Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:10][OH:11])[CH2:8][CH2:7][C:6](=[CH2:9])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:1][CH2:2][C:3]2([CH2:10][OH:11])[CH2:8][CH2:7][C:6](=[CH2:9])[CH2:5][CH2:4]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: C=C1CCC(CO)(CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C1CCC(CO)(COS(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of Compound 100b (0.25 g, 1.6 mmol) and pyridine (0.40 mL) in dichloromethane was added at 0° C. a solution of para-toluenesulphonyl chloride (0.336 g, 1.76 mmol) in 1 mL of dichloromethane. The reaction mixture was stirred at 0° C. for 30 min., then at r.t. for 3.5 h. Dilution with dichloromethane, washing with 1M aqueous NaHSO4 and brine, drying with Na2SO4, afforded, after evaporation, a crude which was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Dichloromethane-Methanol from 1:0 to 95:5) to give the title
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=1[CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]1=[O:17].Br.O>C(O)(=O)C>[OH:8][C:7]1[CH:2]=[C:3]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]2=[O:17])[CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCCCC(C2=C(Cl)C(=O)CCC2)C1=O
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CN1CCCCC(c2cccc(O)c2)C1=O

Procedure:
Using acetic acid as solvent. A solution of 3-(2-chloro-3-oxocyclohex-1-enyl)-hexahydro-1-methylazepin-2-one (5.12 g) in glacial acetic acid (50 ml) was treated with 48% HBr in acetic acid (2 ml). After 12 hours the reaction mixture was poured on to water and the resulting precipitate removed by filtration to yield the title compound m.p. 192°-3° C. (EtOAc).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([CH2:15][C:16]#[N:17])[C:12]([N+:18]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Ni].CCO.C(O)(=O)C>[NH2:18][C:12]1[C:13]([CH2:15][C:16]#[N:17])=[N:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: N#CCc1nc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CCO
Product: N#CCc1nc(OCc2ccccc2)ccc1N

Procedure:
11 g (40 mmol) (6-benzyloxy-3-nitro-pyridin-2-yl)-acetonitrile and 1.7 g Raney nickel (washed with abs. EtOH) in 120 mL EtOH and 50 mL acetic acid were hydrogenated at RT in a hydrogen atmosphere of 3 bar. The catalyst was filtered off and the filtrate was evaporated down. The residue was combined with 30 mL water and adjusted to pH=10 with solid sodium carbonate. The aqueous phase was extracted several times with EtOAc. The combined organic phases were dried on magnesium sulphate, filtered and evaporated down. The residue was purified by flash chromatography. The product-containing fractions were combined and evaporated down.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[N:24][CH:23]=[CH:22]2.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.[Pd].C([O-])(=O)C>[CH:25]1[C:26]2[C:21](=[CH:20][C:19]([N:8]3[CH2:7][CH2:6][C:5]4([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]4)[CH2:10][CH2:9]3)=[CH:28][CH:27]=2)[CH:22]=[CH:23][N:24]=1
Reactant: Brc1ccc2cnccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccc4cnccc4c3)CC2)C1
Temperature: 120 °C
Yield: 52 %

Procedure:
Sodium t-butylate (6.24 mmol, 3.0 eq.) was added to a solution of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (2.08 mmol, 1.0 eq.) and 6-bromoisoquinoline (2.08 mmol, 1.0 eq.) in toluene (10 ml) and the reaction mixture was degassed with N2. BINAP (0.124 mmol, 0.06 eq.) and Pd acetate (0.04 mmol, 0.02 eq.) were added and the mixture was heated at 120° C. for 12 h. The reaction mixture was filtered over Celite and the filtrate was concentrated on a rotary evaporator. The crude product was purified by means of column chromatography (silica gel, 5% methanol in methylene chloride) in order to obtain the desired product. Yield: 52%
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[F:42][CH2:43][C:44]([CH2:46][F:47])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.O.CC(O)=O.O1CCOCC1>[F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:23][CH2:24][N:25]([CH:44]([CH2:46][F:47])[CH2:43][F:42])[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[CH:7]=1
Reactant: O=C(CF)CF
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: NC(=O)c1cnc(Nc2ccc(C3CCN(C(CF)CF)CC3)cc2)cc1NCc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.2 %

