Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([NH:27][S:28]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[CH:38]=[CH:39][CH:40]=2)(=[O:30])=[O:29])[CH:19]=1>>[Br:15][C:10]1[CH:9]=[C:8]([CH2:7][C@H:5]([NH:6][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][C:20]=2[NH:27][S:28]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[CH:38]=[CH:39][CH:40]=2)(=[O:30])=[O:29])[C:4]([OH:3])=[O:16])[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(F)c(Br)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
The title compound was prepared from 3-bromo-4-fluoro-L-phenylalanine methyl ester hydrochloride and 4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in Example 1, Part C, followed by hydrolysis of the resulting methyl ester as in EXAMPLE 2, Part E. HPLC: RT=9.46 min. MS (ESI−): mass calcd. for C24H17BrClFN4O5S, 607.84; m/z found, 605/607 [M−H]−. 1H NMR (400 MHz, acetone-d6): 11.66 (s, 1H), 8.99-8.93 (m, 2H), 8.63-8.57 (m, 1H), 8.37-8.31 (m, 1H), 8.02-7.97 (m, 2H), 7.78-7.75 (m, 1H), 7.65-7.60 (m, 1H), 7.58-7.53 (m, 1H), 7.41-7.34 (m, 1H), 7.24-7.17 (m, 1H), 6.97 (dd, J=8.3, 1.6, 1H), 5.00-4.92 (m, 1H), 3.37-3.28 (m, 1H), 3.18-3.10 (m, 1H).
Reaction SMILES: N1C=CC=CC=1.C(O)C.[Cl-:10].[CH2:11]([N+:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]CCCC>CO.[Br-].CCOCC.C(O)C>[Cl-:10].[CH2:11]([N+:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCC[n+]1ccc(O)cc1
Agent: [Br-]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCO
Solvent: CO
Product: CCCCCCCCCCCC[n+]1ccccc1
Reaction time: 6 h
Yield: 70 %

Procedure:
The corresponding compounds of pyridine or substituted pyridine, as six-member heterocycle, can be prepared from the corresponding alkyl bromides or iodides in methanol at 35° C. and pyridine or substituted pyridines with a yield of 70%. The corresponding molar amounts of the alkyl bromide, almost all of which are available commercially but which must be subsequently preparatively purified by high-pressure liquid chromatography (HPLC), are firstly dissolved in methanol (10 times excess volume with respect to pyridine) and under nitrogen the stoichiometric amount of pyridine, also dissolved in methanol, added dropwise whilst stirring. Heating is carried out for 6 hours under reflux whilst stirring at 70° C. so that the reaction yield is almost quantitative. Thus, for example, the yield of hexadecyl-4-hydroxypyridinium chloride or bromide in methanol as solvent is 95%, with ethanol 80% and in ether/ethanol only 40%. Dodecylpyridinium chloride is obtained with a yield of almost 70%. 3,5-dihydroxydodecylpyridinium bromide is formed quantitatively in accordance with the above procedure from dodecyl bromide and 3,5-dihydroxypyridine in boiling chloroform after 4 hours (melting point 180° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[O:9]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10]1>>[O:9]1[CH:13]=[CH:12][C:11]([C:4]2[N:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=2)=[CH:10]1
Reactant: OB(O)c1ccoc1
Reactant: Nc1cccc(Cl)n1
Product: Nc1cccc(-c2ccoc2)n1
Yield: 54.3 %

