Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.N#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(Nc2ccccc2)cc1
Yield: 99.2 %

Procedure:
96.4 g (452 mmol) of 1-bromo-4-tert-butylbenzene and 42.1 g (452 mmol) of aniline are dissolved in toluene and saturated with N2 for 15 min. 2.85 g (5 mmol) of DPPF, followed by 1.13 g (5 mmol) of Pd(OAc)2 and 56.8 g (588 mmol) of NaOtBu are subsequently added successively, and the mixture is refluxed for 6 h. The organic phase is separated off, washed twice with water and filtered through Celite, rinsed with toluene and evaporated in a rotary evaporator, leaving 101 g of ochre-coloured solid (99% of theory), which is employed without further purification in the subsequent reaction.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]3[NH:12][C:13](=[O:18])[O:14][C:15]([CH3:17])([CH3:16])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C(N(CC)CC)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>[CH3:16][C:15]1([CH3:17])[O:14][C:13](=[O:18])[NH:12][C:11]2[CH:19]=[CH:20][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:3]=3)=[CH:9][C:10]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(Br)c3)cc21
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(C#C[Si](C)(C)C)c3)cc21
Temperature: 80 °C
Yield: 91.8 %

Procedure:
A mixture of 6-(3-bromo-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.8 g, 2.4 mmol), trimethylsilylacetylene (1 g, 10 mmol), tetrakis(triphenylphosphine)palladium (0) (0.17 g, 0.24 mmol), and cuprous (I) iodide (0.05 g, 0.28 mmol) in triethyl amine (20 mL) was heated under nitrogen at 80° C. for 3 hours. The reaction mixture was cooled to rt and the solvent was removed. The residue was taken up in ethyl acetate (50 mL) and washed with 1N aqueous HCl (3×20 mL) and brine (20 mL). The organic layer was separated and dried (MgSO4). After removal of solvent, the residue was purified by a silica gel chromatography (hexane:ethyl acetate/3:1) to afford the title compound as a white solid (0.77 g, 92%): mp 240-242° C.; 1H-NMR (DMSO-d6) δ 10.3 (s, 1H), 7.74-7.69 (m, 2H), 7.61-7.58 (m, 2H), 7.48-7.40 (m, 2H), 6.96 (d, 1H, J=7.98 Hz), 1.67 (s, 6H), 0.25 (s, 9H); MS (EI) m/z 349([M+], 50%); Anal. Calc. For C21H23NO2Si.0.2 EtOAc: C, 71.32; H, 6.75; N, 3.82. Found: C, 71.08; H, 6.64; N, 3.82.
Reaction SMILES: [CH3:1][S:2]C1C=C2C(=CC=1)C=NCC2.N[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18].O(CC)C([S-])=S.[Na+].S(OC)(OC)(=O)=O>>[CH3:1][S:2][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18]
Reactant: CSc1ccc2c(c1)CCN=C2
Reactant: Nc1cccc(C(=O)O)c1
Agent: CCOC(=S)[S-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Product: CSc1cccc(C(=O)O)c1

Procedure:
Scheme 3 depicts the synthesis of 6-methylsulfanyl-3,4-dihydro-isoquinoline (XII). 3-Amino-benzoic acid (IV) is diazotized, reacted with sodium ethyl xanthate, followed by saponification, and is alkylated with dimethyl sulfate to give 3-methylsulfanyl-benzoic acid (V). This acid is reduced with Red-Al® (sodium bis (2-methoxyethoxy) aluminum hydride in toluene, Aldrich, Milwaukee, Wis., USA) to yield the alcohol (VI) which is converted to a benzyl chloride (VII) using thionyl chloride. The benzyl nitrile compound (VIII) is synthesized by treating (VII) with potassium cyanide in the presence of 18-crown-6. Standard reduction conditions (e.g., Raney nickel) gives phenethyl carbamate (IX), and deprotection yields the phenethylamine (X). (XI) is obtained by treating (X) with ethyl formate, followed by ring closure using phosphorus oxychloride to give the desired dihydroisoquinoline (XII).
Reaction SMILES: C([NH:9][C:10]([NH:22][CH2:23][CH2:24][CH2:25][C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)=[N:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=O)C1C=CC=CC=1>Cl>[NH:29]1[CH:30]=[C:26]([CH2:25][CH2:24][CH2:23][NH:22][C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[NH:9])[N:27]=[CH:28]1
Reactant: O=C(NC(=NCCCCc1ccccc1)NCCCc1c[nH]cn1)c1ccccc1
Agent: Cl
Product: N=C(NCCCCc1ccccc1)NCCCc1c[nH]cn1

