Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].[C:5]([C:8]1[CH:21]=[CH:20][C:11]([O:12][CH2:13][CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:10][CH:9]=1)(=[O:7])[NH2:6]>CN(C)C=O>[C:1]([NH:6][C:5]([C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:20][CH:21]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: NC(=O)c1ccc(OCCn2ccnc2)cc1
Reactant: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)NC(=O)c1ccc(OCCn2ccnc2)cc1
Reaction time: 0.08 h
Yield: 16.6 %

Procedure:
N,N'-Carbonyldiimidazole (4.9 g) was dissolved in dry N,N-dimethylformamide (10 ml) and acetic acid (1.8 g) was added. The solution was stirred for 5 minutes and then 1-[2-(4-carbamoylphenoxy)ethyl]imidazole (4.6 g) was added. The solution was heated under reflux for 3 hours and then evaporated. The residue was treated with aqueous sodium bicarbonate and the mixture was extracted several times with ethyl acetate. The combined ethyl acetate extracts were washed with water, dried (Na2SO4) and evaporated to give an oil which was chromatographed on silica gel. Elution with chloroform gave some impurity. Further elution with chloroform/methanol (50:1) gave a solid which was crystallised from 2-butanone to give 1-[2-(4-acetylcarbamoylphenoxy)ethyl]imidazole (0.9 g), m.p. 164°-165° C. Found: C, 61.28; H, 5.54; N, 15.51. C14H15N3O3 requires: C, 61.53; H, 5.53; N, 15.38%.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[Hg](C#N)C#N.[C:17]([O:20][C@@H:21]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@@H:22]1Br)(=[O:19])[CH3:18]>>[C:17]([O:20][C@@H:21]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@H:22]1[S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:1])([F:10])[F:11])(=[O:19])[CH3:18]
Reactant: FC(F)(F)c1ccccc1S
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Agent: N#C[Hg]C#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccccc2C(F)(F)F)SC[C@H]1OC(C)=O
Yield: 34 %

Procedure:
If the procedure described in Preparation I is followed starting from 1.8 g (10.10-3 mol) of 2-trifluoromethylbenzenethiol, 2.55 g (10.10-3 mol) of mercuric cyanide (Hg(CN)2) and 3.95 g (11.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 1.53 g (yield: 34%) of the expected product are obtained.
Reaction SMILES: O[CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH2:21][CH2:22][CH3:23])[CH:4]=1.C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:25][CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH2:21][CH2:22][CH3:23])[CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCCc1cc(CO)ccc1OC(C(=O)OC)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCc1cc(CBr)ccc1OC(C(=O)OC)c1ccccc1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a stirred (0° C.) solution of 0.750 g (2.31 mmol) of the product of Step G, and 0.949 g (2.86 mmol) of carbon tetrabromide dissolved in 7 mL of methylene chloride was added 0.751 g of triphenylphosphine (2.86 mmol) in portions. After the addition was complete, the reaction mixture was stirred and allowed to warm to room temperature over 1 hour. The reaction mixture was then evaporated in vacuo, and the residue was purified on a silica gel flash chromatography column eluted with 10% ethyl acetate/hexane to afford 0.703 g (78%) of the title compound.
Reaction SMILES: [CH2:1]([CH:3]([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5])[CH3:2].[CH2:10]([Li])CCC.C(NC(C)C)(C)C.CI>>[CH2:1]([C:3]([CH3:10])([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5])[CH3:2]
Reactant: CCC(CC)C(=O)OC
Reactant: [Li]CCCC
Solvent: CI
Solvent: CC(C)NC(C)C
Product: CCC(C)(CC)C(=O)OC

Procedure:
A 16.5 Kg portion of methyl 2-ethylbutyrate was reacted with 60 Kg of n-butyl lithium, diisopropylamine, and 19.1 Kg of methyl iodide to provide 17.4 Kg of methyl 2-ethyl-2-methylbutyrate. A 7.5 Kg portion of the ester thus formed was reacted with 3.25 Kg of acetonitrile and 5.03 g of sodium hydride in 33 liters of tetrahydrofuran to provide 1-ethyl-1-methylpropyl cyanomethyl ketone. The ketone thus formed was reacted with 4.35 Kg of hydroxylamine hydrochloride and 2.54 Kg of sodium hydroxide in 44 liters of water to provide 5.65 Kg of 5-amino-3-(1-ethyl-1-methylpropyl)isoxazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:14][C:15]([C:17]1[CH:26]=[C:25]([OH:27])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)=[O:16])[CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:40]([O:47][C:48](=[O:51])[CH2:49]Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O>[CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:14][C:15]([C:17]1[CH:26]=[C:25]([O:27][CH2:49][C:48]([O:47][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:51])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)=[O:16])[CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(O)c2ccccc2n1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(OCC(=O)OCc2ccccc2)c2ccccc2n1
Reaction time: 16 h

