Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][N:23]1[C:27]([C:28](Cl)=[O:29])=[CH:26][C:25]([CH3:31])=[N:24]1>>[CH3:22][N:23]1[C:27]([C:28]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[O:29])=[CH:26][C:25]([CH3:31])=[N:24]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Product: Cc1cc(C(=O)N2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)n(C)n1

Procedure:
Compound 42 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride and conditions outlined in procedure N. M.p.=244-245° C.; 300 MHz 1H NMR (DMSO-d6) δ 8.07 (d, 1H), 7.67 (d, 1H), 7.65 (t, 1H), 7.56 (t, 1H), 6.16 (s, 1H), 3.40 (m, 2H), 3.86 (s, 3H), 3.01 (s, 2H), 2.26 (s, 3H), 2.24 (m, 2H), 1.92 (m, 2H), 1.62 (m, 2H); LCMS: 424 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[C:4]([F:10])[CH:3]=1.C(O[CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])C.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:14]([O:15][CH2:16][CH3:17])[O:18][CH2:19][CH3:20])=[C:4]([F:10])[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: O=Cc1ccc(Br)cc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCOC(OCC)c1ccc(Br)cc1F

Procedure:
The title compound was prepared as described in Example 15, Step 2 using 4-bromo-2-fluorobenzaldehyde (102 g, 0.5 mol), triethylorthoformate (88.8 g, 0.6 mol), and PPTS (2.52 g, 0.05 mol) as starting materials. 1H NMR (400 MHz, CDCl3): δ 7.41 (d, 1H), 7.21 (d, 1H), 7.14 (d, 1H), 5.60 (s, 1H), 3.68 (q, 2H), 3.49 (q, 2H), 1.17 (t, 6H).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1>O>[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[N+:6]([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]cnc2cc(Br)ccc12
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1[nH]cnc2cc(Br)c([N+](=O)[O-])cc12
Yield: 65 %

Procedure:
To a mixed solution of concentrated sulfuric acid (3 mL) and fuming nitric acid (3 mL) was added 7-bromo-3H-quinazolin-4-one (1.67 g, 7.42 mmol), and the mixture was heated at an oil bath temperature of 95° C. to 100° C. for 1 hr. The reaction mixture was poured into water (50 mL), and the product was collected by filtration, washed with water and dried under reduced pressure to give an about 5.6:1 mixture (1.3 g, 65%) of the objective 7-bromo-6-nitro-3H-quinazolin-4-one and 7-bromo-8-nitro-3H-quinazolin-4-one.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]([C:18]1[O:19][C:20]([CH3:25])=[C:21]([CH:23]=O)[CH:22]=1)=[O:17].C([BH3-])#N.[Na+]>CO>[CH3:14][O:15][C:16]([C:18]1[O:19][C:20]([CH3:25])=[C:21]([CH2:23][NH:7][C:4]2[CH:3]=[CH:2][C:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:5]=2)[CH:22]=1)=[O:17]
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1cc(C=O)c(C)o1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(CNc2ccc(-c3ccccc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.1 %

Procedure:
A solution of biphenyl-4-ylamine (150 mg, 0.883 mmoles) and 4-formyl-5-methyl-furan-2-carboxylic acid methyl ester (157) (135 mg, 0.803 mmoles) in methanol (2.0 ml) was stirred over molecular sieves (type 3 Å) for 1 hour. Sodium cyanoborohydride (55 mg, 0.883 mmoles) was added and the mixture stirred for 18 hour at room temperature. The mixture was concentrated and partitioned between ethyl acetate (25 ml) and saturated aqueous sodium bicarbonate (30 ml). The aqueous phase was re-extracted with ethyl acetate (2×25 ml) and the combined extracts were washed with brine (50 ml) and dried (MgSO4). After removal of the solvent, the residue was purified by flash chromatography, using a gradient elution of petrol/diethyl ether 9:1 v/v to 4:1 v/v, to afford compound 158 (75 mg).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([Cl:13])[N:5]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)[N:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:13][C:6]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[N:3]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:33]=[CH:32][C:27]4[C:26](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)[N:5]=1
Reactant: C1CCNC1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N1CCCC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 92.5 %

