Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:16]([O-])=O.N1CCOCC1>C(O)C.CO.[C].[Rh]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[NH2:16]
Reactant: O=[N+]([O-])c1cc(/C=C\c2ccccc2)ccc1Cl
Agent: [Rh]
Solvent: CCO
Solvent: CO
Solvent: C1COCCN1
Product: Nc1cc(CCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a suspension of 4-chloro-3-nitrobenzaldehyde (1 g) and benzyltriphenylphosphonium bromide (2.34 g) in toluene (35 mL) was added sodium hydride (55%, 0.28 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with methylene chloride. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give 2-chloro-5-((Z)-2-phenylvinyl)-1-nitrobenzene (0.79 g). The obtained 2-chloro-5-((Z)-2-phenyl -vinyl)-1-nitrobenzene (0.16 g) was dissolved in ethanol (6 mL) -methanol (2 mL). To the solution was added 5% rhodium-carbon powder (20 mg) and morpholine (5 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give the title compound (87 mg).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:19][CH2:20][NH:21][C:22]([NH2:24])=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]([F:42])([F:41])[CH2:33][S:34]([CH2:37][C:38](O)=[O:39])(=[O:36])=[O:35].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH:16][C:38](=[O:39])[CH2:37][S:34]([CH2:33][C:32]([F:41])([F:31])[F:42])(=[O:35])=[O:36])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:19][CH2:20][NH:21][C:22]([NH2:24])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CS(=O)(=O)CC(F)(F)F
Reactant: CC(C)(C)OC(=O)C1=C(C(CCNC(N)=O)Sc2nnn[nH]2)CS[C@@H]2C(N)C(=O)N12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1=C(C(CCNC(N)=O)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)CS(=O)(=O)CC(F)(F)F)C(=O)N12
Reaction time: 12 h

Procedure:
To a solution of 8.6 g. (0.019 mol.) of 7-amino-3-[1-(2-ureidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 3.9 g. (0.019 mol.) of 2,2,2-trifluoroethylsulfonylacetic acid in tetrahydrofuran is added dropwise a solution of 3.9 g. (0.019 mol.) of dicyclohexylcarbodiimide in 100 ml. of tetrahydrofuran. The reaction mixture is stirred at 25° for 12 hours, then filtered and concentrated to about 10 ml. The residue is filtered and evaporated to dryness to give 7-(2,2,2-trifluoroethylsulfonylacetamido)-3-[1-(2-ureidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([PH:12](=O)[C:13]2[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([N:22]([CH3:24])[CH3:23])=[C:15]([CH:25]([CH3:27])[CH3:26])[CH:14]=2)=[CH:5][C:4]=1[CH:29]([CH3:31])[CH3:30].[BH3:33].O1CCCC1>C1(C)C=CC=CC=1>[CH3:32][N:2]([CH3:1])[C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([PH:12][C:13]2[CH:18]=[C:17]([CH:19]([CH3:20])[CH3:21])[C:16]([N:22]([CH3:24])[CH3:23])=[C:15]([CH:25]([CH3:27])[CH3:26])[CH:14]=2)=[CH:5][C:4]=1[CH:29]([CH3:31])[CH3:30].[BH3:33]
Reactant: CC(C)c1cc([PH](=O)c2cc(C(C)C)c(N(C)C)c(C(C)C)c2)cc(C(C)C)c1N(C)C
Agent: B
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)c1cc(Pc2cc(C(C)C)c(N(C)C)c(C(C)C)c2)cc(C(C)C)c1N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
Under an argon atmosphere, to a solution of bis(4-dimethylamino-3,5-diisopropylphenyl)phosphine oxide (8.08 g, 18 mmoL) synthesized in Example 7 in toluene (48 mL) was added borane-tetrahydrofuran solution (60 mL, 3.3 equivalents) at 25° C. to 30° C. over 2 hr. Then, silica gel (7.0 g, 6.3 equivalents) was added to the mixture, and the mixture was stirred at room temperature for 1 hr. Then, silica gel was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from n-hexane to give the title compound (5.5 g, white crystals). yield 67%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:11])[S-:10])=[N:6][CH:7]=1.C([NH+](CC)CC)C.[CH2:19]=[CH:20][C:21](=[O:24])[CH2:22][CH3:23]>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:10])[S:11][CH2:19][CH2:20][C:21](=[O:24])[CH2:22][CH3:23])=[N:6][CH:7]=1
Reactant: C=CC(=O)CC
Reactant: S=C([S-])Nc1ccc(Cl)cn1
Agent: CC[NH+](CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCC(=O)CCSC(=S)Nc1ccc(Cl)cn1
Reaction time: 2 h
Yield: 56.7 %

