Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([O:14][P:15]([O-:19])[O:16][CH2:17][CH3:18])[CH3:13].S(=O)(=O)(O)O.[CH2:25](OCOCC)C>O>[CH2:12]([O:14][P:15]([CH2:25][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])(=[O:19])[O:16][CH2:17][CH3:18])[CH3:13]
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCOCOCC
Reactant: CCOP([O-])OCC
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOP(=O)(CNc1ccc(Cl)cc1[N+](=O)[O-])OCC
Temperature: 95 °C
Yield: 94.9 %

Procedure:
With stirring and under a nitrogen atmosphere 4-chloro-2-nitroaniline (5 g, 28.9 mmole) was dissolved in diethylphosphite (21.44 g, 155 mmole), followed by the addition of a solution of sulfuric acid (0.1 mL) and water (0.1 mL). Under a continuous flow of nitrogen the solution was heated to 95° C., after which diethoxymethane (9.05 g, 86.8 mmole) was added in a dropwise manner over a period of 1.5 hours while maintaining the temperature between 93°-97° C. Once all the diethoxymethane was added, the reaction was kept at 95°-105° C. for another hour after which the mixture was cooled to 45°-50° C. and cold water (70 mL) was added over 20 minutes. The resulting suspension was filtered, washed first with water (10 mL), then with heptane (10 mL). The obtained orange solid was dried at 30°-40° C. for 16 hours to yield 8.85 g (95%) of the title compound, mp 94°-5° C.
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:8]([O:14][CH3:15])[O:9][CH:10]([O:12][CH3:13])[CH:11]=2)=[CH:3][CH:2]=1.C1(C2C=COC=2)C=CC=CC=1>>[CH3:15][O:14][CH:8]1[C:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)=[CH:11][CH:10]([O:12][CH3:13])[O:9]1
Reactant: COC1C=C(c2ccc(-c3ccccc3)cc2)C(OC)O1
Agent: c1ccc(-c2ccoc2)cc1
Product: COC1C=C(c2ccccc2)C(OC)O1
Yield: 82 %

Procedure:
According to the procedure described in Example 1(a) for the preparation of 3-biphenyl-4-yl-2,5-dihydro-2,5-dimethoxyfuran, 3-phenylfuran (see Pridgen, L. N.; Jones, S. S. J. Org. Chem. 1982, 47, 1590-1592 and Yang, Y.; Wong, H. N. C. Tetrahedron 1994, 32, 9583-9608; 848 mg, 5.89 mmol) provided 1.00 g (82%) of 2,5-dihydro-2,5-dimethoxy-3-phenylfuran as a yellow oil, which was an approximately 80:20 mixture of diastereomers by 1H NMR and used without fuirther purification. 1H NMR (CDCl3): δ 7.64-7.52 (m, 2H), 7.44-7.30 (m, 3H), 6.36-6.30 (m, 0.9H, major+minor isomer), 6.28 (dd, 0.1H, minor isomer, J=1.2, 3.7 Hz), 6.04-6.00 (m, 0.9H, major+minor isomer), 5.70 (d, 0.8H, major isomer, J=1.2 Hz), 3.52 (s, 2.2H, major isomer), 3.46 (s, 0.60H, minor isomer), 3.43 (s, 2.2H, major isomer), 3.40 (s, 0.60H, minor isomer); Anal. Calculated for Cl2H14 03.0.04 Br2 : C, 67.78; H, 6.64. Found: C, 67.79; H, 6.45.
Reaction SMILES: F[C:2]([F:14])(F)[C:3]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1)=[O:4].N=C=N.Cl.[NH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].CCN(CC)CC>C(Cl)Cl>[O:22]=[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][NH:19][C:10]([C:8]1[S:9][C:5]([C:3](=[O:4])[CH2:2][F:14])=[CH:6][CH:7]=1)=[O:12]
Reactant: NCC(=O)c1ccccc1
Reactant: O=C(O)c1ccc(C(=O)C(F)(F)F)s1
Agent: Cl
Agent: N=C=N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNC(=O)c1ccc(C(=O)CF)s1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 1, A1 in DCM was added Pol-supported carbodiimide (2 eq) and the suspension was stirred at RT for 30 min. A solution of 2-aminoacetophenone HCl (1.1 eq) and Et3N (1.1 eq) in DCM was added and the resulting suspension was stirred at RT overnight. The resin was filtered, washed with DCM, and the filtrate was evaporated at reduced pressure. Purification by flash chromatography on silica gel eluting with DCM gave the title compound as a solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:19])[C:14]=1[O:15][C:16](=[O:18])[CH3:17])[C:9](O)=[O:10]>>[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:19])[C:14]=1[O:15][C:16](=[O:18])[CH3:17])[C:9]([Cl:3])=[O:10]
Reactant: CC(=O)Oc1c(C)cc(C(=O)O)cc1C
Reactant: O=S(Cl)Cl
Product: CC(=O)Oc1c(C)cc(C(=O)Cl)cc1C
Temperature: 25 °C

