Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:33])[N:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:53]([O:57][C:58](=[O:64])[NH:59][CH2:60][CH2:61][CH2:62]O)([CH3:56])([CH3:55])[CH3:54].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:53]([O:57][C:58]([NH:59][CH2:60][CH2:61][CH2:62][O:23][C:22]([C:21]1[N:12]([N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH3:33])[C:13](=[O:32])[C:14]2[C:19]([C:20]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:18][C:17]([Cl:31])=[CH:16][CH:15]=2)=[O:24])=[O:64])([CH3:56])([CH3:55])[CH3:54]
Reactant: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)n1c(C(=O)OCCCNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Yield: 56 %

Procedure:
To a mixture of 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg), triphenylphosphine (140 mg), (3-hydroxypropyl)carbamic acid tert-butyl ester (92 mg) and THF (4.0 ml), 0° C. with stirring, diethyl azodicarboxylate (90 μl) was added, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was purified by medium pressure preparative LC (hexane/ethyl acetate=5/1-3/2) to give the title compound (150 mg) as a colorless powder.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.Cl[C:12]1[N:17]=[CH:16][N:15]=[C:14]([NH2:18])[CH:13]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.CC(O)C>[CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([NH:9][C:12]2[CH:13]=[C:14]([NH2:18])[N:15]=[CH:16][N:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: CN(C)c1cccc(N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CN(C)c1cccc(Nc2cc(N)ncn2)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of N,N-dimethyl-m-phenylenediamine (1.36 g, 10 mmol), 6-chloro-pyrimidin-4-ylamine (1.30 g, 10 mmol), 2-propanol (10 mL) and HCl conc. (0.45 mL, ˜5 mmol) is shaken for 16 h at 90° C. After cooling to room temperature, the reaction mixture is distributed between half-concentrated Na2CO3 solution and ethyl acetate. The organic layer is dried over Na2SO4, evaporated, and the residue purified by flash chromatography (ethyl acetate/CH3OH). The combined pure fractions are evaporated to afford the title compound. Beige solid, HPLC: tR=1.53 min (gradient F), ESI-MS: 230.3 [MH]+.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ONC(=O)CCC(N)=O.C(Cl)CCl.[NH2:41][CH2:42][C:43]1[CH:51]=[CH:50][C:46]([C:47]([OH:49])=[O:48])=[CH:45][CH:44]=1>ClCCl>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:41][CH2:42][C:43]4[CH:44]=[CH:45][C:46]([C:47]([OH:49])=[O:48])=[CH:50][CH:51]=4)=[O:24])=[CH:26][CH:27]=3)(=[O:17])=[O:18])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Reactant: NCc1ccc(C(=O)O)cc1
Agent: NC(=O)CCC(=O)NO
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(O)c1ccc(CNC(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)cc1
Yield: 48.1 %

