Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH2:21])[CH3:20]>>[CH2:19]([N:21]([CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH3:20]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CC1CCCCC1
Product: CCN(CC(CC1CCCCC1)NC(=O)OC(C)(C)C)CC(CC1CCCCC1)NC(=O)OC(C)(C)C

Procedure:
The product from Example 15A and ethylamine were processed as described in Example 7B to provide the title compound.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl[C:7]1[S:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([Cl:12])[N:11]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[NH:16]([C:7]1[S:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([Cl:12])[N:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1sc(Nc2ccccc2)nc1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
252 g (3.0 mols) of sodium bicarbonate are added to a solution of 360 g (1.8 mols) of 2,4-dichloro-5-nitrothiazole in 1.5 l of acetonitrile. A mixture of 139.5 g (1.5 mols) of aniline and 1,500 ml of acetonitrile is then added dropwise at -10° C. to -15° C. in the course of about 4.5 hours and the mixture is subsequently stirred at the same temperature for a further 4 hours. It is then stirred into 15 l of ice-water and the precipitate is filtered off, washed with water and dried. To remove excess 2,4-dichloro-5-nitrothiazole, the product is stirred into 2.4 l of petroleum ether at room temperature, filtered off, washed with petroleum ether and dried. 361.7 g (94.4% of theory) of 2-anilino-4-chloro-5-nitrothiazole of melting point 186° C. to 187° C. (decomposition) are obtained.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][OH:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][O:23][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: Brc1ccncc1
Product: c1cc(OCC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)ccn1
Yield: 60 %

Procedure:
The title compound (75 mg, 60%) was prepared from {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methanol and 4-bromopyridine similarly to the procedure used for example 152. 1H NMR (400 MHz, CDCl3) δ 1.76-1.82 (m, 4H), 1.98-2.04 (m, 2H), 2.12-2.17 (m, 4H), 2.49-2.58 (m, 4H), 2.61-2.66 (m, 2H), 3.54-3.60 (m, 2H), 3.81-3.85 (m, 2H), 3.87 (s, 2H), 4.03 (t, 2H), 6.71 (d, 2H), 6.91 (d, 2H), 7.29 (d, 2H), 8.36 (d, 2H). HRMS ESI+ m/z 397.2479 [MH]+.
Reaction SMILES: [C:1]1([NH2:12])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:13]=[C:14]1[NH:23][C:22]2[N:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH:28]=O)[CH:19]=[CH:18][C:17]=2[CH2:16][CH2:15]1>>[C:1]1([N:12]2[CH2:17][CH2:22][N:21]([CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:20]3[N:21]=[C:22]4[C:17]([CH2:16][CH2:15][C:14](=[O:13])[NH:23]4)=[CH:18][CH:19]=3)[CH2:20][CH2:19]2)[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc2c1CCCCC2
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5c4CCCCC5)CC3)nc2N1

Procedure:
In a manner similar to that of other examples above, 6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamine (0.178 g) was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound as the hydrochloride salt (0.109 g). MS: APCI: M+1: 449.3 (Exact Mass: 448.26).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[CH2:14]([NH2:16])[CH3:15]>C(#N)C>[CH2:14]([NH:16][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[CH3:15]
Reactant: N#Cc1ccc(OCC2CO2)cc1
Reactant: CCN
Solvent: CC#N
Product: CCNCC(O)COc1ccc(C#N)cc1

Procedure:
86.0 g of 4-(oxiranylmethoxy) benzonitrile was dissolved in 250 ml acetonitrile and mixed with 29.7 g ethylamine in an autoclave. The mixture was heated in a boiling water-bath over night, evaporated and the residue was dissolved in 2-M hydrochloric acid. This acidic waterlayer was washed twice with ether, alkalized with 10-M sodium hydroxide and extracted with three portions of dichloromethane.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:4][N:3]=1.[F:40][C:41]1[CH:42]=[C:43]([NH2:49])[CH:44]=[N:45][C:46]=1[O:47][CH3:48].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:40][C:41]1[CH:42]=[C:43]([NH:49][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[N:9]=3)=[CH:6][C:5]([CH:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:4][N:3]=2)[CH:44]=[N:45][C:46]=1[O:47][CH3:48]
Reactant: COc1ncc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C4CCOCC4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C4CCOCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reaction time: 0.25 h
Yield: 85 %

