Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[NH:11][C:10](=[O:15])[N:9]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[N:18]=[C:8]3[C:7]=2[CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[ClH:33]>C(OCC)(=O)C>[ClH:33].[CH3:26][N:2]([CH2:3][CH:5]1[CH2:14][CH2:13][C:12]2[NH:11][C:10](=[O:15])[N:9]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[N:18]=[C:8]3[C:7]=2[CH2:6]1)[CH3:1]
Reactant: CN(C)C(=O)C1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Product: CN(C)CC1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Reaction time: 0.33 h

Procedure:
To 100 mL of anhydrous tetrahydrofuron was added 9-(N,N-Dimethylcarbamyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (70 mg). The mixture was refluxed until the solid had completely dissolved. Refluxing was ceased and 100 mg of lithium aluminum hydride was added to the solution. This mixture was allowed to stand for 20 min before being quenched with ethyl acetate. The quenched reaction mixture was filtered through celite and the solvent removed in vacuo to yield an oil. The oil was then dissolved in 5 mL of ethyl acetate and to this ethyl acetate solution was added 1 mL of HCl saturated ethyl acetate. A solid precipitated was collected and dried to yield 9-(N,N-Dimethylaminomethyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one monohydrochloride (Compound 24), m.p.>325° C.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:12]([F:13])=[CH:11][C:10]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[N:24]=[N:23][C:22]([CH3:25])=[N:21]4)[O:16][C:15]3=[O:26])=[CH:9][C:8]=2[F:27])[CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:29].[Na+].CO>ClCCl>[O:29]=[S:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([F:27])=[CH:9][C:10]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[N:24]=[N:23][C:22]([CH3:25])=[N:21]4)[O:16][C:15]3=[O:26])=[CH:11][C:12]=2[F:13])[CH2:3][CH2:2]1
Reactant: Cc1nnn(C[C@H]2CN(c3cc(F)c(C4CCSCC4)c(F)c3)C(=O)O2)n1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1nnn(C[C@H]2CN(c3cc(F)c(C4CCS(=O)CC4)c(F)c3)C(=O)O2)n1
Yield: 9.1 %

Procedure:
(5R)-3-[4-(Tetrahydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[(5-methyl-2H-tetrazol-2-yl)methyl]oxazolidin-2-one (Example 34) (0.53 g, 1.34 mmol) was oxidized with sodium periodate (0.314 g, 1.47 mmol) as described for Intermediates 42 and 43. Chromatography on silica gel with 0-5% methanol in dichloromethane gave a mixture together with the corresponding E-isomer, which was separated on a Chiracel OD chiral chromatography column using hexanes/isopropanol (1:1) as eluant to give the title compound (50 mg) as a colourless solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:15][CH2:16][C:17](=O)[CH2:18][CH3:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:18]([C:17]1[CH2:16][CH2:15][C@@H:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1)[CH3:19]
Reactant: CCOC(=O)[C@H](CCC(=O)CC)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCC(CC)=N1

Procedure:
Ethyl (2S)-2-((tert-butoxycarbonyl)amino)-5-oxoheptanoate and trifluoroacetic acid (3 mL) were stirred in dichloromethane (3 mL) at room temperature for 3 hours. The mixture was concentrated under reduced pressure to provide the titled compound. MS (ESI) m/z 170 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5].C1(C2C=CC(N)=CC=2)CCCCC1.[Si]([O:43][CH2:44][CH2:45][O:46][C:47]1[C:54]([CH3:55])=[CH:53][C:50]([CH:51]=O)=[CH:49][C:48]=1[CH3:56])(C(C)(C)C)(C)C>C(O)C>[CH:13]1([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:1]=[C:51]3[C:50]3[CH:53]=[C:54]([CH3:55])[C:47]([O:46][CH2:45][CH2:44][OH:43])=[C:48]([CH3:56])[CH:49]=3)=[CH:8][CH:9]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cc1cc(C=O)cc(C)c1OCCO[Si](C)(C)C(C)(C)C
Reactant: Nc1ccccc1C(=O)Nc1ccc(C2CCCCC2)cc1
Agent: Nc1ccc(C2CCCCC2)cc1
Solvent: CCO
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(C3CCCCC3)cc2)cc(C)c1OCCO
Yield: 55 %

