Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[C:40]([C:42]([NH:44][CH2:45][C:46]([OH:48])=O)=[O:43])[N:39]=[N:38]2)[CH:32]=1.NC1C=NC=CC=1.Cl.[F:57][C:58]1[CH:59]=[C:60]([CH:66]=[C:67]([C:69]([F:72])([F:71])[F:70])[CH:68]=1)[O:61][CH:62]1[CH2:65][NH:64][CH2:63]1>CN(C=O)C>[F:57][C:58]1[CH:59]=[C:60]([CH:66]=[C:67]([C:69]([F:71])([F:70])[F:72])[CH:68]=1)[O:61][CH:62]1[CH2:65][N:64]([C:46](=[O:48])[CH2:45][NH:44][C:42]([C:40]2[N:39]=[N:38][N:37]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)[CH:41]=2)=[O:43])[CH2:63]1
Reactant: O=C(O)CNC(=O)c1cn(-c2cccnc2)nn1
Reactant: Fc1cc(OC2CNC2)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CC(Oc2cc(F)cc(C(F)(F)F)c2)C1)c1cn(-c2cccnc2)nn1
Reaction time: 0.03 h
Yield: 16.4 %

Procedure:
DIPEA (143 mg, 1.1 mmol) followed by HOBt (39 mg, 0.29 mmol) and EDCI (56 mg, 0.29 mmol) was added to a stirred solution of [(1-pyridin-3-yl-1H-[1,2,3]triazole-4-carbonyl)-amino]-acetic acid (prepared by the method used for the synthesis of Intermediate 64, starting from 3-aminopyridine, and subsequently, application of Step 3 of the General Scheme) (68.3 mg, 0.27 mmol) in DMF (2 mL). After 2 minutes of stirring, 3-(3-fluoro-5-trifluoromethyl-phenoxy)-azetidine hydrochloride (prepared by the method used for the synthesis of Intermediate 71) (75 mg, 0.27 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between cold water and ethyl acetate. The organic layer was, dried over sodium sulfate and concentrated under reduced pressure. Purification by preparative HPLC afforded 21 mg (16.4% Yield) of 1-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylic acid {2-[3-(3-fluoro-5-trifluoromethyl-phenoxy)-azetidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 465, 93.03%. 1H NMR (300 MHz, DMSO-d6): δ 9.5 (s, 1H), 9.2 (d, 1H), 8.7 (m, 2H), 8.4 (m, 1H), 8.3 (s, 1H), 7.65 (m, 1H), 7.3 (d, 1H), 7.1 (m, 2H), 5.2 (m, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 4.2 (m, 1H), 3.8 (m, 3H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[NH2:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[C:20](O)(=[O:24])[C:21](O)=[O:22]>Cl>[CH:1]1([N:7]2[C:8]3[C:9](=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=3)[NH:17][C:21](=[O:22])[C:20]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cc([N+](=O)[O-])ccc1NC1CCCCC1
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2n(C2CCCCC2)c1=O
Temperature: 25 °C
Yield: 22.3 %

Procedure:
A mixture of 0.9 g (3.1 mmol) N-cyclohexyl-2-amino-4-nitroaniline and 1.0 g (7.9 mmol) oxalic acid dihydrate in 50 ml 4 N hydrochloric acid was refluxed for 5 h. After cooling to 25° C. the product was filtered off. The crude product was recrystallized (ether-water) to give 0.2 g (19%) 1-cyclohexyl-6-nitroquinoxaline-2,3(1H,4H)-dione. M.p. (DSC): decomp. 1H-NMR (DMSO-d6): 12.2 (1H, broad s), 8.1-7.7 (3H, m), 3.0-1.0 (11H, m).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[C:17]1([CH:22]=[CH2:23])[CH2:21][CH2:20][CH2:19][CH2:18]1)(=O)=O.[F:26][C:27]1[C:28](B(O)O)=[CH:29][C:30]([O:33][CH3:34])=[N:31][CH:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:26][C:27]1[C:28]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=2[C:17]2([CH:22]=[CH2:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:29][C:30]([O:33][CH3:34])=[N:31][CH:32]=1
Reactant: C=CC1(c2cc(C(=O)OC)ccc2OS(=O)(=O)C(F)(F)F)CCCC1
Reactant: COc1cc(B(O)O)c(F)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Product: C=CC1(c2cc(C(=O)OC)ccc2-c2cc(OC)ncc2F)CCCC1
Temperature: 90 °C

