Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[CH:17]=2)=[O:7])=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[O:7])=[CH:24][CH:25]=1
Reactant: COc1cccc(C2CCCN2CCNC(=O)c2ccc(Cl)cc2)c1
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Product: O=C(NCCN1CCCC1c1cccc(O)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
To a solution of 4-chloro-N-{2-[2-(3-methoxyphenyl)-1-pyrrolidinyl]ethyl}benzamide (0.58 g) in chloroform (30 ml) was added boron tribromide (99.0%, 0.61 ml) at -10° C., under nitrogen. The cooling bath was removed after 15 mins, and the reaction mixture was allowed to warm to ambient temperature. Crushed ice was added followed by 5:1-chloroform/2-propanol. The layers were separated, and the aqueous phase was extracted with 5:1 chloroform/2-propanol (2 times). The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 30% ethyl acetate/dichloromethane). The appropriate fractions were collected and concentrated to afford 0.29 g (52%) of 4-chloro-N-{2-[2-(3-hydroxyphenyl)-1-pyrrolidinyl]ethyl}benzamide.
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:5]=[C:6]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:7]([N:9]([CH2:11][C@H:12]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH2:13][CH2:14][N:15]1[CH2:18][CH:17]([N:19]2[CH2:24][CH2:23][N:22]3[C:25](=[O:29])[CH2:26]CC[CH:21]3[CH2:20]2)[CH2:16]1)[CH3:10])=[O:8].C(N(CC)CC)C.Cl.Cl.C(N1CCN(C2CNC2)CC1)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.O>[Br:3][C:4]1[CH:5]=[C:6]([CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=1)[C:7]([N:9]([CH2:11][C@H:12]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH2:13][CH2:14][N:15]1[CH2:18][CH:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25](=[O:29])[CH3:26])[CH2:23][CH2:24]2)[CH2:16]1)[CH3:10])=[O:8]
Reactant: CN(C[C@@H](CCN1CC(N2CCN3C(=O)CCCC3C2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: CC(=O)N1CCN(C2CNC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: CC(=O)N1CCN(C2CN(CC[C@H](CN(C)C(=O)c3cc(Br)cc(C(F)(F)F)c3)c3ccc(F)cc3)C2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 54.1 %

Procedure:
3-Bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see Method 3; 11.2 g, 25 mmol) was dissolved in methanol (50 mL) together with triethylamine (3.5 mL, 25 mmol). Together with another portion of triethylamine (3.5 mL, 25 mmol) the solution was transferred to a flask containing 1-acetyl-4-azetidin-3-ylpiperazine dihydrochloride (see WO 96/05193; 8.4 g, 32.6 mmol). The mixture was stirred at RT for 45 min and then sodium triacetoxyborohydride (8.0 g, 37.6 mmol) was added by installments during one hour. The reaction mixture was stirred at RT for 45 min. Water (0.45 mL) was added and then most of the solvent was removed by evaporation. The residue was dissolved in toluene (56 mL) and then an aqueous 10% solution of NaOH (55 mL) was added while heating to 40° C. The mixture was stirred vigorously at 45° C. for 5 min. The aqueous layer was separated off and the organic solution was left in the hood overnight. After several attempts to crystallize the product from different solvents the compound was purified by means of silica gel chromatography (ammonia saturated methanol-methylene chloride 1% to 10%). There was obtained 8.3 g (54%) of the title compound as a white foam. 1H NMR (500 MHz, CDCl3): 1.4-1.8 (cm, 2H), 2.0 (s, 3H), 2.1-3.8 (cm, 21H), 6.8-7.4 (cm, 6H), 7.7 (s, 1H); LCMS: m/z 614 (M+1)+.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:21]([NH:23][C@H:24]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C@@H:25]([CH3:27])[OH:26])=[O:22])[CH2:19][OH:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:21]([NH:23][C@H:24]([C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[C@@H:25]([CH3:27])[OH:26])=[O:22])[CH2:19][OH:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[F:45][C:46]([C:47]([OH:49])=[O:48])([F:51])[F:50]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)[C@@H](N)CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)O
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
32 g of BOC-Asn-Leu-Ser-Thr-OBzl are dissolved in 192 ml of 90% strength trifluoroacetic acid and the solution left for 45 minutes at 20° C. Thereafter the solution is concentrated to about 40ml, mixed with 400 ml of ether whilst stirring and stirred for about 20 minutes at 35° C. under reflux. The crystal suspension is then cooled to -10° C. and is left to stand overnight at -10° C. The precipitate is filtered off, washed three times with ether and dried in vacuo over sodium hydroxide. Melting point 125°- 127° C.; Rf4 = 0.33 (on silica gel).
Reaction SMILES: FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CN(CC1C([N:25]([CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH2:26][CH:27]2[CH2:29][CH2:28]2)=NC2C(C=1)=CC=CC=2C)C1N=NNN=1.[OH-].[Na+].ClCCl.S(OC)(OC)(=O)=O>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:27]1([CH2:26][NH:25][CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH2:29][CH2:28]1
Reactant: Cc1cccc2cc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nn[nH]n3)c(N(CC3CC3)CC3CC3)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: ClCCl
Product: C1CC1CNCC1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 249.6 %

