Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[N:24][NH:25][CH:26]=4)[CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:34]O>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[CH:26]=[N:25][N:24]([CH3:34])[C:23]=4[C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)[CH:19]=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: CO
Reactant: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)cc1
Product: Cc1ccc(-c2c(-c3ccnc(Nc4ccc(CN5CCN(C)CC5)cc4)n3)cnn2C)cc1

Procedure:
The title compound is prepared as described in Example 54 starting from [4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (Example 60) and methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[CH:22][NH:21][C:20]=1[CH:33]=O>C(O)C.N1CCCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:20]2[NH:21][CH:22]=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3cccc(Br)c3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 48.6 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72.0 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(3-bromo-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (61.4 mg, 49%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[C:15]([I:16])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])C.[OH-].[Na+].Cl.O>O1CCOCC1>[Cl:12][C:10]1[CH:11]=[C:6]([C:4]([OH:5])=[O:3])[C:7]2[C:15]([I:16])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=1
Reactant: CCOC(=O)c1cc(Cl)nc2c1c(I)nn2C1CCCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(Cl)nc2c1c(I)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 7 h
Yield: 73.6 %

Procedure:
To a solution of 6-chloro-3-iodo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (25 g, 57 mmol) in 1,4-dioxane (200 mL) was added an aqueous sodium hyroxide solution (1M, 180 mL). The reaction mixture was stirred at room temperature for 7 hours and then an aqueous HCl solution (1M, 200 mL) was carefully added. Water (140 mL) was added, and after 5 minutes of stirring the precipitate was filtered, washed with water, cyclohexane and then dried to afford the title compound as a yellow solid (17.1 g, 73%).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:5]=1[CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]([O:14]CC)=[O:13])[N:8]=1.Cl>C(O)C>[F:3][C:4]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:5]=1[CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[N:8]=1
Reactant: CCOC(=O)c1noc(Cc2cc(F)ccc2F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1noc(Cc2cc(F)ccc2F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
A solution of sodium hydroxide 1M (2 ml, 2 mmol) was added to a mixture of ethyl 5-(2,5-difluorobenzyl)-1,2,4-oxadiazole-3-carboxylate (0.150 g; 0.559 mmol) in ethanol (1 mL) and the reaction was stirred at room temperature for 1 hour. The pH of the solution was adjusted to 1 by addition of a solution of hydrochloric acid 6N. The precipitate was collected by filtration and dried under reduced pressure to afford 0.124 g (92%) of 5-(2,5-difluorobenzyl)-1,2,4-oxadiazole-3-carboxylic acid as a white solid.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[CH:29]2.[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CCOCC.O>[CH2:35]([N:31]1[C:32]2[C:28](=[CH:27][C:26]([Cl:25])=[CH:34][CH:33]=2)[CH:29]=[CH:30]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: BrCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: Clc1ccc2c(ccn2Cc2ccccc2)c1
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a solution of 0.8 g (3.03 mmoles) of 18-crown-6 in 100 mL of dry ether was added 4.39 g (39.12 mmoles) potassium tert-butoxide. The mixture was stirred while 5.08 g (33.51 mmoles) of 5-chloroindole was added. The stirring was continued for 0.5 hour. Most of the solid dissolved. Then 6.69 g (39.11 mmoles) of benzyl bromide in 40 mL of ether was added during 0.5 hours. The stirring was continued for 27 hours. Water (100 mL) was added. The layers were separated. The aqueous layer was extracted with ether (2×75 mL). The combined ether phases were washed with 50 mL of brine and dried over MgSO4. Evaporation of the solvent left 9.17 g of orange oil. The oil was chromatographed on a 700 g column of silica gel. The column was eluted with 1:2 CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed by silica gel tlc (2×8") (1:2 CH2Cl2 -Skellysolve B). Fractions 10-14 were combined giving 7.26 g (90%) of 1-benzyl-5-chloroindole as a yellow oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.O.[O:12]1[C@H:14]2[CH2:15][C@H:16]3[C@:29]([CH3:31])([CH2:30][C@@H:13]12)[C@@H:28]1[C@H:19]([C@H:20]2[C@@:24]([CH2:26][CH2:27]1)([CH3:25])[C@@H:23]([OH:32])[C@@H:22]([N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:21]2)[CH2:18][CH2:17]3>C(#N)C>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C@H:13]3[CH2:30][C@@:29]4([CH3:31])[C@@H:16]([CH2:17][CH2:18][C@@H:19]5[C@@H:28]4[CH2:27][CH2:26][C@@:24]4([CH3:25])[C@H:20]5[CH2:21][C@H:22]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[C@@H:23]4[OH:32])[CH2:15][C@@H:14]3[OH:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Solvent: CC#N
Solvent: O
Product: C[C@]12C[C@H](N3CCC4(CC3)OCCO4)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12