Procedure:
The reaction mixture of methyl 4-(trifluoromethylsulfonyloxy)-3-(1-vinylcyclopentyl)benzoate 26.4 (0.29 g, 0.8 mmol), 5-fluoro-2-methoxypyridin-4-ylboronic acid (0.2 g, 1.0 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA), potassium phosphate (0.5 g, 2.0 mmol), S-phos (0.06 g, 0.2 mmol) and palladium acetate (0.02 g, 0.08 mmol) in DMF (1.5 mL) was purged with nitrogen three times. The resulting mixture was heated at 90° C. for 2 hours. After work up, the product was purified by CombiFlash® silica gel column chromatography, eluting with hexane/EtOAc 9/1, to give the compound 26.5. 1H NMR (500 MHz, CDCl3) δ ppm 8.20 (1H, d, J=1.7 Hz), 8.00 (1H, s), 7.91 (1H, dd, J=7.8, 1.7 Hz), 7.10 (1H, d, J=8.1 Hz), 6.63 (1H, d, J=4.9 Hz), 5.87 (1H, dd, J=17.4, 10.5 Hz), 4.97 (1H, d, J=10.5 Hz), 4.69 (1H, d, J=17.4 Hz), 3.98 (3H, s), 3.85 (3H, s), 2.00-2.20 (1H, m), 1.80-1.96 (1H, m), 1.51-1.75 (6H, m). MS ESI (pos.) m/e: 355.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]#[C:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]([CH3:22])[CH:12]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C([Si](C)(C)C)#C.BrC1C(N)=NC=C(Br)N=1.IC1C2C(=CC=C(OC)C=2)N(C)C=1.CC([O-])(C)C.[K+]>O.CN1C(=O)CCC1>[Br:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:10]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH3:22])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc2c(c1)c(C#Cc1nc(Br)cnc1N)cn2C
Agent: C#C[Si](C)(C)C
Agent: CC(C)(C)[O-]
Agent: COc1ccc2c(c1)c(I)cn2C
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc2c(c1)c(-c1cc3nc(Br)cnc3[nH]1)cn2C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60 %

Procedure:
To a round bottom flask was added 5-bromo-3-((5-methoxy-1-methyl-1H-indol-3-yl)ethynyl)pyrazin-2-amine (11.1 g, 30.9 mmol, prepared using General Procedure A from ethynyltrimethylsilane with 3,5-dibromopyrazine-2-amine, Q, A with 3-iodo-5-methoxy-1-methyl-1H-indole (Preparation #11, Step A), NMP (100 mL) and KOt-Bu (6.94 g, 61.9 mmol). The mixture was stirred at rt for about 45 min and then warmed to about 45° C. for about 1.25 h. The mixture was cooled to about 0° C. and then diluted with water (550 mL). The solid was collected by filtration and washed with water (100 mL). The material was dried under vacuum at about 65° C. overnight to give 2-bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine (6.61 g; 60%): LC/MS (Table 2, Method a) Rt=2.47 min; MS m/z 357 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH:7]=[CH:6][C:5]=1[OH:30].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH:7]=[CH:6][C:5]=1[O:30][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(OCCCCCCOc2ccc(-c3ccccc3)cc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCCCCCCOc2ccc(-c3ccccc3)cc2)ccc1OCc1ccccc1
Yield: 89 %