Procedure:
To 21 ml of thionyl chloride was suspended 9.3 g/45 mmol of 3,5-dimethyl-4-acetoxybenzoic acid, and the suspension was refluxed under heat for 90 minutes. After cooling to room temperature, excessive thionyl chloride was distilled off under reduced pressure to obtain 9.9 g of the desired 3,5-dimethyl-4-acetoxybenzoyl chloride.
Reaction SMILES: [CH2:1]([CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=2)[NH:17]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+:29]>C(O)C>[CH2:1]([CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][C:20]([C:25]([O-:27])=[O:26])=[CH:21][CH:22]=2)[NH:17]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Na+:29]
Reactant: CCCCCCCCCCCCCCCC1Cc2ccc(C(=O)O)cc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCC1Cc2ccc(C(=O)[O-])cc2N1

Procedure:
(RS)-2-(n-pentadecyl)indoline-6-carboxylic acid (10.0 g) in hot ethanol (250 ml) was treated with an aqueous sodium hydroxide solution (20 ml, of strength 10% w/v). The mixture was left to cool and a solid precipitated and was collected. The solid was washed with a little water and then acetone and was recrystallised from a mixture of ethanol and water (95:5) to give sodium (RS)-2-(n-pentadecyl)indoline-6-carboxylate (4.9 g), in the form of colourless crystals, m.p. greater than 320° C. (with decomposition).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[CH:14]([C:17]1[C:18]([CH:23]=O)=[N:19][CH:20]=[CH:21][CH:22]=1)([CH3:16])[CH3:15]>>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:23][C:18]1[C:17]([CH:14]([CH3:16])[CH3:15])=[CH:22][CH:21]=[CH:20][N:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)c1cccnc1C=O
Reactant: CC(C)(C)OC(=O)NCCCCN
Product: CC(C)c1cccnc1CNCCCCNC(=O)OC(C)(C)C

Procedure:
A pale yellow oil prepared from (4-amino-butyl)-carbamic acid tert-butyl ester and 3-isopropyl-pyridine-2-carbaldehyde. 1H NMR (CDCl3) δ 1.23 (d, 6H, J=6.6 Hz), 1.43 (s, 9H), 1.53-1.61 (m, 4H), 2.67-2.74 (m, 2H), 3.10-3.21 (m, 3H), 3.94 (s, 2H), 4.73 (s, br. 1H), 7.11-7.17 (m, 1H), 7.54-7.58 (m, 1H), 8.37-7.40 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([Cl:34])[CH:29]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([Cl:34])[CH:29]=3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2ccnc(Cl)c2)n1
Reactant: Clc1cc(Br)ccn1
Product: Cc1cc(-c2ccnc(Cl)c2)cc(C(=O)Nc2ccnc(Cl)c2)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (2-chloro-pyridin-4-yl)-amide in accordance with the general method of example 131, step 2 using 4-Bromo-2-chloropyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=359.1, 361.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13]C)[CH:8]=1)=[O:5].Br>C(O)(=O)C>[F:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5]
Reactant: COc1cc(NC(=O)c2ccc(C(F)(F)F)cc2F)ccn1
Agent: Br
Solvent: CC(=O)O
Product: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1F
Temperature: 100 °C
Reaction time: 6 h
Yield: 76.6 %

