Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[N:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[F:40][C:41]1[CH:42]=[C:43]([CH:59]=[CH:60][CH:61]=1)[CH2:44][N:45]1[CH:49]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH:47]=[N:46]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:40][C:41]1[CH:42]=[C:43]([CH:59]=[CH:60][CH:61]=1)[CH2:44][N:45]1[CH:49]=[C:48]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[N:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[CH:47]=[N:46]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cn4)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(F)c3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cn4)cnc32)cc1
Yield: 74.6 %

Procedure:
Using the same reaction conditions as described in step-ii of example-1, tert-butyl 4-(6-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)piperazine-1-carboxylate (Intermediate 66M) (1.0 g, 1.515 mmol) was coupled with 1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 11) (596 mg, 1.969 mmol) using sodium carbonate (402 mg, 3.787 mmol) and Pd(PPh3)2Cl2 (54 mg, 0.075 mmol) in toluene/ethanol/water (10/3/3 mL) to afford 800 mg (74.6% yield) of the titled compound after purification by column (Silica gel 60/120) using 1.5% methanol in DCM as eluent. MS: m/z=708.3 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH2:10][CH2:11][S:12](=[O:15])(=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12.[C:27](OC(=N)N(C(C)C)C(C)C)([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([O:23][C:22]([C:5]1[N:4]2[C:25](=[O:26])[CH:2]([NH2:1])[C@H:3]2[S:8][CH2:7][C:6]=1[CH:9]([S:16][C:17]1[NH:18][N:19]=[N:20][N:21]=1)[CH2:10][CH2:11][S:12](=[O:14])(=[O:15])[NH2:13])=[O:24])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)N(C(=N)OC(C)(C)C)C(C)C
Reactant: NC1C(=O)N2C(C(=O)O)=C(C(CCS(N)(=O)=O)Sc3nnn[nH]3)CS[C@H]12
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1=C(C(CCS(N)(=O)=O)Sc2nnn[nH]2)CS[C@@H]2C(N)C(=O)N12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 21.1 g. (0.05 mol.) of 7-amino3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4carboxylic acid in 500 ml. of dry methylene chloride is added in one portion a solution of 30.0 g. (0.15 mol.) of O-t-butyldiisopropylpseudourea in 50 ml. of methylene chloride. The mixture is stirred at ambient temperature for 24 hours. The precipitate is removed by filtration and the filtrate evaporated to a residue which is taken up in 200 ml. of benzene and filtered again. The filtrate is extracted with three 100 ml. portions of cold 1N hydrochloric acid. The acidic aqueous extracts are layered with ethyl acetate and the pH adjusted to 7.5 with solid sodium bicarbonate. The organic layer is separated and the aqueous phase is extracted with two 150 ml. portions of ethyl acetate. The combined extracts are dried (MgSO4), filtered and evaporated to give 7-amino-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=2)[CH3:19])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.B(Br)(Br)[Br:29].O.CCOC(C)=O>C(Cl)Cl>[Br:29][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:17][C@H:18]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH3:19])[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: BrB(Br)Br
Reactant: COc1cccc([C@H](C)Nc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: C[C@H](Nc1nc(Nc2cccc(CBr)c2)ncc1Cl)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of {3-[(5-chloro-4-{[(1S)-1-(3-methoxyphenyl)ethyl]amino}pyrimidin-2-yl)amino]phenyl}methanol (0.30 g, 0.78 mmol) in methylene chloride (5.0 mL) was added slowly a solution of boron tribromide in methylene chloride (3.9 mL, 3.9 mmol, 1.0 M) at 0° C. The mixture was allowed to warm up to rt and stirred overnight. The resultant mixture was cooled in a dry ice bath when water was added. The mixture was allowed to warm up to rt. Water and EtOAc were added. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as a white powder (0.255 g, 75%). LCMS for C19H19BrClN4O (M+H)+: m/z=433.0, 435.0.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C(C1C=C(B(O)O)C=CC=1)=O.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:3]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[CH:11][C:4]=3[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=2)=[CH:35][CH:34]=1
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Reactant: OB(O)c1ccc(F)cc1
Agent: O=Cc1cccc(B(O)O)c1
Product: CN1C(=O)CN=C(c2ccc(F)cc2)c2cc(-c3ccccc3)ccc21
Yield: 14 %

