Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].CO.[CH3:13][O:14][C:15](=[O:29])[CH:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C@@H:21]([CH3:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH3:13][O:14][C:15](=[O:29])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C@@H:21]([CH3:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]
Reactant: COC(=O)C1CCCN1[C@@H](C)c1ccccc1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)[C@@H]1CCCN1[C@@H](C)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
L-tartaric acid (9.51 g) was mixed with methanol (14.18 g) and heated to 40° C. To the resulting solution was added dropwise a 50% toluene solution (28.93 g) of N-[(S)-α-methylbenzyl]-(RS)-proline methyl ester obtained in Example 1 at that temperature. After stirred at the temperature for 1 hour, the reaction mixture was cooled to 0° C. over 14 hours and stirred at that temperature for 2 hours. The crystallized solid was separated by filtration and washed with cold methanol to yield a salt of N-[(S)-α-methylbenzyl]-(S)-proline methyl ester and L-tartaric acid (11.50 g) in 98.8% diastereomeric excess (hereinafter referred to as “d.e.”) and a yield of 40.0%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C:10]1([O:36][CH3:37])[C:34](=[O:35])[N:12]2[C:13]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:14]([CH3:17])[CH2:15][S:16][C@H:11]12)=[O:8].[Br-].[K+]>C(O)(=O)C.C([O-])(=O)C.[Mn+3].C([O-])(=O)C.C([O-])(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C:10]1([O:36][CH3:37])[C:34](=[O:35])[N:12]2[C:13]([C:18]([O:20][CH:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:19])=[C:14]([CH2:17][O:20][C:18](=[O:19])[CH3:13])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)CS[C@@H]21
Agent: [Mn+3]
Agent: CC(=O)[O-]
Agent: [Br-]
Solvent: CC(=O)O
Product: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(C)=O)CS[C@@H]21
Temperature: 70 °C

Procedure:
Manganese (III) acetate (5.0 g.) in acetic acid (60 ml.) is heated to 70°C. under nitrogen. To the stirred solution is added benzhydryl 7-(2-thienylacetamido)-7-methoxy-3-methyl-3-cephem-4-carboxylate (4.0 g.) and potassium bromide (0.5 g.). The solution is maintained at 70°C. for about eight hours. The reaction mixture is cooled and manganese (II) acetate is filtered from the cooled solution. The solvent is removed under vacuum to afford benzhydryl 7-(2-thienylacetamido)-7 -methoxy-3-acetoxymethyl-3-cephem-4-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[C:39]1[CH:40]=[CH:41][C:42]([C:45]#[N:46])=[N:43][CH:44]=1>C(COC)OC.O.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:16]=[CH:17][C:18]([C:39]3[CH:44]=[N:43][C:42]([C:45]#[N:46])=[CH:41][CH:40]=3)=[CH:19][CH:20]=2)[O:10][C:9]1([CH3:30])[CH3:31])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)OC1(C)C
Reactant: N#Cc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3ccc(C#N)nc3)cc2)OC1(C)C
Temperature: 90 °C
Yield: 42.4 %

Procedure:
To stirred solution of (4S,5R)-4-Fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidine-3-carboxylic acid tert-butyl ester (0.75 g, 1.72 mmol) in dimethoxyethane:water (8:2, 10 mL) is added Cs2CO3 (1.12 g, 3.44 mmol) and 5-Bromo-pyridine-2-carbonitrile (0.347 g, 1.89 mmol). Reaction mixture is degassed with nitrogen for 30 minutes, followed by addition of Pd(PPh3)4 (0.199 g, 0.172 mmol). The resulting reaction mixture heated to 90° C. for 3 hours. Diluted with water (20 mL) and ethyl acetate (40 mL). The organic layer is separated, dried over sodium sulphate and solvent is evaporated in vacuo to get crude material purified by column chromatography eluting in 15% ethyl acetate in hexane to afford title compound (0.3 g). 1H-NMR (400 MHz, DMSO-d6): δ: 1.43 (s, 9H), 1.51 (s, 3H), 1.63 (s, 3H), 3.83-3.90 (m, 1H), 4.47-4.58 (m, 2H), 4.75-4.93 (m, 2H), 5.15 (d, 1H, J=7.2 Hz), 7.64 (d, 2H, J=8.28 Hz), 7.87 (d, 2H, J=8.24 Hz), 8.15 (d, 1H, J=8.16 Hz), 8.36 (dd, 1H, J=8.2 Hz, J=2.2 Hz), 9.12 (d, 1H, J=2.24 Hz), LC-MS (m/z): [M+H]=412.1.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:13][CH2:12][C:5]2(C(=O)CCC2=O)[CH2:4][CH2:3]1.CC(C)=[O:17]>Cl>[F:1][C:2]1([F:14])[CH2:13][CH2:12][C:5](=[O:17])[CH2:4][CH2:3]1
Reactant: CC(C)=O
Reactant: O=C1CCC(=O)C12CCC(F)(F)CC2
Agent: Cl
Product: O=C1CCC(F)(F)CC1

