Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:7](C)[C:8]([NH2:17])([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.F[C:20](F)(F)C(O)=O.N>C(Cl)CCl>[C:13]1([CH3:16])[CH:12]=[CH:11][C:10]([CH:8]2[C:7]3[CH:1]=[CH:2][O:6][C:5]=3[CH2:4][CH:3]([CH3:20])[NH:17]2)=[CH:15][CH:14]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc(C(N)(O)C(C)Cc2ccco2)cc1
Agent: N
Solvent: ClCCCl
Product: Cc1ccc(C2NC(C)Cc3occc32)cc1

Procedure:
Twenty grams (0.08 mol) of 2-furfuryl-2-methyl-amino-1-p-methyl-phenyl-ethanol were dissolved in 100 ml of ethylene chloride and heated to boiling point for three hours with 100 ml of trifluoroacetic acid. The reaction mixture was poured onto ice and neutralized with concentrated ammonia. The organic constituents were extracted with ether. Aftery drying, the ether was distilled off in vacuo. The residue was purified over silica gel [cyclohexane/ethyl acetate (1:1)]. After the solvent was distilled off in vacuo, the residue was dissolved in acetate. After addition of ethereal hydrochloric acid, the hydrochloride of the title compound crystallized out.
Reaction SMILES: [CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[NH:23][CH:24]=[CH:25][N:26]=1)=O>>[CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH:19][CH2:20][C:22]4[NH:23][CH:24]=[CH:25][N:26]=4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Nc1ccc2c(c1)COC(NC1CCCCCC1)=N2
Reactant: O=Cc1ncc[nH]1
Product: c1c[nH]c(CNc2ccc3c(c2)COC(NC2CCCCCC2)=N3)n1
Yield: 73.7 %

Procedure:
Prepared from N2-cycloheptyl-4H-benzo[d][1,3]oxazine-2,6-diamine (example 92) (150 mg, 0.58 mmol) and 2-formylimidazole (67 mg, 0.70 mmol) according to the procedure described for example 88. Obtained the title compound as an off-white foam (145 mg, 74%), MS (ISP) m/e=338.5 [(M−H)+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16])[C:5](N(OC)C)=[O:6].[CH3:18][Mg]Br.O.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH3:18])[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:16])[CH3:17]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(OC(C)C)c(F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(OC(C)C)c(F)c1
Yield: 98.8 %

Procedure:
To a solution of 3-fluoro-4-(1-methylethoxy)-N-methoxy-N-methylbenzamide (117 mg, 0.485 mmol) in tetrahydrofuran (2.4 mL), methylmagnesium bromide (750 μL, 0.728 mmol) was added under ice-cold conditions, and the resultant mixture was stirred for 1 hour under ice-cold conditions. The reaction solution was added with water and 5% aqueous solution of hydrochloric acid under ice-cold conditions, and extracted with ethyl acetate. Subsequently, the organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. 1-(3-Fluoro-4-(1-methylethoxy)phenyl)ethanone (94 mg, yield 99%) was obtained as a yellow oil.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:14][CH3:15])=[C:10]([CH:13]=1)[C:11]#[N:12])[CH3:3].[CH2:16]([OH:18])[CH3:17]>>[ClH:1].[CH2:2]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:14][CH3:15])=[C:10]([CH:13]=1)[C:11](=[NH:12])[O:18][CH2:16][CH3:17])[CH3:3]
Reactant: CCOCc1ccc(OC)c(C#N)c1
Reactant: CCO
Agent: Cl
Product: CCOCc1ccc(OC)c(C(=N)OCC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrogen chloride gas was passed through a solution of 5-ethoxymethyl-2-methoxy-benzonitrile (181 mg, 0.947 mmol) in anhydrous ethanol (30 mL) at room temperature. After 2 h, hydrogen chloride gas was stopped and the reaction vessel was sealed. After stirring at room temperature for 12 h, the reaction vessel was cooled to 0° C. and opened. The solvent was evaporated in vacuo to dryness to afford crude ethyl 5-ethoxymethyl-2-methoxy-benzimidate hydrochloride. meso-1,2-Bis-(4-chloro-phenyl)-ethane-1,2-diamine (253 mg, 0.9 mmol), triethylamine (186 μL, 1.5 mmol) and ethanol (10 mL) were added and the resulting mixture was heated at reflux for 12 h. The solvent was removed and the residue was taken up in methylene chloride (2 mL) and sodium bicarbonate solution (2 mL). The product was extracted with methylene chloride (2×30 mL). The organic layers were washed with brine (1×5 mL) and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 70-100% ethyl acetate in hexanes to afford 4,5-bis-(4-chloro-phenyl)-2-(5-ethoxymethyl-2-methoxy-phenyl)-4,5-dihydro-1H-imidazole (136 mg, 33%). LR-MS (APCI): 455 [(M+H)+].
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[O:16][N:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:26][C:23]=1[CH:24]=O>>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:26][C:23]=1/[CH:24]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[O:16][N:15]=2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2cc(C)on2)cc1
Reactant: COc1cc(OC)c(N2CCCC2)cc1C=O
Product: COc1cc(OC)c(N2CCCC2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)Nc2cc(C)on2)cc1