Procedure:
Prepared from 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using 3-formylbenzene boronic acid, we used 4-fluorophenyl boronic acid. The title compound (19 mg) was obtained as a beige solid, (yield=14%).
Reaction SMILES: C(O[C:4](=[O:15])[CH:5]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:6](=O)[CH3:7])C.[NH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17].CC[O-].[Na+].Cl>C(O)C.O.C(O)(=O)C>[CH3:7][C:6]1[NH:17][N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:4](=[O:15])[C:5]=1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: NNc1ccccn1
Reactant: CCOC(=O)C(C(C)=O)c1cccnc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1[nH]n(-c2ccccn2)c(=O)c1-c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
22 μl glacial acetic acid are added to a solution of 58 mg (0.28 mmol) of the compound from Example 18A and 34 mg (0.31 mmol) 2-hydrazinopyridine in 0.4 ml absolute ethanol and the mixture is stirred overnight at RT. 19 mg sodium ethylate are added and the mixture is subsequently stirred at RT for 30 min and then neutralized with 1 N hydrochloric acid. After addition of water, the mixture is extracted with methylene chloride and the organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is stirred with diisopropyl ether and the solid is filtered off with suction. After drying, 13.5 mg (19% of th.) of the title compound are obtained.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([O:9]C)[CH:8]=1.NC(C(O)=O)CCSC>CS(O)(=O)=O>[OH:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([OH:9])[CH:8]=1
Reactant: COC(=O)c1cccc(-c2cc(OC)cc(OC)c2)c1
Agent: CS(=O)(=O)O
Agent: CSCCC(N)C(=O)O
Product: COC(=O)c1cccc(-c2cc(O)cc(O)c2)c1
Temperature: 40 °C
Reaction time: 10 h

Procedure:
A mixture of methyl 3-(3,5-dimethoxyphenyl)benzoate (0.83 g) and d,l-methionine (9.10 g) in methanesulfonic acid (19.8 ml) was stirred at 40° C. for 10 hours. The mixture was poured onto ice-water and then the product was extracted with ethyl acetate and washed with sodium hydrogencarbonate solution and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and acetone (5:1). The fractions containing the desired product was collected and evaporated in vacuo to give methyl 3-(3,5-dihydroxyphenyl)benzoate.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=CC=CN=1)=[CH2:2].[O-]O.[C:11]1([CH:17](C)[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.NCCNCCNCCNCCN.[K]>O>[CH2:2]=[CH:1][CH:3]=[CH2:8].[CH2:18]=[CH:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=Cc1ccccn1
Reactant: CC(C)c1ccccc1
Agent: NCCNCCNCCNCCN
Agent: [K]
Agent: [O-]O
Solvent: O
Product: C=CC=C
Product: C=Cc1ccccc1

Procedure:
In a laboratory Banbury 100 grams of butadienestyrene copolymer rubber (SBR 1502), 40 grams of 2-vinylpyridine, 3 grams of cumene hydroperoxide and 1 gram of tetraethylenepentamine were mixed for 3 minutes at temperatures in excess of 325° F to cause polar grafting of the batch of rubber. This grafting operation was repeated to produce 3 more batches and the four batches of grafted product were cooled and dissolved in 16 kilograms of mixed xylenes, with the aid of agitation, over a period of 12 hours. To the grafted SB-R cement was added 240 grams of the potassium salt of coconut oil fatty acids and 20 liters of water and after mixing a coarse emulsion was formed. The coarse emulsion was converted to a fine emulsion of precursor latex sized particles ready for stripping by twice passing through the homogenizing apparatus employed in Example 2 hereof. Further treatment by the procedures of Example 1, produced a substantially quantitative yield, dry solids basis, of dilute and concentrated latices of 2-vinyl pyridine grafted butadiene-styrene rubber.
Reaction SMILES: FC(F)(F)C([O-])=[O:4].FC1C=CC(C2C(C[P+](CCCC)(CCCC)CCCC)=C(C(C)C)N=C(N(C)S(C)(=O)=O)N=2)=CC=1.C[Si](C)(C)N[Si](C)(C)C.[Na].[Si:54]([O:61][C@H:62]1[CH2:67][C:66](=[O:68])[O:65][C@H:64]([CH:69]=[O:70])[CH2:63]1)([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55]>C1(C)C=CC=CC=1>[Si:54]([O:61][C@@H:62]1[CH2:63][C@@H:64]([CH:69]([OH:4])[OH:70])[O:65][C:66](=[O:68])[CH2:67]1)([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](C=O)C1
Reactant: O=C([O-])C(F)(F)F
Agent: CCCC[P+](CCCC)(CCCC)Cc1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](C(O)O)C1
Reaction time: 1 h

