Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7]N.O=[C:11]([CH2:15][CH3:16])[C:12]([OH:14])=[O:13].[CH2:17](O)[CH3:18]>>[CH3:16][C:15]1[C:3]2[C:2](=[C:1]([CH3:9])[CH:6]=[CH:5][CH:4]=2)[NH:7][C:11]=1[C:12]([O:14][CH2:17][CH3:18])=[O:13]
Reactant: Cc1ccccc1NN
Reactant: CCC(=O)C(=O)O
Reactant: CCO
Product: CCOC(=O)c1[nH]c2c(C)cccc2c1C
Temperature: 50 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
A suspension of 1-o-tolylhydrazine (3.8 g, 30.9 mmol) in ethanol was warmed to 50° C. A solution of α-ketobutyric acid (3.16 g, 30.9 mmol) in ethanol was added and the mixture stirred at rt overnight. Hydrogen chloride was bubbled through the solution for 30 min and the mixture heated at reflux for 2 h then evaporated in vacuo. The crude reaction was chromatographed over silica gel eluting with ethyl acetate/hexane (5%) to afford the title compound (1.84 g, 27%). 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.09 (d, J=6.9 Hz, 1H), 7.03 (t, J=7.6 Hz, 1H), 4.41 (q, J=7.1 Hz, 2H), 2.59 (s, 3H), 2.48 (s, 3H), 1.44 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH2:23])=[CH:10][C:11]=3[C:12]2([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1.[CH2:24]([C:28]1([CH2:42][CH2:43][CH2:44][CH3:45])[C:40]2[CH:39]=[C:38](I)[CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:25][CH2:26][CH3:27].[OH-].[K+].N1[C:61]2[C:52](=[CH:53][CH:54]=[C:55]3[C:60]=2N=[CH:58][CH:57]=[CH:56]3)C=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([N:23]([C:52]4[CH:53]=[CH:54][C:55]5[C:56]6[C:57](=[CH:58][CH:3]=[CH:2][CH:14]=6)[C:5]([CH2:13][CH2:12][CH2:15][CH3:16])([CH2:6][CH2:11][CH2:10][CH3:9])[C:60]=5[CH:61]=4)[C:31]4[CH:32]=[CH:33][C:34]5[C:35]6[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=6)[C:28]([CH2:42][CH2:43][CH2:44][CH3:45])([CH2:24][CH2:25][CH2:26][CH3:27])[C:29]=5[CH:30]=4)=[CH:10][C:11]=3[C:12]2([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1
Reactant: CCCCC1(CCCC)c2cc(N)ccc2-c2ccc(Br)cc21
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: CCCCC1(CCCC)c2ccccc2-c2ccc(I)cc21
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCC1(CCCC)c2ccccc2-c2ccc(N(c3ccc4c(c3)C(CCCC)(CCCC)c3ccccc3-4)c3ccc4c(c3)C(CCCC)(CCCC)c3cc(Br)ccc3-4)cc21
Temperature: 120 °C

Procedure:
Under N2 atmosphere, 0.37 parts of 7-bromo-9,9-dibutyl-9H-fluoren-2-ylamine (31), 0.89 parts of 9,9-dibutyl-2-iodo-9H-fluorene (32), 0.17 parts of potassium hydroxide, 0.11 parts of 1,10-phenanthroline, and 0.03 parts of cuprous chloride were added into 10 parts of toluene, followed by stirring and mixing. Then, the reaction mixture was heated to 120° C. and reacted under reflux for 24 hours. After the reaction was quenched by water, diethyl ether was used for extracting the product, and magnesium sulfate was used for dehydration. After removing the solvent, the residual was purified with column chromatography method by using dichloromethane/hexane co-solvent as an eluent, to obtain a compound (33) of the present example. This compound was in a form of a tangerine solid, and the yield of this compound was 57%.
Reaction SMILES: CS[C:3]([N:7]1[CH:11]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH2:10][CH:9]=[N:8]1)=[N:4][CH2:5][CH3:6].[Cl:17][C:18]1[CH:19]=[C:20]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>C(#N)C>[Cl:17][C:18]1[CH:19]=[C:20]([S:24]([N:27]=[C:3]([NH:4][CH2:5][CH3:6])[N:7]2[CH:11]([C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)[CH2:10][CH:9]=[N:8]2)(=[O:25])=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: CCN=C(SC)N1N=CCC1c1ccsc1
Reactant: NS(=O)(=O)c1cccc(Cl)c1
Solvent: CC#N
Product: CCNC(=NS(=O)(=O)c1cccc(Cl)c1)N1N=CCC1c1ccsc1
Yield: 0.1 %

