Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11](Cl)[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)=[C:11]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=c1c(Cl)c(Cl)c(OCc2ccccc2)nn1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c(OCc2ccccc2)nn1Cc1ccccc1
Temperature: 100 °C
Reaction time: 36 h
Yield: 68.6 %

Procedure:
To a round bottom flask was added 2-benzyl-6-(benzyloxy)-4,5-dichloropyridazin-3(2H)-one (20 gm, 55.4 mmol), 4-chlorophenylboronic acid (19.07 gm, 121.88 mmol), 2N sodium carbonate (124.7 ml, 249.3 mmol), toluene (200 ml) and Pd(PPh3)4 (3.2 gm, 2.77 mmol). The reaction was stirred at 100° C. for 36 hours. After this time, the solution was cooled to r.t and the organic layer was separated. The organic layer was washed with water (100 ml), saturated aqueous NaCl (100 ml). The organic layer was dried (MgSO4), filtered and concentrated. The crude material was recrystallized from methanol (150 ml) at −25° C. The solid was collected by filtration to give the title compound, 2-benzyl-6-(benzyloxy)-4,5-bis(4-chlorophenyl)pyridazin-3(2H)-one, (19.5 gm, 70% yield) as light yellow solid. MS (M+H)=513.1.
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9]O)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.O=S(Cl)[Cl:16]>C(Cl)(Cl)Cl>[Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9][Cl:16])=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cc(CO)n(CCBr)n1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(CCl)n(CCBr)n1
Temperature: -5 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
A 50-mL three-necked round-bottomed flask equipped with a nitrogen inlet and a reflux condenser was purged with nitrogen and charged with 296b (438 mg, 1.76 mmol) and chloroform (10 mL). The reaction was cooled to −5° C. using an ice/acetone bath and SOCl2 (628 mg, 5.28 mmol) was added portion-wise. The cooling bath was removed and the reaction was stirred at 70° C. for 3 h. After this time, the solvent was removed under reduced pressure. ethyl acetate was added to the residue and the resulting solution was cooled to −5° C. Saturated aqueous sodium bicarbonate (3 mL) was added until a pH of 8.5 was reached. The mixture was partitioned between ethyl acetate and water. The combined organic layer was washed with saturated aqueous sodium carbonate (2×5 mL), brine (10 mL), and dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure to afford 296c (284 mg, 60%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:10][CH2:11][C@H:12]2[C@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([F:26])[CH:20]=3)[O:17][CH2:16][CH2:15][N:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13]2)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>CN(C=O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@@H:18]2[O:17][CH2:16][CH2:15][N:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13][C@H:12]2[CH2:11][NH:10][C:8]([C:3]2[C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:7][CH:6]=[CH:5][N:4]=2)=[O:9])=[CH:20][C:21]=1[F:26]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNC(=O)c2ncccc2N)C1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNC(=O)c2ncccc2NS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (6R,7R)-6-({[(3-aminopyridin-2-yl)carbonyl]amino}methyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate (110 mg) in DMF (3 ml) was added 60% sodium hydride at 0° C., and the mixture was stirred for 30 min. Methanesulfonyl chloride (53 μL) was added, and the mixture was warmed to room temperature, and stirred overnight. The reaction mixture was poured into water, and the mixture was partitioned twice with ethyl acetate. The organic layers were combined, and the mixture was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (44.4 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]1[O:11][CH:10]1[CH2:12][OH:13]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]([OH:11])[CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: OCC1CO1
Solvent: c1ccncc1
Product: OCC(O)COc1ccc(Cl)cc1
Yield: 53.7 %