Procedure:
Combine 4-(3-Phenyl-indole-1-sulfonyl)-benzoic acid (1.324 mmole) with N-hydroxy-succinamide (NHS− 1.457 mmoles), and EDC (1.324 mmoles) and stir in 20 ml dichloromethane for 15 hr. Condense the reaction to produce a solid. Isolate 0.613 g (yield=97.6%). React 1.05 mmole of residue with 4-aminomethyl-benzoic acid (1.05 mmole) in 3 ml dichloromethane for 15 hrs. Dilute reaction mixture and wash with 1 N HCl. Treat dichloromethane with MgSO4 and concentrate. Isolate a mixture of 4-(3-Phenyl-indole-1-sulfonyl)-benzoic acid and the title compound 0.258 g (48%): MS ES+ 5.10-77 MS ES− 509.21.
Reaction SMILES: [Cl:1][SiH2:2][Cl:3].[CH:4]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH:6]=[CH:5]2>C1(C)C(C)=CC=CC=1.[Pt]>[CH:4]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][CH:5]2[Si:2]([CH:5]1[CH2:6][CH:7]2[CH2:10][CH:4]1[CH2:9][CH2:8]2)([Cl:3])[Cl:1]
Reactant: C1=CC2CCC1C2
Reactant: Cl[SiH2]Cl
Agent: [Pt]
Solvent: Cc1ccccc1C
Product: Cl[Si](Cl)(C1CC2CCC1C2)C1CC2CCC1C2
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
Dichlorosilane (18.5 g, 0.18 mol) is condensed into a cold trap at −78° C. and dissolved in precooled xylene (200 ml). The temperature is −10° C. after the addition. First norbornene (34.5 g, 0.37 mol) and then the catalyst [COD]PtCl2 (1% solution in in CH2Cl2, 2.50 ml) are added, whereupon an exothermic reaction starts spontaneously. The temperature rises to 46° C. and an ice bath is used to reduce the temperature to 40° C. After 15 min, the temperature begins to fall again. According to GC (gas chromatography), about 50% of the norbornene is consumed. The reaction mixture is heated to 80° C. for 15 min, then held at 40° C. for a further 1.5 h. The conversion of the norbornene according to GC is >90%. The reaction mixture is fractionally distilled. The main fraction at b.p. 118° C./1 mbar consists of 49.8 g of dichlorodinorbornylsilane. Yield 94%. Purity 95.7% (GC).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:31][C@H:32](OC1C=CC(C2C=CC=CC=2C([O-])=O)=CC=1[N+]([O-])=O)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[CH3:31][C@H:32]([O:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:22]([N+:28]([O-:30])=[O:29])[CH:23]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: O=[N+]([O-])c1cc(O)ccc1OCc1ccccc1
Reactant: CCCCCC[C@H](C)Oc1ccc(-c2ccccc2C(=O)[O-])cc1[N+](=O)[O-]
Agent: CCOC(=O)/N=N/C(=O)OCC
Product: CCCCCC[C@H](C)Oc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Yield: 76 %

Procedure:
DEAD (777 mg, 4.46 mmol), TPP (1.171 g, 4.46 mmol), R-2-octanol (511 mg, 3.93 mmol), and compound 54 (875 mg, 3.57 mmol) were reacted according to the procedure for compound 32a. The crude product was purified via flash chromatography over silica gel with gradual elutions from 95/5-80/20 (Hex/EtOAc). Evaporation of solvent yielded 972 mg (76%) of a light yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:24][C:14]3=[N:15][C:16](Cl)=[C:17]([N+:20]([O-:22])=[O:21])[C:18](=[O:19])[N:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:25]>C(O)C.CN(C)C=O>[NH2:25][C:16]1[N:15]=[C:14]2[S:24][C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)=[N:12][N:13]2[C:18](=[O:19])[C:17]=1[N+:20]([O-:22])=[O:21]
Reactant: N
Reactant: CC(C)(C)c1ccc(-c2nn3c(=O)c([N+](=O)[O-])c(Cl)nc3s2)cc1
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2nn3c(=O)c([N+](=O)[O-])c(N)nc3s2)cc1

Procedure:
1.9 g of 2-(4-tert-butylphenyl)-7-chloro-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one was suspended in a mixture of 20 ml of ethanol and 10 ml of dimethylformamide, and 5 ml of concentrated aqueous ammonia was added dropwise to the suspension while maintaining at a temperature of 60° C. to 70° C. After heating at that temperature for 2 hours, the mixture was cooled and the precipitate formed was separated by filtration to obtain 1.3 g of 7-amino-2-(4-tert-butylphenyl)-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as pale yellow prisms having a melting point higher than 300° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].[N+:9]([O-])([OH:11])=[O:10]>C(OC(=O)C)(=O)C.C(O)(=O)C>[N+:9]([C:4]1[CH:3]=[C:2]([C:6]([OH:8])=[O:7])[S:1][CH:5]=1)([O-:11])=[O:10]
Reactant: O=C(O)c1cccs1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1cc([N+](=O)[O-])cs1