Procedure:
To a stirred suspension of ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)methyl)tributylphosphonium 2,2,2-trifluoro-acetate (VI′) (504 mg, 0.77 mmol) at room temperature in dry toluene (8 mL), sodium hexamethyldisilazane in toluene (1.3 mL of 0.6 M, 0.77 mmol) is added portionwise in 10 minutes. The reaction mixture is stirred is for 60 min and treated at room temperature with a solution of (2S,4R)-4-(tert-butyldimethylsilyl oxy)-6-oxo-tetrahydro-2H-pyran-2-carbaldehyde (IV′) (200 mg, 0.77 mmol) in 25 mL of dry toluene obtained by dissolution of (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(dihydroxymethyl)-tetrahydropyran-2-one (V′) (214 mg, 0.77 mmol) in toluene and removal of released water. After 24 hours of stirring at room temperature the solution is treated with saturated ammonium chloride solution or water. The aqueous phase is extracted with tBuMeO (2×20 mL), and the combined organic layers dried and concentrated. The residue is purified by silica gel chromatography (elution with tBuMeO/hexane mixture) to give 273 mg (61%) of N-(5-((E)-2-((2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxo-tetrahydro-2H-pyran-2-yl)vinyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:16])[C:7]=1[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1.C(N(CC)CC)C>CO.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(Cl)Cl>[CH3:8][O:9][C:10](=[O:11])[C:2]1[C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[C:6]([Cl:16])[CH:5]=[N:4][CH:3]=1
Reactant: Clc1cncc(Cl)c1COC1CCCCO1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cncc(Cl)c1COC1CCCCO1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of 3,5-dichloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridine (400 mg, 1.533 mmol), triethylamine (278 μL, 1.993 mmol), (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II)•DCM (PdCl2(dppf)2•DCM, 63 mg, 0.077 mmol) and 4 Å molecular sieves (600 mg) in MeOH (10 mL) was stirred at 120° C. for 5 h under an atmosphere of carbon monoxide (15 bar). The reaction was filtered and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel (elution with mixtures of hexane/EA) to give the title compound. MS (m/z): 286.0 [M+H+].
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@H:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:18])[O:7]2.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>ClCCl.CS(C)=O>[CH:2]([C@H:3]1[C@H:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:18])[O:7]2)=[O:1]
Reactant: O=C1C[C@@H]2[C@H](CO)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1

