Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([N:9]2[C:14](=[O:15])[NH:13][CH:12]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[NH:11][C:10]2=[O:21])[CH:6]=[CH:7][CH:8]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:4]=[C:5]([N:9]2[C:14](=[O:15])[NH:13][CH:12]([N:16]([CH2:17][CH2:18][CH2:19][CH3:20])[C:24](=[O:26])[CH3:25])[NH:11][C:10]2=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: CCCCNC1NC(=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1
Reactant: CC(=O)OC(C)=O
Product: CCCCN(C(C)=O)C1NC(=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1
Yield: 66 %

Procedure:
A mixture of 3-(3-trifluoromethylphenyl)-6-n-butylaminotetrahydro-1,3,5-triazine-2,4-dione (4.0 g.) and acetic anhydride (40 ml.) was heated under reflux for 2 hours. The mixture was then distilled at atmospheric pressure over 2 hours, fresh acetic anhydride being added to maintain the original volume. The mixture was then distilled at atmospheric pressure so that the final volume was about 10 ml. Ether (60 ml.) and petroleum ether (b.p. 40°-60° C.) [hereinafter referred to as "40-60 petrol"] (20 ml.) was then added. The white solid which precipitated was washed with ether (2×30 ml.) and air dried to give 3-(3-trifluoromethylphenyl)-6-[(N-acetyl)-n-butylamino]-tetrahydro-1,3,5-triazine-2,4-dione (3.7 g., 66%), m.p. 146°-148° C.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:17]([OH:18])[C@H:16]([F:19])[C@@H:15]([CH2:20][OH:21])[O:14][C@H:5]1[O:6]CC1C=CC=CC=1)=[N+]=[N-].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([NH:1][C@H:4]1[C@@H:17]([OH:18])[C@H:16]([F:19])[C@@H:15]([CH2:20][OH:21])[O:14][CH:5]1[OH:6])(=[O:24])[CH3:23]
Reactant: [N-]=[N+]=N[C@@H]1[C@H](OCc2ccccc2)O[C@H](CO)[C@@H](F)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](F)[C@@H]1O

Procedure:
The present invention provides a process for preparing 5-acetamido-3,5,7-trideoxy-7-fluoro-D-glycero-1-D-lacto-2-nonulopyranosidonic acid comprising hydrogenating benzyl 2-azido-2,4-dideoxy-4-fluoro-β-D-mannopyranoside in the presence of acetic anhydride to obtain N-acetyl-4-deoxy-4-fluoro-D-mannosamine, and subsequently reacting the product with sodium piruvate, bovine serum albumin and aldolase sialate.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.Br.Br[CH2:24][C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:26]>>[O:26]1[CH2:24][C@H:25]1[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Product: c1cncc([C@@H]2CO2)c1

Procedure:
The title compound was prepared from (R)-2-methyl-CBS-oxazaborolidine monohydrate and 3-(2-bromoacetyl)pyridine hydrobromide in substantially the same manner, as described in Example 123. The product was obtained as an oil; 1H NMR (300 MHz, DMSO-d6) δ 2.94-2.97 (m, 1H), 3.14-3.17 (m, 1H), 3.99-4.01 (m, 1H), 7.36-7.40 (m, 1H), 7.63-7.66 (m, 1H), 8.51-8.55 (m, 2H); MS (ES) m/z: 121 (M+).
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[N:13][S:14][CH:15]=2)=[CH:7][CH:6]=1.[C:17]([C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][NH2:27])=[CH:22][CH:21]=1)(=[O:19])[NH2:18]>C(O)C>[C:17]([C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][NH:27][CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]=[N:13][S:14][CH:15]=3)=[CH:7][CH:6]=2)=[CH:22][CH:21]=1)(=[O:19])[NH2:18]
Reactant: c1cc(-c2csnn2)ccc1OCC1CO1
Reactant: NCCOc1ccc(C(N)=O)cc1
Solvent: CCO
Product: NC(=O)c1ccc(OCCNCC(O)COc2ccc(-c3csnn3)cc2)cc1

