Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]1[C@@H:25]([N:26]2[CH2:30][C@@H:29]([CH2:31][F:32])[CH2:28][C:27]2=[O:33])[CH2:24][N:11]2[CH2:12][CH2:13][C:14]3[C:19]([C@@H:10]2[CH2:9]1)=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)([CH3:4])([CH3:3])[CH3:2].N[C@@H]1[C@@H](N2C[C@@H](CF)CC2=O)CN2CCC3C([C@@H]2C1)=CC(OC)=C(OC)C=3.Cl>CC(O)C>[C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]1[C@@H:25]([N:26]2[CH2:30][C@H:29]([CH2:31][F:32])[CH2:28][C:27]2=[O:33])[CH2:24][N:11]2[CH2:12][CH2:13][C:14]3[C:19]([C@@H:10]2[CH2:9]1)=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(cc1OC)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)[C@@H](N3C[C@@H](CF)CC3=O)CN1CC2
Agent: COc1cc2c(cc1OC)[C@@H]1C[C@H](N)[C@@H](N3C[C@@H](CF)CC3=O)CN1CC2
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)[C@@H](N3C[C@H](CF)CC3=O)CN1CC2
Temperature: 25 °C
Reaction time: 64 h
Yield: 85.1 %

Procedure:
[(S,S,S)-3-((S)-4-Fluoromethyl-2-oxo-pyrrolidin-1-yl)-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester (2.40 g, 5.02 mmol) was converted to (S)-1-((S,S,S)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one in accordance with the general method of Example 1e. The product was dissolved in 2-propanol (10 mL) and treated with hydrogen chloride (5–6 M in 2-propanol, 37 mL). The suspension formed was stirred for 64 h at r.t., then the precipitate was collected by filtration and dried, to afford the title compound (2.04 g, 91%). White solid, m.p. >300° C.
Reaction SMILES: Br.[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15](O)=O)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[F:18][C:19]1[C:20]([NH:31][NH2:32])=[N:21][CH:22]=[C:23]([C:25]2[O:29][N:28]=[C:27]([CH3:30])[CH:26]=2)[CH:24]=1>>[F:18][C:19]1[C:20]2[N:21]([C:15]([CH2:14][O:13][C:7]3[C:6]4[C:11](=[CH:12][C:3]([OH:2])=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[N:32][N:31]=2)[CH:22]=[C:23]([C:25]2[O:29][N:28]=[C:27]([CH3:30])[CH:26]=2)[CH:24]=1
Reactant: O=C(O)COc1ccnc2cc(O)ccc12
Reactant: Cc1cc(-c2cnc(NN)c(F)c2)on1
Agent: Br
Product: Cc1cc(-c2cc(F)c3nnc(COc4ccnc5cc(O)ccc45)n3c2)on1

Procedure:
The material was prepared using general method A (with 2-(7-hydroxyquinolin-4-yloxy)acetic acid hydrobromide and 1-(3-fluoro-5-(3-methylisoxazol-5-yl)pyridin-2-yl)hydrazine
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH3:23])[C:9]3[N:13]=[C:12]([C:14]4[C:15](=[O:21])[NH:16][CH:17]=[CH:18][C:19]=4I)[NH:11][C:10]=3[CH:22]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:24]1([C@@H:30]([CH2:32][OH:33])[NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN1CCOCC1>CN(C=O)C>[OH:33][CH2:32][C@@H:30]([NH:31][C:19]1[CH:18]=[CH:17][NH:16][C:15](=[O:21])[C:14]=1[C:12]1[NH:11][C:10]2[CH:22]=[C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:7]=[C:8]([CH3:23])[C:9]=2[N:13]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(I)cc[nH]c3=O)nc12
Reactant: N[C@H](CO)c1ccccc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(N[C@H](CO)c4ccccc4)cc[nH]c3=O)nc12
Temperature: 80 °C
Yield: 52.1 %

