Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][C@@H:8]([CH2:20]O)[NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:47]I>>[C:1]([O:5][C:6](=[O:22])[CH2:7][C@@H:8]([CH2:20][I:47])[NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C[C@@H](CO)NC(=O)OCc1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)C[C@@H](CI)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-benzyloxycarbonyl-3(S)-hydroxymethyl -β-alanine tert-butyl ester (2.0 g), triphenylphosphine (1.87 g), imidazole (0.66 g) and I2 (1-80 g) was stirred for 30 minutes at room temperature. The precipitate was filtered off and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with 5% (EtOAc/n-hexane) to give N-benzyloxycarbonyl-3(S)-iodomethyl-β-alanine tert-butyl ester (1.8 g) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]([C:10]1[C:14]([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[C:21]([I:23])[CH:20]=[N:19][C:18]=2[O:24][CH2:25][CH2:26][CH3:27])=[C:13]([CH2:29][CH3:30])[NH:12][N:11]=1)=[O:9].I[CH:32]1[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]1>CN(C)C=O>[NH2:7][C:8]([C:10]1[C:14]([NH:15][C:16]([C:17]2[C:18]([O:24][CH2:25][CH2:26][CH3:27])=[N:19][CH:20]=[C:21]([I:23])[CH:22]=2)=[O:28])=[C:13]([CH2:29][CH3:30])[N:12]([CH:32]2[CH2:33][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35]2)[N:11]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: CCCOc1ncc(I)cc1C(=O)Nc1c(C(N)=O)n[nH]c1CC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCOc1ncc(I)cc1C(=O)Nc1c(C(N)=O)nn(C2CN(C(=O)OC(C)(C)C)C2)c1CC
Temperature: 80 °C

