Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[NH:19]1[CH:23]=[C:22]([C:24]2[S:25][C:26]([C:29](=[O:32])[CH2:30][CH3:31])=[CH:27][N:28]=2)[CH:21]=[N:20]1>C1COCC1>[NH:20]1[CH:21]=[C:22]([C:24]2[S:25][C:26]([C:29]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)([OH:32])[CH2:30][CH3:31])=[CH:27][N:28]=2)[CH:23]=[N:19]1
Reactant: CCC(=O)c1cnc(-c2cn[nH]c2)s1
Reactant: Ic1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(O)(c1ccncc1)c1cnc(-c2cn[nH]c2)s1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 7 %

Procedure:
A solution of 4-iodopyridine (133 mg, 0.65 mmol) in THF (15 mL) was cooled to −78° C., 1.6 M n-BuLi in hexane (0.81 mL, 1.3 mmol) slowly added at −78° C., the reaction mixture stirred for 20 min at −78° C., and 1-(2-(1H-pyrazol-4-yl)thiazol-5-yl)propan-1-one (135 mg, 0.65 mmol) in THF (5 mL) added. The resulting mixture was stirred at −78° C. for 2 h. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with ethyl acetate (2×250 mL). The combined extracts were washed with brine solution (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by preparative TLC (mobile phase: 5% methanol in dichloromethane) to afford 1-(2-(1H-pyrazol-4-yl)thiazol-5-yl)-1-(pyridin-4-yl)propan-1-ol as pale yellow liquid (13 mg, 5% yield) in 99.4% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 13.19 (br s, 1H), 8.51 (d, 2H), 8.24 (br s, 1H), 7.87 (br s, 1H), 7.65 (s, 1H), 7.45 (d, 2H), 6.29 (s, 1H), 2.32-2.23 (m, 2H), 0.77 (t, 3H); LC-MS m/z calculated for [M+H]+287.09, found 287.1
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[Cl:12].CCN(CC)CC.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH2:2][N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1
Reactant: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a solution of crude 1-(bromomethyl)-2-chloro-4-nitro-benzene (29.1 mmol; 50% pure) in 30 mL of DCM was added Et3N (4.2 mL, 30 mmol) and 1-methylpiperazine (3.4 mL, 30 mmol). After stirring for 3 h at ambient temperature, aq. NaHCO3 was added and the mixture was extracted with DCM. The combined organic layer was dried over Na2SO4, filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluted with 5% MeOH/DCM) to provide 6.80 g of product as a dark yellow oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:6]1[O:10][N:9]=[C:8]([NH2:11])[CH:7]=1)([CH3:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)=[O:22]>C1COCC1>[F:13][C:2]([F:1])([F:12])[C:3]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH:7]=1)([CH3:5])[CH3:4]
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CC(C)(c1cc(N)no1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(c1cc(NC(=O)Oc2ccc(Cl)cc2)no1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine (123 mg, 0.63 mmol) in THF (2 mL) was treated with potassium carbonate (113 mg, 0.819 mmol) and p-chlorophenyl chloroformate (180 mg, 0.95 mmol). The reaction mixture was stirred at rt overnight. The mixture was filtered through a celite pad, washed with ethyl acetate and concentrated to dryness. The residue was taken into ethyl acetate, washed with brine, and the organics dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (hexane/ethyl acetate 8:2) to give 4-chlorophenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (85 mg, 39%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.83 (brs, 1H), 7.38 (d, J=9 Hz, 2H), 7.15 (d, J=9 Hz, 2H), 6.82 (s, 1H), 1.59 (s, 6H); LC-MS (ESI) m/z 349 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[NH2:26][CH2:27][CH:28]([C:30]1[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=1)[OH:29]>>[CH2:1]([O:3][C:4](=[O:25])[C:5](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][CH:21]([NH:26][CH2:27][CH:28]([OH:29])[C:30]3[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=3)[CH2:22][CH2:23]2)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Reactant: CCOC(=O)C(=Cc1ccc(N2CCC(=O)CC2)cc1)C(=O)OCC
Product: CCOC(=O)C(=Cc1ccc(N2CCC(NCC(O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1)C(=O)OCC

