Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:21]=[C:20]([CH3:22])[S:19][CH:18]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>>[CH3:22][C:20]1[S:19][CH:18]=[C:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH:21]=1
Reactant: Cc1cc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)cs1
Agent: Cl
Product: Cc1cc(-c2ccc3c(c2)CNC3)cs1

Procedure:
Prepared in analogy to Example A3(e) from 5-(5-Methyl-thiophen-3-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and using trifluoacetic acid instead of hydrochloride acid. Light yellow solid. MS (m/e): 216.1 ([M+H]+, 100%)
Reaction SMILES: [CH3:1][C@@H:2]([NH:22]C(=O)OC(C)(C)C)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH3:21])=[CH:8][CH:7]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[CH3:21][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=1[O:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C@@H:2]([CH3:1])[NH2:22])=[CH:7][CH:8]=1
Reactant: COc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N)cc2)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 114.7 %

Procedure:
1,1-dimethylethyl {(1R)-1-methyl-2-[(4-{[2-methyl-5-(methyloxy)phenyl]oxy}phenyl)amino]-2-oxoethyl}carbamate (Intermediate 15, 150 mg) was dissolved in 3 mL of dry dichloromethane. To this solution at 0° C. under argon was added dropwise 30 equivalents of TFA (0.866 mL, 11.24 mmol). The reaction was stirred at 0° C. for 4 hours. The reaction mixture was evaporated. The residue obtained was purified with an SCX cartridge (the cartridge was washed with 3 CV of methanol, then the compound was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1N)). Evaporation of the volatiles, afforded the title compound (129 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH2:24]([N:31]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>O1CCCC1>[CH2:24]([N:31]1[CH2:37][CH2:36][CH2:35][N:34]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:3]=2)[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: c1ccc(CN2CCCNCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCN(Cc3ccccc3)CC2)nc1-c1ccc(C)cc1
Yield: 59.8 %

Procedure:
This compound was prepared according to the method C from methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.095 g; 0.285 mmol), 1-benzyl-1,4-diazepane (0.178 g, 0.937 mmol) and triethyl amine (0.200 mL; 1.43 mmol) in tetrahydrofuran (2 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.083 g (54%) of the titled compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[OH:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:11]=[CH:10]2
Reactant: Oc1cccc2ccc(Cl)nc12
Reactant: C1CNCCN1
Product: Oc1cccc2ccc(N3CCNCC3)nc12

Procedure:
The quinoline from step (a) above (0.18 g, 1 mmol) and piperazine (0.172 g, 2 mmol, Aldrich) reacted under the conditions of Example 3a to give the title compound as a white solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:16])[C:6]([CH3:15])([S:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH3:7])[CH3:3].C(N(CC)C(C)C)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1COCC1>[CH2:2]([O:4][C:5](=[O:16])[C:6]([S:8][CH:9]1[CH2:10][CH2:11][N:12]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:13][CH2:14]1)([CH3:15])[CH3:7])[CH3:3]
Reactant: CCOC(=O)C(C)(C)SC1CCNCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)SC1CCN(S(C)(=O)=O)CC1
Yield: 41.9 %

Procedure:
To a solution of 4.47 g (16.74 mmol) of 2-methyl-2-(piperidin-4-ylsulfanyl)-propionic acid ethyl ester hydrochloride salt in anhydrous THF (30 mL) are added 13.45 mL (77.36 mmol) of N,N-diisoproylethylamine, followed by 2.98 mL (38.58 mmol) of methanesulfonyl chloride. The reaction mixture is heated for 2 d to 60° C. The mixture is concentrated under reduced pressure and the residue is partitioned between saturated aqueous NaHCO3 solution (75 mL) and ethyl acetate (75 mL). The basic aqueous layer is extracted with ethyl acetate (2×50 mL). The combined organic layer is separated and washed with brine (50 mL), dried over MgSO4 and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by column chromatography (silica, eluent: heptanes, 30% ethyl acetate) to give 2.17 g of 2-(1-methanesulfonyl-piperidin-4-ylsulfanyl)-2-methyl-propionic acid ethyl ester as a brown solid. Yield: 42%, ES-MS: m/z 310 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.22 (3H, t, J=7.11 Hz), 1.47 (6H, s), 1.59-1.69 (2H, m), 1.92-2.00 (2H, m), 2.70 (3H, s), 2.90-2.99 (3H, m), 3.39-3.47 (2H, m), 4.10 (2H, q, J=7.12 Hz)
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][O:12][C:13]([C@H:15]1[C@H:20]([CH3:21])[O:19][C@@H:18]([CH3:22])[CH2:17][N:16]1[S:23]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])=[O:14]>>[CH3:11][O:12][C:13]([C@H:15]1[C@H:20]([CH3:21])[O:19][C@@H:18]([CH3:22])[CH2:17][N:16]1[S:23]([C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:2][C:3]#[C:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:30][CH:31]=1)(=[O:25])=[O:24])=[O:14]
Reactant: ClCC#Cc1ccccc1
Reactant: COC(=O)[C@H]1[C@H](C)O[C@@H](C)CN1S(=O)(=O)c1ccc(O)cc1
Product: COC(=O)[C@H]1[C@H](C)O[C@@H](C)CN1S(=O)(=O)c1ccc(OCC#Cc2ccccc2)cc1