Procedure:
The product of Step A, 8,8-difluoro-1,4-dioxospiro[4.5]decane was dissolved in acetone (90 ml) and 3N HCl (900 ml), and stirred until the reaction finished. Then, the reaction mixture was extracted with DCM, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The obtained residue was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[CH:5][C:6]2[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]4[CH2:20][C@H:19]4[CH2:21]OS(C)(=O)=O)[CH2:13][CH2:12]3)=[CH:9][S:8][C:7]=2[CH:27]=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CC#N>[N:30]([CH2:21][C@@H:19]1[CH2:20][C@H:18]1[CH2:17][N:14]1[CH2:13][CH2:12][N:11]([C:10]2[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:28])([F:29])[F:1])=[CH:27][C:7]=3[S:8][CH:9]=2)[CH2:16][CH2:15]1)=[N+:31]=[N-:32]
Reactant: CS(=O)(=O)OC[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: [N-]=[N+]=NC[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Temperature: 47 °C
Reaction time: 4 h
Yield: 42.5 %

Procedure:
A mixture of Methanesulfonic acid (1R, 2R )-2-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl )-piperazin-1-ylmethyl]-cyclopropylmethyl ester (3.995 g, 8.92 mmol), NaN3 (1.16 g, 17.85 mmol ) and anhydrous CH3CN (60 mL ) was stirred at 47° C. under N2 for 4 h, then an additional quantity of NaN3 (580 mg, 8.92 mmol ) was added. Stirring was continued at 47° C. for a further 4 h. After cooling to rt, the mixture was filtered through Celite 545, washed with CH3CN. The combined filtrate and washings were concentrated and then separated by Prep LC (heptane/EtOAc—70:30, 60:40, 50:50, 40:60, 30:70, 20:80, 100% EtOAc) to give the desired product (1.5 g, 43%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1.C(N(CC)CC)C>O1CCCC1.O>[O:11]=[C:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=O)C1
Reaction time: 0.08 h

Procedure:
To a solution of 25.63 g (0.2942 M) of 3-pyrrolidinol in tetrahydrofuran (150 ml)-ethanol (50 ml) was added 70.6 g (0.324 M) of di-tert-butyl dicarbonate dropwise at room temperature and the mixture was stirred at room temperature for 1 hour. The solvent was then distilled off under reduced pressure to provide crude t-butyl 3-hydroxypyrrolidine-1-carboxylate. To a solution of 56.0 g (0.441 M) of oxalyl chloride in 400 ml of tetrahydrofuran was added 62.6 ml (0.883 M) of dimethyl sulfoxide dropwise at −78° C. and the mixture was stirred for 5 minutes. Then, a solution of the above crude tert-butyl 3-hydroxypyrrolidine-1-carboxylate in 150 ml of tetrahydrofuran was added dropwise and the mixture was stirred at −78° C. for 15 minutes. To this reaction mixture was added 246 ml (1.77 M) of triethylamine, and after room temperature was reestablished, the mixture was poured in water and extracted with 3 portions of ethyl acetate. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure. This crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:11][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[CH3:11][O:9][C:8]([C:3]1[C:2]([CH3:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1nccnc1C(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1nccnc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methyl-pyrazine-2-carboxylic acid (4.7 g) in toluene (70 ml) and methanol (30 ml) at ambient temperature was added drop wise (trimethylsilyl)diazomethane (2M in diethyl ether) (26 ml). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated and purified by passing through a pad of silica and eluting with 30% v/v ethyl acetate in iso-hexane to give 3-methyl-pyrazine-2-carboxylic acid methyl ester (3.10 g). 1H-NMR (400 MHz, CDCl3): 8.63 (d, 1H), 8.53 (d, 1H), 4.02 (s, 3H), 2.87 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:14][CH:15]=2)[C:10]([S:31]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:44]([NH:46][CH2:47][CH3:48])[CH3:45]>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][N:46]([CH2:47][CH3:48])[CH2:44][CH3:45])=[CH:14][CH:15]=2)[C:10]([S:31]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2ccccc2)cc1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2Cc1ccccc1
Temperature: 80 °C
Reaction time: 16.5 h