Procedure:
To a solution of 6.5 g of (S)-2-[(4-Hydroxy-quinoline-2-carbonyl)-amino]-pentanedioic acid 5-tert-butyl ester 1-methyl ester 50 ml of DMF, 6.5 g of cesium carbonate and 4.2 g of Bromo-acetic acid benzyl ester was added and stirred for 16 h. Then, the reaction mixture was diluted with water and extracted with DCM (3×150 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was used in the next reaction step. Yield: 8.9 g.
Reaction SMILES: C[Si](C)(C)Cl.Br[CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:14]1(=[O:18])[CH2:17][CH2:16][CH2:15]1.N>CCOCC.[Zn]>[OH:18][C:14]1([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)C(C)Br
Reactant: O=C1CCC1
Agent: C[Si](C)(C)Cl
Agent: N
Agent: [Zn]
Solvent: CCOCC
Product: CCOC(=O)C(C)C1(O)CCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trimethylchlorosilane (950 μL, 7.43 mmol) was added by syringe to a suspension of zinc powder (6.65 g, 0.102 mol) in absolute Et2O (170 mL). The mixture was stirred for 15 minutes at room temperature, heated to reflux, the heat source removed, and ethyl 2-bromopropionate (10.1 mL, 77.8 mmol) was added at such a rate that the ether gently boiled. After being heated to reflux for 1 hour, the mixture was stirred for 1 hour at room temperature. A solution of cyclobutanone (5.00 g, 63.2 mmol) in Et2O (10 mL) was added while the temperature of the mixture was maintained at 19-20° C. by intermittent cooling. After stirring for 1 hour at room temperature, the mixture was poured into iced 25% ammonia (400 mL). The aqueous phase was extracted with ether, the combined organic phases were dried over K2CO3, and concentrated. the title compound was given as a colorless oil (12.9 g, 100%). 1H-NMR (400 MHz, CDCl3) δ 1.21 (3H, d, J=6.8 Hz), 1.29 (3H, t, J=7.3 Hz), 1.51-1.64 (1H, m), 1.80-1.90 (1H, m), 1.96-2.17 (4H, m), 2.70 (1H, q, J=7.3 Hz), 3.44 (1H, s), 4.18 (2H, qd, J=7.3 and 1.2 Hz).
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43](O)=[O:44])=[CH:31][CH:32]=2)[N:27]=1.C(N(CC)C(C)C)(C)C.[CH:55]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=[CH:57][C:56]=1[C@H:65]([NH2:67])[CH3:66]>CN(C)C=O>[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([NH:67][C@@H:65]([C:56]3[CH:57]=[CH:58][C:59]4[C:64](=[CH:63][CH:62]=[CH:61][CH:60]=4)[CH:55]=3)[CH3:66])=[O:44])=[CH:31][CH:32]=2)[N:27]=1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reactant: C[C@@H](N)c1ccc2ccccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1ccc2c(N3CCN(C)CC3)nc(N)nc2c1)c1ccc2ccccc2c1
Reaction time: 0.17 h
Yield: 48.6 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (40 mg, 0.1 mmol) was added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (20 mg, 0.07 mmol) in N,N-dimethylformamide (1 mL) and N,N-diisopropylethylamine (24 μL, 0.14 mmol). The reaction mixture was stirred for 10 minutes, and then (1R)-1-(2-naphthyl)ethanamine (24 mg, 0.14 mmol) was added. The crude reaction mixture stirred for 18 h. at r.t. and then was purified on RP-HPLC (pH=2) to afford the title product (15 mg, 27%) as a TFA salt as an off white amorphous solid. 1H NMR (300 MHz, DMSO): δ 1.52 (d, 3H), 2.82 (s, 3H), 3.22 (m, 2H), 3.65 (m, 4H), 4.65 (m, 2H), 5.32 (m, 1H), 7.44 (m, 2H), 7.54 (dd, 1H), 7.76-7.86 (m, 5H), 7.92 (d, 1H), 8.02 (d, 1H); Analytic LCMS (M+H)+: m/z=441.2.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][NH:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH3:25].N1CCCC1>C(O)C>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[C:18](=[CH:22][CH2:23][CH2:24][CH3:25])[NH:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCCC=O
Reactant: O=C1CNC(=O)N1CCCCSc1cccc2nccn12
Solvent: C1CCNC1
Solvent: CCO
Product: CCCC=C1NC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.00 g (3.29 mmol) of 3-[4-(imidazo-[1,2-a]pyridin-5-ylthio)butyl]hydantoin and 0.30 ml (3.29 mmol) of n-butyraldehyde in 10 ml of ethanol, 0.05 ml (0.6 mmol) of pyrrolidine was added, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate/ethanol=10/1→chloroform/methanol=10/1) to yield 0.43 g (36.5%, orange-yellow oily substance) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[O:18][CH2:19][CH2:20][O:21][S:22]([C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:7]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:6]([N:8]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[O:18][CH2:19][CH2:20][O:21][S:22]([C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:39](=[O:41])[CH3:40])[CH:7]=1
Reactant: COc1ccc(OCCOS(=O)(=O)c2ccc(C)cc2)c(CNc2cc(F)ccc2Oc2ccccc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(OCCOS(=O)(=O)c2ccc(C)cc2)c(CN(C(C)=O)c2cc(F)ccc2Oc2ccccc2)c1
Yield: 74.5 %

