Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[S:7][C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=3[N:12]=2)=[CH:5][CH:4]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C1C=CC=CC=1>[N:20]1([CH2:2][C:3]2[S:7][C:6]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=4[N:12]=3)=[CH:5][CH:4]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc2oc(-c3ccc(CBr)s3)nc2c1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc2oc(-c3ccc(CN4CCOCC4)s3)nc2c1
Yield: 91.7 %

Procedure:
2-(5-Bromomethyl-2-thienyl)-5-nitrobenzoxazole (2.0 g, 0.006 mole) and morpholine (2.6 g, 0.03 mole) are dissolved in 100 ml of benzene and heated at reflux for 36 hours. The precipitated morpholine hydrobromide is removed by filtration and the benzene is evaporated yielding an oil. Crystallization from ethanol yields 1.9 g of product, melting point 149°-151° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[N:7][C:6]([N:9]2[C:17]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[CH:11]=[N:10]2)=[CH:5][CH:4]=1.Cl[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH:28]2[CH2:31][CH2:30][CH2:29]2)[CH2:24][CH2:23]1)=[O:21].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:2][C:3]1[N:8]=[N:7][C:6]([N:9]2[C:17]3[CH2:16][CH2:15][N:14]([CH2:19][C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH:28]5[CH2:31][CH2:30][CH2:29]5)[CH2:24][CH2:23]4)=[O:21])[CH2:13][C:12]=3[CH:11]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C(CCl)N1CCN(C2CCC2)CC1
Reactant: Clc1ccc(-n2ncc3c2CCNC3)nn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CN1CCc2c(cnn2-c2ccc(Cl)nn2)C1)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(6-chloropyridazin-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine hydrochloride (1.05 g, 3.86 mmol), 1-(chloroacetyl)-4-cyclobutylpiperazine (840 mg, 3.86 mmol), K2CO3 (2.11 g, 15.4 mmol) and KI (66 mg, 0.4 mmol) in CH3CN (20 mL) is stirred at rt overnight. The solvent is removed in vacuo and the residue is partitioned between water (20 mL) and EtOAc (20 mL). The layers are separated and the aqueous layer is extracted with EtOAc (3×20 mL). The combined extracts are washed with brine (30 μL), dried and evaporated. The resultant oil is purified by flash column with DCM/MeOH/NH4OH (100:5:0.5) to give the title compound as a light yellow solid. 1H NMR (6, CDCl3): 8.16 (d, 1H), 7.57 (d, 1H), 7.51 (s, 1H), 3.58-3.62 (m, 6H), 3.40 (s, 2H), 3.35 (t, 2H), 2.86 (t, 2H), 2.62-2.72 (m, 1H), 2.27 (q, 4H), 1.62-2.02 (m, 6H). MS (M+1): 416.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10]([F:16])([F:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]([F:16])([F:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)(F)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)C(F)(F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.4 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-3,3-difluoro-4-oxopiperidine (Synthonix, 0.100 g, 0.426 mmol, 1.0 eq) in dichloromethane (1.5 mL) was added benzylamine (0.070 mL, 0.638 mmol, 1.5 eq) followed by sodium triacetoxyborohydride (0.180 g, 0.851 mmol, 2.0 eq). The reaction was stirred at room temperature for 16 hours before adding Rochelle's salt (2 mL) and stirring for 1 hour. The reaction mixture was partitioned between NaHCO3 (50 mL) and CH2Cl2 (50 mL). The aqueous phase was extracted with CH2Cl2 (2×50 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (30→70% EtOAc-hexane) yielded the title compound (0.045 g, 32%) as a colourless oil; 1H nmr (CDCl3) δ 7.33 (4H, m, 4H of C6H5), 7.27 (1H, m, 1H of C6H5), 4.02 (1H, m), 3.92 (2H, s, CH2C6H5), 3.76 (1H, m), 3.32 (1H, ddd, J 21.5, 14.0, 4.5 Hz), 3.11 (1H, m), 2.97 (1H, m), 1.90 (1H, m), 1.67-1.59 (1H, m), 1.46 (9H, s, C(CH3)3); 19F nmr (CDCl3) δ −109.0 (dd, J 243.0, 115.5 Hz), −119.5 (d, J 251.0 Hz); m/z: 327 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:19]([C:23]([F:26])([F:25])[F:24])[O:20]2)=[CH:15][C:14]=1[Cl:32]>>[Cl:32][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:13]=1[CH2:12][N:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]1=[O:8])[O:20][CH:19]([C:23]([F:26])([F:25])[F:24])[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17]2
Reactant: Oc1ccc(Cl)cn1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(CBr)cc2OC1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C1=Cc2cc(Cl)c(Cn3cc(Cl)ccc3=O)cc2OC1C(F)(F)F
Yield: 38.1 %

