Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].P(Cl)(OC1C=CC=CC=1)([O:11][C:12]1C=CC=C[CH:13]=1)=O.C(N(CC)CC)C.C(O)(=O)C>C(OCC)(=O)C>[C:6]1(=[O:7])[N:2]([O:1][C:12](=[O:11])[CH3:13])[C:3](=[O:8])[CH2:4][CH2:5]1
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(=O)ON1C(=O)CCC1=O
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
1.27 g (0.011 mol) of N-hydroxysuccinimide were initially introduced into 10 ml of ethyl acetate, a solution of 3.22 g (0.012 mol) of diphenyl chlorophosphate in 10 ml of ethyl acetate was added and then a solution of 2.53 g (0.025 mol) of triethylamine in 10 ml of ethyl acetate was added dropwise in the course of 10 minutes, the temperature rising to 41° C. A thick, white suspension resulted, which was treated with a solution of 0.6 g (0.01 mol) of acetic acid in 10 ml of ethyl acetate and heated at 45°-55° C. for 16 hours. After ending of the reaction, the solid was filtered off and washed with 2×3 ml of ethyl acetate. The combined filtrates were evaporated in vacuo and the semicrystalline residue which remained was washed by stirring with 20 ml of ethanol for 30 minutes. The white solid thus obtained was filtered off, washed with 2×3 ml of ethanol, sucked dry and then washed by stirring with 10 ml of isopropanol. After filtering off, washing with 2×2 ml of isopropanol and drying in vacuo, 1.1 g (70%) of white acetic acid succinimidyl ester were obtained.
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:5]([CH:21]=[N:22][N:23]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)#[N:2].[C:24]1([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH2:36]=O>C(O)(=O)C.C(Cl)Cl>[C:15]1([CH:12]2[CH2:13][CH2:14][N:9]([C:8]3[CH:7]=[CH:6][N:5]4[C:21]([CH2:36][N:33]5[CH2:32][CH2:31][CH:30]([C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=6)[CH2:35][CH2:34]5)=[N:22][N:23]=[C:4]4[C:3]=3[C:1]#[N:2])[CH2:10][CH2:11]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=O
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: N#Cc1c(N2CCC(c3ccccc3)CC2)ccn2cnnc12
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#Cc1c(N2CCC(c3ccccc3)CC2)ccn2c(CN3CCC(c4ccccc4)CC3)nnc12
Temperature: 80 °C

Procedure:
To a solution of D8 (0.301 g, 0.992 mmol) in acetic acid (4.5 ml) were added 4-phenylpiperidine (0.160 g, 0.992 mmol) and formaldehyde (0.223 ml, 0.992 mmol; 37%). The resulting mixture was heated in a sealed tube at 80° C. for 16 h. The reaction mixture was diluted with DCM and washed with 2M NaOH. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The crude product thus obtained was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 2% as eluent). The desired fractions were collected and concentrated in vacuo to yield a residue that was purified by HPLC (C18Xbridge 19×100; mobile phase AcONH4/CH3CN gradient as eluent). The desired fractions were collected and concentrated in vacuo to yield final compound E12 (0.085 g, 18%).
Reaction SMILES: [OH:1][CH:2]([CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21]1)[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]>C(O)C>[O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[C:26]1([N:23]2[CH2:24][CH2:25][NH:20][CH2:21][CH2:22]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(C2CCC(=O)N2)cc1OCC(O)CN1CCN(c2ccccc2)CC1
Solvent: CCO
Product: COc1ccc(C2CCC(=O)N2)cc1OCC1CO1
Product: c1ccc(N2CCNCC2)cc1
Yield: 95 %