Procedure:
A mixture of 25.7 g (3.2 mole) of 4-chlorophenol, 18.5 g (0.25 mole) of glycidol and 1 ml of pyridine was stirred and heated at 85°-90° C. overnight. The pot residue was partitioned between ethyl ether and water. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated to give a gum which crystallized when triturated with petroleum ether (boiling point range, 30°-60° C.). The solid was collected by filtration and recrystallized from isopropyl ether to yield 27.2 g (67%) of off-white solid, mp 73°-75° C. (lit1 mp 77° C.).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([OH:17])=[C:14]([C:18]#[N:19])[C:13](=[O:20])[NH:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.C(NCC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45](#[N:51])[CH2:46][CH2:47][CH2:48][C:49]#[CH:50]>CN(C=O)C.[Cu]I>[C:45]([CH2:46][CH2:47][CH2:48][C:49]#[C:50][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([OH:17])=[C:14]([C:18]#[N:19])[C:13](=[O:20])[NH:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1)#[N:51]
Reactant: C#CCCCC#N
Reactant: N#Cc1c(O)c2c(-c3ccc(I)cc3)csc2[nH]c1=O
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: N#CCCCC#Cc1ccc(-c2csc3[nH]c(=O)c(C#N)c(O)c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-(4-iodo-phenyl)-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (60 mg, 0.15 mmol) in 1.5 mL DMF was added diethylamine (0.16 mL, 1.5 mmol), followed by copper(I) iodide (trace), Pd(PPh3)Cl2 (3.5 mg, 0.005 mmol), and triphenylphosphine (12 mg, 0.04 mmol). The resulting mixture was stirred at rt for 5 min, after which hex-5-ynenitrile (50 μL, 0.5 mmol) was added. The reaction was then heated to 90° C. using microwave reactor for 20 min, filtered, concentrated and purified by reverse phase HPLC to give the titled compound. MS (ESI) m/e 358 (M−H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.82–1.91 (m, 2H), 2.56 (t, J=7.12 Hz, 2H), 2.65 (t, J=7.12 Hz, 2H), 6.67 (s, 1H), 7.31 (d, J=8.48 Hz, 2H) 7.43 (d, J=8.48, 2H), 10.80 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:6])[CH3:5].Cl[C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[N:11]=[C:10]2[N:20]([CH2:23][CH3:24])[CH:21]=[N:22][C:9]=12>C1C=CC=CC=1>[CH2:23]([N:20]1[C:10]2=[N:11][C:12]([CH3:19])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]([O:6][CH:4]([CH3:5])[CH3:3])=[C:9]2[N:22]=[CH:21]1)[CH3:24]
Reactant: CCOC(=O)c1c(C)nc2c(ncn2CC)c1Cl
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)c1c(C)nc2c(ncn2CC)c1OC(C)C
Reaction time: 10 h

Procedure:
0.03 g. of sodium hydride and 0.6 g. of propane-2-ol are refluxed with stirring in 50 ml. dry benzene for 10 hours. After this time, 2.7 g. of 7-chloro-3-ethyl-5-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester obtained in Example 1 d are added and heating is continued for an additional 10 hours. The inorganic precipitate is filtered off and the solvent removed by distillation. The oily residue is distilled to obtain 3-ethyl-5-methyl-7-(1-methylethoxy)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester, b.p. 180°-185° /0.05. Yield 2 g. (69%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([NH:15][CH:16]([CH3:18])[CH3:17])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:21][O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][N:15]([CH:12]2[CH2:11][CH2:10][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:20]=[CH:19][C:5]=4[N:6]=3)[CH2:14][CH2:13]2)[CH:16]([CH3:18])[CH3:17])[CH:26]=1
Reactant: COC(=O)Cc1cccc(CBr)c1
Reactant: CC(C)NC1CCN(c2nc3ccc(Cl)cc3s2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cccc(CN(C(C)C)C2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
A mixture of [1-(6-chlorobenzothiazole-2-yl)piperidine-4-yl]isopropylamine (159 mg), (3-bromomethylphenyl)acetic acid methyl ester (138 mg), potassium carbonate (107 mg) and dimethylformamide (2 mL) was stirred at 80° C. for 8 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (90 mg). Yield: 37%.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[CH:17][CH3:18])[C:8]=1[C:9]([OH:11])=[O:10])=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][CH3:18])[C:8]=1[C:9]([OH:11])=[O:10])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CC=Cc1cccc(NC(=O)OCC)c1C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CCCc1cccc(NC(=O)OCC)c1C(=O)O
Reaction time: 3 h
Yield: 87.5 %

Procedure:
A solution of 2-ethoxycarbonylamino-6-propenylbenzoic acid (220 mg) in ethanol was hydrogenated at 50 psi hydrogen over 10% palladium on charcoal. After 3 hours, the catalyst was filtered through Celite and the filtrate evaporated to give an oily solid (194 mg). IR νmax =1680-1740 (br), 2500-3200 (br).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:31])[C:8]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)=[C:9]2[O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.CO>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:31])[C:8]([C:24]3[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=3)=[C:9]2[O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc2ccc(O)cc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccc(O)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1cc2ccc(O)cc2c(Oc2ccc(CCC(=O)O)cc2)c1-c1ccc(O)cc1