Procedure:
The title compound was prepared in a similar manner as Ex-1 using 4-acetyl-N-(5-methyl-isoxazol-3-yl)benzenesulfonamide (Ex-1B, 0.30 g, 1.07 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-ylbenzaldehyde (Ex-38B, 0.25 g, 1.07 mmol) as a dark red solid, mp 164–165° C. 1H-NMR (300 MHz, CDCl3) δ 8.09–7.93 (m, 4H), 7.35 (d, J=15.3 Hz, 1H), 7.05 (s, 1H), 6.48 (s, 1H), 6.24 (s, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.29–3.18 (m, 4H), 2.38 (s, 3H), 2.02–1.91 (s, 4H). MS m/z: 498 (M+), 100%.
Reaction SMILES: [F:1][C:2]1[C:7](C(O)=O)=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14].[OH-].[Ca+2].[OH-]>C(O)CO>[F:1][C:2]1[C:3]([F:14])=[C:4]([F:13])[C:5]([F:12])=[C:6]([F:11])[CH:7]=1
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1F
Agent: [Ca+2]
Agent: [OH-]
Solvent: OCCO
Product: Fc1cc(F)c(F)c(F)c1F
Reaction time: 6 h

Procedure:
In a three-necked flask provided with a stirring device, a reflux condenser, and a thermometer, 13.90 g (66 m.mols) of pentafluorobenzoic acid, 40 g of ethylene glycol, and 0.82 g (11 m.mols) of calcium hydroxide were placed and heated and the ensuant reaction was continued for 6 hours, with the reaction temperature gradually lowered meanwhile from the initial level of 140° C. to the terminal level of 110° C. After the reaction was completed, pentafluorobenzene was isolated by distillation. By the distillation, pentafluorobenzene was obtained in an amount of 8.02 g (48 m.mols), i.e. in a yield of 72.8%. By gas chromatography, the product was found to have purity of not less than 99.0%. The solution remaining after the distillation could be recycled through the subsequent cycle of reaction, though the pentafluorobenzoic acid as the starting material remained in the solution.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[C:20]([F:26])[CH:19]=1>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:23][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][C:20]=3[F:26])[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1ccc(Cl)cc1F
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3ccc(Cl)cc3F)c21
Yield: 63.8 %

Procedure:
The title compound (cis/trans=24:76) was prepared as a white powder in 63.8% yield in a similar procedure to that described in Example 1 by using using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=24/76) and 4-chloro-2-fluorobenzyl alcohol.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[C:23]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)=[O:24]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[C:23]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[O:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1nccs1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2nccs2)cc1

