Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[CH:9][CH:8]=1)(=O)=O.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[ClH:46].[N:47]12[CH2:54][CH2:53][CH:50]([CH2:51][CH2:52]1)[C@H:49]([NH:55][C:56]([C:58]1[S:59][C:60]3[C:66](Br)=[CH:65][CH:64]=[CH:63][C:61]=3[CH:62]=1)=[O:57])[CH2:48]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:46].[N:47]12[CH2:52][CH2:51][CH:50]([CH2:53][CH2:54]1)[C@H:49]([NH:55][C:56]([C:58]1[S:59][C:60]3[C:66]([C:7]4[CH:8]=[CH:9][C:10]([C:13]([N:15]5[CH2:16][CH2:17][O:18][CH2:19][CH2:20]5)=[O:14])=[CH:11][CH:12]=4)=[CH:65][CH:64]=[CH:63][C:61]=3[CH:62]=1)=[O:57])[CH2:48]2
Reactant: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Reactant: O=C(c1ccc(OS(=O)(=O)C(F)(F)F)cc1)N1CCOCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cccc(-c3ccc(C(=O)N4CCOCC4)cc3)c2s1

Procedure:
244.0 mg (0.65 mmol) of 4-(4-morpholinylcarbonyl)phenyl trifluoromethanesulphonate (Example 18A), 189.6 mg (0.75 mmol) of bis(pinacolato)diboron, 158.8 mg (1.62 mmol) of potassium acetate, 18.2 mg (0.02 mmol) of PdCl2(dppf), 200.0 mg (0.50 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 22A), 1.24 ml of 2 M sodium carbonate solution and a further 18.2 mg (0.02 mmol) of PdCl2(dppf) in 2.5 ml of DMF are reacted by general method D. Drying under high vacuum results in 76.8 mg (30.1% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:11]=[N:12][CH:13]=2)=[C:6]([NH:26][C@H:27]([C:29]2[N:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:33](=[O:41])[C:32]3=[C:42]([CH3:45])[CH:43]=[CH:44][N:31]3[N:30]=2)[CH3:28])[N:5]=[CH:4][N:3]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:11]=[N:12][CH:13]=2)=[C:6]([NH:26][C@H:27]([C:29]2[N:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:33](=[O:41])[C:32]3=[C:42]([CH3:45])[CH:43]=[CH:44][N:31]3[N:30]=2)[CH3:28])[N:5]=[CH:4][N:3]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cncc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cncc(NS(=O)(=O)c4ccc(O)cc4)c3)n(-c3ccccc3)c(=O)c12
Yield: 15 %

Procedure:
(S)—N-(5-(4-Amino-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)pyridin-3-yl)-4-methoxybenzenesulfonamide (132 mg, 0.11 mmol) was treated with boron tribromide (1M in dichloromethane, 337 μl, 0.34 mmol) in dichloromethane (10 ml) according to the method described in Example 23. The residue was purified by reverse phase using SP1® Purification System to give 10 mg (15% yield) as a solid. Purity 99%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:27]=[CH:28][C:29]([C:2]3[CH:7]=[C:6]([O:8][C:9]4[C:10]([CH3:18])=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=4)[CH:5]=[CH:4][N:3]=3)=[CH:30][CH:31]=2)[CH2:22][CH2:21]1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
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: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(-c2ccc(N3CCN(C)CC3)cc2)c1
Temperature: 90 °C
Yield: 32.2 %