Procedure:
To 2-fluoro-N-(2-methoxy-4-pyridyl)-4-(trifluoromethyl)benzamide (1.00 g, 3.18 mmol) in acetic acid (6.0 mL) was added HBr (33% in acetic acid) (3.9 mL of 33% w/v, 15.91 mmol) and the mixture stirred at 100° C. for 6 hours. Additional HBr (2 mL, 33% in acetic acid) was added and the mixture was stirred at room temperature overnight. The mixture was then heated at 100° C. for 2 hours before it was cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with water and brine (2×), dried over sodium sulfate, filtered and concentrated under reduced pressure. The solid was slurried in methyl-tert-butyl ether and filtered to give 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (731 mg, 76%). ESI-MS m/z calc. 301.05. found 301.3 (M+1)+; Retention time: 1.35 minutes (3 minute run). 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 10.70 (s, 1H), 7.96-7.85 (m, 2H), 7.75 (d, J=8.2 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 6.81 (d, J=1.9 Hz, 1H), 6.41 (dd, J=7.2, 2.1 Hz, 1H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][C:19]1[N:20]=[CH:21][CH:22]=[C:23]2[CH:27]=[CH:26][S:25][C:24]=12)=[O:5])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:36])C=1.C([O-])(O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>CCOCC.O>[CH2:1]([O:3][C:4]([O:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([CH2:18][C:19]1[N:20]=[CH:21][CH:22]=[C:23]2[CH:27]=[CH:26][S:25][C:24]=12)=[O:36])=[O:5])[CH3:2]
Reactant: CCOC(=O)OCn1c(SCc2nccc3ccsc23)nc2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)OCn1c(S(=O)Cc2nccc3ccsc23)nc2ccccc21
Reaction time: 1 h

Procedure:
To a solution of 279.6 mg (0.700 mmol) of 1-ethoxycarbonyloxymethyl-2-[(thieno[2, 3-c]pyridin-7-yl)methylthio]benzimidazole (Ib-11) in 30 ml of CHCl, was mixed with 226.5 mg (1.05 mmol) of 80% m-CPBA at -10° to -15° C., and stirred for 1 hr. The mixture was treated with 3 ml of saturated aqueous NaHCO3 and 0.6 ml of 10% aqueous sodium sulfite, and after bringing back to room temperature, the solution was mixed with water and extracted with CHCl3. After drying CHCl3 layer over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, whereby brown viscous liquid was obtained. After silica gel column chromatography, the crystals were dispersed with 3 ml of ether, followed by filtration and washed with ether, whereby 158.0 mg (Yield : 54.3%) of the objective compound (Ic-17), 1-ethoxycarbonyloxymethyl-2-[(thieno[2, 3-c]pyridin-7-yl]methylsulfinyl]benzimidazole was obtained as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:8][C:9]=1[NH:10]2.C(Cl)CCl.C1C=CC2N(O)N=[N:33]C=2C=1.[OH-].[NH4+]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:16])[NH2:33])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:8][C:9]=1[NH:10]2
Reactant: On1nnc2ccccc21
Reactant: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)ccc(Br)c23)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)C1CCc2c([nH]c3c(C(N)=O)ccc(Br)c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
A suspension of 5-bromo-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (Intermediate 46-1, 12.28 g, 33.5 mmol), EDC (7.71 g, 40.2 mmol), and HOBT (6.16 g, 40.2 mmol) in THF-DCM (4:1, 335 mL) was treated with 28% aqueous ammonium hydroxide (7.83 mL, 201 mmol), and the resulting suspension was stirred at rt overnight. The mixture was concentrated and the residue was suspended in water. The precipitate was collected by filtration, washed with water and EtOAc and dried to give ethyl 5-bromo-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate (8.92 g). The filtrate was concentrated and the residue was suspended in methanol. A solid was collected by filtration, washed with methanol and air dried to afford additional product (0.39 g) for a total of 9.31 g (76%). 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H) 8.02 (br. s., 1H) 7.43 (d, J=8.13 Hz, 1H) 7.39 (br. s., 1H) 7.14 (d, J=8.13 Hz, 1H) 4.02-4.17 (m, 2H) 3.07-3.18 (m, 1H) 2.97-3.06 (m, 1H) 2.86-2.98 (m, 2H) 2.77-2.86 (m, 1H) 2.09-2.19 (m, 1H) 1.72-1.86 (m, 1H) 1.20 (t, J=7.14 Hz, 3H). Mass spectrum m/z 365, 367 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][C@@:8]2([CH3:28])[N:12]3[C:13]([C:16]([OH:18])=O)=[CH:14][N:15]=[C:11]3[N:10]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)[C:9]2=[O:27])=[CH:5][CH:4]=1)#[N:2].[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C:41]([NH2:56])([C:44](=[O:55])[NH:45][C:46]2([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)[CH2:48][CH2:47]2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C:41]([NH:56][C:16]([C:13]2[N:12]3[C@@:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:30][CH:29]=4)([CH3:28])[C:9](=[O:27])[N:10]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=4)[C:11]3=[N:15][CH:14]=2)=[O:18])([C:44](=[O:55])[NH:45][C:46]2([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)[CH2:48][CH2:47]2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(=O)NC2(c3ccccn3)CC2)CC1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)O)n21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)(C(=O)NC2(c3ccccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 99.2 %

