Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of isovanillin (200 g) in dimethylformamide (500 ml) is added potassium carbonate (236 g) under ice-cooling, and thereto is added dropwise benzyl bromide (203 ml), and the mixture is stirred overnight. The insoluble materials in the resulting residue are removed by filtration, and washed with acetone, and the filtrate is concentrated under reduced pressure to remove the solvent. The residue is washed again with ether and water, and concentrated under reduced pressure to remove the solvent to give 3-benzyloxy-4-methoxybenzaldehyde as an oily product.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][CH:7]=[C:8]([CH3:9])[C:4]=2[CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>C(#N)C.O>[Br:19][C:7]1[S:6][C:5]2[CH:10]=[CH:11][C:2]([F:1])=[CH:3][C:4]=2[C:8]=1[CH3:9]
Reactant: Cc1csc2ccc(F)cc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: Cc1c(Br)sc2ccc(F)cc12
Temperature: 40 °C
Reaction time: 0.58 h

Procedure:
A mechanically-stirred solution of 5-fluoro-3-methylbenzo[b]thiophene (50.32 g, 0.303 mol, 1.0 equiv) in acetonitrile (350 mL) is treated with NBS (56.32 g, 0.318 mol, 1.05 equiv). An initial endotherm reduces the reaction temperature to 17° C. A subsequent exotherm then increases the reaction temperature to 40° C. over a 10 min. period, at which time the reaction is cooled to 18-20° C. by application of an ice water bath. The reaction is stirred at RT for an additional 35 min. and the resultant slurry is slowly diluted with water (350 mL). The slurry is stirred for 10 min and the product is filtered, washed with 50:50 acetonitrile:water (100 mL) and dried to a colorless crystalline solid (65.56 g, 88%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]2[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:34][N:33]=[N:32][N:31]=4)=[CH:20][CH:19]=3)[C:13]([CH2:15][CH3:16])=[N:14][C:9]2=[C:8]([CH3:35])[CH:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.CC(O)=O>C1COCC1>[CH2:15]([C:13]1[N:12]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:22][CH:23]=2)[C:10]2=[N:11][C:6]([CH2:4][OH:3])=[CH:7][C:8]([CH3:35])=[C:9]2[N:14]=1)[CH3:16]
Reactant: CCOC(=O)c1cc(C)c2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(CO)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
To 5-(ethoxycarbonyl)-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (50 mg) in THF (1 mL) at -78° C. was added Diisobutylaluminum hydride (0.534 mL, 1M/THF). After 1 hour at -78° C., the mixture was warmed to RT and 1% aqueous HOAc (2 mL) was added. Extractive workup (EtOAc), and purification (SiO2, 80/20/1 CH2Cl2 /MeOH/NH4OH) gave 28 mg of a solid.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH:5]=1.C([Li])CCC.Cl[C:18]([O:20][CH3:21])=[O:19]>C1COCC1.C(=O)(O)[O-].[Na+]>[CH3:21][O:20][C:18](=[O:19])[C:2]#[C:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH:5]=1
Reactant: Fc1cccc(C=C(Br)Br)c1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C#Cc1cccc(F)c1
Yield: 110.3 %

Procedure:
To a stirred solution of 1-(2,2-dibromo-vinyl)-3-fluoro-benzene (23.8 g) in anhydrous THF (350 ml) cooled to −78° was added dropwise over 30 minutes, n-butyllithium (2.2 eq, 1.6M in hexanes). The mixture was stirred for a further 30 minutes at −78° before methyl chloroformate (11.6 g, 9.5 ml) was added and the resultant mixture allowed to warm to 0° for 1 hour before being diluted with 1:1 saturated aqueous sodium bicarbonate:ammonium chloride (100 ml) and extracted into ether (2×100 ml). The combined organic extract was washed with brine (25 ml), dried (Na2SO4) and evaporated to dryness to give the title compound as a brown oil (16.7 g, 100%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.C(N(CC)CC)C.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].Cl>O1CCCC1.CN(C)C1C=CN=CC=1>[O:7]([CH:5]1[CH2:6][C:2](=[O:1])[CH:3]=[CH:4]1)[Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: O=C1C=CC(O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1C=CC(=O)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