Procedure:
From 10 mmol of 5-[3-(2,3-epoxypropoxy)-4-methoxyphenyl]-2-pyrrolidone and 10 mmol of 1-phenylpiperazine (95% strength), 5-{3-[2-hydroxy-3-(4-phenylpiperazin-1-yl)propoxy]-4-methoxyphenyl }-2-pyrrolidone, m.p. 127°-131° (ethanol) is obtained in 52% yield, analogously to the process of Example 1.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)[CH2:2][CH3:3].C(O[O:17][C:18]([CH3:21])(C)C)(C)(C)C.[C]=O.[CH2:24]([OH:26])C>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:24]([O:17][CH2:18][CH3:21])=[O:26])=[CH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: CCO
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: CCCOc1ccc(C)cc1
Agent: [C]=O
Product: CCCOc1ccc(CC(=O)OCC)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
4-n-propoxytoluene (1.8 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 88 mg ethyl 2-(4-n-propoxyphenyl)acetate was obtained by column chromatography, in a yield of 79%. 1HNMR (400 MHz, CDCl3) δ 1.00 (t, J=7.6 Hz, 3H), 1.23 (t, J=7.2 Hz, 3H), 1.75-1.84 (m, 2H), 3.54 (s, 2H), 3.88 (t, J=6.4 Hz, 2H), 4.11 (q, J=7.2 Hz, 2H), 6.83-6.87 (m, 2H), 7.16-7.20 (m, 2H); 13CNMR (100 MHz, CDCl3) δ 10.5, 14.2, 22.6, 40.6, 60.8, 69.5, 114.6, 126.0, 130.2, 158.2, 171.9; HRMS (ESI) calcd. for C13H18NaO3 [M+Na]: 245.1148. found: 245.1157. The ethyl 2-(4-n-propoxyphenyl)acetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 73 mg product 2-(4-n-propoxyphenyl)acetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 95%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:19][CH:18]=2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.CCO>[F:16][C:13]([F:14])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:6]2[NH:5][C:4]([C:17]3[CH2:22][CH2:21][N:20]([C:23]4[C:28]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:19][CH:18]=3)=[N:3][C:2]=2[C:43]2[CH2:42][CH2:41][N:40]([C:38]([O:37][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:39])[CH2:45][CH:44]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: FC(F)(F)c1ccc(-c2[nH]c(C3=CCN(c4ncccc4C(F)(F)F)CC3)nc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2nc(C3=CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2-c2ccc(C(F)(F)F)cc2)CC1
Temperature: 130 °C

Procedure:
A mixture of 2-(4-(4-chloro-5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)-5,6-dihydropyridin-1(2H)-yl)-3-(trifluoromethyl)pyridine (60 mg, 0.127 mmol, Example 23(c)), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (59 mg, 0.19 mmol, Chemshop), dichloro-bis(triphenyl-phosphine) palladium (II) (5 mg, 0.006 mmol, Aldrich), sodium carbonate (27 mg, 0.254 mmol), and DME/H2O/EtOH (7:3:2) solution (0.8 mL) was heated at 130° C. in a microwave synthesizer for 2 h. The reaction mixture was cooled to RT and filtered. The filter cake was washed with MeOH (2×1 mL) and the combined filtrates were concentrated in vacuo. The residue was dissolved in DMSO (1 mL) and purified by by preparative HPLC [gradient 10-85% MeCN (0.1% TFA)/H2O (0.1% TFA)]. The fractions containing the desired product were combined and treated with sat. aqueous solution of NaHCO3 (15 mL) at 0° C. for 24 h. The organic layer was separated, dried over MgSO4, and filtered. The filtrate was evaporated and the residue dried in vacuo to give the title compound as an orange solid. MS (ESI, positive ion) m/z: 620 (M+1).
Reaction SMILES: P([O-])(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)O.[OH-].[Na+]>C(C(C)=O)C(C)C>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1Cl
Agent: [Na+]
Agent: [O-]P(Oc1ccccc1)Oc1ccccc1
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Product: Clc1ccccc1C(c1ccccc1)(c1ccccc1)n1ccnc1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
A mixture of methyl isobutyl ketone (150 ml), diphenyl phosphite (32.8 g), imidazole (13.6 g) and o-chlorophenyldiphenylmethanol (29.5 g) obtained in Example 1 (A) was refluxed for 4 hours. A 10% aqueous sodium hydroxide solution (250 ml) was added thereto and the resultant mixture was refluxed for 1 hour. After cooling to room temperature, the organic layer was separated, washed with water, and evaporated to give a crystalline mass. Recrystallization from methyl isobutyl ketone gave 26.5 g of 1-(o-chlorophenyldiphenylmethyl)imidazole. Yield, 77%. M.P., 142°-143° C.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([C:17]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[N:20][N:19]4[CH2:28][CH2:29][CH2:30][C:18]=34)=[CH:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>O1CCCC1.O>[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([C:17]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[N:20][N:19]4[CH2:28][CH2:29][CH2:30][C:18]=34)=[CH:12][C:13]([CH:1]([CH3:3])[CH3:2])=[N:14]2)=[CH:9][CH:8]=1
Reactant: Brc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reactant: CC(C)[Mg]Cl
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)c1cc(-c2c(-c3ccccn3)nn3c2CCC3)c2ccc(Br)cc2n1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A 2 M solution of isopropyl magnesium chloride in tetrahydrofuran (65 μL, 0.13 mmol) is added to solution of 7-bromo-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline (50.0 mg, 0.13 mmol) in tetrahydrofuran (1 mL) at room, temperature with stirring for 2 h. The mixture is cooled to −78° C. and triethylamine (21.4 μL, 0.154 mmol) and methanesulfonyl chloride (11 μL, 0.14 mmol) added. The mixture is warmed to room temperature and allowed to stand 18 h. The mixture is treated with water, extracted with ethyl acetate, dried (sodium sulfate), filtered, and concentrated in vacuo. The residue is chromatographed on SiO2 (dichloromethane to 75% ethyl acetate/dichloromethane) to yield the title compound as a solid, 4.5 mg (9%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Brc1ccccn1
Reactant: O=Cc1ccccc1O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=Cc1ccccc1Oc1ccccn1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
A solution of 2-hydroxybenzaldehyde (10.00 g, 81.9 mmol), 2-bromopyridine (26.91 g, 170.3 mmol), potassium carbonate (17.54 g, 126.9 mmol), and copper (2.60 g, 40.95 mmol) in pyridine (80 mls) was refluxed for 3 days. The reaction was then cooled to r.t., filtered through Celite, diluted with ethylacetate (500 mls) and washed with water (3×300 mls). The organic was then dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, 9:1 hexanes:ether) to afford 16.21 g (99%) of 2-(2-pyridyloxy)benzaldehyde as a yellow oil.
Reaction SMILES: C(NC(C)C)(C)C.[Cl:8][C:9]1[CH:13]=[CH:12][S:11][CH:10]=1.[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH:28]=[O:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>O1CCCC1.C([Li])CCC.C(OCC)(=O)C>[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH:28]([C:10]2[S:11][CH:12]=[CH:13][C:9]=2[Cl:8])[OH:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1ccsc1
Reactant: O=CCC1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: OC(CC1CCN(Cc2ccccc2)CC1)c1sccc1Cl
Reaction time: 1 h
Yield: 59 %