Procedure:
To a mixture of (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (80 mg, 0.18 mmol) and 4-amino-4-(1-pyridin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (74 mg, 0.20 mmol) in DMF (1 mL) was added HATU (76 mg, 0.19 mmol) and diisopropylethylamine (47 mg, 0.36 mmol). The reaction was stirred at room temperature for 7 h. After addition of water (10 mL) the mixture was extracted with EtOAc (2×15 mL). The organic layer was washed with brine and dried over Na2SO4. The solvent was removed in vacuo and the remaining residue was purified via reverse phase HPLC to afford 4-{[(R)-5-(4-cyanobenzyl)-7-(3,5-dichlorophenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-4-(1-pyridin-2-yl-cyclopropyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (140 mg), m/z 784.9 [M+1]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][PH:6]([C:8](OCC)(OCC)[CH3:9])=[O:7])[CH3:4].BrC[CH:18]1[CH2:23][CH2:22]C=[CH:20][CH2:19]1.O>O1CCCC1>[CH2:3]([O:5][PH:6]([CH2:8][CH:9]1[CH2:22][CH2:23][CH:18]=[CH:19][CH2:20]1)=[O:7])[CH3:4]
Reactant: CCO[PH](=O)C(C)(OCC)OCC
Reactant: BrCC1CC=CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCO[PH](=O)CC1CC=CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen, 8.7 g of sodium hydride (99%) dissolved in 600 ml of tetrahydrofuran are cooled to 15° and 75 g of 1,1-diethoxyethylphosphinic acid ethyl ester in 100 ml of tetrahydrofuran are added thereto in the course of 1 hour, the reaction temperature being maintained at less than 25°. The resulting suspension is stirred at room temperature for 2 hours and then a solution of 57.2 g of bromomethylcyclohex-3-ene in 100 ml of anhydrous tetrahydrofuran is added thereto in the course of 30 minutes. The mixture is heated at reflux for 24 hours, then cooled to 0°; 10 ml of water are added and the solvent is removed. The residue is dissolved in dichloromethane, washed twice with water, dried over sodium sulfate, concentrated to dryness by evaporation and distilled. The resulting 1,1-diethoxyethyl-(cyclohex-3-ene)-phosphinic acid ethyl ester is dissolved in 300 ml of dichloromethane that contains 10% by volume ethanol and left to stand at room temperature for 24 hours. Removal of the solvent and distillation yield cyclohex-3-enylmethylphosphinic acid ethyl ester;, 31P-NMR (CDCl3): δ=37.1 (s).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[CH:9][CH:8]=1.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[C:23]([C:12]1[CH:13]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])[C:15]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:6][CH3:5])[CH:16]=2)(=[O:25])[CH3:24]
Reactant: COc1ccc2cccc(CCNC(C)=O)c2c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc2cc(C(C)=O)cc(CCNC(C)=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.45 mol (60 g) of aluminium chloride are added at 0° C. to a solution of 0.16 mol (40 g) of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide (described in Patent EP 447 285) in 350 ml of dichloromethane. 0.21 mol (15.3 ml) of acetyl chloride is then added dropwise at 0° C. The reaction medium is stirred at room temperature for 1 hour and then poured onto ice. The organic phase is decanted and concentrated to yield the expected compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[S:20]1[CH:24]=[C:23]([C:25]([O-])=[O:26])[N:22]=[C:21]1[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[Cl:17][C:11]1[C:10]([CH3:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:25]([C:23]3[N:22]=[C:21]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[S:20][CH:24]=3)=[O:26])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: CCOC(=O)c1nc(C(=O)[O-])cs1
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Product: CCOC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3C)n2)cs1
Yield: 16.1 %