Procedure:
0.8 g (2 mmol) of N-benzoyl-N'-[3-(imidazol-4-yl) propyl]-N"-(4-phenylbutyl)-guanidine are heated under reflux in 45 ml of 20% hydrochloric acid for 7 hours and then worked up by a method analogous to that of Example 58. 0.60 g (81%) of a highly hygroscopic, noncrystalline solid is obtained.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([S:36][CH2:37][CH2:38][CH2:39][C:40]([NH:42][C@H:43]([C:49]([O:51][CH3:52])=[O:50])[CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])=[O:41])[NH:26][C:27]=2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:19][CH:18]=1.C(N(CC)CC)C.O>C(Cl)Cl>[C:1]12([C:11]([NH:48][CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]([C:49]([O:51][CH3:52])=[O:50])[NH:42][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][S:36][C:25]3[NH:26][C:27]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[C:23]([C:20]4[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=4)[N:24]=3)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COC(=O)[C@H](CCCCN)NC(=O)CCCSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)[nH]1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CCCCNC(=O)C12CC3CC(CC(C3)C1)C2)NC(=O)CCCSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)[nH]1
Reaction time: 2 h
Yield: 70.9 %

Procedure:
A solution of 1-adamantanecarbonyl chloride (0.159 g, 0.000804 mol) in methylene chloride (2 ml) was added to a mixture of N2-[4-[4,5-bis(4-methoxyphenyl)-1H-imidazol-2-ylthio]-1-oxobutyl]-L-lysine, methyl ester hydrobromide (0.5 g, 0.000804 mol), triethyl amine (0.24 g, 0.0024 mol) and methylene chloride (20 ml) at ambient temperature under a nitrogen atmosphere. The reaction mixture was stirred for 2 hours, poured into water and extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous ammonium chloride, water, brine, dried over magnesium sulfate and concentrated to give a foam. The foam was purified by flash chromatography on silica gel (50 ml) eluting ethyl acetate to give the title compound (0.4 g, 0.00057 mol, 71% yield) as a white foam, mp 98°-104°. 1H NMR (DMSO-d6) δ8.22(d, 1H), 7.35-7.25(m, 5H), 6.87(d, 4H), 4.2-4.12(m, 1H), 3.75(s, 6H), 3.57(s, 3H), 3.1-2.93(m, 4H), 2.27(t, 2H), 1.97-1.5(m, 19H), 1.37-1.17(m, 4H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:18][C:17]=2[O:32][CH3:33])=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[NH:8]2.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][C:37]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:33][O:32][C:17]1[CH:18]=[C:19]([O:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH:20]=[CH:21][C:16]=1[C:4]1[C:3]([CH2:2][O:1][C:37]2[CH:38]=[C:39]([N+:42]([O-:44])=[O:43])[CH:40]=[CH:41][C:36]=2[O:35][CH3:34])=[C:12]2[C:7]([NH:8][C:9]([CH3:14])([CH3:15])[C:10](=[O:13])[NH:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: COc1cc(OC(=O)c2ccccc2C)ccc1-c1ccc2c(c1CO)NC(=O)C(C)(C)N2
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])cc1OCc1c(-c2ccc(OC(=O)c3ccccc3C)cc2OC)ccc2c1NC(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41.2 %

Procedure:
A mixture of 8-hydroxymethyl-7-[2-methoxy-4-(2-methylbenzoyloxy)phenyl]-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 23, 40.1 mg, 0.0898 mmol), 2-methoxy-5-nitrophenol (22.8 mg, 0.135 mmol), and tri n-butylphosphine (33.7 μL, 0.135 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL), 1,1′-(azodicarbonyl)dipiperidine (34.0 mg, 0.135 mmol) was added thereto, and then the mixture was stirred at room temperature. After 20 minutes, 2-methoxy-5-nitrophenol (23.1 mg, 0.137 mmol), tri n-butylphosphine (33.7 μL, 0.135 mmol), and 1,1′-(azodicarbonyl)dipiperidine (33.9 mg, 0.134 mmol) were added thereto, and after 80 minutes, 2-methoxy-5-nitrophenol (22.9 mg, 0.135 mmol), tri-n-butylphosphine (33.7 μL, 0.135 mmol), and 1,1′-(azodicarbonyl)dipiperidine (34.0 mg, 0.135 mmol) were added further. The stir was stopped 3 hours later and the reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (22.1 mg) as a pale yellow amorphous product. (Yield 41%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C[O:11][C:12](=[O:41])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=3Br)[CH:23]=2)=[CH:17][C:16]=1[CH3:40]>>[CH3:40][C:16]1[CH:17]=[C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:31][C:30]=3[C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:23]=2)[CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13][C:12]([OH:41])=[O:11]
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3-c3cccnc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 89 by using 3-pyridyl boronic acid and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 277 mg (88%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C28H22NO4F3 493, found 494 (M+1, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:25]=[CH:24][C:19]([O:20][CH2:21][CH2:22][OH:23])=[C:18]([CH3:26])[CH:17]=3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[CH3:27][S:28]([O:23][CH2:22][CH2:21][O:20][C:19]1[CH:24]=[CH:25][C:16]([C:15]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][N:12]=2)=[CH:17][C:18]=1[CH3:26])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCO
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCOS(C)(=O)=O