Procedure:
Cesium carbonate (3.59 mmol) was added to a stirred solution of the product from stage b) (1.79 mmol) and the product from stage c) (2.15 mmol) in N,N-dimethylformamide (10 ml) under a nitrogen atmosphere. The mixture was heated at 80° C. for 24 h. The mixture was cooled and extracted from water with ethyl acetate. The organics were dried (MgSO4) and concentrated to give a brown oil. Purification by flash column chromatography (gradient elution from 100% dichloromethane to 90% dichloromethane/MeOH) gave the title product; 1H NMR (400 MHz, DMSO): δ=0.95 (t, 3H), 1.05 (t, 3H), 1.40 (s, 9H), 1.78-1.88 (m, 2H), 2.68 (q, 2H), 4.22-4.35 (m, 4H), 4.40 (t, 2H), 5.3 1H), 7.35 (bs, 1H), 7.52 (bs, 1H), 8.40 (s, 1H), 8.55 (s, 1H), 10.10 (s, 1H); LRMS (TSP—positive ion) 373.2 (MH+—BOC and I); Anal. Found C, 45.11; H, 5.07; N, 13.56 Calcd for C23H31O5N6I. 0.2 DCM: C, 45.28;H, 5.14; N, 13.66.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:12]([O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:28]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[N:27][N:26]=4)=[CH:20][CH:19]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:41][N:42]([CH3:49])[CH2:43][C:44]([CH3:48])([CH3:47])[CH2:45][NH2:46]>CS(C)=O>[CH3:41][N:42]([CH3:49])[CH2:43][C:44]([CH3:48])([CH3:47])[CH2:45][NH:46][C:5]1[N:10]=[C:9]([C:11]2[C:12]([O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]4[C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[C:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[N:27][N:26]=4)=[CH:20][CH:19]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CN(C)CC(C)(C)CN
Reactant: CS(=O)(=O)c1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)n1
Solvent: CS(C)=O
Product: CN(C)CC(C)(C)CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)n1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A resealable pressure vial was charged with N-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine (100 mg, 0.180 mmol) and N1,N1,2,2-tetramethylpropane-1,3-diamine (0.12 ml, 0.73 mmol) and DMSO (1.2 ml, 0.15 M). The reaction vessel was sealed and the mixture was stirred at 70° C. for 16 hrs. The reaction was cooled to RT and diluted with 3 ml of DMSO. The solution was purified by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA). The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with ethyl acetate. The organic portion was dried with Na2SO4, filtered, and concentrated to afford pure N-(4-(3-(2-(3-(dimethylamino)-2,2-dimethylpropylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)4-phenylphthalazin-1-amine as a yellow solid. MS m/z=597 [M+H]+. Calc'd for C36H36N8O: 596.72.
Reaction SMILES: C1(=O)[N:5]([CH:6]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:7][P:8]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:15]2=[O:26])([O:10][CH2:11][CH3:12])=[O:9])[C:4](=[O:34])[C:3]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:2]12.O.NN>O1CCOCC1>[C:4]([NH:5][CH:6]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:7][P:8]([NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:15]1=[O:26])([O:10][CH2:11][CH3:12])=[O:9])(=[O:34])[C:3]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:2]=1
Reactant: CCOC(=O)CN1CCC[C@H](NP(=O)(CC(Cc2ccccc2)N2C(=O)c3ccccc3C2=O)OCC)C1=O
Agent: NN
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CN1CCC[C@H](NP(=O)(CC(Cc2ccccc2)NC(=O)c2ccccc2)OCC)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (S)-3-[[[2-phthalimido-3-phenylpropyl]ethoxyphosphinyl]amino]-2-oxo-1-piperidineacetic acid, ethyl ester in dioxane is treated with hydrazine hydrate and stirred for 24 hours at room temperature. The mixture is then partitioned between ethyl acetate-water and the ethyl acetate phase is washed with water and saturated sodium chloride, dried (Na2SO4), and evaporated. The residue is taken up in dry toluene and refluxed for one hour. The mixture is filtered, treated with triethylamine and benzoyl chloride and stirred at room temperature for 30 minutes. The mixture is diluted with ethyl acetate, washed successively with 5% potassium bisulfate, saturated sodium bicarbonate, and saturated sodium chloride, dried (Na2SO4), and evaporated. The residue is chromatographed on silica gel to give (S)-3-[[[2-(benzoylamino)-3-phenylpropyl]ethoxyphosphinyl]amino]-2-oxo-1-piperidineacetic acid, ethyl ester.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:12]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(Cl)([Cl:21])=O.C(Cl)(Cl)Cl>C1C=CC=CC=1>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:12][Cl:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CO)cc1O[Si](C)(C)C(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc(CCl)cc1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Yield: 98.5 %

Procedure:
To a cooled solution of 3-[(tert-Butyldimethylsilyl)oxy]-4-methoxybenzyl alcohol 14 (9.5 g, 35.4 mmol) in benzene (50 mL) under nitrogen, thionyl chloride (6.32 g or 3.87 mL, 53.1 mmol) dissolved in benzene (5 mL) was added over 10 min and maintained the temperature at 0° C. for 2 h. The completion of reaction was checked by TLC (chloroform on silica gel plate). Ice was added to the reaction mixture and the solution was extracted with ethylacetate. The organic layer was washed with saturated bicarbonate solution and water and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded 15. Yield: 98.5%; yellow oil. 1H NMR: δ 0.16 (s, 6H, 2×CH3), 1.00 (s, 9H, 3×CH3), 3.80 (s, 3H, OCH3), 4.44 (s, 2H, CH2), 6.70-7.01 (m, 3H, Ar—H). Anal. Calcd for C14H23ClO2Si: C, 58.62, H, 8.08. Found: C, 58.69, H, 8.03.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([Cl:7])[C:4]([NH:8][C:9]2[NH:13][CH2:12][CH2:11][N:10]=2)=[C:3]([Cl:14])[CH:2]=1.Br[CH2:16][CH2:17][C:18]([CH3:20])=[CH2:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:14][C:3]1[CH:2]=[CH:1][CH:6]=[C:5]([Cl:7])[C:4]=1[N:8]([C:9]1[NH:10][CH2:11][CH2:12][N:13]=1)[CH2:16][CH2:17][C:18]([CH3:20])=[CH2:19]
Reactant: C=C(C)CCBr
Reactant: Clc1cccc(Cl)c1NC1=NCCN1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)CCN(C1=NCCN1)c1c(Cl)cccc1Cl
Temperature: 120 °C