Procedure:
The title compound was prepared in a manner similar to the preparation in Preparation 3 from (3-chloro-prop-1-ynyl)-benzene and (2S,3R,6S)4-(4-hydroxy-benzenesulfonyl)-2,6-dimethyl-morpholine-3-carboxylic acid methyl ester. Calculated for C23H25NO6S (M+H): 444.14. Found: 444.0.
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@@H:11]([C:19]2[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C@H:6]([CH3:32])[CH2:5]1)[CH:2]=[CH2:3].C1(O)C=CC=CC=1.[C:40]([Si:44](Cl)([CH3:46])[CH3:45])([CH3:43])([CH3:42])[CH3:41].N1C=CN=C1>C1(C)C=CC=CC=1.C(#N)C.O>[CH3:32][C@@H:6]1[CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[C@H:9]([CH3:10])[CH2:8][N:7]1[C@@H:11]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:25]([CH2:26][CH3:27])[CH2:28][CH3:29])=[O:24])=[CH:30][CH:31]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si:44]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:46])[CH3:45])[CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCN1C[C@@H](C)N([C@@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(O)c2)C[C@H]1C
Agent: c1c[nH]cn1
Solvent: CC#N
Solvent: Oc1ccccc1
Solvent: Cc1ccccc1
Product: CCCN1C[C@@H](C)N([C@@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)C[C@H]1C
Reaction time: 4 h
Yield: 33.5 %

Procedure:
(−)-4-((αS)-α-((2R,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (0.200 g, 0.46 mmol, Example 2) was dissolved in toluene (10 mL) and stirred for 4 hours under a hydrogen atmosphere. The solution was filtered through celite to give 0.182 g of crude product. The phenol was reprotected as follows to improve chromatographic resolution. A mixture of crude product (0.18 g), tert-butylchlorodimethylsilane (0.93 g), and imidazole (0.070 g) in 10 mL of acetonitrile was stirred overnight at room temperature. The reaction solution was poured into 100 mL of water and extracted with two 50 mL portions of dichloromethane. The combined extracts were dried over sodium sulfate and the solvent removed. The residue was purified on a column of silica gel with ethanol (0-4%) in dichloromethane to give 0.085 g of 4-((αS)-α-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3(tert-butyldimethylsilyloxy)benzyl)-N,N-diethylbenzamide as a light-brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:15]1[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:15]3[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:16]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: Cc1nc(-c2ccccc2)nc(Cl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)nc(N2CCN(c3ccc(O)cc3)CC2)c1C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A solution of 1.89 (10.6 mmol) of 1-(4-hydroxyphenyl)piperazine and 2.19 g (10 mmol) of 4-chloro-5,6-dimethyl-2-phenylpyrimidine in 30 ml of absolute N,N-dimethylformamide (DMF) was warmed to 80° C., and 234 mg of powdered K2CO3 were added at 80° C., with stirring, under a nitrogen atmosphere in each case after 10 minutes, after a further 25 minutes and after a further 60 minutes (total addition of 702 mg (5.08 mmol) of K2CO3). The mixture was stirred for a further 6 hours at 90° C., the DMF was substantially removed by distillation in an oil-pump vacuum in a rotary evaporator, the residue remaining was taken up in CH2Cl2 /water, and the pH was adjusted to 7-8 using dilute hydrochloric acid. After thoroughly mixing and separating the phases, the aqueous phase was extracted a further twice with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated in vacuo. The crystalline residue (3.6 g) was chromatographed on a silica gel S/CH2Cl2 column (diameter 2.0 cm, height 38 cm) by elution with CH2Cl2 and CH2Cl2 /C2H5OH mixtures with increasing C2H5OH content (to a maximum of 10% by volume of C2H5OH). The substance was drawn onto the column using 60 ml of a CH2Cl2 /tetra-hydrofuran 2:1 mixture. The eluted, not completely pure, crystalline substance was purified by boiling with a little CH2Cl2 and filtering off under suction. 2.22 g (=61.5% yield) of pure 1-(4-hydroxyphenyl)-4-(5,6-dimethyl-2-phenylpyrimidin-4-yl)piperazine, melting point 202°-03° C., were obtained;
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[O:3].[CH2:6]([NH:13][C:14]([NH2:16])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([N:13]1[CH:1]([OH:5])[C:2](=[O:3])[NH:16][C:14]1=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=CC(=O)O
Reactant: NC(=O)NCc1ccccc1
Product: O=C1NC(=O)N(Cc2ccccc2)C1O
Temperature: 100 °C

