Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14]CC)[C:5]1[N:6]=[CH:7][NH:8][C:9]=1[C:10](OC)=[O:11])C.C(O)(=O)C>O>[CH:10]([C:9]1[N:8]=[CH:7][NH:6][C:5]=1[C:4]([O:3][CH3:1])=[O:14])=[O:11]
Reactant: CCOC(OCC)c1nc[nH]c1C(=O)OC
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1[nH]cnc1C=O
Reaction time: 6 h

Procedure:
To a solution of Intermediate 1B (5.65 g, 24.75 mmol) in water (12 mL) was added acetic acid (49 mL, 0.86 mol). The resulting mixture was stirred under nitrogen for 6 hours. The reaction mixture was azeotroped with toluene and dried under vacuum to give the desired aldehyde, Intermediate 1C in quantitative yield as a white solid, which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:10]([OH:12])=O)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[CH2:47]([O:49][C:50]([N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)=[O:51])[CH3:48]>CN(C=O)C.C(=O)([O-])O.[Na+]>[CH2:47]([O:49][C:50]([N:52]1[CH2:53][CH2:54][N:55]([C:10](=[O:12])[C@@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])[CH2:56][CH2:57]1)=[O:51])[CH3:48]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)CC1
Reaction time: 16 h

Procedure:
To a solution of 15 g of (S)-2-Benzyloxycarbonylamino-pentanedioic acid 5-tert-butyl ester, 20.4 g of NEM and 14.5 g of TOTU in 75 ml of DMF, 7.4 g of Piperazine-1-carboxylic acid ethyl ester was added at RT and stirred for 16 h. The reaction mixture was then diluted with saturated aqueous sodium hydrogen carbonate solution and then extracted with 300 ml of ethyl acetate. The organic phase was washed with diluted saturated aqueous sodium hydrogen carbonate solution and dried over MgSO4. The solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with n-heptane/ethyl acetate (1/1). The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 20.6 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:21][C:20]3[C:11](=[CH:12][C:13]4[CH2:14][C@@H:15]([C:31](O)=[O:32])[N:16]([C@H:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:23][CH3:24])[CH2:17][C:18]=4[CH:19]=3)[N:10]([CH3:34])[C:9]2=[O:35])=[CH:4][CH:3]=1.Cl.[CH3:37][O:38][C:39](=[O:57])[C@@H:40]([NH2:56])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1.COC(=O)[C@@H](NC([C@@H]1CC2C=C3C(O[C@H](C4C=CC(O)=CC=4)C(=O)N3C)=CC=2CN1[C@H](C1C=CC=CC=1)CC)=O)CC1C=CC(C2C=CC(Cl)=CC=2)=CC=1.COC(=O)[C@@H](NC([C@@H]1CC2C=C3C(O[C@H](C4C=CC(O)=CC=4)C(=O)N3C)=CC=2CN1[C@H](C1C=CC=CC=1)CC)=O)CC1C=CC(C2C=CC(F)=CC=2)=CC=1.COC(=O)[C@@H](NC([C@@H]1CC2C=C3C(O[C@H](C4C=CC(O)=CC=4)C(=O)N3C)=CC=2CN1[C@H](C1C=CC=CC=1)CC)=O)CC1C=CC(C2C=CC(OC)=CC=2)=CC=1>>[CH3:37][O:38][C:39](=[O:57])[C@@H:40]([NH:56][C:31]([C@@H:15]1[CH2:14][C:13]2[CH:12]=[C:11]3[C:20]([O:21][C@H:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)[C:9](=[O:35])[N:10]3[CH3:34])=[CH:19][C:18]=2[CH2:17][N:16]1[C@H:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][CH3:24])=[O:32])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@@H](c1ccc(O)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Agent: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(O)cc1)O3
Agent: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(F)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(O)cc1)O3
Agent: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(OC)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(O)cc1)O3
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(O)cc1)O3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (84 mg) was prepared from (3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (100 mg) and (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride following general procedure A. A similar procedure was used to prepare the following compounds: (S)-3-(4′-chloro-biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester, (S)-3-(4′-fluoro-biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester, and (S)-2-{[(3R,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-methoxy-biphenyl-4-yl)-propionic acid methyl ester.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12](=[O:20])[NH:13][C:14]([CH3:19])([CH3:18])[CH2:15][CH2:16][OH:17])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C>ClCCl>[C:7]([O:11][C:12]([NH:13][C:14]([CH3:19])([CH3:18])[CH2:15][CH:16]=[O:17])=[O:20])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(CCO)NC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CC=O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
##STR105## Dimethylsufoxide (1.22 ml, 17.2 mmol) was added to a solution of oxalyl chloride (1.1 ml, 12.9 mmol) at -78° C. in dichloromethane (15 ml). The mixture was stirred for 15 min at -78° C. A solution of 3-hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester (1.75 g, 8.6 mmol) in dichloromethane (10 ml) was added dropwise over a period of 15 min. The solution was stirred at -78° C. for another 15 min. Triethylamine (6.0 ml, 43 mmol) was added. The solution was stirred at -78° C. for 5 min and then warmed to room temperature. The solution was diluted with dichloromethane (100 ml) and extracted with 1N hydrochloric acid (100 ml). The aqueous phase was extracted with dichloromethane (50 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by column chromatography on silica (140 g) with ethyl acetate/heptane (1:3) to give 1.10 g of 3-(tert-butoxycarbonylamino)-3-methylbutanal.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[C:14]([O:18][C:19]([N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][C:25](Br)=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd]Cl>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:25]2[CH:24]=[C:23]3[C:28]([CH2:29][CH2:30][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:22]3)=[CH:27][CH:26]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Br)cc2C1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2C1
Yield: 92.7 %