Procedure:
To a solution of 5.75 g (10.7 mmol) crude 5b in 50 ml pyridine was added 4.37 g (42.8 mmol) acetic acid anhydride. The reaction mixture was stirred over night and poured into ice-cold ethyl acetate. The organic phase was washed with water and brine and were dried with magnesium sulfate. The crude product was purified by silica column chromatography (ethyl acetate:hexane gradient 1:8→1:4). The desired product 5c was obtained in 74.5% yield (4.62 g, 7.97 mmol).
Reaction SMILES: [F:1][C:2]([F:7])(F)[C:3](O)=O.FC(F)(F)C(O)=O.[O:15]1[CH2:18][CH:17]([N:19]2[CH:23]=[C:22]([C:24]3[N:29]=[C:28]([C:30]4[CH:31]=[N:32][N:33]([C:35]5([CH2:39][C:40]#[N:41])[CH2:38][NH:37][CH2:36]5)[CH:34]=4)[N:27]4[CH:42]=[CH:43][N:44]=[C:26]4[CH:25]=3)[CH:21]=[N:20]2)[CH2:16]1.FC(F)(F)S(OCC(F)F)(=O)=O.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:1][CH:2]([F:7])[CH2:3][N:37]1[CH2:36][C:35]([CH2:39][C:40]#[N:41])([N:33]2[CH:34]=[C:30]([C:28]3[N:27]4[CH:42]=[CH:43][N:44]=[C:26]4[CH:25]=[C:24]([C:22]4[CH:21]=[N:20][N:19]([CH:17]5[CH2:16][O:15][CH2:18]5)[CH:23]=4)[N:29]=3)[CH:31]=[N:32]2)[CH2:38]1
Reactant: N#CCC1(n2cc(-c3nc(-c4cnn(C5COC5)c4)cc4nccn34)cn2)CNC1
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC1(n2cc(-c3nc(-c4cnn(C5COC5)c4)cc4nccn34)cn2)CN(CC(F)F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
2-(3-(4-(7-(1-(Oxetan-3-yl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile bis(2,2,2-trifluoroacetate) (0.080 g, 0.089 mmol), 2,2-difluoroethyl trifluoromethanesulfonate (0.038 g, 0.178 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.093 mL, 0.534 mmol) were suspended in DMF (5 mL) and stirred at ambient temperature for 1 hour. The reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography, eluting with 2.5-3.5% (9:1 MeOH:NH4OH)/DCM to provide 2-(1-(2,2-difluoro ethyl)-3-(4-(7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (0.005 g, 0.011 mmol, 12% yield). MS (apci) m/z=466.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]Cl>>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: COCCOCCl
Product: COCCOCOc1ccc(C=O)cc1OCOCCOC
Yield: 79.3 %

Procedure:
The hydroxyl groups of 3,4-dihydroxybenzaldehyde (2.0 g) were protected by use of 2-methoxyethoxymethyl chloride (3.6 g) in accordance with (production process 1), to thereby produce 3,4-bis(methoxyethoxymethoxy)benzaldehyde (3.6 g, yield: 89%). The thus-produced 3,4-bis(methoxyethoxymethoxy)benzaldehyde (3.5 g) and 3,4-dimethoxybenzyl cyanide (2.0 g) were subjected to condensation in accordance with process A of (production process 2), to thereby yield an MEM form of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (1.6 g, yield: 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-])=[CH:5][CH:4]=1.COS(OC)(=O)=O.[C-:25]#[N:26].[Na+]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[N:12]=[C:13]([C:25]#[N:26])[CH:14]=[CH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: COc1ccc(C=Cc2cccc[n+]2[O-])cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(C=Cc2cccc(C#N)n2)cc1