Procedure:
A mixture of 6.9 gm (0.03 mol) of clonidine, 5.6 gm of 4-bromo-2-methyl-1-butene, and 5 ml of triethylamine in 25 ml of toluene was heated for 24 hours at 120° C. After cooling, the solvent was decanted, and the residue remaining was dissolved in 1 N hydrochloric acid. After extraction with ether several times (the ethereal extracts were abandoned), the solution was extracted with ether in fractions at stepwisely rising pH values (alkalizing with 2 N sodium hydroxide solution). The thin-layer chromatographically uniform ether extracts were united and dried over MgSO4, and the ether was evaporated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6](=[O:17])[C:5]2([C:20]1[C:21]([OH:29])=[CH:22][C:23]2[O:27][CH2:26][CH2:25][C:24]=2[CH:28]=1)[CH2:18]O.ClC1C=CC(Cl)=C2C=1C(C1C(O)=CC3OCOC=3C=1)(CO)C(=O)N2CCCCC>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6](=[O:17])[C:5]12[CH2:18][O:29][C:21]2[CH:22]=[C:23]3[C:24](=[CH:28][C:20]1=2)[CH2:25][CH2:26][O:27]3
Reactant: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)OCC3)c2cc(Cl)ccc21
Agent: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2c(Cl)ccc(Cl)c21
Product: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2cc(Cl)ccc21
Yield: 90 %

Procedure:
Following the procedure as described in EXAMPLE 1.22, and making non-critical variations using ethyl [5-chloro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate to replace 4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 90% yield as a colorless solid: MS (ES+) m/z 400.8 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].O.Br[C:9]1[N:13]([C:14]2[C:22]3[C:18](=[N:19][O:20][N:21]=3)[CH:17]=[CH:16][CH:15]=2)[C:12]([C:23]2[CH:24]=[N:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)=[N:11][N:10]=1>C(Cl)(Cl)Cl>[N:19]1[O:20][N:21]=[C:22]2[C:14]([N:13]3[C:12]([C:23]4[CH:24]=[N:25][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:27][CH:28]=4)=[N:11][N:10]=[C:9]3[N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:6])=[CH:15][CH:16]=[CH:17][C:18]=12
Reactant: CNCCOC
Reactant: Brc1nnc(-c2ccc(-c3ccccc3)nc2)n1-c1cccc2nonc12
Solvent: O
Solvent: ClC(Cl)Cl
Product: COCCN(C)c1nnc(-c2ccc(-c3ccccc3)nc2)n1-c1cccc2nonc12
Temperature: 160 °C
Reaction time: 6 h
Yield: 19 %

Procedure:
In a sealed tube, N-(2-methoxyethyl)methylamine (3 ml) and water (3 ml) were added to 4-[3-bromo-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzooxadiazol (336 mg) prepared in the Production Example 5, and stirred at 160° C. for 6 hours. After the reaction solution was cooled to ambient temperature, chloroform was added to the solution, which was then washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting solid was recrystallized from ethyl acetate, to afford the entitled compound as white crystal (66 mg, 19%). The physico-chemical values are as follows.
Reaction SMILES: [NH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[C:2]1=[S:13].[OH-].[Na+].Cl.Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>C(O)C>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[CH2:18][S:13][C:2]1[N:3]2[C:12]3[C:7]([CH2:6][CH2:5][CH2:4]2)=[CH:8][CH:9]=[CH:10][C:11]=3[N:1]=1
Reactant: S=c1[nH]c2cccc3c2n1CCC3
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc2nc(CSc3nc4cccc5c4n3CCC5)ccc2c1
Temperature: 25 °C
Yield: 55.4 %