Procedure:
The procedure of Example 6 is followed but triethylammonium 5-chloropyrid-2-yldithiocarbamate (91.5 g) and pent-1-en-3-one (28.0 g) in anhydrous chloroform (600 cc) are used as the starting materials at a maximum temperature of 5° C. The reaction is allowed to proceed for 2 hours at a maximum temperature of 5° C. The crude product (90.0 g) is dissolved in methylene chloride (400 cc). The solution is chromatographed on a column of diameter 6.5 cm, containing silica (0.063-0.2 mm; 750 g). Elution is carried out with methylene chloride (1,500 cc), this eluate being discarded, and then with methylene chloride (6 liters), this eluate being collected and evaporated to dryness. The product obtained (59.1 g) is purified by recrystallisation from a mixture of acetonitrile (60 cc) and diisopropyl ether (120 cc). 3-Oxopentyl 5-chloropyrid-2-yldithiocarbamate (49.0 g) (structure determined by IR spectroscopy in petroleum jelly), which melts at 80° C., is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([CH3:18])[CH:9]=2)[CH:5]=[C:4]([CH3:19])[N:3]=1.[Br:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[Br:20][C:21]1[CH:26]=[C:25]([C:2]2[N:3]=[C:4]([CH3:19])[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([CH3:18])[CH:9]=3)[N:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(Cl)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3-methyl-4-trifluoromethyl-phenyl)-6-methyl-pyrimidine (example A.40) (0.401 g, 1.4 mmol) and commercially available 3-bromo-benzene-boronic acid (0.366 g, 1.82 mmol) according to the general procedure IVb. Obtained as a light yellow oil (0.13 g, 23%). MS (ISP) 409.2 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10](=O)C(F)(F)F)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].IC>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1
Reactant: O=C(Nc1nc(Cl)cc(Cl)n1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: O
Product: CNc1nc(Cl)cc(Cl)n1
Reaction time: 12 h
Yield: 85.7 %

Procedure:
To a mixture of N-(4,6-dichloro-pyrimidin-2-yl)-2,2,2-trifluoro-acetamide (4.6 g, 17.7 mmol) and potassium carbonate (4.9 g, 35.4 mmol) in acetone (100 ml) was added iodomethane (1.3 ml, 21.2 mmol). After stirring for 12 hours, the mixture was filtered through a pad of celite under suction. The filtrate was concentrated under reduced pressure and the residue was treated with methanol (150 ml) tetrahydrofuran (30 ml), and a solution of potassium carbonate (5.0 g, 51 mmol) in water (15 ml). After stirring for 1 hour, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (150 ml) and saturated aqueous sodium chloride solution (100 ml). The organic phase was dried over magnesium sulfate. After evaporation of the solvent under reduced pressure, the residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:6 followed by 1:4) to give N-(4,6-dichloro-pyrimidin-2-yl)-methyl-amine (2.7 g, 85% yield). 1H NMR (CDCl3) δ 3.04 (d, 3H, J=5.1 Hz, CH3), 5.50 (br s, 1H, NH), 6.63 (s, 1H, Ar).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@@H:3]1[C:11]([OH:13])=O.[F:15][C:16]([F:24])([F:23])[C:17]1[CH:21]=[C:20]([NH2:22])[NH:19][N:18]=1>>[CH3:14][C:2]1([CH3:1])[C@@H:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:3]1[C:11]([NH:22][C:20]1[NH:19][N:18]=[C:17]([C:16]([F:24])([F:23])[F:15])[CH:21]=1)=[O:13]
Reactant: CC1(C)[C@@H](C(=O)O)[C@@H]1c1ccccc1
Reactant: Nc1cc(C(F)(F)F)n[nH]1
Product: CC1(C)[C@@H](C(=O)Nc2cc(C(F)(F)F)n[nH]2)[C@@H]1c1ccccc1
Yield: 92.6 %