Procedure:
The title compound was prepared following procedure described for intermediate A1 step a), but starting from 2-amino-6-chloropyridine (25.0 g; 194.5 mmol; 1.0 eq.) and furan-3-boronic acid (26.11 g; 233.4 mmol; 1.2 eq.). The crude was purified by flash chromatography (EtOAc/c-Hex, 50:50) to give the title compound as a brown oil (16.91 g; 54%). 1H NMR (DMSO-d6) δ 7.96 (s, 1H), 7.42 (m, 2H), 6.82 (m, 2H), 6.37 (d, J=7.2 Hz, 1H), 4.54 (m, 2H). HPLC, Rt: 1.30 min. (purity 84.9%). LC/MS, M+(ESI): 161.4.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]([C:20](Cl)=[O:21])[CH2:4][C:3]1=[O:23].[NH3:24]>CO>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]([C:20](=[O:21])[NH2:24])[CH2:4][C:3]1=[O:23]
Reactant: N
Reactant: CN1C(=O)CN(C(=O)Cl)C(c2ccccc2)c2cc(Cl)ccc21
Solvent: CO
Product: CN1C(=O)CN(C(N)=O)C(c2ccccc2)c2cc(Cl)ccc21
Yield: 72 %

Procedure:
A suspension of 1.7 g. (4.87 mmoles) of 1-methyl-4-chlorocarbonyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 3.5 ml. of concentrated ammonia and 7 ml. of methanol is stirred at room temperature overnight. The mixture is diluted with 30 ml. of water, the separated crude product is filtered off, and recrystallized from ethanol without drying. 1.16 g. (72%) of 1-methyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are obtained; m.p.: 212°-215° C.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[F:30][C:31]1[CH:39]=[C:38]2[C:34]([CH2:35][CH2:36][NH:37]2)=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:30][C:31]1[CH:39]=[C:38]2[C:34]([CH2:35][CH2:36][N:37]2[C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:28])=[CH:33][CH:32]=1
Reactant: Fc1ccc2c(c1)NCC2
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2ccc(F)cc21

