Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].O[C:4](=[CH:8][C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)[C:5]([OH:7])=[O:6].[NH2:14][C@H](C([O-])=O)CC([O-])=O>>[CH:13]1[C:9]([CH2:8][C@H:4]([NH2:14])[C:5]([OH:7])=[O:6])=[CH:10][S:11][CH:12]=1
Reactant: O=C(O)C(O)=Cc1ccsc1
Reactant: N[C@@H](CC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: N[C@@H](Cc1ccsc1)C(=O)O
Yield: 39.3 %

Procedure:
The procedure was largely as in Example 8. However, solution 1 contained only 20 g of hydroxy-3-(3-thienyl)acrylic acid and 19 g of L-aspartate. The product concentration was 11.5 g/l (58%) after the reaction. After ion-exchange chromatography, 7.9 g (40%) of L-3-(3-thienyl)alanine (2B) were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[S:23][C:24]=1[C@H:25](O)[CH3:26].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][C@H:25]([C:24]3[S:23][C:22]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=4)=[N:21][C:20]=3[CH3:19])[CH3:26])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1[C@@H](C)O
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1[C@H](C)Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with (R)-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol [ee=79%; PCT Int. Appl. (2002), WO 02/062774 A1] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to obtain (S)-(6-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester as colorless liquid. The configuration was tentatively assigned as S according to R. Cadilla et al., PCT Int. Appl. (2002), WO 02/062774 A1 and the generally accepted SN2-type mechanism of the Mitsunobu reaction.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)=[O:3].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:11][C:7]1[CH:6]=[C:5]([N:4]([C:2](=[O:3])[CH3:1])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: Brc1ccccc1
Reactant: CC(=O)Nc1cccc(F)c1
Product: CC(=O)N(c1ccccc1)c1cccc(F)c1
Yield: 21.2 %

Procedure:
Using 3-fluoroacetanilide (4.6 g) and bromobenzene (9.4 g), a reaction was made in the same manner as in 1) of Production Example 14. The subsequent purification by silica gel column chromatography (developing solvent, ethyl acetate:hexane=1:2) produced 3-fluoro-N-phenylacetanilide (1.46 g; yield, 21%) as a purple oil.
Reaction SMILES: [C:1]1(=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:18](O)[CH3:19]>[Pd]>[CH2:9]([C:15]1[CH:16]=[CH:17][C:12]([NH:11][CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[CH:13][CH:14]=1)[CH2:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:18][CH3:19]
Reactant: c1ccc(N=C2CCCc3ccccc32)cc1
Reactant: CCO
Agent: [Pd]
Product: CCCCCCCCCCCCc1ccc(NC2CCCc3ccccc32)cc1

Procedure:
N-(1,2,3,4-tetrahydronaphthylidene) aniline (XXVI) (38 g) prepared as described in example XXXIA was hydrogenated using 5% Pd/C as the catalyst and 95% ethanol as the solvent. The crude product was crystallized from ethanol to give 1-(p-dodecylanilino)-1,2,3,4-tetrahydronaphthalene (XXVII). XXVII had a melting point of 34° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[N:5]=[C:4]([CH:13]=[O:14])[C:3]=1[Cl:15].CC(=CC)C.P([O-])([O-])(O)=[O:22].[Na+].[Na+].Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH:10]2[CH2:11][CH2:12]2)[N:5]=[C:4]([C:13]([OH:22])=[O:14])[C:3]=1[Cl:15]
Reactant: O=P([O-])([O-])O
Reactant: Nc1c(F)c(CC2CC2)nc(C=O)c1Cl
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: Nc1c(F)c(CC2CC2)nc(C(=O)O)c1Cl
Temperature: 70 °C