Procedure:
2-Thiophenecarboxylic acid (6.4 g, 50 mM) was suspended in acetic anhydride (15 ml) and fuming nitric acid (16 ml) in glacial acetic acid (25 ml) added slowly over 1 hour with stirring, while keeping the temperature of the reaction mixture below 30° C. The reaction mixture was stirred at ambient temperature for 2 hours. The product was purified by subjecting to chromatography (470 ml) on HP20SS resin using methanol/(water+1% acetic acid): 0/100→50/50 as eluant. The pure title compound was obtained (1.3 g) together with a mixture of 4- and 5- nitrothiophene-2-carboxylic acid (4.4 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:13][CH2:12][CH2:11][N:10]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:9]2=[O:14])=[CH:20][CH:19]=1
Reactant: CCOC(=O)CBr
Reactant: O=C1NCCCC1(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To the product from Example 90B (0.43 g, 1.50 mmol) as a solution in tetrahydrofuran (20 mL) was added potassium tert-butoxide (1.0 M in tetrahydrofuran) (1.80 mL, 1.80 mmol) via syringe under nitrogen followed by the addition of ethyl 2-bromoacetate (0.18 mL, 1.65 mmol). The reaction mixture heated at 80° C. and stirred overnight. The reaction mixture was cooled to room temperature, concentrated, diluted with ethyl acetate, washed with water and brine, dried with MgSO4, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:4) gave the title compound. MS (DCI) m/z 374 (M+H)+.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[C:10]([C@@:14]([NH:30][S:31]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:33])=[O:32])([B:16]([O:18][C:19]2([CH3:29])[CH2:24][CH2:23][CH:22]3[CH2:25][C:20]2([OH:28])[C:21]3([CH3:27])[CH3:26])[OH:17])[CH3:15])[CH:11]=[CH:12][CH:13]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([C:8]1[CH:9]=[C:10]([C@@:14]([NH:30][S:31]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)(=[O:33])=[O:32])([B:16]([O:18][C:19]2([CH3:29])[CH2:24][CH2:23][CH:22]3[CH2:25][C:20]2([OH:28])[C:21]3([CH3:26])[CH3:27])[OH:17])[CH3:15])[CH:11]=[CH:12][CH:13]=1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)c1cccc([C@@](C)(NS(=O)(=O)Cc2ccccc2)B(O)OC2(C)CCC3CC2(O)C3(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(OB(O)[C@](C)(NS(=O)(=O)Cc2ccccc2)c2cccc(C(=O)O)c2)CCC2CC1(O)C2(C)C
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
A solution of 15b (90 mg, 0.16 mmol) in dichloromethane (2 mL) was cooled to −10° C. and treated with an excess of trifluoroacetic acid (10% v/v soln in dichloromethane, 2 mL). After 10 min at −10° C., the mixture was allowed to react at room temperature for 5 h. The solution was concentrated in vacuo and the residue crystallized from diethyl ether affording (+)-pinanediol (1R)-2-[3-carboxyphenyl]-1-(phenylmethanesulfonylamino)ethaneboronate (79 mg, 100% yield) as a cream coloured solid. Mp 155-158° C. [α]D+25.9 (c 0.6, CHCl3). 1H-NMR (400 MHz, CDCl3): δ 0.87 (3H, s, pinanyl CH3), 1.06 (1H, d, J 10.8, pinanyl Hendo), 1.31 (3H, s, pinanyl CH3), 1.33 (3H, s, pinanyl CH3), 1.88-2.38 (5H, m, pinanyl protons), 2.99 (1H, dd, J 13.7, 6.0, CHCH2), 3.15 (1H, dd, J 13.7, 5.6, CHCH2), 3.37 (1H, br, BCH), 4.31 (2H, s, CH2SO2), 4.40 (1H, d, J 7.7, CHOB), 4.51 (1H, br, SO2NH), 7.30-7.58 (7H, m, HArom), 7.97-8.01 (2H, m, HArom), 10.2 (1H, br, COOH). 13C-NMR (100 MHz, CDCl3): δ 24.0, 26.3, 27.0, 28.3, 35.0, 38.2, 38.5, 39.4, 42.4 (CB), 51.1, 59.2, 78.8, 87.3, 128.5, 128.6, 128.7, 127.2, 129.3, 129.4, 130.8, 131.2, 135.6, 139.0, 171.8. Anal. Calcd. for C26H32BNO6S: C, 62.78; H, 6.48; N, 2.82; S, 6.45. Found: C, 62.61; H, 6.72; N, 2.64; S, 6.21.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([F:9])=[C:7](F)[N:6]=[C:5]([F:11])[C:4]=1[F:12].O.[NH2:14][NH2:15]>C(O)C>[OH:1][CH2:2][C:3]1[C:8]([F:9])=[C:7]([NH:14][NH2:15])[N:6]=[C:5]([F:11])[C:4]=1[F:12]
Reactant: OCc1c(F)c(F)nc(F)c1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1nc(F)c(F)c(CO)c1F