Procedure:
Following the method described for Example 21, 2-amino-N-(4-cyclohexylphenyl)benzamide was made from 4-cyclohexylaniline in 70% yield and isolated as a white solid. 2-Amino-N-(4-cyclohexylphenyl)-benzamide (4.58 mmol), 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylbenzaldehyde (1.41 g, 4.58 mmol), anhydrous CuCl2 (1.84 g, 13.74 mmol) were combined in anhydrous ethanol (100 mL) and heated at reflux for 7 hours. The mixture was concentrated, diluted with ethyl acetate (300 mL), washed with water (100 mL) and then brine (150 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography on silica gel, eluting with 50% ethyl acetate/hexanes to 100% ethyl acetate, afforded the title compound in 55% yield, as a white solid. 1H-NMR (300 MHz, DMSO-6): δ 8.18 (d, J=7.5 Hz, 1H), 7.86-7.92 (m, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.55-7.60 (m, 1H), 7.15-7.17 (m, 4H), 6.96 (s, 2H), 4.84 (t, J=5.3 Hz, 1H), 3.62-3.36 (m, 4H), 2.48-2.50 (m, 1H), 2.06 (s, 6H), 1.67-1.78 (m, 5H), 1.32-1.39 (m, 5H). MS (ESI) m/z: 469 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:24]=2[N:23]([CH3:25])[C:22]([CH3:26])=[CH:21]3)[C:7]1=[O:27].O.[OH-].[Li+]>C1COCC1.O>[CH3:25][N:23]1[C:24]2[C:20](=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][N:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:6]([CH2:5][CH2:4][C:3]([OH:28])=[O:2])[C:7]2=[O:27])[CH:21]=[C:22]1[CH3:26]
Reactant: COC(=O)CCn1c(=O)n(Cc2cccc3cc(C)n(C)c23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2cccc(Cn3c(=O)n(CCC(=O)O)c4ccccc43)c2n1C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a stirred solution of 3-[3-(1,2-dimethyl-1H-indol-7-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid methyl ester (90 mg, 0.24 mmol) in THF (3 ml) and water (0.5 ml) was added lithium hydroxide monohydrate (15 mg, 0.36 mmol). The reaction was stirred for 0.5 h and concentrated to low volume. The remaining residue was diluted with water and acetic acid (0.3 ml). The resulting suspension was stirred at ambient temperature over night. The precipitate was collected via filtration, washed with water and then suspended in 1:1 acetonitrile/water. The solid precipitate was isolated via filtration and dried to give 65 mg (87%) of 3-[3-(1,2-dimethyl-1H-indol-7-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid. LCMS (ESMS): m/z 364.41 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][CH2:6]1)=[O:4]>[Pd].CCO.CCO.C1COCC1>[CH3:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4]
Reactant: CNC(=O)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)N1CCNCC1
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Palladium on carbon (300 mg, 10% by wt.) was placed under an inert atmosphere and suspended in EtOH (10 mL). A solution of 4-benzyl-piperazine-1-carboxylic acid methylamide (1.50 g, 6.43 mmol) dissolved in 2:1 v/v EtOH/THF (96 mL) was added. The reaction mixture was placed under H2 atmosphere (1 atmosphere pressure) and stirred overnight. The resulting mixture was filtered through a pad of Celite® and the solvent was concentrated in vacuo to give 916 mg (99%) of the title compound as clear oil. 1H-NMR (300 MHz, DMSO-d6) 6.30 (broad d, 1H), 3.15 to 3.12 (m, 5H), 2.59 to 2.55 (m, 4H), 2.53 (d, 3H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][NH:27][CH:28]([CH3:30])[CH3:29])=[CH:8][CH:7]=1)([OH:5])[CH3:4].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:30][CH:28]([N:27]([CH2:26][C@H:13]1[CH2:14][N:15]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])[CH2:16][CH2:17][N:12]1[C:9]1[CH:8]=[CH:7][C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:31])[F:32])=[CH:11][CH:10]=1)[S:39]([C:35]1[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=1)(=[O:41])=[O:40])[CH3:29]
Reactant: CC(C)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1)S(=O)(=O)c1cccnc1
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of 1,1,1-trifluoro-2-(4-((2S)-2-(((1-methylethyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.100 g, 0.203 mmol, Example 195, Step 1) in CH2Cl2 (5.0 mL) was added 4-dimethylaminopyridine (0.005 g, 0.061 mmol), pyridine-3-sulfonyl chloride (0.072 g, 0.407 mmol, WAKO, Richmond, Va.) and Hünig's base (0.106 mL, 0.610 mmol). After 2 h at room temperature, the solvent was removed and the crude product was purified by column chromatography (40 g of silica, 20 to 40% acetone in hexanes) to give N-(1-methylethyl)-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-pyridinesulfonamide (0.120 g) as a mixture of two isomers.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)SC)#[N:2].[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15]>N1C=CC=CC=1>[C:1]([NH:3][C:4]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[N:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])#[N:2]
Reactant: CSC(=NC#N)SC
Reactant: NCCCCCO
Solvent: c1ccncc1
Product: N#CNC(=NCCCCCO)NCCCCCO

