Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[O:4][C:5]1[C:10]2[CH2:11][C@@H:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:13][C@@H:14]([CH2:15][N+:16]([O-:18])=[O:17])[C:9]=2[CH:8]=[CH:7][CH:6]=1.Cl>CO>[OH:4][C:5]1[C:10]2[CH2:11][C@@H:12]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[O:13][C@@H:14]([CH2:15][N+:16]([O-:18])=[O:17])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COCOc1cccc2c1C[C@@H](c1ccccc1)O[C@H]2C[N+](=O)[O-]
Agent: Cl
Solvent: CO
Product: O=[N+]([O-])C[C@@H]1O[C@H](c2ccccc2)Cc2c(O)cccc21
Yield: 65.7 %

Procedure:
A solution of 135 mg (0.4 mmol) of [1R,3S] 3,4-dihydro-5-methoxymethoxy-1-nitromethyl-3-phenyl-1H-2-benzopyran, from Step 1, in 5 mL of methanol was saturated with anhydrous hydrogen chloride. The resultant mixture was stirred at reflux temperature for 2 h and then concentrated in vacuo. The residue was purified on silica gel eluted with 5% methanol in methylene chloride to afford 75 mg (66% yield) of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:35])[CH2:16][NH:17][C@H:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:23][CH:24]=3)[CH2:19]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C>[OH:35][C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)[CH2:16][NH:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][C:30]([N:32]([CH3:33])[CH3:34])=[O:31])=[CH:23][CH:24]=2)[CH2:19]1
Reactant: CN(C)C(=O)COc1ccc2c(c1)C[C@@H](NC[C@H](O)c1ccc(OCc3ccccc3)cc1)CC2
Agent: [Pd]
Solvent: CCO
Product: CN(C)C(=O)COc1ccc2c(c1)C[C@@H](NC[C@H](O)c1ccc(O)cc1)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.4 %

Procedure:
2-[(2S)-2-[[(2R)-2-(4-Benzyloxyphenyl)-2-hydroxyethyl]-amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]-N,N-dimethylacetamide (273 mg) and 10% palladium on activated carbon (60 mg) were suspended in ethanol (5.5 ml). After the mixture was stirred at room temperature for 12 hours under hydrogen atmosphere, the catalyst was filtered off and the filtrate was concentrated in vacuo. Recrystallization of the resulting residue from methanol gave 2-[(2S)-2-[[(2R)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]-N,N-dimethylacetamide (200 mg) having a melting point of 169-172° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([OH:27])=[O:26]>>[CH2:1]([NH:8][C:9](=[O:10])[NH:11][C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([C:25]([OH:27])=[O:26])[CH:33]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)NCc1ccccc1
Reactant: O=C(O)c1cccc(B(O)O)c1
Product: Cc1noc(-c2ccc(-c3cccc(C(=O)O)c3)cc2)c1NC(=O)NCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-benzyl-3-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-urea and 3-carboxyphenylboronic acid.
Reaction SMILES: [O:1]([CH2:13][CH3:14])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:15](O)(=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[C:15]([O:12][CH2:11][C@H:9]1[O:10][CH:2]([O:1][CH2:13][CH3:14])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8])(=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CCOC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Product: CCCCCCCCCCCC(=O)OC[C@H]1OC(OCC)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 96.7 %

Procedure:
To a mixture of crude ethyl D-glucopyranoside (578 g, 2.78 mol, prepared according to example 10) and dodecanoic acid (751 g, 3.75 mol) in a stirred batch reactor at 70° C. was added immobilized lipase derived from Candida antarctica (29 g, prepared as described in Danish patent application No. 3250/88). Stirring was continued under reduced pressure (0.05 bar) and the progress of the ester synthesis was monitored by HPLC. After 23 hours the enzyme was removed by filtration (at 70° C.). Excess fatty acid was removed by repeated molecular distillation (105° C., 0.04 mbar) yielding 96% (1050 g) of crude product along with 2% ethyl D-glucoside and 2% of a mixture of diesters (HPLC analysis). The crude product was purified by chromatography Identification by 1H NMR-analysis showed a 1:1 mixture of α and β anomers (tables 42/46).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH2:18][C@H:19]([CH2:24][OH:25])[CH2:20][CH:21]([CH3:23])[CH3:22].C([O-])([O-])=O.[K+].[K+]>O>[CH3:22][CH:21]([CH3:23])[CH2:20][C@H:19]([NH:18][C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2)[CH2:24][OH:25]
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: CC(C)C[C@H](N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(N[C@H](CO)CC(C)C)c2nc(-c3ccccc3)cc-2[nH]1
Yield: 56.4 %