Procedure:
After adding 63 g of 1,4-dioxa-8-azaspiro[4.5]decane and 13 ml of water to 17 g of 2α,3α-epoxy-16β-(1-pyrrolidinyl)-5α-androstane-17β-ol, the reaction mixture is maintained at 100° to 105° C. for 80 hours while introducing nitrogen. After completion of the reaction, the solution containing a precipitate is diluted with 200 ml of acetonitrile and after filtering, the precipitate is thoroughly washed with water and then with acetonitrile, dried and recrystallized from methanol to give the title product in a yield of 18.2 g (76.5%), m.p.: 184°-187° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH:19]12[CH2:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH:20]2[NH2:26]>>[CH:19]12[CH2:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH:20]2[NH:26][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1]
Reactant: NC1CC2CCC1C2
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NC1CC2CCC1C2)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-bicyclo[2.2.1]hept-2-yl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.31 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.45 mmol of bicyclo[2.2.1]hept-2-ylamine. LC/MS [10.01 min; 452 (M+1)]
Reaction SMILES: [OH-:1].[K+].[Sn:3]([Cl:7])([Cl:6])([Cl:5])[Cl:4]>>[OH2:1].[OH2:1].[OH2:1].[OH2:1].[OH2:1].[Sn:3]([Cl:7])([Cl:6])([Cl:5])[Cl:4]
Reactant: [OH-]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [K+]
Product: O

Procedure:
A tin (IV) chloride pentahydrate (Aldrich) solution was prepared by addition of the solid to distilled water; 20% colloidal alumina (AL-20, PQ Corp.) was stirred into this solution and a white precipitate formed. An aqueous potassium hydroxide (Fisher) solution was added to the tin chloride solution and stirred; colloidal silica (HS-40, DuPont) was added to the mixture (to give a final reactant ratio of 2K2O:3.8SiO2 :SnO2 :0.1Al2O3 :80H2O) and the resulting gel stirred until homogeneous. The gel was reacted in a polytetrafluoroethylene-lined autoclave (Parr) at 200° C. for 21 days to produce a white solid after the reactor was cooled to room temperature. This solid was washed repeatedly with distilled water, filtered, and dried to yield a fine white powder (Phase G). Chemical analysis indicated 13.67% K, 22.82% Sn, 18.69% Si, and 0.92% Al. A typical X-ray diffraction pattern for Phase G is given in Table 6.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([CH:30]=O)[CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:30][C:22]2[CH:21]=[N:20][C:29]3[C:24]([CH:23]=2)=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cnc2ccccc2c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cnc2ccccc2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available quinoline-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions B): tR=0.68 min.; [M+H]+: 377.36 g/mol.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12](=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])(OCC)=O)C.[Si:22]([O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O>C1COCC1>[Si:22]([O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1/[CH:32]=[CH:11]/[C:12](=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: CCOP(=O)(CC(=O)CCCCC(=O)OC)OCC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCCC(=O)/C=C/c1ccccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 0.26 g (10.87 mmol) of sodium hydride was added to a solution of 3.20 g (10.87 mmol) of methyl 7-(diethoxyphosphoryl)-6-oxoheptanoate from Ex. XIIb in 53 ml of THF. The mixture was stirred at room temperature for 30 min, a solution of 9.06 mmol of 2-{[tert-butyl(dimethyl)silyl]oxy}benzaldehyde from Ex. XIIa in 20 ml of THF was added and the mixture was stirred at room temperature for 18 h. Water was added, the mixture was extracted with ethyl acetate, the combined organic phases were dried over Na2SO4 and the solvent was removed. The product was purified chromatographically (silica gel, cyclohexane/EA 10:1). This gave 2.51 g (67.8%) of a colorless liquid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C([O-])(=[S:56])C.C(N(C(C)C)CC)(C)C.N#N>O1CCOCC1>[SH:56][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11]
Reactant: CC([O-])=S
Reactant: O=C1CCc2c(Br)cccc21
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C1CCc2c(S)cccc21
Temperature: 120 °C
Yield: 54 %

