Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:13])[CH:3]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:13][Br:14])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(F)c(Br)cc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(F)c(Br)cc1CBr
Yield: 92 %

Procedure:
A mixture of methyl 4-bromo-5-fluoro-2-methylbenzoate (1.0 g, 4.0 mmol) (Ellanoval Laboratories Cat. No. 38-0304), N-bromosuccinimide (900. mg, 5.06 mmol) and benzoyl peroxide (50 mg, 0.2 mmol) in carbon tetrachloride (50 mL) was refluxed under a nitrogen atmosphere for 4 h. After cooling the mixture was diluted with methylene chloride. The organic solution was washed with brine, then dried over Na2SO4. After filtration the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (1.2 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH:20]([C:26]([CH3:28])=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CO.C(OCC)(=O)C>[CH3:28][C:26]1[N:1]=[C:2]2[C:7]([O:8][CH2:9][C:10]3([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:12][CH2:11]3)=[CH:6][CH:5]=[CH:4][N:3]2[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Nc1ncccc1OCC1(c2ccccc2)CC1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nc2c(OCC3(c4ccccc4)CC3)cccn12
Yield: 8.6 %

Procedure:
A stirred mixture of 2-amino-3-[(1-phenylcyclopropyl)methoxy]pyridine (2.82 g, 11.7 mmol, see example 23), ethyl 2-chloroacetoacetate (6.5 mL, 47 mmol) and molecular sieves (15.1 g, type 4 Å, beads, 8–12 mesh) in anhydrous methanol (55 mL) was refluxed for 39 h under argon. The molecular sieves were filtered off and the filtrate was concentrated in vacuo to give an oil which was dissolved in ethyl acetate (200 mL) and then washed successively with a 1:1 (v/v) mixture of saturated aq sodium bicarbonate and water (2×25 mL), and water (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the crude product. Purification by dry column (600 mL funnel with 450 mL of silica gel 10–40μ, Sigma cat. S-6628) eluted with a mixture of ethyl acetate-hexanes (1:3 v/v, containing 0.5% v/v isopropylarnine) afforded 0.352 g (8.6% yield) of ethyl 2-methyl-8-[(1-phenylcyclopropyl)methoxy]imidazo[1,2-α]pyridine-3-carboxylate (Rf=0.30 in ethyl acetate-hexanes, 1:3 v/v, containing 0.5% v/v isopropylamine). A stirred solution of ethyl 2-methyl-8-[(1-phenylcyclopropyl)methoxy]imidazo[1,2-α]pyridine-3-carboxylate (0.190 g, 0.542 mmol) in a mixture of dichloromethane (3.5 mL) and anhydrous diethyl ether (3 mL) was treated with ethereal hydrogen chloride to form the hydrochloride salt. Concentration of the solution in vacuo gave a residue which was triturated in anhydrous diethyl ether to afford the title compound as an off-white solid (0.168 g, 80% yield). 1H-NMR (300 MHz, CDCl3) δ 16.91 (br s, 1H, +NH), 9.05 (d, 1H, Ar), 7.65 (d, 2H, Ar), 7.18 (m, 4H, Ar), 6.92 (d, 1H, Ar), 4.45 (q, 2H, CH3CH2), 4.32 (s, 2H, CH2O), 3.03 (s, 3H, CH3), 1.42 (t, 3H, CH3CH2), 1.15 (m, 4H, CH2CH2); 13C-NMR (75 MHz, CDCl3, APT) δ 159.49 (+), 145.10 (+), 143.90 (+), 142.24 (+), 133.68 (+), 130.21 (−), 128.26 (−), 126.78 (−), 120.27 (−), 118.13 (−), 113.77 (+), 112.02 (−), 78.61 (+), 62.09 (+), 25.48 (+), 14.14 (−), 12.56 (−), 11.51 (+); LRMS-FAB m/z: MH+ 351 (100%); Anal. calcd for C21H22N2O3.HCl: C, 65.20; H, 5.99; N, 7.24%. found: C, 64.87; H, 5.96; N, 7.20%.
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[C@@H:25]12[CH2:31][C@@H:28]([CH2:29][CH2:30]1)[CH2:27][C@H:26]2[O:32][C:33]1[C:41]([CH:42]2[CH2:44][CH2:43]2)=[CH:40][C:36]([C:37]([OH:39])=O)=[C:35]([F:45])[CH:34]=1.COCCS(N)(=O)=O.[CH:54]1([S:57]([NH2:60])(=[O:59])=[O:58])[CH2:56][CH2:55]1>>[C@@H:25]12[CH2:31][C@@H:28]([CH2:29][CH2:30]1)[CH2:27][C@H:26]2[O:32][C:33]1[C:41]([CH:42]2[CH2:43][CH2:44]2)=[CH:40][C:36]([C:37]([NH:60][S:57]([CH:54]2[CH2:56][CH2:55]2)(=[O:59])=[O:58])=[O:39])=[C:35]([F:45])[CH:34]=1
Reactant: O=C(O)c1cc(C2CC2)c(O[C@@H]2C[C@@H]3CC[C@H]2C3)cc1F
Reactant: NS(=O)(=O)C1CC1
Agent: COCCS(N)(=O)=O
Agent: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(O[C@@H]2C[C@@H]3CC[C@H]2C3)cc1F
Yield: 67 %

