Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N+](C1C=CC(C([O:19][CH2:20][C:21]2([CH3:24])[CH2:23][O:22]2)=O)=CC=1)([O-])=O.C(N(CC)CC)C.Cl.S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>[Cl:1][C:2]1[N:3]([CH2:23][C:21]([OH:22])([CH3:24])[CH2:20][OH:19])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: CC1(COC(=O)c2ccc([N+](=O)[O-])cc2)CO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 72.7 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (6.78 g, 46 mmol) and 2-methyloxiran-2-ylmethyl 4-nitrobenzoate (12 g, 51 mmol) were dissolved in ethyl acetate (24 ml), and triethylamine (1.3 ml, 9.2 mmol) was added to the solution. The resulting mixture was stirred under reflux for 14 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride (40 ml) was added to the residue. The resulting precipitates were filtered off, and dissolved in methanol (120 ml). To the solution, potassium carbonate (318 mg, 2.3 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. To the resulting mixture, 6 N hydrochloric acid (0.8 ml) and magnesium sulfate (8 g) were added in this order with cooling on ice-bath, and the resulting mixture was stirred for 30 minutes. Insoluble matters were removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. To the residue, ethyl acetate (6 ml) and toluene (60 ml) were added. The resulting precipitates were filtered off and dried at 50° C. to afford 2-chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole (7.88 g, yield 72%) as a white powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[O:16][N:15]=2)=[CH:10][CH:9]=1)(C)(C)C.C(OC(=O)NC1C=CC(C(=N)NO)=CC=1)(C)(C)C.FC(F)(F)OC1C=CC(C=O)=CC=1>C(O)(=O)C.C(Cl)(Cl)Cl>[F:29][C:26]([F:27])([F:28])[O:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[O:16][N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][CH:10]=3)[N:18]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2noc(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: CC(C)(C)OC(=O)Nc1ccc(C(=N)NO)cc1
Agent: O=Cc1ccc(OC(F)(F)F)cc1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Nc1ccc(-c2noc(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 15 %

Procedure:
{4-[5-(4-Trifluoromethoxyphenyl)-[1,2,4]oxadiazol-3-yl]-phenyl}-carbamic acid tert-butyl ester. To a stirred solution of tert-butyl-4-(N-hydroxycarbamimidoyl)-phenylcarbamate (Ace Synthesis) (500 mg; 1.99 mmol) dissolved in 2.5 mL of acetic acid was added 4-trifluoromethoxybenzaldehyde (1.7 mL; 11.94 mmol), and the reaction mixture was stirred at room temperature for 4 d. The mixture was diluted with CHCl3 (20 mL) and filtered through a pad of Celite®. The pad was washed with CHCl3 (20 mL). Heptane (20 mL) was then added to the solution and the solution was concentrated under reduced pressure. This procedure was repeated twice. The residue was purified via radial chromatography using a 3:1 hexane/EtOAc solution as the eluent. Two fractions were isolated. The first fraction isolated (Rf=0.42) was shown to be the title compound (127 mg; 15%). 1H NMR (300 MHz, CDCl3) δ 8.26 (d, J=8.9 Hz, 2H), 8.09 (d, J=8.9 Hz, 2H), 7.52 (d, J=8.6 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H), 6.70 (s, 1H), 1.54 (s, 9H); EI/MS 421 [M]+. The second fraction isolated (Rf=0.11) was shown to be the 4,5-dihydro-1,2,4-oxadiazole (96 mg; 11%). 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J=8.9 Hz, 2H), 8.00 (d, J=8.9 Hz, 2H), 7.51 (d, J=8.9 Hz, 2H), 7.22-7.31 (m, 3H), 6.87 (s, 1H), 1.54 (s, 9H); EI/MS 423 [M]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl-].[CH3:12][C:13]1[CH:22]=[CH:21][C:16]([CH:17]=[N+:18]([CH3:20])[CH3:19])=[CH:15][CH:14]=1.CC1C=CC(C=O)=CC=1.CNC>>[CH3:19][N:18]([CH3:20])[CH:17]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1])[C:16]1[CH:21]=[CH:22][C:13]([CH3:12])=[CH:14][CH:15]=1
Reactant: Cc1ccc(C=[N+](C)C)cc1
Reactant: Cc1cc2ccccc2[nH]1
Agent: CNC
Agent: Cc1ccc(C=O)cc1
Agent: [Cl-]
Product: Cc1ccc(C(c2c(C)[nH]c3ccccc23)N(C)C)cc1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-methyl-1H-indole and (4-methyl-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 4-methyl-benzaldehyde and dimethylamine.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[S:27][CH:28]=[CH:29][N:30]=4)[CH2:23][CH2:22][C:21]([C:31]([O:33]C)=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[S:27][CH:28]=[CH:29][N:30]=4)[CH2:23][CH2:22][C:21]([C:31]([OH:33])=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2nccs2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2nccs2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-(thiazol-2-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (212 mg) in a mixture of tetrahydrofuran (18 ml) and methanol (18 ml) was added 1N sodium hydroxide solution (6 ml), and the mixture was stirred at room temperature overnight. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutral, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(thiazol-2-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (153 mg) as yellow crystals.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:15])=[N:12][NH:13][CH:14]=1.[CH:16](O)=[O:17]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:15][CH:16]=[O:17])=[N:12][NH:13][CH:14]=1
Reactant: O=CO
Reactant: Nc1n[nH]cc1-c1nc2ccccc2s1
Product: O=CNc1n[nH]cc1-c1nc2ccccc2s1
Yield: 90 %