Procedure:
A microwave vial equipped with a magnetic stir bar was charged with 4-amino-3-chloro-6-(cyclopropylmethyl)-5-fluoropicolinaldehyde (63 mg, 0.276 mmol) and t-butanol (1.378 mL). The mixture was treated with H2O (0.459 mL), 2-methylbut-2-ene (0.3 mL, 0.276 mmol), sodium hydrogenphosphate (78 mg, 0.551 mmol), and finally sodium chlorite (74.8 mg, 0.827 mmol) was added in one portion. The mixture was heated to 70° C. in the microwave for 2 h. An aliquot of the reaction mixture was analyzed by LC-MS. LC-MS analysis showed one major product with the correct mass for the desired product. The reaction mixture was evaporated to dryness under N2. Purification via reverse phase chromatography yielded 4-amino-3-chloro-6-(cyclopropylmethyl)-5-fluoropicolinic acid (6.2 mg, 9.5%); 1H NMR (400 MHz, CDCl3) δ 11.60 (s, 1H), 5.00 (m, 2H), 2.70 (dd, J=7.0, 2.6 Hz, 2H), 1.17-1.02 (m, 1H), 0.60-0.48 (m, 2H), 0.27 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −139.97; ESIMS m/z 243.2 ([M−H]−).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>O1CCOCC1>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:14]2[N:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])[CH2:9][CH2:8]1
Reactant: OCCOCCN1CCNCC1
Reactant: O=C(O)c1cccnc1Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccnc1N1CCN(CCOCCO)CC1
Reaction time: 48 h

Procedure:
Grams 5.9 of 1-(2-hydroxyethoxyethyl)piperazine and 2.7 g of 2-chloronicotinic acid in 50 ml dioxane were refluxed for 3 days. The reaction mixture was then cooled and allowed to rest for 2 days, afterwards the solvent was removed and the residue crystallized from absolute ethanol, gave 1.1 g of 2-{4-[2-(2-hydroxy ethoxy)ethyl]piperazin-1-yl}nicotinic acid melting at 172°-174° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:23]=[CH:24][CH:25]=3)[O:17][CH:18]([CH3:22])[C:19]([NH2:21])=O)=[N:9]2)=[CH:4][CH:3]=1.C(#N)C>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:23]=[CH:24][CH:25]=3)[O:17][CH:18]([CH3:22])[C:19]#[N:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(Oc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1)C(N)=O
Solvent: CC#N
Solvent: ClCCl
Product: CC(C#N)Oc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1

Procedure:
Using (+)-2-(3-(2-(7-Chloroquinolin-2-yl)ethenyl)phenoxy)propanoamide from Example 75 in place of the (+)-enantiomer in example 76, gave the title compound, mp 147°-149° C. (ex acetonitrile), D -134.4° (c 0.98 in dichloromethane).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:18]([NH:20][CH:21]([CH3:23])[CH3:22])[CH3:19]>>[Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([N:20]([CH2:18][CH3:19])[CH:21]([CH3:23])[CH3:22])=[O:17])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCNC(C)C
Reactant: O=C(O)C1CCc2c(sc3ncnc(Cl)c23)C1
Product: CCN(C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1)C(C)C

Procedure:
500 mg (1.86 mmol) (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 31b) were transformed in analogy to example 3 using N-ethylpropan-2-amine to give after working up and purification 513 mg (82%) of the title compound.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][C:10]1[N:14]=[C:13]([CH3:15])[N:12]([C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18](/[CH:23]=[CH:24]/[C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)[CH:17]=2)[N:11]=1.O>CS(C)=O>[CH3:9][C:10]1[N:14]=[C:13]([CH3:15])[N:12]([C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([C@@H:23]3[CH2:2][C@H:24]3[C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)[CH:17]=2)[N:11]=1
Reactant: C[S+](C)(C)=O
Reactant: Cc1nc(/C=C/c2ccc3ccccc3n2)cc(-n2nc(C)nc2C)n1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc([C@@H]2C[C@H]2c2ccc3ccccc3n2)cc(-n2nc(C)nc2C)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of trimethylsulfoxonium iodide (59.0 mg, 0.268 mmol, 1.3 eq.) in anhydrous DMSO (1.5 mL) was added sodium hydride (5.4 mg, 0.227 mmol, 1.1 eq.) and the reaction was heated to 50° C. for 30 minutes. The reaction was then cooled to room temperature and a solution of (E)-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)vinyl)quinoline (1-4) (70.0 mg, 0.205 mmol, 1.0 eq.) in DMSO (1.5 mL) was added. The reaction was stirred at room temperature for 1 hour, poured into water (5.0 mL) and extracted using ethyl acetate (3×5.0 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (10-40% ethyl acetate in hexanes) to afford trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropyl)quinoline (1-5) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.03 (br d, 1H, J=8.5 Hz), 7.98 (br d, 1H, J=8.4 Hz), 7.75 (br dd, 1H, J=8.0, 1.0 Hz), 7.67 (ddd, 1H, J=8.5, 7.0, 1.5 Hz), 7.60 (br s, 1H), 7.46 (ddd, 1H, J=8.0, 7.0, 1.0 Hz), 7.33 (d, 1H, J=8.5 Hz), 2.96-2.83 (m, 2H), 2.89 (s, 3H), 2.68 (s, 3H), 2.06-1.94 (m, 2H). LRMS m/z (M+H+) 357 found, 357 required. m.p. 140-141° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH3:12].[Mg].[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH3:12][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:21]
Reactant: Cc1ccc2ccccc2c1Br
Reactant: O=Cc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc2ccccc2c1C(O)c1ccccc1
Reaction time: 0.75 h
Yield: 78.7 %