A solution of 4-hydroxy-2-cyclopentenone (191 g, 1.95 mol, prepared in example 1) and triethylamine (430 mL, 3.09 mol) in anhydrous tetrahydrofuran (1 L) is treated with 4-dimethylaminopyridine (4.90 g, 40.0 mmol). The solution is cooled to 0° C. and treated portionwise, over 10 minutes, with tert-butyldimethylsilyl chloride (278 g, 1.84 mol) maintaining the temperature at or below 10° C. The reaction is then allowed to stir overnight at room temperature. It is then poured into aqueous HCl (0.5N, 1 L). The phases are separated and the aqueous phase is extracted with heptane (2×1 L). The organic phase and organic extracts are combined, washed with aqueous HCl (0.5N, 2×500 mL), then 5% sodium bicarbonate (500 mL), then brine (500 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum (40° C., 20 mmHg) to provide the title compound (325 g). This is purified by Kugelrohr distillation (70°-80° C., 1 mmHg) to provide the title compound (282 g, 72% yield) as a light yellow oil, Rf =0.55, 20% ethyl acetate/hexane, GC retention time is 14.97 minutes; 1H NMR (CDCl3) δ 7.48 (dd, J=5.7, 2.4 Hz, 1 H), 6.20 (d, J=5.7 Hz, 1 H), 4.95-4.99 (m, 1 H), 2.72 (dd, J=18.2, 6.0 Hz, 1 H), 2.25 (dd, J=18.2, 2.3 Hz, 1 H), 0.88 (s, 9 H), 0.11 (s, 6 H); 13 C NMR (CDCl3) δ 206.4, 163.8, 134.4, 70.8, 44.9, 25.7, 25.6, 18.0; IR (neat) νmax 2957, 2931, 2887, 2858, 1725 cm-1 ; MS (EI) m/e (% relative intensity) 212 (M+, 5), 155 (M+ -57, 100).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH:7]1[C:12](N=C=S)=[CH:11][C:10]2[C:16]([O:18][C:19]3([C:29]4[CH:30]=[CH:31][C:32]([OH:34])=[CH:33][C:28]=4[O:27][C:21]4[CH:22]=[C:23]([OH:26])[CH:24]=[CH:25][C:20]3=4)[C:9]=2[CH:8]=1)=[O:17]>P([O-])([O-])([O-])=O.CC(C)=O>[CH:7]1[CH:12]=[CH:11][C:10]([C:16]([OH:18])=[O:17])=[C:9]([C:19]2[C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=3[O:27][C:28]3[C:29]=2[CH:30]=[CH:31][C:32]([CH:33]=3)=[O:34])[CH:8]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12

Procedure:
One mg of HIgG (Human IgG) dissolved in 0.4 ml of 0.1 M phosphate buffer pH 7.5, was brought to pH 9.5 with crystalline Na2CO3. A solution (10 μl) of FITC (70 μg) in acetone was added with stirring and mixed for 3 hrs at room temperature. The resulting solution was separated two times on Sephadex G-25(M) column (1×15 cm) equilibrated with 0.05 M phosphate buffer pH 8.0. The eluted FITC-hIgG conjugate solution was 0.58 mg/ml in concentrated and had D/P=5.5 (M/M) as determined by the Wells' nomograph.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.CCCCC.C([Li])(C)(C)C.[C:21]([O:29][CH2:30][CH2:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>C(OCC)C>[C:21]([O:29][CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH:36]([C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[O:4][CH2:3][O:2][CH3:1])[OH:37])=[CH:38][CH:39]=1)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=Cc1ccc(CCOC(=O)c2ccccc2)cc1
Reactant: COCOc1cccnc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: CCOCC
Product: COCOc1cnccc1C(O)c1ccc(CCOC(=O)c2ccccc2)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