Procedure:
A mixture 4-(trifluoromethyl)phenylboronic acid (987 mgs, 5.2 mmol), 7-Bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.2 g, 4.0 mmol), potassium carbonate (1.1 g, 8.0 mmol), PdCl2 (dppf) (146 mgs, 0.2 mmol) in toluene/ethanol/water (3 mL/1.5 mL/1.5 mL) was heated in pressure vessel at 120° C. for 2 h. The mixture was then concentrated and chromatographed (40 grams of SiO2, 30% EtOAc/hexanes) to provide the title compound (1.4 g, 92% yield over two steps).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:11][CH2:10][N:9]([CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][CH:13]=[C:14]([CH3:15])[CH3:16])[CH2:8][CH2:7]2)(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CC=C(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CC=C(C)C)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperidine-4- carboxylic acid ethyl ester (6.2 g, 16 mmol) dissolved in ethanol (15 mL), 10N sodium hydroxide (10 mL) and tetrahydrofiran (75 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.2 g (21%). brown solid mp 196-197° C., MS: 367.9 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][O:7][CH2:8][CH2:9]Cl.[OH-].[Na+]>O>[CH3:6][O:7][CH2:8][CH2:9][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2]
Reactant: COCCCl
Reactant: CCNCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CCOC

Procedure:
A solution prepared by mixing together 100 mL of diethylamine and 85 mL of 2-methoxyethyl chloride (both available from Kanto Chemical) was placed in an autoclave and reacted at 120° C. for 12 hours. The internal pressure during the reaction was 0.28 MPa (2.9 kgf/cm2). This yielded a mixture of deposited crystals and reaction solution to which was added, following the 12 hours of reaction, 200 mL of an aqueous solution prepared by dissolving 40 g of sodium hydroxide (Katayama Chemical Industries Co., Ltd.) in 200 mL of water. Each of the two divided organic phases that formed as a result was separated off with a separatory funnel and subjected twice to extraction with 250 mL of tetrahydrofuran (Wako Pure Chemical Industries, Ltd.). The separated organic phases were then combined and washed with a saturated saline solution, following which potassium carbonate (Wako Pure Chemical Industries) was added to remove water and vacuum filtration was carried out. The solvent in the resulting organic phase was distilled off in a rotary evaporator, after which the residue was subjected to normal-pressure distillation, yielding 21 g of 2-methoxyethyldiethylamine.
Reaction SMILES: [NH:1]1C2(CCCCC2)[NH:4][CH2:3][C:2]1=[O:11].[O:12]1[CH2:22][CH:13]1[CH2:14][C:15]([O:17]CC(C)C)=O>>[CH2:14]1[C:15](=[O:17])[N:4]([CH2:3][C:2]([NH2:1])=[O:11])[CH2:22][CH:13]1[OH:12]
Reactant: CC(C)COC(=O)CC1CO1
Reactant: O=C1CNC2(CCCCC2)N1
Product: NC(=O)CN1CC(O)CC1=O

Procedure:
1.3 g of 1,4-diazaspiro[4,5]decan-2-one ((5); R4 +R5 =--(CH2)5 --) (8.4 mmoles) are heated and stirred with magnetic stirring, with 1.5 g 2-methylpropyl 3,4-epoxybutanoate ((4), X=isobutyl) (9.5 mmoles) up to 110° (external temperature) for 24 h. The mixture is cooled, and the dark mass obtained is washed with 10 ml boiling ethyl acetate. This is decanted, and the solid obtained is crystallised from methanol to give oxiracetam as a crystalline white powder, m.p. 167°-70° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].O>ClCCl>[CH3:17][S:18]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1])(=[O:20])=[O:19]
Reactant: OCc1ccccc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccccc1F
Reaction time: 3 h