Procedure:
The formation of the ester was performed according to the procedure outlined in Example 157 Step 4 starting with 97 mg of 5-chloro-2-pyridinol, 20.7 mg of sodium hydride (60% dispersion in mineral oil) and 300 mg of the bromide from Example 157 Step 3. The compound was purified on the FlashMaster® chromatography system eluting with 25% EA/hexane then 50% EA/hexane to give 128 mg (38%) of the desired compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]3([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH2:21][CH2:20]3)=[O:18])[N:10]=2)[CH:6]=[CH:5][N:4]=1.C[Si](I)(C)C>C(Cl)(Cl)Cl>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]2([C:17]([NH:16][C:11]3[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([C:7]4[CH:6]=[CH:5][NH:4][C:3](=[O:2])[CH:8]=4)[N:10]=3)=[O:18])[CH2:21][CH2:20]2)=[CH:23][CH:24]=1
Reactant: COc1ccc(C2(C(=O)Nc3ccc(C)c(-c4ccnc(OC)c4)n3)CC2)cc1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2(C(=O)Nc3ccc(C)c(-c4cc[nH]c(=O)c4)n3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-(2′-Methoxy-3-methyl-2,4′-bipyridin-6-yl)-1-(4-methoxyphenyl)cyclopropanecarboxamide (TFA salt) (˜39 mg, ˜0.10 mmol) was dissolved in chloroform (1 mL) in a reaction tube. Trimethylsilyliodide (56 μL, 0.40 mmol was added and the reaction mixture was stirred at room temperature for 4 hours. The resulting material was filtered and evaporated under reduced pressure. The crude product was dissolved in DMSO (1 mL), filtered, and purified by reverse phase preparative HPLC to yield 1-(4-methoxyphenyl)-N-(5-methyl-6-(2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclo-propanecarboxamide. ESI-MS m/z calc. 375.2. found 376.5 (M+1)+. Retention time 1.45 minutes.
Reaction SMILES: [C:1]([CH:3]1[NH:6][C:5](=[O:7])[C@H:4]1[NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:2].C(N(CC)CC)C.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>C(Cl)Cl>[Si:35]([N:6]1[CH:3]([C:1]#[N:2])[C@H:4]([NH:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]1=[O:7])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#CC1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1C#N
Yield: 44 %

Procedure:
To a mixture of 1.10 g of (3S,4RS)-4-cyano-3-tritylamino-2-azetidinone, 0.50 g of triethylamine and 20 ml of methylene chloride is added 0.56 g of tert-butyldimethylsilyl chloride under ice-cooling and stirring. The mixture is stirred at room temperature (approx. 25° C.) for 30 minutes and the reaction mixture is concentrated under reduced pressure. The residue is chromatographed on a a silicagel column [eluant: ethyl acetate-n-hexane (1:3)] to give 0.64 g of (3S,4RS)-1-tert-butyldimethylsilyl-4-cyano-3-tritylamino-2-azetidinone.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15](O)[C:14]=2[CH:13]=[CH:12][CH:11]=1.C(N(S(F)(F)[F:30])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[F:30][CH:15]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:2]3[NH:1][C:9]4[CH:8]=[CH:7][N:6]=[CH:5][C:4]=4[N:3]=3)[C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2
Reactant: CCN(CC)S(F)(F)F
Reactant: OC1c2ccccc2-c2c(-c3nc4ccncc4[nH]3)cccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC1c2ccccc2-c2c(-c3nc4cnccc4[nH]3)cccc21
Reaction time: 0.75 h

Procedure:
In a 10-ml round-bottomed flask under an argon atmosphere, dissolve 85 mg of 4-(3H-imidazo[4,5-c]pyridin-2-yl)-fluoren-9-ol, obtained in Example 3, in 3 ml of dichloromethane. Cool the solution obtained to −60° C. then add, dropwise using a syringe, 41 μL of diethylamino sulphur trifluoride (DAST). Leave to return to room temperature and stir for 45 minutes, then pour the reaction mixture into an aqueous solution with 10% of sodium hydrogen carbonate and extract twice with dichloromethane. Combine the organic phases, dry over sodium sulphate and concentrate under reduced pressure. After purification by chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and methanol (95-5 by volume), we obtain 44 mg of 2-[9(R,S)-fluoro-9H-fluoren-4-yl]-1H-imidazo[4,5-c]pyridine, in the form of a white powder with the following characteristics:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9]3([CH2:21][CH2:20]3)[C:10]2=[N:13]S(C(C)(C)C)=O)=[CH:5][CH:4]=1.C(OCC)C>O1CCOCC1>[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9]3([CH2:21][CH2:20]3)[C:10]2=[NH:13])=[CH:5][CH:4]=1
Reactant: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CCC12CC2
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N=C1c2cc(Br)ccc2CCC12CC2
Yield: 85.6 %

