Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26].O.[NH2:35][NH2:36].C(=O)([O-])O.[Na+]>CN(C=O)C>[C:27]1([CH:25]([C:24]2[C:3]3[C:4](=[O:23])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:20])[F:21])[CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:36][N:35]=2)[CH3:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NN
Reactant: CC(C(=O)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1ccccc1)c1n[nH]c2c1c(=O)n(-c1cccc(OC(F)(F)F)c1)c1ncccc21
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-phenylpropionyl)-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (276 mg, 0.61 mmol) produced in Synthesis Example 32 in DMF (3 mL) was added hydrazine monohydrate (purity of 80%, 100 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution, and an oily substance was collected. To the oily substance was added isopropyl ether, and the mixture was heated. Then the resulting matter was allowed to stand to a room temperature for crystallization. The resulting crystal was separated by filtration and dried to give 3-(1-phenylethyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one as a form of crystal (140 mg, yield 51%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:12]3[CH2:21][CH2:20][C:15]4(OCC[O:16]4)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.Cl>O1CCCC1.CC(C)=O>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:12]3[CH2:13][CH2:14][C:15](=[O:16])[CH2:20][CH2:21]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2c1c(I)cn2C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C1CCC(n2cc(I)c3c(Cl)ncnc32)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 68.6 %

Procedure:
A mixture of 4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (20 g, 47.7 mmol) and 6 N HCl(aq) (60 mL, 360 mmol) in tetrahydrofuran (120 mL) and acetone (600 mL) was stirred at ambient temperature under an atmosphere of nitrogen for 17 hours. The solvent was removed under reduced pressure and 6NHCl(aq) (20 mL), tetrahydrofuran (60 mL), and acetone (300 mL) were added to the mixture. The mixture was stirred at ambient temperature under an atmosphere of nitrogen for 4.5 hour. The solvent was removed under reduced pressure and the yellow colored residue was washed with water to yield 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-cyclohexanone (12.3 g, 32.7 mmol). RP-HPLC (Hypersil C18, 5 μm, 250×4.6 mm; 25%-100% over 15 min with 0.05 M ammonium acetate, 1 mL/min) Rt 10.20 min.
Reaction SMILES: [C:1]([C:4]1[C:8]2[C:9](=[O:19])[CH2:10][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][C:7]=2[O:6][CH:5]=1)(O)=[O:2].CC[N:22]=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.N>ClCCl.O>[C:1]([C:4]1[C:8]2[C:9](=[O:19])[CH2:10][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][C:7]=2[O:6][CH:5]=1)(=[O:2])[NH2:22]
Reactant: O=C(O)c1coc2c1C(=O)CC(c1ccccc1)C2
Reactant: CCN=C=NCCCN(C)C
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1coc2c1C(=O)CC(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 28.2 %

Procedure:
To a suspension of 3-carboxy-4-oxo-6-phenyl-4,5,6,7-tetrahydrobenzofuran (1.28 g) in dichloromethane (25 ml) were added, under ice-cooling, WSC (1.15 g) and N-hydroxybenzotriazole (0.92 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added concentrated ammonia solution (4.1 g), and the mixture was stirred at room temperature overnight (12 hours). To the reaction solution was added water, and the mixture was subjected to extraction. The lower layer was washed with saturated brine, dried (anhydrous magnesium sulfate) and concentrated under reduced pressure, and the residue was washed with ethyl acetate and isopropylether to give 3-carbamoyl-6-phenyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.36 g).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6](C2CCCCO2)[N:5]=[CH:4][C:3]=1[O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19].Cl>CO.O>[Cl:1][C:2]1[C:7](=[O:8])[NH:6][N:5]=[CH:4][C:3]=1[O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: N#Cc1ccccc1Oc1cnn(C2CCCCO2)c(=O)c1Cl
Agent: Cl
Solvent: O
Solvent: CO
Product: N#Cc1ccccc1Oc1cn[nH]c(=O)c1Cl
Temperature: 90 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
A solution of 2-[5-chloro-6-oxo-1-(tetrahydro-pyran-2-yl)-1,6-dihydro-pyridazin-4-yloxy]-benzonitrile (61.8 g, 0.19 mol) in methanol (370 mL) was treated with a 6N aqueous hydrochloric acid solution (185 mL). The reaction was stirred at 90° C. for 4 h and then was allowed to cool to 25° C. The reaction was diluted with water. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to afford 2-(5-chloro-6-oxo-1,6-dihydro-pyridazin-4-yloxy)-benzonitrile (43.1 g, 94%); ESI-MS 248 [M+H+]; HPLC: >99% (purity). 1H-NMR (300 MHz, DMSO-d6) δ 13.63 (s, 1H), 7.96-7.99 (m, 2H), 7.71-7.77 (m, 1H), 7.37-7.45 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:50])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C@@H:32]([C:34]([O:36]CC3C=CC=CC=3)=[O:35])[CH3:33])[N:28]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:50])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C@@H:32]([C:34]([OH:36])=[O:35])[CH3:33])[N:28]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@H](C)C(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@H](C)C(=O)O)n(-c3ccccc3)n2)CC1
Reaction time: 16 h