Procedure:
2,2-Dimethyl-trans-3-phenylcyclopropanecarboxylic acid (250 mg, 1.32 mmol) and 3-trifluoromethyl-1H-pyrazole-5-ylamine (198 mg, 1.31 mmol) were reacted as described under General Procedure D to furnish the title compound (392 mg, 93%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.32-7.22 (m, 6H), 5.72-5.64 (m, 2H), 3.43 (d, J=6.1 Hz, 1H), 2.98 (d, J=6.1 Hz, 1H), 1.42 (s, 3H), 1.07 (s, 3H). mp 68-71° C. ESIMS m/z [M+H]+ 324.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][CH:50](O)[CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41].CCOC(/N=N/C(OCC)=O)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][CH:50]([N:12]2[CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[N:11]2)[CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1cccc(-c2n[nH]cc2-c2ccncc2)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccncc3)c(-c3cccc([N+](=O)[O-])c3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-[3-(3-nitro-phenyl)-1H-pyrazol-4-yl]-pyridine (200 mg, 0.750 mmol) in anhydrous tetrahydrofuran (3 mL) at 0° C. triphenylphosphine (293 mg, 1.12 mmol, 1.5 eq), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.750 mmol, 1 eq) and DEAD (176 μL, 1.12 mmol, 1.5 eq) were added. The reaction was allowed to warm to room temperature and stirred under nitrogen atmosphere overnight. The regioisomeric ratio was 1:4 at 254 nm in favor of the N1-alkylated product. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (DCM/ethanol 97:3) to give 950 mg of major regioisomer contaminated with triphenylphosphinoxide.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([O-:4])=O.[CH3:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14].[O-]CC.[Na+].OS(O)(=O)=O>C(O)C.O>[O:4]=[C:2]([CH2:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCCCC(C)=O
Reactant: CCOC(=O)C(=O)[O-]
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCC(=O)CC(=O)C(=O)OCC
Temperature: 0 °C
Yield: 80.4 %

Procedure:
A mixture of ethyl oxalate (97.21 g) and hexan-2-one (66.58 g) was added dropwise to a solution of sodium ethoxide (50.1 g) in ethanol (160 ml) at reflux. The resultant mixture was heated at reflux for 2 h. The cooled reaction mixture was poured into a stirring mixture of ice (500 g) and water (100 ml) and the resultant slurry adjusted to pH 1.5(conc.H2SO4). The two layers were separated and the bottom layer extracted with toluene (2×200 ml). The combined organics were washed with brine (200 ml), dried and concentrated in vacuo to give a residue (107 g) which was purified by distillation to afford the title compound as a colourless liquid (67.2 g).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH:3]=1.C1(C)C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)(=O)C([Cl:29])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([Cl:29])=[O:10])[CH2:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1=CC[C@@H](C(=O)O)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1=CCC(C(=O)Cl)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(1S)-4-Methyl-cyclohex-3-enecarboxylic acid (209 mg, 1.5 mmol), azeotropically dried by evaporation from toluene, was treated with potassium phosphate tribasic (383 mg, 1.8 mmol), suspended in dichloromethane (4 mL) and treated with dimethylformamide (2 drops). The reaction mixture was cooled to 0° C. and treated dropwise with oxalyl chloride (0.3 mL, 3.2 mmol). The reaction mixture was allowed to warm to ambient temperature while stirring for 2 h. After filtering the solids, the solution was concentrated, treated with hexanes and concentrated again to afford 4-methyl-cyclohex-3-enecarbonyl chloride (S) as a light yellow oil which was used immediately in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18].N1CC[CH2:24][CH2:23]1>CN(C=O)C>[N+:9]([C:6]1[CH:5]=[CH:4][C:3]([O:12][CH3:13])=[C:2]([Cl:1])[C:7]=1[CH:8]=[CH:19][N:17]1[CH2:16][CH2:24][CH2:23][CH2:18]1)([O-:11])=[O:10]
Reactant: C1CCNC1
Reactant: COC(OC)N(C)C
Reactant: COc1ccc([N+](=O)[O-])c(C)c1Cl
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(C=CN2CCCC2)c1Cl
Reaction time: 8 h
Yield: 75.4 %