Procedure:
A solution of 4-benzothiazol-2-yl-1H-pyrazol-3-ylamine (1.1 g, 5.0 mmol) in 20 mL of formic acid was heated to 70° C. overnight. The formic acid was evaporated under reduced pressure and the resulting crude material was recrystallized from ethanol to yield 1.1 g (90%) of N-(4-benzothiazol-2-yl-1H-pyrazol-3-yl)-formamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][S:15]([N:18]2[CH2:23][CH2:22][C:21]([NH2:26])([C:24]#[N:25])[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[C:9]([CH3:27])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([O:36][C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[C:40](O)=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(C(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.C(OCC)C>[C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][S:15]([N:18]2[CH2:23][CH2:22][C:21]([NH:26][C:40](=[O:41])[C:39]3[CH:43]=[C:44]([C:46]([F:48])([F:49])[F:47])[CH:45]=[C:37]([O:36][CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:38]=3)([C:24]#[N:25])[CH2:20][CH2:19]2)(=[O:16])=[O:17])=[C:9]([CH3:27])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC(N)(C#N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC(C#N)(NC(=O)c2cc(OCc3ccccc3)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[2-(4-Amino-4-cyano-piperidine-1-sulfonyl)-ethyl]-3-methyl-benzoic acid tert-butyl ester (500.0 mg, 1.23 mmol), 3-benzyloxy-5-trifluoromethyl-benzoic acid (436.1 mg, 1.47 mmol) and DIPEA (0.321 ml, 1.85 mmol) were dissolved in DMF (5.50 ml). HATU (561.2 mg, 1.47 mmol) was added and the mixture was stirred at room temperature for one hour. The reaction solution was diluted with diethyl ether, and the organic layer was washed with a 1 M aqueous hydrochloric acid solution, an aqueous sodium bicarbonate solution and saline. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane-ethyl acetate) to give 4-{2-[4-(3-benzyloxy-5-trifluoromethyl-benzoylamino)-4-cyano-piperidine-1-sulfonyl]-ethyl}-3-methyl-benzoic acid tert-butyl ester as a yellow amorphous (796.2 mg, 94.4% in two steps).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([N:10]1[C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14][C:5]=3[C:6]=2[CH2:7][CH2:8][CH2:9]1)=[O:29]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Clc1ccc2c(c1)CCC1=C2CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)N2CCCC3=C2CCc2cc(Cl)ccc23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
14.3 g (0.066 mol) of 8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline were dissolved in 143 ml of methylene chloride, treated with 6.68 g (0.066 mol) of triethylamine and 11.3 g (0.066 mol) of m-methoxybenzoyl chloride in 60 ml of methylene chloride were added dropwise thereto at 0°. After stirring at room temperature for 1 hour the mixture was extracted with water, dried with magnesium sulphate and the solvent was distilled off in vacuo. Chromatography (silica gel, toluene-ethyl acetate, 19:1) and crystallization (methylene chloride-ether) gave 4-(m-methoxybenzoyl)-8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline as white crystals of melting point 133°.
Reaction SMILES: C1([N-]C2CCCCC2)CCCCC1.[Li+].[C:15]([O:19][C:20](=[O:22])[CH3:21])([CH3:18])([CH3:17])[CH3:16].Br[C:24]1[CH:25]=[C:26]([CH3:56])[C:27]([N:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:41]=[C:40]([C:42]4[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=4)[N:39]=[C:38]([N:49]4[CH2:53][CH2:52][CH2:51][C@H:50]4[CH3:54])[N:37]=3)[C@H:32]([CH3:55])[CH2:31]2)=[N:28][CH:29]=1.CC(P(C(C)(C)C)C(C)(C)C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:15]([O:19][C:20](=[O:22])[CH2:21][C:24]1[CH:29]=[N:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:41]=[C:40]([C:42]4[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=4)[N:39]=[C:38]([N:49]4[CH2:53][CH2:52][CH2:51][C@H:50]4[CH3:54])[N:37]=3)[C@H:32]([CH3:55])[CH2:31]2)=[C:26]([CH3:56])[CH:25]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(=O)OC(C)(C)C
Reactant: Cc1cc(Br)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(N3CCC[C@H]3C)n2)[C@H](C)C1
Agent: [Pd]
Agent: C1CCC([N-]C2CCCCC2)CC1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: Cc1cc(CC(=O)OC(C)(C)C)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(N3CCC[C@H]3C)n2)[C@H](C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To lithium dicyclohexyl amide add a solution of acetic acid tert-butyl ester (62 μL, 0.46 mmol) in toluene (2 mL). Stir for 10 min at room temperature, and then add 4-[4-(5-bromo-3-methyl-pyridin-2-yl)-2-(R)-methyl-piperazin-1-yl]-6-(4-fluoro-phenyl)-2-(2-(R)-methyl-pyrrolidin-1-yl)-pyrimidine (200 mg, 0.38 mmol), Pd2(dba)3 (3.5 mg, 1%) and P(t-bu)3 (0.8 mg, 1%). De-gas the suspension for 5 min and stir for 16 h at room temperature. Dilute with EtOAc, wash with brine, dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify using flash chromatography eluting with EtOAc-Hexanes (1:4) to give the title ester.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OC([N:61]([C:69]1[S:78][CH2:77][C@H:76]2[C@@:71]([C:79]3[S:80][CH:81]=[C:82]([NH2:84])[CH:83]=3)([CH2:72][O:73][CH2:74][CH2:75]2)[N:70]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[NH2:61][C:69]1[S:78][CH2:77][C@H:76]2[C@@:71]([C:79]3[S:80][CH:81]=[C:82]([NH:84][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=4)=[O:11])[CH:83]=3)([CH2:72][O:73][CH2:74][CH2:75]2)[N:70]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(c3cc(N)cs3)COCC[C@H]2CS1
Reactant: N#Cc1ccc(C(=O)O)nc1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C(=O)Nc2csc([C@@]34COCC[C@H]3CSC(N)=N4)c2)nc1
Reaction time: 8 h
Yield: 79.7 %