Procedure:
75 parts by weight of a 50% strength aqueous glyoxylic acid (0.5 mol glyoxylic acid) and the catalyst are placed in a heatable, stirred apparatus. The mixture is subsequently heated to an internal temperature of 100° C. while stirring. 75 parts by weight of benzylurea (corresponds to 0.5 mol) are then added at a constant rate over a period of 30 minutes. After addition of the benzylurea is complete, the reaction mixture is stirred at 100° C. for another 30 minutes, a sample is taken and analysed by HPLC. Table 1 shows the composition of the organic components of the reaction mixtures examined. The following reaction equation shows the formulae of the compounds which can be formed.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:13][C:14]1[N:15]2[C:21]([CH:22]=[O:23])=[CH:20][N:19]=[C:16]2[S:17][CH:18]=1>CCOCC>[CH3:13][C:14]1[N:15]2[C:21]([CH:22]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[OH:23])=[CH:20][N:19]=[C:16]2[S:17][CH:18]=1
Reactant: BrCCCCc1ccccc1
Reactant: Cc1csc2ncc(C=O)n12
Agent: [Mg]
Solvent: CCOCC
Product: Cc1csc2ncc(C(O)CCCCc3ccccc3)n12

Procedure:
Magnesium (0.15 g) in ether (15 mL) was treated with 1-bromo-4-phenylbutane (prepared by the procedure described in Kamijo et al., Chem. Phar. Bull., 1983, 31, 4189) (1.50 g) at 0° and the mixture was reacted at 25° for 2.5 hours. The suspension was cooled to 0°, solid 3-Methylimidazo[2,1-b]thiazole-5-carboxaldehyde (FIG. C-6) (0.332 g) was added and the mixture was reacted at 25° for 3 hours. The solution was decanted into 5% NH4Cl solution and extracted with ethyl acetate. The extract was dried, evaporated and the residue (0.55 g) was crystallized from acetonitrile solution to yield pure 3-Methyl-α-(4-phenylbutyl)imidazo-[2,1-b]thiazole-5-methanol (FIG. C-7) (0.39 g), m.p. 120-121°.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:14][CH2:13]2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[C:16]1[CH:17]=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O>[Cl:22][C:19]1[N:20]=[CH:21][C:16]([NH:1][C:2]2[CH:11]=[CH:10][C:9]([CH:12]3[CH2:14][CH2:13]3)=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:17][N:18]=1
Reactant: COC(=O)c1cc(C2CC2)ccc1N
Reactant: Clc1ncc(Br)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C2CC2)ccc1Nc1cnc(Cl)nc1
Temperature: 100 °C

Procedure:
In a schlenck tube, a mixture of methyl 2-amino-5-cyclopropylbenzoate (described in Intermediate 8 (step A) (26.15 mmol, 5 g), 5-bromo-2-chloropyrimidine (26.93 mmol, 5.21 g), Xantphos (1.07 mmol, 0.6 g), Pd2(dba)3 (1.07 mmol, 0.6 g) and Cs2CO3 (36.65 mmol, 11.9 g) in dioxane (210 ml) was heated at 100° C. overnight. Water and ethyl acetate were added to the reaction crude. The aqueous phase was extracted again with more ethyl acetate. The organic phase was washed with water and brine, dried, filtered and concentrated in vacuo. The crude mixture was purified by reverse chromatography (Water: MeOH/AcN 1:1 from 0% to 100%) affording 6 g (60% of yield) of the expected product.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][O:12][CH2:13][CH2:14][O:15]C(=O)C1C=CC=CC=1.[NH3:24]>CO>[OH:15][CH2:14][CH2:13][O:12][CH2:11][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH2:24]
Reactant: O=C(OCCOCn1cnc2c(Cl)ncnc21)c1ccccc1
Reactant: N
Solvent: CO
Product: Nc1ncnc2c1ncn2COCCO
Yield: 70 %

