloride solution. The aqueous phase was then extracted with ethyl acetate and THF (1:1, 300 mL) and the combined organic phases dried over sodium sulfate and evaporated to afford the title compound (50.7 g, 92%) which was obtained as a light yellow solid. MS: m/e=222.3 [M−H]−.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:17][CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].Cl.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:17][CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 4 °C
Reaction time: 24 h

Procedure:
102.2 g (442 mmoles) Boc-Leu-OH, 98.1 g (485 mmoles) Gly-OBzl.HCl and 55.9 g (478 mmoles HONSu were dissolved in 760 ml dichloromethane added 54 ml N-methylmorpholine. Cooling to 4° C. and addition of a cold solution (4° C.) of 100.1 g (485 mmoles) DCC in 190 ml dichloromethane. The stirring was kept for one day at 4° C.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]([F:60])([F:59])[C:14]1[CH:15]=[C:16]([C@H:24]([N:26]([CH3:58])[C:27]([N:29]2[CH2:49][CH2:48][C@:32]3([N:36]([C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:38])[CH:35]([OH:47])[CH2:34][CH2:33]3)[CH2:31][C@@H:30]2[C:50]2[CH:55]=[CH:54][C:53]([F:56])=[CH:52][C:51]=2[CH3:57])=[O:28])[CH3:25])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.O>C(Cl)Cl>[F:60][C:13]([F:12])([F:59])[C:14]1[CH:15]=[C:16]([C@H:24]([N:26]([CH3:58])[C:27]([N:29]2[CH2:49][CH2:48][C@:32]3([N:36]([C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:38])[C:35](=[O:47])[CH2:34][CH2:33]3)[CH2:31][C@@H:30]2[C:50]2[CH:55]=[CH:54][C:53]([F:56])=[CH:52][C:51]=2[CH3:57])=[O:28])[CH3:25])[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=1
Reactant: Cc1cc(F)ccc1[C@H]1C[C@]2(CCC(O)N2C(=O)OCc2ccccc2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CCC(=O)N2C(=O)OCc2ccccc2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a suspension of Pyridinium chlorochromate (PCC) (66.5 mg, 0.307 mmol) in DCM (2 ml) was added a solution of phenylmethyl(5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-hydroxy-1,8-diazaspiro[4.5]decane-1-carboxylate (Intermediate 32, 107 mg) in DCM (2 ml) and the reaction mixture was left stirring at rt for 1 hr. Further pyridinium chlorochromate (PCC) (66.5 mg, 0.307 mmol) was added and the reaction mixture was left stirring overnight. To the mixture were added H2O and further DCM. The two phases were separated and the organic one was washed two times with water and filtered through a phase separator tube. The crude obtained after evaporation was purified by Flash Chromatography (20 g cartridge; eluting from 2:1 to 1:1 Cy:EtOAc). Relevant fractions were collected and the solvent removed in vacuo obtaining the title compound (86 mg) as a white solid; UPLC: Rt=0.95 mins, m/z=694 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6]P(OCC)(OCC)=O)=[O:5].[H-].[Na+].[C:17]([O:21][C:22](=[O:41])[N:23]([CH:25]([CH:39]=O)[CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:24])([CH3:20])([CH3:19])[CH3:18].S([O-])(O)(=O)=O.[K+]>O1CCCC1.O.C(OCC)(=O)C.CCCCC>[CH2:2]([O:3][C:4](=[O:5])[CH:6]=[CH:39][CH:25]([N:23]([C:22]([O:21][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:41])[CH3:24])[CH:26]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:1]
Reactant: CN(C(=O)OC(C)(C)C)C(C=O)C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C=CC(C(c1ccccc1)c1ccccc1)N(C)C(=O)OC(C)(C)C

Procedure:
A solution of 14 ml (68 mmol) of phosphonoacetic acid triethyl ester in 130 ml of tetrahydrofuran is added at 0C to a solution of 3.7 g (84 mmol) of 55-65% sodium hydride dispersion (washed three times with pentane) in 130 ml of tetrahydrofuran. After 1 hour a solution of 13.6 g (40 mmol) of (1-formyl-2,2-diphenyl-ethyl)-methyl-carbamic acid tert-butyl ester in 130 ml of tetrahydrofuran is added dropwise thereto. After 4 hours the reaction mixture is rendered neutral with 1M potassium hydrogen sulfate and then diluted with water and ethyl acetate. The organic phase is washed three times with water, dried over magnesium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel using methylene chloride/methanol (99:1 to 98:2). The title compound is obtained in the form of a yellow oil. TLC: methylene chloride/methanol (98:2) Rf=0.45.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH:35]2[CH2:39][CH2:38][NH:37][CH2:36]2)=[O:33])=[CH:4][N:3]=1.[C:40](O)(=[O:42])[CH3:41].C(=O)([O-])[O-]>>[C:40]([N:37]1[CH2:38][CH2:39][CH:35]([NH:34][C:32]([C:5]2[C:6]3[S:10][CH:9]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]5[N:21]([CH3:29])[C:22]6[C:27]([CH:28]=5)=[CH:26][CH:25]=[CH:24][CH:23]=6)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=4)[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=2)=[O:33])[CH2:36]1)(=[O:42])[CH3:41]
Reactant: COc1cc(-c2csc3c(C(=O)NC4CCNC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Product: COc1cc(-c2csc3c(C(=O)NC4CCN(C(C)=O)C4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 20 h

Procedure:
4-Amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)-N-pyrrolidin-3-ylthieno[3,2-c]pyridine-7-carboxamide (100 mg, 0.185 mmol) and acetic acid (9.6 μL, 0.168 mmol) were treated according to General Procedure D. MP-carbonate (184 mg, 0.504 mmol) was added and mixture placed on shaker for 20 hours. The mixture was then filtered and solvent removed in vacuo. The product was purified via flash chromatography to furnish the title compound as a off-white powder. (3.2 mg, 0.0051 mmol): LCMS (Conditions b): MH+=583, Rt=2.85 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.50 (1 H), 8.62 (1 H), 8.54 (1 H), 8.00 (1 H), 7.71 (1 H), 7.59 (2 H), 7.35 (2 H), 7.19 (1 H), 7.15 (1 H), 7.06 (1 H), 6.04 (2 H), 4.46-4.56 (1 H), 4.04 (3 H), 3.91 (3 H), 3.80 (1 H), 3.61 (1 H), 3.50 (1 H), 3.39 (1 H), 2.00-2.22 (2 H), 1.96 (3 H).
Reaction SMILES: [Li+].[Cl-].[BH4-].[Na+].C[O:6][C:7](=O)/[CH:8]=[CH:9]/[CH2:10][C@H:11]1[CH2:13][C@@H:12]1[C:14]1[CH:15]=[N:16][CH:17]=[C:18]([O:20][CH2:21][C@@H:22]2[CH2:25][CH2:24][N:23]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:19]=1>CCO.C1COCC1>[C:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][C@H:22]1[CH2:21][O:20][C:18]1[CH:19]=[C:14]([C@H:12]2[CH2:13][C@@H:11]2[CH2:10][CH2:9][CH2:8][CH2:7][OH:6])[CH:15]=[N:16][CH:17]=1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)/C=C/C[C@H]1C[C@@H]1c1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@H]2C[C@@H]2CCCCO)c1
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
LiCl (138 mg, 3.27 mmol, 5.0 equiv.) was added to a stirred solution of NaBH4 (124 mg, 3.27 mol, 5.0 equiv.) in dry EtOH (10 mL) at 0° C., and the mixture was stirred at that temperature for 10 min. Then 4-[(1S,2S)-2-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]cyclopropyl]-2-trans-butenoic acid methyl ester (263 mg, 653 μmol) dissolved in THF (10 mL) was cannulated into the reaction mixture, which was subsequently refluxed for 24 h. The reaction was then quenched cautiously with saturated aqueous NH4Cl solution (10 mL), and the mixture was extracted with EtOAc (2×100 mL). The organic extracts were washed with water (50 mL) and brine (50 mL) and dried over Na2SO4. After concentration in vacuo, the crude product was purified by CC (SiO2, 3-4% MeOH in CH2Cl2 as the eluent) to provide 4-[(1S,2S)-2-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]cyclopropyl]-1-butanol (207 mg, 84%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 8.10 (s, 1H), 8.01 (s, 1H), 6.84 (s, 1H), 4.56-4.43 (m, 1H), 4.37-4.23 (m, 1H), 4.11 (dd, 1H, J=9.8, 3.01 Hz), 3.89 (t, 2H, J=7.3 Hz), 3.66 (t, 2H, J=6.4 Hz), 2.43-2.19 (m, 1H), 1.69-1.45 (m, 7H), 1.41 (s, 9H), 1.12-0.98 (m, 1H), 0.97-0.87 (m, 1H), 0.86-0.76 (m, 1H). MS (ESI) m/z 376 (M+).