Procedure:
The title compound was prepared by the reaction of 4-t-butylbenzenesulfonyl chloride with (2-Amino-5-chloro-phenyl)-thiazol-2-yl-methanone following the general procedure. MS: m/z 435.0 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[O:9][C:5]=2[CH:4]=1.CS(O[CH2:18][CH2:19][CH2:20][C:21]([Br:24])([F:23])[F:22])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([S:10][CH2:18][CH2:19][CH2:20][C:21]([Br:24])([F:23])[F:22])[O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(S)oc2c1
Reactant: CS(=O)(=O)OCCCC(F)(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc2nc(SCCCC(F)(F)Br)oc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 6-methoxy-2-mercaptobenzoxazole (1.77 g, 9.8 mmoles), 4-bromo-4,4-difluorobutyl methanesulphonate (2.4 g, 9 mmoles), potassium carbonate (5 g, 36.2 mmoles) and acetone (60 cm3) was stirred at the ambient temperature for 18 hours. The precipitate which formed was removed by filtration and the filtrate evaporated under reduced pressure to give a brown oil which was purified by chromatography on silica gel, eluted with a 1:4 mixture of ethyl acetate and hexane, to give the title intermediate product as a light yellow oil. 1H NMR (CDCl3): δ7.48(d,1H); 7.00(d,1H); 6.90(dd,1H); 3.85(s,3H); 3.38(t,2H); 2.50-2.68(m,2H).
Reaction SMILES: [C:1]([C:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH:8]=[CH:7][CH2:6][CH:5]=[CH:4]1)#[N:2].[NH4+].[OH-]>[Pd].CO>[NH2:2][CH2:1][C:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: N#CC1(CC(=O)O)C=CCC=C1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NCC1(CC(=O)O)CCCCC1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 105.1 %

Procedure:
Added 5% Pd/C catalyst (0.33 g, 0.16 mmol) to a solution of (1-cyanocyclohexa-2,5-dienyl)acetic acid (0.25 g, 1.5 mmol) and 28% NH4OH (70 μL, 63 μg, 0.50 mmol) in MeOH (20 mL). After shaking the reaction mixture under 50 psi H2 at 50° C. for 3.5 hours, the pressure was slowly released, and the reaction was cooled to room temperature. The reaction was filtered and concentrated under reduced pressure to afford 0.27 g (102%) of crude product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1.[CH3:11][NH:12][C:13]([C:15]1[C:16](=[O:32])[C:17]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[C:18]([CH3:21])[NH:19][CH:20]=1)=[O:14]>>[CH3:11][NH:12][C:13]([C:15]1[C:16](=[O:32])[C:17]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[C:18]([CH3:21])[N:19]([CH2:2][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=2)[CH:20]=1)=[O:14]
Reactant: CNC(=O)c1c[nH]c(C)c(-c2ccnc(C(F)(F)F)c2)c1=O
Reactant: N#Cc1ccc(CBr)nc1
Product: CNC(=O)c1cn(Cc2ccc(C#N)cn2)c(C)c(-c2ccnc(C(F)(F)F)c2)c1=O

Procedure:
Example 44 is prepared as described for example 2.1, substituting benzyl bromide with 6-bromomethyl-nicotinonitrile and substituting preparation 5 with preparation 36a. ESI mass spectrum: [M+H]+=428; Retention time HPLC: 0.99 min (Z018_S04).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]=[O:14])=[N:11][CH:12]=1.[OH:18]O>O=[Mn]=O.CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:18])=[O:14])=[N:11][CH:12]=1
Reactant: OO
Reactant: O=Cc1ccc(OCc2cccc(F)c2)cn1
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(OCc2cccc(F)c2)cn1
Yield: 97.7 %

Procedure:
A mixture of 5-(3-fluoro-benzyloxy)-pyridine-2-carbaldehyde (600 mg, 2.6 mmol), hydrogen peroxide (aq. 35%, 4 ml, 118 mmol) acetone (20 ml) and a catalytic amount of MnO2 was heated under reflux for 4 h. The solvent was evaporated and the residue was triturated with water. The precipitate was collected to give the title compound as a white solid (628 mg, 98%). MS: m/e =247.1 (M+).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19](O)=[O:20])=[O:5].[NH2:30][CH2:31][CH:32]1[CH2:34][CH2:33]1>>[CH:32]1([CH2:31][NH:30][C:19]([C:8]2[C:9]3[C:13]([CH3:14])([CH3:15])[O:12][C:11]([CH3:16])([CH3:17])[C:10]=3[S:18][C:7]=2[NH:6][C:4](=[O:5])[C:3]2[C:22]([C:26]([F:28])([F:29])[F:27])=[CH:23][CH:24]=[CH:25][C:2]=2[F:1])=[O:20])[CH2:34][CH2:33]1
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Reactant: NCC1CC1
Product: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)NCC1CC1