Procedure:
To a solution of 1.0 g (0.0055 mole) of 4-hydroxymethyl-2,3,5,6-tetrafluoropyridine (from Example 5) in 50 ml of ethanol was added 0.2 g (0.004 mole) of hydrazine hydrate. This mixture was stirred for approximately twenty-four hours during which a white precipitate formed. The reaction mixture was filtered, and the filtrate was concentrated by evaporating the solvent under reduced pressure. Water and ether were added to this residue. The ether layer was separated, dried, and the solvent evaporated, leaving a yellow solid, (4-hydroxymethyl-2,3,5-trifluoropyridin-6-yl)hydrazine. The structure and nmr data are set forth in Table 1C.
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[O:11]=[CH:12][C:13]1[CH:21]=[CH:20][C:18]([OH:19])=[C:15]([O:16][CH3:17])[CH:14]=1>CN(C=O)C.C(OCC)C>[CH:1]([O:19][C:18]1[CH:20]=[CH:21][C:13]([CH:12]=[O:11])=[CH:14][C:15]=1[O:16][CH3:17])([CH3:3])[CH3:2]
Reactant: CC(C)Br
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc(C=O)ccc1OC(C)C
Temperature: 80 °C

Procedure:
Isopropyl bromide (40.0 mL; 421 mmol) was added to a suspension of K2CO3 (48.0 g, 348 mmol) and vanillin (40 g, 263 mmol) in DMF (150 mL) and the stirring slurry heated to 80° C. for 15 h. The reaction mixture was then cooled to room temperature, diluted with diethyl ether (200 mL) and washed with H2O (4×200 mL), dried (MgSO4) and concentrated under reduced pressure giving the title compound as a slightly tan oil (51.0 g, 100%) which required no further purification. The spectra of this material are identical with that previously reported (M. F. Comber and M. V. Sargent, J. Chem. Soc., Perkin Trans. 1, 1991, 2783).
Reaction SMILES: [Br-].[C:2]1(=[O:34])[N:6]([CH2:7][CH2:8][CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:5](=[O:29])[C:4]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:3]12.[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH:39]=O.CC(C)([O-])C.[K+].O>O1CCCC1>[Cl:35][C:36]1[CH:37]=[C:38](/[CH:39]=[CH:9]\[CH2:8][CH2:7][N:6]2[C:2](=[O:34])[C:3]3=[CH:33][CH:32]=[CH:31][CH:30]=[C:4]3[C:5]2=[O:29])[CH:41]=[CH:42][CH:43]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: O=C1c2ccccc2C(=O)N1CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC/C=C\c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 64.3 %

Procedure:
A mixture of 3-phthalimidopropyltriphenylphosphonium bromide (15.1 g) and 3-chlorobenzaldehyde (4.0 g, Aldrich, U.S.A.) in tetrahydrofuran (150 mL) was cooled to −78° C. in a dry ice/acetone bath. Potassium tert-butoxide (3.2 g) was added and the mixture was stirred for 20 min, then allowed to warm to 0° C. After four hours, the solution was poured into 200 mL water and extracted three times with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate, and reduced in vacuo. The residue was dissolved in 200 mL of a 1:1 mixture of ethyl acetate/hexanes, and filtered through a short silica gel plug to remove the triphenylphosphine oxide byproduct. Evaporation of the filtrate yielded 5.7 g of cis-N-[4-(3-chlorophenyl)-but-3-enyl]-phthalimide in a 10:1 ratio of cis:trans isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([CH:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH3:15])[CH2:12][N:11]([C:27](Cl)=[O:28])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[CH3:37][N:38]([CH3:47])[CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([CH:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)[CH3:15])[CH2:12][N:11]([C:27]([N:44]3[CH2:45][CH2:46][N:41]([CH2:40][CH2:39][N:38]([CH3:47])[CH3:37])[CH2:42][CH2:43]3)=[O:28])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)CCN1CCNCC1
Reactant: CC(Oc1ccc(C(F)(F)F)cc1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(C(F)(F)F)cc1)C1CN(C(=O)N2CCN(CCN(C)C)CC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 63 %

