Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH2:12]CCl)=[CH:8][S:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[I:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH2:12][O:29][C:26]2[CH:27]=[CH:28][C:23]([I:22])=[CH:24][CH:25]=2)=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cscc1NC(=O)CCCl
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cscc1NC(=O)COc1ccc(I)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of 4-(3-chloro-propionylamino)-thiophene-3-carboxylic acid methyl ester ([51486-30-7], 2.0 g, 8.6 mmol) in dimethylformamide (30 mL) was added potassium carbonate (1.77 g, 12.8 mmol) and 4-iodophenol (2.26 g, 10.3 mmol) and the reaction mixture was then stirred overnight at 90° C. To the reaction mixture was added ethyl acetate (approximately 30 mL). The solid was filtered and washed with ethyl acetate. The filtrate was then reduced in vacuo and dissolved in dichloromethane (approximately 50 mL). The solution was filtered again over charcoal and to the filtrate was added isopropylether. After reducing the solution slowly in vacuo the solid was filtered to yield the title compound (3.57 g, 79%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH3:12])=[C:10]([C:13](=[O:15])[CH3:14])[C:9]([CH3:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17](OC(C)C)=[O:18].[Na]>C(O)C>[C:1]1([N:7]2[C:11]([CH3:12])=[C:10]([C:13](=[O:15])[CH:14]=[N:17][OH:18])[C:9]([CH3:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)ON=O
Reactant: CC(=O)c1c(C)nn(-c2ccccc2)c1C
Agent: [Na]
Solvent: CCO
Product: Cc1nn(-c2ccccc2)c(C)c1C(=O)C=NO
Temperature: 7 °C
Reaction time: 18 h

Procedure:
1-Phenyl-3,5-dimethyl-4-acetyl pyrazole (Chem. Abs. 63, 16332) (53 g) was dissolved in absolute ethanol (120 ml) and cooled to 7° C. Isopropyl nitrite (29.3 g) was added followed by a solution of sodium (5.7 g) in absolute ethanol (110 ml). The mixture was stirred 18 hours at 0°-10° C. and the fawn coloured sodium salt of the oxime filtered and washed with acetone (25 ml). The filter cake was then dissolved in water (40 ml) and the solution acidified with acetic acid (7 ml). The mixture was then extracted with chloroform (200 ml) and the chloroform extract dried over anhydrous sodium sulphate and then concentrated under vacuum to give 1-phenyl-3,5-dimethyl-4-(2'-oximino acetyl)-pyrazole as a yellow coloured solid.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[C:7]([NH:26][C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)=[N:8][C:9]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[NH:18]C(=O)OC(C)(C)C)=[CH:10][C:5]=2[CH2:4][NH:3]1.Cl.O1CCOCC1>>[NH2:18][C@H:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]1[NH:11][C:9]1[N:8]=[C:7]([NH:26][C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)[C:6]2[C:2](=[O:1])[NH:3][CH2:4][C:5]=2[CH:10]=1
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)cc3c2C(=O)NC3)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.6 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (50.0 mg, 0.111 mmol) and 4N HCl in dioxane (2 mL, 8.00 mmol) was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure, the residue was purified by reverse phase preparative HPLC. The fractions were collected, concentrated, diluted with EtOAc, and basified with saturated aq NaHCO3 solution. The organic extract was dried and evaporated to give the title compound as a white solid (10 mg, 25.7%). 1H NMR (500 MHz, CDCl3) δ ppm 1.19-1.77 (m, 8 H), 2.29 (s, 3 H), 3.20 (br s, 1 H), 3.99 (br s, 1 H), 4.19 (s, 2 H), 6.06 (s, 1 H), 6.75 (d, J=7.32 Hz, 2H), 7.14 (t, J=7.81 Hz, 1 H), 7.48 (d, J=7.32 Hz, 1 H), 7.60 (s, 1 H), 7.90 (s, 1 H), 8.87 (s, 1 H). [M+H] calc'd for C20H25N5O, 352; found, 352.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.CN(C)C=O.[H-].[Na+].Br[CH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>O>[O:25]1[CH2:26][CH2:27][CH:22]([CH2:21][N:7]2[C:6]3[CH:12]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:9][C:8]2=[O:11])[CH2:23][CH2:24]1
Reactant: BrCC1CCOCC1
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc2c(c1)N(CC1CCOCC1)C(=O)CO2
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
4.9 g (0.03 mol) of 6-amino-3,4-dihydro-2H-1,4-benzoxazin-3-one is introduced into 50 ml of dimethylformamide. At 5° C., 0.79 g (0.033 mol) of sodium hydride is added, and the mixture is stirred for 30 minutes at this temperature. Subsequently, 5.9 g (0.033 mol) of 4-bromomethyltetrahydropyran is added, the mixture is stirred for 3 hours at 60° C., 200 ml of water is added, extraction is carried out twice with methylene chloride, followed by drying and evaporation of the solvent under reduced pressure. There is obtained 5 g (64%) of 4-(tetrahydropyran-4-ylmethyl)-6-amino-3,4-dihydro-2H-1,4-benzoxazin-3-one as an oil.
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=[O:6])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.[OH-].[Na+]>CCOC(C)=O>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[CH2:2][C:1]([OH:7])=[O:12])=[O:6])=[CH:16][CH:15]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C1Cc2ccccc2C(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccccc1C(=O)Nc1ccc(Cl)cc1
Reaction time: 16 h
Yield: 47.7 %

