Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:32]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]([NH:38][C:35]1[CH:34]=[CH:33][C:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:37][CH:36]=1)=[O:5])[CH3:9]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 105.3 %

Procedure:
To a stirred solution of monoethyl malonate (0.86 g, 0.00649 mole) in DMF (20 mL) was added HOBt (0.795 g, 0.0059 mole) and DMAP (0.790 g, 0.00649 mole). The mixture was cooled to 10° C. and EDCI.HCl (1.7 g, 0.008 mole) followed by biphenyl-4-ylamine (1.0 g, 0.0059 mole) were added and the resulting mixture was stirred at the ambient temperature for overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration and dried to afford 1.76 g (94%) of N-biphenyl-4-yl-malonamic acid ethyl ester. To a solution of N-biphenyl-4-yl-malonamic acid ethyl ester (1.7 g, 0.0060 mole) in a mixture of methanol (5 mL), THF (10 mL) and H2O (10 mL) was added LiOH.H2O (0.5 g, 0.012 mole). The reaction mixture was stirred for 2 hours at ambient temperature. The mixture was then concentrated and the residue was diluted with water acidified with conc. HCl. The resulting precipitate was isolated by filtration and dried to afford 1.5 g (98%) of N-biphenyl-4-yl-malonamic acid. LC-MS purity: 95.4%, 1H NMR (DMSO-d6): δ 10.3 (s, 1H), 7.7 (m, 6H), 7.4 (t, 2H), 7.32 (t, 1H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:8]=1)=O.[CH3:27][C:28]([CH3:33])([CH3:32])[CH2:29][NH:30][NH2:31]>CO>[CH3:27][C:28]([CH3:33])([CH3:32])[CH2:29][N:30]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:31]1
Reactant: CC(C)(C)CNN
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(N3CCOCC3)cc2)ccc1=O
Solvent: CO
Product: CC(C)(C)Cn1nccc1-c1nn(-c2ccc(N3CCOCC3)cc2)ccc1=O
Yield: 22.4 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-morpholin-4-ylphenyl)pyridazin-4(1H)-one (300 mg, 0.85 mmol) in 20 mL of methanol, 2,2-dimethylpropylhydrazine (346 mg, 3.39 mmol) was added, the resulting mixture was refluxed for 4 hours, and then concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1 M acetic acid aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (75 mg, 22% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3): δ 0.83 (9H, s), 3.22-3.25 (4H, m), 3.88-3.90 (4H, m), 4.41 (2H, s), 6.70 (1H, d, J=7.6 Hz), 7.00 (2H, d, J=9.2 Hz), 7.08 (1H, d, J=2.0 Hz), 7.45 (2H, d, J=9.2 Hz), 7.58 (1H, d, J=2.0 Hz), 8.14 (1H, d, J=8.0 Hz); LCMS (mobile phase: from 70% water and 30% CH3CN to 5% water and 95% CH3CN in 6 min, finally under these conditions for 0.5 min.) purity is >95%, Rt=2.656 min; MS Calcd.: 393, MS Found: 394 (M++H).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]1[C@@H:10]([CH3:11])[CH2:9][N:8]([C:12]2[C:21]([F:22])=[CH:20][C:19]3[C:23](=[O:29])[C:24]([C:26]([OH:28])=[O:27])=[CH:25][N:17]4[C:18]=3[C:13]=2[CH2:14][CH2:15][N:16]4[CH3:30])[CH2:7]1.[CH3:31]O>>[NH2:5][C@H:6]1[C@@H:10]([CH3:11])[CH2:9][N:8]([C:12]2[C:21]([F:22])=[CH:20][C:19]3[C:23](=[O:29])[C:24]([C:26]([O:28][CH3:31])=[O:27])=[CH:25][N:17]4[C:18]=3[C:13]=2[CH2:14][CH2:15][N:16]4[CH3:30])[CH2:7]1
Reactant: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2CCN4C)C[C@H]1N
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cn2c3c(c(N4C[C@@H](N)[C@@H](C)C4)c(F)cc3c1=O)CCN2C
Temperature: 25 °C
Yield: 72 %

Procedure:
2 ml of thionyl chloride was added to 20 ml of methanol while cooling on ice, and then this solution was stirred at room temperature. 358 mg of the compound (30) obtained in Example 5 was added to the solvent, and the solution was heated at reflux for 8 hours. The solvent was removed and 40 ml of chloroform and 20 ml of water were added to the residue. The solution was alkalized with sodium hydrogen carbonate, and the organic layer was dried over magnesium sulfate. The solvent was removed by distillation. To the residue, ether was added and then ethyl acetate was added to form crystals. They were filtered off and washed with ethyl acetate in this order to obtain 270 mg of a title compound (121) (yield: 72%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[CH2:10][C:11](=[NH:13])[NH2:12].C[O-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([CH:29]3[CH2:31][CH2:30]3)[C:27](=[O:32])[N:26]([CH2:33][C:34]([NH:36]N)=O)[N:25]=2)=[CH:20][CH:19]=1>CO>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([CH:29]3[CH2:31][CH2:30]3)[C:27](=[O:32])[N:26]([CH2:33][C:34]3[NH:12][C:11]([CH2:10][C:4]4[C:3]([Cl:2])=[CH:8][CH:7]=[CH:6][C:5]=4[Cl:9])=[N:13][N:36]=3)[N:25]=2)=[CH:20][CH:19]=1
Reactant: N=C(N)Cc1c(Cl)cccc1Cl
Reactant: NNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=c1n(Cc2nnc(Cc3c(Cl)cccc3Cl)[nH]2)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
58 mg (0.24 mmol) of 2-(2,6-dichlorophenyl)ethaneimidamide hydrochloride were initially charged in 1 ml of dry methanol, 66 μl (0.24 mmol) of a 25% strength methanolic sodium methoxide solution were added and the mixture was stirred at RT for 1 h. 50 mg (0.16 mmol) of the compound from Example 21A, dissolved in 0.6 ml of methanol, were then added. The reaction was stirred at room temperature overnight. The precipitated colorless solid was filtered off with suction, washed with a little methanol and dried under high vacuum. The solid was then suspended in xylene and stirred under reflux for 4 h. After cooling, the mixture was concentrated under reduced pressure and the residue was purified by chromatography [Method 19]. This gave 30 mg (39% of theory) of the target compound as a colorless solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[C:9]1[N:14]=[N:13][C:12]([C:15]23[CH2:22][N:19]([CH2:20][CH2:21]2)[CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=1>CN(C)C=O>[N:1]1([C:9]2[N:14]=[N:13][C:12]([C:15]34[CH2:22][N:19]([CH2:20][CH2:21]3)[CH2:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Clc1ccc(C23CCCN(CC2)C3)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cn(-c2ccc(C34CCCN(CC3)C4)nn2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.228 g (3.35 mmol) of imidazole in solution in 4 ml of dimethylformamide is introduced into a 10 ml three-necked round-bottomed flask. 0.137 g (3.42 mmol) of sodium hydride as a 60% dispersion in oil is subsequently added and the mixture is stirred at ambient temperature for 1 hour. The mixture is then added to a solution of (+)-5-(6-chloropyridazin-3-yl)-1-azabicyclo[3.2.1]octane (obtained by resolution of the racemic mixture prepared in stage 1.5 of Example 1, by liquid chromatography on a chiral support) (0.15 g, 0.67 mmol) in dimethylformamide and the reaction medium is heated at 90° C. for 15 hours and then at 110° C. for 3 hours, and the solvent is evaporated off under reduced pressure. The residue is taken up in 10 ml of chloroform and 10 ml of a saturated aqueous sodium carbonate solution. The aqueous phase is extracted again with 10 ml of chloroform and the combined organic phases are washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel plate chromatography, elution being carried out with a mixture of chloroform, methanol and aqueous ammonia in the proportions 85/15/1.5. 0.111 g of expected product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:49]1([NH:52][CH2:53][C@@H:54]2[NH:58][CH2:57][C@H:56]([OH:59])[CH2:55]2)[CH2:51][CH2:50]1>CN(C=O)C>[CH:49]1([NH:52][CH2:53][C@H:54]2[CH2:55][C@@H:56]([OH:59])[CH2:57][N:58]2[C:31](=[O:32])[CH2:30][C:26]2[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH2:51][CH2:50]1
