Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:43][C@H:44]1[CH2:48][C@@H:47]([CH2:49][S:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:46]([C:57]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=2)=[O:58])[CH2:45]1.C(OCC)(=O)C>C(#N)C>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])=[C:18]([S:43][C@H:44]3[CH2:48][C@@H:47]([CH2:49][S:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[N:46]([C:57]([O:59][CH2:60][C:61]4[CH:62]=[CH:63][C:64]([N+:67]([O-:69])=[O:68])=[CH:65][CH:66]=4)=[O:58])[CH2:45]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](S)C[C@H]1CSc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](CSc4ccccc4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Temperature: 5 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (2.24 g, 3.78 mmol) in acetonitrile (70 ml), DIPA (0.9 ml, 5.16 mmol) was added under cooling with ice, and then a solution of (3S,5S)-3-mercapto-1-p-nitrobenzyloxycarbonyl-5-(phenylthiomethyl)pyrrolidine (1.39 g, 3.42 mmol) in acetonitrile (15 ml) was dropwise added thereto. The reaction solution was stirred at 5° C. overnight, and ethyl acetate (300 ml) was added to the reaction solution. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate), to give p-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(3S,5S)-1-p-nitrobenzyloxycarbonyl-5-(phenylthiomethyl)pyrrolidin-3-ylthio]-1-carbapen-2-em-3-carboxylate (1.55 g, yield: 60%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[C:11](Cl)(=[O:15])[CH:12]([CH3:14])[CH3:13]>N1C=CC=CC=1>[C:7]([C:5]1[O:4][N:3]=[C:2]([NH:1][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)c1cc(N)no1
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Yield: 91.7 %

Procedure:
To a solution of 3-amino-5-t-butylisoxazole (2.80 g) in pyridine (10 ml) is dropwise added isobutyryl chloride (2.34 g) keeping the mixture below 10° C. The reaction mixture is stirred with cooling for 30 minutes and at room temperature for 1 hour and evaporated to remove the pyridine. The residue is mixed with 5% hydrochloric acid solution (40 ml) and shaken with methylene chloride. The methylene chloride layer is separated, washed with saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and evaporated to remove the methylene chloride. The residue is chromatographed on a column of silica gel and recrystallized from n-hexane to give N-(5-t-butyl-3-isoxazolyl)isobutyramide (3.85 g) as colorless needles melting at 123.0° to 124.0° C.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH2:7][NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][S:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=2)=[CH:4][CH:3]=1.B.C1COCC1.CO.C(O)(C(F)(F)F)=O>C1COCC1>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][S:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCCc1ccc(F)cc1)c1cccc(CSCCc2ccccc2)c1
Agent: B
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Fc1ccc(CCNCc2cccc(CSCCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a solution of N-(4-fluorophenethyl)-3-(phenethylthiomethyl)benzamide (0.3 g, 0.76 mmol) in THF (5 mL) was added borane-THF complex (1 M solution in THF, 12 mL, 12 mmol). The reaction mixture was stirred at rt for overnight. To the reaction mixture was added MeOH and 2 mL of TFA, and the resulting mixture was stirred for 3 h. The resulting mixture was concentrated and the residue was diluted with saturated NaHCO3 solution and ethyl acetate. The organic layer was separated, washed with brine, and dried over MgSO4. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography silica gel eluting with 20% ethyl acetate in hexanes, which contained 10% of 2 M ammonia in MeOH to give the desired product (0.18 g, 58%) as a colorless oil. 1H NMR (CDCl3) δ 7.32-7.14 (m, 11H), 7.01-6.95 (m, 2H), 3.84 (s, 2H), 3.72 (s, 2H), 2.91-2.80 (m, 6H), 2.73-2.64 (m, 2H). MS (ESI): 380.1 (M+H)+.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[CH3:9][N:10]1[C:14]([C:15]2[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[S:18][CH:19]=2)=[C:13]([CH3:24])[CH:12]=[N:11]1>O1CCCC1>[Cl:8][C:12]1[C:13]([CH3:24])=[C:14]([C:15]2[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[S:18][CH:19]=2)[N:10]([CH3:9])[N:11]=1
Reactant: COC(=O)c1cc(-c2c(C)cnn2C)cs1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2c(C)c(Cl)nn2C)cs1
Temperature: 100 °C
Yield: 91 %