Procedure:
To a solution of 3-(6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl)-4-iodo-1H-pyridin-2-one (30 mg, 0.072 mmol) in DMF (1 mL) were added (S)-(−)-2-phenylglycinol (26 mg, 0.18 mmol) and N-methylmorpholine (0.1 mL). The reaction mixture was heated to 80° C. for 6 h and cooled to room temperature. The solvent was removed under vacuum and the residue was purified by prep. HPLC to yield the title compound (16 mg, 52%). 1H NMR (300 MHz, CD3OD) δ 8.07 (1H, narrow t, J=1.7 Hz), 7.76 (2H, s), 7.27–7.48 (7H, m), 7.21 (1H, d, J=7.5 Hz), 6.11 (1H, d, J=7.5 Hz), 4.92 (1H, m), 4.03 (1H, dd, J=4.5, 11.2 Hz), 3.95 (1H, dd, J=6.2, 11.2 Hz), 2.75 (3H, s). LCMS (M+H)+ m/z 427 (t=1.44 min.)
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[F:23])[C:17](Cl)=[O:18]>N1C=CC=CC=1.C1(C)C=CC=CC=1.O>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([O:12][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:22]([F:23])=[C:14]([F:13])[CH:15]=2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CCCCC[C@H]1CC[C@H](O)CC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC[C@H]1CC[C@H](OC(=O)c2ccc(F)c(F)c2)CC1
Temperature: 60 °C

Procedure:
To a solution of trans-4-pentylcyclohexanol (1.9 g 0.011 mol) dissolved in dry pyridine (5 ml) was added a solution of 3,4-difluorobenzoyl chloride (2.0 g, 0.011 mol) dissolved in dry toluene (10 ml), followed by heating the mixture at 60° C. for 3 hours, thereafter pouring the reaction mixture in water (100 ml), separating the toluene layer, washing it with 6N hydrochloric acid, then with 2N-NaOH aqueous solution and further with water, drying with anhydrous sodium sulfate, distilling off toluene from the resulting toluene solution and recrystallizing the remaining oily product from ethanol to obtain the objective 3,4-difluorobenzoic acid-trans-4-pentylcyclohexyl ester (2.4 g, 0.0077 mol) (yield: 70%). This product has a m.p. of 26.9° C., and its N-I point sought from a mixture thereof with trans-4-alkyl-(4-cyanophenyl)cyclohexanes according to extrapolation method was -6.0° C. Further its elemental analysis values were as follows: C: 70.03%, H: 7.81% (calculated values, C: 69.65% and H: 7.79%).
Reaction SMILES: [NH2-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH:5]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][CH2:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)[CH2:4]1.[CH2:25](Br)[CH3:26].O>C1C=CC=CC=1>[CH2:25]([N:3]1[CH2:8][CH2:7][O:6][CH:5]([CH2:9][N:10]2[C:11]3[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=3[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=3)[CH2:4]1)[CH3:26]
Reactant: CCBr
Reactant: c1ccc2c(c1)CCc1ccccc1N2CC1CNCCO1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCN1CCOC(CN2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium amide (0.08 g) in benzene was added a solution of 5-(2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine (0.5 g) in benzene under ice cooling, and the resulting mixture was stirred at room temperature for 30 minutes. to the reaction mixture was added a solution of ethyl bromide (0.22 g) in benzene under ice cooling, and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was cooled, admixed with water and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 5-(4-ethyl-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine as an oily substance.
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:9]([C:11]([CH3:13])=[O:12])=[CH2:10].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH:7]1[C:1]2([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:10][CH2:9][C:11](=[O:12])[CH:13]=1
Reactant: O=CC1CCCCC1
Reactant: C=CC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1C=CC2(CCCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cyclohexanecarbaldehyde (10.7 mL) in toluene (100 mL) were added successively methyl vinyl ketone (15 mL) and concentrated sulfuric acid (0.1 mL). The reaction mixture was stirred at room temperature for 1 hour and then heated under reflux while stirring for 4 hours. After cooling down to room temperature, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by separation of the organic layer. Then, after the aqueous layer was extracted with toluene, the organic layers were combined, washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:20 to 1:12) to give spiro[5.5]undec-1-en-3-one (8.9 g).
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH2:7][CH2:8][CH:9]=[CH:10][Sn](CCCC)(CCCC)CCCC)([CH3:4])([CH3:3])[CH3:2].OS(C(F)(F)F)(=O)=O.[C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:38][CH:37]=1)#[N:35]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([Si:5]([CH3:24])([CH3:25])[O:6][CH2:7][CH2:8][CH:9]=[CH:10][C:45]1[CH:44]=[CH:43][C:42]([C:39]2[CH:38]=[CH:37][C:36]([C:34]#[N:35])=[CH:41][CH:40]=2)=[CH:47][CH:46]=1)([CH3:2])([CH3:3])[CH3:4].[NH3:35]
Reactant: CCCC[Sn](C=CCCO[Si](C)(C)C(C)(C)C)(CCCC)CCCC
Reactant: N#Cc1ccc(-c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC=Cc1ccc(-c2ccc(C#N)cc2)cc1
Product: N
Temperature: 25 °C