Next, to a mixture of 3-(methoxymethoxy)pyridine (2.4 g, 17.4 mmol) and diethyl ether (240 ml), a 1.47 mol/L t-butyllithium n-pentane solution (15 ml, 22.0 mmol) was added dropwise at −70° C. over 15 minutes. After stirring at −70° C. for 1 hour, a diethyl ether solution of 4-(2-benzoyloxyethyl)benzaldehyde (5.35 g, 21.0 mmol) was added over 10 minutes and stirred at −70° C. for 1.5 hours. After warming to room temperature, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:80) to give [4-(2-benzoyloxyethyl)phenyl]-[3-(methoxymethoxy)pyridin-4-yl]-methanol (2.2 g, 32%) as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:16]=[O:17]>C1COCC1.CCOCC>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH:16]=[O:17])=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1ccc(Br)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
2,5-Dibromopyridine 9.48 g (40 mmol) was dissolved in 60 mL of THF and 150 mL of anhydrous ether. After the solution was cooled to −78° C., 16 mL of n-butyllithium (2.5 M, 40 mmol) was slowly dropped through a syringe in 30 min. After being stirred at −78° C. for 30 minutes, N,N-dimethylformamide (3.5 g, 48 mmol) was added. The reaction mixture was warmed up to room temperature during two hours and then quenched by addition of 10 ml water. The mixture was extracted twice using EtOAc. The combined extracts were dried and concentrated. After flash column using 30-40% EtOAc in hexane, 2.80 g white solid was obtained (28% yield), MS: (M+H)+ 186.0, 188.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH3:12][O-:13].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([O:13][CH3:12])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
To a cooled (0° C.) solution of 5-bromo-2-chloro-3-nitropyridine (50 g, 211 mmol) in methanol (200 mL) was added dropwise over 10 minutes 20% sodium methoxide (50 mL, 211 mmol) solution. The reaction, which quickly became heterogeneous, was allowed to warm to ambient temperature and stirred for 16 h. The reaction was filtered and the precipitate diluted with water (200 mL) and stirred for 1 h. The solids were filtered, washed with water (3×100 mL) and dried in a vac oven (40° C.) to give 5-bromo-2-(methyloxy)-3-nitropyridine (36 g, 154 mmol, 73.4% yield) as a pale yellow powder. The original filtrate was concentrated in vacuo and diluted with water (150 mL). Saturated ammonium chloride (25 mL) was added and the mixture stirred for 1 h. The solids were filtered, washed with water, and dried in a vac oven (40° C.) to give a second crop of 5-bromo-2-(methyloxy)-3-nitropyridine (9 g, 38.6 mmol, 18.34% yield). Total yield=90%. MS(ES)+ m/e 232.8, 234.7 [M+H]+.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CN(C)CCN(C)C.[Li]CCCC.[I:27]I>C1COCC1>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[I:27])=[O:6]
Reactant: CC(C)(C)C(=O)Nc1cccnc1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cnccc1I
Temperature: -78 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
The 3-(Pivaloylamino)pyridine 15 (1.9 g, 11 mmol) and tetramethylethylene-diamine (4.0 mL, 26 mmol) were dissolved in dry THF (60 mL) and cooled to −78° C. While maintaining the temperature between −78° C. and −65° C., nBuLi (2.5 M solution in hexanes, 10.6 mL, 26.5 mmol) was added dropwise. The reaction was allowed to warm to −10° C. for 2 h, and then cooled back down to −78° C. Iodine (6.73 g, 26.5 mmol) dissoved in dry THF (20 mL) was added slowly. After stirring for 2 h at −78° C., the reaction was quenched with ice. Excess iodine was destroyed with addition of saturated potassium thiosulfate solution. The product was extracted with CH2Cl2, and the organic layers were washed with brine. The mixture was concentrated in vacuo to a black oil which was chromatographed (1:1 EtOAc/Hexanes; 2:1 EtOAc/Hexanes) to give 700 mg (23%) of 2,2-dimethyl-N-(4-iodo-3-pyridinyl)propanamide as a yellow solid. 1HNMR (DMSO-d6 300 MHz) δ 9.24 (s, 1H), 8.35 (s, 1H), 8.04 (d, 1H), 7.95 (d, 1H), 1.26 (s, 9H). MS (ES+)=305.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)C>C(O)C.O1CCCC1>[CH2:26]([N:22]([CH2:23][CH2:24][CH3:25])[C:19]1([C:16]2[CH:17]=[CH:18][C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:29])=[O:3])=[CH:10][CH:9]=3)=[CH:14][CH:15]=2)[CH2:20][CH2:21]1)[CH2:27][CH3:28]