Procedure:
To a solution of 5.90 g 4-((S)-2-{[5-((R)-1-Benzyloxycarbonyl-ethoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 30 ml ethyl acetate were added under argon 1.0 g Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (1 bar) for 16 h. The suspension was filtered over a plug of Celite® and washed with ethyl acetate. The crude product obtained after evaporation of the solvent was dried under vacuo. Yield: 4.69 g.
Reaction SMILES: C(OC([N:8]1[C:11]2([CH2:14][N:13]([C:15](=[O:26])[NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:27][C:28]([F:40])([F:39])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>>[C:20]1([CH2:19][CH2:18][CH2:17][NH:16][C:15]([N:13]2[CH2:12][C:11]3([N:8]([S:35]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[C:28]([F:27])([F:39])[F:40])(=[O:37])=[O:36])[CH2:9][CH2:10]3)[CH2:14]2)=[O:26])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC12CN(C(=O)NCCCc1ccccc1)C2
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Product: O=C(NCCCc1ccccc1)N1CC2(CCN2S(=O)(=O)c2ccccc2C(F)(F)F)C1

Procedure:
In analogy to the experimental procedure of example 6b) 6-(3-phenyl-propylcarbamoyl)-1,6-diaza-spiro[3.3]heptane-1-carboxylic acid tert-butyl ester instead of tert-butyl 1-(2,4-dichlorobenzylcarbamoyl)-1,6-diazaspiro[3.3]heptane-6-carboxylate was converted using 2-trifluoromethylbenzene-1-sulfonyl chloride instead of 4-chlorobenzene-1-sulfonyl chloride into the title compound which was obtained as an off-white solid (38 mg, 25%). MS m/e: 468 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)=[C:4]([C:17]#[N:18])[CH:3]=1>C(OCC)(=O)C.[Pd]>[NH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:7][C:5]1[S:6][C:2]([CH3:1])=[CH:3][C:4]=1[C:17]#[N:18]
Reactant: Cc1cc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)c(Nc2ccccc2N)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile, prepared as described in the previous step, (43.3 g, 0.157 mol) in ethyl acetate (500 mL) was added 10% palladium on carbon (8 g). The black mixture was stirred at room temperature overnight under an atmosphere of hydrogen gas. When LCMS showed that most of 5-methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile was consumed completely, the mixture was filtered and the filtrate was concentrated to provide 2-((2-aminophenyl)amino)-5-methylthiophene-3-carbonitrile. 1H NMR (400 MHz, CDCl3) δ 7.29-7.21 (m, 1H), 7.11-7.10 (m, 1H), 6.86-6.79 (m, 2H), 6.48-6.47 (m, 1H), 6.42 (brs, 1H), 3.75-3.70 (br, 2H), 2.28 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:4].[CH3:20][O:21][C:22]1[C:33]([CH2:34][CH:35]=O)=[CH:32][C:25]2[N:26]([CH3:31])[C:27](=[O:30])[O:28][CH2:29][C:24]=2[CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:20][O:21][C:22]1[C:33]([CH2:34][CH2:35][N:17]2[CH2:18][CH2:19][CH:14]([N:11]3[C:12]4[C:8](=[CH:7][CH:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:13]=4)[CH:9]=[CH:10]3)[CH2:15][CH2:16]2)=[CH:32][C:25]2[N:26]([CH3:31])[C:27](=[O:30])[O:28][CH2:29][C:24]=2[CH:23]=1
Reactant: COc1cc2c(cc1CC=O)N(C)C(=O)OC2
Reactant: CNC(=O)c1ccc2ccn(C3CCNCC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNC(=O)c1ccc2ccn(C3CCN(CCc4cc5c(cc4OC)COC(=O)N5C)CC3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
80 mg of N-methyl-1-(piperidin-4-yl)-1H-indole-6-carboxamide and 83 mg of (6-methoxy-1-methyl-2-oxo-1,4-dihydro-2H-benz[d][1,3]oxazin-7-yl)acetaldehyde were dissolved in 6 ml of methylene chloride. Thereafter, 0.04 ml of acetic acid and 99 mg of sodium triacetoxyborohydride were added to the reaction solution, and the obtained mixture was then stirred at room temperature for 3 hours. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, and then extracted with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate), so as to obtain 141 mg of the subject compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[N:3]=[CH:2]1.Cl[CH2:11][C:12]1[CH:30]=[CH:29][C:15]([C:16]([N:18]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])=[CH:14][N:13]=1>CC(N(C)C)=O>[CH:24]1([N:18]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[C:16]([C:15]2[CH:14]=[N:13][C:12]([CH2:11][N:9]3[CH:8]=[CH:7][C:6]4=[N:3][CH:2]=[N:1][C:5]4=[CH:4]3)=[CH:30][CH:29]=2)=[O:17])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(c1ccc(CCl)nc1)N(C1CCCC1)C1CCCC1
Reactant: c1cnc2nc[nH]c2c1
Solvent: CC(=O)N(C)C
Product: O=C(c1ccc(Cn2ccc3ncnc-3c2)nc1)N(C1CCCC1)C1CCCC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a stirred solution of imidazopyridine (540 mg, 4.5 mmol) in dimethylacetamide (100 mL) under argon, the product of Example D (1.6 g,) was added in one portion. The reaction temperature was slowly raised to 80°-85° C. and was stirred for 60 h. The reaction flask was cooled to room temperature and the solvent was removed under reduced pressure at <45° C. The residue obtained was triturated with excess of dry ether and filtered.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:35]=[CH:34][C:15]([C:16]([NH:18][C:19]2[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:22]=[CH:21][C:20]=2[OH:33])=O)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1Cl>[CH2:1]([O:11][C:12]1[CH:35]=[CH:34][C:15]([C:16]2[O:33][C:20]3[CH:21]=[CH:22][C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][C:19]=3[N:18]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(C(=O)Nc2cc(CCCCCCCC)ccc2O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: CCCCCCCCCCOc1ccc(-c2nc3cc(CCCCCCCC)ccc3o2)cc1
Reaction time: 0.62 h
Yield: 61.3 %