Procedure:
A mixture of methyl {4,6-dichloro-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate (0.100 g, 0.21 mmol), pyrrolidine (0.019 mL, 0.23 mmol), and N,N-diisopropylethylamine (0.109 mL, 0.62 mmol) in anhydrous DMF (2 mL) was stirred at 80° C. for 5 hours. After cooling to room temperature, the solvent was evaporated and the remaining residue dissolved in EtOAc. This organic solution was sequentially washed with 1N HCl, water, and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by preparative TLC then afforded methyl {4-chloro-2-[4-(2-naphthoylamino)benzyl]-6-pyrrolidin-1-ylpyrimidin-5-yl}-acetate (0.100 g, 95% yield) as a white powder.
Reaction SMILES: [Na+].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][C:15]([F:21])([F:20])[S:16]([O-:19])(=[O:18])=[O:17])=[O:12])=[CH:6][CH:5]=1.[Na].FC(F)(F)S([O-])(=O)=O.[C:31]1([CH:37]([SH+:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:38]1([CH:37]([SH+:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1.[F:21][C:15]([F:20])([S:16]([OH:19])(=[O:18])=[O:17])[CH2:14][O:13][C:11](=[O:12])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=1
Reactant: COc1ccc(CC(=O)OCC(F)(F)S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Agent: [Na]
Product: COc1ccc(CC(=O)OCC(F)(F)S(=O)(=O)O)cc1
Yield: 95.9 %

Procedure:
<2> The reaction described in <3> of Synthesis Example 1 was performed under the same conditions, except that the 4-methoxyphenylacetyloxymethyl difluoromethanesulfonic acid sodium salt (0.8 g) produced in <1> of Synthesis Example 4 above was used instead of the benzoyloxymethyldifluorosulfonic acid sodium salt in the reaction with diphenylmethylphenylsulfonium trifluoromethanesulfonic acid sodium salt, and thus 3.95 g (yield 95.9%) of 4-methoxyphenylacetic acid 2,2-difluoro-2-sulfoethyl ester diphenylmethylphenylsulfonium salt as shown in the following reaction scheme 9 was obtained. The structure of the product was confirmed by 1H-NMR (see FIG. 8).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])=[N:8][C:7](=O)[C:6]=2[CH:20]=1.C(N(CC)CC)C.Cl.[NH:29]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[NH2:30]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])[N:29]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:30]=2)[CH:20]=1
Reactant: CCOC(=O)CNN
Reactant: O=c1nc(-c2cc(Cl)ccc2O)oc2ccc(Cl)cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)Cn1nc(-c2cc(Cl)ccc2O)nc1-c1cc(Cl)ccc1O

Procedure:
6.0 g of chloro-2-(5-chloro-2-hydroxyphenyl)benz[e][1,3]oxazin-4-one (Example 16), 3.0 triethylamine and 3.3 g of ethyl hydrazinoacetate hydrochloride are boiled under reflux for 2 h in 60 ml of ethanol. On cooling, the product precipitates in crystalline form. It is filtered off and washed with ethanol. After drying, ethyl [3,5-bis(5-chloro-2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate is obtained as colorless crystals of m.p. 195-200° C.
Reaction SMILES: I[C:2]1[NH:6][C:5]([C:7]#[N:8])=[N:4][CH:3]=1.[CH3:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.COCCOC>[C:7]([C:5]1[NH:6][C:2]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][C:10]=2[CH3:9])[C:14]([O:16][CH3:17])=[O:15])=[CH:3][N:4]=1)#[N:8]
Reactant: N#Cc1ncc(I)[nH]1
Reactant: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(C)c(-c2cnc(C#N)[nH]2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 20.7 %