Procedure:
4-Bromo-indanone (500 mg, 2.37 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (137 mg, 0.24 mmol), thioacetate (541 mg, 4.74 mmol) and diisopropylethylamine (1.64 mL, 5.69 mmol) are dissolved in 1,4-dioxane (2 mL). The mixture is degassed with N2 and tris(dibenzylideneacetone)palladium(0) (217 mg, 0.24 mmol) is added and heated under microwave irradiation at 120° C. for 2 hours. The solution is concentrated under vacuum. The crude product obtained is purified by flash chromatography (10-80% ethyl acetate in cyclohexane) to give the title compound (Yield: 210 mg). LC (METHOD 5): tR=0.89 min; Mass spectrum (ES−): m/z=163 [M−H]−.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:7]=[C:6]([O:27][CH3:28])[C:3]=1[C:4]#[N:5].O.[NH2:30][NH2:31]>C(O)C>[CH3:26][NH:25][C:12]1[N:11]=[C:10]([C:8]2[CH:9]=[C:2]3[C:3]([C:4]([NH2:5])=[N:30][NH:31]3)=[C:6]([O:27][CH3:28])[CH:7]=2)[CH:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH:22]([CH3:23])[CH3:24])[N:13]=1
Reactant: CNc1nc(-c2cc(F)c(C#N)c(OC)c2)cc(N2CCOC[C@H]2C(C)C)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CNc1nc(-c2cc(OC)c3c(N)n[nH]c3c2)cc(N2CCOC[C@H]2C(C)C)n1
Temperature: 100 °C

Procedure:
To a solution of 2-fluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-6-(methyloxy)benzonitrile (350 mg, 0.91 mmol) in ethanol (10 mL) was added hydrazine monohydrate (2.5 mL) in one portion. The mixture was heated at 100° C. for 20 hours, cooled to room temperature and concentrated in vacuo. The residue was taken up in water (10 mL) as a suspension. The solids were collected by filtration, washed with water (2×2 mL), and dried under vacuum at room temperature over P2O5 for 20 hours. The solids were washed with hexane (2×3 mL). Drying under vacuum at 65° C. for 20 hours afforded the title compound (302 mg) as a cream-colored solid. LC-MS (ES) m/z=398 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 0.89 (d, J=6.8 Hz, 3H), 1.11 (d, J=6.6 Hz, 3H), 2.45-2.55 (m, 1H), 2.96 (s, 3H), 3.25-3.35 (m, 1H), 3.53-3.61 (m, 2H), 3.94 (dd, J=11.1, 3.5 Hz, 1H), 4.04 (s, 3H), 4.11 (d, J=11.9 Hz, 1H), 6.38 (s, 1H), 6.89 (s, 1H), 7.35 (s, 1H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[C@@H:23]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:30](Cl)(=[O:32])[CH3:31]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[C@@H:23]1[CH2:24][CH2:25][C@H:26]([NH:29][C:30](=[O:32])[CH3:31])[CH2:27][CH2:28]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](N)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N[C@H]1CC[C@@H](c2ccc(O[Si](C)(C)C(C)(C)C)cc2O[Si](C)(C)C(C)(C)C)CC1
Reaction time: 24 h
Yield: 50 %