Procedure:
To a stirred solution of (3RS,4SR)-3-(3,4-dichloro-phenyl)-4-[(RS)-1-(4-trifluoromethyl-phenoxy)-ethyl]-pyrrolidine-1-carbonyl chloride (58 mg, 0.12 mmol) in CH2Cl2 (2 ml) were added Et3N (0.02 mL, 0.15 mmol) and dimethyl-(2-piperazin-1-yl-ethyl)-amine (0.03 mL) (commercially available). Stirring was continued overnight, and the reaction mixture was concentrated under vacuo and directly purified by flash chromatography (SiO2, CH2Cl2/MeOH/NH3, 9/4/1) to yield 46 mg (63%) of the title compound as light yellow oil. ES-MS m/e: 587.3 (M+H+).
Reaction SMILES: [Na].FS(O)(=O)=O.[CH2:7]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=[NH:15])[CH:8]([CH3:10])[CH3:9].C([O:23][CH:24]=[C:25]([C:31](OCC)=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27])C.C(O)(=O)C>C(O)C>[O:23]=[C:24]1[NH:16][C:14]([C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:7][CH:8]([CH3:10])[CH3:9])=[N:15][CH:31]=[C:25]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)COc1ccccc1C(=N)N
Agent: O=S(=O)(O)F
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2OCC(C)C)[nH]c1=O
Temperature: 0 °C
Yield: 84.9 %

Procedure:
To a solution of sodium (161 mg., 7 mg-atoms) in ethanol (10 ml.) was added 2-isobutoxybenzamidine fluorosulfonate (1.02 g., 3.5 mmole). The mixture was warmed to give a clear solution to which was added a solution of diethyl ethoxymethylenemalonate (756 mg., 3.5 mmole) in ethanol (2 ml.). The solution was heated under reflux for 3 hours. The cooled mixture was added to ice-water (50 ml.) and was acidified to pH 5 with glacial acetic acid. After brief stirring, the solid was collected by filtration, washed with water, and dried to give the title compound (0.94 g., 86%), m.p. 90-91°.
Reaction SMILES: Cl.[NH2:2][C:3]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)([CH3:6])[C:4]#[N:5].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[S:9]1[CH:10]=[CH:11][C:7]([C:3]([NH:2][S:20]([CH3:19])(=[O:22])=[O:21])([CH3:6])[C:4]#[N:5])=[CH:8]1
Reactant: CC(N)(C#N)c1ccsc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C#N)(NS(C)(=O)=O)c1ccsc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 2.7 g (0.0143 mole) 2-amino-2-(3-thienyl)-propionitrile hydrochloride (the product of Example 8) in 50 ml methylene chloride, 3.6 g (5 ml [0.036 mole]) triethylamine were added, followed by 2 g (1.4 ml [0.018 mole]) methanesulfonyl chloride. The reaction mixture was stirred at room temperature for three hours. The reaction mixture was then washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and stripped to give the above-identified product which was used in Example 10 without further purification.
Reaction SMILES: Br[C:2]1[C:3]([O:20][CH:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:4][C:5]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12](=[O:19])[C:11]3[C:6]=2[C:7]=1[CH:8]=[CH:9][CH:10]=3.C(=O)([O-])[O-].[Na+].[Na+].[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[SH:43].CN(C=O)C>O>[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43][C:2]1[C:3]([O:20][CH:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:4][C:5]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12](=[O:19])[C:11]3[C:6]=2[C:7]=1[CH:8]=[CH:9][CH:10]=3
Reactant: CC(C)CC(CC(C)C)Oc1cc2c3c(cccc3c1Br)C(=O)c1ccccc1-2
Reactant: Nc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CC(CC(C)C)Oc1cc2c3c(cccc3c1Sc1ccccc1N)C(=O)c1ccccc1-2
Temperature: 125 °C