Procedure:
Compound 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (100 mg, 0.21 mmol) was stirred in 5 mL 1,2-dichloroethane and 5 mL dioxane as a slurry. To it were added DIEA (150 μL, 0.84 mmol) and then 1,3-difluoroacetone (100 mg, 1.05 mmol). The mixture was stirred at RT for 2 h. To the mixture were then added HOAc (200 μL) and NaBH(OAc)3 (222 mg, 1.05 mmol). The mixture was stirred at RT for overnight (incomplete reaction). To it was added water, and the mixture was concentrated in vacuo and subjected to reverse phase preparative HPLC to isolate the desired product (10 mg) and remaining starting compound. MS found for C27H29F4N5O as (M+H)+ 516.4. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.18 (1H, s), 7.38 (2H, d, J=8.0 Hz), 7.25 (1H, m), 7.19-7.09 (4H, m), 5.82 (1H, s), 5.15-4.90 (5H, m), 4.55 (2H, s), 3.77 (2H, m), 3.48 (2H, m), 3.03 (1H, m), 2.18 (4H, m) ppm.
Reaction SMILES: [C:1]([NH:20][C@@H:21]1[C@@H:25]([CH:26](C(=O)C2C=CC(OC)=CC=2)[OH:27])[O:24][C@@H:23]([N:38]2[CH:46]=[C:44]([CH3:45])[C:42](=[O:43])[NH:41][C:39]2=[O:40])[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.CO>[C:1]([NH:20][C@@H:21]1[C@@H:25]([CH2:26][OH:27])[O:24][C@@H:23]([N:38]2[CH:46]=[C:44]([CH3:45])[C:42](=[O:43])[NH:41][C:39]2=[O:40])[CH2:22]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc(C(=O)C(O)[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2NC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
The 5'-O-anisoyl protecting group was removed by dissolving 2t (30.1 g, 48.7 mmol) in 57:43 1,4-dioxane/MeOH (150 mL), followed by the addition of 2M aq. NaOH (73.1 mL, 146.2 mmol). After stirring for 1.5 h at ambient temperature, the reaction mixture was neutralized with Dowex 50W-X8 cation exchange resin (ca. 150 g of dry pyridinium H+ -form, 1.6 meq/g). Once the pH was neutral (ca. 10 min), the resin was filtered, washed extensively with CH2Cl2 and MeOH, and the crude product was concentrated in vacuo. The residue was redissolved in EtOAc (500 mL) and extracted with saturated. aq. NaHCO3 (2×250 mL), H2O (250 mL), and saturated. aq. NaCl (250 mL). After drying over Na2SO4 and filtration, the solvents were removed in vacuo, and the resulting foam was redissolved in 95:5 CH2Cl2 /MeOH (300 mL). This solution was added slowly to a rapidly stirring mixture of 1:1 Et2O/hexane (1250 mL) to precipitate the pure 3'-(Trityl)amino-3'-deoxythymidine, 3t, in 90% yield (21.2 g, 43.8 mmol). Conversion to phosphoramidite monomers and/or succinylated nucleoside is described in Examples 5-7 below.
Reaction SMILES: [Na].[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].Cl[C:9]1[C:13]([C:14]2[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][CH:19]=2)=[N:12][S:11][N:10]=1>C(O)CCCCCC>[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].[CH2:2]([O:7][C:9]1[C:13]([C:14]2[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][CH:19]=2)=[N:12][S:11][N:10]=1)[CH2:3][CH2:9][CH2:13][CH2:14][CH2:19][CH3:18]
Reactant: CN1CCC=C(c2nsnc2Cl)C1
Agent: O=C(O)C(=O)O
Agent: [Na]
Solvent: CCCCCCCO
Product: CCCCCCCOc1nsnc1C1=CCCN(C)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of sodium (120 mg, 5 mmol) in 1-heptanol (10 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine oxalate (310 mg, 1 mmol). The reaction mixture was stirred at 50° C. for 18 h. After evaporation the residue was dissolved in water and extracted with ethyl acetate. The ethyl acetate phase was dried and evaporated to give an oil. Crystallization as the oxalate salt from acetone gave the title compound. Yield: 270 mg (70%). (M.p. 152° C.; M+ : 295; Compound 21).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:12])[CH2:9][CH2:10][OH:11]>O=O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([OH:12])[CH2:9][CH2:10][OH:11]
Reactant: COC(=O)CCCCC(=O)CCO
Agent: O=O
Product: COC(=O)CCCC[C@H](O)CCO
Reaction time: 20 h
Yield: 81.5 %

