Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:8][O:7][C:1](=[O:6])[CH2:2][CH2:3][C:4]#[C:5][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2
Reactant: C#CCCC(=O)OC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, methyl 4-pentynoate (163 mg, 1.45 mmol) (see below) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (300 mg, 1.03 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (30 mg) and CuI (15 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 70° C. for 14 h to yield (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester. (Yield 120 mg, 33%).
Reaction SMILES: [F:1][C:2]1([F:11])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.CN(CCN(C)C)C.C([Li])CCC.[CH2:25]([O:27][C:28](=[O:36])[C:29](=[CH:32]OCC)[C:30]#[N:31])[CH3:26]>C1(C)C=CC=CC=1.O>[CH2:25]([O:27][C:28](=[O:36])/[C:29](/[C:30]#[N:31])=[CH:32]/[C:10]1[C:4]2[O:3][C:2]([F:1])([F:11])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)[CH3:26]
Reactant: FC1(F)Oc2ccccc2O1
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C#N)=C/c1cccc2c1OC(F)(F)O2

Procedure:
40.0 g (253 mmol) of 2,2-difluoro-1,3-benzodioxole in 29.5 g (254 mmol) of TMEDA and 35 ml of toluene are metallated analogously to Example 2c) at from -15° to -10° C. with 106.2 g (307 mmol) of n-butyllithium solution (18.5% in toluene). 52.1 g (308 mmol) of ethoxymethylenecyanoacetic acid ethyl ester in 115 ml of toluene are added to the reaction mixture at from -15° to -10° C. over a period of 2 hours. The resulting suspension is poured, after 20 minutes at +10° C., into 350 ml of water, the aqueous phase is separated off and the organic phase is concentrated by evaporation in a vacuum rotary evaporator to yield the desired product.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[N:16]1([C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([N:16]2[CH2:17][CH2:18][N:19]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([CH:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)[CH2:7][CH2:6]3)=[O:4])[CH2:20][CH2:21]2)=[CH:27][CH:26]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C(CBr)N1CCN(C2CCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(N2CCN(CC(=O)N3CCN(C4CCCC4)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-bromo-1-(4-cyclopentyl-piperazin-1-yl)-ethanone (1.2 mmol), 1-(4-piperazin-1-yl-phenyl)-ethanone (1.2 mmol) and potassium carbonate (2.4 mmol) in acetonitrile (10 mL) is stirred at rt overnight. The solvent is removed in vacuo and to the residue is added DCM (40 mL) and aqueous sodium bicarbonate (15 mL). The layers are separated and aqueous layer is extracted with DCM (15 mL). The combined organic layers are dried (MgSO4) and solvent removed in vacuo to give the crude product, which is purified by PTLC (5% MeOH in DCM) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:3]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:38]1[CH2:42]OC[CH2:39]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:3]=1[CH:23]([CH2:39][CH2:38][CH3:42])[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1Cc1ccc(OC)cc1)CCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1Cc1ccc(OC)cc1)CCC3

Procedure:
This compound was prepared according to the procedure C from Methyl [2-methyl-4-(p-anisyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.245 g; 0.667 mmol), LHMDS 1N in THF (0.733 mL; 0.733 mmol), 1-iodopropane (0.098 mL; 1.000 mmol) in DMF (2.6 mL) for 18 h.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:15][C:14]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:12])[CH2:5]2.Cl[CH2:39][CH2:40][O:41][CH2:42][CH2:43]Cl.CCN(C(C)C)C(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1C(=O)CCC1>[CH2:31]([O:30][C:14]1[CH:15]=[C:16]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:17]([CH:19]([CH3:21])[CH3:20])=[CH:18][C:13]=1[C:11]([N:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([N:1]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:3]=2)[CH2:7]1)=[O:12])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: ClCCOCCCl
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc(N)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(C(=O)N2Cc3ccc(N4CCOCC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 150 °C