Procedure:
A 500 ml three neck round bottom flask was equipped with a mechanical stirrer, heating mantle and condenser. To the flask was added 52.5 g (0.11 mole) of 3-bromo-2-(1-isobutyl-3-methylbutoxy)-7H-benzo[de]anthracene-7-one (4), 9.2 g (0.087 mole) sodium carbonate, 16.0 g (0.13 mole) 2-aminothiophenol and 170 g DMF. The mixture was agitated well and heated at 120-130° C. for three hours. The reaction was cooled to 25° C. and 300 g water was added. The reaction mixture was extracted twice with 250 g chloroform. The organic layers were combined and washed twice with 250 g water. The solvent was removed on a rotary evaporator. The yield of crude product was 55 g of a dark brown oil which was used as such in the next step.
Reaction SMILES: [ClH:1].C([C:4](=[C:10]([CH3:16])[CH:11]=[CH:12][N:13](C)[CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6])#N>C(O)C>[Cl:1][C:14]1[N:13]=[CH:12][CH:11]=[C:10]([CH3:16])[C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Cl
Reactant: CCOC(=O)C(C#N)=C(C)C=CN(C)C
Solvent: CCO
Product: CCOC(=O)c1c(C)ccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
Hydrogen chloride was introduced to a stirred mixture of 164 g (0.839 mole) of crude ethyl 2-cyano-5-(N,N-dimethylamino)-3-methyl-2,4-pentadienoate (5) in 500 mL ethanol at 20-45° C. The mixture was stirred at ambient temperature overnight, then heated to reflux for 8 hours. The ethanol was removed under reduced pressure and the residue distilled under high vacuum at 84-94° C., to give 47.7 g (30.4%) of a yellow oil, MH+ 200, NMR (CDCl3), ppm: 1.42 (t,3H); 2.36 (s,3H); 4.46 (q,2H); 7.12 (d,lH); 8.28 (d,1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)=[O:3].O1CCOCC1.[Br:24]Br>[Cl-].[Al+3].[Cl-].[Cl-].O1CCCC1>[Br:24][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Yield: 76 %

Procedure:
After dissolving 4.0 g of 4-benzyloxyacetophenone into 20 ml of 1,4-dioxane and 20 ml of tetrahydrofuran, 0.1 g of anhydrous aluminum chloride and 3.1 g of bromine were added under ice cooling and stirring. Further, after stirring for 5 hours under ice cooling, the reaction solution was concentrated to solid. Water and chloroform were added to the residue to separate liquid layers. Then, the chloroform layer was dried over anhydrous sodium sulfate and then concentrated to solid followed by purification by silica gel column chromatography using benzene/n-hexane (1:1) as an elute, to obtain 4.1 g of 2-bromo-1-(4-benzyloxy-phenyl)-ethanone. Then, using 3.0 g of the thus obtained bromide, 2.2 g of (Z)-2-(4-methyl-piperazin-1-yl)-1-(4-benzyloxy-phenyl)-ethanone oxime hydrochloride with the melting point of from 208° to 210° C. (decomposition) and 0.7 g of (E)-2-(4-methyl-piperazin-1-yl)-1-(4-benzyloxy-phenyl)-ethanone oxime hydrochloride with the melting point of from 210° to 212° C. were obtained in the same manner as in Example 1.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[CH2:36](O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl.CN(C1C=CN=CC=1)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([O:5][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.7 %

Procedure:
Boc-Pro-OH (50.0 g, 0.23 mol) was dissolved in dichloromethane (500 mL), and EDCI (89.1 g, 0.46 mol), DMAP (5.7 g, 0.05 mol), DIPEA (162 mL, 0.93 mol) and benzyl alcohol (48 mL, 0.46 mol) were added dropwise. The mixture was stirred at room temperature for 12 hours. The mixture was washed several times with an aqueous solution of 5% citric acid. The organic layer was dried over sodium sulfate, and filtered and distilled under reduced pressure to obtain the title compound as yellow oil (70.0 g, 99%).