Procedure:
0.10 g (0.24 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 35 mg (0.26 mmol) 6-fluoro-2,3-dihydro-1H-indole, 0.10 mL (0.72 mmol) TEA and 90 mg (0.28 mmol) TBTU in 1.8 mL DMF were stirred for 1 h at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:32][C:33]=1[CH3:34])[C:9]1[CH:27]=[CH:26][C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][C:22]([O:24]C)=[O:23])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.CO>[C:1]([O:5][C:6]([N:8]([CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:32][C:33]=1[CH3:34])[C:9]1[CH:27]=[CH:26][C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][C:22]([OH:24])=[O:23])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccccc1OCc1ccc(N(Cc2nc(-c3ccccc3)oc2C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CN(C(=O)OC(C)(C)C)c1ccc(COc2ccccc2CC(=O)O)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a mixture of methyl 2-[2-[4-[(t-butoxycarbonyl)[(5-methyl-2-phenyl-4-oxazolyl)methyl]amino]benzyloxy]phenyl]acetate (0.30 g), tetrahydrofuran (1.0 mL) and methanol (1.0 mL) was added a 1N aqueous sodium hydroxide solution (1.0 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (1.0 mL) and water were added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 2-[2-[4-[(t-butoxycarbonyl)[(5-methyl-2-phenyl-4-oxazolyl)methyl]amino]benzyloxy]phenyl]acetic acid as a colorless amorphous compound (0.19 g, 66%).
Reaction SMILES: C([N:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])C.[Cl:16][CH2:17][C:18](=O)[CH2:19][C:20](OCC)=[O:21].OS(O)(=O)=O>>[C:4]([NH:3][C:9]1[CH:10]=[C:11]2[C:12]([C:18]([CH2:17][Cl:16])=[CH:19][C:20](=[O:21])[O:15]2)=[CH:13][CH:14]=1)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)N(CC)c1cccc(O)c1
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=S(=O)(O)O
Product: CCOC(=O)Nc1ccc2c(CCl)cc(=O)oc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
A suspension of ethyl 3-hydroxyphenylurethane (1.81 g, 0.01 mole), ethyl 4-chloroacetoacetate (1.81 mL, 0.011 mole) and 70% H2SO4 (50 mL) is stirred for 4 hours at room temperature. The clear solution is poured into 400 mL of ice-water, with constant stirring, to yield a yellowish precipitate. The solid is filtered, washed with water and dried. The product is recrystallized from methanol to give colorless needles (86%).
Reaction SMILES: [NH2:1][C:2]1([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[F:53])[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:15]=[C:14]3[C:39]2[CH:44]=[CH:43][N:42]=[C:41]([CH3:45])[CH:40]=2)=[O:10])[CH2:3]1.[SiH](CC)(CC)CC>C(O)(C(F)(F)F)=O>[NH2:1][C:2]1([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[F:53])[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[C:39]2[CH:44]=[CH:43][N:42]=[C:41]([CH3:45])[CH:40]=2)=[O:10])[CH2:3]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(N)(Cc5ccccc5F)C4)cc23)ccn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2n[nH]c3ccc(C(=O)NC4CCCC(N)(Cc5ccccc5F)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N-(3-amino-3-(2-fluorobenzyl)cyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide was stirred in neat TFA at room temperature for 10 minutes, and then Et3SiH (5 equiv.) was added. The reaction mixture was stirred at room temperature for 5 minutes, and then concentrated. The product was obtained and purified by reverse phase HPLC.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][N:8]=1.[CH3:11][C:12]([CH3:14])=[O:13]>O>[CH3:3][C:4]1[S:5][C:6]([CH:9]=[CH:11][C:12](=[O:13])[CH3:14])=[CH:7][N:8]=1
Reactant: CC(C)=O
Reactant: Cc1ncc(C=O)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1cnc(C)s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
An aqueous solution of 2% sodium hydroxide (3 ml) was added to a solution of 2-methyl-thiazole-5-carboxaldehyde (2.5 g) in acetone (20 ml) and water (10 ml). The mixture was stirred for 24 hours at ambient temperature, diluted with water (150 ml) and extracted with chloroform (2×50 ml). The organic layer was washed with water then dried over anhydrous magnesium sulphate and filtered. Evaporation of the solvent gave 1-(2-methyl-5-thiazolyl)but-1-en-3-one as a low-melting point solid (1.4 g, 43%). Pmr spectrum (CDCl3 ; δ in ppm): 2.30 (3H, s); 2.72 (3H, s); 6.36 (1H, d); 7.56 (1H, d); 7.74 (1H, s).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]=2[O:14][CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C([O:24][B:25](OC(C)C)[O:26]C(C)C)(C)C.Cl>C1COCC1.CCOCC>[C:1]1([C:7]2[CH:12]=[C:11]([B:25]([OH:26])[OH:24])[CH:10]=[CH:9][C:8]=2[O:14][CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)cc1-c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cc1-c1ccccc1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
To a mixture of 2-phenyl-4-bromoanisole (26.00 g, 0.0988 mol) in THF (240 mL) cooled to −75° C. under an atmosphere of argon was added n-BuLi (68 mL, 1.6 M, 0.109 mol) dropwise maintaining a temperature below −70° C. The resulting suspension was stirred for 30 minutes and triisopropylborate (34.2 mL, 27.87 g, 0.148 mol) was added dropwise. The mixture was warmed to 0° C. over 1 hour and 1.0 N HCl (190 mL) was slowly added and allowed to warm to RT overnight. The mixture was diluted with ether and the layers separated, the aqueous layer was extracted ether (3×) and the organic layers combined. The resulting organic layer was washed with water, brine and dried (Mg2SO4). The mixture was filtered, evaporated and the resulting reddish residue solidified overnight. The solid was collected and washed with hexane and dried under high vacuum to afford 17.29 g of 3-phenyl-4-methoxyphenyl boronic acid (77%). 1H NMR (300 MHz; DMSO-d6): δ 3.78 (s, 3H), 7.07 (d, J=8.1 Hz, 1H), 7.28–7.50 (m, 5H), 7.72–7.80 (m, 2H), 7.92 (brs, 2H).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:7]2[CH2:8][CH2:9][C:10]([CH3:12])=[CH:11][C@@H:6]2[C@H:5]([C:13]([C:15]([OH:17])=[O:16])=[CH2:14])[CH2:4][CH2:3]1.[CH3:18][C@H:19]1[C@@H:29]2[CH2:30][CH2:31][C@:32]3([CH3:36])O[O:35][C@:28]42[C@H:22]([C@@H:23]([CH3:37])[C:24]([O:26][C@@H:27]4[O:33]3)=[O:25])[CH2:21][CH2:20]1>>[CH3:1][C@H:2]1[C@@H:7]2[CH2:8][CH2:9][C:10]([CH3:12])=[CH:11][C@@H:6]2[C@H:5]([C:13]([C:15]([OH:17])=[O:16])=[CH2:14])[CH2:4][CH2:3]1.[CH3:18][C@H:19]1[C@@H:29]2[CH2:30][CH2:31][C@:32]3([CH3:36])[O:35][C:28]42[C@H:22]([C@@H:23]([CH3:37])[C:24]([O:26][C@@H:27]4[O:33]3)=[O:25])[CH2:21][CH2:20]1
Reactant: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@]4(C)CC[C@@H]1[C@]32OO4
Agent: C=C(C(=O)O)[C@@H]1CC[C@@H](C)[C@@H]2CCC(C)=C[C@@H]21
Product: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@]4(C)CC[C@@H]1C32O4