Procedure:
A mixture of (5-amino-1,3-dihydro-isoindol-2-yl)-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-methanone (100 mg; 0.2 mmol), bis(2-chloroethyl)ether (30 μl; 1.1 equiv.), Hunigs base (125 μl; 3.5 equiv.) and tetrabutylammonium iodide (10 mg) in NMP (1 ml) was heated in a CEM microwave synthesiser at 150° C. for 30 minutes. A further 30 μl of Hunigs base and 125 μl of bis(2-chloroethyl)ether were added and heating repeated for the same time. The reaction mixture was partitioned between EtOAc and saturated NH4Cl solution, the EtOAc layer was separated, washed with more saturated NH4Cl solution, then brine, dried (MgSO4) and evaporated. Purification by flash column chromatography (1:2 then 1:1 then 2:1 EtOAc/P.E. as eluant) gave 60 mg of (2,4-bis-benzyloxy-5-isopropyl-phenyl)-(5-morpholin-4-yl-1,3-dihydro-isoindol-2-yl)-methanone. MS: [M+H]+ 563.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C@@H:28]([NH:33][C:34]([CH2:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=1)=[O:35])[C:29]([F:32])([F:31])[F:30]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:42][CH2:41][C:40]1[CH:39]=[CH:38][C:37]([CH2:36][C:34](=[O:35])[NH:33][C@H:28]([CH3:27])[C:29]([F:32])([F:30])[F:31])=[CH:44][CH:43]=1
Reactant: C[C@@H](NC(=O)Cc1ccc(CN)cc1)C(F)(F)F
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: C[C@@H](NC(=O)Cc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)C(F)(F)F
Yield: 44.7 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (84 mg, 0.196 mmol) and (R)-4-[(1-methyl-2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzylamine (102 mg, 0.39 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain (R)-7-chloro-6-{4-[(1-methyl-2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (47 mg, 45%). MS (ES+) m/z: 536 (M+H)+.
Reaction SMILES: Br[C:2]1[O:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[S:29][CH:28]=[N:27][CH:26]=1)CCC>>[S:29]1[C:25]([C:2]2[O:6][C:5]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[CH:4][CH:3]=2)=[CH:26][N:27]=[CH:28]1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)o1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2cncs2)o1

Procedure:
The title compound was prepared by a method analogous to that described in Example 14 from (R)-3′-(5-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 5-(tri-n-butylstannyl)thiazole. The title compound (40 mg) was obtained as a pale solid, m/z 332 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9](Cl)[N:8]=1)[CH3:2].C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>CC#N>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9]([NH:30][CH2:29][C:28]2[CH:31]=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:27]=2[O:26][CH3:25])[N:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)COc1nc(NCc2ccc(OC)cc2OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
To a cooled (˜10° C.) solution of (6-chloro-3-nitro-pyridin-2-yloxy)-acetic acid ethyl ester (8.0 g, 30.8 mmol) in MeCN (80 mL) was added a solution of triethylamine (6.4 mL, 46 mmol) and 2,4-dimethoxybenzylamine (5.5 mL, 37 mmol). The mixture was then stirred for 16 hours at ambient temperature and then concentrated in vacuo. The residue was partitioned between EtOAc and aqueous potassium hydrogenphosphate solution. The EtOAc layer was then washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified using SiO2 chromatography (10-50% EtOAc/Petrol) to give [6-(2,4-dimethoxy-benzylamino)-3-nitro-pyridin-2-yloxy]acetic acid ethyl ester (9.53 g) as a yellow solid. MS: [M+H]+ 392
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[C:19]([O:22][CH2:23][CH2:24]Br)(=[O:21])[CH3:20].O>CN(C=O)C>[C:19]([O:22][CH2:23][CH2:24][S:12][C:9]1[CH:8]=[CH:7][C:6]([S:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:11][CH:10]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OCCBr
Reactant: CCC(C)Sc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)Sc1ccc(SCCOC(C)=O)cc1