Procedure:
To a suspension (3-{[(3,5-bistrifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine (0.132 g, 0.224 mmol) in water (2 mL), sodium hydroxide (0.018 g, 0.448 mmol) was added and stirred for 15 min at RT followed by the addition of dichloromethane (2 mL). To this reaction mixture, dimethyl sulphate (0.032 g, 0.26 mmol) was added followed by the addition of tetra butyl ammonium bromide (0.003 g, 0.011 mmol). The reaction was stirred for 1 h. The organic layer was separated from aqueous layer and the aqueous layer was extracted with DCM (3×10 mL), the combined organic layer was washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford the crude residue which was purified by column chromatography over 100-200 mesh silica gel using 8% ethyl acetate and petroleum ether to afford (3-{[3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazole-5-yl)-amino]-methyl-}-8-methyl-quinoline-2-yl)-bis-cyclopropylmethyl-amine (0.07 g, 52%).
Reaction SMILES: C(O[C:6]([N:8]([C:41](OC(C)(C)C)=O)[C:9](=[O:40])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[C:33]([CH3:39])[N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C>O1CCCC1.CNC>[O:22]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH2:20][N:16]1[C:14]1[CH:13]=[CH:12][C:11]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[C:33]([CH3:39])[N:32]=3)[CH2:27][CH2:26]2)=[O:24])=[C:10]([CH:15]=1)[C:9]([N:8]([CH3:41])[CH3:6])=[O:40]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)nc1C
Agent: CNC
Solvent: C1CCOC1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N(C)C)CC2)nc1C
Yield: 43.3 %

Procedure:
Using N,N-di-tert-butyloxycarbonyl-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]benzamide (202 mg) described in Example 768 and 2 mol/L dimethylamine tetrahydrofuran solution (180 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (65 mg) was obtained.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:12])/[CH:7]=[CH:8]\[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH2:18]>C(N(CC)CC)C>[CH3:4][CH2:3][CH2:2][CH2:1][O:5][C:6](=[O:12])[C@H:7]([CH2:8][C:9]([OH:11])=[O:10])[NH:18][CH2:17][CH2:16][CH2:15][N:14]([CH3:19])[CH3:13]
Reactant: CN(C)CCCN
Reactant: CCCCOC(=O)/C=C\C(=O)O
Solvent: CCN(CC)CC
Product: CCCCOC(=O)[C@H](CC(=O)O)NCCCN(C)C
Yield: 86.7 %