Procedure:
A solution of 5,6-dihydro-4H-imidazo[4,5,1-ij]-quinoline-2(1H)-thione (2.02 g, 11.6 mmol) in ethanol (25 ml) and 1N-sodium hydroxide was treated with 2-(chloromethyl)quinoline hydrochloride (2.48 g, 11.6 mmol) heated to reflux, cooled to room temperature, and the ethanol removed by evaporation in vacuo. The aqueous mixture was filtered and the precipitate washed with water (5×50 ml), dried in vacuo, and recrystallised from cyclohexane - EtOAc to give 5,6-dihydro-2-(quinolin-2-ylmethylthio)-4H-imidazo[4,5,1-ij]quinoline (2.13 g, 55%) as yellow crystals mp 125°-126° C. (Found: C, 72.8; H, 5.3; N,12.4 C20H17N3S requires C, 72.5; H, 5.2; N, 12.7%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][NH:17][C:16](=[O:20])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.OC1(C2C=CC=CC=2)CCN(C2N=CNC(=O)N=2)CC1.CC1C=CC(S(O[CH2:53][N:54]2[CH:58]=[CH:57][C:56]([C:59]([F:62])([F:61])[F:60])=[N:55]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[OH:21][C:8]1([C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][N:17]([CH2:53][N:54]3[CH:58]=[CH:57][C:56]([C:59]([F:62])([F:61])[F:60])=[N:55]3)[C:16](=[O:20])[N:15]=2)[CH2:10][CH2:9]1
Reactant: O=c1nc(N2CCC(O)(c3ccc(Cl)cc3)CC2)nc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCn2ccc(C(F)(F)F)n2)cc1
Agent: O=C([O-])[O-]
Agent: O=c1nc(N2CCC(O)(c3ccccc3)CC2)nc[nH]1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(N2CCC(O)(c3ccccc3)CC2)ncn1Cn1ccc(C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 6.8 %

Procedure:
An N,N-dimethylformamide suspension (1.4 mL) of a mixture of 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1,3,5-triazin-2(1H)-one synthesized in Reference Synthesis Example 22a and 4-(4-hydroxy-4-phenylpiperidin-1-yl)-1,3,5-triazin-2(1H)-one (140 mg), [3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl 4-methylbenzenesulfonate (282 mg, 0.91 mmol) synthesized in Reference Synthesis Example 15, and potassium carbonate (252 mg, 1.83 mmol) was stirred at 80° C. for 3 hours. After completion of the reaction, water was added thereto and extraction with ethyl acetate from the resultant mixture was performed. The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/4 (v/v)) and preparative high-performance liquid chromatography to obtain the title compound (14 mg, yield 6.8%) in Reference Synthesis Example 91a and the title compound (7.4 mg, yield 3.9%) in Reference Synthesis Example 91b.
Reaction SMILES: CS[C:3]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:16][O:17][NH3+:18].[Cl-].C(N(CC)CC)C>C(O)C(C)C>[CH3:16][O:17][N:18]=[C:3]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:4][N+:5]([O-:7])=[O:6]
Reactant: CSC(=C[N+](=O)[O-])NCc1cccnc1
Reactant: CO[NH3+]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC(C)CO
Product: CON=C(C[N+](=O)[O-])NCc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
To 3 ml of isobutyl alcohol was added 0.75 g (0.0033 mole) of 1-methylthio-1-(3-pyridylmethyl)amino-2-nitroethylene, followed by addition of 0.56 g of 0-methylhydroxylamine hydrochloride at 100-110° C. Then, a solution of 0.93 ml of triethylamine in 1 ml of isobutyl alcohol was added dropwise at the same temperature with stirring over a period of 30 minutes. After completion of dropwise addition, the reaction mixture was allowed to cool to room temperature and the solvent was distilled off. The residue was purified by silica gel column chromatography [eluents: MeOH—CHCl3 (1:3) in the first run and MeOH—CHCl3 (1:10) in the second run] to give 0.23 g of the title compound as yellow crystals.
Reaction SMILES: Cl.[CH3:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:4]=1.[NH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20](Cl)[C:19]([Cl:26])=[CH:18][N:17]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[NH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20]([N:12]2[CH2:11][CH2:10][N:9]([CH2:8][C:5]3[N:4]=[C:3]([CH3:2])[O:7][N:6]=3)[CH2:14][CH2:13]2)[C:19]([Cl:26])=[CH:18][N:17]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: Cc1nc(CN2CCNCC2)no1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1nc(CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)no1
Temperature: 45 °C
Yield: 70.2 %