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.449 g, 0.733 mmol) and diethylamine (2.0 mL, 19 mmol) in THF (7.5 mL) was stirred at 70° C. in a sealed tube for 3 hours. More diethylamine (2.0 mL, 19 mmol) was then added, and the reaction mixture was stirred at 80° C. in a sealed tube for 16.5 hours. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 82° C. in vacuo for 35 minutes gave {2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-diethyl-amine as a light brown-yellow semi-solid (0.365 g, 97.1% mmol). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried for 13 hours in vacuo at 81° C. The result was the hydrochloride as a light orange semi-solid (0.332 g); Mass Spectrum (+EI, [M+H]+) m/z 514. 1HNMR (500 MHz, DMSO-d6): δ10.15-10.18 (s, 1H), 8.74-8.76 (m, 1H), 8.56 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.26 (d, 1H, J=8.29 Hz), 8.02-8.05 (m, 1H), 7.78 (d, 1H, J=9.15 Hz), 7.70-7.74 (m, 1H), 7.58-7.65 (m, 2H), 7.26 (s, 1H), 7.08-7.19 (m, 6H), 5.70 (s, 2H), 4.25 (s, br, 2H), 3.39-3.55 (br, s, 2H), 3.15 (br, s, 3H), 1.13-1.19 ppm (s, br, 6H). Elemental Analysis for C30H31N3O3S.1.00 HCl.0.75 mol H2O: Calcd: C, 63.93; H, 5.99; N, 7.46; Found: C, 63.59; H, 5.94; N, 7.23.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[NH2:18].[C:20](OC(OCC)OCC)(=O)C.[OH-].[Na+]>O>[CH3:1][CH:2]([CH3:19])[CH2:3][N:4]1[C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]3[N:15]=[N:16][N:17]=[C:7]3[C:6]=2[N:18]=[CH:20]1
Reactant: CC(C)CNc1c(N)c2nnnn2c2ccccc12
Reactant: CCOC(OCC)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)Cn1cnc2c1c1ccccc1n1nnnc21

Procedure:
N5-(2-Methylpropyl)tetrazolo[1,5-a]quinoline-4,5-diamine (0.2 g, 0.78 mmole, Example 16) was combined with diethoxymethyl acetate (2 mL) and heated on a steam bath for 3 hours. Water (10 mL) and 10% sodium hydroxide (2 mL) were added and the reaction mixture was heated on a steam bath for 1 hour. A solid was isolated by filtration then recrystallized from methanol/ethyl acetate to provide 0.16 g of 6-(2-methylpropyl)-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline as a white crystalline solid, m.p. 210-212° C. Analysis: Calculated for C14H14N6: % C, 63.14; % H, 5.30; % N, 31.56; Found: % C, 63.12; % H, 5.32; % N, 31.61.
Reaction SMILES: [CH3:1][C:2]([C:6]1[NH:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1)([CH3:5])[CH2:3][NH2:4].[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[N:20]=1>>[CH3:5][C:2]([C:6]1[NH:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1)([CH3:1])[CH2:3][NH:4][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([C:21]2[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=2)[CH:25]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1nc(-c2ccccc2)n[nH]1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1nc(-c2ccccc2)n[nH]1
Yield: 25 %

Procedure:
This compound was synthesized from 2-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (35 mg, yield 25%). 1H NMR (400 MHz, MeOD) δ 8.55 (s, 1H), 8.29-8.27 (d, J=7.8 Hz, 1H), 8.06-7.97 (m, 3H), 7.71-7.67 (t, J=8.7 Hz, 1H), 7.50-7.41 (m, 3H), 3.75 (s, 2H), 1.54-1.51 (m, 6H). MS (ESI) m/z: Calculated for C22H19F3N6O2: 456.15. found: 457.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]([OH:16])[CH2:13][N:12]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:11][CH:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O)(=O)=O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH:10]2[O:16][CH:14]([CH2:13][N:12]([S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)(=[O:18])=[O:19])[CH2:11]2)[CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccccc1)N1CC(O)CN(Cc2ccccc2)CC(O)C1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)N1CC2CN(Cc3ccccc3)CC(C1)O2
Temperature: 110 °C
Yield: 15 %