Procedure:
A solution of 10 g (45 mmol) of 1-bromo-2-methylnaphthalene in 75 mL of THF was refluxed with 1.2 g (50 mmol) of magnesium turnings for three hours. The reaction was cooled on ice and 4.8 mL (43 mmol) of benzaldehyde was added. The ice was removed, the reaction was stirred 45 minutes and quenched with 5 mL of 1N HCl followed by 50 mL of water. The reaction was extracted into ethyl acetate, dried over sodium sulfate and flash chromatographed through silica gel with 5-10% ethyl acetate in hexane to provide 8.4 g (75%) of 2-methyl-a-phenyl-1-naphthalenemethanol as a pale yellow gum.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)([S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:8]#[N:9].Cl.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][NH:35][CH2:34][CH2:33]2.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:34][CH2:33][C:32]3[C:37](=[CH:38][C:39]([O:40][CH3:41])=[C:30]([O:29][CH3:28])[CH:31]=3)[CH2:36]2)[C:8]#[N:9])[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: COc1ccc(C(C#N)(CCCCCBr)Sc2ccccn2)cc1OC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(C(C#N)(CCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccccn2)cc1OC
Yield: 58.4 %

Procedure:
A mixture, under argon, of 1.5 g of product from Example 118, 0.790 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, 7 ml of N,N-diisopropyl ethylamine and 60 ml of acetonitrile is heated at reflux temperature overnight. The reaction is cooled and concentrated in vacuo to give an oil. The oil is purified by chromatography (silica gel: 1 and 2% methyl alcohol/methylene chloride) to give 1.1 g of the desired product as a glassy yellow solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=O)[CH2:4][OH:5].[C:10]([O:14][CH3:15])(=[O:13])C=C.OS(O)(=O)=O>CCOCC.CS(C)=O>[CH3:15][O:14][C:10]([CH:9]1[C:4](=[O:5])[CH2:3][O:7][CH2:8]1)=[O:13]
Reactant: C=CC(=O)OC
Reactant: CCOC(=O)CO
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: COC(=O)C1COCC1=O
Temperature: 25 °C