Procedure:
Synthesized in a manner similar to Example 47 using (2E)-3-(4-{[7-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-naphthalenyl]oxy}phenyl)-2-propenoic acid (267). 1H NMR (CD3OD, 400 MHz) δ 7.68 (d, J=9.5 Hz, 1H), 7.54 (s, 1H), 7.03-7.00 (m, 2H), 6.95-6.91 (m, 4H), 6.67 (d, J=8.4 Hz, 2H), 6.45 (d, J=8.4 Hz, 2H), 2.78-2.74 (m, 2H), 2.49-2.47 (m, 2H), 2.18 (s, 3H). LRMS (ESI) m/z 413 (M−1)−. TLC (90:10; CHCl3/MeOH): Rf=0.21.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([N+:12]([O-])=O)=[CH:5][C:4]=1[O:15][CH3:16].[Br:17][CH2:18][C:19](=O)[C:20](=[O:22])C.[C:24](O)(=O)C>[Pd]>[Br:17][CH2:18][C:19]1[C:20]([O:22][CH3:24])=[N:9][C:7]2[C:6](=[CH:5][C:4]([O:15][CH3:16])=[C:3]([O:2][CH3:1])[CH:8]=2)[N:12]=1
Reactant: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1OC
Reactant: CC(=O)C(=O)CBr
Reactant: CC(=O)O
Agent: [Pd]
Product: COc1cc2nc(CBr)c(OC)nc2cc1OC

Procedure:
11.4 g (50 mmols) of 1,2-dimethoxy-4,5-dinitrobenzene are dissolved in 100 ml of glacial acetic acid and, after adding 0.6 g of 10% strength palladium-on-charcoal, hydrogenated under normal pressure; the temperature can rise to 60° C. during the hydrogenation. Consumption of hydrogen: 7,300 ml (100% of theory). The catalyst is filtered off and the filtrate is cooled, under nitrogen, to 5° to 10° C. Whilst stirring well, 9 g (55 mmols) of 1-bromo-2,3-butanedione are added dropwise at 10° C. The solution is stirred for 60 minutes, during which time the desired product starts to precipitate out. The reaction mixture is discharged into 300 ml of cold water and the mixture is stirred for 10 minutes. The product which has precipitated is filtered off, washed with water and dried in vacuo at 60° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1.[CH3:14][C:15](OC(C)=O)=[O:16]>C1COCC1>[C:15]([NH:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1)(=[O:16])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1nc(Br)ccc1N
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(Br)ccc1NC(C)=O
Temperature: 60 °C

Procedure:
To a solution of ethy 3-amino-6-bromo-pyridine-2-carboxylate (10 g, 40.8 mmol) in THF (50 ml) was added Ac2O (12 ml, 127.8 mmol) at ambient temperature then the solution was heated to 60° C. for 3 h. The solution was allowed to cool to ambient temperature then concentrated under reduced pressure and dissolved in ethyl acetate. This afforded the product in crystalline form. The mother liquor was purified using flash chromatography eluting with ethyl acetate/heptane, gradient, giving ethyl 3-acetamido-6-bromo-pyridine-2-carboxylate as a yellow solid.
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.[CH2:23]([O:25][P:26]([CH2:31][CH2:32][NH2:33])(=[O:30])[O:27][CH2:28][CH3:29])[CH3:24].[Cl:34][C:35]1[CH:36]=[C:37]([CH:51]=[CH:52][C:53]=1[Cl:54])[CH2:38][N:39]([CH3:50])[C:40]([C:42]1[CH2:43]N(C)[C:45](=[O:48])[C:46]=1[OH:47])=[O:41]>C(Cl)Cl.CCCCCC>[CH2:28]([O:27][P:26]([CH2:31][CH2:32][N:33]1[CH2:43][C:42]([C:40](=[O:41])[N:39]([CH2:38][C:37]2[CH:51]=[CH:52][C:53]([Cl:54])=[C:35]([Cl:34])[CH:36]=2)[CH3:50])=[C:46]([OH:47])[C:45]1=[O:48])(=[O:30])[O:25][CH2:23][CH3:24])[CH3:29]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: CCOP(=O)(CCN)OCC
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOP(=O)(CCN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O)OCC
Yield: 44 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and (2-aminoethyl)phosphonic acid diethylester as described in the preparation of Compound 12. Trituration with CH2Cl2/hexane gave the title compound (106 mg, 44% yield). 1H NMR (300 MHz, CDCl3) δ: 7.41 (d, 1H, J=8.05), 7.35 (s, 1H), 7.10 (dd, 1H, J=8.05, J=1.47), 4.60 (s, 2H), 4.25 (s, 2H), 4.11 (m, 4H), 3.77 (m, 2H), 3.02 (s, 3H), 2.17 (m, 2H), 1.31 (t, 6H, J=7.32). HRMS (M−H) calcd for C19H24PN2Cl2O6: 477.0749. found: 477.0749.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].S(=O)(=O)(O)O.[I:22]I>>[F:1][C:2]([F:15])([F:16])[C:3]([C:5]1[CH:6]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:8]=[C:9]([I:22])[CH:10]=1)=[O:4]
Reactant: II
Reactant: O=C(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=C(c1cc(I)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: 50 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
A mixture of 2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethanone (2.42 g), 30% fuming sulfuric acid (6.0 mL) and iodine (1.90 g) was stirred at 50° C. for 5 hours. After the completion of the reaction, the mixture was poured into ice-water (10 g) and extracted with diethyl ether (20 mL×1). The organic layer was washed with saturated aqueous sodium sulfite solution (10 mL×1) and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide the title compound as a pale yellow oil (2.56 g).
Reaction SMILES: FC(F)(F)C1C=CC(CN([C:12]2[CH:17]=[CH:16]C(C#N)=CC=2)N)=CC=1.CO[CH:24]([O:29]C)[CH2:25]N=C=S.[CH2:31]([OH:33])[CH3:32]>>[CH:24]([O:29][CH:17]([CH3:16])[CH3:12])([CH3:31])[CH3:25].[CH2:31]([OH:33])[CH3:32]
Reactant: N#Cc1ccc(N(N)Cc2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(CN=C=S)OC
Solvent: CCO
Product: CC(C)OC(C)C

