Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[NH:17][O:18][C:19](=[O:21])[N:20]=3)=[C:12]([Cl:22])[CH:11]=2)=[C:5]([CH3:7])[N:6]=1.[S:23]1[C:27](B(O)O)=[CH:26][C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[S:23]1[C:27]([C:2]2[S:3][C:4]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[NH:17][O:18][C:19](=[O:21])[N:20]=4)=[C:12]([Cl:22])[CH:11]=3)=[C:5]([CH3:7])[N:6]=2)=[CH:26][C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]1=2
Reactant: Cc1nc(Br)sc1COc1ccc(-c2nc(=O)o[nH]2)c(Cl)c1
Reactant: OB(O)c1cc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2cc3ccccc3s2)sc1COc1ccc(-c2nc(=O)o[nH]2)c(Cl)c1
Temperature: 40 °C
Yield: 46.1 %

Procedure:
A mixture of 3-[4-(2-Bromo-4-methyl-thiazol-5-ylmethoxy)-2-chloro-phenyl]-2H-[1,2,4]oxadiazol-5-one (300 mg, 0.7 mmol), Benzo[b]thiophene-2-boronic acid (142 mg, 0.8 mmol) and cesium carbonate (730 mg, 2.2 mol) in dimethylformamide (5 mL) and water (1 mL) is degassed using a stream of argon for 15 min. Tetrakis-triphenylphosphine-palladium (0) (34 mg, 0.03 mmol) is added and the mixture is warmed to 40° C. for 4 hours. The solvent is removed under reduced pressure and the residue is taken up in water (10 mL) and ethylacetate (30 mL). The phases are separated and the water phase is additionally extracted two-times with ethylacetate. The combined organic phases are dried over MgSO4 and the solvent is removed under reduced pressure. The crude product is purified using reverse phase HPLC to obtain 147 mg 3-[4-(2-Benzo[b]thiophen-2-yl-4-methyl-thiazol-5-ylmethoxy)-2-chloro-phenyl]-2H-[1,2,4]oxadiazol-5-one as an amorphous lyophilisate.
Reaction SMILES: [H-].[Na+].[C:3]1([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]#[N:18])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:19][N:20]([CH2:24][CH2:25]Cl)[CH2:21][CH2:22][Cl:23].Cl.Cl>CN(C)C=O.CCOCC>[ClH:23].[C:17]([C:16]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:25][CH2:24][N:20]([CH3:19])[CH2:21][CH2:22]1)#[N:18]
Reactant: CN(CCCl)CCCl
Reactant: N#CCc1ccccc1Sc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1CCC(C#N)(c2ccccc2Sc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.6 g of 99% sodium hydride are added portionwise to a solution of 4.4 g of 2-(phenylthio)phenylacetonitrile in 50 ml of dimethylformamide. The resulting reddish brown mixture is stirred for 30 minutes before adding dropwise a solution of 4.0 g of mechlorethamine hydrochloride in 50 ml of dimethylformamide, maintaining gas evolution at a slow rate. After total addition, the mixture is stirred at 80°-85° C. for 15 hours. Thereafter, 100 g of ice are added before the mixture is extracted thrice with ether. The combined ether extracts are dried over potassium carbonate and then the solvent is removed under vacuum leaving a brownish oil. The oil is dissolved in a small amount of ether and passed through, with additional ether, an alumina column which is packed in ether. The effluent is concentrated leaving an oil which is converted to its hydrochloride which is recrystallized from an acetone-ether mixture, leaving 4-cyano-1-methyl-4-(2-phenylthiophenyl)piperidine hydrochloride.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[F-].[K+].CN(C=O)C.[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH:22]=[CH:23][C:24]=1[OH:25]>O>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27](=[O:31])[N:28]([CH3:29])[CH3:30])[CH:22]=[CH:23][C:24]=1[O:25][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CCl)c1ccccc1
Reactant: CN(C)C(=O)Nc1ccc(O)c(Cl)c1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)Nc1ccc(OCC(=O)c2ccccc2)c(Cl)c1
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
A mixture of α-chloroacetophenone (4,64 g; 0.03 mol), anhydrous potassium fluoride and DMF (200 ml) is stirred for 15 minutes. Next, 3-(3-chloro-4-hydroxyphenyl)-1,1-dimethylurea (6.44 g; 0.03 mol) is added and the mixture stirred for 20 hours at room temperature and then for 24 hours at 80° C. The mixture is then drowned in water, and extracted with methylene chloride. The organic layer is separated, washed with water and filtered through a 5 cm pad of neutral alumina. The pad is washed with acetonitrile, filtrate and washings are combined and evaporated under vacuum to give a brown-yellow oil (7.0 g, 70.1%). This oil is purified by chromatographing on silica gel (eluent: methylene chloride) to afford the title compound: 6.75 g of a cream colored solid, m.p. 148°-150° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([N-:14]CC)[CH3:13].[Li+].BrCC#N>C1COCC1>[C:8]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:13][C:12]#[N:14])([O:10][CH3:11])=[O:9]
