Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[S:7][CH:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[CH:5]=[CH:4][CH:3]=[N:2]1>C(Cl)(Cl)Cl.O=[Mn]=O>[N:1]1([C:6]2[S:7][CH:8]=[C:9]([CH:11]=[O:12])[N:10]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: OCc1csc(-n2cccn2)n1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1csc(-n2cccn2)n1

Procedure:
MnO2 (10.8 g; 125 mmol) was added to a solution of (2-pyrazol-1-ylthiazole-4-yl)methanol (1.13 g; 6.24 mmol), prepared as described in the above step, in chloroform (100 ml).
Reaction SMILES: [CH3:1][NH2:2].S(O[CH2:14][CH2:15][O:16][C@H:17]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@H:19]([CH2:20][CH2:21][C@@H:22]3[C@@H:31]2[CH2:30][CH2:29][C@@:27]2([CH3:28])[C@:23]3([OH:41])[CH2:24][CH2:25][C@@H:26]2[C:36]2[CH:40]=[CH:39][O:38][CH:37]=2)[CH2:18]1)(C1C=CC(C)=CC=1)(=O)=O>CO>[CH3:1][NH:2][CH2:14][CH2:15][O:16][C@H:17]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@H:19]([CH2:20][CH2:21][C@@H:22]3[C@@H:31]2[CH2:30][CH2:29][C@@:27]2([CH3:28])[C@:23]3([OH:41])[CH2:24][CH2:25][C@@H:26]2[C:36]2[CH:40]=[CH:39][O:38][CH:37]=2)[CH2:18]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCCO[C@H]2CC[C@@]3(C)[C@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](c5ccoc5)CC[C@]43O)C2)cc1
Solvent: CO
Product: CNCCO[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1

Procedure:
To 7 ml of a solution of methylamine 3.2M in methanol, 0.090 g of 3β-(2-tosyloxyethoxy)-17β-(3-furyl)-5β-androstan-14β-ol, prepared as an intermediate in Ex.7, were added. The solution was kept at reflux under nitrogen for 11 hrs, then was evaporated. The resulting solid was washed with n-hexane to give 0.045 g of the title compound (I-an) as a light yellow pasty solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:18]=[O:19]>CN(C=O)C>[OH:19][CH2:18][C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:9]#[N:10]
Reactant: C=O
Reactant: CCCCCC(C#N)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC(C#N)(CO)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
The crude (4-fluorophenyl)heptanenitrile obtained in stage 9-1-1 is added to a suspension of 1.62 g of 60% NaH in 50 ml of DMF cooled to 0° C. After stirring for 30 minutes, 8.9 g (296 mmol) of paraformaldehyde are added portionwise. The reaction medium is left to stir at ambient temperature for 3 hours and then hydrolysed with ice and extracted with dichloromethane. The organic phase is dried over sodium sulphate, filtered and evaporated under pressure. The crude product obtained is purified by silica gel chromatography (eluent 8/2 heptane/ethyl acetate). 3.85 g in the form of a pale yellow oil are obtained with a yield of 44%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8].C(=O)([O-])[O-].[Li+].[Li+].Br[CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]/[C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)=[C:11]([OH:16])[CH:10]=1)=[O:8]
Reactant: COC(=O)CCCC(=O)c1ccc(O)c(O)c1
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)CCCC(=O)c1ccc(OCCCC/C=C/c2ccc(OC)cc2)c(O)c1
Yield: 14.6 %

Procedure:
Under the conditions of example 2C, 1.8g of 5-(3,4-dihydroxyphenyl)-5-oxo-pentanoic acid methyl ester in 19 ml of dimethylformamide is reacted in the presence of 1.4g of lithium carbonate with 2.05g of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene, worked up and chromatographed. 470 mg of 5-(3-hydroxy-4[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-phenyl)-5-oxo-pentanoic acid methyl ester of melting point 78°-80° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][C:5]=1[OH:12].CCN(CC)CC.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23].[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][C:5]=1[O:12][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:23])=[O:21]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc(C=O)ccc1O
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 74.4 %