Procedure:
(S)-ethyl 4-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazole-2-carboxylate was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (400 mg, 1.165 mmol) and 2,4-thiazoledicarboxylic acid, 2-ethyl ester 234 mg, 1.165 mmol). The product was purified by Flash-chromatography. Yield 16.1%. 1H-NMR (400 MHz; CDCl3): δ 1.31 (d, 3H), 1.44 (t, 3H), 2.55 (s, 3H), 4.31-4-46 (m, 2H), 4.50 (q, 2H), 4.56-4.68 (m, 1H), 6.42 (d, 1H), 7.50 (d, 1H), 7.54-7.61 (m, 2H), 7.80 (bd, 1H), 8.34 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:20])=O>>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: O=C(O)c1ccc(C(F)(F)C(F)(F)F)cc1F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(C(F)(F)C(F)(F)F)cc1F
Temperature: 60 °C
Reaction time: 22 h
Yield: 93.4 %

Procedure:
To 2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoic acid (1 g, 3.87 mmol) was added thionyl chloride (3.67 mL, 50.36 mmol) and the reaction was stirred at 60° C. for 22 hours. Excess thionyl chloride was removed in vacuo to yield 2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoyl chloride (1 g, 93%) as a viscous yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([O:30]CC(Cl)(Cl)Cl)=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Cl-].[NH4+]>O1CCCC1.O.[Zn]>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([OH:30])=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)c3csc(N)n3)[C@H]2SC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
To a solution of 7-[2-(2-aminothiazol-4-yl)-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (0.5 g) in tetrahydrofuran (2.5 ml) were added zinc powder (0.5 g) and an aqueous ammonium chloride (0.3 g) in water (4 ml) at ambient temperature with stirring, and the stirring was continued at ambient temperature for 30 minutes. After the zinc powder was removed by filtration, the filtrate was adjusted to pH 2.3 with 10% hydrochloric acid and then extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride, followed by drying over magnesium sulfate. The solution was evaporated under reduced pressure, and the residue was triturated with diisopropyl ether to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (0.11 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[Br:11]Br.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:11][C:6]1[CH:5]=[C:4]([CH3:9])[C:3]([OH:10])=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: BrBr
Reactant: Cc1ccc(C)c(O)c1C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Br)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2,3,6-trimethylphenol (40 g; 0.294 mol) in DCM (600 ml) at ambient temperature was added a solution of bromine (16.6 ml; 0.294 mol) in DCM (300 ml) dropwise over 30 mins. Reaction stirred for a further 5 hrs at ambient temperature. A solution of 1M sodium sulfite (300 ml) was added. The layers were separated and the aq. layer extracted with DCM (150 ml). Organics combined, washed with half sat. brine (300 ml), dried (anh. MgSO4), filtered and the solvent evaporated to give a white solid (66.2 g; 105% Th.). 1H NMR (300 MHz, CDCl3), δ/ppm; 2.19 (3H, s, Ar—CH3), 2.22 (3H, s, Ar—CH3), 2.34 (3H, s, Ar—CH3), 7.18 (1H, s, Ar—H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][CH3:12].N1C=CC=CC=1.[Cl:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Cl:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29]([NH:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][CH3:12])(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)CCCCCl
Reactant: CCOC(=O)c1cc(N)c2[nH]cc(CC)c2c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(NS(=O)(=O)CCCCCl)c2[nH]cc(CC)c2c1
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a solution of ethyl 7-amino-3-ethyl-1H-indole-5-carboxylate (D222) (150 mg, 0.65 mmol, 1 equiv) in CH2Cl2 (10 ml) at room temperature were added pyridine (115 μl, 1.42 mmol, 2.2 equiv), 4-chloro-1-butanesulfonyl chloride (D20) (259 mg, 1.36 mmol, 2.1 equiv) and DMAP (8 mg, 0.065 mmol, 0.1 equiv) and the resulting mixture was stirred for 1 h then diluted with AcOEt and washed with a 2N aqueous HCl solution and brine, then dried over MgSO4 and concentrated in vacuo to give ethyl 7-{[(4-chlorobutyl)sulfonyl]amino}-3-ethyl-1H-indole-5-carboxylate (D242) (230 mg, 92%) as a purple oil which was used in the next step without further purification. [M+H]+=387.3, RT=3.35 min.