Procedure:
A solution of Example 31B (4.95 g, 10.4 mmol), 4′-cyanobiphenyl triflate (3.1 g, 9.48 mmol, prepared from 4′-hydroxybiphenyl-4-carbonitrile by standard methods), and Pd(PPh3)2Cl2 (0.332 g, 0.47 mmol) in DMF (20 mL) was stirred at 80° C. overnight. The mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (97.5:2.5 hexane/ethyl acetate) to provide the title compound, 1H NMR (300 MHz, CDCl3): δ 0.07 (s, 6H), 0.91 (s, 9H), 2.46 (q, J=6 Hz, 2H), 3.75 (t, J=6 Hz, 2H), 6.32 (d, J=16 Hz, 1H), 6.48 (d, J=16 Hz, 1H), 7.44 (d, J=9 Hz, 2H), 7.54 (d, J=9 Hz, 2H), 7.65-7.74 (m, 4H) MS (DCl—NH3) m/z 364 (M+H)+, m/z 359 (M+NH4)+
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1(C)C=CC(S(O[CH2:25][CH2:26][O:27][CH3:28])(=O)=O)=CC=1.Cl>O.C(OCC)C>[CH3:28][O:27][CH2:26][CH2:25][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: COCCc1ccc(-c2ccccc2)cc1
Temperature: 35 °C
Reaction time: 3 h
Yield: 26.7 %