Procedure:
In the apparatus described in Example 1, 500 ml of triethylamine are added with cooling, within 2 hours and 35 minutes, at 4°-10° C. internal temperature to 430.5 g (2.5 mols) of maleic acid-mono-n-butyl ester. There are subsequently quickly added 306.5 g (2.5 mols+20% excess) of 3-dimethylaminopropylamine, and the mixture is reacted for 30 minutes at 90°-95° C. The reaction product is processed in a manner analogous to that described in Example 1 to obtain a yield of 595 g (86.8% of theory) of a crystalline aspartic acid derivative, which melts at 154°-157.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:18]=[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:5][CH2:4]1.Cl[C:25]1([N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])[N:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26]1.CCN(C(C)C)C(C)C.[OH-].[Na+]>C(#N)CCC.C(OCC)(=O)C>[CH2:38]([N:35]([CH2:36][CH3:37])[C:25]1[N:34]=[C:33]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]3[N:18]=[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:5][CH2:4]2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)[CH3:39]
Reactant: CCN(CC)C1(Cl)N=Cc2ccccc2N1
Reactant: CCN(CC)c1nc(N2CCC(CN)CC2)nc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCC#N
Product: CCN(CC)c1nc(NCC2CCN(c3nc(N(CC)CC)c4ccccc4n3)CC2)c2ccccc2n1

Procedure:
A mixture of the compound of Example III (500 mg, 1.8 mmol), 2-chloro-2-diethylaminoquinazoline (467 mg, 2.0 mmol) and Hunig's base (0.4 ml), 2.7 mmol) in 5 ml of butyronitrile was reacted for 12 hours at 120° C. After cooling, ethyl acetate (50 ml) and 50 ml of sodium hydroxide (10%) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×25 ml). The combined organic phases were dried (Na2SO4), concentrated on a rotary evaporator and purified by chromatography on silica gel (eluent: methylene chloride/ethanol/ammonia, 100/10/1) to give the free base as a solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1.ClCCl.CN1CCOCC1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: O=C(Cl)c1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(Nc1cc(C2CC2)n[nH]1)c1ccccc1
Reaction time: 16 h
Yield: 85.8 %

Procedure:
To a solution of 0.37 g (3 mmol) of 3-cyclopropyl-5-amino-1H-pyrazole in 15 ml of dichloromethane 0.8 ml (7.3 mmol) of N-methylmorpholine and 0.8 ml (6.9 mmol) of benzoyl chloride were successively added at room temperature. After 16 hours under stirring the mixture was concentrated and the residue was dissolved in 15 ml of methanol. 3.5 ml of sodium hydrate 2.5 M were added dropwise and 10 ml of tetrahydrofuran were finally added in order to obtain a homogeneous solution. After 15 minutes the mixture was concentrated and poured into water. The precipitate was filtered and dried in vacuum to afford 585 mg (86% yield) the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:31])([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=1)/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([NH:8][C@:9]([CH3:31])([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=1)[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCOc1ccc(CC[C@](C)(/C=C/C(=O)O)NC(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(CC[C@](C)(CCC(=O)O)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred solution of (E)-(R)-4-tert-butoxycarbonylamino-6-(4-heptyloxy-phenyl)-4-methyl-hex-2-enoic acid (53 mg, 0.12 mMol) in AcOEt (10 ml) is added palladium on charcoal (10 mg, 10%). The reaction is stirred under a H2-atmosphere at RT for 17 hours. The reaction mixture is filtered over Celite and the filtrate is concentrated under reduced pressure to give the title compound as a colourless oil. The crude product is sufficiently pure to be used in the next stage without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:26]4[CH:41]=[CH:40][C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])=[CH:28][CH:27]=4)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:42]1([CH3:52])[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=1.O>C(Cl)Cl.N1C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:26]4[CH:27]=[CH:28][C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][S:48]([C:45]5[CH:46]=[CH:47][C:42]([CH3:52])=[CH:43][CH:44]=5)(=[O:50])=[O:49])=[CH:40][CH:41]=4)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCCCCCCOc1ccc(-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)ccc32)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCCCCCCOc2ccc(-n3c4ccc(-c5ccccc5)cc4c4cc(-c5ccccc5)ccc43)cc2)cc1
Temperature: 25 °C
Yield: 54 %