Procedure:
A mixture of Example A6 (0.676 g, 2.55 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (1 g, 3.31 mmol), K2CO3 (1.055 g, 7.64 mmol) and Pd(PPh3)4 (0.147 g, 0.127 mmol) in dioxane (8 mL) was sparged with Ar and heated at 90° C. overnight. The mixture was cooled to RT, treated with brine, extracted with EtOAc (4×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 1-methyl-4-(4-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)phenyl)piperazine (333 mg, 32%). 1H NMR (400 MHz, DMSO-d6): δ 8.55 (d, J=5.6 Hz, 1 H), 8.22 (d, J=8.7 Hz, 1 H), 7.95 (d, J=8.8 Hz, 2 H), 7.81 (d, J=8.7 Hz, 1 H), 7.58 (d, J=2.3 Hz, 1 H), 6.98 (d, J=8.8 Hz, 2 H), 6.94 (dd, J=5.6, 2.3 Hz, 1 H), 3.24-3.18 (m, 4 H), 2.52 (s, 3 H), 2.45-2.41 (m, 4 H), 2.21 (s, 3H); MS (ESI) m/z: 406.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[N:11]1>>[CH2:8]([C:5]1[CH:4]=[CH:3][C:2]([N:11]2[N:12]=[CH:13][CH:14]=[N:10]2)=[CH:7][N:6]=1)[CH3:9]
Reactant: CCc1ccc(Br)cn1
Reactant: c1c[nH]nn1
Product: CCc1ccc(-n2nccn2)cn1

Procedure:
The title compound was prepared from 5-bromo-2-ethylpyridine (Preparation 65) and 1,2,3-triazole by a similar method to Preparation 1. The regioisomeric product were separated by column chromatography on silica by gradient elution with ethyl acetate/hexane (1:1→1:0). Fractions containing the title compound eluted first, these were combined and evaporated under reduced pressure to yield an oil, which was distilled b.p.135° C. @ 0.05 mmHg (Kugelrohr).
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:61][C:62]([F:78])([F:77])[C:63]1[CH:64]=[C:65]([C:69]2[O:73][C:72]([C:74](O)=[O:75])=[CH:71][CH:70]=2)[CH:66]=[CH:67][CH:68]=1>CN(C=O)C.O>[O:20]=[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]1)[CH2:18][NH:17][C:74]([C:72]1[O:73][C:69]([C:65]2[CH:66]=[CH:67][CH:68]=[C:63]([C:62]([F:78])([F:61])[F:77])[CH:64]=2)=[CH:70][CH:71]=1)=[O:75]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(-c2cccc(C(F)(F)F)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2cccc(C(F)(F)F)c2)o1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 36.1 %

Procedure:
DIPEA (75 mg, 0.1 mL, 0.59 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt (100 mg, 0.23 mmol) in DMF (1 mL). HOBT (32 mg, 0.23 mmol) and EDCI.HCl (44 mg, 0.23 mmol) were then added at room temperature. After 2 minutes, 5-(3-trifluoromethyl-phenyl)-furan-2-carboxylic acid (50 mg, 0.20 mmol) was added. The resulting mixture was stirred at room temperature for four hours. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 40 mg (37% yield) of 5-(3-trifluoromethyl-phenyl)-furan-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity %: 86.88, HPLC 92.52%, 1H NMR (DMSO-d6): δ 8.8-8.7 (bt, 1H), 8.3 (s, 1H), 8.2 (bt, 1H), 7.9-7.6 (m, 5H), 7.6-7.5 (bt, 1H), 7.4-7.3 (d, 1H), 7.3-7.2 (m, 1H), 4.3-4.1 (m, 2H), 3.8-3.4 (m, 6H), 3.2-3.1 (m, 2H).
Reaction SMILES: C([O-])=O.[NH4+].[N+:5]([C:8]1[C:17]2[O:16][CH2:15][CH2:14][O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-])=O>CO>[O:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([NH2:5])[C:17]=2[O:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1cccc2c1OCCO2
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1cccc2c1OCCO2
Yield: 74 %