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:12]/[C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16])=[N+]=[N-]>C1(C)C=CC=CC=1>[F:21][C:20]1[C:13]([N:12]2[CH:11]=[C:5]3[CH:6]=[N:7][CH:8]=[C:9]([F:10])[C:4]3=[N:1]2)=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]
Reactant: N#Cc1cccc(F)c1/N=C/c1cncc(F)c1N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: N#Cc1cccc(F)c1-n1cc2cncc(F)c2n1
Yield: 86.2 %

Procedure:
A solution of 2-{[1-(4-azido-5-fluoropyridin-3-yl)meth-(E)-ylidene]amino}-3-fluorobenzonitrile (5.19 g, 18.2 mmol) in toluene (90 mL) was heated under reflux for 4 hours. The resultant mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (50-100% ethyl acetate in cyclohexane) to afford the title compound as a beige solid (4.02 g, 86% yield). LCMS (Method C): RT=2.41 min, m/z: 257 [M+H+].
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Br:20][CH2:21][C:22](OC)=[O:23]>>[Br:20][CH2:21][C:22]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:23]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: COC(=O)CBr
Product: CCCCCCCC/C=C\CCCCCCCCOC(=O)CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Technical grade oleyl alcohol (85 wt %; 10 g; 37.2 mmol) was combined with Novozym 435 (200 mg) in an amber bottle. Methyl bromoacetate (6.84 g; 44.7 mmol; 1.2 equiv.) was added, and the mixture was sealed and stirred at room temperature overnight to afford about 50% conversion to oleyl bromoacetate. The mixture was then purged with a subsurface stream of nitrogen 2.5 days to afford 98.5% conversion of oleyl alcohol to oleyl bromoacetate according to GC analysis. The mixture was filtered, and the solid was washed with toluene. The filtrate was concentrated to give the desired product as a viscous colorless oil (13.19 g, 91%). The product was used in the subsequent reactions without further purification.
Reaction SMILES: C([O:3][CH:4](OCC)/[CH:5]=[CH:6]/[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:8]=1[F:16])C.[Br:20]N1C(C)(C)C(=O)N(Br)C1=O.S(=O)(=O)(O)O>>[Br:20][C:10]1[CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:7](/[CH:6]=[CH:5]/[CH:4]=[O:3])=[C:8]([F:16])[CH:9]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CCOC(/C=C/c1c(F)cccc1[N+](=O)[O-])OCC
Agent: O=S(=O)(O)O
Product: O=C/C=C/c1c(F)cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
A mixture of (E)-2-(3,3-diethoxyprop-1-enyl)-1-fluoro-3-nitrobenzene (63.5 mg, 0.22 mmol), 1,3-dibromo-5,5-dimethylhydantoin (63.5 mg, 0.222 mmol, Aldrich) and sulfuric acid, 95% (0.5 mL, 7.14 mmol) was stirred at room temperature for 4 h. Ice (5 g) was added and the mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with saturated NaCl (6 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow oil. The crude product was purified by silica gel chromatography eluting with 20% EtOAc/hexanes to give (E)-3-(4-bromo-2-fluoro-6-nitrophenyl)acrylaldehyde (46 mg, 0.168 mmol, 39.3% yield). 1H NMR (300 MHz, CDCl3) δ 7.47-7.58 (m, 1H) 7.58-7.71 (m, 1H) 8.10 (d, J=8.33 Hz, 1H) 8.15 (s, 1H) 9.50 (s, 1H). m/z (ESI, +ve ion) 273 (M+H)+.