Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][O:6][C@@H:7]1[CH2:13][C@H:12]2[N:14](C(OC(C)(C)C)=O)[C@@H:8]1[CH2:9][O:10][CH2:11]2)[CH3:2].Cl.O1CCOCC1>C(Cl)Cl>[CH:12]12[NH:14][CH:8]([CH:7]([O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH2:13]1)[CH2:9][O:10][CH2:11]2
Reactant: CCOC(=O)CO[C@@H]1C[C@@H]2COC[C@H]1N2C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)COC1CC2COCC1N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.6 %

Procedure:
To a solution of (1R,5R,6R)-tert-butyl 6-(2-ethoxy-2-oxoethoxy)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate 50a (racemic, 200 mg, 0.63 mmol) in DCM (10 mL) was added HCl/dioxane (2 mL, 7 M). The resulting mixture was stirred at room temperature for 2 h. The organic solvent was removed in vacuo to give the compound 50b (150 mg, 94%). MS: calc'd (MH+) 216, measured (MH+) 216; 1H NMR (CDCl3, 400 MHz): 4.28 (m, 8H), 3.79 (m, 1H), 3.70 (s, 1H), 3.57 (d, J=12.4 Hz, 1H), 2.50 (m, 1H), 2.31 (m, 1H), 1.28 (m, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:13])[O:11][CH3:12])=O.S([O-])([O-])(=O)=O.[Mg+2].Cl.[Br:21][CH2:22][CH2:23][CH2:24][NH2:25].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:21][CH2:22][CH2:23][CH2:24][N:25]=[CH:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:13])[O:11][CH3:12]
Reactant: COC(=O)Nc1ccccc1C=O
Reactant: NCCCBr
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1ccccc1C=NCCCBr
Reaction time: 24 h
Yield: 94.3 %

Procedure:
Methyl 2-formylphenylcarbamate (7, 2.5 g, 14 mmol) and magnesium sulfate (5 g) were added to a solution of 3-bromopropylamine hydrochloride (3.68 g, 16.8 mmol) and triethylamine in chloroform (30 mL) and mixture was stirred for 24 h. The mixture was filtered and the residue was washed with chloroform (2×30 mL). The combined filtrates were washed with water (2×30 mL), brine (30 mL), dried with sodium sulfate, and concentrated to afford 21 as a yellow oil (3.95 g, 94.5%). IR (film) 1730, 1638 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.38 (d, J=8.4 Hz, 1 H), 8.30 (s, 1 H), 7.35 (t, J=7.7 Hz, 2 H), 7.26 (d, J=7.7 Hz, 1 H), 7.00 (t, J=7.4 Hz, 1 H), 3.74 (s, 3 H), 3.69 (t, J=6.3 Hz, 2 H), 3.50 (t, J=6.6 Hz, 2 H), 2.20 (pent, J=6.3 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 164.74, 154.30, 140.07, 133.00, 131.32, 121.25, 119.79, 117.69, 58.17, 52.87, 33.16, 31.15; ESIMS m/z (rel intensity) 299/301 (MH+, 100/99); EIHRMS m/z M+ calcd. for C12H15BrN2O2, 298.0317; found, 298.0320.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[O:13]([CH2:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)C>CCCCCC.O1CCCC1>[O:22]=[C:21]([CH2:20][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: O=C(Cl)COc1ccccc1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COP(=O)(CC(=O)COc1ccccc1)OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyl lithium (69 ml. of a 1.2 M solution in hexane) was added to a solution of dimethyl methylphosphonate (10.3 g.) in dry tetrahydrofuran at -78° C. in an atmosphere of nitrogen. After 10 minutes, a solution of phenoxyacetylchloride (4.1 g.) in dry tetrahydrofuran (20 ml.) was added dropwise, and the mixture was stirred for 4 hours at -78° C. The reaction mixture was neutralised with acetic acid and the solvents were removed under reduced pressure. The residue was shaken with a mixture of ether (100 ml.) and water (20 ml.), and the organic phase was separated and washed with brine. The solution was dried, the solvents were evaporated and the residue was distilled in a bulb distillation apparatus at an oven temperature of 160° C. and 0.1 mm. pressure, to give dimethyl 2-oxo-3-phenoxypropylphosphonate.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:18][CH:19]=C)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]=[O+][O-]>C(Cl)Cl>[CH2:1]([O:8][CH:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH2:18][CH:19]=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC(Cc1ccccc1C)OCc1ccccc1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: Cc1ccccc1CC(CC=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(2-(benzyloxy)pent-4-enyl)-2-methylbenzene (5.0 g, 18.72 mmol) in DCM (100 ml) was passed O3 gas at −78° C. for 3 h. The reaction mixture was quenched with TEA (5 ml) at −78° C., and stirred for room temperature for 5 h. The title compound was purified by separation methods A and E. (Yield 2.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](O)[CH:6]=[C:5]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1.O=P(Cl)(Cl)[Cl:24]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:24])[CH:6]=[C:5]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1
Reactant: Oc1cc(Nc2ccc(Cl)c(Cl)c2)c2cc(Br)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc(Nc2ccc(Cl)c(Cl)c2)c2cc(Br)ccc2n1
Yield: 60 %