Procedure:
The title compound was prepared from 2-[4-(4-oxo-piperidin-1-yl)-benzylidene]-malonic acid diethyl ester (which was obtained in Example 153) and N-[5-(-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 180 as a yellowish solid; mp>80° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.21 (t, J=7.0 Hz, 3 H), 1.23 (t, J=7.0 Hz, 3 H), 1.75–1.95 (m, 2 H), 2.50–3.50 (m, 7 H), 2.92 (s, 3 H), 3.75–3.90 (m, 2 H), 4.21 (q, J=7.0 Hz, 2 H), 4.31 (q, J=7.0 Hz, 2 H), 4.47 (dd, J=8.0, 4.2 Hz, 1 H), 6.81 (d, J=8.2 Hz, 1 H), 6.94 (d, J=9.0 Hz, 2 H), 7.00 (dd, J=8.2, 2.0 Hz, 1 H), 7.17 (d, J=2.0 Hz, 1 H), 7.33 (d, J=9.0 Hz, 2 H), 7.52 (s, 1 H); MS (ES) m/z: 576.1 (MH+); HRMS Calcd. for C28H38N3O8S(MH+): 576.2374. Found: 576.2375.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Br:16][CH2:17][C:18](Br)=[O:19]>ClCCl.O>[Br:16][CH2:17][C:18]([NH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])=[O:19]
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: O=C(Br)CBr
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)Nc1ccccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
98.6 g of 2-aminobenzophenone were dissolved in a mixture of 650 ml of dichloromethane and 50 ml of water. A solution of 116.1 g of bromoacetyl bromide in 150 ml of dichloromethane was added dropwise to this mixture at a temperature of -10° C. The reaction mixture was then stirred at room temperature for a further 2 hours. The reaction mixture was worked up by adding water, separating the organic phase, washing again with water, drying and evaporating under reduced pressure. The crude product remaining as a residue was crystallized from ether/petroleum ether. 142 g of 2-[(2-bromoacetyl)-amino]-benzophenone having a melting point of 96-98° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH2:21]O)=[N:6][CH:7]=1.N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:48]>C(Cl)Cl.O>[Br:48][CH2:21][C:10]1[N:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:13][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(-c2nc(CBr)c(Sc3ccc(Cl)cn3)o2)cc1
Reaction time: 1 h

Procedure:
To a solution of {5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methanol (intermediate B1.1, 0.30 g, 0.89 mmol) in 3.3 mL of DCM at 0° C. was added imidazole (0.02 g, 0.36 mmol), Ph3P (0.28 g, 1.07 mmol) and CBr4 (0.36 g, 1.07 mmol). After 1 h at 0° C., water was added and the reaction mixture was extracted with EtOAc. The combined organics were washed with 10% KHSO4, satd. NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The reaction was purified by flash chromatography (silica, 0-25% EtOAc/hexanes) to give 2-{[4-(bromomethyl)-2-(4-fluorophenyl)-1,3-oxazol-5-yl]sulfanyl}-5-chloropyridine as white solid. LCMS [M+H]+=401.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:3][CH:2]=1.Br[CH2:15][C:16]#[N:17]>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:15][C:16]#[N:17])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1
Reactant: c1cc(CN2CCNCC2)ccn1
Reactant: N#CCBr
Product: N#CCN1CCN(Cc2ccncc2)CC1

Procedure:
The title compound is synthesized by coupling of 1-Pyridin-4-ylmethyl-piperazine (commercially available from ABCR GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=217.2: 1HNMR(CDCl3) 8.55 (d, 2H), 7.25 (d, 2H), 3.50 (s, 4H), 2.70-2.40 (m, 8H).
Reaction SMILES: [C:1]1(=[CH:6][C:7]#[N:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:9]>CO>[NH2:9][C:1]1([CH2:6][C:7]#[N:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: N#CC=C1CCCC1
Solvent: CO
Product: N#CCC1(N)CCCC1