Procedure:
0.47 g (1 mol equiv.) N-Ethyl-5-thiophen-3-yl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester and 0.37 g (1.05 mol equiv.) 3-chlorobenzenesulfonamide were added to 7 mL acetonitrile. The reaction mixture was refluxed overnight and volatiles were removed under reduced pressure. The residue was taken up in ethyl acetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (Et2O) afforded 0.44 g (49%) 3-chloro-N-[ethylamino-(5-thiophen-3-yl-4,5-dihydro-pyrazol-1-yl)-methylene]-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 1.19 (t, J=7.2, 3H), 2.78 (ddd, J=18.6, 6.0, 1.4 Hz, 1H), 3.31 (ddd, J=18.6, 11.8, 1.4 Hz, 1H), 3.54-3.70 (m, 2H), 5.62 (dd, J=11.8, 6.0 Hz, 1H), 6.75 (d, J=4.3 Hz, 1H), 6.92 (d, J=2.0 Hz, 1H), 7.02 (br.s., 1H), 7.17-7.23 (m, 2H), 7.36 (m, 2H), 7.54 (br.s., 1H).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([C:11]#[N:12])=[C:9]([NH:13][CH:14]2[CH2:16][CH2:15]2)[N:8]=[C:7]([NH:17][CH:18]([CH3:20])[CH3:19])[N:6]=1>CO>[CH:14]1([NH:13][C:9]2[N:8]=[C:7]([NH:17][CH:18]([CH3:20])[CH3:19])[N:6]=[C:5]([O:2][CH3:1])[C:10]=2[C:11]#[N:12])[CH2:16][CH2:15]1
Reactant: CC(C)Nc1nc(Cl)c(C#N)c(NC2CC2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(NC(C)C)nc(NC2CC2)c1C#N
Yield: 89.1 %

Procedure:
To a stirred solution of 0.9 gram of sodium methoxide in 100 ml of methanol was added, in one portion, 4.0 grams of 4-chloro-6-cyclopropylamino-2-isopropylamino-5-pyrimidinecarbonitrile. The reaction mixture was then heated under reflux for 3 hours. The methanol was removed by evaporation under reduced pressure to give a residue. The residue was washed with water, and the solid was collected by filtration to yield 3.5 grams of 6-cyclopropylamino-2-isopropylamino-4-methoxy-5- pyrimidinecarbonitrile; mp, 142°-147°.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([O:12][CH3:13])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.C(O)(=[O:16])C>O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:11][C:10]1[C:2]([Cl:1])=[C:3]2[C:7]([CH2:6][CH2:5][C:4]2=[O:16])=[CH:8][C:9]=1[O:12][CH3:13]
Reactant: COc1cc2c(c(Cl)c1Cl)CCC2
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)CC2
Reaction time: 1 h