Procedure:
A 100 ml autoclave was charged under argon with 3.8 g (20 mmol) of 8-hydroxy-6-oxo-octanoic acid methyl ester, with the Ru-(S)-BINAP catalyst solution prepared under Example 2, and with 20 ml of oxygen-free methanol. The hydrogenation was carried out for 20 hours at 60° C., at a constant pressure of 40 bar pure H2 and with intensive stirring. When the reaction was complete, the solvent was distilled off using a rotary evaporator. Purification of the residue by column chromatography (silica gel, ethyl acetate/n-hexane) yielded 3.1 g (82%) of (S)-6,8-dihydroxyoctanoic acid methyl ester having an enantiomeric excess of 96% (chiral GC).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[Li]CCCC.[Si:14]([O:21][CH2:22][C@@H:23]([N:30]=[CH:31][C:32]([F:42])([F:41])[O:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[CH2:24][S:25][CH2:26][CH:27]1[CH2:29][CH2:28]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1COCC1.C(OCC)C>[Si:14]([O:21][CH2:22][C@@H:23]([NH:30][C@@H:31]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:32]([F:41])([F:42])[O:33][C:34]1[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=1)[CH2:24][S:25][CH2:26][CH:27]1[CH2:28][CH2:29]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](CSCC1CC1)N=CC(F)(F)Oc1ccc(F)cc1
Reactant: Fc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H](CSCC1CC1)N[C@@H](c1ccc(F)cc1)C(F)(F)Oc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of 4-fluorobromobenzene (0.589 ml, 5.36 mmol) in anhydrous THF (5 ml) at −78° C., under nitrogen, a solution of 2.5 M of BuLi in hexanes (2.1 ml, 5.36 mmol) was added. After stirring the reaction mixture for 1 h at −78° C., a solution of [2-(tert-butyldimethylsilanyloxy)-1(R)-cyclopropylmethylsulfanylmethylethyl]-[2,2-difluoro-2-(4-fluorophenoxy)ethylidene]amine (0.8 g, 1.78 mmol) in THF (5 ml) was added. After stirring for 2 h at −40° C., the reaction mixture was diluted with ethyl ether and the solution was washed with 10% ammonium chloride solution, brine and dried over sodium sulfate. Concentration under vacuum followed by column chromatography over silica gel with ethyl acetate/hexanes (1/10) gave [2-(tert-butyldimethylsilanyloxy)-1(R)-cyclopropylmethylsulfanylmethylethyl]-[2,2-difluoro-2-(4-fluorophenoxy)-1(S)-(4-fluorophenyl)-ethyl]amine (0.75 g, 77%) as an oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:4]([OH:9])=[N:5][CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>>[N+:17]([C:7]1[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[C:4]([OH:9])=[N:5][CH:6]=1)([O-:19])=[O:18]
Reactant: Oc1ncccc1C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cnc(O)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
3-(Trifluoromethyl)pyridin-2-ol (2.3 g) was added to concentrated sulfuric acid (15 mL) at 0° C. The mixture was stirred at 0° C. for 5 minutes. To this solution was added nitric acid (fuming, 6 mL) dropwise over 5 minutes. The reaction mixture was stirred at room temperature for 2 hours, and then heated at 50° C. for 3 hours. After cooling, the reaction mixture was poured into ice (200 g), and the mixture was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound.
Reaction SMILES: C1C(CCCO)=CC(O)=C(O)C=1.[OH:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[OH:25])[CH:17](O)[C:18]([OH:20])=[O:19]>[Pd]>[OH:13][C:14]1[CH:15]=[C:16]([CH2:17][C:18]([OH:20])=[O:19])[CH:22]=[CH:23][C:24]=1[OH:25]
Reactant: O=C(O)C(O)c1ccc(O)c(O)c1
Agent: [Pd]
Agent: OCCCc1ccc(O)c(O)c1
Product: O=C(O)Cc1ccc(O)c(O)c1