Procedure:
Heating dimethyl N-cyanodithioimidocarbonate with an excess of 5-aminopentan-1-ol in pyridine gives N-cyano-N',N"-bis(5-hydroxypentyl)guanidine, which may be treated with p-toluenesulphonyl chloride in pyridine and the product heated with thiourea in acetone to give N-cyano-N', N"-bis(5-(S-isothioureido)pentyl)guanidine.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14](=[CH:20][N:21](C)[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:25])=[C:7]([F:24])[CH:8]=2)[N:3]=1.[CH:26]1(N)C[CH2:27]1>ClC(Cl)Cl>[CH:22]1([N:21]2[C:2]3[N:3]=[C:4]4[CH:5]=[C:6]([F:25])[C:7]([F:24])=[CH:8][C:9]4=[CH:10][C:11]=3[C:12](=[O:13])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20]2)[CH2:27][CH2:26]1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)cc2nc1Cl
Reactant: NC1CC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
A solution of ethyl 2-(2-chloro-6,7-difluoro-3-quinolinecarbonyl)-3-(dimethylamino)acrylate (20 g) and cyclopropylamine (9.25 g) in trichloromethane (80 cc) is stirred at a temperature in the region of 20° C. for 5 hours. The solution is concentrated under reduced pressure (20 kPa) at approximately 40° C. The residue is taken up in ethanol (300 cc), treated with DBU (8.2 g) and heated with stirring to approximately 75° C. for 30 minutes. After cooling to approximately 20° C., the insoluble matter is drained and washed with ethanol (2×30 cc). 1-Cyclopropyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (11.1 g) is obtained in the form of a yellow solid, m.p. 230° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[BH4-].[Na+]>CO>[CH2:8]([NH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: NCCNCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NCCNCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A stirred solution of 108.26 ml (998 mmol) of 1,4,7-triaza-heptane in 750 absolute methanol is mixed at 0° C. drop by drop with a solution of 20.0 g (188 mmol) of benzaldehyde in 100 ml of absolute methanol. After a reaction time of 2 hours at 0° C., it is mixed in portions with a total of 7.13 g (188 mmol) of sodium borohydride and stirred for another 12 hours at 25° C. For working-up, the reaction mixture is filtered on diatomaceous earth, and the solvent is drawn off in a vacuum. The remaining oily residue is mixed with dichloromethane (250 ml) and water (250 ml) and extracted. After extraction of the aqueous phase is again performed with dichloromethane, the combined organic phases are dried on sodium sulfate, filtered, and the solvent is drawn off in a vacuum. The residue is chromatographed on silica gel (eluant: methanol/aqueous ammonia solution 20/1).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][C:7]([C:9](O)=[O:10])=[CH:8][C:4]=2[CH:3]=1>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][C:7]([CH2:9][OH:10])=[CH:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1cc2cc(Br)ccc2s1
Solvent: C1CCOC1
Product: OCc1cc2cc(Br)ccc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
Dissolve 5-bromo-benzo[b]thiophene-2-carboxylic acid (21.2 g, 82.5 mmol) in THF (150 mL). Cool to 0° C. with an ice bath. Add 2M BH3 dimethyl sulfide complex in THF (82.5 mL). Stir to room temperature over 2 hours. Quench by careful addition of water. Partition between ether and saturated NaHCO3, wash with water, brine, dry, and concentrate. Purify via column chromatography eluting with 3:1 hexanes:ethyl acetate to afford a white solid (10.3 g): 1H NMR (CDCl3) δ 7.87 (m, 1H), 7.67 (d, 1H), 7.41 (dd, 1H), 7.15 (m, 1H), 4.94 (d, 2H), 1.91 (t, 1H).
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][CH:18]=[O:19])[C:15](=[O:20])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.C(OCC1C(C(O)=O)N2[C:35](=O)[C@@H:36](NC=O)[C@H:29]2[S:28][CH:27]=1)(=O)C.S1C=CC=C1.FC(F)(F)C(O)=O>>[CH:18]([NH:17][C@@H:16]1[C:15](=[O:20])[N:10]2[CH:11]([C:12]([OH:14])=[O:13])[C:6]([CH2:5][C:27]3[S:28][CH:29]=[CH:36][CH:35]=3)=[CH:7][S:8][C@H:9]12)=[O:19]
Reactant: CC(=O)OCC1=CS[C@@H]2[C@H](NC=O)C(=O)N2C1C(=O)O
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Solvent: c1ccsc1
Solvent: O=C(O)C(F)(F)F
Product: O=CN[C@@H]1C(=O)N2C(C(=O)O)C(Cc3cccs3)=CS[C@H]12
Reaction time: 0.33 h