Reactant: CCCN(CCC)C1(c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc2)CC1
Solvent: CCO
Solvent: C1CCOC1
Product: CCCN(CCC)C1(c2ccc(C#Cc3ccc(C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
Using General Procedure I; a solution of ethyl4-[4-(1-dipropylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound 109, 51.0 mg, 0.13 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NAOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 32.0 mg (70%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[C:14](=[O:15])[CH:13]=[CH:12][NH:11][CH:10]=2)=[CH:5][CH:4]=1.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](Br)[N:20]=1>CS(C)=O>[Br:18][C:19]1[N:20]=[C:21]([N:11]2[CH:12]=[CH:13][C:14](=[O:15])[C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=3)=[CH:10]2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc(COc2c[nH]ccc2=O)cc1
Reactant: Brc1cccc(Br)n1
Solvent: CS(C)=O
Product: COc1ccc(COc2cn(-c3cccc(Br)n3)ccc2=O)cc1

Procedure:
A mixture of 3-[(4-methoxybenzyl)oxyJpyridin-4(1H)-one (2.31 g, 10 mmol), 2,6-dibromopyridine (4.74 g, 20 mmol), and K2C03 (3.45 g, 25 mmol) in DMSO was heated at 120° C. overnight. After cooling to it, the solid was removed by filtration and the DMSO solution was purified by flash chromatography to give 6′-bromo-3-[(4-methoxybenzyl)oxy]-4H-1,2′-bipyridin-4-one. ′H NMR (600 MHz, DMSO): δ 8.42 (dd, J−7.7, 2.4 Hz, 1H); 8.22 (d, J=2.4 Hz, 1H); 8.03-7.96 (m, 1H); 7.96-7.89 (m, 1H); 7.71 (t, J−7.7 Hz, 1H); 7.40 (d, J=8.4 Hz, 2H); 6.96 (d, J=8.4 Hz, 2H); 6.42 (d, J=7.7 Hz, 1H); 5.03 (s, 2H); 3.76 (s, 3H). 264.1; MS (M+H)+387.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21](OC)=[O:22])[CH:18]=2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:22][CH2:21][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH2:13][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:20]2
Reactant: COC(=O)c1ccc2c(c1)C[C@@H](NC(=O)OCc1ccccc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(N[C@H]1Cc2ccc(CO)cc2C1)OCc1ccccc1
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To (S)-methyl 2-(benzyloxycarbonylamino)-2,3-dihydro-1H-indene-5-carboxylate (7.38 mmol, 2.4 g) at 0° C. in THF (36.9 mL) under an argon atmosphere was added Lithium aluminium hydride in THF (7.38 mmol, 7.38 mL) dropwise. The reaction was left to stir for 1.5 hrs at 0 degrees. The reaction was quenched with water before the addition of 5N HCl (aq) to adjust the pH to 3. DCM was added before separating the aqueous and washing once with water and once with brine. The DCM layer was dried over MgSO4 before removing the solvent in vacuo. The crude product was purified by silica chromatography (2:1 Heptane/EtOAc to 2:1 EtOAc/Heptane, 100 g silica cartridge) to give the product as a white solid (1.8 g, 82%). 1H NMR (400 MHz, CDCl3) δ 1.60 (t, 1H), 2.81 (m, 2H), 3.27 (m, 2H), 4.53 (d, 1H), 4.66 (d, 2H), 4.95 (brs, 1H), 5.12 (s, 2H), 7.17 (d, 2H), 7.23 (m, 1H), 7.33 (m, 5H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[OH:11][CH2:12][CH:13]1[CH2:17]OC(=O)[O:14]1>>[F:1][C:2]([F:10])([F:9])[C:3]1([C:5]([F:8])([F:7])[F:6])[O:14][CH:13]([CH2:12][OH:11])[CH2:17][O:4]1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: O=C1OCC(CO)O1
Product: OCC1COC(C(F)(F)F)(C(F)(F)F)O1
Yield: 66 %

Procedure:
8.5 grams of this hydroxyethyl hemiketal of hexafluoroacetone is then reacted with 3 grams of glycerol carbonate at 115°-141° C. for 103 hours. The yield is 66% 2,2-bis(trifluoromethyl)-4-hydroxymethyl-1,3-dioxolane.