Procedure:
5-Cyanopyridine-2-carboxylic acid (19.0 mg), diisopropylethylamine (50.7 μl) and PyBOP (83.5 mg) were sequentially added to a solution of (+)-N,N-di(tert-butyloxycarbonyl)-[(4aR*,8aS*)-8a-(4-aminothiophen-2-yl)-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl]amine (50 mg) in dichloromethane (5.0 ml) in an ice bath. The mixture was returned to room temperature and stirred overnight. The solvent was evaporated under reduced pressure and the residue was purified by NH-silica gel column chromatography. The resulting intermediate was dissolved in dichloromethane (4.0 ml) and TFA (1.0 ml) was added. After stirring at room temperature for four hours, ice was added to terminate the reaction. The mixture was neutralized with a sodium bicarbonate solution, and the aqueous layer was neutralized with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (33.9 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:15])[C:12]([O-:14])=O.[K+].[C:17]([N:25]1[CH2:30][CH2:29][NH:28][C@H:27]([CH3:31])[CH2:26]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([N:25]1[CH2:30][CH2:29][N:28]([C:12](=[O:14])[C:11]([C:7]2[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][N:5]=3)[NH:9][CH:8]=2)=[O:15])[C@H:27]([CH3:31])[CH2:26]1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1
Reactant: O=C([O-])C(=O)c1c[nH]c2c(Cl)ccnc12
Agent: [K+]
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2c(Cl)ccnc12