Reactant: O[C@H]1CN[C@@H](CNC2CC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1C[C@H](O)C[C@@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (250 mg, 0.48 mmol), HOBt (78 mg, 1.2 eq.), EDC (110 mg, 1.2 eq.), TEA (0.17 mL, 2.5 eq.) and (3R,5R)-5-cyclopropylaminomethyl-pyrrolidin-3-ol (300 mg, 4 eq.) in DMF (10 mL) was stirred at rt for overnight. The reaction was concentrated, washed with water, sodium bicarbonate and brine, dried and concentrated. The residue was purified on a silica gel column to give 100 mg of the titled compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]\[CH:10]=[O:11])/[CH3:8])[CH3:3].CC(=CCC/C(=C/C=O)/C)C>>[CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3]
Reactant: CC(C)=CCC/C(C)=C\C=O
Agent: CC(C)=CCC/C(C)=C/C=O
Product: CC(C)=CCCC(C)CC=O

Procedure:
The complexes derived from Rh4 (CO)12 or Rh6 (CO)16 and from 1,2-bis-(diarylphosphinomethyl)-cyclobutanes are very particularly suitable for the asymmetric hydrogenation of neral and geranial to give enantiomers of citronellal, because they simultaneously provide a high hydrogenation rate, a good selectivity with respect to citronellal and a good optical purity.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1)([O-])=O>CO>[NH2:1][C:4]1[S:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])s1
Solvent: CO
Product: COC(=O)c1ccc(N)s1
Reaction time: 6.5 h

Procedure:
To a Parr flask was added methyl 5-nitrothiophene-2-carboxylate (5.00 g, 26.71 mmol) and MeOH (100 mL). The solution was purged with a stream of Ar, and 5% platinum on sulfide carbon (2.00 g) was added. The mixture was hydrogenated on a Parr apparatus set at 50 psi for 6.5 hours. The reaction was then filtered through celite and the solvents removed in vacuo to yield methyl 5-aminothiophene-2-carboxylate as an olive green oil.
Reaction SMILES: [F:1][CH2:2][C:3]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([F:18])=[C:14](F)[CH:15]=2)[C:10](=[O:19])[C:9]([C:20]([OH:22])=[O:21])=[CH:8]1)([CH3:6])[CH2:4][F:5].[C@H:23]12[CH2:31][NH:30][CH2:29][C@H:28]1[NH:27][CH2:26][CH2:25][O:24]2.N12CCN(CC1)CC2>C(#N)C>[F:1][CH2:2][C:3]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([F:18])=[C:14]([N:30]3[CH2:31][C@H:23]4[C@H:28]([NH:27][CH2:26][CH2:25][O:24]4)[CH2:29]3)[CH:15]=2)[C:10](=[O:19])[C:9]([C:20]([OH:22])=[O:21])=[CH:8]1)([CH3:6])[CH2:4][F:5]
Reactant: CC(CF)(CF)n1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: C1CO[C@H]2CNC[C@H]2N1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CC(CF)(CF)n1cc(C(=O)O)c(=O)c2cc(F)c(N3C[C@@H]4OCCN[C@@H]4C3)cc21
Temperature: 25 °C

Procedure:
A solution of 1-(1-fluoromethyl-1-methyl-2-fluoroethyl)-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (400 mg, 1.26 mmol), (1S,6R)-2-oxa-5,8-diazabicyclo[4.3.0]nonane (176 mg, 1.39 mmol) and 1,4-diazabicyclo[2.2.2]octane (141 mg, 1.26 mmol) in absol. acetonitrile (20 ml) is heated under reflux overnight. After cooling the reaction mixture to room temperature, the precipitated crystals are filtered off and washed with acetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]34[CH2:20][CH2:19][C:16]([C:21](O)=[O:22])([CH2:17][CH2:18]3)[CH2:15][CH2:14]4)[O:10][N:9]=2)=[CH:4][CH:3]=1.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([NH:30][NH2:31])=O.[Cl-].ClC1N(C)CC[NH+]1C.C(N(CC)CC)C>ClCCl.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]34[CH2:20][CH2:19][C:16]([C:21]5[O:22][C:28]([C:27]6[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=6[C:25]([F:24])([F:36])[F:37])=[N:30][N:31]=5)([CH2:15][CH2:14]3)[CH2:17][CH2:18]4)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C12CCC(c3nc(-c4ccc(F)cc4)no3)(CC1)CC2