Procedure:
A solution of homophthalic anhydride (4.0 g, 24.7 mmol) in 250 mL of CHCl3 was treated with 4-chloroaniline (3.31 g, 25.9 mmol). After 16 h, the mixture was poured into EtOAc and 1 N NaOH. The aqueous layer was washed with EtOAc, then brought to a pH of 2-3 by addition of 1 N HCl. The aqueous layer was washed with EtOAc (2×), and the combined extracts were dried (MgSO4) and concentrated. Recrystallization of the residue from EtOAc/hexanes yielded 3.41g (48%) of the title compound.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:7][N+:8]([O-])=O)C>CCOC(C)=O.CCO.[Ni]>[CH2:20]([O:19][C:12]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[CH:6]1[CH2:7][NH:8][C:4](=[O:3])[CH2:5]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)CC(C[N+](=O)[O-])c1ccc(OC)cc1OCc1ccccc1
Agent: [Ni]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C2CNC(=O)C2)c(OCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 10 h
Yield: 72.4 %

Procedure:
3-(2-Benzyloxy-4-methoxyphenyl)-4-nitro-butyric acid ethyl ester (5.2 g) was dissolved in 20 mL EtOAc and 30 mL of EtOH. Raney Ni was added and the mixture was stirred under H2 for 10 h. The mixture was filtered through celite, heated at 90° C. for 20 h and then cooled down to r.t. The mixture was then concentrated and purified on silica gel to give 3 g of the desired product. Yield: 72%.
Reaction SMILES: C(OC(=O)C)C.[ClH:7].[Cl:8][C:9]1[CH:55]=[CH:54][C:12]2[NH:13][CH2:14][CH2:15][CH2:16][CH:17]([O:18][C:19]([CH:21]([N:41]3[CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43][CH2:42]3)[C:22](=[O:40])[C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:37])=[CH:25][C:24]=3[CH3:39])=[O:20])[C:11]=2[CH:10]=1>C(OCC)(=O)C>[ClH:8].[ClH:7].[Cl:8][C:9]1[CH:55]=[CH:54][C:12]2[NH:13][CH2:14][CH2:15][CH2:16][CH:17]([O:18][C:19]([CH:21]([N:41]3[CH2:42][CH2:43][NH:44][CH2:45][CH2:46]3)[C:22](=[O:40])[C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:37])=[CH:25][C:24]=3[CH3:39])=[O:20])[C:11]=2[CH:10]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)C(C(=O)OC2CCCNc3ccc(Cl)cc32)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)C(C(=O)OC2CCCNc3ccc(Cl)cc32)N2CCNCC2)c(C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 4N hydrogen chloride ethyl acetate solution (3.7 ml) was added to an ethyl acetate solution (15 ml) of tert-butyl 4-{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethyl}-piperazine-1-carboxylate (1.2 g, 1.8 mmol), and the mixture was stirred at room temperature for 12 hours. The precipitates were collected by filtration, washed with ethyl acetate, and dried to obtain 800 mg of 1-{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethyl}-piperazine dihydrochloride as yellow powder.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:31]([C:28]1[CH:27]=[CH:26][C:25]([CH2:24][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH2:14][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[CH3:6])=[CH:30][CH:29]=1)[CH3:32]
Reactant: CCc1ccc(CCc2ccccc2OCCC2CCCCN2C(=O)OC(C)(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ccc(CCc2ccccc2OCCC2CCCCN2C)cc1
Yield: 80.9 %