Procedure:
A solution of Corey lactone, (1S,5R,6R,7R)-6-(hydroxymethyl)-7-(tetrahydropyranyioxy)-2-oxabicyclo[3.3.0]octan-3-one (1), (6.800 g) in dichloromethane (40 ml) was oxidized by means of Swern oxidetion with using a solution of oxalyl chloride (2M dichloromethan solution, 30 ml) in dichloromethane (100 ml), DMSO (8.45 ml), and triethylamine (16.9 ml). After the usual work up, Corey aldehyde, (1S,5R,6R,7R)-6-formyl-7-(tetrahydropyranyloxy)-2-oxabicyclo [3.3.0]octan-3-one (2) was obtained.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:15](=[CH:16][CH:17]=1)[O:14][C:8]1([CH2:13][CH2:12][CH2:11][O:10][CH2:9]1)[CH2:7][C:6]2=[N:18]S(C(C)(C)C)=O>O1CCOCC1>[Br:2][C:3]1[CH:4]=[C:5]2[C:15](=[CH:16][CH:17]=1)[O:14][C:8]1([CH2:13][CH2:12][CH2:11][O:10][CH2:9]1)[CH2:7][C:6]2=[NH:18]
Reactant: CC(C)(C)S(=O)N=C1CC2(CCCOC2)Oc2ccc(Br)cc21
Agent: Cl
Solvent: C1COCCO1
Product: N=C1CC2(CCCOC2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
HCl (4 M in 1,4-dioxane) (0.395 mL, 12.99 mmol) was added to a suspension of N-(6-bromo-5′,6′-dihydro-4′H-spiro[chromene-2,3′-pyran]-4(3H)-ylidene)-2-methylpropane-2-sulfinamide (Example 45 Step 1, 520 mg, 1.30 mmol) in anhydrous 1,4-dioxane (6 mL) and the resulting mixture was stirred under a nitrogen atmosphere at r.t. for 2 days. A precipitate was formed. The precipitate was filtered off and washed with Et2O. The solid was then dissolved in DCM and sat. aq. NaHCO3. The mixture was poured into a phase separator, the organic layer was collected and concentrated. The title compound was used directly in the next step without any further purification.
Reaction SMILES: [H-].[Na+].C(=[C:6]([CH:8]([CH2:10][OH:11])[OH:9])[OH:7])(C)C.C1(C)C=CC(S(O[CH2:22][CH2:23][CH:24]([CH3:41])[CH2:25][CH2:26][CH2:27][C@H:28]([CH3:40])[CH2:29][CH2:30][CH2:31][C@H:32]([CH3:39])[CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])(=O)=O)=CC=1.O.[CH3:44][CH2:45][CH2:46]CC>CN(C)C=O>[CH3:44][C:45]1([CH3:46])[O:9][CH:8]([CH2:6][O:7][CH2:22][CH2:23][CH:24]([CH3:41])[CH2:25][CH2:26][CH2:27][C@H:28]([CH3:40])[CH2:29][CH2:30][CH2:31][C@H:32]([CH3:39])[CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:10][O:11]1
Reactant: CCCCC
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)cc1
Reactant: CC(C)=C(O)C(O)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCCC(C)CCOCC1COC(C)(C)O1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
5.25 g (175 mmol) of sodium hydride (80%) were washed twice with 10 ml of pentane. Thereafter, 400 ml of dimethylformamide and 120 mmol of isopropylideneglycerol were added. The reaction mixture was stirred at 60° C. for 1 hour. After cooling to room temperature 100 mmol of (3RS,7R,11R)-3,7,11,15-tetramethylhexadecyl p-toluenesulphonate in 100 ml of dimethylformamide were added. The reaction mixture was stirred at 60° C. for 2 hours. After the addition of a small amount of water the majority of the solvent was removed at 65° C. The residue was suspended in toluene, filtered and freed from solvent. After chromatography of the crude product on silica gel there was obtained (RS)-2,2-dimethyl-4-[[[(3RS,7R,11R)-3,7,11,15-tetramethylhexadecyl]oxy]methyl]-1,3-dioxolane.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[CH:11][CH:12]=[CH:13][CH3:14])([O-:3])=[O:2].[C:15]1(=[O:21])[O:20][C:18](=O)[CH:17]=[CH:16]1.C1(C)C=CC=CC=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O.C(OCC)(=O)C>[CH2:29]([N:36]1[C:15](=[O:21])[CH:16]2[CH:13]([CH3:14])[CH:12]=[CH:11][CH:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[CH:17]2[C:18]1=[O:20])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1C=CC(=O)O1
Reactant: NCc1ccccc1
Reactant: CC=CC=Cc1ccccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1C=CC(c2ccccc2[N+](=O)[O-])C2C(=O)N(Cc3ccccc3)C(=O)C12
Temperature: 150 °C
Reaction time: 5 h
Yield: 30 %