Procedure:
Metallic magnesium (14.6 g, 0.6 mol) was placed in a completely dried 2 l three-neck flask and dry nitrogen gas was passed through the inside of the vessel to completely dry it, followed by adding anhydrous ethyl ether (45 ml) and a trace of iodine. A dry ethyl ether solution (500 ml) of p-bromobiphenyl (140 g, 0.6 mol) was gradually added with stirring while maintaining the reaction temperature at 30° to 35° C., and after the addition, the reaction was further carried out at the same temperature for 3 hours. At an inner temperature of 35° C., an anhydrous ethyl ether solution (300 ml) of β-methyloxyethyl p-toluenesulfonate (276 g, 1.2 mol) obtained in step A was gradually added. During the addition, reflux began to occur due to the reaction heat. After the addition, the mixture was placed under reflux for 2 hours while maintaining it on a water bath at an inner temperature of 35° C. After completion of the reaction, the reaction liquid was cooled and 500 ml of water was added and then 6 N--HCl (1.5 l) was added. The reaction liquid was transferred into a separating funnel and subjected to extraction with toluene (500 ml). The resulting toluene layer was separated from the resulting aqueous layer, and this aqueous layer was further subjected to extraction with toluene (100 ml). The toluene layers were combined together, and insoluble matters therein were removed by suction filtration. The resulting toluene layer was washed once with 2 N--NaOH aqueous solution (200 ml) and filtered through a pleated filter paper, followed by distilling off toluene under reduced pressure. To the residue were added NaOH (10 g), water (20 ml) and ethanol (500 ml), and the mixture was placed under reflux on a water bath for 30 minutes. The mixture liquid was cooled and poured in 1 l of water, and toluene (300 ml) was added, followed by transferring the mixture into a separating funnel, washing the upper toluene layer 3 times with 300 ml of water and distilling off toluene under reduced pressure. The residue was then distilled under reduced pressure and fractions of b.p. 137°~140° C./1.5 mmHg were collected to obtain 4-(β-methyloxyethyl)-biphenyl (IV) (34 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.[C:13](Cl)(=O)[CH3:14].O.Cl>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:13][CH3:14])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCSc2ccccc21
Reactant: CC(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCc1ccc2c(c1)SCCC2(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 14.3 g (80.21 mmol) of 4,4-dimethylthiochroman (Compound 61) and 6.76 g (86.12 mmol) of acetyl chloride in 65 ml benzene was cooled in an ice bath and treated dropwise with 26.712 g (102.54 mmol) of stannic chloride. The mixture was stirred at room temperature for 12 hours, then treated with 65 ml water and 33 ml conc. hydrogen chloride and heated at reflux for 0.5 hours. After being cooled to room temperature, the organic layer was separated and the aqueous layer extracted with 5×50 ml benzene. The recovered organic fractions were combined and washed with 5% sodium carbonate, water, saturated NaCl and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) followed by kugelrohr distillation (150 degrees C, 0.7 mm) to give the title compound as a pale yellow oil. PMR (CDCl3): & 1.35 (6H, s), 1.92-1.98 (2H, m) 2.54 (3H, s), 3.02-3.08 (2H, m), 7.13 (1H, d, J~8.6 Hz), 7.58 (1H, dd, J~8.6 Hz, 2 Hz), 7.99 (1H, d, J~2 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:15][CH2:14][C:11]3([O:13][CH2:12]3)[CH2:10][CH2:9]2)[CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][C:25](=[O:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:12][C:11]2([OH:13])[CH2:14][CH2:15][N:8]([C:4]3[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][N:5]=3)[CH2:9][CH2:10]2)[C:25](=[O:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Clc1cc(N2CCC3(CC2)CO3)ncn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCN(CC2(O)CCN(c3cc(Cl)ncn3)CC2)C(=O)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of 6-(6-chloropyrimidine-4-yl)-1-oxa-6-azaspiro[2,5]octane (4.00 g) and 4-(tert-butoxycarbonyl)-2-piperazinone (3.38 g) in tert-butylalcohol (50 ml) was added potassium tert-butoxide (0.57 g), and the mixture was stirred at 80° C. overnight. The reaction solution was concentrated, and the residue was diluted with ethyl acetate (100 ml), washed with 0.5N hydrochloric acid and saturated brine, dried and concentrated. The residue was purified with silica gel column chromatography (eluent:ethyl acetate) and crystallized from a mixture of ethyl acetate and diethylether to give colorless crystals of 4-(tert-butoxycarbonyl)-1-[1-(6-chloro-4-pyrimidinyl)-4-hydroxypiperidin-4-ylmethyl]piperazin-2-one (5.51 g).
Reaction SMILES: C([N:3](CC)CC)C.Cl.[C:9]([O:13][C:14](=[O:24])[C@H:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH2:16])([CH3:12])([CH3:11])[CH3:10].[C:25](N1C=CN=C1)([N:27]1[CH:31]=CN=C1)=[O:26].CNN>C(Cl)Cl.C(Cl)(Cl)Cl.CO>[C:9]([O:13][C:14](=[O:24])[C@H:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:16][C:25](=[O:26])[N:27]([CH3:31])[NH2:3])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN(CC)CC
Agent: CNN
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CN(N)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Triethylamine (0.28 ml; 2 mmol) was added to a slurry of (L)-phenylalanine t-butyl ester hydrochloride (0.50 g; 1.94 mmol) in methylene chloride (4 ml). Carbonyldiimidazole (0.325 g; 2 mmol) was added, and stirring was continued for 30 minutes. Then methylhydrazine (0.11 ml; 2 mmol) was added over 5 minutes. Stirring was continued for 18 hours. Solvent was removed, and the resulting solid residue was partitioned between ether and water. The ether layer was washed twice with water and once with brine, and dried (MgSO4). Removal of solvent gave crude carbazide 11 as a colorless oil. Flash chromatography on silica gel (E. Merck No. 9385; 2×12 cm) in 100:1 methylene chloride: methanol gave pure 11 (0.480 g; 1.63 mmol; 84%): TLC (20:1 CH2Cl2 :CH3OH) Rf=0.3. MS m/e 294 (M+). Analysis: Calculated for C15H24N3O3 : C, 61.20 H, 8.22 N, 14.27. Found: C, 61.75 H, 8.28 N, 14.00. NMR (CDCl3) δ1.33 (9H,s); 3.00 (3H,s); 3.05 (2H,d,J=6); 3.6 (2H,bs); 4.63 (1H,d of t; J=8,6); 6.7-7.0 (1H, m); 7.25 (5H,s); IR (CHCl3): 3450, 3000, 1730, 1650 cm-1.
Reaction SMILES: Cl.[CH:2]([NH: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])([CH3:4])[CH3:3].[C:17]([NH:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25])(=[O:20])[CH2:18][CH3:19]>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[NH:21][C:17](=[O:20])[CH2:18][CH3:19])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: CCC(=O)Nc1ccccc1C(=O)Cl
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Agent: Cl
Product: CCC(=O)Nc1ccccc1C(=O)Oc1ccc(C(=O)CNC(C)C)cc1O

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and o-propionamidobenzoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(o-propionamidobenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with methanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(o-propionamidobenzoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol methanesulfonate.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[C:18](Cl)(=[O:22])[C:19](Cl)=[O:20]>>[CH2:9]([O:8][C:6]([C:5]1[CH:16]=[CH:17][C:2]([O:1][C:18](=[O:22])[C:19]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:7])=[CH:16][CH:17]=2)=[O:20])=[CH:3][CH:4]=1)=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Product: O=C(Oc1ccc(C(=O)OCc2ccccc2)cc1)C(=O)Oc1ccc(C(=O)OCc2ccccc2)cc1