Procedure:
Following a procedure similar to that described in Example 38(a), 1.00 g of 1-t-butoxycarbonyl-2-(2-{2-[2-(4-ethylphenyl)ethyl]phenoxy}ethyl)piperidine [prepared as described in Example 69(a)] were reacted with 0.173 g of lithium aluminum hydride dispersed in 20 ml of tetrahydrofuran. The mixture was then worked up as described in Example 38(a), and the crude product thus obtained was purified by column chromatography through silica gel using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.650 g (yield 81%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[N:17][C:18]([NH2:30])=[C:19]([C:21]4[O:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)[CH:20]=3)[C:12]([CH:31]=O)=[N:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:33][NH2:34].[Na]>CO.ClCCl.ClCCl.CO>[NH2:30][C:18]1[N:17]=[CH:16][C:15]([C:13]2[C:12]([CH2:31][NH:34][CH3:33])=[N:11][N:10]([CH:7]3[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]3)[CH:14]=2)=[CH:20][C:19]=1[C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1
Reactant: CC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)c(C=O)n2)CC1
Reactant: CN
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Product: CNCc1nn(C2CCN(C(C)=O)CC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.8 %

Procedure:
Over a period of 5 minutes, a solution of 1-(1-acetylpiperidin-4-yl)-4-(6-amino-5-(1,3-benzoxazol-2-yl)pyridin-3-yl)-1H-pyrazole-3-carbaldehyde (132 mg) in MeOH/dichloromethane (1:1) that had been cooled to 0° C., was added to a stirred solution of methylamine (0.153 ml, 0.31 mmol) dissolved in dichloromethane (6 ml) and methanol (6 ml). The resulting solution was stirred at 0° C. for 20 minutes. Sodium triacetoxyhydroborate (78 mg) was added at 0° C. to the mixture and stirred at 0° C. for 5 hours. The mixture was evaporated. A saturated solution of sodium bicarbonate was added and the mixture was extracted with methylene chloride, dried over magnesium sulphate, filtered and evaporated under reduced pression. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 micron silica, 19 mm diameter, 100 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness, tritured with hot acetonitrile, filtered and dried under reduce pressure to afford 1-[4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-(methylaminomethyl)pyrazol-1-yl]-1-piperidyl]ethanone (23 mg) as a solid. NMR Spectrum: (CDCl3) 1.86-2.11 (m, 2H), 2.15 (s, 3H), 2.13-2.24 (m, 1H), 2.24-2.33 (m, 1H), 2.60 (s, 3H), 2.73-2.84 (m, 1H), 3.21-3.32 (m, 1H), 3.96 (s, 2H), 3.97-4.06 (m, 1H), 4.31-4.42 (m, 1H), 4.70-4.85 (m, 1H), 6.97 (bs, 2H), 7.32-7.41 (m, 2H), 7.54 (s, 1H), 7.57 (dd, 1H), 7.73 (dd, 1H), 8.32 (s, 1H), 8.42 (s, 1H); Mass spectrum: M+H+ 446;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[CH3:8].[N-:17]=[N+:18]=[N-:19].[Na+].[Cl-].C([NH+](CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]2[NH:19][N:18]=[N:17][N:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(-c2ccccc2C#N)cc1F
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1F