Procedure:
This compound was prepared according to the method described in Example 2 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (100 mg, 0.41 mmol), (S)-(+)-leucinol (Aldrich Chemical Company) (0.26 mL, 2.05 mmol) and K2CO3 (0.567 g, 4.1 mmol) in H2O (2.5 mL) to give 75 mg (56%) of the title compound as shiny off-white crystals. Mp: 267-269° C. (dec.). 1H NMR (DMSO-d6; 400 MHz): δ 0.91-0.95 (m, 6), 1.48-1.52 (m, 2), 1.66-1.70 (m, 1), 2.37 (s, 3), 3.50 (br s, 2), 4.39 (br s, 1), 4.90 (br s, 1), 6.65 (d, 1, J=8.4), 6.72 (s, 1), 7.36-7.52 (m, 3), 7.79 (d, 2, J=7.9), 11.35 (br s, 1). MS m/z: 325 (M+1), 323 (M−1). Anal. Calcd for C,19H24N4O: C, 70.34; H, 7.46; N, 17.27. Found: C, 70.14; H, 7.35; N, 17.13.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].C(C1NC=CN=1)(C1[NH:14]C=CN=1)=O.N.C(OCC)C>C(Cl)Cl>[F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([NH2:14])=[O:5]
Reactant: CC(C)(C(=O)O)C(F)(F)F
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: N
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C(N)=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.9 %

Procedure:
A mixture of 2 g (12.81 mmol) 3,3,3-trifluoro-2,2-dimethylpropionic acid (Aldrich), 2.077 g (12.81 mmol) carbonyl-diimidazole and 5.55 ml (64.1 mmol) aqueous ammonia in 50 ml CH2Cl2 was stirred at room temperature for 20 h. After that, diethyl ether was added and the resulting mixture was washed with 0.1 N HCL, 0.1 N NaOH, water and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford 1.15 g of the title compound as white crystals, that were used in the next step without further purification. MS: M+H=156.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[C:26]([Si:23]([CH3:24])([CH3:25])[O:22][CH2:21][C:20]([N:12]1[C:13]2[C:18]([F:19])=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:41](=[O:42])[CH2:40][C:37]3[CH:36]=[CH:35][C:34]([C:33]([F:44])([F:32])[F:45])=[CH:39][CH:38]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:31])[CH3:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(C(F)(F)F)cc3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 29, 35 mg, 79 μmol), (4-trifluoromethyl-phenyl)-acetic acid (21.8 mg, 106 μmol) and DIPEA (48.94 μL, 277 μmol) in THF (3 mL), T3P (166 μL, 277 μmol) was added and the mixture stirred at 25° C. for 18 hours. The reaction was evaporated under reduced pressure, the residue partitioned between water and ethyl acetate, the organic extracts washed with saturated sodium bicarbonate solution, dried over sodium sulphate, evaporated in vacuo and triturated with pentane-ether to afford the title compound as a white solid. (91%, 45 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:19]=[C:18]([CH3:20])[C:13]3[NH:14][C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)=[O:9])[CH:5]=[C:4]([Cl:21])[N:3]=1.[H-].[Na+].I[CH3:25]>CN(C=O)C>[Cl:21][C:4]1[CH:5]=[C:6]([C:8]([C:10]2[CH:19]=[C:18]([CH3:20])[C:13]3[N:14]([CH3:25])[C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)=[O:9])[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: CI
Reactant: Cc1cc(C(=O)c2cc(Cl)nc(Cl)c2)cc2oc(=O)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(Cl)nc(Cl)c2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere 2.30 g (7.12 mmol) 6-(2,6-dichloro-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 10 mL DMF were combined at 0° C. with 310 mg (7.10 mmol) sodium hydride (55%, suspension in mineral oil). The reaction mixture was stirred for 30 min at RT. Then 0.44 mL (7.10 mmol) iodomethane were added and the mixture was stirred overnight at RT. The reaction mixture was poured onto water and the precipitated product was suction filtered, washed with water and dried.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:8]=[O:9])[N:5]([CH3:7])[CH:6]=1.C([Sn](CCCC)(CCCC)[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)CCC>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.CN(C=O)C>[CH3:7][N:5]1[CH:6]=[C:2]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[N:3]=[C:4]1[CH:8]=[O:9]
Reactant: Cn1cc(Br)nc1C=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1cc(-c2cccs2)nc1C=O
Temperature: 160 °C
Yield: 50.6 %