Procedure:
To a solution of 5-formyl-2-hydroxy-benzoic acid methyl ester (1.0 g, 5.6 mmol) in CH2Cl2 (10 mL) at −78° C. was added Et3N (0.85 mL, 6.1 mmol) and DMAP (68 mg, 0.56 mmol) followed by dropwise addition of Tf2O (1.03 mL, 6.1 mmol) over 20 min. The reaction mixture was then warmed to room temperature and poured into saturated aqueous NH4Cl and extracted with CH2Cl2 (3×25 mL). The combined extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiO2, 15% EtOAc/hexanes) to afford Example 236A (1.3 g, 76%) as a colorless oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[H-].[H-].[H-].[Li+].[Al+3].[C:11]1([C@@H:17]2[NH:21][C:20](=O)[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[C:11]1([C@H:17]2[CH2:18][CH2:19][CH2:20][NH:21]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CC[C@H](c2ccccc2)N1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: c1ccc([C@H]2CCCN2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 81.5 %

Procedure:
To a cooled (0° C.) anhydrous aluminum chloride (208 mg, 1.56 mmol) was added anhydrous THF (10 mL) via syringe under an argon atmosphere. After 5 min of stirring at 0° C., a 1.0 M LiAlH4 solution in THF (4.68 mL, 4.68 mmol) was added. The resulting cloudy solution was allowed to warm to room temperature and stirred for 20 minutes to give the alane solution. To this stirred alane solution at -78° C. was added a solution of 5(R)-phenyl-2-pyrrolidinone (160 mg, 1.0 mmol) in 10 mL of THF under an argon atmosphere. The reaction mixture was stirred at -78° C. for 1 h. and then at room temperature for 12 h, recooled to 0° C. and quenched with 1 N HCl solution (5 mL). The resulting slurry was diluted with 20 mL of water, basified with 3 N aqueous sodium hydroxide solution to pH 12, extracted with methylene chloride (4×20 mL). The combined organic extract was washed with brine, dried over anhydrous MgSO4, concentrated to afford a crude product. Bulb to bulb distillation with Kugelrohr (88° C./0.9 mmHg) gave 120 mg of product (82% yield) as a colorless oil, 1H NMR (CDCl3) δ 1.57-1.71 (m, 1H),1.74-1.96 (m, 2H), 2.101 (s, 1H), 2.11-2.22 (m, 1H), 2.972 (ddd, J=6.9, 8.1, 9.9 Hz, 1H, NCH), 3.172 (ddd, J=5.4, 7.5, 10.2 Hz, 1H, NCH), 4.073 (t, J=7.5 Hz, 1H, benzyl), 7.16-7.40 (m, 5H, aryl); 13C NMR (CDCl3) δ 25.39 (C4), 34.15 (C3), 46.78 (C5), 62.37 (C2), 126.29 (aromatic), 126.52, 128.11, 144.65.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C@H:2]1[CH2:5][OH:6].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]([N:1]1[CH2:4][CH2:3][C@H:2]1[CH2:5][OH:6])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC[C@@H]1CCN1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(OCc1ccccc1)N1CC[C@H]1CO
Reaction time: 14 h
Yield: 75 %