Reactant: NNC(=O)c1ccccc1C(F)(F)F
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2noc(C34CCC(c5nnc(-c6ccccc6C(F)(F)F)o5)(CC3)CC4)n2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of the acid (7-C) (138.9 mg, 0.439 nmol) and 2-(trifluoromethyl)benzoic hydrazide (7-D) (89.7 mg, 0.439 mmol) was first co-evaporated with toluene three times. Dichloromethane (7 mL) was added to the mixture as solvent. To the resulting suspension was added 2-chloro-1,3-dimethylimidazolinium chloride (743 mg, 4.39 mmol) followed by triethylamine (1.2 mL, 8.78 mmol). The mixture was allowed to stir at room temperature under nitrogen for 48 h to ensure the completion of the reaction. The reaction mixture was then diluted with dichloromethane, washed with water, 1N HCl, saturated sodium bicarbonate aqueous solution, and lastly brine. The organics were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography using hexane/ethyl acetate (3/1) as eluent to give 3-(4-fluorophenyl)-5-(4-{5-[2-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole (7-E) as a white solid. 1H NMR (500 MHz, CDCl3) δ 2.25 (s, 12H), 7.21 (t, J=8.7 Hz, 2H), 7.74-7.76 (m, 2H), 7.91 (m, 1H), 8.11-8.15 (m, 3H) ppm. ESI-MS m/z (M+H) 485.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH:24]([CH3:26])[CH3:25])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:29][N:30]([CH3:47])[CH2:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1>>[CH3:29][N:30]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH:24]([CH3:25])[CH3:26])=[O:15])[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=3[CH:10]=2)=[CH:34][CH:33]=1)[CH3:47]
Reactant: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1cc(C(C)C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Product: Cc1cc(C(C)C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)cc3)cc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-1-(1-methylethyl)-N-{[6-methyl-4-(1-methylethyl)-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-1H-indazole-4-carboxamide (90 mg, 0.202 mmol) and dimethyl{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}amine (90 mg, 0.303 mmol). The product was collected as a white solid (54 mg, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (br. s., 1H) 8.69 (br. s., 1H) 8.37 (s, 1H) 8.10 (s, 1H) 7.86 (s, 1H) 7.82 (s, 1H) 7.80 (s, 1H) 7.42 (s, 1H) 7.40 (s, 1H) 6.02 (s, 1H) 5.17 (dt, J=13.14, 6.57 Hz, 1H) 4.47 (d, J=4.80 Hz, 2H) 3.44 (s, 2H) 3.24 (dt, J=13.71, 6.92 Hz, 1H) 2.17 (s, 6H) 2.15 (s, 3H) 1.51 (s, 3H) 1.49 (s, 3H) 1.11 (s, 3H) 1.09 (s, 3H). LC-MS (ES) m/z=500.1 [M+H]+
Reaction SMILES: [S:1]1[C:12]2[C:11]3[NH:10][CH:9]=[CH:8][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=[C:2]1[NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[CH2:17]([NH:16][C:14]([NH:13][C:2]1[S:1][C:12]2[C:11]3[NH:10][CH:9]=[CH:8][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1)=[O:15])[CH3:18]
Reactant: CCNC(=O)Nc1nc2c(s1)-c1[nH]ccc1CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2ccc3cc[nH]c3c2s1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
To a suspension of N-(5,8-dihydro-4H-[1,3]thiazolo[4,5-g]indol-2-yl)-N′-ethylurea (81 mg, 0.308 mmol) in toluene (3.5 mL) was added DDQ (78 mg, 0.34 mmol). The reaction mixture was stirred at about 45° C. for about 4 hrs. The reaction mixture was pumped down and the crude material was purified by preparative HPLC. 3 mg (4%, 2 steps) pure product was isolated. LC/MS 262 (MH+); RP-BPLC RT 10.45 min.