Procedure:
A mixture of 234 mg. of 4-[4(2,3-epoxypropoxy)phenyl]-1,2,3-thiadiazole, 180 mg. of 4-carbamoylphenoxyethylamine and 5 ml. of ethanol is stirred at room temperature for 68 hours. The formed precipitate is collected by filtration and recrystallized from methanol thus obtaining the pure 4-[4{3-(4-carbamoylphenoxyethylamino)2-hydroxypropoxy}phenyl]-1,2,3-thiadiazole, m.p. 173°-174° C; λmax 255 nm (ε 32,300); ir 3,345, 1605, 1570 cm-1.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[Mg+2].[Br-].[Br-].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([C:48]([C:50]2[C:51]3[CH:61]=[CH:60][C:59]([O:62][CH2:63][C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)=[CH:58][C:52]=3[S:53][C:54]=2N(C)C)=[O:49])[CH:38]=[CH:39][C:40]=1[CH2:41][N:42]1[CH2:47][CH2:46]O[CH2:44][CH2:43]1>C1COCC1>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([C:48]([C:50]2[C:51]3[CH:61]=[CH:60][C:59]([O:62][CH2:63][C:64]4[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=4)=[CH:58][C:52]=3[S:53][C:54]=2[C:22]2[CH:21]=[CH:20][C:11]([O:12][CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:23]=2)=[O:49])[CH:38]=[CH:39][C:40]=1[CH2:41][N:42]1[CH2:43][CH2:44][CH2:46][CH2:47]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1OCCN1CCCC1
Reactant: COc1cc(C(=O)c2c(N(C)C)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCOCC1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Mg+2]
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)c(CO[Si](C)(C)C(C)(C)C)c3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 11.1 %

Procedure:
To a solution of (142 mg, 0.343 mmol) 1-[2-(2-t-butyldimethylsilyloxymethyl-4-bromophenoxy)ethyl]pyrrolidine (Part B) in 15 mL of freshly distilled THF cooled to −78° C. was added 0.24 mL of n-BuLi. The solution was stirred at −78° C. for 1 h 20 min. To the solution was added 1.0 mL of freshly prepared MgBr2 (prepared by reacting 54 mL of dibromoethane with 13 mg of etched magnesium ribbon in 1.0 mL of THF) via cannula at −78° C. and stirred for 10 min. The ice bath was removed and the solution was stirred at room temperature for 30 min. The Grignard reagent was then added dropwise via a cannula to (177 mg, 0.343 mmol) 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 3-methoxy-4-[(4-morpholinyl)methyl]phenyl ketone (Example 49, Part C) dissolved in 1.0 mL of THF at room temperature. The reaction was stirred for 5.5 h. The reaction was quenched by adding 4 mL of satd. NH4Cl solution. The mixture was then extracted with EtOAc (2×40 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 46:46:8 CHCl3-Hexanes-2 M NH3 in MeOH) afforded 30.8 mg (0.0381 mmol, 11%) of a yellow foam.
Reaction SMILES: [CH:1]1([C:4]2[S:5][CH:6]=[C:7]([NH:9][C:10](=[O:34])[NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH:15]=[CH:14][CH:13]=3)[N:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([C:4]2[S:5][CH:6]=[C:7]([NH:9][C:10]([NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)[N:17]=3)=[O:34])[N:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2cccc(NC(=O)Nc3csc(C4CC4)n3)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(OCCC2CCNCC2)n1)Nc1csc(C2CC2)n1

Procedure:
In a manner similar to that described in Example 2, 2-cyclopropylthiazole-4-carbonylazide (133.0 mg, 0.686 mmol) and tert-butyl 4-[2-(6-amino-pyridin-2-yloxy)-ethyl]-piperidine-1-carboxylate (220.0 mg, 0.686 mmol) were heated in toluene (20 mL) to give the BOC-protected product as a yellow oil. In a similar manner to Example 274, tert-butyl 4-(2-{6-[3-(2-cyclopropyl-thiazol-4-yl)-ureido]-pyridin-2-yloxy}-ethyl)-piperidine-1-carboxylate (7.6 mg, 0.016 mmol) was heated in CH2Cl2 (10 mL) in the presence of TFA (2 mL) to give the product as yellow oil. MS m/z: 388.3 (M+H). Calc'd. for C19H26N5O2S-388.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[N:6][CH:7]=1.[CH:29]1(B(O)O)[CH2:31][CH2:30]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:29]1([C:2]2[CH:3]=[CH:4][C:5]([O:8][C:9]3[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=3)[CH:12]=[C:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=2)[CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(Br)cn3)c2)CC1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(C4CC4)cn3)c2)CC1
Temperature: 80 °C
Yield: 87 %