Procedure:
HCl (4 M in 1,4-dioxane) (8.38 mL, 33.5 mmol) was added to a warm solution of N-(7′-bromo-3′,4′-dihydro-1′H-spiro[cyclopropane-1,2′-naphthalene]-1′-ylidene)-2-methylpropane-2-sulfinamide (Intermediate 10, 1.19 g, 3.35 mmol) in dry dioxane (12 mL) under Ar (g). The mixture was stirred at r.t. for 40 min after which diethyl ether was added. The precipitate was filtered and washed with diethyl ether and then taken up in CH2Cl2 and washed twice with sat. aq. NaHCO3. The organic phase was dried (Na2SO4), filtered and concentrated to give the title compound (0.717 g, 85% yield). MS (ES+) m/z 250.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[NH2:26][CH2:27][CH:28]([C:30]1[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=1)[OH:29]>>[CH2:1]([O:3][C:4](=[O:25])[C:5](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][CH:21]([NH:26][CH2:27][CH:28]([OH:29])[C:30]3[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=3)[CH2:22][CH2:23]2)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc(N2CCC(=O)CC2)cc1)C(=O)OCC
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: CCOC(=O)C(=Cc1ccc(N2CCC(NCC(O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1)C(=O)OCC

Procedure:
The title compound was prepared from 2-[4-(4-oxo-piperidine-1-yl)-benzylidene]-malonic acid diethyl ester (which was obtained in Example 153) and N-[5-(-2-amino-1-hydroxy- ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 180 as a yellowish solid; mp >80° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.21 (t, J=7.0 Hz, 3H), 1.23 (t, J=7.0 Hz, 3H), 1.75-1.95 (m, 2H), 2.50-3.50 (m, 7H), 2.92 (s, 3H), 3.75-3.90 (m, 2H), 4.21 (q, J=7.0 Hz, 2H), 4.31 (q, J=7.0 Hz, 2H), 4.47 (dd, J=8.0, 4.2 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.94 (d, J=9.0 Hz, 2H), 7.00 (dd, J=8.2, 2.0 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.33 (d, J=9.0 Hz, 2H), 7.52 (s, 1H); MS (ES) m/z: 576.1 (MH+); HRMS Calcd. for C28H38N3O8S(MH+): 576.2374. Found: 576.2375.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[CH:7][N:8]=[CH:9][CH:10]=[C:5]2[C:4]([CH:11]=[O:12])=[CH:3]1.CC(=CC)C.[O-:18]Cl=O.[Na+]>C1COCC1.C(O)(C)(C)C.O>[CH3:1][N:2]1[C:6]2=[CH:7][N:8]=[CH:9][CH:10]=[C:5]2[C:4]([C:11]([OH:18])=[O:12])=[CH:3]1
Reactant: Cn1cc(C=O)c2ccncc21
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: Cn1cc(C(=O)O)c2ccncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
1-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde (WO 05066132) (6.5 g, 40.6 mmol) was dissolved in a mixture of THF (120 mL) and tert-butyl alcohol (40 mL) under nitrogen. 2-Methyl-2-butene (120 mL of a 2M solution in THF, 46 mmol) was added followed by a solution of NaClO2 (11.0 g, 122 mmol) and NaH2PO4 (21.9 g, 183 mmol) in water (30 mL). The reaction mixture was stirred at room temperature overnight under nitrogen. The reaction mixture was concentrated in vacuo to remove organic solvents, and the residue was filtered. The precipitate contained the title compound as a white solid in 57% yield, 4.1 g.
Reaction SMILES: [C:1]([C:4]1[C:8]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:7]([NH2:13])[N:6]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:5]=1)(=[O:3])[CH3:2].[SH:26][CH:27](O)[CH3:28].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.[Cl-].[Zn+2].[Cl-]>[NH2:13][C:7]1[N:6]([C:14]2[C:15]([Cl:25])=[CH:16][C:17]([C:21]([F:23])([F:22])[F:24])=[CH:18][C:19]=2[Cl:20])[N:5]=[C:4]([C:1]2([CH3:2])[S:26][CH2:27][CH2:28][O:3]2)[C:8]=1[S:9]([CH3:12])(=[O:10])=[O:11]
Reactant: CC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)(=O)=O
Reactant: CC(O)S
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(c2nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c(N)c2S(C)(=O)=O)OCCS1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