Procedure:
Because there is far more artemisinic acid (Compound 1) than artemisinin (Compound 3) in Artemisia annua, the conversion of the former to the latter has received a great deal of attention. Prior synthetic conversion of 1 to 3 required a greater number of steps, produced a yield of approximately 7% and required the use of column chromatography for purification of the resulting artemisinin. Other attempts to simplify the process resulted in conversion of artemisinic acid into desoxyartemisinin, but did not . result in conversion to artemisinin.
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[CH2:4][C:5]1=[O:11]>CO.[Pd]>[CH:7]12[O:10][CH:1]([CH2:9][CH2:8]1)[CH:2]1[CH:6]2[C:5](=[O:11])[CH2:4][C:3]1=[O:12]
Reactant: O=C1CC(=O)C2C3C=CC(O3)C12
Agent: [Pd]
Solvent: CO
Product: O=C1CC(=O)C2C3CCC(O3)C12
Temperature: 25 °C

Procedure:
(1RS,2SR,6RS,7SR)-10-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (2.1 g, 12.8 mmol), prepared in Step 1, is dissolved in warm methanol (180 ml) and the mixture is allowed to cool to room temperature. The mixture is then hydrogenated in the presence of 5% palladium on carbon (approx. 50 mg) at 3.5 bar for 4 hours. The catalyst is removed by filtration through diatomaceous earth and the filtrate is concentrated under reduced pressure to afford (1RS,2SR,6RS,7SR)-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[Cl:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2nc(Cl)n(Cc3ccccc3)c2c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ccc2nc(Cl)n(Cc3ccccc3)c2c1
Yield: 82.6 %

Procedure:
A mixture of 1-benzyl-2-chloro-6-methoxy-1H-benzoimidazole (600 mg), hydrobromic acid (48%, 11 ml) and glacial acetic acid (6 ml) was heated under reflux for 1 hour. After cooling the mixture was neutralised by addition of 10% sodium bicarbonate solution then extracted 3 times with dichloromethane (30 ml). The combined extracts were dried over magnesium sulfate and then evaporated to give 3-benzyl-2-chloro-3H-benzoimidazol-5-ol (470 mg) as a yellow solid. Mass spectrum: 259 [M+H]+ retention time=3.4 minutes.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[CH3:18][Si:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][O:14][CH2:13][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([NH2:1])[CH:12]=2)[CH:8]=[N:9]1
Reactant: C[Si](C)(C)CCOCn1ncc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: C[Si](C)(C)CCOCn1ncc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.4 %