Procedure:
To a solution of tert-butyl 4-(3-(5-bromopyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (Example 33, step 4) (1.64 g, 3.68 mmol) in toluene (12 mL) and water (0.6 mL) under a N2 atmosphere was added cyclopropyl boronic acid (410 mg, 4.77 mmol), potassium phosphate (2.24 g, 12.9 mmol), tricyclohexyl phosphine (103 mg, 0.367 mmol) and palladium acetate (41.2 mg, 0.184 mmol). The mixture was heated at 80° C. overnight. The reaction was cooled to RT and water was added. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over MgSO4 and concentrated. Purification by silica gel column chromatography (0-50% EtOAc/hexane) gave the title compound as an oil that solidified on the vacuum pump (1.3 g, 87% yield).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][N:9]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:10]([CH:12]2[C:21]3[C:16](=[C:17]([OH:22])[CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[N:4]1)[CH3:2].Cl.Cl[CH2:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38]>>[CH3:38][N:37]([CH3:39])[CH2:36][CH2:35][CH2:34][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[CH2:15][CH2:14][CH2:13][CH:12]2[C:10]([N:9]([CH2:8][C:6]1[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=1)[C:23]1[CH:24]=[CH:25][C:26]([CH:29]([CH3:30])[CH3:31])=[CH:27][CH:28]=1)=[O:11]
Reactant: CN(C)CCCCl
Reactant: CCn1cc(CN(C(=O)C2CCCc3c(O)cccc32)c2ccc(C(C)C)cc2)cn1
Agent: Cl
Product: CCn1cc(CN(C(=O)C2CCCc3c(OCCCN(C)C)cccc32)c2ccc(C(C)C)cc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 106 using N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g) and 3-chloro-N,N-dimethylpropylamine hydrochloride (0.24 g) as starting materials, 5-[3-(dimethylamino)propoxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide was obtained. This was dissolved in ethyl acetate, and oxalic acid (0.12 g) was added. The precipitated solid was collected by filtration to give 5-[3-(dimethylamino)propoxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide 3/2 oxalate (0.36 g). melting point: 142.6° C.
Reaction SMILES: [C:1]1(/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9]C)=[O:8])[CH:2]=1.[OH-].[Na+]>COCOC.CO>[C:1]1(/[CH:11]=[CH:12]/[C:13]2[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=[O:8])[CH:2]=1
Reactant: COC(=O)c1ccc(/C=C/c2cccc(C(=O)OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COCOC
Product: O=C(O)c1ccc(/C=C/c2cccc(C(=O)O)c2)cc1

Procedure:
A solution of 2.2 g of dimethyl (E)-stilbene-3,4'-dicarboxylate in 25 ml of dimethoxymethane and 12 ml of methanol was treated with 10 ml of 2M sodium hydroxide solution and heated under reflux for 18 hours. The reaction solution was concentrated. The aqueous residue was again diluted with water and acidified to pH 1 with 2N hydrochloric acid. The precipitate was filtered off under suction, rinsed with ice-water and dried at 60° C. overnight in a drying oven. There was obtained (E)-stilbene-3,4'-dicarboxylic acid as a light coloured powder, MS: m/z 268 (M+).
Reaction SMILES: [I-].[CH:2]1([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:37][O:38][C:39](=[O:50])[C:40]([C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=1)=O>O1CCCC1>[CH3:37][O:38][C:39](=[O:50])[C:40]([C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=1)=[CH:7][CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: c1ccc([P+](CC2CCCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)C(=O)c1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(=CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 49.2 %