Procedure:
In a 30 ml-round-bottomed flask, 1.00 g (2.08 mM) of 2-(4-decyloxybenzoylamino)-4-octylphenol, 0.07 g (0.68 mM) of p-toluenesulfonic acid monohydrate and 10 ml of o-dichlorobenzene were placed, followed by stirring for 37 min. at 188°-193° C. After the reaction, o-dichlorobenzene was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene) to obtain 0.59 g of 2-(4-decyloxyphenyl)-5-octylbenzoxazole (yield: 61.3%). ##STR75##
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]([N:11]1[C:19]2[C:18]([F:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:13]([C:21]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:42])[CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)[CH:26]=[N:27][CH:28]=2)=[O:22])=[CH:12]1)([CH3:10])[CH3:9])(C)(C)C>C1COCC1>[F:20][C:18]1[C:19]2[N:11]([C:8]([CH3:10])([CH3:9])[CH2:7][OH:6])[CH:12]=[C:13]([C:21]([C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:42])[CH2:31][C:32]4[CH:33]=[CH:34][C:35]([C:38]([F:39])([F:41])[F:40])=[CH:36][CH:37]=4)[CH:26]=[N:27][CH:28]=3)=[O:22])[C:14]=2[CH:15]=[N:16][CH:17]=1
Reactant: 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
Solvent: C1CCOC1
Product: CC(C)(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(C(F)(F)F)cc3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of N-(5-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridine-3-carbonyl}-pyridin-3-yl)-2-(4-trifluoromethyl-phenyl)-acetamide (Preparation 1, 45 mg, 49 μmol) in THF (5 mL) 4M dioxane-HCl (0.5 mL) was added and stirred at room temperature for 2 hours. The reaction was evaporated in vacuo and triturated with pentane-ether to afford the title compound as a yellow solid in 83% yield, 30 mg.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C.O>[CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])([C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Temperature: 15 °C