Procedure:
The obtained 8-[4-(3,6-diphenylcarbazol-9-yl)phenoxy]octan-1-ol (2.80 g, 5.2 mmol) was dissolved in a solvent mixture of methylene chloride (10 mL) and pyridine (5 mL). Then, p-toluenesulfonyl chloride (1.20 g, 6.3 mmol) was added to the resultant solution at −10° C., followed by stirring at room temperature. Next, the mixture was poured to water, followed by extraction with ethyl acetate. In addition, the mixture was washed with diluted hydrochloric acid and water, and dried and the solvent was evaporated, to thereby obtain a crude product. The crude product was purified through silica gel column chromatography using as an eluent a solvent mixture of ethyl acetate/toluene (1/19 by volume), to thereby obtain 1.95 g of toluene-4-sulfonic acid 8-[4-(3,6-diphenylcarbazol-9-yl)phenoxy]octyl ester as colorless plate-like crystals.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][S:13][C:7]2=[N:6][C:5]=1[CH3:14].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[OH:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CC(C)CC(=O)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([OH:23])[CH:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[CH2:11][CH2:12][S:13][C:7]4=[N:6][C:5]=3[CH3:14])[CH2:26][CH2:25]2)=[CH:18][CH:17]=1
Reactant: Cc1nc2n(c(=O)c1CCBr)CCS2
Reactant: OC(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: Cc1nc2n(c(=O)c1CCN1CCC(C(O)c3ccc(F)cc3)CC1)CCS2
Yield: 42 %

Procedure:
A mixture of 6.8 parts of 6-(2-bromoethyl)-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one, 3.15 parts of α-(4-fluorophenyl)-4-piperidinemethanol, 4.8 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone was stirred and refluxed for 24 hours. The reaction mixture was cooled, washed with 50 parts of water, dried, filtered and evaporated. The residue was purified by columnchromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue solidified upon triturating in acetonitrile. The product was filtered off, washed twice with acetonitrile and dried, yielding 2.5 parts (42%) of 6-[2-[4-[(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]ethyl]-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one; mp. 204.3° C. (compound 33).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:10][NH:11][C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[CH:34]=[CH2:35].C(N1C(C2C=CC(S(C)(=O)=O)=CC=2)=C(C2C=CC(F)=CC=2)C(C(F)(F)F)=N1)C=C>CN(C=O)C>[CH2:35]([N:11]1[C:12]([C:13]([F:16])([F:14])[F:15])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)=[N:10]1)[CH:34]=[CH2:33]
Reactant: C=CCBr
Reactant: CS(=O)(=O)c1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Agent: C=CCn1nc(C(F)(F)F)c(-c2ccc(F)cc2)c1-c1ccc(S(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1nc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c1C(F)(F)F
Yield: 40.8 %

Procedure:
Reaction of 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole (Example 1, Step 3) (0.1 g) with 0.08 g of potassium carbonate and 2.0 g of allyl bromide in 5 mL of DMF gave a crude mixture of 1-allyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole and 1-allyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-5 (trifluoromethyl)-1H-pyrazole. HPLC purification with 50% ethyl acetate-hexane and recrystallization from ether-hexane gave 1-allyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole (45 mg, 41%): mp 115.5-119° C.
Reaction SMILES: C1(N(C2C=CC=CC=2)[C:8]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])C=CC=CC=1.C(O)(=[O:26])C.S(=O)(=O)(O)O>O>[CH:10]([C:8]([OH:9])=[O:26])=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(C=Cc1ccccc1)N(c1ccccc1)c1ccccc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C=Cc1ccccc1
Temperature: 25 °C