Procedure:
NCS (1.78 g, 13.09 mmol) was added in portions to a 125 mL sealed tube reactor containing methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.07 g, 8.76 mmol) in Tetrahydrofuran (THF) (40 ml) at room temperature. The mixture was heated to 100° C. for 1 hour. Upon completion the product was partitioned between CHCl3 and H2O, the organic layer dried with Na2SO4, solvents removed by vacuum distillation affording the title compound (2.18 g, 7.97 mmol, 91%) which was used without further purification: LC-MS (ES) m/z=271 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(OCC)(=O)C>CN(C)C=O>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:6]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1cccc(C=O)c1

Procedure:
3-Hydroxybenzaldehyde (30.0 g, 0.246 mol) was dissolved in dimethylformamide (20 mL). Subsequently, potassium carbonate (51.00 g, 0.369 mol), and then ethyl 2-bromoisobutyrate (144.00 g, 0.737 mol) were added thereto, and the resultant mixture was stirred overnight at 80° C. The temperature of the reaction mixture was returned to room temperature. Ethyl acetate was added. Washing was performed sequentially with water and saturated brine, followed by drying over sodium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate=5/1), whereby a colorless oil was obtained (57.70 g, 0.244 mol, 99.3%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C[O-].[Na+].[Cl:9][C:10]1[CH:22]=[C:21]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]([C:23]([OH:34])([CH2:32]Cl)[CH2:24][C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)=[CH:18][C:19]=3[CH2:20]2)=[CH:12][CH:11]=1.O>CO.CN(C)C=O>[Cl:9][C:10]1[CH:22]=[C:21]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]([C:23]([OH:34])([CH2:32][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH2:24][C:25]4[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=4)=[CH:18][C:19]=3[CH2:20]2)=[CH:12][CH:11]=1
Reactant: c1c[nH]cn1
Reactant: OC(CCl)(Cc1ccc(Cl)cc1)c1ccc2c(c1)Cc1cc(Cl)ccc1-2
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: OC(Cc1ccc(Cl)cc1)(Cn1ccnc1)c1ccc2c(c1)Cc1cc(Cl)ccc1-2
Temperature: 60 °C
Yield: 62.5 %

Procedure:
9 g (0.12 mol) of imidazole are added to a solution of 4.2 g (0.078 mols) of sodium methylate in 22 ml of methanol; a solution of 2-(7-chlorofluoren-2-yl)-3-chloro-1-(4-chlorophenyl)-propan-2-ol in 45 ml of dimethylformamide is then added dropwise and the mixture is warmed to 60° C. for 90 minutes. The mixture is poured into 2,000 ml of water, the crystalline mass which has separated out is dissolved in methylene chloride, the solution is washed with water, dried over sodium sulphate and filtered and the filtrate is concentrated in vacuo. The residue is made to crystallise by stirring with diethyl ether; the crystals are stirred with a little methyl alcohol and filtered off. 16.2 g (62.5% of theory) of 2-(7-chlorofluoren-2-yl)-1-(4-chlorophenyl)-3-(imidazol-1-yl)-propan-2-ol of melting point 218° C. are obtained.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:5]([CH3:16])([CH3:15])[S:4]1)[OH:2].[CH3:17][N:18]=[C:19]=[O:20]>>[CH3:17][NH:18][C:19]([O:2][N:1]=[C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:5]([CH3:16])([CH3:15])[S:4]1)=[O:20]
Reactant: CC1(C)SC(=NO)N=C1c1ccc(Cl)cc1
Reactant: CN=C=O
Product: CNC(=O)ON=C1N=C(c2ccc(Cl)cc2)C(C)(C)S1

Procedure:
2-oxo-4-(p-chlorophenyl)-5,5-dimethyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4-(p-chlorophenyl)-5,5-dimethyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 147°-149° C. The 2-oxo-4-(p-chlorophenyl)-5,5-dimethyl-3-thiazoline-oxime starting material melts at 205°-207° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](=[NH:7])[NH2:6].O=[C:12]([CH2:19][CH3:20])[CH2:13][C:14](OCC)=[O:15].C[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:6][C:14](=[O:15])[CH:13]=[C:12]([CH2:19][CH3:20])[N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(=O)CC
Reactant: N=C(N)c1cccc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1cc(=O)[nH]c(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Yield: 25.7 %