Reactant: CC[N-]CC
Reactant: COC(=O)Cc1ccccc1
Agent: N#CCBr
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(CC#N)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of methyl phenylacetate (200 g, 1.33 mol) in THF (300 mL) is added, dropwise, to a -78° C. solution of lithium diethylamide (LDA, 1.4 mol) in THF (2500 mL). After addition is complete, a precipitate forms, and additional THF (200 mL) is added. The resulting mixture is vigorously stirred while a solution of bromoacetonitrile (168 g, 1.4 mol) in THF (400 mL) is slowly added. After 20 minutes the cooling bath is removed and the reaction mixture is quenched with saturated NH4Cl solution (500 mL). After allowing the mixture to slowly warm to ambient temperature any solid material is removed by filtration and the solvent is removed in vacuo. The residue is dissolved in ET2O (1000 mL) and diluted with H2O (1000 mL). The organic phase is then washed with 0.5N HCl (1×1000 mL), saturated NaCl solution (2×1000 mL) and concentrated in vacuo. The residue is then vacuum distilled (~1 mm Hg) and the fraction boiling between 125° C. and 145° C. is collected to give β-(carbomethoxy)-β-phenylpropionitrile which solidifies upon standing.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:28])[C:15]([C:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][C:18]=1[CH2:26][CH3:27])=[O:16])=[CH:7]2.Br[CH2:30][C:31]#[N:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:11]([O:12][CH2:30][C:31]#[N:32])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:28])[C:15]([C:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][C:18]=1[CH2:26][CH3:27])=[O:16])=[CH:7]2
Reactant: CCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2c(Br)c(O)ccc2c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2c(Br)c(OCC#N)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A mixture of 2-ethyl-benzofuran-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (0.5 g, 1.14 mmol), prepared in the previous step, bromoacetonitrile (95 μL, 1.36 mmol) and potassium carbonate (0.79 g, 5.7 mmol) in 20 mL of DMF was stirred under nitrogen at room temperature for 18 h (overnight). The reaction was diluted with ethyl acetate and extracted multiple times with water. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give a dark brown oil. The oil was chromatographed on 50 g of silica gel (230-400 mesh) using 5% ethyl acetate in methylene chloride as the eluent. Isolation of the desire component gave 2-ethyl-benzofuran-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (0.39 g, 72%) as a light yellow foam, MS m/z: 477 [M+H]+.
Reaction SMILES: C([Mg]Br)C.[O:5]([CH2:12][C:13]#[CH:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH2:16][C:17]#[C:18][CH2:19][C:20]#[CH:21].S(=O)(=O)(O)O>CCOCC.O1CCCC1>[O:5]([CH2:12][C:13]#[C:14][CH2:16][C:17]#[C:18][CH2:19][C:20]#[CH:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCOc1ccccc1
Reactant: C#CCC#CCBr
Agent: CC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CCC#CCC#CCOc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4.81 ml (1.92 g, 14.4 mmol) of a 3N solution of ethylmagnesium bromide in ether was added dropwise under argon to a solution of 2 g (15.15 mmol) of 3-phenoxy-1-propyne (G. Pourcelot, et al., Bull. Soc. Chim., France, (1966), pp 3016-24, in 15 ml of anhydrous tetrahydrofuran. The rate of addition was adjusted to maintain the temperature at 0° C. Thereafter, the reaction mixture was stirred for 1 hour further at 0°-5° C. Then, 77 mg of cuprous cyanide was added. After stirring 20 minutes more, a solution of 1.13 g (7.22 mmol) of 1-bromo-2,5-hexadiyne in 10 ml of anhydrous tetrahydrofuran was added dropwise. The temperature was maintained at between 0°-5° C.The resulting mixture was stirred at room temperature for 3 additional hours, then poured into 60 ml of 1N sulfuric acid and ice, and the resulting solution extracted with ether (3×100 ml). The combined organic extracts were concentrated in vacuo to a small volume, and washed several times with EDTA and water, dried over sodium sulfate and evaporated. The crude material was purified by TLC using hexane:methylene chloride (80:20) as the eluant, and the product crystallized from methylene chloride-hexane, to yield 9-phenoxy-1,4,7-nonatriyne, as an oil.The product was stored in dry ice.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][CH2:7][N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2Cl)[CH3:2].C(N(CC)C(C)C)(C)C.[C:28]([O:32][C:33](=[O:48])[C@@H:34]([NH:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH2:35][NH2:36])([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][CH2:7][N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[NH:36][CH2:35][C@H:34]([NH:37][C:38]([O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39])[C:33]([O:32][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:48])[CH3:2]