Procedure:
To a mixture of 4-(1-methylpropylthio)benzenethiol (53.7 g, 271.0 mmol) and potassium carbonate (49.4 g, 358.0 mmol) in DMF under N2 and with stirring is added dropwise 2-bromoethyl acetate (34.0 ml, 298.0 mmol). The mixture is stirred at RT overnight, after which water is added and the mixture is extracted with ether. The combined organic layers are washed with water and brine, dried, the solvent removed and the residue purified by distillation to give 2[4-(1-methylpropylthio)phenylthio]ethyl acetate. To the acetate (60.9 g, 214.0 mmol) in 200 ml of ethanol is added 50% sodium hydroxide (20 ml). The reaction mixture is stirred at RT for 7 hours and is then neutralized by addition of 10% sulfuric acid and extracted with ether. The organic layer is washed with water and brine, dried and the solvent removed to give 2-[4-(1-methylpropylthio)phenylthio]ethanol.
Reaction SMILES: C[C@@H]1O[C@@H](O[C@@H]2C[C@:17]3(O)[C@@:12](CO)([C@H:13]4[C@H:26]([OH:27])C[C@@]5(C)[C@](O)(CC[C@@H]5C5COC(=O)C=5)[C@@H:14]4[CH2:15][CH2:16]3)[C@H](O)C2)[C@H](O)[C@H](O)[C@H]1O.[OH-].[Na+].Cl.[CH3:45][C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[C:47]=1[NH:53][CH2:54][CH:55]([OH:57])[CH3:56].C(Cl)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[CH3:52][C:48]1[CH:49]=[CH:50][CH:51]=[C:46]([CH3:45])[C:47]=1[N:53]([CH2:54][CH:55]([OH:57])[CH3:56])[C:26](=[O:27])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:12]=1
Reactant: C[C@@H]1O[C@@H](O[C@H]2C[C@@H](O)[C@]3(CO)[C@H]4[C@H](O)C[C@]5(C)[C@@H](C6=CC(=O)OC6)CC[C@]5(O)[C@@H]4CC[C@]3(O)C2)[C@H](O)[C@H](O)[C@H]1O
Reactant: Cc1cccc(C)c1NCC(C)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O=C(Cl)c1ccccc1
Product: Cc1cccc(C)c1N(CC(C)O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
100 ml of a 2 n aqueous sodium hydroxide solution are added dropwise, under ice cooling and vigorous stirring, to a suspension of 21.6 g (0.1 moles) of 1-(2,6-dimethylphenyl-amino)-2-propanol hydrochloride in 100 ml of benzene, and then 12.2 ml (14.6 g, 0.1 moles) of benzoyl chloride are dropped into the mixture at room temperature. The resulting mixture is stirred at room temperature for 5 hours and allowed to stand overnight. The aqueous phase is separated, the benzene phase is washed twice with 50 ml of water, twice with 50 ml of a 1 n hydrochloric acid solution and then thrice with 50 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. 26.6 g (94%) of 1-[N-(2,6-dimethylphenyl)-benzamido]-2-propanol are obtained as a white, crystalline substance; m.p.: 121°-122° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[CH2:12]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[C:20]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13][CH2:12][C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]1=2
Reactant: c1ccc2c(c1)CCc1ccccc1C2
Reactant: COc1ccc(F)c(C=O)c1
Product: COc1ccc(F)c(C=C2c3ccccc3CCc3ccccc32)c1
Yield: 6.4 %

Procedure:
Following procedures essentially as described in Example 28 and using 2-fluoro-5-methoxybenzaldehyde (1.59 g, 10.3 mmol) and dibenzosuberane (1.94 g, 10 mmol), provides 210 mg of title compound as white crystals. mp 110.7° C. (hexane). HPLC shows 99% purity.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([SH:11])[NH:10][C:6]=2[CH:5]=1)[CH3:2].CC(C)([O-])C.[K+].Br.Br[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[CH2:23]Br>CC(O)(C)C>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]3[CH2:23][CH:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[S:11][C:9]3=[N:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2nc(S)[nH]c2c1
Reactant: BrCC(Br)c1ccccn1
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOc1ccc2c(c1)nc1n2CC(c2ccccn2)S1
Reaction time: 1 h

Procedure:
5-Ethoxy-2-mercaptobenzimidazole (6.03 g) was suspended in 2-methylpropan-2-ol (100 ml) at 50° C. Potassium tert-butoxide (3.48 g) was added and the mixture stirred for 1 hour. The temperature was allowed to fall to 35° C. and 2-(1,2-dibromoethyl)pyridine hydrobromide (10.76 g) was added. The resulting mixture was stirred for 1 hour at 35° C. and then 2 hours at reflux.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][C:8]1([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13](=[O:14])[O:12]C(C)(C)[O:10][C:9]1=[O:17])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[C:22]([O:21][C:19](=[O:20])[CH2:18][C:8]([C:13]([OH:14])=[O:12])([C:9]([OH:17])=[O:10])[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:26])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)OC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(CC(=O)OC(C)(C)C)(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The compound of Example 165 (200 mg, 0.54 mmol) was dissolved in a mixture of THF (10 mL) and water (2 mL). Lithium hydroxide monohydrate (46 mg, 1.07 mmol) was added and the mixture was stirred for 24 h at room temperature. The solvent was evaporated and the residue was dissolved in water (5 mL) and extracted with ether. The water phase was acidified by HCl to pH1 and extracted with ethyl acetate. After drying over sodium sulfate, filtration and evaporation, the solvent was evaporated to dryness. 1H NMR(CDCl3, 300 MHz): 1.43(s, 18H); 3.10(s, 4H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4].[CH2:15]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)C>[CH2:15]([CH:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)=[O:4])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1ccc([N+](=O)[O-])cc1