Procedure:
The crude product from step (ii) above was dissolved in warm toluene (150 mL) and treated with anhydrous methanesulfonic acid (50 mL). Toluene (105 mL) was removed from the mixture by distillation at reduced pressure (28 mbar). The remaining mixture was then heated to 110° C. for 6.5 h. The mixture was allowed to cool to 30° C. and the remaining toluene removed by distillation under reduced pressure (25 mbar). The mixture was cooled in an ice/water bath to 40° C. and then treated with water (100 mL), which caused the internal temperature to rise to 70° C. After cooling to 20° C. dichloromethane (80 mL) was added. The mixture was basified by the portionwise addition of aqueous sodium hydroxide solution (10 M, 80 mL), such that the internal temperature remained below 30° C. This took 20 minutes. The dicholoromethane layer was separated and evaporated nearly to dryness in vacuo. Methanol (50 mL) was added and the solvent was again removed in vacuo. The resulting solid was suspended in MeOH (50 mL) and filtered. The filter cake was washed with methanol (20 mL) and the resulting solid dried by air suction to give the title compound as a white crystalline solid (3.46 g, 15% over 3 steps).
Reaction SMILES: [I:1]I.[CH2:3]([O:10][C@H:11]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:14][C@H:13]([CH2:34][Hg]Cl)[C@@H:12]1[OH:37])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)Cl>[CH2:3]([O:10][C@H:11]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:14][C@H:13]([CH2:34][I:1])[C@@H:12]1[OH:37])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H]1C[Hg]Cl
Reactant: II
Solvent: ClCCl
Product: O[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H]1CI
Reaction time: 16 h
Yield: 80.7 %

Procedure:
A solution of iodine (3.36 g, 13.2 mmol, 1.2 equiv) in DCM (168 mL) was added to a solution of (((2S,3R,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-hydroxytetrahydro-2H-pyran-2-yl)methyl)mercury(II) chloride (7.5 g, 11.0 mmol, 1.0 equiv) in dry DCM (26 mL) under nitrogen atmosphere. The mixture was stirred for 16 hours and then the reaction was quenched with aqueous sodium thiosulfate solution (20 g in 50 mL water). The mixture was stirred until colorless, the layers were separated, and the organic layer was washed with saturated sodium chloride solution (75 mL) and then water (75 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material thus obtained was then purified by silica gel chromatography, eluting with 15% EtOAc in petroleum ether, to give (2S,3R,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(iodomethyl)tetrahydro-2H-pyran-3-ol as a colorless oil (5.1 g, 81%). 1H NMR (300 MHz, CDCl3) δ 7.40-7.20 (m, 15H), 4.65-4.49 (m, 6H), 4.12 (td, J=5.5, 2.9 Hz, 1H), 4.02 (ddd, J=8.3, 5.8, 2.5 Hz, 1H), 3.85 (dd, J=10.1, 6.0 Hz, 2H), 3.74 (dt, J=10.4, 5.1 Hz, 2H), 3.63 (t, J=3.8 Hz, 1H), 3.40 (dd, J=10.3, 5.8 Hz, 1H), 3.29 (dd, J=10.5, 8.5 Hz, 1H), 3.11 (d, J=9.2 Hz, 1H). ESI (M+23) 597.0; calc for C28H31IO5 574.1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][N:12]1[CH2:17][CH2:16][C:15]([CH2:24][NH2:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:25][CH2:24][C:15]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]1)=[O:6]
Reactant: Cc1ccccc1C(=O)O
Reactant: CN1CCC(CN)(c2ccccc2)CC1
Product: Cc1ccccc1C(=O)NCC1(c2ccccc2)CCN(C)CC1

Procedure:
From 2-methylbenzoic acid and C-(1-methyl-4-phenyl-piperidin-4-yl)-methylamine. LCMS (MH+): m/z=323.1, tR (minutes, Method A)=0.56
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][CH3:12].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH3:12])=[C:4]([CH2:3][OH:2])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)ccc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1CO
Temperature: 0 °C
Yield: 999.5 %