Reactant: CCOC(=O)CCCn1cnc2c(Cl)ncnc21
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cnc2c(NC[C@H](NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)ncnc21
Temperature: 80 °C
Reaction time: 48 h

Procedure:
1 g (3.72 mmol) of 4-(6-chloro-purin-9-yl)-butyric acid ethyl ester was dissolved in dimethylformamide (3 ml) and 2.6 ml (14.9 mmol) of N,N-diisopropylethylamine was added. 1.09 g (3.72 mmol) of (2S)-3-amino-2-benzyloxycarbonylamino-propionic acid tert-butyl ester and dimethylformamide (2 ml) were added. The reaction was stirred at 80° C. for 2 days. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with 10% aqueous citric acid solution and three times with water. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. Residual amounts of 4-(6-chloro-purin-9-yl)-butyric acid ethyl ester were removed as follows: the residue was dissolved in tetrahydrofuran and 2 g of a macroporous aminomethyl polystyrene resin was added. The suspension was heated at 60° C. for 5 hours, then stirred gently at room temperature for 16 hours. The resin was filtered off, washed with tetrahydrofuran, and the combined organic phase was dried in vacuo. Yield: 908 mg.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[O:17]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[O:17]([C:24]1[CH:25]=[CH:26][C:27]([CH2:28][NH:29][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[CH:30][CH:31]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCc1ccc(Oc2ccccc2)cc1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Product: O=c1c(NCc2ccc(Oc3ccccc3)cc2)c(Nc2ccncc2)c1=O
Yield: 55 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and 4-phenoxybenzylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][CH2:7]2.[CH3:13][CH:14](O)[CH:15]=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>ClC(Cl)(Cl)Cl>[CH2:13]([CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[C:10]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: C=CC(C)O
Reactant: O=C1CCCc2cccc(Cl)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC=CCC1CCc2cccc(Cl)c2C1=O
Yield: 35 %

Procedure:
8.85 g of 8-chloro-1-tetralone were dissolved in 90 ml of tetrachloromethane under argon and added to 21.0 ml of 3-buten-2-ol and 190 mg of p-toluenesulfonic acid. The reaction solution was heated to reflux on a water separator for 9 days. The solvent was removed in a vacuum and the residue was chromatographed on 200 g of silica gel firstly with hexane/ethyl acetate 9:1 and then with hexane/ethyl acetate 4:1. In addition to large amounts of unreacted educt (8.3 g), there were obtained 4.1 g (35%) of 2-(2-buten-1-yl)-8-chloro-1-tetralone as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][CH:13]2[CH2:18][CH2:17][CH:16]([C:19](O)=[O:20])[CH2:15][CH2:14]2)[NH:3]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[F:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][NH2:40]>CN(C=O)C>[F:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][NH:40][C:19]([C@H:16]1[CH2:15][CH2:14][C@@H:13]([CH2:12][C:4]2[NH:3][C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:18][CH2:17]1)=[O:20]
Reactant: NCc1ccccc1F
Reactant: O=C(O)C1CCC(Cc2nc3ccccc3c(=O)[nH]2)CC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=c1[nH]c(C[C@H]2CC[C@@H](C(=O)NCc3ccccc3F)CC2)nc2ccccc12
Reaction time: 1 h

Procedure:
To a solution of 4-(4-oxo-3,4-dihydro-quinazolin-2-ylmethyl)-cyclohexanecarboxylic acid (275 mg, 1.05 mmol), EDC (200 mg, 1.05 mmol) and HOAt (142 mg, 1.05 mmol) in anhydrous DMF (4 mL) was added 2-fluorobenzylamine (131 mg, 1.05 mmol), and the resulting reaction mixture was stirred for 1 h. The reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc, and the organic layer washed 2× with water. The EtOAc was dried with MgSO4 and concentrated to give a yellow solid. Preparative chromatography eluting with chloroform:methanol gave the cis 4-(4-oxo-3,4-dihydro-quinazolin-2-ylmethyl)-cyclohexanecarboxylic acid 2-fluoro-benzylamide as a white solid: mass spectrum m/z 394 [(M+H)+; calcd for C23H24FN3O2: 393].