Procedure:
A mixture of 1.4 g (3.3 mmol) of 5-[[6-([1,1'-biphenyl]-4-yloxy) hexyl]oxy]-2-hydroxybenzoic acid methyl ester, 0.6 ml (5 mmol) of benzyl bromide and 2.5 g (16.5 mmol) of potassium carbonate in 50 ml of acetone and 5 ml of DMF was stirred at reflux for 24 hours. After the usual workup, the crude product was recrystallized from ethyl acetate-hexane to give 1.5 g (89% yield, mp 85°-87°) of 5-[[6-([1,1'-biphenyl]-4-yloxy)hexyl]oxy]-2-(phenylmethoxy)benzoic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>C1COCC1>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][C:4]2[S:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=2)=[CH:11][CH:10]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: Cc1ccsc1C
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccc(Br)cc2)sc1C
Yield: 60.5 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 1 using 2,3-dimethylthiophene (5.10 g, 45.5 mmol), 2.5M BuLi/hexanes (18.2 mL, 45.5 mmol) and 4-bromobenzyl bromide (11.4 g, 45.5 mmol) in THF. Purification on Biotage KP-Sil eluting with 100% pet ether gave 7.74 g (60%) of the title compound. 1H NMR: consistent.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[C:19]([O:24][CH3:25])[C:20]=1[N+:21]([O-:23])=[O:22])[O:12][CH2:13][C:14]([O:16]C)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C(N=C=S)=CC=CC=1.[OH-].[Na+]>C(O)C.Cl.[Pd]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[C:19]([O:24][CH3:25])[C:20]=1[N+:21]([O-:23])=[O:22])[O:12][CH2:13][C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)COc1cc(OC)c([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: [Pd]
Agent: Cc1ccccc1N=C=S
Agent: Cl
Solvent: CCO
Product: COc1cc(OCC(=O)O)cc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In ethanol (50 ml) was dissolved methyl 3-benzyloxy-5-methoxy-4-nitrophenoxyacetate (1.53 g, 4.41 mmol), followed by the addition of 5% palladium/carbon (1 g). At room temperature and normal pressure, the mixture was subjected to catalytic hydrogenation for 15 hours. The reaction mixture was filtered through Celite under reduced pressure to remove the insoluble matter. The filtrate was stirred at room temperature. To the filtrate was added 2-tolyl isothiocyanate (711 μl, 5.29 mmol). After stirring at room temperature for 15 hours, mercuric oxide (yellow) (1.62 g, 7.50 mmol) was added and the mixture was heated and refluxed for 4 hours. After cooling to room temperature, the reaction mixture was filtered through Celite under reduced pressure to remove the insoluble matter. The filtrate was then distilled under reduced pressure to remove the solvent. The resulting oily residue was dissolved in THF (35 ml). To the solution was added 0.25N NaOH (35 ml, 8.75 mmol) and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured in 1N HCl (100 ml), followed by extraction with a chloroform-methanol (4:1, 2×200 ml) mixture. The extract was dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent. Chloroform-hexane was added to the residue to crystallize the same, whereby the title compound (487 mg, 34%) was obtained as a pale yellow amorphous substance.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:28])[CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]3[S:25][C:24]([CH3:26])=[N:23][C:22]=3[CH:27]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[CH3:26][C:24]1[S:25][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][C@H:15]([OH:28])[CH2:14][N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:27][C:22]=2[N:23]=1
Reactant: Cc1nc2cc(OCC(O)CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2s1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-piperazine-1-carboxylic acid tert-butyl ester (2.9 g, 7.1 mmol), a compound of formula (5), was dissolved in a 4N solution of HCl in dioxane (20 ml) and allowed to stir at room temperature for 4 hours. The solvent was evaporated under reduced pressure to yield a white solid. The white solid was dried under high vacuum, and then dissolved in methanol (250 ml). AG 1-X8 resin was added and the mixture shaken. Additional resin was added until a neutral pH was obtained. The resin beads were removed by filtration, and methanol removed from the filtrate under reduced pressure, and the residue placed under high vacuum overnight, to yield (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-piperazinylpropan-2-ol as an oil.
Reaction SMILES: OS(O)(=O)=O.[CH2:6]1[CH:11]2[CH2:12][C:13]3(O)[CH2:15][CH:9]([CH2:10]2)[CH2:8][CH:7]1[CH2:14]3.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[C:22]([C:13]23[CH2:14][CH:7]4[CH2:8][CH:9]([CH2:10][CH:11]([CH2:6]4)[CH2:12]2)[CH2:15]3)[CH:23]=1
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 48.2 %

Procedure:
Reagent grade concentrated H2SO4 (11 mL) was added dropwise to a solution of 1-adamantol (30.25 g, 200 mmol) and 4-bromoanisole (37.21 g, 200 mmol) in 130 mL of CH2Cl2. The light pink solution was stirred at ambient temperature for 20 hours. The solvent was decanted, water (100 mL) and hexane (100 mL) were added and the solid was filtered and washed with hexane and dried to give 31 g of the product as a white powder. The supernatant was diluted with hexane, washed with water and brine, dried over MgSO4 and filtered thru a silica gel pad. The solvent was removed and the solid was recrystallized from hexane to yield 17 g of the product as a white powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.Cl.[O:29]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30]1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[C:5]([C:25]([NH:34][C@H:31]2[CH2:32][CH2:33][O:29][CH2:30]2)=[O:26])[CH:4]=[N:3]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: N[C@H]1CCOC1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N[C@H]2CCOC2)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reaction time: 0.33 h
Yield: 99.1 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), (S)-tetrahydrofuran-3-ylamine hydrochloride (68.2 mg, 552 μmol), diisopropylethylamine (193 μl, 1.1 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7 ml) is refluxed for 18 hours. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording (S)-1-methyl-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N4-(tetrahydrofuran-3-yl)-1H-pyrazole-4,5-dicarboxamide (118 mg, 99.1%) as a white solid. mp.: >250° C. MS: m/z=432.4 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:3][CH2:2]1.[CH:13]1(O)CCCC1>>[CH:4]1([O:5][C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:1][CH2:3][CH2:2][CH2:13]1
Reactant: OC1CCCC1
Reactant: Nc1cc(OCC2CC2)ncn1
Product: Nc1cc(OC2CCCC2)ncn1
Yield: 86 %