Procedure:
trans/cis-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine (27 mg) was dissolved in pyridine (0.5 ml). Acetyl chloride (6 μl) and 4-dimethylaminopyridine (2 mg) were added sequentially and the reaction mixture stirred for 24 hr. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (10 ml) and water (2 ml). The aqueous phase was extracted with ethyl acetate (2×5 ml) and the combined organic phases were washed with brine (10 ml), dried over anhydrous magnesium sulphate, and concentrated to give a brown oil. Purification via flash column chromatography (SiO2 eluting with ethyl acetate:petroleum ether, 7:3 v/v) afforded the title product as a white solid (15 mg, 50%) and a mixture of diastereoisomers. δH (CDCl3): 0.17 (3H, s), 0.19 (3H, s), 0.21 (3H, s), 0.22 (3H, s), 0.96 (9H, s), 1.02 (9H, s), 1.06-1.20 (2H, m), 1.36-1.54 (2H, m), 1.60-1.75 (2H, m), 1.80-1.92 (2H, m), 1.95 (1.5H, s), 2.00 (1.5H, s), 2.75-2.90 (1H, m), 3.76-3.87 (1H, m), 5.34-5.39 (0.5H, d), 5.72-5.77 (0.5H, d), 6.26-6.29 (1H, m), 6.38-6.41 (1H, m), 6.93 (0.5H, d), 6.95 (0.5H, d); m/z (ES+) 478 (M+1)+.
Reaction SMILES: Br[C:2]1[C:7]([O:8][C:9]([F:14])([F:13])[CH:10]([Cl:12])[F:11])=[CH:6][C:5]([Cl:15])=[CH:4][N:3]=1.[OH:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)C>[Cl:15][C:5]1[CH:6]=[C:7]([O:8][C:9]([F:14])([F:13])[CH:10]([Cl:12])[F:11])[C:2]([O:16][C:17]2[CH:18]=[CH:19][C:20]([O:21][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:29][CH:30]=2)=[N:3][CH:4]=1
Reactant: FC(Cl)C(F)(F)Oc1cc(Cl)cnc1Br
Reactant: CCOC(=O)C(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2OC(F)(F)C(F)Cl)cc1

Procedure:
9.75 g (30 mmol) of 2-bromo-5-chloro-3-(2-chloro-1,1,2-trifluoroethoxy)pyridine, 6.94 g (33 mmol) of ethyl 4-hydroxyphenoxypropionate and 6.6 g of anhydrous potassium carbonate in 40 ml of absolute dimethyl sulfoxide were stirred for 9 hours at 80° C. under argon. After cooling, the mixture was diluted with 300 ml of diethyl ether, the potassium carbonate was filtered off, and the organic phase was washed with 5% strength KOH and subsequently with water until neutral. After drying, the compound of Example 1 was obtained in a crude yield of 13.4 g (98% of theory).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]([NH:13][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=O)=O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([O:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]2[S:27][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=3)=[CH:14][N:13]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc(C(=O)NCC(=O)c2ccc(Br)cc2)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCOc1ccc(-c2ncc(-c3ccc(Br)cc3)s2)cc1
Reaction time: 1.5 h
Yield: 105.5 %

Procedure:
To a solution of 2-(4-pentyloxybenzamido)-4′-bromoacetophenone (3.39 g) in tetrahydrofuran (34 ml) was added phosphorus pentasulfide (2.43 g), and refluxed for 30 minutes. The reaction mixture was cooled, and poured into saturated sodium hydrogen carbonate aqueous solution (400 ml), and stirred for 1.5 hours. The resulting precipitate was collected by filtration to give 2-(4-pentyloxyphenyl)-5-(4-bromophenyl)thiazole (2.32 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Na].Br[CH2:8][CH:9]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C(O)C>[CH:9]1([CH2:8][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: BrCC1CCCCCCC1
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CCO
Product: c1cn(CC2CCCCCCC2)cn1
Reaction time: 15 h