Procedure:
The title compound was prepared from the product of Example 45A and commercially available aminomethylcyclopropane using the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 0.15-0.20 (m, 2H), 0.35-0.41 (m, 2H), 0.91-1.01 (m, 1H), 1.46 (s, 6H), 1.48 (s, 6H), 3.03 (dd, J=6.1, 6.0 Hz, 2H), 7.67-7.80 (m, 3H), 8.11 (t, J=5.6 Hz, 1H), 11.56 (br s, 1H). MS (ESI+) m/z 485 (M+H)+.
Reaction SMILES: NC1C=CC(OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=NC=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:42][CH:41]([OH:43])[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([O:44][C:45]4[CH:50]=[CH:49][C:48]([N+:51]([O-])=O)=[CH:47][N:46]=4)[CH:39]=3)[O:34]2)=[CH:29][CH:28]=1>[Zn]>[NH2:51][C:48]1[CH:49]=[CH:50][C:45]([O:44][C:38]2[CH:39]=[C:40]3[C:35](=[CH:36][CH:37]=2)[O:34][CH:33]([C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[CH2:42][CH:41]3[OH:43])=[N:46][CH:47]=1
Reactant: COc1ccc(C2CC(O)c3cc(Oc4ccc([N+](=O)[O-])cn4)ccc3O2)cc1
Agent: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: [Zn]
Product: COc1ccc(C2CC(O)c3cc(Oc4ccc(N)cn4)ccc3O2)cc1

Procedure:
6-(5-Aminopyridin-2-yloxy)-2-(4-methoxyphenyl)chroman-4-ol was prepared as described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26 using 105 mg 2-(4-methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol (Example 94(c)) and 348 mg of Zn. 1H NMR (400 MHz, d6-DMSO) δ: 7.52 (d, 1H, J 3.0 Hz), 7.38 (d, 2H, J 8.8 Hz), 7.06 (dd, 1H, J 8.7, 3.0 Hz), 7.04 (d, 1H, J 2.9 Hz), 6.96 (d, 2H, J 8.8 Hz), 6.77 (dd, 1H, J 8.7, 2.9 Hz), 6.72 (d, 1H, J 8.7 Hz), 6.70 (d, 1H, J 8.6 Hz), 5.52 (d, 1H, J 6.6 Hz), 5.15 (d, 1H, J 10.7 Hz), 5.01 (s, 2H), 4.87-4.93 (m, 1H), 3.77 (s, 3H), 2.22-2.26 (m, 1H), 1.90-1.99 (m, 1H).
Reaction SMILES: [I:1]Cl.[Br:3][C:4]1[N:12]=[CH:11][C:10]2[NH:9][C:8]3[N:13]=[CH:14][CH:15]=[CH:16][C:7]=3[C:6]=2[CH:5]=1.C([O-])(=O)C.[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C>[Br:3][C:4]1[N:12]=[CH:11][C:10]2[NH:9][C:8]3[N:13]=[CH:14][C:15]([I:1])=[CH:16][C:7]=3[C:6]=2[CH:5]=1
Reactant: Brc1cc2c(cn1)[nH]c1ncccc12
Reactant: ClI
Agent: CC(=O)[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1cc2c(cn1)[nH]c1ncc(I)cc12
Temperature: 25 °C
Yield: 84.2 %

