Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]Cl.[CH3:3][O:4][CH2:5][C:6]([N:8]([CH:17]1[CH2:21][CH2:20][O:19][C:18]1=[O:22])[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16])=[O:7]>C(O)=O.[Fe](Cl)(Cl)Cl>[CH3:3][O:4][CH2:5][C:6]([N:8]([CH:17]1[CH2:21][CH2:20][O:19][C:18]1=[O:22])[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([Cl:1])[C:10]=1[CH3:16])=[O:7]
Reactant: ClCl
Reactant: COCC(=O)N(c1c(C)cccc1C)C1CCOC1=O
Agent: Cl[Fe](Cl)Cl
Solvent: O=CO
Product: COCC(=O)N(c1c(C)ccc(Cl)c1C)C1CCOC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
Over 2 hours, 74.6 g (1.05 moles) of chlorine are introduced at 25°-30° C. into a solution of 277 g (1.0 mole) of N-methoxyacetyl-N-(2-oxotetrahydro-3-furyl)-2,6-dimethylaniline and 5 g of iron(III) chloride in 300 ml of 85% formic acid. The reaction is exothermic and virtually no gas evolves. When the addition of chlorine is complete, the reaction mixture is stirred for 30 minutes at 25° C., the formic acid is then distilled off in vacuo, the residue is taken up in 500 ml of toluene and the toluenic solution is washed with 100 ml of water. The oily residue obtained after the toluene has been distilled off is crystallised from a mixture of isopropanol and hexane, affording 287 g (92% of theory) of N-methoxyacetyl-N-(2-oxotetrahydro-3-furyl)-3-chloro-2,6-dimethylaniline with a melting point of 80°-82° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[C:18]([F:27])=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([CH3:26])=[CH:20]4)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:28][CH3:29].[C:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[CH3:31]>CN(C=O)C>[C:30]([N:33]1[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10]([O:16][C:17]4[C:18]([F:27])=[C:19]5[C:23](=[CH:24][CH:25]=4)[NH:22][C:21]([CH3:26])=[CH:20]5)=[N:11][CH:12]=[N:13]3)=[CH:8][C:7]=2[O:28][CH3:29])[CH2:35][CH2:34]1)(=[O:32])[CH3:31]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCBr
Reactant: CC(=O)N1CCNCC1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Yield: 100 %