Procedure:
Sodium metal (23 gram, 1 mole) was dissolved in dry ethanol (500 ml) with stirring. To this 160 gram (1 mole) of diethyl malonate (compound [2]) was added in 30 minutes. The reaction mixture was cooled to 15° C. and ethyl chloroacetate (compound [1], 117 gm, 0.095 mole) was then added drop wise in 30 minutes. On completion of addition the reaction mass was refluxed for 6 hours and then poured in 2 liters of water. The organic materials were extracted with dichloromethane (three times with 500 ml). Next, the organic extracts were dried over sodium sulfate, filtered and evaporated to give an oily substance which was then vacuum distilled to give 220 gm (89% of the theoretical maximum yield) of triethyl ethane-1,1,2-tricarboxylate, compound [3].
Reaction SMILES: C([O:8][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:24](=[O:25])[C:23]2[CH2:26][CH2:27][CH:28]=[CH:29][C:22]=2[O:21][C:20]2[CH:30]=[CH:31][CH:32]=[CH:33][C:19]1=2)[CH:10]=[O:11])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:24](=[O:25])[C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[O:21][C:20]2[CH:30]=[CH:31][CH:32]=[CH:33][C:19]1=2)[CH:10]=[O:11]
Reactant: [H][H]
Reactant: O=CN(CCCCCCN1C(=O)C2=C(C=CCC2)Oc2ccccc21)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=CN(O)CCCCCCN1C(=O)c2ccccc2Oc2ccccc21
Yield: 6.5 %

Procedure:
Title compound 403 (348 mg, 0.783 mmol) was dissolved in methanol (10 mL). The 10% palladium on charcoal (120 mg, 33% by wt) was added. The reaction mixture was stirred for 3 hours under 1 atmosphere of hydrogen at room temperature. The reaction mixture was filtered to remove the catalyst and the filtrate was evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and evaporated to afford title compound 404 (18 mg, 6%) as a white solid. 1H NMR (CD3OD) δ (ppm): 8.24, 7.89 (2s, rotamers, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.54-7.46 (m, 2H), 7.33 (dt, J=7.4, 2.0 Hz, 1H), 7.28-7.21 (m, 4H), 4.19 (br s, 2H), 3.50 (t, J=6.8 Hz, 1H), 3.44 (t, J=6.8 Hz, 1H), 1.70-1.55 (m, 4H), 1.44-1.29 (m, 4H). MS (m/z): 355.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[CH:21]=[C:14]3[C:15](Cl)=[N:16][CH:17]=[C:18]([F:19])[C:13]3=[N:12]2)=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].[Br:22][Si](C)(C)C>C(#N)CC>[Br:22][C:15]1[C:14]2=[CH:21][N:11]([C:3]3[C:2]([Cl:1])=[CH:9][C:8]([F:10])=[CH:7][C:4]=3[C:5]#[N:6])[N:12]=[C:13]2[C:18]([F:19])=[CH:17][N:16]=1
Reactant: C[Si](C)(C)Br
Reactant: N#Cc1cc(F)cc(Cl)c1-n1cc2c(Cl)ncc(F)c2n1
Solvent: CCC#N
Product: N#Cc1cc(F)cc(Cl)c1-n1cc2c(Br)ncc(F)c2n1
Temperature: 80 °C
Yield: 99.9 %

Procedure:
3-Chloro-2-(4-chloro-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-5-fluorobenzonitrile (735 mg, 2.26 mmol) was suspended in propionitrile (44 mL), under an atmosphere of nitrogen and bromotrimethylsilane (0.82 mL, 5.64 mmol) was added. The reaction mixture was heated at 80° C. for 5 hours. The resultant mixture was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a beige solid (834 mg, 100% yield). 1H NMR (300 MHz, CDCl3): δ 8.38 (d, J=2.3 Hz, 1H), 8.03 (d, J=3.0 Hz, 1H), 7.65 (dd, J=7.6, 2.8 Hz, 1H), 7.56 (dd, J=7.0, 2.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[F:14].Cl[C:20]1[CH:36]=[C:24]2[N:25](C(OC(C)(C)C)=O)[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:37])[N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:20]2[CH:36]=[C:24]3[NH:25][CH2:26][CH2:27][CH2:28][N:23]3[C:22](=[O:37])[N:21]=2)=[CH:8][C:7]=1[F:14]
Reactant: OCc1ccc(Oc2ccc(F)c(F)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCCn2c1cc(Cl)nc2=O
Product: O=c1nc(OCc2ccc(Oc3ccc(F)c(F)c3)c(F)c2)cc2n1CCCN2