Procedure:
Precursor 5d, 1-benzoyl-3-(R)-methyl-4-[(7-chloro-4-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a, starting from Potassium (7-chloro-4-azaindol-3-yl)-oxoacetate, Precursor 4e, and 1-benzoyl-3-(R)— methyl piperazine. MS m/z: (M+H)+ calcd for C21H20ClN4O3 411.12, found 411.04. HPLC retention time: 1.10 minutes (column A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][C:3]=1[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:12])[CH:4]=1
Reactant: Cc1cc(CCCO)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(CCCBr)ccc1Cl
Yield: 89.6 %

Procedure:
Compound 67-2 (2.49 g) was dissolved in methylene chloride (45 ml), triphenylphosphine (3.90 g) and N-bromosuccinimide (2.64 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2.5 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.99 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:16])=[C:11]([OH:15])[CH:12]=2)[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4].Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)=[CH:30][CH:29]=1)=[O:27].C(=O)(O)[O-].[Na+].C1CCN2C(=NCCC2)CC1>CN(C=O)C.O.CCOC(C)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:25][C@@:26]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=5)=[CH:30][CH:29]=4)([OH:27])[O:16][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4]
Reactant: COC(=O)[C@@H]1Cc2cc(O)c(O)cc2CN1C(=O)OC(C)(C)C
Reactant: O=C(CBr)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@](O)(c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Temperature: 25 °C
Yield: 101.1 %

Procedure:
(S)-6,7-Dihydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (30.0 g), 2-bromo-1-[4-(3,4-dichloro-benzyloxy)-phenyl]-ethanone (34.7 g), and sodium bicarbonate (7.8 g) were stirred together in 600 mL anhydrous DMF. While stirring at rt, DBU (6.95 mL) was added all at once and the mixture was stirred at rt for 18 hours. The reaction mixture was then poured into 1 L EtOAc and 500 mL water and the layers were separated. The organic layer was washed with water three times and brine once, then dried over sodium sulfate and concentrated to provide 57.8 g of orange foam which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:7]1[C:8](=[O:12])[CH2:9][CH2:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(O)C.C(O)(=O)C.[C-:20]#[N:21].[K+]>O>[CH2:1]([CH:7]1[CH:11]([C:20]#[N:21])[CH2:10][CH2:9][C:8]1=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [C-]#N
Reactant: CCCCCCC1=CCCC1=O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCCCCCC1C(=O)CCC1C#N
Temperature: 35 °C
Reaction time: 3 h