Reaction SMILES: [Br:1][C:2]1[C:14]([F:15])=[CH:13][C:12]([C:16](O)=[O:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:8][C:9]=1[NH:10]2.C(Cl)CCl.C1C=CC2N(O)N=[N:40]C=2C=1.[NH4+].[OH-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:14]([F:15])=[CH:13][C:12]([C:16](=[O:17])[NH2:40])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:8][C:9]=1[NH:10]2
Reactant: On1nnc2ccccc21
Reactant: CCOC(=O)C(C(=O)OCC)C1CCc2c([nH]c3c(C(=O)O)cc(F)c(Br)c23)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)C(C(=O)OCC)C1CCc2c([nH]c3c(C(N)=O)cc(F)c(Br)c23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-bromo-2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (0.981 g, 2.09 mmol), EDC (0.600 g, 3.13 mmol) and HOBT (0.383 g, 2.50 mmol) in THF (5 mL) was stirred at room temperature for 60 min. The mixture was treated with NH4OH (1.74 mL, 12.5 mmol) and stirred at room temperature overnight. The mixture was diluted with EtOAc, washed sequentially with saturated aqueous Na2CO3 and brine. The combined aqueous layers were extracted with EtOAc, and the combined organic phases were dried and concentrated. The residue was purified by column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (gradient from 0-100%), to provide diethyl 2-(5-bromo-8-carbamoyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)malonate as a slightly yellow solid (440 mg, 45% yield). Mass spectrum m/z 469, 471 (M+H)+.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].[NH2:8][CH2:9][CH2:10][CH2:11][C@:12]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[OH:13].C(N(CC)CC)C.C(OC(=O)C)(=O)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([NH:8][CH2:9][CH2:10][CH2:11][C@:12]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[OH:13])(=[O:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](O)(CCCN)c2cccc(Cl)c2)C1
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a 100 mL, round bottom flask were added TFA salt of (R)-tert-butyl 3-((S)-4-amino-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate (0.374 g, 0.75 mmol, 1.0 equiv), DMAP (0.1615 g), CH2Cl2 (10 mL), and triethylamine (3 mL). The mixture was cooled in an ice bath and a solution of acetic anhydride (0.280 g, 2.74 mmol, 3.6 equiv) in CH2Cl2 (10 mL) was added. The reaction mixture was allowed to slowly warm to rt while stirring overnight (16 h). After the solvents were removed in vacuo, the residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100A, 250×21.20 mm, 5 micron, 70%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 1.5 min, flow rate 25 mL/min) to give 0.2589 g (81%) of (R)-tert-butyl 3-((S)-4-acetamido-1-(3-chlorophenyl)-1-hydroxybutyl)-piperidine-1-carboxylate. LC-MS (3 min) tR=1.72 min, m/z 447, 449 (MNa+), 425 (MH+), 325, 327; 1H NMR (400 MHz, CDCl3) □ 7.38-7.37 (m, 1H), 7.28-7.18 (m, 3H), 6.06 (br s, 1H), 4.36-4.34 (m, 1H), 3.97-3.95 (m, 1H), 3.35-3.26 (m, 1H), 3.13-3.05 (m, 1H), 2.99 (br s, 2H), 2.55-2.49 (m, 2H), 1.97 (s, 3H), 1.44 (s, 9H), 1.95-1.15 (m, 6H); 13C NMR (100 MHz, CDCl3) □ 171.41, 155.17, 146.75, 134.24, 129.33, 126.63, 126.01, 123.83, 79.68, 77.60, 46.34, 44.69, 39.71, 35.91, 28.43, 25.40, 25.23, 24.15, 22.99.