Procedure:
4,5-Dichloro-6-methoxy-2,3-dihydro-1H-indene (21 gm., 0.097 mole) is dissolved in acetic acid (280 ml.) and chromium trioxide (14 gm., 0.14 mole) in a mixture of water (15 ml.) and acetic acid (40 ml.) is added dropwise with stirring over a period of one hour. The mixture is poured, with stirring into cold water (1200 ml.) and the solid that separates is removed by filtration, washed with water and dried. The product, which consists of a mixture of the desired material and the isomer described in Step D, is subjected to column chromatographic separation using 225 gm. of silica gel and chloroform is used for elution. Evaporation of the solvent gives 6,7-dichloro-5-methoxy-2,3-dihydro-1H-inden-1-one, 5.2 gm., m.p. 154°-156° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[C:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[CH3:21][C:22]1([CH3:32])[N:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:25]2[C:24](=[O:31])[NH:23]1.C(N(CC)CC)C>CN(C)C=O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:28][CH2:27][N:26]3[C:22]([CH3:32])([CH3:21])[NH:23][C:24](=[O:31])[CH:25]3[CH2:30]2)=[CH:8][CH:9]=1
Reactant: CC1(C)NC(=O)C2CNCCN21
Reactant: Fc1ccc(C(=CCCCBr)c2ccc(F)cc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)C2CN(CCCC=C(c3ccc(F)cc3)c3ccc(F)cc3)CCN21
Temperature: 70 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of 51 parts of 1,1'-(5-bromo-1-penten-1-ylidene)bis[4-fluorobenzene], 25.4 parts of hexahydro-3,3-dimethylimidazo-[1,5-a]pyrazin-1(5H)-one, 35.5 parts of N,N-diethylethanamine and 270 parts of N,N-dimethylformamide was stirred overnight at 70° C. After evaporation, the residue was taken up in trichloromethane. The organic layer was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 60 parts (94.0%) of 7-[5,5-bis(4-fluorophenyl)-4-pentenyl]hexahydro-3,3-dimethylimidazo[1,5-a]pyrazin-1(5H)-one as a residue (int. 24).
Reaction SMILES: CC1(C)CC(=O)CC(=O)C1.C(OC([O:17][C@@H:18]([C@H:20]1[C:35](=[O:36])[N:22]2[C:23]([C:29]([O:31]CC=C)=[O:30])=[C:24]([CH2:27]O)[C@H:25]([CH3:26])[C@H:21]12)[CH3:19])=O)C=C.C(OC([NH:43][CH2:44][CH2:45][NH:46][C:47]([C:49]1[N:50]2[CH:56]=[N:55][CH:54]=[C:51]2[S:52][CH:53]=1)=[O:48])=O)C=C>>[OH:17][C@@H:18]([C@H:20]1[C:35](=[O:36])[N:22]2[C:23]([C:29]([O-:31])=[O:30])=[C:24]([CH2:27][N:55]3[CH:54]=[C:51]4[S:52][CH:53]=[C:49]([C:47](=[O:48])[NH:46][CH2:45][CH2:44][NH2:43])[N+:50]4=[CH:56]3)[C@H:25]([CH3:26])[C@H:21]12)[CH3:19]
Reactant: C=CCOC(=O)NCCNC(=O)c1csc2cncn12
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Agent: CC1(C)CC(=O)CC(=O)C1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(C(=O)NCCN)[n+]4c3)[C@H](C)[C@H]12
Yield: 5.4 %

Procedure:
The same procedure as in Example 1 was repeated except that dimedone was used as a trapping agent in a deprotective reaction, and 145 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 340 mg of 3-[N-(2-allyloxycarbonylaminoethyl)carbamoyl]imidazo[5,1-b]thiazole were used, thereby obtaining 9.3 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:16](Cl)(Cl)[S:17]Cl.[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1>C(Cl)(Cl)Cl>[S:23]1[CH:24]=[CH:25][N:26]=[C:22]1[N:21]=[C:16]1[N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[N:1][S:17]1
Reactant: Nc1nccs1
Reactant: Nc1ccccn1
Reactant: ClSC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: c1ccn2c(=Nc3nccs3)snc2c1
Reaction time: 0.17 h

Procedure:
A solution of 5.6 g (60 mmol) of 2-aminopyridine and 8.3 ml of triethylamine in 50 ml of chloroform is added dropwise at 0° C. to a solution of 6.6 ml (60 mmol) of trichloromethanesulphenyl chloride in 900 ml of chloroform. The mixture is stirred for 10 min and a solution of 6.0 g (60 mmol) of 2-aminothiazole and 25 ml of triethylamine in 100 ml of chloroform is added dropwise. After stirring at room temperature for 3 h, the mixture is concentrated and the precipitate is washed with methanol. 8.9 g of title compound (63% of theory) of m.p. 169-171° C. remain.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[C:11]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.O.C(O)C>[C:11]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[CH:15][C:14]([C:2]2[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(Br)s1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc(-c3ccccc3)cc2)s1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A mixture of compound 1021 (5.0 g, 22.6 mmol), biphenyl-4-ylboronic acid (5.4 g, 27.1 mmol), sodium carbonate (5.9 g, 56.5 mmol), tetrakis(triphenylphosphine)palladium(0) (2.65 g, 2.3 mmol), toluene (200 mL), ethanol (100 mL) and water (50 mL) was heated to reflux for 12 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, and extracted with dichloromethane (2×250 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography with silica gel (5% EtOAc in hexane) to give compound 1022 (5.0 g). 1H NMR (CDCl3, 300 MHz) δ 3.92 (s, 3H), 7.32-7.49 (m, 4H), 7.62-7.80 (m, 7H).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH3:12])=[O:22]
Reactant: COc1ccccc1N=C=O
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: COc1ccccc1NC(=O)Nc1ccc([N+](=O)[O-])cc1O
Yield: 27 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(2-methoxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 2-methoxyphenylisocyanate(1 mmol.) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (82 mg, 27%). EI-MS m/z 302(M−H)−.
Reaction SMILES: O1CCCC1.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Br:13])[CH:12]=1.C([Mg]Cl)(C)C.[CH2:19]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1)[CH3:20]>O>[Br:13][C:11]1[CH:12]=[C:7]([CH:26]([C:25]2[CH:28]=[CH:29][C:22]([O:21][CH2:19][CH3:20])=[CH:23][CH:24]=2)[OH:27])[CH:8]=[N:9][CH:10]=1
Reactant: CCOc1ccc(C=O)cc1
Reactant: Brc1cncc(Br)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(C(O)c2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.9 %