Procedure:
In a 3-L three necked flask fitted with a mechanical stirrer, a reflux condenser, a dropping funnel and a thermometer, are placed 83 g of 2-n-hexyl-cyclopentenone, 1.75 L 95% ethyl alcohol and 30 g of glacial acetic acid. The mixture is warmed up with sirring to 35°C and a solution of 65 g of potassium cyanide in 190 ml of water is added over a period of 15 minutes. Stirring is continued for 3 hours, the temperature being maintained at 35°C. The methanol is then distilled off at a reduced pressure the organic layer is separated, and the water phase is extracted with ether. The combined organic layer and other extract are washed with sodium carbonate solution and water and dried over anhydrous sodium sulphate. The solvent is removed at atmospheric pressure and the residue is distilled through a short Vigreux column. 2-n-Hexyl-3-cyanocyclopentanone is collected at 106°-110°C/0,2 mm, yield 85 g (88%), nD20 1.4658.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[H-].[Na+].CS(C)=O.C[O:13][C:14](=O)[C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([NH2:22])=[C:17]([CH3:23])[CH:16]=1>C(O)(=O)C.O>[NH2:22][C:18]1[C:19]([CH3:21])=[CH:20][C:15]([C:14](=[O:13])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])=[CH:16][C:17]=1[CH3:23]
Reactant: COC(=O)c1cc(C)c(N)c(C)c1
Reactant: CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C(=O)CS(C)(=O)=O)cc(C)c1N
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A suspension of 33 g. of dimethylsulfone and 11 g. of sodium hydride (50% dispersion in oil) in 160 ml. of absolute dimethylsulfoxide was stirred at 50° C. under an atmosphere of nitrogen and the exclusion of moisture for 3 hours. Then, 18 g. of 4-amino-3,5-dimethyl-benzoic acid methyl ester were added. The mixture was stirred at 80° C. for 30 minutes and at room temperature for 1 hour and then dissolved in 400 ml. of water. The solution was neutralized with glacial acetic acid. The precipitate which formed was removed by filtration with suction, washed with water, dried and recrystallized from ethyl acetate, whereby there was obtained 4'-amino-3',5'-dimethyl-2-(methylsulfonyl)-acetophenone having a melting point of 179°-180° C.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[N+:7]([O-:9])=[O:8].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13](OB(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[N+:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1sccc1Br
Reactant: Cc1ccc(OB(O)O)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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2ccsc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
A mixture of 0.8 g of 3-bromo-2-nitrothiophene, 0.52 g of 4-tolylboric acid, 5 ml of a 2M-aqueous potassium carbonate solution, 2.5 ml of ethanol and 30 ml of toluene was stirred at room temperature for 30 minutes in a nitrogen atmosphere. Successively 0.15 g of Pd(PPh3)4 was added and refluxed by heating for 7 hours. After separating into two layers, the organic layer was washed with water and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.56 g (70% yield) of the product as a yellow crystal. 1H-NMR(CDCl3, δ value):2.42(3H, s), 7.01(1H, d, J=5.1), 7.25(2H, d, J=8.1), 7.37(2H, d, J=8.1), 7.47(1H, d, J=5.1)
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:23])[O:6][C:7]2[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH3:18])[CH:12]=[C:11]([O:19][CH2:20][CH2:21][CH3:22])[C:8]=2[C:9]=1[CH3:10].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][C:4]2[C:5](=[O:23])[O:6][C:7]3[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH3:18])[CH:12]=[C:11]([O:19][CH2:20][CH2:21][CH3:22])[C:8]=3[C:9]=2[CH3:10])[CH2:34][CH2:33]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCCOc1cc(OCCC)c2c(C)c(CCCl)c(=O)oc2c1
Product: CCCOc1cc(OCCC)c2c(C)c(CCN3CCN(c4ccccc4OC)CC3)c(=O)oc2c1
Yield: 47 %

Procedure:
Process B; starting materials: 3-(2-chloroethyl)-4-methyl-5,7-dipropoxy-2H-1-benzopyran-2-one (Example 38) and 1-(2-methoxyphenyl)piperazine; yield 47% of crude product.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:23]([C:26]1[O:30][C:29]([C:31]2[C:35]([C:36]([OH:38])=[O:37])=[CH:34][N:33]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:32]=2)=[CH:28][CH:27]=1)([O-:25])=[O:24]>O1CCOCC1.N1C=CC=CC=1>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]([O:38][C:36]([C:35]3[C:31]([C:29]4[O:30][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=4)=[N:32][N:33]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:34]=3)=[O:37])=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: O=C(O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C(OC(=O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1

Procedure:
Add a solution of 0.64 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid chloride dropwise to a warm solution of 0.60 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid in 10 ml of dioxane and 0.48 ml of pyridine at 40° C. Stir the resulting reaction mixture at from 45° to 50° C for 6 hours. Draw off the formed precipitate and recrystallize it from dimethylformamide to obtain 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid anhydride [m.p. 262° to 264° C].