Procedure:
Following the procedure as described in Example 271 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 4-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace 2-methoxyethanesulfonamide with cyclopropanesulfonamide. Purification by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compound as a colorless solid (0.090 g, 67%): 1H NMR (300 MHz, DMSO-d6) δ 11.54 (br s, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.84 (d, J=13.1 Hz, 1H), 4.82-4.73 (m, 1H), 3.08-2.98 (m, 1H), 2.60-2.53 (m, 1H), 2.26-1.18 (m, 1H), 2.18-2.05 (m, 1H), 2.03-1.93 (m, 1H), 1.91-1.79 (m, 1H), 1.62-1.48 (m, 1H), 1.47-1.18 (m, 4H), 1.12-1.03 (m, 4H), 0.97-0.79 (m, 3H), 0.68-0.59 (m, 2H); MS (ES+) m/z 394.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8]C(=O)[O:10][C:11](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:14][C:15]1[C:16]([CH3:22])=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>C1(C)C(C)=CC=CC=1>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=1[C:11]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([Br:14])[C:16]=1[CH3:22])=[O:10]
Reactant: O=c1[nH]c2c(Cl)cccc2c(=O)o1
Reactant: Cc1c(N)cccc1Br
Solvent: Cc1ccccc1C
Product: Cc1c(Br)cccc1NC(=O)c1cccc(Cl)c1N
Yield: 91.1 %

Procedure:
A suspension of 8-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (4.00 g, 20.3 mmol) and 3-bromo-2-methylaniline (5.65 g, 30.4 mmol) in xylene (20 mL) was heated at reflux for 2.5 h. The cooled mixture formed a yellow precipitate. The mixture was diluted with hexanes, and the precipitate was collected by filtration, washed with hexanes and dried to give 2-amino-N-(3-bromo-2-methylphenyl)-3-chlorobenzamide as a yellow solid (6.28 g, 91% yield). Mass spectrum m/z 339, 341 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 7.68 (d, J=8.1 Hz, 1H), 7.61 (br. s., 1H), 7.52-7.43 (m, 3H), 7.15 (t, J=8.0 Hz, 1H), 6.70 (t, J=7.8 Hz, 1H), 6.12 (br. s., 2H), 2.44 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>N1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: C1=COCC1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
In 40 ml of pyridine were dissolved 5.2 g of 5-fluorouracil. The solution was ice cooled and 0.8 g of titanium tetrachloride was added thereto. Then, 6 ml of 2,3-dihydrofuran in 20 ml of pyridine were added to the mixture in 1.5 hours while stirring it at 80° C. The reaction was continued for 4 hours. After completion of the reaction, pyridine was removed from the reaction liquid by distillation and 500 ml of chloroform and 5 g of silica gel were added to the residue. The mixture was decolored and filtered and the filtrate was concentrated to obtain 5.5 g of 1-(2-tetrahydrofuryl)-5-fluorouracil in a yield of 69%.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4](=[O:10])[NH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17](I)([CH3:19])[CH3:18]>CN(C=O)C>[CH:17]([N:3]1[C:4](=[O:10])[C:5]2[CH:9]=[CH:8][NH:7][C:6]=2[N:1]=[CH:2]1)([CH3:19])[CH3:18]
Reactant: CC(C)I
Reactant: O=c1[nH]cnc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cnc2[nH]ccc2c1=O
Temperature: 55 °C
Reaction time: 13 h