Procedure:
WO 2007/009590 A1 describes a process for the preparation of hydroxytyrosol via 3,4-dihydroxymandelic acid, which is hydrogenated by metal catalysts such as palladium/carbon to give 3,4-dihydroxyphenylacetic acid. Subsequently, the reduction to hydroxytyrosol takes place. According to the examples, the hydroxytyrosol obtained has purities between 67.9% and 93.8%. Apart from one example, which describes a product with a purity of 98% without stating the pure yield by recrystallization, the precursor obtained from 3,4-dihydroxymandelic acid ester, methyl 3,4-dihydroxyphenyl acetate, is described as product with purities between 51.2% and 83.5%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[N:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[N:16]=2)[CH:9]1[CH3:23])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:22][C:17]1[CH:18]=[C:19]([CH3:21])[N:20]=[C:15]([NH:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]2[CH3:23])[N:16]=1
Reactant: Cc1cc(C)nc(NC2CCCN(C(=O)OC(C)(C)C)C2C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)nc(N[C@@H]2CCCN[C@H]2C)n1
Yield: 102.6 %

Procedure:
To the title compound from Step A (75 mg, 0.23 mmol) in DCM (4 mL) was added TFA (4 mL). Upon completion (˜3 h), the reaction was concentrated, neutralized with 5% Na2CO3 (aq) and extracted with DCM (3×). The combined organics were dried (Na2SO4) to give the title compound (52 mg) which was used without further purification. MS (ESI) mass calcd. for C12H20N4, 220.2; m/z found 221.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([C:18]3[NH:19][CH:20]=[C:21]([CH2:23][C:24]([CH3:31])([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH2:26])[N:22]=3)([OH:17])[CH3:16])=[CH:10][CH:9]=2)=[N:6][CH:7]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([C:18]3[NH:19][CH:20]=[C:21]([CH2:23][C:24]([CH3:31])([C:27]([F:30])([F:29])[F:28])[CH2:25][CH3:26])[N:22]=3)([OH:17])[CH3:16])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: C=CC(C)(Cc1c[nH]c(C(C)(O)Cc2ccc(-c3ccc(F)cn3)cc2)n1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CCC(C)(Cc1c[nH]c(C(C)(O)Cc2ccc(-c3ccc(F)cn3)cc2)n1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pd (10 wt % on activated carbon) (catalytic) was added to a degassed, ambient temperature solution of 1-[4-(5-fluoropyridin-2-yl)phenyl]-2-{4-[2-methyl-2-(trifluoromethyl)but-3-en-1-yl]-1H-imidazol-2-yl}propan-2-ol (Example 34) (8 mg, 0.02 mmol) in methanol (1 mL). After stirring at ambient temperature under an atmosphere of hydrogen for 1 h, the reaction mixture was filtered through cotton and concentrated in vacuo to afford the title compound. (M+H) found: 436.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.ClC1C=C2C(C(O[Si](C)(C)C)=NC(O[Si](C)(C)C)=N2)=CC=1.Cl[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].Br[Si](C)(C)C>C1(=O)OC(C)CO1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[N:9]2[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCl
Reactant: O=c1[nH]c(=O)c2ccc(Cl)cc2[nH]1
Agent: C[Si](C)(C)Br
Agent: C[Si](C)(C)Oc1nc(O[Si](C)(C)C)c2ccc(Cl)cc2n1
Solvent: CC1COC(=O)O1
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Reaction time: 8 h
Yield: 97 %

Procedure:
As in Example 1, 7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline (20 g) was silylated and the toluene was distilled off to give a concentrate containing 7-chloro-2,4-bis(trimethylsilyloxy)quinazoline. To this concentrate were added propylene carbonate (40 ml), ethyl chloroacetate (16.21 g) and bromotrimethylsilane (3.11 g), and the reaction was carried out at an internal temperature of 125˜140° C. for 8 hours. This reaction mixture was cooled to ≦70° C. and worked up as in Example 1 to provide ethyl 2-(7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl)acetate (27.90 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.O.[NH2:20][NH2:21]>C(O)C>[NH:20]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1)[NH2:21]
Reactant: NN
Reactant: Fc1cccc(Oc2ccc(C(F)(F)F)cc2)n1
Solvent: CCO
Solvent: O
Product: NNc1cccc(Oc2ccc(C(F)(F)F)cc2)n1
Temperature: 40 °C
Yield: 47.8 %