Procedure:
Prepared using general procedure 3; 6-Bromo-2-hydroxy-4-(3,4-dichlorophenyl)aminoquinoline (1.94 g, 5.05 mmol) and 30 mL of POCl3 were heated to 120° C. for 4 h. Isolation afforded 1.209 g of material (3.00 mmol, 60%). 1H NMR (300 MHz, DMSO): 9.69(s, 1H), 8.71(s, 1H), 7.91(d, 1H, J=8.88 Hz), 7.78(d, 1H, J=8.88 Hz), 7.69(d, 1H, J=8.88 Hz), 7.68(s, 1H), 7.44(dd, 1H, J=8.68, 2.22 Hz), 6.91(m, 1H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH2:38][CH:39]=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)#[N:25]>COC(C)(C)C.O1CCCC1>[CH3:2][O:3][CH:4]=[CH:39][CH2:38][C@H:35]1[CH2:34][CH2:33][C@H:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=2)[CH2:37][CH2:36]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc([C@H]2CC[C@H](CC=O)CC2)cc1
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COC=CC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 22.2 g of methoxymethyl-triphenylphosphonium chloride in 150 ml of t-butyl methyl ether was treated with 7.4 g of solid potassium t-butylate at 0° C. within 3 minutes while gassing with argon in a sulphonation flask provided with a mechanical stirrer. The orange suspension was stirred at 0° C. for 1 hour and then treated dropwise within 10 minutes with a solution of 9.8 g of 2-[trans-4-(p-cyanophenyl)cyclohexyl]acetaldehyde in 100 ml of tetrahydrofuran. Subsequently, the suspension was left to warm slowly to room temperature while stirring. After 15 hours, the suspension was partitioned three times in diethyl ether/water. The organic extracts were washed twice with water, dried over magnesium sulphate, filtered and evaporated. In order to separate triphenylphosphine oxide, the residue was dissolved in ethyl acetate and the solution was diluted with petroleum ether, filtered and evaporated. Chromatographic separation of the resulting, yellowish oil (13.7 g) on silica gel with ethyl acetate/petroleum ether (vol. 5:95) gave 10.5 g (96%) of p-[trans-4-(3-methoxy-2-propenyl)cyclohexyl]benzonitrile as a colourless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH3:20])[CH:14]=1>>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:14][C:15]=1[CH3:20]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1cc(Br)ccc1O
Product: Cc1cc(-c2ccc(C#N)cc2)ccc1O
Yield: 50 %

Procedure:
4-Cyanophenylboronic acid and 4-bromo-2-methylphenol were processed as described in Example 167A to provide the title compound (50% yield). 1HNMR (300 MHz, CDCl3) δ2.40 (s, 3H), 4.85 (bs, 1H), 6.83-7.65 (m, 7H); MS (CDI) m/z 210 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH2:18][C@@H:17]1[C:32]([O:34]C)=[O:33].[OH-].[Na+].[ClH:38]>CO.O>[ClH:38].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH2:18][C@@H:17]1[C:32]([OH:34])=[O:33]
Reactant: COC(=O)[C@H]1CN(CCSc2ccccc2F)CC[C@H]1CCCc1ccnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CCSc4ccccc4F)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A mixture of 0.12 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(2-fluorophenylthio)ethyl]piperidine-3-carboxylate and 0.6 cm3 of N aqueous sodium hydroxide in 1.8 cm3 of methanol was stirred for 20 hours at a temperature in the region of 60° C. The reaction mixture was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was taken up in 5 cm3 of water and acidified with 1 cm3 of 2N aqueous hydrochloric acid. The mixture was again evaporated under the same conditions as above and then the new residue was triturated in 5 cm3 of a dichloromethane/methanol (90/10 by volume) mixture. After filtering and evaporating the filtrate under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained was triturated in 3 cm3 of diisopropyl ether. The insoluble material was filtered off, washed with 2 times 1 cm3 of diisopropyl ether, and dried in the air. 0.14 g of (3R,4R)-4-(3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(2-fluorophenylthio)ethyl]piperidine-3-carboxylic acid hydrochloride was obtained in the form of a solid with a beige color which melts with softening at approximately 148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:13]#N)[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C1C=CC(C2(C=[O:29])CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:13]=[O:29])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(c2cccc(Cl)c2)CCCC1
Reactant: O=CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Product: O=CC1(c2cccc(Cl)c2)CCCC1