Procedure:
A mixture of 4-(2-fluoro-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (210 mg, 0.397 mmol) and 5-fluoro-6-methoxypyridin-3-amine (85 mg, 0.595 mmol) in 1.5 mL of THF at 0° C. was treated with sodium bis(trimethylsilyl)amide (0.99 mL of 1.0 M solution in tetrahydrofuran, 0.99 mmol). It was stirred at this temperature for 15 min, then quenched with sat NH4Cl (5 mL) and extracted with 2×10 mL of EtOAc. The combined organic solution was dried with sodium sulfate and concentrated. The residue was purified on a silica gel column and eluted with 10-30% EtOAc in DCM to give the title compound (220 mg, 85% yield) as a brown amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.65 (s, 1H), 8.56 (d, J=2.6 Hz, 1H), 8.26 (d, J=2.4 Hz, 1H), 8.07 (m, 2H), 7.29 (d, J=8.6 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 4.87 (s, 2H), 4.80 (s, 2H), 3.96 (m, 2H), 3.91 (s, 3H), 3.74 (s, 3H), 3.69 (s, 3H), 3.45 (m, 2H), 2.78 (m, 1H), 2.57 (s, 3H), 1.67 (m, 4H). m/z (ESI, positive ion) 652.0 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[C:3]1=[O:18].OS(O)(=O)=O.[N+:24]([O-])([OH:26])=[O:25]>>[CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:24]([O-:26])=[O:25])[CH:9]=2)[N:4]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[C:3]1=[O:18]
Reactant: CC1C(=O)N(C2CCN(C)CC2)c2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC1C(=O)N(C2CCN(C)CC2)c2ccc([N+](=O)[O-])cc21
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A solution of 3-methyl-1-(1-methylpiperidin-4-yl)indolin-2-one(0.18 g, 0.736 mmol) in con. H2SO4 (2 mL) was treated with fuming HNO3 (0.034 mL, 0.736 mmol) at −5 to −10° C. (ice+salt) and resulting solution was stirred for 30 min. at this same temperature. The reaction was quenched with addition of crushed ice, and then basified with 1 N NaOH and product was extracted into CH2Cl2 (2×20 mL). The combined CH2Cl2 layer was washed with brine (10 mL) and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 2.5:97.5) to obtain compound 3-methyl-1-(1-methylpiperidin-4-yl)-5-nitroindolin-2-one (0.13 g, 61%) as a solid. 1H NMR (DMSO-d6) δ: 1.39 (d, 3H, J=7.5 Hz), 1.55-1.62 (m, 2H), 2.01 (t, 2H, J=11.4 Hz), 2.20 (s, 3H), 2.31-2.39 (m, 2H), 2.87 (d, 2H, J=11.4 Hz), 3.63 (q, 1H), 4.06-4.16 (m, 1H), 7.39 (d, 1H, J=9.3 Hz), 8.18-8.22 (m, 2H); ESI-MS (m/z, %) 290 (MH+, 100).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)([O-:16])=[O:15].Cl>C(OCC)(=O)C>[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([N:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Yield: 47 %