Procedure:
2.26 g (10.7 mmol) of the compound from Example IV are boiled under reflux with 3.48 g (53.6 mmol) of sodium azide and 7.37 g (53.6 mmol) of triethylammonium chloride in 30 ml of analytical grade dimethylformamide for 24 hours. After cooling, the mixture is partitioned between ether and 1M sulphuric acid, the organic phase is washed with water and dried over sodium sulphate and the solvent is evaporated off. The crude product is extracted by stirring in toluene and, after filtration with suction, the product is dried in vacuo (1.89 g, 7.2 mmol). The mother liquor is evaporated on a rotary evaporator and the residue is purified again as above (0.43 g, 1.7 mmol).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[F:11][C:12]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1.Cl[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38]>C(Cl)Cl>[F:11][C:12]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:31]2)=[CH:26][CH:27]=1
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cc2)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3F)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
Diisopropylethylamine (0.14 mL, 0.75 mmol) was added to a suspension of 4-({[2′-fluoro-4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride (0.10 g, 0.25 mmol) in CH2Cl2 (7 mL). The mixture was cooled to 0° C. in an ice bath, and isopropyl chloroformate (1.0M in toluene, 0.28 mL, 0.28 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature, and stirred overnight. The mixture was then concentrated to give the crude product as a colorless oil. The crude product was purified by chromatography on a silica gel column eluted with 5:6 EtOAc/hexane to give 0.11 g (98%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.80-7.70 (m, 2H), 7.65-7.55 (m, 1H), 7.50 (d, 2H, J=8.8 Hz), 6.98 (d, 2H, J=8.6 Hz), 4.92 (septet, 1H, J=6.1 Hz), 4.25-4.15 (m, 2H), 3.86 (d, 2H, J=6.3 Hz), 3.09 (s, 3H), 2.85-2.75 (m, 2H), 2.10-1.90 (m, 1H), 1.90-1.80 (m, 2H), 1.35-1.10 (m, 8H); LRMS (ESI), m/z 450 (M+H).
Reaction SMILES: [N:1]([C@@H:4]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([CH3:26])[O:14][C@H:6]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[N+:2]=[N-:3].C1C=C(Cl)C=C(C(OO)=[O:45])C=1>C(Cl)Cl>[N:1]([C@@H:4]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([CH3:26])[O:14][C@H:6]([S:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:45])[C@H:5]1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[N+:2]=[N-:3]
Reactant: COc1ccc(CO[C@H]2[C@H](N=[N+]=[N-])[C@H](OC(=O)c3ccccc3)[C@H](C)O[C@@H]2Sc2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(CO[C@H]2[C@H](N=[N+]=[N-])[C@H](OC(=O)c3ccccc3)[C@H](C)O[C@@H]2S(=O)c2ccccc2)cc1
Temperature: -20 °C

Procedure:
To a solution of phenyl 3-azido-4-O-benzoyl-3,6-di-deoxy-2-O-(4-methoxybenzyl)-1-thio-β-L-galactopyranoside (β-16, prepared above), (350 mg, 0.7 mmol) in 10 mL of CH2Cl2 at -78° C. is added a solution of mCPBA (170 mg, 1.1 mmol) in 2 mL of CH2Cl2. The reaction mixture is allowed to warm to -20° C. and then quenched with TEA (500 μL, 3.59 mmol). The reaction mixture is diluted with 10 mL of CH2Cl2, washed with saturated NaHS3 (10 mL), saturated NaHCO3 (10 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography (EtOAc/petroleum ether) to give the title compound as a mixture of diastereomers.
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:21]([O:23][CH3:24])=[O:22])[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].CO>[C:1]1([NH:7][C:8]2([C:21]([O:23][CH3:24])=[O:22])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: COC(=O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(Nc2ccccc2)CCNCC1
Yield: 85 %

Procedure:
A mixture of 32.5 parts of methyl 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylate and 200 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue solidifies on scratching in 2,2'-oxybispropane. The product is filtered off and dried in vacuo, yielding 20 parts (85%) of methyl 4-(phenylamino)-4-piperidinecarboxylate; mp. 139.1° C.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.[CH2:26]([O:28][C:29]([C:31]1[CH:32]=[C:33]2[CH:38]=[N:37][N:36]=[C:35]([NH:39][C:40]3[CH:45]=[C:44]([C:46](O)=[O:47])[CH:43]=[CH:42][C:41]=3[O:49][CH3:50])[N:34]2[C:51]=1[CH3:52])=[O:30])[CH3:27]>CN(C=O)C.O>[CH2:26]([O:28][C:29]([C:31]1[CH:32]=[C:33]2[CH:38]=[N:37][N:36]=[C:35]([NH:39][C:40]3[CH:45]=[C:44]([C:46](=[O:47])[NH:25][CH:22]4[CH2:24][CH2:23]4)[CH:43]=[CH:42][C:41]=3[O:49][CH3:50])[N:34]2[C:51]=1[CH3:52])=[O:30])[CH3:27]
Reactant: CCOC(=O)c1cc2cnnc(Nc3cc(C(=O)O)ccc3OC)n2c1C
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cnnc(Nc3cc(C(=O)NC4CC4)ccc3OC)n2c1C
Reaction time: 8 h