Procedure:
1-[(5-Methyl-1,2,4-oxadiazol-3-yl)methyl]piperazine hydrochloride (217 mg, 0.99 mmol) and 2-amino-4,5-dichloro-3-nitropyridine (208 mg, 1.0 mmol) were stirred in 2-propanol (5 mL) and diisopropylethylamine (523 μL, 387 mg, 3.0 mmol) was added. The mixture was stirred and heated at 45° C. for 23 h. The reaction was cooled and the product filtered off and washed with 2-propanol. Drying in vacuum gave the product (246 mg, 69%). 1H-NMR (500 MHz, CDCl3), 2.63 (s, 3H, CH3), 2.77 (br m, 4H, piperazine C—H), 3.29 (m, 4H, piperazine C—H), 3.76 (s, 2H, CH2), 5.27 (s, 2H, NH2), 8.02 (s, 1H, pyridine 6-H).
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13].[C:16](Cl)(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>N1C=CC=CC=1>[C:16]([O:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13])(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCC(=O)Cl
Reactant: On1c(C(F)(F)F)nc2ncc(Cl)cc21
Solvent: c1ccncc1
Product: CCCCCCCC(=O)On1c(C(F)(F)F)nc2ncc(Cl)cc21
Reaction time: 0.33 h

Procedure:
To 1-hydroxy-6-chloro-2-(trifluoromethyl)-1H-imidazo-(4,5-b)pyridine (2.37 grams) in 5 milliliters of pyridine was added octanoyl chloride (1.63 grams). The addition was carried out portionwise with stirring and resulted in the precipitation of a white solid. The reaction mixture was set on a steam bath for 20 minutes, then poured over ice cold aqueous HCl. An oil separated and subsequently crystallized on vigorous stirring. This precipitate was removed by filtration, dissolved in ether, dried over magnesium sulfate, filtered, and ether removed by evaporation under vacuum. The substance was purified by distillation, m.p., 33.5°-35.5°C.
Reaction SMILES: [CH:1]([O:4]C(C)C)(C)[CH3:2].[C:8]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)(=[O:11])[CH:9]=[CH2:10].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:8]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:1](=[O:4])[CH3:2])=[CH:18][CH:19]=1)(=[O:11])[CH:9]=[CH2:10]
Reactant: CC(C)OC(C)C
Reactant: C=CC(=O)OCc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: C=CC(=O)OCc1ccc(OC(C)=O)cc1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
1400 g of isopropyl ether, 100 g of 4-hydroxybenzyl acrylate and 53 g of pyridine were charged into a separable flask of the same type as used in Reference Example 3, and the flask inside gas was replaced with a nitrogen gas over 30 minutes, while ice cooling the flask. Then, 125 g of acetic anhydride was dropwise added thereto at 3° C. over 2 hours, and stirring was continued at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed with 0.5N hydrochloric acid and then with water. By distilling off isopropyl ether from the reaction mixture, 113 g of 4-acetoxybenzyl acrylate of the following chemical formula was obtained (yield:91%): ##STR2##
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])=[N:18][NH:19]2)=[CH:15][CH:14]=1)=O>>[O:10]=[C:2]1[NH:1][C:9]2[C:4](/[C:3]/1=[CH:11]\[C:13]1[CH:21]=[C:20]3[C:16]([C:17](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])=[N:18][NH:19]3)=[CH:15][CH:14]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=Cc1ccc2c(/C=C/C(=O)O)n[nH]c2c1
Reactant: O=C1Cc2ccccc2N1
Product: O=C(O)/C=C/c1n[nH]c2cc(/C=C3/C(=O)Nc4ccccc43)ccc12
Yield: 21.1 %