Procedure:
Said solution of (S)-azetidine-2-methanol was adjusted to pH 10 by adding 10% sulfuric acid, sodium hydrogen carbonate (0.88 g, 10.5 mmol) was then added, and benzyloxycarbonyl chloride (1.76 g, 10.3 mmol) was added thereto at room temperature, followed by 14 hours of stirring. The solution was adjusted to pH 7 and extracted with ethyl acetate (50 mL ×2), the extract was washed with water (50 mL×1), dried over magnesium sulfate and filtered, and the filtrate was concentrated. The concentrate was subjected to column chromatography (Wakogel C-200) using toluene/ethyl acetate (1/1) as a mobile phase for separation/purification, to give (S)-N-benzyloxycarbonylazetidine-2-methanol (0.781 g, yield 75%) as a pale yellow oil. (S)-2-N-benzyloxycarbonyl-1,4-butanediol was obtained as a byproduct (0.096 g, yield 9%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH:17](OC)(OC)OC>CO>[CH3:17][O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=1)[OH:11]
Reactant: O=C(O)c1cc(F)ccc1O
Reactant: COC(OC)OC
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc(F)ccc1O
Temperature: 66 °C

Procedure:
5-Fluorosalicylic acid (272.6 g, 1.74 mol) was dissolved in methanol (1.3 L) to form a clear solution. Concentrated sulfuric acid (50 ml) was slowly added to the methanol solution with vigorous stirring. The solution was heated to reflux for 4 hours. Trimethyl orthoformate (200 ml) was added slowly to the reaction solution. 300 ml of solvents (methyl formate and methanol) was distilled off. The remaining reaction solution was heated at 66° C. (refluxing temperature) for 16 hours. HPLC analysis indicated that the reaction was complete. Reaction solution was cooled to ambient temperature. Solvent was removed under reduced pressure. The residue was partitioned between water (140 ml) and methylene chloride (220 ml). Organic layer was separated. Aqueous layer was extracted with methylene chloride (3×220 ml). The combined organic layer was washed with water (270 ml), brine (270 ml) and dried with MgSO4. The organic solution was concentrated to dryness to afford crude product (293.8 g). This crude material was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 3.96 (s, 3H), 6.94 (dd, 1H, J=4.5 Hz and J=9.0 Hz), 7.19 (m, 1H), 7.50 (dd, 1H, J=3.3 Hz and J=8.7 Hz), 10.508 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][C:10]1[CH:32]=[CH:31][C:13]([O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[C:23]([C:28](O)=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][N:34](C)[C:35]1C=CC=CC=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.C(=O)([O-])O.[Na+].CN(C)C=O>[CH3:33][N:34]([CH3:35])[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][O:14][C:13]2[CH:31]=[CH:32][C:10]([CH2:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:11][CH:12]=2)[CH:17]=1)=[O:29]
Reactant: CN(C)c1ccccc1
Reactant: CC(C)(C)OC(=O)CCc1ccc(OCc2cccc(-c3ccccc3C(=O)O)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccccc1-c1cccc(COc2ccc(CCC(=O)OC(C)(C)C)cc2)c1

Procedure:
To a mixture of 3′-[4-(2-tert-butoxycarbonylethyl)phenoxymethyl]biphenyl-2-carboxylic acid (0.24 g, 0.56 mmol), dimethylaniline (2M tetrahydrofuran solution, 0.42 mL, 0.84 mmol), 1-hydroxybenzotriazole monohydrate (0.13 g, 0.84 mmol) and N,N-dimethylformamide (6.0 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.16 g, 0.84 mmol) at room temperature with stirring, and the mixture was stirred at the same temperature for 12 hrs. The reaction mixture was diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-1/2) to give tert-butyl 3-(4-((2′-((dimethylamino)carbonyl)biphenyl-3-yl)methoxy)phenyl)propanoate as a colorless oil. This compound was dissolved in trifluoroacetic acid (2 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was purified by preparative HPLC (gradient cycle A) to give the title compound (58 mg, yield 26%) as colorless crystals. MS (APCI−): 402 (M−H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[C:8]([CH2:14][NH:15][CH:16]=O)=[N:9][CH:10]=[C:11]([F:13])[CH:12]=1>C1(C)C=CC=CC=1>[F:13][C:11]1[CH:12]=[C:7]([F:6])[C:8]2[N:9]([CH:16]=[N:15][CH:14]=2)[CH:10]=1
Reactant: O=CNCc1ncc(F)cc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Fc1cc(F)c2cncn2c1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 45 %