Procedure:
A solution of 6-chloro-9-(2-benzoyloxyethoxymethyl) purine (50 g) and ammonia (31 g) in methanol (120 ml) was heated in a bomb at 95° C. for 18 hours. The reaction mixture was removed from the bomb and the solvent evaporated under reduced pressure at 50° C. The resulting solid was triturated first with water and then, after drying, with chloroform. The solid, 9-(2-hydroxyethoxymethyl)adenine, was retained, and the aqueous triturate was extracted several times with chloroform. The aqueous extracts were treated with a strongly basic ion exchange resin and then evaporated to dryness under reduced pressure. The remaining solid was combined with that from the trituration step, and recrystallized from isopropanol to give 22 g (70% of theoretical) of white 9-(2-hydroxyethoxymethyl) adenine, m.p. 199.5°-200° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[CH:6]([CH3:9])[CH2:7][NH2:8])[CH3:3].[C:11]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:2]([O:4][C:5](=[O:10])[CH:6]([CH3:9])[CH2:7][NH:8][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:3]
Reactant: O=C1CCCC1
Reactant: CCOC(=O)C(C)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C(C)CNC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.8 %

Procedure:
To a mixture of (rac)-3-amino-2-methylpropanoic acid ethyl ester hydrochloride (prepared from 3.09 g, 0.030 mole of (rac)-3-amino-2-methylpropanoic acid, thionyl chloride and ethanol) and 2.8 mL (0.0315 mole) of cyclopentanone and 100 mL of dichloromethane was added 5.4 g (0.066 mole) of sodium acetate and 9.54 g (0.045 mole) of sodium triacetoxyborohydride. The mixture was stirred at ambient temperature for 3 hrs and then quenched by the addition of 50 mL of 10% sodium bicarbonate solution. The aqueous layer was extracted with twice with 100 mL of dichloromethane, and the combined dichloromethane layers dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-95:5 gradient) to give 2.86 g of (rac)-3-cyclopentylamino-2-methyl-propanoic acid ethyl ester.
Reaction SMILES: Cl[CH:2]([CH3:6])[C:3](=[O:5])[CH3:4].[C:7]([OH:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(#N)C>[C:7]([O:15][CH:2]([CH3:6])[C:3](=[O:5])[CH3:4])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(=O)C(C)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)C(C)OC(=O)c1ccccc1

Procedure:
A mixture of 3-chlorobutanone (10.6 g), benzoic acid (15.0 g), triethylamine (30 ml) and acetonitrile (100 ml) was heated under reflux for 1 hour 30 minutes. The mixture was cooled and filtered to remove precipitated triethylamine hydrochloride. The acetonitrile was removed from the filtrate under reduced pressure and the residue dissolved in ethyl acetate and washed with water. The organic extracts were dried over magnesium sulphate, filtered over active carbon and the solvent was removed from the filtrate under reduced pressure, to give a yellow oil of 3-benzoyloxybutan-2-one. Yield 16.7 g. The oil was used directly without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CO[NH3+:13].[Cl-].CC(C)([O-])C.[K+]>CN(C=O)C.[Cu]Cl>[NH2:13][C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][C:4]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: CO[NH3+]
Agent: Cl[Cu]
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Nc1c(Br)cccc1[N+](=O)[O-]
Yield: 5.5 %

Procedure:
A mixture of 3-bromonitrobenzene (6.06 g, 30 mmol) and o-methylhydroxylamine hydrochloride (3.13 g, 37.5 mmol) were reacted in the presence of copper (I) chloride (0.59 g, 6 mmol) and potassium t-butoxide (10.1 g, 90 mmol) in DMF (75 mL). Aqueous work-up and chromatography gave 2-amino-3-bromonitrobenzene (0.36 g, 6%) as an orange powder. 1H NMR (CDCl3) δ 6.60 (t, 1H, J=9 Hz), 7.70 (d, 1H, J=9 Hz), 8.14 (d, 1H, J=9 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]2[C:13]([O:32]C)=[CH:14][C:15]([O:30]C)=[C:16]([C:18]3[N:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])[N:21]=[CH:20][CH:19]=3)[CH:17]=2)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2]>CCOCC>[C:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]2[C:13]([OH:32])=[CH:14][C:15]([OH:30])=[C:16]([C:18]3[N:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])[N:21]=[CH:20][CH:19]=3)[CH:17]=2)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: COc1cc(OC)c(-c2ccnn2-c2ccccc2Cl)cc1CCc1cccc(C(=O)O)c1
Solvent: CCOCC
Product: O=C(O)c1cccc(CCc2cc(-c3ccnn3-c3ccccc3Cl)c(O)cc2O)c1