Procedure:
To a stirred slurry of sodium hydride (1.67 g, 60% in mineral oil, 44.0 mmol) in dried ether was added with ethyl glycolate, dropwise over 15 minutes. The reaction was warmed up to room temperature for 30 min while stirring and concentrated in vacuo to provide white solid. The solid was treated with methyl acrylate (4.16 g, 49 mmol) in DMSO (20 mL) at 0° C. for 15 minutes and room temperature for 45 minutes. The mixture was poured into 5% H2SO4 and extracted with ethyl acetate. Organic layer was washed with brine, dried over Mg2SO4 and concentrated to give 4-oxo-tetrahydro-furan-3-carboxylic acid methyl ester as a colorless oil.
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([O:22][CH3:23])[N:3]=1.N(OCCC(C)C)=O.[ClH:32]>C(#N)C.[Cu](Cl)Cl>[Cl:32][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([O:22][CH3:23])[N:3]=1
Reactant: COc1nc(N)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COc1nc(Cl)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.3 g (10.634 mmol) of 2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-methoxypyridine-3,5-dicarbonitrile are initially charged in 300 ml of acetonitrile, 8.578 g (63.806 mmol) of copper(II) chloride and 8.59 ml (63.806 mmol) of isoamyl nitrite are added and the mixture is stirred at room temperature overnight. 1N hydrochloric acid is added, and the reaction mixture is extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium bicarbonate solution and water, dried over sodium sulphate and concentrated. The reaction mixture is purified by preparative HPLC (acetonitrile/water: 10:90→95:5). This gives 2.11 g (58% of theory) of the target compound.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:15]=[C:16]1[O:20][C@H:19]([C:21]([Cl:24])([Cl:23])[Cl:22])[N:18]2[CH2:25][CH2:26][CH2:27][C@@:17]12[CH:28]=[O:29]>ClCCCl.C(Cl)Cl>[OH:29][CH2:28][C@@:17]12[CH2:27][CH2:26][CH2:25][N:18]1[C@@H:19]([C:21]([Cl:24])([Cl:23])[Cl:22])[O:20][C:16]2=[O:15]
Reactant: O=C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@]12CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium triacetoxyborohydride (544 mg, 2.57 mmol) was added to (3R,7aR)-1-oxo-3-trichloromethyl-dihydro-pyrrolo[1,2-c]oxazole-7a-carbaldehyde (obtained as described in J. Org. Chem. 2006, 71(1), 97-102, 500 mg, 1.835 mmol) in DCE (4 mL). The RM was stirred 18 h at rt then taken up in DCM, the organic layer washed with water, dried over Na2SO4 and evaporated. The crude product was purified using a 20 g RediSep® silica gel column (eluent DCM to 10% MeOH in DCM) to give the title compound as a clear pale yellow oil.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:27]([C:24]1[CH:23]=[N:22][C:21]([NH:19][CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:11])[CH2:17][CH2:16]2)=[N:26][CH:25]=1)[CH3:28]
Reactant: NCC1CCN(C(=O)[C@@H]2C[C@H]2c2ccccc2)CC1
Reactant: CCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cnc(NCC2CCN(C(=O)[C@@H]3C[C@H]3c3ccccc3)CC2)nc1
Temperature: 150 °C

Procedure:
The stirred reaction mixture of (1-{[(1R,2R)-2-phenylcyclopropyl]carbonyl}piperidin-4-yl)methylamine (EXAMPLE 154, STEP 2) (0.100 g, 0.387 mmol), 2-chloro-5-ethyl-pyrimidine ([111196-81-7], 0.055 g, 0.387 mmol) and cesium carbonate (0.252 g, 0.774 mmol) in DMF (5 mL) was heated at 150° C. for 7 h. The reaction mixture was cooled to RT, diluted with ethyl acetate (100 mL), washed with water (5×20 mL), and brine (10 mL), then dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60, eluting with 10:1–20:89–70 CH2Cl2:2-propanol:hexane to give the title compound. M.S. (M+1): 365.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[C:28](Cl)(=[O:39])[O:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:28]([O:29][C:30]1[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=1)=[O:39]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (1.5 g, 3.57 mmol), and DMAP (0.436 g, 3.57 mmol) were dissolved in DCM (50 ml), and 4-nitrophenyl carbonochloridate (0.863 g, 4.28 mmol) was added portion wise. The mixture was stirred at RT overnight. After 18 hours, the solvent was evaporated and the crude purified by silica gel flash chromatography (petroleum ether:EtOAc 3:7) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)carbonyloxy)-ethyl)pyridine 1-oxide (1.609 g, 2.75 mmol, 77% yield, MS/ESI+ 585 [MH]+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[O:15]=[C:16]1[NH:20][CH2:19][C:18](=[O:21])[N:17]1[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:27]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:17]3[C:18](=[O:21])[CH2:19][NH:20][C:16]3=[O:15])=[CH:30][CH:29]=1)=[N:1]2
Reactant: O=Cc1ccc(CN2C(=O)CNC2=O)cc1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(CN4C(=O)CNC4=O)cc3)nc2c1
Temperature: 115 °C
Reaction time: 17 h