Procedure:
A mixture of 4.6 g of an approximately 1:3-mixture of 3-acetyloxymethyl-7β-formylamino-ceph-3-em-4-carboxylic acid and 3-acetyloxymethyl-7β-formylamino-ceph-2-em-4ξ-carboxylic acid (prepared as described below), 7 ml of thiophene and 28 ml of trifluoroacetic acid is allowed to stand for 20 minutes at room temperature and then evaporated to dryness while repeatedly adding toluene. The semi-crystalline residue is dissolved in hot methyl acetate and the solution diluted with methylene chloride and cyclohexane, whereupon a slightly yellow, coarsely crystalline precipitate forms, which is filtered off and dried, to yield the 7β-formylamino-3-(2-thenyl)-ceph-2-em-4ξ-carboxylic acid, m.p. 164°-166° (decomposition starts at 160°); thinlayer chromatogram (silica gel); Rf = 0.60 (system: n-butanol/acetic acid/water 75:7.5:21), Rf = 0.47 (system: n-butanol/ethanol/water 40:10:50), Rf = 0.66 (system: n-butanol/acetic acid/water 40:10:40) and Rf = 0.55 (system: ethyl acetate/pyridine/acetic acid/water 62:21:6:11); ultraviolet absorption spectrum (in 95% ethanol):λmax = 234 mμ (ε = 13900) and λmax = 216 mμ (ε =10900); infrared absorption spectrum (in mineral oil): characteristic bands at 3,08μ, 3,87μ, 5,68μ, 5,80μ, 6,04μ, 6,52μ 7,07μ, 8,06μ, 8,23μ, 8,53μ, 8,69μ, 9,65μ, 9,74μ, 11,79μ and 14,24μ. A further quantity of the desired product is obtained if the mother liquor is chromatographed on 50 times its weight of silica gel; the 7β-formulamino-3-(2-thenyl)-ceph-2-em-4ξ-carboxylic acid is eluted with a 3:1-mixture of methylene chloride and ethyl acetate.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:22](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:22][NH:19][CH2:18][C:12]1([C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CNCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 54.7 %

