Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:12](=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CCOCC>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[CH:12]=[O:20])=[CH:24][CH:23]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium carbonate (33.17 g) and DMF (180 ml) were added to salicylaldehyde (24.42 g), and the mixture was stirred at room temperature for 10 minutes. Then a mixture of 4-chlorobenzyl chloride (33.82 g) and DMF (20 ml) was added at room temperature over 15 minutes, and the mixture was stirred at 60° C. for 3 hours. After completion of the reaction, ether (500 ml) was added, and the mixture was washed with water (400 ml) three times, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude 2-(4-chlorobenzyloxy)benzaldehyde. The ethanol (200 ml) and hydroxylamine hydrochloride (27.80 g) was added to the crude product, and the mixture was stirred at 80° C. overnight. After completion of the reaction, water (400 ml) was added, and the mixture was extracted with methylene chloride (200 ml) three times, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was recrystallized from ethyl acetate/n-hexane to give 2-(4-chlorobenzyloxy)benzaldehyde oxime (32.06 g) as colorless crystals. mp. 122.5°-123.5° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10](Br)=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH:21]([CH3:26])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:10]2[C:4]3[O:3][C:2]([CH3:1])=[CH:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)[CH:21]([CH3:26])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: Cc1cc2cccc(Br)c2o1
Product: Cc1cc2cccc(C3(O)CCN(Cc4ccccc4)CC3C)c2o1
Yield: 66.7 %

Procedure:
Beginning with 1.0 gm (4.74 mMol) 2-methyl-7-bromobenzofuran and 1.01 gm (4.98 mMol) 1-benzyl-3-methyl-4-oxopiperidine, 1.06 gm of the desired compound was prepared as an orange oil essentially as described in EXAMPLE 19.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7](Br)[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].C([Li])CCC.[C:17]1(=[O:27])[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12>O1CCCC1.[Cl-].[NH4+]>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[C:17]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])=[O:27])[CH:2]=[CH2:3]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: C=CCOc1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCOc1cccc(C(=O)c2ccccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To a solution of 3-(allyloxy)bromobenzene (15.0 g, 70.5 mmol) in tetrahydrofuran (750 mL) at −70° C. was added 1.6M n-butyllithium (44.1 mL, 70.5 mmol). After stirring for 1 hour, a solution of phthalic anhydride (11.4 g, 77.0 mmol) in tetrahydrofuran (100 mL, previously cooled to −70° C.) was added over 1 hour. The mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was diluted with saturated ammonium chloride solution and extracted with diethyl ether. The organic layer was washed three times with 1N sodium hydroxide solution and the combined aqueous layers were back-extracted with a fresh portion of diethyl ether. The aqueous layer was adjusted to pH˜3 with aqueous hydrochloric acid and extracted three times with fresh diethyl ether. The combined organic layers were washed once with water, once with saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo to reveal an off-white solid. Recrystallization from ether/hexane provided 10.3 g (52%) of the title intermediate as a white crystalline material: mp 109° C.; NMR (CDCl3) 8.20 (d, J=8 Hz, 1H), 7.65 (t, J=8 Hz, 1H), 7.60 (t, J=8 Hz, 1H), 7.30-7.45 (m, 3H), 7.28 (d, J=8 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 6.02 (m, 1H), 5.35 (d, J=16 Hz, 1H), 5.30 (d, J=11 Hz, 1H), 4.55 (d, J=6 Hz, 2H); MS-FD m/e 283 (p+1, 27), 282 (p, 100).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7][NH:8]C(OC(C)(C)C)=O)(=[O:4])=[O:3].C(O)C.[ClH:19]>CO>[ClH:19].[NH2:8][CH2:7][CH2:6][NH:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NCCNS(C)(=O)=O
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CS(=O)(=O)NCCN
Yield: 79.3 %