Procedure:
Ammonium formate (3.40 g, 0.054 mol) and 10% passadium on charcoal (1.44 g) were added to a stirred solution of the product of Example 1 (2.45 g, 0.0135 mol) in methanol (15 ml). After the considerable effervescence had ceased, the mixture was filtered, evaporated in vacuo and triturated with acetonitrile. The residue was purified by chromatography (silica; ether) to give the product (1.51 g).
Reaction SMILES: [CH3:1][C:2]1(C)[CH2:7][CH2:6][N:5]([C:8]2[N:13]3[CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=[C:12]3[CH:11]=[C:10]([CH3:22])[C:9]=2[C@H:23]([OH:28])[C:24]([O:26][CH3:27])=[O:25])[CH2:4][CH2:3]1>C(Cl)Cl.C(OC(C)(C)C)(=O)C>[CH2:17]([O:18][C:2]1([CH3:1])[CH2:7][CH2:6][N:5]([C:8]2[N:13]3[CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=[C:12]3[CH:11]=[C:10]([CH3:22])[C:9]=2[C@H:23]([O:28][C:2]([CH3:7])([CH3:3])[CH3:1])[C:24]([O:26][CH3:27])=[O:25])[CH2:4][CH2:3]1)[CH:15]=[CH2:14]
Reactant: CCOC(=O)c1cn2c(N3CCC(C)(C)CC3)c([C@H](O)C(=O)OC)c(C)cc2n1
Solvent: CC(=O)OC(C)(C)C
Solvent: ClCCl
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(C(=O)OCC)cn23)CC1
Reaction time: 2 h
Yield: 84.2 %

Procedure:
(S)-Ethyl 5-(4,4-dimethylpiperidin-1-yl)-6-(1-hydroxy-2-methoxy-2-oxoethyl)-7-methylimidazo[1,2-a]pyridine-2-carboxylate (1.3 g, 3.22 mmol, 1 equiv) was suspended in DCM (3 mL) and tert-butyl acetate (10 mL). To this mixture was added 70% HClO4 (0.831 mL, 9.67 mmol, 3 equiv) through sealed rubber stopper. After 2 h, LCMS indicated about 60% conversion. The reaction was washed with 1 N NaOH, dried (Na2SO4), and concentrated in vacuo. The crude product was purified via silica gel flash chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (0.68 g, 46%). 1H NMR (400 MHz, CDCl3) 8.22 (d, J=0.8 Hz, 1H), 7.31 (s, 1H), 6.02 (s, 1H), 4.47 (q, J=7.2 Hz, 2H), 3.70 (s, 3H), 3.60 (td, J=11.4, 2.8 Hz, 1H), 3.49 (td, J=11.5, 2.6 Hz, 1H), 3.10 (dt, J=11.9, 3.5 Hz, 1H), 2.95-2.86 (m, 1H), 2.44 (d, J=1.0 Hz, 3H), 1.73-1.48 (m, 7H), 1.45 (t, J=7.0 Hz, 4H), 1.24 (s, 10H), 1.15 (s, 3H), 1.08 (s, 3H); LCMS (ESI, M+1): 502.35.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].N1CC[C@H:23]([OH:26])[CH2:22]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:19][CH2:22][C@H:23]([OH:26])[CH2:20]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: O[C@H]1CCNC1
Reactant: COc1cc(N2CCC(N(C)C)CC2)ccc1[N+](=O)[O-]
Product: COc1cc(N2CCC(N3CC[C@H](O)C3)CC2)ccc1[N+](=O)[O-]

Procedure:
(S)-1-[1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-yl]-pyrrolidin-3-ol was prepared in an analogous fashion to [1-(3-Methoxy-4-nitro-phenyl)-piperidine-4-yl]dimethyl-amine of Example 475a replacing Dimethylamine with (S)-Pyrrolidin-3-ol. The crude material was purified via trituration with Et2O to yield a yellow solid, MP 137-139° C. (197 mg, 51%). LC/MS (E/I+) 322.14 (M+H).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][O:5][CH:4]1[CH2:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[OH:11].[CH3:19]I>C1COCC1>[CH3:19][O:11][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:9][CH2:8][CH:4]1[O:5][CH2:6][CH2:7][O:3]1
Reactant: Cc1ccccc1C(O)CCC1OCCO1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(CCC1OCCO1)c1ccccc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
To a suspension of NaH (468 mg of a 60% dispersion in mineral oil, 11.7 mmol) in 35 mL THF was slowly added 3-[1,3]Dioxolan-2-yl-1-o-tolyl-propan-1-ol (290.0 mg, 1.3 mmol) as a solution in 15 mL THF at room temperature followed by the dropwise addition of methyl iodide (624 L, 1.4 g, 9.6 mmol). The mixture was stirred for 3 h at room temperature before being quenched by the careful addition of saturated aqueous NH4Cl (40 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL) and the combined organic layers washed with brine (2×20 mL) and dried over sodium sulfate. The solvents were evaporated under reduced pressure and the product isolated by flash column chromatography eluting with 0% to 30% ethyl acetate/hexane to give 285 mg of the title compounds as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[I-].[Na+].ICCCCC(OC)=O.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1C=CC=CC=1.CC(C)=O>[N:21]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)CCCCCl
Reactant: C1CCNCC1
Agent: COC(=O)CCCCI
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: COC(=O)CCCCN1CCCCC1