Procedure:
A glass vial was charged with 4-bromo-1-methyl-1H-imidazole-2-carbaldehyde (1420 mg, 7.5 mmol), tributyl-(2-thienyl)-stannane (3.50 g, 9.38 mmol), DMF (15 mL) and the slurry was deoxygenated by bubbling argon through then tetrakis(triphenylphosphine)palladium(0) (216 mg, 0.1875 mmol) was added and the vessel sealed and heated in a microwave reactor at 160° C. for 30 minutes. The volatiles were removed in vacuo then EtOAc (50 mL) was added followed by saturated sodium bicarbonate solution (25 mL). The organic layer was separated and the aqueous extracted with EtOAc (50 mL). The combined extracts were dried over Na2SO4, filtered and the volatiles removed in vacuo. The residue was purified by column chromatography on silica gel (Gradient: n-heptane/EtOAc=4/1 to EtOAc 100%) to yield the title compound (730 mg, 51%) as a yellow solid. 1H NMR (500 MHz, CDCl3): δ 9.72 (s, 1H), 7.99 (s, 1H), 7.49-7.47 (m, 1H), 7.40-7.38 (m, 1H), 7.12-7.08 (m, 1H), 3.95 (s, 3H).
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[CH3:10][NH2:11].Cl.[CH3:13][NH2:14].[C-]#N.[K+]>O>[CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6]([NH:14][CH3:13])([C:10]#[N:11])[CH2:5][CH2:4]1
Reactant: CN
Reactant: CON1CCC(=O)CC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CNC1(C#N)CCN(OC)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1-methoxy-piperidin-4-one [prepared according to Journal of Organic Chemistry (1961), 26, 1867-74] (100 g, 0.77 mol), aqueous methylamine (40 wt. % in H2O, 86 ml) and methylamine hydrochloride (57.5 g, 0.85 mol) in water (700 ml) at 0° C. was added a solution of potassium cyanide (55.5 g, 0.85 mol) in water (150 ml) dropwise over one hour. The reaction mixture was stirred at room temperature for two days. Over the next five days, the mixture was further treated with methylamine hydrochloride (5×2.6 g, total 13.0 g), aqueous methylamine (5×4.3 ml, total 21.5 ml) and potassium cyanide (5×2.5 g, total 12.5 g), and stirring continued at room temperature until the reaction was judged complete by thin layer chromatography. The aqueous reaction mixture was extracted with dichloromethane (1×500 ml, and 4×200 ml), the combined organic phases dried over sodium sulfate and evaporated. Yield: 113.0 g of 1-methoxy-4-methylamino-piperidine-4-carbonitrile (compound P5.1) as a red liquid. This material was used without further purification in the next step.
Reaction SMILES: [N+:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])([O-:3])=[O:2].[I:12]I>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[I:12][C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[OH:6]
Reactant: II
Reactant: O=[N+]([O-])c1c(O)cccc1O
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1c(O)ccc(I)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A mixture of 1 g (6.4 mmol) of 2-nitroresorcinol, 1.42 g (6.4 mmol) of silver trifluoroacetate and 1.64 g (6.4 mmol) of iodine in 25 mL of chloroform was stirred overnight at room temperature. The reaction mixture was filtered through celite, washed with 20 mL of dichloromethane. The combined filtrate was washed with 10% aqueous sodium metabisulfite, water, brine and dried over anhydrous magnesium sulfate, evaporated to dryness to give 1.6 g of crude 4-iodo-2-nitroresorcinol [H1 NMR (CDCl3) 6.52 (d, 1H, CH, J=8.9 Hz); 7.85 (d, 1H, CH, J=8.9 Hz); 10.67 (s, 1H, OH); 11.43 (s, 1H, OH)] which was used in the next step without further purification. To a mixture of above product in 10 mL of anhydrous dimethylformamide 1.77 g (12.8 mmol) of anhydrous potassium carbonate was added at room temperature followed by 3 mL (48 mmol) of methyl iodide. After stirring overnight at room temperature resulting mixture was diluted to 150 mL with ethyl acetate, washed with water (3×15 mL) brine and dried over anhydrous magnesium sulfate, filtered off and filtrate evaporated to dryness to give 1.6 g of crude product, which was purified by flash column chromatography (silica gel hexane dichloromethane 7:3) to give 1.1 g (56%) of the title compound as a colourless crystals. H1 NMR (CDCl3) 3.87 (s, 3H, OMe); 3.91 (s, 1H, OMe); 6.6 (d, 1H, CH, J=8.9 Hz); 7.75 (d, 1H, CH, J=8.9 Hz).
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[F:6][S:7]([C:10]([F:15])([F:14])[C:11]([OH:13])=[O:12])(=[O:9])=[O:8]>>[F:6][S:7]([C:10]([F:15])([F:14])[C:11]([O:13][Si:2]([CH3:4])([CH3:3])[CH3:1])=[O:12])(=[O:9])=[O:8]
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: C[Si](C)(C)Cl
Product: C[Si](C)(C)OC(=O)C(F)(F)S(=O)(=O)F
Temperature: 25 °C
Yield: 75.6 %