Procedure:
A solution of 15.91 g (0.15 mol) of cyclopentylideneacetonitrile in 170 ml of an aqueous ammonia solution (29%) and 57 ml of methanol was heated at 100° C. in a sealed tube for 24 h. The reaction mixture was concentrated, and the residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 90/10 to afford 12.15 g of the product as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:27][CH2:26][C:15]2[C:16]3[CH:17]([OH:25])[C:18]([F:24])([F:23])[CH2:19][C:20]=3[CH:21]=[CH:22][C:14]=2[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[CH3:30]I>C1COCC1.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:27][CH2:26][C:15]2[C:16]3[CH:17]([O:25][CH3:30])[C:18]([F:23])([F:24])[CH2:19][C:20]=3[CH:21]=[CH:22][C:14]=2[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCc2ccc3c(c2CC1)C(O)C(F)(F)C3
Reactant: CI
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC1c2c(ccc3c2CCN(C(=O)OCc2ccccc2)CC3)CC1(F)F
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
To a stirred solution of the product from step (c) (0.13 g, 0.35 mmol) dissolved in THF (2 ml) at 0° C. was added NaH (0.046, 0.86 mmol). The reaction mixture was allowed to stir for 10 minutes followed by the addition of methyl iodide (0.053 mL, 0.86 mmol). The reaction mixture was stirred at RT for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate extracts were washed with brine, dried (Na2SO4), and solvent evaporated in vacuo to give the sub-titled compound as a yellow oil (0.10 g). MS: ESI (positive): 388 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1.[CH3:25][N:26]=[C:27]=[O:28]>C(Cl)Cl>[CH3:25][NH:26][C:27]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1)=[O:28]
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N1CCCC(C(C)Nc2nccc(-n3cnc4ccccc43)n2)C1

Procedure:
To a solution of 2-[1-(piperidin-3-yl)-ethylamino]-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 18) (51 mg, 0.16 mmol) in CH2Cl2 (1.6 mL) was added methylisocyanate (10.5 lL, 0.176 mmol) at room temperature. After the reaction was complete (2-3 h), the solvent was removed under reduced pressure, and the crude product was purified by preparative thin layer chromatography (4:1 acetone:hexane system as an eluent) to obtain the title compound. Partial 1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H); 8.36 (d, J=5.0 Hz, 1H); 8.16 (d, J=7.6 Hz, 1H); 7.85 (d, J=7.1 Hz, 1H); 7.38 (m, 2H); 6.78 (d, J=5.5 Hz, 1H); 4.17 (m, 1H); 4.07 (d, J=11 Hz, 1H); 3.76 (d, J=12.6 Hz, 1H); 2.78 (d, J=4.6 Hz, 3H); 1.31 (d, J=6.6 Hz, 3H). Mass spectrum 380.3 (ESI, M+1).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:36](Br)[CH:37]=[CH2:38]>>[CH2:38]([O:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:37]=[CH2:36]
Reactant: C=CCBr
Reactant: CCOC(=O)c1ccc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)cc1O
Product: C=CCOc1cc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)ccc1C(=O)OCC