Procedure:
A 1-L round bottomed flask was charged with 3-chlorobenzimidamide (23.9 g, 154 mmol, 1 eq.), ethyl 3-oxopentanoate (27.8 g, 193 mmol, 1.25 eq.), and ethanol (500 mL). To the mixture was added sodium methoxide (10.0 g, 185 mmol, 1.20 eq.). The resulting mixture was stirred under reflux for 20 hr. After cooling to room temperature, the mixture was evaporated under reduced pressure to 50 mL. The residual slurry was cautiously treated with 2N HCl (219 mL). Solid was collected by filtration and washed with water followed by ether to afford 2-(3-chlorophenyl)-6-ethylpyrimidin-4(3H)-one (9.3 g, 39% yield), which was carried forward into the next step without further purification. 1H NMR (CD3OD, 500 MHz) δ 8.07 (s, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.62-7.58 (m, 1H), 7.52 (t, J=8.0, Hz, 1H), 6.27 (s, 1H), 2.66 (q, J=7.5 Hz, 2H), 1.29 (t, J=7.5 Hz, 3H).
Reaction SMILES: C(O)C#C.[H-].[Na+].[C:7]([O-:11])(=O)[C:8]#[CH:9].[Na+].Cl[C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH3:29])[N:22]=2)[N:15]=1>O1CCCC1.C(Cl)(Cl)Cl>[CH3:20][C:18]1[CH:19]=[C:14]([O:11][CH2:7][C:8]#[CH:9])[N:15]=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH3:29])[N:22]=2)[N:17]=1
Reactant: C#CC(=O)[O-]
Reactant: CCCc1cccc(-c2nc(C)cc(Cl)n2)n1
Agent: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: C#CCOc1cc(C)nc(-c2cccc(CCC)n2)n1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of propargyl alcohol (0.82 g) in anhydrous tetrahydrofuran (80 ml) was added 60 % oily sodium hydride (0.58 g) to prepare sodium propargylate. To this solution was added at room temperature 4-chloro-6-methyl-2-(6-n-propyl-2-pyridinyl)pyrimidine (3 g). The mixture was stirred for one hour and then concentrated under reduced pressure. To the redidue obtained was added chloroform (100 ml). The mixture was washed twice with water (30 ml each) and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The crystalline residue obtained was washed with hexane to obtain 4-methyl-6-propargyloxy-2-(6-n-propyl-2-pyridinyl)pyrimidine (2.7 g, yield: 83 %).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:12][CH3:13])(=[O:11])[CH:8]([CH3:10])[OH:9].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([O:9][CH:8]([CH3:10])[C:7]([O:12][CH3:13])=[O:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)C(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)OCc1ccccc1
Reaction time: 5 h

Procedure:
To a pre-cooled solution of potassium tertiary butoxide (538.4 g) in DMF (1750 ml) at −20 to −10° C., added racemic methyl lactate compound of formula-11 (500 g) followed by benzyl chloride (547 g) at −20 to −10° C. and the reaction mixture was stirred for 5 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with water and the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and 10% sodium chloride solution and then distilled off the solvent from ethyl acetate layer under reduced pressure to get the title compound as a residue. The obtained residue was taken into next step without isolation.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH2:21][N:22]3[CH:30]([OH:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])[CH2:17][CH:18]=2)=[CH:9][CH:8]=1.N.[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36]>CO.C(Cl)Cl.C(C(C)=O)C>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[CH3:34][O:32][CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30](=[O:31])[N:22]1[CH2:21][CH2:20][CH2:19][N:16]1[CH2:15][CH:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)[CH2:18][CH2:17]1
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccc(F)cc2)CC1
Agent: N
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COC1c2ccccc2C(=O)N1CCCN1CC=C(c2ccc(F)cc2)CC1
Reaction time: 5 h
Yield: 153.1 %