Procedure:
Under argon gas, 7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.0 g) was dissolved in DMF (35 ml) with warming. Then, anhydrous potassium carbonate (1.02 g) and isopropyl iodide (1.1 ml) were added and the mixture was stirred at 55° C. for 13 hours. The insoluble matter was filtered off and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography (silica gel; hexane: ethyl acetate=4:1→1:1) to provide the title compound (110 mg). 1 H-NMR (CDCl3) δ: 1.48(6H,d,J=7.OHz), 5.31(1H,m), 6.74(1H,dd,J=2.2&3.4Hz), 6.96(1H,dd,J=2.2&3.4Hz), 7.95(1H,s), 9.20(1H,brs).
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][C:4]1([C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH2:2].[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC.C1(C(C2CC2)=O)CC1>>[C:6]([C:4]1[CH2:5][CH:3]([CH:1]=[CH2:2])[O:18][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C=CC1CC1(C(=O)OCC)C(=O)c1ccccc1
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: O=C(C1CC1)C1CC1
Agent: [Cl-]
Product: C=CC1CC(C(=O)OCC)=C(c2ccccc2)O1

Procedure:
4-Carbethoxy-5-phenyl-2-vinyl-2,3-dihydrofuran was obtained in the usual manner by isomerizing ethyl 2-vinyl-1-benzoylcyclopropane-1-carboxylate. To catalyze the isomerization, tricaprylylmethylammonium chloride was employed at a 20 percent weight level. The mixture was heated at 150° C. for about two hours after which time only about 7 percent of the cyclopropyl ketone remained. After two distillations of the resulting isomerized product, essentially pure 4-carbethoxy-5-phenyl-2-vinyl-2,3-dihydrofuran was obtained (B.P. 110° C. @ 0.1 mm Hg; nD25° 1.5570). The product had a pleasing aroma that was somewhat coumarin-like in odor character.
Reaction SMILES: ClC1C=CC(C2[C:9]([CH:14]=[O:15])=[CH:10][CH:11]=[CH:12]C=2)=CC=1.[NH:16]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17]1.N1(C(OC(C)(C)C)=O)CCNCC1>>[O:15]1[CH2:14][CH2:9][CH:10]([N:16]2[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:17]2)[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C2CCOCC2)C1

Procedure:
The title compound was prepared by substituting dihydro-2H-pyran-4(3H)-one for 4′-chlorobiphenyl-2-carboxaldehyde and (S)-tert-butyl pyrrolidin-3-ylcarbamate for tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.
Reaction SMILES: [NH2:1][C@@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.S(=O)(=O)(O)O.C(O)C.[CH:24](=O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CO>[CH2:25]([CH:24]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][C@H:2]([C:13]([OH:15])=[O:14])[NH:1]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCC=O
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CO
Product: CCCCCCCC1N[C@@H](C(=O)O)Cc2c1[nH]c1ccccc21
Temperature: 45 °C
Reaction time: 72 h

Procedure:
A mixture containing 147 mmol of D-tryptophan, 294 ml of 1 N sulfuric acid, 300 ml of ethanol and 294 mmol of octanal is stirred at 45° C. for 72 hours. The solution is concentrated and the residue is taken up in a water/methanol/ammonium hydroxide mixture. The methanol is evaporated at 45° C. and the precipitate is filtered off, washed with water and dried. The solid obtained is solubilized at high temperature in methanol. After cooling, the compound of preparation F crystallizes. It is then filtered and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([C:23]2[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=2)[CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:36]([CH:38]1[O:40][CH2:39]1)Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH:14][C:15]1[CH:16]=[C:17]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:36][CH:38]3[CH2:39][O:40]3)[CH:24]=2)[N:18]=[C:19]([O:21][CH3:22])[N:20]=1
Reactant: ClCC1CO1
Reactant: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(O)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(OCC3CO3)c2)n1
Reaction time: 4 h
Yield: 50.8 %

Procedure:
To a suspension of 3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenol (280 mg, 0.68 mmol), and Cs2CO3 (0.44 g, 1.36 mmol) in DMF (2 mL) is added epichlorohydrin (80 μL, 1.02 mmol) at room temperature. After 4 h at 20° C., the mixture is diluted with water (10 mL), and extracted with EtOAc (2×10 mL). The extracts are washed with water (2×20 mL), dried (MgSO4), filtered, and concentrated. The residue is chromatographed on SiO2 eluting with 50% EtOAc in heptane to afford [2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-[2-methoxy-6-(3-oxiranylmethoxy-phenyl)-pyrimidin-4-yl]-amine [0.16 g, Example 66]. LCMS: RT=2.62 minutes; MS: 464 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:2]=1.C(O)(=O)C.[CH3:16][C:17]([CH3:21])=[CH:18][CH:19]=[O:20]>C1COCC1>[CH3:16][C:17]([CH3:21])([N:10]1[CH:11]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=[CH:9]1)[CH2:18][CH:19]=[O:20]
Reactant: c1cncc(-c2c[nH]cn2)c1
Reactant: CC(C)=CC=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(CC=O)n1cnc(-c2cccnc2)c1