Procedure:
A tetrahydrofuran solution (25 mL) of 3,5-dibromo pyridine (5 g, 0.0211 mol) was added dropwise to a mixture of a tetrahydrofuran solution (21.1 mL) of 1M isopropyl magnesium chloride and tetrahydrofuran (10 mL) at 4° C. for 15 minutes. After stirred at room temperature for 2.5 hours, the reaction mixture was added with 4-ethoxybenzaldehyde (2.93 mL, 0.0211 mol) and stirred for further 1.5 hours. After the reaction mixture was added with water while cooled on ice and extracted with ethyl acetate, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain (5-bromopyridine-3-yl)(4-ethoxyphenyl)methanol (5.0 g, 77%) as a yellow oily substance.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH:14]=[O:15])=[C:9]([Cl:16])[CH:8]=1)(=O)=O.[Si]([O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(C(C)(C)C)(C)C>>[Cl:16][C:9]1[CH:8]=[C:7]([C:30]2[CH:31]=[CH:32][C:27]([OH:26])=[CH:28][CH:29]=2)[CH:12]=[C:11]([Cl:13])[C:10]=1[CH:14]=[O:15]
Reactant: O=Cc1c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Product: O=Cc1c(Cl)cc(-c2ccc(O)cc2)cc1Cl

Procedure:
The title compound was prepared by reacting 3,5-dichloro-4-formyl-phenyl trifluoromethanesulfonate (0.73 g, 2.26 mmol) with 4-tert-butyldimethylsilyloxyphenyl boronic acid (0.80 g, 3.2 mmol) according to method C to yield 0.30 g (50%) of a yellow solid: mp:178-180° C.; 1H NMR (DMSO-d6): δ 6.88 (2H, d, J=8.84 Hz), 7.72 (2H, d, J=8.71 Hz), 7.84 (2H, s), 9.95 (1H, s), 10.38 (1H, s); MS (EI) m/z 266.0/268.0/270.0 (M+).
Reaction SMILES: S(O[C@H:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C@H:14]([CH2:27]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.[S-2:39].[Na+].[Na+].CCOC(C)=O>CS(C)=O>[C@H:12]12[CH2:13][C@H:14]([N:15]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:16]1)[CH2:27][S:39]2
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(=O)(=O)c3ccc(C)cc3)CN2C(=O)OCc2ccccc2)cc1
Reactant: [S-2]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1C[C@@H]2C[C@H]1CS2
Temperature: 110 °C
Reaction time: 17 h
Yield: 60.6 %