Procedure:
Analogous reaction of “E2a” with 3-carboxystyrene gives the compound 5-[5-(3-carboxystyryl)-2,4-dimethoxyphenyl]1-(2-chlorophenyl)-1H-pyrazole and hydrogenation thereof gives 5-{5-[2-(3-carboxyphenyl)ethyl]2,4-dimethoxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole. Ether cleavage gives 5-{5-[2-(3-carboxyphenyl)ethyl]2,4-dihydroxyphenyl}-1-(2-chlorophenyl)-1H-pyrazole.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH:8]([C:11]([O:13]CC)=O)[C:6](=[O:7])[N:5]([CH3:16])[C:3]1=[S:4].[CH3:17][C:18]1[C:19]([O:24][C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)=[N:20][CH:21]=[CH:22][N:23]=1>C(O)C>[CH3:16][N:5]1[C:6](=[O:7])[CH:8]([C:11](=[O:13])[NH:29][C:28]2[CH:27]=[CH:26][C:25]([O:24][C:19]3[C:18]([CH3:17])=[N:23][CH:22]=[CH:21][N:20]=3)=[CH:31][CH:30]=2)[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[S:4]
Reactant: Cc1nccnc1Oc1ccc(N)cc1
Reactant: CCOC(=O)C1C(=O)N(C)C(=S)N(C)C1=O
Solvent: CCO
Product: Cc1nccnc1Oc1ccc(NC(=O)C2C(=O)N(C)C(=S)N(C)C2=O)cc1
Reaction time: 20 h

Procedure:
2.5 g (10 mmol) of 1,3-dimethyl-5-ethoxycarbonyl-2-thiobarbituric acid, 2.0 g (10 mmol) of 4-(3-methylpyrazin-2-yloxy)aniline and 30 ml of ethanol are mixed and, with stirring, are kept at 60° C. for 20 hours. The mixture is then allowed to cool and the crystalline precipitate formed is isolated by filtration, washed with ethanol and dried in vacuo at 80° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH3:19])[CH:3]=1.[I:20]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH3:19])[C:3]=1[I:20]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Solvent: CC#N
Product: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reaction time: 8 h

Procedure:
To a stirred solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methyl pyrazole (9 g) in acetonitrile (200 ml) at room temperature was added N-iodosuccinimide (5.5 g). The mixture was heated under reflux for one hour and then left at room temperature overnight. The mixture was evaporated and the residue was triturated with hot hexane. The precipitate obtained upon cooling was filtered off and dried to give the title compound as an off-white solid, m.p. 116-118° C.
Reaction SMILES: [OH:1][CH:2]([CH2:14][Br:15])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>ClCCl>[O:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[O:1][CH:2]([CH2:14][Br:15])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: O=C(CC(O)CBr)OCc1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(CC(CBr)OC1CCCCO1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.9 %

Procedure:
The product of step 2 (845 mg, 3.09 mmoles) was dissolved in dichloromethane (10 mL), and dihydropyran (300 μL, 277 mg, 3.29 mmole) and p-toluenesulfonic acid monohydrate (3 crystals) were added. The solution was stirred at room temperature for 1.5 h. Diethyl ether (40 mL) was then added, and the solution was washed with saturated sodium bicarbonate (2×40 mL), dried over anhydrous sodium sulfate, and evaporated. Purification by column chromatography using ethyl acetate-hexanes (3:7) gave benzyl 3-[2-tetrahydropyranyloxy]-4-bromobutanoate (1.07 g, 97%) as a 1:1 mixture of diastereisomers. IR (neat): 3033, 1737 cm−1. Mass spectrum (CI, m/z): 357, 3539 (M+1, m+3). Calcd. for C16H21BrO4: C 53.75; H 5.88. Found: C 53.65; H 5.60.