Procedure:
A solution of 7-(3-bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline (0.25 g, 0.543 mmol) and 1-acetylpiperazine (0.208 g, 1.63 mmol) in DMF (4 ml) was stirred at 80° C. for 2.5 hours. The volatiles were removed under vacuum and the residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride and methanol. The fractions containing the expected product were combined and evaporated. The residue was triturated under diethyl ether and the resulting solid was filtered, washed with diethyl ether and dried under vacuum to give 7-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline (0.25 g, 0.543 mmol).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][N:9]([C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=2[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:12])[CH2:8][CH2:7][N:6]1C(OC(C)(C)C)=O)=O.[BH4-].[Li+]>C1COCC1>[OH:2][CH2:3][CH:5]1[NH:6][CH2:7][CH2:8][N:9]([C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=2[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:12])[CH2:10]1
Reactant: COC(=O)C1CN(C(=O)c2c(Oc3ccccc3)n(-c3ccccc3)c3ccccc23)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1c(Oc2ccccc2)n(-c2ccccc2)c2ccccc12)N1CCNC(CO)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
The compound of step 1 (100 mg, 0.18 mmol) was dissolved in THF (3.6 ml), lithium borohydride (11.8 mg, 0.54 mmol) was added, and the reaction was stirred at room temperature for 2 h. The mixture was partitioned between a saturated ammonium chloride solution and EA. The organic phase was washed with a saturated sodium hydrogencarbonate solution and water, dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in DCM (20 ml), TFA (5 ml) was added, and the mixture was stirred at room temperature for 1 h. The solvents were evaporated and the obtained solid was purified by preparative HPLC. The eluate was lyophilized overnight, the residue dissolved in a small quantity of MOH, mixed with hydrochloric acid (0.1 M) and lyophilized overnight. 53 mg of the title compound were obtained in the form of the (3-hydroxymethyl-piperazin-1-yl)-(2-phenoxy-1-phenyl-1H-indol-3-yl)-methanone hydrochloride.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=O)=[CH:5][N:4]=[CH:3]1.Cl.[NH2:15][OH:16]>N1C=CC=CC=1>[OH:16][N:15]=[C:7]([C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1)[C:9]1[S:10][CH:11]=[CH:12][CH:13]=1
Reactant: NO
Reactant: Cn1cncc1C(=O)c1cccs1
Agent: Cl
Solvent: c1ccncc1
Product: Cn1cncc1C(=NO)c1cccs1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A solution of (1-methyl-1H-imidazol-5-yl)(2-thienyl)methanone (10.14 g, 52.7 mmol) and hydroxylamine hydrochloride (12.8 g, 185 mmol) in pyridine (60 mL) was stirred for 9 h at 50° C., then for 8 h at 60° C. Hydroxylamine hydrochloride (6.40 g, 92 mmol) was added again and the reaction mixture was stirred for 6 h at 110° C. After removal of the solvent in vacuo and addition of water (200 mL), the pH of the aqueous solution was adjusted to pH>7 by addition of aq. NaOH (1 M), which resulted in precipitation of a yellow solid. After filtration, the solid was washed with water and pentane, and dried in vacuo to afford a first crop of N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-(2-thienyl)methanimine. The combined aqueous phases were extracted with dichloromethane, the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified recrystallized from diisopropylether to afford a second crop of N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-(3-thienyl)methanimine. The crops were combined and recrystallized from diisopropylether to afford final N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-(2-thienyl)methanimine [8.22 g, yield 71%; HPLC/MS: m/z=208 (M+H); log P(HCOOH)=0.45].
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[CH2:28]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:38]=1[NH:37][CH:36]=[C:35]2[C:39]1[CH2:40][CH2:41]NCC=1)[CH3:29]>CS(C)=O>[CH2:28]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:38]=1[NH:37][CH:36]=[C:35]2[CH2:39][CH:40]1[CH2:41][CH2:23][N:22]([CH2:12][CH:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)[CH2:21][CH2:20]1)[CH3:29]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)ccc4c3O2)cc1
Reactant: CCc1cccc2c(C3=CCNCC3)c[nH]c12
Solvent: CS(C)=O
Product: CCc1cccc2c(CC3CCN(CC4COc5ccc6nc(C)ccc6c5O4)CC3)c[nH]c12
Temperature: 75 °C

Procedure:
(2R)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl 4-methylbenzenesulfonate (0.60 g, 1.6 mmole) and 7-ethyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (1.0 g, 4.4 mmole) were combined in 10 mL of DMSO. The mixture was heated at 70-80° C. under nitrogen for 6 hours. After cooling to room temperature, the mixture was partitioned between 400 mL each of ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was removed, washed with 400 mL portions of water and saturated brine, dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was column chromatographed on silica gel using 0-2% methanol/chloroform. The product fractions were concentrated in vacuum and the residue triturated with ether to give 0.16 g of the (S)-enantiomer of the title compound as a yellow solid, m.p. 85-90° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=1>C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cc1cc(Cl)ccn1
Solvent: CC(=O)O
Product: Cc1cc(N2CCN(Cc3ccccc3)CC2)ccn1
Yield: 97.4 %