Reaction SMILES: [C:1](=[S:9])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12](=O)[CH2:13]Cl>CCO.C1COCC1>[Cl:10][CH2:11][C:12]1[N:8]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:9][CH:13]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)c1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: ClCc1csc(-c2ccccc2)n1
Temperature: 65 °C
Yield: 72.9 %

Procedure:
Benzothioamide (0.8 g, 5.83 mmol) was dissolved in a mixture EtOH (26.0 ml) and THF (10.4 ml), and the solution was heated to 65° C. 1,3-Dichloropropan-2-one (0.81 g, 6.41 mmol) was added, and the mixture was heated to reflux overnight (UPLC-MS: complete conversion). The solvents were evaporated, and the residue was taken up with EtOAc (100 ml) and washed with an aqueous solution of NaHCO3. The organic phase was dried (Na2SO4), filtered and evaporated to dryness. The crude was purified by flash chromatography eluting with petroleum ether/EtOAc=97/3 to obtain 4-chloromethyl-2-phenyl-thiazole (891 mg, 72.9% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[CH3:11][C:12]1([CH3:34])[CH2:21][CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[C:18]2[CH:17]=[C:16]([C:30]([O:32][CH3:33])=[O:31])[CH:15]=[CH:14][C:13]1=2>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH3:11][C:12]1([CH3:34])[CH2:21][CH:20]=[C:19]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:18]2[CH:17]=[C:16]([C:30]([O:32][CH3:33])=[O:31])[CH:15]=[CH:14][C:13]1=2
Reactant: COC(=O)c1ccc2c(c1)C(OS(=O)(=O)C(F)(F)F)=CCC2(C)C
Reactant: c1ccsc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C(c1cccs1)=CCC2(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(Compound E5) To a solution of 329.0 mg (3.93 mmol) of thiophene in 2.0 mL THF at 0° C. was added 251.8 mg (3.93 mmol, 1.56 mL of 2.5M solution in hexanes) of n-butyllithium. After stirring for 3 h at 0° C., a solution of 845.0 mg (6.28 mmol) of ZnCl2 in 5.0 mL THF was added and the resulting solution stirred for 30 minutes. This solution was added to a second flask containing 570.0 mg (1.57 mmol) of methyl 5,5-dimethyl-5,6-dihydro-8-(trifluoromethylsulfonyl)oxy-naphthalene-2-carboxylate (Compound E4) and 76.0 mg (0.063 mmol) of tetrakis(triphenyphosphine)palladium(0) in 4.0 mL THF, and the resulting solution was heated to 50° C. for 3 h. Upon cooling to room temperature the reaction was quenched by the addition of saturated aqueous NH4Cl. Extraction with EtOAc was followed by washing of the combined organic layers with H2O and saturated aqueous NaCl, and drying over MgSO4. The dry solution was concentrated under reduced pressure and the title compound was isolated from the residue as a yellow oil by column chromatography (5-10% EtOAc/hexanes).