Procedure:
In a round-bottomed flask, N-(3,5-difluoro-pyridin-2-ylmethyl)-formamide (crude from Step 2) was dissolved in toluene (14 ml) and phosphorus oxychloride (0.65 ml, 7.0 mmol) was added. The reaction mixture was stirred at 100° C. in an oil bath for 3.5 h then cooled to 0° C. and carefully quenched with ice. Aqueous 25% ammonium hydroxide was added until pH=˜9. The mixture was diluted with water and extracted with dichloromethane (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient 0-60% EtOAc) to give 319 mg (45%, 2 steps) of 6,8-difluoro-imidazo[1,5-a]pyridine as a yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.36 (d, J=3.0 Hz, 1H), 7.84 (d, J=3.4 Hz, 1H), 7.65 (s, 1H), 6.39-6.57 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>O>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:10]2[O:9][C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[NH:1][C:21](=[O:23])[CH3:22])=[N:12][C:11]=2[CH:13]=1
Reactant: Nc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 60 °C

Procedure:
A mixture of 0.28 g of 2-(3-aminopyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 3 ml of acetic anhydride was stirred while heating at 60° C. for two hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethyl acetate to give 0.17 g of N-[4-(5-trifluoromethylbenzoxazole-2-yl)pyridin-3-yl]acetamide (hereinafter, referred to as “active compound 82”).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=2)=[O:22])[CH2:17][CH2:16]1.[H][H]>C(O)C.O.[C].[Pd]>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:21]([N:18]2[CH2:17][CH2:16][N:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:20][CH2:19]2)=[O:22])=[CH:25][CH:26]=1
Reactant: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc([N+](=O)[O-])cc4)CC3)c2cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(N)cc4)CC3)c2cc1OC
Yield: 29 %

Procedure:
In 50 ml of ethanol was suspended 1.5 g (3.7 mmol) of 4-(6,7-dimethoxy-4-quinazolinyl)-N-(4-nitrophenyl)-1-piperazinecarboxamide obtained in Example 77, and a suspension of 500 mg of 10% palladium-carbon in 10 ml of water and 10 ml of ethanol was added thereto, followed by stirring in a stream of hydrogen at room temperature for 5 hours. After the catalyst was separated by filtration using Celite, the solvent was evaporated. Then, the residue was purified by silica gel chromatography and recrystallized from ethyl acetate to give the desired compound as colorless crystals.
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH:35]1[CH2:39][CH2:38][CH2:37][O:36]1)[C:4]1[C:5]2[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23][C:6]=2[N:7]=[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])=[CH:13][CH:12]=2)[N:9]=1)[CH3:2].Cl>CO>[CH2:1]([N:3]([CH2:34][CH:35]1[CH2:39][CH2:38][CH2:37][O:36]1)[C:4]1[C:5]2[CH2:26][NH:25][CH2:24][CH2:23][C:6]=2[N:7]=[C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])=[CH:15][CH:16]=2)[N:9]=1)[CH3:2]
Reactant: CCN(CC1CCCO1)c1nc(Nc2ccc(-n3ccnc3C)cc2)nc2c1CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Product: CCN(CC1CCCO1)c1nc(Nc2ccc(-n3ccnc3C)cc2)nc2c1CNCC2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(ethyl((tetrahydrofuran-2-yl)methyl)amino)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (253 mg, 0.47 mmol) was dissolved in methanol (3 mL). Hydrochloric acid (0.017 mL, 0.47 mmol) was added and the reaction mixture was stirred at 80° C. for 1 h. The solvent was evaporated and the crude N4-ethyl-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (190 mg, 92%) was used as such in the next step. MS (ES+) m/z 434.3 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:11]2[CH:12]=[C:13]([CH:16]=[O:17])[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([CH:16]=[O:17])[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1coc2ccc(C=O)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1coc2ccc(C=O)cc12
Reaction time: 12 h
Yield: 79.3 %