Procedure:
A solution of 1-benzylpiperazine (6.8 g) and 4-chloro-2-methylpyridine (4.9 g) in acetic acid (20 ml) was heated under reflux for 15 hours, and then concentrated under reduced pressure. The residue was dissolved in water, and the reaction mixture was basified with potassium carbonate and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with basic silica gel column (ethyl acetate) to obtain the title compound as a brown oil (10 g, quantitative).
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Br[CH:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([Cl:35])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[C:14]([O:16][CH3:17])=[O:15].O>CO.C1C=CC=CC=1.[I-].[K+]>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([Cl:35])=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)c3ccccc23)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CO
Solvent: O
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Oc2ccc(Cl)c3ccccc23)cc1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
To a solution of 1.19 g of sodium methoxide, 3.21 g of p-chlorophenol and 50 mg of potassium iodide in 40 ml of methanol was added 8.12 g of methyl α-bromo-α-[p-(4-chloro-1-naphthyloxy)phenyl]acetate in 10 ml of benzene. The mixture was refluxed overnight, cooled to room temperature, and then poured into 100 ml of water. The mixture was extracted with 2 × 75 ml of ether. The combined extracts were washed with 2 × 50 ml of 5% NaOH, 2 × 50 ml of water, 50 ml saturated brine, and dried (MgSO4). Evaporation of the solvent yielded an amber oil which was subjected to chromatography on 100 g silica gel (benzene) to afford 6.7 g of an amber glass.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]1([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[O:13][CH2:15][CH2:16][OH:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1cccc(-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
In a nitrogen atmosphere, 3-phenylphenol 2.65 g, 2-bromoethanol 2.92 g and potassium carbonate 6.51 g were dissolved in N,N-dimethylformamide 16 ml and stirred at 100° C. After 5 hours, the reaction mixture was cooled to room temperature and partitioned by adding water and diethyl ether. The organic layer was washed with water and then with brine, dried over magnesium sulfate anhydride, and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound (1.78 g, 53%) was obtained as a colorless crystalline.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[OH:28])C.Br.Br[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.[H-].[Na+].[Li+].[OH-]>O1CCCC1>[CH3:21][C:20]1[O:19][C:18]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:17][C:16]=1[CH2:15][CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:29])=[C:8]([O:28][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH:9]=1
Reactant: BrCc1ccccn1
Reactant: CCOC(=O)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1O
Agent: Br
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)O)c(OCc2ccccn2)c1
Reaction time: 24 h
Yield: 7.3 %

Procedure:
3-{2-Hydroxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (100 mg, 0.25 mmol) and 2-bromomethylpyridine hydrobromide (70 mg, 0.28 mmol) were combined in anhydrous tetrahydrofuran (1 mL) and purged with nitrogen. Sodium hydride (60% in mineral oil, 21 mg, 0.53 mmol) was added. After stirring 24 hours, excess LiOH (1 M) was added, and stirring was continued an additional 24 hours. The reaction mixture was evaporated and chromatographed (silica gel, gradient of 5% ethyl acetate in hexanes to 2% methanol in ethyl acetate) to give 8.4 mg of the title compound. MS m/z 487 (M+H)+.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[CH:14]=[CH:13]2>O1CCCC1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16]([C:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:14][CH2:13]2)=[CH:17][CH:18]=1
Reactant: COc1ccc2c(c1)C=CC2=O
Reactant: CCCCC[Mg]Br
Solvent: C1CCOC1
Product: CCCCCC1=CCc2cc(OC)ccc21

Procedure:
A solution of pentyl magnesium bromide (2M; 83 mL) was added with stirring to a chilled (-5° C.) solution of 5-methoxy-1-indenone (24.33 g) in dry tetrahydrofuran (100 mL) and the mixture was stirred at room temperature for 1.5 hours. A few chips of ice were added to destroy excess reagent and after the solvents had been removed under reduced pressure, the residue was taken up in a mixture of dichloromethane (250 mL) and 2N hydrochloric acid and stirred at room temperature for 3 hours. The separated aqueous phase was extracted with dichloromethane (150 mL) then the combined organic layers were dried (MgSO4) and evaporated to provide 30 g of crude product as an oil. Purification of the material by HPLC (dichoromethane-hexane; 2:5) gave 21.62 g of 6-methoxy-3-pentyl-1H-indene as an oil
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9](=[N:11][OH:12])[CH3:10])[CH:3]=1.[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19]Cl>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][O:12][N:11]=[C:9]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1)[CH3:10]
Reactant: COc1ccc(CCl)c(OC)c1
Reactant: CC(=NO)c1cc(C)cc(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CON=C(C)c2cc(C)cc(C)n2)c(OC)c1
Reaction time: 0.5 h