Procedure:
A mixture of 0.167 mole of methyl δ-chlorovalerate and 0.25 mole of sodium iodide in 120 ml. of acetone is stirred and heated at reflux for 16 hours. After cooling the mixture, a solid is removed by suction filtration, and the acetone is distilled off using a rotary evaporator. The residue is dissolved in 300 ml. of diethyl ether, and additional solid is removed by filtration. The ethereal solution is washed twice with a 10% sodium thiosulfate solution, one with water and dried over sodium sulfate. The ether is evaporated and the residue distilled at b.p. 107°-110° C. (15 mm.) to give 30.0 g. (74%) of methyl δ-iodovalerate as a light yellow liquid. 30.0 g. (0.124 mole) of methyl δ-iodovalerate and 42.5 g. (0.50 mole) of piperidine are dissolved in 250 ml. of benzene and heated at 60° C. for 3 hours with stirring. A colorless solid begins to appear shortly after the materials are combined. The solid is removed by suction filtration, and the benzene evaporated to give methyl δ-piperidinovalerate which distills as 23.5 g. (95%) of colorless liquid, b.p., 122°-24° C. (12.5 mm.).
Reaction SMILES: C([O:3][C:4](=[O:28])/[C:5](=[N:25]\[O:26][CH3:27])/[C:6]1[S:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)C.[OH-].[Na+]>CO.O1CCCC1>[CH3:27][O:26]/[N:25]=[C:5](/[C:6]1[S:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)\[C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)/C(=N\OC)c1ccc(OCCOc2ccc3ccccc3c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)O)c1ccc(OCCOc2ccc3ccccc3c2)s1
Temperature: 53 °C
Yield: 76.4 %