Procedure:
1-(3-Chlorophenyl)cyclopentanecarbaldehyde (495) was synthesized from 1-(3-chlorophenyl)cyclopentanecarbonitrile (494) following the procedure described for 1-(4-trifluoromethyl-phenyl)-cyclopentanecarbaldehyde (238).
Reaction SMILES: BrC[C:3]1([CH3:17])[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([F:16])=[CH:9][CH:4]1[C:5]([O:7]C)=[O:6]>O1CCOCC1.O>[F:16][C:10]1[CH:9]=[C:4]2[C:3]([CH2:17][O:7][C:5]2=[O:6])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=1
Reactant: COC(=O)C1C=C(F)C=C([N+](=O)[O-])C1(C)CBr
Solvent: O
Solvent: C1COCCO1
Product: O=C1OCc2c1cc(F)cc2[N+](=O)[O-]
Yield: 79.2 %

Procedure:
A mixture of methyl 5-fluoro-2-methyl-3-nitrobenzoate (28 g, 130.5 mmol), NBS (27.8 g, 156.6 mmol) and BPO (3.13 g, 13.1 mmol) in CCl4 (400 mL) was heated to reflux overnight. TLC (petroleum ether/EtOAc=15:1) showed the starting material was consumed completely. Water (200 mL) was added and CCl4 was removed under reduced pressure. The residue was extracted with DCM (200 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated to give crude methyl 2-(bromomethyl)-5-fluoro-2-methyl-3-nitrobenzoate (36 g, yield 94%) as a brown oil. A mixture of methyl 2-(bromomethyl)-5-fluoro-2-methyl-3-nitrobenzoate (36 g, 123 mmol) in 1,4-dioxane (250 mL) and water (62.5 mL) was heated to reflux for 4 days. TLC (petroleum ether/EtOAc=15:1) showed the starting material was consumed completely. Dioxane was removed under reduced pressure. The residue was extracted with EtOAc (300 mL×4). The combined organic layers were washed with brine, dried over Na2SO4, concentrated to give crude product. The crude product was purified by gel chromatography (petroleum ether to petroleum ether/EtOAc=5:1) to give 6-fluoro-4-nitroisobenzofuran-1(3 H)-one (19.2 g, yield 79%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 5.74 (s, 2H), 7.97-7.98 (dd, 1H), 8.24-8.27 (dd, 1H); LC-MS (ESI) m/z: 198 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC1C=CC(O[CH2:20][C:21]#[N:22])=CC=1.CC(C)([O-])C.[K+].Cl>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][C:9]=1[CH2:20][C:21]#[N:22])([O-:3])=[O:2]
Reactant: N#CCOc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1cc(C(F)(F)F)ccc1[N+](=O)[O-]
Temperature: -10 °C