Procedure:
Following the general method described in example 2b, 2-[2-(4-methoxy-phenyl)-vinyl]-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and crystallization the title compound was obtained as a yellow crystalline material. Mp. 121-122° C. (isopropanol), MS: m/e=236 (M+)
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:23](O)[CH3:24]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:23][CH3:24])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C=Cc1ccc(O)cc1

Procedure:
To a solution of 4- hydroxycinnamic acid (16.4 g) in ethanol (100 ml) was added sulfuric acid (10 ml). The mixture was refluxed with heating for 4 hours, Aqueous sodium bicarbonate solution was added to the reaction solution so as to make basic. Then, the reaction solution was extracted with chloroform. The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum to yield a raw product of ethyl 4-hydroxycinnamate. In a manner similar to Reference Example 1, this raw product was reacted with geranyl bromide (21.7 g) and then hydrolyzed to yield 13.9 g (46%) of 4-geranyloxycinnamic acid.
Reaction SMILES: [CH3:1][N:2]([CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][O:24][CH2:25]/[CH:26]=[CH:27]/[CH2:28][NH:29][CH3:30])[CH2:19][CH2:18]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[N:33]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:1][N:2]([CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][O:24][CH2:25]/[CH:26]=[CH:27]/[CH2:28][N:29]([CH3:30])[C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[N:33]=2)[CH2:19][CH2:18]1)[S:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([F:15])([F:13])[F:14])=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: Cc1nccc(Cl)n1
Reactant: CNC/C=C/COC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nccc(N(C)C/C=C/COC[C@H]2CC[C@H](CN(C)S(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)n1
Temperature: 25 °C

Procedure:
A solution of 77 mg (0.17 mmol) trans-N-methyl-N-[4-(4-methylamino-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide (example 20.6), 0.044 g (0.34 mmol) of 4-chloro-2-methyl-pyrimidine [Ger. Offen. (1990), DE3905364 A1] and 0.06 ml (0.34 mmol) N-ethyl-diisopropylamine in 1 ml of N,N-dimethylformamide was stirred for 2 hours at 80° C. The reaction mixture was then cooled to room temperature, poured into 30 ml of ice-water and extracted 3 times with 10 ml of ether. The combined ether phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 95:5:1 v/v/v mixture of dichloromethane, methanol and saturated aqueous ammonia as the eluent giving 55 mg (59%) trans-N-methyl-N-(4-{4-[methyl-(2-methyl-pyrimidin-4-yl)-amino]-(E)-but-2-enyloxymethyl}-cyclohexylmethyl)-4-trifluoromethyl-benzenesulfonamide as yellowish viscous oil, MS: 541 (MH+).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][CH:13]2[CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]2[CH3:33])=[CH:8][CH:7]=1)([OH:5])[CH3:4].I([O-])(=O)(=O)=[O:37].[Na+]>CCOC(C)=O.O.O.O=[Ru]=O>[CH3:33][C@@H:28]1[N:27]([CH2:26][C@H:13]2[CH2:14][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:19])=[O:20])[CH2:16][CH2:17][N:12]2[C:9]2[CH:8]=[CH:7][C:6]([C@@:3]([OH:5])([CH3:4])[C:2]([F:1])([F:34])[F:35])=[CH:11][CH:10]=2)[C:32](=[O:37])[CH2:31][O:30][CH2:29]1
Reactant: C[C@H]1COCCN1CC1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H]1COCC(=O)N1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc([C@](C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 24.5 %