Procedure:
A suspension of cyclopentylmethyl triphenylphosphonium iodide (prepared in Example 3, 3.95 g, 8.37 mmol) in dry tetrahydrofuran (10 mL) was cooled to 0° C. and then treated dropwise with a 1.0M solution of sodium bis(trimethylsilyl)amide (8.4 mL, 8.37 mmol). The bright orange reaction mixture was stirred at 0° C. for 45 min. The reaction mixture was then treated with a solution of (3,4-dichloro-phenyl)-oxo-acetic acid methyl ester (1.30 g, 5.58 mmol) in tetrahydrofuran (4 mL). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred for 64 h. The reaction mixture was then concentrated in vacuo to remove tetrahydrofuran. The residue was diluted with water (150 mL) and then extracted with diethyl ether (1×200 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 19/1 hexanes/ethyl acetate) afforded the 3 cyclopentyl-2-(3,4-dichloro-phenyl)-acrylic acid methyl ester (821.1 mg, 49%) as a yellow oil consisting of a 4.5:1 mixture of (E):(Z) isomers. The isomeric mixture was used without further separation and characterization.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH2:6][CH:5]([C:12]2SC=C[CH:16]=2)[N:4]=1.[H][H]>[Pd].C(O)C>[ClH:1].[NH2:2][C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH2:6][CH:5]([CH2:12][CH3:16])[N:4]=1
Reactant: [H][H]
Reactant: NC1=NC(c2cccs2)Cc2ccsc21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCC1Cc2ccsc2C(N)=N1
Yield: 65.2 %

Procedure:
Palladium on charcoal (57 mg) was added as a slurry in ethanol to 7-amino-5-ethynyl-4,5-dihydrothieno[2,3-c]pyridine hydrochloride (Example 56) (113 mg, 0.531 mmol) in ethanol (6 ml) and the mixture stirred for 16 h under 3 atm. of hydrogen. The mixture was then filtered through celite, evaporated and triturated with dichloromethane to afford a white powder (75 mg), m.p. 221-223° C.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:22][CH3:23])=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][C:7]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=O.CN.[C:26]([BH3-])#[N:27].[Na+].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>C(OCC)(=O)C.C(O)(=O)C.CO>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[CH3:23][O:22][C:4]1[C:3]([CH2:1][NH:27][CH3:26])=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: COc1c(C=O)cccc1Oc1cc(C(F)(F)F)ccc1C#N
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cccc(Oc2cc(C(F)(F)F)ccc2C#N)c1OC
Yield: 30.4 %

Procedure:
2-(3-Formyl-2-methoxy-phenoxy)-4-trifluoromethyl-benzonitrile (0.46 g, 1.43 mmol), methylamine (2M in methanol, 22.2 mL, 4.4 mmol) and sodium cyanoborohydride (0.13 g, 2.1 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (70 mL) for 20 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. Fumaric acid (0.15 g, 1.3 mmol) was added to the separated ethyl acetate layer and the solvent removed in vacuo. The residue was triturated with diethyl ether overnight, filtered and dried to give 2-(2-methoxy-3-methylaminomethyl-phenoxy)-4-trifluoromethyl-benzonitrile fumarate (179 mg, 28%) as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][C:9]=2[O:16]C)=[CH:4][CH:3]=1.B(Br)(Br)Br>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=2[OH:16])=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2ccc(I)cc2)c(OC)c1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2ccc(I)cc2)c(O)c1

Procedure:
Reaction Scheme 5 illustrates the synthesis of 4-(4-Iodophenyl)resorcinol (31). 2,4-Dimethoxyphenylboronic acid and 1-bromo-4-nitrobenzene in the presence of tetrakis(triphenylphosphine) palladium yielded 4-(4-nitrophenyl)-2,4-methoxybenzene (28). Hydrogenation of 28 in the presence of a palladium catalyst yielded the crude amine (29) which without purification was diazotized and treated with KI solution to yield the desired 4-(4-iodophenyl-2,4-dimethoxybenzene (30). The dimethoxy analog (30) was treated with boron tribromide to yield the desired 4-(4-iodophenyl)resorcinol (31).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:35](=[O:36])[N:12]2[C:13]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])=[C:14](OS(C)(=O)=O)[CH2:15][S:16][C@H:11]12)=[O:8].CN(C=O)C.[N-:42]=[N+:43]=[N-:44].[Na+].II>C1(C)C=CC=CC=1.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:35](=[O:36])[N:12]2[C:13]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])=[C:14]([N:42]=[N+:43]=[N-:44])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CS(=O)(=O)OC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: [N-]=[N+]=[N-]
Agent: II
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.554 g. of p-nitrobenzyl 7β-(2-thienylacetamido)-3-methylsulfonyloxy-3-cephem-4-carboxylate in 10 ml. of DMF was added one molar equivalent (0.065 g.) of sodium azide and the mixture stirred at room temperature for 30 minutes. The mixture was transferred to a separatory funnel with ethyl acetate and the solution was washed three times with water, once with brine, dried over sodium sulfate and evaporated to dryness. The product, 0.523 g, obtained as a yellow froth showed a single spot on silica gel thin layer chromatography using 1:1, ethyl acetate:toluene for development and iodine for visualization.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.CS(O[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:28][S:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)=[CH:19][CH:20]=1)(=[O:27])=[O:26]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CS(=O)(=O)OCCc1ccc(OS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1
Yield: 67.9 %