Procedure:
This was prepared in a manner analogous to 6-(cyclopropylmethoxy)pyrimidin-4-amine, where cyclopentanol was used as the alcohol. 6-(cyclopentyloxy)pyrimidin-4-amine (0.238 g, 1.328 mmol, 86% yield) was obtained as a white solid. m/z (ESI) 180.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:5]=C1C1C(N)=NON=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([NH:3][C:11]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[NH2:5])[CH3:2]
Reactant: CCn1c(-c2nonc2N)nc2cnccc21
Agent: [Pd]
Solvent: CCO
Product: CCNc1ccncc1N
Yield: 93.9 %

Procedure:
The product from Step 1 (8.7 g, 52.0 mmol) in ethanol (150 ml) was hydrogenated for 18 hours in the presence of 10% palladium on carbon. After filtration of the catalyst through Kieselguhr, the filtrate was concentrated in vacuo to afford the title compound (6.7 g, 94%); MS (ES+) m/e 138 [M+H]+.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH:10]1([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([NH2:30])=[N:25][CH:26]=[C:27]([F:29])[CH:28]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1COCC1>[CH:10]1([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]4=[N:30][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:25]4[CH:26]=[C:27]([F:29])[CH:28]=3)=[CH:19][CH:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: Nc1ncc(F)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=C(F)C=C(c3ccc(OC4CCCCC4)cc3)C2=N1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 153 mg) in THF (dry) (15 mL) was added 2-chloroethanesulfonyl chloride (0.403 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(cyclohexyloxy)phenyl)-5-fluoropyridin-2-amine (366 mg) in THF (dry) (15 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen for 15 hr and at 50° C. for 1 hr. The mixture was quenched with water at 0° C. carefully and water was added to form precipitates. The precipitate was crystallized from THF-MeOH/IPE to give the title compound (170 mg) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+]>CS(C)=O.O.ClCCl.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]>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][CH:2]=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([CH3:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1nc(-c2cn3c(n2)-c2ccccc2OCC3)n(C(C)C)n1
Temperature: 85 °C

Procedure:
A 25-mL round-bottomed flask was charged with 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 411 (1.0 g, 2.6 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (bispinacolato bisboronate, 0.719 g, 2.83 mmol), potassium acetate (0.76 g, 7.7 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in complex with dichloromethane (1:1) (0.21 g, 0.26 mmol) under a nitrogen atmosphere. The combined mixture was diluted with dimethylsulfoxide (8.5 mL) and heated at 85° C. for 12 h. The reaction mixture was then cooled to room temperature and diluted with water and dichloromethane. The phases were partitioned and the aqueous portion was extracted thrice with dichloromethane. The organic layers were combined, dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography to afford 232 as a protio-dehalogenated by-product (66 mg, 7% yield). MS (ESI+) m/z 310.2 (M+H+), calcd. 310.4. 1H NMR (500 MHz, DMSO) δ 8.41 (dd, J=8.0, 1.6 Hz, 1H), 7.89 (s, 1H), 7.33 (dd, J=11.0, 4.3 Hz, 1H), 7.16 (t, J=7.6 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 5.83 (dt, J=13.0, 6.6 Hz, 1H), 4.51 (q, J=5.6 Hz, 4H), 2.26 (s, 3H), 1.46 (d, J=6.6 Hz, 6H)
Reaction SMILES: ClC1N=C(N[C@H]([C:11]2[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:13](=[O:27])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)C)C(I)=CN=1.[OH-].[NH4+]>O1CCOCC1>[CH3:26][N:24]1[CH:25]=[C:21]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[C:13](=[O:27])[N:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:11]=[CH:20]3)[CH:22]=[N:23]1
Reactant: C[C@H](Nc1nc(Cl)ncc1I)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1-c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1cc(-c2cccc3ccn(-c4ccccc4)c(=O)c23)cn1
Temperature: 110 °C
Reaction time: 16 h
Yield: 107 %