Procedure:
(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (300 mg, 1.1 mmol) was dissolved in 1,2-dichloroethane (30 mL) and cooled to 0° C. Formaline solution (˜0.1 mL, 35%) was added to the solution, followed by sodiumtriacetoxy borohydride (0.16 g, 0.76 mmol). The reaction mixture was further stirred for 45 min maintaining the same temperature. The reaction mixture was then quenched with 10% NaHCO3 solution and diluted with CH2Cl2. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica 60-120 mesh, eluent 10-20% MeOH in CHCl3) to afford N-methyl-1-(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (120 mg, yield 38%). 1H NMR (300 MHz, CDCl3) δ 7.90-7.88 (m, 2H), 7.48 (s, 1H), 7.44-7.34 (m, 3H), 3.93-3.86 (m, 2H), 3.75-3.67 (ddd, J=12.0 Hz, 8.9 Hz, 3.0 Hz, 2H), 3.01 (s, 2H), 2.49 (s, 3H), 2.36-2.39 (m, 2H), 2.09-2.01 (m, 2H). MS (ESI) m/z: Calculated for C16H20N2OS: 288.13. found: 289.2 (M+H)+.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C@H:12]3[NH:15][CH2:16][CH2:17][C@:6]4([C@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)[C:5]=2[CH:4]=[C:3]([C:18](=[O:20])[CH3:19])[CH:2]=1.C(=O)(O)[O-].[Na+].[CH3:26][C:27]([CH3:31])=[CH:28][CH2:29]Br>CN(C)C=O>[CH3:26][C:27]([CH3:31])=[CH:28][CH2:29][N:15]1[CH2:16][CH2:17][C@@:6]23[C:5]4[CH:4]=[C:3]([C:18](=[O:20])[CH3:19])[CH:2]=[CH:1][C:14]=4[CH2:13][C@@H:12]1[C@@H:11]2[CH2:10][CH2:9][CH2:8][CH2:7]3
Reactant: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: CC(C)=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(CC=C(C)C)CC3
Temperature: 25 °C
Yield: 93.1 %

Procedure:
To a mixture of 1.8 g of (-)-1-(morphinan-3-yl)ethanone, 0.6 g of sodium bicarbonate and 25 ml of dimethylformamide, was added 1.0 g of dimethylallyl bromide. After the mixture had been heated at 50° for 16 hours, it was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was partitioned between 50 ml of methylene chloride and 30 ml of water. The methylene chloride solution was washed with water and dried over magnesium sulfate. Removal of the solvent gave 2.1 g (93%) of crude (-)-1-[17-(3-methyl-2-butenyl)morphinan-3-yl]ethanone. For analysis, a sample of this compound was distilled, bp 185°-195° (0.05 mm), [α]25D-76.53° (c 0.98, MeOH).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:2]2.C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:2]2[CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]3[CH2:7][CH:1]2[CH2:6][CH2:5]3)=[O:27])=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1NC2CCC1C2
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1C2CCC(C2)N1C(=O)c1ccc(OC)cc1
Yield: 73.6 %