To a stirred solution of 54.34 grams (0.131 mole) of 3-acetyl-5-amino-1-[2,6-dichloro-4-(trifluromethyl)phenyl]-4-methylsulfonyl-1H-pyrazole in 500 mL of dioxane was added, in sequence, 36.7 mL (0.522 mole) of mercaptoethanol, 71.1 grams (0.522 mole) of anhydrous zinc chloride and 62.1 grams (0.522 mole) of anhydrous sodium sulfate while cooling at 0° C. in an ice bath. The mixture was then stirred for a period of approximately 17 hours while allowing it to warm to room temperature. The mixture was filtered to remove salts and the filtrate concentrated under reduced pressure and diluted with 40 mL of acetonitrile, collecting the product by filtering at 35° C. The filtrate was further diluted with acetonitrile to obtain a second crop of product. The combined crops of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-3-(2-methyl-1,3-oxathiolane-2-yl)-4-methylsulfonyl-1H-pyrazole gave 30.53 grams of material, having a melting point of 201° C. This compound is hereinafter referred to as Compound No. 23.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([C:16](OCC)=[O:17])[C:11](OCC)=[O:12])=[C:4]([Cl:29])[CH:3]=1.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].Cl>C(O)C.O1CCCC1.O>[C:25]([O:24][C:22](=[O:23])[NH:21][C:10]([CH2:11][OH:12])([CH2:16][OH:17])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[Cl:29])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)C(CCc1ccc(Br)cc1Cl)(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CO)(CO)CCc1ccc(Br)cc1Cl
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
Diethyl 2-[2-(4-bromo-2-chlorophenyl)ethyl]-2-[(tert-butoxycarbonyl)amino]malonate (217 g) of Reference Example 19 was dissolved in a mixed solution of ethanol (2170 mL), tetrahydrofuran (543 mL) and water (1085 mL), calcium chloride (97.7 g) was added at room temperature, and the mixture was stirred for 20 min. To the solution was added sodium borohydride (66.6 g) by portions at 0° C., and the mixture was stirred at the same temperature for 1 hr and further stirred at room temperature for 14 hr. 1M Hydrochloric acid (1085 mL) was added dropwise to the reaction mixture. The reaction solvent was evaporated under reduced pressure. 0.1M Hydrochloric acid (2713 mL) and ethyl acetate (3800 mL) were added to the residue. The organic layer was partitioned and extracted, and the extract was washed with 25% brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (175 g) as white crystals.
Reaction SMILES: [CH2:1]([O:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25].C(ON(CCCCC#N)C(=O)CCCCCl)C1C=CC=CC=1.CCCCCC.CCOC(C)=O>C(Cl)Cl.[OH-].[Na+]>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:25])[N:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15]
Reactant: N#CCCCCNOCc1ccccc1
Reactant: O=C(Cl)CCCCCCCBr
Agent: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCCCBr

Procedure:
Compound 2 (n=4) (3.2 g, 15.7 mmol) was treated with 8-bromooctanoyl chloride (4.55 g, 18.8 mmol) in CH2Cl2 and 1N NaOH following the procedure used for (3). Silica gel column chromatography with 2:1 hexane/EtOAc afforded 3.8 g (59%) of [I] as an oil: NMR δ 1.17-2.00 (m, 14 H), 2.23-2.50 (m, 4 H), 3.37 (t, 2 H, J=6), 3.63 (t, 2 H, J=6), 4.77 (s, 2 H), 7.33 (s, 5 H). Anal. (C20H29BrN2O2) C, H, N.
Reaction SMILES: [Cl:1]CC([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=1[OH:27])[CH2:10][C:11]1[C:12]([Cl:23])=[C:13]([Cl:22])[C:14]2[O:18][CH:17]([CH2:19][OH:20])[CH2:16][C:15]=2[CH:21]=1)=O.Cl>C(O)C>[ClH:1].[NH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=1[OH:27])[CH2:10][C:11]1[C:12]([Cl:23])=[C:13]([Cl:22])[C:14]2[O:18][CH:17]([CH2:19][OH:20])[CH2:16][C:15]=2[CH:21]=1
Reactant: O=C(CCl)NCc1cc(Cc2cc3c(c(Cl)c2Cl)OC(CO)C3)ccc1O
Agent: Cl
Solvent: CCO
Product: NCc1cc(Cc2cc3c(c(Cl)c2Cl)OC(CO)C3)ccc1O