Procedure:
13.6 g (0.1 mole) p-hydroxyacetophenone, 29.4 g (0.1 mole) 4-(methylsulfonyloxy)phenethyl methanesulfonate and 42.4 g (0.3 mole) potassium carbonate in acetonitrile were refluxed over night. The salts were filtered off and the solvent was evaporated in vacuo. The residue was crystallized in isopropyl alcohol. The crystals were dissolved in dichloromethane, washed with diluted potassium carbonate, dried (magnesium sulfate), filtered and evaporated to give 22.7 g (yield 68%) 4-[2-(4-acetylphenoxy)ethyl]phenyl methanesulfonate.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]2[CH2:15][O:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(O)C>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:15][CH:13]([OH:14])[CH2:12][O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH2:19][CH2:18]1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Reactant: CN1CCNCC1
Solvent: CCO
Product: CN1CCN(CC(O)COc2cccc3ccccc23)CC1
Yield: 61.3 %

Procedure:
To a solution of 2-((1-naphthyloxy)methyl)oxirane (50 mg, 0.25 mmol) in ethanol (0.50 mL) was added 4-methylpiperazine (33 μL, 0.30 mmol) at room temperature. The mixture was stirred under reflux for 1 hr. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give HUHS1008 (46 mg, 61%).
Reaction SMILES: [C:1]([C:4]1[C:5]([F:13])=[C:6]([CH:9]=[C:10](Cl)[CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].C(N(CC)CC)C>CO.[H][H].[Pd]>[C:1]([C:4]1[C:5]([F:13])=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)c1cc(Cl)cc(C#N)c1F
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc(C#N)c1F

Procedure:
Reduction of 3-acetyl-5-chloro-2-fluorobenzonitrile in methanol using H2 /Pd-C for 3 h under 45 p.s.i.g. of H2 in the presence of triethylamine affords 3-acetyl-2-fluorobenzonitrile, which is the starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[N:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:39]2[CH2:40][CH2:41][N:36]([C:33]4[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=4)[CH2:37][CH2:38]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(c4ccncc4)CC3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 1-(pyridin-4-yl)piperazine (32 mg, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[4-(pyridin-4-yl)piperazin-1-ylmethyl]indol-2-yl)isoindolinone.
Reaction SMILES: [C:1]([C:3]1([O:11]C(=O)CCC)[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].CO.[OH-].[Na+]>O.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>[C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2]
Reactant: C#CC1(OC(=O)CCC)CN2CCC1CC2
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C#CC1(O)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 18.3 %

Procedure:
A solution of (±)-3-ethynyl-3-butyryloxyquinuclidine (4.42 g) in deionised water (700 ml) containing methanol (35 ml) was adjusted to pH 7.0 using an 0.1M aqueous sodium hydroxide solution (dispensed by a pH autotitrater). A suspension of pig liver eaterase (8.0 ml, 9200 units, in 3.2M aqueous ammonium sulphate solution at pH8; Sigma Chemical Company Ltd) was added to the reaction mixture and the mixture was stirred at ambient temperature whilst maintaining the pH at 7.0 using 0.1M aqueous sodium hydroxide solution (dispensed by a pH autotitrater). After 5.5 hours, 7.3 ml of the sodium hydroxide solution had been consumed, indicating that the hydrolysis was 35% complete. The pH of the reaction mixture was adjusted to 2.5 using 2M aqueous hydrochloric acid and the mixture was stirred for 10 minutes. 2M aqueous sodium hydroxide solution was then added to the mixture to give a pH of 7.05 and the mixture extracted with diethyl ether (3×200 ml, followed by 12×150 ml). The aqueous phase was separated, and freeze dried over a period of 48 hours to give a solid which was dissolved in deionised water (30 ml). The solution was filtered and the filtrate was basified to pH9 using 10.8M sodium hydroxide solution to give a solid. The solid was collected by filtration to give (+)-3-ethynyl-3-hydroxyquinuclidine, (554 mg) m.p. 204°-207° C., [α]20D =54.5° (C=0.99, methanol).