Procedure:
To a solution of 4-pyridin-3-yl-imidazole (1 g) in THF (34 mL) was added acetic acid (1.6 mL) and 3-methyl-2-butenal (3.3 mL) and the resulting solution was heated under gentle reflux for 24 hours. THF was then removed in vacuo and the residue was purified on a Flash 75 long column eluting with MeOH—CH2Cl2 to give the title compound as slightly yellow oil.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[CH:11]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18]C(C)(C)C)=[O:17])=[CH:14][C:13]=1[Cl:25])[CH2:8]2.FC(F)(F)C(O)=O>ClCCl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[CH:11]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:12]1[CH:24]=[CH:23][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=1[Cl:25])[CH2:8]2
Reactant: CC(C)(C)OC(=O)c1ccc(C(OCc2ccccc2)C2C3CC4CC(C3)CC2C4)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(C(OCc2ccccc2)C2C3CC4CC(C3)CC2C4)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 4-(adamantan-2-yl(benzyloxy)methyl)-3-chlorobenzoate (0.43 g, 1.05 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL) and the reaction mixture was stirred for 2 hour at ambient temperature. Removal of all volatiles under reduced pressure gave 4-(adamantan-2-yl(benzyloxy)methyl)-3-chlorobenzoic acid as an oily residue (0.43 g, quant.), which was used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[CH2:17][C:16]1([CH3:30])[CH3:29])=O)(C)(C)C>C(Cl)Cl>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:18]1[CH2:17][C:16]([CH3:29])([CH3:30])[NH:15][CH2:20][C:19]1=[O:21]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2ccccc2Cl)CC1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CN(c2ccccc2Cl)C(=O)CN1
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
7.0 ml of trifluoroacetic acid (91 mmol) was added to a solution of 3.07 g of 4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (1j) (9.1 mmol) in methylene chloride (14 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate aqueous solution was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=10/1) to obtain 2.14 g of the title compound (yield: 98%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].[Cl:11][C:12]1[C:13]([Cl:20])=[N:14][CH:15]=[C:16]([CH:19]=1)[CH:17]=O.CCO.C([BH3-])#N.[Na+]>CC(O)=O>[Cl:11][C:12]1[CH:19]=[C:16]([CH2:17][N:8]2[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]2)[CH:15]=[N:14][C:13]=1[Cl:20]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=Cc1cnc(Cl)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CS(=O)(=O)N1CCN(Cc2cnc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
1-methanesulfonylpiperazine (1.1 g, 6.8 mmol) followed by a catalytic amount of AcOH (0.020 mL, 0.34 mmol) were added to a stirred solution of 5,6-dichloronicotinaldehyde (1.20 g, 6.8 mmol) in EtOH (100 mL, 1713 mmol), the mixture was stirred at room temperature for 1 h (white precipitate formed), and the resulting suspension was treated portionwise with sodium cyanoborohydride (0.43 g, 6.8 mmol) (slightly exothermic) and stirred for another 2 h. The mixture was concentrated and quenched with 1 N HCl (aq), water (10 mL each) and EtOAc (50 mL). The separated aqueous layer was extracted with ethyl acetate (2×50 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a crude residue which was purified with flash column chromatography (ISCO Combiflash system, pure DCM to 3% 2 M NH3/MeOH in DCM) to give 1-((5,6-dichloropyridin-3-yl)methyl)-4-(methylsulfonyl)piperazine (1.16 g, 52%) as a white solid. LCMS (API-ES) m/z 325 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H) 7.78 (s, 1H) 3.54 (s, 2H) 3.26 (br. s., 4H) 2.80 (s, 3H) 2.57 (br. s., 4H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[NH2:14]>CO.O>[NH2:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:11]([NH2:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19]
Reactant: Nc1ccc([N+](=O)[O-])c(N)c1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CO
Solvent: O
Product: Nc1cc(Nc2ncc(F)c(Nc3ccc([N+](=O)[O-])c(N)c3)n2)ccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) was dissolved in a mixture of MeOH (1 ml) and H2O (0.1 ml). 3-amino-4-nitroaniline (184 mg, 1.2 mmol) was added and the mixture was refluxed for 3 days (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 2:1) to give N2,N4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6+CD3OD): δ 8.21 (d, 1H, J=2.9 Hz), 7.89 (m, 3H), 7.56 (d, 1H, J=2.3 Hz), 7.01 (m, 1H), 6.81 (dd, 1H, J=2.3, 9.4 Hz); LCMS: purity: 91.1%; MS (m/e): 401.00 (M+, 100).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[CH2:7](O)[CH2:8][OH:9]>>[C:1]([CH2:3][C:4]([O:6][CH2:7][CH2:8][OH:9])=[O:5])#[N:2]
Reactant: OCCO
Reactant: N#CCC(=O)O
Product: N#CCC(=O)OCCO
Yield: 74 %

