Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[C:11]=1[CH2:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>CN(C)C=O.ClCCl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[C:11]=1[CH2:12][CH2:13][CH2:14][NH:15][C:26]([CH:23]1[CH2:25][CH2:24]1)=[O:27]
Reactant: O=C(Cl)C1CC1
Reactant: NCCCc1c(Br)ccc2c1CCO2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCCCc1c(Br)ccc2c1CCO2)C1CC1
Reaction time: 0.25 h
Yield: 77.6 %

Procedure:
A mixture of 3-(5-bromo-2,3-dihydro-benzofuran-4-yl)-propylamine hydrochloride (100 mg), dimethylformamide (3 drops), triethylamine (0.35 ml) and dichloromethane (3 ml) was stirred in ice for 15 minutes. Cyclopropanecarbonyl chloride (36 mg) was added and stirring continued for 2 hours. The mixture was purified by chromatography on silica to give the title compound as a white solid (86 mg).
Reaction SMILES: C([Mg]Br)C.[CH:5]([NH:8]C(C)C)(C)[CH3:6].C(#N)C.[CH2:15]([O:22][C:23]1[CH:30]=[C:29]2[C:26]([CH2:27][C:28]2([S:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]#[N:32])=[CH:25][C:24]=1[O:40][CH3:41])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)C.O1CCCC1>[NH2:32][C:31]([C:28]1([S:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:27][C:26]2[C:29]1=[CH:30][C:23]([O:22][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[C:24]([O:40][CH3:41])[CH:25]=2)=[CH:6][C:5]#[N:8]
Reactant: COc1cc2c(cc1OCc1ccccc1)C(C#N)(Sc1ccccc1)C2
Reactant: CC(C)NC(C)C
Agent: CC[Mg]Br
Solvent: CC#N
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc2c(cc1OCc1ccccc1)C(Sc1ccccc1)(C(N)=CC#N)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
To a stirred solution of ethylmagnesium bromide (3.0 mL of a 3M solution in diethyl ether, 9.0 mmol) in anhydrous tetrahydrofuran (10 mL) at 0° C. under nitrogen is added diisopropylamine (2.5 mL, 17.8 mmol). The mixture is stirred at 0° C. for 1 hour and acetonitrile (0.25 mL, 4.8 mmol) and a solution of 4-benzyloxy-3-methoxy-7-phenylsulfanylbicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile (0.83 g, 2.2 mmol) in anhydrous tetrahydrofuran (3 mL) are added successively, and the resulting mixture is stirred for an additional hour. The reaction is quenched with aqueous ammonium chloride and the product is extracted with ethyl acetate. The extract is washed with brine, dried over anhydrous sodium sulfate and evaporated to yield a solid. The crude product is purified by silica gel chromatography, utilizing a 9:1 to 4:1 gradient of hexane/ethyl acetate to yield 0.527 g of 3-amino-3-(4-benzyloxy-3-methoxy-7-phenylsulfanylbicyclo[4.2.0]octa-1,3,5-trien-7-yl)acrylonitrile as a white solid, mp 122-125° C.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([NH:9][C@H:10]([C:15](O)=[O:16])[C@@H:11]([CH2:13][CH3:14])[CH3:12])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])N.[CH3:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[N:32]=[C:33]=[S:34]>>[C:1]([O:5][NH:6][C:7]([NH:9][C@H:10]([CH2:15][OH:16])[C@H:11]([CH3:12])[CH2:13][CH3:14])=[O:8])([CH3:3])([CH3:4])[CH3:2].[CH3:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[N:32]=[C:33]1[NH:9][C@@H:10]([C@@H:11]([CH2:13][CH3:14])[CH3:12])[CH2:15][S:34]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC[C@@H](C)[C@H](NC(=O)NOC(C)(C)C)C(=O)O
Agent: NC(=O)[O-]
Product: CC[C@@H](C)[C@@H](CO)NC(=O)NOC(C)(C)C
Product: CC[C@@H](C)[C@H]1CSC(=Nc2ccc([N+](=O)[O-])cc2C)N1