Procedure:
The glass from Example 18 (500 mg.) was dissolved in ethanol (20 ml.) and treated with 3 N aqueous HCl (100 ml.) at reflux for four hours. The resulting solution was partially evaporated and chilled on an ice bath to yield a white crystalline precipitate (400 mg., 87.78%), m.p. 227°-230° (dec.).
Reaction SMILES: Br[C:2]1[C:3]([O:14][CH2:15][O:16][CH3:17])=[C:4]([CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:10]([C:8]1[CH:9]=[C:2]([C:23]2[CH:22]=[N:21][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:25][CH:24]=2)[C:3]([O:14][CH2:15][O:16][CH3:17])=[C:4]([CH:7]=1)[CH:5]=[O:6])([CH3:13])([CH3:12])[CH3:11]
Reactant: COCOc1c(Br)cc(C(C)(C)C)cc1C=O
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COCOc1c(C=O)cc(C(C)(C)C)cc1-c1ccc(C(F)(F)F)nc1
Temperature: 80 °C
Yield: 75.7 %

Procedure:
To a degassed (argon) solution of 3-bromo-5-(tert-butyl)-2-(methoxymethoxy)benzaldehyde (4.0 g, 13.3 mmol) and 2-(trifluoromethyl)pyridine-5-boronic acid [purchased from Frontier Scientific] (2.79 g, 14.6 mmol) in 2M aqueous sodium carbonate solution (26.7 mL, 53.2 mmol) and dimethoxy ethane (80 mL) was added tetrakis(triphenylphosphine)palladium(0) (770 mg, 0.665 mmol), the mixture was degassed for five minutes and then heated at 80° C. for 16 hours. The cooled reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried (Na2SO4), filtered and concentrated under reduced pressure to give an orange syrup. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes to give the 5-(tert-butyl)-2-(methoxymethoxy)-3-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde (3.7 g, 76% yield) as a grey-green solid.
Reaction SMILES: [CH2:1](C([SnH3])=C(CCCC)CCCC)[CH2:2]CC.Br[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[C:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:21]=[C:20]2[O:35][C@H:36]1[CH2:40][N:39](C(OC(C)(C)C)=O)[C@H:38]([C:48]([O:50][CH3:51])=[O:49])[CH2:37]1.[ClH:52]>C1(C)C=CC=CC=1.O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[ClH:52].[CH3:28][O:27][C:26]1[CH:25]=[C:24]2[C:19]([C:20]([O:35][C@H:36]3[CH2:40][NH:39][C@H:38]([C:48]([O:50][CH3:51])=[O:49])[CH2:37]3)=[CH:21][C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:23]2)=[CH:18][C:17]=1[CH:1]=[CH2:2]
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)c(Br)cc23)CN1C(=O)OC(C)(C)C
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: C=Cc1cc2c(O[C@H]3CN[C@H](C(=O)OC)C3)cc(-c3ccccc3)nc2cc1OC
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Tributylvinylstannane (1.15 eq.) and tetrakis(triphenylphosphine) palladium(0) (0.07 eq.) were added to a solution of compound 116 in toluene (0.09 M) and the reaction mixture was heated at 100° C. After 20 h volatiles were removed in vacuo and the residue was purified by column chromatography (SiO2, PE:EtOAc with EtOAc from 1 to 60%) to give a pale yellow solid, that was taken up in a 4N solution of HCl in dioxane (0.31 M). The reaction mixture was stirred for 1 h and the resulting white solid recovered by filtration, washed with EtOAc/petroleum ether affording the title compound 117 (99%) as a pale yellow solid. MS (ES+) m/z 405 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([S:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([S:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCSc1cnc(NC(=O)OC(C)(C)C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncc(SCCC(=O)O)s1
Yield: 81.3 %

Procedure:
Methyl 3-[2-(tert-butoxycarbonylamino)thiazol-5-yl]sulfanylpropanoate (9.0 g, 28.3 mmol) was dissolved in THF/H2O (3:1, 200 ml) and LiOH (1.4 g, 57.0 mmol) and the reaction mixture stirred at ambient temperature for 18 hours. The solvent was evaporated under vacuum then diluted with water and acidified with 1 M HCl to pH (4˜5). The solid formed was filtered, and washed with water and dried to give the title compound as a yellow solid (7.0 g, 80% yield) 1H NMR (400 Mz, CDCl3) δ1.57 (s, 9H), 2.69 (t, 2H), 2.98 (t, 2H), 7.33 (s, 1H).