Procedure:
The title compound is prepared from 2-chloro-N-(4-nitro-phenyl)-acetamide [J. Amer. Chem. Soc. 45, 1997. (1923)] and 4-benzyl-piperidine according to the method described in Example 142b. Melting Point: 126-128° C. (diethylether)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9](OC)[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].B(Br)(Br)Br.[OH2:19]>C(Cl)Cl>[OH:19][C:8]1[CH:9]=[C:10]([O:11][CH3:12])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1cc(O)c(C=O)cc1OC
Temperature: 0 °C
Reaction time: 10 h
Yield: 87 %

Procedure:
To solution of 3,4,5-trimethoxybenzaldehyde (5 g, 25.5 mmol) in CH2Cl2 (125 ml) at 0° C. was added BBr3 (6.39 g, 25.5 mmol). The resulting dark mixture was stirred at 0° C. for 10 hrs after completion of the reaction checked by TLC H2O (100 mL) was then added and the mixture was stirred for 10 min and the aqueous phase was extracted by CH2Cl2. The organic phase was dried over Na2SO4, and evaporated under reduced pressure. The resulting residue was purified by silica gel (CH2Cl2) afforded the 2-hydroxy 4,5dimethoxybenzaldehyde A1 (4.3 g) in 87% yield isolated yellow solid: 1H NMR (500 MHz, CDCl3) δ 11.33 (s, 1H), 9.63 (s, 1H), 6.83 (s, 1H), 6.40 (s, 1H), 3.87 (s, 3H), 3.81 (s, 3H) ppm. Mass: ESI [M+Na]+: 225.06; Elemental anal. calcd. for C9H10O4; C, 59.34; H, 5.53; O, 35.13. found C, 59.14; H, 5.13; O, 34.90.
Reaction SMILES: [CH2:1]1[O:8][C@@H:7]2[O:9][C@H:2]1[CH:3]=[CH:4][C:5]2=[O:6].[BH4-].[Na+].CC(C)=O>O>[C@@H:7]12[O:8][CH2:1][C@@H:2]([O:9]1)[CH:3]=[CH:4][C@@H:5]2[OH:6]
Reactant: O=C1C=C[C@H]2CO[C@@H]1O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O[C@H]1C=C[C@H]2CO[C@@H]1O2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 34.1 %

Procedure:
16.0 g (127 mmol) of levoglucosenone was dissolved in 700 ml of water, followed by adding 8.00 g (211 mmol) of sodium borohydride to! the solution. The resultant system was kept stirred at room temperature for 5 minutes. Then, 400 ml of acetone was added to the mixture, and solvent was removed by distillation under reduced pressure, followed by adding chloroform to the residue so as to remove insoluble components by means of filtration. The filtrate was distilled under reduced pressure so as to remove the solvent. Further, the residue was recrystallized from a mixed solvent consisting of 4 parts of hexane and 1 part of diethyl ether so as to obtain 5.55 g of 1,6-anhydro-3,4-dideoxy-β-D-threo-hex-3-enopyranose (compound 2). The yield of the compound 2 was 34.1%. Further, the mother liquor after the recrystallization was refined with a silica gel column chromatograph by using, as an eluent, a mixed solvent consisting of 1 part of hexane and 1 to 2 parts of ether, and recrystallization was achieved again using a mixed solvent consisting of 1 part of hexane and 3 parts of ethyl acetate so as to obtain 2.14 g of the compound (2). The total yield of the compound (2) was 7.69 g, i.e., 60.1%. The 1H-NMR spectrum of the compound (2) thus obtained was found to be as follows, which was equal to that of the compound (2) obtained in step a) of Example 1:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:16][O:17][C:18]=2[CH2:19][OH:20])=[CH:8][N:7]=1)=O)C.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[CH:28]1([NH:31][C:4]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]3[C:15]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)=[N:16][O:17][C:18]=3[CH2:19][OH:20])=[CH:8][N:7]=2)=[O:3])[CH2:30][CH2:29]1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Reaction time: 8 h
Yield: 26 %