Procedure:
Prepared analogously to Example 4.1a from 310 mg (0.93 mmol) 2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethanol and 88 μL (1.12 mmol) methanesulphonic acid chloride.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[I-:10].[K+].[OH-].[Na+]>CO.O>[I:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: [I-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Ic1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 500 mL 3-necked round bottom flask, was placed a solution of 1H-indole (10 g, 85.40 mmol) in MeOH/H2O (150/30 mL). To this was added potassium iodide (15.6 g, 93.98 mmol). To the mixture was added sodium hydroxide (3.76 g, 94.00 mmol). To the above was added 12 (23.88 g, 94.02 mmol) in several batches. The resulting solution was allowed to react, with stirring, for 3 hours while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:10). The reaction mixture was then quenched by the adding 100 mL of H2O. A filtration was performed. The filter cake was washed 3 times with 200 mL of water. This resulted in 18 g (84%) of 3-iodo-1H-indole as a light yellow solid.
Reaction SMILES: [OH:1][CH:2]1[O:10][C@H](CO)[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1N.[OH2:13]>>[C:7]([OH:8])(=[O:13])[CH:5]([CH2:3][C:2]([OH:1])=[O:10])[OH:6]
Reactant: O
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Product: O=C(O)CC(O)C(=O)O

Procedure:
In this connection, it was found that the highest glucosamine content was observed when the raw material was treated with pure water and then treated in an autoclave.
Reaction SMILES: [CH:1]1([CH:4]([OH:7])[CH:5]=[CH2:6])[CH2:3][CH2:2]1.N#N.CCN(CC)CC.[Si:17](OS(C(F)(F)F)(=O)=O)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl>[Si:17]([O:7][C@@H:4]([CH:1]1[CH2:3][CH2:2]1)[CH:5]=[CH2:6])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: C=CC(O)C1CC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C[C@@H](O[Si](C)(C)C(C)(C)C)C1CC1
Reaction time: 1 h
Yield: 76.9 %

Procedure:
R)-3-Cyclopropyl-3-hydroxy-1-propene (150 mg, 1.53 mmole) was dissolved in anhydrous CH2Cl2 (5 ml) and the mixture was stirred at 0° C./N2. Then Et3N (248 mg, 341 μL, 2.45 mmole) and t-butyl(dimethyl)silyl-trifluoromethane-sulfonate (525 mg, 456 mL, 1.99 mmol) were added. After 1 h 10% aq. KHCO3 (5 mL) was added and the mixture was stirred at room temp. for 1 h. CH2Cl2 (5 mL) was added, the phases were separated, the organic phase was washed with 10% aq. KHCO3 solution (3×8 mL). The combined organic phases were dried over anhydrous K2CO3, filtered and concentrated in vacuo. The crude product was purified on the column with silica gel (230-400 mesh, 10 g, hexane). After drying the product under vacuum (0° C., 10 mm Hg), (3R)-3-t-butyl(dimethyl)silyloxy-3-cyclopropyl-1-propene as a colourless oil (250 mg, 77%) was obtained; C12H24OSi; E1 MS m/z 212 (M+, 3%); [α]D=+8.0° (20° C., c=1, CHCl3); 1H-NMR (200 MHz, CDCl3) δ 5.89 (1H, ddd: 16.9, 10.4, 5.6 Hz), 5.16 (1H, ddd: 17.2,2.0, 1.2 Hz), 5.02 (1H, ddd: 10.4, 1.8, 1.2 Hz), 3.65 (1H, bt: 6.3 Hz), 0.90 (9H, s), 0.89 (1H, m), 0.43 (2H, m), 0.30 (1H, m), 0.26 (1H, m), 0.05 (3H, s), 0.03 (3H, s) ppm.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[CH2:26]([N:22]([CH2:23][CH2:24][OH:25])[C:3]1[C:2]([C:31]2[CH:32]=[N:33][CH:34]=[C:29]([F:28])[CH:30]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1)[CH3:27]
Reactant: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Reactant: OB(O)c1cncc(F)c1
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncc(F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using 5-bromo-6-(ethyl(2-hydroxyethyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 156.1) and (5-fluoropyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (Condition 3) tR=1.09 min, m/z=465.3 [M+H]+, m/z=463.4 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.90 (t, J=7.03 Hz, 3H) 3.16 (q, J=7.03 Hz, 2H) 3.35-3.42 (m, 2H) 3.49 (br. s, 2H) 4.62 (br. s, 1H) 7.36 (d, J=8.41 Hz, 2H) 7.80-7.89 (m, 2H) 7.98 (m, J=2.70, 1.82 Hz, 1H) 8.08 (d, J=2.38 Hz, 1H) 8.60 (d, J=2.76 Hz, 1H) 8.64 (t, J=1.63 Hz, 1H) 8.76 (d, J=2.38 Hz, 1H) 10.26 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]([CH3:19])([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH3:9])[CH2:4][CH2:3]1>CCO.[Pd]>[CH3:19][C:8]([C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)([CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[CH3:9]
Reactant: CN1CC=C(C(C)(C)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCC(C(C)(C)c2ccc(N)cc2)CC1