Procedure:
Prepared from ethyl 2-hydroxy-4-[N-(α-phenyl-2-piperidinobenzyl)-aminocarbonylmethyl]-benzoate, using allyl bromide.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.F[C:17]1[N:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].C(O)(=O)C.Cl>>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:17]2[N:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])=[CH:11][CH:10]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COc1cnc(F)c(C(=O)O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cnc(Oc2ccc(Br)cc2)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
To a slurry of sodium hydride (60% dispersion) (21.74 g, 543 mmol) in DMF (351 mL, 175 mmol) at 0° C. was added 4-bromophenol (60.7 g, 351 mmol) over the course of 5 minutes. Stirred at 0° C. for two minutes then removed from the ice bath and stirred for an additional 5 minutes at room temperature. Added 2-fluoro-5-methoxynicotinic acid (30 g, 175 mmol) portionwise over 10 minutes and heated the resulting slurry at 140° C. After cooling to RT the mixture was then poured onto 1 kg of ice and was quenched with acetic acid (50.2 mL, 877 mmol) and then 75 mL of 6 N HCl. Stirred vigorously for 1 hour, leading to the formation of a red slurry containing a very fine white precipitate. The slurry was filtered to provide 2-(4-bromophenoxy)-5-methoxynicotinic acid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.O[C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:11][O:10][C:8]([C@H:5]1[CH2:4][CH2:3][C@H:2]([O:1][C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)=[O:9]
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Reactant: COC(=O)[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](Oc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Reaction time: 3 h

Procedure:
2.20 g of methyl cis-4-hydroxycyclohexanecarboxylate (13.88 mmol, 1 eq.), 2.70 g of tert-butyl 4-hydroxybenzoate (13.88 mmol, 1 eq.) and 5.46 g of triphenylphosphine (20.82 mmol, 1.5 eq.) are placed in 30 mL of tetrahydrofuran at room temperature. 4.04 mL of diisopropyl azodicarboxylate (20.82 mmol, 1.5 eq.) are added dropwise to the reaction medium with stirring. After 3 hours at room temperature, the medium is concentrated to dryness and taken up in diethyl ether. The triphenylphosphine oxide is filtered off. The organic phase is washed successively with sodium hydroxide solution and then with water, dried over sodium sulfate, filtered and evaporated to give a residue. This residue is chromatographed on silica gel, eluting with a gradient of ethyl acetate in heptane ranging from 10% to 50%. 1.6 g of tert-butyl trans-4-(4-methoxycarbonylcyclohexyloxy)benzoate are obtained.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH:25][CH2:26][CH:27]([CH2:29]O)[OH:28]>>[CH3:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:24][CH2:29][CH:27]([OH:28])[CH2:26][OH:25])=[O:23]
Reactant: OCC(O)CO
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO

Procedure:
The preferred source of monoglycerides for use in the esterification process of the present invention is at least about 90%, preferably at least about 95%, and most preferably at least about 98%, pure monobehenin. This preferred monoglyceride can be obtained by hydrolysis of substantially completely hydrogenated (i.e., I.V. about 10 or less) high erucic acid rapeseed oil, solventless fractionation of the resulting fatty acid mixture to provide a behenic fatty acid-enriched fraction, and then esterification of glycerol with this behenic acid-enriched fraction to provide a crude mixture of monoglycerides. This crude monoglyceride mixture can be subsequently purified by molecular distillation, solvent (e.g., ethyl alcohol) crystallization, liquid/liquid extraction or adsorption on a weak acid ion exchange resin to yield a source of monoglycerides having the desired purity monobehenin.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1O)=[C:9]1[O:13][CH2:14][CH2:15][O:16][C:8]1=[CH:7][CH:6]=2.P(Br)(Br)[Br:18].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:18][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:16][CH2:15][CH2:14][O:13][C:9]3=2)[N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: Oc1c(Cl)cnc2ccc3c(c12)OCCO3
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cnc2ccc3c(c2c1Br)OCCO3
Temperature: 25 °C
Yield: 90 %

Procedure:
9-Chloro-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-10-ol (3.12 g, 13.1 mmol) in dry DMF (16.7 mL) was cooled in ice and phosphorus tribromide (4.78 mL) added drop-wise, and the mixture was stirred, with ice-cooling for 30 minutes then allowed to warm to room temperature and stirred for a further 2 hours. It was cooled in ice and sodium carbonate solution was added and the solid was collected, washed well with water, and dried in vacuo, to afford a pale yellow solid (3.55 g, 90%). LC/MS (ES) m/z 300 (MH+ 100%); 1H-NMR (400 MHz, DMSO), 8.73 (1H, s, CHNHC), 7.62 (1H, d, J=9.12, CHCOCH2), 7.47 (1H, d, J=9.08, CHCN), 4.43 (4H, m, 2×(CH2O)).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(Cl)Cl>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2]2[CH:3]=[C:4]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[CH:18][CH:17]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(Cl)cc2)c1