Procedure:
A mixture of 5.0 g of 1-nitro-2-(1,3-pentadienyl)benzene and 2.9 g of maleic anhydride was stirred at 150° C. for 5 hours. Thereto were added 150 ml of toluene and 3.2 ml of benzylamine. The resulting mixture was azeotropically refluxed for 2 hours, and then cooled to room temperature. Thereto were added 150 ml of ethyl acetate and 100 ml of water. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=1/0 to 20/1) to obtain 3.0 g (yield: 30%) of N-benzyl-3-methyl-6-(2-nitrophenyl)-1,2,3,6-tetrahydrophthalimide as colorless crystals.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=1[OH:14])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[CH2:21]([CH:23]1[O:25][CH2:24]1)Cl>CC(C)=O>[CH2:1]([O:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=1[O:14][CH2:21][CH:23]1[O:25][CH2:24]1)[CH:2]=[CH2:3]
Reactant: ClCC1CO1
Reactant: C=CCOc1c(O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1c(OCC2CO2)cccc1[N+](=O)[O-]

Procedure:
10.0 g of 2-allyloxy-3-nitrophenol, 27 g of potassium carbonate and 54 ml of epichlorohydrin in 300 ml of acetone are stirred under reflux for 15-20 hours. After filtering the reaction mixture and evaporating the filtrate, crude 2-allyloxy-1-(2,3-epoxy-propoxy)-3-nitrobenzene is obtained and this can be used further as such.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:34])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20]([NH:24]CC4C=CC(OC)=CC=4)=[CH:21][C:22]=3[CH3:23])=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[NH2:24][C:20]1[N:19]=[CH:18][C:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[C:5]([CH3:34])=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=3)[CH2:10][CH2:11]2)=[O:16])=[C:22]([CH3:23])[CH:21]=1
Reactant: CCc1cnc(N2CCN(C(=O)c3cnc(NCc4ccc(OC)cc4)cc3C)CC2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnc(N2CCN(C(=O)c3cnc(N)cc3C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (320 mg) described in Preparation Example 176 was added 4-methoxybenzylamine (1 mL), and the mixture was stirred at 160° C. for 6 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl][6-(4-methoxybenzylamino)-4-methylpyridin-3-yl)methanone (330 mg). The obtained [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl][6-(4-methoxybenzylamino)-4-methylpyridin-3-yl)methanone (330 mg) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated from the reaction mixture, 1N aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography to give (6-amino-4-methylpyridin-3-yl) [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone. The obtained (6-amino-4-methylpyridin-3-yl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone and triethylamine (0.30 mL) were dissolved in dichloromethane (10 mL), 3-chloropropane-1-sulfonyl chloride (0.18 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 3.5 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (10 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography to give the title compound (220 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]2[N:9]=[C:10]([NH:13][C:14]3[C:19]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:18][C:17]([S:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:16][N:15]=3)[S:11][CH:12]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(Cl)Cl.CO.Cl>O1CCOCC1>[CH3:1][CH:2]1[CH:7]([C:8]2[N:9]=[C:10]([NH:13][C:14]3[C:19]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:18][C:17]([S:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:16][N:15]=3)[S:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1c1csc(Nc2ncc(Sc3ccccn3)cc2Oc2ccccc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CC1CNCCC1c1csc(Nc2ncc(Sc3ccccn3)cc2Oc2ccccc2)n1
Reaction time: 1 h
Yield: 82.6 %

Procedure:
A 25 mL flask was charged with tert-butyl 3-methyl-4-(2-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate (0.296 g, 0.514 mmol), CH2Cl2 (3 mL) and MeOH (3 mL). 4N HCl in dioxane (6 mL) was added and the reaction was stirred for 1 hour and then concentrated. The crude material was dissolved in CH2Cl2 and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated to afford N-(4-(3-methylpiperidin-4-yl)thiazol-2-yl)-3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-amine (0.202 g, 82% yield)