Procedure:
A similar procedure to Example 1 is carried out by using 22.8 g of benzyl p-hydroxybenzoate and 6.4 g of oxalic acid dichloride to yield di(p-benzyloxycarbonylphenyl)oxalate, m.p. 106°-108° C., as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:40]=[C:14]3[N:15](CC4C=CC(OC)=CC=4)[CH:16]=[N:17][C:18]([O:19][C:20]4[C:21]([F:30])=[C:22]5[C:26](=[CH:27][CH:28]=4)[NH:25][C:24]([CH3:29])=[CH:23]5)=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2]>C1COCC1.CN1CCN(C)C1=O.C1COCC1.O.[Pd]>[CH2:1]([O:3][C:4](=[O:41])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:40][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C:20]4[C:21]([F:30])=[C:22]5[C:26](=[CH:27][CH:28]=4)[NH:25][C:24]([CH3:29])=[CH:23]5)[C:13]=3[CH:12]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc3c(Oc4ccc5[nH]c(C)cc5c4F)ncn(Cc4ccc(OC)cc4)c-3n2)cc1
Agent: [Pd]
Solvent: O
Solvent: CN1CCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2cc3c(Oc4ccc5[nH]c(C)cc5c4F)ncnc3[nH]2)cc1

Procedure:
Hydrogenation of 0.50 g (0.91 mMol) of 4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoic acid ethyl ester in 150 ml of THF and 15 ml of 1,3-dimethyl-2-imidazolidinone in the presence of 0.2 g of Pd/C (10%; “Engelhard 5125”), filtration and concentration gives the crude product. Stirring in THF/water, filtration and washing with water gives the title compound; MS-ES+: (M+H)+=431; elemental analysis for C, H, N and F within 0.4% of calculated value.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.[CH2:6]([O:8][C:9]([C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:13]([C:22]2[N:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=2)[N:12]=1)=[O:10])C>CO>[CH3:6][O:8][C:9]([C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:13]([C:22]2[N:23]=[N:24][C:25]([O:2][CH3:1])=[CH:26][CH:27]=2)[N:12]=1)=[O:10]
Reactant: CCOC(=O)c1cc(-c2ccccn2)n(-c2ccc(Cl)nn2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(-c2ccccn2)n(-c2ccc(OC)nn2)n1

Procedure:
28% Sodium methoxide-methanol (3 mL) was added to the above-obtained 1-(6-chloro-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid ethyl ester (1.50 g) in methanol (45 mL), and the resultant mixture was refluxed under heat for 2 hours, and then cooled in air. The reaction solvent was removed under reduced pressure, and the residue was partitioned by use of ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was dried over magnesium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and the residue was purified through silica gel chromatography (ethyl acetate-hexane), to thereby give 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid methyl ester as a solid (480 mg, 34%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[Cl:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([NH:19][NH2:20])=[O:18])=[CH:15][CH:14]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:11])[NH:20][NH:19][C:17](=[O:18])[C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:22][CH:21]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: Cc1ccc(N=C=O)c(C)c1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)NNC(=O)c2ccc(Cl)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared from a mixture 2,4-dimethylphenylisocyanate (50 mg, 34 mmol) and 4-chlorobenzoic acid hydrazide (63 mg, 37 mmol) in methylenedichloride (10 ml). The mixture was stirred at room temperature for 2 h and the resultant precipitate was collected by filtration and isolated as pale white solid (90 mg, 89%). 1H NMR (DMSO-d6): 10.39 (s, 1H), 8.34 (s, 1H), 8.05 (s, 1H), 7.94 (d, J=6.6 Hz, 1H), 7.57 (d, J=6.6 Hz, 1H), 7.44 (d, J=7.5 Hz, 1H), 6.96 (s, 1H), 6.92 (d, J=7.5 Hz, 1H), 2.72 (s, 3H), 2.22 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH:19]1([CH:24]([C:26]2[S:30][C:29]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)=[N:28][C:27]=2[CH3:41])O)[CH2:23][CH2:22][CH2:21][CH2:20]1.[CH2:42](P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:24]([C:26]2[S:30][C:29]([C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=3)=[N:28][C:27]=2[CH3:41])[C:19]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:42]=2)=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCCCP(CCCC)CCCC
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C1CCCC1
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OC(c2ccccc2)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with [rac]-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-phenyl-methanol [PCT Int. Appl. (2002), WO 02/062774 A1] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield 2-ethoxy-3-(2-methyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-phenyl-methoxy}-phenyl)-propionic acid ethyl ester as a mixture of two diastereomeric racemates as colorless liquid.