Procedure:
Into a 100-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 5-iodo-1H-imidazole-2-carbonitrile (compound 234.2, 700 mg, 3.20 mmol) in a solvent mixture of DME and H2O (30/3 mL). Methyl 4-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4, 1.06 g, 3.84 mmol), K3PO4 (2.71 g, 12.8 mmol), Xphos (152 mg, 0.32 mmol), Pd(PPh3)4 (369 mg, 0.32 mmol) were added to the reaction. The reaction mixture was stirred overnight at 90° C., then concentrated under reduced pressure. The residue was diluted with 50 mL of ethyl acetate, then was washed with 3×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel chromatography with ethyl acetate/petroleum ether (1/2) as eluent to furnish 160 mg (21%) of the title compound as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1([CH2:12][C:13]([O:15]CC)=[O:14])[CH2:11][O:10][CH2:9]1.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>CCCCCCC.C(OCC)(=O)C.COC(C)(C)C.O>[CH2:22]([O:21][C:19]([NH:7][C:8]1([CH2:12][C:13]([OH:15])=[O:14])[CH2:9][O:10][CH2:11]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CC1(N)COC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCCC
Product: O=C(O)CC1(NC(=O)OCc2ccccc2)COC1
Temperature: 5 °C
Reaction time: 18 h
Yield: 73.3 %

Procedure:
tert-Butyl methyl ether (2.5 L) and an aqueous solution of sodium carbonate (750 g in 2.2 L water, 7.07 mol) were stirred. Ethyl (3-aminooxetan-3-yl)acetate (Preparation 30, 875 g, 5.5 mol) was added to the reaction followed by further tert-butyl methyl ether (2.5 L). The reaction was cooled to 5° C. and benzyl chloroformate (1.21 Kg, 7.09 mol) added in a controlled manner such as to maintain the temperature below 20° C. A precipitate was observed so further water (5 L) and tert-butyl methyl ether (1.5 L) were added to solubilise the reaction mixture. The biphasic mixture was separated. The organic layer was basified with 2M aqueous solution of sodium hydroxide (3.5 L) and stirred vigorously for 18 hours. The aqueous layer was separated and the remaining organic layer washed with water (1.5 L). The aqueous layers were combined and cooled to 15° C. Isopropyl acetate (5 L) was added followed by controlled addition of a 6M aqueous solution of hydrogen chloride (1.2 L), maintaining the temperature below 17° C. The reaction was stirred for 30 minutes. Solid crystallised out in the reactor so was dissolved in a mixture of ethyl acetate and methanol (˜20 L). The solution was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo to afford solid material. Ethyl acetate (5 L) was added and concentrated in vacuo. Further ethyl acetate (5 L) was added and the slurry heated to reflux to give an orange solution. The solution was cooled to 50° C. and heptane (2.5 L) added. A thick slurry was observed that was stirred at room temperature for 18 hours. The solid was filtered and dried on a sinter for 3 hours before drying in vacuo at 40° C. for 18 hours to afford the title compound as a white crystalline solid (1.07 Kg, 73% yield).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH3:8])[C:3](Cl)=[O:4].[C:9]1([S:15][CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH3:1][CH:2]([CH2:6][CH2:7][CH3:8])[C:3]([C:12]1[CH:13]=[CH:14][C:9]([S:15][CH3:16])=[CH:10][CH:11]=1)=[O:4]
Reactant: CSc1ccccc1
Reactant: CCCC(C)C(=O)Cl
Product: CCCC(C)C(=O)c1ccc(SC)cc1