Procedure:
3-Chloro-4-nitrobenzenesulphonamide (1.08 g; 4.53 mmol), 4-chlorothiophenol (0.66 g; 4.53 mmol) and K2CO3 (0.64 g; 4.60 mmol) were refluxed in dioxan (30 ml) for 3 hours. The mixture was then diluted with CH2Cl2, filtered and washed with water. The organic phase was dried over MgSO4 and evaporated down. The product was recrystallised from petroleum ether/ethyl acetate. Yield: 1.0 g=64% 13C (100 MHz, DMSO-d6) δ 148.57, 146.43, 138.07, 137.08, 135.76, 130.70, 128.74, 127.27, 125.43, 123.52
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37]([CH:39]([CH3:45])[C:40]([O:42]CC)=[O:41])[CH:38]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:22]([F:25])([F:24])[CH2:21][NH:20][C:18]([NH:17][C:13]1[CH:12]=[C:11]([C:8]2[N:5]3[N:6]=[CH:7][C:2]([C:34]4[CH:35]=[N:36][N:37]([CH:39]([CH3:45])[C:40]([OH:42])=[O:41])[CH:38]=4)=[CH:3][C:4]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1)=[O:19]
Reactant: CCOC(=O)C(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)cnn23)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Temperature: 100 °C

Procedure:
A mixture of N-[3-(7-chloroimidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (0.206 g, 0.556 mmol, Example 30, Step 3), ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanoate (0.18 g, 0.61 mmol), tetrakis(triphenylphosphine)palladium(0) (32.1 mg, 0.00278 mmol) and K3PO4 (0.30 g, 1.4 mmol) in 1,4-dioxane (3.0 mL) and water (2.0 mL) was heated at 100° C. under an atmosphere of nitrogen for 3 h. After cooling, the reaction mixture was adjusted to pH=4, extracted with ethyl acetate (3×30 mL), and washed with brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford the crude product without further purification. LCMS (M+H)+: m/z=474.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([O:16]C)=[O:15])=[CH:12][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:10]2)=[CH:5][CH:4]=1.O.[OH-].[Li+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc(C(=O)OC)n(-c2ccc(OC)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(=O)O)n(-c2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution 1-[(4-methoxy)phenyl]-3-(ethoxycarbonyl)-5-(methoxycarbonyl)pyrazole (4.0 g, 13.2 mmol) in 40 mL of tetrahydrofuran and 20 mL of water was added an aqueous solution of lithium hydroxide monohydrate (0.55 g, 13.2 mmol). The reaction was allowed to stir at ambient temperature for 1 h. The tetrahydrofuran was removed in vacuo and the aqueous was extracted with ether to remove unreacted diester. The aqueous layer was acidified with HCl and extracted with ethyl acetate. The organics were washed with brine, dried (MgSO4) and concentrated to afford 3.2 g (84%) of the title compound, which was used without further purification. LRMS (ES−): 289.0 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[CH3:21][C:17]1[C:15]2[N:16]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[S:13][C:14]=2[CH:20]=[CH:19][CH:18]=1
Reactant: C#CCCc1nc2c(C)cccc2s1
Reactant: Brc1ccccn1
Product: Cc1cccc2sc(CCC#Cc3ccccn3)nc12
Yield: 25.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (193 mg, 1.22 mmol) and 2-but-3-ynyl-4-methyl-benzo[d]thiazole (246 mg, 1.22 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 86 mg (0.31 mmol, 25%) of 4-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a brown oil.