Procedure:
N-(tert-Butoxycarbamoyl)-(1S,2R)-1-(hydroxymethyl)-2methylbutylamine was prepared from N-(tert-butoxycarbamoyl)-(L)-allo-isoleucine as described in Method B1a, Step 2. The carbamate was converted to (1S,2R)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7b. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S,2R)-1-(chloromethyl)-2-methylbutanammonium chloride to Method C1e to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-((2R)-2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-((2R)-2-butyl)-3-isobutyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)#N.C([O-])([O-])=[O:13].[K+].[K+].[CH3:18][C:19]1([CH3:28])[CH2:24][CH:23]([OH:25])[CH2:22][C:21]([CH3:27])([CH3:26])[NH:20]1>CC(=O)CC>[O:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[C:1]([O:25][CH:23]1[CH2:22][C:21]([CH3:27])([CH3:26])[NH:20][C:19]([CH3:28])([CH3:18])[CH2:24]1)=[O:13]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1nc2ccccc2o1
Agent: [K+]
Solvent: CCC(C)=O
Product: CC1(C)CC(OC(=O)c2nc3ccccc3o2)CC(C)(C)N1

Procedure:
A mixture of 2-cyanobenzoxazole, a catalytic amount of K2CO3, and 2,2,6,6-tetramethylpiperidin-4-ol in 2-butanone was refluxed for 10 hours. After the precipitate was filtered and heated with aqueous HCl for 2 hours, product I was obtained by filtration.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[N:18]=[C:19](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:20][CH:21]=2)=[CH:11][CH:10]=1)(=O)=O.[N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[NH:32][CH:31]=1>>[C:24]1(/[CH:23]=[CH:22]/[C:19]2[O:20][CH:21]=[C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][N:30]4[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=5[N:32]=[CH:31]4)=[CH:14][CH:13]=3)[N:18]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: c1ccc2[nH]cnc2c1
Product: C(=C/c1nc(COc2ccc(CCCn3cnc4ccccc43)cc2)co1)\c1ccccc1
Yield: 49 %

Procedure:
In substantially the same manner as in Working Example 25, 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate was allowed to react with benzimidazole to give 1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]benzimidazole. The yield was 49%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 115-117° C.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].N[C:6]1[CH:31]=[CH:30][C:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[S:20][C:21]4[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=4[N:23]=3)=[CH:15][CH:14]=2)=[O:11])=[C:8]([C:32]([F:35])([F:34])[F:33])[CH:7]=1.C=O.[CH2:38](Cl)Cl.CCOC(C)=O>CC(O)=O>[CH3:38][N:2]([CH3:1])[C:6]1[CH:31]=[CH:30][C:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[S:20][C:21]4[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=4[N:23]=3)=[CH:15][CH:14]=2)=[O:11])=[C:8]([C:32]([F:35])([F:34])[F:33])[CH:7]=1
Reactant: [BH3-]C#N
Reactant: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(N)cc4C(F)(F)F)cc3)sc2c1
Reactant: ClCCl
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(N(C)C)cc4C(F)(F)F)cc3)sc2c1
Yield: 37 %