Procedure:
To a suspension of N1-(4-trifluoromethylphenylmethyl)-N1-(4-cyanophenyl)hydrazine (7.5 g, 0.025 mol) in ethanol (100 ml) was added dropwise 2,2-dimethoxyethylisothiocyanate (4 g, 0.027 mol) and the reaction mixture was heated to reflux for 2 h. After cooling the solvent was evaporated under vacuum, the resulting residue was poured into 2N H2SO4 (20 ml) and the suspension was heated to reflux for 0.3 h. After extraction with ethyl acetate, the organic layer was washed with water, dried over sodium sulfate and concentrated under vacuum. Flash chromatography on silica gel (toluene/dioxane: 8/2) and trituration from diisopropyl ether/ethanol afforded a yellow solid (2.7 g, 28%), mp 200° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[O:22][N:21]=2)=[CH:16][CH:15]=1.O>CN(C=O)C>[N:1]1([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[O:22][N:21]=3)=[CH:18][CH:19]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(Cn3nnc4ccccc43)cc2)no1
Reaction time: 0.33 h
Yield: 35.1 %

Procedure:
To a mixture of benzotriazole (13 mg, 0.11 mmol) in DMF (1 mL) was added NaH (60% dispersion; 5 mg, 0.125 mmol). The mixture was stirred for 20 min and then a solution of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at room temperature overnight. H2O was added and the mixture was extracted with EtOAc (3×25 mL). The combined organic layers were washed three times with H2O/brine, dried (Na2SO4), evaporated, and purified by chromatography (10-25% acetone/CH2Cl2) to give 3-(4-benzotriazol-1-ylmethyl-phenyl)-isoxazole-5-carboxylic acid amide (12 mg, 35%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.36 (br. s., 1H) 8.06 (d, J=8.2 Hz, 1H) 7.98 (br. s., 1H) 7.81-7.91 (m, 3H) 7.49-7.59 (m, 2H) 7.34-7.48 (m, 3H) 6.06 (s, 2H).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[Br:7]Br.[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl>[Br:7][CH2:6][C:2](=[O:1])[CH2:3][C:4]([O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5]
Reactant: OCc1ccccc1
Reactant: C=C1CC(=O)O1
Reactant: BrBr
Solvent: ClCCl
Product: O=C(CBr)CC(=O)OCc1ccccc1
Temperature: -25 °C
Reaction time: 0.25 h
Yield: 96.5 %