Procedure:
The title compound (7 mg, 21%) was synthesized as an orange solid according to the method described for Example A67 using oxindole (13.3 mg, 0.1 mmol) and (E)-3-(6-formyl-1H-indazol-3-yl)acrylic acid (21.6 mg, 0.1 mmol). NMR (400 MHz, DMSO-d6) δ 13.80 (br. s, 1H, NH), 10.64 (s, 1H, CO2H), 8.20 (d, J=8.4 Hz, 1H), 7.94 (s, 1H), 7.85 (d, J=16.4 Hz, 1H), 7.78 (s, 1H), 7.58-7.53 (m, 2H), 7.24 (t, J=7.6 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.84 (t, J=7.8 Hz, 1H), 6.75 (d, J=16.0 Hz, 1H); MS ESI 332.1 [M+H]+, calcd for [C19H13N3O3+H]+ 322.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[CH2:11][C@@H:10]([N:15]([CH3:23])[C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.O.[NH2:34][NH2:35]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[CH2:11][C@@H:10]([N:15]([CH3:23])[C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:34][NH:35]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: NN
Reactant: C[C@@H]1C[C@@H](N(C)C(=O)CC(C)(C)C)CN(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Solvent: O
Solvent: CCO
Product: C[C@@H]1C[C@@H](N(C)C(=O)CC(C)(C)C)CN(c2cc(-c3ccc4c(N)n[nH]c4c3)nc(N)n2)C1
Temperature: 120 °C
Reaction time: 4 h
Yield: 42.7 %

Procedure:
To N-{(3R,5R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-5-methyl-3-piperidinyl}-N,3,3-trimethylbutanamide (82 mg, 0.187 mmol) in ethanol (4 mL) was added hydrazine monohydrate (1 mL, 20.4 mmol), and the reaction mixture was stirred for 4 hours at 120° C. into a sealed vessel. The reaction was allowed to cool down to room temperature, and poured onto water (˜120 mL). The resulting aqueous mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound (36 mg) as an off-white solid as a 3:2 mixture of rotamers. LC-MS (ES) m/z=451 [M+H]+. 1H NMR (400 MHz, DMSO-d6+1 drop D2O): δ 0.98 (m, 12H), 1.41 and 1.52 (m, 1H), 1.87-2.41 (m, 4H), 2.76 and 2.90 (s, 3H), 2.99-3.25 (m, 2H), 3.84-3.99 (m, 1H), 4.01-4.26 (m, 1H), 4.39-4.66 (m, 1H), 6.57-6.62 (s, 1H), 7.50-7.60 (m, 1H), 7.70 (m, 1H), 7.92 (s, 1H).
Reaction SMILES: ClC1C=CC=CC=1.Cl.[F:9][C:10]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=1[NH2:12].[C:18]12([NH:28][C:29]#[N:30])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2>Cl.CO>[C:18]12([NH:28][C:29]([NH:12][C:11]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:10]=3[F:9])=[NH:30])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2
Reactant: N#CNC12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc(F)cc1F
Agent: Cl
Solvent: CO
Solvent: Clc1ccccc1
Product: N=C(Nc1ccc(F)cc1F)NC12CC3CC(CC(C3)C1)C2

Procedure:
A single neck glass 100 ml round bottom flask was charged with chlorobenzene (20 ml), 2,4-difluoroaniline hydrochloride (prepared from the free base, Aldrich, by dissolving in 5% HCl in MeOH and concentrating, 2.0 g, 12 mmol) and 1-adamantylcyanamide (2.13 g, 12 mmol).