Procedure:
To a solution of 2-Fluorobenzyl alcohol (10 g, 79.28 mmol) in dry dichloromethane (200 ml) was added triethylamine (12.03 g, 118.9 mmol) under argon at room temperature. Methanesulfonyl chloride (10.71 g, 93.5 mmol) was added to the above reaction mixture at 0° C., and stirring was continued for another 3 hours. Water (100 ml) was added to the reaction mixture and the mixture was extracted twice with dichloromethane. The combined organic layers were washed with water and brine. The reaction mixture was dried over Na2SO4, filtered and concentrated to give the title compound as an yellow oil which was used without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[O:46][CH3:47])[CH2:34][N:35]1[CH:39]=[CH:38][N:37]=[CH:36]1.[SH:48][C:49]1[CH:58]=[CH:57][C:52]([C:53]([O:55][CH3:56])=[O:54])=[CH:51][CH:50]=1.[Cl-].[Na+]>O1CCCC1>[CH3:47][O:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[CH:33]([S:48][C:49]1[CH:50]=[CH:51][C:52]([C:53]([O:55][CH3:56])=[O:54])=[CH:57][CH:58]=1)[CH2:34][N:35]1[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: COc1ccccc1C(O)Cn1ccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccccc2OC)cc1
Reaction time: 0.33 h
Yield: 23.2 %

Procedure:
685 mg of triphenylphosphine were added, at a temperature between 0° and 5° C., to a solution of 500 mg of diethyl azodicarboxylate in 6.17 ml of tetrahydrofuran, and the mixture was stirred for 20 minutes. A solution of 570 mg of 1-[2-hydroxy-2-(2-methoxyphenyl)ethyl]imidazole in 7 ml of tetrahydrofuran was added to the resulting solution at a temperature between -10° and -15° C., and the mixture was stirred for 20 minutes. A solution of 439 mg of methyl 4-mercaptobenzoate in 8.4 ml of tetrahydrofuran was added at the same temperature to the mixture, which was then stirred at between 0° and 5° C. for 30 minutes, and then at room temperature for 25 minutes. A saturated aqueous solution of sodium chloride was added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation, and the residue was purified by the same method as described in Example 13, to give 223 mg of the title compound. This compound was identical with that obtained as described in Example 9 in its infrared absorption spectrum and nuclear magnetic resonance spectrum.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][C:13](=[O:16])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCC(=O)CC2)cc1
Yield: 58 %

Procedure:
A solution of 1-(4-nitro-phenyl)-piperidin-4-one (150 mg, 0.68 mmol) was dissolved in methanol (4 ml) and hydrogenated over 10% Pd/C (20 mg) at atmospheric pressure until no further gas uptake was observed. The reaction mixture was then filtered over celite and concentrated to yield the crude compound, which was purified by column chromatography using ethyl acetate/hexane (3:2) to give 1-(4-aminophenyl)-piperidin-4-one (75 mg, 57%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O>O1CCCC1.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)/C=C/c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cccc(N)c1
Yield: 60.7 %