Procedure:
100 mg of 3-(5-Formyl-benzofuran-3-yl)-acrylic acid ethyl ester (intermediate 62) were dissolved in EtOAc in the presence of Palladium on charcoal and Argon. To this was connected a H2-balloon and hydrogenation was carried out for 12 h. The palladium was filtered off and the solvents were evaporated affording pure title compound (80 mg, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.Cl[CH2:11][CH:12]=O.C(=O)([O-])O.[Na+]>O.C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]2[CH:11]=[CH:12][N:9]=[C:5]2[CH:4]=1
Reactant: COc1ccnc(N)c1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccn2ccnc2c1
Yield: 45 %

Procedure:
A stirred suspension of 4-methoxypyridin-2-ylamine (4.50 g, 36.3 mmol), chloroacetaldehyde (8.54 g of a 50 wt % solution in water, 54.4 mmol) and sodium hydrogencarbonate (6.09 g, 72.6 mmol) in ethanol (70 ml) was heated under reflux for 4 h. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried and evaporated to give an orange oil. Purification by silica gel chromatography eluting with 2% methanol in dichloromethane gave 7-methoxyimidazo[1,2-α]pyridine (2.40 g, 45%) as a brown oil. 1H NMR (400 MHz, CDCl3) δH 3.85 (3H, s), 6.50 (1H, d, J 7), 6.88 (1H, s), 7.41 (1H, s), 7.48 (1H, s), 7.92 (1H, d, J 7).
Reaction SMILES: C(O[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]([CH3:14])[N:5]=1)C.[NH2:15][NH2:16]>>[NH:15]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]([CH3:14])[N:5]=1)[NH2:16]
Reactant: CCOC1=NC(C)Cc2ccccc21
Reactant: NN
Product: CC1Cc2ccccc2C(NN)=N1

Procedure:
The reaction between 1-ethoxy-3-methyl-3,4-dihydroisoquinoline and hydrazine, which produced 1-hydrazino-3-methyl-3,4-dihydroisoquinoline, also produced a dimer, recrystallization of which from methanol-ethanol afforded 1,1'-azinobis(3-methyl-1,2,3,4-tetrahydroisoquinoline) (II: Y=CH3, Y' =Z=Z' =H) (2.2 g., m.p. 168°-171° C.).
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](Cl)=[N:18][N:17]=1.CCN(CC)CC.CN1C(=O)CCC1>O>[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=3)[CH2:6][CH2:5]2)=[N:18][N:17]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: N#Cc1ccc(N2CCNCC2)nc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(N2CCN(c3nnc(Cl)c4ccccc34)CC2)nc1
Temperature: 80 °C
Yield: 51.1 %

Procedure:
To a 100-mL round-bottom flask is added 6-piperazin-1-yl-nicotinonitrile (9.60 g, 50 mmol), 1,4-dichlorophthalazine (11.2 g, 55.1 mmol, 1.1 eq), Et3N (3.5 mL, 250 mmol, 5 eq.), and NMP (100 mL). The mixture is heated to 80° C. for 2.5 h. Upon cooling to room temperature, the reaction is poured into H2O (500 mL) and the precipitate isolated by filtration, rinsing with additional H2O. Crude material is purified by recrystallization (CH2Cl2:heptanes) to afford 8.96 g title compound as a beige solid.
Reaction SMILES: CN[C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[CH:24][N:23]=3)=[O:20])=[C:14](F)[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=O.CNC(C1C(OC2C=CC(N)=C(F)C=2)=CC=CN=1)=O.CC1C=C(OC2C=CC(N)=CC=2)C=CN=1>CCOC(C)=O>[F:31][C:28]([F:29])([F:30])[C:26]1[N:25]=[CH:24][N:23]=[C:22]([NH:21][C:19](=[O:20])[NH:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][C:9]3[CH:8]=[CH:7][N:6]=[C:5]([CH3:3])[CH:10]=3)=[CH:13][CH:14]=2)[CH:27]=1
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(F)(F)F)ncn3)c(F)c2)ccn1
Agent: CNC(=O)c1ncccc1Oc1ccc(N)c(F)c1
Agent: Cc1cc(Oc2ccc(N)cc2)ccn1
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccc(NC(=O)Nc3cc(C(F)(F)F)ncn3)cc2)ccn1