Procedure:
In a 500 ml reaction flask, tert-butyl 2-methylsulfonamidoethylaminoformate (25 g) and 350 ml of a mixture of ethanol and methanol were added. The mixture was stirred by an electromagnetic stirrer, fed with dry hydrogen chloride gas for 3 h, stirred at room temperature overnight, concentrated under a reduced pressure to a small volume, subjected to suction filtration to obtain 14.6 g of brown-gray powdery solid, yield 79.3%.
Reaction SMILES: CO[C:3](=[O:15])[CH:4](Br)[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[CH3:16][NH:17][CH2:18][CH2:19][NH:20][CH3:21]>C(O)C>[CH3:16][N:17]1[CH2:18][CH2:19][N:20]([CH3:21])[CH:4]([C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)[C:3]1=[O:15]
Reactant: COC(=O)C(Br)c1ccc([N+](=O)[O-])cc1
Reactant: CNCCNC
Solvent: CCO
Product: CN1CCN(C)C(c2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
Bromo-(4-nitro-phenyl)-acetic acid methyl ester (547 mg, 2.00 mmol) was dissolved in ethanol (5.50 mL) and N,N′-dimethyl-ethane-1,2-diamine (1.07 mL, 9.98 mmol) was added. The reaction was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-10% MeOH/DCM as the eluting solvent to obtain 1,4-dimethyl-3-(4-nitro-phenyl)-piperazin-2-one as an orange solid (450 mg, 90%). m.p.=99-102° C.; LCMS (m/e) 250 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.19 (d, 2H, J=8.6 Hz), 7.61 (d, 2H, J=8.6 Hz), 3.83 (s, 1H), 3.81-3.70 (m, 1H), 3.26-3.18 (m, 1H), 3.08-3.00 (m, 1H), 2.97 (s, 3H), 2.78-2.68 (m, 1H), 2.18 (s, 3H).
Reaction SMILES: [Br-].[CH3:2]OC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]1[CH:32]=[C:33]([C@H:37]2[CH2:42][CH2:41][C@H:40]([CH:43]=O)[CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1.O>C1COCC1.C1(C)C=CC=CC=1>[F:30][C:31]1[CH:32]=[C:33]([C@H:37]2[CH2:42][CH2:41][C@H:40]([CH:43]=[CH2:2])[CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1
Reactant: O=C[C@H]1CC[C@H](c2cccc(F)c2)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: C=C[C@H]1CC[C@H](c2cccc(F)c2)CC1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
Well-dried methoxymethyltriphenylphosphonium bromide (26.0 g) and THF (200 ml) were mixed under a nitrogen atmosphere, and cooled to −30° C. Then, potassium t-butoxide (t-BuOK; 8.2 g) was put in thereto in twice in the temperature range of −30° C. to 20° C. After the mixture had been stirred at −20° C. for 30 minutes, the compound (37) (10.0 g) dissolved in THF (50 ml) was added dropwise thereto in the temperature range of −30° C. to −20° C. After the reaction mixture had been stirred at −10° C. for 30 minutes, it was poured into a mixture of water (200 ml) and toluene (200 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The eluent obtained was concentrated under reduced pressure, giving 9.0 g of 1-(3-fluorophenyl)-trans-4-ethenylcyclohexane (38). The yield based on the compound (37) was 90.9%.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:17]Br.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:12][C:11]1[C:2]([Cl:1])=[C:3]([CH:8]=[CH:9][C:10]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:4]([O:6][CH3:7])=[O:5]
Reactant: BrBr
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
12.1 g of methyl 2-chloro-4-methanesulfonyl-3-methylbenzoate was dissolved in 250 ml of carbon tetrachloride, and the solution was refluxed under stirring. Then, 7.5 g of bromine and 1 g of benzoyl peroxide were gradually added thereto over a period of 30 minutes, and the solution was further refluxed for 4 hours under heating. After cooling, 200 ml of chloroform was added thereto, and the mixture was washed with a 5% sodium hydrogensulfite aqueous solution. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product. The crude product was washed with ethyl ether to obtain 13.2 g of crystals of the desired product. Melting point: 77°-78° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[O:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[CH2:35]O.[K+].[Br-].Cl>>[O:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[CH2:35][O:24][C:23]([C:18]1([C:20]([O:22][CH2:35][CH:31]2[CH2:32][CH2:33][CH2:34][O:30]2)=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25]
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: OCC1CCCO1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC1CCCO1)(C(=O)OCC1CCCO1)O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and tetrahydrofuran-2-ylmethanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400 MHz) δ 1.1 (d, J=6.37 Hz, 3H, CH3), 1.43-1.6 (m, 2H, CH2) 1.65-1.8 (m, 4H, CH2), 1.98-2.0 (m, 2H, CH2), 2.6 (m, 1H, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, 1H, CH), 3.57-3.7 (m, 4H, CH2), 4.05 (m, 2H, CH2), 4.2 (m, 2H, CH2), 4.3 (m, 2H, CH2), 5.04 (m, 1H, CH), 6.34 (d, J=3.95 Hz, 1H, OH), 6.84 (dd, J=8.13, 1.32 Hz, 1H, Ar--H), 7.07 (m, 2H, Ar--H), 7.36-7.44 (m, 3H, Ar--H), 7.48 (s, 1H, Ar--H), 8.77 (brs, 1H, NH), 9.2 (brs, 1H, NH); IR (KBr, cm-1) 3400 (OH), 2900 (NH), 1760 (CO); MS m/e 590 (M+H)+ ; Analysis for: C30H36ClNO9 ×HCl: Calc'd: C, 57.51; H, 5.95; N, 2.24; Found: C, 56.37; H, 5.90; N, 2.20.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([NH:7][C:8](=[O:19])OC1C=CC([N+]([O-])=O)=CC=1)[C:5]#[CH:6]>C1COCC1.ClCCl>[CH3:1][N:2]([CH3:3])[C:8]([NH:7][CH2:4][C:5]#[CH:6])=[O:19]
Reactant: CNC
Reactant: C#CCNC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#CCNC(=O)N(C)C
Yield: 79 %