Procedure:
Imidazole (2.0 g, 0.03 mol) was added to a solution of sodium (0.7 g, 0.03 mol) in dry ethanol (50 ml). The mixture was stirred and heated to boiling when bromomethylcyclooctane (5.5 g, 0.027 mol) was added dropwise. Following the addition, the reaction mixture was stirred and boiled for 15 h.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([CH3:16])[C:9]([F:15])=[C:10]([F:14])[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([O:20]CC)=[O:19])=[CH:4]1)[CH3:2].Cl>C(O)(=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([CH3:16])[C:9]([F:15])=[C:10]([F:14])[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2c(F)c(F)c(F)c(C)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2c(C)c(F)c(F)c(F)c21
Yield: 93.3 %

Procedure:
Employing ethyl 1-ethyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-caboxylate (6.51 g) and conc. hydrochloric acid: 90% acetic acid (1:4) (100 ml), the procedure of Reference Example 23 is repeated to give 1-ethyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (5.53 g), as colorless needles (recrystallized from dichloromethane - n-hexane), m.p. 203°-204° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26]I)=[CH:14][CH:13]=3)[CH:10]([CH2:28][CH2:29][CH:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[OH:31])[C:9]2=[O:39])=[CH:4][CH:3]=1.[CH3:40][NH:41][CH2:42][CH:43]([OH:52])[CH:44]([OH:51])[CH:45]([OH:50])[CH:46]([OH:49])[CH2:47][OH:48]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][N:41]([CH3:40])[CH2:42][CH:43]([OH:52])[CH:44]([OH:51])[CH:45]([OH:50])[CH:46]([OH:49])[CH2:47][OH:48])=[CH:14][CH:13]=3)[CH:10]([CH2:28][CH2:29][CH:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[OH:31])[C:9]2=[O:39])=[CH:4][CH:3]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCOCCOCCI)cc2)N1c1ccc(F)cc1
Reactant: CNCC(O)C(O)C(O)C(O)CO
Solvent: CN(C)C=O
Product: CN(CCOCCOCCOc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)CC(O)C(O)C(O)C(O)CO
Temperature: 50 °C
Reaction time: 2 h

Procedure:
230 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{2-[2-(2-iodoethoxy)ethoxy]ethoxy}phenyl)azetidin-2-one are dissolved in 5 ml of absolute dimethylformamide. 280 mg of 6-methylaminohexane-1,2,3,4,5-pentaol are then added, and the reaction solution is stirred at 50° C. for 2 h. After concentration using a rotary evaporator and oil pump vacuum at 40° C., the residue is purified by preparative HPLC. The product is obtained as an oil. C37H48F2N2O10 (718) MS (ESI): M+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:14](Cl)=[O:15])[CH2:11][C:10]2([CH3:13])[CH3:12])=[CH:5][CH:4]=1.Cl.[NH2:18][C:19]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH:34][CH3:35])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:14]([NH:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]([C:25]4[CH:26]=[CH:27][C:28]([S:31](=[O:33])(=[O:32])[NH:34][CH3:35])=[CH:29][CH:30]=4)[N:24]=3)=[O:15])[CH2:11][C:10]2([CH3:13])[CH3:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C(=O)Cl)CC2(C)C)cc1
Reactant: CNS(=O)(=O)c1ccc(-c2cccc(N)n2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CNS(=O)(=O)c1ccc(-c2cccc(NC(=O)C3(c4ccc(OC)cc4)CC3(C)C)n2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1-(4-Methoxyphenyl)-2,2-dimethylcyclopropanecarbonyl chloride (0.20 mmol) was added to a solution of 4-(6-aminopyridin-2-yl)-N-methylbenzenesulfonamide HCl salt (60 mg, 0.20 mmol) in pyridine (1 mL) at room temperature. The reaction was stirred at 60° C. overnight and then was concentrated, dissolved in DMSO and purified by LC-MS to yield 1-(4-methoxyphenyl) -2,2-dimethyl-N-(6-(4-(N-methylsulfamoyl)-phenyl)pyridin-2-yl)cyclo-propanecarboxamide. ESI-MS m/z calc. 465.2, found 466.5 (M+1)+. Retention time 1.98 minutes.