Procedure:
To a solution of 5-chloro-2-methoxy-benzoic acid methyl ester (20 g, 9.97 mmol) in THF (100 mL) at 0° C. was added dropwise a solution of lithium aluminum hydride (210 mL, 210 mmol, 1M soln. in THF). The solution was then warmed to reflux for 2 hours. The reaction was cooled to 0° C. and carefully quenched by the addition of cold water. The mixture was filtered through celite and the filter cake was washed with diethyl ether. The filtrate was washed with saturated aqueous sodium hydrogen carbonate then dried over magnesium sulfate. Concentration in vacuo gave the title compound (17.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11](O)=O)[CH:4]=1.[NH2:14][C:15]1[C:20]([NH2:21])=[CH:19][C:18]([I:22])=[CH:17][N:16]=1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]2[NH:14][C:15]3=[N:16][CH:17]=[C:18]([I:22])[CH:19]=[C:20]3[N:21]=2)[CH:4]=1
Reactant: Nc1cc(I)cnc1N
Reactant: COc1ccnc(CCC(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Temperature: 140 °C
Yield: 61.2 %

Procedure:
With stirring, a mixture of 8.06 g of 3-(4-methoxypyridin-2-yl)propionic acid (starting material B1), 9.5 g of 2,3-diamino-5-iodopyridine (Cugola et al., Bioorg.Med. Chem.Let 22, 2749-2754 (1996)) and 150 g of polyphosphoric acid (PPA) is heated at 140° C. for 22 hours. After cooling, the mixture is poured into about 1000 ml of ice-water and then neutralized (pH 7-8) using 6N aqueous sodium hydroxide solution. The mixture is extracted four times with ethyl acetate and the combined organic phases are evaporated to dryness. The residue is crystallized first from ethyl acetate and then from methanol, giving 9.4 g of the title compound as a light-beige powder of m.p. 207-208° C.; the mass spectrum shows the molecular peak MH+ at 381.2 Da.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:26][NH2:27].O>C(O)CCC.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[C:11](=[N:26][NH2:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1C(=O)c1ccccc1OCc1ccccc1
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCO
Product: COc1ccccc1C(=NN)c1ccccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A stirred suspension 2-benzyloxy-2′-methoxybenzophenone (13) (7.98 g, 0.025 mol) in hydrazine monohydrate (16 mL, 0.328 mol) and 1-butanol (25 mL) was heated to reflux overnight. After cooling to room temperature, the reaction mixture was poured into water saturated with salt and diluted with tetrahydrofuran. The organic phase which forms was separated, washed with water, saturated salt, and evaporated to dryness by rotary evaporation followed by application of high vacuum and mild heating. The resulting oil, 2-benzyloxy-2′-methoxybenzophenone hydrazone (14), which sometimes solidifies, still contains n-butanol and was used without further purification.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][C:6]([CH2:7][O:8][N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH2:20][C:21]([OH:23])=O)=[CH:15][CH:14]=2)[CH2:11][CH3:12])=[CH:5][CH:4]=1.Cl.[O:29]1[CH2:34][CH2:33][CH:32]([CH2:35][NH2:36])[CH2:31][CH2:30]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N1CCOCC1)C>CN(C=O)C>[O:29]1[CH2:34][CH2:33][CH:32]([CH2:35][NH:36][C:21](=[O:23])[CH2:20][NH:19][C:16]2[CH:15]=[CH:14][C:13]([C:10](=[N:9][O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:27])([F:1])[F:26])=[CH:25][CH:24]=3)[CH2:11][CH3:12])=[CH:18][CH:17]=2)[CH2:31][CH2:30]1
Reactant: CCC(=NOCc1ccc(C(F)(F)F)cc1)c1ccc(NCC(=O)O)cc1
Reactant: NCC1CCOCC1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCC(=NOCc1ccc(C(F)(F)F)cc1)c1ccc(NCC(=O)NCC2CCOCC2)cc1
Reaction time: 5 h
Yield: 14.9 %

Procedure:
To a solution of the product of step 4 (6.5 g, 0.0171 moles) in DMF (40 mL), (tetrahydro-2H-pyran-4-yl)methanamine hydrochloride (2.6 gm, 0.0171 moles), HOBT (2.31 gm, 0.0171 moles), EDC.HCl (4.24 gm, 0.0222 moles) and N-ethyl morpholine (5.9 gm, 0.0513 moles) were added and reaction mixture was srirred at 25° C. for 5 hours under nitrogen atmosphere. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evapourated under reduced pressure. The crude product was purified by coloumn chromatography using 1% MeOH in chloroform as eluent to yield 1.22 g (15%) of product as white solid.