Procedure:
A solution of iodine monochloride (32.5 g, 200 mmol) in acetic acid (120 mL) was added portionwise over 2 h to a mixture of 6-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (5.0 g, 20 mmol) and sodium acetate (18.2 g, 221 mmol) in acetic acid (120 mL) at 100° C. The reaction mixture was cooled to ambient temperature and poured into saturated sodium metabisulfite solution (20% w/w, 400 mL). The resultant precipitate was collected by filtration and the solid was washed with water (50 mL) and diethyl ether (2×50 mL) then dried at 45° C. until constant weight was achieved, to afford the title compound as a grey solid (6.3 g, 83%). 1H NMR (DMSO-D6, 300 MHz): 12.49 (s, 1 H), 9.14 (d, J=2.1 Hz, 1H), 8.79 (d, J=2.1 Hz, 1H), 8.71 (s, 1H), 8.49 (s, 1H). LCMS (Method B): RT=3.40 min, M+H+=374/376.
Reaction SMILES: [H-].[Na+].[C:3](Cl)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:12]1([C:18]2[N:19]=[C:20]3[NH:28][C@H:27]([C:29]([F:32])([F:31])[F:30])[CH2:26][CH2:25][N:21]3[C:22](=[O:24])[CH:23]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[C:3]([N:28]1[C:20]2=[N:19][C:18]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:23][C:22](=[O:24])[N:21]2[CH2:25][CH2:26][C@H:27]1[C:29]([F:30])([F:31])[F:32])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N1c2nc(N3CCOCC3)cc(=O)n2CC[C@H]1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
35.7 mg of sodium hydride and then, after 10 minutes of stirring, 0.135 ml de of benzoyl chloride are added, under an argon atmosphere, to a solution of 300 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) in 3 ml of tetrahydrofuran. After stirring for six hours at ambient temperature, a saturated solution of sodium bicarbonate and ethyl acetate are added to the reaction mixture. The organic phase is separated and then successively washed with a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue obtained is purified by silica chromatography (eluent: CH2Cl2) so as to give 74 mg of (S)-9-benzoyl-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[CH3:10][N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=[O:17]>ClCCl>[CH3:10][N:11]1[CH:15]=[C:14]([C:5](=[O:8])[CH2:6][CH3:7])[CH:13]=[C:12]1[CH:16]=[O:17]
Reactant: CCC(=O)Cl
Reactant: Cn1cccc1C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1cc(C=O)n(C)c1
Yield: 94.8 %

Procedure:
To a suspension of aluminium chloride (22.9 g, 172 mmol) in anhydrous dichloromethane (100 ml) and propionylchloride (5.3 g, 57.3 mmol)was added a solution of 1-methyl pyrrole-2-carboxaldehyde (5 g, 46 mmol) in anhydrous dichloromethane (20 ml). The mixture was refluxed for 90 min, poured into ice and stirred until melted. The layers were separated and aqueous layer was extracted with dichloromethane (2×100 ml). The organic phase and extracts were combined, dried over sodium sulfate. The solvent was removed in vacuo to give the title compound (7.2 g, 95%), 1H NMR (d6-DMSO) d 9.6 (s, 1H), 7.9 (s, 1H), 7.4 (s, 1H), 3.9 (s, 3H), 2.8 (q, 2H), 1.06 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH3:12])[N:6]=[CH:5]2.C([Li])CCC.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C>O1CCCC1.CCCCCC>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([B:18]([OH:23])[OH:19])=[CH:10][CH:9]=2)[CH:5]=[N:6]1)[CH3:12]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCn1ncc2cc(Br)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCn1ncc2cc(B(O)O)ccc21
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
A solution of 5-bromo-1-ethyl-1H-indazole (598 mg, 2.67 mmol) in dry tetrahydrofuran (30 mL) was cooled below −60° C. Then a solution of butyllithium in hexane (2.5 ml, 2.5M) was added dropwise. It was warmed to −10° C. during 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below −60° C. followed by dropwise addition of triisopropyl borate (1.5 g, 7.98 mmol). After warming to room temperature the mixture was quenched with hydrochloric acid (3N) and stirred for 1 h. The alkaline aqueous layer was brought to pH 5 and extracted with ethyl acetate (3×80 ml). All organic layers were combined, dried over sodium sulfate, and concentrated in vacuum to give 1-ethyl-1H-indazol-5-ylboronic acid (450 mg, 89%) which was used for the next step without further purification.
Reaction SMILES: [Br:1]Br.[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9]2)([O-:5])=[O:4]>C(Cl)(Cl)Cl.CO>[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH:10]([Br:1])[CH2:9]2)([O-:5])=[O:4]
Reactant: BrBr
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc21
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1c2ccc([N+](=O)[O-])cc2CC1Br
Temperature: 25 °C