Procedure:
To a solution of (S)-3-(1-((2-chloro-5-iodopyrimidin-4-yl)amino)ethyl)-8-(1-methyl-1H-pyrazol-4-yl)-2-phenylisoquinolin-1(2H)-one (64) (964 mg, 1.65 mmol) in anhydrous 1,4-dioxane (5 mL) in a sealed tube, ammonium hydroxide (6 mL) was added and the resulting mixture was stirred at 110° C. for 16 h. An additional amount of ammonium hydroxide (3 mL) was added to the reaction mixture and stirring was continued for 16 h. The mixture was allowed to cool to RT, quenched with water and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO (silica gel cartridge, 0-8% MeOH-DCM) to afford the product, (S)-3-(14(2-amino-5-iodopyrimidin-4-yl)amino)ethyl)-8-(1-methyl-1H-pyrazol-4-yl)-2-phenylisoquinolin-1(2H)-one (65) (532 mg, 57% yield) as a light tan solid. ESI-MS m/z: 564.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:20]=[C:21](\[CH3:27])/[C:22]([O:24]CC)=[O:23])[C:6]2[C:11]([C:12]=1[O:13]COC)=[C:10]([CH2:17][CH2:18][CH3:19])[CH:9]=[CH:8][CH:7]=2>CC(C)=O>[OH:13][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:17][CH2:18][CH3:19])[C:5](/[CH:20]=[C:21](/[CH3:27])\[C:22]([OH:24])=[O:23])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCCc1cccc2c(/C=C(\C)C(=O)OCC)cc(OC)c(OCOC)c12
Solvent: CC(C)=O
Product: CCCc1cccc2c(/C=C(/C)C(=O)O)cc(OC)c(O)c12
Yield: 37.4 %

Procedure:
196.5 g of ethyl (E)-3-(3-methoxy-4-methoxymethoxy-5-propyl-1-naphthyl)-2-methylpropenoate was dissolved in 2.6 liters of acetone and irradiated with light from a high pressure mercury lamp through a Pyrex filter for 2.5 hours. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (3% ethyl acetate/hexane) to obtain 59.2 g of the titled compound as a pale yellow oil. At the same time, 136.4 g of a mixture of the E and Z isomers was recovered.
Reaction SMILES: Cl.Cl[CH2:3][N:4]1[CH:8]=[C:7]2[CH2:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:6]2=[N:5]1.[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:12][C:11]1([CH3:13])[C:6]2=[N:5][N:4]([CH2:3][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])[CH:8]=[C:7]2[CH2:9][CH2:10]1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: CC1(C)CCc2cn(CCl)nc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CCc2cn(CC(C#N)(C#N)CCC(F)(F)F)nc21
Yield: 33.2 %

Procedure:
0.58 g of 2-(chloromethyl)-6,6-dimethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole hydrochloride and 0.43 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 8 ml of N,N-dimethylformamide. 0.73 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.27 g of [(6,6-dimethyl-5,6-dihydro-cyclopenta[c]pyrazole-2(4H)-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (5), hereinafter) shown by below formula.
Reaction SMILES: C(N(CC)CC)C.[N-:8]=[N+:9]=[N-:10].[Na+].[N+]([C:15]1[CH:33]=[CH:32][CH:31]=[C:17]2[C:18]([N:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:21](=[O:22])[C:16]=12)=[O:19])([O-])=O>CS(C)=O>[N:8]([C:31]1[CH:32]=[CH:33][CH:15]=[C:16]2[C:21]([N:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:18](=[O:19])[C:17]=12)=[O:22])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)CCCCCN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1cccc2c1C(=O)N(CCCCCC(=O)O)C2=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
2.58 ml (0.018 mol) of triethylamine, followed by 1.3 g (0.0198 mol) of sodium azide, are added to a mixture of 5.7 g (0.018 mol) of 6-(3-nitrophthalimidyl)-caproic acid in 35 ml of dimethylsulphoxide. The reaction mixture is heated for 6 hours at 50° C. and is then concentrated in vacuo, diluted with 100 ml of water and acidified with 4 ml of concentrated hydrochloric acid. The resulting suspension of the reaction product is stirred for 18 hours and filtered with suction, and the filter residue is washed with 20 ml of water and dried for 24 hours at 60° C./0.100. mm Hg, over phosphorus pentoxide. 5.1 g (94% of theory) of 6-(3-azidophthalimidyl)-caproic acid are obtained; melting point 87°-90° C. (with decomposition). IR spectrum (CH2Cl2): 1780 and 1725 cm-1 (CO--N--CO); 2130 cm-1 (N3).