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E111 starting from (4-(3,4-difluorophenoxy)-3-fluorophenyl)methanol and tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidine-1-carboxylate.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[N:7]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[N:14][CH:15]=1)=[C:8]=[S:9]>>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:8](=[S:9])[NH:7][C:10]2[CH:15]=[N:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:3]1
Reactant: COc1ccc(N=C=S)cn1
Reactant: O[C@H]1CCNC1
Product: COc1ccc(NC(=S)N2CC[C@H](O)C2)cn1
Yield: 99 %

Procedure:
The title compound was prepared from (S)-3-hydroxypyrrolidine and 5-isothiocyanato-2-methoxypyridine (J. Org. Chem. (1980), 45, 4219), using the same method as that described for preparation 35, in 99% yield. 1H NMR (400 MHz, CD3OD) δ: 1.91-2.22 (m, 2H), 3.69-3.81 (m, 4H), 3.88 (s, 3H), 4.40-4.52 (m, 1H), 6.78 (d, 1H), 7.69 (dd, 1H), 8.00 (m, 1H); LCMS m/z 254 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=4)[CH2:21][CH2:20]3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[OH:35])=[CH:4][CH:3]=1.Br>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=4)[CH2:21][CH2:20]3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[OH:35])=[CH:6][CH:7]=1
Reactant: COc1ccc(CCN2CCC(Cc3nc4c(O)ncnc4n3Cc3ccc(F)cc3)CC2)cc1
Agent: Br
Solvent: O
Product: Oc1ccc(CCN2CCC(Cc3nc4c(O)ncnc4n3Cc3ccc(F)cc3)CC2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
A mixture of 2.7 parts of 9-[(4-fluorophenyl)methyl]-8-[[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-methyl]-9H-purin-6-ol and 75 parts of a hydrobromic acid solution 48% in water was stirred for 4 hours at 80° C. After evaporation, the residue was taken up in water and treated with sodium carbonate. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from ethanol and acetonitrile. The product was filtered off and dried, yielding 1 part (38.6%) of 9-[(4-fluorophenyl)methyl]-8-[[1-[2-(4-hydroxyphenyl)ethyl]-4-piperidinyl]-methyl]-9H-purin-6-ol; mp. 215.7° C. (compound 186).
Reaction SMILES: [Li].Br[C:3]1(Br)[CH2:8][CH:7]=[CH:6][CH:5]=[C:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Si:16](Cl)(Cl)([Cl:18])[Cl:17]>CCCCC.CCOCC>[Cl:17][Si:16]1([Cl:18])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:4]2[C:3]1=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: BrC1(Br)CC=CC=C1c1ccccc1
Agent: [Li]
Solvent: CCOCC
Solvent: CCCCC
Product: Cl[Si]1(Cl)c2ccccc2-c2ccccc21

Procedure:
Lithium wire (3.33 g, 0.08 mol) was washed with pentane, carefully cut into small pieces, and suspended in 150 mL of Et2O. While stirring, 2,2-dibromobiphenyl (25 g, 0.08 mol) 100 mL of diethyl ether was added dropwise over 1 hour and the contents were allowed to stir for 10 hours. The mixture was filtered through a frit to remove any unreacted Li and LiBr. The filtrated was loaded into an addition funnel and slowly dropped into a solution containing SiCl4 (50 g, 0.08 mol) in 200 nL of Et2O. After addition, the contents were stirred at room temperature for 5 hours. The solvent was removed in vacuo and 300 mL of pentane was added. The solution was filtered to remove LiCl and the solvents were again removed in vacuo. The solids were then loaded into a sublimator and allowed to sublime at 150° C. under full vacuum. Yield was 10.0 g (51%).
Reaction SMILES: C([CH:4]([CH2:12][CH2:13][CH2:14]C)[CH:5]([OH:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8])C=C.[CH2:16](C(CC=C)C=O)[CH:17]([CH3:19])[CH3:18]>>[OH:11][CH:5]([CH2:4][CH2:12][CH:13]=[CH2:14])[CH:6]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:7]([O:9][CH3:10])=[O:8]
Reactant: C=CCC(CCCC)C(O)CC(=O)OC
Reactant: C=CCC(C=O)CC(C)C
Product: C=CCCC(O)C(CC(C)C)C(=O)OC

Procedure:
The compound of interest (4.5 g, 61%) was obtained as an oil substance (diastereomeric mixture) in the same way as in paragraph (10-a) using 2-isobutyl-4-pentenal.