Procedure:
1-Methyl-4-[1-methyl-1-(4-nitro-phenyl)-ethyl]-1,2,3,6-tetrahydro-pyridine (Step B) was hydrogenated with Pd/C 10% at atmospheric pressure at RT in EtOH to yield the title compound.
Reaction SMILES: [C:1]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH2:4][CH3:5])([CH3:3])C.BrC1C(CO)=CN(C2CCC2)N=1>>[CH:1]1([N:6]2[CH:14]=[C:13]3[C:8]([C:9](=[O:20])[NH:10][C:11]4([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]4)[CH2:12]3)=[N:7]2)[CH2:4][CH2:5][CH2:3]1
Reactant: CCC(C)(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2
Agent: OCc1cn(C2CCC2)nc1Br
Product: O=C1NC2(CCNCC2)Cc2cn(C3CCC3)nc21

Procedure:
The title compound was prepared by a method analogous to that described for Intermediate 5, Steps 3-5, using (3-bromo-1-cyclobutyl-1H-pyrazol-4-yl)methanol. +ESI (M+H) 261.3; 1H NMR (400 MHz, CD3OD, 6): 7.62 (s, 1H), 4.84-4.92 (m, 1H), 3.21-3.36 (m, 4H), 2.93 (s, 2H), 2.50-2.63 (m, 2H), 2.40-2.50 (m, 2H), 1.82-2.05 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:33]([NH:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:34])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C=Nc1ccccc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4)cc3)cc2C1=O

Procedure:
The compound of example 15 was prepared analogous to compound of example 7 by reaction of compound of example 6 with phenyl isocyanate. The compound of example 15 was used directly without isolation for the preparation of compound of example 16.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH:12]=[C:13]2[C:18](=[O:19])OC(C)(C)OC2=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O(C1C=CC=CC=1)C1C=CC=CC=1>CCCCCC>[CH3:10][O:9][C:8]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:11]=[CH:12][CH:13]=[C:18]2[OH:19]
Reactant: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1OC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: COc1cc2nccc(O)c2cc1OC
Reaction time: 0.08 h
Yield: 95.6 %

Procedure:
5-((3,4-Dimethoxyphenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (16.1 g, 52 mmol) was added to a pre-heated 1000 mL round-bottom flask containing 1-phenoxy benzene (100 mL) at 230° C. The reaction was stirred for 5 min, and then cooled to 120° C. n-Hexane (100 mL) was added to the solution to allow the product to precipitate out from the reaction solution. The mixture was further stirred at rt overnight. The solid was collected and crystallized in a solution of EtOAc/n-hexane (50 mL, v/v=10/1) to afford the title compound as a brown solid (10.2 g, 95%).
Reaction SMILES: [OH:1][C@H:2]([C@H:5]1[O:9][C:8](=[O:10])[C@H:7]([CH3:11])[CH2:6]1)[CH2:3][CH3:4].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:12]([O:1][C@H:2]([C@@H:5]1[CH2:6][C@@H:7]([CH3:11])[C:8](=[O:10])[O:9]1)[CH2:3][CH3:4])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC[C@H](O)[C@@H]1C[C@@H](C)C(=O)O1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC[C@H](OC(=O)c1ccccc1)[C@@H]1C[C@@H](C)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
To a solution of (3R,5S)-5-[(1S)-1-hydroxypropyl]-3-methyl-tetrahydrofuran-2-one (compound 28g, 1.0 g, 6.3 mmol), TEA (3.2 g, 31.2 mmol) and DMAP (100 mg) in DCM (50 mL) was added benzoyl chloride (1.8 g, 12.6 mmol) slowly at 0° C. The mixture was stirred at 25° C. for 4 hours and then quenched by saturated NaHCO3 solution, extracted with EtOAc (100 mL) twice. The organic layers were combined, washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:20 to 1:5 EtOAc in petroleum ether) to afford 1.4 g of [(1S)-1-[(2S,4R)-4-methyl-5-oxo-tetrahydrofuran-2-yl]propyl] benzoate (compound 28h) as a colourless oil.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.[NH:15]([CH2:19][CH2:20][OH:21])[CH2:16][CH2:17][OH:18].[OH-].[Na+].O>ClCCl>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:15]([CH2:19][CH2:20][OH:21])[CH2:16][CH2:17][OH:18])(=[O:12])=[O:13])=[CH:9][CH:10]=1
Reactant: OCCNCCO
Reactant: CC(=O)Oc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(c1ccc(O)cc1)N(CCO)CCO
Temperature: 5 °C