Procedure:
As described for example 29e, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid ethyl ester (75 mg, 0.2 mmol) was converted, at 85° C. overnight, using cyclopropylamine instead of isopropylamine, to the title compound (20 mg, 26%), which was obtained as a colourless gum. MS: m/e=384.2 [M+H]+.
Reaction SMILES: C([O:9][C@H:10]([CH3:31])[C@H:11]1[O:15][C@@H:14]([N:16]2[CH:23]=[C:22]([CH3:24])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[C@H:13]([O:25][CH2:26][CH2:27][O:28][CH3:29])[C@@H:12]1[OH:30])(=O)C1C=CC=CC=1.N1C=CN=C1.[Si:37](Cl)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]>CN(C=O)C.CCOC(C)=O.N>[CH3:29][O:28][CH2:27][CH2:26][O:25][C@@H:13]1[C@H:12]([O:30][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C@@H:11]([C@@H:10]([CH3:31])[OH:9])[O:15][C@H:14]1[N:16]1[CH:23]=[C:22]([CH3:24])[C:20](=[O:21])[NH:19][C:17]1=[O:18]
Reactant: COCCO[C@@H]1[C@H](O)[C@@H]([C@@H](C)OC(=O)c2ccccc2)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: N
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCO[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]([C@@H](C)O)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
A mixture of Compound 10 (1.33 g, 3.06 mmol) and imidazole (2.09, 30.70 mmol) was dissolved in anhydrous DMF (11.4 mL). To this solution tert-butyldimethylsilyl chloride (2.31 g, 15.33 mmol) was added with stirring at room temperature for 16 h under an atmosphere of argon. The reaction mixture was diluted with EtOAc (75 mL) and washed with saturated aqueous NaHCO3 (2×60 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue obtained was dissolved in methanolic ammonia (20 mL, 7 M) and stirred for 24 h at 55° C. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography and eluted with 50% EtOAc in hexanes to yield Compound 11 (1.21 g, 89%). ES MS m/z 455.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24]1>>[NH2:28][C@H:25]1[CH2:26][CH2:27][N:23]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[C:8]=3[NH:12][C:13](=[O:21])[CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:3]=2)[CH2:24]1
Reactant: Cc1ccc2nc(Cl)ccc2c1NC(=O)CC1CCCCC1
Reactant: N[C@H]1CCNC1
Product: Cc1ccc2nc(N3CC[C@H](N)C3)ccc2c1NC(=O)CC1CCCCC1
Yield: 68.7 %

Procedure:
Prepared according to the method of example 30, using N-(2-Chloro-6-methyl-5-quinolinyl)-cyclohexaneacetamide (Example 15(a)) (0.2 g) and (3S)-3-pyrrolidinamine (0.163 g) which after recrystallisation from ethanol afforded the title compound (0.159 g).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1)[CH3:2].C(O)(=O)C.[I:13]Cl>C(Cl)Cl>[CH2:1]([C:3]1[N:4]=[C:5]([NH2:8])[S:6][C:7]=1[I:13])[CH3:2]
Reactant: CCc1csc(N)n1
Reactant: ClI
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc(N)sc1I
Reaction time: 1 h

Procedure:
4-Ethyl-thiazol-2-ylamine (0.960 g, 7.49 mmol) was dissolved in 17 mL of CH2Cl2 and 3.5 mL of acetic acid and treated at 0° C. with iodine monochloride (7.86 mL of 1M in CH2Cl2, 1.05 eq.) and kept at this temperature for 1 h. Pouring onto crashed ice/Na2CO3, twofold extraction with ethyl acetate, washing with water and brine, drying over sodium sulfate, and evaporation to dryness afforded 1.67 g of the title compound as almost black viscous oil, sufficiently pure to be used for the next step.