Procedure:
The N,N-diphenylstyrenyl carboxamide-2% divinylbenzene copolymer from example 7(a) (53.0g) was heated with stirring at 130°-135° for 44 hours with a mixture of glacial acetic acid (670 ml.), concentrated sulphuric acid (500 ml.) and water (300 ml.). After cooling to room temperature, the mixture was filtered and the polymer washed successively with water (4 × 400 ml.), acetone (3 × 200 ml.); methanol (3 × 200ml.), water (2 × 400 ml.) and acetone (2 × 200 ml.); and dried in vacuo at 40° to constant weight. The title polymer (36.58g) was green in colour and exhibited ν max (NuJol) 1690 (C=O) and 3700-2400 (OH) cm-1. Titration was effected by suspending the product (0.500g) in 95% ethanol (50 ml.) adding 0.5M sodium hydroxide (50 ml.), warming the mixture to reflux, cooling and back titrating with 0.5M hydrochloric acid using phenolphthalein as the indicator; it was found that 47.12 ml. of acid were required for neutralisation indicating 2.88 m.mole carboxyl/g of polymer.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:21](I)[CH3:22]>CN(C=O)C>[CH2:21]([O:1][C:2]1[CH:9]=[C:8]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:22]
Reactant: CCI
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(N(CC)CC)ccc1C=O
Reaction time: 48 h

Procedure:
To a mixture of 2-hydroxy-4-(diethylamino)benzaldehyde (10.0 g, 51.75 mmol), K2CO3 (14.3 g) and DMF (150 ml) at room temperature was added ethyl iodide (4.1 ml). The reaction mixture as stirred for about two days, filtered and the filtrate was concentrated in vacuo. The residue was partitioned between ether and saturated Na2CO3, and the organic layer was separated, dried over MgSO4, treated with charcoal, filtered and concentrated in vacuo. The solid product was recrystallized from hexane to afford, as a pink crystalline solid, 9.8 g of 2-ethoxy-4-(diethylamino)benzaldehyde, m.p. 58-59° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:21])[CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:22](Cl)(=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C(Cl)(Cl)Cl>[CH2:38]([C:39]1[N:13]([CH2:12][CH2:11][CH2:10][N:9]([CH3:8])[CH3:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=1)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CN(C)CCCNc1ccccc1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2ccccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Triethylamine (0.62 ml) was added to a solution containing N-[3-(dimethylamino)propyl]-1,2-benzenediamine (0.78 g) in chloroform (4 ml) and then stearoyl chloride (1.22 g) was added thereto while being cooled with ice. After being stirred for 2 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (3.33 ml) was added to a solution containing the residue (1.93 g) in n ethanol (20 ml). After being stirred for 5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (1.73 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=50:1), thereby yielding the entitled compound (1.53 g) as pale brown wax.
Reaction SMILES: CSC.[CH:4]1([Mg]Br)[CH2:6][CH2:5]1.Br[CH:10]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:17](=[O:27])[CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][N:22]=3)[N:20]=[C:11]12>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[CH:4]1([CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]3[C:17](=[O:27])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][N:22]=4)[N:20]=[C:11]23)[CH2:6][CH2:5]1
Reactant: Br[Mg]C1CC1
Reactant: O=c1cc(-c2ccncn2)nc2n1CCCCC2Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CSC
Product: O=c1cc(-c2ccncn2)nc2n1CCCCC2C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
To a solution of 1.33 g (6.48 mmol) of CuBr.DMS in 25 mL of dry tetrahydrofuran at −78° C., was slowly added 12.45 mL (6.23 mmol) of cyclopropyl magnesium bromide (0.5 M in tetrahydrofuran). The resulting mixture was stirred at room temperature for 30 min. 0.800 g (2.49 mmol) of (+/−)-10-bromo-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one dissolved in 10 mL of dry tetrahydrofuran was added at −78° C. and the resulting mixture was stirred for 1.5 hours and allowed to warm to room temperature. The mixture was dissolved in a saturated solution of ammonium chloride and ethyl acetate. The organic phases were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography (dichloromethane/methanol/ammoniac in proportions of 99/1/0.1) to afford 0.230 g (33%) of a white solid.