Procedure:
Next, a reaction flask was loaded with 2-fluoro-6-(4-trifluoromethylphenoxy)pyridine (8.0 g) and ethanol (60 ml), and heated up to 40° C. with stirring. To this mixture, hydrazine monohydrate (7.6 g) was dropwise added in 30 minutes. The temperature of the mixture was raised to the reflux temperature, followed by stirring for 20 hours. Thereafter, the heating was stopped, and the reaction mixture was cooled, followed by filtration to remove insoluble components. The filtrate was condensed by an evaporator to give 2-hydrazino-6-(4-trifluoromethylphenoxy)pyridine (4.0 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.CCCCCC.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][C:27]=1[CH3:34]>C1COCC1.O>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([CH:30]([C:29]2[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[C:27]([CH3:34])[CH:28]=2)[OH:31])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[CH3:12]
Reactant: CCOc1cc(Br)ccc1OC
Reactant: COc1ccc(C=O)cc1C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1cc(C(O)c2ccc(OC)c(C)c2)ccc1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-bromo-2-ethoxy-1-methoxy-benzene (1.7 g, 7.4 mmol) in THF (20 mL) was added a solution of n-butyllitium in hexane (2.8 mL, 2.5 N, 7.0 mmol) at −78° C. and kept for 20 min. To the mixture was added 4-methoxy-3-methyl-benzaldehyde (1.0 g, 90% pure, 6.0 mmol) at −78° C. After 18 h, water (30 mL) was added to the mixture, and the cold bath was removed. The mixture was stirred at room temperature for 20 min. The mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with HCl (0.5 N, 50 mL), sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent gave (3-ethoxy-4-methoxy-phenyl)-(4-methoxy-3-methyl-phenyl)-methanol as a solid (2.0 g, 100% crude yield). The sample was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:42])[CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23][C:24]#[C:25][CH3:26])[C:18]([N:27]3[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28]3)=[N:17][C:16]=2[N:15]([CH3:41])[C:13]1=[O:14])([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].C1CCCCC1.C(OCC)(=O)C>COCCO.O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:42])[CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23][C:24]#[C:25][CH3:26])[C:18]([N:27]3[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:28]3)=[N:17][C:16]=2[N:15]([CH3:41])[C:13]1=[O:14]
Reactant: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1[N+](=O)[O-])c(=O)n2C
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCO
Solvent: O
Product: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1N)c(=O)n2C

Procedure:
Prepared by reduction of 1-[2-(2-nitrophenyl)-2-oxoethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butyloxycarbonylamino)piperidin-1-yl]xanthine with sodium dithionite in a mixture of methyl glycol and water (3:2) at 100° C. Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate (4:6)).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH:13][CH2:14][CH2:15][OH:16])[CH3:12]>>[CH2:11]([N:13]([CH2:14][CH2:15][OH:16])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCNCCO
Product: CCN(CCO)c1ccc([N+](=O)[O-])cc1
Temperature: 135 °C
Reaction time: 1 h

Procedure:
To a pressure tube containing 1-fluoro-4-nitrobenzene (5.3 mL) and is added 2-(ethylamino)-1-ethanol (10.7 g). The reaction is tightly sealed and heated to 135° C. with stirring. After 1 hour, the reaction is cooled to room temperature and concentrated under reduced pressure. The residue is dried in vacuo. The residue is chromatographed on silica eluting with ethyl acetate. The product-containing fractions are evaporated to give 10.1 g of 2-(ethyl-4-nitroanilino)-1-ethanol as an orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.C1CCCCC=1>[Pd].C(O)C>[NH2:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[OH:1])[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: NC(=O)c1ccc(O)c(N)c1

Procedure:
A mixture of 4-hydroxy-3-nitrobenzamide D125 (0.49 g, 2.69 mmol), cyclohexene (1.105 g, 13.45 mmol) and 10% palladium on carbon (0.143 g, 0.135 mmol) in ethanol (20 mL) was heated to reflux under argon for 3 hr. The cooled mixture was filtered through celite and the filtrate concentrated to dryness in vacuo to afford a yellow/brown solid. The product was purified by silica gel chromatography eluting with 0-15% 2M ammonia in MeOH/DCM. The title compound was isolated as a pale brown powder, 0.26 g, 57.2%.