Procedure:
Prepared as described in the Amination section using sodium cyanoborohydride (66 mg, 1.05 mmol), 4-amino-2-trifluoromethyl-N-[4-(6-methoxybenzothiazol-2-yl)-phenyl]-benzamide (100 mg, 0.226 mmol) and paraformaldehyde (63 mg, 2.11 mmol) in AcOH (3 ml) to give the title compound (39 mg, 37%) as a colourless solid after work-up and flash chromatography (20:1 DCM/EtOAc).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][C:10]#[N:11])[CH:4]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]>CN(C)C=O>[C:10]([CH:9]([C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])#[N:11]
Reactant: N#CCc1cccnc1
Reactant: COC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCC(C#N)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To as suspension of 8.6 g of sodium hydride (50% dispersion in mineral oil) in 200 ml of dimethylformamide is added a solution of 17.7 g of 3-pyridylacetonitrile in 15 ml of dimethylformamide over a period of 0.5 h. The reaction mixture is stirred for a further 0.5 h at room temperature, then cooled to -20° before adding 30 g of methyl 5-bromovalerate. The reaction mixture is then allowed to warm up to room temperature over a period of several hours and left to stand for 18 h. The reaction mixture is then poured into 300 ml of ice water and extracted with 300 ml of ethyl acetate. The extract is washed with 3 portions of 75 ml of 1N hydrochloric acid and the aqueous solution neutralized with aqueous ammonia and extracted with ethyl acetate. The extract is dried over magnesium sulfate, filtered and evaporated to yield methyl 6-cyano-6-(3-pyridyl)-hexanoate.
Reaction SMILES: [CH3:1][S:2]([CH3:4])=[O:3].[H-].[Na+].C1COCC1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](OC)=[O:18]>O>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](=[O:18])[CH2:1][S:2]([CH3:4])=[O:3]
Reactant: CS(C)=O
Reactant: COC(=O)c1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)CC(=O)c1ccco1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
DMSO (35 ml., dry, distilled from CaH2) and NaH (3.08 g., 0.076 mol as a 60% suspension in oil) was heated under nitrogen until evolution of H2 was complete, cooled to 0° C., and diluted with 35 ml. THF. Methyl furan-2-carboxylate (5 ml., 5.89 g., 0.047 mol) was added, the mixture warmed to ambient temperature, stirred 2 hours, poured into an equal volume of water, and extracted with one half volume of ether. The aqueous layer was adjusted to pH3 with 6N HCl and extracted 3×150 ml. CHCl3. The CHCl3 extracts were combined, dried and evaporated to an oil which crystallized on standing in vacuum. The latter was slurried in minimal 1:1 CHCl3 :hexane and recovered by filtration, 2.84 g.; tlc Rf 0.7 (3:1 ethyl acetate: methanol); 1H-nmr 2.75 (s, 3H), 4.21 (ABq, 2H), 6.58 (dd, 1H), 7.32 (d, 1H), 7.62 (d, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[NH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(#N)C>[CH2:22]([O:21][C:19](=[O:20])[CH:18]([N:17]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)[CH3:23]
Reactant: CCOC(=O)C(N)c1ccc(Cl)c(Cl)c1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(N=Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (170 mL) and benzaldehyde (130 mL) were added to a suspension of ethyl amino-(3,4-dichlorophenyl)-acetate hydrochloride (350 g) in acetonitrile (1.5 L), followed by stirring at room temperature overnight. The insoluble matter was removed through Celite, followed by washing with ethyl acetate. The filtrate was subjected to partitioning with water and then extraction with ethyl acetate. The thus-obtained organic layer was washed with saturated brine, and then dried over sodium sulfate anhydrate. The solvent was removed under reduced pressure, to thereby give the title compound (425 g). The title compound was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(O[CH:14]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)(=O)C>C1C=CC=CC=1>[CH:16]1[C:15]2[CH:14]([N:6]3[CH2:7][CH2:8][CH:3]([N:2]([CH3:9])[CH3:1])[CH2:4][CH2:5]3)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:21][C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: CN(C)C1CCNCC1
Solvent: c1ccccc1
Product: CN(C)C1CCN(C2c3ccccc3Oc3ccccc32)CC1

Procedure:
A solution of 2.14 g. of 4-dimethylaminopiperidine and 4.0 g. of 9-acetoxyxanthene in 100 ml. of sieve dried benzene was refluxed for 24 hours. The mixture was then washed with a 5 percent aqueous solution of sodium carbonate, dried and the solvent removed in vacuo. The residue was recrystallized three times from hexane to afford 1-(9-xanthenyl)-4-dimethylaminopiperidine, m.p. 92°-93°C.
Reaction SMILES: [Br:1]C1C=CC2OCC(=O)NC=2N=1.[H-].[Na+].CS(OCCN1CCC([NH:28][C:29]([O:31][C:32](C)(C)C)=O)CC1)(=O)=O.[C:36]([O:40][C:41](=[O:64])[NH:42][CH:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][N:51]2[C:60]3[C:55](=[CH:56][CH:57]=C(OC)C=3)C=C[C:52]2=[O:63])[CH2:45][CH2:44]1)([CH3:39])([CH3:38])[CH3:37]>CO.ClCCl>[C:36]([O:40][C:41](=[O:64])[NH:42][CH:43]1[CH2:44][CH2:45][N:46]([CH2:49][CH2:50][N:51]2[C:52](=[O:63])[CH2:32][O:31][C:29]3[N:28]=[CH:57][C:56]([Br:1])=[CH:55][C:60]2=3)[CH2:47][CH2:48]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: O=C1COc2ccc(Br)nc2N1
Reactant: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ncc(Br)cc32)CC1
Yield: 93 %