Procedure:
(2S,4R)-benzyl 4-(tosyloxy)-2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (10 g, 17.87 mmol) and sodium sulfide (1.125 mL, 26.8 mmol) were combined in DMSO (80 mL) in a 150 mL medium pressure flask. The reaction mixture was purged with N2 (g) and the resulting slurry was heated to 110° C. under a N2 (g) atmosphere. The reaction became deep blue immediately. After 17 h, the resulting black reaction mixture was cooled to rt, diluted with 1:1 EtOAc:Et2O (150 mL) and washed with H2O (100 mL). The aqueous layer was extracted with 1:1 EtOAc:Et2O (100 mL). The combined organic layer was washed with 1N HCl (100 mL), brine, dried over MgSO4, filtered and concentrated to give dark red viscous oil. The crude material was loaded onto a silica gel column (60 g) and eluted with 3:1 hex:EtOAc to give (1S,4S)-benzyl 2-thia-5-azabicyclo[2.2.1]heptane-5-carboxylate (2.7 g, 61% yield) as red viscous oil. LC/MS: m/e 250.0 (M+H)+, 2.22 min (method 3). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.39-7.31 (m, 5H), 5.18-5.06 (m, 2H), 4.79-4.65 (m, 1H), 3.64 (d, J=7.8 Hz, 2H), 3.59 (br. s., 1H), 3.22-3.04 (m, 1H), 3.04-2.96 (m, 1H), 2.16 (t, J=10.0 Hz, 1H), 1.88 (d, J=10.3 Hz, 1H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.Br[C:10]1[CH:18]=[C:17]2C(C[C:15]3(CCC(=O)CC3)[C:16]2=[O:19])=C[CH:11]=1.CON(C)C(C1[N:32]=[N:33]C=CC=1)=O>C1COCC1>[N:32]1[CH:11]=[CH:10][CH:18]=[C:17]([CH:16]([OH:19])[CH3:15])[N:33]=1
Reactant: O=C1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Reactant: CON(C)C(=O)c1cccnn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1cccnn1
Temperature: -60 °C
Reaction time: 1 h
Yield: 106.6 %

Procedure:
To a solution of LDA (23.4 mL, 42.1 mmol, 1.8 M in THF) in THF (150 mL) was added slowly a solution of compound 1 (3.6 g, 21.05 mmol) in THF (77 mL) at −60° C. under a N2 atmosphere. After being stirred at −60° C. for 1 h, a solution of compound 2 (7.05 g, 18.9 mmol)) in THF (23 mL) was added slowly to the above solution. The resulting mixture was stirred at −60° C. for 2 h. The reaction mixture was quenched with water (15 mL). The aqueous layer was extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel (petroleum:ethyl acetate, 10:1) to give compound 3 (2.5 g, yield 26%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C1COCC1>[CH3:24][S:25]([O:16][CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1

Procedure:
A solution of 4-(2-hydroxyethyl)-piperidine-1-carboxylic acid tert-butyl ester (Aldrich, 0.50 g, 2.2 mmol), triethylamine (0.91 mL, 6.5 mmol), and methanesulfonyl chloride (0.25 mL, 3.3 mmol) in 10 mL THF were processed as described in Example 1C to give the crude title compound which was used directly in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:22]#[N:23])=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
A mixture of 4.00 g (10.8 mmol) of 4-[(3-bromophenyl)amino]-6-nitro-quinoline-3-carbonitrile and 12.2 g (54.2 mmol) of SnCl2 dihydrate in 160 mL of ethanol was refluxed under N2 for 1.3 h. After cooling to 25° C., ice water and sodium bicarbonate were added and the mixture was stirred for 2 h. Extraction with chloroform, treatment with Darco, drying (magnesium sulfate) and solvent removal gave 3.9 g of brown crystals: mass spectrum (electrospray, m/e): M+H 339.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=1)=[O:7])([CH3:4])[CH3:3].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([NH:26][CH3:27])=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:17][C:13]1[CH:12]=[C:11]([CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[C:18]([N:26]([C:25]2[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=2)[CH3:27])=[O:20])[CH:16]=[CH:15][CH:14]=1
Reactant: CNc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(Br)c1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)[C@H](Cc1cccc(Br)c1)NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
Boc-L-3-BromoPhe (5 g, 14.5 mmol) was dissolved in 50 mL of DMF and to it were added 4-chloro-N-methylaniline (2.1 mL, 17.4 mmol) and N,N-diisopropylethylamine (7.6 mL, 43.5 mmol). The reaction mixture was cooled to 0° C. and to it was added HATU portion wise (6.6 g, 17.4 mmol). The reaction mixture was allowed to stir at ambient temperature overnight and then was partitioned between ethyl acetate and water. The organic layer was separated and washed with 5% aqueous LiCl, saturated aqueous NaHCO3 and brine. The mixture was then dried over MgSO4, filtered and concentrated to afford crude product which was purified by silica gel chromatography eluting with ethyl acetate/hexanes to afford 5.6 g of (S)-tert-butyl 3-(3-bromophenyl)-1-((4-chlorophenyl)(methyl)amino)-1-oxopropan-2-ylcarbamate as a white solid. MS (m/z): 469.1 [M+H]+; HPLC retention time 4.39 min (5-99% acetonitrile:water with 0.05% formic acid).