Procedure:
After dissolving 1.3 ml of diisopropylamine in 20 ml of tetrahydrofuran, 3.5 ml of n-butyllithium (2.66 M, n-hexane solution) was added dropwise while stirring at below −30° C. After stirring for 30 minutes while cooling on ice, 0.86 ml of 3-chlorothiophene was added dropwise. The mixture was stirred for another 30 minutes, and then a solution of 1.68 g of 1-benzyl-4-piperidineacetaldehyde in tetrahydrofuran (5 ml) was added and stirring was continued for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (1.53 g, 59% yield).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]=[CH2:13])[CH:8]=2)[CH:3]=1.[CH3:14][CH:15]1[CH2:19][CH2:18][CH2:17][NH:16]1.C([Li])CCC>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][CH2:13][N:16]1[CH2:17][CH2:18][CH2:19][CH:15]1[CH3:14])[CH:6]=[CH:5]2
Reactant: CC1CCCN1
Reactant: C=Cc1ccc2cc(Br)ccc2c1
Agent: [Li]CCCC
Product: CC1CCCN1CCc1ccc2cc(Br)ccc2c1

Procedure:
2-Bromo-6-vinyl-naphthalene is treated with a 2-methylpyrrolidine anion generated with n-butyllithium to provide 1-[2-(6-bromo-naphthalen-2-yl)-ethyl]-2-methyl-pyrrolidine. Preferably, about 1.2 to about 2.5 molar equivalents of 2-methylpyrrolidine are used for the reaction. The reaction typically is accomplished in an organic solvent, for example, THF, methyl-t-butyl ether (MTBE), Et2O, and DME. The preferred solvent is tetrahydrofuran (THF). The n-butyllithium is added to a THF solution of 2-methylpyrrolidine in a controlled fashion, typically in a dropwise manner. To this solution is added a THF solution of 2-bromo-6-vinyl-naphthalene. Alternatively, it is also suitable to the THF solution of 2-bromo-6-vinyl-naphthalene to the solution of 2-methylpyrrolidine and n-butyllithium. The reaction is accomplished at below room temperature, typically in a temperature range from about 0° C. to about −20° C. From about 0.3 to about 0.7 molar equivalents of n-butyllithium are used relative to the 2-bromo-6-vinylnaphthalene compound. The resulting compound is 1-[2-(6-bromo-naphthalen-2-yl)-ethyl]-2-methyl-pyrrolidine.
Reaction SMILES: [NH:1]([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[C@H:2]([C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:30]([NH:32][C@H:33]([C:38](OCC1C=CC=CC=1)=[O:39])[CH2:34][CH2:35][S:36][CH3:37])=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])=[O:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:58][NH2:59]>CN(C=O)C>[NH:1]([C:48]([O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:49])[C@H:2]([C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:30]([NH:32][C@H:33]([C:38]([NH:58][NH2:59])=[O:39])[CH2:34][CH2:35][S:36][CH3:37])=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])=[O:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: NN
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)NN

Procedure:
Compound I, Z-Tyr-Gly-Gly-Phe-Met-OBzl (0.85 g, 1.07 mmol) was dissolved in DMF (10 ml, purged with Argon for 15 min) and treated with 0.34 ml of H2NNH2 for 72 hr. at 25° C. The solvent was removed under reduced pressure to yield a crystalline residue which was triturated with H2O to form a crystalline product, yield 0.65g (84.2%). Recrystallized from DMF and ethanol to give colorless needles; mp 209°-213° C.; [α]D25 -27.6° (c 1, DMF). Anal. Calcd for C35H43N7O8S1 (721.84): C, 58.24; H, 6.00; N, 13.58; S, 4.44. Found: C, 57.50; H, 6.04; N, 13.75; S, 4.67.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][C:13]1([CH3:34])[CH2:18][O:17][CH:16](/[CH:19]=[CH:20]/[C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH:29]([CH2:31][CH2:32][CH3:33])[OH:30])[O:15][CH2:14]1.[CH3:35][C:36]([CH3:42])([CH2:40][CH3:41])[C:37](Cl)=[O:38]>C1COCC1>[CH3:12][C:13]1([CH3:34])[CH2:14][O:15][CH:16](/[CH:19]=[CH:20]/[C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH:29]([O:30][C:37](=[O:38])[C:36]([CH3:42])([CH3:35])[CH2:40][CH3:41])[CH2:31][CH2:32][CH3:33])[O:17][CH2:18]1
Reactant: CCCC(O)c1cc(C)cc(C)c1/C=C/C1OCC(C)(C)CO1
Reactant: CCC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC(OC(=O)C(C)(C)CC)c1cc(C)cc(C)c1/C=C/C1OCC(C)(C)CO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.6 %

Procedure:
A 1.4M solution of n-butyllithium in hexane (2.6 mL, 3.61 mmol) was added dropwise under a nitrogen atmosphere to a solution of (E)-2-[2-(5,5-dimethyl-1,3-dioxan-2-yl)ethenyl]-3,5-dimethyl-α-propylbenzenemethanol (956.8 mg, 3.01 mmol) in 100 mL of dry THF. After the addition, the solution was stirred at room temperature for 15 minutes. 2,2-Dimethylbutyryl chloride (500 μl, 3.61 mmol) was then added and the solution stirred at room temperature for 30 minutes. The reaction was partitioned between 1N HCl-EtoAc and extracted. The organic layer was washed with water (two times), dried (anh. K2CO3) and the solvent removed under reduced pressure. Purification of the residual oil on 250 g of silica gel (Merck, 230-400 mesh) using 3:2 CH2Cl2 -hexane as an eluent gave 2,2-dimethylbutanoic acid (E)-1-[2-[2-(5,5-dimethyl-1,3-dioxan-2-yl)ethenyl]-3,5-dimethylphenyl]butyl ester (534 mg, 43%) as an oil: IR (film) 2945, 2860, 1720 and 1605 cm-1 ; NMR (DMSO-d6) δ 0.68-0.80 (6H, m), 0.86 (3H, t, J=6 Hz), 1.07 (3H, s), 1.08 (3H, s), 1.12 (3H, s), 1.14-1.44 (2H, m), 1.46-1.66 (3H, m), 1.68-1.86 (1H, m), 1.18 (3H, s), 2.23 (3H, s), 3.54 (2H, d, J=10 Hz), 3.64 (2H, d, J=10 Hz), 5.09 (1H, d, J=5 Hz), 5.68 (1H, dd, J=5, 15 Hz), 5.74-5.86 (1H, m), 6.78 (1H, d, J=15 Hz), 6.98 (2H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:44][C:43]([O:45][CH2:46][CH2:47][OH:48])=[N:42][CH:41]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:38][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:49][C:50]1[C:51](O)=[N:52][N:53]([CH3:59])[C:54]=1[C:55]([F:58])([F:57])[F:56]>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:44][C:43]([O:45][CH2:46][CH2:47][O:48][C:51]4[C:50]([Cl:49])=[C:54]([C:55]([F:58])([F:57])[F:56])[N:53]([CH3:59])[N:52]=4)=[N:42][CH:41]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:37][CH2:38]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1nc(O)c(Cl)c1C(F)(F)F
Reactant: COc1cccc(CN(C(=O)C2=C(c3cnc(OCCO)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Product: COc1cccc(CN(C(=O)C2=C(c3cnc(OCCOc4nn(C)c(C(F)(F)F)c4Cl)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C