Procedure:
6-Bromo-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Intermediate 211) (460 mg, 2.0 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (2.1 mmol) as described for Intermediate 2. Chromatography on silica gel with methanol/dichloromethane gave the product as an oil (0.85 g, 93% yield).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([N:16]1[CH:22]([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(P(N(C)C)(N(C)C)=O)C.C([C:38]([O:40][CH3:41])=[O:39])#N>C1COCC1>[CH2:9]([N:16]1[CH:22]([CH3:23])[CH2:21][CH2:20][CH2:19][CH:18]([C:38]([O:40][CH3:41])=[O:39])[C:17]1=[O:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC1CCCCC(=O)N1Cc1ccccc1
Reactant: COC(=O)C#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C1CCCC(C)N(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of lithium diisopropylamide in THF (1.8 M, 10 mL, 18 mmol, 1.3 equiv) freshly prepared at −78° C. was added a solution of 1-benzyl-7-methylazepan-2-one (2-3, 3.8 g, 18 mmol, 1.0 equiv) in THF (10 mL) was added. The reaction mixture was warmed to 0° C. and stirred for 1 h, then cooled to −78° C. HMPA (3.0 mL, 17 mmol, 0.99 equiv) was added followed by methyl cyanoformate (1.8 mL, 23 mmol, 1.3 equiv). After stirring 10 minutes at −78° C. the mixture was partitioned between water (40 mL) and diethyl ether (2×40 mL). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes gradient) to yield methyl 1-benzyl-7-methyl-2-oxoazepane-3-carboxylate (2-4). LRMS m/z (M+H) 276.2 found, 276.2 required.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Br[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: Oc1ccc(OCCBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(NCCOc2ccc(O)cc2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 18.5 %

Procedure:
4-methoxy-aniline (124 mg, 1.0 mmol) and compound 5a (200 mg, 0.92 mmol) were reacted in acetonitrile (10.0 mL) for 30 mins and diisopropylethylamine was added (0.28 mL, 2.0 mmol) dropwise. After the addition was complete, the reaction was stirred at 60° C. for 12 hours. The reaction mixture was concentrated, purified by column chromatography to isolate the compound 5 as a colorless oil (45 mg, 0.17 mmol, 19% yield). MS (ESI, positive) m/z calcd. for C15H18NO3 [M+H]+: 260.13, found: 259.94. 1H NMR (CDCl3, 400 MHz) δ 6.66-6.84 (m, 8H), 4.45 (bs, 1H), 4.12 (t, J=5.2 Hz, 2H), 3.89 (bs, 1H), 3.77 (s, 3H), 3.47 (t, J=5.2 Hz, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)=[N:11][C:4]=2[NH:3]1.[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCOCC>ClC(Cl)C>[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:10]2[CH:9]=[CH:8][C:5]3[O:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=3[N:11]=2)[CH2:28][CH2:27]1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CO2
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(Cl)Cl
Product: O=C1COc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.3 %

Procedure:
To a solution of 4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yloxy)-butyraldehyde (0.325 g, 1.37 mmol) in dichloroethane (6 mL) was added a solution of 1-(2,3-dichloro-phenyl)-piperazine (0.318 g, 1.37 mmol) in dichloroethane (3 mL) via cannula. The mixture was stirred for 20 minutes at room temperature and NaBH(OAc)3 (0.377 g, 1.78 mmol) was added. The reaction was stirred for 2.5 h and quenched with saturated NaHCO3 and water. The mixture was extracted with EtOAc and the organic layer was washed with saturated NaHCO3, water and brine, dried over Na2SO4 and concentrated. Purification by chromatography on silica gel (0–5% MeOH/CH2Cl2) gave a foam. Et2O was added and product crashed out. The precipitate was filtered and dried to give the title compound as a white solid (0.386 g, 0.854 mmol, 63%). MS: APCI: M+1: 451.1 (Exact Mass: 450.12).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][NH2:12])[OH:10])=[CH:4][C:3]=1[Cl:13].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1>CN(C=O)C>[NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([CH:9]([CH2:11][NH:12][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)[OH:10])=[CH:6][C:7]=1[Cl:8]
Reactant: BrCCCCCCOCCCCCCc1cnccn1
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Solvent: CN(C)C=O
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCCCCCc2cnccn2)cc1Cl
Yield: 56.3 %

Procedure:
A solution of 4-amino-α-(aminomethyl)-3,5-dichlorobenzenemethanol (1.2g), DEA (0.72 ml) and [6-[(6-bromohexyl)oxy]hexyl]pyrazine (1.16 g) in DMF (10 ml) was heated at 100°-110° for 3 h. The resulting dark solution was evaporated in vacuo and the residue purified by FCC eluting with System B (96:2:2→93:5:2) to give the title compound as pale yellow crystals (0.92 g), m.p. 60°-63°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][CH:5]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:21]=O)[C:16]([O:19][CH3:20])=[N:17][CH:18]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>O.C(#N)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:21][C:15]2[C:16]([O:19][CH3:20])=[N:17][CH:18]=[C:13]([F:12])[CH:14]=2)=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: COc1ncc(F)cc1C=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(NCc2cc(F)cnc2OC)nc1
Yield: 83.3 %