Procedure:
To 12.5 g (0.07 mol) of mechanically stirred 1-benzylpiperazine was added 10.0 g (0.07 mol) of 4-nitrofluorobenzene. After 10 minutes of a mildly exothermic reaction, the mixture solidified. The yellow solid was suspended in 50 mL of ethyl acetate and ethereal HCl was slowly added to the stirring mixture under a nitrogen atmosphere. The solid was collected (filtration) and partitioned between 10% sodium hydroxide solution and benzene. The benzene layer was washed with ten 100 mL portions of water, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to give a yellow oil. Upon cooling, the oil crystallized. The solid was recrystallized from 2-propanol/petroleum ether (60°-110°) to give 9.8 g (47%) of yellow solid, mp 115°-118° C.
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][N:26]=1)[C:21](O)=[O:22].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][N:26]=1)[C:21]([NH:14][CH:12]([C:9]1[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=1)[CH3:13])=[O:22]
Reactant: Nc1cc(C(=O)O)ccn1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccnc(N)c1)c1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a mixture of (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (300 mg, 1.17 mmol, Amine-1, single enantiomer), 2-aminoisonicotinic acid (161 mg, 1.17 mmol), and N,N-diisopropylethylamine (0.82 mL, 4.68 mmol) in N,N-dimethylformamide (12 mL) is added HBTU (665 mg, 1.75 mmol) at room temperature. After stirring at room temperature for 1 hour, the mixture is poured onto water (20 mL), and the mixture is extracted with ethyl acetate (20 mL). The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with dichloromethane/methanol (10:1) to give 252 mg (63% yield) of the title compound as a slight brown solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][N:19]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:20]3=[O:30])=[C:13]([Cl:31])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO.C(OCC)(=O)C>[Cl:31][C:13]1[CH:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)[CH:16]=[C:15]([Cl:17])[C:14]=1[CH2:18][N:19]1[CH2:23][CH2:22][CH:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:20]1=[O:30]
Reactant: COC(=O)c1ccc(-c2cc(Cl)c(CN3CCC(N4CCCCC4)C3=O)c(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1ccc(-c2cc(Cl)c(CN3CCC(N4CCCCC4)C3=O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
Treat a solution of 3′,5′-Dichloro-4′-(2-oxo-3-piperidin-1-yl-pyrrolidin-1-ylmethyl)-biphenyl-4-carboxylic acid methyl ester (0.190 g, 0.41 mmol) in methanol (15 mL) with 5N NaOH (0.82 mL), heat to reflux, and cool and stir at room temperature for 16 hours. Remove the solvent in vacuo to give a residue and neutralize with 1N HCl. Dilute the mixture with ethyl acetate and wash with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, purify with a 0 to 10% methanol in CH2Cl2 gradient to afford 0.106 g (58%) of the titled product. Rf=0.50 (4/1 CH2Cl2/methanol). ES MS (m/z): 447 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH:27]2[CH2:31][O:30]C(C)(C)[O:28]2)[CH:22]=[CH:21][C:20]=1[F:34])=[O:18]>C(O)(C(F)(F)F)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH:27]([OH:28])[CH2:31][OH:30])[CH:22]=[CH:21][C:20]=1[F:34])=[O:18]
Reactant: CC1(C)OCC(COc2ccc(F)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)O1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(c1cc(OCC(O)CO)ccc1F)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 315 was dissolved in TFA:water (3:1, 8 mL) and stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and purified by continuously gradient flash chromatography using EtOAc/petroleum ether (40-60)(v:v=1:2 to 100:0) as the eluent, affording the title compound as a yellow foam. 13C NMR (DMSO-d6) δ 189.3, 158.8 (dd), 155.7 (dd), 154.9 (d), 153.8 (d), 149.5, 133.5, 133.4, 127.8 (d), 126.5 (dd), 126.3, 124.1 (dd), 119.7 (d), 117.1 (d), 114.9 (d), 114.7, 112.0 (dd), 111.7, 105.0 (dd), 70.4, 69.8, 62.5
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[NH:9][CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3C(O)=O)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:20].[C:21](=O)=O>C(O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][CH:15]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:20]
Reactant: O=C(O)c1ncn2c1CNC(=O)c1c-2ccc(F)c1Cl
Reactant: O=C=O
Solvent: CCO
Product: CN1Cc2cncn2-c2ccc(F)c(Cl)c2C1=O

Procedure:
11.64 g (37.5 mmol) of 7-chloro-8-fluoro-5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid was heated to 285° in a metal bath until the CO2 cleavage has finished. The melt was poured into 50 ml of ethanol and the precipitated product was filtered off under suction and washed with ethanol. After drying there was obtained 7-chloro-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 234°-235°.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[C:15]([CH3:17])=[CH2:16])[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH:15]([CH3:17])[CH3:16])[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: C=C(C)c1cccc2cccc(OC(C)=O)c12
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Oc1cccc2cccc(C(C)C)c12
Reaction time: 20 h
Yield: 47.4 %