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (0.19 g, 0.98 mmol) in N,N-dimethylacetamide (4 mL) were added 4-(2,5-dioxo-imidazolidin-1-ylmethyl)-benzaldehyde (0.19 g, 0.89 mmol), sodium hydrogen sulfite (58.5 wt %, 0.24 g, 1.30 mmol) and p-toluenesulfonic acid monohydrate (34 mg, 0.18 mmol) and the reaction mixture was stirred at 115° C. for 17 hours under nitrogen, then cooled to room temperature. The precipitate was filtered, washed with methanol, water, then methanol, and dried in air. The solid was suspended in hot DMSO (approximately 3 mL); saturated aqueous NaHCO3 (approximately 3 mL) and water were added. The solid was filtered, washed with water, then methanol, and air dried to give the title compound as a light yellow solid. Yield: 0.16 g (46%). MP 317-318° C. 1H NMR (400 MHz, DMSO-d6): δ 12.05 (s, 1H), 8.17 (s, 1H), 8.12 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 6.74 (d, J=2.0 Hz, 1H), 6.54 (d, J=2.0 Hz, 1H), 4.61 (s, 2H), 4.02 (s, 2H), 3.89 (s, 3H), 3.85 (s, 3H). MS (ES+) m/z: 395.09 (M+1).
Reaction SMILES: [CH2:1]([N:8]([C:13]1[N:18]=[C:17]([CH3:19])[N:16]=[C:15]2[N:20]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:26]=3[Cl:33])[N:21]=[C:22]([S:23][CH3:24])[C:14]=12)[CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:36][N:37]=[C:38]=[O:39]>C1COCC1>[CH3:36][NH:37][C:38]([O:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:13]1[N:18]=[C:17]([CH3:19])[N:16]=[C:15]2[N:20]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:26]=3[Cl:33])[N:21]=[C:22]([S:23][CH3:24])[C:14]=12)=[O:39]
Reactant: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c2nc(C)nc(N(CCCO)Cc3ccccc3)c12
Reactant: CN=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(=O)OCCCN(Cc1ccccc1)c1nc(C)nc2c1c(SC)nn2-c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 71.3 %

Procedure:
A solution of 3-{benzyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-propan-1-ol (100 mg, 0.191 mmol) in 2 ml of dry THF was treated with 6 mg of 60% sodium hydride in oil and methyl isocyanate (39 mg, 6.78 mmol) at room temperature and stirred at room temperature for 10 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 110 mg of white form. The form was purified through silica gel column chromatography to give 79 mg of the title compound as a white glass form. 1H NMR (CDCl3): 2.03(m,2H), 2.51(s,3H), 2.59(s,3H), 2.77(d,3H), 3.79(t,2H), 4.12(t,2H), 4.50(brs,1H), 5.17(s,2H), 7.2-7.45(m,5H), 7.51(s,2H)ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24]([OH:26])=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].O[N:28]=[C:29]([NH2:33])[CH:30]([CH3:32])[CH3:31]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH:11]([C:24]3[O:26][N:33]=[C:29]([CH:30]([CH3:32])[CH3:31])[N:28]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[O:16])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1C
Reactant: CC(C)C(N)=NO
Product: Cc1ccc(C2CC(c3nc(C(C)C)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1C

Procedure:
80 mg (0.222 mmol) of the compound from Example 128A and 35 mg (0.333 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 2.
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[H][H]>O1CCCC1>[C:5]1([CH2:4][OH:3])[C:10]([CH2:1][OH:2])=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1OCc2ccccc21
Reactant: [H][H]
Solvent: C1CCOC1
Product: OCc1ccccc1CO

Procedure:
Phthalide (5 mmol), a ruthenium complex 1 (0.025 mmol), and tetrahydrofuran (2 mL) were charged into a 100-mL autoclave equipped with a stirrer. Then, the mixture was subjected to hydrogenation at a hydrogen pressure of 5 MPa at 100° C. for 16 hours. The reaction liquid was analyzed by gas chromatography. As a result, 1,2-benzenedimethanol was obtained at a conversion rate of 66% and a selectivity of 99% or more.