Procedure:
6-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (19.2 g, 65.4 mmol) and Pd\C (10 wt %, 1.920 g) were combined in MeOH (60 mL). The mixture was allowed to stir under an atmosphere of H2 at ambient pressure and at rt for about 18 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, 10:1 Hex/EtOAc) to give 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-amine (12.3 g, 71%): LC/MS (Table 2, Method h) Rt=2.09 min; MS m/z: 264 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH2:15][CH:14]([CH2:16][CH3:17])[C:13](=[O:18])[C:12]([CH2:20][CH3:21])([CH3:19])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:15][CH:14]([CH2:16][CH3:17])[CH:13]([OH:18])[C:12]([CH2:20][CH3:21])([CH3:19])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCC1CN(Cc2ccccc2)CC(C)(CC)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC1CN(Cc2ccccc2)CC(C)(CC)C1O
Reaction time: 1 h

Procedure:
Sodium borohydride (0.18 g, 4.8 mmole) was added to the stirred solution of 1-benzyl-3,5-diethyl-3-methylpiperidin-4-one (2.0 g, 7.72 mmole) in methanol (20 ml) at 0-5° C. over a period of 5 min, and stirring was continued for 1 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water (20 ml) and extracted with ethyl acetate. The ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 1-benzyl-3,5-diethyl-4-hydroxy-3-methylpiperidine as oil. Yield 1.8 g (89%), C17H27NO, m/z 262 (M+l).
Reaction SMILES: [CH3:1]/[C:2](=[CH:9]\[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)/[CH2:3][CH2:4][C:5](OC)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1]/[C:2](=[CH:9]\[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)/[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: COC(=O)CC/C(C)=C/c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C/C(=C\c1ccc(C)cc1)CCCO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
A solution of methyl (4E)-4-methyl-5-(4-methylphenyl)-4-pentenoate (17.18 g, 0.079 mol) in dry THF (300 ml) was treated, at −78° C. under nitrogen, with solid lithium aluminum hydride (3.15 g, 0.079 mol) in one portion. After 5 minutes the cooling bath was removed and the reaction allowed to reach room temperature and then cooled to 0° C. and treated successively with water (3.15 ml), 5% aqueous sodium hydroxide (9.45 ml) and water (3.15 ml). The reaction was stirred at room temperature for 30 minutes. Anhydrous solid sodium sulfate was added (10 g) and stirring continued for 5 minutes. The solid was filtered off, rinsed with diethyl ether and solvents were removed under vacuum. The product was purified by column chromatography on silica gel (eluent: heptanes/ethyl acetate 5:1 to 1:1) followed by bulb-to-bulb distillation (120° C./0.001 mbar). 12.54 g (yield=66%) of the desired product were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[N:10]=2)=[CH:4][CH:3]=1.[C:28]([CH2:30][C:31](O)=[O:32])#[N:29]>>[O:25]1[CH2:26][CH2:27][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:11]3[N:10]=[C:9]([S:8][C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:31](=[O:32])[CH2:30][C:28]#[N:29])=[CH:3][CH:4]=4)[CH:14]=[CH:13][N:12]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1
Reactant: Nc1ccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Reactant: N#CCC(=O)O
Product: N#CCC(=O)Nc1ccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Yield: 67.2 %

Procedure:
In a procedure analogous to Example 15, reaction of 4-(4-aminophenylthio)-N-(4-morpholinophenyl)pyrimidin-2-amine (60 mg, 0.16 mmol) and cyanoacetic acid (46 mg, 0.32 mmol) furnished the product (48 mg, 68%).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:10](=O)([O:13]C)[O:11][CH3:12].C[O-].[Na+].Cl>O.C1(C)C=CC=CC=1>[O:7]1[CH2:8][CH2:9][CH:4]([C:1](=[O:3])[CH2:2][C:10]([O:11][CH3:12])=[O:13])[CH2:5][CH2:6]1
Reactant: COC(=O)OC
Reactant: CC(=O)C1CCOCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CC(=O)C1CCOCC1
Temperature: 7.5 °C
Yield: 80.5 %