Procedure:
Following the procedure described for Example 1, Step 1, the title compound was prepared from 2-methyvaleryl chloride and thioanisole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([I:11])[CH:5]=1.N([O-])=O.[Na+].Cl.[N-:18]=[N+:19]=[N-].[Na+]>O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N+:18]=[N-:19])=[C:6]([I:11])[CH:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(N)c(I)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(N=[N+]=[N-])c(I)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a suspension of the 4-amino-3-iodo-benzoic acid methyl ester from Step 1 (1.0 eq) in water (0.36M) was added NaNO2 (1.2 eq). The resulting mixture was cooled to 0° C. and aqueous HCl (6M; 2.5 eq) was added dropwise over 45 min. The mixture was stirred at 0° C. for 4 h, then NaN3 (1.1) dissolved in water (1.0M) was added over 30 min. The final mixture was stirred at room temperature for 1 h and extracted with Et2O (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 4:1) afforded the desired compound as a light brown solid.
Reaction SMILES: [C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Cl-].[Li+]>[O:13]1[CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:1]12
Reactant: O=C1CCCCCCCCCCC1
Agent: [Cl-]
Agent: [Li+]
Product: C1CCCCCC2OC2CCCC1
Yield: 94 %

Procedure:
For example, German Patent (DE) No. 3,601,380 discloses a method in which cyclodeca-3,7-diene-1-one is produced in a yield of 98.7% by an isomerization reaction of 1,2-epoxycyclododeca-5,9-diene in the presence of sodium iodide catalyst in a reaction medium consisting of polyethyleneglycol. Also, German Patent (DE) No. 3,744,094 discloses a method in which cyclododecanone is produced in a yield of 94% by an isomerization reaction of an epoxycyclododecane in the presence of a lithium chloride catalyst in a reaction medium consisting of N-methylpyrrolidone and/or N,N′-dimethylethyleneurea.
Reaction SMILES: [CH2:1]=[C:2]1[C:9]2=[N:10][C:11]3[C:16]([C:17](=[O:18])[N:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[CH:15][CH:14]=[C:13]([C:19]([OH:21])=[O:20])[CH:12]=3.[H][H]>CO.[Pd]>[CH3:1][CH:2]1[C:9]2=[N:10][C:11]3[C:16]([C:17](=[O:18])[N:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[CH:15][CH:14]=[C:13]([C:19]([OH:21])=[O:20])[CH:12]=3
Reactant: C=C1CCCCCn2c1nc1cc(C(=O)O)ccc1c2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1CCCCCn2c1nc1cc(C(=O)O)ccc1c2=O

Procedure:
6-methylene-13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxylic acid (50 mg) was dissolved in MeOH (5 mL). To the mixture was added a catalytic amount of Pd/C. The reaction mixture was vacuumed and then back filled with hydrogen gas three times. After completion, the reaction was filtered and washed with methanol. The filtrate was concentrated to give the desired product. MS (ESI): 287 (MH+).
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:10])[CH2:5][CH:6]([CH3:9])[C:7]=1[CH3:8].Cl>>[OH:2][C:3]1[C:4](=[O:10])[CH2:5][CH:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: COC1=C(C)C(C)CC1=O
Agent: Cl
Product: CC1=C(O)C(=O)CC1C
Yield: 71.3 %

Procedure:
0.70 g (5 mmol) of crude 2-methoxy-3,4-dimethyl-2-cyclopenten-1-one is held at reflux temperature for 3 hours with 7 g (10 fold amount by weight) of 5N hydrochloric acid. The reaction mixture is extracted 3 times with 50 ml of CH2Cl2 each time. The combined organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator to give 0.45 g (71.4%) of 2-hydroxy-3,4-dimethyl-2-cyclopenten-1-one, content 90.6%. The data for this material are:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][CH3:19])=[CH:11][N:10]=2)=[CH:5][CH:4]=1>C(OCC)(=O)C.[Pd]>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:13][N:14]=2)=[CH:7][CH:8]=1
Reactant: CCCC#Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Yield: 94.5 %