Procedure:
A mixture of 4-Nitrobenzotrifluoride (25.0 g, 131 mmol) and 4-chlorophenoxyacetonitrile (24.1 g, 144 mmol) in dry DMF (200 mL) was added dropwise over 1 h to a stirred solution of potassium tert-butoxide (32.3 g, 288 mmol) in dry DMF (200 mL) at −10° C. After complete addition the resulting purple solution was maintained at −10° C. for 3 h then poured into a mixture of ice water (200 mL) and 5 N aqueous HCl (200 mL). The resulting mixture was extracted with dichloromethane (3×300 mL). The combined extracts were washed with 10% aqueous NaOH, 5 N HCl, brine, dried over sodium sulfate, and concentrated in vacuo to give the crude (2-nitro-5-trifluoromethylphenyl) acetonitrile. The crude (2-nitro-5-trifluoromethylphenyl) acetonitrile (24.6 g, 107 mmol) was dissolved in 9:1 EtOH:H2O (300 mL) and glacial acetic acid (3.0 mL). This mixture was hydrogenated over 10% Pd/C (10.0 g) at 50 psi for 16 h at room temperature. The reaction was filtered through celite and evaporated in vacuo. The residue was partitioned between saturated aqueous sodium carbonate and dichloromethane (2×200 mL) and the combined organic extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (hexanes/ethyl acetate, 20:1, 9:1, 5:1) to afford 12.9 g (65% yield) of 5-trifluoromethyl-1H-indole as a yellow solid: 1H NMR (400 MHz, CDCl3) 8.34, (1H, br s), 7.95 (1H, s), 7.45 (2H, m), 7.32 (1H, m), 6.65 (1H, m); MS m/e 184 (M−H)−. Anal calcd. for C9H6F3N.0.15 H2O: C, 57.55; H, 3.38; N, 7.46. Found: C, 57.25; H, 2.98; N, 7.29.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Solvent: C1COCCO1
Product: CN1CCN(C(=O)Nc2cc(CN3C(=O)N(c4ccc(C(C)(C)C)cc4)C(=O)C3(C)C)ccn2)CC1

Procedure:
A solution of 100 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9 in 2 mL of dioxane and 31 μl of N-methylpiperazine is heated by microwave at 130° C. for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by HPLC (gradient: water/acetonitrile containing 0.1% formic acid) to give 94 mg of N-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-4-methylpiperazine-1-carboxamide, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[N:10]=[CH:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]=2[CH:6]=[CH:5][C:4]=1[N+:19]([O-])=O)[CH3:2]>CO.[Pd]>[NH2:19][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH:9]=[N:10][C:11]=2[C:3]=1[CH2:1][CH3:2]
Reactant: CCc1c([N+](=O)[O-])ccc2c1ncn2C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCc1c(N)ccc2c1ncn2C(=O)OC(C)(C)C
Reaction time: 6 h
Yield: 74.3 %

Procedure:
To a solution of tert-butyl 4-ethyl-5-nitro-1H-benzo[d]imidazole-1-carboxylate (20.0 g, 0.07 mol) in dry MeOH (500 mL) was added Pd/C (1.5 g). The suspension was then stirred under hydrogen (3 kg pressure) for 6 h. After completion, the reaction mixture was filtered through a celite pad and concentrated to give tert-butyl 5-amino-4-ethyl-1H-benzo[d]imidazole-1-carboxylate (13.6 g, 76% yield). The crude product was used for the next step without further purification.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:25])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[C:12]([C:10]1[N:11]=[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])[C:7]([OH:25])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[C:9]=12)#[N:13]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(F)cc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccn(Cc3ccc(F)cc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 7-cyano-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 369 (M+H)+.
Reaction SMILES: [Br:1][CH:2]([Br:6])[C:3]([OH:5])=[O:4].O[N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[Br:1][CH:2]([Br:6])[C:3]([O:5][N:8]1[C:9](=[O:18])[C:10]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]2[C:12]1=[O:13])=[O:4]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C(O)C(Br)Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(ON1C(=O)c2ccccc2C1=O)C(Br)Br

Procedure:
Dibromoacetic acid (0.1 mmole) and N-hydroxyphthalimide (0.1 mmole) are mixed and coupled in THF in the presence of DCC for 2 hours. The product, (N-dibromoacetoxyphthalimide) is isolated by filtration and dried. Radical-induced dehalogenation (0.1 mmole scale) using the general method with tributyltin deuteride furnished the N-deuterioacetoxyphthalimide with two atoms of deuterium. The N-ditritioacetoxyphthalimide can be prepared the same way.
Reaction SMILES: [Na+].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH2:16][S:17]([O-:20])(=O)=[O:18])[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C)C=O.C(Cl)(=O)C([Cl:29])=O>C1COCC1.C(OCC)C>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH2:16][S:17]([Cl:29])(=[O:20])=[O:18])[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)([O-])Cc1cccc(OCc2ccccc2)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=S(=O)(Cl)Cc1cccc(OCc2ccccc2)c1
Reaction time: 0.25 h