Procedure:
On the other hand, 0.50 g (3.05 mmol) of 1-(4,6-dimethyl-2-pyridinyl)ethanone oxime was dissolved in 5 ml of N,N-dimethylformamide, and the resultant solution was added with 0.12 g (3.00 mmol) of sodium hydride (60%, oiliness) while cooling the solution with ice. The obtained solution was stirred for 30 min. at a temperature below 0° C. and subsequently added with the whole amount of the toluene solution of 2,4-dimethoxybenzyl chloride prepared previously under cooling with ice. The resultant solution was stirred for 1.5 hours while cooling with ice, and the reacted solution was then poured into icewater, and the ice water containing the reacted solution was extracted with diethyl ether. The resultant nonaqueous layer was separated and washed with water and then dried with anhydrous magnesium sulfate. The dried layer was then condensed under reduced pressure to obtain a crude product. Then, said crude product was purified by means of silica gel column chromatography (eluate; hexane:ethyl acetate=7:3 (v/v)) to obtain the target compound in an amount of 0.62 g. nD20.7; 1.5722
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][OH:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[C:24](OC(=O)C)(=[O:26])[CH3:25].N1C=CC=CC=1>ClCCl.[Cl-].[Na+].O>[C:24]([O:15][CH2:14][C@@H:13]([NH:16][C:17]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:23])[CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:7][CH:8]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC#CCOc1ccc(C[C@@H](CO)NC(=O)OC(C)(C)C)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC#CCOc1ccc(C[C@@H](COC(C)=O)NC(=O)OC(C)(C)C)cc1
Reaction time: 7 h
Yield: 102.8 %

Procedure:
tert-Butyl [(S)-2-(4-but-2-ynyloxy-phenyl)-1-hydroxymethyl-ethyl]-carbamate (402 mg, 1.26 mmol) was dissolved in dichloromethane (6.3 mL), and acetic anhydride (0.179 mL, 1.89 mmol) and pyridine (204 μL, 2.52 mmol) were added at room temperature. The reaction mixture was stirred for 7 hours, then poured into a saturated brine, and extracted with ethyl acetate. The organic extract was dried over magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (468 mg).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:17]1(B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:17]1([C:2]2[CH:16]=[CH:15][C:5]([O:6][C:7]3[N:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][CH:8]=3)=[CH:4][CH:3]=2)[CH2:19][CH2:18]1
Reactant: O=Cc1ccc(Oc2ccc(Br)cc2)nc1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(Oc2ccc(C3CC3)cc2)nc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 22.2 %

Procedure:
A mixture of the compound (3.22 g) obtained in step (1) above, 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.89 g), tetrakis(triphenylphosphine)palladium(0) (669 mg), cesium carbonate (11.3 g), toluene (20.0 mL) and water (10.0 mL) was stirred at 100° C. for 6 hours. After cooling the reaction mixture to room temperature, the precipitate was removed by filtration through Celite (registered trademark). To the filtrate, water and ethyl acetate were added and extraction was conducted with ethyl acetate. The combined organic layers were washed with water and saturated brine successively and after passage through a phase separator, they were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-50:50) and further purified by preparative HPLC. A saturated aqueous solution of sodium hydrogencarbonate was then added and extraction was conducted with ethyl acetate. The combined organic layers were passed through a phase separator and thereafter concentrated under reduced pressure to give the titled compound as a colorless oil (614 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH:16](SC)[C:17]([NH2:19])=[O:18]>O1CCCC1.[Ni]>[NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([NH2:19])=[O:18]
Reactant: CSC(C(N)=O)c1cccc(C(=O)c2ccccc2)c1N
Agent: [Ni]
Solvent: C1CCOC1
Product: NC(=O)Cc1cccc(C(=O)c2ccccc2)c1N
Yield: 73.7 %

Procedure:
To an agitated solution of 9.7 g (0.032 mole) of 2-amino-3-benzoyl-α-(methylthio)-phenylacetamide in 100 ml of tetrahydrofuran was added 80 g of wet Raney nickel (washed 3 times with water and 3 times with tetrahydrofuran). After 10 minutes the mixture was filtered to remove Raney nickel and the filtrate concentrated under vacuum. The residue was crystallized from isopropyl alcohol to give 6.0 g (73%) of yellow needles, m.p. 178.5°-180.0° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH2:10]([C:12]1([CH2:16][CH:17]=O)[CH2:15][O:14][CH2:13]1)[CH3:11]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:11]/[CH2:10][C:12]1([CH2:16][CH3:17])[CH2:15][O:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1(CC=O)COC1
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CCC1(C/C=N/CC(=O)OC(C)(C)C)COC1
Yield: 100.9 %