Procedure:
Dimethylamine (3.0 ml of a 2.0M solution in THF, 6.0 mmol) and 4-nitrophenyl prop-2-yn-1-ylcarbamate (800 mg (80% purity), 2.91 mmol) in dichloromethane (7 ml) were stirred at room temperature for 4 hr. then the reaction solution purified by chromatography on silica using ethyl acetate as eluent to give N,N-dimethyl-N′-prop-2-yn-1-ylurea (289 mg, 79%) as a colourless solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C:8]1=[O:20])=[O:6])[CH3:3].C(=O)(O)[O-].[Na+].[CH3:26][CH2:27]OC(C)=O>>[CH2:2]([O:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:9]([CH2:26][CH3:27])[C:8]1=[O:20])=[O:6])[CH3:3]
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: CCOC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C1CCN(Cc2ccccc2)C(CC)C1=O
Reaction time: 2 h

Procedure:
To a stirred suspension of 1-benzyl-3-oxo-piperidine-4-carboxylic acid ethyl ester hydrochloride salt (25 g) in EtOAc (500 mL) was added saturated sodium bicarbonate solution (200 mL) and continued stirring for 2 h. The organic layer was separated, dried over Na2SO4, filtered and concentrated to provide ethyl 1-benzyl-3-oxo-piperidine-4-carboxylic acid ethyl ester (22.00 g). To a solution of ethyl 1-benzyl-3-oxo-piperidine-4-carboxylic acid ethyl ester (22 g, 84.18 mmol) in EtOAc (75 mL) was added (Boc)2O (20.21 g, 92.59 mmol) followed by 10% Pd—C (2.4 g) and the resultant reaction mixture was subjected to hydrogenation at 50 psi of hydrogen for 14 h. The catalyst was filtered by passing through a pad of celite, washed the celite pad with EtOAc (200 mL) and the combined filtrate was concentrated. The residue was purified by flash silica gel column chromatography by eluting with 0.5% ethyl acetate in hexanes to provide ethyl 3-oxo-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (34 g).
Reaction SMILES: [CH3:1]N1CCCC1=O.[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:27]=[C:26]([NH:28][CH2:29][C:30]4[C:35]([F:36])=[CH:34][CH:33]=[C:32]([F:37])[C:31]=4[F:38])[C:25]([C:39]([NH2:41])=[O:40])=[CH:24][N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.CI.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]3[N:27]=[C:26]([NH:28][CH2:29][C:30]4[C:35]([F:36])=[CH:34][CH:33]=[C:32]([F:37])[C:31]=4[F:38])[C:25]([C:39]([NH2:41])=[O:40])=[CH:24][N:23]=3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1
Reactant: NC(=O)c1cnc(Nc2ccc(OC3CCNCC3)cc2)nc1NCc1c(F)ccc(F)c1F
Reactant: CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CN1CCC(Oc2ccc(Nc3ncc(C(N)=O)c(NCc4c(F)ccc(F)c4F)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 10 ml portion of 1-methyl-2-pyrrolidone solution containing 800 mg of 2-{[4-(piperidin-4-yloxy)phenyl]amino}-4-[(2,3,6-trifluorobenzyl)amino]-pyrimidine-5-carboxamide was mixed with 0.12 ml of methyl iodide and 300 mg of potassium carbonate, followed by stirring at room temperature for 1 hour and then at 60° C. for 30 minutes. A 0.1 ml portion of methyl iodide was further added thereto, followed by stirring for 30 minutes. The reaction mixture was cooled down to room temperature, mixed with water and then extracted with an ethyl acetate-THF mixed solvent. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by a silica gel column chromatography (chloroform-methanol-aqueous ammonia) and further recrystallized from ethanol to obtain 197 mg of 2-({4-[(1-methylpiperidin-4-yl)oxy]phenyl}amino)-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamide as colorless crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=[O:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[Mn]([O-])(=O)(=O)=[O:19].[K+].CO>CC(C)=O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:19])=[O:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: CCn1c2ccccc2c2cc(C(=O)O)ccc21
Reaction time: 3 h
Yield: 61.6 %