Procedure:
After reaction of 2-chloro-3-methyl-4-nitroanisole (32.1 g, 159 mmol) with dimethylformamide dimethylacetal (22.6 g, 190 mmol) and pyrrolidine (13.4 g, 188 mmol) in DMF (150 ml) at 120°-140° C. for 1 hour under a slow current of nitrogen, the volatile components were removed under vacuum. To the residue was added dichloromethane (90 ml) and methanol (360 ml) and the solution was evaporated to about half its original volume by heating on a steam bath. After cooling, the solution was left refrigerated overnight to yield 2-nitro-5-methoxy-6-chloro-β-pyrrolidinostyrene as red crystals (33.9 g) m.p. 89°-92° C.
Reaction SMILES: [OH-].[NH4+:2].[C:3]([C:5]1[N:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4]>>[C:3]([C:5]1[N:10]=[CH:9][C:8]([S:11]([NH2:2])(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4]
Reactant: [NH4+]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cn1
Agent: [OH-]
Product: N#Cc1ccc(S(N)(=O)=O)cn1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To an ice-cold solution of ammonium hydroxide (75 ml, 25% w/v) is added 6-cyanopyridine-3-sulfonyl chloride (12.5 g) portionwise and the mixture is stirred for 30 minutes at 0-5° C. The reaction mixture is then concentrated to ⅕th of its original volume and cooled. The precipitate is filtered and dried under vacuum to afford the title compound as light brown solid (9 g, Yield 80%). 1H NMR (DMSO-d6:400 MHz) δ 9.10 (1H, s), 8.33-8.35 (1H, m), 8.23-8.25(1H, d); 7.88-8.03 (2H, bs); HPLC (max plot) 98%, Rt 4.67 min; LC/MS: (ES+) 183.8.
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[N+:15]([C:18]1[CH:19]=[C:20]([CH:42]=[C:43]([N+:45]([O-:47])=[O:46])[CH:44]=1)[C:21]([NH:23][C@H:24]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:25][C:26](ON1C(=O)CCC1=O)=[O:27])=[O:22])([O-:17])=[O:16].Cl>O.O1CCCC1>[N+:15]([C:18]1[CH:19]=[C:20]([CH:42]=[C:43]([N+:45]([O-:47])=[O:46])[CH:44]=1)[C:21]([NH:23][C@H:24]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:25][C:26]([NH:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5])=[O:27])=[O:22])([O-:17])=[O:16]
Reactant: N[C@@H](CC(=O)O)c1ccccc1
Reactant: O=C(C[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@H](NC(=O)C[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5.65 g of (S)-3-amino-3-phenylpropionic acid were suspended in 70 ml of water, the pH of the suspension was adjusted to 10.5-11 by adding sodium hydroxide solution, and 70 ml of tetrahydrofuran were added. The mixture was cooled to 0-5° C. in an icebath and 13 g of 2,5-dioxopyrrolidin-1-yl (S)-3-(3,5-dinitrobenzamido)-3-phenylpropionate were added in portions with stirring over a period of 15 min. On completion of addition, the pH of the reaction mixture was kept between 9-9.5 by adding sodium hydroxide solution. On attainment of a constant pH with virtually full conversion (HPLC monitoring; <0.5 area % of reactant), the solution was diluted to a volume of about 800 ml with water, a pH of 1.5-2 was established by adding 4 N hydrochloric acid and the mixture was stirred for a further 30 min. The solid was filtered off with suction, washed with water and dried at 50° C. under reduced pressure. The dried solid was digested in 250 ml of tetrahydrofuran at 40° C. for 20 min, the suspension was cooled and the solid (product fraction 1) was filtered off with suction. The mother liquor was concentrated at a water bath temperature of 40° C. to a volume of about 70-80 ml, the resulting suspension was cooled to room temperature, and the solid (product fraction 2) filtered off with suction. The product fractions were combined and dried at 50° C. under reduced pressure. The yield was 11.1 g; HPLC purity>99.5 area %; 1H NMR (DMSO) δ (ppm): 2.64 (d, 2H), 2.77 (m, 2H), 5.15 (m, 1H), 5.52 (m, 1H), 7.10-7.20 (m, 5H), 7.25 (t, 1H), 7.31 (t, 2H), 7.39 (d, 2H), 8.44 (d, 1H), 8.95 (m, 1H), 9.01 (m, 2H), 9.53 (d, 1H), 12.17 (s, 1H, CO2H).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]([N:18]([CH2:40][CH2:41][CH2:42][CH3:43])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29](=O)[C:28]=2[O:36][CH3:37])=[C:21]([O:38][CH3:39])[CH:20]=1)[CH2:15][CH2:16][CH3:17].O>O1CCCC1.C(OCC)(=O)C>[CH2:14]([N:18]([CH2:40][CH2:41][CH2:42][CH3:43])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29](=[CH:5][C:3]#[N:4])[C:28]=2[O:36][CH3:37])=[C:21]([O:38][CH3:39])[CH:20]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN(CCCC)c1ccc(C=CC2=C(OC)C(=O)CC(C)(C)C2)c(OC)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)c1ccc(C=CC2=C(OC)C(=CC#N)CC(C)(C)C2)c(OC)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 52.9 %