Procedure:
Under argon protection and at 0° C., trimethylsilyl chloride (11.5 g, 106 mmol) was added dropwise slowly into 2-(fluorosulphonyl)difluoroacetic acid (5 g, 28 mmol). Then the mixture was stirred over weekend at r.t. Then the solvent was removed to give 5.3 g crude product as a liquid.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([C@H:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([CH:27]=[CH2:28])[NH:22]2)=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12].[CH:29]([CH2:31][C:32](O)=[O:33])=[CH2:30].Cl>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([C@H:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([CH:27]=[CH2:28])[N:22]2[C:32](=[O:33])[CH2:31][CH:29]=[CH2:30])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12]
Reactant: C=CCC(=O)O
Reactant: C=C[C@@H]1CCC[C@H](c2ccc(C(=O)OC)cc2)N1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCC(=O)N1[C@H](C=C)CCC[C@@H]1c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diethyl cyanophosphonate (0.78 mL) was added to a solution of (2R*,6S*)-2-(4-carbomethoxyphenyl)-6-vinylpiperidine (422 mg), vinylacetic acid (0.44 mL), and triethylamine (1.44 mL) in DMF (5 mL), and the reaction solution was stirred at room temperature for one hour. Ethyl acetate and 1 N aqueous hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with saturated sodium bicarbonate water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane->heptane:ethyl acetate=1:1) to obtain 281 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([CH3:23])[CH:14]=2)=[O:10])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[NH:33]1[CH:37]=[C:36]([CH2:38][CH2:39][CH2:40][C:41](Cl)=[O:42])[N:35]=[N:34]1>C(Cl)Cl>[NH:33]1[CH:37]=[C:36]([CH2:38][CH2:39][CH2:40][C:41]([NH:2][CH:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[C:15]([CH3:23])[CH:14]=3)=[O:10])[CH2:7][CH2:8]2)=[O:42])[N:35]=[N:34]1
Reactant: Cc1cc(COC(=O)N2CCC(N)CC2)cc(C(F)(F)F)c1
Reactant: O=C(Cl)CCCc1c[nH]nn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(COC(=O)N2CCC(NC(=O)CCCc3c[nH]nn3)CC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 3-methyl-5-(trifluoromethyl)benzyl 4-aminopiperidine-1-carboxylate hydrochloride salt (201 mg, 0.570 mmol) in DCM (5 mL) at RT under nitrogen was added Huenig's Base (0.199 mL, 1.140 mmol). 4-(1H-1,2,3,-triazol-4-yl)butanoyl chloride (99 mg, 0.570 mmol) in DCM (2 mL) was added and the reaction mixture stirred at RT for 2 hours. The reaction mixture was diluted with DCM and washed with a 10% solution of citric acid, and saturated brine solution, before the organic portion was dried over MgSO4, filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica using 0-10% MeOH in DCM as eluent to afford the title product;
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]1[C:12]([O:14]CC)=[O:13])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[CH:1]([N:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]1[C:12]([OH:14])=[O:13])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cn1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)n1cc([N+](=O)[O-])cc1C(=O)O
Temperature: 0 °C
Yield: 95352.4 %