Procedure:
To a solution of ethyl 2-azabicyclo[2.2.1]heptane-3-carboxylate (181 mg, 1.07 mmol) obtained in Example 1 (b) in chloroform (2 ml) were added triethylamine (0.16 ml, 1.18 mmol) and 4-methoxybenzoyl chloride (201 mg, 1.18 mmol) while being cooled with ice. After a reaction at room temperature for 1 hour, the reaction mixture was washed with 1N hydrochloric acid, saturated sodium bicarbonate water and saturated brine successively, and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (25%–40% ethyl acetate/hexane), to give ethyl 2-(4-methoxybenzoyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (239 mg, 74%).
Reaction SMILES: [SH:1][C:2](=[C:4]([C:7]#[N:8])[C:5]#[N:6])[SH:3].[Na].[Na].O.C[N:13]([CH:15]=[O:16])C>>[O:16]=[C:15]1[NH:13][N:6]=[CH:5][C:4]2[S:1][C:2](=[C:4]([C:7]#[N:8])[C:5]#[N:6])[S:3][C:2]1=2
Reactant: N#CC(C#N)=C(S)S
Reactant: CN(C)C=O
Agent: [Na]
Solvent: O
Product: N#CC(C#N)=C1Sc2cn[nH]c(=O)c2S1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a stirred solution of 20 g (0.1 mole) disodiumdimercaptomethylene malononitrile dissolved in 250 ml of DMF was added 16.5 g (0.1 mole) of 4,5-dichloro-3-pyridiazone. The reaction mixture was stirred at room temperature (approximately 20° C.) for 0.25 hours and was thereafter poured with stirring into 1 liter of water. The resulting mixture was allowed to stand for four hours during which time a yellow-gray precipitate slowly formed. This precipitate was separated by filtration, washed with water, and dried in vacuo to yield 21.1 g (90% yield from the pyridiazone) of a yellow-gray solid, m.p. (decomposition) 310°-340° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:15][P:16]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][C:34]([CH3:43])([CH3:42])[C:35]([O:37]C(C)(C)C)=[O:36])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([O:15][P:16]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][C:34]([CH3:43])([CH3:42])[C:35]([OH:37])=[O:36])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)COCCOCCOP(=O)(OCc1ccccc1)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(COCCOCCOP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.1 %

Procedure:
TFA (6.63 mL, 86 mmol) was added dropwise to a stirred solution of tert-butyl 3-(2-(2-((bis(benzyloxy)phosphoryl)oxy)ethoxy)ethoxy)-2,2-dimethylpropanoate (50) (4.5 g, 8.61 mmol) in DCM (43 mL) and the reaction mixture was allowed to stir at RT for 16 h then concentrated in vacuo. The crude product was dissolved in EtOAc (150 mL) and washed with 1M HCl (aq.) (50 mL), water (2×50 mL), and brine (50 mL) the organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford 3-(2-(2-((bis(benzyloxy)phosphoryl)oxy)ethoxy)ethoxy)-2,2-dimethylpropanoic acid (51) (3.98 g, 99%) as a colourless oil: m/z 467 (M+H)+ (ES+); 465 (M−H)− (ES−). 1H NMR (400 MHz, CDCl3) δ: 7.36-7.31 (m, 10H), 5.12-5.03 (m, 4H), 4.14-4.09 (m, 2H), 3.69-3.64 (m, 2H), 3.60 (s, 4H), 3.47 (s, 2H), 1.20 (s, 6H).
Reaction SMILES: N1C=CC=CC=1.[S:7]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[CH3:23][Si:24]([CH2:27][OH:28])([CH3:26])[CH3:25].C1(C)C=CC=CC=1>O>[S:7]([O:17][CH:18]([CH3:22])[C:19]([O:28][CH2:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[O:20])([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)OC(C)C(=O)Cl)cc1
Reactant: C[Si](C)(C)CO
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC(C)C(=O)OC[Si](C)(C)C)cc1

Procedure:
33 g (0.41 mole) of pyridine are slowly added dropwise to a mixture of 109 g (0.41 mole) of the S-enantiomer of tosyloxy-propionic acid chloride, 43.4 g (0.41 mole) of trimethylsilyl-methanol and 250 ml of toluene at 20° C., with stirring. The mixture is subsequently stirred at room temperature for 24 hours. Working up is then carried out by a procedure in which the reaction mixture is poured into water and extracted with toluene and the organic phase is concentrated by stripping off the diluent under reduced pressure. 130 g (96% of theory) of the S-enantiomer of trimethylsilyl-methyl 2-tosyloxy-propionate are obtained in this manner in the form of an oily product.