Procedure:
To 0.18 g (7.5 mmol) of sodium hydride, 12 ml of tetrahydrofuran was added. To this mixture, 0.98 g (5.5 mmol) of diethyl cyanomethylphosphonate was added dropwise under ice cooling. To the mixture, 0.915 g (2.2 mmol) of 3-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]-2-methoxy-5,5-dimethyl-2-cyclohexenone in tetrahydrofuran was added dropwise. After the mixture was stirred at 60° C. for 24 hours, water was added to the mixture and extraction with ethyl acetate was performed. The extract was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 0.51 g of an orange oily matter (yield: 52.9%).
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[CH2:22][N:21]([CH3:23])[CH2:20][CH2:19][CH:18]=4)[CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1)(=O)[CH3:2].Cl.[CH2:27]([O:29][NH2:30])[CH3:28]>C(O)C>[CH2:27]([O:29][N:30]=[C:1]([C:4]1[CH:25]=[CH:24][C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[CH2:22][N:21]([CH3:23])[CH2:20][CH2:19][CH:18]=4)[CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1)[CH3:2])[CH3:28]
Reactant: CC(=O)c1ccc2c(c1)ncn2-c1cccc(C2=CCCN(C)C2)c1
Reactant: CCON
Agent: Cl
Solvent: CCO
Product: CCON=C(C)c1ccc2c(c1)ncn2-c1cccc(C2=CCCN(C)C2)c1

Procedure:
To a solution of 5-acetyl-1-[3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl]benzimidazole (7) (free base from above) in ethanol was added O-ethyl hydroxylamine hydrochloride. The mixture was heated to reflux for 1.5 hours whereafter the solvent was removed under reduced pressure. The residue was triturated with a mixture of diethyl ether and ethanol leaving 5-acetyl-1-[3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl]benzimidazole O-ethyl oxime (3f8) as hygroscopic crystals. Mp 138-143° C., m/e 374.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.[CH3:13][N:14](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[Cl:12][C:4]1[CH:3]=[C:2]([C:13]#[N:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1ccc(C#N)cc1Cl
Temperature: 90 °C

Procedure:
The product from Example 143 Part A (1.0 g, 4.0 mmol), Zn(CN)2 (0.52 g, 4.8 mmol), Pd(PPh3)4 (0.23 g, 0.2 mmol) were added together with 9 mL of DMF. The mixture was degassed and then heated at 90° C. for 6 h. Water and EtOAc were added to the reaction mixture. It was filtered to remove inorganic solids. The layers were separated and the EtOAc layer was washed with water and brine. It was dried over MgSO4, concentrated, and purified by flash chromatography (silica, EtOAc/hexane) to give 0.28 g of the desired product. MS: 196.1 (M+1)+.
Reaction SMILES: [Li+].[OH-].[CH2:3]([O:10][P:11]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31]C)=[O:30])=[CH:24][CH:23]=1)([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C1COCC1.CO>[CH2:14]([O:13][P:11]([O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:26][CH:27]=1)([O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1ccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.3 %

Procedure:
LiOH (1N, 9 mL, 5 mmol) was added into a mixture of methyl 2-(4-(bis(benzyloxy)phosphoryloxy)phenyl)acetate (1.53 g, 3.59 mmol) in THF (15 mL) and methanol (5 mL) at 0° C. The reaction was stirred at 0° C. for 3.5 h, than 0.5 h at rt. The reaction was monitored by LC-MS until the hydrolysis was completed. The mixture was cooled to 0° C. and acidified by 1N HCl to pH=2. The mixture was concentrated and extracted by ethyl acetate (50 mL×3). The extraction was dried over Na2SO4 and concentrated to dryness to give the acid (1.5 g, 67.6% yield) as a light yellow oil.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:18][CH2:19][C@H:20]([OH:22])[CH3:21]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:13]([C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:18]([CH2:19][C@H:20]([OH:22])[CH3:21])[C:5]=32)=[CH:10][CH:9]=1)([CH3:15])[CH3:14]
Reactant: CC(C)c1ccc2c(c1)C(=O)C(CC=O)C2
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2
Reaction time: 0.75 h
Yield: 69.8 %

Procedure:
A solution of 2.16 g of (RS)-2-(2-oxoethyl)-6-isopropyl-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which time the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.78 g (70%) of (R)-1-(7-isopropyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.