Procedure:
(E)-Ethyl 3-(3-nitrophenyl)acrylate (12.1 g, 52.9 mmol) in tetrahydrofuran (100 ml) was hydrogenated over 10% palladium-Carbon (2.80 g) at atmospheric pressure. After removal of the catalyst, the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel (100 g) with hexane-ethyl acetate (3:1) to give ethyl 3-(3-aminophenyl)propionate as a yellow oil (6.21 g, 61%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][C:10]1([CH3:20])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[S:13][CH2:12][CH2:11]1>C(Cl)Cl>[CH3:6][C:5]([C:17]1[CH:18]=[CH:19][C:14]2[S:13][CH2:12][CH2:11][C:10]([CH3:9])([CH3:20])[C:15]=2[CH:16]=1)=[O:7]
Reactant: CC(=O)Cl
Reactant: CC1(C)CCSc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCS2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
37 g of aluminium chloride were suspended at 0° C. in 200 ml of methylene chloride and the suspension was treated slowly with 22 g of acetyl chloride while stirring vigorously. After 30 minutes, a solution of 49.4 g of 3,4-dihydro-4,4-dimethyl 2H-1-benzothiopyran in 150 ml of methylene chloride was added dropwise thereto. After stirring at 0° C. for 1 hour, the mixture was poured into ice/water and extracted with methylene chloride. The organic phase was washed neutral with 1N sodium hydroxide solution and water, dried and evaporated. The oily crude product was filtered over a short column of silica gel [eluting agent: hexane/ether (9:1)]. There were obtained 51.5 g of 3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl methyl ketone in the form of a colorless oil which solidifies upon standing in a refrigerator.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:14]1)=O>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@@H](c2cccc(F)c2)C1
Solvent: C1CCOC1
Product: Fc1cccc([C@@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Yield: 60 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(3-fluorophenyl)piperidin-1-yl]methanone (19 mg, 0.056 mmol) was treated with BH3 THF according to the above general procedure. Flash chromatography gave 11 mg of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[C:12]([Cl:19])[CH:11]=1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>CN(C)C=O.C1(C)C=CC=CC=1.O>[Br:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][OH:15])=[C:12]([Cl:19])[CH:11]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CI
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: OCc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (1.38 g, 10 mmol) and methyl iodide (0.623 ml, 10 mmol) were added to a solution of 4-bromo-2-chlorobenzoic acid (2.0 g, 8.5 mmol) in N,N-dimethylformamide (8 ml) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give an oily residue. After diisobutyl aluminum hydride-11.0M toluene solution (24 ml, 24 mmol) was added dropwise to a solution of the obtained residue in toluene (30 ml) at −78° C., the temperature of the mixture was raised to room temperature over 3 hours. After sodium sulfate decahydrate (12 g) was added to the reaction mixture and the mixture was stirred at room temperature for 30 minutes, Celite (12 g) and anhydrous magnesium sulfate (12 g) were added thereto and the mixture was stirred at room temperature for 30 minutes. After the insolubles were removed by filtration, the solvent was removed from the obtained filtrate under reduced pressure to give crudely purified (4-bromo-2-chlorophenyl)methanol as a solid. According to a method similar to Example (17-1), from crude (4-bromo-2-chlorophenyl)methanol obtained in the above, (4-bromo-2-chlorophenyl)acetonitrile was obtained as a pale yellow solid (1.4 g, yield: 71%).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH2:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:9]([O:7][C:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[CH:2]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccccc1
Reactant: O=C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C=C(OCc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To a flask equipped with magnetic stirrer and Dean Stark apparatus was added 1,3-cyclohexanedione (70.0 g, 624 mmol), toluene (500 ml), p-toluenesulfonic acid monohydrate (1.68 g, 8.83 mmol) and benzyl alcohol (65.6 g, 606 mmol). The resulting solution was heated under reflux for 2 hr. The reaction mixture was cooled to room temperature and washed with saturated aqueous sodium carbonate solution (4×50 ml). The organic layer was washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo, affording a brown oil which crystallised upon standing. The crude crystalline material was triturated in isopropyl ether (100 ml) and stirred at 0° C. for 2 hr. The mixture was filtered and the crystalline material was washed with ice cold isopropyl ether (3×100 ml) followed by cold petroleum ether (100 ml). The resulting solid was dried overnight under reduced pressure to furnish the title compound (85.3 g, 68%). m/z (ES+) 203 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N+:13]([O-])=O)[CH:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:1]([N:8]1[CH2:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH:11]([NH2:13])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 53.8 %

Procedure:
To a stirred solution of rac-(3R,4S)-1-benzyl-3-(3,4-dichloro-phenyl)-4-nitro-pyrrolidine (11.60 g, 33.0 mmol) in EtOAc (200 mL) was added in one portion 5 nCl2.2H2O (37.26 g, 0.165 mol). The reaction mixture was then heated at reflux for 4 hours, cooled down to ambient temperature and a saturated aqueous solution of NaHCO3 was added. The salts were filtered off and the product extracted with EtOAc. The organic phases were then dried over Na2SO4, and concentration under vacuum gave 5.7 g (54%) of rac-(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylamine as a yellow oil. The product was then used in the next step without further purification. ES-MS m/e: 321.2 (M+H+).
Reaction SMILES: CC1CS[C@@H]2[C@H](N)C(=O)N2C=1C(O)=O.[CH3:15][C:16]([O:18][CH2:19][C:20]1[CH2:29][S:28][C@@H:23]2[C@H:24](N)[C:25](=[O:26])[N:22]2[C:21]=1[C:30]([OH:32])=[O:31])=[O:17]>>[CH3:15][C:16]([O:18][CH2:19][C:20]1[CH2:29][S:28][C@@H:23]2[CH2:24][C:25](=[O:26])[N:22]2[C:21]=1[C:30]([OH:32])=[O:31])=[O:17]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1

Procedure:
7-Amino desacetoxy cephalosporanic acid (7-ADCA) and 7-aminocephalosporonic acid (7-ACA) are known to be the most important intermediates for the production of antibiotics used in the pharmaceutical industry. 7-ADCA is for example obtained by chemical or enzymatic cleavage (deacylation) of phenylacetyldesacetoxy cephalosporanic acid yielding 7-amino desacetoxy cephalosporanic acid and phenyl acetic acid.