Procedure:
Bromine (1.79 ml) in chloroform (125 ml) was added dropwise over 15 minutes to a stirred solution of 5-nitroindan-1-one (6.17 g) in chloroform (200 ml) at 5° C. The stirred solution was allowed to warm to room temperature and after one hour, when the bromine colour had discharged, the solution was washed with water and dried. Evaporation of the filtered solution under reduced pressure afforded an oil which was diluted with methanol and crystallised (with seeding) to give 5-nitro-2-bromoindan-1-one, m.p. 88.5°-90.5° C. (recrystallised from methanol).
Reaction SMILES: CO[C:3](=[O:21])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][C:8]([F:12])([F:11])[CH2:7]1.[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:20][C:15]1[CH:14]=[C:13]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][C:8]([F:11])([F:12])[CH2:7]2)[C:3]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: COC(=O)C(CC1CCC(F)(F)C1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nccs1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCC(F)(F)C1)c1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Yield: 49.6 %

Procedure:
A mixture of 2-(3,4-dichloro-phenyl)-3-(3,3-difluoro-cyclopentyl)-propionic acid methyl ester (75 mg, 0.22 mmol) and 2-aminothiazole (27 mg, 0.26 mmol) in a solution of magnesium methoxide in methanol (7.4 wt. % , 0.63 mL, 0.44 mmol) was heated to 110° C. for 18 h. At this time, the reaction mixture was cooled to 25° C. and then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(3,3-difluoro-cyclopentyl)-N-thiazol-2-yl-propionamide (44.2 mg, 49%) as an off-white solid: mp 154-156° C.; FAB-HRMS m/e calcd for C17H16F2Cl2N2OS (M+H)3 405.0402. found 405.0404.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][Mg]Cl.Cl[CH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:14]#[N:15].Br>COCCOC>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:19]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:18]2[C:11](=[CH:12][C:13]([C:14]#[N:15])=[CH:16][CH:17]=2)[CH2:10][O:27]1
Reactant: CN(C)CCC[Mg]Cl
Reactant: N#Cc1ccc(C(=O)c2ccc(F)cc2)c(CCl)c1
Agent: Br
Solvent: COCCOC
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Yield: 75 %

Procedure:
A solution of freshly prepared 3-dimethylaminopropylmagnesium chloride (0.6 M in THF, 7.6 ml) was added to a cooled solution of 3-chloromethyl-4-(4-fluoro-benzoyl)-benzonitrile (0.5 g) in ethylene glycol dimethyl ether (4 ml) so that the temperature did not raise above −40° C. The mixture was stirred for 30 minutes at −15° C. and 100 minutes at room temperature before 0.5N hydrobromic acid was added to adjust the pH to 10. The phases were separated and the aqueous phase was extracted twice with toluene (25 ml). The combined organic phases were dried over sodium sulfate, filtered and dried in vacuo to give a viscous oil (0.44 g, 75%). Spectral and analytical data were in accordance with the literature.
Reaction SMILES: [N:1]12[CH2:8]CC([CH2:5][CH2:6]1)[CH2:3][CH:2]2O.[C:10]1([CH3:21])[CH:15]=[CH:14][C:13]([S:16]([O:19]C)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[CH3:22][C:23]([CH3:25])=[O:24]>>[C:10]1([CH3:21])[CH:11]=[CH:12][C:13]([S:16]([O-:19])(=[O:17])=[O:18])=[CH:14][CH:15]=1.[CH3:8][N+:1]12[CH2:6][CH2:5][CH:25]([CH2:3][CH2:2]1)[CH:23]([OH:24])[CH2:22]2
Reactant: CC(C)=O
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: OC1CC2CCN1CC2
Product: C[N+]12CCC(CC1)C(O)C2
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C

Procedure:
In 10 ml of acetone was dissolved 1.27 g of quinuclidinol, and 1.86 g of methyl p-toluenesulfonate was added dropwise to the resulting solution. The mixture was stirred at room temperature, heated under reflux, and cooled to precipitate crystals. The crystals were collected by filtration and dried to give 2.81 g of the desired product.