Procedure:
Cyanoacetic acid was esterified with ethylene glycol according to U.S. Pat. No. 3,644,466 (col. 7-8, Ex. 3) to give the product in 74% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CN1CCNCC1
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: O
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
To a solution of 1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-one (4.96 g, 0.020 mol) in dichloroethane (50 ml) is added N-methylpiperazine (2.7 ml, 0.024 mol) at 0° C. and the mixture is stirred at room temperature. After 4 h, sodium triacetoxy-borohydride (5.04 g, 0.024 mol) is added and the mixture is further stirred at room temperature for 24 h. After addition of 1N sodium hydroxide at 0° C., the mixture is poured into water and extracted three times with dichloromethane. The organic layer is combined and extracted three times with 1N hydrochloride. The water layer is basified with 2N sodium hydroxide and extracted three times with dichloromethane. The organic layer is washed with brine, dried over sodium sulfate, and evaporated in vacuo to give the title compound as yellow solids (6.04 g) in 91% yield.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23]O)[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: OCc1ccc(Cl)c(Cl)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)c(Cl)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3,4-dichlorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.12 (2H, s), 5.66 (1H, d, J=1.6 Hz), 7.20 (1H, d, J=2.0 Hz), 7.35 (1H, dd, J=1.2, 5.2 Hz), 7.40 (1H, d, J=8.0 Hz), 7.52 (2H, m), 7.98 (1H, s), 8.64 (1H, d, J=4.8 Hz). [M+H] Calc'd for C16H10C12N4O, 345. Found, 345.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].Cl.[Cl:18][C:19]1[CH:20]=[C:21]([NH:31]C(=O)C2C=CN=C(OCC)C=2)[CH:22]=[CH:23][C:24]=1[C@H:25]1[O:30][CH2:29][CH2:28][NH:27][CH2:26]1>>[ClH:18].[Cl:18][C:19]1[CH:20]=[C:21]([NH:31][C:14]([C:12]2[CH:11]=[N:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[CH:13]=2)=[O:16])[CH:22]=[CH:23][C:24]=1[C@@H:25]1[O:30][CH2:29][CH2:28][NH:27][CH2:26]1
Reactant: CCOc1cc(C(=O)Nc2ccc([C@@H]3CNCCO3)c(Cl)c2)ccn1
Reactant: N#Cc1ccc(-n2cc(C(=O)O)cn2)cc1
Agent: Cl
Product: N#Cc1ccc(-n2cc(C(=O)Nc3ccc([C@H]4CNCCO4)c(Cl)c3)cn2)cc1

Procedure:
In analogy to example 83, step a) using 1-(4-cyanophenyl)-1H-Pyrazole-4-carboxylic acid (CAS 1152945-21-5) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-2-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (preparation described in example 91) instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester. Yellow solid. MS (ISP): 408.2 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]3[N:13]([C:14]=2[CH2:15][C:16](O)=[O:17])[C:12]2[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=2[S:10]3)=[CH:4][CH:3]=1.[NH3:23]>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]3[N:13]([C:14]=2[CH2:15][C:16]([NH2:23])=[O:17])[C:12]2[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=2[S:10]3)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2nc3sc4ccccc4n3c2CC(=O)O)s1
Reactant: N
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3sc4ccccc4n3c2CC(N)=O)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.6 g (0.005 mole) of 2-(5-methylthien-2-yl)imidazo[2,1-b]-benzothiazole-3-acetic acid are treated, at room temperature, with 0.85 g (0.005 mole) of N,N'-carbonyldiimidazole in 30 ml of anhydrous tetrahydrofuran for 3 h 30 min. The mixture is cooled using an ice bath, an excess of ammonia in 10 ml of anhydrous tetrahydrofuran cooled to -10° C. is added, and the mixture is stirred for 4 h at room temperature. The solvent is evaporated under reduced pressure, the solid is collected by filtration, it is washed with water up to neutral pH, then with ethanol, and finally with ethyl ether. After recrystallization from methanol, 1 g of a beige compound is obtained. Melting point: 243°-245° C.