Procedure:
Ethyl 1-isopropyl-4-nitro-1H-pyrrole-2-carboxylate (656 mg, 2.900 mmol; see step (ii) above) was dissolved in ethanol (4 mL) to which was added a solution of NaOH (490 mg, 12.250 mmol in water (10 mL)). The reaction mixture was heated under reflux for 1.5 h and then the ethanol was removed under reduced pressure at 40° C. The reaction mixture was extracted with DCM (10 mL), and the water layer was collected, cooled to 0° C. with ice-water then acidified with HClconc with stirring. The white solid material precipitated was filtered off, washed with water and dried under reduced pressure at 50° C. to give the required product (548 g, 95% yield), m.p. 194-195° C.
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:50]1[CH:55]=[C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[N:53]=[C:52]([S:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([F:69])[C:64]=2[F:70])[N:51]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:70][C:64]1[C:65]([F:69])=[CH:66][CH:67]=[CH:68][C:63]=1[CH2:62][S:61][C:52]1[N:51]=[C:50]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:55]=[C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[N:53]=1
Reactant: CC(C)(C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: NS(=O)(=O)N1CCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 1 step iv) using a mixture of azetidine-1-sulfonamide (prepared according to patent WO 2004/011443, 0.16 g), tris(dibenzylideneacetone)dipalladium (0) (70 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (36 mg), cesium carbonate (0.37 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-(1,1-dimethylethoxy)-pyrimidine (the product from step i) (0.26 g) in dioxane (6 mL). Purification was by column chromatography on silica gel using EtOAc/isohexane (1:9 to 2:8 gradient) as eluent to give the title compound as a white solid.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]([NH2:26])=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:34]>ClCCl.O1CCOCC1>[ClH:34].[ClH:34].[C:23]([C:22]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:26])=[NH:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1)([OH:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C(N)=Nc1cccc(-c2ncccc2C(=O)O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N=C(N)Nc1cccc(-c2ncccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N,N-bis(tert-butoxycarbonyl)-N″-(3-(3-carboxypyridin-2-yl)phenyl)guanidine (220 mg) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 3-(3-carboxypyridin-2-yl)phenylguanidine dihydrochloride (144 mg).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1)[CH:2]=[CH2:3].C1(C)C=CC(S(NN)(=O)=O)=CC=1.CC([O-])=O.[Na+]>C(COC)OC.O>[CH3:12][O:11][C:6]1[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: C=CCc1ccc(O)c(OC)c1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCCc1ccc(O)c(OC)c1
Temperature: 25 °C
Yield: 48.1 %

Procedure:
To a solution of 123 mg (0.75 mmole) of 4-allyl-2-methoxyphenol (eugenol) and 1.4 gm (7.5 mmole)of p-toluenesulfonhydrazide in 15 ml of dimethoxyethane under reflux was added a solution of 1.7 gm of NaOAc in 15 ml water over a 4 hour period. The mixture was cooled to room temperature, poured into 20 ml of water, and extracted three times with 30 ml of CH2Cl2. The combined organic layers were washed with 50 ml of water, dried over MgSO4, and concentrated under vacuo. The resulting solid was flash chromatographed over silica gel using 10% ethyl acetate in hexane to afford 60 mg of 2-methoxy-4-propylphenol in 48% yield.
Reaction SMILES: CN(C)C(=O)[O:4][CH:5]([C:15]1[N:16]([CH3:36])[C:17]([C:26]2[S:27][C:28]3[N:29]=[CH:30][N:31]=[C:32]([NH2:35])[C:33]=3[N:34]=2)=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1)[C:6]1[C:14]2[O:13][CH2:12][O:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.CN(C)C(=O)OC(C1N(C)C(C2SC3N=CN=C(N)C=3N=2)=C(C2C=CC=CC=2)N=1)C1C=CC=CC=1>>[NH2:35][C:32]1[C:33]2[N:34]=[C:26]([C:17]3[N:16]([CH3:36])[C:15]([CH:5]([C:6]4[C:14]5[O:13][CH2:12][O:11][C:10]=5[CH:9]=[CH:8][CH:7]=4)[OH:4])=[N:19][C:18]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:27][C:28]=2[N:29]=[CH:30][N:31]=1
Reactant: CN(C)C(=O)OC(c1cccc2c1OCO2)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C
Agent: CN(C)C(=O)OC(c1ccccc1)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C
Product: Cn1c(C(O)c2cccc3c2OCO3)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 104 but using [5-(7-amino[1,3]thiazolo[5,4-d]pyrimidin-2-yl)-1-methyl-4-phenyl-1H-imidazol-2-yl](1,3-benzodioxol-4-yl)methyl dimethylcarbamate (Intermediate 99) in place of [5-(7-amino[1,3]thiazolo[5,4-d]pyrimidin-2-yl)-1-methyl-4-phenyl-1H-imidazol-2-yl](phenyl)methyl dimethylcarbamate (Intermediate 97). Colourless solid (5 mg, 54%);