Procedure:
The title compound was prepared in the same manner as 4-{3-fluoro-4-[3-(6-trifluoromethyl-pyrimidin-4-yl)-ureido]-phenoxy}-pyridine-2-carboxylic-acid methyl-amide, replacing 4-(4-amino-3-fluorophenoxypyridine-2-carboxylic acid methylamide for 4-(2-methylpyridin-4-yloxy)phenylamine. LC-MS m/z 389.9 [M+H]+; TLC Rf=0.45 (EtOAc).
Reaction SMILES: [N:1]12C[N:5]3[CH2:6][P:7]([CH2:9][N:3](C3)C1)[CH2:8]2.[BrH:11]>O>[BrH:11].[BrH:11].[BrH:11].[NH2:5][CH2:6][P:7]([CH2:9][NH2:3])[CH2:8][NH2:1]
Reactant: C1N2CN3CN1CP(C2)C3
Agent: Br
Solvent: O
Product: NCP(CN)CN
Yield: 74.2 %

Procedure:
Following the procedure outline in Example 6, 3.14 g (0.02 mol) of 1,3,5-triaza-7-phosphaadamantane was hydrolyzed with a solution of 25 g (0.15 mol) of 48% hydrobromic acid and 40 g of water, giving, after workup, 5.4 g (74% yield) of tris(aminomethyl)phosphine trihydrobromide as a white, crystalline solid, dec. 214° C. without melting.
Reaction SMILES: C1O[C:4]([C:6]2[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=2)([CH3:5])[O:3]C1>C(O)CO>[SH:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:3])[CH3:5])=[CH:7][CH:8]=1
Reactant: CC1(c2ccc(S)cc2)OCCO1
Solvent: OCCO
Product: CC(=O)c1ccc(S)cc1

Procedure:
4'-Mercaptoacetophenone ethylene acetal (0.656 g; obtained by the reaction of 4'-mercaptoacetophenone and ethylene glycol using an analogous procedure to that described in the third paragraph of the portion of Example 7 which is concerned with the preparation of starting materials) was added to a mixture of 2,4-dibromothiazole (0.82 g), potassium carbonate (0.468 g) and NMP (4 ml). The mixture was stirred and heated to 90° C. for 2.5 hours. The mixture was cooled to ambient temperature and partitioned between diethyl ether and brine. The organic phase was dried (MgSO4) and evaporated. The mixture was purified by column chromatography using a 3:1 mixture of ethyl acetate and petroleum ether as eluent. There was thus obtained 4'-[4-bromothiazol-2-ylthio]acetophenone ethylene acetal (1.1 g, 90%), m.p. 71° C.
Reaction SMILES: [CH:1]([C:3]1[CH:20]=[CH:19][C:6]([C:7]2[O:8]C3C(C(=O)C=2O)=CC=CC=3)=[CH:5][CH:4]=1)=[CH2:2].OCC(C1C=CC=CC=1)=O>>[CH:1]([C:3]1[CH:20]=[CH:19][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(-c2oc3ccccc3c(=O)c2O)cc1
Agent: O=C(CO)c1ccccc1
Product: C=Cc1ccc(C=O)cc1

Procedure:
4'-vinyl-3-hydroxyflavone. 2-hydroxyacetophenone (Aldrich) was used as received. Ethyl alcohol was distilled prior to use. 4-vinyl benzaldehyde was synthesized using the procedure described in Example 1(a).