Procedure:
28.5 cc of concentrated sulphuric acid is added to an agitated solution of 2-[3-(4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl)propyl]-3-hydroxy-1-isoindolinone (5.7 g) in methanol (145 cc) at a temperature close to 20° C. in the course of 10 minutes. Agitation is continued for 5 hours at a temperature close to 65° C. After cooling the solution to a temperature close to 0° C., 70 cc of a 33% aqueous solution of ammonia is added in the course of 1 hour. The precipitate formed is filtered and washed with methanol (50 cc). The filtrate is diluted with distilled water (200 cc) and a 33% aqueous solution of ammonia (50 cc) and extracted with methylene chloride (3×200 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methylene chloride (10 cc) and the solution poured onto silica (550 g) contained in a column of 8 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (90-10 by volume). The first 900 cc are eliminated and the following 200 cc are evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The residue obtained is dissolved in methyl ethyl ketone (10 cc). A solution of oxalic acid (0.6 g) in methyl ethyl ketone (5 cc) is added and agitation continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 2.4 g of 3-methoxy-2-[3-(4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are obtained, melting at 139° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[N+:18]([O-])=O)[CH2:6][CH2:5]2.[Cl:21]CCl>C(O)C.[Pt]>[ClH:21].[NH2:18][C:12]1[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=1[N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: Cc1ccc(N2CCc3cc(Br)ccc32)c([N+](=O)[O-])c1
Reactant: ClCCl
Agent: [Pt]
Solvent: CCO
Product: Cc1ccc(N2CCc3cc(Br)ccc32)c(N)c1
Product: Cl
Reaction time: 3.5 h
Yield: 39 %

Procedure:
To a warm solution of 4-(5-bromo-1-indolinyl)-3-nitrotoluene (10 g, 0.03 mole) in dichloromethane (40 ml) and ethanol (160 ml) was added 1% platinum-on-carbon (2.0 gm). The mixture was shaken under hydrogen (57 psi) for 3.5 hours. The mixture was filtered and concentrated. The residue was dried under vacuum at 55° C. Purification was accomplished by flash chromatography over silica gel (100 g), eluted with a mixture of hexane:dichloromethane (3:1, 2 l and 1:1, 1 l). The fractions containing pure product were pooled and concentrated. The residue was dissolved in ether (250 ml) and added to a methanol/hydrogen chloride solution, and the mixture was stirred at 0° C. for 10 minutes. The precipitate was filtered and dried to afford 4.0 g (39%) of product, mp 195°-200° C. dec.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=O.[NH2:11][C:12]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=1[NH2:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[NH:11][C:12]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: Cc1ccccc1C(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1nc2ccc([N+](=O)[O-])cc2[nH]1

Procedure:
2-Methylbenzoyl chloride (4.1 g, 0.027 mol) is added to 2-amino-4-nitroaniline (4 g, 0.025 mol) in toluene (100 ml), and the mixture is refluxed for 24 hours. para-Toluenesulfonic acid (1.0 g) is added, the mixture is refluxed for 36 hours and concentrated, and the residue is taken up in ethyl acetate. The solution is washed with NaHCO3 and then with water. The resulting solution is dried and concentrated, and the solid obtained is recrystallized from isopropyl ether. Yield: 3.1 g (48%); Rf (7/3 toluene/ethyl acetate): 0.58; 1H-NMR (d6-DMSO): 8.5 (d, 1H); 8.1 (dd, 1H); 7.7 (m, 2H); 7.4 (m, 3H); 2.6 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
To a stirred solution of methyl 3-amino-2-methyl-5-bromobenzoate (4.06 g, 16.6 mmol) in DCE (60 ml) under a nitrogen atmosphere was added oxan-4-one (3.07 ml, 33.3 mmol) followed by acetic acid (5.71 ml, 99.8 mmol) and the reaction was left to stir for 5 min before the addition of sodium triacetoxyborohydride (10.6 g, 49.9 mmol). The reaction was stirred for 3 h at room temperature whereupon distilled water (50 ml) was added and the solution was neutralised with solid NaHCO3. The phases were separated and then the aqueous phase was washed with EtOAc (2×100 ml), the combined organics were then dried using Na2SO4, filtered and evaporated. The residue was purified by FCC using silica and eluting with a 10% to 40% EtOAc in heptane gradient to afford the title compound as an off-white solid (3.88 g, 71%). LC-MS 100%, 2.10 min (3.5 minute LC-MS method), m/z=327.9/329.8, 1H NMR (500 MHz, Chloroform-d) δ 7.23 (d, J=1.9 Hz, 1H), 6.84 (d, J=1.7 Hz, 1H), 4.02 (dt, J=11.7, 3.5 Hz, 2H), 3.87 (s, 3H), 3.65 (d, J=7.2 Hz, 1H), 3.59-3.45 (m, 3H), 2.23 (s, 3H), 2.05 (d, J=13.8 Hz, 2H), 1.51 (ddd, J=24.1, 10.8, 4.2 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.O=[C:18]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:25]([C:18]1[NH:11][C:12]2=[N:13][NH:14][CH:15]=[C:16]2[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCC(=O)CC(=O)OCC
Reactant: Nc1cc[nH]n1
Reactant: COc1ccccc1C=O
Product: CCCCC1=C(C(=O)OCC)C(c2ccccc2OC)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-methoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketoheptanoate in the same manner as in Example 1.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([NH:16][CH2:17][C:18](O)=[O:19])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:18]([CH2:17][NH:16][C:9](=[O:10])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(I)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(I)c1
Yield: 60 %