Procedure:
--The pentynylphenylpyrimidine 40 (1.00 g, 3.45 mmol) was hydrogenated over 5% Pd/C in ethyl acetate to give the arylpentylpyrimidine 41 (0.96 g, 95%) (from MeOH/H2O), transitions/° C. K 51.0 (SA 42.1) 1; νmax /cm-1 (KBr) 2930, 2860, 1545, 1430, 1315s, 1165, 1140, 1070 and 1015, δ 0.91 (3H, t, Me), 1.37 (4H, m), 1.69 (2H, quint, ArCH2CH2), 2.66 (2H, t, ArCH2), 7.75 (2H, d, 3'- and 5'-H), 8.54(2H, d, 2'- and 6'-H) and 8.66 (2H, s, 4- and 6-H); m/z 294 (M+), 275, 251, 237 (M+ -C4H9), 224, 210 and 172.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1>>[F:36][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][N:17]1[C:9]2=[N:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:12][C:11](=[O:13])[N:10]2[CH2:14][CH2:15][C@H:16]1[C:18]([F:20])([F:21])[F:19]
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2Cc1cccc(F)c1

Procedure:
The product is prepared according to the procedure described in Example 22, using 100 mg of (8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, 214 mg of caesium carbonate and 68 mg of 1-(bromomethyl)-3-fluorobenzene. After purification by preparative HPLC/MS (Method C), 102 mg of (8S)-9-(3-fluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]-pyrimidin-4-one are obtained in the form of an oil, the characteristics of which are the following:
Reaction SMILES: C(OCC)(=O)C.[N+:7]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=1[CH:20]1[CH2:25][CH2:24][O:23][C:21]1=[O:22])([O-])=O.[H][H]>[Pt]=O.C(O)C>[CH3:19][O:18][C:13]1[CH:12]=[C:11]2[C:10](=[CH:15][C:14]=1[O:16][CH3:17])[NH:7][C:21](=[O:22])[CH:20]2[CH2:25][CH2:24][OH:23]
Reactant: [H][H]
Reactant: COc1cc(C2CCOC2=O)c([N+](=O)[O-])cc1OC
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc2c(cc1OC)C(CCO)C(=O)N2
Yield: 99.1 %

Procedure:
An ethyl acetate solution containing 2.0 g of α-(2-nitro-4,5-dimethoxyphenyl)-butyrolactone and 500 mg of platinum oxide was stirred in a 2.0 atm. hydrogen gas atmosphere. Ethanol was added to the reaction mixture, followed by filtration. The solvent was evaporated to yield 1.76 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: NCc1ccncc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCc3ccncc3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 4-(aminomethyl)pyridine (0.010 mL, 0.099 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[(pyridin-4-ylmethyl)amino methyl]indol-2-yl}isoindolinone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(O)cc1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(Oc2ncc(Br)cn2)cc1
Reaction time: 6 h
Yield: 78 %

Procedure:
5-Bromo-2-chloropyrimidine (3.0 g), p-methoxyphenol (2.5 g), methyl ethyl ketone (50 ml--dried over anhydrous potassium carbonate) and anhydrous potassium carbonate (2.5 g) were heated under reflux with stirring for 6 hours. The solvent was evaporated under reduced pressure, the residue treated with water and the precipitated compound collected by filtration. The product was treated with 5% sodium hydroxide aqueous solution and the mixture stirred for approximately 30 minutes. The solid was collected by filtration, washed with water and recrystallised from methanol/water to give the title compound (3.4 g), m.p. 92° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][NH:39][CH2:40][C@H:41]([OH:50])[C@@H:42]([OH:49])[C@H:43]([OH:48])[C@H:44]([OH:47])[CH2:45][OH:46]>>[CH3:38][N:39]([CH2:40][C@H:41]([OH:50])[C@@H:42]([OH:49])[C@H:43]([OH:48])[C@H:44]([OH:47])[CH2:45][OH:46])[C:32]([N:12]1[C@@:13]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)([CH3:24])[C@@:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([CH3:16])[N:15]=[C:11]1[C:8]1[CH:9]=[N:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=1[O:35][CH2:36][CH3:37])=[O:33]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with (2R,3R,4R,5S)-6-methylamino-hexane-1,2,3,4,5-pentaol (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C36H47Cl2N4O7 [(M+H)+] 717.2817, observed 717.2813.