Reaction SMILES: Br.CS(O)(=O)=O.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:32])[C:13]3[C:21](=[O:22])[N:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][CH:24]=4)[N:19]=[C:18]([OH:31])[C:14]=3[NH:15][C:16]=2[CH:17]=1>>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:32])[C:13]3[C:21](=[O:22])[N:20]([C:23]4[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=4)[N:19]=[C:18]([OH:31])[C:14]=3[NH:15][C:16]=2[CH:17]=1
Reactant: COc1ccc(-n2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)cc1
Agent: Br
Agent: CS(=O)(=O)O
Product: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(-c3ccc(O)cc3)c(=O)c12
Temperature: 110 °C

Procedure:
To a 50 mL solution of 5:1 48% HBr:methanesulfonic acid was added 7-chloro-4-hydroxy-2-(4-methoxyphenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione (1.0328 g, 27.9 mM). The resulting suspension was heated to 110° C. over 3.5 hours. HPLC analysis afforded a total conversion to a new material. The suspension was cooled to room temperature and filtered through a Buchner funnel. The yellow solid was washed 2× with 100 mL portions of distilled water followed by 200 mL of a 1:1 solution of THF:ether. The material was then washed with hexanes until the yellow solid was free flowing. This solid was allowed to air dry for 72 hours prior to submission for analysis. No percent yield was recorded for this reaction.
Reaction SMILES: C1CCCCC1.C([O:30][CH:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Br:39])[CH3:32])(=O)CCCCCCCCCCCCCCCCCCCCC>O>[Br:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C@@H:31]([OH:30])[CH3:32]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)OC(C)c1ccccc1Br
Solvent: O
Solvent: C1CCCCC1
Product: C[C@H](O)c1ccccc1Br
Yield: 82 %

Procedure:
Interesterification was carried out by using 5 g of Lipase P of Pseudomonas fluorescens origin (a product of Amano Pharmaceutical Co., Ltd.), 10 g of (R,S)-1-2-(bromophenyl)ethanol, 30 g of tribehen and 450 ml of cyclohexane at 50° C. for 72 hours in the same manner as in Example 8. The water content of the reaction system was 0.01% by weight, and 90% of the lipase particles had a particle size of 30 to 50 μm. Gas chromatography of the reaction mixture revealed that 48 mol % of (R,S)-1-(2-bromophenyl)ethanol had been converted to 1-(2-bromophenyl)ethyl behenate. The reaction mixture was treated in the same manner as in Example 8, and the residue was subjected to simple distillation at 110° C. and 5 mmHg to recover unreacted (S)-(-)-1-(2-bromophenyl)ethanol (yield: 82%; chemical purity: 99.9%; optical purity: 98% ee).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.CCN=C=NCCCN(C)C.C[O:26][C:27](=[O:78])[C@@H:28]([NH:45][C:46]([C@@H:48]1[CH2:57][C:56]2[CH:55]=[C:54]3[O:58][CH2:59][C@H:60]([C:62]4[CH:67]=[CH:66][C:65]([O:68][CH2:69][C:70]5[CH:75]=[CH:74][C:73]([Cl:76])=[C:72]([Cl:77])[CH:71]=5)=[CH:64][CH:63]=4)[O:61][C:53]3=[CH:52][C:51]=2[CH2:50][NH:49]1)=[O:47])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[C:38]=2[CH3:44])=[CH:32][CH:31]=1>C(Cl)Cl>[Cl:77][C:72]1[CH:71]=[C:70]([CH:75]=[CH:74][C:73]=1[Cl:76])[CH2:69][O:68][C:65]1[CH:66]=[CH:67][C:62]([C@H:60]2[CH2:59][O:58][C:54]3=[CH:55][C:56]4[CH2:57][C@@H:48]([C:46]([NH:45][C@@H:28]([CH2:29][C:30]5[CH:35]=[CH:34][C:33]([O:36][C:37]6[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[C:38]=6[CH3:44])=[CH:32][CH:31]=5)[C:27]([OH:78])=[O:26])=[O:47])[N:49]([C:6](=[O:8])[C:5]5[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=5)[CH2:50][C:51]=4[CH:52]=[C:53]3[O:61]2)=[CH:63][CH:64]=1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(Oc3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)cc1OC
Reaction time: 16 h

Procedure:
3,4-Dimethoxybenzoic acid (1 eq.) was stirred in dry DCM with 0.5 eq EDCI at RT for 1 h. (S)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester in dry DCM (10 eq benzoic acid relative to amine) was added and the resulting mixture stirred 16 h, then directly purified by flash chromatography. The resulting compound was hydrolyzed according to General Procedure B to give the title compound (5 mg). LCMS (m/z) 919.