Procedure:
3.6 g of 8-isopropenyl-1-naphthyl acetate was dissolved in 100 ml of ethanol, to which 0.2 g of 10% palladium-carbon (water content of 50%) was added, followed by hydrogenation at normal temperatures and normal pressure for 20 hours. After removal of the palladium-carbon by filtration, the resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3% ethyl acetate/hexane) to obtain 1.72 g of the captioned compound as an oily substance.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=[O:17])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][CH3:16])[CH:9]=1)([CH3:7])[CH3:6].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.CCN(CC)CC>C(Cl)Cl>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]([CH3:7])([CH3:6])[C:4](=[O:17])[CH2:3][NH:2][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[S:27])=[CH:9][C:10]=1[O:15][CH3:16]
Reactant: COc1cc(C(C)(C)C(=O)CN)ccc1F
Reactant: Fc1ccc(N=C=S)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(C)(C)C(=O)CNC(=S)Nc2ccc(F)cc2)ccc1F
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To a mixture of 1-amino-3-(4-fluoro-3-methoxyphenyl)-3-methylbutan-2-one hydrochloride (35.4 g, 0.135 mol) and 4-fluorophenyl isothiocyanate (21.75 g, 0.142 mol) in DCM (500 mL) was added Et3N (37.6 ml, 0.27 mol) at 0° C., and the reaction mixture was warm to room temperature over 1 h. The reaction mixture was washed with 1N HCl (500 mL), satd NaHCO3 (500 mL) and brine (500 mL) successively, dried over MgSO4, filtered and concentrated under reduced pressure give a residue, which was triturated with Hex-EtOAc to afford 1-(3-(4-fluoro-3-methoxyphenyl)-3-methyl-2-oxobutyl)-3-(4-fluorophenyl)thiourea (45 g, 88%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.85 (b, 1H), 7.25 (m, 2H), 7.15 (m, 2H), 7.05 (m, 1H), 6.79 (m, 2H), 6.67 (b, 1H), 3.88 (s, 3H), 1.54 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]([CH:13]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([NH:1][CH2:2][C:3]1[CH:13]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[C:5]([CH:4]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cc(CN)cc(C(=O)OCC)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(CNS(C)(=O)=O)cc(C(=O)OCC)c1
Yield: 35 %

Procedure:
To a stirring solution of crude diethyl 5-(aminomethyl)isophthalate in 30 mL of CH2Cl2 at 0° C. was added 1.2 mL of Et3N and 0.7 mL of MsCl. The ice bath was removed, and after 2 h at r.t. the solution was concentrated, and EtOAc and H2O were added. The organic layer was washed with brine, the aqueous layer was extracted with EtOAc, the combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (1% MeOH/CHCl3) provided 901 mg of diethyl 5-(methylsulfonamidomethyl)isophthalate as a pale yellow solid in 35% yield.
Reaction SMILES: COC(=O)[CH:4]([C:17]#[N:18])[C:5]1([CH3:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[O:8][CH2:7][CH2:6]1.[Cl-].[Na+]>CS(C)=O.O>[F:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2([CH2:4][C:17]#[N:18])[CH3:16]
Reactant: COC(=O)C(C#N)C1(C)CCOc2ccc(F)cc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(CC#N)CCOc2ccc(F)cc21
Reaction time: 4 h
Yield: 86.7 %