Procedure:
A solution of 46.9 g (0.20 mole) of 4-acetoxybenzenesulfonyl chloride (I) in 400 ml dichloromethane contained in a 500-ml round-buttomed flask was dried over magnesium sulfate, then filtered and placed in a 3-liter, 3-necked, round-buttomed flask equipped with a stirrer, an additional funnel, a condenser and a thermometer. After subsequent cooling to 5° C., 142.2 g (0.70 mole) of diethanolamine (II) were added slowly with stirring. The reaction mixture was allowed to reach room temperature and was then stirred for 2 hours, followed by the addition of a mixture of 30 ml sodium hydroxide (50%) and 20 ml water. The resulting two phase mixture was stirred at room temperature for an additional two hours. The aqueous layer was extracted with two 150-ml portions of dichloromethane, and the aqueous phase was cooled in an ice bath and acidified with concentrated HCl to a pH of 2.0. Sodium hydroxide was added to saturate the aqueous phase, which was then extracted with ten 300-ml portions of ethylacetate, followed by roto-evaporation of the combined ethyl acetate extracts to dryness. A white solid (III) was collected, washed with heptane and dried under vacuum. The yield was 24.7 g (42.3%).
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:18])[F:17])(=O)=O.[Cl:20][C:21]1[C:25]([CH2:26][CH3:27])=[N:24][N:23]([CH3:28])[C:22]=1[C:29](O)=[O:30].C(=O)([O-])O.[Na+]>O>[Cl:20][C:21]1[C:25]([CH2:26][CH3:27])=[N:24][N:23]([CH3:28])[C:22]=1[C:29]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:18])[F:17])=[O:30]
Reactant: CCc1nn(C)c(C(=O)O)c1Cl
Reactant: CC(CCCCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(C)c(C(=O)OCCCCC(C)=C(F)F)c1Cl
Temperature: 100 °C
Reaction time: 7 h
Yield: 73.7 %

Procedure:
To 10 ml of N,N-dimethylformamide were dissolved 0.50 g (2.2 mmol) of 6,6-difluoro-5-methyl-5-hexenyl methanesulfonate and 0.45 g (2.4 mmol) of 4-chloro-5-ethyl-2-methyl-2H-pyrazole-3-carboxylic acid, followed by the addition of 0.37 g (4.4 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 7 hours. The reaction liquid was then poured in water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:19) to obtain 0.52 g (yield: 74%) of 6,6-difluoro-5-methyl-5-hexenyl 4-chloro-5-ethyl-2-methyl-2H-pyrazole-3-carboxylate.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH2:7][O:8][CH:9]([OH:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH2:12]=O>[Pd].CO>[CH3:12][N:5]([CH2:6][CH2:7][O:8][CH:9]([OH:11])[CH3:10])[C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(O)OCCNC(C)(C)C
Reactant: C=O
Agent: [Pd]
Solvent: CO
Product: CC(O)OCCN(C)C(C)(C)C
Temperature: 80 °C
Yield: 81.2 %

Procedure:
A total of 145 g of tertiarybutylaminoethoxyethanol, 108 g of 37% aqueous formaldehyde, 10 g of 10% Pd/C, and 1 l of methanol were charged to an autoclave, pressured up to 1000 psi with H2 and heated at 80° C. for 8 hours. Filtration and distillation of the reaction mixture yielded 128 g of N-methyl-N-tertiarybutylaminoethoxyethanol with b.p. of 128° C. at 23 mm.