Reaction SMILES: [CH2:1]([O:3][C:4]#[CH:5])[CH3:2].C([Li])CCC.CN(P(N(C)C)(N(C)C)=O)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:4]([O:3][C:1]#[C:2][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:5]
Reactant: BrCc1ccccc1
Reactant: C#COCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC#CCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of ethoxy acetylene (9.95 g of 50% w/w. solution in hexanes, 70 mmol) in THF (100 ml) at −78° was added n-butyl lithium (31 ml of 2.5M solution in hexanes, 78 mmol). The mixture was stirred at this temperature for 2 h. prior to the addition of HMPA (20 ml), stirring was continued for a further 15 min. before the addition of benzyl bromide (9.2 ml). The reaction mixture was allowed to warm to room temperature overnight before partitioning between EtOAc (300 ml) and water (200 ml). The organics were separated, washed with water (5×200 ml), brine (200 ml), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a mobile brown oil (11.1 g, 99%). δH (300 MHz, CDCl3) 7.15-7.57 (5H, m), 4.12 (2H, q, J 7.1 Hz), 3.60 (2H, s), 1.41 (3H, t, J 7.1 Hz); m/z (ES+, 70V) MH+161.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:23])([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)[CH:11]([F:13])[F:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[F:9][C:10]([F:23])([O:14][C:15]1[CH:16]=[C:17]([CH2:18][NH:1][C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)[CH:20]=[CH:21][CH:22]=1)[CH:11]([F:12])[F:13]
Reactant: Nc1cccc(O)c1
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Oc1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.3 %

Procedure:
EX-20A) To a solution of 3-aminophenol (4.91 g, 45.0 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (10.0 g, 45.0 mmol) in 100 mL of 1,2-dichloroethane was added sodium triacetoxyborohydride (14.28 g 67.5 mmol) and glacial acetic acid (2.7 mL, 47.3 mmol). The reaction mixture was stirred at room temperature for 6 h then quenched with water and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated in vacuo to give 11.82 g (83%) of the desired 3-[[[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]phenol product as a dark orange oil. 1H NMR (acetone-d6) δ 7.01-7.38 (m, 5H), 6.26-6.44 (m, 3H), 6.08 (t, 1H), 5.88 (tt, 1H), 4.34 (s, 2H).
Reaction SMILES: [Br-].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([S:16]([O-:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Mg+2].S(Cl)([Cl:23])(=O)=O>C(Cl)Cl>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([S:16]([Cl:23])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=S([O-])c1cccc(OCc2ccccc2)c1
Agent: [Br-]
Agent: [Mg+2]
Solvent: ClCCl
Product: O=S(=O)(Cl)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Magnesium 3-benzyloxyphenylsulfinate bromide, as described above in Step B, (4.5 g, 14 mmol) was dissolved in dry CH2Cl2 (175 mL) and cooled to 0° C. under argon. Sulfuryl chloride (19 mL of a 1.0 M solution in CH2Cl2, 19 mmol) was added dropwise, and the mixture was stirred for 18 hours at ambient temperature, during which time a precipitate formed. The precipitate was removed by filtration and the filtrate was concentrated under reduced pressure to give the product as a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4](=[O:12])[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH:16][CH:17]1[O:33][C@H:32]([CH2:34][OH:35])[C@@H:22]([O:23][CH2:24][C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)[C@H:20]([OH:21])[C@@H:18]1[OH:19].CN(C=O)C.ON1C2C=CC=CC=2N=N1.[NH:51]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][C:53](O)=[O:54].C(N=C=NCCCN(C)C)C>>[NH:51]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][C:53]([NH:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4](=[O:12])[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:54].[OH:16][CH:17]1[O:33][C@H:32]([CH2:34][OH:35])[C@@H:22]([O:23][CH2:24][C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)[C@H:20]([OH:21])[C@@H:18]1[OH:19]