Procedure:
Under inert gas, 2.36 g of (3-benzyloxyphenyl)methanesulfonic acid sodium salt and 0.61 ml of N,N-dimethylformamide were initially charged in 45 ml of THF, then, at a temperature of −20° C., 4.1.73 ml of oxalyl chloride were added dropwise and the reaction solution was allowed to come to 0° C. within 15 minutes. The reaction solution was diluted with 100 ml of diethyl ether and washed with water, dilute aqueous sodium hydrogencarbonate solution and saturated sodium chloride solution. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. The residue (2.30 g) was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].Cl.[CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19]Cl)([CH3:16])[CH3:15].[H-].[Na+]>CN(C)C=O>[CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5](=[O:12])[C:6]1=[O:11])([CH3:16])[CH3:15]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(CCN1C(=O)C(=O)c2cc(F)ccc21)C(C)C
Temperature: 80 °C
Yield: 85.1 %

Procedure:
To a suspension of 3.30 g of 5-fluoroisatin and 4.00 g of 2-diisopropylaminoethyl chloride hydrochloride in 75 ml of dry N,N-dimethylformamide was added 1.60 g of sodium hydride (60% dispersion in mineral oil) with stirring under ice-cooling. The mixture was stirred for 30 minutes at room temperature and then heated at 80° C. for 17 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with benzene, and the benzene layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane-petroleum benzine (boiling point range of 50°-80° C., and containing 60-70% hexane; distributed by Wako Pure Chemical Industries, LTD) to obtain 4.97 g of 1-(2-diisopropylaminoethyl)-5-fluoroisatin having a melting point of 100°-102° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:15][O:16][C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:15][O:16][C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:12]([C:9]2[CH:10]=[CH:11][C:5]3[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=3[CH:8]=2)=[O:14])[CH2:21][CH2:20]1)=[O:18]
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](NC(=O)c2ccc3c(c2)NC(=O)CS3)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (116 mg, 0.50 mmol, 1.0 eq) is added at room temperature to a stirred solution of trans-4-amino-cyclohexanecarboxylic acid methyl ester (80 mg, 0.50 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed by 1-hydroxybenzotriazole (74 mg, 0.55 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (107 mg, 0.56 mmol, 1.15 eq) and N,N-diisopropylethylamine (192 μL, 1.12 mmol, 2.25 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford trans-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-cyclohexanecarboxylic acid methyl ester as an off-white solid (127 mg, 66% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6]([CH2:8][C:9]([OH:11])=O)=[O:7])=[CH:2]1.[NH2:12][CH:13]1[C:27](=[O:28])[N:15]2[C:16]([C:24]([OH:26])=[O:25])=[C:17]([CH2:20][S:21][CH2:22][CH3:23])[CH2:18][S:19][C@H:14]12>>[S:1]1[CH:5]=[CH:4][C:3]([S:6]([CH2:8][C:9]([NH:12][CH:13]2[C:27](=[O:28])[N:15]3[C:16]([C:24]([OH:26])=[O:25])=[C:17]([CH2:20][S:21][CH2:22][CH3:23])[CH2:18][S:19][C@H:14]23)=[O:11])=[O:7])=[CH:2]1
Reactant: O=C(O)CS(=O)c1ccsc1
Reactant: CCSCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: CCSCC1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)c3ccsc3)[C@H]2SC1

Procedure:
380 mg. of 3-thienylsulfinylacetic acid of the R form and 7-amino-3ethylthiomethyl-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 116 mg. of 7-(3-thienylsulfinylacetamido)-3-ethylthiomethyl-3-cephem-4-carboxylic acid of the R form were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7](=O)[NH:6][C:5]([NH2:9])=[N:4][CH:3]=1.O=P(Cl)(Cl)[Cl:12]>>[Cl:12][C:7]1[C:2]([CH3:1])=[CH:3][N:4]=[C:5]([NH2:9])[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cnc(N)[nH]c1=O
Product: Cc1cnc(N)nc1Cl
Yield: 29 %

Procedure:
A mixture of 5-methylisocytosine (3 g, 24.0 mmol) and POCl3 (20 mL) was refluxed for 45 minutes. Excess of POCl3 was removed under reduced pressure and the residue was poured over ice. The resulting mixture was made basic with ammonia at 10° C. The precipitate was filtrated and crystallized from ethanol to give 4-chloro-2-amino-5-methylpyrimidine (1 g 29.0% yield). 1H NMR (400 MHz, DMSO): δ 8.11 (s, 1H), 6.81 (br s, 2 H), 2.04 (s, 3H).