Procedure:
Step B In a manner similar to the method described in Example 1a, glycine tert-butyl ester (1 g, 7.8 mmol) was reacted with (3-ethyl-oxetan-3-yl)-acetaldehyde (1 g, 7.8 mmol) in CH2Cl2 at room temperature for 18 h to give [2-(3-ethyl-oxetan-3-yl)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a yellow oil (1.9 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[O:8])=[CH:4][C:3]=1[C:31]1[N:35]([CH3:36])[N:34]=[CH:33][C:32]=1[Cl:37].NN>O1CCCC1.CO>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][C:32]=2[Cl:37])[CH:4]=1)=[O:8])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@H](CN)Cc2cccc(F)c2)sc1Cl
Reaction time: 24 h

Procedure:
To a 250 mL round-bottomed flask was added 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide (9 g, 16.15 mmol) and hydrazine (15.69 ml, 323 mmol) in tetrahydrofuran (THF) (75 ml) and methanol (75 mL). After 24 h at RT, the precipitate was filtered, the filtrate was concentrated, and the crude product was purified on a silica gel column [CHCl3/MeOH/NH4OH, 90:9:1] to give the title compound as a white solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C@H:4]1[CH2:8][N:7]([CH3:9])[C@H:6]([C:10]([NH:12][C@@H:13]([CH:25]([OH:27])[CH3:26])[CH:14]2[O:19][C@H:18]([S:20][CH3:21])[C@H:17]([OH:22])[C@@H:16]([OH:23])[C@H:15]2[OH:24])=[O:11])[CH2:5]1.CCC1CN(C)C(C(NC(C(O)C)C2OC(SC)C(O)C(O)C2O)=O)C1>>[CH3:1][CH2:2][CH2:3][C@H:4]1[CH2:8][N:7]([CH3:9])[C@H:6]([C:10]([NH:12][C@H:13]([C@H:25]([OH:27])[CH3:26])[C@H:14]2[O:19][C@H:18]([S:20][CH3:21])[C@H:17]([OH:22])[C@@H:16]([OH:23])[C@H:15]2[OH:24])=[O:11])[CH2:5]1
Reactant: CCC[C@@H]1C[C@@H](C(=O)N[C@@H](C(C)O)C2O[C@H](SC)[C@H](O)[C@@H](O)[C@H]2O)N(C)C1
Agent: CCC1CC(C(=O)NC(C(C)O)C2OC(SC)C(O)C(O)C2O)N(C)C1
Product: CCC[C@@H]1C[C@@H](C(=O)N[C@@H]([C@H]2O[C@H](SC)[C@H](O)[C@@H](O)[C@H]2O)[C@@H](C)O)N(C)C1

Procedure:
A crude crystalline lincomycin A preparation contained 20% of lincomycin B; the remaining solid material was primarily A. This starting material is used for twenty 18 g runs over two Prep PAK C18 cartridges eluted isocratically with (2:1) water-methanol. Pool cuts are made. The B rich pool is concentrated to an aqueous to which enough methanol is added to make a mobile phase; this is reinjected into the Prep 500. Rich eluent from the second hpplc is concentrated as before and rechromatographed a third time. Yield: 24 g of ~99% pure lincomycin B and ca. 125 g of highly pure lincomycin A. The entire isolation scheme is outlined in Chart 2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]OS(C)(=O)=O)[CH:5]=[CH:4][N:3]=1.[C-:14]#[N:15].[K+].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:14]#[N:15])[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)(=O)OCc1ccnc(Br)c1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: N#CCc1ccnc(Br)c1
Reaction time: 72 h

Procedure:
Methanesulfonic acid 2-bromo-pyridin-4-ylmethyl ester (4.24 g, 15.9 mmol) is added to a stirred solution of potassium cyanide (1.02 g, 15.1 mmol) in a mixture of ethanol (30 mL) and water (6 mL) at room temperature. After 72 hours, ethyl acetate (80 mL) and saturated aqueous sodium bicarbonate (40 mL) are added and phases are separated. The organic layer is washed with water (3×40 mL), dried over MgSO4, filtered and concentrated. The resulting residue is purified by silica gel chromatography eluting with a gradient of 0-60% ethyl acetate in heptane to afford (2-bromo-pyridin-4-yl)-acetonitrile (ES+ m/z 197.41; 199.40).