Procedure:
A solution of (2S)-1,1,1-trifluoro-2-(4-(2-(((R)-3-methylmorpholino)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)propan-2-ol (50 mg, 0.094 mmol, Example 45, peak 2) in EtOAc (1 mL) was added to a mixture of dioxoruthenium hydrate (1.42 mg, 9.37 μmol, Sigma Aldrich, St. Louis, Mo.) and 10% aqueous sodium periodate (30.1 mg, 0.141 mmol, Sigma Aldrich, St. Louis, Mo.) in water (1.5 mL). The solution was stirred vigorously for 48 hours at room temperature. The reaction mixture was then concentrated in a GeneVac HT-12 (GeneVac Technologies, IPS Technologies, UK), re-dissolved in MeOH (1.5 mL), filtered through syringe filters (Pall Life Sciences, Acrodic®, 25 mm Syringe Filter w/0.45 μm HT Tuffryn® Membrane) and purified on Prep HPLC (Method: 10 min, 10 to 90% ACN, Water, 0.1% TFA, 254 nm; Column: Phenomenex, Gemini-NX, 5μ, C18, 150×30.00 mm) to afford (S)-5-methyl-4-(((S)-4-(thiophen-2-ylsulfonyl)-1-(4-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl)morpholin-3-one (12.6 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[CH2:13][CH:12]1[C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH:22]1([N:26]2[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@@H:12]1[C:17]([N:29]1[CH2:30][CH2:31][CH2:32][N:26]([CH:22]2[CH2:23][CH2:24][CH2:25]2)[CH2:27][CH2:28]1)=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CC(N2CCCNCC2)C1
Reactant: O=C(O)C1CC(O)CN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C([C@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1)N1CCCN(C2CCC2)CC1
Reaction time: 3 h
Yield: 45.2 %

Procedure:
A solution of cis-D-hydroxyproline (221.1 mg, 1.687 mmol) in CH2Cl2 (15 mL) was treated with diisopropylethylamine (0.60 mL) and chlorotrimethylsilane (0.60 mL). The mixture was stirred for 2 hours, cooled to 0° C. and treated with benzyl chloroformate (0.250 mL). The reaction was stirred for 15 h at rt and then extracted with 1 N NaOH/Et2O. The aqueous layer was acidified with 1 N HCl and extracted with EtOAc. The organic layer was dried and concentrated to give 4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (0.270 g), which was used directly in the next step. A solution of 4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (0.2377 g) in acetonitrile (20 mL) was treated with cyclobutyl-[1,4]diazepane dihydrochloride (0.2411 g), triethylamine (0.400 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.4780 g). After 3 h, the reaction mixture was extracted with 1 N NaOH/CH2Cl2, and the organic layer was dried and concentrated. Purification by FCC provided the desired product (0.1628 g, 24% over two steps). MS (ESI): mass calcd. for C22H31N3O4, 401.50; m/z found, 402.3 [M+H]+.
Reaction SMILES: C([Li])CCC.[C:6](=[O:8])=[O:7].CC(C)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[C:24]([CH3:34])[O:23][N:22]=2)=[CH:17][CH:16]=1.C(=O)=O>C1COCC1>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[C:24]([CH2:34][C:6]([OH:8])=[O:7])[O:23][N:22]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(-c2noc(C)c2-c2ccc(OC)cc2)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-c2noc(CC(=O)O)c2-c2ccc(OC)cc2)cc1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (50 ml of 1.6 molar solution, 80 mmole) is added dropwise to a stirred, cold (dry-ice-acetone bath), solution of 3,4-di(p-methoxyphenyl)-5-methylisoxazol (21.72 g., 73.6 mmole, Ex. 2) in THF (220 ml) under a nitrogen atmosphere. After stirring for 1 hour at -75° C., the red coloured mixture is poured into crushed dry-ice and stirred. The stirred mixture is allowed to warm to room temperature, concentrated, and the residue dissolved in water. The resulting solution is twice extracted with ether, layered with ethyl acetate, cooled in ice and acidified with concentrated hydrochloric acid. The layers are separated and the aqueous layer extracted with ethyl acetate. The combined ethyl acetate layers are dried (MgSO4) and concentrated to give a sticky foam residue. Recrystallization from benzene gives the title compound as a colourless solid, m.p. 142°-143° C. The nmr (CDCl3) spectrum τ 6.2 (8H, s, d, CH3O and --CH2 --), 3.28 to 2.52 (8H, m, aryl H's), 0.45 (1H, broad, COOH) agrees with the assignment.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1>O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:10]2[N:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CCN1CCNCC1
Solvent: O
Product: CCN1CCN(c2ccc(C(=O)OC)cn2)CC1
Yield: 94.7 %

Procedure:
To 100 g of 1-ethylpiperazine warmed to 80° C. was added at 80-100° C. with stirring 50 g of methyl 6-chloropyridine-3-carboxylate. To the reaction solution was added 0.5 1 of water and the mixture was stirred. The crystal thus precipitated out was recovered by filtration, dried under reduced pressure to afford 68.8 g of the title compound as a crystal.