Procedure:
50 g of N-ethylcarbazole-3-carboxaldehyde was dissolved in 1 L of acetone, and the solution was added with 70.6 g of potassium permanganate under ice cooling, stirred for 3 hours, then added with 100 mL of methanol and filtered. The filtrate was evaporated under reduced pressure, and the residue was dissolved in aqueous sodium hydrogencarbonate. Then, the solution was made acidic by adding concentrated hydrochloric acid, and the deposited precipitates were collected to obtain 33 g of N-ethylcarbazole-3-carboxylic acid.
Reaction SMILES: Cl[CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]=[O:4].[O:15]=[C:16]([CH3:23])/[CH:17]=[CH:18]/[C:19]([O:21][CH3:22])=[O:20]>C(Cl)(Cl)Cl>[CH2:5]([C@H:2]1[C@@H:18]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=[C:16]([CH3:23])[O:15][C:3]1=[O:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: COC(=O)/C=C/C(C)=O
Reactant: CCCCCCCCCCC(Cl)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCC[C@@H]1C(=O)OC(C)=C[C@@H]1C(=O)OC
Yield: 71 %

Procedure:
Prepared according to the general procedure from 2-chlorododecanal and (E)-methyl 4-oxopent-2-enoate using 0.5 mol % 1 as the catalyst in 71% yield as a single diastereomer (white solid). [α]D20 (c 1.20, CHCl3)=+204.8; mp=40-42° C.; 1H NMR (400 MHz, CDCl3) δ 5.09 (dd, 1H, J=6.3, 1.1 Hz), 3.68 (s, 3H), 3.30 (dt, 1H, J=6.3, 1.0 Hz), 2.66 (dd, 1H, J=7.0, 6.3 Hz), 1.90 (t, 3H, J=1.0 Hz), 1.35-1.24 (m, 18H), 0.86 (t, 3H, J=6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 171.4, 169.8, 152.3, 98.4, 52.5, 41.5, 40.6, 32.0, 29.7, 29.7, 29.5, 29.5, 27.3, 27.2, 22.8, 18.9, 14.3; IR (thin film) ν 3062, 2925, 2854, 1777, 1740, 1463, 1436, 1383, 1167, 1142 cm−1; HRMS (ESI) calcd for C18H30O4 [M+Na]+ 333.1996, found 333.2021; >99% ee (3S,4S)-isomer as determined by HPLC(OD-H, 20:1 hexanes/i-PrOH), tr (3S,4S)=6.7 min, tr (3R,4R)=6.0 min.
Reaction SMILES: [F:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][C:7]2[CH2:8][S:9][C@@H:10]3[CH:21]([NH:22]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:20](=[O:42])[N:11]3[C:12]=2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[NH2:22][CH:21]1[C:20](=[O:42])[N:11]2[C:12]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:44][CH:43]=3)[CH2:8][S:9][C@H:10]12
Reactant: CC(C)(C)OC(=O)C1=C(Cc2ccc(F)cc2)CS[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)C1=C(Cc2ccc(F)cc2)CS[C@@H]2C(N)C(=O)N12
Temperature: 25 °C
Yield: 64.7 %