Procedure:
Diketene (500 μL, 545 mg, 6.5 mmoles) was dissolved, under nitrogen, in dichloromethane (2 mL), cooled to −25° C., and treated dropwise with a solution of bromine (333 μL, 1.02 g, 6.5 mmoles) in dichloromethane (2 mL). After the addition was complete, the solution was stirred at −25° C. for 15 min, and benzyl alcohol (700 μL, 732 mg, 6.8 mmoles) was added dropwise. Stirring was continued for 15 min, and the solution was warmed to room temperature and evaporated. The residue was dissolved in diethyl ether (20 mL), washed successively with saturated sodium bicarbonate (2×20 mL), water (20 mL) and saturated sodium chloride (20 mL), dried over anhydrous magnesium sulfate and evaporated to give benzyl γ-bromoacetoacetate as a pale yellow oil (1.70 g, 97%). 1HMR (CDCl3, δ): 7.36 (5H, m), 5.19 (2H, s), 4.02 (2H, s), 3.75 (2H, s). IR (neat): 3033, 1734, 1654 cm−1. Mass spectrum (Cl, m/z): 271, 273 (M+1, M+3), Calcd. for C11H11BrO3: C48.69; H 4.05. Found: C 48.55; H 3.94.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>O1CCCC1>[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)(=[O:46])=[O:45])=[CH:40][CH:39]=1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Yield: 92 %

Procedure:
To a suspension of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine (2 g, 0.005 mol) and 0.5 g of triethylamine in 30 ml of tetrahydrofuran is added dropwise a solution of p-fluorophenylsulfonyl chloride in 10 ml of tetrahydrofuran over a 15 minute period. After complete addition, the resultant mixture is stirred for 1 hour at room temperature. The resulting mixture is filtered and the white solid is washed with more tetrahydrofuran and dried. This is re-crystallized from methanol/methylene chloride to give 2.5 g (92%) of white crystalline 1-[(4-fluorophenyl)sulfonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine of melting point 251°-253° C.
Reaction SMILES: ClCCC1NC(C2C=C(C=CC=2C)C([N:15]2[CH2:20][CH2:19][CH:18](C3C=CC(C#N)=CC=3)CC2)=O)=C(C)N=1.O[CH2:34][CH2:35][C:36]1[NH:37][C:38]([C:41]2[CH:42]=[C:43]([CH:48]=[CH:49][C:50]=2[CH3:51])[C:44]([O:46][CH3:47])=[O:45])=[CH:39][N:40]=1.OCCC1NC(C2C=C(C=CC=2C)C(N2CCC(C3C=CC(C#N)=CC=3)CC2)=O)=C(C)N=1.N1CCC1>>[N:15]1([CH2:34][CH2:35][C:36]2[NH:37][C:38]([C:41]3[CH:42]=[C:43]([CH:48]=[CH:49][C:50]=3[CH3:51])[C:44]([O:46][CH3:47])=[O:45])=[CH:39][N:40]=2)[CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)c1ccc(C)c(-c2cnc(CCO)[nH]2)c1
Reactant: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]c(CCCl)nc1C
Agent: C1CNC1
Agent: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]c(CCO)nc1C
Product: COC(=O)c1ccc(C)c(-c2cnc(CCN3CCC3)[nH]2)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compounds 24.1 and 24, except methyl 3-(2-(2-hydroxyethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 157.1) was used in place of 4-(1-(3-(2-(2-hydroxyethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 23) and azetidine was used in place of dimethylamine.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=[O:27]>CCOCC>[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[OH:27]
Reactant: Brc1cccnc1
Reactant: COC1CCCCC1=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COC1CCCCC1(O)c1cccnc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 2.5M n-butyllithium in hexane (13.2 ml, 33 mmol) at -78° C. was added diethyl ether (15 ml) followed by a solution of 3-bromopyridine (4.7 g, 30 mmol) in ether (90 ml) over a period of 10 minutes. After 1 hour at -78° C. a solution of (+)-2-methoxycyclohexanone (3.84 g, 30 mmol) in ether (20 ml) was added dropwise during 10 minutes. After 2 hours at -78° C. and 30 minutes at 0° C. the reaction mixture was warmed to 20° C. and then poured onto ice (150 g). The mixture was extracted with ether (2×50 ml) and then the combined organic extracts were extracted with hydrochloric acid (1M, 50 ml). This aqueous extract was washed with ether (20 ml) and then treated with sodium hydroxide solution (2M, 25 ml) and extracted with ether (3×100 ml). The organic extracts were combined, washed with brine then dried over anhydrous sodium sulphate. Concentration in vacuo gave (+)-2-methoxy-1-(pyrid-3-yl)cyclohexanol (5.0 g, 24 mmol) as a 4:1 mixture of cis and trans isomers;