Procedure:
As in Example 306, a solution of (E)-alpha-(methoxyimino)-5-[2-(2-naphthalenyloxy) ethoxy]-2-thiopheneacetic acid ethyl ester (0.2 g) in methanol (2 mL) and tetrahydrofuran (1 mL) was treated with 3N sodium hydroxide (0.5 mL) and the stirred mixture was heated at 53° C. for 30 minutes. After the normal work up, the product was crystallized from dichloromethane-hexane to furnish 0.142 g of (E)-alpha-(methoxyimino)-5-[2-(2-naphthalenyloxy)ethoxy]-2-thiopheneacetic acid, mp 118°-120° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19].[OH-].[Na+]>O>[C:18]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH:9]=[CH:10][C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1)(=[O:20])[CH3:19]
Reactant: Nc1ccccc1C(=O)C=Cc1ccncc1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccccc1C(=O)C=Cc1ccncc1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
45 g of 1-(2-aminophenyl) 3-(4-pyridyl) 2-propene-1-one (product of Example 14) are contacted with 13.5 ml of acetic anhydride. After 10 minutes at 100° C., the solution obtained is cooled, diluted with 80 ml of water, then the pH is slowly adjusted to 6 (while maintaining the temperature at 5° C.) by the addition of a concentrated solution of sodium hydroxide. After stirring for one hour, the precipitate formed is filtered, washed with water, then dried at 80° C. under vacuum. 53 g of 1-(2-acetylaminophenyl) 3-(4-pyridyl) 2-propene-1-one which melts at 130° C. are obtained.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][CH2:5][CH2:6][CH2:7][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9](OC)=[O:10]>C(O)C>[Cl:4][CH2:5][CH2:6][CH2:7][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([NH:2][NH2:3])=[O:10]
Reactant: COC(=O)C(CCCCl)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)C(CCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl phenylacetate (2.0 g) in DMF (5 mL) was added to a solution of sodium hydride (containing mineral oil at 40%, 590 mg) in DMF (20 mL) under ice-cooling. The reaction solution was stirred for 10 minutes, further stirred at room temperature for 30 minutes and then ice-cooled again. A solution of 1-chloro-3-iodopropane (2.99 g) in DMF (5 mL) was added to the reaction mixture, and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The resulting organic layer washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain a crude product of methyl 5-chloro-2-phenylpentanoate. Hydrazine monohydrate (8 mL) was added to a solution of the resulting crude methyl 5-chloro-2-phenylpentanoate (3.279 g) in ethanol (20 mL), and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. Saturated sodium bicarbonate water and ethyl acetate and were added to the residue, and the organic layer was separated. The resulting organic layer washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 730 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[S:10][C:9]([OH:11])=[N:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:5])[CH3:4]>C(Cl)Cl.C(O)(=O)C>[Br:1][CH2:4][C:3]([C:6]1[S:10][C:9]([OH:11])=[N:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5]
Reactant: BrBr
Reactant: CCOC(=O)c1nc(O)sc1C(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1nc(O)sc1C(=O)CBr
Yield: 94.7 %

Procedure:
A solution of bromine (10.8 g) in methylene chloride (5 ml) was dropwise added to a solution of ethyl 5-acetyl-2-hydroxy-4-thiazolecarboxylate (12.9 g) in a mixture of methylene chloride (150 ml) and acetic acid (10 ml) at 30° C. to 35° C. with stirring and the mixture was stirred at the same temperature for 30 minutes. An insoluble material was filtered off. The filtrate was washed brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with diisopropyl ether to give ethyl 5-(2-bromoacetyl)-2-hydroxy-4-thiazolecarboxylate (16.7 g). mp 105°-108° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH2:21][CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[N:9]=[C:10]([NH:11][C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:5]2=[CH:4][N:3]=1.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(O)(C(F)(F)F)=O>O1CCOCC1>[Cl:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:19])[C:12]=1[NH:11][C:10]1[C:5]2[C:6](=[N:7][C:2]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:3][CH:4]=2)[N:8]([CH2:20][CH2:21][CH:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]2)[N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCn2nc(Nc3c(Cl)cccc3Cl)c3cnc(Cl)nc32)CC1
Reactant: Nc1ccccc1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(Cl)c1Nc1nn(CCC2CCNCC2)c2nc(Nc3ccccc3)ncc12