Procedure:
A mixture of 3.1 g (11.8 mmol) of cyano-(6-fluoro-4-methylchroman4-yl)acetic acid methyl ester and 2.47 g (42.4 mmol) of sodium chloride in 30 mL of wet DMSO was warmed to reflux. The reaction was monitored by TLC. After 4 hours, the reaction was cooled and diluted with water and extracted with diethyl ether. The combined organic layers were washed with four portions of water, brine, dried over magnesium sulfate, and concentrated in vacuo to afford 2.1 g (87%) of (6-fluoro-4-methylchroman-4-yl)acetonitrile as an oil.
Reaction SMILES: [CH2:1]([C@@H:4]([OH:11])[C@H:5]([OH:10])[C@H:6]([OH:9])[CH2:7][OH:8])[CH:2]=[O:3].CC1(CN2C(=O)S/C(=C\C3C=CC(O)=C(C(F)(F)F)C=3)/C2=[O:22])CCCCC1>>[O:3]=[CH:2][C@@H:1]([C@H:4]([C@@H:5]([C@@H:6]([CH2:7][OH:8])[OH:9])[OH:10])[OH:11])[OH:22]
Reactant: O=CC[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC1(CN2C(=O)S/C(=C\c3ccc(O)c(C(F)(F)F)c3)C2=O)CCCCC1
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Glycolytic rate was determined by measuring the conversion of [5-3H]glucose (GE Healthcare, Piscataway, N.J.) to 3H2O according to a published procedure (Ashcroft et al., Biochem J. 126, p. 525-532 (1972)). Briefly, LNCaP cells were seeded in six-well plates (4×105 cells/well) and then treated 24 h later with 10 mM 2-DG or 10 μM OSU-CG12 for various intervals. After washing with PBS, cells were trypsinized and resuspended in 500 μL of Krebs buffer [25 mM NaHCO3, 115 mM NaCl, 2 mM KCl, 2 mM CaCl2, 1 mM MgCl2 and 0.25% BSA (pH, 7.4)] containing 1 mM nonradioactive glucose and 5 μCi/mL [5-3H]glucose for 1 h at 37° C. Aliquots from each treatment group were added to 0.2 N HCl in open tubes that were placed upright in scintillation vials containing 1 mL of H2O. The vials were sealed and H2O produced by glucose consumption was equilibrated with H2O outside the tube for a minimum of 24 h at room temperature. The amount of 3H retained in the tube and the amount that had diffused into the surrounding H2O by evaporation and condensation were determined separately by using a scintillation counter LS6500 (Beckman). [5-3H]glucose-only and 3H2O-only standards were included in each experiment for calculation of the rate of conversion of [5-3H]glucose to H2O using the following equation: glucose utilized (pmol)=[3H] water formed (d.p.m)/[5-3H]glucose (d.p.m/pmol)].
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16]C)[CH:14]=2)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].B(Br)(Br)Br.O>ClCCl>[C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)CC2
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(=O)NCCC1CCc2ccc(O)cc21
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of 1-[2-(acetylamino)ethyl]-6-methoxyindan (6.40 g, 27.4 mmol) in dichloromethane (150 ml) was added dropwise, under ice-cooling, boron tribromide (5.19 ml, 54.8 mmol). The mixture was then stirred for one hour. The reaction mixture was poured into water. The mixture was stirred for 8 hours at room temperature, which was subjected to extraction with chloroform. The extract solution was washed with brine, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was recrystallized from ethyl acetate/isopropyl ether to give 4.70 g (yield 78%) of the above-titled compound, m.p.107-108° C.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:13]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[O:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C@@H:6]1[NH2:20])(=[O:3])[CH3:2].C(N(CC)CC)C.CS[C:30](=[NH:35])[NH:31][N+:32]([O-:34])=[O:33]>CO>[C:1]([NH:4][C@H:5]1[C@H:13]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[O:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C@@H:6]1[NH:20][C:30]([NH2:35])=[N:31][N+:32]([O-:34])=[O:33])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(=O)O)=C[C@@H]1N
Reactant: CSC(=N)N[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(=O)O)=C[C@@H]1NC(N)=N[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 2 h
Yield: 19.2 %

Procedure:
5-(Acetylamino)-4-amino-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonic acid (200 mg, 0.689 mmol) was dissolved in absolute methanol (2.7 ml) by the addition of triethylamine (0.098 ml, 0.690 mmol). 2-Methyl-1-nitro-2-thiopseudourea (103 mg,0.757 mmol) was then added. The mixture was warmed to 40° C. with stirring under nitrogen for 2hrs, then stirred at 21° C. for 16 hr. The addition of reagent and heating and stirring was repeated twice more. The cooled mixture was then filtered and the white solid washed with methanol. Combined filtrate and washings were evaporated and the residue purified by ion exchange chromatography (Dowex 50 W×8(H+) resin, eluting with water. Appropriate fractions were combined and freeze dried. The residue was triturated with warm water (4 ml), and the off-white solid filtered and dried under high vacuum to give the title product (Yield =50 mg).