Procedure:
This compound is prepared from compound E9 and 4-chloro-1-methyl-5-trifluoromethyl-1H-pyrazol-3-ol (Eur. Pat. Appl., 1989, EP 304409), according to the above-described procedure A. LC-MS: tR=1.23 min, ES+: 867.40.
Reaction SMILES: [C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.Cl[CH:15](Cl)[O:16]C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[C:7]([CH:15]=[O:16])[CH:8]=1
Reactant: COC(Cl)Cl
Reactant: COC(=O)Oc1ccc(OC)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Oc1ccc(OC)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, to a solution of 4-methoxyphenyl methyl carbonate (10.0 g) in dichloromethane (125 mL) was added a solution of titanium (IV) chloride (14.3 mL) in dichloromethane (25 mL) at 0° C., and then dichloro(methoxy)methane (5.8 mL) was added dropwise over 30 min. The reaction mixture was warmed to room temperature, and stirred for 30 min. Dichloromethane (about 70 mL) was evaporated, and ice (120 g) and 12N hydrochloric acid were added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (10.5 g) as a yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[C:12](OC(=O)C)(=[O:14])[CH3:13].O>C(O)(=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:12](=[O:14])[CH3:13])=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Cc1ccc(N)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(CC(C)C)cc1
Yield: 67.2 %

Procedure:
70.0 g (0.47 mol) of p-isobutylaniline was dissolved in 126 ml of glacial acetic acid. 59.9 g (0.58 mol) of acetic anhydride was then added dropwise to the solution at a temperature of 30° C. After the completion of dropwise addition, the reaction mixture was then allowed to undergo reaction at a temperature of 40° C. for 1 hour. The reaction solution was then poured into 500 ml of water. The resulting crystal was filtered off, washed with water, and then dried. The crystal thus obtained was then recrystallized from a mixture of 140 ml of toluene and 700 ml of n-hexane to obtain 60.4 g (yield: 67.3%) of p-isobutylacetanilide. The melting point of the crystal was from 124.5° C. to 125.0° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]2)[N:3]=1.C([O-])(=O)C.[K+].[H][H]>C(O)C.[Pd]>[CH2:19]([C@H:16]1[CH2:15][CH2:14][C@H:13]([C:4]2[N:3]=[CH:2][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=2)[CH2:18][CH2:17]1)[CH2:20][CH3:21]
Reactant: CCC[C@H]1CC[C@H](c2ncc(C(=O)OCC)c(Cl)n2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: CCC[C@H]1CC[C@H](c2ncc(C(=O)OCC)cn2)CC1

Procedure:
31.1 g of ethyl trans-4-chloro-2-(4-propylcyclohexyl)-5-pyrimidinecarboxylate are dissolved in 350 ml of ethanol and, after adding 14.1 g of potassium acetate and 2.56 g of palladium/carbon (5% by weight), the mixture is hydrogenated at room temperature until 0.10-0.11 mol of hydrogen have been taken up. The mixture is suction filtered, back-washed with methylene chloride and evaporated in vacuo. Thereby, there are obtained 35.6 g of crude, partly crystalline ethyl trans-2-(4-propylcyclohexyl)-5-pyrimidinecarboxylate which is used in the next step without further purification.