Procedure:
1.15 g of 3-iodoaniline and 097 g of N-BOC-glycine are dissolved in 25 ml of methylene chloride and treated portionwise at 0° with 1.14 g of dicyclohexylcarbodiimide. The separated urea is filtered off and the filtrate is concentrated. Recrystallization from toluene yields tert.butyl [(3-iodo-phenyl-carbamoyl)-methyl]-carbamate as colourless crystals. Yield: 60%. M.p.=126°-128°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([OH:11])[CH:6]=[C:5]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1N2CCN(CC2)C1>C1COCC1.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][C@H:5]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc2c(c1)C(c1ccccc1)=C[C@@H]2O
Agent: C1CN2CCN1CC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)[C@H](c1ccccc1)CC2=O
Yield: 91 %

Procedure:
5-Methyl-3-phenyl-(S)-1H-inden-1-ol (750 mg, 3.41 mmol) and DABCO (190 mg, 1.71 mmol) were dissolved in dry THF:triethylamine 20:1 (15 ml) and refluxed for 3 h. The reaction mixture was evaporated to dryness. Flash chromatography eluting with ethyl acetate:pentane 5:95 gave 690 mg (92%) of the title compound. Rf 0.62 (ethyl acetate:pentane 20:80) (ChiralCel OD-H) 0.5 ml/min of hexane/isopropanol: 95/5 (S)-isomer 19.12 min, (R)-isomer 22.33 min, 89% ee. IR (neat cm−1): 3027, 2361, 1710, 1605, 1280, 1238, 1040. 1H NMR δ: 2.39 (s, 3H), 2.69 (dd, J=3.0, 19.2Hz, 1H), 3.23 (dd, J=8.0, 19.2Hz, 1H), 4.53 (q, J=4Hz, 1H), 7.07 (s, 1H), 7.14 (d, J=8.4Hz, 1H), 7.15 (s, 1H), 7.26 (m, 2H), 7.33 (m, 2H), 7.72 (d, J=7.6Hz, 1H), 13C NMR δ: 22.1, 44.3, 46.9, 123.2, 126.9, 126.9, 127.0, 127.6, 128.9, 134.5, 143.8, 146.3, 158.4, 205.5. MS (EI 70 eV) m/z (rel. intensity): 220 (100) [M+], 207 (55), 194 (19), 178 (60), 144 (10).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:10]([C:13]1[N:18]=[CH:17][C:16]([O:19][C:20]2[CH:27]=[CH:26][C:23](C#N)=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)([F:12])[F:11].[Cl:35]C1C=CC(B(O)O)=CC=1>>[Cl:35][C:23]1[CH:26]=[CH:27][C:20]([O:19][C:16]2[CH:15]=[CH:14][C:13]([C:10]([F:12])([F:11])[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])([OH:34])[CH2:28][N:29]3[CH:33]=[N:32][N:31]=[N:30]3)=[N:18][CH:17]=2)=[CH:21][CH:22]=1
Reactant: N#Cc1ccc(Oc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(Oc2ccc(Cl)cc2)cn1

Procedure:
Compound 7 was prepared in a similar manner to compound 5 from (4-chlorophenyl)boronic acid to afford a solid (50 mg, 0.1 mmol, 35.7%). 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.22 (d, J=2.5 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.46-7.37 (m, 3H), 7.30 (dd, J=3.0, 9.0 Hz, 1H), 7.04-7.00 (m, 2H), 6.80-6.77 (m, 1H), 6.76-6.71 (m, 1H), 5.49 (d, J=14.5 Hz, 1H), 5.16 (d, J=14.5 Hz, 1H). MS (ESI): m/z 479 [M++1]. HPLC: 98.43%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[OH:13].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][O:13][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(O)c(OC)c1OC
Reactant: BrCCCCBr
Product: COc1ccc(OCCCCBr)c(OC)c1OC

Procedure:
The procedure is as for Example 53, Step A, using as substrate 2,3,4-trimethoxyphenol and 1,4-dibromobutane.