Reactant: N[C@@H](CC(=O)OC1CCCCC1)C(=O)O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(CO[C@H]2[C@H](O)[C@H](O)C(O)O[C@@H]2CO)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](CC(=O)OC1CCCCC1)C(=O)O
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To a cold solution of Asp(O-cHex)-Man(4-MBzl) (46.7 g, 86.4 mmol) in DMF (100 mL) diisopropylethylamine (15 mL, 86.1 mmol) was added. N-Hydroxybezotriazole (14.0 g, 104 mmol) was added follwed by Boc-Gly (16.6 g, 94.8 mmol). The reaction mixture was stirred in the cold for a few minutes, and N-ethyl-N'(dimethylaminopropyl)carbodiimide (18.2 g, 94.9 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was concentrated to a small volume and poured into 1.5 L of aqueous 10% K2CO3. The precipitated product was collected by filtration and was washed with water to a neutral pH to afford the titled compound (50.6 g).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[S:11])[NH:9][NH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O>>[CH:1]1([NH:7][C:8](=[S:11])[NH:9][N:10]=[CH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NNC(=S)NC1CCCCC1
Reactant: O=Cc1ccccn1
Product: S=C(NN=Cc1ccccn1)NC1CCCCC1

Procedure:
The title compound was prepared from a mixture of 4-cyclohexyl-3-thiosemicarbazide (100 mg, 0.577 mmol) and 2-pyridinecarboxaldehyde (55 μL, 0.577 mmol) similar to Example 3 and isolated as a white solid (40 mg, 26%). 1H NMR (CDCl3): 9.16 (s, 1H), 8.65-8.63 (m, 1H), 7.87-7.85 (m, 2H), 7.78-7.73 (m, 1H), 7.38 (d, J=7.2 Hz, 1H), 7.34-7.27 (m, 1H), 4.344.27 (m, 1H), 2.18-2.12 (m, 2H), 1.82-1.75 (m, 2H), 1.50-1.22 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:3]=1.[C:20](Cl)(Cl)=[S:21]>O1CCOCC1>[F:11][C:10]([F:12])([F:13])[CH2:9][O:8][C:6]1[CH:5]=[C:4]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[N:3]=[C:2]([N:1]=[C:20]=[S:21])[N:7]=1
Reactant: Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Reactant: S=C(Cl)Cl
Solvent: C1COCCO1
Product: FC(F)(F)COc1cc(OCC(F)(F)F)nc(N=C=S)n1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
2-Amino-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine (20.0 g, 68.7 mmol) was added to a solution of thiophosgene (15.7 mL, 206 mmol) in anhydrous dioxane (100 mL) under an N2 atmosphere. The resulting solution was heated to reflux. After 18 h the heat was removed and the reaction cooled to room temperature. The dioxane was evaporated to give a dark oil. The dark oil was distilled to afford the product as a light yellow oil (13.7 g, 60% yield); bp 83-86° C., (ca 0.2 mmHg): 1H NMR (CDCl3) δ 6.24 (s 1H), 4.78 (q, 4H, J=8.2 Hz); GCMS (EI, 70 eV) m/z 333 (M+).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[O:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1>C1(C)C=CC=CC=1>[CH:9]12[O:8][CH:12]([CH:11]=[CH:10]1)[CH:3]1[CH:2]2[C:1](=[O:7])[O:6][C:4]1=[O:5]
Reactant: c1ccoc1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: O=C1OC(=O)C2C3C=CC(O3)C12
Temperature: 80 °C
Reaction time: 6 h
Yield: 87.3 %

Procedure:
Maleic anhydride (30.00 g, 0.306 mol) was suspended in 150 mL of toluene and the mixture warmed to 80° C. Furan (33.4 mL, 0.459 mol) was added via syringe and the turbid solution stirred for 6 h. The mixture was then cooled to room temperature and the stirring was stopped. After 1 h the resulting white crystals were filtered off and the solid washed with 2×30 mL of petroleum ether. Obtained 44.40 g (0.267 mol, 87% yield) of the desired product as small white needless. m.p. 124-127° C. (dec.) IR (neat): 1857, 1780, 1309, 1282, 1211, 1145, 1083, 1019, 947, 920, 902, 877, 847, 800, 732, 690, 674, 633, 575 cm−1. 1H NMR (400.03 MHz, CDCl3, 298 K) δ=3.17 (s, 2H, CH), 5.45 (t, J=1.0 Hz, 2H, CHO); 6.57 (t, J=1.0 Hz, 2H, CHvinyl). 13C{1H} NMR (100.59 MHz, CDCl3, 298 K) δ=48.85 (2C, CH), 82.35 (2H, CHO), 137.12 (2C, CHvinyl), 170.04 (2C, CO). Anal. Calcd. for C8H6O4: C, 57.84; H, 3.64. Found C, 57.74; H, 3.68.