Procedure:
In a round bottom flask, 6-amino-nicotinic acid methyl ester (90, 0.678 g, 4.46 mmol) was combined with 5-fluoro-2-methoxy-pyridine-3-carbaldehyde (37, 0.532 g, 3.43 mmol), 10.6 mL of acetonitrile, trifluoroacetic acid (1.32 mL, 17.1 mmol) and triethylsilane (3.29 mL, 20.6 mol). The reaction was heated to reflux for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (91, 832 mg). MS (ESI) [M+H+]+=292.4.
Reaction SMILES: [CH2:1]([O:6][C:7](=[O:20])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH2:16][C:17]#[C:18][CH3:19])=[O:13])CC#CC.O(CC)CC>C1(C)C=CC=CC=1>[O:6]1[CH2:1][CH2:19][C:18]#[C:17][CH2:16][CH2:15][O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:20]
Reactant: CC#CCCOC(=O)CCCCC(=O)OCCC#CC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C1CCCCC(=O)OCCC#CCCO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.9 %

Procedure:
In a dry 100 mL Schlenk-tube, which has been flooded with argon, adipic acid dipent-3-inyl ester (135 mg, 485 μmol), complex 23a.OEt2 (10.5 mg, 9.67 μmol, 2 mol %) and molecular sieve (970 mg, 5 Å, powder) were suspended in 24.2 mL of toluene. The reaction solution was stirred for 24 h at room temperature, was filtered for the processing over a short silica gel column, the filtrate was concentrated and the residue was purified by means of column chromatography (SiO2, hexane/EtOAc, 20:1). One obtains 1,8-dioxacyclotetradec-11-in-2,7-dione (100 mg, 92%) as colorless solid. M.p.=109-110° C.; 1H NMR (400 MHz, CD2Cl2): δ=4.13-4.06 (m, 4H), 2.53-2.47 (m, 4H), 2.39-2.30 (m, 4H), 1.76-1.67 (m, 4H); 13C NMR (100 MHz, CD2Cl2): δ=173.2 (2×C), 78.2 (2×C), 62.8 (2×CH2), 35.2 (2×CH2), 25.4 (2×CH2), 19.4 (2×CH2); IR (film): v=2995, 2954, 2937, 2918, 2901, 2872, 1721, 1458, 1425, 1384, 1341, 1272, 1236, 1167, 1140, 1080, 1065, 1021, 981, 931, 843, 124, 699 cm−1; MS (EI) m/z (%): 129 (3), 111 (8), 78 (100), 66 (20), 55 (15), 41 (8); HRMS (ESI): m/z: calculated for C12H16O4+Na: 247.0941; found: 247.0938.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[Si:20]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc2c1
Reaction time: 4 h
Yield: 88.5 %

Procedure:
A 10 mL round bottom flask fitted with magnetic stirrer and pressure-equalizing dropping funnel was charged with 3 mL of DMF which had been dried by vacuum distillation from CaH2. Methyl 6-hydroxy-2-naphthoate (1.01 g, 5 mmol) and t-butyldimethyl silyl chloride (0.83 g, 5.5 mmol) were added and the atmosphere replaced with nitrogen. A solution of imidazole (0.75 g, 11 mmol) in 3 mL of dry DMF was added via the dropping funnel over 15 minutes, and stirring continued for 4 hours TLC analysis (SiO2, 5% ethyl acetate/hexane) showed clean conversion to a new material. The solution was poured into 50 mL of 1% aq. Na2CO3 solution and extracted with 3-35 mL portions of pentane. The combined pentane solutions were washed with 25 mL of water, 25 mL of brine and dried over MgSO4. Evaporation of the pentane yielded 1.45 g of slightly yellow solid. Purification by column chromatography on silica using 5% (V/V) ethyl acetate/hexane as eluent afforded 1.4 g (88%) of white solid after recrystallization from pentane mp 72°-72.5° C.; 1H NMR delta 0.266 (s, 6H), 1.022 (s, 9H), 3.958 (s, 3H), 7.19-8.53 (m, 6H); 13C NMR delta -4.35, 18.23, 25.64, 52,03, 114 74, 122 87, 125 38, 125.62, 126.75, 128.16, 130.87, 130.95, 137.10, 155.69, 167.36; IR (KBr) 2950, 2860, 1715, 1635, 1605, 1480, 1290, 1210 cm-1 ; MS m/e (rel. intensity) 316 (33, 285(7), 260 (33), 259 (100), 200 (11), 185 (13), 141 (8). ##STR24##