Procedure:
t-Butyl 3-p-fluorobenzyl-7-triphenylmethylamino-3-cephem-4-carboxylate (IX) (72 mg) was dissolved in acetone and the solution cooled to 0°. p-Toluene sulphonic acid (25 mg) in acetone (0.5 ml) was added dropwise over a few minutes and the solution left to warm to room temperature with stirring. After 2.5 hours a solid had formed but t.l.c. still showed some unchanged (IX) to be present. The mixture was again cooled to 0° and a further quantity of p-toluene sulphonic acid (5 mg) in acetone added. After leaving at room temperature for a further 1.5 hours, the white solid was filtered off. This solid was suspended in ethyl acetate and treated with saturated sodium bicarbonate solution. The organic layer was washed with brine, dried and evaporated to give t-butyl 7-amino-3-p-fluorobenzyl-3-cephem-4-carboxylate (XI) (28 mg) shown to be pure by t.l.c. ##SPC16##
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48](O)=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)C(C)C)(C)C.[NH2:60][CH:61]([C:68]1[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=1)[CH2:62][CH2:63][S:64]([NH2:67])(=[O:66])=[O:65]>CN1C(=O)CCC1.CO>[Cl:74][C:71]1[CH:70]=[CH:69][C:68]([CH:61]([NH:60][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:28])([CH3:26])[CH3:27])[CH2:34][CH2:35][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:37][CH2:38]2)=[O:49])[CH2:62][CH2:63][S:64](=[O:65])(=[O:66])[NH2:67])=[CH:73][CH:72]=1
Reactant: NC(CCS(N)(=O)=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CCS(N)(=O)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 33.8 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (30.9 mg, 0.08 mmol) was added to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (28 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.016 mL, 0.09 mmol) in NMP (5 mL) at 22° C. The resulting suspension was stirred at 50° C. for 10 minutes. The mixture was cooled to ambient temperature and 3-amino-3-(4-chlorophenyl)propane-1-sulfonamide (Intermediate 104) (19.27 mg, 0.08 mmol) was added as a solution in NMP (2 mL). The mixture was stirred at 22° C. for 3 days. The mixture was diluted with methanol and loaded onto an SCX column. The crude product was purified by ion exchange chromatography; the desired product was eluted from the column using 2M NH3/MeOH and pure fractions were evaporated to dryness. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% (10:1 MeOH/conc. NH3 (aq)) in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 4-(1-(4-chlorophenyl)-3-sulfamoylpropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (16.00 mg, 34.9%) as a white solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1I>>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[F:17])=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: Fc1ccccc1I
Product: Fc1ccccc1Oc1ccc2c(c1)CCN(C1CCC1)CC2

Procedure:
Example 270 (E270) was prepared from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and 2-fluoro iodobenzene using the method described for Example 128; MS (ES+) m/e 312 [M+H]+.
Reaction SMILES: [ClH:1].[C:2]1([NH:11]C(=O)OC(C)(C)C)[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[CH:5]=[CH:4][N:3]=1>C(Cl)Cl>[ClH:1].[C:2]1([NH2:11])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1nccc2c1CCC2
Agent: Cl
Solvent: ClCCl
Product: Nc1nccc2c1CCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
Anhydrous 1M HCl in DCM (20 mL) was added slowly to the title compound of step 3 (570 mg, 2.43 mmol) in DCM (10 mL) at 0° C. After stirring at rt for 1.5 h, evaporation of the volatile components gave the title compound (400 mg, 96%) as a white solid. 1H NMR (CD3OD, 300 MHz): δ 7.66 (d, J=6.6 Hz, 1H), 6.88 (d, J=6.6 Hz, 1H), 3.04 (t, J=7.8, 7.2 Hz, 2H), 2.86 (t, J=7.8, 7.2 Hz, 2H), 2.17-2.27 (m, 2H). LCMS: 135 (M+1)+
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7]([Cl:10])(=O)=O)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17]>>[CH3:1][C:2]1[S:6][C:5]([S:7][Cl:10])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)s1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1sc(SCl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 25.2 g (0.1 mcl) sample of 5-methyl-2-thienylsulfonyl chloride was added slowly to a solution of 100 cc concentrated sulfuric acid and 100 cc concentrated nitric acid. The resulting mixture was allowed to stir overnight at about 25° C. The reaction mixture was then added to ice water and filtered to give the 5-methyl-4-nitro-2-thienylsulfenyl chloride product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[H][H]>[Pd]>[C:4]([CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)([O:3][CH2:1][CH3:2])=[O:12]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [Pd]
Product: CCOC(=O)C1CCC(O)CC1
Reaction time: 5 h

Procedure:
Into an autoclave is placed ethyl-p-hydroxybenzoate (495 grams) and 5% palladium on carbon (4 grams). The reaction mass is hydrogenated at 150° C. and 50-75 psig hydrogen pressure. After five hours, a sample showed 40% ketone and 44% alcohol having the structure: ##STR24##