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:47][CH:48]1[C@H:52]2[C@H:53](OC3CCCCO3)[N:54](C(OC(C)(C)C)=O)[C:55]3[CH:62]=[C:61]([O:63][CH3:64])[CH:60]=[CH:59][C:56]=3[C:57](=[O:58])[N:51]2[CH2:50][CH2:49]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]1[C@H:20]2[C@H:21](OC3CCCCO3)[N:22](C(OC(C)(C)C)=O)[C:23]3[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=3[C:25](=[O:26])[N:19]2[CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:8]([O:47][CH:48]1[C@@H:52]2[CH:53]=[N:54][C:55]3[CH:62]=[C:61]([O:63][CH3:64])[CH:60]=[CH:59][C:56]=3[C:57](=[O:58])[N:51]2[CH2:50][CH2:49]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]1[C@@H:20]2[CH:21]=[N:22][C:23]3[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=3[C:25](=[O:26])[N:19]2[CH2:18][CH2:17]1
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)[C@@H](OC1CCCCO1)[C@@H]1C(OCCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)CCN1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)N=C[C@H]1C(OCCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N=C[C@@H]34)CCN1C2=O
Reaction time: 1 h
Yield: 63.2 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 8e (195 mg, 0.19 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9e (76 mg, 0.12 mmol, 68%) as a solid: [α]20D=+473° (c=0.14, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.41-1.55 (m, 6H, 14-H, 14′-H, 15-H), 1.85-1.94 (m, 4H, 13-H, 13′-H), 2.04-2.10 (m, 4H, 2-H, 2′-H), 2.28-2.38 (m, 4H, 1-H, 1′-H), 3.56-3.63 (m, 2H, 3-H, 3′-H), 3.72-3.76 (m, 2H, 11a-H, 11a′-H), 3.79-3.85 (m, 2H, 3-H, 3′-H), 3.92 (s, 6H, 7-OMe, 7′-OMe), 4.01-4.19 (m, 4H, 12-H, 12′-H), 6.79 (s, 2H, 9-H, 9′-H), 7.49 (s, 2H, 6-H, 6′-H), 7.64 (d, 2H, J=4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.9, 29.0, 29.2, 29.6, 46.6, 53.7, 56.0, 69.1, 109.6, 112.5, 120.2, 140.5, 147.1, 151.6, 162.2, 164.6; IR (neat): 3325, 2935, 1600, 1506, 1448, 1388, 1261, 1217, 1022 cm−1; MS (FAB) m/z (relative intensity) 653 ([M+2×MeOH]+., 14), 621 ([M+MeOH]+., 20), 589 (M+., 100).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]([CH:12]=1)=[N:9][O:10][N:11]=2.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:14][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]([CH:12]=1)=[N:9][O:10][N:11]=2
Reactant: OCCc1ccc2nonc2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCc1ccc2nonc2c1
Reaction time: 0.08 h
Yield: 86.6 %

Procedure:
A solution of 5-(2-hydroxyethyl) benzofurazan (1.0 g, 6.1 mmol) and carbon tetrabromide (2.6 g, 7.9 mmol) in methylene chloride (10 ml) was cooled to 0° C. A solution of triphenylphosphine (1.9 g, 7.3 mmol) in methylene chloride (10 ml) was added dropwise and the reaction was stirred for 5 minutes. Solvent evaporation and flash chromatography (silica gel, ethyl acetate-hexane, 5/95) gave 5-(2-bromoethyl)benzofurazan (1.2 g, 86%); 1H NMR (CDCl3) δ3.32(t,2H), 3.69(t,2H), 7.32(d,1H), 7.69(s,1H), 7.84(d,1H).