Procedure:
In a flask made of glass having an inner volume of 500 ml and equipped with a stirring device, a thermometer, a dropping funnel and a distillation device were charged 35.0 g (273 mmol) of 4-acetyltetrahydropyran synthesized in the same manner as in Reference example 2, 280.0 g (3.1 mol) of dimethyl carbonate and 16.3 g (302 mmol) of sodium methoxide, and the mixture was reacted at 80 to 85° C. for 2 hours with distilling by-producing methanol off. After completion of the reaction, the reaction mixture was cooled to 5 to 10° C., and to the reaction mixture were added 175 ml of toluene, 55 ml (330 mmol) of 6 mol/l hydrochloric acid and 35 ml of water in this order. After the organic layer was separated, the aqueous layer was extracted twice with 70 ml of toluene. The organic layer was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (Fluent; hexane/ethyl acetate=1/1 (volume ratio)) to give 40.9 g (Isolation yield: 76%) of methyl 3-(4-tetrahydropyranyl)-3-oxopropanoate with a purity of 93.9% (analytical value by differential diffractometry) as a colorless liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([CH3:12])([CH3:11])[C:7](=O)[CH2:8]Br)[CH3:2].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[S:21])=[CH:18][CH:17]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([CH3:12])([C:7]1[N:22]=[C:20]([C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:25])([F:14])[F:26])=[CH:24][CH:23]=2)[S:21][CH:8]=1)[CH3:11])[CH3:2]
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CC(C)(C)C(=O)CBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(C)(C)c1csc(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
500 mg (1.99 mmol) of 5-bromo-3,3-dimethyl-4-oxo-pentanoic acid ethyl ester, 408.6 mg (1.99 mmol) of 4-trifluoromethyl-thiobenzamide and 403 mg (3.98 mmol) of triethylamine in 10 ml of toluene were stirred at 80° C. for 2 h. After evaporation, water and dichloromethane were added, the organic phase was separated, washed with water, dried, and evaporated. The product was purified by chromatography (silica gel, n-heptane/ethyl acetate 8:1). Yield: 498.5 mg.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:14](=[O:15])[N:13]3[C:16]4([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[NH:17][C:18](=[O:19])[C:12]3=[C:11]([CH3:25])[CH:10]=2)=CC=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl>[OH:8][C:9]1[C:14](=[O:15])[N:13]2[C:16]3([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[NH:17][C:18](=[O:19])[C:12]2=[C:11]([CH3:25])[CH:10]=1
Reactant: COc1ccc(COc2cc(C)c3n(c2=O)C2(CCCCC2)NC3=O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: Cc1cc(O)c(=O)n2c1C(=O)NC21CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6′-((4-methoxybenzyl)oxy)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (2, 1.5 g, 4.07 mmol) in dichloromethane (20 mL) is added 2,3-dichloro-5,6-dicyano-p-benzoquinone (1.38 g, 6.10 mmol). The reaction is stirred at room temperature for 2 h. The resulting mixture is concentrated and purified via column chromatography to afford 6′-hydroxy-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (3).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=3)[CH:11]=2)[CH:3]=[N:2]1.CC(C)(OC(NC1N=C(C2C=CC3N(C=C(C(O)=O)N=3)C=2)C=CC=1)=O)C>>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=3)[CH:11]=2)[CH:3]=[N:2]1
Reactant: CCOC(=O)c1cn2cc(-c3cn[nH]c3)ccc2n1
Agent: CC(C)(C)OC(=O)Nc1cccc(-c2ccc3nc(C(=O)O)cn3c2)n1
Product: O=C(O)c1cn2cc(-c3cn[nH]c3)ccc2n1
Yield: 52.6 %

Procedure:
128 mg of ethyl 6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylate are saponified under conditions similar to those described for the preparation of Intermediate 11 (step 11.3), to give 60 mg of 6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylic acid.