Procedure:
To a suspension of HOBt (30 mg, 0.20 mmol), EDCI (30 mg, 0.16 mmol), cyclopropyl amine (20 uL, 0.29 mmol) in DMF (0.5 mL) at RT was added 4-(5-carboxy-2-methoxy-phenylamino)-6-methyl-pyrrolo[1,2-d][1,2,4]triazine-7-carboxylic acid ethyl ester (13 mg, 0.035 mmol). The reaction was stirred overnight. Water (1 mL) was added and the precipitate collected. The product was purified by flash chromatography on silica gel (1-3% MeOH in CH2Cl2) giving the title compound, 7 mg, as a yellowish solid. HPLC (condition A) tR 4.37 min. MS m/z 410 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[N:13]=[C:14]([CH3:17])[S:15][CH:16]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[N:13]=[C:14]([CH3:17])[S:15][CH:16]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2oc(-c3csc(C)n3)cc12
Agent: BrB(Br)Br
Product: Cc1nc(-c2cc3c(O)cccc3o2)cs1
Yield: 78.6 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 5 using 4-(4-methoxybenzo(b)furan-2-yl)-2-methylthiazole (2.7 g) obtained in Starting Material Synthesis Example 67 and boron tribromide (7.5 g), 4-(4-hydroxybenzo(b)furan-2-yl)-2-methylthiazole (2.0 g) was obtained as yellow crystals. By the reactions in the same manner as in Starting Material Synthesis Example 2 using this compound, (S)-glycidyl nosylate (2.9 g) and potassium carbonate (3.1 g), (S)-4-(4-glycidyloxybenzo(b)furan-2-yl)-2-methylthiazole (2.1 g) was obtained as a brown oil. By the reactions in the same manner as in Example 1 using the brown oil and 4-(naphthalen-2-yl)piperidine (1.5 g), the title compound (0.3 g) was obtained as white crystals, melting point 148-150° C.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CC(C)=O>[CH2:23]([O:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:7])=[CH:4][CH:3]=1)[CH:22]=[CH2:21]
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)C(=O)OCC)cc1
Temperature: 40 °C

Procedure:
1.62 g (8.39 mmol) ethyl 4-hydroxybenzoylformate and 5.79 g (42 mmol) K2CO3 are dissolved in 70 ml acetone. 1.22 g (10.1 mmol) allyl bromide is added dropwise at room temperature. The mixture is heated at 40° C. for 3.25 hours under nitrogen atmosphere. The mixture is then filtered and evaporated. The phases are separated and water is extracted with toluene. The organic phases are dried over magnesium sulfate. Evaporation of the solvent and chromatography (eluent: hexane ethyl acetate 3:1) give 1.39 g (71 wt %) of a yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][C:18]([CH3:21])([NH2:20])[CH3:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>ClCCl>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][C:18]([NH:20][C:33](=[O:35])[CH3:34])([CH3:19])[CH3:21])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:2][CH2:3]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC(C)(C)N)ccc2n1CC1CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC(C)(C)CS(=O)(=O)c1ccc2c(c1)nc(CC(C)(C)C)n2CC1CC1
Reaction time: 4 h
Yield: 78.6 %

Procedure:
To a solution of 1-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropan-2-amine (step G, of EXAMPLE 18, 39 mg, 0.1 mmol) in dichloromethane (0.5 mL) were added pyridine (0.016 mL, 0.2 mmol) and acetic anhydride (0.012 mL, 0.12 mmol) at room temperature. After 4 h, the reaction was quenched by addition of water (10 mL) and the organic layer was separated. The aqueous layer was extracted with dichloromethane (10 mL×2) and the combined organic layer was washed with water (10 mL), brine (5 mL) and dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel TLC eluting with hexane/ethyl acetate (1/5) to afford 33 mg (78%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:16][CH2:17][OH:18])[CH2:15][CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN1CCOCC1.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:34]([N:37]2[CH:41]=[N:40][N:39]=[N:38]2)=[CH:33][C:29]=1[C:30](Cl)=[O:31]>ClCCl>[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:34]([N:37]2[CH:41]=[N:40][N:39]=[N:38]2)=[CH:33][C:29]=1[C:30]([N:13]1[CH2:14][CH2:15][C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)([CH2:16][CH2:17][OH:18])[CH2:12]1)=[O:31]
Reactant: COc1ccc(C2(CCO)CCNC2)cc1OC
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(C2(CCO)CCN(C(=O)c3cc(-n4cnnn4)ccc3OC)C2)cc1OC
Temperature: -5 °C
Reaction time: 18 h

Procedure:
Combine 3-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine (2.27 g, 9.03 mmol) and N-methylmorpholine (2.48 mL, 22.6 mmol) in anhydrous dichloromethane (100 mL). Cool the reaction mixture to -5° C. with an salt-ice bath. Slowly, add 2-methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride (9.5 mmol) as a solution in dichloromethane (30 mL). Warm to ambient temperature. After 18 hours, extract the reaction mixture with a saturated solution of potassium carbonate. Dry the organic layer over Na2SO4, filter, and concentrate invacuo to obtain the title compound.