Procedure:
A solution of 48.5 mg (0.09 mmol) of tert-butyl 4-(2-(6-chloro-3-(2,6-dichlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)piperidine-1-carboxylate 93 in 5 mL 1,4-dioxane was treated sequentially with 17 μl (0.2 mmol) of aniline and 525 μl (7.1 mmol) of TFA. The resulting orange solution was heated at reflux for 22 h, and then was concentrated. The residue was purified by chromatography on silica gel (CH2Cl2:MeOH, 9:1) to give the title compound 94. 1H-NMR (CD3OD) δ 1.22-1.45 (m, 3H), 1.66-1.78 (m, 2H), 1.91-2.02 (m, 2H), 2.10 (s, 1H), 2.62-2.74 (m, 2H), 3.10-3.23 (m, 2H), 4.15 (t, J=6.3 Hz, 2H), 6.99 (t, J=8.0 Hz, 1H), 7.19 (t, J=8.1 Hz, 1H), 7.23-7.31 (m, 2H), 7.42 (t, J=8.5 Hz, 2H), 7.71 (d, J=8.5 Hz, 2H), 8.56 (s, 1H). Mass Spectrum (ESI) m/e=482.0 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[Cl:17][C:18]1[C:26]([Cl:27])=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([NH:28][S:29]([C:32]2[C:33]3[N:34]=[CH:35][CH:36]=[N:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)(=[O:31])=[O:30])[CH:19]=1.N1C2C=CC=C(S(Cl)(=O)=O)C=2N=CC=1>>[CH3:2][O:3][C:4](=[O:16])[C@@H:5]([NH:6][C:22](=[O:23])[C:21]1[CH:25]=[C:26]([Cl:27])[C:18]([Cl:17])=[CH:19][C:20]=1[NH:28][S:29]([C:32]1[C:33]2[N:34]=[CH:35][CH:36]=[N:37][C:38]=2[CH:39]=[CH:40][CH:41]=1)(=[O:31])=[O:30])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: Cl
Agent: O=S(=O)(Cl)c1cccc2nccnc12
Product: COC(=O)[C@H](Cc1ccc(F)c(Br)c1)NC(=O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
The title compound was prepared from 3-bromo-4-fluoro-L-phenylalanine methyl ester hydrochloride and 4,5-dichloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid (prepared from quinoxaline-5-sulfonyl chloride as in EXAMPLE 14, Part A) as in Example 1, Part C. HPLC: RT=10.50 min. MS (ESI−): mass calcd. for C25H18BrCl2FN4O5S, 656.31; m/z found, 653/655/657 [M−H]−. 1H NMR (400 MHz, CDCl3): 10.99 (s, 1H), 8.96 (d, J=1.7, 1H), 8.93 (d, J=1.7, 1H), 8.55 (dd, J=7.3, 1.1, 1H), 8.33 (dd, J=8.5, 1.1, 1H), 7.91-7.85 (m, 2H), 7.31-7.22 (m, 2H), 7.07-6.94 (m, 2H), 6.52 (d, J=7.3, 1H), 4.89 (q, J=5.8, 1H), 3.81 (s, 3H), 3.21-3.08 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH:30]=[C:29]([NH2:31])[CH:28]=[N:27]1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][C:29]4[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: Cn1cc(N)cn1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)Nc2cnn(C)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (224 mg, 0.65 mmol) and 1-methyl-1H-pyrazol-4-ylamine (0.65 mmol) in THF (6 mL) at 0° C. were added 1-hydroxybenzotriazole hydrate (100.8 mg, 0.65 mmol), N-ethyldiisopropylamine (281.7 μl, 1.613 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidazole hydrochloride (126.2 mg, 0.65 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=3:1 to 1:4) afforded the title compound (201 mg, 73%) which was obtained as a white solid. MS: m/e=424.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:10]([CH3:12])=[CH2:11])[CH2:7][CH2:6][CH:5]([CH3:8])[CH2:4][C:3]1=[O:9].[CH:13](=[N:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH2:13]([N:17]1[CH:18]([CH2:19][CH2:20][CH3:21])[CH2:12][C:10]([CH3:11])=[C:2]([CH3:1])[CH2:7][CH2:6][C@H:5]([CH3:8])[CH2:4][C:3]1=[O:9])[CH2:14][CH2:15][CH3:16]
Reactant: C=C(C)C1(C)CCC(C)CC1=O
Reactant: CCCC=NCCCC
Agent: CCCCN1C(=O)C[C@@H](C)CC/C(C)=C(\C)CC1CCC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCCCN1C(=O)C[C@@H](C)CCC(C)=C(C)CC1CCC

Procedure:
Following the general procedure as described in Example 17, 2,5-dimethyl-2-(prop-1-en-2-yl)cyclohexanone (1.06 g, 6.38 mmol), N-butylidenebutan-1-amine (0.97 g, 7.65 mmol), and SnCl4 (1.66 g, 6.38 mmol) in 1,2-dichloroethane (65 ml) were reacted to give the title product as a colorless liquid (1.28 g, 76% yield). 3 isomers in a ratio of 1:2:8.